BACKGROUND:Both Parkinson's disease (PD) and multiple system atrophy (MSA) exhibit degeneration of brainstem serotoninergic nuclei, affecting multiple subcortical and cortical serotoninergic projections. In MSA, medullary serotoninergic neuron pathology is well documented, but serotonin system changes throughout the rest of the brain are less well characterized. OBJECTIVES:To use serotonin transporter [11 C]3-amino-4-(2-dimethylaminomethyl-phenylsulfaryl)-benzonitrile positron emission tomography (PET) to compare serotoninergic innervation in patients with MSA and PD. METHODS:We performed serotonin transporter PET imaging in 18 patients with MSA, 23 patients with PD, and 16 healthy controls to explore differences in brainstem, subcortical, and cortical regions of interest. RESULTS:Patients with MSA showed lower serotonin transporter distribution volume ratios compared with patients with PD in the medulla, raphe pontis, ventral striatum, limbic cortex, and thalamic regions, but no differences in the dorsal striatal, ventral anterior cingulate, or total cortical regions. Controls showed greater cortical serotonin transporter binding compared with PD or MSA groups but lower serotonin transporter binding in the striatum and other relevant basal ganglia regions. There were no regional differences in binding between patients with MSA-parkinsonian subtype (n = 8) and patients with MSA-cerebellar subtype (n = 10). Serotonin transporter distribution volume ratios in multiple different regions of interest showed an inverse correlation with the severity of Movement Disorders Society Unified Parkinson's Disease Rating Scale motor score in patients with MSA but not patients with PD. CONCLUSIONS:Brainstem and some forebrain subcortical region serotoninergic deficits are more severe in MSA compared with PD and show an MSA-specific correlation with the severity of motor impairments. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Abstract Multiple system atrophy (MSA) is an adult-onset atypical parkinsonian disorder (APD) characterized by either rapidly progressive levodopa-unresponsive parkinsonism or a cerebellar syndrome associated with early autonomic failure. According to current consensus criteria two motor subtypes can be distinguished clinically, namely a parkinsonian variant labelled MSA-P and a cerebellar variant labelled MSA-C . Abundant (oligodendro-)glial cytoplasmic inclusions (GCI) represent the histopathological signature lesion that is accompanied by a selective neuronal multisystem degeneration. The principle component of GCIs is α-synuclein, a finding which firmly places MSA among other α-synucleinopathies such as Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). Currently, the management of MSA patients is based on symptomatic treatment targeting parkinsonian and autonomic features. Although research into disease-modifying strategies has accelerated, effective neuroprotective treatments are still lacking.

OBJECTIVE:Fatigue is a disabling non-motor symptom in Parkinson disease (PD). We investigated the relationship between autonomic dysfunction and fatigue in PD while accounting for possible confounding factors. METHODS:29 subjects with PD (8F/21M; mean age 61.6±5.9; mean disease duration 4.8±3.0years), underwent clinical assessment and completed several non-motor symptom questionnaires, including a modified version of the Mayo Clinic Composite Autonomic Symptom Score (COMPASS) scale and the Fatigue Severity Scale (FSS). RESULTS:The mean modified COMPASS was 21.6±14.2 (range 1.7-44.2) and the mean FSS score was 3.3±1.6 (range 1.0-6.7). There was a significant bivariate relationship between the modified COMPASS and FSS scores (R=0.69, P<0.0001). Stepwise regression analysis was used to assess the specificity of the association between the modified COMPASS and FSS scores while accounting for possible confounder effects from other variables that were significantly associated with autonomic dysfunction. Results showed that the modified COMPASS (R2=0.52, F=28.4, P<0.0001) was highly associated with fatigue, followed by ESS (R2=0.13, F=8.4, P=0.008) but no other co-variates. Post-hoc analysis exploring the association between the different modified COMPASS autonomic sub-domain scores and FSS scores found significant regressor effects for the orthostatic intolerance (R2=0.45, F=21.2, P<0.0001) and secretomotor sub-domains (R2=0.09, F=4.8, P=0.04) but not for other autonomic sub-domains. CONCLUSIONS:Autonomic dysfunction, in particular orthostatic intolerance, is highly associated with fatigue in PD.

The objective of this study was to detect regional patterns of cardiac sympathetic denervation in idiopathic Parkinson disease (IPD) using 11C-hydroxyephedrine (11C-HED) PET and determine the denervation rate over 2 y. Methods: We obtained 62 cardiac 11C-HED PET scans in 39 patients (30 men and 9 women; mean age ± SD, 61.9 ± 5.9 y), including 23 patients with follow-up scans at 2 y. We derived 11C-HED retention indices (RIs; mL of blood/min/mL of tissue) reflecting nerve density and integrity for 480 left ventricular (LV) sectors. We compared IPD patients with 33 healthy controls using z score analysis; RI values ≤ 2.5 SDs were considered abnormal. We expressed global and regional LV denervation as the percentage extent of z score severity and severity-extent product (SEP) on 9-segment bullseye maps and decline in cardiac sympathetic innervation as the 2-y difference in SEP (diff-SEP). Results: Baseline 11C-HED PET in the 39 IPD patients revealed an RI mean of 0.052 ± 0.022 mL of blood/min/mL of tissue. In comparison with data from normal controls, 12 patients had normal 11C-HED PET, 5 showed mild denervation (percentage extent < 30%), and 22 had moderate to severe denervation (percentage extent > 30%, z score ≤ 2.5 SD). In the 23 paired PET scans, worsening cardiac denervation (global diff-SEP > 9) occurred in 14 of 23 (60.9%) patients over 2 y, including percentage LV abnormality (59% increasing to 66%), z-severity (–2.4 down to –2.5), and SEP (–195 to –227) (P = 0.0062). We found a mean annual decline of 4.6% ± 5.6 (maximum, 13%) in 11C-HED retention from a baseline global RI mean of 0.0481 ± 0.0218 to 0.0432 ± 0.0220 (P = 0.0009). At baseline, 5 patients with normal uptake had no interval change; 3 with mild denervation developed interval decline in lateral and inferior segments (diff-SEP –82 to –99) compared with anterior and septal segments (–65 to –79), whereas the reverse pattern occurred in 15 patients with severe baseline denervation. Conclusion: Progressive decline in cardiac sympathetic neural integrity in IPD patients occurs at a modest rate over 2 y on 11C-HED scans with marked heterogeneity and a regional pattern of involvement and decline.

Background Multiple system atrophy is a rare, fatal neurodegenerative disorder with symptoms of autonomic failure plus parkinsonism, cerebellar ataxia, or both. We report results of the first prospective natural history study of multiple system atrophy in the USA, and the effects of phenotype and autonomic failure on prognosis.Methods We recruited participants with probable multiple system atrophy of either the parkinsonism subtype (MSA-P) or the cerebellar ataxia subtype (MSA-C)-at 12 neurology centres in the USA specialising in movement or autonomic disorders. We followed up patients every 6 months for 5 years and assessed them with the Unified Multiple System Atrophy Rating Scale part I (UMSARS I; a functional score of symptoms and ability to undertake activities of daily living), UMSARS II (neurological motor evaluation), and the Composite Autonomic Symptoms Scale (COMPASS)-select (a measure of autonomic symptoms and autonomic functional status). We assessed potential predictors of outcome. We used Cox proportional hazards models to calculate univariate hazard ratios for shorter survival using age at disease onset as a continuous variable and sex, clinical phenotype, and early development of neurological and autonomic manifestations as categorical variables.Findings We recruited 175 participants. Mean age at study entry was 63.4 years (SD 8.6). Median survival from symptom onset was 9-8 years (95% CI 8.8-10.7) and median survival from enrolment was 1.8 years (0.9-2.7). Participants with severe symptomatic autonomic failure (symptomatic orthostatic hypotension, urinary incontinence, or both) at diagnosis (n=62) had a worse prognosis than those without severe disease (n=113; median survival 8.0 years, 95% CI 6.5-9.5 vs 10.3 years, 9.3-11.4; p=0.021). At baseline, patients with MSA-P (n=126) and MSA-C (n=49) had much the same symptoms and functional status: mean UMSARS I 25.2 (SD 8.08) versus 24.6 (8.34; p=0.835); mean UMSARS II 26.4 (8.8) versus 25.4 (10.5; p=0.764); COMPASS-select 43.5 (18.7) versus 42.8 (19.6; p=0.835). Progression over 5 years, assessed by change in UMSARS I, UMSARS II, and COMPASS-select, was modest.Interpretation Probable multiple system atrophy is a late-stage disease with short survival. The natural histories of MSA-P and MSA-C are similar and severe symptomatic autonomic failure at diagnosis is associated with worse prognosis.

OBJECTIVE:Glucocerebrosidase gene (GBA) variants that cause Gaucher disease are associated with Parkinson disease (PD) and dementia with Lewy bodies (DLB). To investigate the role of GBA variants in multiple system atrophy (MSA), we analyzed GBA variants in a large case-control series.METHODS:We sequenced coding regions and flanking splice sites of GBA in 969 MSA patients (574 Japanese, 223 European, and 172 North American) and 1509 control subjects (900 Japanese, 315 European, and 294 North American). We focused solely on Gaucher-disease-causing GBA variants.RESULTS:In the Japanese series, we found nine carriers among the MSA patients (1.65%) and eight carriers among the control subjects (0.89%). In the European series, we found three carriers among the MSA patients (1.35%) and two carriers among the control subjects (0.63%). In the North American series, we found five carriers among the MSA patients (2.91%) and one carrier among the control subjects (0.34%). Subjecting each series to a Mantel-Haenszel analysis yielded a pooled odds ratio (OR) of 2.44 (95% confidence interval [CI], 1.14-5.21) and a P-value of 0.029 without evidence of significant heterogeneity. Logistic regression analysis yielded similar results, with an adjusted OR of 2.43 (95% CI 1.15-5.37) and a P-value of 0.022. Subtype analysis showed that Gaucher-disease-causing GBA variants are significantly associated with MSA cerebellar subtype (MSA-C) patients (P = 7.3 × 10(-3)).INTERPRETATION:The findings indicate that, as in PD and DLB, Gaucher-disease-causing GBA variants are associated with MSA.

Background: We report the first North American prospective natural history study of multiple system atrophy (MSA), and the effect of phenotype and autonomic failure on prognosis. Aim: To determine natural history of MSA, compare MSA-P with MSA-C and to determine predictors of outcome. Methods: 175 subjects with probable MSA, both MSA-P and MSA-C, were prospective-ly followed for 5 years in 12 centers in USA. Subjects were evaluated with a standard minimal dataset, UMSARS I (evaluation of symptoms and activities of daily living), UMSARS II (neurologi-cal motor evaluation), the Composite Autonomic Symptoms Scale (COMPASS)-select (evaluation of autonomic symptom and function). Results: Median survival from symptom onset by Kaplan-Meier analysis was 9.8 years (95% CI, 8.8-10.7) and MSA-P was not significantly different to MSA-C. Subjects with an early and severe autonomic involvement at diagnosis had a worse prognosis, surviving 7.9 years (95% CI, 6.5-9.4) while subjects with late autonomic onset sur-vived a median of 10.3 years (95% CI, 9.3-11.4). At baseline MSA-P and MSA-C were not differ-ent in symptoms and function (UMSARS I), by examination (UMSARS II), or in neurologic status. Median time to death from enrollment was 1.9 years. Conclusions: Probable MSA represents late-stage disease with short survival. Natural history of MSA-P and MSA-C are similar. Early and severe autonomic failure is associated with worse prognosis. These findings provide novel insights on natural history and have implications on the design of treatment trials in that the number needed to power a study is much greater for late stage than early disease.

Background Multiple system atrophy is a complex neurodegenerative disorder for which no effective treatment exists. We aimed to assess the effect of rasagiline on symptoms and progression of the parkinsonian variant of multiple system atrophy.Methods We did this randomised, double-blind, placebo-controlled trial between Dec 15, 2009, and Oct 20, 2011, at 40 academic sites specialised in the care of patients with multiple systemic atrophy across 12 countries. Eligible participants aged 30 years or older with possible or probable parkinsonian variant multiple system atrophy were randomly assigned (1:1), via computer-generated block randomisation (block size of four), to receive either rasagiline 1 mg per day or placebo. Randomisation was stratified by study centre. The investigators, study funder, and personnel involved in patient assessment, monitoring, analysis and data management were masked to group assignment. The primary endpoint was change from baseline to study end in total Unified Multiple System Atrophy Rating Scale (UMSARS) score (parts land II). Analysis was by modified intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00977665.Findings We randomly assigned 174 participants to the rasagiline group (n=84) or the placebo group (n=90); 21 (25%) patients in the rasagiline group and 15 (17%) in the placebo group withdrew from the study early. At week 48, patients in the rasagiline group had progressed by an adjusted mean of 7.2 (SE 1.2) total UMSARS units versus 7.8 (1.1) units in those in the placebo group. This treatment difference of -0.60 (95% CI -3.68 to 2.47; p=0.70) was not significant. 68 (81%) patients in the rasagiline group and 67 (74%) patients in the placebo group reported adverse events, and we recorded serious adverse events in 29 (35%) versus 23 (26%) patients. The most common adverse events in the rasagiline group were dizziness (n=10 [12%]), peripheral oedema (n=9 [11%]), urinary tract infections (n=9 [11%]), and orthostatic hypotension (n=8 [10%]).Interpretation In this population of patients with the parkinsonian variant of multiple system atrophy, treatment with rasagiline 1 mg per day did not show a significant benefit as assessed by UMSARS. The study confirms the sensitivity of clinical outcomes for multiple system atrophy to detect clinically significant decline, even in individuals with early disease.

Background No available treatments slow or halt progression of multiple system atrophy, which is a rare, progressive, fatal neurological disorder. In a mouse model of multiple system atrophy, rifampicin inhibited formation of alpha-synudein fibrils, the neuropathological hallmark of the disease. We aimed to assess the safety and efficacy of rifampicin in patients with multiple system atrophy.Methods In this randomised, double-blind, placebo-controlled trial we recruited participants aged 30-80 years with possible or probable multiple system atrophy from ten US medical centres. Eligible participants were randomly assigned (1:1) via computer-generated permuted block randomisation to rifampicin 300 mg twice daily or matching placebo (50 mg riboflavin capsules), stratified by subtype (parkinsonian vs cerebellar), with a block size of four. The primary outcome was rate of change (slope analysis) from baseline to 12 months in Unified Multiple System Atrophy Rating Scale (UMSARS) I score, analysed in all participants with at least one post-baseline measurement. This study is registered with ClinicalTrials.gov, number NCT01287221.Findings Between April 22,2011, and April 19,2012, we randomly assigned 100 participants (50 to rifampicin and 50 to placebo). Four participants in the rifampicin group and five in the placebo group withdrew from study prematurely. Results of the preplanned interim analysis (n=15 in each group) of the primary endpoint showed that futility criteria had been met, and the trial was stopped (the mean rate of change [slope analysis] of UMSARS I score was 0.62 points [SD 0-85] per month in the rifampicin group vs 0-47 points [0.48] per month in the placebo group; futility p=0.032; efficacy p=0.76). At the time of study termination, 49 participants in the rifampicin group and 50 in the placebo group had follow-up data and were included in the final analysis. The primary endpoint was 0.5 points (SD 0.7) per month for rifampicin and 0.5 points (0.5) per month for placebo (difference 0.0,95% CI -0.24 to 0.24; p=0-82). Three (6%) of 50 participants in the rifampicin group and 12 (24%) of 50 in the placebo group had one or more serious adverse events; none was thought to be related to treatment.Interpretation Our results show that rifampicin does not slow or halt progression of multiple system atrophy. Despite the negative result, the trial does provide information that could be useful in the design of future studies assessing potential disease modifying therapies in patients with multiple system atrophy.

We evaluated PET-based classification of neurodegenerative pathology in mild cognitive impairment (MCI). Methods: Our study was a cross-sectional and prospective evaluation of a cohort of 27 MCI subjects drawn from a university-based cognitive disorders clinic. We compared expert clinical consensus classification of MCI at entry and possible dementia at follow-up with molecular imaging-based classification using C-11-dihydotetrabenazine PET measurement of striatal dopamine terminal integrity and C-11-Pittsburgh compound B (C-11-PiB) PET measurement of cerebral amyloid burden. Results: Eleven subjects were initially classified clinically as amnestic MCI, 7 as multidomain MCI, and 9 as nonamnestic MCI. At a mean follow-up of 3 y, 18 subjects converted to dementia. PET imaging evidence of significant cerebral amyloid deposition or nigrostriatal denervation was a strong predictor of conversion to dementia. There was only moderate concordance between expert clinical classifications and PET-based classifications of dementia subtypes. Conclusion: Combined PET molecular imaging of cerebral amyloid burden and striatal dopamine terminal integrity may be useful for identifying subjects at high risk for progression to dementia and in defining neurochemically differentiated subsets of MCI subjects.

Objective: To determine the effect of rifampicin on clinical progression and progression of autonomic failure in multiple system atrophy (MSA).

Background Progressive supranuclear palsy (PSP) is a neurodegenerative disorder pathologically characterized by intracellular tangles of hyperphosphorylated tau protein distributed throughout the neocortex, basal ganglia, and brainstem. A genome-wide association study identified EIF2AK3 as a risk factor for PSP. EIF2AK3 encodes PERK, part of the endoplasmic reticulum’s (ER) unfolded protein response (UPR). PERK is an ER membrane protein that senses unfolded protein accumulation within the ER lumen. Recently, several groups noted UPR activation in Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis, multiple system atrophy, and in the hippocampus and substantia nigra of PSP subjects. Here, we evaluate UPR PERK activation in the pons, medulla, midbrain, hippocampus, frontal cortex and cerebellum in subjects with PSP, AD, and in normal controls. Results We found UPR activation primarily in disease-affected brain regions in both disorders. In PSP, the UPR was primarily activated in the pons and medulla and to a much lesser extent in the hippocampus. In AD, the UPR was extensively activated in the hippocampus. We also observed UPR activation in the hippocampus of some elderly normal controls, severity of which positively correlated with both age and tau pathology but not with Aβ plaque burden. Finally, we evaluated EIF2AK3 coding variants that influence PERK activation. We show that a haplotype associated with increased PERK activation is genetically associated with increased PSP risk. Conclusions The UPR is activated in disease affected regions in PSP and the genetic evidence shows that this activation increases risk for PSP and is not a protective response.

OBJECTIVE: To asses differences between men and women in subcortical and neocortical cholinergic projection system integrity in Parkinson disease.

Parkinson's disease (PD) is a multisystem neurodegenerative disorder. Heterogeneous clinical features may reflect heterogeneous changes in different brain regions. In contrast to the pronounced nigrostriatal denervation characteristic of PD, cholinergic changes are less marked. We investigated cholinergic innervation activity in PD subjects relative to normal subjects. Nondemented PD subjects ( n=101, age 65.3±7.2 years) and normal subjects ( n=29, age 66.8±10.9 years) underwent clinical assessment and [ 11 C]methyl-4-piperidinyl propionate acetylcholinesterase and [ 11 C]dihydrotetrabenazine monoaminergic positron emission tomography (PET) imaging. Cholinergic projection changes were heterogeneous for 65 out of 101 PD subjects who had neocortical and thalamic acetylcholinesterase activity within the normal range. The remainder had combined neocortical and thalamic (13/101), isolated neocortical (18/101), or isolated thalamic (5/101) acetylcholinesterase activity below the normal range. The low neocortical acetylcholinesterase activity subgroup had significantly lower global cognitive performance compared with the normal range subgroup (F=7.64, P=0.0069) with an independent effect for nigrostriatal denervation (F=7.60, P=0.0074). The low thalamic acetylcholinesterase activity subgroup did not differ from the normal thalamic acetylcholinesterase activity subgroup in cognitive performance or motor impairments except for a history of falls ( P=0.0023). Cholinergic denervation is heterogeneous with reduced neocortical and/or thalamic acetylcholinesterase activity in 36% of nondemented PD subjects with corresponding clinical phenotypic variation. Results also show independent cognitive effects for both cholinergic and dopaminergic system changes in nondemented PD subjects.

The unfolded protein response (UPR), an indicator and modulator of ER stress, is triggered by the presence of mis- or unfolded proteins in the ER lumen and is comprised of three stress sensors: Ire1, ATF6, and PERK. The PERK arm of the UPR has both adaptive and apoptotic effects, depending on the duration of ER stress. The UPR is activated in several neurodegenerative tauopathies, including Alzheimer's disease (AD), Multiple System Atrophy and Progressive Supranuclear Palsy (PSP). A recent genome-wide association study for PSP indicated that the gene encoding the PERK protein is a risk factor for PSP. Our goal for this study was to compare PERK activation in a panel of brain areas sampled from AD and PSP patients, as well as normal controls to determine the relative strength and localization of this stress response across tauopathies. We assayed post-mortem brain tissue from AD patients, PSP patients and normal controls for activation of PERK and its downstream effector eIF2α. Using immunohistochemistry, we stained a panel of six brain areas for activated PERK (pPERK) and activated eIF2α (peIF2α): hippocampus, mid-frontal cortex, midbrain, pons, medulla and folia of the cerebellum. We also used double immunofluorescence to assay the hippocampus and the pons for pPERK and hyperphosphorylated tau (htau). Brains affected by AD had the strongest PERK activation in the hippocampus, followed by the mid-frontal cortex and then the three brainstem regions. Conversely, PSP-affected brains had the strongest PERK activation in the pons and the medulla, followed by the midbrain and the hippocampus. PERK was also activated in the hippocampus of clinically normal controls, and the degree of this activation correlated with advancing age and tau burden. pPERK tended to colocalize with diffuse, pre-fibrillar htau but not with full-blown tangles.