Adenosine a2a receptor antagonists to treat REM sleep behavior disorder and prevent synucleinopathies

Abstract

Adenosine A2A receptor antagonist are useful in methods for treating or preventing REM sleep behavior disorder, treating or preventing REM sleep without atonia, and preventing or delaying onset of a synucleinopathy (e.g., Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, pure autonomic failure, Alzheimer's disease with amygdalar restricted Lewy bodies). In embodiments, the the adenosine A2A receptor antagonist is ciforadenant, enprofylline. vipadenant, preladenant. tozadenant. istradefylline, inupadenant, etrumadenant, taminadenant, TB206-001, PORT-6, M1069, ST1535, or ST4206.

Description

Docket No.048517-559001WO ADENOSINE A2A RECEPTOR ANTAGONISTS TO TREAT REM SLEEP BEHAVIOR DISORDER AND PREVENT SYNUCLEINOPATHIES CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority to US Application No.63 / 635,259 filed April 17, 2024, the disclosure of which is incorporated by reference herein in its entirety. BACKGROUND

[0002] Parkinson's disease is a degenerative disorder of the central nervous system. The neurodegeneration occurring in Parkinson's disease is irreversible and there is currently no cure for the disease. The most obvious symptoms of Parkinson's disease are movement-related and include unilateral tremor, rigidity, akinesia and postural instability. Later, cognitive and behavioral problems may arise, with dementia commonly occurring in the advanced stages of the disease. Other symptoms include sensory, sleep and emotional problems. Diagnosis of Parkinson's disease is currently based on the clinical manifestation of the motor symptoms, and treatments are directed at managing clinical symptoms. When the diagnosis is made based on the manifestation of the motor symptoms, the brain is already severely affected as the motor symptoms of Parkinson's disease arise from the loss of dopamine-generating neurons in the substantia nigra.

[0003] Rapid eye movement sleep behavior disorder (also called rapid eye movement behavior disorder or RBD) is a parasomnia involving dream enactment behavior associated with loss of atonia during rapid eye movement (REM) sleep. RBD affects about 0.4% of adults, 0.5% of older adults, 33% of patients with newly diagnosed Parkinson's disease, and 90% of patients with multiple system atrophy. Consequences of RBD can include injury to the patient and / or injury to a bed partner. RBD is strongly linked to neurodegenerative alpha- synucleinopathies (e.g., Parkinson's disease). In the absence of RBD, REM sleep without atonia may also signal increased risk for alpha-synucleinopathies. Indeed, more than 50% of subjects diagnosed with RBD will develop Parkinson's disease within a time span of 5-10 years. Pham et al, “Rapid Eye Movement Sleep Behavior Disorder,” StatsPearls, NCBI Bookshelf, December 11, 2022.

[0004] There is a need in the art for therapeutic agents that can, inter alia, treat RBD and also prevent synucleinopathies, such as Parkinson's disease. The disclosure is directed to this, as well as other, important ends.BRIEF SUMMARY

[0005] Provided herein are methods for treating or preventing REM sleep behavior disorder and REM sleep without atonia in a patient in need thereof comprising administering to the patient an effective amount of an adenosine A2A receptor antagonist, thereby treating or preventing REM sleep behavior disorder or REM sleep without atonia. In embodiments, the adenosine A2A receptor antagonist is ciforadenant, enprofylline, vipadenant, preladenant, tozadenant, istradefylline, inupadenant, etrumadenant, taminadenant, TB206-001, PORT-6, M1069, ST1535, or ST4206.

[0006] Provided herein are methods for decreasing an elevated level of alpha synuclein in a patient in need thereof comprising administering to the patient an effective amount of an adenosine A2A receptor antagonist, wherein the patient has an elevated level of alpha synuclein relative to a healthy control, thereby decreasing levels of alpha synuclein. In embodiments, the alpha synuclein is an alpha-synuclein aggregate. In embodiments, the adenosine A2A receptor antagonist is ciforadenant, enprofylline, vipadenant, preladenant, tozadenant, istradefylline, inupadenant, etrumadenant, taminadenant, TB206-001, PORT-6, M1069, ST1535, or ST4206.

[0007] Provided herein are methods for delaying onset of a synucleinopathy in a patient in need thereof comprising administering to the patient an effective amount of an adenosine A2A receptor antagonist, thereby delaying onset of the synucleinopathy. In embodiments, the synucleinopathy is Parkinson’s disease, dementia with Lewy bodies, multiple system atrophy, pure autonomic failure, or Alzheimer's disease with amygdalar restricted Lewy bodies. In embodiments, the adenosine A2A receptor antagonist is ciforadenant, enprofylline, vipadenant, preladenant, tozadenant, istradefylline, inupadenant, etrumadenant, taminadenant, TB206-001, PORT-6, M1069, ST1535, or ST4206.

[0008] Provided herein are methods for preventing a synucleinopathy in a patient in need thereof comprising administering to the patient an effective amount of an adenosine A2A receptor antagonist, thereby preventing the synucleinopathy. In embodiments, the synucleinopathy is Parkinson’s disease, dementia with Lewy bodies, multiple system atrophy, pure autonomic failure, or Alzheimer's disease with amygdalar restricted Lewy bodies. In embodiments, the adenosine A2A receptor antagonist is ciforadenant, enprofylline, vipadenant, preladenant, tozadenant, istradefylline, inupadenant, etrumadenant, taminadenant, TB206-001, PORT-6, M1069, ST1535, or ST4206.

[0009] These and other embodiments of the disclosure are described herein. DETAILED DESCRIPTION

[0010] Unless defined otherwise, technical and scientific terms used herein have the same meaning as commonly understood by a person of ordinary skill in the art. See, e.g., Singleton et al., Dictionary of Microbiology and Molecular Biology, 2nd ed., J. Wiley & Sons (New York, NY 1994); Sambrook et al., Molecular Cloning, A Laboratory Manual, Cold Springs Harbor Press (Cold Springs Harbor, NY 1989). Any methods, devices and materials similar or equivalent to those described herein can be used in the practice of this disclosure. The following definitions are provided to facilitate understanding of certain terms used frequently herein and are not meant to limit the scope of the present disclosure.

[0011] The term “REM sleep behavior disorder” or “RBD” or “REM behavior disorder” is a parasomnia in which individuals lose the paralysis of muscles (atonia) that is normal during rapid eye movement (REM) sleep and act out their dreams or have other abnormal movements or vocalizations. Abnormal sleep behaviors are often an early sign of a synucleinopathy.

[0012] The term “REM sleep without atonia” or “RSWA” is a parasomnia characterized by repeated episodes of dream enactment behavior and REM sleep without atonia during polysomnography recording. REM sleep without atonia is characterized by increased phasic or tonic muscle activity seen on polysomnographic electromyogram channels. REM sleep without atonia is a requisite diagnostic feature of REM sleep behavior disorder, but may also be seen in patients without clinical symptoms or signs of dream enactment.

[0013] The term “synucleinopathy” refers to a neurodegenerative disease in which there is abnormal accumulation of aggregates of alpha-synuclein protein in neurons, nerve fibers, or glial cells. In embodiments, the synucleinopathy is Parkinson’s disease, dementia with Lewy bodies, multiple system atrophy, pure autonomic failure, or Alzheimer's disease with amygdalar restricted Lewy bodies.

[0014] The term “inhibition,” “inhibit,” “inhibiting” and the like in reference to a protein- inhibitor interaction (e.g. pathway inhibition) means negatively affecting (e.g. decreasing) the activity or function of the protein relative to the activity or function of the protein in the absence of the inhibitor. In embodiments, inhibition means negatively affecting (e.g. decreasing) the concentration or levels of the protein relative to the concentration or level of the protein in the absence of the inhibitor. In embodiments, inhibition refers to reduction of adisease or symptoms of disease. In embodiments, inhibition refers to a reduction in the activity of a particular protein target. Thus, inhibition includes, at least in part, partially or totally blocking stimulation, decreasing, preventing, or delaying activation, or inactivating, desensitizing, or down-regulating signal transduction or enzymatic activity or the amount of a protein. In embodiments, inhibition refers to a reduction of activity of a target protein resulting from a direct interaction (e.g. an inhibitor binds to the target protein). In embodiments, inhibition refers to a reduction of activity of a target protein from an indirect interaction (e.g. an inhibitor binds to a protein that activates the target protein, thereby preventing target protein activation). The protein may be a receptor for a particular ligand and the inhibitor will block the binding of the ligand to the receptor thereby inhibiting the receptor-ligand interaction and its resulting function.

[0015] The terms “inhibitor” or “antagonist” interchangeably refer to a substance capable of detectably decreasing the expression or activity of a given gene or protein. The antagonist can decrease expression or activity 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more in comparison to a control in the absence of the antagonist. In embodiments, expression or activity is 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold or lower than the expression or activity in the absence of the antagonist.

[0016] The term “adenosine A2A receptor” or “A2A adenosine receptor” as provided herein includes any of the recombinant or naturally-occurring forms of the adenosine A2A receptor or variants or homologs thereof that maintain adenosine A2A receptor protein activity (e.g. within at least 50%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 100% activity compared to adenosine A2A receptor). In embodiments, the variants or homologs have at least 90%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity across the whole sequence or a portion of the sequence (e.g. a 50, 100, 150 or 200 continuous amino acid portion) compared to a naturally occurring adenosine A2A polypeptide. In embodiments, adenosine A2A receptor is the protein as identified by the NCBI sequence reference GI:5921992, homolog or functional fragment thereof.

[0017] “Adenosine A2A receptor antagonist” refers to a molecule that inhibits activity of adenosine A2A receptors, typically through direct action. Adenosine A2A receptor antagonists can be small or large molecule antagonists. In embodiments, the adenosine A2A receptor antagonist is ciforadenant. In embodiments, the adenosine A2A receptor antagonist is ciforadenant, enprofylline, vipadenant, preladenant, tozadenant, or istradefylline. In embodiments, the adenosine A2A receptor antagonist is ciforadenant, enprofylline, vipadenant,preladenant, tozadenant, istradefylline, inupadenant, etrumadenant, taminadenant, TB206-001, PORT-6, M1069, ST1535, or ST4206

[0018] “Biological sample” or “sample” refer to materials obtained from or derived from a subject or patient. Such samples include bodily fluids such as blood and blood fractions or products (e.g., serum, plasma, platelets, red blood cells, and the like), sputum, skin, tissue, cultured cells (e.g., primary cultures, explants, and transformed cells), stool, urine, cerebrospinal fluid, synovial fluid, joint tissue, synovial tissue, synoviocytes, immune cells, hematopoietic cells, fibroblasts, macrophages, T cells, and the like. In embodiments, a biological sample is blood. In embodiments, a biological sample is a peripheral blood sample. In embodiments, a biological sample is a serum sample (e.g., the fluid and solute component of blood without the clotting factors). In embodiments, a biological sample is a plasma sample (e.g, the liquid portion of blood). In embodiments, a biological sample is a cerebrospinal fluid sample. In embodiments, a biological sample is a saliva sample. In embodiments, a biological sample is a skin biopsy (skin sample). In embodiments, a biological sample is a skin biopsy containing cutaneous nerve fibers. Biological samples can be taken from a subject by methods known in the art and can be analyzed by methods known in the art

[0019] The term “gene” means the segment of DNA involved in producing a protein; it includes regions preceding and following the coding region (leader and trailer) as well as intervening sequences (introns) between individual coding segments (exons). The leader, the trailer as well as the introns include regulatory elements that are necessary during the transcription and the translation of a gene.

[0020] The term “gene mutation” refers to a mutation, single nucleotide polymorphism (SNP), deletion variant, missense variant, insertion variant, inversion, or copy number variant in a gene. A gene mutation can be used as a biomarker. In embodiments, a gene mutation can result in increased or decreased expression levels or differential modification. In embodiments, “gene mutation” refers to a gene mutation associated with a synucleinopathy, e.g., a gene mutation that is more likely to occur in a patient who has a synucleinopathy, a patient who is at greater risk of developing a synucleinopathy, or a patient who has a synucleinopathy or symptoms of a synucleinopathy. In embodiments, “gene mutation” refers to a gene mutation associated with Parkinson’s disease, e.g., a gene mutation that is more likely to occur in a patient who has Parkinson’s disease, a patient who is at greater risk of developing Parkinson’s disease, or a patient who has Parkinson’s disease or symptoms of Parkinson’s disease. Gene mutations associated with Parkinson’s disease are well known in the art. Genes that havemutations associated with Parkinson’s disease include GBA1, UCHL1, LRRK2, PARK7,PINK1, PARK2, PRKN, SNCA, GIGYF2, DNAJC13, TMEM230, GCH1, EIF4G1, HTRA2,RIC3, ATXN2, a VPS35, CHCHD2, PTRHD1, PLA2G6, SPG11, FBXO7, DNAJC6, SYNJ1, ATP13A2, VPS13C, PODXL, POLG, DCTN1, LRP10, and RAB39B. In embodiments, the term “gene mutation” refers to a mutation, single nucleotide polymorphism (SNP), deletion variant, missense variant, insertion variant, inversion, or copy number variant in a geneselected from the group consisting of GBA1, UCHL1, LRRK2, PARK7, PINK1, PARK2,PRKN, SNCA, GIGYF2, DNAJC13, TMEM230, GCH1, EIF4G1, HTRA2, RIC3, ATXN2, a VPS35, CHCHD2, PTRHD1, PLA2G6, SPG11, FBXO7, DNAJC6, SYNJ1, ATP13A2, VPS13C, PODXL, POLG, DCTN1, LRP10, and RAB39B, wherein the mutation in the gene is associated with Parkinson’s disease.

[0021] The term “biomarker” refers to a biometric that can be detected in a biological sample (or sample derived from or processed from a biological sample) and compared to a control sample as indicative of a particular condition. Examples of biomarkers include gene mutations, increased or decreased expression levels (determined by detection of chromatin opening, transcription product, or translation product), and differential modification (e.g., methylation of nucleic acids, or phosphorylation, glycosylation, or multimerization of proteins). A “marker gene” is a gene affected by a biomarker. That is, a marker gene can include a gene mutation in its genomic form, be expressed at a higher or lower level, or be differentially modified as indicative of a particular condition, e.g., a synucleinopathy such as Parkinson’s disease.

[0022] In embodiments, a “biomarker” is an electroencephalography (EEG) done in wakeful or sleeping state. The EEG can be monitored over time to determine the status of the disease (e.g., RBD) and response to therapy. In particular REM sleep and polysomnography could be used to determine when to initiate therapy and how well the patient is responding to therapy. Over time, it is possible that the further deterioration of the patient could be delayed or reversed. See Valomon et al, Scientific Reports, Volume 11, Article 4758 (2021); Figorilli et al, Nat Sci Sleep, 15:333-352 (2023). Controls, but not RBD patients, display a decrease in beta power during phasic compared to tonic REM sleep. Compared to controls, patients with RBD display a reduced decline in slow-wave activity from early to late NREM sleep. Overnight changes in the distribution of the amplitude of slow waves are reduced in RBD patients. Without suppression of beta rhythms during phasic REM sleep, RBD patients might demonstrate heightened cortical arousal, favoring the emergence of behavioral episodes. A blunted difference between REM sleep sub-stages constitutes a sensitive biomarker for RBD.Moreover, reduced overnight decline in sleep slow-wave activity indicates a reduced capacity for synaptic plasticity in RBD patients, which may favor progression towards a synucleinopathy, such as Parkinson’s disease. Methods of administering an EEG and interpreting the results of an EEG are well known in the art, and with reference to descriptions in the art about the relationship between EEG results and RBD and REM sleep without atonia.

[0023] The term “diagnosis” refers to a relative probability that a a synucleinopathy is present in the subject. Similarly, the term “prognosis” refers to a relative probability that a certain future outcome may occur in the subject. For example, in the context of the present disclosure, prognosis refers to the likelihood that an individual will develop a synucleinopathy. The terms are not intended to be absolute, as will be appreciated by any one of skill in the field of medical diagnostics.

[0024] The terms “correlating” and “associated,” in reference to determination of a synucleinopathy risk factor, refers to comparing the presence or amount of the risk factor (e.g., presence of a gene mutation in an individual to its presence in persons known to suffer from, or known to be at risk of, a synucleinopathy, or in persons known to be free of a synucleinopathy, and assigning an increased or decreased probability of having or developing the synucleinopathy to an individual based on the assay results.

[0025] “Nucleic acid” refers to nucleotides (e.g., deoxyribonucleotides or ribonucleotides) and polymers thereof in either single-, double- or multiple-stranded form, or complements thereof; or nucleosides (e.g., deoxyribonucleosides or ribonucleosides). In embodiments, “nucleic acid” does not include nucleosides. The terms “polynucleotide,” “oligonucleotide,” “oligo” or the like refer, in the usual and customary sense, to a linear sequence of nucleotides. The term “nucleoside” refers, in the usual and customary sense, to a glycosylamine including a nucleobase and a five-carbon sugar (ribose or deoxyribose). Non limiting examples, of nucleosides include cytidine, uridine, adenosine, guanosine, thymidine and inosine. The term “nucleotide” refers, in the usual and customary sense, to a single unit of a polynucleotide, i.e., a monomer. Nucleotides can be ribonucleotides, deoxyribonucleotides, or modified versions thereof. Examples of polynucleotides contemplated herein include single and double stranded DNA, single and double stranded RNA, and hybrid molecules having mixtures of single and double stranded DNA and RNA. Examples of nucleic acid, e.g. polynucleotides, contemplated herein include any types of RNA, e.g. mRNA, siRNA, miRNA, and guide RNA and any types of DNA, genomic DNA, plasmid DNA, and minicircle DNA, and any fragments thereof. The term “duplex” in the context of polynucleotides refers, in the usual and customary sense, todouble strandedness. Nucleic acids can be linear or branched. For example, nucleic acids can be a linear chain of nucleotides or the nucleic acids can be branched, e.g., such that the nucleic acids comprise one or more arms or branches of nucleotides. Optionally, the branched nucleic acids are repetitively branched to form higher ordered structures such as dendrimers and the like. Nucleic acids can include nonspecific sequences. As used herein, the term “nonspecific sequence” refers to a nucleic acid sequence that contains a series of residues that are not designed to be complementary to or are only partially complementary to any other nucleic acid sequence. By way of example, a nonspecific nucleic acid sequence is a sequence of nucleic acid residues that does not function as an inhibitory nucleic acid when contacted with a cell or organism.

[0026] A polynucleotide is typically composed of a specific sequence of four nucleotide bases: adenine (A); cytosine (C); guanine (G); and thymine (T) (uracil (U) for thymine (T) when the polynucleotide is RNA). Thus, the term “polynucleotide sequence” is the alphabetical representation of a polynucleotide molecule; alternatively, the term may be applied to the polynucleotide molecule itself. This alphabetical representation can be input into databases in a computer having a central processing unit and used for bioinformatics applications such as functional genomics and homology searching. Polynucleotides may optionally include one or more non-standard nucleotide(s), nucleotide analog(s) and / or modified nucleotides.

[0027] “Conservatively modified variants” applies to both amino acid and nucleic acidsequences. With respect to particular nucleic acid sequences, “conservatively modified variants” refers to those nucleic acids that encode identical or essentially identical amino acid sequences. Because of the degeneracy of the genetic code, a number of nucleic acid sequences will encode any given protein. For instance, the codons GCA, GCC, GCG and GCU all encode the amino acid alanine. Thus, at every position where an alanine is specified by a codon, the codon can be altered to any of the corresponding codons described without altering the encoded polypeptide. Such nucleic acid variations are “silent variations,” which are one species of conservatively modified variations. Every nucleic acid sequence herein which encodes a polypeptide also describes every possible silent variation of the nucleic acid. One of skill will recognize that each codon in a nucleic acid (except AUG, which is ordinarily the only codon for methionine, and TGG, which is ordinarily the only codon for tryptophan) can be modified to yield a functionally identical molecule. Accordingly, each silent variation of a nucleic acid which encodes a polypeptide is implicit in each described sequence.

[0028] The term “complement,” as used herein, refers to a nucleotide (e.g., RNA or DNA) ora sequence of nucleotides capable of base pairing with a complementary nucleotide or sequence of nucleotides. As described herein and commonly known in the art the complementary (matching) nucleotide of adenosine is thymidine and the complementary (matching) nucleotide of guanosine is cytosine. Thus, a complement may include a sequence of nucleotides that base pair with corresponding complementary nucleotides of a second nucleic acid sequence. The nucleotides of a complement may partially or completely match the nucleotides of the second nucleic acid sequence. Where the nucleotides of the complement completely match each nucleotide of the second nucleic acid sequence, the complement forms base pairs with each nucleotide of the second nucleic acid sequence. Where the nucleotides of the complement partially match the nucleotides of the second nucleic acid sequence only some of the nucleotides of the complement form base pairs with nucleotides of the second nucleic acid sequence. Examples of complementary sequences include coding and a non-coding sequences, wherein the non-coding sequence contains complementary nucleotides to the coding sequence and thus forms the complement of the coding sequence. A further example of complementary sequences are sense and antisense sequences, wherein the sense sequence contains complementary nucleotides to the antisense sequence and thus forms the complement of the antisense sequence.

[0029] The term “recombinant” when used with reference, e.g., to a cell, or nucleic acid, protein, or vector, indicates that the cell, nucleic acid, protein or vector, has been modified by the introduction of a heterologous nucleic acid or protein or the alteration of a native nucleic acid or protein, or that the cell is derived from a cell so modified. Thus, for example, recombinant cells express genes that are not found within the native (non-recombinant) form of the cell or express native genes that are otherwise abnormally expressed, under expressed or not expressed at all. Transgenic cells and plants are those that express a heterologous gene or coding sequence, typically as a result of recombinant methods.

[0030] The phrase “specifically (or selectively) binds” to an antibody or “specifically (or selectively) immunoreactive with,” when referring to a protein or peptide refers to a binding reaction that is determinative of the presence of the protein, often in a heterogeneous population of proteins and other biologics. Thus, under designated immunoassay conditions, the specified antibodies bind to a particular protein at least two times the background and more typically more than 10 to 100 times background. Specific binding to an antibody under such conditions requires an antibody that is selected for its specificity for a particular protein. For example, polyclonal antibodies can be selected to obtain only a subset of antibodies that arespecifically immunoreactive with the selected antigen and not with other proteins. This selection may be achieved by subtracting out antibodies that cross-react with other molecules. A variety of immunoassay formats may be used to select antibodies specifically immunoreactive with a particular protein. For example, solid-phase ELISA immunoassays are routinely used to select antibodies specifically immunoreactive with a protein (see, e.g., Harlow & Lane, Using Antibodies, A Laboratory Manual (1998) for a description of immunoassay formats and conditions that can be used to determine specific immunoreactivity).

[0031] The terms “isolate” or “isolated”, when applied to a nucleic acid, virus, or protein, denotes that the nucleic acid, virus, or protein is essentially free of other cellular components with which it is associated in the natural state. It can be, for example, in a homogeneous state and may be in either a dry or aqueous solution. Purity and homogeneity are typically determined using analytical chemistry techniques such as polyacrylamide gel electrophoresis or high performance liquid chromatography. An RNA that is the predominant species present in a preparation is substantially purified.

[0032] The terms “polypeptide,” “peptide” and “protein” are used interchangeably herein to refer to a polymer of amino acid residues, wherein the polymer may be conjugated to a moiety that does not consist of amino acids. The terms apply to amino acid polymers in which one or more amino acid residue is an artificial chemical mimetic of a corresponding naturally occurring amino acid, as well as to naturally occurring amino acid polymers and non-naturally occurring amino acid polymers.

[0033] “Percentage of sequence identity” is determined by comparing two optimally aligned sequences over a comparison window, wherein the portion of the polynucleotide or polypeptide sequence in the comparison window may comprise additions or deletions (i.e., gaps) as compared to the reference sequence (which does not comprise additions or deletions) for optimal alignment of the two sequences. The percentage is calculated by determining the number of positions at which the identical nucleic acid base or amino acid residue occurs in both sequences to yield the number of matched positions, dividing the number of matched positions by the total number of positions in the window of comparison and multiplying the result by 100 to yield the percentage of sequence identity. The terms “identical” or percent “identity” in the context of two or more nucleic acids or polypeptide sequences refer to two or more sequences or subsequences that are the same or have a specified percentage of amino acid residues or nucleotides that are the same (i.e., about 60% identity, preferably 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or higher identityover a specified region, when compared and aligned for maximum correspondence over a comparison window or designated region) as measured using a BLAST or BLAST 2.0 sequence comparison algorithms with default parameters described below, or by manual alignment and visual inspection (e.g., www.ncbi.nlm.nih.gov / BLAST / or the like). Such sequences are then the to be “substantially identical.” This definition also refers to, or may be applied to, the compliment of a test sequence. The definition also includes sequences that have deletions and / or additions, as well as those that have substitutions. As described below, the preferred algorithms can account for gaps and the like. Preferably, identity exists over a region that is at least about 25 amino acids or nucleotides in length, or more preferably over a region that is 50-100 amino acids or nucleotides in length.

[0034] The term “about” means a range of values including the specified value, which a person of ordinary skill in the art would consider reasonably similar to the specified value. In embodiments, “about” means within a standard deviation using measurements generally acceptable in the art. In embodiments, “about” means a range extending to + / - 10% of the specified value. In embodiments, “about” includes the specified value.

[0035] The singular terms “a,” “an,” and “the” include the plural reference unless the context clearly indicates otherwise.

[0036] “Treating” or “treatment” as used herein and as well-understood in the art includes any approach for obtaining beneficial clinical results for a patient. Beneficial clinical results includes, but is not limited to, alleviation or amelioration of one or more symptoms of a disease, diminishment of the extent of the disease, stabilizing (i.e., not worsening) the disease, delaying or slowing progression of the disease, amelioration or palliation of the disease, and remission, whether partial or total and whether detectable or undetectable. Treatment may relieve the disease’s symptoms, fully or partially remove the disease’s underlying cause, shorten a disease’s duration, or do a combination of these things. Treatment methods include administering to a subject a therapeutically effective amount of a therapeutic agent, such as the adenosine A2A receptor antagonists described herein. The administering step may comprise a single administration or a series of administrations. The length of the treatment period depends on a variety of factors, such as the severity of the condition, the age of the patient, the concentration of therapeutic agent, the activity of the compositions used in the treatment, or a combination thereof. It will also be appreciated that the effective dosage of therapeutic agent used for the treatment may increase or decrease over the course of a particular treatment regime. Changes in dosage may result and become apparent by standard diagnostic assaysknown in the art. Treating does not include preventing.

[0037] The term “prevent” or “preventing” as used herein and as well-understood in the art includes any approach to stop a disease from occurring or stop the symptoms of a disease from occurring.

[0038] The phrase “delaying onset” refers to preventing a disease from occurring at an earlier point in time than the disease would have occurred absent administration of the therapeutic agent. “Delaying onset” refers to delaying onset of the disease itself or delaying onset of symptoms of the disease. For example, if a patient has biomarkers (e.g., gene mutations, elevated levels of alpha-synuclein) predictive of Parkinson’s disease, administration of the adenosine A2A receptor antagonists to the patient delays the start of Parkinson’s disease or symptoms thereof to a time later than what would have been statistically predicted to be the start time of the disease.

[0039] The term “therapeutically effective amount” and “effective amount” as used herein refer to the amount of therapeutic agent sufficient to treat RBD or prevent synucleinopathy. For any therapeutic agent described herein, the therapeutically effective amount can be initially determined from cell culture assays. Target concentrations will be those concentrations of therapeutic agent that are capable of achieving the methods described herein, as measured using the methods described herein or known in the art. As is known in the art, therapeutically effective amounts for use in humans can also be determined from animal models. For example, a dose for humans can be formulated to achieve a concentration that has been found to be effective in animals. The dosage in humans can be adjusted by monitoring compounds effectiveness and adjusting the dosage upwards or downwards, as described above. Adjusting the dose to achieve maximal efficacy in humans based on the methods described above and other methods is well within the capabilities of the ordinarily skilled artisan. Dosages may be varied depending upon the requirements of the patient and the therapeutic agent being employed. The dose administered to a patient should be sufficient to affect a beneficial therapeutic response in the patient over time. The size of the dose also will be determined by the existence, nature, and extent of any adverse side-effects. Determination of the proper dosage for a particular situation is within the skill of the practitioner. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under circumstances is reached. Dosage amounts and intervals can be adjusted individually to provide levels of the administered compound effective for the particular clinical indicationbeing treated. This will provide a therapeutic regimen that is commensurate with the severity of the individual's disease state. A “therapeutically effective amount” can also be found on the label or Prescribing Information for commercially available therapeutic agents. In embodiments, the effective amount of the adenosine A2A receptor antagonists described herein is about 0.1 mg per day to about 1,000 mg per day. In embodiments, the effective amount of the adenosine A2A receptor antagonist is about 1 mg per day to about 800 mg per day. In embodiments, the effective amount of the adenosine A2A receptor antagonist is about 10 mg per day to about 600 mg per day. In embodiments, the effective amount of ciforadenant is about 10 mg per day to 600 mg per day. In embodiments, the effective amount of ciforadenant is about 50 mg per day to 500 mg per day.

[0040] The term “administering” is used in accordance with its plain and ordinary meaning and includes oral, topical, intravenous, parenteral, intraperitoneal, intramuscular, intralesional, intrathecal, intranasal or subcutaneous administration, or the implantation of a slow-release device, e.g., a mini-osmotic pump, to a subject. Administration is by any route, including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, or transdermal). Parenteral administration includes, e.g., intravenous, intramuscular, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial. Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, and the like. In embodiments, administering does not include administration of any therapeutic agent other than the recited therapeutic agent.

[0041] “Control” is used in accordance with its plain ordinary meaning and refers to an assay, comparison, or experiment in which the subjects or reagents of the experiment are treated as in a parallel experiment except for omission of a procedure, reagent, or variable of the experiment. In embodiments, the control is used as a standard of comparison in evaluating experimental effects. In embodiments, the control is a gene mutation or a gene expression level against which another gene or gene expression level is compared (e.g., to make a diagnostic (e.g., predictive and / or prognostic) and / or therapeutic determination. In embodiments, a control is a healthy patient or a healthy population of patients. In embodiments, the control is an average value from population of healthy patients. In embodiments, a control is a pre-assigned value, e.g., a cut-off value which was previously determined to significantly separate a first group of patients (e.g., patients with Parkinson’s disease or at risk of developing Parkinson’s disease) from a second group of patients (e.g., healthy patients). In embodiments, the cut-off value is the median or mean (preferably median) gene expression level in the referencepopulation. One of skill will recognize that controls can be designed for assessment of any number of parameters. In embodiments, a control is a negative control. One of skill in the art will understand which controls are valuable in a given situation and be able to analyze data based on comparisons to control values.

[0042] Patients

[0043] “Patient” or “subject” or “patient in need thereof” or “subject in need thereof” refers to a living organism that can be treated by administration of a therapeutic agent (e.g., adenosine A2A receptor antagonist) as provided herein. Non-limiting examples of a patient include humans and other mammals, such as dogs and cats. In embodiments, the patient is at risk of developing a synucleinopathy. In embodiments, the patient is at risk of developing Parkinson’s disease. In embodiments, a patient is human. In embodiments, the patient is a human at risk of developing a synucleinopathy. In embodiments, the patient is a human at risk of developing Parkinson’s disease.

[0044] In embodiments of the methods described herein, a patient at risk of developing a synucleinopathy is a patient who has (i) REM sleep behavior disorder and / or REM sleep without atonia; (ii) a family history of a synucleinopathy, (iii) an elevated level of alpha synuclein relative to a control, (iv) a GBA1 gene mutation, a UCHL1 gene mutation, a LRRK2gene mutation, a PARK7 gene mutation, a PINK1 gene mutation, a PARK2 gene mutation, aPRKN gene mutation, a SNCA gene mutation, a GIGYF2 gene mutation, a DNAJC13 gene mutation, a TMEM230 gene mutation, a GCH1 gene mutation, a EIF4G1 gene mutation, a HTRA2 gene mutation, a RIC3 gene mutation, a ATXN2 gene mutation, a VPS35 gene mutation, a CHCHD2 gene mutation a PTRHD1 gene mutation, a PLA2G6 gene mutation, a SPG11 gene mutation, a FBXO7 gene mutation, a DNAJC6 gene mutation, a SYNJ1 gene mutation, a ATP13A2 gene mutation, a VPS13C gene mutation, a PODXL gene mutation, a POLG gene mutation, a DCTN1 gene mutation, a LRP10 gene mutation, a RAB39B gene mutation, or a combination of two or more thereof, or (v) a combination of two or more of (i), (ii), (iii), and (iv). As will be appreciated by the skilled artisan, the gene mutation refers to a gene mutation in patients with a familial history of a synucleinopathy, in patient having a synucleinopathy, or in patients otherwise predisposed to develop a synucleinopathy. In embodiments, the synucleinopathy is Parkinson’s disease, dementia with Lewy bodies, multiple system atrophy, pure autonomic failure, or Alzheimer's disease with amygdalar restricted Lewy bodies.

[0045] In embodiments, a patient at risk of developing a synucleinopathy is a patient who has REM sleep behavior disorder and / or REM sleep without atonia. In embodiments, a patient at risk of developing a synucleinopathy has an abnormal electroencephalography results when compared to a control. In embodiments, the control is a healthy patient. In embodiments, the abnormal electroencephalography results are decreased attenuation of beta frequency electroencephalographic activity during phasic REM sleep compared to tonic REM sleep; reduced overnight decline in slow-wave activity during NREM sleep; decreased overnight modifications in the slow-wave amplitude distribution; or a combination of two or more thereof; wherein each are compared to a control. In embodiments, a patient at risk of developing a synucleinopathy has decreased attenuation of beta frequency electroencephalographic activity during phasic REM sleep compared to tonic REM sleep, compared to a control; reduced overnight decline in slow-wave activity during NREM sleep, compared to a control; decreased overnight modifications in the slow-wave amplitude distribution, compared to a control; or a combination of two or more thereof. In embodiments, a patient at risk of a synucleinopathy has an abnormal polysomnography when compared to control. In embodiments, the control is a healthy patient. In embodiments, a patient at risk of developing a synucleinopathy decreased muscle atonia during REM sleep, compared to a control, as determined by polysomnography.

[0046] In embodiments, a patient at risk of developing a synucleinopathy is a patient who has: (a) REM sleep behavior disorder and / or REM sleep without atonia and (b) a gene mutation selected from the group consisting of a GBA1 gene mutation, a UCHL1 gene mutation, a LRRK2 gene mutation, a PARK7 gene mutation, a PINK1 gene mutation, aPARK2 gene mutation, a PRKN gene mutation, a SNCA gene mutation, a GIGYF2 genemutation, a DNAJC13 gene mutation, a TMEM230 gene mutation, a GCH1 gene mutation, a EIF4G1 gene mutation, a HTRA2 gene mutation, a RIC3 gene mutation, a ATXN2 gene mutation, a VPS35 gene mutation, a CHCHD2 gene mutation a PTRHD1 gene mutation, a PLA2G6 gene mutation, a SPG11 gene mutation, a FBXO7 gene mutation, a DNAJC6 gene mutation, a SYNJ1 gene mutation, a ATP13A2 gene mutation, a VPS13C gene mutation, a PODXL gene mutation, a POLG gene mutation, a DCTN1 gene mutation, a LRP10 gene mutation, a RAB39B gene mutation, or a combination of two or more thereof.

[0047] In embodiments, a patient at risk of developing a synucleinopathy is a patient who has: (a) REM sleep behavior disorder and / or REM sleep without atonia and (b) a gene mutation selected from the group consisting of a GBA1 gene mutation, a LRRK2 genemutation, a PRKN gene mutation, a SNCA gene mutation, a PINK1 gene mutation, a PARK2gene mutation, a PARK7 gene mutation, a VPS35 gene mutation, or a combination of two ormore thereof. In embodiments, a patient at risk of developing a synucleinopathy is a patient who has: (a) REM sleep behavior disorder and / or REM sleep without atonia and (b) a gene mutation selected from the group consisting of a LRRK2 gene mutation, a PARK2 gene mutation, a PARK7 gene mutation, a PINK1 gene mutation, a SNCA gene mutation, or a combination of two or more thereof. In embodiments, a patient at risk of developing a synucleinopathy is a patient who has: (a) REM sleep behavior disorder and / or REM sleep without atonia and (b) a gene mutation selected from the group consisting of a GBA1 gene mutation, a LRRK2 gene mutation, a PRKN gene mutation, a SNCA gene mutation, a PINK1 gene mutation, a PARK7 gene mutation, a VPS35 gene mutation, or a combination of two or more thereof.

[0048] In embodiments, a patient at risk of developing a synucleinopathy is a patient who has: (a) REM sleep behavior disorder and / or REM sleep without atonia and (b) an elevated level of alpha synuclein relative to a control. In embodiments, the control is a healthy patient or a population of healthy patients. In embodiments, the synuclein is an alpha-synuclein aggregate.

[0049] In embodiments, a patient at risk of developing a synucleinopathy is a patient who has: (a) REM sleep behavior disorder and / or REM sleep without atonia, (b) an elevated level of alpha synuclein relative to a control, and (c) a gene mutation selected from the group consisting of a GBA1 gene mutation, a UCHL1 gene mutation, a LRRK2 gene mutation, aPARK7 gene mutation, a PINK1 gene mutation, a PARK2 gene mutation, a PRKN genemutation, a SNCA gene mutation, a GIGYF2 gene mutation, a DNAJC13 gene mutation, a TMEM230 gene mutation, a GCH1 gene mutation, a EIF4G1 gene mutation, a HTRA2 gene mutation, a RIC3 gene mutation, a ATXN2 gene mutation, a VPS35 gene mutation, a CHCHD2 gene mutation a PTRHD1 gene mutation, a PLA2G6 gene mutation, a SPG11 gene mutation, a FBXO7 gene mutation, a DNAJC6 gene mutation, a SYNJ1 gene mutation, a ATP13A2 gene mutation, a VPS13C gene mutation, a PODXL gene mutation, a POLG gene mutation, a DCTN1 gene mutation, a LRP10 gene mutation, a RAB39B gene mutation, or a combination of two or more thereof. In embodiments, the control is a healthy patient or a population of healthy patients. In embodiments, the synuclein is an alpha-synuclein aggregate.

[0050] In embodiments, a patient at risk of developing a synucleinopathy is a patient who has: (a) REM sleep behavior disorder and / or REM sleep without atonia, (b) an elevated level ofalpha synuclein relative to a control, and (c) a gene mutation selected from the group consisting of a GBA1 gene mutation, a LRRK2 gene mutation, a PRKN gene mutation, a SNCA gene mutation, a PINK1 gene mutation, a PARK2 gene mutation, a PARK7 gene mutation, a VPS35 gene mutation, or a combination of two or more thereof. In embodiments, the control is a healthy patient or a population of healthy patients. In embodiments, the synuclein is an alpha-synuclein aggregate. In embodiments, a patient at risk of developing a synucleinopathy is a patient who has: (a) REM sleep behavior disorder and / or REM sleep without atonia, (b) an elevated level of alpha synuclein relative to a control, and (c) a gene mutation selected from the group consisting of a LRRK2 gene mutation, a PARK2 gene mutation, a PARK7 gene mutation, a PINK1 gene mutation, a SNCA gene mutation, or a combination of two or more thereof. In embodiments, the control is a healthy patient or a population of healthy patients. In embodiments, the synuclein is an alpha-synuclein aggregate. In embodiments, a patient at risk of developing a synucleinopathy is a patient who has: (a) REM sleep behavior disorder and / or REM sleep without atonia, (b) an elevated level of alpha synuclein relative to a control, and (c) a gene mutation selected from the group consisting of a GBA1 gene mutation, a LRRK2 gene mutation, a PRKN gene mutation, a SNCA gene mutation, a PINK1 gene mutation, a PARK7 gene mutation, a VPS35 gene mutation, or a combination of two or more thereof. In embodiments, the control is a healthy patient or a population of healthy patients. In embodiments, the synuclein is an alpha-synuclein aggregate.

[0051] In embodiments, a patient at risk of developing a synucleinopathy is a patient who has a family history of a synucleinopathy. In embodiments, the patient has a family history of Parkinson’s disease, dementia with Lewy bodies, multiple system atrophy, pure autonomic failure, or Alzheimer's disease with amygdalar restricted Lewy bodies. In embodiments, the patient has a family history of Parkinson’s disease. In embodiments, the patient has a family history of dementia with Lewy bodies. In embodiments, the patient has a family history of multiple system atrophy. In embodiments, the patient has a family history of pure autonomic failure. In embodiments, the patient has a family history of Alzheimer's disease with amygdalar restricted Lewy bodies.

[0052] In embodiments, a patient at risk of developing a synucleinopathy is a patient who has an elevated level of alpha synuclein relative to a control. In embodiments, the control is a healthy patient or a population of healthy patients. In embodiments, the synuclein is an alpha- synuclein aggregate.

[0053] In embodiments of the methods described herein, a patient at risk of developingParkinson’s disease is a patient who has (i) REM sleep behavior disorder and / or REM sleep without atonia; (ii) a family history of Parkinson’s disease, (iii) an elevated level of alpha synuclein relative to a control, (iv) a GBA1 gene mutation, a UCHL1 gene mutation, a LRRK2gene mutation, a PARK7 gene mutation, a PINK1 gene mutation, a PARK2 gene mutation, aPRKN gene mutation, a SNCA gene mutation, a GIGYF2 gene mutation, a DNAJC13 gene mutation, a TMEM230 gene mutation, a GCH1 gene mutation, a EIF4G1 gene mutation, a HTRA2 gene mutation, a RIC3 gene mutation, a ATXN2 gene mutation, a VPS35 gene mutation, a CHCHD2 gene mutation a PTRHD1 gene mutation, a PLA2G6 gene mutation, a SPG11 gene mutation, a FBXO7 gene mutation, a DNAJC6 gene mutation, a SYNJ1 gene mutation, a ATP13A2 gene mutation, a VPS13C gene mutation, a PODXL gene mutation, a POLG gene mutation, a DCTN1 gene mutation, a LRP10 gene mutation, a RAB39B gene mutation, or a combination of two or more thereof, or (v) a combination of two or more of (i), (ii), (iii), and (iv). As will be appreciated by the skilled artisan, the specific mutation(s) for each gene is the mutation as it relates to Parkinson’s disease and as known and described in the art.

[0054] In embodiments, a patient at risk of developing Parkinson’s disease is a patient who has REM sleep behavior disorder and / or REM sleep without atonia. In embodiments, a patient at risk of developing Parkinson’s disease has an abnormal electroencephalography results when compared to a control. In embodiments, the control is a healthy patient. In embodiments, the abnormal electroencephalography results are decreased attenuation of beta frequency electroencephalographic activity during phasic REM sleep compared to tonic REM sleep; reduced overnight decline in slow-wave activity during NREM sleep; decreased overnight modifications in the slow-wave amplitude distribution; or a combination of two or more thereof; wherein each are compared to a control. In embodiments, a patient at risk of developing Parkinson’s disease has decreased attenuation of beta frequency electroencephalographic activity during phasic REM sleep compared to tonic REM sleep, compared to a control; reduced overnight decline in slow-wave activity during NREM sleep, compared to a control; decreased overnight modifications in the slow-wave amplitude distribution, compared to a control; or a combination of two or more thereof. In embodiments, a patient at risk of developing Parkinson’s disease has decreased attenuation of beta frequency electroencephalographic activity during phasic REM sleep compared to tonic REM sleep, compared to a control. In embodiments, a patient at risk of developing Parkinson’s disease has reduced overnight decline in slow-wave activity during NREM sleep, compared to a control. Inembodiments, a patient at risk of developing Parkinson’s disease has decreased overnight modifications in the slow-wave amplitude distribution, compared to a control; or a combination of two or more thereof. In embodiments, a patient at risk of developing Parkinson’s disease has an abnormal polysomnography when compared to control. In embodiments, the control is a healthy patient. In embodiments, a patient at risk of developing Parkinson’s disease decreased muscle atonia during REM sleep, compared to a control, as determined by polysomnography.

[0055] In embodiments, a patient at risk of developing Parkinson’s disease is a patient who has a family history of Parkinson’s disease.

[0056] In embodiments, a patient at risk of developing Parkinson’s disease is a patient who has: (a) REM sleep behavior disorder and / or REM sleep without atonia and (b) a gene mutation selected from the group consisting of a GBA1 gene mutation, a UCHL1 gene mutation, a LRRK2 gene mutation, a PARK7 gene mutation, a PINK1 gene mutation, aPARK2 gene mutation, a PRKN gene mutation, a SNCA gene mutation, a GIGYF2 genemutation, a DNAJC13 gene mutation, a TMEM230 gene mutation, a GCH1 gene mutation, a EIF4G1 gene mutation, a HTRA2 gene mutation, a RIC3 gene mutation, a ATXN2 gene mutation, a VPS35 gene mutation, a CHCHD2 gene mutation a PTRHD1 gene mutation, a PLA2G6 gene mutation, a SPG11 gene mutation, a FBXO7 gene mutation, a DNAJC6 gene mutation, a SYNJ1 gene mutation, a ATP13A2 gene mutation, a VPS13C gene mutation, a PODXL gene mutation, a POLG gene mutation, a DCTN1 gene mutation, a LRP10 gene mutation, a RAB39B gene mutation, or a combination of two or more thereof.

[0057] In embodiments, a patient at risk of developing Parkinson’s disease is a patient who has: (a) REM sleep behavior disorder and / or REM sleep without atonia and (b) a gene mutation selected from the group consisting of a GBA1 gene mutation, a LRRK2 genemutation, a PRKN gene mutation, a SNCA gene mutation, a PINK1 gene mutation, a PARK2gene mutation, a PARK7 gene mutation, a VPS35 gene mutation, or a combination of two ormore thereof. In embodiments, a patient at risk of developing Parkinson’s disease is a patient who has: (a) REM sleep behavior disorder and / or REM sleep without atonia and (b) a gene mutation selected from the group consisting of a LRRK2 gene mutation, a PARK2 gene mutation, a PARK7 gene mutation, a PINK1 gene mutation, a SNCA gene mutation, or a combination of two or more thereof. In embodiments, a patient at risk of developing Parkinson’s disease is a patient who has: (a) REM sleep behavior disorder and / or REM sleep without atonia and (b) a gene mutation selected from the group consisting of a GBA1 genemutation, a LRRK2 gene mutation, a PRKN gene mutation, a SNCA gene mutation, a PINK1 gene mutation, a PARK7 gene mutation, a VPS35 gene mutation, or a combination of two or more thereof.

[0058] In embodiments, a patient at risk of developing Parkinson’s disease is a patient who has: (a) REM sleep behavior disorder and / or REM sleep without atonia and (b) an elevated level of alpha synuclein relative to a control. In embodiments, the control is a healthy patient or a population of healthy patients. In embodiments, the synuclein is an alpha-synuclein aggregate.

[0059] In embodiments, a patient at risk of developing Parkinson’s disease is a patient who has: (a) REM sleep behavior disorder and / or REM sleep without atonia, (b) an elevated level of alpha synuclein relative to a control, and (c) a gene mutation selected from the group consisting of a GBA1 gene mutation, a UCHL1 gene mutation, a LRRK2 gene mutation, aPARK7 gene mutation, a PINK1 gene mutation, a PARK2 gene mutation, a PRKN genemutation, a SNCA gene mutation, a GIGYF2 gene mutation, a DNAJC13 gene mutation, a TMEM230 gene mutation, a GCH1 gene mutation, a EIF4G1 gene mutation, a HTRA2 gene mutation, a RIC3 gene mutation, a ATXN2 gene mutation, a VPS35 gene mutation, a CHCHD2 gene mutation a PTRHD1 gene mutation, a PLA2G6 gene mutation, a SPG11 gene mutation, a FBXO7 gene mutation, a DNAJC6 gene mutation, a SYNJ1 gene mutation, a ATP13A2 gene mutation, a VPS13C gene mutation, a PODXL gene mutation, a POLG gene mutation, a DCTN1 gene mutation, a LRP10 gene mutation, a RAB39B gene mutation, or a combination of two or more thereof. In embodiments, the control is a healthy patient or a population of healthy patients. In embodiments, the synuclein is an alpha-synuclein aggregate.

[0060] In embodiments, a patient at risk of developing Parkinson’s disease is a patient who has: (a) REM sleep behavior disorder and / or REM sleep without atonia, (b) an elevated level of alpha synuclein relative to a control, and (c) a gene mutation selected from the group consisting of a GBA1 gene mutation, a LRRK2 gene mutation, a PRKN gene mutation, a SNCA gene mutation, a PINK1 gene mutation, a PARK2 gene mutation, a PARK7 gene mutation, a VPS35 gene mutation, or a combination of two or more thereof. In embodiments, a patient at risk of developing Parkinson’s disease is a patient who has: (a) REM sleep behavior disorder and / or REM sleep without atonia, (b) an elevated level of alpha synuclein relative to a control, and (c) a gene mutation selected from the group consisting of a LRRK2 gene mutation, a PARK2 gene mutation, a PARK7 gene mutation, a PINK1 gene mutation, a SNCA gene mutation, or a combination of two or more thereof. In embodiments, a patient at risk ofdeveloping Parkinson’s disease is a patient who has: (a) REM sleep behavior disorder and / or REM sleep without atonia, (b) an elevated level of alpha synuclein relative to a control, and (c) a gene mutation selected from the group consisting of a GBA1 gene mutation, a LRRK2 gene mutation, a PRKN gene mutation, a SNCA gene mutation, a PINK1 gene mutation, a PARK7 gene mutation, a VPS35 gene mutation, or a combination of two or more thereof. In embodiments, the control is a healthy patient or a population of healthy patients. In embodiments, the synuclein is an alpha-synuclein aggregate.

[0061] In embodiments, a patient at risk of developing Parkinson’s disease is a patient having a GBA1 gene mutation, a UCHL1 gene mutation, a LRRK2 gene mutation, a PARK7gene mutation, a PINK1 gene mutation, a PARK2 gene mutation, a PRKN gene mutation, aSNCA gene mutation, a GIGYF2 gene mutation, a DNAJC13 gene mutation, a TMEM230 gene mutation, a GCH1 gene mutation, a EIF4G1 gene mutation, a HTRA2 gene mutation, a RIC3 gene mutation, a ATXN2 gene mutation, a VPS35 gene mutation, a CHCHD2 gene mutation a PTRHD1 gene mutation, a PLA2G6 gene mutation, a SPG11 gene mutation, a FBXO7 gene mutation, a DNAJC6 gene mutation, a SYNJ1 gene mutation, a ATP13A2 gene mutation, a VPS13C gene mutation, a PODXL gene mutation, a POLG gene mutation, a DCTN1 gene mutation, a LRP10 gene mutation, a RAB39B gene mutation, or a combination of two or more thereof.

[0062] In embodiments, a patient at risk of developing Parkinson’s disease is a patient having a GBA1 gene mutation, a UCHL1 gene mutation, a LRRK2 gene mutation, a PARK7gene mutation, a PINK1 gene mutation, a PARK2 gene mutation, a PRKN gene mutation, aSNCA gene mutation, a GIGYF2 gene mutation, a DNAJC13 gene mutation, a TMEM230 gene mutation, a EIF4G1 gene mutation, a HTRA2 gene mutation, a VPS35 gene mutation, a CHCHD2 gene mutation, a PLA2G6 gene mutation, a FBXO7 gene mutation, a DNAJC6 gene mutation, a SYNJ1 gene mutation, a ATP13A2 gene mutation, a VPS13C gene mutation, a POLG gene mutation, a DCTN1 gene mutation, a LRP10 gene mutation, or a combination of two or more thereof

[0063] In embodiments, a patient at risk of developing Parkinson’s disease is a patient having a GBA1 gene mutation, a LRRK2 gene mutation, a PRKN gene mutation, a SNCAgene mutation, a PINK1 gene mutation, a PARK2 gene mutation, a PARK7 gene mutation, aVPS35 gene mutation, or a combination of two or more thereof.

[0064] In embodiments, a patient at risk of developing Parkinson’s disease is a patienthaving a LRRK2 gene mutation, a PARK2 gene mutation, a PARK7 gene mutation, a PINK1 gene mutation, a SNCA gene mutation, or a combination of two or more thereof.

[0065] In embodiments, a patient at risk of developing Parkinson’s disease is a patient having a GBA1 gene mutation, a LRRK2 gene mutation, a PRKN gene mutation, a SNCA gene mutation, a PINK1 gene mutation, a PARK7 gene mutation, a VPS35 gene mutation, or a combination of two or more thereof.

[0066] In embodiments, a patient at risk of developing Parkinson’s disease is a patient having a GBA1 gene mutation. In embodiments, a patient at risk of developing Parkinson’s disease is a patient having a UCHL1 gene mutation. In embodiments, a patient at risk of developing Parkinson’s disease is a patient having a LRRK2 gene mutation. In embodiments, a patient at risk of developing Parkinson’s disease is a patient having a PARK7 gene mutation. In embodiments, a patient at risk of developing Parkinson’s disease is a patient having a PINK1 gene mutation. In embodiments, a patient at risk of developing Parkinson’s disease is apatient having a a PARK2 gene mutation. In embodiments, a patient at risk of developingParkinson’s disease is a patient having a PRKN gene mutation. In embodiments, a patient at risk of developing Parkinson’s disease is a patient having a SNCA gene mutation. In embodiments, a patient at risk of developing Parkinson’s disease is a patient having a GIGYF2 gene mutation. In embodiments, a patient at risk of developing Parkinson’s disease is a patient having a DNAJC13 gene mutation. In embodiments, a patient at risk of developing Parkinson’s disease is a patient having a TMEM230 gene mutation. In embodiments, a patient at risk of developing Parkinson’s disease is a patient having a GCH1 gene mutation. In embodiments, a patient at risk of developing Parkinson’s disease is a patient having a EIF4G1 gene mutation. In embodiments, a patient at risk of developing Parkinson’s disease is a patient having a HTRA2 gene mutation. In embodiments, a patient at risk of developing Parkinson’s disease is a patient having a RIC3 gene mutation. In embodiments, a patient at risk of developing Parkinson’s disease is a patient having a ATXN2 gene mutation. In embodiments, a patient at risk of developing Parkinson’s disease is a patient having a VPS35 gene mutation. In embodiments, a patient at risk of developing Parkinson’s disease is a patient having a CHCHD2 gene mutation. In embodiments, a patient at risk of developing Parkinson’s disease is a patient having a PTRHD1 gene mutation. In embodiments, a patient at risk of developing Parkinson’s disease is a patient having a PLA2G6 gene mutation. In embodiments, a patient at risk of developing Parkinson’s disease is a patient having a SPG11 gene mutation. In embodiments, a patient at risk of developing Parkinson’s disease is a patient having a FBXO7gene mutation. In embodiments, a patient at risk of developing Parkinson’s disease is a patient having a DNAJC6 gene mutation. In embodiments, a patient at risk of developing Parkinson’s disease is a patient having a SYNJ1 gene mutation. In embodiments, a patient at risk of developing Parkinson’s disease is a patient having a ATP13A2 gene mutation. In embodiments, a patient at risk of developing Parkinson’s disease is a patient having a VPS13C gene mutation. In embodiments, a patient at risk of developing Parkinson’s disease is a patient having a PODXL gene mutation. In embodiments, a patient at risk of developing Parkinson’s disease is a patient having a POLG gene mutation. In embodiments, a patient at risk of developing Parkinson’s disease is a patient having a a DCTN1 gene mutation. In embodiments, a patient at risk of developing Parkinson’s disease is a patient having a LRP10 gene mutation. In embodiments, a patient at risk of developing Parkinson’s disease is a patient having a RAB39B gene mutation.

[0067] In embodiments, GBA1 gene mutations for Parkinson’s disease include p.L483P, p.N409S, p.T408M, p.E365K, p.R159W, or a combination of two or more thereof.

[0068] In embodiments, SNCA gene mutations for Parkinson’s disease include A30P, E46K, H50Q, G51D, A53T, or a combination of two or more thereof.

[0069] In embodiments, LRRK2 gene mutations for Parkinson’s disease include R1398H, R1441G, R1441C, R1441H, R1441S, N1437H, Y1699C, G2019S, R1628P, M1646T, Y1699C, G2019S, G2385R, I2020T, or a combination of two or more thereof.

[0070] In embodiments, PRKN gene mutations for Parkinson’s disease include deletion of exon 2, 3, 4, or 7, duplication of exons 2, 3, 4, 6, or 7, R33Q, R33X, P37L, Q40X, R42H, R42C, R42P, D53X, E79X, K161N, C166Y, Q171X, K211N, C212G, C212Y, H215Q, C238Q, C238W, T240M, T240R, C253Y, C253F, R256C, Y267H, C268X, R275W, C298G, Q311X, G328E, R334C, R334H, E395X, A398T, E409X, T415N, C418R, G340D, C431F, C441R, T445X, T453X, and combinations of two or more thereof.

[0071] In embodiments, PINK1 gene mutations for Parkinson’s disease include Q5* C92F, I111S, A168P, V170G, A200fs, R207fs, A217D, E240K, R246*, Y258*, H271Q, R279H, G309D, T313M, L347P, F385L, G409V, E417G, W437*, Q456*, R492*, Q543dup, and combinations of two or more thereof.

[0072] In embodiments, PARK2 gene mutations for Parkinson’s disease include R42P, A46P, I105Phe, A107Pro, Thr154Lys, Pro158del, Glu163Lys, Leu166Pro, Leu172Gln, K211N, C212Y, C253Y, C289G, and C441R, and combinations of two or more thereof.

[0073] In embodiments, PARK7 gene mutations (alternatively referred to as DJ-1 gene mutations) for Parkinson’s disease include L10P, M26I, E64D, A104T, D149A, E163K, L166P and combinations of two or more thereof

[0074] In embodiments, a VPS35 gene mutation for Parkinson’s disease includes p.D620N. In embodiments, the specific VPS35 gene mutations for Parkinson’s disease include L774M, P316S, R524W, I241M, M57I, G51S, R32S, I560T, H599R, M607V, and combinations of two or more thereof.

[0075] Methods for Treating REM Sleep Behavior Disorder

[0076] Provided herein are methods for treating or preventing REM sleep behavior disorder in a patient in need thereof comprising administering to the patient an effective amount of an adenosine A2A receptor antagonist, thereby treating or preventing REM sleep behavior disorder. Provided herein are methods for treating REM sleep behavior disorder in a patient in need thereof comprising administering to the patient an effective amount of an adenosine A2A receptor antagonist, thereby treating REM sleep behavior disorder. Provided herein are methods for preventing REM sleep behavior disorder in a patient in need thereof comprising administering to the patient an effective amount of an adenosine A2A receptor antagonist, thereby preventing REM sleep behavior disorder. In embodiments, the patient is at risk of developing Parkinson’s disease. In embodiments, the patient has an elevated level of alpha synuclein. In embodiments, the patient has an elevated level of alpha synuclein relative to a control. In embodiments, the patient has an elevated level of alpha synuclein relative to a healthy control. In embodiments, the patient has an elevated level of an alpha-synuclein aggregate. In embodiments, the patient has an elevated level of an alpha-synuclein aggregate relative to a control. In embodiments, the patient has an elevated level of an alpha-synuclein aggregate relative to a healthy control. In embodiments, the patient has a family history of Parkinson’s disease. In embodiments, the patient has a GBA1 gene mutation, a UCHL1 gene mutation, a LRRK2 gene mutation, a PARK7 gene mutation, a PINK1 gene mutation, a PARK2 gene mutation, a PRKN gene mutation, a SNCA gene mutation, a GIGYF2 gene mutation, a DNAJC13 gene mutation, a TMEM230 gene mutation, a GCH1 gene mutation, a EIF4G1 gene mutation, a HTRA2 gene mutation, a RIC3 gene mutation, a ATXN2 gene mutation, a VPS35 gene mutation, a CHCHD2 gene mutation a PTRHD1 gene mutation, a PLA2G6 gene mutation, a SPG11 gene mutation, a FBXO7 gene mutation, a DNAJC6 gene mutation, a SYNJ1 gene mutation, a ATP13A2 gene mutation, a VPS13C gene mutation, a PODXL gene mutation, a POLG gene mutation, a DCTN1 gene mutation, a LRP10 genemutation, a RAB39B gene mutation, or a combination of two or more thereof. In embodiments, the patient has (i) a family history of a synucleinopathy (such as Parkinson’s disease), (ii) an elevated level of alpha synuclein relative to a control, (iii) a gene mutation as described herein, or (iv) a combination of two or more of (i), (ii), and (iii) (and embodiments of the foregoing as described herein for a patient at risk). In embodiments, the adenosine A2A receptor antagonist is ciforadenant, enprofylline, vipadenant, preladenant, tozadenant, or istradefylline. In embodiments, the adenosine A2A receptor antagonist is ciforadenant, enprofylline, vipadenant, preladenant, tozadenant, istradefylline, inupadenant, etrumadenant, taminadenant, TB206-001, PORT-6, M1069, ST1535, or ST4206. In embodiments, the adenosine A2A receptor antagonist is ciforadenant. In embodiments, the adenosine A2A receptor antagonist is enprofylline. In embodiments, the adenosine A2A receptor antagonist is vipadenant. In embodiments, the adenosine A2A receptor antagonist is praladenant. In embodiments, the adenosine A2A receptor antagonist is tozadenant. In embodiments, the adenosine A2A receptor antagonist is istradefylline. In embodiments, the adenosine A2A receptor antagonist is inupadenant, In embodiments, the adenosine A2A receptor antagonist is etrumadenant. In embodiments, the adenosine A2A receptor antagonist is taminadenant. In embodiments, the adenosine A2A receptor antagonist is TB206-001. In embodiments, the adenosine A2A receptor antagonist is PORT-6. In embodiments, the adenosine A2A receptor antagonist is M1069. In embodiments, the adenosine A2A receptor antagonist is ST1535. In embodiments, the adenosine A2A receptor antagonist is ST4206. In embodiments, the patient will have serial EEG or polysomnography to monitor therapy and guide dosing. The degree of REM sleep without atonia will be monitored and may be useful as a biomarker. In some cases MRI spectroscopy could be used to complement EEG.

[0077] Provided herein are methods for treating or preventing REM sleep without atonia in a patient in need thereof comprising administering to the patient an effective amount of an adenosine A2A receptor antagonist, thereby treating or preventing REM sleep without atonia. Provided herein are methods for treating REM sleep without atonia in a patient in need thereof comprising administering to the patient an effective amount of an adenosine A2A receptor antagonist, thereby treating REM sleep without atonia. Provided herein are methods for preventing REM sleep without atonia in a patient in need thereof comprising administering to the patient an effective amount of an adenosine A2A receptor antagonist, thereby preventing REM sleep without atonia. In embodiments, the patient is at risk of developing Parkinson’s disease. In embodiments, the patient has an elevated level of alpha synuclein. In embodiments,the patient has an elevated level of alpha synuclein relative to a control. In embodiments, the patient has an elevated level of alpha synuclein relative to a healthy control. In embodiments, the patient has an elevated level of an alpha-synuclein aggregate. In embodiments, the patient has an elevated level of an alpha-synuclein aggregate relative to a control. In embodiments, the patient has an elevated level of an alpha-synuclein aggregate relative to a healthy control. In embodiments, the patient has a family history of Parkinson’s disease. In embodiments, the patient has a GBA1 gene mutation, a UCHL1 gene mutation, a LRRK2 gene mutation, a PARK7 gene mutation, a PINK1 gene mutation, a PARK2 gene mutation, a PRKN gene mutation, a SNCA gene mutation, a GIGYF2 gene mutation, a DNAJC13 gene mutation, a TMEM230 gene mutation, a GCH1 gene mutation, a EIF4G1 gene mutation, a HTRA2 gene mutation, a RIC3 gene mutation, a ATXN2 gene mutation, a VPS35 gene mutation, a CHCHD2 gene mutation a PTRHD1 gene mutation, a PLA2G6 gene mutation, a SPG11 gene mutation, a FBXO7 gene mutation, a DNAJC6 gene mutation, a SYNJ1 gene mutation, a ATP13A2 gene mutation, a VPS13C gene mutation, a PODXL gene mutation, a POLG gene mutation, a DCTN1 gene mutation, a LRP10 gene mutation, a RAB39B gene mutation, or a combination of two or more thereof. In embodiments, the patient has (i) a family history of a synucleinopathy (such as Parkinson’s disease), (ii) an elevated level of alpha synuclein relative to a control, (iii) a gene mutation as described herein, or (iv) a combination of two or more of (i), (ii), and (iii) (and embodiments of the foregoing as described herein for a patient at risk). In embodiments, the adenosine A2A receptor antagonist is ciforadenant, enprofylline, vipadenant, preladenant, tozadenant, or istradefylline. In embodiments, the adenosine A2A receptor antagonist is ciforadenant, enprofylline, vipadenant, preladenant, tozadenant, istradefylline, inupadenant, etrumadenant, taminadenant, TB206-001, PORT-6, M1069, ST1535, or ST4206. In embodiments, the adenosine A2A receptor antagonist is ciforadenant. In embodiments, the adenosine A2A receptor antagonist is enprofylline. In embodiments, the adenosine A2A receptor antagonist is vipadenant. In embodiments, the adenosine A2A receptor antagonist is praladenant. In embodiments, the adenosine A2A receptor antagonist is tozadenant. In embodiments, the adenosine A2A receptor antagonist is istradefylline. In embodiments, the adenosine A2A receptor antagonist is inupadenant, In embodiments, the adenosine A2A receptor antagonist is etrumadenant. In embodiments, the adenosine A2A receptor antagonist is taminadenant. In embodiments, the adenosine A2A receptor antagonist is TB206-001. In embodiments, the adenosine A2A receptor antagonist is PORT-6. In embodiments, the adenosine A2A receptor antagonist is M1069. In embodiments, the adenosine A2A receptor antagonist is ST1535. In embodiments, the adenosine A2A receptor antagonist is ST4206. Inembodiments, the patient will have serial EEG or polysomnography to monitor therapy and guide dosing. The degree of REM sleep without atonia will be monitored and may be useful as a biomarker. In some cases MRI spectroscopy could be used to complement EEG.

[0078] Provided herein are methods for treating or preventing REM sleep behavior disorder in a patient in need thereof comprising administering to the patient an effective amount of ciforadenant, thereby treating or preventing REM sleep behavior disorder. Provided herein are methods for treating REM sleep behavior disorder in a patient in need thereof comprising administering to the patient an effective amount of ciforadenant, thereby treating REM sleep behavior disorder. Provided herein are methods for preventing REM sleep behavior disorder in a patient in need thereof comprising administering to the patient an effective amount of ciforadenant, thereby preventing REM sleep behavior disorder. In embodiments, the patient is at risk of developing Parkinson’s disease. In embodiments, the patient has an elevated level of alpha synuclein. In embodiments, the patient has an elevated level of alpha synuclein relative to a control. In embodiments, the patient has an elevated level of alpha synuclein relative to a healthy control. In embodiments, the patient has an elevated level of an alpha-synuclein aggregate. In embodiments, the patient has an elevated level of an alpha-synuclein aggregate relative to a control. In embodiments, the patient has an elevated level of an alpha-synuclein aggregate relative to a healthy control. In embodiments, the patient has a family history of Parkinson’s disease. In embodiments, the patient has a GBA1 gene mutation, a UCHL1 gene mutation, a LRRK2 gene mutation, a PARK7 gene mutation, a PINK1 gene mutation, a PARK2 gene mutation, a PARK2 gene mutation, a PRKN gene mutation, a SNCA gene mutation, a GIGYF2 gene mutation, a DNAJC13 gene mutation, a TMEM230 gene mutation, a GCH1 gene mutation, a EIF4G1 gene mutation, a HTRA2 gene mutation, a RIC3 gene mutation, a ATXN2 gene mutation, a VPS35 gene mutation, a CHCHD2 gene mutation a PTRHD1 gene mutation, a PLA2G6 gene mutation, a SPG11 gene mutation, a FBXO7 gene mutation, a DNAJC6 gene mutation, a SYNJ1 gene mutation, a ATP13A2 gene mutation, a VPS13C gene mutation, a PODXL gene mutation, a POLG gene mutation, a DCTN1 gene mutation, a LRP10 gene mutation, a RAB39B gene mutation, or a combination of two or more thereof. In embodiments, the patient has (i) a family history of a synucleinopathy (such as Parkinson’s disease), (ii) an elevated level of alpha synuclein relative to a control, (iii) a gene mutation as described herein, or (iv) a combination of two or more of (i), (ii), and (iii) (and embodiments of the foregoing as described herein for a patient at risk). In embodiments, the patient will have serial EEG or polysomnography to monitor therapy and guide dosing. Thedegree of REM sleep without atonia will be monitored and may be useful as a biomarker. In some cases MRI spectroscopy could be used to complement EEG.

[0079] Provided herein are methods for treating or preventing REM sleep without atonia in a patient in need thereof comprising administering to the patient an effective amount of ciforadenant, thereby treating or preventing REM sleep without atonia. Provided herein are methods for treating REM sleep without atonia in a patient in need thereof comprising administering to the patient an effective amount of ciforadenant, thereby treating REM sleep without atonia. Provided herein are methods for preventing REM sleep without atonia in a patient in need thereof comprising administering to the patient an effective amount of ciforadenant, thereby preventing REM sleep without atonia. In embodiments, the patient is at risk of developing Parkinson’s disease. In embodiments, the patient has an elevated level of alpha synuclein. In embodiments, the patient has an elevated level of alpha synuclein relative to a control. In embodiments, the patient has an elevated level of alpha synuclein relative to a healthy control. In embodiments, the patient has an elevated level of an alpha-synuclein aggregate. In embodiments, the patient has an elevated level of an alpha-synuclein aggregate relative to a control. In embodiments, the patient has an elevated level of an alpha-synuclein aggregate relative to a healthy control. In embodiments, the patient has a family history of Parkinson’s disease. In embodiments, the patient has a GBA1 gene mutation, a UCHL1 gene mutation, a LRRK2 gene mutation, a PARK7 gene mutation, a PINK1 gene mutation, a PARK2 gene mutation, a PRKN gene mutation, a SNCA gene mutation, a GIGYF2 gene mutation, a DNAJC13 gene mutation, a TMEM230 gene mutation, a GCH1 gene mutation, a EIF4G1 gene mutation, a HTRA2 gene mutation, a RIC3 gene mutation, a ATXN2 gene mutation, a VPS35 gene mutation, a CHCHD2 gene mutation a PTRHD1 gene mutation, a PLA2G6 gene mutation, a SPG11 gene mutation, a FBXO7 gene mutation, a DNAJC6 gene mutation, a SYNJ1 gene mutation, a ATP13A2 gene mutation, a VPS13C gene mutation, a PODXL gene mutation, a POLG gene mutation, a DCTN1 gene mutation, a LRP10 gene mutation, a RAB39B gene mutation, or a combination of two or more thereof. In embodiments, the patient has (i) a family history of a synucleinopathy (such as Parkinson’s disease), (ii) an elevated level of alpha synuclein relative to a control, (iii) a gene mutation as described herein, or (iv) a combination of two or more of (i), (ii), and (iii) (and embodiments of the foregoing as described herein for a patient at risk). In embodiments, the patient will have serial EEG or polysomnography to monitor therapy and guide dosing. The degree of REM sleep without atonia will be monitored and may be useful as a biomarker. In some cases MRI spectroscopycould be used to complement EEG.

[0080] Methods for Preventing Parkinson’s Disease

[0081] Provided herein are methods for preventing Parkinson’s disease in a patient in need thereof comprising administering to the patient an effective amount of an adenosine A2A receptor antagonist, thereby preventing Parkinson’s disease. In embodiments, the patient is at risk of developing Parkinson’s disease. In embodiments, the patient has REM sleep behavior disorder. In embodiments, the patient has REM sleep without atonia. In embodiments, the patient has an elevated level of alpha synuclein. In embodiments, the patient has an elevated level of alpha synuclein relative to a control. In embodiments, the patient has an elevated level of alpha synuclein relative to a healthy control. In embodiments, the patient has an elevated level of an alpha-synuclein aggregate. In embodiments, the patient has an elevated level of an alpha-synuclein aggregate relative to a control. In embodiments, the patient has an elevated level of an alpha-synuclein aggregate relative to a healthy control. In embodiments, the patient has a family history of Parkinson’s disease. In embodiments, the patient has a GBA1 gene mutation, a UCHL1 gene mutation, a LRRK2 gene mutation, a PARK7 gene mutation, a PINK1 gene mutation, a PRKN gene mutation, a PARK2 gene mutation, a SNCA gene mutation, a GIGYF2 gene mutation, a DNAJC13 gene mutation, a TMEM230 gene mutation, a GCH1 gene mutation, a EIF4G1 gene mutation, a HTRA2 gene mutation, a RIC3 gene mutation, a ATXN2 gene mutation, a VPS35 gene mutation, a CHCHD2 gene mutation a PTRHD1 gene mutation, a PLA2G6 gene mutation, a SPG11 gene mutation, a FBXO7 gene mutation, a DNAJC6 gene mutation, a SYNJ1 gene mutation, a ATP13A2 gene mutation, a VPS13C gene mutation, a PODXL gene mutation, a POLG gene mutation, a DCTN1 gene mutation, a LRP10 gene mutation, a RAB39B gene mutation, or a combination of two or more thereof. In embodiments, the patient has (i) REM sleep behavior disorder and / or REM sleep without atonia; (ii) a family history of a synucleinopathy, such as Parkinson’s disease, (iii) an elevated level of alpha synuclein relative to a control, (iv) a gene mutation as described herein, or (v) a combination of two or more of (i), (ii), (iii), and (iv) (and embodiments of the foregoing as described herein for a patient at risk). In embodiments, the adenosine A2A receptor antagonist is ciforadenant, enprofylline, vipadenant, preladenant, tozadenant, or istradefylline. In embodiments, the adenosine A2A receptor antagonist is ciforadenant, enprofylline, vipadenant, preladenant, tozadenant, istradefylline, inupadenant, etrumadenant, taminadenant, TB206-001, PORT-6, M1069, ST1535, or ST4206. In embodiments, the adenosine A2A receptor antagonist is ciforadenant. In embodiments, the adenosine A2Areceptor antagonist is enprofylline. In embodiments, the adenosine A2A receptor antagonist is vipadenant. In embodiments, the adenosine A2A receptor antagonist is praladenant. In embodiments, the adenosine A2A receptor antagonist is tozadenant. In embodiments, the adenosine A2A receptor antagonist is istradefylline. In embodiments, the adenosine A2A receptor antagonist is inupadenant, In embodiments, the adenosine A2A receptor antagonist is etrumadenant. In embodiments, the adenosine A2A receptor antagonist is taminadenant. In embodiments, the adenosine A2A receptor antagonist is TB206-001. In embodiments, the adenosine A2A receptor antagonist is PORT-6. In embodiments, the adenosine A2A receptor antagonist is M1069. In embodiments, the adenosine A2A receptor antagonist is ST1535. In embodiments, the adenosine A2A receptor antagonist is ST4206.

[0082] Provided herein are methods for preventing Parkinson’s disease in a patient in need thereof comprising administering to the patient an effective amount of ciforadenant, thereby preventing Parkinson’s disease. In embodiments, the patient is at risk of developing Parkinson’s disease. In embodiments, the patient has REM sleep behavior disorder. In embodiments, the patient has REM sleep behavior disorder. In embodiments, the patient has REM sleep without atonia. In embodiments, the patient has an elevated level of alpha synuclein. In embodiments, the patient has an elevated level of alpha synuclein relative to a control. In embodiments, the patient has an elevated level of alpha synuclein relative to a healthy control. In embodiments, the patient has an elevated level of an alpha-synuclein aggregate. In embodiments, the patient has an elevated level of an alpha-synuclein aggregate relative to a control. In embodiments, the patient has an elevated level of an alpha-synuclein aggregate relative to a healthy control. In embodiments, the patient has a family history of Parkinson’s disease. In embodiments, the patient has a GBA1 gene mutation, a UCHL1 gene mutation, a LRRK2 gene mutation, a PARK7 gene mutation, a PINK1 gene mutation, a PARK2 gene mutation, a PRKN gene mutation, a SNCA gene mutation, a GIGYF2 gene mutation, a DNAJC13 gene mutation, a TMEM230 gene mutation, a GCH1 gene mutation, a EIF4G1 gene mutation, a HTRA2 gene mutation, a RIC3 gene mutation, a ATXN2 gene mutation, a VPS35 gene mutation, a CHCHD2 gene mutation a PTRHD1 gene mutation, a PLA2G6 gene mutation, a SPG11 gene mutation, a FBXO7 gene mutation, a DNAJC6 gene mutation, a SYNJ1 gene mutation, a ATP13A2 gene mutation, a VPS13C gene mutation, a PODXL gene mutation, a POLG gene mutation, a DCTN1 gene mutation, a LRP10 gene mutation, a RAB39B gene mutation, or a combination of two or more thereof. In embodiments, the patient has (i) REM sleep behavior disorder and / or REM sleep without atonia; (ii) a familyhistory of a synucleinopathy, such as Parkinson’s disease, (iii) an elevated level of alpha synuclein relative to a control, (iv) a gene mutation as described herein, or (v) a combination of two or more of (i), (ii), (iii), and (iv) (and embodiments of the foregoing as described herein for a patient at risk).

[0083] Methods for Delaying the Onset of Parkinson’s Disease

[0084] Provided herein are methods for delaying onset of Parkinson’s disease in a patient in need thereof comprising administering to the patient an effective amount of an adenosine A2A receptor antagonist, thereby delaying onset of Parkinson’s disease. In embodiments, the patient is at risk of developing Parkinson’s disease. In embodiments, the patient has REM sleep behavior disorder. In embodiments, the patient has REM sleep without atonia. In embodiments, the patient has an elevated level of alpha synuclein. In embodiments, the patient has an elevated level of alpha synuclein relative to a control. In embodiments, the patient has an elevated level of alpha synuclein relative to a healthy control. In embodiments, the patient has an elevated level of an alpha-synuclein aggregate. In embodiments, the patient has an elevated level of an alpha-synuclein aggregate relative to a control. In embodiments, the patient has an elevated level of an alpha-synuclein aggregate relative to a healthy control. In embodiments, the patient has a family history of Parkinson’s disease. In embodiments, the patient has a GBA1 gene mutation, a UCHL1 gene mutation, a LRRK2 gene mutation, a PARK7 gene mutation, a PINK1 gene mutation, a PARK2 gene mutation, a PRKN gene mutation, a SNCA gene mutation, a GIGYF2 gene mutation, a DNAJC13 gene mutation, a TMEM230 gene mutation, a GCH1 gene mutation, a EIF4G1 gene mutation, a HTRA2 gene mutation, a RIC3 gene mutation, a ATXN2 gene mutation, a VPS35 gene mutation, a CHCHD2 gene mutation a PTRHD1 gene mutation, a PLA2G6 gene mutation, a SPG11 gene mutation, a FBXO7 gene mutation, a DNAJC6 gene mutation, a SYNJ1 gene mutation, a ATP13A2 gene mutation, a VPS13C gene mutation, a PODXL gene mutation, a POLG gene mutation, a DCTN1 gene mutation, a LRP10 gene mutation, a RAB39B gene mutation, or a combination of two or more thereof. In embodiments, the patient has (i) REM sleep behavior disorder and / or REM sleep without atonia; (ii) a family history of a synucleinopathy, such as Parkinson’s disease, (iii) an elevated level of alpha synuclein relative to a control, (iv) a gene mutation as described herein, or (v) a combination of two or more of (i), (ii), (iii), and (iv) (and embodiments of the foregoing as described herein for a patient at risk). In embodiments, the adenosine A2A receptor antagonist is ciforadenant, enprofylline, vipadenant, preladenant, tozadenant, or istradefylline. In embodiments, the adenosine A2A receptor antagonist is ciforadenant,enprofylline, vipadenant, preladenant, tozadenant, istradefylline, inupadenant, etrumadenant, taminadenant, TB206-001, PORT-6, M1069, ST1535, or ST4206. In embodiments, the adenosine A2A receptor antagonist is ciforadenant. In embodiments, the adenosine A2A receptor antagonist is enprofylline. In embodiments, the adenosine A2A receptor antagonist is vipadenant. In embodiments, the adenosine A2A receptor antagonist is praladenant. In embodiments, the adenosine A2A receptor antagonist is tozadenant. In embodiments, the adenosine A2A receptor antagonist is istradefylline. In embodiments, the adenosine A2A receptor antagonist is inupadenant, In embodiments, the adenosine A2A receptor antagonist is etrumadenant. In embodiments, the adenosine A2A receptor antagonist is taminadenant. In embodiments, the adenosine A2A receptor antagonist is TB206-001. In embodiments, the adenosine A2A receptor antagonist is PORT-6. In embodiments, the adenosine A2A receptor antagonist is M1069. In embodiments, the adenosine A2A receptor antagonist is ST1535. In embodiments, the adenosine A2A receptor antagonist is ST4206.

[0085] Provided herein are methods for delaying onset of Parkinson’s disease in a patient in need thereof comprising administering to the patient an effective amount of ciforadenant, thereby delaying onset of Parkinson’s disease. In embodiments, the patient is at risk of developing Parkinson’s disease. In embodiments, the patient has REM sleep behavior disorder. In embodiments, the patient has REM sleep without atonia. In embodiments, the patient has an elevated level of alpha synuclein. In embodiments, the patient has an elevated level of alpha synuclein relative to a control. In embodiments, the patient has an elevated level of alpha synuclein relative to a healthy control. In embodiments, the patient has an elevated level of an alpha-synuclein aggregate. In embodiments, the patient has an elevated level of an alpha- synuclein aggregate relative to a control. In embodiments, the patient has an elevated level of an alpha-synuclein aggregate relative to a healthy control. In embodiments, the patient has a family history of Parkinson’s disease. In embodiments, the patient has a GBA1 gene mutation, a UCHL1 gene mutation, a LRRK2 gene mutation, a PARK7 gene mutation, a PINK1 gene mutation, a PARK2 gene mutation, a PRKN gene mutation, a SNCA gene mutation, a GIGYF2 gene mutation, a DNAJC13 gene mutation, a TMEM230 gene mutation, a GCH1 gene mutation, a EIF4G1 gene mutation, a HTRA2 gene mutation, a RIC3 gene mutation, a ATXN2 gene mutation, a VPS35 gene mutation, a CHCHD2 gene mutation a PTRHD1 gene mutation, a PLA2G6 gene mutation, a SPG11 gene mutation, a FBXO7 gene mutation, a DNAJC6 gene mutation, a SYNJ1 gene mutation, a ATP13A2 gene mutation, a VPS13C gene mutation, a PODXL gene mutation, a POLG gene mutation, a DCTN1 gene mutation, a LRP10 genemutation, a RAB39B gene mutation, or a combination of two or more thereof. In embodiments, the patient has (i) REM sleep behavior disorder and / or REM sleep without atonia; (ii) a family history of a synucleinopathy, such as Parkinson’s disease, (iii) an elevated level of alpha synuclein relative to a control, (iv) a gene mutation as described herein, or (v) a combination of two or more of (i), (ii), (iii), and (iv) (and embodiments of the foregoing as described herein for a patient at risk).

[0086] Methods for Reducing the Incidence of Parkinson’s Disease

[0087] Provided herein are methods for reducing the incidence of Parkinson’s disease in a patient population in need thereof comprising administering to the patient population an effective amount of an adenosine A2A receptor antagonist, thereby reducing the incidence of Parkinson’s disease. In embodiments, the patient population is at risk of developing Parkinson’s disease. In embodiments, patients in the patient population have REM sleep behavior disorder. In embodiments, patients in the patient population have REM sleep without atonia. In embodiments, patients in the patient population have an elevated level of alpha synuclein. In embodiments, patients in the patient population have an elevated level of alpha synuclein relative to a control. In embodiments, patients in the patient population have an elevated level of alpha synuclein relative to a healthy control. In embodiments, patients in the patient population have an elevated level of an alpha-synuclein aggregate. In embodiments, patients in the patient population have an elevated level of an alpha-synuclein aggregate relative to a control. In embodiments, patients in the patient population have an elevated level of an alpha-synuclein aggregate relative to a healthy control. In embodiments, the patients in the patient population have a family history of Parkinson’s disease. In embodiments, patients in the patient population have a GBA1 gene mutation, a UCHL1 gene mutation, a LRRK2 gene mutation, a PARK7 gene mutation, a PINK1 gene mutation, a PARK2 gene mutation, a PRKN gene mutation, a SNCA gene mutation, a GIGYF2 gene mutation, a DNAJC13 gene mutation, a TMEM230 gene mutation, a GCH1 gene mutation, a EIF4G1 gene mutation, a HTRA2 gene mutation, a RIC3 gene mutation, a ATXN2 gene mutation, a VPS35 gene mutation, a CHCHD2 gene mutation a PTRHD1 gene mutation, a PLA2G6 gene mutation, a SPG11 gene mutation, a FBXO7 gene mutation, a DNAJC6 gene mutation, a SYNJ1 gene mutation, a ATP13A2 gene mutation, a VPS13C gene mutation, a PODXL gene mutation, a POLG gene mutation, a DCTN1 gene mutation, a LRP10 gene mutation, a RAB39B gene mutation, or a combination of two or more thereof. In embodiments, the patients in the patient population have (i) REM sleep behavior disorder and / or REM sleep without atonia; (ii) afamily history of a synucleinopathy, such as Parkinson’s disease, (iii) an elevated level of alpha synuclein relative to a control, (iv) a gene mutation as described herein, or (v) a combination of two or more of (i), (ii), (iii), and (iv) (and embodiments of the foregoing as described herein for a patient at risk). In embodiments, the adenosine A2A receptor antagonist is ciforadenant, enprofylline, vipadenant, preladenant, tozadenant, or istradefylline. In embodiments, the adenosine A2A receptor antagonist is ciforadenant, enprofylline, vipadenant, preladenant, tozadenant, istradefylline, inupadenant, etrumadenant, taminadenant, TB206-001, PORT-6, M1069, ST1535, or ST4206. In embodiments, the adenosine A2A receptor antagonist is ciforadenant. In embodiments, the adenosine A2A receptor antagonist is enprofylline. In embodiments, the adenosine A2A receptor antagonist is vipadenant. In embodiments, the adenosine A2A receptor antagonist is praladenant. In embodiments, the adenosine A2A receptor antagonist is tozadenant. In embodiments, the adenosine A2A receptor antagonist is istradefylline. In embodiments, the adenosine A2A receptor antagonist is inupadenant, In embodiments, the adenosine A2A receptor antagonist is etrumadenant. In embodiments, the adenosine A2A receptor antagonist is taminadenant. In embodiments, the adenosine A2A receptor antagonist is TB206-001. In embodiments, the adenosine A2A receptor antagonist is PORT-6. In embodiments, the adenosine A2A receptor antagonist is M1069. In embodiments, the adenosine A2A receptor antagonist is ST1535. In embodiments, the adenosine A2A receptor antagonist is ST4206.

[0088] Methods for Preventing Synucleinopathy

[0089] Provided herein are methods for preventing a synucleinopathy or delaying onset of a synucleinopathy in a patient in need thereof comprising administering to the patient an effective amount of an adenosine A2A receptor antagonist, thereby preventing a synucleinopathy or delaying onset of a synucleinopathy. Provided herein are methods for preventing a synucleinopathy in a patient in need thereof comprising administering to the patient an effective amount of an adenosine A2A receptor antagonist, thereby preventing a synucleinopathy. Provided herein are methods for delaying onset of a synucleinopathy in a patient in need thereof comprising administering to the patient an effective amount of an adenosine A2A receptor antagonist, thereby delaying onset of a synucleinopathy. In embodiments, the synucleinopathy is Parkinson’s disease, dementia with Lewy bodies, multiple system atrophy, pure autonomic failure, or Alzheimer's disease with amygdalar restricted Lewy bodies. In embodiments, the synucleinopathy is Parkinson’s disease. In embodiments, the synucleinopathy is dementia with Lewy bodies. In embodiments, thesynucleinopathy is multiple system atrophy. In embodiments, the synucleinopathy is pure autonomic failure. In embodiments, the synucleinopathy is Alzheimer's disease with amygdalar restricted Lewy bodies. In embodiments, the patient has REM sleep behavior disorder. In embodiments, the patient has REM sleep without atonia. In embodiments, the patient has an elevated level of alpha synuclein. In embodiments, the patient has an elevated level of alpha synuclein relative to a control. In embodiments, the patient has an elevated level of alpha synuclein relative to a healthy control. In embodiments, the patient has an elevated level of an alpha-synuclein aggregate. In embodiments, the patient has an elevated level of an alpha- synuclein aggregate relative to a control. In embodiments, the patient has an elevated level of an alpha-synuclein aggregate relative to a healthy control. In embodiments, the patient has a family history of Parkinson’s disease. In embodiments, the patient has a GBA1 gene mutation, a UCHL1 gene mutation, a LRRK2 gene mutation, a PARK7 gene mutation, a PINK1 gene mutation, a PARK2 gene mutation, a PRKN gene mutation, a SNCA gene mutation, a GIGYF2 gene mutation, a DNAJC13 gene mutation, a TMEM230 gene mutation, a GCH1 gene mutation, a EIF4G1 gene mutation, a HTRA2 gene mutation, a RIC3 gene mutation, a ATXN2 gene mutation, a VPS35 gene mutation, a CHCHD2 gene mutation a PTRHD1 gene mutation, a PLA2G6 gene mutation, a SPG11 gene mutation, a FBXO7 gene mutation, a DNAJC6 gene mutation, a SYNJ1 gene mutation, a ATP13A2 gene mutation, a VPS13C gene mutation, a PODXL gene mutation, a POLG gene mutation, a DCTN1 gene mutation, a LRP10 gene mutation, a RAB39B gene mutation, or a combination of two or more thereof. In embodiments, the patient has (i) REM sleep behavior disorder and / or REM sleep without atonia; (ii) a family history of a synucleinopathy, (iii) an elevated level of alpha synuclein relative to a control, (iv) a gene mutation as described herein, or (v) a combination of two or more of (i), (ii), (iii), and (iv) (and embodiments of the foregoing as described herein for a patient at risk). In embodiments, the adenosine A2A receptor antagonist is ciforadenant, enprofylline, vipadenant, preladenant, tozadenant, or istradefylline. In embodiments, the adenosine A2A receptor antagonist is ciforadenant, enprofylline, vipadenant, preladenant, tozadenant, istradefylline, inupadenant, etrumadenant, taminadenant, TB206-001, PORT-6, M1069, ST1535, or ST4206. In embodiments, the adenosine A2A receptor antagonist is ciforadenant. In embodiments, the adenosine A2A receptor antagonist is enprofylline. In embodiments, the adenosine A2A receptor antagonist is vipadenant. In embodiments, the adenosine A2A receptor antagonist is praladenant. In embodiments, the adenosine A2A receptor antagonist is tozadenant. In embodiments, the adenosine A2A receptor antagonist is istradefylline. In embodiments, the adenosine A2A receptor antagonist is inupadenant, In embodiments, the adenosine A2Areceptor antagonist is etrumadenant. In embodiments, the adenosine A2A receptor antagonist is taminadenant. In embodiments, the adenosine A2A receptor antagonist is TB206-001. In embodiments, the adenosine A2A receptor antagonist is PORT-6. In embodiments, the adenosine A2A receptor antagonist is M1069. In embodiments, the adenosine A2A receptor antagonist is ST1535. In embodiments, the adenosine A2A receptor antagonist is ST4206.

[0090] Provided herein are methods for preventing a synucleinopathy or delaying onset of a synucleinopathy in a patient in need thereof comprising administering to the patient an effective amount of ciforadenant, thereby preventing a synucleinopathy or delaying onset of a synucleinopathy. Provided herein are methods for preventing a synucleinopathy in a patient in need thereof comprising administering to the patient an effective amount of ciforadenant, thereby preventing a synucleinopathy. Provided herein are methods for delaying onset of a synucleinopathy in a patient in need thereof comprising administering to the patient an effective amount of ciforadenant, thereby delaying onset of a synucleinopathy. In embodiments, the synucleinopathy is Parkinson’s disease, dementia with Lewy bodies, multiple system atrophy, pure autonomic failure, or Alzheimer's disease with amygdalar restricted Lewy bodies. In embodiments, the synucleinopathy is Parkinson’s disease. In embodiments, the synucleinopathy is dementia with Lewy bodies. In embodiments, the synucleinopathy is multiple system atrophy. In embodiments, the synucleinopathy is pure autonomic failure. In embodiments, the synucleinopathy is Alzheimer's disease with amygdalar restricted Lewy bodies. In embodiments, the patient has REM sleep behavior disorder. In embodiments, the patient has REM sleep without atonia. In embodiments, the patient has an elevated level of alpha synuclein. In embodiments, the patient has an elevated level of alpha synuclein relative to a control. In embodiments, the patient has an elevated level of alpha synuclein relative to a healthy control. In embodiments, the patient has an elevated level of an alpha-synuclein aggregate. In embodiments, the patient has an elevated level of an alpha- synuclein aggregate relative to a control. In embodiments, the patient has an elevated level of an alpha-synuclein aggregate relative to a healthy control. In embodiments, the patient has a family history of Parkinson’s disease. In embodiments, the patient has a GBA1 gene mutation, a UCHL1 gene mutation, a LRRK2 gene mutation, a PARK7 gene mutation, a PINK1 gene mutation, a PARK2 gene mutation, a PRKN gene mutation, a SNCA gene mutation, a GIGYF2 gene mutation, a DNAJC13 gene mutation, a TMEM230 gene mutation, a GCH1 gene mutation, a EIF4G1 gene mutation, a HTRA2 gene mutation, a RIC3 gene mutation, a ATXN2 gene mutation, a VPS35 gene mutation, a CHCHD2 gene mutation a PTRHD1 gene mutation,a PLA2G6 gene mutation, a SPG11 gene mutation, a FBXO7 gene mutation, a DNAJC6 gene mutation, a SYNJ1 gene mutation, a ATP13A2 gene mutation, a VPS13C gene mutation, a PODXL gene mutation, a POLG gene mutation, a DCTN1 gene mutation, a LRP10 gene mutation, a RAB39B gene mutation, or a combination of two or more thereof. In embodiments, the patient has (i) REM sleep behavior disorder and / or REM sleep without atonia; (ii) a family history of a synucleinopathy, (iii) an elevated level of alpha synuclein relative to a control, (iv) a gene mutation as described herein, or (v) a combination of two or more of (i), (ii), (iii), and (iv) (and embodiments of the foregoing as described herein for a patient at risk).

[0091] Methods for Preventing Dementia with Lewy Bodies

[0092] Provided herein are methods for preventing dementia with Lewy bodies or delaying onset of dementia with Lewy bodies in a patient in need thereof comprising administering to the patient an effective amount of an adenosine A2A receptor antagonist, thereby preventing dementia with Lewy bodies or delaying onset of dementia with Lewy bodies. Provided herein are methods for preventing dementia with Lewy bodies in a patient in need thereof comprising administering to the patient an effective amount of an adenosine A2A receptor antagonist, thereby preventing dementia with Lewy bodies. Provided herein are methods for delaying onset of dementia with Lewy bodies in a patient in need thereof comprising administering to the patient an effective amount of an adenosine A2A receptor antagonist, thereby delaying onset of dementia with Lewy bodies. In embodiments, the patient has REM sleep behavior disorder. In embodiments, the patient has REM sleep without atonia. In embodiments, the patient has an elevated level of alpha synuclein. In embodiments, the patient has an elevated level of alpha synuclein relative to a control. In embodiments, the patient has an elevated level of alpha synuclein relative to a healthy control. In embodiments, the patient has an elevated level of an alpha-synuclein aggregate. In embodiments, the patient has an elevated level of an alpha-synuclein aggregate relative to a control. In embodiments, the patient has an elevated level of an alpha-synuclein aggregate relative to a healthy control. In embodiments, the patient has a family history of Parkinson’s disease. In embodiments, the patient has a GBA1 gene mutation, a UCHL1 gene mutation, a LRRK2 gene mutation, a PARK7 gene mutation, a PINK1 gene mutation, a PARK2 gene mutation, a PRKN gene mutation, a SNCA gene mutation, a GIGYF2 gene mutation, a DNAJC13 gene mutation, a TMEM230 gene mutation, a GCH1 gene mutation, a EIF4G1 gene mutation, a HTRA2 gene mutation, a RIC3 gene mutation, a ATXN2 gene mutation, a VPS35 gene mutation, a CHCHD2 gene mutation a PTRHD1 gene mutation, a PLA2G6 gene mutation, a SPG11 gene mutation, a FBXO7 genemutation, a DNAJC6 gene mutation, a SYNJ1 gene mutation, a ATP13A2 gene mutation, a VPS13C gene mutation, a PODXL gene mutation, a POLG gene mutation, a DCTN1 gene mutation, a LRP10 gene mutation, a RAB39B gene mutation, or a combination of two or more thereof. In embodiments, the patient has (i) REM sleep behavior disorder and / or REM sleep without atonia; (ii) a family history of a synucleinopathy, such as dementia with Lewy bodies, (iii) an elevated level of alpha synuclein relative to a control, (iv) a gene mutation as described herein, or (v) a combination of two or more of (i), (ii), (iii), and (iv) (and embodiments of the foregoing as described herein for a patient at risk). In embodiments, the adenosine A2A receptor antagonist is ciforadenant, enprofylline, vipadenant, preladenant, tozadenant, or istradefylline. In embodiments, the adenosine A2A receptor antagonist is ciforadenant, enprofylline, vipadenant, preladenant, tozadenant, istradefylline, inupadenant, etrumadenant, taminadenant, TB206-001, PORT-6, M1069, ST1535, or ST4206. In embodiments, the adenosine A2A receptor antagonist is ciforadenant. In embodiments, the adenosine A2A receptor antagonist is enprofylline. In embodiments, the adenosine A2A receptor antagonist is vipadenant. In embodiments, the adenosine A2A receptor antagonist is praladenant. In embodiments, the adenosine A2A receptor antagonist is tozadenant. In embodiments, the adenosine A2A receptor antagonist is istradefylline. In embodiments, the adenosine A2A receptor antagonist is inupadenant, In embodiments, the adenosine A2A receptor antagonist is etrumadenant. In embodiments, the adenosine A2A receptor antagonist is taminadenant. In embodiments, the adenosine A2A receptor antagonist is TB206-001. In embodiments, the adenosine A2A receptor antagonist is PORT-6. In embodiments, the adenosine A2A receptor antagonist is M1069. In embodiments, the adenosine A2A receptor antagonist is ST1535. In embodiments, the adenosine A2A receptor antagonist is ST4206.

[0093] Provided herein are methods for preventing dementia with Lewy bodies or delaying onset of dementia with Lewy bodies in a patient in need thereof comprising administering to the patient an effective amount of ciforadenant, thereby preventing dementia with Lewy bodies or delaying onset of dementia with Lewy bodies. Provided herein are methods for preventing dementia with Lewy bodies in a patient in need thereof comprising administering to the patient an effective amount of ciforadenant, thereby preventing dementia with Lewy bodies. Provided herein are methods for delaying onset of dementia with Lewy bodies in a patient in need thereof comprising administering to the patient an effective amount of ciforadenant, thereby delaying onset of dementia with Lewy bodies. In embodiments, the patient has REM sleep behavior disorder. In embodiments, the patient has REM sleep without atonia. In embodiments,the patient has an elevated level of alpha synuclein. In embodiments, the patient has an elevated level of alpha synuclein relative to a control. In embodiments, the patient has an elevated level of alpha synuclein relative to a healthy control. In embodiments, the patient has an elevated level of an alpha-synuclein aggregate. In embodiments, the patient has an elevated level of an alpha-synuclein aggregate relative to a control. In embodiments, the patient has an elevated level of an alpha-synuclein aggregate relative to a healthy control. In embodiments, the patient has a family history of Parkinson’s disease. In embodiments, the patient has a GBA1 gene mutation, a UCHL1 gene mutation, a LRRK2 gene mutation, a PARK7 gene mutation, a PINK1 gene mutation, a PARK2 gene mutation, a PRKN gene mutation, a SNCA gene mutation, a GIGYF2 gene mutation, a DNAJC13 gene mutation, a TMEM230 gene mutation, a GCH1 gene mutation, a EIF4G1 gene mutation, a HTRA2 gene mutation, a RIC3 gene mutation, a ATXN2 gene mutation, a VPS35 gene mutation, a CHCHD2 gene mutation a PTRHD1 gene mutation, a PLA2G6 gene mutation, a SPG11 gene mutation, a FBXO7 gene mutation, a DNAJC6 gene mutation, a SYNJ1 gene mutation, a ATP13A2 gene mutation, a VPS13C gene mutation, a PODXL gene mutation, a POLG gene mutation, a DCTN1 gene mutation, a LRP10 gene mutation, a RAB39B gene mutation, or a combination of two or more thereof. In embodiments, the patient has (i) REM sleep behavior disorder and / or REM sleep without atonia; (ii) a family history of a synucleinopathy, such as dementia with Lewy bodies, (iii) an elevated level of alpha synuclein relative to a control, (iv) a gene mutation as described herein, or (v) a combination of two or more of (i), (ii), (iii), and (iv) (and embodiments of the foregoing as described herein for a patient at risk).

[0094] Methods for Preventing Multiple System Atrophy

[0095] Provided herein are methods for preventing multiple system atrophy or delaying onset of multiple system atrophy in a patient in need thereof comprising administering to the patient an effective amount of an adenosine A2A receptor antagonist, thereby preventing multiple system atrophy or delaying onset of multiple system atrophy. Provided herein are methods for preventing multiple system atrophy in a patient in need thereof comprising administering to the patient an effective amount of an adenosine A2A receptor antagonist, thereby preventing multiple system atrophy. Provided herein are methods for delaying onset of multiple system atrophy in a patient in need thereof comprising administering to the patient an effective amount of an adenosine A2A receptor antagonist, thereby delaying onset of multiple system atrophy. In embodiments, the patient has REM sleep behavior disorder. In embodiments, the patient has REM sleep without atonia. In embodiments, the patient has anelevated level of alpha synuclein. In embodiments, the patient has an elevated level of alpha synuclein relative to a control. In embodiments, the patient has an elevated level of alpha synuclein relative to a healthy control. In embodiments, the patient has an elevated level of an alpha-synuclein aggregate. In embodiments, the patient has an elevated level of an alpha- synuclein aggregate relative to a control. In embodiments, the patient has an elevated level of an alpha-synuclein aggregate relative to a healthy control. In embodiments, the patient has a family history of Parkinson’s disease. In embodiments, the patient has a GBA1 gene mutation, a UCHL1 gene mutation, a LRRK2 gene mutation, a PARK7 gene mutation, a PINK1 gene mutation, a PARK2 gene mutation, a PRKN gene mutation, a SNCA gene mutation, a GIGYF2 gene mutation, a DNAJC13 gene mutation, a TMEM230 gene mutation, a GCH1 gene mutation, a EIF4G1 gene mutation, a HTRA2 gene mutation, a RIC3 gene mutation, a ATXN2 gene mutation, a VPS35 gene mutation, a CHCHD2 gene mutation a PTRHD1 gene mutation, a PLA2G6 gene mutation, a SPG11 gene mutation, a FBXO7 gene mutation, a DNAJC6 gene mutation, a SYNJ1 gene mutation, a ATP13A2 gene mutation, a VPS13C gene mutation, a PODXL gene mutation, a POLG gene mutation, a DCTN1 gene mutation, a LRP10 gene mutation, a RAB39B gene mutation, or a combination of two or more thereof. In embodiments, the patient has (i) REM sleep behavior disorder and / or REM sleep without atonia; (ii) a family history of a synucleinopathy, such as multiple system atrophy, (iii) an elevated level of alpha synuclein relative to a control, (iv) a gene mutation as described herein, or (v) a combination of two or more of (i), (ii), (iii), and (iv) (and embodiments of the foregoing as described herein for a patient at risk). In embodiments, the adenosine A2A receptor antagonist is ciforadenant, enprofylline, vipadenant, preladenant, tozadenant, or istradefylline. In embodiments, the adenosine A2A receptor antagonist is ciforadenant, enprofylline, vipadenant, preladenant, tozadenant, istradefylline, inupadenant, etrumadenant, taminadenant, TB206-001, PORT-6, M1069, ST1535, or ST4206. In embodiments, the adenosine A2A receptor antagonist is ciforadenant. In embodiments, the adenosine A2A receptor antagonist is enprofylline. In embodiments, the adenosine A2A receptor antagonist is vipadenant. In embodiments, the adenosine A2A receptor antagonist is praladenant. In embodiments, the adenosine A2A receptor antagonist is tozadenant. In embodiments, the adenosine A2A receptor antagonist is istradefylline. In embodiments, the adenosine A2A receptor antagonist is inupadenant, In embodiments, the adenosine A2A receptor antagonist is etrumadenant. In embodiments, the adenosine A2A receptor antagonist is taminadenant. In embodiments, the adenosine A2A receptor antagonist is TB206-001. In embodiments, the adenosine A2A receptor antagonist is PORT-6. In embodiments, the adenosine A2A receptor antagonist is M1069. In embodiments,the adenosine A2A receptor antagonist is ST1535. In embodiments, the adenosine A2A receptor antagonist is ST4206.

[0096] Provided herein are methods for preventing multiple system atrophy or delaying onset of multiple system atrophy in a patient in need thereof comprising administering to the patient an effective amount of ciforadenant, thereby preventing multiple system atrophy or delaying onset of multiple system atrophy. Provided herein are methods for preventing multiple system atrophy in a patient in need thereof comprising administering to the patient an effective amount of ciforadenant, thereby preventing multiple system atrophy. Provided herein are methods for delaying onset of multiple system atrophy in a patient in need thereof comprising administering to the patient an effective amount of ciforadenant, thereby delaying onset of multiple system atrophy. In embodiments, the patient has REM sleep behavior disorder. In embodiments, the patient has REM sleep without atonia. In embodiments, the patient has an elevated level of alpha synuclein. In embodiments, the patient has an elevated level of alpha synuclein relative to a control. In embodiments, the patient has an elevated level of alpha synuclein relative to a healthy control. In embodiments, the patient has an elevated level of an alpha-synuclein aggregate. In embodiments, the patient has an elevated level of an alpha-synuclein aggregate relative to a control. In embodiments, the patient has an elevated level of an alpha-synuclein aggregate relative to a healthy control. In embodiments, the patient has a family history of Parkinson’s disease. In embodiments, the patient has a GBA1 gene mutation, a UCHL1 gene mutation, a LRRK2 gene mutation, a PARK7 gene mutation, a PINK1 gene mutation, a PARK2 gene mutation, a PRKN gene mutation, a SNCA gene mutation, a GIGYF2 gene mutation, a DNAJC13 gene mutation, a TMEM230 gene mutation, a GCH1 gene mutation, a EIF4G1 gene mutation, a HTRA2 gene mutation, a RIC3 gene mutation, a ATXN2 gene mutation, a VPS35 gene mutation, a CHCHD2 gene mutation a PTRHD1 gene mutation, a PLA2G6 gene mutation, a SPG11 gene mutation, a FBXO7 gene mutation, a DNAJC6 gene mutation, a SYNJ1 gene mutation, a ATP13A2 gene mutation, a VPS13C gene mutation, a PODXL gene mutation, a POLG gene mutation, a DCTN1 gene mutation, a LRP10 gene mutation, a RAB39B gene mutation, or a combination of two or more thereof. In embodiments, the patient has a LRP10 gene mutation. In embodiments, the patient has (i) REM sleep behavior disorder and / or REM sleep without atonia; (ii) a family history of a synucleinopathy, such as multiple system atrophy, (iii) an elevated level of alpha synuclein relative to a control, (iv) a gene mutation as described herein, or (v) a combination of two or more of (i), (ii), (iii), and (iv) (and embodiments of the foregoing as described herein for apatient at risk).

[0097] Methods for Preventing Pure Autonomic Failure

[0098] Provided herein are methods for preventing pure autonomic failure or delaying onset of pure autonomic failure in a patient in need thereof comprising administering to the patient an effective amount of an adenosine A2A receptor antagonist, thereby preventing pure autonomic failure or delaying onset of pure autonomic failure. Provided herein are methods for preventing pure autonomic failure in a patient in need thereof comprising administering to the patient an effective amount of an adenosine A2A receptor antagonist, thereby preventing pure autonomic failure. Provided herein are methods for delaying onset of pure autonomic failure in a patient in need thereof comprising administering to the patient an effective amount of an adenosine A2A receptor antagonist, thereby delaying onset of pure autonomic failure. In embodiments, the patient has REM sleep behavior disorder. In embodiments, the patient has REM sleep without atonia. In embodiments, the patient has an elevated level of alpha synuclein. In embodiments, the patient has an elevated level of alpha synuclein relative to a control. In embodiments, the patient has an elevated level of alpha synuclein relative to a healthy control. In embodiments, the patient has an elevated level of an alpha-synuclein aggregate. In embodiments, the patient has an elevated level of an alpha-synuclein aggregate relative to a control. In embodiments, the patient has an elevated level of an alpha-synuclein aggregate relative to a healthy control. In embodiments, the patient has a family history of Parkinson’s disease. In embodiments, the patient has a GBA1 gene mutation, a UCHL1 gene mutation, a LRRK2 gene mutation, a PARK7 gene mutation, a PINK1 gene mutation, a PARK2 gene mutation, a PRKN gene mutation, a SNCA gene mutation, a GIGYF2 gene mutation, a DNAJC13 gene mutation, a TMEM230 gene mutation, a GCH1 gene mutation, a EIF4G1 gene mutation, a HTRA2 gene mutation, a RIC3 gene mutation, a ATXN2 gene mutation, a VPS35 gene mutation, a CHCHD2 gene mutation a PTRHD1 gene mutation, a PLA2G6 gene mutation, a SPG11 gene mutation, a FBXO7 gene mutation, a DNAJC6 gene mutation, a SYNJ1 gene mutation, a ATP13A2 gene mutation, a VPS13C gene mutation, a PODXL gene mutation, a POLG gene mutation, a DCTN1 gene mutation, a LRP10 gene mutation, a RAB39B gene mutation, or a combination of two or more thereof. In embodiments, the patient has (i) REM sleep behavior disorder and / or REM sleep without atonia; (ii) a family history of a synucleinopathy, such as pure autonomic failure, (iii) an elevated level of alpha synuclein relative to a control, (iv) a gene mutation as described herein, or (v) a combination of two or more of (i), (ii), (iii), and (iv) (and embodiments of the foregoing as described herein fora patient at risk). In embodiments, the adenosine A2A receptor antagonist is ciforadenant, enprofylline, vipadenant, preladenant, tozadenant, or istradefylline. In embodiments, the adenosine A2A receptor antagonist is ciforadenant, enprofylline, vipadenant, preladenant, tozadenant, istradefylline, inupadenant, etrumadenant, taminadenant, TB206-001, PORT-6, M1069, ST1535, or ST4206. In embodiments, the adenosine A2A receptor antagonist is ciforadenant. In embodiments, the adenosine A2A receptor antagonist is enprofylline. In embodiments, the adenosine A2A receptor antagonist is vipadenant. In embodiments, the adenosine A2A receptor antagonist is praladenant. In embodiments, the adenosine A2A receptor antagonist is tozadenant. In embodiments, the adenosine A2A receptor antagonist is istradefylline. In embodiments, the adenosine A2A receptor antagonist is inupadenant, In embodiments, the adenosine A2A receptor antagonist is etrumadenant. In embodiments, the adenosine A2A receptor antagonist is taminadenant. In embodiments, the adenosine A2A receptor antagonist is TB206-001. In embodiments, the adenosine A2A receptor antagonist is PORT-6. In embodiments, the adenosine A2A receptor antagonist is M1069. In embodiments, the adenosine A2A receptor antagonist is ST1535. In embodiments, the adenosine A2A receptor antagonist is ST4206.

[0099] Provided herein are methods for preventing pure autonomic failure or delaying onset of pure autonomic failure in a patient in need thereof comprising administering to the patient an effective amount of ciforadenant, thereby preventing pure autonomic failure or delaying onset of pure autonomic failure. Provided herein are methods for preventing pure autonomic failure in a patient in need thereof comprising administering to the patient an effective amount of ciforadenant, thereby preventing pure autonomic failure. Provided herein are methods for delaying onset of pure autonomic failure in a patient in need thereof comprising administering to the patient an effective amount of ciforadenant, thereby delaying onset of pure autonomic failure. In embodiments, the patient has REM sleep behavior disorder. In embodiments, the patient has REM sleep without atonia. In embodiments, the patient has an elevated level of alpha synuclein. In embodiments, the patient has an elevated level of alpha synuclein relative to a control. In embodiments, the patient has an elevated level of alpha synuclein relative to a healthy control. In embodiments, the patient has an elevated level of an alpha-synuclein aggregate. In embodiments, the patient has an elevated level of an alpha-synuclein aggregate relative to a control. In embodiments, the patient has an elevated level of an alpha-synuclein aggregate relative to a healthy control. In embodiments, the patient has a family history of Parkinson’s disease. In embodiments, the patient has a GBA1 gene mutation, a UCHL1 genemutation, a LRRK2 gene mutation, a PARK7 gene mutation, a PINK1 gene mutation, a PARK2 gene mutation, a PRKN gene mutation, a SNCA gene mutation, a GIGYF2 gene mutation, a DNAJC13 gene mutation, a TMEM230 gene mutation, a GCH1 gene mutation, a EIF4G1 gene mutation, a HTRA2 gene mutation, a RIC3 gene mutation, a ATXN2 gene mutation, a VPS35 gene mutation, a CHCHD2 gene mutation a PTRHD1 gene mutation, a PLA2G6 gene mutation, a SPG11 gene mutation, a FBXO7 gene mutation, a DNAJC6 gene mutation, a SYNJ1 gene mutation, a ATP13A2 gene mutation, a VPS13C gene mutation, a PODXL gene mutation, a POLG gene mutation, a DCTN1 gene mutation, a LRP10 gene mutation, a RAB39B gene mutation, or a combination of two or more thereof. In embodiments, the patient has (i) REM sleep behavior disorder and / or REM sleep without atonia; (ii) a family history of a synucleinopathy, such as pure autonomic failure, (iii) an elevated level of alpha synuclein relative to a control, (iv) a gene mutation as described herein, or (v) a combination of two or more of (i), (ii), (iii), and (iv) (and embodiments of the foregoing as described herein for a patient at risk).

[0100] Methods for Detecting a Gene Variant

[0101] The present disclosure provides methods of detecting the gene mutations (biomarkers) described herein. The practice of the present disclosure employs, unless otherwise indicated, conventional methods of analytical biochemistry, microbiology, molecular biology and recombinant DNA techniques within the skill of the art. Such techniques are explained fully in the literature. (See, e.g., Sambrook et al, Molecular Cloning: A Laboratory Manual.3rd, ed., Cold Spring Harbor Laboratory, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, 2000; DNA Cloning: A Practical Approach, Vol. I & II (D. Glover, ed.); Oligonucleotide Synthesis (N. Gait, ed., Current Edition); Nucleic Acid Hybridization (B. Hames & S. Higgins, eds., Current Edition); Transcription and Translation (B. Hames & S. Higgins, eds., Current Edition); CRC Handbook of Parvoviruses, Vol. I & II (P. Tijessen, ed.); Fundamental Virology, 2nd Edition, Vol. I & II (B. N. Fields and D. M. Knipe, eds.)).

[0102] In embodiments, the methods described herein (including embodiments thereof) further comprise detecting a GBA1 gene mutation, a UCHL1 gene mutation, a LRRK2 gene mutation, a PARK7 gene mutation, a PINK1 gene mutation, a PARK2 gene mutation, a PRKN gene mutation, a SNCA gene mutation, a GIGYF2 gene mutation, a DNAJC13 gene mutation, a TMEM230 gene mutation, a GCH1 gene mutation, a EIF4G1 gene mutation, a HTRA2 gene mutation, a RIC3 gene mutation, a ATXN2 gene mutation, a VPS35 gene mutation, a CHCHD2 gene mutation a PTRHD1 gene mutation, a PLA2G6 gene mutation, a SPG11 genemutation, a FBXO7 gene mutation, a DNAJC6 gene mutation, a SYNJ1 gene mutation, a ATP13A2 gene mutation, a VPS13C gene mutation, a PODXL gene mutation, a POLG gene mutation, a DCTN1 gene mutation, a LRP10 gene mutation, a RAB39B gene mutation, or a combination of two or more thereof in a biological sample obtained from the patient. In embodiments, the gene mutation is any gene mutation known in the art to be associated with Parkinson’s disease. In embodiments, the biological sample is a cerebrospinal fluid sample, a blood sample, or a saliva sample. In embodiments, the biological sample is a cerebrospinal fluid sample. In embodiments, the biological sample is a blood sample. In embodiments, the biological sample is a saliva sample. In embodiments, the biological sample is a In embodiments, the biological sample is a skin biopsy.

[0103] In embodiments, the methods described herein (including embodiments thereof) further comprise detecting a GBA1 gene mutation, a UCHL1 gene mutation, a LRRK2 gene mutation, a PARK7 gene mutation, a PINK1 gene mutation, a PARK2 gene mutation, a PRKN gene mutation, a SNCA gene mutation, a GIGYF2 gene mutation, a DNAJC13 gene mutation, a TMEM230 gene mutation, a EIF4G1 gene mutation, a HTRA2 gene mutation, a VPS35 gene mutation, a CHCHD2 gene mutation, a PLA2G6 gene mutation, a FBXO7 gene mutation, a DNAJC6 gene mutation, a SYNJ1 gene mutation, a ATP13A2 gene mutation, a VPS13C gene mutation, a POLG gene mutation, a DCTN1 gene mutation, a LRP10 gene mutation, or a combination of two or more thereof in a biological sample obtained from the patient. In embodiments, the gene mutation is any gene mutation known in the art to be associated with Parkinson’s disease. In embodiments, the biological sample is a cerebrospinal fluid sample, a blood sample, or a saliva sample. In embodiments, the biological sample is a cerebrospinal fluid sample. In embodiments, the biological sample is a blood sample. In embodiments, the biological sample is a saliva sample. In embodiments, the biological sample is a In embodiments, the biological sample is a skin biopsy.

[0104] In embodiments, the methods described herein (including embodiments thereof) further comprise detecting a GBA1 gene mutation, a LRRK2 gene mutation, a PRKN gene mutation, a SNCA gene mutation, a PINK1 gene mutation, a PARK2 gene mutation, a PARK7 gene mutation, a VPS35 gene mutation, or a combination of two or more thereof in a biological sample obtained from the patient. In embodiments, the methods described herein (including embodiments thereof) further comprise detecting a LRRK2 gene mutation, a PARK2 gene mutation, a PARK7 gene mutation, a PINK1 gene mutation, a SNCA gene mutation, or a combination of two or more thereof in a biological sample obtained from the patient. Inembodiments, the methods described herein (including embodiments thereof) further comprise detecting a GBA1 gene mutation, a LRRK2 gene mutation, a PRKN gene mutation, a SNCA gene mutation, a PINK1 gene mutation, a PARK7 gene mutation, a VPS35 gene mutation, or acombination of two or more thereof in a biological sample obtained from the patient. Inembodiments, the gene mutation is any gene mutation known in the art to be associated with Parkinson’s disease. In embodiments, the biological sample is a cerebrospinal fluid sample, a blood sample, or a saliva sample. In embodiments, the biological sample is a cerebrospinal fluid sample. In embodiments, the biological sample is a blood sample. In embodiments, the biological sample is a saliva sample. In embodiments, the biological sample is a In embodiments, the biological sample is a skin biopsy.

[0105] In embodiments, the methods described herein (including embodiments thereof) further comprise detecting a GBA1 gene mutation in a biological sample obtained from the patient. In embodiments, the methods described herein (including embodiments thereof) further comprise detecting a UCHL1 gene mutation in a biological sample obtained from the patient. In embodiments, the methods described herein (including embodiments thereof) further comprise detecting a LRRK2 gene mutation in a biological sample obtained from the patient. In embodiments, the methods described herein (including embodiments thereof) further comprise detecting a PARK7 gene mutation in a biological sample obtained from the patient. In embodiments, the methods described herein (including embodiments thereof) further comprise detecting a PINK1 gene mutation in a biological sample obtained from the patient. In embodiments, the methods described herein (including embodiments thereof) further comprise detecting a PARK2 gene mutation in a biological sample obtained from the patient. In embodiments, the methods described herein (including embodiments thereof) further comprise detecting a PRKN gene mutation in a biological sample obtained from the patient. In embodiments, the methods described herein (including embodiments thereof) further comprise detecting a SNCA gene mutation in a biological sample obtained from the patient. In embodiments, the methods described herein (including embodiments thereof) further comprise detecting a GIGYF2 gene mutation in a biological sample obtained from the patient. In embodiments, the methods described herein (including embodiments thereof) further comprise detecting a DNAJC13 gene mutation in a biological sample obtained from the patient. In embodiments, the methods described herein (including embodiments thereof) further comprise detecting a TMEM230 gene mutation in a biological sample obtained from the patient. In embodiments, the methods described herein (including embodiments thereof)further comprise detecting a GCH1 gene mutation in a biological sample obtained from the patient. In embodiments, the methods described herein (including embodiments thereof) further comprise detecting a EIF4G1 gene mutation in a biological sample obtained from the patient. In embodiments, the methods described herein (including embodiments thereof) further comprise detecting a HTRA2 gene mutation in a biological sample obtained from the patient. In embodiments, the methods described herein (including embodiments thereof) further comprise detecting a RIC3 gene mutation in a biological sample obtained from the patient. In embodiments, the methods described herein (including embodiments thereof) further comprise detecting a ATXN2 gene mutation in a biological sample obtained from the patient. In embodiments, the methods described herein (including embodiments thereof) further comprise detecting a VPS35 gene mutation in a biological sample obtained from the patient. In embodiments, the methods described herein (including embodiments thereof) further comprise detecting a CHCHD2 gene mutation in a biological sample obtained from the patient. In embodiments, the methods described herein (including embodiments thereof) further comprise detecting a PTRHD1 gene mutation in a biological sample obtained from the patient. In embodiments, the methods described herein (including embodiments thereof) further comprise detecting a PLA2G6 gene mutation in a biological sample obtained from the patient. In embodiments, the methods described herein (including embodiments thereof) further comprise detecting a SPG11 gene mutation in a biological sample obtained from the patient. In embodiments, the methods described herein (including embodiments thereof) further comprise detecting a FBXO7 gene mutation in a biological sample obtained from the patient. In embodiments, the methods described herein (including embodiments thereof) further comprise detecting a DNAJC6 gene mutation in a biological sample obtained from the patient. In embodiments, the methods described herein (including embodiments thereof) further comprise detecting a SYNJ1 gene mutation in a biological sample obtained from the patient. In embodiments, the methods described herein (including embodiments thereof) further comprise detecting a ATP13A2 gene mutation in a biological sample obtained from the patient. In embodiments, the methods described herein (including embodiments thereof) further comprise detecting a VPS13C gene mutation in a biological sample obtained from the patient. In embodiments, the methods described herein (including embodiments thereof) further comprise detecting a PODXL gene mutation in a biological sample obtained from the patient. In embodiments, the methods described herein (including embodiments thereof) further comprise detecting a POLG gene mutation in a biological sample obtained from the patient. In embodiments, the methods described herein (including embodiments thereof)further comprise detecting a DCTN1 gene mutation in a biological sample obtained from the patient. In embodiments, the methods described herein (including embodiments thereof) further comprise detecting a LRP10 gene mutation in a biological sample obtained from the patient. In embodiments, the methods described herein (including embodiments thereof) further comprise detecting a RAB39B gene mutation in a biological sample obtained from the patient. In embodiments, the gene mutation is any gene mutation known in the art to be associated with Parkinson’s disease. In embodiments, the biological sample is a cerebrospinal fluid sample, a blood sample, or a saliva sample. In embodiments, the biological sample is a cerebrospinal fluid sample. In embodiments, the biological sample is a blood sample. In embodiments, the biological sample is a saliva sample. In embodiments, the biological sample is a In embodiments, the biological sample is a skin biopsy.

[0106] In embodiments, a genetic mutation described herein is compared to a control, such as a standard set or reference group of genetic mutations that have been associated with a synucleinopathy or associated with a risk of developing a synucleinopathy. In embodiments, the reference group of genetic mutations is determined according to a statistical procedure for risk prediction. In embodiments, the control is patient or patient population having a synucleinopathy, wherein presence of the genetic mutation in the patient and the control is predictive of the patient having a synucleinopathy or at risk of developing a synucleinopathy. In embodiments, the control is healthy patient or a population of healthy patients, wherein presence of the gene mutation in the patient, but not in the healthy control, is predictive of the patient having a synucleinopathy or at risk of developing a synucleinopathy. In embodiments, the synucleinopathy is Parkinson’s disease.

[0107] The presence of the genetic mutation can be detected by obtaining a genomic DNA sample from the patient and determining the presence of the genetic mutation, e.g., at the specific locus. In embodiments, the presence of the genetic mutation is determined by multiplexed locus-specific PCR amplification, multiplexed single-based extension (SBE) from locus-specific amplicons, and multiplexed resolution of SBE products using matrix-assisted laser desorption / ionization time-of-flight (MALDI-TOF) mass spectrometry.

[0108] In embodiments, the presence of the genetic mutation is determined by obtaining RNA from the biological sample, generating cDNA from the RNA, and optionally amplifying the cDNA with probes or primers for genetic locations containing the genetic mutation, thereby determining the presence of the genetic mutation in the biological sample.

[0109] In embodiments, the means to detect the genetic mutation includes a nucleic acid probe having at least 10 to 50 contiguous nucleic acids of the nucleic acid sequence comprising the genetic mutation. The nucleic acid probes are disposed on an assay surface that may include a chip, array, or fluidity card. The assay system can include a control selected from information containing a predetermined genetic mutation having that has been correlated with having a synucleinopathy or being at risk of developing a synucleinopathy. In embodiments, the step of detecting comprises using a nucleotide probe that hybridizes to at least one genetic location comprising the genetic mutation. In embodiments, the probe is a chimeric probe (e.g., that hybridizes to more than one of the genetic mutations). In embodiments, the step of detecting a genetic mutation can include detecting the number of copies of the genetic mutation in one or more cells in the biological sample (i.e., determining whether the individual is heterozygous or homozygous in the genetic mutation).

[0110] Typically, the target genomic segment is amplified and separated from non-target sequence, e.g., through use of a biotinylated primer and chromatography. A probe that is specific for the particular allele is added to the amplification product. The probe can be designed to hybridize specifically to a variant sequence or to the dominant allelic sequence. The probe can be either labeled with or added in the presence of a molecule that fluoresces when bound to double-stranded DNA. The signal intensity is then measured as temperature is increased until the Tm can be determined. A non-matching sequence (either gene mutation or dominant allelic sequence, depending on probe design), will result in a lower than expected Tm.

[0111] Dynamic allele-specific hybridization (DASH) can be used to detect a gene mutation. DASH genotyping takes advantage of the differences in the melting temperature in DNA that results from the instability of mismatched base pairs. The process can be vastly automated and encompasses a few simple principles. DASH genotyping relies on a quantifiable change in Tm, and is thus capable of measuring many types of mutations, not just SNPs. Other benefits of DASH include its ability to work with label free probes and its simple design and performance conditions.

[0112] Molecular beacons can also be used to detect a gene mutation. This method makes use of a specifically engineered single-stranded oligonucleotide probe. The oligonucleotide is designed such that there are complementary regions at each end and a probe sequence located in between. This design allows the probe to take on a hairpin, or stem-loop, structure in its natural, isolated state. Attached to one end of the probe is a fluorophore and to the other end afluorescence quencher. Because of the stem-loop structure of the probe, the fluorophore is in close proximity to the quencher, thus preventing the molecule from emitting any fluorescence. The molecule is also engineered such that only the probe sequence is complementary to the targeted genomic DNA sequence. If the probe sequence of the molecular beacon encounters its target genomic DNA sequence during the assay, it will anneal and hybridize. Because of the length of the probe sequence, the hairpin segment of the probe will be denatured in favor of forming a longer, more stable probe-target hybrid. This conformational change permits the fluorophore and quencher to be free of their tight proximity due to the hairpin association, allowing the molecule to fluoresce. If on the other hand, the probe sequence encounters a target sequence with as little as one non-complementary nucleotide, the molecular beacon will preferentially stay in its natural hairpin state and no fluorescence will be observed, as the fluorophore remains quenched. The unique design of these molecular beacons allows for a simple diagnostic assay to identify SNPs at a given location. If a molecular beacon is designed to match a wild-type allele and another to match a mutant of the allele, the two can be used to identify the genotype of an individual. If only the first probe’s fluorophore wavelength is detected during the assay, then the individual is homozygous to the wild type. If only the second probe’s wavelength is detected then the individual is homozygous to the mutant allele. Finally, if both wavelengths are detected, then both molecular beacons must be hybridizing to their complements and thus the individual must contain both alleles and be heterozygous.

[0113] A microarray can also be used to detect gene mutations. Hundreds of thousands of probes can be arrayed on a small chip, allowing for many gene mutations or SNPs to be interrogated simultaneously. Because SNP alleles only differ in one nucleotide and because it is difficult to achieve optimal hybridization conditions for all probes on the array, the target DNA has the potential to hybridize to mismatched probes. This can be addressed by using several redundant probes to interrogate each SNP. Probes can be designed to have the SNP site in several different locations as well as containing mismatches to the SNP allele. By comparing the differential amount of hybridization of the target DNA to each of these redundant probes, it is possible to determine specific homozygous and heterozygous alleles.

[0114] Restriction fragment length polymorphism (RFLP) can be used to detect gene mutations. RFLP makes use of the many different restriction endonucleases and their high affinity to unique and specific restriction sites. By performing a digestion on a genomic sample and determining fragment lengths through a gel assay it is possible to ascertain whether or not the enzymes cut the expected restriction sites. A failure to cut the genomic sample results in anidentifiably larger than expected fragment implying that there is a mutation at the point of the restriction site which is rendering it protected from nuclease activity.

[0115] PCR- and amplification-based methods can be used to detect gene mutations. For example, tetra-primer PCR employs two pairs of primers to amplify two alleles in one PCR reaction. The primers are designed such that the two primer pairs overlap at a SNP location but each matches perfectly to only one of the possible alleles. As a result, if a given allele is present in the PCR reaction, the primer pair specific to that allele will produce product but not the alternative allele with a different allelic sequence. The two primer pairs can be designed such that their PCR products are of a significantly different length allowing for easily distinguishable bands by gel electrophoresis, or such that they are differently labeled.

[0116] Primer extension can also be used to detect gene mutations. Primer extension first involves the hybridization of a probe to the bases immediately upstream of the SNP nucleotide followed by a ‘mini-sequencing’ reaction, in which DNA polymerase extends the hybridized primer by adding a base that is complementary to the SNP nucleotide. The incorporated base that is detected determines the presence of the SNP allele. Because primer extension is based on the highly accurate DNA polymerase enzyme, the method is generally very reliable. Primer extension is able to genotype most SNPs under similar reaction conditions making it also highly flexible. The primer extension method is used in a number of assay formats, and can be detected using e.g., fluorescent labels or mass spectrometry.

[0117] Oligonucleotide ligation assays can also be used to detect gene mutations. DNA ligase catalyzes the ligation of the 3' end of a DNA fragment to the 5' end of a directly adjacent DNA fragment. This mechanism can be used to interrogate a SNP by hybridizing two probes directly over the SNP polymorphic site, whereby ligation can occur if the probes are identical to the target DNA. For example, two probes can be designed; an allele-specific probe which hybridizes to the target DNA so that its 3' base is situated directly over the SNP nucleotide and a second probe that hybridizes the template upstream (downstream in the complementary strand of the SNP polymorphic site providing a 5' end for the ligation reaction. If the allele- specific probe matches the target DNA, it will fully hybridize to the target DNA and ligation can occur. Ligation does not generally occur in the presence of a mismatched 3' base. Ligated or unligated products can be detected by gel electrophoresis, MALDI-TOF mass spectrometry or by capillary electrophoresis.

[0118] The 5’-nuclease activity of Taq DNA polymerase can be used for detecting genemutations. The assay is performed concurrently with a PCR reaction and the results can be read in real-time. The assay requires forward and reverse PCR primers that will amplify a region that includes the SNP polymorphic site. Allele discrimination is achieved using FRET, and one or two allele-specific probes that hybridize to the SNP polymorphic site. The probes have a fluorophore linked to their 5’ end and a quencher molecule linked to their 3’ end. While the probe is intact, the quencher will remain in close proximity to the fluorophore, eliminating the fluorophore’s signal. During the PCR amplification step, if the allele-specific probe is perfectly complementary to the SNP allele, it will bind to the target DNA strand and then get degraded by 5’-nuclease activity of the Taq polymerase as it extends the DNA from the PCR primers. The degradation of the probe results in the separation of the fluorophore from the quencher molecule, generating a detectable signal. If the allele-specific probe is not perfectly complementary, it will have lower melting temperature and not bind as efficiently. This prevents the nuclease from acting on the probe.

[0119] Förster resonance energy transfer (FRET) detection can be used for detection in primer extension and ligation reactions where the two labels are brought into close proximity to each other. It can also be used in the 5'-nuclease reaction, the molecular beacon reaction, and the invasive cleavage reactions where the neighboring donor / acceptor pair is separated by cleavage or disruption of the stem-loop structure that holds them together. FRET occurs when two conditions are met. First, the emission spectrum of the fluorescent donor dye must overlap with the excitation wavelength of the acceptor dye. Second, the two dyes must be in close proximity to each other because energy transfer drops off quickly with distance. The proximity requirement is what makes FRET a good detection method for a number of allelic discrimination mechanisms. A variety of dyes can be used for FRET, and are known in the art. The most common ones are fluorescein, cyanine dyes (Cy3 to Cy7), rhodamine dyes (e.g. rhodamine 6G), the Alexa series of dyes (Alexa 405 to Alexa 730). Some of these dyes have been used in FRET networks (with multiple donors and acceptors). Optics for imaging all of these require detection from UV to near IR (e.g. Alex 405 to Cy7), and the Atto series of dyes (Atto-Tec GmbH). The Alexa series of dyes from Invitrogen cover the whole spectral range. They are very bright and photostable.

[0120] Methods for Detecting Biomarker Levels

[0121] The biomarkers of the disclosure, e.g., alpha-synuclein, are detected by any method known in the art, including without limitation enzyme-linked immunosorbent assays (ELISA), Luminex®, single molecule arrays, electrochemiluminescence, immunomagnetic reduction(IMR), LC-MS, GC-MS, immunoassays, hybridization, and enzyme assays. The detection may be quantitative or qualitative. A wide variety of conventional techniques are available, including mass spectrometry, chromatographic separations, binding assays (e.g., immunoassays), and competitive inhibition assays. Any effective method in the art for measuring the presence or level or activity of a polypeptide or polynucleotide is included in the disclosure. It is within the ability of one of ordinary skill in the art to determine which method would be most appropriate for measuring a specific marker. Thus, for example, a ELISA assay may be best suited for use in a physician’s office while a measurement requiring more sophisticated instrumentation may be best suited for use in a clinical laboratory.

[0122] In embodiments, the level of biomarkers (e.g., alpha-synuclein) is determined using a standard immunoassay, such as sandwiched ELISA using matched antibody pairs and chemiluminescent detection. Commercially available or custom monoclonal or polyclonal antibodies are typically used. However, the assay can be adapted for use with other reagents that specifically bind to the marker. Standard protocols and data analysis are used to determine the marker concentrations from the assay data.

[0123] In embodiments, the level of alpha-synuclein is determined by any method known in the art. Exemplary methods include SYN-ONE TEST® by CND Life Sciences and SYNTap® Test by Aprion Inc. and those described by Yan et al, “Neuronally Derived Extracellular Vesicle α-Synuclein as a Serum Biomarker for Individuals at Risk of Developing Parkinson Disease,” JAMA Neurol, 2024; 81(1):59-68; Coughlin et al, Fluid and Biopsy Based Biomarkers in Parkinson’s Disease, Neurotherapeutics, 2023; 20(4):932-954; Chang et al, Plasma and Serum Alpha-Synuclein as a Biomarker of Diagnosis in Patients with Parkinson’s Disease, Front Neurol, 2019; 10:1388; Tsao et al, Detection and assessment of alpha-synuclein in Parkinson disease, Neurochemistry International, Volume 158 (September 2022); and Kluge et al, Detection of neuron-derived pathological α-synuclein in blood, Brain, 2022; 145(9):3058-3071; the disclosures of which are incorporated by reference herein in their entirety.

[0124] Embodiments 1-120.

[0125] Embodiment 1. A method for treating REM sleep behavior disorder in a patient in need thereof, the method comprising administering to the patient an effective amount of an adenosine A2A receptor antagonist, thereby treating REM sleep behavior disorder.

[0126] Embodiment 2. A method for treating REM sleep without atonia in a patient in needthereof, the method comprising administering to the patient an effective amount of an adenosine A2A receptor antagonist, thereby treating REM sleep without atonia.

[0127] Embodiment 3. A method for preventing Parkinson’s disease in a patient in need thereof, the method comprising administering to the patient an effective amount of an adenosine A2A receptor antagonist, thereby preventing Parkinson’s disease.

[0128] Embodiment 4. A method for delaying onset of Parkinson’s disease in a patient in need thereof, the method comprising administering to the patient an effective amount of an adenosine A2A receptor antagonist, thereby delaying onset of Parkinson’s disease.

[0129] Embodiment 5. A method for preventing a synucleinopathy in a patient in need thereof, the method comprising administering to the patient an effective amount of an adenosine A2A receptor antagonist, thereby preventing synucleinopathy.

[0130] Embodiment 6. A method for delaying onset of a synucleinopathy in a patient in need thereof, the method comprising administering to the patient an effective amount of an adenosine A2A receptor antagonist, thereby delaying onset of the synucleinopathy.

[0131] Embodiment 7. The method of embodiment 5 or 6, wherein the synucleinopathy is Parkinson’s disease, dementia with Lewy bodies, multiple system atrophy, pure autonomic failure, or Alzheimer's disease with amygdalar restricted Lewy bodies.

[0132] Embodiment 8. The method of embodiment 5 or 6, wherein the synucleinopathy is dementia with Lewy bodies.

[0133] Embodiment 9. The method of embodiment 5 or 6, wherein the synucleinopathy is multiple system atrophy.

[0134] Embodiment 10. The method of embodiment 5 or 6, wherein the synucleinopathy is pure autonomic failure.

[0135] Embodiment 11. The method of embodiment 5 or 6, wherein the synucleinopathy is Alzheimer's disease with amygdalar restricted Lewy bodies.

[0136] Embodiment 12. The method of any one of embodiments 1 to 11, wherein the patient has an elevated level of alpha-synuclein relative to a healthy control.

[0137] Embodiment 13. The method of embodiment 12, wherein the alpha synuclein is an alpha-synuclein aggregate.

[0138] Embodiment 14. A method for decreasing an elevated level of alpha synuclein in apatient in need thereof, the method comprising administering to the patient an effective amount of an adenosine A2A receptor antagonist, wherein the patient has an elevated level of alpha synuclein relative to a healthy control, thereby decreasing the level of alpha synuclein.

[0139] Embodiment 15. The method of embodiment 14, wherein the alpha synuclein is an alpha-synuclein aggregate.

[0140] Embodiment 16. The method of any one of embodiments 1 to 15, wherein the patient is at risk of developing Parkinson’s disease.

[0141] Embodiment 17. The method of any one of embodiments 1 to 16, wherein the patient has REM sleep behavior disorder.

[0142] Embodiment 18. The method of any one of embodiments 1 to 17, wherein the patient has REM sleep without atonia.

[0143] Embodiment 19. The method of any one of embodiments 1 to 18, wherein the patient has a family history of Parkinson’s disease.

[0144] Embodiment 20. The method any one of embodiments 1 to 19, wherein the patient has a GBA1 gene mutation, a UCHL1 gene mutation, a LRRK2 gene mutation, a PARK7 gene mutation, a PINK1 gene mutation, a PARK2 gene mutation, a PRKN gene mutation, a SNCA gene mutation, a GIGYF2 gene mutation, a DNAJC13 gene mutation, a TMEM230 gene mutation, a GCH1 gene mutation, a EIF4G1 gene mutation, a HTRA2 gene mutation, a RIC3 gene mutation, a ATXN2 gene mutation, a VPS35 gene mutation, a CHCHD2 gene mutation, a PTRHD1 gene mutation, a PLA2G6 gene mutation, a SPG11 gene mutation, a FBXO7 gene mutation, a DNAJC6 gene mutation, a SYNJ1 gene mutation, a ATP13A2 gene mutation, a VPS13C gene mutation, a PODXL gene mutation, a POLG gene mutation, a DCTN1 gene mutation, a LRP10 gene mutation, a RAB39B gene mutation, or a combination of two or more thereof.

[0145] Embodiment 21. The method any one of embodiments 1 to 19, wherein the patient has a GBA1 gene mutation, a UCHL1 gene mutation, a LRRK2 gene mutation, a PARK7 gene mutation, a PINK1 gene mutation, a PARK2 gene mutation, a PRKN gene mutation, a SNCA gene mutation, a GIGYF2 gene mutation, a DNAJC13 gene mutation, a TMEM230 gene mutation, a EIF4G1 gene mutation, a HTRA2 gene mutation, a VPS35 gene mutation, a CHCHD2 gene mutation, a PLA2G6 gene mutation, a FBXO7 gene mutation, a DNAJC6 gene mutation, a SYNJ1 gene mutation, a ATP13A2 gene mutation, a VPS13C gene mutation, a POLG gene mutation, a DCTN1 gene mutation, a LRP10 gene mutation, or a combination oftwo or more thereof.

[0146] Embodiment 22. The method any one of embodiments 1 to 19, wherein the patient has a GBA1 gene mutation, a LRRK2 gene mutation, a PRKN gene mutation, a SNCA gene mutation, a PINK1 gene mutation, a PARK2 gene mutation, a PARK7 gene mutation, a VPS35 gene mutation, or a combination of two or more thereof.

[0147] Embodiment 23. The method any one of embodiments 1 to 19, wherein the patient has a LRRK2 gene mutation, a PARK2 gene mutation, a PARK7 gene mutation, a PINK1 gene mutation, a SNCA gene mutation, or a combination of two or more thereof.

[0148] Embodiment 24. The method any one of embodiments 1 to 19, wherein the patient has a GBA1 gene mutation, a LRRK2 gene mutation, a PRKN gene mutation, a SNCA gene mutation, a PINK1 gene mutation, a PARK7 gene mutation, a VPS35 gene mutation, or a combination of two or more thereof.

[0149] Embodiment 25. The method any one of embodiments 1 to 19, wherein the patient has a GBA1 gene mutation.

[0150] Embodiment 26. The method any one of embodiments 1-19 and 25, wherein the patient has a UCHL1 gene mutation.

[0151] Embodiment 27. The method any one of embodiments 1-19, 25, and 26, wherein the patient has a LRRK2 gene mutation.

[0152] Embodiment 28. The method any one of embodiments 1-19 and 25-27, wherein the patient has a PARK7 gene mutation.

[0153] Embodiment 29. The method any one of embodiments 1-19 and 25-28, wherein the patient has a PINK1 gene mutation.

[0154] Embodiment 30. The method any one of embodiments 1-19 and 25-29. wherein the patient has a PRKN gene mutation.

[0155] Embodiment 31. The method any one of embodiments 1-19 and 25-30, wherein the patient has a SNCA gene mutation.

[0156] Embodiment 32. The method any one of embodiments 1-19 and 25-31, wherein the patient has a GIGYF2 gene mutation.

[0157] Embodiment 33. The method any one of embodiments 1-19 and 25-32, wherein the patient has a DNAJC13 gene mutation.

[0158] Embodiment 34. The method any one of embodiments 1-19 and 25-33, wherein the patient has a TMEM230 gene mutation.

[0159] Embodiment 35. The method any one of embodiments 1-19 and 25-34, wherein the patient has a GCH1 gene mutation.

[0160] Embodiment 36. The method any one of embodiments 1-19 and 25-35, wherein the patient has a EIF4G1 gene mutation.

[0161] Embodiment 37. The method any one of embodiments 1-19 and 25-36, wherein the patient has a HTRA2 gene mutation.

[0162] Embodiment 38. The method any one of embodiments 1-19 and 25-37, wherein the patient has a RIC3 gene mutation.

[0163] Embodiment 39. The method any one of embodiments 1-19 and 25-38, wherein the patient has a ATXN2 gene mutation.

[0164] Embodiment 40. The method any one of embodiments 1-19 and 25-39, wherein the patient has a VPS35 gene mutation.

[0165] Embodiment 41. The method any one of embodiments 1-19 and 25-40, wherein the patient has a CHCHD2 gene mutation.

[0166] Embodiment 42. The method any one of embodiments 1-19 and 25-41, wherein the patient has a PTRHD1 gene mutation.

[0167] Embodiment 43. The method any one of embodiments 1-19 and 25-42, wherein the patient has a PLA2G6 gene mutation.

[0168] Embodiment 44. The method any one of embodiments 1-19 and 25-43, wherein the patient has a SPG11 gene mutation.

[0169] Embodiment 45. The method any one of embodiments 1-19 and 25-44, wherein the patient has a FBXO7 gene mutation.

[0170] Embodiment 46. The method any one of embodiments 1-19 and 25-45, wherein the patient has a DNAJC6 gene mutation.

[0171] Embodiment 47. The method any one of embodiments 1-19 and 25-46, wherein the patient has a SYNJ1 gene mutation.

[0172] Embodiment 48. The method any one of embodiments 1-19 and 25-47, wherein thepatient has a ATP13A2 gene mutation.

[0173] Embodiment 49. The method any one of embodiments 1-19 and 25-48, wherein the patient has a VPS13C gene mutation.

[0174] Embodiment 50. The method any one of embodiments 1-19 and 25-49, wherein the patient has a PODXL gene mutation.

[0175] Embodiment 51. The method any one of embodiments 1-19 and 25-50, wherein the patient has a POLG gene mutation.

[0176] Embodiment 52. The method any one of embodiments 1-19 and 25-51, wherein the patient has a DCTN1 gene mutation.

[0177] Embodiment 53. The method any one of embodiments 1-19 and 25-52, wherein the patient has a LRP10 gene mutation.

[0178] Embodiment 54. The method any one of embodiments 1-19 and 25-53, wherein the patient has a RAB39B gene mutation.

[0179] Embodiment 55. The method any one of embodiments 1-19 and 25-54, wherein the patient has a PARK2 gene mutation.

[0180] Embodiment 56. The method any one of embodiments 1 to 19, further comprising detecting a GBA1 gene mutation, a UCHL1 gene mutation, a LRRK2 gene mutation, a PARK7 gene mutation, a PARK2 gene mutation, a PINK1 gene mutation, a PRKN gene mutation, a SNCA gene mutation, a GIGYF2 gene mutation, a DNAJC13 gene mutation, a TMEM230 gene mutation, a GCH1 gene mutation, a EIF4G1 gene mutation, a HTRA2 gene mutation, a RIC3 gene mutation, a ATXN2 gene mutation, a VPS35 gene mutation, a CHCHD2 gene mutation a PTRHD1 gene mutation, a PLA2G6 gene mutation, a SPG11 gene mutation, a FBXO7 gene mutation, a DNAJC6 gene mutation, a SYNJ1 gene mutation, a ATP13A2 gene mutation, a VPS13C gene mutation, a PODXL gene mutation, a POLG gene mutation, a DCTN1 gene mutation, a LRP10 gene mutation, a RAB39B gene mutation, or a combination of two or more thereof in a biological sample obtained from the patient.

[0181] Embodiment 57. The method any one of embodiments 1 to 19, further comprising detecting a GBA1 gene mutation, a UCHL1 gene mutation, a LRRK2 gene mutation, a PARK7 gene mutation, a PINK1 gene mutation, a PARK2 gene mutation, a PRKN gene mutation, a SNCA gene mutation, a GIGYF2 gene mutation, a DNAJC13 gene mutation, a TMEM230 gene mutation, a EIF4G1 gene mutation, a HTRA2 gene mutation, a VPS35 gene mutation, aCHCHD2 gene mutation, a PLA2G6 gene mutation, a FBXO7 gene mutation, a DNAJC6 gene mutation, a SYNJ1 gene mutation, a ATP13A2 gene mutation, a VPS13C gene mutation, a POLG gene mutation, a DCTN1 gene mutation, a LRP10 gene mutation, or a combination of two or more thereof in a biological sample obtained from the patient.

[0182] Embodiment 58. The method any one of embodiments 1 to 19, further comprising detecting a GBA1 gene mutation, a LRRK2 gene mutation, a PRKN gene mutation, a SNCA gene mutation, a PINK1 gene mutation, a PARK2 gene mutation, a PARK7 gene mutation, a VPS35 gene mutation, or a combination of two or more thereof in a biological sample obtained from the patient.

[0183] Embodiment 59. The method any one of embodiments 1 to 19, further comprising detecting a LRRK2 gene mutation, a PARK2 gene mutation, a PARK7 gene mutation, a PINK1 gene mutation, a SNCA gene mutation, or a combination of two or more thereof in a biological sample obtained from the patient.

[0184] Embodiment 60. The method any one of embodiments 1 to 19, further comprising detecting a GBA1 gene mutation, a LRRK2 gene mutation, a PRKN gene mutation, a SNCA gene mutation, a PINK1 gene mutation, a PARK7 gene mutation, a VPS35 gene mutation, or a combination of two or more thereof in a biological sample obtained from the patient.

[0185] Embodiment 61. The method any one of embodiments 1 to 19, further comprising detecting a GBA1 gene mutation in a biological sample obtained from the patient.

[0186] Embodiment 62. The method any one of embodiments 1-19 and 61, further comprising detecting a UCHL1 gene mutation in a biological sample obtained from the patient.

[0187] Embodiment 63. The method any one of embodiments 1-19, 61, and 62, further comprising detecting a LRRK2 gene mutation in a biological sample obtained from the patient.

[0188] Embodiment 64. The method any one of embodiments 1-19 and 60-63, further comprising detecting a PARK7 gene mutation in a biological sample obtained from the patient.

[0189] Embodiment 65. The method any one of embodiments 1-19 and 60-64, further comprising detecting a PINK1 gene mutation in a biological sample obtained from the patient.

[0190] Embodiment 66. The method any one of embodiments 1-19 and 60-65, further comprising detecting a PARK2 gene mutation in a biological sample obtained from the patient.

[0191] Embodiment 67. The method any one of embodiments 1-19 and 60-66, further comprising detecting a PRKN gene mutation in a biological sample obtained from the patient.

[0192] Embodiment 68. The method any one of embodiments 1-19 and 60-67, further comprising detecting a SNCA gene mutation in a biological sample obtained from the patient.

[0193] Embodiment 69. The method any one of embodiments 1-19 and 60-68, further comprising detecting a GIGYF2 gene mutation in a biological sample obtained from the patient.

[0194] Embodiment 70. The method any one of embodiments 1-19 and 60-69, further comprising detecting a DNAJC13 gene mutation in a biological sample obtained from the patient.

[0195] Embodiment 71. The method any one of embodiments 1-19 and 60-70, further comprising detecting a TMEM230 gene mutation in a biological sample obtained from the patient.

[0196] Embodiment 72. The method any one of embodiments 1-19 and 60-71, further comprising detecting a GCH1 gene mutation in a biological sample obtained from the patient.

[0197] Embodiment 73. The method any one of embodiments 1-19 and 60-72, further comprising detecting a EIF4G1 gene mutation in a biological sample obtained from the patient.

[0198] Embodiment 74. The method any one of embodiments 1-19 and 60-73, further comprising detecting a HTRA2 gene mutation in a biological sample obtained from the patient.

[0199] Embodiment 75. The method any one of embodiments 1-19 and 60-74, further comprising detecting a RIC3 gene mutation in a biological sample obtained from the patient.

[0200] Embodiment 76. The method any one of embodiments 1-19 and 60-75, further comprising detecting a ATXN2 gene mutation in a biological sample obtained from the patient.

[0201] Embodiment 77. The method any one of embodiments 1-19 and 60-76, further comprising detecting a VPS35 gene mutation in a biological sample obtained from the patient.

[0202] Embodiment 78. The method any one of embodiments 1-19 and 60-77, further comprising detecting a CHCHD2 gene mutation in a biological sample obtained from the patient.

[0203] Embodiment 79. The method any one of embodiments 1-19 and 60-78, further comprising detecting a PTRHD1 gene mutation in a biological sample obtained from the patient.

[0204] Embodiment 80. The method any one of embodiments 1-19 and 60-79, furthercomprising detecting a PLA2G6 gene mutation in a biological sample obtained from the patient.

[0205] Embodiment 81. The method any one of embodiments 1-19 and 60-80, further comprising detecting a SPG11 gene mutation in a biological sample obtained from the patient.

[0206] Embodiment 82. The method any one of embodiments 1-19 and 60-81, further comprising detecting a FBXO7 gene mutation in a biological sample obtained from the patient.

[0207] Embodiment 83. The method any one of embodiments 1-19 and 60-82, further comprising detecting a DNAJC6 gene mutation in a biological sample obtained from the patient.

[0208] Embodiment 84. The method any one of embodiments 1-19 and 60-83, further comprising detecting a SYNJ1 gene mutation in a biological sample obtained from the patient.

[0209] Embodiment 85. The method any one of embodiments 1-19 and 60-84, further comprising detecting a ATP13A2 gene mutation in a biological sample obtained from the patient.

[0210] Embodiment 86. The method any one of embodiments 1-19 and 60-85, further comprising detecting a VPS13C gene mutation in a biological sample obtained from the patient.

[0211] Embodiment 87. The method any one of embodiments 1-19 and 60-86, further comprising detecting a PODXL gene mutation in a biological sample obtained from the patient.

[0212] Embodiment 88. The method any one of embodiments 1-19 and 60-87, further comprising detecting a POLG gene mutation in a biological sample obtained from the patient.

[0213] Embodiment 89. The method any one of embodiments 1-19 and 60-88, further comprising detecting a DCTN1 gene mutation in a biological sample obtained from the patient.

[0214] Embodiment 90. The method any one of embodiments 1-19 and 60-89, further comprising detecting a LRP10 gene mutation in a biological sample obtained from the patient.

[0215] Embodiment 91. The method any one of embodiments 1-19 and 60-90, further comprising detecting a RAB39B gene mutation in a biological sample obtained from the patient.

[0216] Embodiment 92. The method any one of embodiments 1 to 91, further comprisingdetecting an elevated level of alpha synuclein, relative to a control, in a biological sample obtained from the patient.

[0217] Embodiment 93. The method of embodiment 92, wherein the alpha synuclein is an alpha-synuclein aggregate.

[0218] Embodiment 94. The method of embodiment 92 or 93, wherein the control is a healthy control.

[0219] Embodiment 95. The method of any one of embodiments 56 to 94, wherein the biological sample is a cerebrospinal fluid sample.

[0220] Embodiment 96. The method of any one of embodiments 56 to 94, wherein the biological sample is a blood sample.

[0221] Embodiment 97. The method of any one of embodiments 56 to 94, wherein the biological sample is a saliva sample.

[0222] Embodiment 98. The method of any one of embodiments 56 to 94, wherein the biological sample is a skin biopsy.

[0223] Embodiment 99. The method of any one of embodiments 56 to 94, wherein the biological sample is a serum sample.

[0224] Embodiment 100. The method of any one of embodiments 56 to 94, wherein the biological sample is a plasma sample.

[0225] Embodiment 101. The method of any one of embodiments 1 to 100, further comprising administering an electroencephalogram to the patient and detecting a decreased attenuation of beta frequency electroencephalographic activity during phasic REM sleep compared to tonic REM sleep, compared to a control.

[0226] Embodiment 102. The method of any one of embodiments 1 to 101, further comprising administering an electroencephalogram to the patient and detecting reduced overnight decline in slow-wave activity during NREM sleep, compared to a control.

[0227] Embodiment 103. The method of any one of embodiments 1 to 102, further comprising administering an electroencephalogram to the patient and detecting decreased overnight modifications in the slow-wave amplitude distribution, compared to a control.

[0228] Embodiment 104. The method of any one of embodiments 1 to 103, further comprising administering a polysomnogram to the patient and detecting decreased muscleatonia during REM sleep, compared to a control.

[0229] Embodiment 105. The method of any one of embodiments 1 to 104, wherein the adenosine A2A receptor antagonist is ciforadenant.

[0230] Embodiment 106. The method of any one of embodiments 1 to 104, wherein the adenosine A2A receptor antagonist is enprofylline.

[0231] Embodiment 107. The method of any one of embodiments 1 to 104, wherein the adenosine A2A receptor antagonist is vipadenant.

[0232] Embodiment 108. The method of any one of embodiments 1 to 104, wherein the adenosine A2A receptor antagonist is praladenant.

[0233] Embodiment 109. The method of any one of embodiments 1 to 104, wherein the adenosine A2A receptor antagonist is tozadenant.

[0234] Embodiment 110. The method of any one of embodiments 1 to 104, wherein the adenosine A2A receptor antagonist is istradefylline.

[0235] Embodiment 111. The method of any one of embodiments 1 to 104, wherein the adenosine A2A receptor antagonist is ciforadenant, enprofylline, vipadenant, preladenant, tozadenant, or istradefylline.

[0236] Embodiment 112. The method of any one of embodiments 1 to 111, wherein the effective amount of the adenosine A2A receptor antagonist is from about 1 mg to about 1,000 mg.

[0237] Embodiment 113. The method of any one of embodiments 1 to 111, wherein the effective amount of the adenosine A2A receptor antagonist is from about 1 mg to about 500 mg.

[0238] Embodiment 114. The method of any one of embodiments 1 to 111, wherein the effective amount of the adenosine A2A receptor antagonist is from about 1 mg to about 250 mg.

[0239] Embodiment 115. The method of any one of embodiments 1 to 111, wherein the effective amount of the adenosine A2A receptor antagonist is from about 10 mg to about 250 mg.

[0240] Embodiment 117. The method of any one of embodiments 1 to 111, wherein the effective amount of the adenosine A2A receptor antagonist is from about 20 mg to about 250mg.

[0241] Embodiment 119. The method of any one of embodiments 1 to 111, wherein the effective amount of the adenosine A2A receptor antagonist is from about 30 mg to about 250 mg.

[0242] Embodiment 120. The method of any one of embodiments 1 to 111, wherein the effective amount of the adenosine A2A receptor antagonist is from about 40 mg to about 250 mg.

[0243] Embodiment 120. The method of any one of embodiments 1 to 111, wherein the effective amount of the adenosine A2A receptor antagonist is from about 50 mg to about 250 mg. EXAMPLE

[0244] Ciforadenant was administered to rats and marmoset in models of caralepsy, haloperidol-induced hypolocomotion, and MTP-induced Parkinson’s disease. The results are shown in the table below. Assay Species Dose (mg / kg) Response s o

[0245] A ciforadenant dose of 10 mg / kg in rats and marmosets is equivalent to about 1.6 mg / kg in humans or about 128 mg in an 80 kg human. A ciforadenant dose of 2.5 mg / kg in cynos is equivalent to about 0.8 mg / kg in humans or about 65 mg in an 80 kg human.

[0246] While various embodiments and aspects are shown and described herein, it will be clear to the skilled artisan that such embodiments and aspects are provided by way of example. It will be understood that various alternatives to the embodiments described herein can be used. All patents and publications cited herein are incorporated by reference in their entirety and for all purposes.

Claims

CLAIMS What is claimed is:

1. A method for treating REM sleep behavior disorder in a patient in need thereof, the method comprising administering to the patient an effective amount of an adenosine A2A receptor antagonist, thereby treating REM sleep behavior disorder.

2. A method for treating REM sleep without atonia in a patient in need thereof, the method comprising administering to the patient an effective amount of an adenosine A2A receptor antagonist, thereby treating REM sleep without atonia.

3. A method for preventing Parkinson’s disease in a patient in need thereof, the method comprising administering to the patient an effective amount of an adenosine A2A receptor antagonist, thereby preventing Parkinson’s disease.

4. A method for delaying onset of Parkinson’s disease in a patient in need thereof, the method comprising administering to the patient an effective amount of an adenosine A2A receptor antagonist, thereby delaying onset of Parkinson’s disease.

5. A method for preventing a synucleinopathy in a patient in need thereof, the method comprising administering to the patient an effective amount of an adenosine A2A receptor antagonist, thereby preventing synucleinopathy.

6. A method for delaying onset of a synucleinopathy in a patient in need thereof, the method comprising administering to the patient an effective amount of an adenosine A2A receptor antagonist, thereby delaying onset of the synucleinopathy.

7. The method of claim 5 or 6, wherein the synucleinopathy is Parkinson’s disease, dementia with Lewy bodies, multiple system atrophy, pure autonomic failure, or Alzheimer's disease with amygdalar restricted Lewy bodies.

8. The method of claim 1, wherein the patient has an elevated level of alpha- synuclein relative to a healthy control.

9. A method for decreasing an elevated level of alpha synuclein in a patient in need thereof, the method comprising administering to the patient an effective amount of an adenosine A2A receptor antagonist, wherein the patient has an elevated level of alpha synuclein relative to a healthy control, thereby decreasing the level of alpha synuclein.

10. The method of claim 1, wherein the patient has a GBA1 gene mutation, a UCHL1 gene mutation, a LRRK2 gene mutation, a PARK7 gene mutation, a PINK1 gene mutation, a PARK2 gene mutation, a PRKN gene mutation, a SNCA gene mutation, a GIGYF2 gene mutation, a DNAJC13 gene mutation, a TMEM230 gene mutation, a GCH1 gene mutation, a EIF4G1 gene mutation, a HTRA2 gene mutation, a RIC3 gene mutation, a ATXN2 gene mutation, a VPS35 gene mutation, a CHCHD2 gene mutation, a PTRHD1 gene mutation, a PLA2G6 gene mutation, a SPG11 gene mutation, a FBXO7 gene mutation, a DNAJC6 gene mutation, a SYNJ1 gene mutation, a ATP13A2 gene mutation, a VPS13C gene mutation, a PODXL gene mutation, a POLG gene mutation, a DCTN1 gene mutation, a LRP10 gene mutation, a RAB39B gene mutation, or a combination of two or more thereof.

11. The method of claim 1, further comprising detecting a GBA1 gene mutation, a UCHL1 gene mutation, a LRRK2 gene mutation, a PARK7 gene mutation, a PARK2 gene mutation, a PINK1 gene mutation, a PRKN gene mutation, a SNCA gene mutation, a GIGYF2 gene mutation, a DNAJC13 gene mutation, a TMEM230 gene mutation, a GCH1 gene mutation, a EIF4G1 gene mutation, a HTRA2 gene mutation, a RIC3 gene mutation, a ATXN2 gene mutation, a VPS35 gene mutation, a CHCHD2 gene mutation a PTRHD1 gene mutation, a PLA2G6 gene mutation, a SPG11 gene mutation, a FBXO7 gene mutation, a DNAJC6 gene mutation, a SYNJ1 gene mutation, a ATP13A2 gene mutation, a VPS13C gene mutation, a PODXL gene mutation, a POLG gene mutation, a DCTN1 gene mutation, a LRP10 gene mutation, a RAB39B gene mutation, or a combination of two or more thereof in a biological sample obtained from the patient.

12. The method of claim 1, further comprising detecting an elevated level of alpha synuclein, relative to a control, in a biological sample obtained from the patient.

13. The method of claim 12, wherein the alpha synuclein is an alpha-synuclein aggregate.

14. The method of claim 12, wherein the biological sample is a cerebrospinal fluid sample, a blood sample, a saliva sample, a skin biopsy, a serum sample, or a plasma sample.

15. The method of claim 1, further comprising administering an electroencephalogram to the patient and detecting a decreased attenuation of beta frequency electroencephalographic activity during phasic REM sleep compared to tonic REM sleep, compared to a control.

16. The method of claim 1, further comprising administering an electroencephalogram to the patient and detecting reduced overnight decline in slow-wave activity during NREM sleep, compared to a control.

17. The method of claim 1, further comprising administering an electroencephalogram to the patient and detecting decreased overnight modifications in the slow-wave amplitude distribution, compared to a control.

18. The method of claim 1, further comprising administering a polysomnogram to the patient and detecting decreased muscle atonia during REM sleep, compared to a control.

19. The method of claim 1, wherein the adenosine A2A receptor antagonist is ciforadenant, enprofylline, vipadenant, preladenant, tozadenant, istradefylline, inupadenant, etrumadenant, taminadenant, TB206-001, PORT-6, M1069, ST1535, or ST4206.

20. The method of claim 1, wherein the adenosine A2A receptor antagonist is ciforadenant.

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