In this cross-sectional study, patients with PD (n = 64, 48 male and 16 female, mean age 69.2 ± 6.7 years, Hoehn & Yahr stage 2.7 ± 0.5, Montreal Cognitive Assessment score 25.3 ± 3.0) underwent [<sup>11</sup>C]Pittsburgh compound B β-amyloid, [<sup>11</sup>C]dihydrotetrabenazine vesicular monoamine transporter type 2 (VMAT2), and [<sup>11</sup>C]methyl 4 piperidinyl propionate acetylcholinesterase brain PET imaging and clinical assessments, including the Marin Apathy Evaluation Scale, Clinician Version.
This study investigated whether there exist distinctive patterns of presynaptic monoamine transporter densities in the basal ganglia depending on the degree of depression in patients with PD.
The present results support further investigation of the role of VMAT2, and associated changes in neural circuitry in the improvement of motor and non-motor symptoms with STN DBS in PD.
We apply the method to [<sup>11</sup>C]-DTBZ (VMAT2 marker) and [<sup>11</sup>C]-MP (DAT marker) data from 15 early Parkinson's disease (PD) subjects; the behavior of these two tracers/targets is well characterized providing robust reference information for the method's outcome.
135 patients with Parkinson's Disease (PD) completed vesicular monoamine transporter type2 (VMAT2) and acetylcholinesterase PET scanning to assess the integrity of nigrostriatal dopaminergic, thalamic cholinergic, and cortical cholinergic pathways, and a behavioral test (Stroop + task-switching) that puts high demands on conflict processing, an important aspect of executive control.
[<sup>18</sup>F]9-fluoropropyl-(+)-dihydrotetrabenazine (<sup>18</sup>F-(+)DTBZ) is a recently developed PET tracer to investigate the vesicular monoamine transporter type 2 (VMAT2) activity in measuring dopaminergic degeneration in vivo and monitoring the severity of Parkinson's disease (PD).
In vivo imaging of the striatal vesicular monoamine transporter type 2 (VMAT2) distribution using 18F-FP-(+)-DTBZ animal PET is a useful method to evaluate the efficacy of therapeutic drugs i.e., magnolol, for the management of PD.
To circumvent this limitation, we created VMAT2-KO mice specific to the dopamine (DA) nigrostriatal pathway to analyze VMAT2's involvement in DA depletion-induced motor features associated to PD and examine the relevance of DA toxicity in the pathogenesis of neurodegeneration.
The aromatic L-amino-acid decarboxylase (AADC) defect appears to be consistently smaller than the dopamine transporter and vesicular monoamine transporter 2 defects, suggesting upregulation of AADC function in PD.
Recent studies found that two polymorphisms (rs363371 and rs363324) in VMAT2 might be a risk factor for Parkinson's disease (PD) in Caucasians, while the two other variants (rs1990622 and rs3173615) in TMEM106B increased the risk for frontotemporal dementia (FTD).
Based on human genetic association and meta-analysis, we first confirm the human VMAT2 (hVMAT2 or SLC18A2) promoter as a risk factor for PD in both family and unrelated US white people: marker rs363324 at -11.5 kb in the hVMAT2 promoter is reproducibly associated with PD in a cohort of nuclear families (p = 0.04506 in early-onset PD) and 3 unrelated US white people (meta-analysis p = 0.01879).
We validated these indices in transgenic mice with very low vesicular uptake VMAT2-Lo) or with knockouts of the genes encoding ALDH1A1 and ALDH2 (ALDH1A1,2 KO), applied these indices in PD putamen, and estimated the percent decreases in vesicular uptake and ALDH activity in PD.
This study adds to the previous evidence suggesting that variability in VMAT2 promoter region may confer a reduced risk of developing PD, presumably via mechanisms of gene overexpression.
Bakuchiol analogs, especially Delta3,2-hydroxybakuchiol, are monoamine transporter inhibitors involved in regulating dopaminergic and noradrenergic neurotransmission and may have represented potential pharmacotherapies for disorders such as Parkinson's disease, depression, and cocaine addiction.
In addition, the altered dopamine homeostasis resulting from reduced VMAT2 function may be conducive to pathogenic mechanisms induced by genetic or environmental factors thought to be involved in Parkinson's disease.
Vesicular monoamine transporter-2 and aromatic L-amino acid decarboxylase gene therapy prevents development of motor complications in parkinsonian rats after chronic intermittent L-3,4-dihydroxyphenylalanine administration.