Correlation between Dopamine Transporter Degradation and Striatocortical Network Alteration in Parkinson's Disease.
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ABSTRACT:
SUBMITTER: Lin WC
PROVIDER: S-EPMC5511968 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundResearch suggests that independent and joint effects of genetic variability in the dopamine transporter (DAT) locus and pesticides may influence Parkinson's disease (PD) risk.MaterialsMethodsIn 324 incident PD patients and 334 population controls from our rural California case-control study, we genotyped rs2652510, rs2550956 (for the DAT 5' clades), and the 3' variable number of tandem repeats (VNTR). Using geographic information system methods, we determined residential exposure to agricultural maneb and paraquat applications. We also collected occupational pesticide use data. Employing logistic regression, we calculated odds ratios (ORs) for clade diplotypes, VNTR genotype, and number of susceptibility (A clade and 9-repeat) alleles and assessed susceptibility allele-pesticide interactions.ResultsPD risk was increased separately in DAT A clade diplotype carriers [AA vs. BB: OR = 1.66; 95% confidence interval (CI), 1.08-2.57] and 3' VNTR 9/9 carriers (9/9 vs. 10/10: OR = 1.8; 95% CI, 0.96-3.57), and our data suggest a gene dosing effect. Importantly, high exposure to paraquat and maneb in carriers of one susceptibility allele increased PD risk 3-fold (OR = 2.99; 95% CI, 0.88-10.2), and in carriers of two or more alleles more than 4-fold (OR = 4.53; 95% CI, 1.70-12.1). We obtained similar results for occupational pesticide measures.DiscussionUsing two independent pesticide measures, we a) replicated previously reported gene-environment interactions between DAT genetic variants and occupational pesticide exposure in men and b) overcame previous limitations of nonspecific pesticide measures and potential recall bias by employing state records and computer models to estimate residential pesticide exposure.ConclusionOur results suggest that DAT genetic variability and pesticide exposure interact to increase PD risk.
| S-EPMC2702414 | biostudies-literature
Project description:Background: Sarcopenia is critically associated with morbidity and mortality in the progression of Parkinson's disease (PD). However, analyses of clinical severity and brain changes, such as white matter (WM) alterations in PD patients with sarcopenia are limited. Further understanding of the factors associated with sarcopenia may provide a focused screen and potential for early intervention in PD patients. Methods: 52 PD patients and 19 healthy participants accepted dual-energy X-ray absorptiometry to measure the body composition. Using diffusion tensor imaging, the difference of WM integrity was measured between PD patients with sarcopenia (PDSa) and without sarcopenia (PDNSa). Multivariate analysis was performed to explore the relationships between clinical factors, WM integrity, and sarcopenia in PD patients. Results: 21 PD patients (40.4%) had sarcopenia. PDSa had a higher Unified Parkinson's Disease Rating Scale (UPDRS III) score, lower body mass index (BMI) and lower fat weight compared with the PDNSa. Additionally, PDSa patients exhibited lower fractional anisotropy accompanied by higher radial diffusivity and/or higher mean diffusivity in the fronto-striato-thalamic circuits, including bilateral cingulum, left superior longitudinal fasciculus, left genu of corpus callosum, and right anterior thalamic radiation, which participate in the executive function. In addition, decreased muscle mass was associated with worse WM integrity in these regions. Multiple linear regression analysis revealed that WM integrity in the left cingulum, right anterior thalamic radiation, together with gender (male) significantly predicted muscle mass in PD patients. Conclusions: WM alterations in the executive network, such as the fronto-striato-thalamic circuits, may indicate a risk factor for ongoing sarcopenia in PD patients. The effectiveness of using executive function to serve as a prodromal marker of sarcopenia in PD patients should be evaluated in future studies.
| S-EPMC6950743 | biostudies-literature
Project description:BackgroundThe neurophysiological correlates of gastrointestinal symptoms (GISs) in Parkinson's disease (PD) are not well understood. It has been proposed that in patients with a gastrointestinal origin of PD dopaminergic neurodegeneration would be more symmetric.ObjectivesThe aim is to assess the associations between GISs and asymmetry of nigrostriatal dopaminergic neurodegeneration in PD.MethodsNinety PD patients were assessed using motor and GIS scales and 123 I-FP-CIT SPECT. We calculated the asymmetry index and the predominant side of motor symptoms and dopamine transporter (DAT) imaging defect and assessed their association with GISs.ResultsThere were no significant differences in GISs between symmetric and asymmetric dopaminergic defect. Left predominant defect was related to more GIS and higher constipation scores.ConclusionsGISs were associated with left predominant reduction in putaminal DAT binding but not asymmetry per se. It remains open whether left-sided DAT deficit is related to more pronounced GI involvement or symptom perception in PD. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society.
| S-EPMC9314058 | biostudies-literature
Project description:Dopaminergic therapy in Parkinson's disease (PD) can improve some cognitive functions while worsening others. These opposite effects might reflect different levels of residual dopamine in distinct parts of the striatum, although the underlying mechanisms remain poorly understood. We used functional magnetic resonance imaging (fMRI) to address how apomorphine, a potent dopamine agonist, influences brain activity associated with working memory in PD patients with variable levels of nigrostriatal degeneration, as assessed via dopamine-transporter (DAT) scan. Twelve PD patients underwent two fMRI sessions (Off-, On-apomorphine) and one DAT-scan session. Twelve sex-, age-, and education-matched healthy controls underwent one fMRI session. The core fMRI analyses explored: (1) the main effect of group; (2) the main effect of treatment; and (3) linear and nonlinear interactions between treatment and DAT levels. Relative to controls, PD-Off patients showed greater activations within posterior attentional regions (e.g., precuneus). PD-On versus PD-Off patients displayed reduced left superior frontal gyrus activation and enhanced striatal activation during working-memory task. The relation between DAT levels and striatal responses to apomorphine followed an inverted-U-shaped model (i.e., the apomorphine effect on striatal activity in PD patients with intermediate DAT levels was opposite to that observed in PD patients with higher and lower DAT levels). Previous research in PD demonstrated that the nigrostriatal degeneration (tracked via DAT scan) is associated with inverted-U-shaped rearrangements of postsynaptic D2-receptors sensitivity. Hence, it can be hypothesized that individual differences in DAT levels drove striatal responses to apomorphine via D2-receptor-mediated mechanisms.
| S-EPMC3683285 | biostudies-literature
Project description:Parkinson's disease is primarily characterized by diminished dopaminergic function; however, the impact of these impairments on large-scale brain dynamics remains unclear. It has been difficult to disentangle the direct effects of Parkinson's disease from compensatory changes that reconfigure the functional signature of the whole brain network. To examine the causal role of dopamine depletion in network-level topology, we investigated time-varying network structure in 37 individuals with idiopathic Parkinson's disease, both ON and OFF dopamine replacement therapy, along with 50 age-matched, healthy control subjects using resting state functional MRI. By tracking dynamic network-level topology, we found that the Parkinson's disease OFF state was associated with greater network-level integration than in the ON state. The extent of integration in the OFF state inversely correlated with motor symptom severity, suggesting that a shift toward a more integrated network topology may be a compensatory mechanism associated with preserved motor function in the dopamine depleted OFF state. Furthermore, we were able to demonstrate that measures of both cognitive and brain reserve (i.e. premorbid intelligence and whole brain grey matter volume) had a positive relationship with the relative increase in network integration observed in the dopaminergic OFF state. This suggests that each of these factors plays an important role in promoting network integration in the dopaminergic OFF state. Our findings provide a mechanistic basis for understanding the Parkinson's disease OFF state and provide a further conceptual link with network-level reconfiguration. Together, our results highlight the mechanisms responsible for pathological and compensatory change in Parkinson's disease.
| S-EPMC6904322 | biostudies-literature
Project description:BackgroundParkinson's disease (PD) affects the integrity of the dopamine and serotonin system, and is characterized by a plethora of different symptoms, including cognitive impairments of which the pathophysiology is not yet fully elucidated.ObjectivesInvestigate the role of the integrity of the dopaminergic and serotonergic system in cognitive functioning in early-stage PD using Single Photon Emission Computed Tomography (SPECT) combined with the radiotracer 123I-N-?-fluoropropyl-2?-carbomethoxy-3?-(4-iodophenyl)nortropane (123I-FP-CIT).MethodsWe studied the association between cognitive functions and dopamine transporter (DAT) availability in the caudate nucleus and putamen - as a proxy for striatal dopaminergic integrity - and serotonin transporter (SERT) availability as a proxy for serotonergic integrity in the thalamus and hippocampus using bootstrapped multiple regression. One-hundred-and-twenty-nine (129) PD patients underwent a 123I-FP-CIT SPECT scan and a neuropsychological assessment.ResultsWe showed a positive association between DAT availability in the head of the caudate nucleus and the Stroop Color Word Task - card I (reading words; ? = 0.32, P = 0.001) and a positive association between DAT availability in the anterior putamen and the Trail Making Test part A (connecting consecutively numbered circles; ? = 0.25, P = 0.02). These associations remained after adjusting for motor symptom severity or volume of the region-of-interest and were most pronounced in medication-naïve PD patients. There were no associations between cognitive performance and SERT availability in the thalamus or hippocampus.ConclusionsWe interpret these results as a role for striatal dopamine - and its PD-related decline - in aspects of processing speed.
| S-EPMC7186552 | biostudies-literature
Project description:BackgroundNon-motor symptoms (NMS) are common in Parkinson's disease (PD), but their relationships to nigrostriatal degeneration remain largely unexplored.MethodsWe evaluated 18 NMS scores covering 5 major domains in relation to concurrent and future dopamine transporter (DAT) imaging in 344 PD patients from the Parkinson's Progression and Markers Initiative (PPMI). We standardized NMS assessments into z-scores for side-by-side comparisons. Patients underwent sequential DaTSCAN imaging at enrollment and at months 12, 24, and 48. Specific binding ratios (SBR) were calculated using the occipital lobe reference region. We evaluated the association of striatal DAT binding at the four time points with each baseline NMS using mixed-effects regression models.ResultsMultiple baseline NMS were significantly associated with DAT binding at baseline and at follow-up scans. REM sleep behavior disorder (RBD) symptoms showed the strongest association - mean striatal SBR declined with increasing RBD symptom z-score (average of time-point-specific slopes per unit change in z-score: ?AVG = -0.083, SE = 0.017; p < 0.0001). In addition, striatal DAT binding was linearly associated with increasing baseline z-scores: positively for the memory (?AVG=0.055, SE = 0.022; p = 0.01) and visuospatial (?AVG=0.044, SE = 0.020; p = 0.03) cognitive domains, and negatively for total anxiety (?AVG= -0.059, SE = 0.018; p = 0.001). Striatal DAT binding showed curvilinear associations with odor identification, verbal discrimination recognition, and autonomic dysfunction z-scores (p = 0.001, p = 0.0009, and p = 0.0002, respectively). Other NMS were not associated with DAT binding.ConclusionsMultiple NMS, RBD symptoms in particular, are associated with nigrostriatal dopaminergic changes in early PD.
| S-EPMC7222918 | biostudies-literature
Project description:Missense mutations of PARK20/SYNJ1 (synaptojanin1/Synj1) have been linked to complex forms of familial parkinsonism, however, the molecular and cellular changes associated with dopaminergic dysfunction remains unknown. We now report fast depletion of evoked dopamine (DA) and altered maintenance of the axonal dopamine transporter (DAT) in the Synj1+/- neurons. While Synj1 has been traditionally known to facilitate the endocytosis of synaptic vesicles, we demonstrated that axons of cultured Synj1+/- neurons exhibit an increase of total DAT but a reduction of the surface DAT, which could be exacerbated by neuronal activity. We revealed that the loss of surface DAT is specifically associated with the impaired 5'-phosphatase activity of Synj1 and the hyperactive downstream PI(4,5)P2-PKCβ pathway. Thus, our findings provided important mechanistic insight for Synj1-regulated DAT trafficking integral to dysfunctional DA signaling in early parkinsonism.
| S-EPMC10980101 | biostudies-literature
Project description:BackgroundAsymmetric hemispheric loss of dopaminergic neurons is one of the characteristic features of Parkinson's disease (PD). However, it is still debated if right or left asymmetry differently affects cognitive and motor progression.ObjectivesThe objective of this study was to investigate, for the first time, the relevance of dopamine transporter (DAT) asymmetry on cognitive and motor manifestations at onset and at 4-year progression in drug-naïve PD.MethodsFrom the Parkinson's Progression Markers Initiative multicenter cohort, we identified 249 right-handed patients with PD with baseline asymmetry greater than 20% in putamen DAT binding at single-photon emission computed tomography. A predominant putamen asymmetry was found on the left in 143 patients (PD-left), and on the right side in 106 patients (PD-right); we compared them with 196 healthy controls. Patients were followed longitudinally (2-year and 4-year visits), examining their clinical, cognitive, and imaging data.ResultsAt baseline, the PD-left group showed worse performance on the Symbol Digit Modality Test, an attention and processing-speed test, and lower cerebrospinal fluid β-amyloid levels than the PD-right group. These differences were maintained at follow-up, declining over time in both groups. By contrast, the PD-right group showed greater motor impairment at baseline, which increased over 4 years. Striatal DAT binding decreased over time in both groups, but the PD-right group showed a steeper decline, particularly during the first 2-year follow-up. Putaminal asymmetry assessed at baseline was maintained over time.ConclusionsThese findings suggest that hemispheric asymmetric dopaminergic denervation influences PD cognitive and motor performance as well as progression. Predominant right hemisphere nigrostriatal dopaminergic loss is associated with greater motor severity, whereas more pronounced left hemisphere denervation affects cognitive manifestations at onset and their progression. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
| S-EPMC8596815 | biostudies-literature
Project description:Missense mutations of PARK20/SYNJ1 (synaptojanin1/Synj1) were found in complex forms of familial Parkinsonism. However, the Synj1-regulated molecular and cellular changes associated with dopaminergic dysfunction remain unknown. We now report a fast depletion of evoked dopamine and impaired maintenance of the axonal dopamine transporter (DAT) in the Synj1 haploinsufficient (Synj1+/-) neurons. While Synj1 has been traditionally known to facilitate the endocytosis of synaptic vesicles, we provide in vitro and in vivo evidence demonstrating that Synj1 haploinsufficiency results in an increase of total DAT but a reduction of the surface DAT. Synj1+/- neurons exhibit maladaptive DAT trafficking, which could contribute to the altered DA release. We showed that the loss of surface DAT is associated with the impaired 5'-phosphatase activity and the hyperactive PI(4,5)P2-PKCβ pathway downstream of Synj1 deficiency. Thus, our findings provided important mechanistic insight for Synj1-regulated DAT trafficking integral to dysfunctional DA signaling, which might be relevant to early Parkinsonism.
| S-EPMC11310474 | biostudies-literature