Methods for ameliorating nervous system diseases and disorders

Abstract

In various aspects and embodiments, compositions and methods are provided for identifying patients who need cognitive improvement and / or treatment for neurodegenerative diseases, and for treating such patients.More specifically, the present disclosure in some embodiments includes administering a β-AR agonist and a peripherally acting β-blocker (PABRA) to a patient who needs it.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority under 35 U.S.C. §119(e) of U.S. Patent No. 62 / 950,077, filed December 18, 2019, and U.S. Patent No. 63 / 034,364, filed June 3, 2020, the entire contents of both of which are incorporated herein by reference in their entireties.

[0002] FIELD OF THE INVENTION The present disclosure relates generally to compositions and methods for improving cognition and / or treating neurodegenerative diseases in patients. [Background technology]

[0003] background U.S. Patent Application Publication No. 2013 / 0096126 (Patent Document 1) discloses "a method for enhancing learning or memory, or both, in a mammal having impairments in learning or memory, or both, due to a neurodegenerative disorder, the method comprising the step of administering at least one compound that is a β1-adrenergic receptor agonist, partial agonist, or receptor ligand, or a salt thereof, in an amount effective to improve learning or memory, or both, in the mammal."

[0004] U.S. Patent Application Publication No. 2014 / 0235726 (Patent Document 2) discloses "a method for improving cognition in a patient with Down syndrome, the method comprising administering to the patient one or more β2 adrenergic receptor agonists in an amount and frequency effective to improve the patient's cognition as measured by a contextual learning test."

[0005] U.S. Patent Application Publication No. 2016 / 0184241 (Patent Document 3) discloses "a method for improving cognition in patients with Down syndrome, the method comprising intranasally administering to the patient one or more β2-AR agonists or pharmaceutically acceptable salts thereof, or both, in an amount and frequency effective to improve the patient's cognition as measured in a contextual learning test."

[0006] PCT Publication No. 2017 / 115873 (Patent Document 4) discloses "a combination of two or more compounds selected from the group consisting of compounds represented by compound numbers 1 to 130, which is a preventive or therapeutic agent for Alzheimer's disease (AD)," and states that "to achieve the aforementioned object, the inventors used neurons induced to differentiate from iPS cells derived from AD patients to screen an existing drug library consisting of 1,280 pharmaceutical compounds approved by the U.S. Food and Drug Administration (FDA), and extracted 129 compounds (including one concomitant drug) that ameliorate Aβ pathology in neurons as candidate therapeutic agents for AD."

[0007] PCT Application Publication No. 2006 / 108424 (Patent Document 5) states, "The present invention further relates to a dermatological composition which does not cause skin sensitization and which contains an enantiomerically pure enantiomer of a β2 adrenergic receptor agonist."

[0008] PCT Publication No. 2018 / 195473 (Patent Document 6) provides "a method for treating a subject having a synucleinopathy (e.g., Parkinson's disease), comprising administering to a subject in need of such treatment a therapeutically effective amount of a β2 adrenergic receptor agonist and at least one therapeutic agent." [Prior art documents] [Patent documents]

[0009] [Patent Document 1] U.S. Patent Application Publication No. 2013 / 0096126 [Patent Document 2] U.S. Patent Application Publication No. 2014 / 0235726 [Patent Document 3] U.S. Patent Application Publication No. 2016 / 0184241 [Patent Document 4] PCT Application Publication No. 2017 / 115873 [Patent Document 5] PCT Application Publication No. 2006 / 108424 [Patent Document 6] PCT Application Publication No. 2018 / 195473 Summary of the Invention

[0010] overview In one aspect, a method for improving cognitive function and / or treating a neurodegenerative disease is provided, the method comprising administering to a patient a therapeutically effective amount of a β-AR agonist and a subtherapeutic peripherally acting β-blocker (PABRA). In one embodiment, a method for improving cognitive function and / or treating a neurodegenerative disease is provided, the method comprising administering to a patient a therapeutically effective amount of a β2-AR agonist and a subtherapeutic peripherally acting β-blocker (PABRA). In one embodiment, a method for improving cognitive function and / or treating a neurodegenerative disease is provided, the method comprising administering to a patient a therapeutically effective amount of a β1-AR agonist and a subtherapeutic peripherally acting β-blocker (PABRA).

[0011] In some embodiments of the methods and compositions provided herein, the purpose of the PABRA is not to directly treat a particular disease indication or condition, but to offset the undesirable peripheral side effects of β-AR agonists (e.g., PABRA can be administered to reduce, limit, or counteract any adverse effects of β-AR agonists, such as cardiac or performance-enhancing effects, thus reducing the potential for abuse). Thus, in some embodiments, the PABRA dose may be lower than that commonly used in previously approved therapeutic settings and indications for which the PABRA is intended to directly treat a particular disease. As used herein, the term "subtherapeutic dose" refers to a dose of a drug that is less than the lowest dose that is independently effective for treating a particular disease indication. In some embodiments, a subtherapeutic dose is less than the lowest dose at which a drug is independently approved by a regulatory agency to treat any particular disease indication. In some embodiments, a subtherapeutic dose is less than the lowest dose at which a drug is approved by the U.S. FDA to treat any particular disease indication. In some embodiments, a subtherapeutic dose is less than the minimum dose at which a drug is approved by a regulatory agency (such as the US FDA) to treat any particular disease indication. In certain embodiments, a subtherapeutic dose of PABRA is sufficient to offset or counteract one or more undesirable side effects of β-AR agonists, but the dose is less than that typically administered to treat a disease or disorder independently. For example, in some embodiments, a sub-therapeutic dose is 90% or less, or 85% or less, or 80% or less, or 75% or less, or 70% or less, or 65% or less, or 60% or less, or 55% or less, or 50% or less, or 45% or less, or 40% or less, or 35% or less, or 30% or less, or 25% or less, or 20% or less, or 15% or less, or 10% or less, or 5% or less, or 4% or less, or 3% or less, or 2.5% or less, or 2% or less, or 1.5% or less, or 1% or less, or 0.5% or less of the dose at which the agent is effective or approved to treat a particular disease indication.In certain embodiments, a sub-therapeutic dose of PABRA can be about 90%, or about 85%, or about 80%, or about 75%, or about 70%, or about 65%, or about 60%, or about 55%, or about 50%, or about 45%, or about 40%, or about 35%, or about 30%, or 25%, or about 20%, or about 15%, or about 10% or less, or about 5%, or about 4%, or about 3%, or about 2.5%, or about 2%, or about 1.5% or less, or about 1%, or about 0.5% of the dose at which the agent is effective or approved to treat a particular disease indication. For example, a 40 mg once daily dose of PABRA nadolol is approved in the United States for the treatment of high blood pressure and angina pectoris; therefore, in certain embodiments, a subtherapeutic dose of nadolol is a dose less than 40 mg daily; for example, a subtherapeutic dose of nadolol is 90% or less, or 85% or less, or 80% or less, or 75% or less, or 70% or less, or 65% or less, or 60% or less, or 55% or less, or 50% or less, or 45% or less, or 40% or less, or 35% or less, or 30% or less, or 25% or less, or 20% or less, or 15% or less, or 10% or less, or 5% or less, or 4% or less, or 3% or less, compared to a 40 mg daily dose. %, or 2.5% or less, or 2% or less, or 1.5% or less, or 1% or less, or 0.5% or less, or in some embodiments, a subtherapeutic dose of nadolol can be about 90%, or about 85%, or about 80%, or about 75%, or about 70%, or about 65%, or about 60%, or about 55%, or about 50%, or about 45%, or about 40%, or about 35%, or about 30%, or 25%, or about 20%, or about 15%, or about 10% or less, or about 5%, or about 4%, or about 3%, or about 2.5%, or about 2%, or about 1.5% or less, or about 1%, or about 0.5% of a 40 mg daily dose.In some embodiments, the peripherally acting beta blocker (PABRA) is nadolol and is administered at a total daily dose of about 0.01-15 mg, 0.1-15 mg, 0.1-10 mg, 0.1-1 mg, 0.1-0.5 mg, 0.2-0.3 mg, 0.23-0.27 mg; 0.1-5 mg, 1-15 mg, 1-10 mg, 1-5 mg, 5-10 mg, 10 mg or less, 7 mg or less, 5 mg or less, 1 mg or less, about 0.01 mg, about 0.05 mg; about 0.1 mg, about 0.2 mg, about 0.25 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, or about 10 mg. In some embodiments, the nadolol dose is a weekly dose or a twice-weekly dose. Another example of a PARA that can be used in the methods described herein is atenolol. Atenolol is approved for a variety of indications, including hypertension, prophylaxis of angina, angina pectoris, and myocardial infarction, at doses ranging from 25 to 200 mg once daily.Thus, in certain embodiments, a subtherapeutic dose of atenolol is a dose of less than 25 mg daily, for example, a subtherapeutic dose of atenolol is 90% or less, or 85% or less, or 80% or less, or 75% or less, or 70% or less, or 65% or less, or 60% or less, or 55% or less, or 50% or less, or 45% or less, or 40% or less, or 35% or less, or 30% or less, or 25% or less, or 20% or less, or 15% or less, or 10% or less, or 5% or less, or 4% or less, or 3% or less, or 2.5% or less, or 2% or less, or or 1.5% or less, or 1% or less, or 0.5% or less, or in some embodiments a sub-therapeutic dose of atenolol can be about 90%, or about 85%, or about 80%, or about 75%, or about 70%, or about 65%, or about 60%, or about 55%, or about 50%, or about 45%, or about 40%, or about 35%, or about 30%, or 25%, or about 20%, or about 15%, or about 10% or less, or about 5%, or about 4%, or about 3%, or about 2.5%, or about 2%, or about 1.5% or less, or about 1%, or about 0.5% of a 25 mg daily dose. In some embodiments, the peripherally acting beta blocker (PABRA) is atenolol and is administered at a dose of about 0.01 to 15 mg, 0.1 to 15 mg, 0.1 to 10 mg, 0.1 to 1 mg, 0.1 to 0.5 mg, 0.2 to 0.3 mg, 0.23 to 0.27 mg; 0.1 to 5 mg, 1 to 15 mg, 1 to 10 mg, 1 to 5 mg, 5 to 10 mg, 10 mg or less, 7 mg or less, 5 mg or less, 1 mg or less, about 0.01 mg, about 0.05 mg; about 0.1 mg, about 0.2 mg, about 0.25 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, or about 10 mg. In some embodiments, the dose of atenolol is a weekly dose or a twice-weekly dose.

[0012] In certain embodiments, PABRAs as used herein may have relatively limited CNS (blood-brain barrier) penetration and thus may be preferentially active in the periphery.

[0013] In certain embodiments of the methods and compositions disclosed herein, the β-AR agonist is administered at a dose that is therapeutically effective for improving cognition and / or treating a neurodegenerative disease in a patient. In some embodiments, the β-AR agonist can be administered at a dose of about 30 to 160 μg. In some embodiments, the β-AR agonist can be administered at a dose of about 50 to 160 μg. In some embodiments, the β-AR agonist is administered in an amount of about 1 to 300 μg, 5 to 200 μg, 10 to 180 μg, 10 to 40 μg, 20 to 50 μg, 40 to 80 μg, 50 to 100 μg, 100 to 200 μg, 30 to 160 μg, 50 to 160 μg, 80 to 160 μg, 100 to 160 μg, 120 to 160 μg, 140 to 160 μg, 150 to 170 μg, 30 to 140 μg, 50 to 140 μg, 80 to 140 μg, 100 to 140 μg, 120 to 140 μg, 30 to 120 μg, 50 to 120 μg, 80 to 120 μg It can be administered in a dose of about 10 μg, about 20 μg, about 25 μg, about 30 μg, about 40 μg, about 50 μg, about 60 μg, about 70 μg, about 80 μg, about 90 μg, about 100 μg, about 110 μg, about 120 μg, about 125 μg, about 130 μg, about 140 μg, about 150 μg, or about 160 μg, about 170 μg, about 175 μg, about 180 μg, about 190 μg, or about 200 μg. In some embodiments, the β-AR agonist can be administered at a dose of 150 μg to 1 mg, or 200 μg to 500 μg, or about 250 μg, or about 300 μg, or about 400 μg, or about 500 μg. In some embodiments, the β-AR agonist can be administered at a dose of 0.5 to 20 mg, or 1 to 10 mg, or 2 to 8 mg, or about 1 mg, or about 2 mg, or about 3 mg, or about 4 mg, or about 5 mg, or about 6 mg, or about 7 mg, or about 8 mg, or about 10 mg.In some embodiments of the aspects or embodiments provided herein, the β-AR agonist is clenbuterol and the doses are 1-300 μg, 5-200 μg, 10-180 μg, 10-40 μg, 20-50 μg, 40-80 μg, 50-100 μg, 100-200 μg, 30-160 μg, 50-160 μg, 80-160 μg, 100-160 μg, 120-160 μg, 140-160 μg, 150-170 μg, 30-140 μg, 50-140 μg, 80-140 μg, 100-140 μg, 120-140 μg, 30- 120μg, 50 to 120μg, 80 to 120μg, 100 to 120μg, 30 to 100μg, 50 to 100μg, 80 to 100μg, 30 to 80μg, 50 to 80μg, 30 to 50μg, about 10μg, about 20μg, about 25μg, about 30μg, about 40μg, about 50μg, about 60μg, about 70μg, about 80μg, about 90μg, about 100μg, about 110μg, about 120μg, about 125μg, about 130μg, about 140μg, about 150μg, or about 160μg, about 170μg, about 175μg, about 180μg, about 190μg, or about 200μg. In some embodiments of the aspects or embodiments provided herein, the β-AR agonist is tulobuterol, and the dosage is 0.5-20 mg, or 1-10 mg, or 2-8 mg, or about 1 mg, or about 2 mg, or about 3 mg, or about 4 mg, or about 5 mg, or about 6 mg, or about 7 mg, or about 8 mg, or about 10 mg. In some embodiments, the dosage is a daily dose, a twice-daily dose, a weekly dose, or a twice-weekly dose.

[0014] In some embodiments, the dose of any agent provided herein can be a total daily dose.In some embodiments, the total daily dose provided herein is achieved by administering once a day, in some embodiments, the total daily dose is achieved by administering twice a day, and in still other embodiments, the total daily dose is achieved by administering three or more times a day.In certain embodiments, the dose of any agent provided herein can be administered weekly or twice a week.In some embodiments, a therapeutically effective amount of β-AR agonist and a subtherapeutic dose of peripherally acting β-blocker (PABRA) are administered for several weeks or more, or for 3 weeks or more, or for 5 weeks or more, or for 10 weeks or more, or for 20 weeks or more, or for 1 year or more.

[0015] In one aspect, a method for improving cognitive function and / or treating a neurodegenerative disease is provided, the method comprising administering to a patient therapeutically effective amounts of a β-AR agonist and a peripherally acting β-blocker (PABRA), wherein the peripherally acting β-blocker (PABRA) is administered at a dose of about 15 mg or less. In some embodiments, the peripherally acting beta blocker (PABRA; e.g., nadolol or atenolol) is atenolol and is administered in a dose of about 0.01 to 15 mg, 0.1 to 15 mg, 0.1 to 10 mg, 0.1 to 1 mg, 0.1 to 0.5 mg, 0.2 to 0.3 mg, 0.23 to 0.27 mg; 0.1 to 5 mg, 1 to 15 mg, 1 to 10 mg, 1 to 5 mg, 5 to 10 mg, 10 mg or less, 7 mg or less, 5 mg or less, 1 mg or less, about 0.01 mg, about 0.05 mg; about 0.1 mg, about 0.2 mg, about 0.25 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, or about 10 mg. In some embodiments not specifically stated, the above-mentioned dosage is the total dosage per day.In some, the above-mentioned dosage is the total dosage per week.In some embodiments, the therapeutically effective amount of β-AR agonist and peripherally acting β-blocker (PABRA) is administered for a period of several weeks or more.

[0016] The methods provided herein may further include subjecting the patient to brain imaging to determine regional metabolic activation and / or cerebral perfusion in the cerebral cortex, forebrain, midbrain, and brainstem regions, and / or to identify whether the patient needs or desires cognitive improvement and / or treatment for neurodegenerative diseases. In some embodiments, the brain imaging is fluorodeoxyglucose positron emission tomography (FDG-PET), used alone or in combination with other imaging techniques such as magnetic resonance imaging (MRI) and CT. In some embodiments, the brain imaging is or can include magnetic resonance imaging-arterial spin labeling (MRI-ASL) or magnetic resonance imaging-blood oxygen level-dependent computed tomography (MRI-BOLD). In some embodiments, the brain imaging can include MRI-ASL, which is used to monitor cerebral blood flow, including, for example, cerebral blood flow to the hippocampus or thalamus. In some embodiments of the aspects and embodiments disclosed herein, "improving cognition and / or treating neurodegenerative diseases" in a patient can include improving cognitive and executive function in a patient, improving inflammatory conditions in cerebral or cerebrospinal fluid (CSF) samples, reducing protein load (e.g., based on imaging or CSF samples), and / or improving regional cerebral metabolic conditions (reversing hypometabolism) or improving hypoperfusion.In certain embodiments of the methods and compositions disclosed herein, the β-AR agonist is administered at a dose that is therapeutically effective for improving cognition and / or treating neurodegenerative diseases in a patient. Similarly, in certain embodiments, "identifying patients in need of or desiring improved cognitive function and / or treatment of a neurodegenerative disease" may include identifying patients in need of or desiring improved cognitive and executive function, improved inflammatory status in a cerebrospinal fluid or CSF sample, attenuation of protein load (e.g., based on imaging or a CSF sample), and / or improved regional cerebral metabolism / perfusion status (reversal of hypometabolism / hypoperfusion).In another aspect, a method is provided that includes subjecting a patient to brain imaging to determine regional metabolic or perfusion activation in the cerebral cortex, forebrain, midbrain, and brainstem regions and / or to identify whether improved cognitive function and / or treatment of a neurodegenerative disease is necessary or desirable for the patient; and administering to the patient a β-AR agonist and a peripherally acting β-blocker (PABRA) to improve cognition and / or treat the neurodegenerative disease in the patient, wherein the peripherally acting β-blocker (PABRA) is administered at a dose of about 15 mg or less. In a similar aspect, a method is provided that includes subjecting a patient to brain imaging to determine regional metabolic or perfusion activation in the cerebral cortex, forebrain, midbrain, and brainstem regions and / or to identify whether improved cognitive function and / or treatment of a neurodegenerative disease is necessary or desirable for the patient, and administering to the patient a β-AR agonist and a peripherally acting β-blocker (PABRA) to improve cognition and / or treat the neurodegenerative disease in the patient, wherein the peripherally acting β-blocker (PABRA) is administered at a subtherapeutic dose.

[0017] Method can further comprise having the patient undergo brain imaging again to assess the local metabolic activation in cerebral cortex, forebrain, midbrain and brainstem regions, any improvement in cognitive function and / or treatment of the neurodegenerative disease.In some embodiments, brain imaging is FDG-PET, used alone or in combination with other imaging methods such as MRI and CT.In some embodiments, brain imaging is or can include MRI-ASL or MRI-BOLD.

[0018] In yet another embodiment, a method is provided, comprising: having a patient undergo brain imaging to assess regional metabolic activation in the forebrain, midbrain, and brainstem regions; and administering a β-AR agonist and a peripherally acting β-blocker (PABRA) to the patient, wherein the peripherally acting β-blocker (PABRA) is administered at a dose of about 15 mg or less. In a related embodiment, a method is provided, comprising: having a patient undergo brain imaging to assess regional metabolic activation in the forebrain, midbrain, and brainstem regions; and administering a β-AR agonist and a peripherally acting β-blocker (PABRA) to the patient, wherein the peripherally acting β-blocker (PABRA) is administered at a subtherapeutic dose. The method can further comprise having the patient undergo brain imaging again thereafter to assess regional metabolic or perfusion activation in the cerebral cortex, limbic system, forebrain, midbrain, and brainstem regions, and any improvement in cognitive function. In some embodiments, brain imaging diagnosis is FDG-PET, which is used alone or in combination with other imaging diagnostic methods such as MRI and CT.In some embodiments, brain imaging diagnosis can be or include MRI-ASL or MRI-BOLD.In some embodiments, brain imaging diagnosis can include, for example, MRI-ASL, which is used to monitor cerebral blood flow, including cerebral blood flow to hippocampus, and the improvement of cerebral blood flow (for example, cerebral blood flow to hippocampus) in subsequent MRI-ASL indicates the effective action of β-AR agonist in patients and / or improved cognition.

[0019] In some embodiments, detectable labels are provided that can generate spatial patterns in brain imaging results. 18 F]fluoro-2-deoxy-D-glucose ( 18 FDG) can be used in FDG-PET, which can provide characteristic spatial patterns of cerebral perfusion and help clinicians make reasonably accurate and early diagnoses for appropriate management or prognosis.

[0020] In some embodiments, detectable labels on blood water molecules are generated by magnetic RF treatment of blood in the neck, which can generate spatial patterns of cerebral perfusion as brain imaging results. In some such embodiments, MRI-ASL is used, which can provide characteristic spatial patterns of cerebral perfusion and can help clinicians make reasonably accurate and early diagnoses for appropriate management or prognosis.

[0021] In some embodiments, methods for improving cognitive function and / or treating a neurodegenerative disease are provided, the methods comprising administering to a patient a β-AR agonist and a peripherally acting β-blocker (PABRA) to improve cognition and / or treat a neurodegenerative disease in the patient, wherein the peripherally acting β-blocker (PABRA) is administered at a dose of about 15 mg or less. In some related embodiments, methods for improving cognitive function and / or treating a neurodegenerative disease are provided, the methods comprising administering to a patient a β-AR agonist and a peripherally acting β-blocker (PABRA) to improve cognition and / or treat a neurodegenerative disease in the patient, wherein the peripherally acting β-blocker (PABRA) is administered at a subtherapeutic dose.

[0022] In some embodiments, the method may further include subjecting the patient to brain imaging to determine regional metabolic activity in the forebrain, midbrain, and brainstem regions and / or to identify whether cognitive improvement and / or neurodegenerative disease treatment is necessary or desirable for the patient. In some embodiments, the brain imaging is fluorodeoxyglucose positron emission tomography (FDG-PET), used alone or in combination with other imaging techniques such as magnetic resonance imaging (MRI) and CT. In some embodiments, the brain imaging is or can include MRI-ASL or MRI-BOLD. In some embodiments of the aspects and embodiments disclosed herein, "improving cognition and / or treating neurodegenerative disease" in a patient may include improving cognitive and executive function, improving inflammatory status in cerebral fluid or cerebrospinal fluid (CSF) samples, attenuating protein load (e.g., based on imaging or CSF samples), and / or improving regional cerebral metabolic status (reversing hypometabolism) in the patient. Similarly, in certain embodiments, "identifying a patient in need of or desiring improvement in cognitive function and / or treatment of a neurodegenerative disease" can include identifying a patient in need of or desiring improvement in cognitive and executive function, improvement in inflammatory status in cerebrospinal fluid or CSF samples, attenuation of protein load (e.g., based on imaging or CSF samples), and / or improvement in regional brain metabolic status (reversal of hypometabolism). In another aspect, a method is provided, comprising: subjecting a patient to brain imaging to determine regional metabolic activation in the forebrain, midbrain, and brainstem regions and / or to identify whether the patient needs or desiring improvement in cognitive function and / or treatment of a neurodegenerative disease; and administering to the patient a β-AR agonist and a peripherally acting β-blocker (PABRA) to improve cognition and / or treat the neurodegenerative disease in the patient, wherein the peripherally acting β-blocker (PABRA) is administered at a dose of about 15 mg or less.In a related aspect, a method is provided, the method includes: subjecting a patient to brain imaging to determine the regional metabolic activation in the forebrain, midbrain and brainstem regions, and / or to identify whether the patient needs or desires to improve cognitive function and / or treat neurodegenerative diseases; and administering to the patient a β-AR agonist and a peripherally acting β-blocker (PABRA), wherein the peripherally acting β-blocker (PABRA) is administered at a subtherapeutic dose, to improve cognition and / or treat neurodegenerative diseases in the patient. In some embodiments, the peripherally acting β-blocker (PABRA) can be administered to reduce, limit or counter any adverse effects of the β-AR agonist, such as performance-enhancing effects, thereby reducing the potential for abuse.

[0023] The method may further comprise having the patient undergo brain imaging again to assess the regional metabolic or perfusion activation in the cerebral cortex, forebrain, midbrain, and brainstem regions, any improvement in cognitive function, and / or treatment of the neurodegenerative disease. In some embodiments, the brain imaging is FDG-PET, used alone or in combination with other imaging methods such as MRI and CT. In some embodiments, the brain imaging is or can include MRI-ASL or MRI-BOLD. In yet another aspect, a method is provided, comprising: having the patient undergo brain imaging to assess the regional metabolic activation in the forebrain, midbrain, and brainstem regions; administering a β-AR agonist and a peripherally acting β-blocker (PABRA) to the patient; and then having the patient undergo brain imaging again to assess the regional metabolic activation in the forebrain, midbrain, and brainstem regions, any improvement in cognitive function. In some embodiments, the brain imaging is FDG-PET, used alone or in combination with other imaging methods such as MRI and CT. In some embodiments, the brain imaging is or can include MRI-ASL or MRI-BOLD. In some embodiments, the patient does not have Alzheimer's disease. In some embodiments, the patient does not have Down's syndrome. In some embodiments, the patient does not have Parkinson's disease. In some embodiments, the patient does not have dementia with Lewy bodies.

[0024] In some embodiments, the β-AR agonist can be administered at a dose of about 30-160 μg. In some embodiments, the β-AR agonist can be administered at a dose of about 50-160 μg. In some embodiments, the β-AR agonist can be administered at a dose of about 30-160 μg, 50-160 μg, 80-160 μg, 100-160 μg, 120-160 μg, 140-160 μg, 30-140 μg, 50-140 μg, 80-140 μg, 100-140 μg, 120-140 μg, 30-120 μg, 50-120 μg, 80-120 μg , 100-120 μg, 30-100 μg, 50-100 μg, 80-100 μg, 30-80 μg, 50-80 μg, 30-50 μg, 30 μg, 40 μg, 50 μg, 60 μg, 70 μg, 80 μg, 90 μg, 100 μg, 110 μg, 120 μg, 130 μg, 140 μg, 150 μg, or 160 μg. In some embodiments, the β2-AR agonist can be administered at a dose of 0.5-20 mg, 1-10 mg, 2-8 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, or about 10 mg. In some embodiments, the above doses are total daily doses. In some embodiments, the doses mentioned above are total weekly doses. In some embodiments, the doses of the β-AR agonist and the peripherally acting β-blocker (PABRA) are administered weekly for a period of several weeks or longer.

[0025] In one embodiment, a method for improving cognitive function and / or treating neurodegenerative diseases is provided, the method comprising administering clenbuterol and nadolol to a patient to improve cognition and / or treat neurodegenerative diseases in the patient, wherein nadolol is administered at a dose of about 15 mg or less.In one embodiment, a method for improving cognitive function and / or treating neurodegenerative diseases is provided, the method comprising administering clenbuterol and nadolol to a patient to improve cognition and / or treat neurodegenerative diseases in the patient, wherein nadolol is administered at a subtherapeutic dose.The method may further comprise having the patient undergo brain imaging to determine regional metabolic activation in the forebrain, midbrain, and brainstem regions, and / or to identify whether the patient needs or desires to improve cognitive function and / or treat neurodegenerative diseases.

[0026] In some embodiments, nadolol is a mixture of four diastereomers. In some embodiments, the nadolol administered is a specific enantiomerically pure isomer.

[0027] In some embodiments, the brain imaging is fluorodeoxyglucose positron emission tomography (FDG-PET), used alone or in combination with other imaging modalities such as magnetic resonance imaging (MRI) and CT. In some embodiments, the brain imaging can be or include MRI-ASL or MRI-BOLD. In some embodiments of the aspects and embodiments disclosed herein, "improving cognition and / or treating neurodegenerative diseases" in a patient can include improving cognitive and executive function, improving inflammatory conditions in cerebral fluid or cerebrospinal fluid (CSF) samples, attenuating protein load (e.g., based on imaging or CSF samples), and / or improving regional cerebral metabolic conditions (reversing hypometabolism) in a patient. Similarly, in certain embodiments, "identifying a patient in need of or desiring improved cognitive function and / or treatment of a neurodegenerative disease" can include identifying a patient in need of or desiring improved cognitive and executive function, improved inflammatory status in a cerebrospinal fluid or CSF sample, attenuation of protein load (e.g., based on imaging or a CSF sample), and / or improved regional brain metabolic status (reversal of hypometabolism). In another aspect, a method is provided that includes subjecting a patient to brain imaging to determine regional metabolic activity in the forebrain, midbrain, and brainstem regions and / or to identify whether improved cognitive function and / or treatment of a neurodegenerative disease is necessary or desirable for the patient, and administering clenbuterol and nadolol to the patient to improve cognition and / or treat the neurodegenerative disease, wherein nadolol is administered at a dose of about 15 mg or less.In a related aspect, a method is provided that includes subjecting a patient to brain imaging to determine regional metabolic activation in forebrain, midbrain, and brainstem regions and / or to identify whether improved cognitive function and / or treatment of a neurodegenerative disease is necessary or desirable for the patient, and administering clenbuterol and nadolol to the patient to improve cognition and / or treat the neurodegenerative disease in the patient, wherein nadolol is administered at a subtherapeutic dose.

[0028] In some embodiments, nadolol is a mixture of four diastereomers. In some embodiments, the nadolol administered is a specific enantiomerically pure isomer.

[0029] The method may further comprise having the patient undergo brain imaging again to assess regional metabolic activation in the forebrain, midbrain, and brainstem regions, any improvement in cognitive function, and / or treatment of the neurodegenerative disease. In some embodiments, the brain imaging is FDG-PET, used alone or in combination with other imaging techniques such as MRI and CT. In some embodiments, the brain imaging is or can include MRI-ASL or MRI-BOLD. In yet another aspect, a method is provided, comprising having the patient undergo brain imaging to assess regional metabolic activation in the forebrain, midbrain, and brainstem regions, administering clenbuterol and nadolol to the patient, wherein nadolol is administered at a dose of about 15 mg or less, and then having the patient undergo brain imaging again to assess regional metabolic activation in the forebrain, midbrain, and brainstem regions, any improvement in cognitive function. In a similar aspect, a method is provided that includes subjecting a patient to brain imaging to determine regional metabolic activation in the forebrain, midbrain, and brainstem regions; administering clenbuterol and nadolol to the patient, wherein nadolol is administered at a subtherapeutic dose; and then subjecting the patient to brain imaging again to determine regional metabolic activation in the forebrain, midbrain, and brainstem regions and any improvement in cognitive function.

[0030] Clenbuterol is a beta-2 agonist with the following chemical structure: TIFF0007744344000001.tif26128

[0031] In certain embodiments, clenbuterol as used herein refers to a racemic mixture. In other embodiments, clenbuterol as used herein can be (S)-clenbuterol substantially free of the (R)-clenbuterol isomer. In other embodiments, clenbuterol as used herein can be (R)-clenbuterol substantially free of the (S)-clenbuterol isomer. In one aspect, a method for improving cognitive function and / or treating a neurodegenerative disease is provided, comprising administering to a patient clenbuterol and PABRA to improve cognition and / or treat a neurodegenerative disease in the patient, wherein PABRA is administered at a dose of about 15 mg or less. In one aspect, a method for improving cognitive function and / or treating a neurodegenerative disease is provided, comprising administering to a patient clenbuterol and nadolol (PABRA) to improve cognition and / or treat a neurodegenerative disease in the patient, wherein nadolol is administered at a dose of about 15 mg or less. In one embodiment, a method for improving cognitive function and / or treating a neurodegenerative disease is provided, the method comprising administering clenbuterol and PABRA to a patient to improve cognition and / or treat a neurodegenerative disease in the patient, wherein PABRA is administered at a subtherapeutic dose. In one embodiment, a method for improving cognitive function and / or treating a neurodegenerative disease is provided, the method comprising administering clenbuterol and nadolol to a patient to improve cognition and / or treat a neurodegenerative disease in the patient, wherein nadolol is administered at a subtherapeutic dose. The method may further comprise subjecting the patient to brain imaging to determine regional metabolic activation in the forebrain, midbrain, and brainstem regions and / or to identify whether the patient requires or desires cognitive function improvement and / or treatment of a neurodegenerative disease.In some embodiments, nadolol is administered in doses of about 0.01-15 mg, 0.1-15 mg, 0.1-10 mg, 0.1-1 mg, 0.1-0.5 mg, 0.2-0.3 mg, 0.23-0.27 mg, 0.1-5 mg, 1-15 mg, 1-10 mg, 1-5 mg, 5-10 mg, 10 mg or less, 7 mg or less, 5 mg or less, 1 mg or less, about 0.01 mg, about 0.05 mg, about 0.1 mg, about 0.2 mg, about 0.25 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, or about 10 mg. In some embodiments, clenbuterol is administered in doses of about 30-160 μg. In some embodiments, clenbuterol can be administered in doses of about 50-160 μg or 80-160 μg. In some embodiments, the doses are total daily doses. In some embodiments, the doses are weekly doses. In some embodiments, the doses of clenbuterol and nadolol are administered over a period of several weeks or longer. In some embodiments, nadolol is a mixture of four diastereomers. In some embodiments, the administered nadolol is a specific enantiomerically pure isomer.

[0032] In some embodiments, the brain imaging is fluorodeoxyglucose positron emission tomography (FDG-PET), used alone or in combination with other imaging modalities such as magnetic resonance imaging (MRI) and CT. In some embodiments, the brain imaging can be or include MRI-ASL or MRI-BOLD. In some embodiments of the aspects and embodiments disclosed herein, "improving cognition and / or treating neurodegenerative diseases" in a patient can include improving cognitive and executive function, improving inflammatory conditions in cerebral fluid or cerebrospinal fluid (CSF) samples, attenuating protein load (e.g., based on imaging or CSF samples), and / or improving regional cerebral metabolic conditions (reversing hypometabolism) in a patient. Similarly, in certain embodiments, "identifying a patient in need of or desiring cognitive improvement and / or neurodegenerative disease treatment" can include identifying a patient in need of or desiring cognitive and executive function improvement, improvement of inflammatory status in cerebrospinal fluid or CSF samples, attenuation of protein load (e.g., based on imaging or CSF samples), and / or improvement of regional brain metabolic status (reversal of hypometabolism). In another aspect, a method is provided that includes subjecting a patient to brain imaging to determine regional metabolic activity in the forebrain, midbrain, and brainstem regions and / or to identify whether cognitive improvement and / or neurodegenerative disease treatment is necessary or desirable for the patient, and administering clenbuterol or tulobuterol and nadolol to the patient to improve cognition and / or treat the neurodegenerative disease, wherein nadolol is administered at a dose of about 15 mg or less.In a related aspect, a method is provided that includes subjecting a patient to brain imaging to determine regional metabolic activation in forebrain, midbrain, and brainstem regions and / or to identify whether improved cognitive function and / or treatment of a neurodegenerative disease is necessary or desirable for the patient, and administering clenbuterol or tulobuterol and nadolol to the patient to improve cognition and / or treat the neurodegenerative disease in the patient, wherein nadolol is administered in a subtherapeutic dose.

[0033] The method may further include subjecting the patient to brain imaging again to assess regional metabolic activation in the forebrain, midbrain, and brainstem regions, any improvement in cognitive function, and / or treatment of the neurodegenerative disease. In some embodiments, the brain imaging is FDG-PET, used alone or in combination with other imaging techniques such as MRI and CT. In some embodiments, the brain imaging is or can include MRI-ASL or MRI-BOLD. In yet another aspect, a method is provided, comprising subjecting the patient to brain imaging to assess regional metabolic activation in the forebrain, midbrain, and brainstem regions, administering to the patient clenbuterol or tulobuterol and nadolol to improve cognition and / or treat the neurodegenerative disease in the patient, wherein nadolol is administered at a dose of about 15 mg or less, and then subjecting the patient to brain imaging again to assess regional metabolic activation in the forebrain, midbrain, and brainstem regions, any improvement in cognitive function. In some embodiments, the brain imaging is FDG-PET, used alone or in combination with other imaging techniques such as MRI and CT. In some embodiments, the brain imaging can be or include MRI-ASL or MRI-BOLD.

[0034] Tulobuterol is a long-acting beta-2 agonist with the following chemical structure: TIFF0007744344000002.tif27128

[0035] Tulobuterol is commercially available in Japan as a racemic mixture for administration as a transdermal patch. In certain embodiments, tulobuterol as used herein refers to a racemic mixture. In other embodiments, tulobuterol as used herein may be (S)-tulobuterol substantially free of (R)-tulobuterol isomer. In other embodiments, tulobuterol as used herein may be (R)-tulobuterol substantially free of (S)-tulobuterol isomer. In one aspect, a method for improving cognitive function and / or treating a neurodegenerative disease is provided, comprising administering tulobuterol and PABRA to a patient to improve cognition and / or treat a neurodegenerative disease in the patient, wherein PABRA is administered at a subtherapeutic dose. In one embodiment, a method for improving cognitive function and / or treating a neurodegenerative disease is provided, comprising administering tulobuterol and nadolol to a patient to improve cognition and / or treat a neurodegenerative disease in the patient, wherein nadolol is administered at a dose of about 15 mg or less. In one embodiment, a method for improving cognitive function and / or treating a neurodegenerative disease is provided, comprising administering tulobuterol and PABRA to a patient to improve cognition and / or treat a neurodegenerative disease in the patient, wherein PABRA is administered at a subtherapeutic dose. In one embodiment, a method for improving cognitive function and / or treating a neurodegenerative disease is provided, comprising administering tulobuterol and nadolol to a patient to improve cognition and / or treat a neurodegenerative disease in the patient, wherein nadolol is administered at a subtherapeutic dose. The method may further include subjecting the patient to brain imaging to determine regional metabolic activation in the forebrain, midbrain, and brainstem regions and / or to identify whether improvement of cognitive function and / or treatment of a neurodegenerative disease is necessary or desirable for the patient.In some embodiments, nadolol is administered in a dose of about 0.01 to 15 mg, 0.1 to 15 mg, 0.1 to 10 mg, 0.1 to 1 mg, 0.1 to 0.5 mg, 0.2 to 0.3 mg, 0.23 to 0.27 mg; 0.1 to 5 mg, 1 to 15 mg, 1 to 10 mg, 1 to 5 mg, 5 to 10 mg, 10 mg or less, 7 mg or less, 5 mg or less, 1 mg or less, about 0.01 mg, about 0.05 mg; about 0.1 mg, about 0.2 mg, about 0.25 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, or about 10 mg. In some embodiments, tulobuterol can be administered in doses of 0.5 to 20 mg, or 1 to 10 mg, or 2 to 8 mg, or about 1 mg, or about 2 mg, or about 3 mg, or about 4 mg, or about 5 mg, or about 6 mg, or about 7 mg, or about 8 mg, or about 10 mg. In some embodiments, the doses described above are total daily doses. In some embodiments, the doses described above are weekly doses. In some embodiments, the doses of tulobuterol and nadolol are administered over a period of several weeks or longer. In some embodiments, nadolol is a mixture of four diastereomers. In some embodiments, the administered nadolol is a specific enantiomerically pure isomer.

[0036] In some aspects, a method is provided that includes treating a subject identified as having reduced cognitive function and / or in need of or desiring improved cognitive function and / or treatment of a neurodegenerative disease by administering to the subject a pharmaceutical composition comprising a β1-AR agonist, a β2-AR agonist, a peripherally acting β-blocker (PABRA), or any combination thereof. In some embodiments, the method further includes evaluating the effectiveness of the treatment. In some embodiments, the treatment is evaluated by subjecting the subject to a test to evaluate improved cognitive function or remission of the neurodegenerative disease. In some embodiments, the method further includes adjusting the administration of the pharmaceutical composition by adjusting the dosage and / or timing of administration of the pharmaceutical composition.

[0037] In some embodiments of any of the aspects or embodiments provided herein, the method or composition comprises a β-AR agonist and a PABRA. In some embodiments of any of the aspects or embodiments provided herein, the method or composition comprises a β2-AR agonist and a PABRA. In some embodiments, the pharmaceutical composition comprises clenbuterol and nadolol. In some embodiments, the pharmaceutical composition comprises clenbuterol and atenolol. In some embodiments, the β2-AR agonist can be administered at a dose of about 30-160 μg. In some embodiments, the β2-AR agonist can be administered at a dose of about 50-160 μg. In some embodiments, the β2-AR agonist is administered in an amount of about 1 to 300 μg, 5 to 200 μg, 10 to 180 μg, 10 to 40 μg, 20 to 50 μg, 40 to 80 μg, 50 to 100 μg, 100 to 200 μg, 30 to 160 μg, 50 to 160 μg, 80 to 160 μg, 100 to 160 μg, 120 to 160 μg, 140 to 160 μg, 150 to 170 μg, 30 to 140 μg, 50 to 140 μg, 80 to 140 μg, 100 to 140 μg, 120 to 140 μg, 30 to 120 μg, 50 to 120 μg, 80 to 120 μg It can be administered in a dose of about 10 μg, about 20 μg, about 25 μg, about 30 μg, about 40 μg, about 50 μg, about 60 μg, about 70 μg, about 80 μg, about 90 μg, about 100 μg, about 110 μg, about 120 μg, about 125 μg, about 130 μg, about 140 μg, about 150 μg, or about 160 μg, about 170 μg, about 175 μg, about 180 μg, about 190 μg, or about 200 μg. In some embodiments, the β2-AR agonist can be administered at a dose of 150 μg to 1 mg, or 200 μg to 500 μg, or about 250 μg, or about 300 μg, or about 400 μg, or about 500 μg.In some embodiments, the β2-AR agonist can be administered at a dose of 0.5 to 20 mg, or 1 to 10 mg, or 2 to 8 mg, or about 1 mg, or about 2 mg, or about 3 mg, or about 4 mg, or about 5 mg, or about 6 mg, or about 7 mg, or about 8 mg, or about 10 mg. In some embodiments of the aspects or embodiments provided herein, the β2-AR agonist is clenbuterol and the doses are 1-300 μg, 5-200 μg, 10-180 μg, 10-40 μg, 20-50 μg, 40-80 μg, 50-100 μg, 100-200 μg, 30-160 μg, 50-160 μg, 80-160 μg, 100-160 μg, 120-160 μg, 140-160 μg, 150-170 μg, 30-140 μg, 50-140 μg, 80-140 μg, 100-140 μg, 120-140 μg, 30- 120μg, 50 to 120μg, 80 to 120μg, 100 to 120μg, 30 to 100μg, 50 to 100μg, 80 to 100μg, 30 to 80μg, 50 to 80μg, 30 to 50μg, about 10μg, about 20μg, about 25μg, about 30μg, about 40μg, about 50μg, about 60μg, about 70μg, about 80μg, about 90μg, about 100μg, about 110μg, about 120μg, about 125μg, about 130μg, about 140μg, about 150μg, or about 160μg, about 170μg, about 175μg, about 180μg, about 190μg, or about 200μg. In some embodiments of the aspects or embodiments provided herein, the β2-AR agonist is tulobuterol, and the dosage is 0.5 to 20 mg, or 1 to 10 mg, or 2 to 8 mg, or about 1 mg, or about 2 mg, or about 3 mg, or about 4 mg, or about 5 mg, or about 6 mg, or about 7 mg, or about 8 mg, or about 10 mg. In some embodiments, the dosage is a total daily dose. In some embodiments, the dosage is a total weekly dose. In some embodiments, the dosages of the agonist and PABRA are administered over a period of several weeks or longer.

[0038] As used herein, the term "β1 agonist" refers to a β1 adrenergic receptor agonist or a β1-AR agonist. In certain embodiments, the term β1 agonist is understood to include compounds that are primarily β1 agonists but may also exhibit some peripheral activating effects on other adrenergic receptors, such as β2-adrenergic receptors. In this application, the terms "β1-adrenergic receptor agonist," "β1-AR agonist," "β1AR agonist," and "β1 agonist" may be used interchangeably. In certain embodiments, the term β1-AR agonist explicitly includes both selective agonists and partial agonists, as well as biased and unbiased agonists. Examples of β1 adrenergic agonists include, for example, xamoterol, noradrenaline, isoprenaline, dopamine, and dobutamine, as well as pharmaceutically acceptable salts of any of the above. The partial agonist and ligand of β1-AR are known.In addition, by using the methodology of Kolb et al., but instead for β1-AR, those skilled in the art can determine new ligand by structure-based discovery.See Proc.Natl.Acad.Sci.USA 2009,106,6843-648.

[0039] As used herein, the term "β2 agonist" refers to a β2-adrenergic receptor agonist or a β2-AR agonist. In certain embodiments, the term β2 agonist is understood to include compounds that are primarily β2 agonists but may also exhibit some peripheral activating effects on other adrenergic receptors, such as β1-adrenergic receptors. In this application, the terms "β2-adrenergic receptor agonist," "β2-AR agonist," "β2AR agonist," and "β2 agonist" may be used interchangeably. In some embodiments, the term β2-AR agonist explicitly includes both selective agonists and partial agonists. β2 agonists that can be used according to various aspects and embodiments of the present disclosure can be short-acting, long-acting, or ultra-long-acting. Examples of short-acting β2 agonists that can be used include salbutamol, levosalbutamol, terbutaline, pirbuterol, procaterol, metaproterenol, bitolterol mesilate, ritodrine, isoprenaline, salmefamol, fenoterol, terbutaline, albuterol, and isoetharin.Examples of long-acting β2 agonists that can be used include salmeterol, bambuterol, formoterol, and clenbuterol.Examples of ultra-long-acting β2 agonists include indacaterol, vilanterol, and olodaterol.Other examples of β2 agonists include tulobuterol, mabuterol, and ritodrine.

[0040] As used herein, the term "peripherally acting beta-blocker (PABRA)" refers to a beta-adrenergic receptor antagonist, or simply a beta-1, beta-2, or non-selective beta-blocker. Examples of selective peripherally acting beta-blockers (PABRA) that can be used in certain embodiments of the methods disclosed herein include nadolol, atenolol, sotalol, and labetalol. In certain embodiments, the beta-blocker that can be used in the methods herein is one or more selected from the group consisting of acebutolol, betaxolol, bisoprolol, celiprolol, esmolol, metaprolol, and nebivolol; in other embodiments, the method does not use acebutolol, betaxolol, bisoprolol, celiprolol, esmolol, metaprolol, or nebivolol as a beta-blocker. Peripherally acting beta blockers (PABRA) can be used to reduce, limit or counteract any adverse effects of beta 1-AR agonists and / or beta 2-AR agonists, such as performance-enhancing effects, thereby reducing the risk of abuse.For example, nadolol can be used to reduce, limit or counteract any peripheral beta agonist effects of clenbuterol.

[0041] As used herein, the term "about" refers to a quantitative term plus or minus 10%. For example, "about 3%" encompasses 2.7-3.3%, and "about 10%" encompasses 9-11%. Furthermore, when "about" is used herein in conjunction with a quantitative term, it is understood that the exact value of the quantitative term is contemplated and described in addition to the value of plus or minus 10%. For example, the term "about 3%" expressly contemplates, describes, and includes the exact 3%.

[0042] In certain embodiments, the peripherally acting beta-blocker (PABRA) is administered to the patient prior to the administration of the beta-AR agonist, beta-AR agonist, clenbuterol, and / or tulobuterol. In other embodiments, the peripherally acting beta-blocker (PABRA) is administered to the patient simultaneously with the administration of the beta-AR agonist, beta-AR agonist, clenbuterol, and / or tulobuterol. In other embodiments, the peripherally acting beta-blocker (PABRA) is administered to the patient simultaneously in a single-dose formulation, in a single tablet, and / or in a single capsule.

[0043] In certain embodiments of the compositions and methods provided herein, one or more peripherally acting beta-blockers (PABRAs) are administered before or simultaneously with the administration of a beta-AR agonist, a beta-AR agonist, clenbuterol, and / or tulobuterol to inhibit or eliminate the activation of peripheral beta- and / or beta-adrenergic receptors by the beta-AR agonist, a beta-AR agonist, clenbuterol, and / or tulobuterol. In various embodiments, blocking peripheral beta- and / or beta-adrenergic receptors is preferred in accordance with the compositions and methods of the present disclosure to eliminate or at least minimize any adverse effects on the treated person, such as peripheral cardiac effects.

[0044] In certain embodiments of the methods provided herein, the β1-AR agonist, β2-AR agonist, clenbuterol, and / or tulobuterol are administered orally, intravenously, intramuscularly, transdermally, by inhalation, or intranasally.In certain embodiments of the methods provided herein, the β1-AR agonist, β2-AR agonist, clenbuterol, and / or tulobuterol are administered orally.

[0045] In certain embodiments of the methods provided herein, the peripherally acting beta blocker (PABRA) is administered orally, intravenously, intramuscularly, by inhalation, or intranasally. In certain embodiments of the methods provided herein, the peripherally acting beta blocker (PABRA) is administered orally.

[0046] In certain embodiments of the methods provided herein, the β1-AR agonist, β2-AR agonist, clenbuterol, and / or tulobuterol, and the peripherally acting β-blocker (PABRA) are administered to a patient in a single formulation. In some embodiments, the single formulation is in the form of a tablet. In some embodiments, both agents (β-AR agonist and PABRA) are present in the tablet. In some embodiments, the tablet contains 30-160 μg of clenbuterol and / or 0.1 mg-10 mg of tulobuterol, and about 0.1-15 mg of the peripherally acting β-blocker (PABRA). In some embodiments, the tablet contains 30-160 μg of clenbuterol and / or 0.1 mg-10 mg of tulobuterol, and a subtherapeutic dose of PABRA. In some embodiments, the tablet contains about 0.5-20 mg of a β1-AR agonist, a β2-AR agonist, clenbuterol, and / or tulobuterol, and about 0.1-15 mg of a peripherally acting β-blocker (PABRA). In some embodiments, the tablet contains a subtherapeutic dose of a peripherally acting β-blocker (PABRA). In some embodiments, the tablet comprises an amount of a peripherally acting beta blocker (PABRA) that is 0.01 to 15 mg, 0.1 to 15 mg, 0.1 to 10 mg, 0.1 to 1 mg, 0.1 to 0.5 mg, 0.2 to 0.3 mg, 0.23 to 0.27 mg; 0.1 to 5 mg, 1 to 15 mg, 1 to 10 mg, 1 to 5 mg, 5 to 10 mg, 10 mg or less, 7 mg or less, 5 mg or less, 1 mg or less, about 0.01 mg, about 0.05 mg; about 0.1 mg, about 0.2 mg, about 0.25 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, or about 10 mg.In some embodiments, the tablet contains a peripherally acting beta-blocker (PABRA, e.g., Nadro) in an amount that results in a dose of about 90% or less, or 85% or less, or 80% or less, or 75% or less, or 70% or less, or 65% or less, or 60% or less, or 55% or less, or 50% or less, or 45% or less, or 40% or less, or 35% or less, or 30% or less, or 25% or less, or 20% or less, or 15% or less, or 10% or less, or 5% or less, or 4% or less, or 3% or less, or 2.5% or less, or 2% or less, or 1.5% or less, or 1% or less, or 0.5% or less compared to 5 mg twice daily (or 10 mg total per day). In some embodiments, the sub-therapeutic dose of PABRA in the tablet may be about 90%, or about 85%, or about 80%, or about 75%, or about 70%, or about 5%, or about 60%, or about 55%, or about 50%, or about 45%, or about 40%, or about 35%, or about 30%, or about 25%, or about 20%, or about 15%, or about 10% or less, or about 5%, or about 4%, or about 3%, or about 2.5%, or about 2%, or about 1.5% or less, or about 1%, or about 0.5% of the dose at which the drug is effective or approved for treating a particular disease indication. In some embodiments, tablets having the aforementioned doses are administered daily. In some embodiments, tablets having the aforementioned doses are administered weekly. In some embodiments, the tablet contains a peripherally acting beta-blocker (PABRA) in an amount of about 5-10 mg. In some embodiments, the beta-AR agonist, beta-AR agonist, clenbuterol, and / or tulobuterol are present in the tablet in an amount of about 50-160 μg or 80-160 μg.In some embodiments, the β1-AR agonist, β2-AR agonist, clenbuterol, and / or tulobuterol are present in the tablet in an amount of about 30-160 μg, 50-160 μg, 80-160 μg, 100-160 μg, 120-160 μg, 140-160 μg, 30-140 μg, 50-140 μg, 80-140 μg, 100-140 μg, 120-140 μg, 3 It is present in the range of 0-120μg, 50-120μg, 80-120μg, 100-120μg, 30-100μg, 50-100μg, 80-100μg, 30-80μg, 50-80μg, 30-50μg, 30μg, 40μg, 50μg, 60μg, 70μg, 80μg, 90μg, 100μg, 110μg, 120μg, 130μg, 140μg, 150μg, or 160μg. In some embodiments, the β1-AR agonist, β2-AR agonist, clenbuterol, and / or tulobuterol are present in the tablet in amounts of 0.5 to 20 mg, 1 to 10 mg, 2 to 8 mg, or about 1 mg, or about 2 mg, or about 3 mg, or about 4 mg, or about 5 mg, or about 6 mg, or about 7 mg, or about 8 mg, or about 10 mg. In some embodiments, the above-mentioned doses are total daily doses. In some embodiments, the above-mentioned doses are weekly doses. In some embodiments, the doses of the β1-AR agonist, β2-AR agonist, clenbuterol, and / or tulobuterol and the peripherally acting beta-blocker (PABRA) in the tablet are administered over a period of several weeks or longer.

[0047] In certain embodiments of the methods provided herein, the β1-AR agonist, β2-AR agonist, clenbuterol, and / or tulobuterol, and the peripherally acting β-blocker (PABRA) are administered to the patient in a combined formulation. In some embodiments, the combined formulation comprises approximately 30-160 μg of the β1-AR agonist, β2-AR agonist, clenbuterol, and / or tulobuterol, and 15 mg or less of the peripherally acting β-blocker (PABRA). In some embodiments, the combined formulation comprises approximately 0.5-20 mg of the β1-AR agonist, β2-AR agonist, clenbuterol, and / or tulobuterol, and 15 mg or less of the peripherally acting β-blocker (PABRA). In some embodiments, the combined formulation contains a peripherally acting beta-blocker (PABRA) in an amount of about 0.1-15 mg, 0.1-10 mg, 0.1-1 mg, 0.1-5 mg, 1-15 mg, 1-10 mg, 1-5 mg, 10 mg or less, 7 mg or less, 5 mg or less, 1 mg or less, 0.1 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, or 10 mg. In some embodiments, the combined formulation contains a peripherally acting beta-blocker (PABRA) in an amount of about 5-10 mg. In some embodiments, the β1-AR agonist, β2-AR agonist, clenbuterol, and / or tulobuterol are present in the combined formulation in an amount of about 50-160 μg or 80-160 μg. In some embodiments, the β1-AR agonist, β2-AR agonist, clenbuterol, and / or tulobuterol are present in the combined formulation in an amount of about 30-160 μg, 50-160 μg, 80-160 μg, 100-160 μg, 120-160 μg, 140-160 μg, 30-140 μg, 50-140 μg, 80-140 μg, 100-140 μg, 120-140 μg, 30-120μg, 50-120μg, 80-120μg, 100-120μg, 30-100μg, 50-100μg, 80-100μg, 30-80μg, 50-80μg, 30-50μg, 30μg, 40μg, 50μg, 60μg, 70μg, 80μg, 90μg, 100μg, 110μg, 120μg, 130μg, 140μg, 150μg, or 160μg.In some embodiments, the β1-AR agonist, β2-AR agonist, clenbuterol, and / or tulobuterol are present in the combined formulation in an amount of about 0.5 to 20 mg. In some embodiments, the β1-AR agonist, β2-AR agonist, clenbuterol, and / or tulobuterol are present in the combined formulation in an amount of 0.5 to 20 mg, 1 to 10 mg, 2 to 8 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, or about 10 mg. In some embodiments, the above-mentioned doses are total doses per day. In some embodiments, the doses of the combined formulation are administered weekly, and the doses are total doses per week. In some embodiments, doses of the β1-AR agonist, β2-AR agonist, clenbuterol, and / or tulobuterol, and peripherally acting beta blocker (PABRA) are administered daily or weekly for a period of several weeks or longer.

[0048] In some embodiments of the methods and compositions provided herein, both clenbuterol and nadolol are orally administered to a patient. In some embodiments of the methods provided herein, clenbuterol and nadolol are orally administered to a patient, and both agents are present in a tablet. In some embodiments, the tablet contains about 30-160 μg of clenbuterol and about 0.1-15 mg of nadolol. In some embodiments, the tablet contains nadolol in an amount of about 5-10 mg. In some embodiments, the tablet contains nadolol in an amount of about 0.1-15 mg, 0.1-10 mg, 0.1-1 mg, 0.1-5 mg, 1-15 mg, 1-10 mg, 1-5 mg, 10 mg or less, 7 mg or less, 5 mg or less, 1 mg or less, 0.1 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, or 10 mg. In some embodiments, nadolol is a mixture of four diastereomers. In some embodiments, the nadolol administered is a specific enantiomerically pure isomer.

[0049] In some embodiments, clenbuterol is present in the tablet at about 50-160 μg or 80-160 μg. In some embodiments, clenbuterol is present in the tablet at about 30-160 μg, 50-160 μg, 80-160 μg, 100-160 μg, 120-160 μg, 140-160 μg, 30-140 μg, 50-140 μg, 80-140 μg, 100-140 μg, 120-140 μg, 30-120 μg, 50-120 μg, 8 The dosages are 0-120 μg, 100-120 μg, 30-100 μg, 50-100 μg, 80-100 μg, 30-80 μg, 50-80 μg, 30-50 μg, 30 μg, 40 μg, 50 μg, 60 μg, 70 μg, 80 μg, 90 μg, 100 μg, 110 μg, 120 μg, 130 μg, 140 μg, 150 μg, or 160 μg. In some embodiments, the tablets are a total daily dose, intended to be administered daily for a period of several weeks or longer. In some embodiments, the tablets are a total weekly dose, intended to be administered weekly for a period of several weeks or longer. In some embodiments, nadolol can reduce, limit, or counter any adverse effects of clenbuterol, such as performance-enhancing effects, thereby reducing the potential for abuse.

[0050] In some embodiments of the methods and compositions provided herein, both tulobuterol and nadolol are orally administered to a patient. In some embodiments of the methods provided herein, tulobuterol and nadolol are orally administered to a patient, and both agents are present in a tablet. In some embodiments, the tablet contains about 0.5-20 mg of tulobuterol and about 0.1-15 mg of nadolol. In some embodiments, the tablet contains nadolol in an amount of about 0.1-15 mg, 0.1-10 mg, 0.1-1 mg, 0.1-5 mg, 1-15 mg, 1-10 mg, 1-5 mg, 10 mg or less, 7 mg or less, 5 mg or less, 1 mg or less, 0.1 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, or 10 mg. In some embodiments, the tablet contains nadolol in an amount of about 5-10 mg. In some embodiments, nadolol is a mixture of four diastereomers. In some embodiments, the administered nadolol is a specific enantiomerically pure isomer. In some embodiments, tulobuterol is present in the tablet at about 0.5 to 20 mg or 2 to 8 mg. In some embodiments, the tablet is intended to be administered daily for a total daily dose of several weeks or longer. In some embodiments, the tablet is intended to be administered weekly for a total weekly dose of several weeks or longer.

[0051] Clenbuterol and certain other β-agonists have side effects of hypertrophic and lipolytic properties that lead to their misuse by athletes and individuals who want to build muscle, improve athletic performance, and / or lose weight. These side effects and abuse potential pose a hurdle to regulatory approval (such as FDA approval) and create a certain level of public health risk. However, the hypertrophic and lipolytic effects are largely caused by the activation of peripheral β-receptors. Therefore, co-administration of PABRA as disclosed herein in combination with a β-agonist can reduce, mitigate, or eliminate the hypertrophic and lipolytic side effects and abuse potential. In particular, if a β-agonist and PABRA are produced and sold only in a single formulation containing both drugs as described herein, it will be very difficult or impossible for those who wish to misuse or abuse the drug to misuse a product that is effective for building muscle, improving athletic performance, or losing weight. Thus, in some aspects and embodiments, compositions and methods are provided that involve a single formulation (e.g., an oral tablet, etc.) having a β-agonist and a PABRA that is effective in improving cognition (CNS effects) but has a reduced risk of misuse / abuse compared to a formulation having only a β-agonist without a PABRA. In many embodiments, a subtherapeutic dose of PABRA is sufficient to counteract the side effects of the β-agonist, and thus a single formulation (e.g., an oral tablet) having a β-agonist and a PABRA as described herein can have a therapeutically active dose of the β-agonist and a subtherapeutic dose of PABRA.

[0052] In some embodiments of the aspects and embodiments provided herein, the patient has MCI (mild cognitive impairment), aMCI (amnestic MCI), vascular dementia, mixed dementia, FTD (frontotemporal dementia; Pick's disease), HD (Huntington's disease), Rett syndrome, PSP (progressive supranuclear palsy), CBD (corticobasal degeneration), SCA (spinocerebellar ataxia), MSA (multiple system atrophy), SDS (Shy-Drager syndrome), olivopontocerebellar atrophy, TBI (traumatic brain injury), CTE (chronic traumatic encephalopathy), stroke, WKS (well-defined syndrome), or The patient is identified as having one or more neurodegenerative diseases selected from the group consisting of Nicke-Korsakoff syndrome; alcoholic dementia and thiamine deficiency), normal pressure hydrocephalus, hypersomnia / narcolepsy, ASD (autism spectrum disorder), FXS (fragile X syndrome), TSC (tuberous sclerosis complex), prion-related diseases (such as CJD), depressive disorder, DLB (dementia with Lewy bodies), PD (Parkinson's disease), PDD (PD dementia), ADHD (attention deficit hyperactivity disorder), Alzheimer's disease (AD), early AD, and Down's syndrome (DS). In some embodiments, the patient has MCI, aMCI, vascular dementia, mixed dementia, FTD (frontotemporal dementia, Pick's disease), HD (Huntington's disease), Rett syndrome, PSP (progressive supranuclear palsy), CBD (corticobasal degeneration), SCA (spinocerebellar ataxia), MSA (multiple system atrophy), SDS (Shy-Drager syndrome), olivopontocerebellar atrophy, TBI (traumatic brain injury), CTE (chronic traumatic encephalopathy), stroke, WKS (Wernicke-Collins syndrome), or other conditions. In some embodiments, the patient is identified as having a neurodegenerative disease that is one or more selected from the group consisting of: Sackhoff's syndrome, alcoholic dementia and thiamine deficiency, normal pressure hydrocephalus, hypersomnia / narcolepsy, ASD (autism spectrum disorder), FXS (fragile X syndrome), TSC (tuberous sclerosis), prion-related diseases (such as CJD), depressive disorders, DLB (dementia with Lewy bodies), PD (Parkinson's disease), PDD (PD dementia), and ADHD (attention deficit hyperactivity disorder). In some embodiments, the patient does not have Alzheimer's disease (AD). In some embodiments, the patient does not have Down's syndrome. In some embodiments, the patient does not have Parkinson's disease. In some embodiments, the patient does not have dementia with Lewy bodies.

[0053] In some embodiments, the patient undergoes a cognitive test or model after said administration. In some embodiments, the patient undergoes a cognitive test or model after said administration, where the cognitive test or model is a memory test; a mental status, brain function, a diagnostic indicator of a mental condition; a contextual learning test, and / or brain imaging. In some embodiments, the patient undergoes a cognitive test or model before said administration. In some embodiments, the patient undergoes a cognitive test or model before said administration, where the cognitive test or model is a memory test; a mental status, brain function, a diagnostic indicator of a mental condition; a contextual learning test, and / or brain imaging. In some embodiments, the patient undergoes a cognitive test or model, such as a memory test; a mental status, brain function, a diagnostic indicator of a mental condition; a contextual learning test, and / or brain imaging, before said administration, and the cognitive test or model is used to identify patients in need of or desiring improved cognitive function and / or treatment of a neurodegenerative disease according to the methods and compositions provided herein. In some embodiments, the patient undergoes a cognitive test or model before and after said administration. In some embodiments, the patient undergoes a cognitive test or model before and after said administration, the cognitive test or model being a memory test; a diagnostic indicator of mental status, brain function, mental condition; a contextual learning test, and / or brain imaging.

[0054] In certain embodiments, the patient demonstrates improved cognition after said administration, hi some embodiments, the patient demonstrates improved cognition as evidenced by improvements in the patient's cognitive tests or models; memory tests; mental status, brain function, diagnostic measures of mental condition; contextual learning tests; brain imaging, etc.

[0055] "Improved cognition," "improved cognition," or "improvement in cognition" refers to an improvement in an individual's cognitive ability, memory, or the like. In certain embodiments, the methods described herein result in improved cognition, as demonstrated, for example, by an improvement in a cognitive test, a memory test, brain imaging, and / or a contextual learning test in the patient. In some embodiments, the methods described herein result in an improvement in a contextual learning test in the patient, where the contextual learning test is the Spatial Contextual Learning Test or the Arizona Cognitive Test Battery (ACTB).

[0056] In some embodiments, the patient is a mammal. In some embodiments, the patient is a human. In some embodiments, the patient is a pediatric human. In some embodiments, the patient is an adult human. As used herein, pediatric refers to a human between about 5 and 20 years of age. As used herein, adult refers to a human about 21 years of age or older. [The present invention 1001] β 2 administering to a patient an -AR agonist and a peripherally acting beta blocker (PABRA), wherein the peripherally acting beta blocker (PABRA) is administered at a subtherapeutic dose. A method comprising: [The present invention 1002] administering a beta-2-AR agonist and a peripherally acting beta-blocker (PABRA) to a patient to improve cognition and / or treat a neurodegenerative disease in the patient, wherein the peripherally acting beta-blocker (PABRA) is administered at a subtherapeutic dose. A method comprising: [The present invention 1003] Any of the preceding methods of the present invention further comprising subjecting said patient to brain imaging to assess cognitive function and / or identify whether improvement of cognitive function and / or treatment of a neurodegenerative disease is necessary or desirable for said patient. [The present invention 1004] Any of the methods of the preceding inventions, further comprising identifying a particular type of neurodegenerative disease based on the spatial pattern of brain imaging results. [The present invention 1005] Any of the preceding methods of the invention further comprising subsequently subjecting said patient to repeat brain imaging to determine any improvement in cognitive function and / or treatment of said neurodegenerative disease. [The present invention 1006]

[0023] Any of the methods of the preceding invention, wherein said brain imaging is fluorodeoxyglucose positron emission tomography (FDG-PET) scan, magnetic resonance imaging-arterial spin labeling (MRI-ASL), or magnetic resonance imaging-blood oxygen level dependent computed tomography (MRI-BOLD). [The present invention 1007] Said β 2 Any of the methods of the preceding invention, wherein the -AR agonist is administered at a dose of about 30 to 160 μg. [The present invention 1008] Said β 2 Any of the methods of the preceding invention, wherein the -AR agonist is administered at a dose of about 50-160 μg. [The present invention 1009] Said β 2 Any of the prior methods of the invention, wherein said dose of -AR agonist is a total daily dose and is administered daily for a period of several weeks or more. [The present invention 1010] Any of the methods of the preceding invention, wherein said peripherally acting beta blocker (PABRA) is administered at a dose of about 0.1 to 15 mg. [The present invention 1011] Any of the methods of the preceding invention, wherein said peripherally acting beta blocker (PABRA) is administered at a dose of about 5-10 mg. [The present invention 1012] Any of the prior methods of the present invention, wherein said dose of said peripherally acting beta blocker (PABRA) is a total daily dose and is administered daily for a period of several weeks or more. [The present invention 1013] Said β 2 Any of the prior methods of the present invention, wherein the -AR agonist is one or more selected from the group consisting of tulobuterol, mabuterol, ritodrine, salmeterol, bambuterol, formoterol, and clenbuterol. [The present invention 1014] subjecting the patient to brain imaging to assess cognitive function and / or identify whether improvement of cognitive function and / or treatment of a neurodegenerative disease is necessary or desirable for the patient; Identifying specific types of neurodegenerative diseases based on spatial patterns of brain imaging results; and then administering clenbuterol and a peripherally acting beta blocker (PABRA) to said patient, wherein said peripherally acting beta blocker (PABRA) is administered in a dose of about 15 mg or less; A method comprising: [The present invention 1015] subjecting the patient to brain imaging to assess cognitive function and / or identify whether improvement of cognitive function and / or treatment of a neurodegenerative disease is necessary or desirable for the patient; Identifying specific types of neurodegenerative diseases based on spatial patterns of brain imaging results; and then administering clenbuterol and a peripherally acting beta blocker (PABRA) to the patient, wherein the peripherally acting beta blocker (PABRA) is administered in a subtherapeutic dose; A method comprising: [The present invention 1016] subjecting the patient to brain imaging to assess cognitive function and / or identify whether improvement of cognitive function and / or treatment of a neurodegenerative disease is necessary or desirable for the patient; Identifying specific types of neurodegenerative diseases based on spatial patterns of brain imaging results; and administering clenbuterol and a peripherally acting beta blocker (PABRA) to the patient to improve cognition and / or treat a neurodegenerative disease in the patient, wherein the peripherally acting beta blocker (PABRA) is administered at a dose of about 15 mg or less; Thereafter, the patient is subjected to brain imaging again to determine any improvement in cognitive function and / or treatment of the neurodegenerative disease. A method comprising: [The present invention 1017] subjecting the patient to brain imaging to assess cognitive function and / or identify whether improvement of cognitive function and / or treatment of a neurodegenerative disease is necessary or desirable for the patient; Identifying specific types of neurodegenerative diseases based on spatial patterns of brain imaging results; and administering clenbuterol and a peripherally acting beta blocker (PABRA) to the patient to improve cognition and / or treat a neurodegenerative disease in the patient, wherein the peripherally acting beta blocker (PABRA) is administered at a subtherapeutic dose; Thereafter, the patient is subjected to brain imaging again to determine any improvement in cognitive function and / or treatment of the neurodegenerative disease. A method comprising: [The present invention 1018] subjecting the patient to brain imaging to assess cognitive function in the patient; Identifying specific types of neurodegenerative diseases based on spatial patterns of brain imaging results; and administering clenbuterol and a peripherally acting beta blocker (PABRA) to the patient, wherein the peripherally acting beta blocker (PABRA) is administered in a dose of about 15 mg or less; The subjects will then undergo brain imaging again to determine any improvement in cognitive function. A method comprising: [The present invention 1019] subjecting the patient to brain imaging to assess cognitive function in the patient; Identifying specific types of neurodegenerative diseases based on spatial patterns of brain imaging results; and administering clenbuterol and a peripherally acting beta blocker (PABRA) to the patient, wherein the peripherally acting beta blocker (PABRA) is administered in a subtherapeutic dose; The subjects will then undergo brain imaging again to determine any improvement in cognitive function. A method comprising: [The present invention 1020] subjecting the subject to brain imaging to assess cognitive function and / or identify whether improvement of cognitive function and / or treatment of a neurodegenerative disease is necessary or desirable for the subject; Identifying specific types of neurodegenerative diseases based on spatial patterns of brain imaging results; and then administering tulobuterol and a peripherally acting beta blocker (PABRA) to said patient, wherein said peripherally acting beta blocker (PABRA) is administered in a dose of about 15 mg or less; A method comprising: [The present invention 1021] subjecting the subject to brain imaging to assess cognitive function and / or identify whether improvement of cognitive function and / or treatment of a neurodegenerative disease is necessary or desirable for the subject; Identifying specific types of neurodegenerative diseases based on spatial patterns of brain imaging results; and then administering tulobuterol and a peripherally acting beta blocker (PABRA) to said patient, wherein said peripherally acting beta blocker (PABRA) is administered at a subtherapeutic dose; A method comprising: [The present invention 1022] subjecting the patient to brain imaging to assess cognitive function and / or identify whether improvement of cognitive function and / or treatment of a neurodegenerative disease is necessary or desirable for the patient; Identifying specific types of neurodegenerative diseases based on spatial patterns of brain imaging results; and administering tulobuterol and a peripherally acting beta blocker (PABRA) to the patient to improve cognition and / or treat a neurodegenerative disease in the patient, wherein the peripherally acting beta blocker (PABRA) is administered at a dose of about 15 mg or less; Thereafter, the patient is subjected to brain imaging again to determine any improvement in cognitive function and / or treatment of the neurodegenerative disease. A method comprising: [The present invention 1023] subjecting the patient to brain imaging to assess cognitive function and / or identify whether improvement of cognitive function and / or treatment of a neurodegenerative disease is necessary or desirable for the patient; Identifying specific types of neurodegenerative diseases based on spatial patterns of brain imaging results; and administering tulobuterol and a peripherally acting beta blocker (PABRA) to the patient to improve cognition and / or treat a neurodegenerative disease in the patient, wherein the peripherally acting beta blocker (PABRA) is administered at a subtherapeutic dose; Thereafter, the patient is subjected to brain imaging again to determine any improvement in cognitive function and / or treatment of the neurodegenerative disease. A method comprising: [The present invention 1024] subjecting the patient to brain imaging to assess cognitive function in the patient; Identifying specific types of neurodegenerative diseases based on spatial patterns of brain imaging results; and administering tulobuterol and a peripherally acting beta blocker (PABRA) to the patient, wherein the peripherally acting beta blocker (PABRA) is administered at a dose of about 15 mg or less; The patient then undergoes brain imaging again to determine any improvement in cognitive function. A method comprising: [The present invention 1025] subjecting the patient to brain imaging to assess cognitive function in the patient; Identifying specific types of neurodegenerative diseases based on spatial patterns of brain imaging results; and administering tulobuterol and a peripherally acting beta blocker (PABRA) to the patient, wherein the peripherally acting beta blocker (PABRA) is administered at a subtherapeutic dose; The patient then undergoes brain imaging again to determine any improvement in cognitive function. A method comprising: [The present invention 1026] The method of any of the preceding inventions, wherein said peripherally acting beta blocker (PABRA) is one or more selected from the group consisting of nadolol, atenolol, sotalol, and labetalol. [The present invention 1027] The method of any of the prior inventions, wherein said peripherally acting beta blocker (PABRA) is nadolol. [The present invention 1028] 1021. The method of claim 1021, wherein nadolol is a mixture of four diastereomers. [The present invention 1029] The method of claim 1022, wherein the nadolol administered is a specific enantiomerically pure isomer. [The present invention 1030] The method of any of the prior inventions, wherein said peripherally acting beta blocker (PABRA) is atenolol. [The present invention 1031] Any of the methods of the preceding invention, wherein said β2-AR agonist and peripherally acting β-blocker (PABRA) are each administered orally. [The present invention 1032] Any of the methods of the preceding invention, wherein the β2-AR agonist is administered at a dose of about 30 to 160 μg. [The present invention 1033] Any of the methods of the preceding invention, wherein the β2-AR agonist is administered at a dose of about 50 to 160 μg. [The present invention 1034] Any of the methods of the prior invention, wherein said dose of said β2-AR agonist is a total daily dose and is administered daily for a period of several weeks or more. [This invention 1035] Any of the methods of the prior invention, wherein said dose of said β2-AR agonist is a weekly dose and is administered weekly for a period of two weeks or more. [The present invention 1036] Any of the methods of the preceding invention, wherein said peripherally acting beta blocker (PABRA) is administered at a dose of about 0.1 to 15 mg. [This invention 1037] Any of the methods of the preceding invention, wherein said peripherally acting beta blocker (PABRA) is administered at a dose of about 5-10 mg. [The present invention 1038] Any of the prior methods of the present invention, wherein said dose of said peripherally acting beta blocker (PABRA) is a total daily dose and is administered daily for a period of several weeks or more. [This invention 1039] Any of the prior methods of the present invention, wherein said dose of said peripherally acting beta blocker (PABRA) is a weekly dose and is administered weekly for a period of two weeks or more. [The present invention 1040] The neurodegenerative disease is MCI, aMCI, vascular dementia, mixed dementia, FTD (frontotemporal dementia; Pick's disease), HD (Huntington's disease), Rett syndrome, PSP (progressive supranuclear palsy), CBD (corticobasal degeneration), SCA (spinocerebellar ataxia), MSA (multiple system atrophy), SDS (Shy-Drager syndrome), olivopontocerebellar atrophy, TBI (traumatic brain injury), CTE (chronic traumatic encephalopathy), stroke, WKS (Wernicke-Korsakoff syndrome), any of the preceding methods of the present invention, wherein the condition is one or more selected from the group consisting of: dementia with lewy bodies, dementia with lewy bodies (lewy bodies), ... [The present invention 1041] The neurodegenerative disease may be MCI, aMCI, vascular dementia, mixed dementia, FTD (frontotemporal dementia; Pick's disease), HD (Huntington's disease), Rett syndrome, PSP (progressive supranuclear palsy), CBD (corticobasal degeneration), SCA (spinocerebellar ataxia), MSA (multiple system atrophy), SDS (Shy-Drager syndrome), olivopontocerebellar atrophy, TBI (traumatic brain injury), CTE (chronic traumatic encephalopathy), stroke, WKS (Wernicke-Korsakoff syndrome), or any of the preceding methods of the present invention, wherein the condition is one or more selected from the group consisting of: ASD (autism spectrum disorder), FXS (fragile X syndrome), TSC (tuberous sclerosis), prion-related diseases (such as CJD), depressive disorders, DLB (dementia with Lewy bodies), PD (Parkinson's disease), PDD (PD dementia), and ADHD (attention deficit hyperactivity disorder). [The present invention 1042] Any of the methods of the preceding invention, wherein said patient does not have Alzheimer's disease. [This invention 1043] The method of any of the preceding inventions, wherein said patient does not have Down's syndrome. [This invention 1044] The method of any of the preceding inventions, wherein said patient does not have Parkinson's disease. [This invention 1045] The method of any of the prior inventions, wherein said patient does not have Dementia with Lewy Bodies. [The present invention 1046] The method of any of the preceding inventions, wherein the tulobuterol is (S)-tulobuterol substantially free of (R)-tulobuterol. [This invention 1047] The method of any of the preceding inventions, wherein the tulobuterol is (R)-tulobuterol substantially free of (S)-tulobuterol. [This invention 1048] subjecting the patient to a test to determine cognitive function and / or to identify whether improvement of cognitive function and / or treatment of a neurodegenerative disease is necessary or desirable for the patient; Identifying specific types of neurodegenerative diseases based on spatial patterns of test results; and then administering to the patient a pharmaceutical composition comprising a β1-AR agonist, a β2-AR agonist, a peripherally acting β-blocker (PABRA), or any combination thereof, wherein the peripherally acting β-blocker (PABRA) is administered in a dose of about 15 mg or less; A method comprising: [This invention 1049] subjecting the patient to a test to determine cognitive function and / or to identify whether improvement of cognitive function and / or treatment of a neurodegenerative disease is necessary or desirable for the patient; Identifying specific types of neurodegenerative diseases based on spatial patterns of test results; and then administering to the patient a pharmaceutical composition comprising a β1-AR agonist, a β2-AR agonist, a peripherally acting β-blocker (PABRA), or any combination thereof, wherein the peripherally acting β-blocker (PABRA) is administered in a subtherapeutic dose; A method comprising: [The present invention 1050] subjecting the patient to a test to determine cognitive function and / or to identify whether improvement of cognitive function and / or treatment of a neurodegenerative disease is necessary or desirable for the patient; Identifying specific types of neurodegenerative diseases based on spatial patterns of test results; and administering a pharmaceutical composition to the patient to improve cognition and / or treat a neurodegenerative disease in the patient, wherein the pharmaceutical composition comprises a β1-AR agonist, a β2-AR agonist, a peripherally acting β-blocker (PABRA), or any combination thereof, and wherein the peripherally acting β-blocker (PABRA) is administered at a dose of about 15 mg or less; and then subjecting the patient to the test again to determine any improvement in cognitive function and / or treatment of the neurodegenerative disease. A method comprising: [This invention 1051] subjecting the patient to a test to determine cognitive function and / or to identify whether improvement of cognitive function and / or treatment of a neurodegenerative disease is necessary or desirable for the patient; Identifying specific types of neurodegenerative diseases based on spatial patterns of test results; and administering a pharmaceutical composition to the patient to improve cognition and / or treat a neurodegenerative disease in the patient, wherein the pharmaceutical composition comprises a β1-AR agonist, a β2-AR agonist, a peripherally acting β-blocker (PABRA), or any combination thereof, and wherein the peripherally acting β-blocker (PABRA) is administered at a sub-therapeutic dose; Thereafter, subjecting the patient to the test again to determine any improvement in cognitive function and / or treatment of the neurodegenerative disease. A method comprising: [This invention 1052] administering a test to the patient to determine cognitive function in the patient; Identifying specific types of neurodegenerative diseases based on spatial patterns of test results; and administering to the patient a pharmaceutical composition comprising a β1-AR agonist, a β2-AR agonist, a peripherally acting β-blocker (PABRA), or any combination thereof, wherein the peripherally acting β-blocker (PABRA) is administered at a dose of about 15 mg or less; The patient is then re-submitted to the test to determine any improvement in cognitive function. A method comprising: [This invention 1053] administering a test to the patient to determine cognitive function in the patient; Identifying specific types of neurodegenerative diseases based on spatial patterns of test results; and administering to the patient a pharmaceutical composition comprising a β1-AR agonist, a β2-AR agonist, a peripherally acting β-blocker (PABRA), or any combination thereof, wherein the peripherally acting β-blocker (PABRA) is administered at a sub-therapeutic dose; The patient is then re-submitted to the test to determine any improvement in cognitive function. A method comprising: [This invention 1054] Treating a subject identified as having impaired cognitive function and / or in need of or desiring improvement of cognitive function and / or treatment of a neurodegenerative disease by administering to said subject a pharmaceutical composition comprising a β1-AR agonist, a β2-AR agonist, a peripherally acting β-blocker (PABRA), or any combination thereof, wherein said peripherally acting β-blocker (PABRA) is administered at a dose of about 15 mg or less. A method comprising: [This invention 1055] Treating a subject identified as having impaired cognitive function and / or in need of or desiring improvement of cognitive function and / or treatment of a neurodegenerative disease by administering to said subject a pharmaceutical composition comprising a β1-AR agonist, a β2-AR agonist, a peripherally acting β-blocker (PABRA), or any combination thereof, wherein said peripherally acting β-blocker (PABRA) is administered at a sub-therapeutic dose. A method comprising: [This invention 1056] The method of any of the prior inventions, wherein said test is brain imaging. [This invention 1057] The method of any of the preceding inventions, wherein said test is a fluorodeoxyglucose positron emission tomography (FDG-PET) scan, magnetic resonance imaging-arterial spin labeling (MRI-ASL), or magnetic resonance imaging-blood oxygen level dependent computed tomography (MRI-BOLD). [This invention 1058] The method of any of the preceding inventions, wherein said pharmaceutical composition comprises a β2-AR agonist and a PABRA. [This invention 1059] The method of any of the preceding inventions, wherein said pharmaceutical composition comprises clenbuterol and PABRA. [The present invention 1060] The method of any of the prior inventions, wherein said pharmaceutical composition comprises tulobuterol and PABRA. [This invention 1061] Any of the methods of the preceding invention, wherein the β2-AR agonist is administered at a dose of about 30 to 160 μg. [The present invention 1062] Any of the methods of the preceding invention, wherein the β2-AR agonist is administered at a dose of about 50 to 160 μg. [The present invention 1063] The method of any of the preceding inventions, wherein said β2-AR agonist is one or more selected from the group consisting of tulobuterol, mabuterol, ritodrine, salmeterol, bambuterol, formoterol, and clenbuterol. [This invention 1064] Any of the methods of the prior invention, wherein said dose of said β2-AR agonist is a total daily dose and is administered daily for a period of several weeks or more. [This invention 1065] The method of any of the preceding inventions, wherein the tulobuterol is (S)-tulobuterol substantially free of (R)-tulobuterol. [The present invention 1066] The method of any of the preceding inventions, wherein the tulobuterol is (R)-tulobuterol substantially free of (S)-tulobuterol. [This invention 1067] The method of any of the prior inventions, wherein the dosage of said pharmaceutical composition is adjusted based on said test results. [The present invention 1068] The method of any of the prior inventions, wherein said peripherally acting beta blocker (PABRA), if present, is one or more selected from the group consisting of nadolol, atenolol, sotalol, and labetalol. [This invention 1069] The method of any of the prior inventions, wherein said peripherally acting beta blocker (PABRA) is nadolol. [The present invention 1070] The method of any of the prior inventions, wherein said peripherally acting beta blocker (PABRA) is atenolol. [This invention 1071] Any of the methods of the preceding invention, wherein said peripherally acting beta blocker (PABRA) is administered at a dose of about 0.1 to 15 mg. [This invention 1072] Any of the methods of the preceding invention, wherein said peripherally acting beta blocker (PABRA) is administered at a dose of about 5-10 mg. [This invention 1073] Any of the prior methods of the present invention, wherein said dose of said peripherally acting beta blocker (PABRA) is a total daily dose and is administered daily for a period of several weeks or more. [This invention 1074] Any of the prior methods of the present invention, wherein said dose of said peripherally acting beta blocker (PABRA) is a weekly dose and is administered weekly for a period of several weeks or more. [This invention 1075] The method of any of the preceding inventions, wherein said pharmaceutical composition is administered orally. [This invention 1076] The neurodegenerative disease is MCI, aMCI, vascular dementia, mixed dementia, FTD (frontotemporal dementia; Pick's disease), HD (Huntington's disease), Rett syndrome, PSP (progressive supranuclear palsy), CBD (corticobasal degeneration), SCA (spinocerebellar ataxia), MSA (multiple system atrophy), SDS (Shy-Drager syndrome), olivopontocerebellar atrophy, TBI (traumatic brain injury), CTE (chronic traumatic encephalopathy), stroke, WKS (Wernicke-Korsakoff syndrome), any of the preceding methods of the present invention, wherein the condition is one or more selected from the group consisting of: dementia with lewy bodies, dementia with lewy bodies (lewy bodies), ... [This invention 1077] The neurodegenerative disease may be MCI, aMCI, vascular dementia, mixed dementia, FTD (frontotemporal dementia; Pick's disease), HD (Huntington's disease), Rett syndrome, PSP (progressive supranuclear palsy), CBD (corticobasal degeneration), SCA (spinocerebellar ataxia), MSA (multiple system atrophy), SDS (Shy-Drager syndrome), olivopontocerebellar atrophy, TBI (traumatic brain injury), CTE (chronic traumatic encephalopathy), stroke, WKS (Wernicke-Korsakoff syndrome), or any of the preceding methods of the present invention, wherein the condition is one or more selected from the group consisting of: ASD (autism spectrum disorder), FXS (fragile X syndrome), TSC (tuberous sclerosis), prion-related diseases (such as CJD), depressive disorders, DLB (dementia with Lewy bodies), PD (Parkinson's disease), PDD (PD dementia), and ADHD (attention deficit hyperactivity disorder). [This invention 1078] Any of the methods of the preceding invention, wherein said patient does not have Alzheimer's disease. [This invention 1079] The method of any of the preceding inventions, wherein said patient does not have Down's syndrome. [The present invention 1080] The method of any of the preceding inventions, wherein said patient does not have Parkinson's disease. [This invention 1081] The method of any of the prior inventions, wherein said patient does not have Dementia with Lewy Bodies. [This invention 1082] a therapeutically effective amount of a β2-AR agonist; Peripherally acting beta-blockers (PABRA) in doses of 15 mg or less 10. A pharmaceutical tablet comprising: [This invention 1083] a therapeutically effective amount of a β2-AR agonist; A peripherally acting beta-blocker (PABRA) in an amount that achieves a subtherapeutic dose and 10. A pharmaceutical tablet comprising: [This invention 1084] a β2-AR agonist in an amount of about 30 to 160 μg; Peripherally acting beta-blockers (PABRA) in doses of 15 mg or less 10. A pharmaceutical tablet comprising: [This invention 1085] a β2-AR agonist in an amount of about 30 to 160 μg; Subtherapeutic doses of peripherally acting beta-blockers (PABRA) and 10. A pharmaceutical tablet comprising: [This invention 1086] a therapeutically effective amount of a β2-AR agonist; A peripherally acting beta-blocker (PABRA) in an amount that achieves a subtherapeutic dose and A combined preparation comprising: [This invention 1087] a β2-AR agonist in an amount of about 30 to 160 μg; Peripherally acting beta-blockers (PABRA) in doses of 15 mg or less A combined preparation comprising: [This invention 1088] a therapeutically effective amount of a β2-AR agonist; A peripherally acting beta-blocker (PABRA) in an amount that achieves a subtherapeutic dose and 10. A single formulation comprising: [This invention 1089] Any of the methods or compositions of the preceding inventions, wherein said PABRA is administered in a sub-therapeutic dose. [The present invention 1090] Any of the preceding methods or compositions of the present invention, wherein the dose of the PABRA is 90% or less, or 85% or less, or 80% or less, or 75% or less, or 70% or less, or 65% or less, or 60% or less, or 55% or less, or 50% or less, or 45% or less, or 40% or less, or 35% or less, or 30% or less, or 25% or less, or 20% or less, or 15% or less, or 10% or less, or 5% or less, or 4% or less, or 3% or less, or 2.5% or less, or 2% or less, or 1.5% or less, or 1% or less, or 0.5% or less, compared to the dose at which the agent is effective or approved to treat a particular disease indication. [This invention 1091] Any of the preceding methods or compositions of the present invention, wherein the PABRA is administered at a sub-therapeutic dose, wherein the sub-therapeutic dose is 90% or less, or 85% or less, or 80% or less, or 75% or less, or 70% or less, or 65% or less, or 60% or less, or 55% or less, or 50% or less, or 45% or less, or 40% or less, or 35% or less, or 30% or less, or 25% or less, or 20% or less, or 15% or less, or 10% or less, or 5% or less, or 4% or less, or 3% or less, or 2.5% or less, or 2% or less, or 1.5% or less, or 1% or less, or 0.5% or less of the dose at which the agent is approved to treat a particular disease indication. [This invention 1092] The total daily dose of the β2-AR agonist is about 1 to 300 μg, 5 to 200 μg, 10 to 180 μg, 10 to 40 μg, 20 to 50 μg, 40 to 80 μg, 50 to 100 μg, 100 to 200 μg, 30 to 160 μg, 50 to 160 μg, 80 to 160 μg, 100 to 160 μg, 120 to 160 μg, 140 to 160 μg, 150 to 170 μg, 30 to 140 μg, 50 to 140 μg, 80 to 140 μg, 100 to 140 μg, 120 to 140 μg, 30 to 120 μg, 50 to 120 μg, 80 to 120 μg, 10

[0023] Any of the methods or compositions of the preceding inventions, wherein the amount of the IgG antibody is 0 to 120 μg, 30 to 100 μg, 50 to 100 μg, 80 to 100 μg, 30 to 80 μg, 50 to 80 μg, 30 to 50 μg, about 10 μg, about 20 μg, about 25 μg, about 30 μg, about 40 μg, about 50 μg, about 60 μg, about 70 μg, about 80 μg, about 90 μg, about 100 μg, about 110 μg, about 120 μg, about 125 μg, about 130 μg, about 140 μg, about 150 μg, or about 160 μg, about 170 μg, about 175 μg, about 180 μg, about 190 μg, or about 200 μg. [This invention 1093] Any of the methods or compositions of the preceding inventions, wherein the β2-AR agonist is administered at a dose of 0.5 to 20 mg, or 1 to 10 mg, or 2 to 8 mg, or about 1 mg, or about 2 mg, or about 3 mg, or about 4 mg, or about 5 mg, or about 6 mg, or about 7 mg, or about 8 mg, or about 10 mg. [This invention 1094] The β2-AR agonist is clenbuterol, and the total daily dose is 1 to 300 μg, 5 to 200 μg, 10 to 180 μg, 10 to 40 μg, 20 to 50 μg, 40 to 80 μg, 50 to 100 μg, 100 to 200 μg, 30 to 160 μg, 50 to 160 μg, 80 to 160 μg, 100 to 160 μg, 120 to 160 μg, 140 to 160 μg, 150 to 170 μg, 30 to 140 μg, 50 to 140 μg, 80 to 140 μg, 100 to 140 μg, 120 to 140 μg, 30 to 120 μg, 50 to 120 μg, 80 to 120 μg,

[0033] Any of the preceding methods or compositions of the present invention, wherein the amount of the IgG antibody is 0 μg, 100 to 120 μg, 30 to 100 μg, 50 to 100 μg, 80 to 100 μg, 30 to 80 μg, 50 to 80 μg, 30 to 50 μg, about 10 μg, about 20 μg, about 25 μg, about 30 μg, about 40 μg, about 50 μg, about 60 μg, about 70 μg, about 80 μg, about 90 μg, about 100 μg, about 110 μg, about 120 μg, about 125 μg, about 130 μg, about 140 μg, about 150 μg, or about 160 μg, about 170 μg, about 175 μg, about 180 μg, about 190 μg, or about 200 μg. [This invention 1095] Any of the methods or compositions of the preceding inventions, wherein the β2-AR agonist is tulobuterol and the total daily dose is 0.5 to 20 mg, or 1 to 10 mg, or 2 to 8 mg, or about 1 mg, or about 2 mg, or about 3 mg, or about 4 mg, or about 5 mg, or about 6 mg, or about 7 mg, or about 8 mg, or about 10 mg. [Brief explanation of the drawings]

[0057] The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate various embodiments of the present invention and, together with the description, serve to explain and illustrate the principles of the present disclosure. The drawings are intended only to illustrate major features of exemplary embodiments in a diagrammatic manner.

[0058] [Figure 1] 1 shows a graph of cerebral blood flow in a patient after receiving a single dose of clenbuterol and / or nadolol compared to the patient's baseline. [Figure 2] 1 shows a graph of cerebral blood flow in a patient after receiving a single dose of clenbuterol and / or nadolol compared to the patient's baseline. [Figure 3] 1 shows graphs of cerebral blood flow in a patient after receiving a single dose of clenbuterol and in a patient after receiving a single dose of pindolol compared to the patient's baseline. [Figure 4] 1 shows a graph of cerebral blood flow in patients after receiving a single dose of various amounts of clenbuterol compared to the patient's baseline. [Figure 5] 1 shows graphs of cerebral blood flow in patients after receiving various amounts of a single dose of clenbuterol and in patients after receiving a single dose of clenbuterol and / or nadolol compared to the patient's baseline. [Figure 6] This shows that there is an overall increase in cerebral perfusion after administration of a single dose of 160 μg of clenbuterol. The legend on the right indicates the different regions of interest (ROIs). The data are plotted as the change from baseline in cerebral blood flow in different regions of the brain. [Figure 7] Perfusion MRI-ASL images of the hippocampus as a region of interest (ROI) are shown. Six healthy subjects, aged 44-52 years, were treated with a single dose of 80 μg of clenbuterol. Baseline vs. post-dose paired t-test result: p=0.019. The color scale is shown in the center, with low values ​​of cerebral blood flow indicated in red and high values ​​indicated in yellow. [Figure 8] For Cohort 5 of the study, the "estimated dose" of clenbuterol was based on the dose equivalent calculated from PK modeling of exposure at 24 hours (estimated dose of 50 μg) and 48 hours (estimated dose of 30 μg) following a single 80 μg dose of clenbuterol administered to subjects on Day 1. [Figure 9] Showing improved adaptive tracking in response to clenbuterol. [Figure 10] 1 shows the effects of clenbuterol and a β2-AR antagonist / β1-AR partial agonist on the visual verbal learning test (VVLT). DETAILED DESCRIPTION OF THE INVENTION

[0059] Detailed Description In certain aspects and embodiments of the present disclosure, the compositions and methods result in improved cognition, increased brain metabolic activity, and / or improved inflammation control in patients. In some embodiments, the methods described herein result in improved cognition, as demonstrated, for example, by improvements in a patient's cognitive test or model; memory test; diagnostic indicators of mental status, brain function, or mental conditions; contextual learning test; or the like. Such cognitive tests, diagnoses, and models are well known in the art. In various aspects and embodiments, any of a number of accepted contextual learning tests for animals or humans can be used to assess baseline cognitive function and / or measure or quantify improvement in cognitive function. In some embodiments, the compositions and methods described herein may result in improvements in one or more tests, diagnoses, and models, such as: Increased brain metabolic activity and improved inflammation control, in certain embodiments, can be imaged via FDG-PET and via cerebrospinal fluid (CSF) sampling, allowing for measurement of inflammatory cytokines and markers of glial cell activation. In some embodiments, magnetic resonance imaging-arterial spin labeling (MRI-ASL) can be used for neuroimaging. In some embodiments, magnetic resonance imaging-blood oxygen level dependent computed tomography (MRI-BOLD) can be used for neuroimaging. In various embodiments, FDG-PET can be used alone or in combination with CT and / or MRI, including MRI-ASL and / or MRI-BOLD. For example, FDG-PET and MRI-BOLD can be used, or FDG-PET and MRI-ASL can be used. Alternatively, FDG-PET, MRI-BOLD, and MRI-ASL can be used. Alternatively, MRI, including MRI-BOLD and MRI-ASL, can be used alone or in combination, and optionally with CT.

[0060] Human Models / Testing In various embodiments, there are many contextual learning tests that are recognized and / or accepted in the art, and can be used in conjunction with the compositions and methods disclosed herein to assess baseline cognitive function and / or measure or quantify the improvement of cognitive function in human subjects.For example, the contextual learning test used can be based on single-task learning, multi-task learning, or spatial contextual memory.The contextual learning test assessment based on spatial contextual memory can be advantageous, for example, when assessing how well an individual can navigate shopping malls, their neighborhood, or city transport or subway system, and when assessing any improvement in the ability to perform these tasks that results from the treatment methods described herein.

[0061] An example of a simple spatial context learning test is contextual cueing, where humans learn to use repetitive spatial configurations to facilitate target search. A higher-order spatial context learning test is sequence learning, where humans learn to use subtle sequence regularities to respond more quickly and accurately to a sequence of events. For example, see JH Howard Jr., et al., Neuropsychology, Vol. 18(1), January 2004, 124-134.

[0062] In some embodiments, cognition may be assessed using the Mini-Mental State Examination (MMSE) and / or the Montreal Cognitive Assessment (MOCA).

[0063] Arizona Cognitive Test Battery (ACTB). A testing protocol that can be used in various embodiments is the Arizona Cognitive Test Battery (ACTB). See Edgin, J., et al. J. Neurodevelop. Disord. (2010) 2:149-164. The ACTB was developed specifically to assess the cognitive phenotype in DS and includes a variety of tests with varying task demands and associations with brain function. More specifically, tests include: 1) benchmarks such as the KBIT II verbal subscale and KBIT II nonverbal subscale IQ tests; 2) hippocampal function; 3) prefrontal cortex function; 4) cerebellar function; 5) finger sequencing task; 6) NEPSY visual-motor accuracy; and 7) simple reaction time.

[0064] In some embodiments, cognition can be assessed using the Cambridge Neuropsychological Test Automated Battery (CANTAB) assessment (see, e.g., Sahakian, et al., (1988) Brain. 111(3):695-718). Cognitive domains such as attention, visuospatial working memory, episodic memory, processing speed, and executive function can be assessed using the CANTAB battery tests, including: ●Reaction time (RTI), ● Paired Associate Learning (PAL), ●Verbal recognition memory (VRM) immediate free recall, Rapid visual processing (RVP), ●Spatial working memory (SWM), Adaptive tracking, and VRM delayed free recall and forced choice recognition

[0065] The domains / exams assessed according to ACTB, exam descriptions, and correlations of key competencies are provided below. TIFF0007744344000003.tif147170

[0066] In some embodiments, the above test battery can be performed in its entirety to assess all major cognitive processes balanced by the time constraints and practical needs of the test. The cognitive tests herein may, in certain embodiments, be used in patients receiving the treatments herein to monitor their cognitive status and progress.

[0067] In some embodiments, a test battery can be conducted on test and control groups of individuals to demonstrate the effectiveness of various aspects and embodiments of the compositions and methods described herein. The test group can be treated with any of the treatment regimens described herein, and the control group is treated with a placebo, such as a 5% dextrose saline solution administered intranasally.

[0068] The improvement of cognitive function as defined herein is, for example, in at least one, preferably two or more of the tests listed in ATCB, the score improves by at least 10%, preferably at least 20%.Any of the domains / tests listed for the above-mentioned ATCB can be included in the evaluation of whether improvement has occurred.Tests can be carried out after or during treatment to determine whether dosage or treatment frequency needs to be changed.

[0069] Brain Imaging. Generally, any non-invasive procedure can be used to establish both a baseline (presence or absence) of brain pathology and, from there, a baseline for a treatment protocol. However, in some embodiments, magnetic resonance imaging (MRI) may be preferred for neuroimaging because it allows for accurate measurement of three-dimensional (3D) volumes of brain structures, particularly the hippocampus and related regions. Such techniques are well known, as described in U.S. Pat. No. 6,490,472, which is incorporated herein in its entirety.

[0070] Additionally, non-invasive optical imaging systems can also be used to monitor neuropathological events. See, e.g., U.S. Patent Publication No. 2011 / 0286932, which is incorporated herein in its entirety. The techniques described herein involve administering to a human a fluorescent marker for staining Aβ peptide, imaging the retina of the DS human with an optical imaging system, and examining the image for stained Aβ peptide to determine whether the onset of brain pathology (such as AD brain pathology) has occurred.

[0071] In certain embodiments, fluorodeoxyglucose positron emission tomography (FDG-PET) can be used in neuroimaging to assess cognitive function and / or identify neurodegenerative diseases according to the compositions and methods described herein. The use of FDG-PET to monitor cognitive function and / or diagnose cognitive impairment or neurodegenerative diseases, and / or identify patients who require or require treatment to improve cognitive function is described, for example, in Brown et al., RadioGraphics, (2014) 34:684-701 and Shivamurthy et al., AJR, (2015) 204:W76-W85, both of which are incorporated herein by reference in their entirety. In various embodiments, FDG-PET can be used alone or in combination with CT and / or MRI, including MRI-ASL and / or MRI-BOLD. For example, FDG-PET and MRI-BOLD can be used, or FDG-PET and MRI-ASL can be used. Alternatively, FDG-PET, MRI-BOLD, and MRI-ASL can be used. Alternatively, MRI, including MRI-BOLD and MRI-ASL, may be used alone or in combination, and optionally with CT.

[0072] Alzheimer's disease AD brain pathology refers to the accumulation of highly degradation-resistant amyloid fibrils that cause lesions in adjacent brain regions. The accumulation of these amyloid fibrils to neurotoxic levels leads to the destruction of nerve fibers and the observed behaviors associated with Alzheimer's disease. Observed behavioral symptoms, which become progressively more severe as the disease progresses, often include vocabulary loss, incorrect word substitutions (paraphasias), loss of reading and writing skills, falls, wandering, speech loss, lethargy, and an increased risk of muscle mass loss.

[0073] Down syndrome The generation of several trisomic mouse models has greatly facilitated elucidation of the neurobiological basis of cognitive impairment in DS. Among these mouse models, the Ts65Dn mouse is the most well-characterized. It contains an additional copy of approximately 140 mouse genes on chromosome 16, orthologous to genes on human chromosome 21 (HSA21). Nearly all of the genes in HSA21, which have potential roles in nervous system abnormalities, are also found in Ts65Dn mice. Similar to DS, alterations in hippocampal structure and function, as well as the failure to induce long-term potentiation (LTP), have been widely reported in Ts65Dn mice. The Ts65Dn mouse is the most widely used mouse model in DS research and is considered to be the art-accepted model for investigating human DS. Olson, LE, et al., Dev. Dyn. 2004 July;230(3):581-9.

[0074] DS is characterized by the degeneration and dysfunction of multiple neuronal populations in the central nervous system (CNS). Among these, the hippocampal formation (i.e., the primary site for contextual learning processes) displays significant abnormalities in DS. As a result, contextual learning deficits are common in humans with DS. To clarify the neurobiological basis of contextual learning deficits in DS, the integrity of subcortical regions that project extensively to the hippocampal formation has been investigated. Through extensive innervation, these subcortical regions exert a strong modulating influence on hippocampal neurons. Among these subcortical regions, the LC is particularly important. LC neurons in the brainstem are the sole source of a large number of norepinephrine (NE)-ergic nerve terminals for the hippocampus and play important roles in alertness, attention, and navigational memory. Ts65Dn mice exhibited significant age-related degeneration of NE-ergic neurons in the LC. Interestingly, loss of LC nerve terminals in Ts65Dn mice further exacerbates cognitive impairment in these mice. Similarly, LC neurons undergo extensive age-related degeneration in DS. The important role of NE-ergic dysfunction in the cognitive impairment of Ts65Dn is supported by the fact that increasing NE levels in the brain with L-threo-3,4-dihydroxyphenylserine (L-DOPS), an NE prodrug, restored contextual learning in Ts65Dn. L-DOPS is in phase III clinical trials for the treatment of primary autonomic dysfunction associated with Parkinson's disease, but it is not yet approved by the FDA, and its long-term effects, particularly in children, have not yet been studied.

[0075] With respect to the agents described herein, the terms "modulate" and "modulation" refer to the upregulation (i.e., activation or stimulation) or downregulation (i.e., inhibition or suppression) of a response. A "modulator" is a modulating agent, compound, or molecule, and can be, for example, an agonist, antagonist, activator, stimulator, suppressor, or inhibitor. The terms "inhibit," "reduce," and "eliminate," as used herein, refer to any inhibition, reduction, decrease, suppression, downregulation, or prevention of expression, activity, or symptoms, including partial or complete inhibition of activity or symptoms. Partial inhibition may refer to a level of expression, activity, or symptom that is, for example, less than 95%, less than 90%, less than 85%, less than 80%, less than 75%, less than 70%, less than 65%, less than 60%, less than 55%, less than 50%, less than 45%, less than 40%, less than 35%, less than 30%, less than 25%, less than 20%, less than 15%, less than 10%, or less than 5% of the uninhibited expression, activity, or symptom. The terms "eliminate" or "eradicate" refer to a complete reduction in activity or symptom.

[0076] As used herein, the term "disorder" or "disease" refers to any disturbance or abnormality of function, i.e., a morbid physical or mental condition. See Dorland's Illustrated Medical Dictionary, (WB Saunders Co. 27th ed. 1988).

[0077] As used herein, in one embodiment, the term "treating" or "treatment" of any disease or disorder refers to ameliorating the disease or disorder (i.e., slowing, halting, or reducing the onset of the disease or at least one of its clinical symptoms). In another embodiment, "treating" or "treatment" refers to alleviating or ameliorating at least one physical parameter, including those that may not be discernible by the patient. In yet another embodiment, "treating" or "treatment" refers to modulating the disease or disorder, either physically (e.g., stabilization of discernible symptoms), physiologically (e.g., stabilization of physical parameters), or both. In yet another embodiment, "treating" or "treatment" refers to preventing or delaying the onset, development, or progression of the disease or disorder.

[0078] In some embodiments, optically pure (S)-β agonists are used to the extent that the β2 agonist has a stereocenter that is substantially free of (R)-β agonists. In some embodiments, optically pure (R)-β agonists are used, which are substantially free of (S)-β agonists. The term "pure," as used herein, refers to substances that are essentially associated with, or that have been separated from at least some or most components with which they are associated when originally produced or prior to purification. Generally, such purification requires human intervention. A pure agent may be partially purified, substantially purified, or pure. Such agents may be, for example, at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or greater than 99% pure. In some embodiments, nucleic acids, polypeptides, or small molecules are purified to constitute at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or more of the total nucleic acid, polypeptide, or small molecule material, respectively, present in the preparation. In some embodiments, organic material, e.g., nucleic acids, polypeptides, or small molecules, is purified to constitute at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or more of the total organic material present in the preparation. Purity may be based, for example, on dry weight, peak size on a chromatographic tracing (GC, HPLC, etc.), molecular abundance, electrophoresis, band intensity on a gel, spectroscopic data (e.g., NMR), elemental analysis, high-throughput sequencing, mass spectrometry, or any art-accepted quantification method. In some embodiments, water, buffers, ions, and / or small molecules (e.g., synthetic precursors such as nucleotides or amino acids) can optionally be present in the purified preparation. The purification agent may be prepared by separating the purification agent from other substances (eg, other foam materials) or by processing in a manner to achieve the desired purity.

[0079] In some embodiments, contemplated methods may include, for example, administering a prodrug of a compound described herein or a pharmaceutical composition thereof. The term "prodrug" refers to a compound that is transformed in vivo to yield a disclosed compound or a pharmaceutically acceptable salt, hydrate, or solvate of the compound. Transformation can occur by various mechanisms (e.g., by esterases, amidases, phosphatases, oxidative and / or reductive metabolism, etc.) in various locations (e.g., within the intestinal lumen, or during transport through the intestine, blood, or liver). Prodrugs are well known in the art (see, e.g., Rautio, Kumpulainen, et al., Nature Reviews Drug Discovery 2008, 7, 255). In some embodiments, the prodrug structure is constructed according to the disclosure of U.S. Pat. No. 9,849,134, the entire contents of which are incorporated herein by reference.

[0080] For example, if a compound of the disclosure, or a pharmaceutically acceptable salt, hydrate, or solvate of the compound, contains a carboxylic acid functional group, the prodrug may be 1-8 ) alkyl, (C 2-12 ) alkylcarbonyloxymethyl, 1-(alkylcarbonyloxy)ethyl having 4 to 9 carbon atoms, 1-methyl-1-(alkylcarbonyloxy)-ethyl having 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having 3 to 6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl having 4 to 7 carbon atoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl having 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having 3 to 9 carbon atoms, 1-(N-(alkoxycarbonyl)amino)ethyl having 4 to 10 carbon atoms, 3-phthalidyl, 4-crotonolactonyl, gamma-butyrolactone-4-yl, di-N,N-(C 1-2 ) alkylamino-(C 2-3 ) alkyl (β-dimethylaminoethyl, etc.), carbamoyl-(C 1-2 ) alkyl, N,N-di(C 1-2) alkylcarbamoyl-(C 1-2 ) alkyl and piperidino-, pyrrolidino- or morpholino (C 2-3 ) alkyl and the like.

[0081] Similarly, if a compound of the present disclosure contains an alcohol functional group, the prodrug may be 1-6 ) alkylcarbonyloxymethyl, 1-((C 1-6 ) alkylcarbonyloxy) ethyl, 1-methyl-1-((C 1-6 ) alkylcarbonyloxy) ethyl, (C 1-6 )alkoxycarbonyloxy)methyl, N--(C 1-6 ) alkoxycarbonylaminomethyl, succinoyl, (C 1-6 ) alkylcarbonyl, α-amino (C 1-4 ) alkylcarbonyl, arylalkylcarbonyl, and α-aminoalkylcarbonyl, or α-aminoalkylcarbonyl α-aminoalkylcarbonyl, wherein each α-aminoalkylcarbonyl group is independently selected from the group consisting of naturally occurring L-amino acids, P(O)(OH), —P(O)(O(C 1-6 ) alkyl) 2, or glycosyl (the radical resulting from removal of the hemiacetal hydroxyl group of a carbohydrate).

[0082] When the compounds of the present disclosure incorporate an amine functional group, prodrugs can be formed, for example, by creating amides or carbamates, N-alkylcarbonyloxyalkyl derivatives, (oxodioxolenyl)methyl derivatives, N-Mannich bases, imines, or enamines.In addition, secondary amines can be metabolically cleaved to generate bioactive primary amines, or tertiary amines can be metabolically cleaved to generate bioactive primary or secondary amines.See, for example, Simplicio, et al., Molecules 2008, 13, 519 and references therein.

[0083] As used herein, a "therapeutically effective amount" refers to an amount of a compound or composition (as described herein) that induces at least one desired change in a cell, cell population, tissue, individual, patient, or the like. In some embodiments, a therapeutically effective amount as used herein refers to an amount of a compound or composition (as described herein) that prevents or provides a clinically significant change (e.g., a reduction of at least about 30 percent, at least about 50 percent, or at least about 90 percent) in a disease or condition or one or more characteristics of a disease or condition described herein. In some embodiments, the term "therapeutically effective amount" refers to an amount of a compound or composition as described herein that is effective or sufficient to improve cognition and / or treat a neurodegenerative disease in a patient. The term "frequency" in this context refers to the number of times administration is administered to a patient to achieve the result of improved cognition and / or treatment of a neurodegenerative disease in the patient.

[0084] Diagnostic and therapeutic evaluation In various aspects, the methods of the present disclosure include making a diagnosis or otherwise identifying whether cognitive improvement and / or treatment of a neurodegenerative disease is necessary or desirable for a patient. As provided herein, this may be done in a variety of ways, as provided herein and known in the art. For example, a patient may be diagnosed by brain imaging. In various embodiments, FDG-PET may be used alone or in combination with CT and / or MRI, including MRI-ASL and / or MRI-BOLD. For example, FDG-PET and MRI-BOLD may be used, or FDG-PET and MRI-ASL may be used. Alternatively, FDG-PET, MRI-BOLD, and MRI-ASL may be used. Alternatively, MRI, including MRI-BOLD and MRI-ASL, may be used alone or in combination, optionally with CT.

[0085] In addition to identifying patients suitable for treatment, the diagnosis allows further decisions to be made regarding various aspects of the type and mode of treatment to be administered, for example, depending on the diagnosis, decisions may be made regarding the pharmaceutically active agent to be administered, the dosage of such active agent, and the timing schedule for administration.

[0086] Diagnostic methods utilized with the methods of the present disclosure may utilize detectable labels to diagnose or otherwise identify patients in need of or desirable cognitive improvement and / or treatment for neurodegenerative diseases. The term "label" (also referred to as "detectable label") refers to any moiety that facilitates detection and, optionally, quantification of the entity that constitutes or is bound to it. A label can be conjugated to or otherwise bound to a variety of entities, whether biological or otherwise. Generally, a label may be detectable, for example, by spectroscopic, photochemical, biochemical, immunochemical, electrical, optical, chemical, or other means. In some embodiments, a detectable label generates an optically detectable signal (e.g., light emission and / or absorption), which can be detected, for example, visually or using suitable instrumentation, such as a light microscope, spectrophotometer, fluorescence microscope, fluorescent sample reader, fluorescence-activated cell sorter, camera, or any device containing a light detector. Labels that can be used in various embodiments include, for example, organic materials (including small organic molecule fluorophores (sometimes referred to as "dyes"), quenchers (e.g., dark quenchers), polymers, fluorescent proteins); enzymes; inorganic materials such as metal chelates, metal particles, colloidal metals, metal and semiconductor nanocrystals (e.g., quantum dots); compounds that emit light upon enzyme-catalyzed oxidation, such as natural or synthetic luciferins (e.g., firefly luciferin or coelenterazine, and structurally related compounds); haptens (e.g., biotin, dinitrophenyl, digoxigenin); radioactive atoms (e.g., 3 H, 14 C. 32 P, 33 P, 35 S, 125radioactive isotopes such as I), stable isotopes (e.g. 13 C. 2H); magnetic or paramagnetic molecules or particles, etc. Fluorescent dyes include, for example, acridine dyes, BODIPY, coumarin, cyanine dyes, naphthalenes (e.g., dansyl chloride, dansylamide), xanthene dyes (e.g., fluorescein, rhodamine), and derivatives of any of the foregoing. Examples of fluorescent dyes include Cy3, Cy3.5, Cy5, Cy5.5, Cy7, Alexa® Fluor dyes, DyLight® Fluor dyes, FITC, TAMRA, Oregon Green dyes, and Texas Red, to name a few. Fluorescent proteins include green fluorescent protein (GFP), blue fluorescent protein, sapphire fluorescent protein, yellow fluorescent protein, red fluorescent protein, orange fluorescent protein, and fluorescent variants such as enhanced GFP (eGFP), mFruits such as mCherry, mTomato, and mStrawberry; R-phycoerythrin, etc. Enzymes useful as labels include, for example, enzymes that act on substrates to produce colored, fluorescent, or luminescent substances. Examples include luciferase, β-galactosidase, horseradish peroxidase, and alkaline phosphatase. Luciferases include those derived from various insects (e.g., fireflies, beetles) and marine organisms (e.g., Cnidaria such as Renilla (e.g., Renilla reniformis), Copepods such as Gaussia (e.g., Gaussia princeps), or Metridia (e.g., Metridia longa, Metridia pacifica)), as well as modified versions of native proteins. A wide variety of systems for labeling and / or detecting labels or labeled entities are known in the art.Numerous detectable labels and methods for their use, detection, modification, and / or incorporation or conjugation (e.g., covalent or non-covalent attachment) to biomolecules such as nucleic acids or proteins are described in Iain Johnson, I., and Spence, M.T.Z. (Eds.), The Molecular Probes® Handbook—A Guide to Fluorescent Probes and Labeling Technologies, 11th edition (Life Technologies / Invitrogen Corp.), available online at the Life Technologies website (invitrogen.com / site / us / en / home / References / Molecular-Probes-The-Handbook.html), and Hermanson, G.T., Bioconjugate Techniques, 2nd ed., Academic Press (2008). Many labels are available as derivatives that are attached to or incorporate reactive functional groups so that the labels can be conveniently conjugated to biomolecules or other entities of interest that contain an appropriate second functional group (which may be naturally occurring in the biomolecule or introduced during or after synthesis). For example, active esters (e.g., succinimidyl esters), carboxylates, isothiocyanates, or hydrazine groups can react with amino groups; carbodiimides can react with carboxyl groups; maleimides, iodoacetamides, or alkyl bromides (e.g., methyl bromide) can react with thiols (sulfhydryls); and alkynes can react with azides (via click chemistry reactions such as copper-catalyzed or copper-free azide-alkyne cycloaddition). Thus, for example, N-hydroxysuccinimide (NHS)-functionalized derivatives of fluorophores or haptens (such as biotin) can react with primary amines such as those present in lysine side chains in proteins or aminoallyl-modified nucleotides that are incorporated into nucleic acids during synthesis.In various embodiments, a label can be directly attached to the entity or can be attached to the entity via, for example, an alkyl, alkylene, aminoaryl, aminoalkynyl, or oligoethylene glycol spacer or linking group, which can be, for example, 1 and 4, 4 to 8, 8 to 12, 12 to 20 atoms, or more in length. A label or labeled entity can, in various embodiments, be directly detectable or indirectly detectable. A label or labeled moiety can be directly detectable (i.e., no additional reaction or reagent is required to be detectable; e.g., a fluorophore is directly detectable) or indirectly detectable (e.g., made detectable through reaction or conjugation with another entity that is detectable; e.g., a hapten can be detected by immunostaining after reaction with an appropriate antibody containing a reporter such as a fluorophore or enzyme, which acts on a substrate to generate a directly detectable signal). Labels can be used for a variety of purposes in addition to, or instead of, detecting the label or labeled entity. For example, the label can be used to separate or purify a substance that contains or to which the label is attached.

[0087] The term "labeled" is used herein to indicate that an entity (e.g., a biological or small molecule, organic compound, probe, cell, tissue, or other molecule) contains or is physically associated with (e.g., via covalent or non-covalent bonding) a label so that the entity can be detected. In some embodiments, the detectable label is selected to generate a signal that is measurable and whose intensity is related to (e.g., proportional to) the amount of label. In some embodiments, two or more different labels or labeled entities are used or present in a composition. In some embodiments, the labels may be selected to be distinguishable from one another. For example, they may absorb or emit light of different wavelengths. In some embodiments, the labels may be selected to interact with one another. For example, a first label may be a donor molecule that transfers energy to a second label that functions as an acceptor molecule via non-radioactive dipole coupling, as in resonance energy transfer (RET), e.g., Förster resonance energy transfer (FRET, commonly also referred to as fluorescence resonance energy transfer).

[0088] Nuclear imaging is one of the most important tools in diagnostic medicine, with an estimated 12-14 million nuclear medicine procedures performed annually in the United States alone. Diagnostic nuclear imaging is therefore important for studies that determine the cause of medical problems based on organ function, as opposed to radiological studies that determine the presence of disease based on static structural appearance.

[0089] Diagnostic radiopharmaceuticals and radiotracers are often designed or selected to selectively bind to specific receptors via binding moieties such as antibodies, specific inhibitors, or other target-specific ligands. Therefore, these target markers can be more rapidly concentrated in regions of interest, such as inflamed tissue, tumors, dysfunctional organs, or organs with increased expression of certain proteins. Therefore, circulating radiopharmaceuticals are collected in specific organs or pathological tissues to a different extent than in other or non-pathological tissues. For example, highly vascularized tissues (e.g., those in growing tumors) may be more concentrated with the radiopharmaceutical, while ischemic tissues may be less concentrated with the radiopharmaceutical than surrounding tissues. Nuclear imaging relies on these general phenomena, where the distribution of radiopharmaceuticals varies depending on different tissues and pathologies. As a result, certain tissue types (e.g., tumor tissue) can be distinguished from other tissues in radioactive emission imaging.

[0090] Radiopharmaceuticals that can be used in the differential diagnosis of pathologies may be conjugated to targeting (recognition binding) moieties, and as described below, include a wide range of radioisotopes. Thus, such radiopharmaceuticals include, for example, recognition moieties such as monoclonal antibodies (which bind to highly specific predetermined targets), fibrinogen (which is converted to fibrin during blood clotting), glucose, and other chemical moieties and drugs. Commonly used diagnostic conjugated radiopharmaceuticals include, for example, 2-[ 18 F]fluoro-2-deoxy-D-glucose ( 18 FDG), 111 In-pentetreotide ([ 111 In-DTPA-D-Phe 1 ]-octreotide), L-3-[ 123 I]-iodo-α-methyl-tyrosine (IMT), O-(2-[ 18 F]fluoroethyl)-L-tyrosine (L-[ 18 F]FET), 111 In-capromab pendetide (CYT-356, Prostascint) and 111 In-satumomab pendetide (Oncoscint) is included.

[0091] Two basic techniques are widely used in nuclear imaging: positron emission tomography (PET) and single-photon emission computed tomography (SPECT). PET detects photons generated through positron annihilation from a diagnostic radiopharmaceutical tracer placed in the subject being imaged, e.g., a patient, and analyzes the photon energy and trajectory to generate a tomographic image of the patient. SPECT generates images through computer analysis of photon emission events from a diagnostic radiopharmaceutical tracer containing a gamma-emitting isotope. Both PET and SPECT require the detection and analysis of single-photon events, which are characterized by a low signal-to-noise ratio and rarity compared to background radiation. Other constraints on PET and SPECT image quality include the sensitivity, temporal and spatial resolution, dynamic range, response time, and count rate characteristics of the data acquisition probe device (e.g., photomultiplier tube).

[0092] Radioisotopes that emit both high-energy gamma and / or low-energy gamma, beta and / or positron radiation and can be used by themselves or as part of compounds as radiopharmaceuticals include technetium-99m ( 99m Tc), gallium-67( 67 Ga), thallium-201( 201 Tl), 111 Indium-( 111 In), iodine-123( 123 I), iodine-125( 125 I), iodine-131( 131 I), xenon-133( 133 Xe), and fluorine-18( 18 F), but are not limited to these. 99m Tc, 131 I, 133 All of these isotopes, except for Xe, are produced in particle accelerators.

[0093] A non-limiting example of a commonly used radiotracer is a monoclonal antibody for imaging colon tissue affected by colorectal cancer.99m Tc-altitumomab (CEA-Scan™), for imaging a subject's heart for myocardial perfusion 99m Tc-sestamibi (Cardiolite™) and 99m Tc-tetrofosmin (Myoview™), a monoclonal antibody for imaging prostate tissue affected by prostate cancer 111 In-capromab pendetide (ProstaScint™), a monoclonal antibody for imaging inflammatory and infected tissue 99m Tc-fanolesomab (NeutroSpec™), a monoclonal antibody against the CD20 antigen present on the surface of normal and malignant B lymphocytes 90 Y / 111In-Zevalin (ibritumomab tiuxetan) is an example.

[0094] Any diagnostic radiopharmaceutical may be utilized in the kit of this embodiment. Exemplary radiopharmaceuticals that may be utilized in this context of the present invention include: 3 H-water, 3 H-inulin, 11 C - carbon monoxide, 13 N-ammonia, 14 C-inulin, 15 O--H2O, 15 O--O2, 18 F-fluorodeoxyglucose, 18 F - sodium fluoride, 51 Cr-red blood cells (RBC), 57 Co-vitamin B12 (cyanocobalamin), 58 Co-vitamin B12 (cyanocobalamin), 59 Fe-citrate, 60 Co-vitamin B12 (cyanocobalamin), 67 Ga-citrate, 68 Ga-citrate, 75 Se-selenomethionine, 81m Kr-krypton (for inhalation, oral administration, or injection), 82 Rb, 85 Sr-nitrate, 90 Y / 111 In-ibritumomab tiuxetan ( 90 Y / 111 In-Zevalin), 99m Tc-albumin microspheres, 99m Tc-disofenin, lidofenin, and mebrofenin, 99 mTc-DMSA, 99m Tc-DTPA (injection), 99m Tc-DTPA (aerosol), 99m Tc-ECD (ethylenecystate dimer), 99m Tc-examethadime (HMPAO), 99m Tc-glucoheptonate, 99m Tc-HEDP, 99m Tc-HMDP, 99m Tc-HSA, 99m Tc-MAA, 99m Tc-MAG.sub.3, 99m Tc-MDP, 99m Tc-tetrofosmin (Myoview), 99m Tc-sestamibi (Cardiolite), 99m Tc-oral agent, 99m Tc-pertechnetate, 99m Tc-pyrophosphate, 99m Tc-RBC in vitro and in vivo labeling 99m Tc-sulfur colloid, 99m Tc-teboroxime, 99m Tc-leukocytes, 111 In-ibritumomab tiuxetan ( 111 In-Zevalin), 111 In-DTPA, 111 In-platelets, 111 In-RBC, 111 In-white blood cells, 123 I-hipran, 123 I-IMP, 123 I-mIBG, 123 I - sodium iodide, 124 I - sodium iodide, 125 I-fibrinogen, 125 I-IMP, 125 I-mIBG, 125 I - sodium iodide,126 I - sodium iodide, 130 I - sodium iodide, 131 I-hipran, 131 I-HSA, 131 I-MAA, 131 I-mIBG, 131 I - Rose Bengal, 131 I - sodium iodide, 127 Xe - inhalation and injection, 133 Xe - inhalation and injection, 197 Hg-chlormerodrin, 198 Au-colloid, and 201 These include, but are not limited to, Tl-chloride.

[0095] The diagnostic methods described herein may also be used to evaluate the effectiveness of a particular therapeutic regimen. For example, patients identified as needing or desiring cognitive improvement and / or neurodegenerative disease treatment and being treated may be diagnosed or otherwise evaluated to determine the effectiveness of the therapeutic regimen. Diagnosis or evaluation may be performed by any method known in the art, although cognitive testing or brain imaging may be used to determine cognitive improvement or disease remission. In embodiments, cognitive testing or brain imaging may be used alone or in combination. In embodiments where brain imaging is used, FDG-PET may be used alone or in combination with CT and / or MRI, including MRI-ASL and / or MRI-BOLD. For example, FDG-PET and MRI-BOLD may be used, or FDG-PET and MRI-ASL may be used. Alternatively, FDG-PET, MRI-BOLD, and MRI-ASL may be used. Alternatively, MRI, including MRI-BOLD and MRI-ASL, may be used alone or in combination, optionally with CT.

[0096] The evaluation of therapeutic efficacy can be used to modify a patient's treatment regimen. For example, the evaluation can be used to modify the dosage, administration timing, and / or activity of the pharmaceutical composition. In embodiments, the dosage of a particular pharmaceutical administered to a patient can be reduced by administering it in combination with a different drug. In this way, treatment can be optimized by modifying the pharmaceutical composition to include a different combination of a β1-AR agonist, a β2-AR agonist, and a peripherally acting β-blocker (PABRA). The dosage can also be modified depending on the administration timing. For example, a shorter period between administrations of the pharmaceutical composition may require a lower dosage of the active agent, while a longer period between administrations of the pharmaceutical composition may require a higher dosage of the active agent, either of which may improve the treatment regimen as determined by the patient's diagnosis or evaluation.

[0097] In one embodiment, a patient may be evaluated once during treatment to optimize the treatment regimen, or alternatively, a patient may be evaluated multiple times during treatment to continually optimize the treatment regimen as directed by a medical professional.

[0098] Dosage, Administration, and Pharmaceutical Formulations The term "pharmaceutically acceptable salt" refers to an acid addition salt that is commonly used in human or veterinary medicine and is deemed safe for use. Examples of the present disclosure include, but are not limited to, salts obtained from the following acids: acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, edisylic acid, fumaric acid, gentisic acid, gluconic acid, glucuronic acid, glutamic acid, hippuric acid, hydrobromic acid, isethionic acid, lactic acid, nitric acid, phosphoric acid, succinic acid, sulfuric acid, and tartaric acid. Any hydrates of such salts are also included in this definition. Thus, for example, both fumarate and hemifumarate salts are specifically contemplated, along with their hydrates. For example, fumarate dihydrate may be specifically mentioned.

[0099] In some embodiments, the pharmaceutical preparation may be in unit dosage form. In such dosage form, the preparation is subdivided into unit doses containing appropriate amounts of active ingredients. The unit dosage form may be a packaged preparation, the package containing discrete amounts of the preparation, such as packeted tablets, capsules, and powders in vials or ampoules. The unit dosage form may also be a capsule, tablet, cachet, or lozenge itself, or any appropriate number of these in packaged dosage form. Preferably, the unit dosage form is a tablet. The composition may also contain other compatible therapeutic agents if desired. A preferred pharmaceutical preparation can deliver the compound of the present disclosure in a sustained-release formulation.

[0100] For binders, compositions, or compounds according to the present disclosure, the dosage form may optionally be a liquid dosage form. Solutions can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose or an emulsifier such as polysorbate. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, DMSO, and mixtures thereof with or without alcohol, as well as in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms. Conventional procedures and ingredients for the selection and preparation of suitable formulations are described, for example, in Remington's Pharmaceutical Sciences (2003-20th edition) and The United States Pharmacopeia: The National Formulary (USP 24 NF19), published in 1999. Formulations optionally contain excipients, including, but not limited to, buffers, antioxidants, stabilizers, carriers, diluents, and pH-adjusting agents. Pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.Acceptable carriers, excipients, or stabilizers are non-toxic to recipients at the dosages and concentrations employed and include buffers such as phosphate, citric acid, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (octadecyldimethylbenzylammonium chloride, hexamethonium chloride, benzalkonium chloride, benzethonium chloride, phenol, butyl, or benzyl alcohol, alkyl parabens such as methyl or propyl paraben, catechol, resorcinol, cyclohexanol, 3-pentanol, and m-cresol); low molecular weight (less than about 10 residues) polypeptides; serum, albumin, and the like. The composition may comprise a protein such as erythritol, gelatin, or immunoglobulin, a hydrophilic polymer such as polyvinylpyrrolidone, an amino acid such as glycine, glutamine, asparagine, histidine, arginine, or lysine, a monosaccharide base including glucose, mannose, or dextrin, a disaccharide base, and other carbohydrates, a chelating agent such as EDTA, a sugar such as sucrose, mannitol, trehalose, or sorbitol, a salt-forming counterion such as sodium, a metal complex (e.g., Zn-protein complex), and / or a non-ionic surfactant such as TWEEN, PLURONICS, or polyethylene glycol (PEG).

[0101] In various embodiments, the dosage of the agent may be determined by the body weight of the human patient. For example, the absolute dose of the agent may be about 30 to 160 μg for a pediatric human patient weighing about 0 to about 5 kg (e.g., about 0, or about 1, or about 2, or about 3, or about 4, or about 5 kg); or about 30 to 160 μg for a pediatric human patient weighing about 6 to about 8 kg (e.g., about 6, or about 7, or about 8 kg); or about 30 to 160 μg for a pediatric human patient weighing about 9 to about 13 kg (e.g., 9, or about 10, or about 11, or about 12, or about 13 kg); or about 30 to 160 μg for a pediatric human patient weighing about 14 to about 20 kg (e.g., about 14, or about 16, or about 18, or about 20 kg), or about 30 to 160 μg for a pediatric human patient weighing about 21 to about 30 kg (e.g., about 21, or about 23, or about 25, or about 27, or about 30 kg). or about 30-160 μg for a pediatric human patient weighing about 31 to about 33 kg (e.g., about 31, or about 32, or about 33 kg); or about 30-160 μg for an adult human patient weighing about 34 to about 50 kg (e.g., about 34, or about 36, or about 38, or about 40, or about 42, or about 44, or about 46, or about 48, or about 50 kg); or about 30-160 μg for an adult human patient weighing about 51 to about 75 kg (e.g., about 51, or about 55, or about 60, or about 65, or about 70, or about 75 kg); or about 30-160 μg for an adult human patient weighing more than about 114 kg (e.g., about 114, or about 120, or about 130, or about 140, or about 150 kg).

[0102] In certain embodiments, the agents according to the methods provided herein are administered orally, subcutaneously (sc), intravenously (iv), intramuscularly (im), intranasally, or topically. Administration of the agents described herein can be, independently, 1 to 4 times daily, or 1 or 2 times weekly, or 1 to 4 times monthly, or 1 to 6 times per year, or once every 2, 3, 4, or 5 years. Administration can be daily or over a period of 1, 2, 3, 6 months, 1, 2, 3 years, or even over the lifespan of the human patient. Dosages can be administered as a single dose or divided into multiple doses. In some embodiments, the agent is administered about 1 to about 3 times (e.g., 1, 2, or 3 times). [Example]

[0103] The present disclosure is further described in the following examples, which are not intended to limit the scope of the disclosure.

[0104] Example 1: Treatment of human patients Patients will be screened using FDG-PET brain imaging for MCI, aMCI, vascular dementia, mixed dementia, FTD (frontotemporal dementia; Pick's disease), HD (Huntington's disease), Rett syndrome, PSP (progressive supranuclear palsy), CBD (corticobasal degeneration), SCA (spinocerebellar ataxia), MSA (multiple system atrophy), SDS (Shy-Drager syndrome), olivopontocerebellar atrophy, TBI (traumatic brain injury), CTE (chronic traumatic encephalopathy), stroke, and WKS (Wernicke-Korsakoff syndrome). Identify as having a diagnosis of one or more of the following: Alcoholic Dementia and Thiamin Deficiency Syndrome, Normal Pressure Hydrocephalus, Hypersomnia / Narcolepsy, ASD (Autism Spectrum Disorder), FXS (Fragile X Syndrome), TSC (Tuberous Sclerosis Complex), Prion-Related Disease (e.g., CJD), Depressive Disorder, DLB (Dementia with Lewy Bodies), PD (Parkinson's Disease), PDD (PD Dementia), or ADHD (Attention Deficit Hyperactivity Disorder).

[0105] Patients were given a single dose of clenbuterol in amounts ranging from 30 to 160 μg. A single dose of nadolol was also administered to some patients in an amount of 5 mg to counter any adverse effects of clenbuterol. Patients were followed for three days after the single dose of clenbuterol and / or nadolol. Patients demonstrated a robust overall increase in cerebral blood flow from baseline after treatment with clenbuterol and / or nadolol.

[0106] As shown in Figure 1, a first group of patients received a single 160 μg dose of clenbuterol, and a second group of patients received a single 160 μg dose of clenbuterol and a single 5 mg dose of nanodolol. Compared to the baseline before the single dose of treatment, clenbuterol resulted in a robust overall increase in cerebral blood flow (CBF) compared to the baseline of these patients. A second group of patients, who were also administered nadolol along with clenbuterol to counter any adverse effects of clenbuterol, also demonstrated a robust overall increase in CBF compared to the baseline of these patients.

[0107] As shown in Figure 3, one group of patients received a single 160 μg dose of clenbuterol, and a second group of patients received a single 60 mg dose of pindolol. Treatment with clenbuterol demonstrated a significant increase in cerebral blood flow compared to baseline. Treatment with pindolol demonstrated a significant decrease in cerebral blood flow compared to baseline.

[0108] As shown in Figures 4 and 5, one group of patients received single doses of clenbuterol in varying amounts ranging from 30 to 160 μg, while another group received a single dose of 160 μg of clenbuterol and 5 mg of nadolol to counter any adverse effects of clenbuterol. Patients were followed over the course of three days. Compared to baseline before single-dose treatment, clenbuterol in amounts ranging from 30 to 160 μg resulted in a robust overall increase in cerebral blood flow (CBF) compared to baseline in these patients. Patients receiving a single dose of 160 μg of clenbuterol and 5 mg of nadolol also demonstrated a robust overall increase in CBF compared to baseline.

[0109] In some embodiments, cognitive testing and / or FDG-PET imaging can be used. In some embodiments, magnetic resonance imaging-arterial spin labeling (MRI-ASL) can be used for neuroimaging. In some embodiments, magnetic resonance imaging-blood oxygen level dependent computed tomography (MRI-BOLD) can be used for neuroimaging.

[0110] Example 2: Preparation of substantially free tulobuterol stereoisomers Optically pure (S)-tulobuterol is prepared according to the following scheme using chemical synthesis methods well known in the art. TIFF0007744344000004.tif24165

[0111] Those skilled in the art can purify the mixture from the above reaction using routine purification techniques such as HPLC or flash chromatography to obtain optically pure (S)-tulobuterol that is substantially free of (R)-tulobuterol. Alternatively, optically pure (S)-tulobuterol can be isolated from the racemic mixture by, for example, following the procedures outlined in Patent JP54151935, or by using routine chiral HPLC separation techniques (Journal of Pharmaceutical and Biomedical Analysis, 2018, 70-81) and SFC separation techniques (Journal of Chromatography A, 2014, 85-97).

[0112] Conversely, the optically pure (R)-tulobuterol that is substantially free of (S)-tulobuterol can be prepared according to the above-mentioned scheme, but by replacing (R)-2-methyl-CBS-oxazaborolidine with (S)-2-methyl-CBS-oxazaborolidine in the scheme.Also, the optically pure (R)-tulobuterol that is substantially free of (S)-tulobuterol can be isolated from the racemic mixture using the above-mentioned method to obtain the optically pure (S)-tulobuterol.

[0113] Example 3: Cerebral perfusion Several recent studies have demonstrated the clinical relevance of cerebral perfusion (De Vis 2018, Staffaroni 2019). These studies demonstrate that cerebral perfusion decreases with age, correlates with the progression of AD, and is strongly correlated with cognitive performance, such that subjects with higher cerebral perfusion tend to perform better on cognitive tests. In addition, a study in AD patients demonstrated that the increased perfusion seen after a single dose of the drug can predict the clinical efficacy of donepezil, as subjects with increased perfusion after acute administration were the same subjects who experienced improved cognitive function six months after treatment with the drug (Tepmongkol 2019). In a clinical study, healthy subjects were administered doses of clenbuterol ranging from 20 to 160 μg, and ASL MRI was performed before and after administration to determine whether this neuroimaging method could detect clinically relevant CNS signals. Neuroimaging data from the study using ASL MRI demonstrated a clinically relevant signal of increased cerebral perfusion after a single dose of clenbuterol. Specifically, 160 μg of clenbuterol caused a robust global increase in cerebral perfusion, particularly in regions such as the hippocampus, thalamus, and cortex, all of which are highly relevant to the pathogenesis of neurodegenerative disorders (see Figure 6).

[0114] Region-of-interest (ROI) analysis focused on the hippocampus, a region well understood to be affected in neurodegenerative disorders, demonstrated that a single 80 μg dose of clenbuterol caused a robust increase in perfusion (see Figure 7). In this cohort of six healthy subjects treated with a single 80 μg dose of clenbuterol, all subjects had an increase in hippocampal perfusion, which averaged 25%. Neuroimaging data from a study using ASL MRI demonstrated that doses of 80 and 160 μg of clenbuterol stimulated a robust overall increase in perfusion. In particular, brain regions thought to be associated with the neuropathology of neurodegenerative disorders demonstrate significant improvements in perfusion, in the range of 25% (Figures 6 and 7). ROI analysis of the hippocampus in six healthy subjects aged 44–52 demonstrates a robust increase in this region of the brain in each subject (Figure 7). Combined with other cohorts who underwent ASL MRI, a clear dose-response relationship between clenbuterol dose and cerebral perfusion is observed (Figure 8). Doses below 30 μg did not result in a significant increase in cerebral perfusion, as measured by CBF, and a dose of 40 μg resulted in a minimal increase. Meanwhile, doses of 80 and 160 μg resulted in an overall increase in cerebral perfusion, with robust increases of 20%–25% in brain regions associated with neurodegenerative disorders, particularly the hippocampus and thalamus (Figure 8; Bartsch 2015, Leh 2016). Our hypothesis is that by improving cerebral perfusion, particularly in brain regions associated with symptoms commonly seen in neurodegenerative disorders such as PD and AD, administration of β2-AR agonists will have a beneficial effect on clinically relevant symptoms, such as memory and cognition. With regard to cognition specifically, preliminary data from the present study suggest that a single dose of 160 μg of clenbuterol improves cognition in healthy subjects as measured by adaptive tracking and word recall.

[0115] Example 4: Clinical Efficacy Adaptive tracking measures visuomotor coordination and vigilance. In this test, subjects use a joystick to move a small dot, attempting to keep it within a continuously moving circle on a computer screen (Boland 1984). During the test, the speed of the circle is adjusted depending on the subject's ability to keep the dot within the circle, ensuring that the test is adapted to each individual subject. Results suggest that after a single dose of 160 μg of clenbuterol, subjects' performance in adaptive tracking improves, as measured by the percentage of time they are able to keep the small dot within the moving circle (see Figure 9). The improvements shown by subjects are within the same range as those seen in subjects treated with donepezil, an acetylcholinesterase inhibitor used clinically to treat mild to moderate AD (Groeneveld 2016).

[0116] The Visual Verbal Learning Test (VVLT) is a test of learning and memory (de Haas 2009). Subjects are presented with 30 words, one at a time, on a screen for 1 second, with a 1-second interval between words, for a total of 1 minute. This is repeated for three trials. After each trial, subjects are asked to recall as many words as possible. After the third trial, there is a 2.5-hour delay, and then subjects are tested once for delayed recall. Clenbuterol improved performance on the VVLT in both immediate recall (trial 1, not shown) and delayed recall (see Figure 10). The effect of clenbuterol is a clinically meaningful improvement in correctly recalled words of approximately 1.5 to 2 words. Because this was a crossover study, all participants who completed Part A received the three drugs and a placebo. Interestingly, both the β2-AR agonists tested in this study, clenbuterol and salbutamol, had positive effects on the VVLT. In contrast, pindolol, a β2-AR antagonist / β1-AR partial agonist, had adverse effects on this learning and memory test.

[0117] Aspects and Embodiments of the Disclosure In one aspect, the present disclosure provides a method comprising administering to the patient a β2-AR agonist and a peripherally acting β-blocker (PABRA), wherein the peripherally acting β-blocker (PABRA) is administered at a dose of about 15 mg or less. The method may further comprise subjecting the patient to brain imaging to determine cognitive function and / or to identify whether the patient needs or desires cognitive improvement and / or treatment for a neurodegenerative disease, and / or identifying a specific type of neurodegenerative disease based on the spatial pattern of the brain imaging results.

[0118] In another aspect, the present disclosure provides a method for improving cognition and / or treating a neurodegenerative disease in a patient, comprising administering a β2-AR agonist and a peripherally acting β-blocker (PABRA) to the patient, wherein the peripherally acting β-blocker (PABRA) is administered at a dose of about 15 mg or less. The method may further include subjecting the patient to brain imaging to assess cognitive function and identify whether the patient needs or desires cognitive function improvement and / or neurodegenerative disease treatment, identifying the specific type of neurodegenerative disease based on the spatial pattern of the brain imaging results, and / or subsequently subjecting the patient to brain imaging again to determine any cognitive function improvement and / or neurodegenerative disease treatment.

[0119] In yet another aspect, the present disclosure provides a method including subjecting a patient to brain imaging to determine cognitive function in the patient; identifying a specific type of neurodegenerative disease based on a spatial pattern of the brain imaging results; administering a β2-AR agonist and a peripherally acting β-blocker (PABRA) to the patient, wherein the peripherally acting β-blocker (PABRA) is administered at a dose of about 15 mg or less; and then subjecting the patient to another brain imaging to determine any improvement in cognitive function.

[0120] In yet another aspect, the present disclosure provides a method comprising administering to the patient a β2-AR agonist and a peripherally acting β-blocker (PABRA), wherein the peripherally acting β-blocker (PABRA) is administered at a dose of about 15 mg or less. The method may further comprise subjecting the patient to brain imaging to assess cognitive function and / or to identify whether the patient needs or desires cognitive function improvement and / or neurodegenerative disease treatment, and / or identifying a specific type of neurodegenerative disease based on the spatial pattern of the brain imaging results.

[0121] In another aspect, the present disclosure provides a method for improving cognition and / or treating a neurodegenerative disease in a patient, comprising administering a β2-AR agonist and a peripherally acting β-blocker (PABRA) to the patient, wherein the peripherally acting β-blocker (PABRA) is administered at a dose of about 15 mg or less. The method may further include subjecting the patient to brain imaging to assess cognitive function and / or to identify whether the patient needs or desires cognitive function improvement and / or neurodegenerative disease treatment, identifying the specific type of neurodegenerative disease based on the spatial pattern of the brain imaging results, and / or subsequently subjecting the patient to brain imaging again to assess any cognitive function improvement and / or neurodegenerative disease treatment.

[0122] In another aspect, the disclosure provides a method including subjecting a patient to brain imaging to determine cognitive function in the patient; identifying a specific type of neurodegenerative disease based on a spatial pattern of the brain imaging results; administering a β2-AR agonist and a peripherally acting β-blocker (PABRA) to the patient, wherein the peripherally acting β-blocker (PABRA) is administered at a dose of about 15 mg or less; and then subjecting the patient to another brain imaging to determine any improvement in cognitive function.

[0123] In another aspect, the present disclosure provides a method comprising administering clenbuterol and a peripherally acting beta-blocker (PABRA) to the patient, wherein the peripherally acting beta-blocker (PABRA) is administered at a dose of about 15 mg or less. The method may further include subjecting the patient to brain imaging to determine cognitive function and / or to identify whether improvement of cognitive function and / or treatment of a neurodegenerative disease is necessary or desirable for the patient, and / or identifying a particular type of neurodegenerative disease based on the spatial pattern of the brain imaging results.

[0124] In another aspect, the present disclosure provides a method for improving cognition and / or treating a neurodegenerative disease in a patient, comprising administering clenbuterol and a peripherally acting beta-blocker (PABRA) to the patient, wherein the peripherally acting beta-blocker (PABRA) is administered at a dose of about 15 mg or less. The method may further include subjecting the patient to brain imaging to assess cognitive function and / or to identify whether improvement of cognitive function and / or treatment of a neurodegenerative disease is necessary or desirable for the patient, identifying the specific type of neurodegenerative disease based on the spatial pattern of the brain imaging results, and then subjecting the patient to another brain imaging to assess any improvement of cognitive function and / or treatment of the neurodegenerative disease.

[0125] In another aspect, the disclosure provides a method including subjecting a patient to brain imaging to determine cognitive function in the patient; identifying a specific type of neurodegenerative disease based on a spatial pattern of the brain imaging results; administering clenbuterol and a peripherally acting beta blocker (PABRA) to the patient, wherein the peripherally acting beta blocker (PABRA) is administered at a dose of about 15 mg or less; and then subjecting the patient to brain imaging again to determine any improvement in cognitive function.

[0126] In another aspect, the present disclosure provides a method comprising administering tulobuterol and a peripherally acting beta blocker (PABRA) to the patient, wherein the peripherally acting beta blocker (PABRA) is administered at a dose of about 15 mg or less. The method may further include subjecting the patient to brain imaging to determine cognitive function and / or to identify whether the patient needs or desires cognitive improvement and / or treatment for a neurodegenerative disease, and / or identifying a specific type of neurodegenerative disease based on the spatial pattern of the brain imaging results, and then administering tulobuterol and a peripherally acting beta blocker (PABRA) to the patient.

[0127] In another aspect, the present disclosure provides a method for improving cognition and / or treating a neurodegenerative disease in a patient, comprising administering tulobuterol and a peripherally acting beta-blocker (PABRA) to the patient, wherein the peripherally acting beta-blocker (PABRA) is administered at a dose of about 15 mg or less. The method may further include subjecting the patient to brain imaging to assess cognitive function and / or to identify whether the patient needs or desires improved cognitive function and / or treatment for the neurodegenerative disease, identifying the specific type of neurodegenerative disease based on the spatial pattern of the brain imaging results, and / or subsequently subjecting the patient to brain imaging again to assess any improvement in cognitive function and / or treatment for the neurodegenerative disease.

[0128] In another aspect, the present disclosure provides a method including subjecting a patient to brain imaging to determine cognitive function in the patient; identifying a specific type of neurodegenerative disease based on a spatial pattern of brain imaging results; administering tulobuterol and a peripherally acting beta blocker (PABRA) to the patient, wherein the peripherally acting beta blocker (PABRA) is administered at a dose of about 15 mg or less; and then subjecting the patient to brain imaging again to determine any improvement in cognitive function.

[0129] In another aspect, the present disclosure provides a method for treating a subject identified as having impaired cognitive function and / or in need of or desiring improved cognitive function and / or treatment of a neurodegenerative disease by administering to the subject a pharmaceutical composition comprising a β1-AR agonist, a β2-AR agonist, a peripherally acting β-blocker (PABRA), or any combination thereof, wherein the peripherally acting β-blocker (PABRA) is administered at a dose of about 15 mg or less. In some embodiments, the method further comprises evaluating the effectiveness of the treatment, which can be evaluated by subjecting the subject to a test to evaluate improved cognitive function or remission of the neurodegenerative disease. In some embodiments, the method further comprises adjusting the administration of the pharmaceutical composition by adjusting the dosage and / or timing of the pharmaceutical composition.

[0130] In one aspect, the present disclosure provides a method comprising administering to the patient a β2-AR agonist and a peripherally acting β-blocker (PABRA), wherein the peripherally acting β-blocker (PABRA) is administered at a subtherapeutic dose. The method may further comprise subjecting the patient to brain imaging to assess cognitive function and / or to identify whether the patient needs or desires cognitive improvement and / or treatment for a neurodegenerative disease, and / or identifying a specific type of neurodegenerative disease based on the spatial pattern of the brain imaging results.

[0131] In another aspect, the present disclosure provides a method for improving cognition and / or treating a neurodegenerative disease in a patient, comprising administering a β2-AR agonist and a peripherally acting β-blocker (PABRA) to the patient, wherein the peripherally acting β-blocker (PABRA) is administered at a subtherapeutic dose.The method can further include subjecting the patient to brain imaging to assess cognitive function and identify whether the patient needs or desires to improve cognitive function and / or treat a neurodegenerative disease; identifying the specific type of neurodegenerative disease based on the spatial pattern of the brain imaging results; and / or subsequently subjecting the patient to brain imaging again to determine any improvement in cognitive function and / or treatment of the neurodegenerative disease.

[0132] In yet another aspect, the present disclosure provides a method including subjecting a patient to brain imaging to determine cognitive function in the patient; identifying a specific type of neurodegenerative disease based on a spatial pattern of the brain imaging results; administering a β2-AR agonist and a peripherally acting β-blocker (PABRA) to the patient, where the peripherally acting β-blocker (PABRA) is administered at a sub-therapeutic dose; and then subjecting the patient to brain imaging again to determine any improvement in cognitive function.

[0133] In yet another aspect, the present disclosure provides a method comprising administering to the patient a β2-AR agonist and a peripherally acting β-blocker (PABRA), wherein the peripherally acting β-blocker (PABRA) is administered at a subtherapeutic dose. The method may further comprise subjecting the patient to brain imaging to assess cognitive function and / or to identify whether the patient needs or desires cognitive function improvement and / or neurodegenerative disease treatment, and / or identifying a specific type of neurodegenerative disease based on the spatial pattern of the brain imaging results.

[0134] In another aspect, the present disclosure provides a method for improving cognition and / or treating a neurodegenerative disease in a patient, comprising administering a β2-AR agonist and a peripherally acting β-blocker (PABRA) to the patient, wherein the peripherally acting β-blocker (PABRA) is administered at a subtherapeutic dose. The method may further include subjecting the patient to brain imaging to assess cognitive function and / or to identify whether the patient needs or desires cognitive function improvement and / or neurodegenerative disease treatment, identifying the specific type of neurodegenerative disease based on the spatial pattern of the brain imaging results, and / or subsequently subjecting the patient to brain imaging again to assess any cognitive function improvement and / or neurodegenerative disease treatment.

[0135] In another aspect, the disclosure provides a method including subjecting a patient to brain imaging to determine cognitive function in the patient; identifying a specific type of neurodegenerative disease based on a spatial pattern of brain imaging results; administering a β2-AR agonist and a peripherally acting β-blocker (PABRA) to the patient, where the peripherally acting β-blocker (PABRA) is administered at a sub-therapeutic dose; and then subjecting the patient to brain imaging again to determine any improvement in cognitive function.

[0136] In another aspect, the present disclosure provides a method comprising administering clenbuterol and a peripherally acting beta-blocker (PABRA) to the patient, wherein the PABRA is administered at a subtherapeutic dose. The method may further include subjecting the patient to brain imaging to determine cognitive function and / or to identify whether improvement of cognitive function and / or treatment of a neurodegenerative disease is necessary or desirable for the patient, and / or identifying a particular type of neurodegenerative disease based on the spatial pattern of the brain imaging results.

[0137] In another aspect, the present disclosure provides a method for improving cognition and / or treating a neurodegenerative disease in a patient, comprising administering clenbuterol and a peripherally acting beta-blocker (PABRA) to the patient, wherein the peripherally acting beta-blocker (PABRA) is administered at a subtherapeutic dose. The method may further include subjecting the patient to brain imaging to assess cognitive function and / or to identify whether improvement of cognitive function and / or treatment of a neurodegenerative disease is necessary or desirable for the patient, identifying a specific type of neurodegenerative disease based on a spatial pattern of the brain imaging results, and then subjecting the patient to another brain imaging to assess any improvement of cognitive function and / or treatment of the neurodegenerative disease.

[0138] In another aspect, the disclosure provides a method including subjecting a patient to brain imaging to determine cognitive function in the patient; identifying a specific type of neurodegenerative disease based on a spatial pattern of brain imaging results; administering clenbuterol and a peripherally acting beta blocker (PABRA) to the patient, wherein the peripherally acting beta blocker (PABRA) is administered at a sub-therapeutic dose; and then subjecting the patient to brain imaging again to determine any improvement in cognitive function.

[0139] In another aspect, the present disclosure provides a method comprising administering tulobuterol and a peripherally acting beta-blocker (PABRA) to the patient, wherein the peripherally acting beta-blocker (PABRA) is administered at a subtherapeutic dose. The method may further include subjecting the patient to brain imaging to assess cognitive function and / or to identify whether the patient needs or desires cognitive improvement and / or treatment for a neurodegenerative disease, and / or identifying a specific type of neurodegenerative disease based on the spatial pattern of the brain imaging results, and then administering tulobuterol and a peripherally acting beta-blocker (PABRA) to the patient.

[0140] In another aspect, the present disclosure provides a method for improving cognition and / or treating a neurodegenerative disease in a patient, comprising administering tulobuterol and a peripherally acting beta-blocker (PABRA) to the patient, wherein the peripherally acting beta-blocker (PABRA) is administered at a subtherapeutic dose. The method may further include subjecting the patient to brain imaging to assess cognitive function and / or to identify whether the patient needs or desires improved cognitive function and / or treatment for the neurodegenerative disease, identifying the specific type of neurodegenerative disease based on the spatial pattern of the brain imaging results, and / or subsequently subjecting the patient to brain imaging again to assess any improvement in cognitive function and / or treatment for the neurodegenerative disease.

[0141] In another aspect, the present disclosure provides a method including subjecting a patient to brain imaging to determine cognitive function in the patient; identifying a specific type of neurodegenerative disease based on a spatial pattern of brain imaging results; administering tulobuterol and a peripherally acting beta blocker (PABRA) to the patient, wherein the peripherally acting beta blocker (PABRA) is administered at a sub-therapeutic dose; and then subjecting the patient to brain imaging again to determine any improvement in cognitive function.

[0142] In another aspect, the present disclosure provides a method for treating a subject identified as having impaired cognitive function and / or in need of or desiring improved cognitive function and / or treatment of a neurodegenerative disease by administering to the subject a pharmaceutical composition comprising a β1-AR agonist, a β2-AR agonist, a peripherally acting β-blocker (PABRA), or any combination thereof, wherein the peripherally acting β-blocker (PABRA) is administered at a subtherapeutic dose. In some embodiments, the method further comprises evaluating the effectiveness of the treatment, which can be evaluated by subjecting the subject to a test to evaluate improved cognitive function or remission of the neurodegenerative disease. In some embodiments, the method further comprises adjusting the administration of the pharmaceutical composition by adjusting the dosage of the pharmaceutical composition and / or the timing of administration of the pharmaceutical composition.

[0143] In an embodiment of any aspect or embodiment of the present disclosure described herein, the brain imaging is fluorodeoxyglucose positron emission tomography (FDG-PET) scan, magnetic resonance imaging-arterial spin labeling (MRI-ASL), or magnetic resonance imaging-blood oxygen level dependent computed tomography (MRI-BOLD).

[0144] In an embodiment of any aspect or embodiment of the disclosure described herein, the β2-AR agonist is administered at a dose of about 30 to 160 μg.

[0145] In an embodiment of any aspect or embodiment of the disclosure described herein, the β2-AR agonist is administered at a dose of about 50-160 μg.

[0146] In an embodiment of any aspect or embodiment of the disclosure described herein, the β2-AR agonist may be administered in an amount of about 30 to 160 μg, 50 to 160 μg, 80 to 160 μg, 100 to 160 μg, 120 to 160 μg, 140 to 160 μg, 30 to 140 μg, 50 to 140 μg, 80 to 140 μg, 100 to 140 μg, 120 to 140 μg, 30 to 120 μg, 50 to 1 It is administered in doses of 20μg, 80-120μg, 100-120μg, 30-100μg, 50-100μg, 80-100μg, 30-80μg, 50-80μg, 30-50μg, 30μg, 40μg, 50μg, 60μg, 70μg, 80μg, 90μg, 100μg, 110μg, 120μg, 130μg, 140μg, 150μg, or 160μg.

[0147] In an embodiment of any aspect or embodiment of the disclosure described herein, the β2-AR agonist is administered at a dose of about 0.5 to 20 mg, or 1 to 10 mg, or 2 to 8 mg, or about 1 mg, or about 2 mg, or about 3 mg, or about 4 mg, or about 5 mg, or about 6 mg, or about 7 mg, or about 8 mg, or about 10 mg.

[0148] In an embodiment of any aspect or embodiment of the disclosure described herein, the doses mentioned above are total daily doses of the β2-AR agonist, administered daily for a period of several weeks or longer.

[0149] In an embodiment of any aspect or embodiment of the disclosure described herein, the doses mentioned above are total weekly doses of the β2-AR agonist, administered weekly for a period of several weeks or more.

[0150] In an embodiment of any aspect or embodiment of the disclosure described herein, the β2-AR agonist is one or more selected from the group consisting of tulobuterol, mabuterol, ritodrine, salmeterol, bambuterol, formoterol, and clenbuterol.

[0151] In an embodiment of any aspect or embodiment of the disclosure described herein, the β2-AR agonist is clenbuterol.

[0152] In an embodiment of any aspect or embodiment of the disclosure described herein, the β2-AR agonist is tulobuterol.

[0153] In an embodiment of any aspect or embodiment of the disclosure described herein, the peripherally acting beta blocker (PABRA) is nadolol.

[0154] In an embodiment of any aspect or embodiment of the disclosure described herein, nadolol is a mixture of four diastereomers.

[0155] In an embodiment of any aspect or embodiment of the present disclosure described herein, the nadolol administered is a specific enantiomerically pure isomer.

[0156] In an embodiment of any aspect or embodiment of the disclosure described herein, the peripherally acting beta blocker (PABRA) is administered in a dose of about 0.1 mg to 15 mg.

[0157] In an embodiment of any aspect or embodiment of the disclosure described herein, the peripherally acting beta blocker (PABRA) is administered at a dose of about 0.1-15 mg, 0.1-10 mg, 0.1-1 mg, 0.1-5 mg, 1-15 mg, 1-10 mg, 1-5 mg, 5-10 mg, 10 mg or less, 7 mg or less, 5 mg or less, 1 mg or less, 0.1 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, or 10 mg.

[0158] In an embodiment of any aspect or embodiment of the disclosure described herein, the doses mentioned above are total daily doses of the peripherally acting beta blocker (PABRA) and are administered daily for a period of several weeks or longer.

[0159] In an embodiment of any aspect or embodiment of the disclosure described herein, the β1-AR agonist, β2-AR agonist, and / or peripherally acting β-blocker (PABRA) are each administered orally.

[0160] In an embodiment of any aspect or embodiment of the disclosure described herein, the β2-AR agonist and the peripherally acting β-blocker (PABRA) are each administered orally and both agents are present in a tablet.

[0161] In an embodiment of any aspect or embodiment of the present disclosure described herein, clenbuterol and nadolol are each administered orally and both agents are present in a tablet.

[0162] In an embodiment of any aspect or embodiment of the disclosure described herein, the tablet comprises clenbuterol in an amount of about 30-160 μg and nadolol in an amount of about 15 mg or less.

[0163] In an embodiment of any aspect or embodiment of the disclosure described herein, nadolol is provided in an amount of about 0.1-15 mg, 0.1-10 mg, 0.1-1 mg, 0.1-5 mg, 1-15 mg, 1-10 mg, 1-5 mg, 5-10 mg, 10 mg or less, 7 mg or less, 5 mg or less, 1 mg or less, 0.1 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, or 10 mg.

[0164] In an embodiment of any aspect or embodiment of the present disclosure described herein, the doses of clenbuterol and nadolol mentioned above are total daily doses and are administered daily for a period of several weeks or more.

[0165] In an embodiment of any aspect or embodiment of the present disclosure described herein, the doses of clenbuterol and nadolol described above are weekly doses, administered weekly for a period of several weeks or more.

[0166] In an embodiment of any aspect or embodiment of the present disclosure described herein, tulobuterol and nadolol are each administered orally and both agents are present in a tablet.

[0167] In an embodiment of any aspect or embodiment of the disclosure described herein, the tablet comprises tulobuterol in an amount of 0.5 to 20 mg, or 1 to 10 mg, or 2 to 8 mg, or about 1 mg, or about 2 mg, or about 3 mg, or about 4 mg, or about 5 mg, or about 6 mg, or about 7 mg, or about 8 mg, or about 10 mg, and nadolol in an amount of about 15 mg or less.

[0168] In an embodiment of any aspect or embodiment of the disclosure described herein, nadolol is provided in an amount of about 0.1-15 mg, 0.1-10 mg, 0.1-1 mg, 0.1-5 mg, 1-15 mg, 1-10 mg, 1-5 mg, 5-10 mg, 10 mg or less, 7 mg or less, 5 mg or less, 1 mg or less, 0.1 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, or 10 mg.

[0169] In an embodiment of any aspect or embodiment of the disclosure described herein, the doses of tulobuterol and nadolol mentioned above are total daily doses administered daily for a period of several weeks or longer.

[0170] In an embodiment of any aspect or embodiment of the disclosure described herein, the doses of tulobuterol and nadolol described above are weekly doses, administered weekly for a period of several weeks or more.

[0171] In an embodiment of any aspect or embodiment of the disclosure described herein, the neurodegenerative disease is MCI, aMCI, vascular dementia, mixed dementia, FTD (frontotemporal dementia; Pick's disease), HD (Huntington's disease), Rett's syndrome, PSP (progressive supranuclear palsy), CBD (corticobasal degeneration), SCA (spinocerebellar ataxia), MSA (multiple system atrophy), SDS (Shy-Drager syndrome), olivopontocerebellar atrophy, TBI (traumatic brain injury), CTE (chronic traumatic brain injury), and one or more of the following: dementia, stroke, Wernicke-Korsakoff syndrome (alcoholic dementia and thiamine deficiency), normal pressure hydrocephalus, hypersomnia / narcolepsy, ASD (autism spectrum disorder), FXS (fragile X syndrome), TSC (tuberous sclerosis), prion-related disease (CJD, etc.), depressive disorder, DLB (dementia with Lewy bodies), PD (Parkinson's disease), PDD (PD dementia), ADHD (attention deficit hyperactivity disorder), and Down syndrome.

[0172] In an embodiment of any aspect or embodiment of the disclosure described herein, the neurodegenerative disease is MCI, aMCI, vascular dementia, mixed dementia, FTD (frontotemporal dementia; Pick's disease), HD (Huntington's disease), Rett syndrome, PSP (progressive supranuclear palsy), CBD (corticobasal degeneration), SCA (spinocerebellar ataxia), MSA (multiple system atrophy), SDS (Shy-Drager syndrome), olivopontocerebellar atrophy, TBI (traumatic brain injury), CTE (chronic encephalopathy), or a combination thereof. One or more of the following are selected from: traumatic encephalopathy), stroke, WKS (Wernicke-Korsakoff syndrome; alcoholic dementia and thiamine deficiency), normal pressure hydrocephalus, hypersomnia / narcolepsy, ASD (autism spectrum disorder), FXS (fragile X syndrome), TSC (tuberous sclerosis complex), prion-related disease (CJD, etc.), depressive disorder, DLB (dementia with Lewy bodies), PD (Parkinson's disease), PDD (PD dementia), and ADHD (attention deficit hyperactivity disorder).

[0173] In an embodiment of any aspect or embodiment of the disclosure described herein, the patient does not have Alzheimer's disease.

[0174] In an embodiment of any aspect or embodiment of the disclosure described herein, the patient does not have Down's syndrome.

[0175] In an embodiment of any aspect or embodiment of the present disclosure described herein, the patient does not have Parkinson's disease.

[0176] In an embodiment of any aspect or embodiment of the disclosure described herein, the patient does not have dementia with Lewy bodies.

[0177] In an embodiment of any aspect or embodiment of the disclosure described herein, the tulobuterol is (S)-tulobuterol substantially free of (R)-tulobuterol.

[0178] In an embodiment of any aspect or embodiment of the disclosure described herein, the tulobuterol is (R)-tulobuterol substantially free of (S)-tulobuterol.

[0179] In an embodiment of any aspect or embodiment of the disclosure described herein, a pharmaceutical tablet is provided comprising a β2-AR agonist in an amount of about 30 to 160 μg and a peripherally acting β-blocker (PABRA) in an amount of about 15 mg or less.

[0180] In an embodiment of any aspect or embodiment of the disclosure described herein, the β2-AR agonist is in an amount of about 50-160 μg.

[0181] In an embodiment of any aspect or embodiment of the disclosure described herein, the β2-AR agonist is in an amount of about 80 to 160 μg.

[0182] In an embodiment of any aspect or embodiment of the disclosure described herein, the β2-AR agonist may be administered in an amount of about 30 to 160 μg, 50 to 160 μg, 80 to 160 μg, 100 to 160 μg, 120 to 160 μg, 140 to 160 μg, 30 to 140 μg, 50 to 140 μg, 80 to 140 μg, 100 to 140 μg, 120 to 140 μg, 30 to 120 μg, 50 to 1 It is administered in doses of 20μg, 80-120μg, 100-120μg, 30-100μg, 50-100μg, 80-100μg, 30-80μg, 50-80μg, 30-50μg, 30μg, 40μg, 50μg, 60μg, 70μg, 80μg, 90μg, 100μg, 110μg, 120μg, 130μg, 140μg, 150μg, or 160μg.

[0183] In an embodiment of any aspect or embodiment of the disclosure described herein, the dose of β2-AR agonist mentioned above is a total daily dose and is administered daily for a period of several weeks or more.

[0184] In an embodiment of any aspect or embodiment of the disclosure described herein, the dose of the β2-AR agonist described above is weekly and is administered weekly for a period of two weeks or more.

[0185] In an embodiment of any aspect or embodiment of the disclosure described herein, the peripherally acting beta blocker (PABRA) is provided in an amount of about 0.1-15 mg, 0.1-10 mg, 0.1-1 mg, 0.1-5 mg, 1-15 mg, 1-10 mg, 1-5 mg, 5-10 mg, 10 mg or less, 7 mg or less, 5 mg or less, 1 mg or less, 0.1 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, or 10 mg.

[0186] In an embodiment of any aspect or embodiment of the disclosure described herein, the peripherally acting beta blocker (PABRA) is provided in an amount of about 0.1 to 15 mg.

[0187] In an embodiment of any aspect or embodiment of the disclosure described herein, the peripherally acting beta blocker (PABRA) is provided in an amount of 5-10 mg.

[0188] In an embodiment of any aspect or embodiment of the disclosure described herein, the dose of peripherally acting beta blocker (PABRA) mentioned above is a total daily dose and is administered daily for a period of several weeks or more.

[0189] In an embodiment of any aspect or embodiment of the disclosure described herein, the dose of peripherally acting beta blocker (PABRA) is a weekly dose, administered weekly for a period of several weeks or more.

[0190] In an embodiment of any aspect or embodiment of the disclosure described herein, the β2-AR agonist is clenbuterol.

[0191] In an embodiment of any aspect or embodiment of the disclosure described herein, the β2-AR agonist is tulobuterol.

[0192] In an embodiment of any aspect or embodiment of the disclosure described herein, the peripherally acting beta blocker (PABRA) is nadolol.

[0193] In an embodiment of any aspect or embodiment of the disclosure described herein, nadolol is a mixture of four diastereomers.

[0194] In an embodiment of any aspect or embodiment of the present disclosure described herein, the nadolol administered is a specific enantiomerically pure isomer.

[0195] In an embodiment of any aspect or embodiment of the disclosure described herein, a combination formulation is provided comprising a β2-AR agonist in an amount of about 30 to 160 μg and a peripherally acting β-blocker (PABRA) in an amount of 15 mg or less.

[0196] In an embodiment of any aspect or embodiment of the disclosure described herein, the β2-AR agonist is in an amount of about 50-160 μg.

[0197] In an embodiment of any aspect or embodiment of the disclosure described herein, the β2-AR agonist is in an amount of about 80 to 160 μg.

[0198] In an embodiment of any aspect or embodiment of the disclosure described herein, the β2-AR agonist is in an amount of about 0.5 to 20 mg.

[0199] In an embodiment of any aspect or embodiment of the disclosure described herein, the β2-AR agonist is in an amount of about 2 to 8 mg.

[0200] In an embodiment of any aspect or embodiment of the disclosure described herein, the dose of β2-AR agonist mentioned above is a total daily dose and is administered daily for a period of several weeks or more.

[0201] In an embodiment of any aspect or embodiment of the disclosure described herein, the dose of the β2-AR agonist described above is a weekly dose and is administered weekly for a period of two weeks or more.

[0202] In an embodiment of any aspect or embodiment of the disclosure described herein, the peripherally acting beta blocker (PABRA) is in an amount of about 0.1 to 15 mg.

[0203] In an embodiment of any aspect or embodiment of the disclosure described herein, the peripherally acting beta blocker (PABRA) is in an amount of about 5-10 mg.

[0204] In an embodiment of any aspect or embodiment of the disclosure described herein, the dose of peripherally acting beta blocker (PABRA) mentioned above is a total daily dose and is administered daily for a period of several weeks or more.

[0205] In an embodiment of any aspect or embodiment of the disclosure described herein, the β2-AR agonist is clenbuterol.

[0206] In an embodiment of any aspect or embodiment of the disclosure described herein, the β2-AR agonist is tulobuterol.

[0207] In an embodiment of any aspect or embodiment of the disclosure described herein, the peripherally acting beta blocker (PABRA) is nadolol.

[0208] In an embodiment of any aspect or embodiment of the disclosure described herein, nadolol is a mixture of four diastereomers.

[0209] In an embodiment of any aspect or embodiment of the present disclosure described herein, the nadolol administered is a specific enantiomerically pure isomer.

[0210] In an embodiment of any aspect or embodiment of the disclosure described herein, a single formulation is provided comprising a β2-AR agonist in an amount of about 30 to 160 μg and a peripherally acting β-blocker (PABRA) in an amount of 15 mg or less.

[0211] In an embodiment of any aspect or embodiment of the disclosure described herein, the β2-AR agonist is in an amount of about 50-160 μg.

[0212] In an embodiment of any aspect or embodiment of the disclosure described herein, the β2-AR agonist is in an amount of about 80 to 160 μg.

[0213] In an embodiment of any aspect or embodiment of the disclosure described herein, the dose of β2-AR agonist mentioned above is a total daily dose and is administered daily for a period of several weeks or more.

[0214] In an embodiment of any aspect or embodiment of the disclosure described herein, the peripherally acting beta blocker (PABRA) is in an amount of about 0.1 to 15 mg.

[0215] In an embodiment of any aspect or embodiment of the disclosure described herein, the peripherally acting beta blocker (PABRA) is in an amount of about 5-10 mg.

[0216] In an embodiment of any aspect or embodiment of the disclosure described herein, the dose of peripherally acting beta blocker (PABRA) mentioned above is a total daily dose and is administered daily for a period of several weeks or more.

[0217] In an embodiment of any aspect or embodiment of the disclosure described herein, the β2-AR agonist is clenbuterol.

[0218] In an embodiment of any aspect or embodiment of the disclosure described herein, the β2-AR agonist is tulobuterol.

[0219] In an embodiment of any aspect or embodiment of the disclosure described herein, the peripherally acting beta blocker (PABRA) is nadolol.

[0220] In an embodiment of any aspect or embodiment of the disclosure described herein, nadolol is a mixture of four diastereomers.

[0221] In an embodiment of any aspect or embodiment of the present disclosure described herein, the nadolol administered is a specific enantiomerically pure isomer.

[0222] While the present disclosure has been particularly shown and described with reference to certain embodiments, some of which are preferred embodiments, it should be understood by those skilled in the art that various changes in form and details can be made therein without departing from the spirit and scope of the present disclosure as disclosed herein.

[0223] All references cited in this disclosure are incorporated herein by reference in their entirety. Various embodiments of the present disclosure may be characterized by potential claims, which are listed in the paragraph following this paragraph (and before the actual claims provided at the end of this application). These potential claims form part of the specification of this application. Accordingly, the subject matter of the following potential claims may be presented as actual claims in a subsequent proceeding involving this application or any application claiming priority based on this application. The inclusion of such potential claims should not be construed to mean that the actual claims do not encompass the subject matter of the potential claims. Accordingly, a decision not to present these potential claims in a subsequent proceeding should not be construed as granting the subject matter to the public.

[0224] The embodiments of the present disclosure described above are intended to be merely illustrative, and numerous variations and modifications will be apparent to those skilled in the art. All such variations and modifications are intended to be within the scope of the present disclosure as defined in any appended claims.

Claims

1. 1. A pharmaceutical composition for use in a method of improving cognition and / or treating a neurodegenerative disease in a patient by administration in combination with nadolol, comprising clenbuterol at a dose of 30 to 160 μg, A pharmaceutical composition wherein nadolol is administered in a dose of 0.1 to 5 mg.

2. The method comprises: subjecting the patient to brain imaging to assess cognitive function and / or identify whether improvement of cognitive function and / or treatment of a neurodegenerative disease is necessary or desirable for the patient. further comprising The method comprises: (a) identifying specific types of neurodegenerative diseases based on spatial patterns of brain imaging findings; and / or (b) then subjecting the patient to repeated brain imaging to assess improvement in cognitive function and / or treatment of the neurodegenerative disease. further comprising the brain imaging is fluorodeoxyglucose positron emission tomography (FDG-PET) scan, magnetic resonance imaging-arterial spin labeling (MRI-ASL), or magnetic resonance imaging-blood oxygen level dependent computed tomography (MRI-BOLD); The pharmaceutical composition of claim 1.

3. 1. A pharmaceutical composition for use in a method of improving cognitive function and / or treating a neurodegenerative disease by administration in combination with nadolol, comprising clenbuterol at a dose of 30 to 160 μg, said method comprising: subjecting the patient to brain imaging to assess cognitive function and / or identify whether improvement of cognitive function and / or treatment of a neurodegenerative disease is necessary or desirable for the patient; Identifying specific types of neurodegenerative diseases based on spatial patterns of brain imaging results; and then administering the pharmaceutical composition and nadolol to the patient, wherein nadolol is administered at a dose of 0.1 to 5 mg; Thereafter, the patient is subjected to brain imaging again to determine improvement in cognitive function and / or treatment of the neurodegenerative disease. A pharmaceutical composition comprising:

4. 4. The pharmaceutical composition of claim 3 for use in a method for improving cognitive function by administration in combination with nadolol, said method comprising: subjecting the patient to brain imaging to assess cognitive function in the patient; Identifying specific types of neurodegenerative diseases based on spatial patterns of brain imaging results; and administering the pharmaceutical composition and nadolol to the patient, wherein nadolol is administered at a dose of 0.1 to 5 mg; The patient then undergoes brain imaging again to determine improvement in cognitive function. A pharmaceutical composition comprising:

5. 5. The method of any one of claims 1 to 4, wherein the dose of clenbuterol is (a) a total daily dose administered daily for a period of several weeks or more, and / or (b) a weekly dose administered weekly for a period of two weeks or more.

6. (a) the brain imaging is fluorodeoxyglucose positron emission tomography (FDG-PET) scan, magnetic resonance imaging-arterial spin labeling (MRI-ASL), or magnetic resonance imaging-blood oxygen level dependent computed tomography (MRI-BOLD), and / or (b) the pharmaceutical composition comprises clenbuterol and nadolol, and / or (c) clenbuterol is administered at a dose of 50 to 160 μg; and / or (d) the dose of clenbuterol is a total daily dose administered daily for a period of several weeks or more; and / or (e) the dosage of the pharmaceutical composition is adjusted based on the brain imaging results; and / or (f) nadolol is a mixture of four diastereomers, or the nadolol administered is a specific enantiomerically pure isomer; and / or (g) The dose of nadolol is a total daily dose administered daily for a period of several weeks or more; and / or (h) the dose of nadolol is a weekly dose administered weekly for a period of several weeks or more; and / or (i) Clenbuterol and nadolol are each orally administered, or the pharmaceutical composition is orally administered; The pharmaceutical composition according to any one of claims 2 to 5.

7. (a) The neurodegenerative disease is MCI, aMCI, vascular dementia, mixed dementia, FTD (frontotemporal dementia; Pick's disease), HD (Huntington's disease), Rett syndrome, PSP (progressive supranuclear palsy), CBD (corticobasal degeneration), SCA (spinocerebellar ataxia), MSA (multiple system atrophy), SDS (Shy-Drager syndrome), olivopontocerebellar atrophy, TBI (traumatic brain injury), CTE (chronic traumatic encephalopathy), stroke, WKS (Wernicke-Corsace syndrome), Cough syndrome; alcoholic dementia and thiamine deficiency), normal pressure hydrocephalus, hypersomnia / narcolepsy, ASD (autism spectrum disorder), FXS (fragile X syndrome), TSC (tuberous sclerosis), prion-related diseases (such as CJD), depressive disorders, DLB (dementia with Lewy bodies), PD (Parkinson's disease), PDD (PD dementia), ADHD (attention deficit hyperactivity disorder), and Down's syndrome; and / or (b) The neurodegenerative disease is MCI, aMCI, vascular dementia, mixed dementia, FTD (frontotemporal dementia; Pick's disease), HD (Huntington's disease), Rett syndrome, PSP (progressive supranuclear palsy), CBD (corticobasal degeneration), SCA (spinocerebellar ataxia), MSA (multiple system atrophy), SDS (Shy-Drager syndrome), olivopontocerebellar atrophy, TBI (traumatic brain injury), CTE (chronic traumatic encephalopathy), stroke, WKS (Wernicke's syndrome), Korsakoff's syndrome; alcoholic dementia and thiamine deficiency), normal pressure hydrocephalus, hypersomnia / narcolepsy, ASD (autism spectrum disorder), FXS (fragile X syndrome), TSC (tuberous sclerosis complex), prion-related diseases (such as CJD), depressive disorders, DLB (dementia with Lewy bodies), PD (Parkinson's disease), PDD (PD dementia), and ADHD (attention deficit hyperactivity disorder), and / or (c) the patient does not have Alzheimer's disease, Down's syndrome, Parkinson's disease, and / or dementia with Lewy bodies; The pharmaceutical composition according to any one of claims 1 to 6.

8. 10. The pharmaceutical composition of claim 1, which is a pharmaceutical tablet.

9. (a) the dose of nadolol is 90% or less, or 85% or less, or 80% or less, or 75% or less, or 70% or less, or 65% or less, or 60% or less, or 55% or less, or 50% or less, or 45% or less, or 40% or less, or 35% or less, or 30% or less, or 25% or less, or 20% or less, or 15% or less, or 10% or less, or 5% or less, or 4% or less, or 3% or less, or 2.5% or less, or 2% or less, or 1.5% or less, or 1% or less, or 0.5% or less of the dose at which the drug is effective or approved for the treatment of a particular disease indication; and / or (b) A total daily dose of clenbuterol of 40-80 μg, 50-100 μg, 30-160 μg, 50-160 μg, 80-160 μg, 100-160 μg, 120-160 μg, 140-160 μg, 30-140 μg, 50-140 μg, 80-140 μg, 100-140 μg, 120-140 μg, 30-120 μg, 50-120 μg, 80-120 μg, 100-120 μg, 30-100 μg, 50-100 μg, 80-100 μg, 30-80 μg, 50-80 μg, 30-50 μg, 30 μg, 40 μg, 50 μg, 60 μg, 70 μg, 80 μg, 90 μg, 100 μg, 110 μg, 120 μg, 125 μg, 130 μg, 140 μg, 150 μg, or 160 μg, The pharmaceutical composition according to any one of claims 1 to 8.

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