METHODS OF TREATING A NEURODEGENERATIVE DISEASE

1 .- 35 . (canceled)

36 . A method of treating a neurodegenerative disease in a subject in need thereof comprising: administering to said patient a high daily dose of 3-phenylsulfonyl-8-piperazinyl-1yl-quinoline Formula I

or pharmaceutically acceptable salts thereof,

wherein the high daily dose of 3-phenylsulfonyl-8-piperazinyl-1ul-quinoline or pharmaceutically acceptable salts-thereof is provided at least once a day; and

wherein the high daily dose of 3-phenylsulfonyl-8-piperazinyl-1yl-quinoline or pharmaceutically acceptable salts thereof is greater than about 36 mg.

37 . The method of claim 36 , wherein the high daily dose of 3-phenylsulfonyl-8-piperazinyl-1yl-quinoline or pharmaceutically acceptable salts thereof is provided to the subject by at least one route of administration selected from the group consisting of: orally; nasally; topically; bucally; sublingually; rectally; vaginally; and parenterally.

38 . The method of claim 37 , wherein the at least one route of administration is orally.

39 . The method of claim 36 , wherein the high daily dose of 3-phenylsulfonyl-8-piperazinyl-1yl-quinoline or pharmaceutically acceptable salts thereof is administered once a day.

40 . The method of claim 39 , wherein the high daily dose of 3-phenylsulfonyl-8-piperazinyl-1yl-quinoline or pharmaceutically acceptable salts thereof is about 36 mg to about 300 mg.

41 . The method of claim 40 , wherein the high daily dose is about 50 mg to about 270 mg.

42 . The method of claim 40 , wherein the high daily dose is about 60 mg to about 230 mg.

43 . The method of claim 40 , wherein the high daily dose is about 70 mg to about 200 mg.

44 . The method of claim 36 , wherein the neurodegenerative disease is selected from Alzheimer's disease, Alzheimer's disease with Lewy bodies, Parkinson's disease, autosomal-dominant Parkinson's disease, Diffuse Lewy Body Disease also known as Dementia with Lewy Bodies, Pure Autonomic Failure, Lewy body dysphagia, Incidental LBD, Inherited LBD, multiple system atrophy, Olivopontocerebellar Atrophy, Striatonigral Degeneration, Shy-Drager Syndrome, combined Alzheimer's and Parkinson disease and/or MSA, Huntington's disease, synucleinopathies, disorders or conditions characterized by the presence of Lewy bodies, multiple sclerosis, Amyotrophic lateral sclerosis (ALS) dementia, vascular dementia, Lewy body dementia, Parkinson's dementia, frontotemporal dementia, Down syndrome, Psychosis, Parkinson's disease psychosis, Alzheimer's disease psychosis, Lewy body dementia psychosis, dyskinesia, agitation, conditions associated with dopaminergic therapy, dystonia, myoclonus, synucleinopathies, diseases, disorders or conditions associated with abnormal expression, stability, activities and/or cellular processing of α-synuclein, diseases, disorders or conditions characterized by the presence of Lewy bodies, and combinations thereof.

45 . The method of claim 36 , wherein the high daily dose of 3-phenylsulfonyl-8-piperazinyl-1yl-quinoline is selected from a dose of 3-phenylsulfonyl-8-piperazinyl-1yl-quinoline that causes convulsions in a subject to which it is administered; would be expected to exceed the maximum tolerated dose for the subject to which it is administered; is associated with systemic exposures characterized by an AUCtau-ss of about 8.2 μg·h/ml, a Cmax of about 0.26 μg/ml; or a combination thereof; is associated with systemic exposures characterized by an AUC, Cmax, or combinations thereof, that are about 2 to about 3 times higher than the mean clinical exposure achieved at the proposed clinical dose for monotherapy with 3-phenylsulfonyl-8-piperazinyl-1yl-quinoline (i.e. mean AUCtau-ss of about 3.2 μg·h/ml and Cmax of about 0.180 μg/ml); or is associated with a recorded systemic clinical exposure that is greater than the highest recorded systemic clinical exposure (AUC0-∞ of about 9.25 μg·h/ml and Cmax of about 0.293 pig/ml); a dose of 3-phenylsulfonyl-8-piperazinyl-1yl-quinoline that is greater than about 10 mg/kg/day; a dose of 3-phenylsulfonyl-8-piperazinyl-1yl-quinoline that is greater than 15 mg/day; a dose of 3-phenylsulfonyl-8-piperazinyl-1yl-quinoline that is greater than about 36 mg/day or any combination thereof per day.

46 . The method of claim 36 , further comprising administering to said patient a therapeutically effective amount of an acetylcholinesterase inhibitor.

47 . The method of claim 46 , wherein the acetylcholinesterase inhibitor is donepezil or pharmaceutically acceptable salts thereof.

48 . The method of claim 47 , wherein the therapeutically effective amount of donepezil is selected from about 5 mg, about 10 mg and about 23 mg per day.

49 . The method of claim 47 , wherein the high daily dose of 3-phenylsulfonyl-8-piperazinyl-1yl-quinoline or pharmaceutically acceptable salts thereof is provided to the subject by at least one route of administration selected from the group consisting of: orally; nasally; topically; bucally; sublingually; rectally; vaginally; and parenterally.

50 . The method of claim 49 , wherein the at least one route of administration is orally.

51 . The method of claim 47 , wherein the high daily dose of 3-phenylsulfonyl-8-piperazinyl-1yl-quinoline or pharmaceutically acceptable salts thereof is administered once a day.

52 . The method claim 36 , wherein the high daily dose of 3-phenylsulfonyl-8-piperazinyl-1yl-quinoline or pharmaceutically acceptable salts thereof is about 70 mg.

53 . The method of claim 44 , wherein the neurodegenerative disease is Alzheimer's disease and the Alzheimer's disease is selected from mild or early-stage Alzheimer's disease, mild to moderate Alzheimer's disease, moderate or mid-stage Alzheimer's disease, moderate to severe Alzheimer's disease, moderately severe Alzheimer's disease, or severe Alzheimer's disease.

54 . The method of claim 44 , wherein the neurodegenerative disease is Parkinson's disease and wherein the Parkinson's disease is selected from Parkinson's disease chemically induced by exposure to environmental agents such as pesticides, insecticides, or herbicides and/or metals such as manganese, aluminum, cadmium, copper, or zinc, SNCA gene-linked Parkinson's disease, sporadic or idiopathic Parkinson's disease, or Parkin- or LRRK2-linked Parkinson's disease.

55 . The method of claim 44 , wherein the neurodegenerative disease is agitation and the agitation is selected from agitation caused by a neurodegenerative disease or associated with dopaminergic therapy.

56 . The method of claim 44 , wherein the neurodegenerative disease is Down syndrome.