In Vivo Assessment of Vesicular Monoamine Transporter Type 2 in Dementia With Lewy Bodies and Alzheimer Disease

AbstractDespite different embryological origins, islet β-cells and neurons share the expression of many genes and display multiple functional similarities. One shared gene product, vesicular monoamine transporter type 2 (VMAT2, also known as SLC18A2), is highly expressed in human β-cells relative to other cells in the endocrine and exocrine pancreas. Recent reports suggest that the monoamine dopamine is an important paracrine and/or autocrine regulator of insulin release by β-cells. Given the important role of VMAT2 in the economy of monoamines such as dopamine, we investigated the possible role of VMAT2 in insulin secretion and glucose metabolism. Using a VMAT2-specific antagonist, tetrabenazine (TBZ), we studied glucose homeostasis, insulin secretion both in vivo and ex vivo in cultures of purified rodent islets. During intraperitoneal glucose tolerance tests, control rats showed increased serum insulin concentrations and smaller glucose excursions relative to controls after a single intravenous dose of TBZ. One hour following TBZ administration we observed a significant depletion of total pancreas dopamine. Correspondingly, exogenous l-3,4-dihydroxyphenylalanine reversed the effects of TBZ on glucose clearance in vivo. In in vitro studies of rat islets, a significantly enhanced glucose-dependent insulin secretion was observed in the presence of dihydrotetrabenazine, the active metabolite of TBZ. Together, these data suggest that VMAT2 regulates in vivo glucose homeostasis and insulin production, most likely via its role in vesicular transport and storage of monoamines in β-cells.

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Dementia with Lewy bodies—associated ß-synuclein mutations V70M and P123H cause mutation-specific neuropathological lesions

Human Molecular Genetics ◽

10.1093/hmg/ddab036 ◽

2021 ◽

Author(s):

Maryna Psol ◽

Sofia Guerin Darvas ◽

Kristian Leite ◽

Sameehan U Mahajani ◽

Mathias Bähr ◽

...

Keyword(s):

Neuronal Network ◽

Dementia With Lewy Bodies ◽

Lewy Bodies ◽

Sporadic Case ◽

Network Activity ◽

Proteinase K ◽

Neuronal Network Activity ◽

Distinct Disease

Abstract ß-Synuclein (ß-Syn) has long been considered to be an attenuator for the neuropathological effects caused by the Parkinson’s disease-related α-Synuclein (α-Syn) protein. However, recent studies demonstrated that overabundant ß-Syn can form aggregates and induce neurodegeneration in CNS neurons in vitro and in vivo, albeit at a slower pace as compared to α-Syn. Here we demonstrate that ß-Syn mutants V70M, detected in a sporadic case of Dementia with Lewy Bodies (DLB), and P123H, detected in a familial case of DLB, robustly aggravate the neurotoxic potential of ß-Syn. Intriguingly, the two mutations trigger mutually exclusive pathways. ß-Syn V70M enhances morphological mitochondrial deterioration and degeneration of dopaminergic and non-dopaminergic neurons, but has no influence on neuronal network activity. Conversely, ß-Syn P123H silences neuronal network activity, but does not aggravate neurodegeneration. ß-Syn WT, V70M and P123H formed proteinase K (PK) resistant intracellular fibrils within neurons, albeit with less stable C-termini as compared to α-Syn. Under cell free conditions, ß-Syn V70M demonstrated a much slower pace of fibril formation as compared to WT ß-Syn, and P123H fibrils present with a unique phenotype characterized by large numbers of short, truncated fibrils. Thus, it is possible that V70M and P123H cause structural alterations in ß-Syn, that are linked to their distinct neuropathological profiles. The extent of the lesions caused by these neuropathological profiles is almost identical to that of overabundant α-Syn, and thus likely to be directly involved into etiology of DLB. Over all, this study provides insights into distinct disease mechanisms caused by mutations of ß-Syn.

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Cerebrospinal Fluid Hypocretin and Nightmares in Dementia Syndromes

Dementia and Geriatric Cognitive Disorders Extra ◽

10.1159/000509585 ◽

2021 ◽

pp. 19-25

Author(s):

Lynn Marie Trotti ◽

Donald L. Bliwise ◽

Glenda L. Keating ◽

David B. Rye ◽

William T. Hu

Keyword(s):

Cerebrospinal Fluid ◽

Alzheimer Disease ◽

Cholinesterase Inhibitor ◽

Dementia With Lewy Bodies ◽

Lewy Bodies ◽

Cognitively Normal ◽

Dementia Patients ◽

Sleep Questionnaires ◽

Sleep Alterations ◽

Normal Controls

Background/Aims: Hypocretin promotes wakefulness and modulates REM sleep. Alterations in the hypocretin system are increasingly implicated in dementia. We evaluated relationships among hypocretin, dementia biomarkers, and sleep symptoms in elderly participants, most of whom had dementia. Methods: One-hundred twenty-six adults (mean age 66.2 ± 8.4 years) were recruited from the Emory Cognitive Clinic. Diagnoses were Alzheimer disease (AD; n = 60), frontotemporal dementia (FTD; n = 21), and dementia with Lewy bodies (DLB; n = 20). We also included cognitively normal controls (n = 25). Participants and/or caregivers completed sleep questionnaires and lumbar puncture was performed for cerebrospinal fluid (CSF) assessments. Results: Except for sleepiness (worst in DLB) and nocturia (worse in DLB and FTD) sleep symptoms did not differ by diagnosis. CSF hypocretin concentrations were available for 87 participants and normal in 70, intermediate in 16, and low in 1. Hypocretin levels did not differ by diagnosis. Hypocretin levels correlated with CSF total τ levels only in men (r = 0.34; p = 0.02). Lower hypocretin levels were related to frequency of nightmares (203.9 ± 29.8 pg/mL in those with frequent nightmares vs. 240.4 ± 46.1 pg/mL in those without; p = 0.05) and vivid dreams (209.1 ± 28.3 vs. 239.5 ± 47.8 pg/mL; p = 0.014). Cholinesterase inhibitor use was not associated with nightmares or vivid dreaming. Conclusion: Hypocretin levels did not distinguish between dementia syndromes. Disturbing dreams in dementia patients may be related to lower hypocretin concentrations in CSF.

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Cognitive Loss in Dementia With Lewy Bodies and Alzheimer Disease

Archives of Neurology ◽

10.1001/archneur.55.12.1547 ◽

1998 ◽

Vol 55 (12) ◽

pp. 1547 ◽

Cited By ~ 58

Author(s):

Tatsuo Shimomura ◽

Etsuro Mori ◽

Hikari Yamashita ◽

Toru Imamura ◽

Nobutsugu Hirono ◽

...

Keyword(s):

Alzheimer Disease ◽

Dementia With Lewy Bodies ◽

Lewy Bodies

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Olfactory impairment is more marked in patients with mild dementia with Lewy bodies than those with mild Alzheimer disease

Journal of Neurology Neurosurgery & Psychiatry ◽

10.1136/jnnp.2008.155895 ◽

2009 ◽

Vol 80 (6) ◽

pp. 667-670 ◽

Cited By ~ 51

Author(s):

S S Williams ◽

J Williams ◽

M Combrinck ◽

S Christie ◽

A D Smith ◽

...

Keyword(s):

Alzheimer Disease ◽

Dementia With Lewy Bodies ◽

Lewy Bodies ◽

Mild Dementia ◽

Olfactory Impairment

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Comparisons of vesicular monoamine transporter type 2 signals in Parkinson's disease and Parkinsonism secondary to carbon monoxide poisoning

NeuroToxicology ◽

10.1016/j.neuro.2021.11.004 ◽

2021 ◽

Author(s):

Ing-Tsung Hsiao ◽

Yu-Tzu Chang ◽

Yi-Hsin Weng ◽

Shih-Wei Hsu ◽

Kun-Ju Lin ◽

...

Keyword(s):

Parkinson’S Disease ◽

Carbon Monoxide ◽

Parkinson's Disease ◽

Carbon Monoxide Poisoning ◽

Vesicular Monoamine Transporter ◽

Monoamine Transporter

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Diagnostic accuracy of imaging brain vesicular monoamine transporter type 2 (VMAT2) in clinically uncertain parkinsonian syndrome (CUPS): a 3-year follow-up study in community patients

BMJ Open ◽

10.1136/bmjopen-2018-025533 ◽

2018 ◽

Vol 8 (11) ◽

pp. e025533 ◽

Cited By ~ 3

Author(s):

San San Xu ◽

Paschal K Alexander ◽

Yenni Lie ◽

Vincent Dore ◽

Svetlana Bozinovski ◽

...

Keyword(s):

Diagnostic Accuracy ◽

Clinical Diagnosis ◽

Pet Scan ◽

Vesicular Monoamine Transporter ◽

Monoamine Transporter ◽

Rubral Tremor ◽

Diagnostic Changes ◽

Community Patients

ObjectivesTo further validate the diagnostic utility of 18F-AV-133 vesicular monoamine transporter type 2 (VMAT2) positron emission tomography (PET) in patients with clinically uncertain parkinsonian syndromes (CUPS) by comparison to clinical diagnosis at 3 years follow-up.Design, setting and participantsIn a previous study, we reported that 18F-AV-133 PET in community patients with CUPS changed diagnosis and management and increased diagnostic confidence. The current diagnosis of this cohort was obtained from the patient and treating specialist and compared with the diagnosis suggested 3 years earlier by the 18F-AV-133 PET. A second 18F-AV-133 PET was available in those with a discordant or inconclusive final diagnosis.Study outcome measuresThe primary end point was the proportion of patients who had a follow-up clinical diagnosis, which was concordant with their initial 18F-AV-133 PET scan. Secondary end points were the proportion of patients who had the same diagnosis at follow-up as that reached after the initial scan and the stability of diagnostic changes made after the first scan.Results81 of the 85 patients previously recruited to the CUPS study had follow-up of which 79 had a clinical diagnosis and 2 remained CUPS. The diagnosis was in agreement with the initial 18F-AV-133 PET scan result in 74 cases. Five patients had a discordant diagnosis; one patient with rubral tremor had a severely abnormal scan that had worsened when rescanned; four cases with normal initial and repeat scans had a clinical diagnosis of Parkinson’s disease. Two patients with suspected genetic disorders remained classified as CUPS and both had normal scans. In the 24 CUPS cohort patients where 18F-AV-133 PET initially changed diagnosis, this change was supported by follow-up diagnosis in all but the one rubral tremor case.Conclusion18F-AV-133 PET is a useful tool in improving diagnostic accuracy in CUPS providing results and diagnostic changes that remain robust after 3 years follow-up.

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P2-191: IN VIVO MEASUREMENT OF CHOLINERGIC BASAL FOREBRAIN ATROPHY IN DEMENTIA WITH LEWY BODIES

Alzheimer s & Dementia ◽

10.1016/j.jalz.2014.05.867 ◽

2014 ◽

Vol 10 ◽

pp. P541-P541

Author(s):

Michel J. Grothe ◽

Christina Schuster ◽

Florian Bauer ◽

Johannes Prudlo ◽

Stefan Teipel

Keyword(s):

Basal Forebrain ◽

Dementia With Lewy Bodies ◽

Lewy Bodies ◽

In Vivo Measurement ◽

Cholinergic Basal Forebrain

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Clinical Aspects of Non-Alzheimer Disease Dementias

10.2310/fm.1336 ◽

2017 ◽

Author(s):

David Knopman

Keyword(s):

Cognitive Impairment ◽

Alzheimer Disease ◽

Cerebrovascular Disease ◽

Lewy Body ◽

Dementia With Lewy Bodies ◽

Lewy Bodies ◽

Lewy Body Disease ◽

Clinical Aspects ◽

Key Words Dementia ◽

Sleep Behavior

There are a relatively small number of disorders that account for the majority of dementia in the elderly that is not Alzheimer disease (AD): cerebrovascular disease, Lewy body disease (α-synucleinopathies), and the frontotemporal lobar degenerations. Cerebrovascular disease and Lewy body disease account for most non-AD dementia among persons in the eighth decade of life and beyond. These two frequently co-occur with AD but can occur in their pure forms rarely (in the case of dementia associated with cerebrovascular disease) or more commonly (in the case of Lewy body disease). There is no one cognitive or behavioral syndrome associated with cerebrovascular disease; however, attempts to isolate a common theme suggest that cognitive slowing is typical of cerebrovascular contributions to cognitive impairment. Cerebrovascular pathology relevant to cognitive impairment accumulates subclinically more commonly than it causes acute, strokelike declines in cognition. Dementia with Lewy bodies is a multidimensional disorder that includes a nonamnestic dementia, Parkinson disease or at least some parkinsonian features, a disorder of sleep and wakefulness, autonomic disturbances, and depression. The disorders of sleep prominently include rapid eye movement sleep behavior disorder, excessive daytime sleepiness, visual hallucinations, and marked fluctuations in level of alertness. The frontotemporal lobar degenerations are nearly as common as causes of dementia in persons under age 65 as is AD. The group of disorders includes two cognitive syndromes (primary progressive aphasia and behavior variant frontotemporal dementia) and two neuropathologic subtypes (tauopathy and TDP43 proteinopathy) and is associated with three major autosomal dominant genetic mutations (in MAPT, GRN, and C9ORF72). Key words: dementia with Lewy bodies, frontotemporal lobar degenerations, vascular cognitive impairment

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