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Background: Using 11 C-(R)-PK11195-PET, we found increased microglia activation in isolated REM sleep behavior disorder (iRBD) patients. Their role remains to be clarified., Objectives: The objective is to assess relationships between activated microglia and progression of nigrostriatal dysfunction in iRBD., Methods: Fifteen iRBD patients previously scanned with 11 C-(R)-PK11195 and 18 F-DOPA-PET underwent repeat 18 F-DOPA-PET after 3 years. 18 F-DOPA K i changes from baseline were evaluated with volumes-of-interest and voxel-based analyses., Results: Significant 18 F-DOPA K i reductions were found in putamen and caudate. Reductions were larger and more widespread in patients with increased nigral microglia activation at baseline. Left nigral 11 C-(R)-PK11195 binding at baseline was a predictor of 18 F-DOPA K i reduction in left caudate (coef = -0.0426, P = 0.016)., Conclusions: Subjects with increased baseline 11 C-(R)-PK11195 binding have greater changes in nigrostriatal function, suggesting a detrimental rather than protective effect of microglial activation. Alternatively, both phenomena occur in patients with prominent nigrostriatal dysfunction without a causative link. The clinical and therapeutic implications of these findings need further elucidation. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Background: Patients with Lewy body diseases exhibit variable degrees of cortical and subcortical hypometabolism. However, the underlying causes behind this progressive hypometabolism remain unresolved. Generalized synaptic degeneration may be one key contributor., Objective: The objective of this study was to investigate whether local cortical synaptic loss is proportionally linked to the magnitude of hypometabolism in Lewy body disease., Method: Using in vivo positron emission tomography (PET) we investigated cerebral glucose metabolism and quantified the density of cerebral synapses, as measured with [ 18 F]fluorodeoxyglucose ([ 18 F]FDG) PET and [ 11 C]UCB-J, respectively. Volumes-of-interest were defined on magnetic resonance T1 scans and regional standard uptake value ratios-1 values were obtained for 14 pre-selected brain regions. Between-group comparisons were conducted at voxel-level., Results: We observed regional differences in both synaptic density and cerebral glucose consumption in our cohorts of non-demented and demented patients with Parkinson's disease or dementia with Lewy bodies compared to healthy subjects. Additionally, voxel-wise comparisons showed a clear difference in cortical regions between demented patients and controls for both tracers. Importantly, our findings strongly suggested that the magnitude of reduced glucose uptake exceeded the magnitude of reduced cortical synaptic density., Conclusion: Here, we investigated the relationship between in vivo glucose uptake and the magnitude of synaptic density as measured using [ 18 F]FDG PET and [ 11 C]UCB-J PET in Lewy body patients. The magnitude of reduced [ 18 F]FDG uptake was greater than the corresponding decline in [ 11 C]UCB-J binding. Therefore, the progressive hypometabolism seen in Lewy body disorders cannot be fully explained by generalized synaptic degeneration. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Background: Patients with Parkinson's disease (PD) often develop dementia, but the underlying substrate is incompletely understood. Generalized synaptic degeneration may contribute to dysfunction and cognitive decline in Lewy body dementias, but in vivo evidence is lacking., Objective: The objective of this study was to assess the density of synapses in non-demented PD (nPD) subjects (N = 21), patients with PD-dementia or Dementia with Lewy bodies (DLB) (N = 13), and age-matched healthy controls (N = 15)., Method: Using in vivo PET imaging and the novel synaptic-vesicle-glycoprotein 2A (SV2A) radioligand [11C]UCB-J, SUVR-1 values were obtained for 12 pre-defined regions. Volumes-of-interest were defined on MRI T1 scans. Voxel-level between-group comparisons of [11C]UCB-J SUVR-1 were performed. All subjects underwent neuropsychological assessment. Correlations between [11C]UCB- J PET and domain-specific cognitive functioning were examined., Results: nPD patients only demonstrated significantly reduced SUVR-1 values in the substantia nigra (SN) compared to HC. DLB/PDD patients demonstrated reduced SUVR-1 values in SN and all cortical VOIs except for the hippocampus and amygdala. The voxel-based analysis supported the VOI results. Significant correlation was seen between middle frontal gyrus [11C]UCB-J SUVR-1 and performance on tests of executive function., Conclusion: Widespread cortical reduction of synaptic density was documented in a cohort of DLB/PDD subjects using in vivo [11C]UCB-J PET. Our study confirms previously reported synaptic loss in SN of nPD patients. [11C]UCB-J binding in selected cortical VOIs of the DLB/PDD patients correlated with their levels of cognitive function across relevant neuropsychological domains. These findings suggest that the loss of synaptic density contributes to cognitive impairment in nPD and DLB/PDD. © 2021 International Parkinson and Movement Disorder Society., (© 2021 International Parkinson and Movement Disorder Society.)

Reduced noradrenaline levels have been reported to occur in the motor cortices of PD patients postmortem. Imaging techniques have recently become available to specifically study noradrenergic terminal function in vivo using PET. The objective of this study was to evaluate cortical 11 C-MeNER binding in PD patients. Thirty PD patients and 12 healthy control subjects comparable in age, sex, and cognitive performance underwent PET imaging with 11 C-MeNER, a specific ligand of the noradrenaline transporter. Cortical noradrenaline transporter binding was compared at a voxel level using Statistical Parametric Mapping, whereas cortical thickness was assessed using FreeSurfer software with MRI. PD patients showed reduced 11 C-MeNER binding in the primary motor cortex unrelated to cortical thickness; other cortical regions did not differ between groups. In a subgroup analysis, patients with higher Hoehn & Yahr stage exhibited more pronounced 11 C-MeNER binding reductions. Loss of cortical noradrenergic projections to the primary motor cortex occurs in PD associated with disease stage. © 2018 International Parkinson and Movement Disorder Society., (© 2018 International Parkinson and Movement Disorder Society.)

Background: We hypothesized that tonsillectomy modifies the risk of PD., Objectives: To test the hypothesis in a nationwide population-based cohort study., Methods: We used Danish medical registries to construct a cohort of all patients in Denmark with an operation code of tonsillectomy 1980-2010 (n = 195,169) and a matched age and sex general population comparison cohort (n = 975,845). Patients were followed until PD diagnosis, death, censoring, or end of follow-up 30 November 2013. Using Cox regression, we computed hazard ratios for PD and corresponding 95% confidence intervals, adjusting for age and sex by study design, and potential confounders., Results: We identified 100 and 568 patients diagnosed with PD among the tonsillectomy and general population comparison cohort, respectively, finding similar risks of PD (adjusted hazard ratio = 0.95 [95% confidence interval: 0.76-1.19]; for > 20 years' follow-up (adjusted hazard ratio = 0.96 [95% confidence interval: 0.64-1.41])., Conclusion: Tonsillectomy is not associated with risk of PD, especially early-onset PD. © 2017 International Parkinson and Movement Disorder Society., (© 2017 International Parkinson and Movement Disorder Society.)

Parkinson's disease (PD) is a multisystem disorder with involvement of the peripheral nervous system. Misfolding and aggregation of α-synuclein is central to the pathogenesis of PD, and it has been postulated that the disease may originate in olfactory and gastrointestinal nerve terminals. The prion-like behavior of α-synuclein has been convincingly demonstrated in vitro and in animal models of PD. Lewy-type pathology have been detected in peripheral organs many years prior to PD diagnosis, and 2 independent studies have now suggested that truncal vagotomy may be protective against the disorder. Other lines of evidence are difficult to reconcile with a peripheral onset of PD, most importantly the relative scarcity of post mortem cases with isolated gastrointestinal α-synuclein pathology without concomitant CNS pathology. This Scientific Perspectives article revisits some important topics with implications for the dual-hit hypothesis. An account of the neuroanatomical pathways necessary for stereotypical α-synuclein spreading is presented. Parallels to the existing knowledge on true prion disorders, including Creutzfeld-Jakob disease, are examined. Finally, the vagotomy studies and the somewhat inconsistent findings in the growing literature on peripheral α-synuclein pathology are discussed. It is concluded that the dual-hit hypothesis remains a potential explanation for PD pathogenesis, but several issues need to be resolved before more firm conclusions can be drawn. © 2017 International Parkinson and Movement Disorder Society., (© 2017 International Parkinson and Movement Disorder Society.)

Background: Alzheimer's disease copathology is common in PD at autopsy. In non-PD subjects with mild cognitive impairment, tau depositions can be detected using 18F-AV-1451 PET. We hypothesized that 18F-AV-1451 PET would show tau aggregation in PD with mild cognitive impairment and correlate with cognitive dysfunction., Objectives: To describe tau aggregation in PD patients., Methods: Twenty-six PD patients and 23 controls had 18F-AV-1451 PET and neuropsychological assessment to detect mild cognitive impairment., Results: Nine PD patients (35%) were identified with mild cognitive impairment. Regional analyses showed no significant differences between groups. Voxel-wise analyses showed no correlation with cognitive domain z-scores within patients. One patient with mild cognitive impairment was estimated Braak tau stage 5; all other patients were stage 0., Conclusion: Our results indicate that tau pathology, as detected by 18F-AV-1451, is uncommon in PD with mild cognitive impairment and shows no significant correlation with cognitive dysfunction at this stage. © 2017 International Parkinson and Movement Disorder Society., (© 2017 International Parkinson and Movement Disorder Society.)

Constipation is among the first nonmotor symptoms to develop in the prodromal phase of PD. Pathological alpha-synuclein deposition is present throughout the gastrointestinal tract up to 20 years preceding diagnosis. Nevertheless, constipation in the context of PD remains ill defined and poorly understood. In this review, we summarize current knowledge of subjective symptoms and objective measures of constipation in PD. More than 10 different definitions of constipation have been used in the PD literature, making generalizations difficult. When pooling results from the most homogeneous studies in PD, a median constipation prevalence of 40% to 50% emerges, but with large variation across individual studies. Also, constipation prevalence tends to increase with disease progression. A similar prevalence is observed among patients with idiopathic rapid eye movement sleep behavior disorder. Interestingly, we detected a correlation between constipation prevalence in PD patients and healthy control groups in individual studies, raising concerns about how various constipation questionnaires are implemented across study populations. More than 80% of PD patients exhibit prolonged colonic transit time, and the same is probably true for de novo PD patients. Thus, the prevalence of objective colonic dysfunction exceeds the prevalence of subjective constipation. Colonic transit time measures are simple, widely available, and hold promise as a useful biomarker in manifest PD. More research is needed to elucidate the role of gastrointestinal dysfunction in disease progression of PD. Moreover, colonic transit measures may have utility as a more accurate risk factor for predicting PD in the prodromal phase. © 2016 International Parkinson and Movement Disorder Society., (© 2016 International Parkinson and Movement Disorder Society.)

Objectives: The appendix may be a key site for the initiation of Parkinson's disease (PD) pathology. We examined the hypothesis that appendectomy is associated with lower PD risk., Methods: We used Danish medical and administrative registries to construct a cohort of all patients in Denmark with an operation code of appendectomy during 1980-2010 (n = 265,758) and a matched general population comparison cohort (n = 1,328,790). Using Cox regression, we computed hazard ratios and corresponding 95% confidence intervals for PD, adjusting for potential confounders and stratifying on age at appendectomy (≤45 years / > 45 years), sex, and follow-up time., Results: During follow-up ( > 10 years), PD incidence was 0.19 and 0.15 per 1,000 person-years at risk in the appendectomy cohort and in the general population comparison cohort, respectively, yielding a slightly increased risk of PD (adjusted hazard ratio = 1.14; 95% confidence interval 1.03-1.27). Findings were consistent after more than 20 years of follow-up and when stratified on age of appendectomy and sex., Conclusion: Appendectomy was associated with a small increase in PD risk 10 or more years after surgery. © 2016 International Parkinson and Movement Disorder Society., (© 2016 International Parkinson and Movement Disorder Society.)

Objective: It has been hypothesized that Lewy pathology initiates in the enteric nervous system years prior to debut of clinical motor symptoms in Parkinson disease patients. This study investigates whether Lewy pathology is present in various gastrointestinal tract tissues from Parkinson disease patients in the prodromal phase., Methods: We used the Danish National Pathology Registry to identify archived paraffin-embedded tissue blocks from 57 Parkinson disease patients (98 blocks) and 90 control subjects (98 blocks). We employed 2 different immunohistochemistry techniques visualizing aggregated α-synuclein and phosphorylated α-synuclein., Results: Thirty-nine Parkinson disease patients contributed tissues obtained in the prodromal disease phase, whereas 18 Parkinson disease patients contributed tissues obtained solely after Parkinson diagnosis. Prodromal tissues were obtained on average 7.0 years prior to diagnosis (range = 20 years to 4 months), and postdiagnosis tissue on average 2.8 years after diagnosis (range = 2 days to 18 years). Phosphorylated α-synuclein positivity was seen in 22 of 39 (56%) prodromal Parkinson disease subjects and 30 of 67 (45%) prodromal tissue blocks. These fractions were significantly higher compared to control subjects (p = 0.0001 and p = 0.0032, respectively). In contrast, no significant difference was seen in the positivity rate between prodromal Parkinson disease patients and controls when using the aggregated α-synuclein immunohistochemistry technique., Interpretation: We detected Lewy pathology in the gastrointestinal tract of patients up to 20 years prior to their Parkinson disease diagnosis. These findings are in accordance with a hypothesized prodromal disease phase spanning 10 to 20 years. Ann Neurol 2016;79:940-949., (© 2016 American Neurological Association.)

Objective: Parkinson's disease (PD) may be caused by an enteric neurotropic pathogen entering the brain through the vagal nerve, a process that may take over 20 years. We investigated the risk of PD in patients who underwent vagotomy and hypothesized that truncal vagotomy is associated with a protective effect, whereas superselective vagotomy has a minor effect., Methods: We constructed cohorts of all patients in Denmark who underwent vagotomy during 1977-1995 and a matched general population cohort by linking Danish registries. We used Cox regression to compute hazard ratios (HRs) for PD and corresponding 95% confidence intervals (CIs), adjusting for potential confounders., Results: Risk of PD was decreased in patients who underwent truncal (HR = 0.85; 95% CI = 0.56-1.27; follow-up of >20 years: HR = 0.58; 95% CI: 0.28-1.20) compared to superselective vagotomy. Risk of PD was also decreased after truncal vagotomy when compared to the general population cohort (overall adjusted HR = 0.85; 95% CI: 0.63-1.14; follow-up >20 years, adjusted HR = 0.53; 95% CI: 0.28-0.99). In patients who underwent superselective vagotomy, risk of PD was similar to the general population (HR = 1.09; 95% CI: 0.84-1.43; follow-up of >20 years: HR = 1.16; 95% CI: 0.80-1.70). Statistical precision of risk estimates was limited. Results were consistent after external adjustment for unmeasured confounding by smoking., Interpretation: Full truncal vagotomy is associated with a decreased risk for subsequent PD, suggesting that the vagal nerve may be critically involved in the pathogenesis of PD., (© 2015 American Neurological Association.)

Olfactory dysfunction is a prodromal and prevalent nonmotor symptom of Parkinson's disease. Unlike olfactory dysfunction in Alzheimer's disease, it is believed to be unrelated to cognitive impairment. However, recent research has implicated cholinergic denervation in Parkinson's disease hyposmia and linked it to verbal memory. This research hypothesized that severe odor identification deficits may identify patients with Parkinson's disease at risk for cognitive impairment. The current study tested this hypothesis by comparing 24 functionally anosmic, nondemented patients with Parkinson's disease and 39 nonanosmic, nondemented patients with Parkinson's disease with 29 healthy control participants on composite scores of memory, processing speed, executive function, and language. The functionally anosmic group had significantly poorer visual and verbal memory than the nonanosmic group, which was indistinguishable from the control group. Furthermore, the functionally anosmic group had reduced processing speed compared with the nonanosmic patients with Parkinson's disease, who, in turn, were outperformed by the control group. On the composite language score, the score of the functionally anosmic group was significantly reduced compared with that of the control group, whereas the nonanosmic group scored in the medium range. The 2 patient groups did not differ on executive functioning. These findings demonstrate co-occurrence between reduced cognitive function and olfactory deficits in functionally anosmic patients with Parkinson's disease and support the notion of more severe cognitive deficits in this group., (Copyright © 2011 Movement Disorder Society.)