Parkinson´s Disease

While Parkinson's disease (PD) is defined clinically by its motor symptoms, it is increasingly recognized that much of the disability and worsened quality of life experienced by patients with PD is attributable to psychiatric symptoms. The authors describe a model of multidisciplinary care that enables these symptoms to be effectively managed. They describe neuropsychiatric complications of PD itself as well as pharmacological and neurostimulation treatments for Parkinsonian motor symptoms, and discuss the management of these complications. Specifically they describe the clinical associations between motor fluctuations and anxiety and depressive symptoms, the compulsive overuse of dopaminergic medications prescribed for motor symptoms (the dopamine dysergulation syndrome) as well as neuropsychiatric complications of these medications including impulse control disorders, psychosis, and manic syndromes. Optimal management of these problems requires close collaboration across disciplines because of the potential for interactions among the pathophysiologic process of PD, motor symptoms, dopaminergic drugs, and psychiatric symptoms. The authors emphasize how their model of multidisciplinary care facilitates close collaboration among psychiatrists, other mental health professionals, neurologists, and functional neurosurgeons and how this facilitates effective care for patients who develop the specific neuropsychiatric complications discussed.

The Consortium to Establish a Registry for Alzheimer's Disease (CERAD) neuropsychological battery was created to assess cognitive impairment in Alzheimer's disease (AD) but it is widely-used for various dementias. The aim of this study was to analyze the efficacy of using the CERAD battery in the assessment of patients with Parkinson's disease. Forty-nine patients with Parkinson's disease were divided into two groups (one with dementia and one without) using the Movement Disorder Society criteria for Parkinson's disease dementia. Cognitive deficits were assessed with the Clinical Dementia Rating Scale as the gold standard, and the CERAD. The ROC curve for the CERAD battery had an area under the curve = 0.989 (95% CI = 0.967 -1, p<0.0001). Among the CERAD subtests, verbal fluency had the worst accuracy, and word list learning had the best accuracy. Despite the limits of this study, the CERAD battery can be efficient for assessment of cognitive deficits in Parkinson's disease patients.

Background: Pain is a frequent non-motor symptom in patients with Parkinson’s disease (PD) and appears to be related to low levels of dopamine. This study describes the characteristics of chronic pain in a group of PD patients undergoing levodopa therapy. Methods: This was a cross-sectional study. The pain was assessed in 21 selected PD patients with chronic pain using several scales and instruments. Changes in pain response from levodopa use (wearing-off phenomenon) were monitored. Results: The most prevalent type of pain was nociceptive (71.4%), musculoskeletal and dystonic, but neuropathic pain accounted for the highest pain score according to the Parkinson’s Disease Pain Classification System (45.5±30.08). Patients with neuropathic, nociplastic, or nociceptive pain upon wearing-off were those who responded to levodopa (p=0.999). According to the McGill questionnaire, patients with pain upon wearing-off had higher scores in the affective/motivational dimension (p=0.022). Conclusi...

The Consortium to Establish a Registry for Alzheimer&#39;s Disease (CERAD) neuropsychological battery was created to assess cognitive impairment in Alzheimer&#39;s disease (AD) but it is widely-used for various dementias. The aim of this study was to analyze the efficacy of using the CERAD battery in the assessment of patients with Parkinson&#39;s disease. Forty-nine patients with Parkinson&#39;s disease were divided into two groups (one with dementia and one without) using the Movement Disorder Society criteria for Parkinson&#39;s disease dementia. Cognitive deficits were assessed with the Clinical Dementia Rating Scale as the gold standard, and the CERAD. The ROC curve for the CERAD battery had an area under the curve = 0.989 (95% CI = 0.967 - 1, p&lt;0.0001). Among the CERAD subtests, verbal fluency had the worst accuracy, and word list learning had the best accuracy. Despite the limits of this study, the CERAD battery can be efficient for assessment of cognitive deficits in Park...

arkinson's disease (PD) is a progressive, neurodegenerative movement disorder and the second most common neurodegenerative disorder in the United States after Alzheimer's disease. While PD is perhaps best characterized by its motor symptoms, non-motor symptoms such as mood and psychotic symptoms can also cause significant changes in patients' emotional wellbeing and affect their and their caregivers' quality of life. Depression and psychosis are common in the PD population and should be screened for, diagnosed and managed. Firstly, a comprehensive, differential diagnostic evaluation should be done to rule out alternative diagnoses and aetiologies. For depression in PD, cognitive behavioral therapy (CBT) is often a first-line treatment due to its efficacy and minimal side-effect profile. If CBT is inadequate, antidepressants such as selective serotonin reuptake inhibitors should be initiated. Electroconvulsive therapy should also be considered as safe and effective for treating depression in PD. For psychosis in Parkinson's disease (PDP), pimavanserin is the first-line pharmacological treatment. While more robust randomized clinical trials are necessary to further investigate alternative treatments, and the definition of and criteria for PDP must be better elucidated, clinicians should employ current strategies to diagnose and manage non-motor symptoms and ensure holistic care for patients with PD.

BackgroundSeveral progressive neurologic disorders begin with cognitive decline or parkinsonism, notably Alzheimer&#39;s disease (AD), Parkinson&#39;s disease (PD), and dementia with Lewy bodies (DLB). We used positron emission tomography (PET) in attempts to differentiate these disorders.MethodsWe performed PET with (+)‐[11C]dihydrotetrabenazine ([11C]DTBZ) to examine blood‐to‐brain ligand transport (K1) and striatal monoaminergic presynaptic binding (distribution volume [DV]) in 25 DLB, 30 PD, and 25 AD patients and 57 elderly controls (NC).Results[11C]DTBZ DV was decreased significantly in caudate nucleus, anterior putamen, and posterior putamen in DLB and PD compared with AD and NC. DLB and PD groups showed an anterior‐to‐posterior gradient of binding loss relative to NC, least in caudate nucleus and largest in posterior putamen. The gradient was significantly steeper in PD than DLB. Both PD and DLB showed significantly greater interhemispheric striatal binding asymmetry than NC...

The major motor symptoms of Parkinson's disease do not occur until a majority of the dopaminergic neurons in the midbrain SNpc have already died. For this reason, it is critical to identify biomarkers that will allow for the identification of presymptomatic individuals. In this study, we examine the baseline expression of the antioxidant protein Glutathione S-transferase pi (GSTpi) in blood of PD and environmental and age-matched controls and compare it to GSTpi levels following exposure to 1-methyl-4-phenylpyridinium (MPP+), an agent that has been shown to induce oxidative stress. We find that 4 hours of exposure to MPP+, significant increases in GSTpi levels can be observed in the leukocytes of PD patients. No changes were seen in other blood components. This suggests that GSTpi and potentially other members of this and other antioxidant families may be viable biomarkers for PD. Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by progressive loss of the pigmented dopaminergic (DA) neurons located in the substantia nigra pars compacta (SNpc) that results in a reduction in the number of its afferent projections to the striatum. PD motor symptoms first manifest when approximately 60% of the SNpc DA neurons have already died, and striatal dopamine is reduced by approximately 80% (esupp ref 1). Because the progression of cell loss is thought to occur over a somewhat protracted period of time in a defined spatiotemporal manner, the onset of PD symptoms is typically insidious. Biological models suggest that the progression of PD includes a long presymptomatic period, thus there is significant potential for interventions that could slow or even arrest PD at this stage of the disease. However, there is currently no appropriate diagnostic test or biomarker that can identify this presymptomatic population.

This Viewpoint discusses insights from basic science and clinical perspectives on coronavirus disease 2019 (COVID-19)/severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection in the brain, with a particular focus on Parkinson's disease. Major points include that neuropathology studies have not answered the central issue of whether the virus enters central nervous system neurons, astrocytes or microglia, and the brain vascular cell types that express virus have not yet been identified. Currently, there is no clear evidence for human neuronal or astrocyte expression of angiotensin-converting enzyme 2 (ACE2), the major receptor for viral entry, but ACE2 expression may be activated by inflammation, and a comparison of healthy and infected brains is important. In contrast to the 1918 influenza pandemic and avian flu, reports of encephalopathy in COVID-19 have been slow to emerge, and there are so far no documented reports of parkinsonism apart from a single case report. We recommend consensus guidelines for the clinical treatment of Parkinson's patients with COVID-19. While a role for the virus in causing or exacerbating Parkinson's disease appears unlikely at this time, aggravation of specific motor and non-motor symptoms has been reported, and it will be important to monitor subjects after recovery, particularly for those with persisting hyposmia.

Parkinson’s disease (PD) is thought to be caused by a combination of genetic and environmental factors. Bacterial or viral infection has been proposed as a potential risk factor, and there is supporting although not entirely consistent epidemiologic and basic science evidence to support its role. Encephalitis caused by influenza has included parkinsonian features. Epidemiological evidence is most compelling for an association between PD and hepatitis C virus. Infection with Helicobacter pylori may be associated not only with PD risk but also response to levodopa. Rapidly evolving knowledge regarding the role of the microbiome also suggests a role of resident bacteria in PD risk. Biological plausibility for the role for infectious agents is supported by the known neurotropic effects of specific viruses, particular vulnerability of the substantia nigra and even the promotion of aggregation of alpha-synuclein. A common feature of implicated viruses appears to be production of high leve...

Importance: While mutations in glucocerebrosidase (GBA1) are associated with an increased risk for Parkinson disease (PD), it is important to establish whether such mutations are also a common risk factor for other Lewy body disorders. Objective: To establish whether GBA1 mutations are a risk factor for dementia with Lewy bodies (DLB). Design: We compared genotype data on patients and controls from 11 centers. Data concerning demographics, age at onset, disease duration, and clinical and pathological features were collected when available. We conducted pooled analyses using logistic regression to investigate GBA1 mutation carrier status as predicting DLB or PD with dementia status, using common control subjects as a reference group. Random-effects meta-analyses were conducted to account for additional heterogeneity. Setting: Eleven centers from sites around the world performing genotyping. Participants: Seven hundred twenty-one cases met diagnostic criteria for DLB and 151 had PD with dementia. We compared these cases with 1962 controls from the same centers matched for age, sex, and ethnicity. Main Outcome Measures: Frequency of GBA1 mutations in cases and controls. Results: We found a significant association between GBA1 mutation carrier status and DLB, with an odds ratio of 8.28 (95% CI, 4.78-14.88). The odds ratio for PD with dementia was 6.48 (95% CI, 2.53-15.37). The mean age at diagnosis of DLB was earlier in GBA1 mutation carriers than in noncarriers (63.5 vs 68.9 years; P Ͻ.001), with higher disease severity scores. Conclusions and Relevance: Mutations in GBA1 are a significant risk factor for DLB. GBA1 mutations likely play an even larger role in the genetic etiology of DLB than in PD, providing insight into the role of glucocerebrosidase in Lewy body disease.

Infections represent a possible risk factor for parkinsonism and Parkinson’s disease (PD) based on information from epidemiology and fundamental science. The risk is unclear for the majority of agents. Moreover, the latency between infection and PD seems to be very varied and often lengthy. In this review, the evidence supporting the potential involvement of infectious microorganisms in the development of Parkinson’s disease is examined. Consequently, it is crucial to determine the cause and give additional treatment accordingly. Infection is an intriguing suggestion regarding the cause of Parkinson’s disease. These findings demonstrate that persistent infection with viral and bacterial microorganisms might be a cause of Parkinson’s disease. As an initiating factor, infection may generate a spectrum of gut microbiota dysbiosis, engagement of glial tissues, neuroinflammation, and alpha-synuclein accumulation, all of which may trigger and worsen the onset in Parkinson’s disease also c...

Abnormal biology of α-synuclein (α-Syn) is directly implicated in the pathogenesis of Parkinson&#39;s disease and other α-synucleinopathies. Herein, we demonstrate that C-terminally truncated α-Syn (α-SynΔC), enriched in the pathological α-Syn aggregates, is normally generated from full-length α-Syn independent of α-Syn aggregation in brains and in cultured cells. The accumulation of α-SynΔC is enhanced in neuronal cells as compared with nonneuronal cells. Significantly, the expression of familial Parkinson&#39;s disease-linked mutant α-Syn is associated with the enhanced cellular accumulation of α-SynΔC. Moreover, substoichiometric amounts of α-SynΔC enhance the in vitro aggregation of the more abundant full-length α-Syn. Finally, cases of α-synucleinopathy exhibit increases in the total soluble α-Syn and a higher proportion of soluble α-SynΔC, a condition favoring the aggregation of α-Syn. Collectively, our results indicate that the biology behind the generation and accumulation o...

The management of motor complications in Parkinson's disease (PD) is an unmet need. This paper proposes an eHealth platform for Parkinson's disease (PD) severity estimation using a cloud-based and deep learning (DL) approach. The system quantifies the hallmark symptoms of PD using motor signals of patients with PD (PwPD). In this study, the dataset named "The Michael J. Fox Foundation-funded Levodopa Response Study" is used for the development and evaluation of computational methods focusing on severity estimation of motor function in response to the levodopa treatment. The data is derived from a wearable inertial device, named Shimmer 3, to collect motion data from a patient's upper limb which is more affected by the disease during the performance of some standard activities selected by MDS-UPDRS III and at home while performing daily life activities (DLAs). Seventeen PwPD were enrolled from two clinical sites, who have varying degrees of motor impairment. An incorporated cloud-based framework is proposed where patients' motion data is saved in MS Azure cloud where an automatic evaluation of patients' motor activities in response to the levodopa dose is performed using continuous wavelet transform and CNN-based transfer learning approach. Experimental results show that the efficiency and the robustness of the proposed procedure are proven by 90.0% accuracy for tremor estimation and 86.4% for bradykinesia, with good performance in terms of sensitivity and specificity in each class.

Growing evidence suggests a crucial role of neuroinflammation in the pathophysiology of Parkinson’s disease (PD). Neuroinflammation is linked to the accumulation and aggregation of a-synuclein (αSyn), the primary pathological hallmark of PD. Toll-like receptors 4 (TLR4) can have implications in the development and progression of the pathology. In this study, we analyzed the expression of TLR4 in the substantia nigra (SN) and medial temporal gyrus (GTM) of well-characterized PD patients and age-matched controls. We also assessed the co-localization of TLR4 with pSer129 αSyn. Using qPCR, we observed an upregulation of TLR4 expression in the SN and GTM in PD patients compared to controls, which was accompanied by a reduction in αSyn expression likely due to the depletion of dopaminergic (DA) cells. Additionally, using immunofluorescence and confocal microscopy, we observed TLR4-positive staining and co-localization with pSer129-αSyn in Lewy bodies of DA neurons in the SN, as well as in...

Neuroinflammation and autoimmune mechanisms have been recognized to have a key part in the pathogenesis of Parkinson's disease (PD). Therefore, we evaluated the role of Toll-like receptors (TLRs) as a link between inflammation and autoimmunity in PD. We performed an in vivo model of PD, by 1-metil 4-fenil 1,2,3,6-tetraidro-piridina (MPTP) administration for 7 days, in single KO mice for TLR7, TLR 8 and TLR9; and in double KO mice for TLR 7/8-/-. All animals were compared with WT animals used as a control group. The result obtained demonstrated that the genetic absence of TLR 7 and 8 modified PD pathway increasing the immunoreactivity for TH and DAT compared to PD groups and decreasing microglia and astrocytes activation. Moreover, the deletion of TLR7 and TLR8 significantly reduced T-cell production in the substantia nigra and lymph nodes, suggesting a reduction of T cell activation. Therefore, our result highlights a possibility that an immunotherapy approach by using a dual antagonist of TLR 7 and 8, could be considered as a possible target to develop new therapies for Parkinson diseases. Michela Campolo has completed her PhD in Experimental medicine at the age of 29 years from University of Messina, Italy. She spent 2 years, 1 as a research student and 1 as a post doc at Yale University in USA. Today she is a post doc in pharmacology at the University of Messina. Her research activity is focused on the evaluation of different therapeutic strategies, through preclinical and in vitro studies, in the field of neurodegenerative and traumatic pathologies of the central nervous system, with particular attention to neuroinflammation She has over 40 publications that have been cited over 200 times, and her publication H-index is 20.

Mutations in the PARK2 gene are associated with early onset Parkinsonism. The Park2−/− mouse, however, does not exhibit neurodegeneration or other Parkinson’s disease (PD) phenotypes. Previously, we discovered that translation of Mcl-1, a pro-survival factor, is upregulated in the Park2−/− mouse, suggesting a compensatory mechanism during development. Here we generated the Park2−/−Mcl-1+/− mouse and show that by reducing Mcl-1 gene dosage by 50%, the Park2−/− genotype is sensitized, conferring both dopaminergic neuron loss and motor impairments. We propose that this murine model could be a useful tool for dissecting PD etiology and developing treatment strategies against this neurodegenerative disease.

BackgroundParkinson&#39;s disease (PD) is a progressive neurodegenerative disorder, diagnosed according to the clinical criteria that occur in already advanced stages of PD. The definition of biomarkers for the early diagnosis of PD represents a challenge that might improve treatment and avoid complications in this disease. Therefore, we propose a set of reliable samples for the identification of altered metabolites to find potential prognostic biomarkers for early PD.MethodsThis case–control study included plasma samples of 12 patients with PD and 21 control subjects, from the Spanish European Prospective Investigation into Cancer and Nutrition (EPIC)-Navarra cohort, part of the EPIC-Spain study. All the case samples were provided by healthy volunteers who were followed-up for 15.9 (±4.1) years and developed PD disease later on, after the sample collection. Liquid chromatography coupled to tandem mass spectrometry was used for the analysis of samples.ResultsOut of 40 that were sele...

The lack of knowledge about the onset and progression of Parkinson’s disease (PD) hampers its early diagnosis and treatment. Metabolomics might shed light on the PD imprint seeking a broader view of the biochemical remodeling induced by this disease in an early and pre-symptomatic stage and unveiling potential biomarkers. To achieve this goal, we took advantage of the great potential of the European Prospective Study on Nutrition and Cancer (EPIC) cohort to apply metabolomics searching for early diagnostic PD markers. This cohort consisted of healthy volunteers that were followed for around 15 years until June 2011 to ascertain incident PD. For this untargeted metabolomics-based study, baseline preclinical plasma samples of 39 randomly selected individuals that developed PD (Pre-PD group) and the corresponding control group were analyzed using a multiplatform approach. Data were statistically analyzed and exposed alterations in 33 metabolites levels, including significantly lower le...

Parkinson's disease (PD) and cancer has been described. However, the association between cancers and genetic forms of PD, in particular the R1441G mutation in the LRRK2 gene, is not well known. The objective of this work was to analyze cancer prevalence in PD patients with R1441G or G2019S mutations in LRRK2, and in idiopathic PD (iPD). A total of 732 patients with PD (70 and 25 carriers of R1441G or G2019S mutations, respectively), and 177 controls, were linked using a population-based cancer registry of the Spanish province of Gipuzkoa. Cancer prevalence was not significantly higher in PD-G2019S carriers (20%) than in PD-R1441G carriers (14.3%), iPD (13.8%), or controls (12.5%). With the exception of a high prevalence of hematological cancers (crude odds ratio of 7.1) in the R1441G group, specific cancer types were not increased in PD mutation carriers. In both the

Aging is a multifactorial process associated with functional deficits, and the brain is more prone to developing chronic degenerative diseases such as Parkinson&#39;s disease. Several groups have tried to correlate the age-related ultrastructural alterations to the neurodegeneration process using in vivo pharmacological models, but due to the limitations of the animal models, particularly in aged animals, the results are difficult to interpret. In this work, we investigated neurodegeneration induced by rotenone, as a pharmacological model of Parkinson&#39;s disease, in both young and aged Wistar rats. We assessed animal mobility, tyrosine hydroxylase staining in the substantia nigra pars compacta (SNpc), and TdT-mediated dUTP-biotin nick end labeling-positive nuclei and reactive oxygen species production in the striatum. Interestingly, the mobility impairment, dopaminergic neuron loss, and elevated number of apoptotic nuclei in the striatum of aged control rats were similar to young...

Technology-assisted physical activity interventions for older adults in their home-based environment have been used to promote physical activity. While previous studies and reviews focused on health-related outcomes of such interventions, this scoping review focuses on the technology used and aims to map its feasibility and acceptability. We identified 8496 sources. After title and abstract screening, 455 full texts were assessed, and 148 were included, representing 12,717 participants aged 74 (SD 6) years. In total, 93 (63%) sources reported on the population's health status. In 15 (10%) sources, the participants were defined as healthy; in 13 (9%) and 12 (8%) sources, the participants lived with cardiovascular diseases and cognitive impairments, respectively. The main purpose of the interventions was balance (51%), strength and power (43%) or cardiorespiratory fitness (20%) enhancement. In studies where the participant's health status was reported as healthy, 53% implemented exergames compared to only 27% in studies with participants with a clinical condition. Mobile apps (20%) and trackers (11%) were implemented likewise in both groups. The technology was embedded to provide continuous exercise information (27%) and exercise feedback (27%) or to record real-time movement data (26%). Adverse events were reported in 68 (46%) of the sources with three quarters (49 sources) reporting no adverse events. Only 2 mild events were related to technology. Dropout rates were reported in 100 (68%) studies, with no differences between intervention (16±15%) and control (14±12%) groups. Dropout reasons related to technology in 3%. Adherence was reported in 78 studies (53%) and was slightly higher in the intervention group (79±20%) compared to the control group (71±25%). General enjoyment of the technology was captured in 55 studies (37%) and was rated positive (91%), neutral (7%) or negative (2%). Occasionally reported wishes were related to goal setting, feedback, technical support, exercise variation, and social setting. In conclusion, various technologies were successfully used in healthy and clinical older populations. The embedded technology was not a reason for additional dropouts, lead to slightly better adherence, and adverse events were rarely related to technology. When assessed, the technology was well accepted and positively enjoyed.

Parkinson&#39;s disease (PD) is a progressively debilitating disorder resulting in reduced quality of life (QoL). Along with the motor symptoms of PD, non-motor symptoms of PD such as pain, restless leg syndrome (RLS) depression also occur. These exacerbate the worsening QoL and must be promptly diagnosed and treated. The objective of this study was to determine the relationship between pain severity, walking, general activity and work (WAW) and rapid eye movements (REM) dimensions of pain interference, and disability with depression and RLS in PD. 120 patients with PD and 120 controls were evaluated for depression using the Hospital Anxiety and Depression Scale (HADS-D). Pain severity and interference was measured using Brief Pain Inventory (BPI). REM and WAW dimensions of pain were also measured. The Pain Disability Index (PDI) was used to assess the disabling effects from chronic pain. The study found a statistically significant direct correlation between the BPI, PDI and PD. A s...

Rasagiline is a novel, potent, and selective MAO-B inhibitor shown to be effective for Parkinson's disease. Traditional nonselective MAO inhibitors have been associated with dietary tyramine interactions that can induce hypertensive reactions. To test safety, tyramine challenges (50 -75 mg) were performed in 72 rasagiline-treated and 38 placebo-treated Parkinson's disease (PD) patients at the end of two double-blind placebo-controlled trials of rasagiline. An abnormal pressor response was prespecified as three consecutive measurements of systolic blood pressure (BP) increases of Ն 30 mm Hg and/or bradycardia of Ͻ 40 beats/min. In the first study involving 55 patients with early PD on rasagiline monotherapy, no patients randomized to rasagiline (1 mg/2 mg; n ϭ 38) or placebo (n ϭ 17) developed systolic BP (SBP) or heart rate changes indicative of a tyramine reaction. In the second trial involving 55 levodopa-treated patients, 3 of 22 subjects on rasagiline 0.5 mg/day and 1 of 21 subjects on placebo developed asymptomatic, self-limiting SBP elevations Ն 30 mm Hg on three measurements. No subject on 1 mg/day rasagiline (0/12) experienced significant BP or heart rate changes following tyramine ingestion. These data demonstrate that rasagiline 0.5 to 2 mg daily is not associated with clinically significant tyramine reactions and can be used as monotherapy or adjunct to levodopa in PD patients without specific dietary tyramine restriction.

Background: Availability of validated Parkinson's disease (PD) questionnaires in languages spoken in Africa will enable the conduct of epidemiological studies. The aims of the current study were to develop cross-cultural translated and validated Arabic and French versions of a PD screening questionnaire, and determine its diagnostic accuracy for recognition of parkinsonism in early and moderateadvanced PD in three countries (Cameroon (French), Egypt (Arabic), and Nigeria (English)). This cross-sectional study screened159 participants (81 PD and 78 controls) using the PD screening questionnaire. The questionnaire was translated into Arabic and French versions using standard protocols. Cognitive function was assessed using the Montreal Cognitive Assessment and the Identification and Intervention for Dementia in Elderly Africans cognitive screen. Co-morbidity burden was documented using the Charlson Comorbidity Index. PD severity and stage were evaluated using the MDS Unified Parkinson Disease Rating Scale and the Hoehn and Yahr scale respectively. Results: Both PD patients and controls were matched regarding age, gender, education, and co-morbidity burden. The PD screening questionnaire scores were significantly higher in PD (median 8.0, IQR 6.0-10.0) in contrast to controls (0.0; IQR 0.0-0.0) (p < 0.0001), with a similar pattern and level of significance across all country sites. In ROC analysis, the questionnaire demonstrated high diagnostic accuracy for PD overall, with an AUC of 0.992 (95% CI 0.981-1.002).

Parkinson's disease is associated with mutations in the glucocerebrosidase gene, which result in the enzyme deficiency causing Gaucher disease, the most common lysosomal storage disorder. We have performed an exhaustive literature search and found that additional lysosomal storage disorders might be associated with Parkinson's disease, based on case reports, the appearance of pathological features such as a-synuclein deposits in the brain, and substantia nigra pathology. Our findings suggest that the search for biochemical and cellular pathways that link Parkinson's disease with lysosomal storage disorders should not be limited exclusively to changes that occur in Gaucher disease, such as changes in glucocerebrosidase activity or in glucosylceramide levels, but rather include changes that might be common to a wide variety of lysosomal storage disorders. Moreover, we propose that additional genetic, epidemiological, and clinical studies should be performed to check the precise incidence of mutations in genes encoding lysosomal proteins in patients displaying Parkinson's symptoms. V

Parkinson's disease is associated with mutations in the glucocerebrosidase gene, which result in the enzyme deficiency causing Gaucher disease, the most common lysosomal storage disorder. We have performed an exhaustive literature search and found that additional lysosomal storage disorders might be associated with Parkinson's disease, based on case reports, the appearance of pathological features such as a-synuclein deposits in the brain, and substantia nigra pathology. Our findings suggest that the search for biochemical and cellular pathways that link Parkinson's disease with lysosomal storage disorders should not be limited exclusively to changes that occur in Gaucher disease, such as changes in glucocerebrosidase activity or in glucosylceramide levels, but rather include changes that might be common to a wide variety of lysosomal storage disorders. Moreover, we propose that additional genetic, epidemiological, and clinical studies should be performed to check the precise incidence of mutations in genes encoding lysosomal proteins in patients displaying Parkinson's symptoms. V

Glutamate Chemical Exchange Saturation Transfer (GluCEST) MRI is a recently developed technique to image glutamate. In the present study, we evaluated the reproducibility and background contamination to the GluCEST and source of the GluCEST changes in a mouse model of Parkinson&#39;s disease. Repeated measurements in five mice demonstrated an intra-animal coefficient of variation (CV) of GluCEST signal to be 2.3 ± 1.3% and inter-animal CV of GluCEST to be 3.3 ± 0.3%. Mice were treated with MPTP to create a localized striatal elevation of glutamate. We found an elevation in the GluCEST contrast of the striatum following MPTP treatment (Control: 23.3 ± 0.8%, n = 16; MPTP: 26.2 ± 0.8%, n = 19; p ≤ 0.001). Additionally, the positive association between glutamate concentration measured viaH MRS and GluCEST signal was used to estimate background contribution to the measured GluCEST. The contribution of signal from non-glutamate sources was found to be ~28% of the total GluCEST. Immunohist...

Autonomic disorders have been recognized as an important non-motor feature in Parkinson's disease (PD). However, there is a paucity of information on the presence and severity of cardiovascular autonomic neuropathy (CAN) among different motor phenotypes. The aims of this study were to examine the feasibility of electrochemical skin conductance (ESC) measured by Sudoscan as a screening service for CAN in patients with PD and investigate the severity of CAN among different motor phenotypes. Design: This was a cross-sectional observational study that enrolled 63 patients with PD. Patients were divided into three phenotypes, postural instability/gait difficulty (PIGD), tremor-dominant (TD), and akinetic-rigid (AR), according to their motor symptoms. Cardiovascular autonomic function was measured, and the presence and severity of CAN was determined according to the composite autonomic scoring scale (CASS). Functional scores were measured by the Hoehn and Yahr (HY) stage and the Unified Parkinson's Disease Rating Scale (UPDRS). The median HY stage was 2.0 [1.5, 3.0]. Median UPDRS total score was 23.0 (17.5, 30.5), 10.0 (6.0, 11.0) and 14.0 (6.3, 23.8) in groups of PIGD, TD and AR, respectively (p = 0.001). Mean CASS was 1.7 ± 1.3, 0.6 ± 0.4, and 1.8 ± 1.5 in groups of PIGD, TD and AR, respectively (p = 0.204). Although the ESC was not strongly associated with the cardiovascular autonomic parameters, the CAN risk score provided by Sudoscan significantly correlated with parameters of cardiovascular autonomic function, including heart rate response to deep breathing (HR_DB), Valsalva ratio (VR), and baroreflex sensitivity (BRS). By receiver-operating characteristic (ROC) analysis, if a patient's CAN risk score is higher than 33.5 (%), it is recommended to be aware of the presence of CAN even in PD patients who are asymptomatic. The area under ROC curve was 0.704. Based on our results, CAN risk score may be used for screening of CAN in patients with PD before resorting to the more sophisticated and specific, but ultimately more time-consuming, complete autonomic function testing.

The association between dopamine neuron loss and functional change in the striatocortical network was analyzed in 31 patients with Parkinson&#39;s disease (PD) [mean disease duration 4.03 ± 4.20 years; Hoehn and Yahr (HY) stage 2.2 ± 1.2] and 37 age-matched normal control subjects. We performed (99m)Tc-TRODAT-1 SPECT/CT imaging to detect neuron losses and resting-state functional magnetic resonance imaging to detect functional changes. Mean striatal dopamine transporter binding ratios were determined by region of interest analysis. The functional connectivity correlation coefficient (fc-cc) was determined in six striatal subregions, and interactions between these binding ratios and the striatocortical fc-cc values were analyzed. The PD patients had significant functional network alterations in all striatal subregions. Lower striatal dopamine transporter binding correlated significantly with lower fc-cc values in the superior medial frontal (SMF) lobe and superior frontal lobe and hi...

Apoptosis of both brain neurons and peripheral blood leukocyte is believed to be an important biomarker for evaluating the functional status of Parkinson’s disease (PD). However, their correlation remains unknown. A better understanding of the pathophysiology of neurodegeneration is essential for the treatment and prevention of PD. The present study demonstrated that leukocyte apoptosis is significantly higher in PD patients and is associated with central dopamine neuron loss by usingTc99m-TRODAT-1 SPECT. The leukocyte apoptosis and striatal dopamine transporter uptake ratios were further associated with increased severity and longer duration of disease. The interaction between brain and systemic inflammation may be responsible for the neurodegenerative disease progression.

Background/Aims: Little is known about the relationship between cognitive functions and higher-level functional capacity (e.g. intellectual activity, social role, and social participation) in Parkinson's disease (PD). The purpose of this study was to clarify neuropsychological characteristics and their association with higher-level functional capacity in PD patients. Methods: Participants were 31 PD patients and 23 demographically matched healthy controls. Neuropsychological tests were conducted. One year later, a questionnaire survey evaluated higherlevel functional capacity in daily living. Results: The PD group scored significantly lower than the control group in all cognitive domains, particularly executive function and processing. Executive function, processing speed, language, and memory were significantly correlated with higher-level functional capacity in PD patients. Stepwise regression showed that only executive function (Trail Making Test-B), together with disease severity (HY stage), predicted the higher-level functional capacity. Conclusion: Our findings provide evidence of a relationship between executive function and higher-level functional capacity in patients with PD.

Alzheimer's and Parkinson's diseases are severe neurodegenerative conditions triggered by complex biochemical routes. Many groups are currently pursuing the search for valuable biomarkers to either perform early diagnostic or to follow the disease's progress. Several studies have reported relevant findings regarding environmental issues and the progression of such diseases. Here the etiology and mechanisms of these diseases are briefly reviewed. Approaches that might reveal candidate biomarkers and environmental stressors associated to the diseases were analyzed under a proteomic perspective.

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most common known cause of autosomal dominant Parkinson's disease (PD) and sporadic PD (sPD). The clinical presentation of LRRK2 PD is similar to sPD, and except for genetic testing, no biochemical or imaging markers can differentiate LRRK2 PD from sPD. Discovery of such biomarkers could indicate neuropathological mechanisms that are unique to or increased in LRRK2 PD. This review discusses findings in 17 LRRK2 -related CSF studies found on PubMed. Most of these studies compared analyte concentrations between four diagnostic groups: LRRK2 PD patients, sPD patients, asymptomatic control subjects carrying PD-associated LRRK2 mutations (LRRK2 CTL), and healthy control subjects lacking LRRK2 mutations (CTL). Analytes examined in these studies included A␤1-42, tau, ␣-synuclein, oxidative stress markers, autophagy-related proteins, pteridines, neurotransmitter metabolites, exosomal LRRK2 protein, RNA species, inflammatory cytokines, mitochondrial DNA (mtDNA), and intermediary metabolites. FINDINGS: Pteridines, ␣-synuclein, mtDNA, 5-hydroxyindolacetic acid, ␤-D-glucose, lamp2, interleukin-8, and vascular endothelial growth factor were suggested to differentiate LRRK2 PD from sPD patients; 8-hydroxy-2'-deoxyguanosine (8-OHdG), 8-isoprostane (8-ISO), 2-hydroxybutyrate, mtDNA, lamp2, and neopterin may differentiate between LRRK2 CTL and LRRK2 PD subjects; and soluble oligomeric ␣-synuclein, 8-OHdG, and 8-ISO might differentiate LRRK2 CTL from CTL subjects. CONCLUSIONS: The low numbers of investigations of each analyte, small sample sizes, and methodological differences limit conclusions that can be drawn from these studies. Further investigations are indicated to determine the validity of the analytes identified in these studies as possible biomarkers for LRRK2 PD patients and/or LRRK2 CTL subjects.

The unloading reflex was tested on both sides of a patient with asymmetrical Parkinsonism. The motor activity after the silent period was significantly greater on the more affected side. The findings support the hypothesis that the response to unloading and the shortening reaction share a common mechanism which is exaggerated in Parkinsonism. estimated the duration of illness to be three or 919 guest. Protected by copyright.

Patients with Parkinson's disease often suffer from OFF symptoms disrupting their daily routines and adding to disabilities. Despite polypharmacy and adjustments to medication schedules, they often do not experience consistent relief from their motor symptoms. As the disease progresses, impaired gastric emptying may evolve, making it even more challenging for dopaminergic drugs to provide consistent results. This review focuses on a group of drugs that have the pharmacokinetic advantage of a much earlier onset of action by virtue of their non-oral routes of absorption. We compare the current marketed options: subcutaneous apomorphine, sublingual apomorphine, and inhaled levodopa. Subcutaneous apomorphine is the speediest to take effect, whereas sublingual apomorphine offers the longest clinical effect. Inhaled levodopa has the most favorable side effect profile among the three options. An inhaled form of apomorphine is currently under development, having passed safety and efficacy studies. Each of these drugs has unique characteristics for the user, including different side effect profiles and onset of action. The best choice for a patient will depend on individual needs and circumstances. In this review, we explore those nuances to allow clinicians to select the best option for their patients.

Parkinson’s disease (PD) is a chronic movement disorder that produces a variety of characteristic movement abnormalities. The ubiquity of wrist-worn accelerometry suggests a possible sensor modality for early detection of PD symptoms and subsequent tracking of PD symptom severity. As an initial proof of concept for this technological approach, we analyzed the U.K. Biobank data set, consisting of one week of wrist-worn accelerometry from a population with a PD primary diagnosis and an age-matched healthy control population. Measures of movement dispersion were extracted from automatically segmented gait data, and measures of movement dimensionality were extracted from automatically segmented low-movement data. Using machine learning classifiers applied to one week of data, PD was detected with an area under the curve (AUC) of 0.69 on gait data, AUC = 0.84 on low-movement data, and AUC = 0.85 on a fusion of both activities. It was also found that classification accuracy steadily impro...

Sodium valproate is a well-known antiepileptic agent with multiple mechanisms of action such as sodium channel blockage and gamma-aminobutyric acid activity induction. Despite its well-described anxiolytic and mood stabilization effects, its mechanism of action in pathological gambling is not clear. However, it has been reported as an effective treatment option in pathological gambling for patients without Parkinson's disease (PD). We presented a male patient with a diagnosis of PD suffering from pathological gambling as an impulse control disorder due to antiparkinsonian drugs who did not respond to drug adjustments but showed complete improvement with sodium valproate, without any worsening in PD symptoms.

Although there are studies linking depressive symptoms with psychiatric diseases, and then, with brain morphometry, scarce is the literature examining the association between depressive symptoms and brain morphometry in the prodromal stage of neurodegenerative disorders. In the current analysis, we used a fair sample of Mild Cognitive Impairment (MCI) stage due to Alzheimer's disease (AD) and Parkinson's disease (PD) patients, to examine the association between different depressive symptoms and a large variety of brain morphometric factors. Methods/ Design: Our sample consisted of 352 patients. The Geriatric Depression Scale (GDS) was used for the association with brain measurements. Principal Components Analysis (PCA) and regression models were used for the analyses. Age, sex, years of education, Addenbrooke's cognitive examination revised (ACE-R), and estimated total intracranial volume were used as covariates. Results: Factor3 was significantly and positively correlated with GDS total, Dysthymia, Anxiety and Hopelessness. r_factor1, r_factor2 and r_factor5 were significantly and positively correlated with Anxiety, while r_factor5 was also correlated with GDS total. Concerning volumes, v_factor3 was found to be correlated with GDS total, Dysthymia, Anxiety and Hopelessness. Conclusions: The association between depressive symptoms and upcoming neurodegenerative disorders is reflected in human brain structural alterations, suggesting specific modifications in network-like patterns and neuronal connectivity. Characterizing differences in the morphometry of brain regions among MCI patients with depressive symptoms may aid the early diagnosis and treatment of these symptoms.

Despite real therapeutic successes, the fundamental physiological mechanisms underlying the effect of deep brain stimulation are still not understood. Several attempts have been made to explore these mechanisms with computational models. Unfortunately so far mathematical models have not had a significant impact on mainstream research on deep brain stimulation in Parkinson&#39;s disease. In this paper we report our internship experience working with a computational model proposed by Rubin and Terman in 2004 which is among the most realistic and comprehensive models published recently.

Disclaimer. The ESC Guidelines represent the views of the ESC and were produced after careful consideration of the scientific and medical knowledge and the evidence available at the time of their publication. The ESC is not responsible in the event of any contradiction, discrepancy, and/or ambiguity between the ESC Guidelines and any other official recommendations or guidelines issued by the relevant public health authorities, in particular in relation to good use of healthcare or therapeutic strategies. Health professionals are encouraged to take the ESC Guidelines fully into account when exercising their clinical judgment, as well as in the determination and the implementation of preventive, diagnostic or therapeutic medical strategies; however, the ESC Guidelines do not override, in any way whatsoever, the individual responsibility of health professionals to make appropriate and accurate decisions in consideration of each patient's health condition and in consultation with that patient and, where appropriate and/or necessary, the patient's caregiver. Nor do the ESC Guidelines exempt health professionals from taking into full and careful consideration the relevant official updated recommendations or guidelines issued by the competent public health authorities, in order to manage each patient's case in light of the scientifically accepted data pursuant to their respective ethical and professional obligations. It is also the health professional's responsibility to verify the applicable rules and regulations relating to drugs and medical devices at the time of prescription.

Introduction: Deep brain stimulation (DBS) is a treatment option for reducing motor symptoms in patients with Parkinson's Disease (PD) when first-line medication becomes ineffective. Existing literature has hypothesized that the clinical outcome of DBS may depend on brain connectivity profiles of the stimulation site to distant brain regions. However, the potential of brain connectivity profiles to predict response to DBS in PD remains unclear. Objective: This study aimed to investigate how changes in structural and functional connectivity may relate to patient response to DBS, through the examination of brain network changes using graph theory. Methods: Ten patients with advanced PD were included in this study. Diffusion tensor imaging (DTI) and resting-state fMRI scans were acquired prior to DBS implantation. Pre-DBS and post-DBS UPDRS-III scores were obtained. Network analysis of the DTI and fMRI scans was performed using GRETNA to compute structural and functional graph theory metrics, respectively. Metrics were correlated with UPDRS-III improvement to identify significant correlations to UPDRS improvement due to DBS. Results: Combined structural and functional graph theory metrics highlighted 32 structures to be significantly correlated with UPDRS-III improvement. Mainly, connections to the cerebellum were found to be significantly correlated with UPDRS-III improvement across several metrics for both structural and functional connectivity. Discussion: This work combined DTI, fMRI, and graph theory analysis to evaluate improvement with DBS. Several imaging biomarkers were identified that are robust predictors for UPDRS-III improvement. This work warrants investigation into the compensatory effect of the cerebellum and other potential biomarkers for identifying DBS candidates.

INTRODUCTION: Although the optimal antithrombotic therapy for extracranial blunt cerebrovascular injury (BCVI) remains unknown, anticoagulation with intravenous heparin has been favored. In the current decade, however, we transitioned our practice to an aspirin-based approach. The purpose of this study was to review the efficacy and bleeding risk of this strategy for BCVI management. METHODS: Patients with BCVI were identified at a level 1 trauma center between 2010 and 2017. Imaging was reviewed and electronic medical records were examined for patient information including demographics, injury type, therapy, complications, outcomes, and follow-up. RESULTS: Over the study period, 13 578 patients were admitted following blunt trauma with 94 (0.7%) patients having confirmed BCVI. Average age was 42 yr, with 68 males (72%). Mean Injury Severity Score and Glasgow Coma Score were 27 and 10, respectively. A total of 130 vessels were found to have been injured, with a predominance of vertebral artery injuries (78, 60%). The majority of vessels sustained Biffl grade I or II injury (53 (38%) and 38 (29%) respectively). Twentysix (28%) patients died during hospitalization. Twelve (13%) patients suffered an ischemic event; 3 following initial diagnosis. Aspirin was primary treatment for 56 (59.6%) patients, 30 (32%) patients received no treatment, and 7 (7.4%) underwent endovascular therapy. FOur (7%) patients treated with aspirin suffered a bleeding complication (2 with progression of intracranial hemorrhage and 2 with GI bleed). Of the 68 survivors, 33(48.5%) patients had follow-up imaging with a mean follow-up of 36 d and 2(6%) patients had progression of injury. Fifteen (46%) patients had improvement. CONCLUSION: An aspirin-based management strategy for BCVI was observed to be both efficacious and relatively safe. The incidence of ischemic events was lower than the majority of previous reports, as was the risk of bleeding. An aspirin-based approach is both simple and effective, and may be the preferred antithrombotic treatment for BCVI.

Parkinson's disease (PD) is a severe disabling syndrome in which neuroinflammation and various signaling pathways are believed to mediate dopaminergic neurodegeneration. Here, the possible disease-modifying effects of the purine nucleoside inosine were examined against rotenone-induced PD. Mice were allocated into six groups, namely, a normal control group receiving dimethylsulfoxide, a PD control group receiving rotenone, a standard treatment group receiving L-dopa/carbidopa together with rotenone, and three treatment groups receiving inosine in low, medium, and high doses together with rotenone. At the end of the experimental protocol, three behavioral tests were performed to assess PD motor manifestations, namely, wirehanging test, wood-walking test, and stair test. After performing the behavioral study, mice striata were isolated for the colorimetric assay of hypoxanthine, the enzyme-linked immunosorbent assay of dopamine, tumor necrosis factor-α, interleukin-6 and nitrite, the Western blot estimation of total and phosphorylated extracellular signal-regulated kinase (tERK and pERK), the polymerase chain reaction estimation of adenosine A 2A receptor (A2AR) expression, as well as the histopathological examination of substantia nigra and striatal tissue. Inosine protected against PD progression in a dose-dependent manner, with the effect comparable to the standard treatment L-dopa/carbidopa, evidenced by behavioral, biochemical, and histologic findings. The beneficial antiparkinsonian effect of inosine could be attributed to the ability of the drug to ameliorate neuroinflammation and oxido-nitrosative stress, together with suppression of ERK phosphorylation and down-regulation of A2AR expression. Inosine could therefore be considered as a disease-modifying agent against PD, but further studies are claimed to confirm such effects clinically.

Loss of cardiac postganglionic sympathetic innervation is a characteristic pathology of Parkinson&#39;s disease (PD). It progresses over time independently of motor symptoms and is not responsive to typical anti-parkinsonian therapies. Cardiac sympathetic neurodegeneration can be mimicked in animals using systemic dosing of the neurotoxin 6-hydroxydopamine (6-OHDA). As in PD, 6-OHDA-induced neuronal loss is associated with increased inflammation and oxidative stress. To assess the feasibility of detecting changes over time in cardiac catecholaminergic innervation, inflammation, and oxidative stress, myocardial positron emission tomography with the radioligands [C]-hydroxyephedrine (MHED), [C]PBR28 (PBR28), and [Cu]diacetyl-((4))-methylthiosemicarbazone (ATSM) was performed in 6-OHDA-intoxicated adult, male rhesus macaques ( = 10; 50 mg/kg i.v.). The peroxisome proliferator-activated receptor gamma (PPARγ) agonist pioglitazone, which is known to have anti-inflammatory and anti-oxidat...

De nombreuses personnes ont contribué d'une manière directe ou indirecte au succès de ce travail de thèse de 3 ans. Le chemin du doctorat, parfois laborieux et difficile, est aussi l'occasion de rencontres. J'espère n'oublier personne dans ce remerciement sans tomber dans l'aspect catalogue. Je pense que je souhaite tout d'abord remercier les rapporteurs de mon jury de thèse, le professeur Hassen Drira et le maître de conférences HDR Amine Lazouni qui m'ont fait l'honneur de lire, de commenter et de rapporter ce travail. Je remercie également la professeur et ophtalmologue Béatrice Cochener d'avoir examiné ce travail. Il m'est impossible d'oublier Mathieu Lempereur qui a accepté de faire partie de mon jury de thèse. Grâce à nos différentes rencontres pour discuter des données de la marche, j'ai pu profiter de votre expérience et savoir. Vous étiez toujours prêt à répondre à toutes mes questions avec une précision accrue et une grande bienveillance. Merci infiniment pour tous vos efforts. Merci également aux membres de mon comité de suivi individuel, Said Andaloussi et Pierre Gasnier pour leurs précieux conseils et leurs encouragements au cours de nos deux rencontres. Pierre-Henri Conze qui m'ont encadrée et soutenue tout au long de ma thèse. J'ai énormément apprécié leur grande disponibilité et leur réactivité. Ils ont été à la fois des encadrants idéaux, mais aussi des personnes avec qui on peut discuter sur un pied d'égalité. Merci du fond du coeur de m'avoir donné l'opportunité de réaliser ce projet à vos côtés. Je tiens à remercier également Gwenolé Quellec pour son aide précieuse au cours de 4 ma thèse et ses suggestions largement pertinentes. Son expérience, ses connaissances et son appétence pour le domaine ont très fortement contribué à la réussite de ce travail. J'ai une pensée toute particulière pour Jean-François Clément qui était toujours là pour me sauver quand un problème technique avec mon matériel informatique survint. Sans toi, j'aurais terriblement galéré. Je remercie les membres du CHU de Brest d'avoir accepté la collaboration nous permettant de disposer des données de la marche essentielles à la réalisation des travaux liés à cette thèse. Les différents échanges que nous avons pu avoir étaient toujours très constructifs et l'intérêt porté à ce projet fut très stimulant. Je souhaite également exprimer ma reconnaissance aux différents membres de l'équipe pédagogique de l'UFR de Sciences et Techniques avec qui j'ai pu avoir l'occasion d'échanger lors des missions d'enseignement. Je pense notamment à Jérémy Rivière, Damien Massé, Laurence Duval et Mickael Kerboeuf. Cette expérience m'a été largement fructueuse. De manière générale, je souhaite également saluer toutes les personnes avec qui j'ai pu échanger des pensées, des joies et des peines au LATIM, pendant ces années : Isa-

Human gut microbiota (GM) has now been accepted as a potential modulator ofhuman biology. Although new to the world of science, GM&#39;s impaction brain and behavior has drawn great attention around the globe. Studies have now proven that GM can directly or indirectly modify brain neurochemistry via various mechanisms like neural, immune and endocrine. The intestinal microbiota influence neurodevelopment, modulate behavior, and contribute to neurological disorders. This presentation is an overview of recent findings regarding the GM -brain axis in PD (Braniste et al. 2014; Sampson et al. 2016) Parkinson disease (PD) is the second-most common neurodegenerative disorder. PD patients show alpha-synuclein deposits and neurodegeneration in the enteric nervous system as well as breakdown of the mucosal barrier, bacterial invasion, and mucosal inflammation in the colon. Alterations in GM and increased gut permeability may influence PD pathophysiology via epigenetic processes that alter αSy...