N-acetylleucine for treatment of prophase alpha-synucleinopathies

Abstract

The present disclosure provides for the prophase treatment of alpha-synucleinopathies, comprising administering N-acetylleucine or a pharmaceutically acceptable salt thereof.

Description

[0001] Cross-reference to related applications

[0002] This application claims priority to U.S. Provisional Application No. 63 / 620,240, filed January 12, 2024; U.S. Provisional Application No. 63 / 554,373, filed February 16, 2024; and U.S. Provisional Application No. 63 / 692,804, filed September 10, 2024, pursuant to 35 U.S. SC §119(e). The contents of each of these applications are incorporated herein by reference in their entirety. Background Technology

[0003] Parkinson's disease (PD) is characterized by the progressive loss of neuronal function and death of neurons that use the neurotransmitter dopamine. Late-stage symptoms of fully manifest PD involve motor (mobility) dysfunction, leading to tremors and rigidity. Prodromal symptoms appear earlier, sometimes up to 15 years before transitioning to manifest PD. Prodromal PD refers to a stage where an individual does not meet the diagnostic criteria for "manifest PD" or "classical PD" (i.e., bradykinesia and at least one other motor sign), but exhibits signs and symptoms indicating a higher-than-average risk of developing motor symptoms and a diagnosis of PD in the future. The best-indicating symptoms of prodromal PD include alterations in autonomic function (constipation), loss of smell (hypopnea), changes in glucose metabolism, and REM sleep behavior disorder (RBD), in which vividly portrays dreams as actions, such as potentially causing unintentional physical harm to a sleeping partner. These prodromal symptoms serve as accurate and predictive early biomarkers for Parkinson's disease because patients with these symptoms have a >85% risk of transitioning to PD or dementia with Lewy bodies (DLB) within 10–15 years (Postuma et al., 2019; Janzen et al., 2022). Therapeutic agents are needed to treat PD and other alpha-synucleinic disorders in the prodromal phase. Summary of the Invention

[0004] In one aspect, this disclosure provides a method for treating the prodromal stage of α-synucleinosis, such as Parkinson's disease (PD), Lewy body dementia (DLB), or multiple system atrophy (MSA), in subjects in need, the method comprising administering a therapeutically effective amount of N-acetylleucine to the subject.

[0005] On the other hand, the subject (i) was not diagnosed with any core clinical feature, syndrome or symptom associated with α-synucleinosis; and (ii) was diagnosed with one or more core clinical features, syndromes or symptom associated with the prodromal phase of α-synucleinosis.

[0006] On the other hand, this disclosure provides a method for treating the prodromal phase of PD, wherein the subject (i) is not diagnosed with tremor, bradykinesia, rigidity, balance disorder and / or coordination disorder; and (ii) is diagnosed with one or more of hyposmia, cognitive impairment, REM sleep behavior disorder (RBD), constipation, depression and / or anxiety.

[0007] On the other hand, this disclosure provides a method for treating the prodromal phase of DLB, wherein the subject (i) is not diagnosed with dementia; and (ii) is diagnosed with one or more of RBD, constipation, hyposmia, depression, and / or orthostatic hypotension / dizziness.

[0008] In another aspect, this disclosure provides a method for treating the prodromal phase of MSA, wherein the subject (i) is not diagnosed with (a) autonomic dysfunction; and (b) poor L-dopamine responsiveness Parkinson's syndrome and / or cerebellar syndrome; and (ii) is diagnosed with one or more of RBD, neurogenic orthostatic hypotension and / or genitourinary dysfunction occurring within 10 minutes of standing or head tilting.

[0009] On the other hand, this disclosure provides a method for treating RBD in a subject in need, the method comprising administering a therapeutically effective amount of N-acetylleucine to the subject. Attached Figure Description

[0010] Figures 1A-1B The text describes the treatment of patient 1 ( ) with N-acetyl-DL-leucine. Figure 1A ) and patient 2 ( Figure 1B The subjective severity score of the REM sleep behavior disorder phenotype was used. The 21 daily scores were totaled to a 3-week total score (RBD-SS-3). The total observation period was three weeks, and the RBD-SS-3 values ​​for the first 18 weeks are shown below. Figures 1A-1B In the first half, the RBD-SS-3 values ​​for the latter 18 weeks are shown in Figures 1A-1B In the latter half.

[0011] Figures 2A-2B The study depicted the effects of N-acetyl-DL-leucine administration on patient 1 ( Figure 2A ) and patient 2 ( Figure 2BThe DAT-SPECT results are shown in the image above. The top image shows a representative DAT-SPECT image of the striatum. The bottom image depicts the striato-occipital ratio in the left striatum (Striatium-L), right striatum (Striatum-R), left caudate nucleus (Caudate-L), right caudate nucleus (Caudate-R), left putamen (Putamen-L), and right putamen (Putamen-R). The DAT-ligand binding ratio (in Putamen-R) is shown below the image in the top image.

[0012] Figures 3A-3B The study depicted patient 1 (before and after administration of N-acetyl-DL-leucine) Figure 3A ) and patient 2 ( Figure 3B FDG-PET results. Detailed Implementation

[0013] I. Definition

[0014] As used herein, a “subject” can be a vertebrate, mammal, or domesticated animal. Therefore, the compositions according to this disclosure can be used to treat any mammal, such as livestock (e.g., horses, cattle, sheep, or pigs), pets (e.g., cats, dogs, rabbits, or guinea pigs), laboratory animals (e.g., mice or rats), or for other veterinary applications. In one embodiment, the subject is a human.

[0015] As used in this article, the singular forms “a,” “one,” and “the” include plural references.

[0016] The terms “approximately” and “about” mean nearly identical to a reference figure or value, including the acceptable degree of error of a quantity measured given the nature or precision of the measurement. As used herein, the terms “approximately” and “about” should generally be understood to cover ±10% of a specified quantity, frequency, or value. Unless otherwise stated, the numerical values ​​given herein are approximate, meaning that the terms “approximately” or “about” can be inferred when not explicitly stated.

[0017] As used herein, the term “administer (administration, administration)” means (1) the combination of the present disclosure provided, administered, given and / or prescribed by a health practitioner or his authorized agent or under his or her guidance, and (2) the combination of the present disclosure administered, taken or consumed by a patient or person himself or her.

[0018] References to “N-acetylleucine” throughout include its pharmaceutically acceptable salts, even if not explicitly stated. Acetyl-leucine can be in its racemic form, meaning the compound contains approximately equal amounts of enantiomers. Alternatively, it can be present in excess as an L-enantiomer or a D-enantiomer. N-acetylleucine can be a single enantiomer of either the L-enantiomer or the D-enantiomer. In one embodiment, the single enantiomer is the L-enantiomer. The racemic and enantiomeric forms of N-acetylleucine can be obtained according to methods known in the art.

[0019] The term "pharmaceutically acceptable carrier" as used herein refers to any known compound or combination of known compounds known to those skilled in the art for use in formulating pharmaceutical compositions. It should be understood that the carrier of a pharmaceutical composition should be a carrier tolerable to the subject to which it is administered.

[0020] The term "pharmaceutically acceptable salt" as used in this article refers to any salt preparation suitable for pharmaceutical use. Pharmaceutically acceptable salts include, but are not limited to, amine salts, such as N,N'-dibenzylethylenediamine, chloroprocaine, choline, ammonia, diethanolamine and other hydroxyalkylamines, ethylenediamine, N-methylglucosamine, procaine, N-benzylphenethylamine, 1-p-chloro-benzyl-2-pyrrolidone-1′-methylbenzimidazole, diethylamine and other alkylamines, piperazine, tris(hydroxymethyl)aminomethane, etc.; alkali metal salts, such as lithium, potassium, sodium, etc.; alkaline earth metal salts, such as barium, calcium, magnesium, etc.; transition metal salts, such as zinc, aluminum, etc.; other metal salts, such as sodium hydrogen phosphate, disodium phosphate, etc.; inorganic acids, such as hydrochlorides, sulfates, etc.; and salts of organic acids, such as acetates, lactates, malates, tartrates, citrates, ascorbic acid salts, succinates, butyrates, valerates, fumarates, etc.

[0021] The "therapeutic effective amount" of a drug is any amount of the drug required to produce the desired effect when administered to a subject; for the purposes of this disclosure, this effect can be therapeutic and / or preventative. Dosage can be determined based on various parameters, such as the specific form of N-acetylleucine used; the age, weight, and condition of the patient to be treated; the type of disease; the route of administration; and the desired regimen. The physician will be able to determine the route of administration and dosage required for any particular patient.

[0022] The terms “symptom,” “syndrome,” or “core clinical feature” refer to any clinical or laboratory manifestation associated with a disease, condition, or symptom, and are not limited to what a subject may feel or observe. Symptoms as described herein include, but are not limited to, neurological and psychiatric symptoms.

[0023] The terms "synucleopathy," "alpha-synucleopathy," or simply "alpha-synucleopathy" refer to neurodegenerative diseases characterized by the abnormal accumulation of alpha-synuclein aggregates in neurons, nerve fibers, or glial cells. There are three main types of synucleopathies: Parkinson's disease (PD), Lewy body dementia (DLB), and multiple system atrophy (MSA). Other rare conditions, such as various axonal dystrophys, also exhibit alpha-synuclein pathology.

[0024] The term "prodromal period" or "precursor period" refers to the time between the appearance of initial signs or symptoms and the onset of the full disease, illness, or condition.

[0025] As used herein, “subjects in need” can be any subject with a disease, condition, symptom, or syndrome characterized by an abnormal accumulation of α-synuclein. Subjects may have been diagnosed with or may not have been diagnosed with a disease, condition, symptom, or syndrome. For example, a subject may not have been diagnosed with (clinical or other) α-synucleinopathy but may have one or more symptoms of α-synucleinopathy.

[0026] The term “and / or” as used herein should be considered as a specific disclosure of each of two specified features or components in the presence or absence of the other. Therefore, the term “and / or” as used in phrases such as “A and / or B” herein is intended to include “A and B”, “A or B”, “A” (alone), and “B” (alone). Similarly, the term “and / or” as used in phrases such as “A, B, and / or C” is intended to cover each of the following: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0027] As used in this article, the phrase “subject not diagnosed” means that the relevant clinical features, syndromes, or symptoms of the disease (e.g., alpha-synucleinopathy or the prodromal phase of classic alpha-synucleinopathy) have not been identified in the subject by examination by a physician or other qualified healthcare provider.

[0028] II. Alpha-synucleinosis

[0029] Alpha-synucleinopathy is a neurodegenerative disease characterized by the abnormal accumulation of alpha-synuclein aggregates in neurons, nerve fibers, or glial cells. The three main types of alpha-synucleinopathy include Parkinson's disease (PD), Lewy body dementia (DLB), or multiple system atrophy (MSA).

[0030] In some embodiments, this disclosure provides a method for treating the prodromal phase of α-synucleinosis in a subject in need, the method comprising administering a therapeutically effective amount of N-acetylleucine to the subject.

[0031] In some implementations, the subject was not diagnosed with any core clinical features, syndromes, or symptoms associated with α-synucleinopathy.

[0032] In some implementations, the subject is diagnosed with one or more core clinical features, syndromes, or symptoms associated with the prodromal phase of α-synucleinosis.

[0033] In some implementations, the subject: (i) has not been diagnosed with any core clinical feature, syndrome, or symptom associated with α-synucleinosis; and (ii) has been diagnosed with one or more core clinical features, syndromes, or symptoms associated with the prodromal phase of α-synucleinosis.

[0034] In some implementations, alpha-synucleinopathy is Parkinson's disease (PD), Lewy body dementia (DLB), or multiple system atrophy (MSA).

[0035] A. Parkinson's disease

[0036] In some embodiments, this disclosure provides a method for treating the prodromal phase of Parkinson's disease in subjects in need, comprising administering a therapeutically effective amount of N-acetylleucine to the subject. These subjects are referred to herein as "prodromal Parkinson's disease subjects" or "PPD subjects".

[0037] In some implementations, the PPD subject was not diagnosed with any core clinical feature, syndrome, or symptom associated with Parkinson's disease. In some implementations, the core clinical feature, syndrome, or symptom associated with Parkinson's disease is tremor, bradykinesia, rigidity, balance disorder, and / or coordination disorder.

[0038] In some implementations, the PPD subject was not diagnosed with any of the following: tremor, bradykinesia, muscle rigidity, balance disorder, and / or coordination disorder.

[0039] In some implementations, the PPD subject was not diagnosed with any two of tremor, bradykinesia, rigidity, balance disorder, and / or coordination disorder.

[0040] In some implementations, the PPD subject was not diagnosed with any three of the following: tremor, bradykinesia, rigidity, balance disorder, and / or coordination disorder.

[0041] In some implementations, the PPD subject was not diagnosed with any four of the following: tremor, bradykinesia, rigidity, balance disorder, and / or coordination disorder.

[0042] In some implementations, the PPD subject was not diagnosed with any of the following: tremor, bradykinesia, rigidity, balance disorder, and coordination disorder.

[0043] In some implementations, the PPD subject is diagnosed with one or more core clinical features, syndromes, or symptoms associated with the prodromal phase of PD. In some implementations, the core clinical features, syndromes, or symptoms associated with the prodromal phase of PD are hyposmia, cognitive impairment, REM sleep behavior disorder (RBD), constipation, depression, and / or anxiety.

[0044] In some embodiments, the PPD subject is diagnosed with one of the following: hyposmia, cognitive impairment, RBD, constipation, depression, and / or anxiety.

[0045] In some implementations, the PPD subject is diagnosed with two of the following: hyposmia, cognitive impairment, RBD, constipation, depression, and / or anxiety.

[0046] In some implementations, PPD subjects are diagnosed with three of the following: hyposmia, cognitive impairment, RBD, constipation, depression, and / or anxiety.

[0047] In some implementations, the PPD subject is diagnosed with four of the following: hyposmia, cognitive impairment, RBD, constipation, depression, and / or anxiety.

[0048] In some implementations, PPD subjects are diagnosed with five of the following: hyposmia, cognitive impairment, RBD, constipation, depression, and / or anxiety.

[0049] In some implementations, the PPD subject was diagnosed with hyposmia, cognitive impairment, RBD, constipation, depression, and anxiety.

[0050] In some implementations, the PPD subject: (i) is not diagnosed with tremor, bradykinesia, rigidity, balance disorder and / or coordination disorder; and (ii) is diagnosed with one or more of hyposmia, cognitive impairment, RBD, constipation, depression and / or anxiety.

[0051] Parkinson's disease (PD) is characterized by certain clinical features, such as bradykinesia, rigidity, and resting tremor, and is associated with progressive neuronal loss in the substantia nigra and other brain regions. A marked response to dopaminergic therapy and the presence of anosmia or cardiac sympathetic denervation are supporting criteria. Furthermore, a clinically established diagnosis of PD requires the absence of features of atypical Parkinsonian syndromes (APS). Atypical Parkinsonian syndromes include multiple system atrophy (MSA), progressive supranuclear palsy, and basal cortical degeneration (Zhao et al., Brain and Behavior, 1–9 (2020)).

[0052] Of the three main symptoms of Parkinson's disease (PD), bradykinesia is the most important and contributes primarily to the disability associated with PD progression. The term bradykinesia refers to the slowness and poorness of voluntary and involuntary movements that characterize Parkinson's syndrome. Muscle rigidity (defined as increased resistance to passive movement of joints) contributes only minimally to the impairment experienced by patients with Parkinson's. The subjective relevance of rigidity is the reduced sensation of rigidity and the ability to relax the muscles of the limbs and trunk. Tremor is the most prominent of the main symptoms of PD and was given the initial name of the disease by James Parkinson in 1817, shock. Parkinson's tremor usually occurs at rest and typically affects the upper limbs, but can also occur in the legs and less frequently in the head. Although resting tremor is not necessarily indicative of disability, many patients suffer considerably, at least because the tremor sets them apart as subjects of Parkinson's disease (Pellicano et al., Neuropsychiatric Disease and Treatment, 3(1), 145-151(2007)).

[0053] Recent neuropathological data indicate that pathological markers of PD (Lewy bodies) can be identified in several neuronal populations in addition to dopaminergic diencephalic muscles. Following an ascending gradient of neuronal involvement throughout disease progression, six neuropathological stages of PD (Braak stages) have been identified: In stages 1 and 2, defined as the “anterior ventricular stage,” Lewy bodies are confined to the anterior olfactory nucleus, olfactory bulbus, dorsal motor nucleus of the glossopharyngeal and vagus nerves, locus coeruleus, and reticular formation. In stages 3 and 4 (“intermediate stages”), neuropathological damage extends to the substantia nigra pars compacta, other midbrain nuclei, forebrain regions, and the lumen-allococortex; during these stages, motor symptoms develop and gradually worsen. Ultimately, in stages 5 and 6 (the “late stages” of PD), the neocortex, prefrontal cortex, and related cortex are pathologically involved; in these late stages, severe motor dysfunction is accompanied by cognitive and behavioral symptoms (Pellicano et al., Neuropsychatan Disease and Treatment, 311, 145-151 (2007); Mahlknecht et al., J Parkinson's Disease, 5, 681-697 (2015)).

[0054] Table 1 Stages of Parkinson's Disease

[0055] (Mahlknecht et al., J Parkinson's Disease, 5, 681-697 (2015)

[0056] The prodromal phase of PD is characterized by a range of nonmotor symptoms that can precede the onset of motor symptoms many years later (Roos et al., J Parkinson's Disease, 12, 967-974 (2022)). These symptoms include constipation, hyposmegma (loss of smell), RBD, depression, anxiety, and cognitive impairment (Hustad et al., Front. Neurol., 11:395 (2020)).

[0057] Symptoms of prodromal Parkinson's disease include sensory symptoms, neuropsychiatric symptoms, behavioral symptoms, autonomic dysfunction, and sleep disturbances. Sensory symptoms of prodromal Parkinson's disease include decreased sense of smell, visual abnormalities (e.g., decreased color vision), and pain. Neuropsychiatric symptoms of prodromal Parkinson's disease include depression, anxiety, pulpotomy, lack of pain, and positive executive dysfunction. Behavioral symptoms of prodromal Parkinson's disease include smoking cessation. Autonomic dysfunction symptoms of prodromal Parkinson's disease include constipation, orthostatic hypotension, and genitourinary dysfunction. Sleep disturbance symptoms of prodromal Parkinson's disease include RBD, excessive daytime sleepiness, sleep fragmentation, insomnia, periodic limb movements during sleep (PLMS), and restless legs syndrome (RLS) (Mahlknecht et al., J Parkinson's Disease, 5, 681-697 (2015)). Nonmotor symptoms of prodromal Parkinson's disease are shown in Table 2.

[0058] Table 2. Nonmotor symptoms of Parkinson's disease (using burette)

[0059] (Mahlknecht et al., J Parkinson's Disease, 5, 681-697 (2015))

[0060] PD, Parkinson's disease; PLMS, Periodic limb movements during sleep; RBD, Rapid eye movement sleep behavior disorder; RLS, Restless legs syndrome. ++= Robust evidence from more than one expected cohort-based or group-based study; += Evidence from one or more expected cohort-based or group-based studies; + / -= No evidence from cohort-based or group-based studies, but corresponding nonmotor symptoms are frequently seen in early PD.

[0061] Some symptoms associated with prodromal Parkinson's disease (PD) are not specific to PD and may also be caused by other diseases. Therefore, it is impossible to diagnose prodromal PD based on a single prodromal marker. Instead, the overlap of multiple markers (risk factors) in a single individual may be a more reliable indicator of prodromal PD. The Honolu-Asia Aging Study (HAAS) examined olfaction, constipation, executive function, and excessive daytime sleepiness in older participants (mean age 79.7 years) and revealed that individuals with two or more risk factors had a 10-fold increased risk of developing PD. Prospective assessment of risk factors used in the PRISP study (including participants with a mean age of 59 years) found that a combination of pre-screening for age, positive family history, and / or olfactory hyposmia, and secondary screening for hyperechoic nigra, predicted PD. In the At-Risk syndrome (PARS) study of Parkinson's disease, the number of other nonmotor symptoms (anxiety, RBD, and constipation) was higher in low-prevalence subjects than in normal-prevalence subjects around 64 years of age (Roos et al., J Parkinson's Disease, 12, 967-974 (2022)).

[0062] In some embodiments, the PPD subject is diagnosed with one or more core clinical features, syndromes, or symptoms associated with the prodromal phase of Parkinson's disease. In some embodiments, the core clinical features, syndromes, or symptoms associated with the prodromal phase of Parkinson's disease are hyposmia, visual abnormalities, decreased color vision, pain, depression, anxiety, allergic reactions, unresponsiveness, positive executive dysfunction, constipation, orthostatic hypotension, genitourinary dysfunction, RBD, excessive daytime sleepiness, sleep fragmentation, insomnia, periodic limb movements during sleep (PLMS), and / or restless legs syndrome (RLS).

[0063] In some implementations, the PPD subject is diagnosed with one or more of the following: hyposmia, visual abnormalities, decreased color vision, pain, depression, anxiety, pulpitis, analgesia, positive executive dysfunction, constipation, orthostatic hypotension, urogenital dysfunction, RBD, excessive daytime sleepiness, sleep fragmentation, insomnia, periodic limb movements during sleep (PLMS), and / or restless legs syndrome (RLS).

[0064] In some implementations, the PPD subject is diagnosed with two or more of the following: hyposmia, visual abnormalities, reduced color vision, pain, depression, anxiety, allergic reactions, analgesia, positive executive dysfunction, constipation, orthostatic hypotension, urogenital dysfunction, RBD, excessive daytime sleepiness, sleep fragmentation, insomnia, periodic limb movements during sleep (PLMS), and / or restless legs syndrome (RLS).

[0065] In some implementations, the PPD subject is diagnosed with three or more of the following: hyposmia, visual abnormalities, reduced color vision, pain, depression, anxiety, allergic reaction, analgesia, positive executive dysfunction, constipation, orthostatic hypotension, urogenital dysfunction, RBD, excessive daytime sleepiness, sleep fragmentation, insomnia, periodic limb movements during sleep (PLMS), and / or restless legs syndrome (RLS).

[0066] In some implementations, the PPD subject is diagnosed with four or more of the following: hyposmia, visual abnormalities, reduced color vision, pain, depression, anxiety, allergic reaction, analgesia, positive executive dysfunction, constipation, orthostatic hypotension, urogenital dysfunction, RBD, excessive daytime sleepiness, sleep fragmentation, insomnia, periodic limb movements during sleep (PLMS), and / or restless legs syndrome (RLS).

[0067] In some implementations, the PPD subject is diagnosed with five or more of the following: hyposmia, visual abnormalities, reduced color vision, pain, depression, anxiety, allergic reaction, analgesia, positive executive dysfunction, constipation, orthostatic hypotension, urogenital dysfunction, RBD, excessive daytime sleepiness, sleep fragmentation, insomnia, periodic limb movements during sleep (PLMS), and / or restless legs syndrome (RLS).

[0068] In some implementations, the PPD subject is diagnosed with six or more of the following: hyposmia, visual abnormalities, reduced color vision, pain, depression, anxiety, allergic reaction, analgesia, positive executive dysfunction, constipation, orthostatic hypotension, urogenital dysfunction, RBD, excessive daytime sleepiness, sleep fragmentation, insomnia, periodic limb movements during sleep (PLMS), and / or restless legs syndrome (RLS).

[0069] In some implementations, the PPD subject is diagnosed with seven or more of the following: hyposmia, visual abnormalities, decreased color vision, pain, depression, anxiety, pulpitis, analgesia, positive executive dysfunction, constipation, orthostatic hypotension, urogenital dysfunction, RBD, excessive daytime sleepiness, sleep fragmentation, insomnia, periodic limb movements during sleep (PLMS), and / or restless legs syndrome (RLS).

[0070] In some implementations, the PPD subject is diagnosed with eight or more of the following: hyposmia, visual abnormalities, reduced color vision, pain, depression, anxiety, allergic reactions, analgesia, positive executive dysfunction, constipation, orthostatic hypotension, urogenital dysfunction, RBD, excessive daytime sleepiness, sleep fragmentation, insomnia, periodic limb movements during sleep (PLMS), and / or restless legs syndrome (RLS).

[0071] In some implementations, the PPD subject is diagnosed with nine or more of the following: hyposmia, visual abnormalities, decreased color vision, pain, depression, anxiety, allergic reaction, analgesia, positive executive dysfunction, constipation, orthostatic hypotension, urogenital dysfunction, RBD, excessive daytime sleepiness, sleep fragmentation, insomnia, periodic limb movements during sleep (PLMS), and / or restless legs syndrome (RLS).

[0072] In some implementations, the PPD subject is diagnosed with ten or more of the following: hyposmia, visual abnormalities, decreased color vision, pain, depression, anxiety, pulpitis, analgesia, positive executive dysfunction, constipation, orthostatic hypotension, urogenital dysfunction, RBD, excessive daytime sleepiness, sleep fragmentation, insomnia, periodic limb movements during sleep (PLMS), and / or restless legs syndrome (RLS).

[0073] In some implementations, the PPD subject is diagnosed with one or more of the following: hyposmia, visual abnormalities, reduced color vision, pain, depression, anxiety, allergic reactions, analgesia, positive executive dysfunction, constipation, orthostatic hypotension, urogenital dysfunction, RBD, excessive daytime sleepiness, sleep fragmentation, insomnia, periodic limb movements during sleep (PLMS), and / or restless legs syndrome (RLS).

[0074] In some implementations, the PPD subject is diagnosed with twelve or more of the following: hyposmia, visual abnormalities, decreased color vision, pain, depression, anxiety, allergic reaction, analgesia, positive executive dysfunction, constipation, orthostatic hypotension, urogenital dysfunction, RBD, excessive daytime sleepiness, sleep fragmentation, insomnia, periodic limb movements during sleep (PLMS), and / or restless legs syndrome (RLS).

[0075] In some embodiments, the PPD subject is diagnosed with thirteen or more of the following: hyposmia, visual abnormalities, decreased color vision, pain, depression, anxiety, allergic reaction, analgesia, positive executive dysfunction, constipation, orthostatic hypotension, urogenital dysfunction, RBD, excessive daytime sleepiness, sleep fragmentation, insomnia, periodic limb movements during sleep (PLMS), and / or restless legs syndrome (RLS).

[0076] In some implementations, the PPD subject is diagnosed with fourteen or more of the following: hyposmia, visual abnormalities, decreased color vision, pain, depression, anxiety, pulpitis, analgesia, positive executive dysfunction, constipation, orthostatic hypotension, genitourinary dysfunction, RBD, excessive daytime sleepiness, sleep fragmentation, insomnia, periodic limb movements during sleep (PLMS), and / or restless legs syndrome (RLS).

[0077] In some implementations, the PPD subject is diagnosed with fifteen or more of the following: hyposmia, visual abnormalities, decreased color vision, pain, depression, anxiety, pulpitis, analgesia, positive executive dysfunction, constipation, orthostatic hypotension, genitourinary dysfunction, RBD, excessive daytime sleepiness, sleep fragmentation, insomnia, periodic limb movements during sleep (PLMS), and / or restless legs syndrome (RLS).

[0078] In some implementations, the PPD subject is diagnosed with sixteen or more of the following: hyposmia, visual abnormalities, reduced color vision, pain, depression, anxiety, allergic reactions, analgesia, positive executive dysfunction, constipation, orthostatic hypotension, urogenital dysfunction, RBD, excessive daytime sleepiness, sleep fragmentation, insomnia, periodic limb movements during sleep (PLMS), and / or restless legs syndrome (RLS).

[0079] In some implementations, PPD subjects are diagnosed with hyposmia, visual abnormalities, decreased color vision, pain, depression, anxiety, allergic reactions, unresponsiveness, positive executive dysfunction, constipation, orthostatic hypotension, urogenital dysfunction, RBD, excessive daytime sleepiness, sleep fragmentation, insomnia, periodic limb movements during sleep (PLMS), and restless legs syndrome (RLS).

[0080] In some implementations, the core clinical features, syndromes, or symptoms associated with the prodromal phase of Parkinson's disease are hyposmia, cognitive impairment, RBD, constipation, depression, and anxiety. In some implementations, the PPD subject is diagnosed with one or more of hyposmia, cognitive impairment, RBD, constipation, depression, and / or anxiety.

[0081] In some embodiments, the PPD subject is diagnosed with two or more of the following: hyposmia, cognitive impairment, RBD, constipation, depression, and / or anxiety. In some embodiments, the PPD subject is diagnosed with three or more of the following: hyposmia, cognitive impairment, RBD, constipation, depression, and / or anxiety. In some embodiments, the PPD subject is diagnosed with four or more of the following: hyposmia, cognitive impairment, RBD, constipation, depression, and / or anxiety. In some embodiments, the PPD subject is diagnosed with five or more of the following: hyposmia, cognitive impairment, RBD, constipation, depression, and / or anxiety. In some embodiments, the PPD subject is diagnosed with hyposmia, cognitive impairment, RBD, constipation, depression, and anxiety.

[0082] In some embodiments, the PPD subject is diagnosed with one or more of hyposmia, RBD, and / or constipation. In some embodiments, the PPD subject is diagnosed with two or more of hyposmia, RBD, and / or constipation. In some embodiments, the PPD subject is diagnosed with hyposmia, RBD, and constipation. In some embodiments, the PPD subject (i) is not diagnosed with any core clinical feature, syndrome, or symptom associated with Parkinson's disease; and the PPD subject (ii) is diagnosed with one or more core clinical features, syndromes, or symptoms associated with the prodromal phase of Parkinson's disease.

[0083] In some implementations, the PPD subject: (i) is not diagnosed with tremor, bradykinesia, muscle rigidity, balance disorder and / or coordination disorder; and the PPD subject (ii) is diagnosed with one or more of the following: hyposmia, visual abnormalities, decreased color vision, pain, depression, anxiety, pulp reduction, unresponsiveness, positive executive dysfunction, constipation, orthostatic hypotension, genitourinary dysfunction, RBD, excessive daytime sleepiness, sleep fragmentation, insomnia, periodic limb movements during sleep (PLMS) and / or restless legs syndrome (RLS).

[0084] In some implementations, the PPD subject: (i) is not diagnosed with tremor, bradykinesia, rigidity, balance disorder and / or coordination disorder; and the PPD subject (ii) is diagnosed with two or more of the following: hyposmia, visual abnormalities, decreased color vision, pain, depression, anxiety, pulpitis, unresponsiveness, positive executive dysfunction, constipation, orthostatic hypotension, genitourinary dysfunction, RBD, excessive daytime sleepiness, sleep fragmentation, insomnia, periodic limb movements during sleep (PLMS) and / or restless legs syndrome (RLS).

[0085] In some implementations, the PPD subject: (i) is not diagnosed with tremor, bradykinesia, rigidity, balance disorder and / or coordination disorder; and the PPD subject (ii) is diagnosed with three or more of the following: hyposmia, visual abnormalities, decreased color vision, pain, depression, anxiety, anaphylaxis, unresponsiveness, positive executive dysfunction, constipation, orthostatic hypotension, urogenital dysfunction, RBD, excessive daytime sleepiness, sleep fragmentation, insomnia, periodic limb movements during sleep (PLMS) and / or restless legs syndrome (RLS).

[0086] In some implementations, the PPD subject: (i) is not diagnosed with tremor, bradykinesia, rigidity, balance disorder and / or coordination disorder; and the PPD subject (ii) is diagnosed with four or more of the following: hyposmia, visual abnormalities, decreased color vision, pain, depression, anxiety, anaphylaxis, unresponsiveness, positive executive dysfunction, constipation, orthostatic hypotension, urogenital dysfunction, RBD, excessive daytime sleepiness, sleep fragmentation, insomnia, periodic limb movements during sleep (PLMS) and / or restless legs syndrome (RLS).

[0087] In some implementations, the PPD subject: (i) is not diagnosed with tremor, bradykinesia, rigidity, balance disorder and / or coordination disorder; and the PPD subject (ii) is diagnosed with five or more of the following: hyposmia, visual abnormalities, decreased color vision, pain, depression, anxiety, pulpitis, unresponsiveness, positive executive dysfunction, constipation, orthostatic hypotension, genitourinary dysfunction, RBD, excessive daytime sleepiness, sleep fragmentation, insomnia, periodic limb movements during sleep (PLMS) and / or restless legs syndrome (RLS).

[0088] In some implementations, the PPD subject: (i) is not diagnosed with tremor, bradykinesia, rigidity, balance disorder and / or coordination disorder; and the PPD subject (ii) is diagnosed with six or more of the following: hyposmia, visual abnormalities, decreased color vision, pain, depression, anxiety, pulpitis, unresponsiveness, positive executive dysfunction, constipation, orthostatic hypotension, genitourinary dysfunction, RBD, excessive daytime sleepiness, sleep fragmentation, insomnia, periodic limb movements during sleep (PLMS) and / or restless legs syndrome (RLS).

[0089] In some implementations, the PPD subject: (i) is not diagnosed with tremor, bradykinesia, rigidity, balance disorder and / or coordination disorder; and the PPD subject (ii) is diagnosed with seven or more of the following: hyposmia, visual abnormalities, decreased color vision, pain, depression, anxiety, pulpitis, unresponsiveness, positive executive dysfunction, constipation, orthostatic hypotension, genitourinary dysfunction, RBD, excessive daytime sleepiness, sleep fragmentation, insomnia, periodic limb movements during sleep (PLMS) and / or restless legs syndrome (RLS).

[0090] In some implementations, the PPD subject: (i) is not diagnosed with tremor, bradykinesia, rigidity, balance disorder and / or coordination disorder; and the PPD subject (ii) is diagnosed with eight or more of the following: hyposmia, visual abnormalities, decreased color vision, pain, depression, anxiety, pulpitis, unresponsiveness, positive executive dysfunction, constipation, orthostatic hypotension, genitourinary dysfunction, RBD, excessive daytime sleepiness, sleep fragmentation, insomnia, periodic limb movements during sleep (PLMS) and / or restless legs syndrome (RLS).

[0091] In some implementations, the PPD subject: (i) is not diagnosed with tremor, bradykinesia, rigidity, balance disorder and / or coordination disorder; and the PPD subject (ii) is diagnosed with nine or more of the following: hyposmia, visual abnormalities, decreased color vision, pain, depression, anxiety, pulpitis, unresponsiveness, positive executive dysfunction, constipation, orthostatic hypotension, genitourinary dysfunction, RBD, excessive daytime sleepiness, sleep fragmentation, insomnia, periodic limb movements during sleep (PLMS) and / or restless legs syndrome (RLS).

[0092] In some implementations, the PPD subject: (i) is not diagnosed with tremor, bradykinesia, rigidity, balance disorder and / or coordination disorder; and the PPD subject (ii) is diagnosed with ten or more of the following: hyposmia, visual abnormalities, decreased color vision, pain, depression, anxiety, pulp reduction, unresponsiveness, positive executive dysfunction, constipation, orthostatic hypotension, genitourinary dysfunction, RBD, excessive daytime sleepiness, sleep fragmentation, insomnia, periodic limb movements during sleep (PLMS) and / or restless legs syndrome (RLS).

[0093] In some implementations, the PPD subject: (i) is not diagnosed with tremor, bradykinesia, rigidity, balance disorder and / or coordination disorder; and the PPD subject (ii) is diagnosed with eleven or more of the following: hyposmia, visual abnormalities, decreased color vision, pain, depression, anxiety, pulp reduction, unresponsiveness, positive executive dysfunction, constipation, orthostatic hypotension, genitourinary dysfunction, RBD, excessive daytime sleepiness, sleep fragmentation, insomnia, periodic limb movements during sleep (PLMS) and / or restless legs syndrome (RLS).

[0094] In some implementations, the PPD subject: (i) is not diagnosed with tremor, bradykinesia, rigidity, balance disorder and / or coordination disorder; and the PPD subject (ii) is diagnosed with twelve or more of the following: hyposmia, visual abnormalities, decreased color vision, pain, depression, anxiety, pulp reduction, unresponsiveness, positive executive dysfunction, constipation, orthostatic hypotension, genitourinary dysfunction, RBD, excessive daytime sleepiness, sleep fragmentation, insomnia, periodic limb movements during sleep (PLMS) and / or restless legs syndrome (RLS).

[0095] In some implementations, the PPD subject: (i) is not diagnosed with tremor, bradykinesia, rigidity, balance disorder and / or coordination disorder; and the PPD subject (ii) is diagnosed with thirteen or more of the following: hyposmia, visual abnormalities, decreased color vision, pain, depression, anxiety, anaphylaxis, unresponsiveness, positive executive dysfunction, constipation, orthostatic hypotension, genitourinary dysfunction, RBD, excessive daytime sleepiness, sleep fragmentation, insomnia, periodic limb movements during sleep (PLMS) and / or restless legs syndrome (RLS).

[0096] In some implementations, the PPD subject: (i) is not diagnosed with tremor, bradykinesia, rigidity, balance disorder and / or coordination disorder; and the PPD subject (ii) is diagnosed with fourteen or more of the following: hyposmia, visual abnormalities, decreased color vision, pain, depression, anxiety, anaphylaxis, unresponsiveness, positive executive dysfunction, constipation, orthostatic hypotension, genitourinary dysfunction, RBD, excessive daytime sleepiness, sleep fragmentation, insomnia, periodic limb movements during sleep (PLMS) and / or restless legs syndrome (RLS).

[0097] In some implementations, the PPD subject: (i) is not diagnosed with tremor, bradykinesia, rigidity, balance disorder and / or coordination disorder; and the PPD subject (ii) is diagnosed with fifteen or more of the following: hyposmia, visual abnormalities, decreased color vision, pain, depression, anxiety, pulpitis, unresponsiveness, positive executive dysfunction, constipation, orthostatic hypotension, genitourinary dysfunction, RBD, excessive daytime sleepiness, sleep fragmentation, insomnia, periodic limb movements during sleep (PLMS) and / or restless legs syndrome (RLS).

[0098] In some implementations, the PPD subject: (i) is not diagnosed with tremor, bradykinesia, muscle rigidity, balance disorder and / or coordination disorder; and the PPD subject (ii) is diagnosed with sixty or more of the following: hyposmia, visual abnormalities, decreased color vision, pain, depression, anxiety, anaphylaxis, unresponsiveness, positive executive dysfunction, constipation, orthostatic hypotension, genitourinary dysfunction, RBD, excessive daytime sleepiness, sleep fragmentation, insomnia, periodic limb movements during sleep (PLMS) and / or restless legs syndrome (RLS).

[0099] In some implementations, PPD subjects: (i) are not diagnosed with tremor, bradykinesia, muscle rigidity, balance disorder and / or coordination disorder; and PPD subjects (ii) are diagnosed with hyposmia, visual abnormalities, decreased color vision, pain, depression, anxiety, anaphylaxis, unresponsiveness, positive executive dysfunction, constipation, orthostatic hypotension, urogenital dysfunction, RBD, excessive daytime sleepiness, sleep fragmentation, insomnia, periodic limb movements during sleep (PLMS), and restless legs syndrome (RLS).

[0100] In some implementations, the PPD subject: (i) has not been diagnosed with any core clinical feature, syndrome or symptom associated with Parkinson's disease, and the PPD subject (ii) has been diagnosed with one or more core clinical features, syndromes or symptoms associated with the prodromal phase of Parkinson's disease.

[0101] In some implementations, the PPD subject: (i) is not diagnosed with tremor, bradykinesia, muscle rigidity, balance disorder and / or coordination disorder; and the PPD subject (ii) is diagnosed with one or more of hyposmia, cognitive impairment, RBD, constipation, depression and / or anxiety.

[0102] In some implementations, the PPD subject: (i) is not diagnosed with tremor, bradykinesia, rigidity, balance disorder and / or coordination disorder; and the PPD subject (ii) is diagnosed with two or more of hyposmia, cognitive impairment, RBD, constipation, depression and / or anxiety.

[0103] In some implementations, the PPD subject: (i) is not diagnosed with tremor, bradykinesia, rigidity, balance disorder and / or coordination disorder; and the PPD subject (ii) is diagnosed with three or more of the following: hyposmia, cognitive impairment, RBD, constipation, depression and / or anxiety.

[0104] In some implementations, the PPD subject: (i) is not diagnosed with tremor, bradykinesia, rigidity, balance disorder and / or coordination disorder; and the PPD subject (ii) is diagnosed with four or more of the following: hyposmia, cognitive impairment, RBD, constipation, depression and / or anxiety.

[0105] In some implementations, the PPD subject: (i) is not diagnosed with tremor, bradykinesia, rigidity, balance disorder and / or coordination disorder; and the PPD subject (ii) is diagnosed with five or more of the following: hyposmia, cognitive impairment, RBD, constipation, depression and / or anxiety.

[0106] In some implementations, PPD subjects: (i) are not diagnosed with tremor, bradykinesia, muscle rigidity, balance disorder and / or coordination disorder; and PPD subjects (ii) are diagnosed with hyposmia, cognitive impairment, RBD, constipation, depression and anxiety.

[0107] In some embodiments, the PPD subject: (i) is not diagnosed with tremor, bradykinesia, rigidity, balance disorder, and / or coordination disorder; and the PPD subject (ii) is diagnosed with one or more of hyposmia, RBD, and constipation. In some embodiments, the PPD subject: (i) is not diagnosed with tremor, bradykinesia, rigidity, balance disorder, and / or coordination disorder; and the PPD subject (ii) is diagnosed with two or more of hyposmia, RBD, and constipation. In some embodiments, the PPD subject: (i) is not diagnosed with tremor, bradykinesia, rigidity, balance disorder, and / or coordination disorder; and the PPD subject (ii) is diagnosed with hyposmia, RBD, and constipation.

[0108] Almost all patients with PD suffer from constipation. Constipation is characterized by infrequent bowel movements, painful bowel movements, or both, and is one of the first most common and disabling nonmotor symptoms, occurring in the precutaneous stage. Constipation is one of the first prodromal signs, occurring up to 20 years before the first motor symptoms (Pellicano et al., Neuropsychiatric Disease and Treatment, 3(1), 145-151 (2007)).

[0109] In some embodiments, the PPD subject was diagnosed with constipation. In some embodiments, administration of N-acetylleucine reduced the frequency of constipation in the PPD subject compared to before administration. In some embodiments, administration of N-acetylleucine reduced the frequency of constipation in the PPD subject compared to before administration. In some embodiments, administration of N-acetylleucine reduced the severity of constipation in the PPD subject compared to before administration.

[0110] Hyposmia (reduced sense of smell) is one of the most common and best-characterized nonmotor features of PD, and is often one of the earliest prodromal features. More than 50% of patients with PD experience anorexia (loss of smell), 35% have severe hyposmia, and 14% have moderate hyposmia (Pellicano et al., Neuropsychiatric Disease and Treatment, 3(1), 145-151 (2007)). Hyposmia can be objectively quantified using standard tests such as sensory olfactory tests, including the 12-item simplified olfactory identification test (B-SIT) and / or the sniffing stick test (SST) which evaluate three different aspects of olfactory function (threshold (T), discrimination (D), and identification (I)), nasal endoscopy, and / or imaging tests, including computed tomography (CT) and magnetic resonance imaging (MRI). In some implementations, PPD subjects are diagnosed with hyposmia. In some implementations, the 12-item simplified olfactory identification test (B-SIT) is used to diagnose PPD subjects with hyposmia. In some implementations, the snoogamous probe test (SST) is used to diagnose PPD subjects with hyposmia.

[0111] In some implementations, the PPD subject was diagnosed with hyposmia. In some implementations, administration of N-acetylleucine reduced the severity of hyposmia in the PPD subject compared to before administration.

[0112] In fact, all patients with PD experience sleep disruption, and there is evidence that this process usually begins early in the course of the disease. RBD is a type of insomnia characterized by drooling behavior that is often associated with unpleasant drooling and loss of normal REM-sleep muscle atrophy, usually involving upper limb vocalization or movement. Patient-reported questionnaires have been developed to identify individuals with RBD, but similar to patients with hyposmia, patients with RBD are often unaware of their symptoms. An accurate incidental history from the bedside is usually required for diagnosis. In cases with problems or for individuals without a bedside, a multispectral approach may be available. Cohort studies have shown that iRBD can convert to PD and other synaptic nuclei diseases, such as Lewy body dementia and multiple system atrophy. In some implementations, subjects with PPD are diagnosed with RBD. In addition to RBD, recent data suggest that excessive daytime sleepiness may also be a premotor marker of PD (Pellicano et al., Neuropsychiatric Disease and Treatment, 3(1), 145-151 (2007)).

[0113] In some implementations, the PDD subject is diagnosed with a sleep disorder. In some implementations, the sleep disorder is an RBD. When unrelated to other neurological disorders, the RBD can be dissociative (iRBD). In some implementations, the PDD subject is diagnosed with iRBD. RBD and iRBD are used interchangeably herein.

[0114] In some implementations, administration of N-acetylleucine reduces the number of RBD attacks compared to the number of RBD attacks prior to administration. In some implementations, administration of N-acetylleucine reduces the daily RBD severity score of PPD subjects compared to the daily RBD severity score of PPD subjects prior to administration.

[0115] In some embodiments, the application of N-acetylleucine reduces the frequency of RBD behaviors compared to before the application. In some embodiments, RBD behaviors are selected from the group consisting of vocalization, simple and complex motor behaviors, and any combination thereof. In some embodiments, the application of N-acetylleucine reduces the severity of RBD behaviors compared to before the application.

[0116] In some implementations, N-acetylleucine administration reduces the number of nights per week in which the PPD subject or their bed partner exhibits harmful behaviors compared to before administration. In some implementations, harmful behaviors are selected from vocalizations, simple and complex motor behaviors, and any combination thereof.

[0117] In some implementations, the number of nightmares per week decreased after N-acetylleucine administration compared to before administration.

[0118] Inhibition is extremely frequent in PD, occurring in up to 45% of cases. Depression is not necessarily related to the severity of motor symptoms in PD and is often missed because reduced facial expressions and reduced voluntary movement are common in both PD and pure depression. Therefore, the identification of depression in PD patients is largely based on subjective perceptions of depressive symptoms, such as helplessness, reduced responsiveness to emotional stimuli, and anhedonia (loss of pleasure) from things or events. The pathophysiology of depression in PD is quite complex and involves damage to norepinephrine, serotonergic, and dopaminergic pathways in the brain. In fact, the pattern of depressive symptoms in PD appears to be different from that of pure depression. Typical signs of depression in PD include increased irritability and restlessness, pessimism about the future, and lower levels of feelings of inadequacy and guilt (Pellicano et al., Neuropsychiatric Disease and Treatment, 3(1), 145-151 (2007)).

[0119] In case-control studies, the occurrence of depression in the last 5 years was significantly associated with the future development of motor symptoms in PD. Longitudinal studies showed that the risk of developing PD was increased in depressed subjects compared with those without depression. Finally, Lauterbach et al. (2004) reported that patients with PD were more likely to have a single diagnosis (before the onset of PD) of simple phobia and secondary atypical depression compared with patients with dystonia (Pellicano et al., Neuropsychiatric Disease and Treatment, 3(1), 145-151 (2007)).

[0120] In some embodiments, the PPD subject was diagnosed with depression. In some embodiments, administration of N-acetylleucine reduced the severity of depression compared to before administration. In some embodiments, administration of N-acetylleucine reduced the number of depressive episodes in the PPD subject compared to before administration.

[0121] Anxiety is also common in PD and may represent a pre-motor risk factor. Anxiety may be present as panic attacks, phobias or general anxiety disorder and may be associated with drug-induced motor fluctuations in PD (Pellicano et al., Neuropsychiatric Disease and Treatment, 3(1), 145-151 (2007)).

[0122] In some implementations, the PPD subject was diagnosed with anxiety. In some implementations, administration of N-acetylleucine reduced the severity of anxiety compared to before administration. In some implementations, administration of N-acetylleucine reduced the frequency of anxiety episodes in the PPD subject compared to before administration.

[0123] The histopathological marker of PD is the presence of Lewy bodies (LB), fibrillary aggregates in which α-synuclein is the main component. Pathological studies have shown a strong correlation between the extent of loss of Lewy body-associated cells in parenchymal Nigra (SN) and the severity of bradykinesia. Nigrostriatal dopaminergic damage can be monitored by functional neuroimaging techniques such as positron emission tomography (PET) or single-photon emission tomography (SPECT) (Meyer et al., J Nuc Med, 58(12), 1888-1898 (2017)).

[0124] Molecular neuroimaging using PET allows for the quantitative visualization of in vivo functions and molecular processes. The radiotracer 18F-2-fluoro-2-deoxy-D-glucose (18F-FDG) is a glucose analogue and allows for the in vivo assessment of brain glucose metabolism using positron emission tomography (PET). 18F-FDG is the most commonly used radiotracer for assessing regional brain glucose metabolism as a marker of neuronal function. Due to the disclosure of disease-specific alterations resulting from synaptic dysfunction, neuronal degeneration, and associated compensatory network changes, 18F-FDG PET has become an important part of diagnostic research for patients with neurodegenerative diseases (Meyer et al., J Nuc Med, 58(12), 1888-1898 (2017)).

[0125] 18F-FDG PET imaging characterized PD with hypometabolism in the parietal, occipital, and sometimes prefrontal lobes (especially in PD with cognitive impairment) and relatively hypermetabolism in the putamen, globus pallidus, thalamic sensorimotor cortex, pons, and cerebellum. Conversely, MSA patients showed significant hypometabolism in the (posterior) putamen, pons, and cerebellum, which may be more pronounced in the striatum or in the pons and cerebellum, depending on the primary aspect of degeneration and therefore on the clinical presentation (substantia nigra / MSA-P and olivopontocerebellum / MSA-C, respectively). Isolated cerebellar hypometabolism may also occur in other causes of cerebellar degeneration (e.g., cerebellar neoplasia or spinocerebellar ataxia). Group analyses also demonstrated positive hypometabolism, which can spread to the parietal lobe and temporal regions simultaneously with the onset of cognitive impairment. However, the latter finding was less obvious in individual analyses and offered little help in the differential diagnosis of 18 F-FDG PET (Meyer et al., J Nuc Med, 58(12), 1888-1898 (2017)).

[0126] In some embodiments, the PPD subject has reduced glucose metabolism in the parietal, occipital, and / or frontal lobes of the brain. In some embodiments, the PPD subject has reduced glucose metabolism in one or more of the parietal, occipital, and / or frontal lobes of the brain. In some embodiments, the PPD subject has reduced glucose metabolism in two or more of the parietal, occipital, and / or frontal lobes of the brain. In some embodiments, the PPD subject has reduced glucose metabolism in the parietal, occipital, and frontal lobes of the brain.

[0127] In some embodiments, administration of N-acetylleucine increases glucose metabolism in the brain of PPD subjects compared to before administration. In some embodiments, administration of N-acetylleucine increases glucose metabolism in the parietal, occipital, and / or frontal lobes of the PPD subjects' brains compared to before administration. In some embodiments, administration of N-acetylleucine increases glucose metabolism in one or more of the parietal, occipital, and / or frontal lobes of the PPD subjects' brains compared to before administration.

[0128] In some embodiments, glucose metabolism is determined by positron emission tomography (PET) scanning. In some embodiments, the PET scan is a fluorodeoxyglucose-positron emission tomography (FDG-PET) scan. In some embodiments, the FDG-PET scan is used to generate the z-score of the PPD subject.

[0129] In some embodiments, administration of N-acetylleucine reduces the z-score of PPD subjects. In some embodiments, administration of N-acetylleucine reduces the z-score of PPD subjects in the parietal, occipital, and / or frontal lobes of the brain. In some embodiments, the z-score of PPD subjects is reduced by at least about 5%, about 10%, about 20%, about 30%, about 40%, or about at least 50% compared to the z-score of PPD subjects before administration of N-acetylleucine.

[0130] Neuronal loss in the pars compacta (SNc) of the solid white matter associated with Lewy body pathology is a pathological hallmark of incidental Parkinson's disease (PD). Reduced dopaminergic function in the nigrostriatal region is associated with known nonmotor symptoms preceding PD. Furthermore, the extent of nigrostriatal dopaminergic denervation has been shown to correlate with the severity of classic motor features of PD, particularly bradykinesia and rigidity. Foot-striatal dopaminergic denervation can be visualized using radiotracers labeled with presynaptic dopaminergic markers, such as striatal dopaminergic transporters (DAT), routinely achieved via single-photon emission computed tomography (SPECT) or decarboxylase activity with 18F-Doppler positron emission tomography (PET) (Mahlknecht et al., J Parkinson's Disease, 5, 681-697 (2015)).

[0131] 123 I-ioflupane single-photon emission computed tomography (SPECT) assesses dopamine transporter (DAT) uptake in the basal ganglia in vivo. SPECT is a nuclear imaging modality that measures the radioactivity of gamma rays emitted from a radioactive compound bound to a tracer. By binding to DAT, 123 I-ioflupane allows imaging of the presynaptic terminal. DAT-SPECT provides a semi-quantitative assessment of striatal dopaminergic afferentization and is a well-established method for assessing and studying PD (Mahlknecht et al., J Parkinson's Disease, 5, 681-697 (2015)).

[0132] In patients with PD, DAT-SPECT showed reduced striatal DAT uptake, indicating that dopaminergic dysfunction in the substantia nigra was more pronounced in the putamen than in the caudate nucleus. The DAT deficiency seen in the RBD was less severe than in established PD, suggesting that dopaminergic imaging may have the potential to quantify progression through the prodromal phase. 18F-Doppler PET studies in PD patients have shown a faster rate of decline in tracer uptake at both earlier and later disease stages, and extrapolation of these exponential curves has led to estimates of approximately 6 years of pre-diagnostic PD based on pathological post-hoc studies (Hustad et al., Front. Neurol., 11:395 (2020)).

[0133] In some embodiments, PPD subjects have reduced dopaminergic function in the basal ganglia. In some embodiments, PPD subjects have reduced DAT uptake in the basal ganglia. In some embodiments, PPD subjects have reduced DAT binding in the basal ganglia. In some embodiments, PPD subjects have reduced amounts of dopamine transporters in the basal ganglia.

[0134] In some embodiments, administration of N-acetylleucine increases dopaminergic function in the basal ganglia of PPD subjects compared to before administration. In some embodiments, administration of N-acetylleucine increases DAT uptake in the basal ganglia of PPD subjects compared to before administration. In some embodiments, administration of N-acetylleucine increases DAT binding in the basal ganglia of PPD subjects compared to before administration. In some embodiments, administration of N-acetylleucine increases the amount of dopamine transporters in the basal ganglia of PPD subjects compared to before administration.

[0135] In some embodiments, the amount of dopamine transporters in PPD subjects is determined by dopamine transporter (DAT) scanning. In some embodiments, the DAT scan is a DAT scan with single-photon emission computed tomography (DAT-SPECT) or a DAT scan with decarboxylase activity using 18F-Doppler positron emission tomography (DAT-PET). In some embodiments, the DAT scan is DAT-SPECT.

[0136] In 1995, Becker et al. reported a highly characteristic amplification of the substantia nigra echo signal (hyperecho) in idiopathic PD. Since then, numerous studies have demonstrated that this method is a valuable tool for the differential diagnosis of PD, which even allows for the identification of PPD subjects at risk of substantia nigra striatum dysfunction (Pellicano et al., Neuropsychiatric Disease and Treatment, 3(1), 145-151 (2007)).

[0137] B. Dementia with Lewy body (DLB)

[0138] In some embodiments, this disclosure provides a preliminary method for treating DLB in subjects in need, comprising administering a therapeutically effective amount of N-acetylleucine to the subject. These subjects are referred to in this section as “Lewy body dementia” or “PDLB subjects”.

[0139] In some embodiments, the PDLB subject has not been diagnosed with dementia. In some embodiments, the PDLB subject has not been diagnosed with one or more of mild cognitive impairment (MCI), hemorrhagic seizures, and / or psychotic episodes. In some embodiments, the PDLB subject has not been diagnosed with dementia, but has been diagnosed with one or more of mild cognitive impairment (MCI), epileptic seizures, and / or psychotic episodes.

[0140] In some embodiments, the PDLB subject has not been diagnosed with any core clinical feature, syndrome, or symptom associated with DLB. In some embodiments, the core clinical feature, syndrome, or symptom associated with DLB is dementia, Parkinson's syndrome, RBD, cognitive / vigilance fluctuations, and / or visual hallucinations. In some embodiments, the PDLB subject has not been diagnosed with dementia, Parkinson's syndrome, RBD, cognitive / vigilance fluctuations, or visual hallucinations. In some embodiments, the PDLB subject has not been diagnosed with dementia.

[0141] Lewy bodies (DLB) are a common form of dementia in older adults, characterized by Lewy bodies primarily composed of α-synuclein in the brain of patients with clinical dementia syndrome. Lewy bodies (DLB) are characterized by a distinct combination of dementia and core clinical features such as Parkinson's syndrome, RBD, cognitive / vigilance fluctuations, and visual hallucinations. Distinguishing between patients with DLB and those with Alzheimer's dementia (AD) is often difficult for clinicians, especially since Alzheimer's pathology may be present to varying degrees in DLB, affecting clinical presentation and imaging findings (McKeith et al., Neurology, 94(17), 743-755 (2020)).

[0142] In some embodiments, the PDLB subject is not diagnosed with dementia and does not possess at least two of the core characteristics listed in Table 3. In some embodiments, the PDLB subject is not diagnosed with dementia, does not possess at least one of the core characteristics listed in Table 3, and does not possess at least one indicative biomarker listed in Table 3.

[0143] Table 3. Diagnostic criteria for Lewy body-related dementia (DLB)

[0144] (Surendranathan et al., Evid Based Menthal Health, 21(2), 61-65 (2018))

[0145] Prodromal DLB refers to the pre-dementia stage characterized by signs or symptoms that indicate the subsequent development of DLB, and encompasses not only cognitive deficits but also a variable mix of non-cognitive clinical features, including motor symptoms and signs, sleep disturbances, autonomic dysfunction, and neuropsychiatric disorders. Specific markers of prodromal DLB include rapid eye movement (REM) sleep behavior disorder (RBD), olfactory dysfunction, autonomic dysfunction, depression, and diffuse occipital hypometabolism on FDG-PET (McKeith et al., Neurology, 94(17), 743-755 (2020)).

[0146] Table 4. Time sequence of symptom development in prodromal DLB.

[0147] (Donaghy et al., Psy Med, 45, 259-268 (2015))

[0148] In some embodiments, PDLB subjects are diagnosed with one or more core clinical features, syndromes, or symptoms associated with the prodromal phase of DLB. In some embodiments, one or more core clinical features, syndromes, or symptoms associated with the prodromal phase of DLB ​​are RBD, constipation, hyposmia, depression, urinary dysfunction, erectile dysfunction, orthostatic hypotension / dizziness, mild motor abnormalities, impaired olfaction, impaired color vision, memory impairment, Parkinson's symptoms, visual hallucinations, anxiety, mild cognitive impairment, attention / executive dysfunction, visuospatial dysfunction, striatal dopaminergic denervation, hyperechoic substantia nigra, and / or increased rCBF in the hippocampus.

[0149] In some embodiments, the PDLB subject is diagnosed with one or more of the following: RBD, constipation, hyposmia, depression, urinary dysfunction, erectile dysfunction, orthostatic hypotension / dizziness, mild motor dysfunction, impaired olfactory function, impaired color vision, memory impairment, Parkinson's symptoms, visual hallucinations, anxiety, mild cognitive impairment, attention / executive dysfunction, visuospatial dysfunction, striatal dopaminergic denervation, substantia nigra hyperechoic and / or increased rCBF in the hippocampus.

[0150] In some implementations, PDLB subjects are diagnosed with two or more of the following: RBD, constipation, hyposmia, depression, urinary dysfunction, erectile dysfunction, orthostatic hypotension / dizziness, mild motor dysfunction, impaired olfactory function, impaired color vision, memory impairment, Parkinson's symptoms, visual hallucinations, anxiety, mild cognitive impairment, attention / executive dysfunction, visuospatial dysfunction, striatal dopaminergic denervation, substantia nigra hyperechoicity, and / or increased rCBF in the hippocampus.

[0151] In some implementations, PDLB subjects are diagnosed with three or more of the following: RBD, constipation, hyposmia, depression, urinary dysfunction, erectile dysfunction, orthostatic hypotension / dizziness, mild motor dysfunction, impaired olfactory function, impaired color vision, memory impairment, Parkinson's symptoms, visual hallucinations, anxiety, mild cognitive impairment, attention / executive dysfunction, visuospatial dysfunction, striatal dopaminergic denervation, substantia nigra hyperechoicity, and / or increased hippocampal rCBF.

[0152] In some implementations, PDLB subjects are diagnosed with four or more of the following: RBD, constipation, hyposmia, depression, urinary dysfunction, erectile dysfunction, orthostatic hypotension / dizziness, mild motor dysfunction, impaired olfactory function, impaired color vision, memory impairment, Parkinson's symptoms, visual hallucinations, anxiety, mild cognitive impairment, attention / executive dysfunction, visuospatial dysfunction, striatal dopaminergic denervation, substantia nigra hyperechoic and / or increased rCBF in the hippocampus.

[0153] In some implementations, PDLB subjects are diagnosed with five or more of the following: RBD, constipation, hyposmia, depression, urinary dysfunction, erectile dysfunction, orthostatic hypotension / dizziness, mild motor dysfunction, impaired olfactory function, impaired color vision, memory impairment, Parkinson's symptoms, visual hallucinations, anxiety, mild cognitive impairment, attention / executive dysfunction, visuospatial dysfunction, striatal dopaminergic denervation, substantia nigra hyperechoicity, and / or increased rCBF in the hippocampus.

[0154] In some implementations, PDLB subjects are diagnosed with six or more of the following: RBD, constipation, hyposmia, depression, urinary dysfunction, erectile dysfunction, orthostatic hypotension / dizziness, mild motor dysfunction, impaired olfactory function, impaired color vision, memory impairment, Parkinson's symptoms, visual hallucinations, anxiety, mild cognitive impairment, attention / executive dysfunction, visuospatial dysfunction, striatal dopaminergic denervation, substantia nigra hyperechoicity, and / or increased hippocampal rCBF.

[0155] In some implementations, PDLB subjects are diagnosed with seven or more of the following: RBD, constipation, hyposmia, depression, urinary dysfunction, erectile dysfunction, orthostatic hypotension / dizziness, mild motor dysfunction, impaired olfactory function, impaired color vision, memory impairment, Parkinson's symptoms, visual hallucinations, anxiety, mild cognitive impairment, attention / executive dysfunction, visuospatial dysfunction, striatal dopaminergic denervation, substantia nigra hyperechoicity, and / or increased rCBF in the hippocampus.

[0156] In some embodiments, the PDLB subject is diagnosed with eight or more of the following: RBD, constipation, hyposmia, depression, urinary dysfunction, erectile dysfunction, orthostatic hypotension / dizziness, mild motor dysfunction, impaired olfactory function, impaired color vision, memory impairment, Parkinson's symptoms, visual hallucinations, anxiety, mild cognitive impairment, attention / executive dysfunction, visuospatial dysfunction, striatal dopaminergic denervation, substantia nigra hyperechoicity, and / or increased rCBF in the hippocampus.

[0157] In some implementations, PDLB subjects are diagnosed with nine or more of the following: RBD, constipation, hyposmia, depression, urinary dysfunction, erectile dysfunction, orthostatic hypotension / dizziness, mild motor dysfunction, impaired olfactory function, impaired color vision, memory impairment, Parkinson's symptoms, visual hallucinations, anxiety, mild cognitive impairment, attention / executive dysfunction, visuospatial dysfunction, striatal dopaminergic denervation, substantia nigra hyperechoicity, and / or increased rCBF in the hippocampus.

[0158] In some implementations, PDLB subjects are diagnosed with ten or more of the following: RBD, constipation, hyposmia, depression, urinary dysfunction, erectile dysfunction, orthostatic hypotension / dizziness, mild motor dysfunction, impaired olfactory function, impaired color vision, memory impairment, Parkinson's symptoms, visual hallucinations, anxiety, mild cognitive impairment, attention / executive dysfunction, visuospatial dysfunction, striatal dopaminergic denervation, substantia nigra hyperechoicity, and / or increased rCBF in the hippocampus.

[0159] In some implementations, PDLB subjects are diagnosed with eleven or more of the following: RBD, constipation, hyposmia, depression, urinary dysfunction, erectile dysfunction, orthostatic hypotension / dizziness, mild motor dysfunction, impaired olfactory function, impaired color vision, memory impairment, Parkinson's symptoms, visual hallucinations, anxiety, mild cognitive impairment, attention / executive dysfunction, visuospatial dysfunction, striatal dopaminergic denervation, substantia nigra hyperechoicity, and / or increased hippocampal rCBF.

[0160] In some implementations, PDLB subjects are diagnosed with twelve or more of the following: RBD, constipation, hyposmia, depression, urinary dysfunction, erectile dysfunction, orthostatic hypotension / dizziness, mild motor dysfunction, impaired olfactory function, impaired color vision, memory impairment, Parkinson's symptoms, visual hallucinations, anxiety, mild cognitive impairment, attention / executive dysfunction, visuospatial dysfunction, striatal dopaminergic denervation, substantia nigra hyperechoicity, and / or increased hippocampal rCBF.

[0161] In some embodiments, the PDLB subject is diagnosed with thirteen or more of the following: RBD, constipation, hyposmia, depression, urinary dysfunction, erectile dysfunction, orthostatic hypotension / dizziness, mild motor dysfunction, impaired olfactory function, impaired color vision, memory impairment, Parkinson's symptoms, visual hallucinations, anxiety, mild cognitive impairment, attention / executive dysfunction, visuospatial dysfunction, striatal dopaminergic denervation, substantia nigra hyperechoicity, and / or increased rCBF in the hippocampus.

[0162] In some implementations, PDLB subjects are diagnosed with fourteen or more of the following: RBD, constipation, hyposmia, depression, urinary dysfunction, erectile dysfunction, orthostatic hypotension / dizziness, mild motor dysfunction, impaired olfactory function, impaired color vision, memory impairment, Parkinson's symptoms, visual hallucinations, anxiety, mild cognitive impairment, attention / executive dysfunction, visuospatial dysfunction, striatal dopaminergic denervation, substantia nigra hyperechoicity, and / or increased rCBF in the hippocampus.

[0163] In some implementations, PDLB subjects are diagnosed with RBD, constipation, hyposmia, depression, urinary dysfunction, erectile dysfunction, orthostatic hypotension / dizziness, mild motor abnormalities, impaired olfactory function, impaired color vision, memory impairment, Parkinson's symptoms, visual hallucinations, anxiety, mild cognitive impairment, attention / executive dysfunction, visuospatial dysfunction, striatal dopaminergic denervation, substantia nigra hyperechoicity, and / or increased hippocampal rCBF in fifteen or more of the following conditions.

[0164] In some implementations, PDLB subjects are diagnosed with sixteen or more of the following: RBD, constipation, hyposmia, depression, urinary dysfunction, erectile dysfunction, orthostatic hypotension / dizziness, mild motor dysfunction, impaired olfactory function, impaired color vision, memory impairment, Parkinson's symptoms, visual hallucinations, anxiety, mild cognitive impairment, attention / executive dysfunction, visuospatial dysfunction, striatal dopaminergic denervation, substantia nigra hyperechoicity, and / or increased hippocampal rCBF.

[0165] In some embodiments, the PDLB subject is diagnosed with seventeen or more of the following: RBD, constipation, hyposmia, depression, urinary dysfunction, erectile dysfunction, orthostatic hypotension / dizziness, mild motor dysfunction, impaired olfactory function, impaired color vision, memory impairment, Parkinson's symptoms, visual hallucinations, anxiety, mild cognitive impairment, attention / executive dysfunction, visuospatial dysfunction, striatal dopaminergic denervation, substantia nigra hyperechoicity, and / or increased rCBF in the hippocampus.

[0166] In some embodiments, the PDLB subject is diagnosed with eighteen or more of the following: RBD, constipation, hyposmia, depression, urinary dysfunction, erectile dysfunction, orthostatic hypotension / dizziness, mild motor dysfunction, impaired olfactory function, impaired color vision, memory impairment, Parkinson's symptoms, visual hallucinations, anxiety, mild cognitive impairment, attention / executive dysfunction, visuospatial dysfunction, striatal dopaminergic denervation, substantia nigra hyperechoicity, and / or increased rCBF in the hippocampus.

[0167] In some embodiments, the PDLB subject is diagnosed with nineteen or more of the following: RBD, constipation, hyposmia, depression, urinary dysfunction, erectile dysfunction, orthostatic hypotension / dizziness, mild motor dysfunction, impaired olfactory function, impaired color vision, memory impairment, Parkinson's symptoms, visual hallucinations, anxiety, mild cognitive impairment, attention / executive dysfunction, visuospatial dysfunction, striatal dopaminergic denervation, substantia nigra hyperechoicity, and / or increased rCBF in the hippocampus.

[0168] In some implementations, PDLB subjects were diagnosed with RBD, constipation, hyposmia, depression, urinary dysfunction, erectile dysfunction, orthostatic hypotension / dizziness, mild motor dysfunction, impaired olfaction, impaired color vision, memory impairment, Parkinson's symptoms, visual hallucinations, anxiety, mild cognitive impairment, attention / executive dysfunction, visuospatial dysfunction, striatal dopaminergic denervation, substantia nigra hyperechoicity, and increased hippocampal rCBF.

[0169] In some implementations, one or more core clinical features, syndromes, or symptoms associated with the prodromal phase of DLB ​​are RBD, constipation, hyposmia, depression, orthostatic hypotension / dizziness, memory impairment, Parkinson's symptoms, visual hallucinations, anxiety, mild cognitive impairment, attention / executive dysfunction, visuospatial dysfunction, and / or striatal dopaminergic denervation.

[0170] In some implementations, PDLB subjects are diagnosed with one or more of the following: RBD, constipation, hyposmia, depression, orthostatic hypotension / dizziness, memory impairment, Parkinson's symptoms, visual hallucinations, anxiety, mild cognitive impairment, attention / executive dysfunction, visuospatial dysfunction, and / or striatal dopaminergic denervation.

[0171] In some implementations, PDLB subjects are diagnosed with two or more of the following: RBD, constipation, hyposmia, depression, orthostatic hypotension / dizziness, memory impairment, Parkinson's symptoms, visual hallucinations, anxiety, mild cognitive impairment, attention / executive dysfunction, visuospatial dysfunction, and / or striatal dopaminergic denervation.

[0172] In some implementations, PDLB subjects are diagnosed with three or more of the following: RBD, constipation, hyposmia, depression, orthostatic hypotension / dizziness, memory impairment, Parkinson's symptoms, visual hallucinations, anxiety, mild cognitive impairment, attention / executive dysfunction, visuospatial dysfunction, and / or striatal dopaminergic denervation.

[0173] In some implementations, PDLB subjects are diagnosed with four or more of the following: RBD, constipation, hyposmia, depression, orthostatic hypotension / dizziness, memory impairment, Parkinson's symptoms, visual hallucinations, anxiety, mild cognitive impairment, attention / executive dysfunction, visuospatial dysfunction, and / or striatal dopaminergic denervation.

[0174] In some implementations, PDLB subjects are diagnosed with five or more of the following: RBD, constipation, decreased sense of smell, depression, orthostatic hypotension / dizziness, memory impairment, Parkinson's symptoms, visual hallucinations, anxiety, mild cognitive impairment, attention / executive dysfunction, visuospatial dysfunction, and / or striatal dopaminergic denervation.

[0175] In some implementations, PDLB subjects are diagnosed with six or more of the following: RBD, constipation, decreased sense of smell, depression, orthostatic hypotension / dizziness, memory impairment, Parkinson's symptoms, visual hallucinations, anxiety, mild cognitive impairment, attention / executive dysfunction, visuospatial dysfunction, and / or striatal dopaminergic denervation.

[0176] In some implementations, PDLB subjects are diagnosed with RBD, constipation, hyposmia, depression, orthostatic hypotension / dizziness, memory impairment, Parkinson's symptoms, visual hallucinations, anxiety, mild cognitive impairment, attention / executive dysfunction, visuospatial dysfunction, and / or striatal dopaminergic denervation.

[0177] In some implementations, PDLB subjects are diagnosed with eight or more of the following: RBD, constipation, hyposmia, depression, orthostatic hypotension / dizziness, memory impairment, Parkinson's symptoms, visual hallucinations, anxiety, mild cognitive impairment, attention / executive dysfunction, visuospatial dysfunction, and / or striatal dopaminergic denervation.

[0178] In some implementations, PDLB subjects are diagnosed with RBD, constipation, hyposmia, depression, orthostatic hypotension / dizziness, memory impairment, Parkinson's symptoms, visual hallucinations, anxiety, mild cognitive impairment, attention / executive dysfunction, visuospatial dysfunction, and / or striatal dopaminergic denervation.

[0179] In some implementations, PDLB subjects are diagnosed with ten or more of the following: RBD, constipation, hyposmia, depression, orthostatic hypotension / dizziness, memory impairment, Parkinson's symptoms, visual hallucinations, anxiety, mild cognitive impairment, attention / executive dysfunction, visuospatial dysfunction, and / or striatal dopaminergic denervation.

[0180] In some implementations, PDLB subjects are diagnosed with RBD, constipation, hyposmia, depression, orthostatic hypotension / dizziness, memory impairment, Parkinson's symptoms, visual hallucinations, anxiety, mild cognitive impairment, attention / executive dysfunction, visuospatial dysfunction, and / or striatal dopaminergic denervation.

[0181] In some implementations, PDLB subjects are diagnosed with RBD, constipation, hyposmia, depression, orthostatic hypotension / dizziness, memory impairment, Parkinson's symptoms, visual hallucinations, anxiety, mild cognitive impairment, attention / executive dysfunction, visuospatial dysfunction, and / or striatal dopaminergic denervation.

[0182] In some implementations, PDLB subjects are diagnosed with constipation, decreased sense of smell, depression, orthostatic hypotension / dizziness, memory impairment, Parkinson's symptoms, visual hallucinations, anxiety, mild cognitive impairment, attention / executive dysfunction, visuospatial dysfunction, and striatal dopaminergic denervation.

[0183] In some embodiments, one or more core clinical features, syndromes, or symptoms associated with the prodromal phase of DLB ​​are RBD, constipation, hyposmia, depression, and / or orthostatic hypotension / dizziness. In some embodiments, the PDLB subject is diagnosed with one or more of RBD, constipation, hyposmia, depression, and / or orthostatic hypotension / dizziness. In some embodiments, the PDLB subject is diagnosed with two or more of RBD, constipation, hyposmia, depression, and / or orthostatic hypotension / dizziness. In some embodiments, the PDLB subject is diagnosed with three or more of RBD, constipation, hyposmia, depression, and / or orthostatic hypotension / dizziness. In some embodiments, the PDLB subject is diagnosed with four or more of RBD, constipation, hyposmia, depression, and / or orthostatic hypotension / dizziness. In some embodiments, the PDLB subject is diagnosed with RBD, constipation, hyposmia, depression, and orthostatic hypotension / dizziness.

[0184] In some embodiments, the PDLB subject: (i) has not been diagnosed with any core clinical feature, syndrome, or symptom associated with DLB, and the PDLB subject (ii) has been diagnosed with one or more core clinical features, syndromes, or symptoms associated with the prodromal phase of DLB. In some embodiments, the PDLB subject: (i) has not been diagnosed with dementia, Parkinson's syndrome, RBD, cognitive / vigilance fluctuations, and visual hallucinations; and the PDLB subject (ii) has been diagnosed with RBD, constipation, hyposmia, depression, urinary dysfunction, erectile dysfunction, orthostatic hypotension / dizziness, minimal motor dysfunction, impaired olfaction, impaired color vision, memory impairment, Parkinson's symptoms, visual hallucinations, anxiety, mild cognitive impairment, attention / executive dysfunction, visuospatial dysfunction, striatal dopaminergic denervation, substantia nigra hyperechoicity, and / or increased rCBF in the hippocampus.

[0185] In some embodiments, the PDLB subject: (i) is not diagnosed with dementia, Parkinson's syndrome, RBD, cognitive / vigilance fluctuations, and visual hallucinations; and the PDLB subject (ii) is diagnosed with RBD, constipation, hyposmia, depression, urinary dysfunction, erectile dysfunction, orthostatic hypotension / dizziness, mild motor dysfunction, impaired olfaction, impaired color vision, memory impairment, Parkinson's symptoms, visual hallucinations, anxiety, mild cognitive impairment, attention / executive dysfunction, visuospatial dysfunction, striatal dopaminergic denervation, substantia nigra hyperechoic and / or increased rCBF in the hippocampus.

[0186] In some implementations, PDLB subjects: (i) are not diagnosed with dementia, Parkinson's syndrome, RBD, cognitive / vigilance fluctuations, and visual hallucinations; and PDLB subjects (ii) are diagnosed with RBD, constipation, hyposmia, depression, urinary dysfunction, erectile dysfunction, orthostatic hypotension / dizziness, mild motor dysfunction, impaired olfaction, impaired color vision, memory impairment, Parkinson's symptoms, visual hallucinations, anxiety, mild cognitive impairment, attention / executive dysfunction, visuospatial dysfunction, striatal dopaminergic denervation, substantia nigra hyperechoic and / or increased rCBF in the hippocampus.

[0187] In some embodiments, the PDLB subject: (i) has not been diagnosed with dementia, Parkinson's syndrome, RBD, cognitive / vigilance fluctuations, and visual hallucinations; and the PDLB subject (ii) has been diagnosed with RBD, constipation, hyposmia, depression, urinary dysfunction, erectile dysfunction, orthostatic hypotension / dizziness, mild motor dysfunction, impaired olfaction, impaired color vision, memory impairment, Parkinson's symptoms, visual hallucinations, anxiety, mild cognitive impairment, attention / executive dysfunction, visuospatial dysfunction, striatal dopaminergic denervation, substantia nigra hyperechoic and / or increased rCBF in the hippocampus.

[0188] In some implementations, PDLB subjects: (i) are not diagnosed with dementia, Parkinson's syndrome, RBD, cognitive / vigilance fluctuations, and visual hallucinations; and PDLB subjects (ii) are diagnosed with RBD, constipation, hyposmia, depression, urinary dysfunction, erectile dysfunction, orthostatic hypotension / dizziness, mild motor dysfunction, impaired olfaction, impaired color vision, memory impairment, Parkinson's symptoms, visual hallucinations, anxiety, mild cognitive impairment, attention / executive dysfunction, visuospatial dysfunction, striatal dopaminergic denervation, substantia nigra hyperechoicity, and / or increased rCBF in the hippocampus.

[0189] In some implementations, PDLB subjects: (i) are not diagnosed with dementia, Parkinson's syndrome, RBD, cognitive / vigilance fluctuations, and visual hallucinations; and PDLB subjects (ii) are diagnosed with RBD, constipation, hyposmia, depression, urinary dysfunction, erectile dysfunction, orthostatic hypotension / dizziness, mild motor dysfunction, impaired olfaction, impaired color vision, memory impairment, Parkinson's symptoms, visual hallucinations, anxiety, mild cognitive impairment, attention / executive dysfunction, visuospatial dysfunction, striatal dopaminergic denervation, substantia nigra hyperechoicity, and / or increased rCBF in the hippocampus.

[0190] In some implementations, PDLB subjects: (i) are not diagnosed with dementia, Parkinson's syndrome, RBD, cognitive / vigilance fluctuations, and visual hallucinations; and PDLB subjects (ii) are diagnosed with seven or more of the following: RBD, constipation, hyposmia, depression, urinary dysfunction, erectile dysfunction, orthostatic hypotension / dizziness, mild motor dysfunction, impaired olfaction, impaired color vision, memory impairment, Parkinson's symptoms, visual hallucinations, anxiety, mild cognitive impairment, attention / executive dysfunction, visuospatial dysfunction, striatal dopaminergic denervation, substantia nigra hyperechoicity, and / or increased rCBF in the hippocampus.

[0191] In some implementations, PDLB subjects: (i) are not diagnosed with dementia, Parkinson's syndrome, RBD, cognitive / vigilance fluctuations, and visual hallucinations; and PDLB subjects (ii) are diagnosed with RBD, constipation, hyposmia, depression, urinary dysfunction, erectile dysfunction, orthostatic hypotension / dizziness, mild motor dysfunction, impaired olfaction, impaired color vision, memory impairment, Parkinson's symptoms, visual hallucinations, anxiety, mild cognitive impairment, attention / executive dysfunction, visuospatial dysfunction, striatal dopaminergic denervation, substantia nigra hyperechoicity, and / or increased rCBF in the hippocampus.

[0192] In some embodiments, the PDLB subject: (i) is not diagnosed with dementia, Parkinson's syndrome, RBD, cognitive / vigilance fluctuations, and visual hallucinations; and the PDLB subject (ii) is diagnosed with nine or more of the following: RBD, constipation, hyposmia, depression, urinary dysfunction, erectile dysfunction, orthostatic hypotension / dizziness, mild motor dysfunction, impaired olfaction, impaired color vision, memory impairment, Parkinson's symptoms, visual hallucinations, anxiety, mild cognitive impairment, attention / executive dysfunction, visuospatial dysfunction, striatal dopaminergic denervation, substantia nigra hyperechoicity, and / or increased rCBF in the hippocampus.

[0193] In some embodiments, the PDLB subject: (i) is not diagnosed with dementia, Parkinson's syndrome, RBD, cognitive / vigilance fluctuations, and visual hallucinations; and the PDLB subject (ii) is diagnosed with RBD, constipation, hyposmia, depression, urinary dysfunction, erectile dysfunction, orthostatic hypotension / dizziness, mild motor dysfunction, impaired olfaction, impaired color vision, memory impairment, Parkinson's symptoms, visual hallucinations, anxiety, mild cognitive impairment, attention / executive dysfunction, visuospatial dysfunction, striatal dopaminergic denervation, substantia nigra hyperechoicity, and / or increased rCBF in the hippocampus.

[0194] In some embodiments, the PDLB subject: (i) has not been diagnosed with dementia, Parkinson's syndrome, RBD, cognitive / vigilance fluctuations, and visual hallucinations; and the PDLB subject (ii) has been diagnosed with RBD, constipation, hyposmia, depression, urinary dysfunction, erectile dysfunction, orthostatic hypotension / dizziness, mild motor dysfunction, impaired olfaction, impaired color vision, memory impairment, Parkinson's symptoms, visual hallucinations, anxiety, mild cognitive impairment, attention / executive dysfunction, visuospatial dysfunction, striatal dopaminergic denervation, substantia nigra hyperechoic and / or increased rCBF in the hippocampus.

[0195] In some embodiments, the PDLB subject: (i) is not diagnosed with dementia, Parkinson's syndrome, RBD, cognitive / vigilance fluctuations, and visual hallucinations; and the PDLB subject (ii) is diagnosed with RBD, constipation, hyposmia, depression, urinary dysfunction, erectile dysfunction, orthostatic hypotension / dizziness, mild motor dysfunction, impaired olfaction, impaired color vision, memory impairment, Parkinson's symptoms, visual hallucinations, anxiety, mild cognitive impairment, attention / executive dysfunction, visuospatial dysfunction, striatal dopaminergic denervation, substantia nigra hyperechoicity, and / or increased rCBF in the hippocampus, twelve or more of these.

[0196] In some embodiments, the PDLB subject: (i) is not diagnosed with dementia, Parkinson's syndrome, RBD, cognitive / vigilance fluctuations, and visual hallucinations; and the PDLB subject (ii) is diagnosed with RBD, constipation, hyposmia, depression, urinary dysfunction, erectile dysfunction, orthostatic hypotension / dizziness, mild motor dysfunction, impaired olfaction, impaired color vision, memory impairment, Parkinson's symptoms, visual hallucinations, anxiety, mild cognitive impairment, attention / executive dysfunction, visuospatial dysfunction, striatal dopaminergic denervation, substantia nigra hyperechoic and / or increased hippocampal rCBF thirteen or more.

[0197] In some embodiments, the PDLB subject: (i) is not diagnosed with dementia, Parkinson's syndrome, RBD, cognitive / vigilance fluctuations, and visual hallucinations; and the PDLB subject (ii) is diagnosed with RBD, constipation, hyposmia, depression, urinary dysfunction, erectile dysfunction, orthostatic hypotension / dizziness, mild motor dysfunction, impaired olfaction, impaired color vision, memory impairment, Parkinson's symptoms, visual hallucinations, anxiety, mild cognitive impairment, attention / executive dysfunction, visuospatial dysfunction, striatal dopaminergic denervation, substantia nigra hyperechoic and / or increased rCBF in the hippocampus fourteen or more.

[0198] In some embodiments, the PDLB subject: (i) has not been diagnosed with dementia, Parkinson's syndrome, RBD, cognitive / vigilance fluctuations, and visual hallucinations; and the PDLB subject (ii) has been diagnosed with RBD, constipation, hyposmia, depression, urinary dysfunction, erectile dysfunction, orthostatic hypotension / dizziness, mild motor dysfunction, impaired olfaction, impaired color vision, memory impairment, Parkinson's symptoms, visual hallucinations, anxiety, mild cognitive impairment, attention / executive dysfunction, visuospatial dysfunction, striatal dopaminergic denervation, substantia nigra hyperechoic and / or increased rCBF in the hippocampus fifteen or more.

[0199] In some embodiments, the PDLB subject: (i) is not diagnosed with dementia, Parkinson's syndrome, RBD, cognitive / vigilance fluctuations, and visual hallucinations; and the PDLB subject (ii) is diagnosed with RBD, constipation, hyposmia, depression, urinary dysfunction, erectile dysfunction, orthostatic hypotension / dizziness, mild motor dysfunction, impaired olfaction, impaired color vision, memory impairment, Parkinson's symptoms, visual hallucinations, anxiety, mild cognitive impairment, attention / executive dysfunction, visuospatial dysfunction, striatal dopaminergic denervation, substantia nigra hyperechoicity, and / or increased hippocampal rCBF.

[0200] In some embodiments, the PDLB subject: (i) is not diagnosed with dementia, Parkinson's syndrome, RBD, cognitive / vigilance fluctuations, and visual hallucinations; and the PDLB subject (ii) is diagnosed with RBD, constipation, hyposmia, depression, urinary dysfunction, erectile dysfunction, orthostatic hypotension / dizziness, mild motor dysfunction, impaired olfaction, impaired color vision, memory impairment, Parkinson's symptoms, visual hallucinations, anxiety, mild cognitive impairment, attention / executive dysfunction, visuospatial dysfunction, striatal dopaminergic denervation, substantia nigra hyperechoicity, and / or increased rCBF in the hippocampus.

[0201] In some embodiments, the PDLB subject: (i) is not diagnosed with dementia, Parkinson's syndrome, RBD, cognitive / vigilance fluctuations, and visual hallucinations; and the PDLB subject (ii) is diagnosed with RBD, constipation, hyposmia, depression, urinary dysfunction, erectile dysfunction, orthostatic hypotension / dizziness, mild motor dysfunction, impaired olfaction, impaired color vision, memory impairment, Parkinson's symptoms, visual hallucinations, anxiety, mild cognitive impairment, attention / executive dysfunction, visuospatial dysfunction, striatal dopaminergic denervation, substantia nigra hyperechoicity, and / or increased rCBF in the hippocampus.

[0202] In some embodiments, the PDLB subject: (i) has not been diagnosed with dementia, Parkinson's syndrome, RBD, cognitive / vigilance fluctuations, and visual hallucinations; and the PDLB subject (ii) is diagnosed with RBD, constipation, hyposmia, depression, urinary dysfunction, erectile dysfunction, orthostatic hypotension / dizziness, mild motor dysfunction, impaired olfaction, impaired color vision, memory impairment, Parkinson's symptoms, visual hallucinations, anxiety, mild cognitive impairment, attention / executive dysfunction, visuospatial dysfunction, striatal dopaminergic denervation, substantia nigra hyperechoicity, and / or increased rCBF in the hippocampus.

[0203] In some embodiments, the PDLB subject: (i) is not diagnosed with dementia, Parkinson's syndrome, RBD, cognitive / vigilance fluctuations, and visual hallucinations; and the PDLB subject (ii) is diagnosed with RBD, constipation, hyposmia, depression, urinary dysfunction, erectile dysfunction, orthostatic hypotension / dizziness, mild motor dysfunction, impaired olfactory function, impaired color vision, memory impairment, Parkinson's symptoms, visual hallucinations, anxiety, mild cognitive impairment, attention / executive dysfunction, visuospatial dysfunction, striatal dopaminergic denervation, substantia nigra hyperechoicity, and increased rCBF in the hippocampus.

[0204] In some implementations, PDLB subjects: (i) are not diagnosed with dementia, Parkinson's syndrome, RBD, cognitive / vigilance fluctuations, and visual hallucinations; and PDLB subjects (ii) are diagnosed with one or more core clinical features, syndromes, or symptoms associated with the prodromal phase of DLB, such as RBD, constipation, hyposmia, depression, orthostatic hypotension / dizziness, memory impairment, Parkinson's symptoms, visual hallucinations, anxiety, mild cognitive impairment, attention / executive dysfunction, visuospatial dysfunction, and / or striatal dopaminergic denervation.

[0205] In some implementations, PDLB subjects: (i) are not diagnosed with dementia, Parkinson's syndrome, RBD, cognitive / vigilance fluctuations, and visual hallucinations; and PDLB subjects (ii) are diagnosed with two or more core clinical features, syndromes, or symptoms associated with the prodromal phase of DLB, namely RBD, constipation, hyposmia, depression, orthostatic hypotension / dizziness, memory impairment, Parkinson's symptoms, visual hallucinations, anxiety, mild cognitive impairment, attention / executive dysfunction, visuospatial dysfunction, and / or striatal dopaminergic denervation.

[0206] In some implementations, PDLB subjects: (i) are not diagnosed with dementia, Parkinson's syndrome, RBD, cognitive / vigilance fluctuations, and visual hallucinations; and PDLB subjects (ii) are diagnosed with three or more core clinical features, syndromes, or symptoms associated with the prodromal phase of DLB, namely RBD, constipation, hyposmia, depression, orthostatic hypotension / dizziness, memory impairment, Parkinson's symptoms, visual hallucinations, anxiety, mild cognitive impairment, attention / executive dysfunction, visuospatial dysfunction, and / or striatal dopaminergic denervation.

[0207] In some implementations, PDLB subjects: (i) are not diagnosed with dementia, Parkinson's syndrome, RBD, cognitive / vigilance fluctuations, and visual hallucinations; and PDLB subjects (ii) are diagnosed with four or more core clinical features, syndromes, or symptoms associated with the prodromal phase of DLB, namely RBD, constipation, hyposmia, depression, orthostatic hypotension / dizziness, memory impairment, Parkinson's symptoms, visual hallucinations, anxiety, mild cognitive impairment, attention / executive dysfunction, visuospatial dysfunction, and / or striatal dopaminergic denervation.

[0208] In some implementations, PDLB subjects: (i) are not diagnosed with dementia, Parkinson's syndrome, RBD, cognitive / vigilance fluctuations, and visual hallucinations; and PDLB subjects (ii) are diagnosed with five or more core clinical features, syndromes, or symptoms associated with the prodromal phase of DLB, namely RBD, constipation, hyposmia, depression, orthostatic hypotension / dizziness, memory impairment, Parkinson's symptoms, visual hallucinations, anxiety, mild cognitive impairment, attention / executive dysfunction, visuospatial dysfunction, and / or striatal dopaminergic denervation.

[0209] In some implementations, PDLB subjects: (i) are not diagnosed with dementia, Parkinson's syndrome, RBD, cognitive / vigilance fluctuations, and visual hallucinations; and PDLB subjects (ii) are diagnosed with six or more core clinical features, syndromes, or symptoms associated with the prodromal phase of DLB, namely RBD, constipation, hyposmia, depression, orthostatic hypotension / dizziness, memory impairment, Parkinson's symptoms, visual hallucinations, anxiety, mild cognitive impairment, attention / executive dysfunction, visuospatial dysfunction, and / or striatal dopaminergic denervation.

[0210] In some implementations, PDLB subjects: (i) are not diagnosed with dementia, Parkinson's syndrome, RBD, cognitive / vigilance fluctuations, and visual hallucinations; and PDLB subjects (ii) are diagnosed with seven or more core clinical features, syndromes, or symptoms associated with the prodromal phase of DLB, namely RBD, constipation, hyposmia, depression, orthostatic hypotension / dizziness, memory impairment, Parkinson's symptoms, visual hallucinations, anxiety, mild cognitive impairment, attention / executive dysfunction, visuospatial dysfunction, and / or striatal dopaminergic denervation.

[0211] In some implementations, PDLB subjects: (i) are not diagnosed with dementia, Parkinson's syndrome, RBD, cognitive / vigilance fluctuations, and visual hallucinations; and PDLB subjects (ii) are diagnosed with eight or more core clinical features, syndromes, or symptoms associated with the prodromal phase of DLB, namely RBD, constipation, hyposmia, depression, orthostatic hypotension / dizziness, memory impairment, Parkinson's symptoms, visual hallucinations, anxiety, mild cognitive impairment, attention / executive dysfunction, visuospatial dysfunction, and / or striatal dopaminergic denervation.

[0212] In some implementations, PDLB subjects: (i) are not diagnosed with dementia, Parkinson's syndrome, RBD, cognitive / vigilance fluctuations, and visual hallucinations; and PDLB subjects (ii) are diagnosed with nine or more core clinical features, syndromes, or symptoms associated with the prodromal phase of DLB, namely RBD, constipation, hyposmia, depression, orthostatic hypotension / dizziness, memory impairment, Parkinson's symptoms, visual hallucinations, anxiety, mild cognitive impairment, attention / executive dysfunction, visuospatial dysfunction, and / or striatal dopaminergic denervation.

[0213] In some implementations, PDLB subjects: (i) are not diagnosed with dementia, Parkinson's syndrome, RBD, cognitive / vigilance fluctuations, and visual hallucinations; and PDLB subjects (ii) are diagnosed with ten or more core clinical features, syndromes, or symptoms associated with the prodromal phase of DLB, namely RBD, constipation, hyposmia, depression, orthostatic hypotension / dizziness, memory impairment, Parkinson's symptoms, visual hallucinations, anxiety, mild cognitive impairment, attention / executive dysfunction, visuospatial dysfunction, and / or striatal dopaminergic denervation.

[0214] In some implementations, PDLB subjects: (i) are not diagnosed with dementia, Parkinson's syndrome, RBD, cognitive / vigilance fluctuations, and visual hallucinations; and PDLB subjects (ii) are diagnosed with eleven or more core clinical features, syndromes, or symptoms associated with the prodromal phase of DLB, namely RBD, constipation, hyposmia, depression, orthostatic hypotension / dizziness, memory impairment, Parkinson's symptoms, visual hallucinations, anxiety, mild cognitive impairment, attention / executive dysfunction, visuospatial dysfunction, and / or striatal dopaminergic denervation.

[0215] In some implementations, PDLB subjects: (i) are not diagnosed with dementia, Parkinson's syndrome, RBD, cognitive / vigilance fluctuations, and visual hallucinations; and PDLB subjects (ii) are diagnosed with twelve or more core clinical features, syndromes, or symptoms associated with the prodromal phase of DLB, namely RBD, constipation, hyposmia, depression, orthostatic hypotension / dizziness, memory impairment, Parkinson's symptoms, visual hallucinations, anxiety, mild cognitive impairment, attention / executive dysfunction, visuospatial dysfunction, and / or striatal dopaminergic denervation.

[0216] In some implementations, the PDLB subject: (i) is not diagnosed with dementia, Parkinson's syndrome, RBD, cognitive / vigilance fluctuations, and visual hallucinations; and the PDLB subject (i) is diagnosed with one or more of RBD, constipation, hyposmia, depression, and / or orthostatic hypotension / dizziness.

[0217] In some implementations, PDLB subjects: (i) are not diagnosed with dementia, Parkinson's syndrome, RBD, cognitive / vigilance fluctuations, and visual hallucinations; and PDLB subjects (i) are diagnosed with two or more of RBD, constipation, hyposmia, depression, and / or orthostatic hypotension / dizziness.

[0218] In some implementations, the PDLB subject: (i) is not diagnosed with dementia, Parkinson's syndrome, RBD, cognitive / vigilance fluctuations, and visual hallucinations; and the PDLB subject (i) is diagnosed with three or more of RBD, constipation, hyposmia, depression, and / or orthostatic hypotension / dizziness.

[0219] In some implementations, PDLB subjects: (i) are not diagnosed with dementia, Parkinson's syndrome, RBD, cognitive / vigilance fluctuations, and visual hallucinations; and PDLB subjects (i) are diagnosed with four or more of RBD, constipation, hyposmia, depression, and / or orthostatic hypotension / dizziness.

[0220] In some implementations, PDLB subjects: (i) are not diagnosed with dementia, Parkinson's syndrome, RBD, cognitive / vigilance fluctuations, and visual hallucinations; and PDLB subjects (i) are diagnosed with RBD, constipation, hyposmia, depression, and orthostatic hypotension / dizziness.

[0221] FDG-PET examination revealed decreased local glucose metabolism in the occipital cortex and primary visual cortex of DLB ​​patients. There are also reports of relative hypoperfusion in the occipital cortex of DLB ​​patients. Involvement of the medial and lateral occipital lobes is a characteristic feature of DLB, and decreased metabolism and hypoperfusion in the occipital lobe are key imaging features that distinguish DLB from Alzheimer's disease (AD) (Ishii et al., Annals of Nuc Med, 18(5), 447-451 (2004); Kantarci et al., NeuroImage: Clinical, 31, 1-7 (2021)).

[0222] In some embodiments, PDLB subjects have reduced glucose metabolism in one or more of the medial occipital lobe, lateral occipital lobe, occipital junction cortex, and / or the primary visual regions of the brain.

[0223] In some embodiments, administration of N-acetylleucine increases glucose metabolism in the brains of PDLB subjects compared to before administration. In some embodiments, administration of N-acetylleucine increases glucose metabolism in the medial occipital lobe, lateral occipital lobe, combined occipital cortex, and / or the primary visual regions of the brain in PDLB subjects compared to before administration. In some embodiments, administration of N-acetylleucine increases glucose metabolism in the medial occipital lobe, lateral occipital lobe, combined occipital cortex, and / or the primary visual regions of the brain in PDLB subjects compared to before administration.

[0224] In some embodiments, glucose metabolism is determined by positron emission tomography (PET) scanning. In some embodiments, the PET scan is a fluorodeoxyglucose-positron emission tomography (FDG-PET) scan. In some embodiments, the FDG-PET scan is used to generate the z-score of PDLB subjects.

[0225] In some embodiments, administration of N-acetylleucine reduces the z-score of PDLB subjects. In some embodiments, administration of N-acetylleucine reduces the z-score of PDLB subjects in the medial occipital lobe, lateral occipital lobe, combined occipital cortex, and / or primary visual regions of the brain. In some embodiments, the z-score of PDLB subjects is reduced by at least about 5%, about 10%, about 20%, about 30%, about 40%, or about at least 50% compared to the z-score of PDLB subjects before administration of N-acetylleucine.

[0226] The utility of DAT scanning, particularly in differentiating DLB from AD, is based on the reduction of dopamine terminals in the striatum seen in DLB compared to their relative preservation in AD. However, DAT imaging may be abnormal in other degenerative diseases in which dopaminergic transmission is impaired, such as frontotemporal dementia (FTD), cortical basal degeneration (CBD), progressive extranuclear palsy, and multiple system atrophy.

[0227] In some embodiments, PDLB subjects have reduced dopaminergic function in the basal ganglia. In some embodiments, PDLB subjects have reduced DAT uptake in the basal ganglia. In some embodiments, PDLB subjects have reduced DAT binding in the basal ganglia. In some embodiments, PDLB subjects have reduced amounts of dopamine transporters in the basal ganglia.

[0228] In some embodiments, administration of N-acetylleucine increases dopaminergic function in the basal ganglia of PDLB subjects compared to before administration. In some embodiments, administration of N-acetylleucine increases DAT uptake in the basal ganglia of PDLB subjects compared to before administration. In some embodiments, administration of N-acetylleucine increases DAT binding in the basal ganglia of PDLB subjects compared to before administration. In some embodiments, administration of N-acetylleucine increases the amount of dopamine transporters in the basal ganglia of PDLB subjects compared to before administration.

[0229] In some embodiments, the amount of dopamine transporters in PDLB subjects is determined by dopamine transporter (DAT) scanning. In some embodiments, the DAT scan is a DAT scan with single-photon emission computed tomography (DAT-SPECT) or a DAT scan with decarboxylase activity using 18F-Doppler positron emission tomography (DAT-PET). In some embodiments, the DAT scan is DAT-SPECT.

[0230] C. Multiple systemic atrophy (MSA)

[0231] In some embodiments, this disclosure provides a method for the preliminary treatment of MSA in subjects in need, including administering a therapeutically effective amount of N-acetylleucine to the subject. These subjects are referred to in this section as “prodromal multiple system atrophy subjects” or “PMSA subjects”.

[0232] In some embodiments, the PMSA subject is not diagnosed with (a) autonomic dysfunction; and (b) L-dopamine-responsive Parkinson's syndrome and / or cerebellar syndrome. In some embodiments, the PMSA subject is diagnosed with one or more of RBD, neurogenic orthostatic hypotension and / or genitourinary dysfunction occurring within 10 minutes of standing or head-up tilting. In some embodiments, the PMSA subject is not diagnosed with (a) autonomic dysfunction; and (b) poor L-dopamine-responsive Parkinson's syndrome and / or cerebellar syndrome; and is diagnosed with one or more of RBD, neurogenic orthostatic hypotension and / or genitourinary dysfunction occurring within 10 minutes of standing or head-up tilting.

[0233] Multiple system atrophy (MSA) is an adult-onset neurodegenerative disease characterized by a combination of Parkinsonian syndromes, autonomic dysfunction, and cerebellar ataxia. Based on the main symptoms of the disease, MSA is classified into two forms: MSA with predominantly Parkinsonian syndromes (MSA-P) and MSA with predominantly cerebellar features (MSA-C). The age of onset, the prevalence of cardiovascular autonomic dysfunction, sleep disturbances, and retinal abnormalities are similar in both phenotypes. Specific neuroimaging markers differ between the cerebellar and Parkinsonian phenotypes, as well as the degree of suldomotor dysfunction that may be more severe in patients with MSA-P and the degree of genitourinary dysfunction that may occur earlier in patients with MSA-C (Palma et al., AutonNeurosci, 211: 15-25 (2018)).

[0234] While in patients with Parkinson's disease, (PD)αSyn primarily accumulates in neurons that form Lewy bodies and Lewy neurites, in patients with MSA, it primarily accumulates in oligodendrocytes that form glial cytoplasmic inclusions (GCIs). A significant percentage of patients with MSA present with urogenital dysfunction and orthostatic hypotension (OH) due to autonomic nervous system dysfunction, often in conjunction with a history of rapid eye movement (REM) sleep behavior disorder (RBD) (Palma et al., Auton Neurosci, 211: 15-25 (2018)). The criteria for diagnosing MSA are shown in Table 5.

[0235] Table 5

[0236] Standards for diagnosing MSA

[0237] (Palma et al., Auton Neurosci, 211: 15-25 (2018))

[0238] In some embodiments, the PMSA subject is not diagnosed with any core clinical feature, syndrome, or symptom associated with MSA. In some embodiments, the core clinical feature, syndrome, or symptom associated with MSA is extensive and abundant neurodegenerative changes in the brain's α-synuclein-positive glial cytoplasmic inclusions, striatum, substantia nigra, or olivopontocerebellum; urinary incontinence; orthostatic hypotension; Parkinson's syndrome with poor levodopa response; cerebellar syndrome; and / or Parkinson's syndrome. In some embodiments, the PMSA subject is not diagnosed with any of the following: extensive and abundant neurodegenerative changes in the brain's α-synuclein-positive glial cytoplasmic inclusions, striatum, substantia nigra, or olivopontocerebellum; urinary incontinence; orthostatic hypotension; Parkinson's syndrome with poor levodopa response; cerebellar syndrome; and / or Parkinson's syndrome.

[0239] In some embodiments, the core clinical feature, syndrome, or symptom associated with MSA is extensive and abundant neurodegenerative changes in α-synuclein-positive glial cytoplasmic inclusions and / or the substantia nigra or olivopontocerebellum. In some embodiments, PMSA subjects are not diagnosed with extensive and abundant neurodegenerative changes in α-synuclein-positive glial cytoplasmic inclusions and / or the substantia nigra or olivopontocerebellum.

[0240] In some implementations, the core clinical features, syndromes, or symptoms associated with MSA are urinary incontinence or orthostatic hypotension; and poor levodopa responsiveness in Parkinson's syndrome or cerebellar syndrome. In some implementations, the PMSA subject is not diagnosed with urinary incontinence or orthostatic hypotension; and has poor levodopa responsiveness in Parkinson's syndrome or cerebellar syndrome.

[0241] In some implementations, the core clinical features, syndromes, or symptoms associated with MSA are Parkinson's syndrome or cerebellar syndrome; and autonomic dysfunction. In some implementations, the PMSA subject has not been diagnosed with Parkinson's syndrome or cerebellar syndrome; and autonomic dysfunction.

[0242] In some embodiments, symptoms of Parkinson's syndrome with poor levodopa responsiveness include bradykinesia with rigidity, tremor, and / or postural instability. In some embodiments, symptoms of cerebellar syndrome include gait ataxia (with cerebellar arterial abnormalities), limb ataxia, and / or cerebellar neuromotor dysfunction. In some embodiments, symptoms of Parkinson's syndrome include bradykinesia with rigid tremor and / or postural instability.

[0243] Table 6. Standards for Precursor MSA

[0244] (Wenning et al., Movement Disorders, 37(6), 1131-1148 (2022))

[0245] In some embodiments, the PMSA subject is diagnosed with one or more core clinical features, syndromes, or symptoms associated with the prodromal phase of MSA. In some embodiments, the core clinical features, syndromes, or symptoms associated with the prodromal phase of MSA are RBD, neurogenic orthostatic hypotension occurring within 10 minutes of standing or head-up tilt, and / or genitourinary dysfunction. In some embodiments, the PMSA subject is diagnosed with one or more of RBD, neurogenic orthostatic hypotension occurring within 10 minutes of standing or head-up tilt, and / or genitourinary dysfunction. In some embodiments, the PMSA subject is diagnosed with two or more of RBD, neurogenic orthostatic hypotension occurring within 10 minutes of standing or head-up tilt, and / or genitourinary dysfunction. In some embodiments, the PMSA subject is diagnosed with RBD, neurogenic orthostatic hypotension occurring within 10 minutes of standing or head-up tilt, and genitourinary dysfunction.

[0246] In some implementations, the PMSA subject: (i) has not been diagnosed with any core clinical feature, syndrome or symptom associated with MSA, and (ii) has been diagnosed with one or more core clinical features, syndromes or symptom associated with the prodromal phase of MSA.

[0247] In some embodiments, the PMSA subject: (i) has not been diagnosed with extensive and abundant neurodegenerative changes in alpha-synuclein-positive glial cytoplasmic inclusions, substantia nigra or olivopontocerebellar regions of the brain, urinary incontinence, orthostatic hypotension, poor response to levodopa, Parkinson's syndrome, cerebellar syndrome, and / or Parkinson's syndrome; and (ii) has been diagnosed with RBD, neurogenic orthostatic hypotension within 10 minutes of standing or bending, and / or genitourinary dysfunction.

[0248] In some embodiments, the PMSA subject: (i) has not been diagnosed with extensive and abundant neurodegenerative changes in alpha-synuclein-positive glial cytoplasmic inclusions, substantia nigra or olivopontocerebellar regions of the brain, urinary incontinence, orthostatic hypotension, poor response to levodopa, Parkinson's syndrome, cerebellar syndrome, and / or Parkinson's syndrome; and (ii) has been diagnosed with two or more of the following: RBD, neurogenic orthostatic hypotension within 10 minutes of standing or bending, and / or genitourinary dysfunction.

[0249] In some embodiments, the PMSA subject: (i) has not been diagnosed with extensive and abundant neurodegenerative changes in alpha-synuclein-positive glial cytoplasmic inclusions, striatum, substantia nigra, or olive-pontine cerebellar regions of the brain, urinary incontinence, orthostatic hypotension, poor response to levodopa, Parkinson's syndrome, cerebellar syndrome, and / or Parkinson's syndrome; and (ii) has been diagnosed with RBD, neurogenic orthostatic hypotension and genitourinary dysfunction occurring within 10 minutes of standing or head tilting.

[0250] In some implementations, PMSA subjects: (i) are not diagnosed with extensive and abundant neurodegenerative changes in the brain's α-synuclein-positive glial cytoplasmic inclusions and / or the substantia nigra or the olive-pontine-cerebellar region; and (ii) are diagnosed with one or more of the following: RBD, neurogenic orthostatic hypotension and / or genitourinary dysfunction occurring within 10 minutes of standing or head tilting.

[0251] In some implementations, PMSA subjects: (i) are not diagnosed with extensive and abundant neurodegenerative changes in the brain's α-synuclein-positive glial cytoplasmic inclusions and / or the substantia nigra or the olive-pontine-cerebellar region; and (ii) are diagnosed with two or more of the following: RBD, neurogenic orthostatic hypotension occurring within 10 minutes of standing or head tilting; and / or genitourinary dysfunction.

[0252] In some implementations, PMSA subjects: (i) are not diagnosed with extensive and abundant neurodegenerative changes in the brain's α-synuclein-positive glial cytoplasmic inclusions and / or the substantia nigra region of the striatum or the olivopontocerebellum region; and (ii) are diagnosed with RBD, neurogenic orthostatic hypotension within 10 minutes of standing or bending, and genitourinary dysfunction.

[0253] In some embodiments, the PMSA subject: (i) has not been diagnosed with urinary incontinence or orthostatic hypotension; and has poor left-handed responsive Parkinson's syndrome or cerebellar syndrome; and (ii) has been diagnosed with one or more of RBD, neurogenic orthostatic hypotension and / or urogenital dysfunction occurring within 10 minutes of standing or head tilting.

[0254] In some embodiments, the PMSA subject: (i) has not been diagnosed with urinary incontinence or orthostatic hypotension; and poor left-handed responsive Parkinson's syndrome or cerebellar syndrome; and (ii) has been diagnosed with two or more of the following: RBD, neurogenic orthostatic hypotension occurring within 10 minutes of standing or head tilting; and / or urogenital dysfunction.

[0255] In some implementations, the PMSA subject: (i) is not diagnosed with urinary incontinence or orthostatic hypotension; and has poor left-handed responsive Parkinson's syndrome or cerebellar syndrome; and (ii) is diagnosed with RBD, neurogenic orthostatic hypotension and urogenital dysfunction occurring within 10 minutes of standing or head tilting.

[0256] In some implementations, the PMSA subject: (i) has not been diagnosed with Parkinson's syndrome or cerebellar syndrome; and autonomic dysfunction; and (ii) has been diagnosed with one or more of RBD, neurogenic orthostatic hypotension and / or genitourinary dysfunction that occurs within 10 minutes of standing or head tilting.

[0257] In some implementations, the PMSA subject: (i) has not been diagnosed with Parkinson's syndrome or cerebellar syndrome; and autonomic dysfunction; and (ii) has been diagnosed with two or more of the following: RBD, neurogenic orthostatic hypotension occurring within 10 minutes of standing or head tilting; and / or genitourinary dysfunction.

[0258] In some implementations, PMSA subjects: (i) were not diagnosed with Parkinson's syndrome or cerebellar syndrome; and autonomic dysfunction; and (ii) were diagnosed with RBD, neurogenic orthostatic hypotension and / or genitourinary dysfunction occurring within 10 minutes of standing or head-tilt position. MSA patients showed significant metabolic insufficiency in the (posterior) putamen, pons, caudate nucleus and cerebellum, which may be more pronounced in the striatum or in the pons and cerebellum, depending on the primary aspect of degeneration and therefore on the clinical presentation (substantia nigra / MSA-P and olivopontocerebellum / MSA-C, respectively).

[0259] In some embodiments, PMSA subjects have reduced glucose metabolism in the putamen, pons, caudate nucleus, and / or cerebellum. In some embodiments, PMSA subjects have reduced glucose metabolism in one or more of the putamen, pons, caudate nucleus, and / or cerebellum.

[0260] In some embodiments, administration of N-acetylleucine increases glucose metabolism in the brain of PMSA subjects compared to before administration. In some embodiments, administration of N-acetylleucine increases glucose metabolism in the putamen, pons, caudate nucleus, and / or cerebellum of PMSA subjects compared to before administration. In some embodiments, administration of N-acetylleucine increases glucose metabolism in one or more of the putamen, pons, caudate nucleus, and / or cerebellum of PMSA subjects compared to before administration.

[0261] The most characteristic finding in patients with MSA-P is a reduction in 18FDG-PET uptake in the bilateral putamen, exhibiting a head-to-tail gradient distribution. This finding has ~95% sensitivity and 100% specificity in PD compared to MSA-P. Reduced 18FDG-PET uptake can also be detected in the thalamus, brainstem, and cortex. Therefore, the current consensus diagnostic criteria for MSA establishes low metabolism in the putamen, midbrain, and cerebellum as a supporting feature for MSA-P. In patients with MSA-C, low metabolism can be observed in the anterior cerebellum and cerebellar vermis one year after the onset of motor symptoms, although low metabolism can also be observed in the putamen and is a supporting feature for the diagnosis of MSA-C (Palma et al., Auton Neurosci, 211: 15-25 (2018); Jellinger K., Annals of Indian Acad Neurol, (2021); Zhao et al., Brain and Behavior, 1-9 (2020)).

[0262] In some embodiments, the PMSA subject has reduced glucose metabolism in the putamen, thalamus, brainstem, midbrain, cerebellum, anterior cerebellar lobe, vermis, and cortical regions. In some embodiments, the PMSA subject has reduced glucose metabolism in the putamen, midbrain, and cerebellum. In some embodiments, the PMSA subject has reduced glucose metabolism in the putamen, cerebellar forebrain, and / or cerebellar vermis. In some embodiments, the PMSA subject has reduced glucose metabolism in the putamen. In some embodiments, the PMSA subject has reduced glucose metabolism in the anterior cerebellar lobe and cerebellar vermis.

[0263] In some embodiments, N-acetylleucine administration increases glucose metabolism in the soft nuclei, thalamus, brainstem, midbrain, cerebellum, anterior cerebellar lobe, vermis, and cortex of PMSA subjects compared to before administration. In some embodiments, N-acetylleucine administration increases glucose metabolism in the occipital nucleus, midbrain, and cerebellum of PMSA subjects compared to before administration. In some embodiments, N-acetylleucine administration increases glucose metabolism in the putamen, forebrain, and / or vermis of PMSA subjects compared to before administration. In some embodiments, N-acetylleucine administration increases glucose metabolism in the thymocyte nuclei of PMSA subjects compared to before administration. In some embodiments, N-acetylleucine administration increases glucose metabolism in the forebrain and vermis of PMSA subjects compared to before administration.

[0264] In some embodiments, glucose metabolism is determined by positron emission tomography (PET) scanning. In some embodiments, the PET scan is a fluorodeoxyglucose-positron emission tomography (FDG-PET) scan. In some embodiments, the FDG-PET scan is used to generate the z-score of the PMSA subject.

[0265] In some embodiments, administration of N-acetyleucine reduces the z-score of PMSA subjects. In some embodiments, administration of N-acetyleucine reduces the z-score of PMSA subjects in the putamen, forebrain hemisphere, and / or vermis. In some embodiments, the z-score of PMSA subjects is reduced by at least about 5%, about 10%, about 20%, about 30%, about 40%, or about 50% compared to the z-score of PMSA subjects before administration of N-acetyleucine.

[0266] In some embodiments, PMSA subjects have reduced dopaminergic function in the basal ganglia. In some embodiments, PMSA subjects have reduced DAT uptake in the basal ganglia. In some embodiments, PMSA subjects have reduced DAT binding in the basal ganglia. In some embodiments, PMSA subjects have reduced amounts of dopamine transporters in the basal ganglia.

[0267] In some embodiments, administration of N-acetylleucine increases dopaminergic function in the basal ganglia of PMSA subjects compared to before administration. In some embodiments, administration of N-acetylleucine increases DAT uptake in the basal ganglia of PMSA subjects compared to before administration. In some embodiments, administration of N-acetylleucine increases DAT binding in the basal ganglia of PMSA subjects compared to before administration. In some embodiments, administration of N-acetylleucine increases the amount of dopamine transporters in the basal ganglia of PMSA subjects compared to before administration.

[0268] In some embodiments, the amount of dopamine transporters in PMSA subjects is determined by dopamine transporter (DAT) scanning. In some embodiments, the DAT scan is a DAT scan with single-photon emission computed tomography (DAT-SPECT) or a DAT scan with decarboxylase activity using 18F-Doppler positron emission tomography (DAT-PET). In some embodiments, the DAT scan is DAT-SPECT.

[0269] III. REM-S Sleep Behavior Disruption (RBD)

[0270] In some embodiments, this disclosure provides a method for treating RBD in a subject of need, the method comprising administering a therapeutically effective amount of N-acetylleucine to the subject. In some embodiments, the RBD is idiopathic RBD. These subjects are referred to herein as "RBD subjects".

[0271] REM-sleep behavior disorder (RBD) is a type of insomnia characterized by drooling behaviors typically involving upper limb vocalization or movement, associated with unpleasant drooling and loss of normal REM-sleep muscle atrophy. REM-sleep behavior disorder is idiopathic when unrelated to neurological disorders, or symptomatic when an underlying cause is present (such as autoimmune or inflammatory diseases, brain injury, or triggering antidepressants). In both idiopathic and symptomatic categories, RBD is strongly associated with neurodegenerative diseases, particularly synucleinopathies, including PD, Lewy body dementia (DLB), multiple system atrophy (MSA), and purely autonomic dysfunction (Claassen et al., Neurology, 75, 494-499 (2010)).

[0272] Rapid eye movement sleep behavior disorder (REM sleep behavior disorder) may initially present as an idiopathic prodromal state, occurring years to decades before the development of synucleinopathy manifestations from obvious motor, cognitive, or autonomic lesions. Painful symptoms and a diagnosis of idiopathic RBD can be accompanied by other subtle prodromal features, such as subjective cognitive symptoms without evidence of neuropsychological impairment, asymptomatic cognitive or motor deficits, hyposmia, constipation, and orthostatic hypotension; many of these features are associated with a higher risk of benzene conversion to a defined neurodegenerative disease. The first study documenting the relationship between RBD and these neurodegenerative diseases reported that nearly 40% of patients with isolated idiopathic RBD subsequently developed Parkinson's disease after a mean of 12.7 years. Subsequent series have confirmed similar findings, with a typical mean interval of approximately ten years from RBD to PD, DLB, or MSA (St. Louis, et al., Mayo Clin Proc., 92(11), 1723–1736 (2017)).

[0273] The diagnosis of RBD requires a clinical history of sleep-related complex motor behavior or REM sleep complex vocal or motor behavior recorded during polysomnography, accompanied by REM sleep without (RSWA). The diagnosis of REM sleep behavior disorder also requires that another disorder (such as obstructive sleep apnea or alternative non-rapid eye movement (NREM) sleep insomnia) does not better explain the sleep disorder. Idiopathic RBD is diagnosed when there is clinical sleep-related complex motor dreaming behavior without a clearly associated underlying pathology (such as PD or associated synucleinopathy). Even when idiopathic, RBD is strongly associated with PD and other synucleinopathy. When REM sleep behavior disorder occurs in direct association with a previously diagnosed PD, DLB, or MSA, or when there is another known underlying pathology such as encephalopathy, it is considered symptomatic RBD (St. Louis, et al., Mayo Clin Proc., 92(11), 1723-1736 (2017)).

[0274] Patient-reported questionnaires have been developed to identify individuals with RBD, but similar to patients with hyposmia, those with RBD are often unaware of their symptoms. An accurate accompanying history from the bedside is usually required for diagnosis. In problematic cases or for individuals without a bedside, a multispectral approach may be available. Cohort studies have shown that iRBD can progress to PD and other synaptic nuclei diseases, such as Lewy body dementia and multiple system atrophy. In some implementations, subjects are diagnosed with RBD (Meles et al., Mol Med, 27:111, 1-14 (2021)).

[0275] In some embodiments, the RBD subject has been diagnosed with prodromal Parkinson's disease (PPD), prodromal dementia with Lewy body (PDLB), or prodromal multiple system atrophy (PMSA). In some embodiments, the RBD subject has not been diagnosed with classic or prodromal Parkinson's disease (PD), classic or prodromal dementia with Lewy body (DLB), or classic or prodromal multiple system atrophy (MSA). In some embodiments, the RBD subject has not been diagnosed with Parkinson's disease, Lewy body dementia, or multiple system atrophy.

[0276] In some embodiments, the RBD subject has not been diagnosed with any core clinical feature, syndrome, or symptom associated with Parkinson's disease, Lewy body dementia, or multiple system atrophy.

[0277] In some embodiments, the RBD subject has not been diagnosed with any core clinical feature, syndrome, or symptom associated with Parkinson's disease. In some embodiments, the core clinical feature, syndrome, or symptom associated with Parkinson's disease is tremor, bradykinesia, rigidity, balance disorder, and / or coordination disorder. In some embodiments, the RBD subject has not been diagnosed with one or more of tremor, bradykinesia, rigidity, balance disorder, and / or coordination disorder. In some embodiments, the RBD subject has not been diagnosed with two or more of tremor, bradykinesia, rigidity, balance disorder, and / or coordination disorder. In some embodiments, the RBD subject has not been diagnosed with three or more of tremor, bradykinesia, rigidity, balance disorder, and / or coordination disorder. In some embodiments, the RBD subject has not been diagnosed with four or more of tremor, bradykinesia, rigidity, balance disorder, and / or coordination disorder. In some embodiments, the RBD subject has not been diagnosed with tremor, bradykinesia, rigidity, balance disorder, and coordination disorder.

[0278] In some respects, RBD subjects were not diagnosed with any core clinical features, syndromes, or symptoms associated with the prodromal phase of Parkinson's disease.

[0279] In some respects, RBD subjects are diagnosed with any core clinical feature, syndrome, or symptom associated with the prodromal phase of Parkinson's disease. In some respects, the core clinical feature, syndrome, or symptom associated with the prodromal phase of Parkinson's disease are RBD, hyposmia, visual abnormalities, decreased color vision, pain, depression, anxiety, pulpitis, analgesia, positive executive dysfunction, constipation, orthostatic hypotension, genitourinary dysfunction, excessive daytime sleepiness, sleep fragmentation, insomnia, periodic limb movements during sleep (PLMS), and / or restless legs syndrome (RLS).

[0280] In some implementations, the RBD subject is diagnosed with one or more of the following: RBD, hyposmia, visual abnormalities, decreased color vision, pain, depression, anxiety, pulpitis, analgesia, positive executive dysfunction, constipation, orthostatic hypotension, urogenital dysfunction, excessive daytime sleepiness, sleep fragmentation, insomnia, periodic limb movements during sleep (PLMS), and / or restless legs syndrome (RLS).

[0281] In some implementations, the RBD subject is diagnosed with two or more of the following: RBD, hyposmia, visual abnormalities, decreased color vision, pain, depression, anxiety, pulpitis, analgesia, positive executive dysfunction, constipation, orthostatic hypotension, urogenital dysfunction, excessive daytime sleepiness, sleep fragmentation, insomnia, periodic limb movements during sleep (PLMS), and / or restless legs syndrome (RLS).

[0282] In some implementations, the RBD subject is diagnosed with three or more of the following: RBD, hyposmia, visual abnormalities, decreased color vision, pain, depression, anxiety, pulpitis, analgesia, positive executive dysfunction, constipation, orthostatic hypotension, urogenital dysfunction, excessive daytime sleepiness, sleep fragmentation, insomnia, periodic limb movements during sleep (PLMS), and / or restless legs syndrome (RLS).

[0283] In some implementations, the RBD subject is diagnosed with four or more of the following: RBD, hyposmia, visual abnormalities, decreased color vision, pain, depression, anxiety, allergic reaction, painlessness, positive executive dysfunction, constipation, orthostatic hypotension, urogenital dysfunction, excessive daytime sleepiness, sleep fragmentation, insomnia, periodic limb movements during sleep (PLMS), and / or restless legs syndrome (RLS).

[0284] In some implementations, the RBD subject is diagnosed with five or more of the following: RBD, hyposmia, visual abnormalities, decreased color vision, pain, depression, anxiety, pulpitis, analgesia, positive executive dysfunction, constipation, orthostatic hypotension, urogenital dysfunction, excessive daytime sleepiness, sleep fragmentation, insomnia, periodic limb movements during sleep (PLMS), and / or restless legs syndrome (RLS).

[0285] In some implementations, the RBD subject is diagnosed with six or more of the following: RBD, hyposmia, visual abnormalities, decreased color vision, pain, depression, anxiety, pulpitis, analgesia, positive executive dysfunction, constipation, orthostatic hypotension, urogenital dysfunction, excessive daytime sleepiness, sleep fragmentation, insomnia, periodic limb movements during sleep (PLMS), and / or restless legs syndrome (RLS).

[0286] In some implementations, the RBD subject is diagnosed with seven or more of the following: RBD, hyposmia, visual abnormalities, decreased color vision, pain, depression, anxiety, pulpitis, analgesia, positive executive dysfunction, constipation, orthostatic hypotension, urogenital dysfunction, excessive daytime sleepiness, sleep fragmentation, insomnia, periodic limb movements during sleep (PLMS), and / or restless legs syndrome (RLS).

[0287] In some implementations, the RBD subject is diagnosed with eight or more of the following: RBD, hyposmia, visual abnormalities, decreased color vision, pain, depression, anxiety, pulpitis, analgesia, positive executive dysfunction, constipation, orthostatic hypotension, urogenital dysfunction, excessive daytime sleepiness, sleep fragmentation, insomnia, periodic limb movements during sleep (PLMS), and / or restless legs syndrome (RLS).

[0288] In some implementations, the RBD subject is diagnosed with nine or more of the following: RBD, hyposmia, visual abnormalities, decreased color vision, pain, depression, anxiety, pulpitis, analgesia, positive executive dysfunction, constipation, orthostatic hypotension, genitourinary dysfunction, excessive daytime sleepiness, sleep fragmentation, insomnia, periodic limb movements during sleep (PLMS), and / or restless legs syndrome (RLS).

[0289] In some implementations, the RBD subject is diagnosed with ten or more of the following: RBD, hyposmia, visual abnormalities, decreased color vision, pain, depression, anxiety, pulpitis, analgesia, positive executive dysfunction, constipation, orthostatic hypotension, urogenital dysfunction, excessive daytime sleepiness, sleep fragmentation, insomnia, periodic limb movements during sleep (PLMS), and / or restless legs syndrome (RLS).

[0290] In some implementations, the RBD subject is diagnosed with eleven or more RBDs, hyposmia, visual abnormalities, decreased color vision, pain, depression, anxiety, pulpitis, analgesia, positive executive dysfunction, constipation, orthostatic hypotension, urogenital dysfunction, excessive daytime sleepiness, sleep fragmentation, insomnia, periodic limb movements during sleep (PLMS), and / or restless legs syndrome (RLS).

[0291] In some implementations, the RBD subject is diagnosed with twelve or more of the following: RBD, hyposmia, visual abnormalities, decreased color vision, pain, depression, anxiety, pulpitis, analgesia, positive executive dysfunction, constipation, orthostatic hypotension, urogenital dysfunction, excessive daytime sleepiness, sleep fragmentation, insomnia, periodic limb movements during sleep (PLMS), and / or restless legs syndrome (RLS).

[0292] In some implementations, the RBD subject is diagnosed with thirteen or more of the following: RBD, hyposmia, visual abnormalities, decreased color vision, pain, depression, anxiety, allergic reaction, painlessness, positive executive dysfunction, constipation, orthostatic hypotension, urogenital dysfunction, excessive daytime sleepiness, sleep fragmentation, insomnia, periodic limb movements during sleep (PLMS), and / or restless legs syndrome (RLS).

[0293] In some implementations, the RBD subject is diagnosed with fourteen or more of the following: RBD, hyposmia, visual abnormalities, decreased color vision, pain, depression, anxiety, allergic reaction, unresponsiveness, positive executive dysfunction, constipation, orthostatic hypotension, urogenital dysfunction, excessive daytime sleepiness, sleep fragmentation, insomnia, periodic limb movements during sleep (PLMS), and / or restless legs syndrome (RLS).

[0294] In some implementations, the RBD subject is diagnosed with fifteen or more of the following: RBD, hyposmia, visual abnormalities, decreased color vision, pain, depression, anxiety, pulpitis, dizziness, positive executive dysfunction, constipation, orthostatic hypotension, urogenital dysfunction, excessive daytime sleepiness, sleep fragmentation, insomnia, periodic limb movements during sleep (PLMS), and / or restless legs syndrome (RLS).

[0295] In some implementations, the RBD subject is diagnosed with RBD, hyposmia, visual abnormalities, decreased color vision, pain, depression, anxiety, allergic reactions, analgesia, positive executive dysfunction, constipation, orthostatic hypotension, urogenital dysfunction, excessive daytime sleepiness, sleep fragmentation, insomnia, periodic limb movements during sleep (PLMS), and / or restless legs syndrome (RLS).

[0296] In some embodiments, the core clinical features, syndromes, or symptoms associated with the prodromal phase of Parkinson's disease are RBD, hyposmia, cognitive impairment, constipation, depression, and anxiety. In some embodiments, the RBD subject is diagnosed with one or more of RBD, hyposmia, cognitive impairment, constipation, depression, and / or anxiety. In some embodiments, the RBD subject is diagnosed with two or more of RBD, hyposmia, cognitive impairment, constipation, depression, and / or anxiety. In some embodiments, the RBD subject is diagnosed with three or more of RBD, hyposmia, cognitive impairment, constipation, depression, and / or anxiety. In some embodiments, the RBD subject is diagnosed with four or more of RBD, hyposmia, cognitive impairment, constipation, depression, and / or anxiety. In some embodiments, the RBD subject is diagnosed with RBD, hyposmia, cognitive impairment, constipation, depression, and anxiety.

[0297] In some embodiments, the RBD subject is diagnosed with one or more of RBD, hyposmia, and / or constipation.

[0298] In some implementations, the RBD subject has not been diagnosed with one or more core clinical features, syndromes, or symptoms associated with Lewy body (DLB) dementia. In some implementations, one or more core clinical features, syndromes, or symptoms associated with DLB are mild cognitive impairment (MCI), productivity episodes, and / or psychotic episodes.

[0299] In some aspects, the RBD subject has not been diagnosed with dementia. In some embodiments, the RBD subject has not been diagnosed with one or more of mild cognitive impairment (MCI), hemorrhagic seizures, and / or psychotic episodes. In some embodiments, the RBD subject has not been diagnosed with dementia, but has been diagnosed with one or more of mild cognitive impairment (MCI), epileptic seizures, and / or psychotic episodes.

[0300] In some embodiments, the RBD subject has not been diagnosed with any core clinical feature, syndrome, or symptom associated with DLB. In some embodiments, the core clinical feature, syndrome, or symptom associated with DLB is dementia, Parkinson's syndrome, cognitive / vigilance fluctuations, and / or visual hallucinations. In some embodiments, the RBD subject has not been diagnosed with dementia, Parkinson's syndrome, cognitive / vigilance fluctuations, and visual hallucinations.

[0301] In some implementations, the RBD subject was not diagnosed with one or more core clinical features, syndromes, or symptoms associated with the prodromal phase of DLB.

[0302] In some embodiments, the subject with RBD is diagnosed with one or more core clinical features, syndromes, or symptoms associated with the prodromal phase of DLB. In some embodiments, one or more core clinical features, syndromes, or symptoms associated with the prodromal phase of DLB ​​are RBD, constipation, hyposmia, depression, urinary dysfunction, erectile dysfunction, orthostatic hypotension / dizziness, mild motor abnormalities, impaired olfaction, impaired color vision, memory impairment, Parkinson's symptoms, visual hallucinations, anxiety, mild cognitive impairment, attention / executive dysfunction, visuospatial dysfunction, striatal dopaminergic denervation, hyperechoic substantia nigra, and / or increased rCBF in the hippocampus.

[0303] In some embodiments, the RBD subject is diagnosed with one or more of the following: RBD, constipation, hyposmia, depression, urinary dysfunction, erectile dysfunction, orthostatic hypotension / dizziness, mild motor dysfunction, impaired olfactory function, impaired color vision, memory impairment, Parkinson's symptoms, visual hallucinations, anxiety, mild cognitive impairment, attention / executive dysfunction, visuospatial dysfunction, striatal dopaminergic denervation, substantia nigra hyperechoic and / or increased rCBF in the hippocampus.

[0304] In some implementations, the RBD subject is diagnosed with two or more of the following: RBD, constipation, hyposmia, depression, urinary dysfunction, erectile dysfunction, orthostatic hypotension / dizziness, mild motor dysfunction, impaired olfactory function, impaired color vision, memory impairment, Parkinson's symptoms, visual hallucinations, anxiety, mild cognitive impairment, attention / executive dysfunction, visuospatial dysfunction, striatal dopaminergic denervation, substantia nigra hyperechoicity, and / or increased rCBF in the hippocampus.

[0305] In some embodiments, the RBD subject is diagnosed with three or more of the following: RBD, constipation, hyposmia, depression, urinary dysfunction, erectile dysfunction, orthostatic hypotension / dizziness, mild motor dysfunction, impaired olfactory function, impaired color vision, memory impairment, Parkinson's symptoms, visual hallucinations, anxiety, mild cognitive impairment, attention / executive dysfunction, visuospatial dysfunction, striatal dopaminergic denervation, substantia nigra hyperechoicity, and / or increased rCBF in the hippocampus.

[0306] In some embodiments, the RBD subject is diagnosed with four or more of the following: RBD, constipation, hyposmia, depression, urinary dysfunction, erectile dysfunction, orthostatic hypotension / dizziness, mild motor dysfunction, impaired olfactory function, impaired color vision, memory impairment, Parkinson's symptoms, visual hallucinations, anxiety, mild cognitive impairment, attention / executive dysfunction, visuospatial dysfunction, striatal dopaminergic denervation, substantia nigra hyperechoicity, and / or increased rCBF in the hippocampus.

[0307] In some implementations, the RBD subject is diagnosed with five or more of the following: RBD, constipation, hyposmia, depression, urinary dysfunction, erectile dysfunction, orthostatic hypotension / dizziness, mild motor dysfunction, impaired olfactory function, impaired color vision, memory impairment, Parkinson's symptoms, visual hallucinations, anxiety, mild cognitive impairment, attention / executive dysfunction, visuospatial dysfunction, striatal dopaminergic denervation, substantia nigra hyperechoicity, and / or increased rCBF in the hippocampus.

[0308] In some implementations, the RBD subject is diagnosed with six or more of the following: RBD, constipation, hyposmia, depression, urinary dysfunction, erectile dysfunction, orthostatic hypotension / dizziness, mild motor dysfunction, impaired olfactory function, impaired color vision, memory impairment, Parkinson's symptoms, visual hallucinations, anxiety, mild cognitive impairment, attention / executive dysfunction, visuospatial dysfunction, striatal dopaminergic denervation, substantia nigra hyperechoicity, and / or increased rCBF in the hippocampus.

[0309] In some implementations, the RBD subject is diagnosed with seven or more of the following: RBD, constipation, hyposmia, depression, urinary dysfunction, erectile dysfunction, orthostatic hypotension / dizziness, mild motor dysfunction, impaired olfactory function, impaired color vision, memory impairment, Parkinson's symptoms, visual hallucinations, anxiety, mild cognitive impairment, attention / executive dysfunction, visuospatial dysfunction, striatal dopaminergic denervation, substantia nigra hyperechoicity, and / or increased rCBF in the hippocampus.

[0310] In some implementations, the RBD subject is diagnosed with eight or more of the following: RBD, constipation, hyposmia, depression, urinary dysfunction, erectile dysfunction, orthostatic hypotension / dizziness, mild motor dysfunction, impaired olfactory function, impaired color vision, memory impairment, Parkinson's symptoms, visual hallucinations, anxiety, mild cognitive impairment, attention / executive dysfunction, visuospatial dysfunction, striatal dopaminergic denervation, substantia nigra hyperechoicity, and / or increased rCBF in the hippocampus.

[0311] In some implementations, the RBD subject is diagnosed with nine or more of the following: RBD, constipation, hyposmia, depression, urinary dysfunction, erectile dysfunction, orthostatic hypotension / dizziness, mild motor dysfunction, impaired olfactory function, impaired color vision, memory impairment, Parkinson's symptoms, visual hallucinations, anxiety, mild cognitive impairment, attention / executive dysfunction, visuospatial dysfunction, striatal dopaminergic denervation, substantia nigra hyperechoicity, and / or increased rCBF in the hippocampus.

[0312] In some implementations, the RBD subject is diagnosed with ten or more of the following: RBD, constipation, hyposmia, depression, urinary dysfunction, erectile dysfunction, orthostatic hypotension / dizziness, mild motor dysfunction, impaired olfactory function, impaired color vision, memory impairment, Parkinson's symptoms, visual hallucinations, anxiety, mild cognitive impairment, attention / executive dysfunction, visuospatial dysfunction, striatal dopaminergic denervation, substantia nigra hyperechoicity, and / or increased rCBF in the hippocampus.

[0313] In some implementations, the RBD subject is diagnosed with eleven or more of the following: RBD, constipation, hyposmia, depression, urinary dysfunction, erectile dysfunction, orthostatic hypotension / dizziness, mild motor dysfunction, impaired olfactory function, impaired color vision, memory impairment, Parkinson's symptoms, visual hallucinations, anxiety, mild cognitive impairment, attention / executive dysfunction, visuospatial dysfunction, striatal dopaminergic denervation, substantia nigra hyperechoicity, and / or increased rCBF in the hippocampus.

[0314] In some implementations, the RBD subject is diagnosed with twelve or more of the following: RBD, constipation, hyposmia, depression, urinary dysfunction, erectile dysfunction, orthostatic hypotension / dizziness, mild motor dysfunction, impaired olfactory function, impaired color vision, memory impairment, Parkinson's symptoms, visual hallucinations, anxiety, mild cognitive impairment, attention / executive dysfunction, visuospatial dysfunction, striatal dopaminergic denervation, substantia nigra hyperechoicity, and / or increased rCBF in the hippocampus.

[0315] In some embodiments, the RBD subject is diagnosed with thirteen or more of the following: RBD, constipation, hyposmia, depression, urinary dysfunction, erectile dysfunction, orthostatic hypotension / dizziness, mild motor dysfunction, impaired olfactory function, impaired color vision, memory impairment, Parkinson's symptoms, visual hallucinations, anxiety, mild cognitive impairment, attention / executive dysfunction, visuospatial dysfunction, striatal dopaminergic denervation, substantia nigra hyperechoicity, and / or increased rCBF in the hippocampus.

[0316] In some implementations, the RBD subject is diagnosed with fourteen or more of the following: RBD, constipation, hyposmia, depression, urinary dysfunction, erectile dysfunction, orthostatic hypotension / dizziness, mild motor dysfunction, impaired olfactory function, impaired color vision, memory impairment, Parkinson's symptoms, visual hallucinations, anxiety, mild cognitive impairment, attention / executive dysfunction, visuospatial dysfunction, striatal dopaminergic denervation, substantia nigra hyperechoicity, and / or increased rCBF in the hippocampus.

[0317] In some implementations, the RBD subject is diagnosed with RBD, constipation, hyposmia, depression, urinary dysfunction, erectile dysfunction, orthostatic hypotension / dizziness, mild motor dysfunction, impaired olfactory function, impaired color vision, memory impairment, Parkinson's symptoms, visual hallucinations, anxiety, mild cognitive impairment, attention / executive dysfunction, visuospatial dysfunction, striatal dopaminergic denervation, substantia nigra hyperechoic and / or increased rCBF in the hippocampus, fifteen or more of these conditions.

[0318] In some implementations, the RBD subject is diagnosed with sixteen or more of the following: RBD, constipation, hyposmia, depression, urinary dysfunction, erectile dysfunction, orthostatic hypotension / dizziness, mild motor dysfunction, impaired olfactory function, impaired color vision, memory impairment, Parkinson's symptoms, visual hallucinations, anxiety, mild cognitive impairment, attention / executive dysfunction, visuospatial dysfunction, striatal dopaminergic denervation, substantia nigra hyperechoicity, and / or increased rCBF in the hippocampus.

[0319] In some embodiments, the RBD subject is diagnosed with seventeen or more of the following: RBD, constipation, hyposmia, depression, urinary dysfunction, erectile dysfunction, orthostatic hypotension / dizziness, mild motor dysfunction, impaired olfactory function, impaired color vision, memory impairment, Parkinson's symptoms, visual hallucinations, anxiety, mild cognitive impairment, attention / executive dysfunction, visuospatial dysfunction, striatal dopaminergic denervation, substantia nigra hyperechoicity, and / or increased rCBF in the hippocampus.

[0320] In some implementations, the RBD subject is diagnosed with eighteen or more of the following: RBD, constipation, hyposmia, depression, urinary dysfunction, erectile dysfunction, orthostatic hypotension / dizziness, mild motor dysfunction, impaired olfactory function, impaired color vision, memory impairment, Parkinson's symptoms, visual hallucinations, anxiety, mild cognitive impairment, attention / executive dysfunction, visuospatial dysfunction, striatal dopaminergic denervation, substantia nigra hyperechoicity, and / or increased rCBF in the hippocampus.

[0321] In some implementations, the RBD subject is diagnosed with nineteen or more of the following: RBD, constipation, hyposmia, depression, urinary dysfunction, erectile dysfunction, orthostatic hypotension / dizziness, mild motor dysfunction, impaired olfactory function, impaired color vision, memory impairment, Parkinson's symptoms, visual hallucinations, anxiety, mild cognitive impairment, attention / executive dysfunction, visuospatial dysfunction, striatal dopaminergic denervation, substantia nigra hyperechoicity, and / or increased rCBF in the hippocampus.

[0322] In some implementations, RBD subjects are diagnosed with RBD, constipation, hyposmia, depression, urinary dysfunction, erectile dysfunction, orthostatic hypotension / dizziness, mild motor abnormalities, impaired olfactory function, impaired color vision, memory impairment, Parkinson's symptoms, visual hallucinations, anxiety, mild cognitive impairment, attention / executive dysfunction, visuospatial dysfunction, striatal dopaminergic denervation, substantia nigra hyperechoicity, and increased hippocampal rCBF.

[0323] In some implementations, one or more core clinical features, syndromes, or symptoms associated with the prodromal phase of DLB ​​are RBD, constipation, hyposmia, depression, orthostatic hypotension / dizziness, memory impairment, Parkinson's symptoms, visual hallucinations, anxiety, mild cognitive impairment, attention / executive dysfunction, visuospatial dysfunction, and / or striatal dopaminergic denervation.

[0324] In some implementations, the RBD subject is diagnosed with one or more of the following: RBD, constipation, hyposmia, depression, orthostatic hypotension / dizziness, memory impairment, Parkinson's symptoms, visual hallucinations, anxiety, mild cognitive impairment, attention / executive dysfunction, visuospatial dysfunction, and / or striatal dopaminergic denervation.

[0325] In some implementations, the RBD subject is diagnosed with two or more of the following: RBD, constipation, hyposmia, depression, orthostatic hypotension / dizziness, memory impairment, Parkinson's symptoms, visual hallucinations, anxiety, mild cognitive impairment, attention / executive dysfunction, visuospatial dysfunction, and / or striatal dopaminergic denervation.

[0326] In some implementations, the RBD subject is diagnosed with three or more of the following: RBD, constipation, hyposmia, depression, orthostatic hypotension / dizziness, memory impairment, Parkinson's symptoms, visual hallucinations, anxiety, mild cognitive impairment, attention / executive dysfunction, visuospatial dysfunction, and / or striatal dopaminergic denervation.

[0327] In some implementations, the RBD subject is diagnosed with four or more of the following: RBD, constipation, hyposmia, depression, orthostatic hypotension / dizziness, memory impairment, Parkinson's symptoms, visual hallucinations, anxiety, mild cognitive impairment, attention / executive dysfunction, visuospatial dysfunction, and / or striatal dopaminergic denervation.

[0328] In some implementations, the RBD subject is diagnosed with five or more of the following: RBD, constipation, decreased sense of smell, depression, orthostatic hypotension / dizziness, memory impairment, Parkinson's symptoms, visual hallucinations, anxiety, mild cognitive impairment, attention / executive dysfunction, visuospatial dysfunction, and / or striatal dopaminergic denervation.

[0329] In some implementations, the RBD subject is diagnosed with six or more of the following: RBD, constipation, decreased sense of smell, depression, orthostatic hypotension / dizziness, memory impairment, Parkinson's symptoms, visual hallucinations, anxiety, mild cognitive impairment, attention / executive dysfunction, visuospatial dysfunction, and / or striatal dopaminergic denervation.

[0330] In some implementations, the RBD subject is diagnosed with RBD, constipation, hyposmia, depression, orthostatic hypotension / dizziness, memory impairment, Parkinson's symptoms, visual hallucinations, anxiety, mild cognitive impairment, attention / executive dysfunction, visuospatial dysfunction, and / or striatal dopaminergic denervation.

[0331] In some implementations, the RBD subject is diagnosed with eight or more of the following: RBD, constipation, decreased sense of smell, depression, orthostatic hypotension / dizziness, memory impairment, Parkinson's symptoms, visual hallucinations, anxiety, mild cognitive impairment, attention / executive dysfunction, visuospatial dysfunction, and / or striatal dopaminergic denervation.

[0332] In some implementations, the RBD subject is diagnosed with nine or more of the following: RBD, constipation, hyposmia, depression, orthostatic hypotension / dizziness, memory impairment, Parkinson's symptoms, visual hallucinations, anxiety, mild cognitive impairment, attention / executive dysfunction, visuospatial dysfunction, and / or striatal dopaminergic denervation.

[0333] In some implementations, the RBD subject is diagnosed with ten or more of the following: RBD, constipation, hyposmia, depression, orthostatic hypotension / dizziness, memory impairment, Parkinson's symptoms, visual hallucinations, anxiety, mild cognitive impairment, attention / executive dysfunction, visuospatial dysfunction, and / or striatal dopaminergic denervation.

[0334] In some implementations, the RBD subject is diagnosed with eleven or more of the following: RBD, constipation, hyposmia, depression, orthostatic hypotension / dizziness, memory impairment, Parkinson's symptoms, visual hallucinations, anxiety, mild cognitive impairment, attention / executive dysfunction, visuospatial dysfunction, and / or striatal dopaminergic denervation.

[0335] In some implementations, the RBD subject is diagnosed with twelve or more of the following: RBD, constipation, hyposmia, depression, orthostatic hypotension / dizziness, memory impairment, Parkinson's symptoms, visual hallucinations, anxiety, mild cognitive impairment, attention / executive dysfunction, visuospatial dysfunction, and / or striatal dopaminergic denervation.

[0336] In some implementations, RBD subjects were diagnosed with constipation, decreased sense of smell, depression, orthostatic hypotension / dizziness, memory impairment, Parkinson's symptoms, visual hallucinations, anxiety, mild cognitive impairment, attention / executive dysfunction, visuospatial dysfunction, and striatal dopaminergic denervation.

[0337] In some embodiments, one or more core clinical features, syndromes, or symptoms associated with the prodromal phase of DLB ​​are RBD, constipation, hyposmia, depression, and / or orthostatic hypotension / dizziness. In some embodiments, the RBD subject is diagnosed with one or more of RBD, constipation, hyposmia, depression, and / or orthostatic hypotension / dizziness. In some embodiments, the RBD subject is diagnosed with two or more of RBD, constipation, hyposmia, depression, and / or orthostatic hypotension / dizziness. In some embodiments, the RBD subject is diagnosed with three or more of RBD, constipation, hyposmia, depression, and / or orthostatic hypotension / dizziness. In some embodiments, the RBD subject is diagnosed with four or more of RBD, constipation, hyposmia, depression, and / or orthostatic hypotension / dizziness. In some embodiments, the RBD subject is diagnosed with RBD, constipation, hyposmia, depression, and orthostatic hypotension / dizziness.

[0338] In some embodiments, the RBD subject is not diagnosed with any core clinical feature, syndrome, or symptom associated with MSA. In some embodiments, the core clinical feature, syndrome, or symptom associated with MSA is extensive and abundant neurodegenerative changes in the brain's α-synuclein-positive glial cytoplasmic inclusions, striatum, substantia nigra, or olivopontocerebellum; urinary incontinence; orthostatic hypotension; poor levodopa response in Parkinson's syndrome; cerebellar syndrome; and / or Parkinson's syndrome. In some embodiments, the RBD subject is not diagnosed with any of the following: extensive and abundant neurodegenerative changes in the brain's α-synuclein-positive glial cytoplasmic inclusions, striatum, substantia nigra, or olivopontocerebellum; urinary incontinence; orthostatic hypotension; poor levodopa response in Parkinson's syndrome; cerebellar syndrome; and / or Parkinson's syndrome.

[0339] In some embodiments, the core clinical feature, syndrome, or symptom associated with MSA is extensive and abundant neurodegenerative changes in α-synuclein-positive glial cytoplasmic inclusions and / or the substantia nigra or olivary pontine-cerebellar region. In some embodiments, the RBD subject is not diagnosed with extensive and abundant neurodegenerative changes in α-synuclein-positive glial cytoplasmic inclusions and / or the substantia nigra or olivary pontine-cerebellar region.

[0340] In some implementations, the core clinical features, syndromes, or symptoms associated with MSA are urinary incontinence or orthostatic hypotension; and poor levodopa responsiveness in Parkinson's syndrome or cerebellar syndrome. In some implementations, the RBD subject is not diagnosed with urinary incontinence or orthostatic hypotension; and poor levodopa responsiveness in Parkinson's syndrome or cerebellar syndrome.

[0341] In some implementations, the core clinical features, syndromes, or symptoms associated with MSA are Parkinson's syndrome or cerebellar syndrome; and autonomic dysfunction. In some implementations, the RBD subject has not been diagnosed with Parkinson's syndrome or cerebellar syndrome; and autonomic dysfunction.

[0342] In some embodiments, symptoms of Parkinson's syndrome with poor levodopa responsiveness include bradykinesia with rigidity, tremor, and / or postural instability. In some embodiments, symptoms of cerebellar syndrome include gait ataxia (with cerebellar arterial abnormalities), limb ataxia, and / or cerebellar neuromotor dysfunction. In some embodiments, symptoms of Parkinson's syndrome include bradykinesia with rigid tremor and / or postural instability.

[0343] In some implementations, the RBD subject was not diagnosed with one or more core clinical features, syndromes, or symptoms associated with the prodromal phase of MSA.

[0344] In some embodiments, the RBD subject is diagnosed with one or more core clinical features, syndromes, or symptoms associated with the prodromal phase of MSA. In some embodiments, the core clinical features, syndromes, or symptoms associated with the prodromal phase of MSA are RBD, neurogenic orthostatic hypotension occurring within 10 minutes of standing or head-up tilting, and / or genitourinary dysfunction. In some embodiments, the RBD subject is diagnosed with one or more of RBD, neurogenic orthostatic hypotension occurring within 10 minutes of standing or head-up tilting, and / or genitourinary dysfunction. In some embodiments, the RBD subject is diagnosed with two or more of RBD, neurogenic orthostatic hypotension occurring within 10 minutes of standing or head-up tilting, and / or genitourinary dysfunction. In some embodiments, the RBD subject is diagnosed with both RBD, neurogenic orthostatic hypotension occurring within 10 minutes of standing or head-up tilting, and genitourinary dysfunction.

[0345] In some implementations, the administration of N-acetylleucine reduces the number of RBD attacks compared to the number of RBD attacks prior to administration.

[0346] In some implementations, administration of N-acetylleucine reduced the daily RBD severity score of RBD subjects compared to the RBD daily severity score before administration of N-acetylleucine.

[0347] In some embodiments, the application of N-acetylleucine reduces the frequency of RBD behaviors compared to before the application. In some embodiments, RBD behaviors are selected from the group consisting of vocalization, simple and complex motor behaviors, and any combination thereof. In some embodiments, the application of N-acetylleucine reduces the severity of RBD behaviors compared to before the application.

[0348] In some implementations, N-acetylleucine administration reduces the number of nights per week in which the RBD subject or their bed partner exhibits harmful behaviors compared to before administration. In some implementations, harmful behaviors are selected from vocalizations, simple and complex motor behaviors, and any combination thereof.

[0349] In some implementations, the number of night sores is reduced weekly after N-acetylleucine administration compared to before administration.

[0350] In some embodiments, the RBD subject receives approximately 0.01 g to approximately 100 g of N-acetylleucine daily. In some embodiments, the RBD subject receives approximately 0.1 g to approximately 20 g, approximately 0.5 g to approximately 15 g, approximately 1 g to approximately 15 g, approximately 1 g to approximately 10 g, or approximately 1 g to approximately 5 g of N-acetylleucine daily. In some embodiments, the RBD subject receives approximately 5 g of N-acetylleucine daily.

[0351] In some implementations, N-acetylleucine is administered orally.

[0352] In some embodiments, the RBD subject is administered N-acetyl-DL-leucine.

[0353] IV. N-acetylleucine

[0354] N-acetylleucine or a pharmaceutically acceptable salt thereof may be formulated and administered to a subject in accordance with teachings known in the art. For example, N-acetylleucine or a pharmaceutically acceptable salt thereof may be formulated into a pharmaceutical composition. A pharmaceutical composition may comprise N-acetylleucine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. References to pharmaceutical compositions include active agents alone or active agents in the form of a pharmaceutical composition.

[0355] The pharmaceutical composition can take any of a variety of different forms, depending on how it is used. Thus, for example, it can be a powder, tablet, capsule, liquid, ointment, cream, gel, hydrogel, aerosol, spray, micelle solution, transdermal patch, liposome suspension, or any other suitable form that can be administered to a person or animal in need of treatment.

[0356] In one embodiment, the pharmaceutically acceptable carrier may be a solid, and the composition may be in the form of a powder or tablet. A pharmaceutically acceptable solid carrier may include, but is not limited to, one or more substances that may also act as a flavoring agent, buffer, lubricant, stabilizer, solubilizer, suspending agent, wetting agent, emulsifier, dye, filler, flow aid, compression aid, inert binder, sweetener, preservative, coating, or tablet disintegrant. The carrier may also be an encapsulating material. In a powder, the carrier may be a finely ground solid mixed with a finely ground active agent according to this disclosure. In a tablet, the active agent may be mixed with a carrier having the necessary compressibility in a suitable proportion and compacted to the desired shape and size. Powders and tablets may, for example, contain up to 99% of the active agent. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugar, lactose, dextrin, starch, gelatin, cellulose, polyvinylpyrrolidone, low-melting-point waxes, and ion exchange resins. In another embodiment, the pharmaceutically acceptable carrier may be a gel, and the composition may be in the form of a cream, etc.

[0357] The carrier may include, but is not limited to, one or more excipients or diluents. Examples of such excipients are gelatin, gum arabic, lactose, microcrystalline cellulose, starch, sodium starch glycolate, calcium hydrogen phosphate, magnesium stearate, talc, colloidal silica, etc.

[0358] In another embodiment, the pharmaceutically acceptable carrier can be a liquid. In one embodiment, the pharmaceutical composition is in the form of a solution. Liquid carriers are used to prepare solutions, suspensions, emulsions, syrups, elixirs, and pressurized compositions. N-acetylleucine can be dissolved or suspended in a pharmaceutically acceptable liquid carrier, such as water, an organic solvent, a mixture of both, or a pharmaceutically acceptable oil or fat. Liquid carriers may contain other suitable pharmaceutical additives, such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavorings, suspending agents, thickeners, colorants, viscosity modifiers, stabilizers, or osmotic modifiers. Suitable examples of liquid carriers for oral and parenteral administration include water (partially containing additives as described above, such as cellulose derivatives, like sodium carboxymethyl cellulose solution), alcohols (including monohydric and polyhydric alcohols, such as diols) and their derivatives, and oils (e.g., fractionated coconut oil and peanut oil). For parenteral administration, the carrier can also be an oily ester, such as ethyl oleate and isopropyl myristate. Sterile liquid carriers can be used in sterile liquid forms of compositions for parenteral administration. The liquid carrier used in the pressurized composition may be a halocarbon or other pharmaceutically acceptable propellant.

[0359] Liquid pharmaceutical compositions, as sterile solutions or suspensions, can be administered, for example, via intramuscular, intrathecal, epidural, intraperitoneal, intravenous, and especially subcutaneous injection. The active agent can be prepared as a sterile solid composition, which can be dissolved or suspended at the time of administration using sterile water, saline, or other suitable sterile injectable media.

[0360] The composition can be administered orally in the form of a sterile solution or suspension containing other solutes or suspending agents (e.g., sufficient saline or glucose to make the solution isotonic), bile salts, gum arabic, gelatin, sorbitan monooleate, polysorbate 80 (oleate of sorbitol and its anhydride copolymerized with ethylene oxide), etc. The composition can also be administered orally in liquid or solid composition form. Compositions suitable for oral administration include solid forms such as pills, capsules, granules, tablets, and powders, and liquid forms such as solutions, syrups, elixirs, and suspensions. Forms suitable for parenteral administration include sterile solutions, emulsions, and suspensions.

[0361] N-acetylleucine and compositions containing it may alternatively be administered by inhalation (e.g., intranasal). The compositions may also be formulated for topical use. For example, a cream or ointment may be applied to the skin.

[0362] N-acetylleucine can be incorporated into slow- or delayed-release devices. Such devices can be inserted, for example, onto or under the skin, and the drug can be released over weeks or even months. Such devices may be advantageous when long-term treatment with N-acetylleucine as used according to this disclosure is required and frequent administration (e.g., at least daily) is typically necessary.

[0363] In one embodiment, the pharmaceutical composition is in tablet form. In the tablet, the active agent may be mixed with a medium (e.g., a pharmaceutically acceptable carrier) having the necessary compressibility in a suitable proportion and compacted into the desired shape and size. The tablet may contain up to 99% active agent by weight.

[0364] For example, N-acetylleucine or a pharmaceutically acceptable salt thereof can be provided in solid dosage forms suitable for oral administration, particularly in tablet form.

[0365] Pharmaceutical compositions in solid oral dosage forms, such as tablets, can be prepared by any method known in the pharmaceutical field. Pharmaceutical compositions are typically prepared by mixing N-acetylleucine or a pharmaceutically acceptable salt thereof with a conventionally pharmaceutically acceptable carrier.

[0366] Tablets can be formulated as known in the art. Tanganil® includes, for example, wheat starch, pregelatinized corn (corn) starch, calcium carbonate, and magnesium stearate as excipients. The same or similar excipients may be used, for example, in this disclosure.

[0367] V. Specific Implementation Methods

[0368] The present invention provides the following specific embodiments.

[0369] Implementation Method 1. A method for treating the prodromal phase of α-synucleinosis in a subject of need, the method comprising administering a therapeutically effective amount of N-acetylleucine to the subject, wherein the subject: (i) Not diagnosed with any core clinical feature, syndrome, or symptom associated with α-synucleopathy; and (ii) Being diagnosed with one or more core clinical features, syndromes, or symptoms associated with the prodromal phase of α-synucleinosis. Alpha-synucleinopathies include Parkinson's disease (PD), Lewy body dementia (DLB), or multiple system atrophy (MSA).

[0370] Implementation Method 2. A method for treating the prodromal phase of PD in a subject in need, according to Implementation Method 1, wherein the subject: (i) Not diagnosed with tremor, bradykinesia, rigidity, balance disorder, and / or coordination disorder; and (ii) diagnosed with one or more of the following: hyposmia, cognitive impairment, REM sleep behavior disorder (RBD), constipation, depression and / or anxiety.

[0371] Implementation Method 3. A method for treating the prodromal phase of DLB ​​in a subject requiring treatment according to Implementation Method 1, wherein the subject: (i) has not been diagnosed with dementia; and (ii) diagnosed with one or more of the following: RBD, constipation, decreased sense of smell, depression and / or orthostatic hypotension / dizziness.

[0372] Implementation Method 4. A method for the pre-treatment phase of MSA in a subject requiring treatment according to Implementation Method 1, wherein the subject: (i) Not diagnosed with (a) autonomic dysfunction; and (b) poor L-dopamine responsiveness Parkinson's syndrome and / or cerebellar syndrome; and (ii) diagnosed with one or more of the following: RBD, neurogenic orthostatic hypotension and / or urogenital dysfunction that occurs within 10 minutes of standing or tilting the head up.

[0373] Implementation Method 5. The method according to any one of Implementation Methods 1-4, wherein the subject has reduced dopaminergic function in the basal ganglia.

[0374] Implementation Method 6. The method according to any one of Implementation Methods 1-5, wherein the administration of N-acetylleucine increases the dopaminergic function of the subject compared with that before administration of N-acetylleucine.

[0375] Implementation Method 7. The method according to Implementation Method 5 or 6, wherein the amount of dopaminergic function in the subject is determined by dopamine transporter (DAT) scanning.

[0376] Implementation Method 8. The method according to any one of Implementation Methods 1-7, wherein the subject has reduced glucose metabolism in the brain.

[0377] Implementation Method 9. The method according to any one of Implementation Methods 1-8, wherein the subject has reduced glucose metabolism in the parietal, occipital, and / or frontal regions of the brain.

[0378] Implementation Method 10. The method according to any one of Implementation Methods 1-8, wherein the subject has reduced glucose metabolism in the occipital cortex and primary visual regions of the brain.

[0379] Implementation Method 11. The method according to any one of Implementation Methods 1-8, wherein the subject has reduced glucose metabolism in the putamen, anterior cerebellar lobe, and / or vermis.

[0380] Implementation Method 12. The method according to any one of Implementation Methods 1-11, wherein the administration of N-acetylleucine increases glucose metabolism in the subject's brain compared to glucose metabolism in the subject prior to administration of N-acetylleucine.

[0381] Implementation Method 13. The method according to any one of Implementation Methods 1-12, wherein the administration of N-acetylleucine increases glucose metabolism in the parietal, occipital, and / or frontal regions of the subject's brain compared to the subject's glucose metabolism prior to administration of N-acetylleucine.

[0382] Implementation Method 14. The method according to any one of Implementation Methods 1-12, wherein the administration of N-acetylleucine increases glucose metabolism in the subject’s occipital cortex and primary visual regions of the brain compared to the subject’s glucose metabolism before administration of N-acetylleucine.

[0383] Implementation Method 15. The method according to any one of Implementation Methods 1-12, wherein the administration of N-acetylleucine increases glucose metabolism in the putamen, anterior cerebellum, and / or vermis of the subject compared with glucose metabolism in the subject prior to administration of N-acetylleucine.

[0384] Implementation Method 16. The method according to any one of Implementation Methods 8-15, wherein glucose metabolism is determined by positron emission tomography (PET) scanning.

[0385] Implementation 17. The method as described in Implementation 16, wherein the PET scan is a fluorodeoxyglucose-positron emission tomography (FDG-PET) scan.

[0386] Implementation Method 18. The method according to Implementation Method 17, wherein FDG-PET scan is used to generate the z-score of the subject.

[0387] Implementation Method 19. The method of Implementation Method 18, wherein administration of N-acetylleucine reduces the z-score of the subject in the parietal, occipital, and / or frontal lobes of the brain.

[0388] Implementation Method 20. The method of Implementation Method 18, wherein administration of N-acetylleucine reduces the z-score of the subject in the frontal, acrosome, and / or occipital regions of the brain.

[0389] Implementation Method 21. The method as described in Implementation Method 18, wherein administration of the N-acetylleucine reduces the subject's z-score in the putamen, anterior cerebellar lobe, and / or vermis.

[0390] Implementation Method 22. The method of any one of Implementation Methods 18-21, wherein the z-score of the subject is reduced by at least about 5%, about 10%, about 20%, about 30%, about 40%, or about 50% compared with the z-score of the subject before administration of N-acetylleucine.

[0391] Implementation Method 23. The method according to any one of Implementation Methods 1-22, wherein the administration of N-acetylleucine reduces the number of RBD attacks compared to the number of RBD attacks prior to administration of N-acetylleucine.

[0392] Implementation Method 24. A method for treating REM-sleep behavior disorder (RBD) in a subject in need, the method comprising administering a therapeutically effective amount of N-acetylleucine to the subject.

[0393] Implementation Method 25. The method as described in Implementation Method 24, wherein the subject has been diagnosed with prodromal Parkinson's disease (PD), prodromal Lewy body dementia (DLB), or prodromal multiple system atrophy (MSA).

[0394] Implementation 26. The method of Implementation 24, wherein the subject has been diagnosed with classic Parkinson's disease (PD), classic dementia with Lewy bodies (DLB), or classic multiple system atrophy (MSA).

[0395] Implementation Method 27. The method according to any one of Implementation Methods 1-26, wherein about 1 g to about 15 g of N-acetylleucine is administered to the subject daily.

[0396] Implementation Method 28. The method according to Implementation Method 27, wherein about 1 g to about 10 g of the N-acetylleucine is administered to the subject daily.

[0397] Implementation Method 29. The method according to Implementation Method 28, wherein about 1 g to about 5 g of the N-acetylleucine is administered to the subject daily.

[0398] Implementation Method 30. The method according to any one of Implementation Methods 1-29, wherein the N-acetylleucine is orally administered to the subject.

[0399] Implementation Method 31. The method of any one of Implementation Methods 1-30, wherein the N-acetylleucine administered to the subject is N-acetyl-DL-leucine.

[0400] Implementation Method 32. The method of any one of Implementation Methods 1-30, wherein the N-acetylleucine administered to the subject is N-acetyl-L-leucine.

[0401] Implementation Method 33. N-acetylleucine for the treatment of the prodromal phase of α-synucleinopathy in a subject in need, wherein the subject: (i) Not diagnosed with any core clinical feature, syndrome, or symptom associated with α-synucleopathy; and (ii) Being diagnosed with one or more core clinical features, syndromes, or symptoms associated with the prodromal phase of α-synucleinosis. Alpha-synucleinopathies include Parkinson's disease (PD), Lewy body dementia (DLB), or multiple system atrophy (MSA).

[0402] Implementation Method 34. N-acetylleucine in the prodromal phase of PD for treating a subject in need, as described in Implementation Method 33, wherein the subject: (i) Not diagnosed with tremor, bradykinesia, rigidity, balance disorder, and / or coordination disorder; and (ii) diagnosed with one or more of the following: hyposmia, cognitive impairment, REM sleep behavior disorder (RBD), constipation, depression and / or anxiety.

[0403] Implementation Method 35. N-acetylleucine of Implementation Method 33, used to treat the pre-DLB phase in subjects in need, wherein the subjects: (i) has not been diagnosed with dementia; and (ii) diagnosed with one or more of the following: RBD, constipation, decreased sense of smell, depression and / or orthostatic hypotension / dizziness.

[0404] Implementation Method 36. N-acetylleucine of Implementation Method 33, used to treat the pre-existing MSA in a subject of need, wherein the subject: (i) Not diagnosed with (a) autonomic dysfunction; and (b) poor L-dopamine responsiveness Parkinson's syndrome and / or cerebellar syndrome; and (ii) diagnosed with one or more of the following: RBD, neurogenic orthostatic hypotension and / or urogenital dysfunction that occurs within 10 minutes of standing or tilting the head up.

[0405] Implementation 37. Use of any one of Implementations 33-36, wherein the subject has reduced dopaminergic function in the basal ganglia.

[0406] Implementation Method 38. Use of any one of Implementation Methods 33-37, wherein administration of N-acetylleucine increases the dopaminergic function of the subject compared with that before administration of N-acetylleucine.

[0407] Implementation Method 39. N-acetylleucine of Implementation Method 37 or 39, wherein the amount of dopaminergic function in the subject is determined by dopamine transporter (DAT) scanning.

[0408] Implementation 40. The use of N-acetylleucine in any of Implementations 33-39, wherein the subject has reduced glucose metabolism in the brain.

[0409] Implementation Method 41. The use of N-acetylleucine in any of Implementation Methods 33-40, wherein the subject has reduced glucose metabolism in the parietal, occipital and / or frontal lobes of the brain.

[0410] Implementation 42. The use of N-acetylleucine in any of Implementations 33-40, wherein the subject has reduced glucose metabolism in the occipital coccygeal cortex and the primary visual region of the brain.

[0411] Implementation Method 43. N-acetylleucine used in any of Implementation Methods 33-40, wherein the subject has reduced glucose metabolism in the putamen, anterior cerebellum and / or cerebellar vermis.

[0412] Implementation 44. The use of N-acetylleucine in any of Implementations 33-43, wherein the administration of N-acetylleucine increases glucose metabolism in the subject's brain compared to glucose metabolism in the subject prior to administration of N-acetylleucine.

[0413] Implementation 45. N-acetylleucine is used in any of Implementations 33-44, wherein the administration of N-acetylleucine increases glucose metabolism in the parietal, occipital, and / or frontal regions of the subject's brain compared to glucose metabolism in the subject prior to administration of N-acetylleucine.

[0414] Implementation 46. N-acetylleucine is used in any of Implementations 33-44, wherein the administration of N-acetylleucine increases glucose metabolism in the occipital cortex and the primary visual regions of the brain of the subject compared with glucose metabolism in the subject before administration of N-acetylleucine.

[0415] Implementation 47. N-acetylleucine is used in any of Implementations 33-44, wherein the administration of N-acetylleucine increases glucose metabolism in the putamen, anterior cerebellum, and / or vermis of the subject compared with glucose metabolism in the subject prior to administration of N-acetylleucine.

[0416] Implementation Method 48. N-acetylleucine used in any of Implementation Methods 40-47, wherein glucose metabolism is determined by positron emission tomography (PET) scanning.

[0417] Implementation Method 49. The N-acetylleucine used in Implementation Method 48, wherein the PET scan is a fluorodeoxyglucose-positron emission tomography (FDG-PET) scan.

[0418] Implementation 50. The N-acetylleucine used in Implementation 49, wherein FDG-PET scans are used to generate the subject's z-score.

[0419] Implementation Method 51. N-acetylleucine is used in Implementation Method 50, wherein administration of N-acetylleucine reduces the z-score of the subject in the parietal, occipital, and / or frontal lobes of the brain.

[0420] Implementation Method 52. The N-acetylleucine used in Implementation Method 50, wherein administration of N-acetylleucine reduced the z-score of the subject in the frontal, parietal, and / or occipital regions of the brain.

[0421] Implementation Method 53. N-acetylleucine is used in Implementation Method 50, wherein administration of N-acetylleucine reduces the z-score of the subject in the putamen, forebrain and / or vermis.

[0422] Implementation 54. The N-acetylleucine used in any of Implementations 50-53, wherein the z-score of the subject is reduced by at least about 5%, about 10%, about 20%, about 30%, about 40%, or about 50% compared with the z-score of the subject before administration of N-acetylleucine.

[0423] Implementation 55. The use of N-acetylleucine in any of Implementations 33-54, wherein the administration of N-acetylleucine reduces the number of RBD attacks compared to the number of RBD attacks prior to administration of N-acetylleucine.

[0424] Implementation method 56. N-acetylleucine for treating REM-sleep behavior disorder (RBD) in subjects in need.

[0425] Implementation Method 57. N-acetylleucine used in Implementation Method 56, wherein the subject has been diagnosed with prodromal Parkinson's disease (PD); prodromal dementia of Lewy body (DLB); or prodromal multiple system atrophy (MSA).

[0426] Implementation 58. N-acetylleucine used in Implementation 56, wherein the subject has been diagnosed with classic Parkinson's disease (PD), classic dementia with Lewy bodies (DLB), or classic multiple system atrophy (MSA).

[0427] Implementation Method 59. N-acetylleucine according to any one of Implementation Methods 33-58, wherein about 1 g to about 15 g of N-acetylleucine is administered to the subject daily.

[0428] Implementation method 60. N-acetylleucine used in implementation method 59, wherein about 1 g to about 10 g of N-acetylleucine is administered to the subject daily.

[0429] Implementation Method 61. N-acetylleucine used in Implementation Method 60, wherein about 1 g to about 5 g of N-acetylleucine is administered to the subject daily.

[0430] Embodiment 62. N-acetylleucine for use in any of Embodiments 33-61, wherein the N-acetylleucine is administered orally to a subject.

[0431] Implementation method 63. N-acetylleucine used in any of implementation methods 33-62, wherein the N-acetylleucine administered to the subject is N-acetyl-DL-leucine.

[0432] Implementation method 64. N-acetylleucine used in any of implementation methods 33-62, wherein the N-acetylleucine administered to the subject is N-acetyl-L-leucine.

[0433] Implementation Method 65. Use of N-acetylleucine in the preparation of a medicament for treating the prodromal phase of α-synucleinosis in a subject of need, wherein the subject: (i) Not diagnosed with any core clinical feature, syndrome, or symptom associated with α-synucleopathy; and (ii) Being diagnosed with one or more core clinical features, syndromes, or symptoms associated with the prodromal phase of α-synucleinosis. Alpha-synucleinopathies include Parkinson's disease (PD), Lewy body dementia (DLB), or multiple system atrophy (MSA).

[0434] Implementation 66. Use of Implementation 65 for treating the prodromal phase of PD in a subject in need, wherein the subject: (i) Not diagnosed with tremor, bradykinesia, rigidity, balance disorder, and / or coordination disorder; and (ii) diagnosed with one or more of the following: hyposmia, cognitive impairment, REM sleep behavior disorder (RBD), constipation, depression and / or anxiety.

[0435] Implementation Method 67. Application of Implementation Method 65 for treating the prodromal phase of DLB ​​in a subject in need, wherein the subject: (i) has not been diagnosed with dementia; and (ii) diagnosed with one or more of the following: RBD, constipation, decreased sense of smell, depression and / or orthostatic hypotension / dizziness.

[0436] Implementation method 68. Use of implementation method 65 for treating the prodromal phase of MSA in a subject in need, wherein the subject: (i) Not diagnosed with (a) autonomic dysfunction; and (b) poor L-dopamine responsiveness Parkinson's syndrome and / or cerebellar syndrome; and (ii) diagnosed with one or more of the following: RBD, neurogenic orthostatic hypotension and / or urogenital dysfunction that occurs within 10 minutes of standing or tilting the head up.

[0437] Implementation 69. The N-use of any one of Implementations 65-68, wherein the subject has reduced dopaminergic function in the basal ganglia.

[0438] Implementation Method 70. The use of N according to any one of Implementation Methods 65-69, wherein the administration of N-acetylleucine increases the dopaminergic function of the subject compared with that before administration of N-acetylleucine.

[0439] Implementation 71. Use of Implementation 69 or 70, wherein the amount of dopaminergic function in the subject is determined by dopamine transporter (DAT) scanning.

[0440] Implementation 72. Use of any one of Implementations 65-71, wherein the subject has reduced glucose metabolism in the brain.

[0441] Implementation 73. Use of any one of Implementations 65-72, wherein the subject has reduced glucose metabolism in the parietal, occipital and / or frontal regions of the brain.

[0442] Implementation 74. Use of any one of Implementations 65-72, wherein the subject has reduced glucose metabolism in the occipital cortex and primary visual regions of the brain.

[0443] Implementation 75. Use of any one of Implementations 65-72, wherein the subject has reduced glucose metabolism in the putamen, anterior cerebellum and / or vermis.

[0444] Implementation 76. Use of any one of Implementations 65-75, wherein administration of N-acetylleucine increases glucose metabolism in the brain of the subject compared to glucose metabolism in the subject prior to administration of N-acetylleucine.

[0445] Implementation 77. The use of N in any of Implementations 65-76, wherein the administration of N-acetylleucine increases glucose metabolism in the parietal, occipital, and / or frontal regions of the subject's brain compared to glucose metabolism in the subject prior to administration of N-acetylleucine.

[0446] Implementation 78. Use of any one of Implementations 65-76, wherein administration of N-acetylleucine increases glucose metabolism in the occipital cortex and primary visual regions of the brain of the subject compared with glucose metabolism in the subject before administration of N-acetylleucine.

[0447] Implementation 79. Use of any one of Implementations 65-76, wherein administration of N-acetylleucine increases glucose metabolism in the putamen, anterior cerebellum, and / or vermis of the subject compared with glucose metabolism in the subject prior to administration of N-acetylleucine.

[0448] Implementation method 80. Use of any one of implementation methods 72-79, wherein glucose metabolism is determined by positron emission tomography (PET) scanning.

[0449] Implementation method 81. Application of implementation method 80, wherein the PET scan is a fluorodeoxyglucose-positron emission tomography (FDG-PET) scan.

[0450] Implementation method 82. Use of implementation method 80, wherein FDG-PET scan is used to generate the z-score of the subject.

[0451] Implementation method 83. Use of implementation method 82, wherein administration of N-acetylleucine reduces the z-score of the subject in the parietal, occipital and / or frontal lobes of the brain.

[0452] Implementation method 84. Use of implementation method 82, wherein administration of N-acetylleucine reduces the z-score of the subject in the frontal, parietal and / or occipital regions of the brain.

[0453] Implementation method 85. Use of N in implementation method 82, wherein administration of N-acetylleucine reduces the z-score of the subject in the putamen, anterior cerebellum and / or cerebellar vermis.

[0454] Implementation 86. Use of any one of Implementations 82-85, wherein the z-score of the subject is reduced by at least about 5%, about 10%, about 20%, about 30%, about 40%, or about 50% compared with the z-score of the subject before administration of N-acetylleucine.

[0455] Implementation method 87. Use of any one of implementation methods 65-86, wherein the administration of N-acetylleucine reduces the number of RBD attacks compared to the number of RBD attacks prior to administration of N-acetylleucine.

[0456] Implementation Method 88. Use of N-acetylleucine in the preparation of a medicament for the treatment of REM-sleep behavior disorder (RBD) in subjects of need.

[0457] Implementation 89. Use of Implementation 88, wherein the subject has been diagnosed with prodromal Parkinson's disease (PD); prodromal dementia with Lewy body (DLB); or prodromal multiple system atrophy (MSA).

[0458] Implementation 90. Use of Implementation 88, wherein the subject has been diagnosed with classic Parkinson's disease (PD), classic dementia with Lewy bodies (DLB), or classic multiple system atrophy (MSA).

[0459] Implementation method 91. Use of any one of implementation methods 65-90, wherein about 1 g to about 15 g of N-acetylleucine is administered to the subject daily.

[0460] Implementation method 92. Use of implementation method 91, wherein about 1g to about 10g of N-acetylleucine is administered to the subject daily.

[0461] Implementation method 93. Use of implementation method 92, wherein about 1g to about 5g of N-acetylleucine is administered to the subject daily.

[0462] Implementation 94. Use of any one of Implementations 65-95, wherein the N-acetylleucine is orally administered to a subject.

[0463] Implementation 95. Use of any one of Implementations 65-94, wherein the N-acetylleucine administered to the subject is N-acetyl-DL-leucine.

[0464] Implementation 96. Use of any one of Implementations 65-94, wherein the N-acetylleucine administered to the subject is N-acetyl-L-leucine.

[0465] VI. References

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[0519] Example

[0520] Example 1

[0521] N-acetyl-DL-leucine was administered to patients with prodromal Parkinson's disease.

[0522] Isolated REM sleep behavior disorder (iRBD) is a prodromal phenotype of Parkinson's disease (PD), occurring 10-15 years after birth. 1,2 The risk of involuntary conversion to Parkinson's disease (PD) or Lewy body dementia (LBD) is >85%. Currently, there are no proven strategies for treating iRBD or slowing PD progression. As part of a long-term observational study with annual clinical surveillance and functional imaging, two iRBD patients were treated with oral N-acetyl-DL-leucine (ADLL) at 5 g / day for over 18 months and monitored. Patients' 3-week-total RBD severity score (RBD-SS-3), dopamine transporter-ligand-binding (DAT)-SPECT, and metabolic “Parkinson's disease-related pattern (PDRP)” z-scores on fluoride-deoxyglucose-positron emission tomography (FDG-PET) were measured annually. No side effects were reported in either patient treated with ADLL.

[0523] Patient 1 is a 74-year-old woman who reported symptoms of recurrent partial recurrent disease (RBD) since 2006. Video polysomnography (MPS) confirmed the diagnosis of involuntary recurrent partial recurrent disease (iRBD) in 2011. Since 2018, she has been taking 0.5 mg clonazepam nightly before bedtime for symptomatic treatment of iRBD. She underwent four pre-treatment DAT-SPECT examinations in 2013, 2014, 2016, and 2019. In September 2021, she began taking 5 g / day of adrug-dependent agonist (ADLL), approximately three years after her last “baseline” ADLL treatment in 2019 and her second ADLL treatment in 2018. After three months of ADLL treatment, she underwent her next DAT-SPECT in February 2022, and another DAT-SPECT in September 2023 while continuing ADLL therapy. Similarly, after 13 months of continuous ADLL treatment, she underwent her third (pre-scheduled) ADLL treatment in December 2022.

[0524] Patient 2 was a 54-year-old male who reported symptoms of iRBD in 2018. The diagnosis was confirmed by video polysomnography in June 2020. The patient did not receive any symptomatic treatment for iRBD or use any other concomitant medications. He underwent a baseline DAT-SPECT scan in August 2020 and an FDG-PET scan in June 2020, 19 months and 17 months respectively, prior to the start of continuous ADLL therapy (5g / day) in January 2022. He underwent a second FDG-PET scan in January 2023, 12 months later; and a second DAT-SPECT scan in July 2023, 18 months after starting treatment.

[0525] REM-S Sleep Behavior Disruption (RBD)

[0526] After the initiation of ADLL treatment, patients and their spouses assessed RBD severity daily in an RBD-diary (daily severity scores ranged from 0 to 4, with 4 representing the highest severity). For this study, daily scores were analyzed for 561 days. Daily scores were summed to form a 3-week total score (RBD-SS-3). The total RBD-SS-3 scores for patients 1 and 2 were... Figure 1A-1B As shown in the image.

[0527] Patient 1's RBD-SS-3 score was 21 before treatment. After 3 weeks of ADLL treatment, Patient 1's RBD-SS-3 score decreased to 5, and intrusive dream content was almost nonexistent. Figure 1A The effect remained at this low level over the subsequent 21 months. At baseline, olfactory function tests showed a decreased sense of smell with a TDI-total score of 6. Regularly assessed UPDRSIII (motor), MoCA, and SCOPAAUT scores were normal and remained unchanged over a treatment period of >20 months.

[0528] Compared to patient 1, patient 2 was less affected by RBD symptoms. Three weeks after starting ADLL treatment, patient 2's RBD-SS-3 score decreased from 7 to 0. Figure 1B The aggressive content in the dreams completely disappeared. The arrows indicate the recurrence of the RBD-phenotype under heavy alcohol consumption during two short holidays (weeks 7–9 and 10–12). Exacerbation of RBD symptoms by alcohol consumption is a known characteristic of RBD. Subsequently, the patient abstained from alcohol completely for the remainder of the study.

[0529] Aside from occasional recurrence of dream-like behaviors, the aforementioned improvements were maintained over the next 18 months of ADLL treatment. Olfactory function testing revealed a decreased sense of smell at baseline with a TDI-total score of 10. Regularly assessed UPDRSIII (motor), MoCA, and SCOPA-AUT scores were normal and remained normal throughout ADLL treatment.

[0530] Substantia nigra striatal dopaminergic denervation

[0531] Evaluation passed 123 I-FP-CIT-SPECT imaging (DAT-SPECT) continuously detects the binding level of presynaptic dopamine transporters (DAT) to monitor changes (progression) in the substantia nigra-striatal dopaminergic system over time. A lower striatum-occipital binding ratio on DAT-SPECT indicates a more severe loss of dopaminergic nerve endings due to neurodegeneration.

[0532] Patient 1's right putamen: Before treatment in February 2013, the DAT ligand binding ratio was 1.88 (normal); it decreased to 1.63 in March 2014; and further decreased to 1.22 in January 2019. Figure 2A The above data indicate that progressive neurodegeneration occurred in the substantia nigra-striatal dopaminergic projection pathway over a 5-year period, a hallmark of the prodromal and early stages of late-stage Parkinson's disease. In February 2022, three months after initiating ADLL treatment, the patient's right putamen DAT-SPECT score slightly improved to 1.43. After 22 months of ADLL treatment, the score further increased to 1.67. This demonstrates that oral ADLL treatment partially reversed the downward trend in the DAT-SPECT score, and the score essentially returned to normal after nearly two years of treatment. Patient 1's DAT-SPECT score results are detailed in Table 7.

[0533] Table 7

[0534] Patient 1: DAT-SPECT score

[0535] Patient 2's imaging biomarkers showed a similar pattern of change to Patient 1 after ADLL treatment. The striatum-occipital ligand binding ratio in Patient 2's DAT-SPECT images is shown below. Figure 2B As shown in the table, the patient's DAT-SPECT value in the right putamen was 1.42 before treatment in August 2020. After 17 months of ADLL treatment, this value rose to 1.72, essentially returning to normal levels. The DAT-SPECT values ​​for the right caudate nucleus, left caudate nucleus, right putamen, left putamen, right striatum, and left striatum are detailed in Table 8. The patient's DAT-SPECT value continued to increase within 30 months of starting treatment.

[0536] Table 8 Patient 2 DAT-SPECT score

[0537] glucose metabolism

[0538] Assessment Series 18 Fluoro-deoxyglucose PET-imaging (FDG-PET) was used to identify pathological metabolic patterns of Parkinson's disease-associated reactivity (PDRP) over time. Quantitative analysis of PDRP expression z-scores in all scan images was performed (higher z-scores indicate stronger PDRP expression). Previous studies have shown that in patients with iRBD and PD, PDRP z-scores increase with disease progression and decrease after effective (symptomatic) treatment.

[0539] Both groups of untreated iRBD patients (transformers and non-transformers) showed a steady increase in PDRP expression over an eight-year period. PDRP expression in both groups of untreated iRBD patients (transformers and non-transformers) showed a continuous upward trend over the eight years. Patient 1's FDG-PETz score corresponding to metabolic PDRP was 1.72 in 2014, rising to 3.28 in 2018, suggesting impaired brain metabolic function. Figure 3A In December 2022, one year after starting ADLL treatment, Patient 1's FDG-PET PDRP-z score was 3.18, similar to the 2018 level. Patient 2's PDRP-z score before treatment in June 2020 was 1.02. Figure 3B When the patient underwent a second FDG-PET scan in January 2023, they had been receiving ADLL treatment for one year and their z-score was 0.30.

[0540] As a control, another 13 iRBD patients (converters and non-converters) who did not receive ADLL treatment underwent FDG-PET scans at similar time points. Their PDRP-z scores continued to rise over 8 years, indicating disease progression. During the 8-year follow-up, 5 of the 13 iRBD patients converted to PD (converters), 1 converted to LBD, and 8 did not convert to PD (non-converters). This demonstrates that ADLL treatment can stabilize or improve metabolic activity in PD-related brain regions.

[0541] DAT-SPECT and FDG-PET data suggest that ADLL treatment may alter the disease course leading to PD phenotype. Striatal DAT-SPECT detected the abundance of cell membrane dopamine transporters (DATs) at the axon terminals of dopaminergic neurons in the substantia nigra. The loss of these axons has long been considered associated with the onset of PD symptoms (Marek, K. et al. Ann Clin Transl Neurol. 5(12):1460-1477 (2018)). In animal models of PD, axonal DAT expression is downregulated before definite neurodegeneration occurs (González-Rodríguez, P. et al. Nature. 599(7886):650-656 (2021)). Similarly, FDG-PET-based PDRP-z-score analysis suggests that ADLL treatment can block progressive neural network dysfunction caused by dopaminergic axon loss. The above conclusions are supported by a longitudinal comparison of FDG-PET PDRP-z scores between 2 patients in the ADLL treatment group and 13 untreated iRBD patients.

[0542] Cardiac sympathetic nerve innervation

[0543] Perform the following standard operating procedures: 123 I]-m-iodobenzylguanidine cardiac scintigraphy (MIBG) was used to identify the effect of ADLL on cardiac sympathetic innervation in patients 1 and 9, disease control iRBD participants, at baseline. Patient 2 underwent the MIBG study in May 2022. Regions of interest (ROIs) were manually placed on the planar anterior image, with rectangular ROIs for the mediastinum and circular ROIs for the left ventricle of the heart.

[0544] For the MIBG test, after blocking the thyroid gland with sodium perchlorate, 185 MBq123I-FP-CIT (GE Healthcare) was administered intravenously to the patient. Exactly 180 minutes after injection, scans were acquired on a dual-head gamma camera (SymbiaS; Siemens, Erlangen, Germany). Images were obtained in 120 projections across a 360° arc using a step-by-step imaging mode (40 seconds per projection). The quality of the DAT-SPECT procedure was independently and repeatedly quality-controlled by the imaging team of the Parkinson's Disease Progression Biomarkers Initiative at the Michael J. Fox Foundation in New York, USA.

[0545] [ 123 The I-MIBG examination results showed that both patients had reduced cardiac sympathetic innervation. Specifically, Patient 1 had […] in May 2014. 123 The I-MIBG combined with a heart / mediastinum ratio of 1.32; Patient 2 in May 2022 [ 123 The I-MIBG combined with a heart / mediastinum ratio of 0.98. 123 An I-MIBG combined with a heart / mediastinum ratio <1.5 is considered abnormal.

[0546] In summary, the above data indicate that the beneficial effects of daily oral administration of ADLL are reflected in three outcome indicators: 1) a significant reduction in the clinical severity of the RBD phenotype as assessed subjectively (disappearance of invasive dream content and reduced recurrence of dream behaviors); 2) stabilization or reversal of the slow, progressive decline in the striatum-occipital junction ratio in DAT-SPECT; and 3) stabilization or reversal of progressive metabolic abnormalities in the PD-related patterns detected by FDG-PET.

[0547] Example 2

[0548] N-acetyl-DL-leucine was administered to patients with RBD.

[0549] A 64-year-old female patient with balance disorder reported experiencing typical REM sleep behavior disorder symptoms. These symptoms occurred approximately four times a week and were of moderate severity.

[0550] The patient took acetylleucine (4 grams) before bedtime. After 4 weeks of continuous acetylleucine use, the patient reported a decrease in the frequency and severity of REM sleep behavior disorder symptoms, with attacks occurring only once a week. After 3 months of treatment, the patient reported slight symptom improvement and a further reduction in the frequency of attacks. The patient has continued treatment for 5 months.

[0551] All features described herein (including any appended claims, abstract, and drawings) and / or all steps of any method so disclosed may be combined with any of the foregoing aspects in any combination, except for combinations in which at least some of such features and / or steps are mutually exclusive.

[0552] It should be understood that the foregoing implementations and examples are not intended to limit the scope of this disclosure in any way, and the claims presented herein are intended to cover all implementations and examples, whether or not explicitly presented herein.

[0553] All patents, patent applications and publications cited in this article are incorporated herein by reference in their entirety.

Claims

1. A method for treating the prodromal phase of α-synucleinosis in a subject of need, the method comprising administering to the subject a therapeutically effective amount of N-acetylleucine, wherein, The subjects: (i) Not diagnosed with any core clinical feature, syndrome, or symptom associated with α-synucleinopathy; and (ii) Being diagnosed with one or more core clinical features, syndromes, or symptoms associated with the prodromal phase of α-synucleinosis. The α-synucleinosis mentioned here refers to Parkinson's disease (PD), Lewy body dementia (DLB), or multiple system atrophy (MSA).

2. The method for treating the prodromal phase of PD in a subject in need of treatment according to claim 1, wherein, The subjects: (i) Not diagnosed with tremor, bradykinesia, rigidity, balance disorder, and / or coordination disorder; and (ii) diagnosed with one or more of the following: hyposmia, cognitive impairment, REM sleep behavior disorder (RBD), constipation, depression and / or anxiety.

3. The method for treating the prodromal phase of DLB ​​in a subject requiring treatment according to claim 1, wherein, The subjects: (i) has not been diagnosed with dementia; and (ii) diagnosed with one or more of the following: RBD, constipation, decreased sense of smell, depression and / or orthostatic hypotension / dizziness.

4. The method for treating the prodromal phase of MSA in a subject requiring treatment according to claim 1, wherein, The subjects: (i) Not diagnosed with (a) autonomic dysfunction; and (b) poor L-dopamine responsiveness Parkinson's syndrome and / or cerebellar syndrome; and (ii) diagnosed with one or more of the following: RBD, neurogenic orthostatic hypotension and / or urogenital dysfunction that occurs within 10 minutes of standing or tilting the head up.

5. The method according to any one of claims 1-4, wherein, The subjects had reduced dopaminergic function in the basal ganglia.

6. The method according to any one of claims 1-5, wherein, Compared with the period before administration of N-acetylleucine, administration of N-acetylleucine increased the dopaminergic function of the subjects.

7. The method according to claim 5 or 6, wherein, The amount of dopaminergic function in the subjects was determined by dopamine transporter (DAT) scanning.

8. The method according to any one of claims 1-7, wherein, The subjects had reduced glucose metabolism in their brains.

9. The method according to any one of claims 1-8, wherein, The subjects had reduced glucose metabolism in the parietal, occipital, and / or frontal lobes of the brain.

10. The method according to any one of claims 1-8, wherein, The subjects had reduced glucose metabolism in the occipital cortex and primary visual regions of the brain.

11. The method according to any one of claims 1-8, wherein, The subjects had reduced glucose metabolism in the putamen, anterior cerebellum, and / or vermis.

12. The method according to any one of claims 1-11, wherein, Compared with the glucose metabolism of the subjects before administration of N-acetylleucine, administration of N-acetylleucine increased glucose metabolism in the brains of the subjects.

13. The method according to any one of claims 1-12, wherein, Compared with the subjects' glucose metabolism prior to administration of N-acetylleucine, administration of N-acetylleucine increased glucose metabolism in the parietal, occipital, and / or frontal regions of the subjects' brains.

14. The method according to any one of claims 1-12, wherein, Compared with the subjects' glucose metabolism prior to administration of the N-acetylleucine, administration of the N-acetylleucine increased glucose metabolism in the occipital coccygeal and primary visual regions of the subjects' brains.

15. The method according to any one of claims 1-12, wherein, Compared with glucose metabolism in the subjects prior to administration of the N-acetylleucine, administration of the N-acetylleucine increased glucose metabolism in the putamen, anterior cerebellum, and / or vermis of the subjects.

16. The method according to any one of claims 8-15, wherein, The glucose metabolism was determined by positron emission tomography (PET) scans.

17. The method according to claim 16, wherein, The PET scan mentioned is a fluorodeoxyglucose-positron emission tomography (FDG-PET) scan.

18. The method according to claim 17, wherein, The FDG-PET scan is used to generate the subject's z-score.

19. The method according to claim 18, wherein, Administration of the N-acetylleucine reduced the z-scores of the subjects in the parietal, occipital, and / or frontal lobes of the brain.

20. The method according to claim 18, wherein, Administration of the N-acetylleucine reduced the z-scores of the subjects in the medial occipital lobe, lateral occipital lobe, combined occipital cortex and / or primary visual regions of the brain.

21. The method according to claim 18, wherein, Administration of the N-acetylleucine reduced the z-scores of the subjects in the putamen, anterior cerebellum, and / or vermis.

22. The method according to any one of claims 18-21, wherein, Compared with the subject's z-score before administration of the N-acetyleucine, the subject's z-score decreased by at least about 5%, about 10%, about 20%, about 30%, about 40%, or about 50%.

23. The method according to any one of claims 1-22, wherein, The number of RBD attacks decreased after administration of N-acetylleucine compared to the number of attacks prior to administration.

24. The method according to any one of claims 1-23, wherein, The subject was diagnosed with hyposmia.

25. The method according to claim 24, wherein, Impaired sense of smell is diagnosed by one or more of the 12-item simplified olfactory identification test (B-SIT) and / or olfactory stick test (SST).

26. A method of treating REM sleep behavior disorder (RBD) in a subject in need, the method comprising administering a therapeutically effective amount of N-acetylleucine to the subject.

27. The method according to claim 26, wherein, The subjects had been diagnosed with prodromal Parkinson's disease (PD), prodromal Lewy body dementia (DLB), or prodromal multiple system atrophy (MSA).

28. The method according to claim 26, wherein, The subjects were not diagnosed with classic Parkinson's disease (PD), classic Lewy body dementia (DLB), or classic multiple system atrophy (MSA).

29. The method according to any one of claims 1-28, wherein, The subject was given approximately 1g to approximately 15g of the N-acetylleucine daily.

30. The method according to claim 29, wherein, The subject was given approximately 1g to approximately 10g of the N-acetylleucine daily.

31. The method according to claim 30, wherein, The subject was given approximately 1g to approximately 5g of the N-acetylleucine daily.

32. The method according to any one of claims 1-31, wherein, The N-acetylleucine was administered orally to the subject.

33. The method according to any one of claims 1-32, wherein, The N-acetylleucine administered to the subject was N-acetyl-DL-leucine.

34. The method according to any one of claims 1-32, wherein, The N-acetylleucine administered to the subject was N-acetyl-L-leucine.

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