Faculty Bibliography

Cerebral accumulation of alpha-synuclein (αSyn) aggregates is the hallmark event in a group of neurodegenerative diseases-collectively called synucleinopathies-which include Parkinson's disease, dementia with Lewy bodies and multiple system atrophy. Currently, these are diagnosed by their clinical symptoms and definitively confirmed postmortem by the presence of αSyn deposits in the brain. Here, we summarize the drawbacks of the current clinical definition of synucleinopathies and outline the rationale for moving toward an earlier, biology-anchored definition of these disorders, with or without the presence of clinical symptoms. We underscore the utility of the αSyn seed amplification assay to detect aggregated αSyn in living patients and to differentiate between neuronal or glial αSyn pathology. We anticipate that a biological definition of synucleinopathies, if well-integrated with the current clinical classifications, will enable further understanding of the disease pathogenesis and contribute to the development of effective, disease-modifying therapies.

BACKGROUND:α-Synuclein seed amplification assay on cerebrospinal fluid (CSF-αSyn-SAA) has shown high accuracy for Parkinson's disease (PD) diagnosis. The analysis of CSF-αSyn-SAA parameters may provide useful insight to dissect the heterogeneity of synucleinopathies. OBJECTIVE:To assess differences in CSF-αSyn-SAA amplification parameters in participants with PD stratified by rapid eye movement (REM) sleep behavior disorder (RBD), dysautonomia, GBA, and LRRK2 variants. METHODS:(T50), time to threshold (TTT), slope, and area under the curve (AUC). Sporadic PD (n = 371) was stratified according to RBD and dysautonomia (DysA) symptoms. Genetic PD included carriers of pathogenic variants of GBA (GBA-PD, n = 52) and LRRK2 (LRRK2-PD, n = 124) gene. RESULTS:CSF-αSyn-SAA was positive in 77% of LRRK2-PD, 92.3% of GBA-PD, and 93.8% of sporadic PD. The LRRK2-PD cohort showed longer T50 and TTT, and smaller AUC than GBA-PD (P = 0.029, P = 0.029, P = 0.016, respectively) and sporadic PD (P = 0.034, P = 0.033, P = 0.014, respectively). In the sporadic cohort, CSF-αSyn-SAA parameters were similar between PD with (n = 157) and without (n = 190) RBD, whereas participants with DysA (n = 193) presented shorter T50 (P = 0.026) and larger AUC (P = 0.029) than those without (n = 150). CONCLUSION/CONCLUSIONS:CSF-αSyn-SAA parameters vary across genetic and non-genetic PD subtypes at the group level. These differences are mostly driven by the presence of LRRK2 variants and DysA. Significant overlaps in the amplification parameter values exist between groups and limit their use at the individual level. Further studies are necessary to understand the mechanisms of CSF-αSyn-SAA parameter differences. © 2024 International Parkinson and Movement Disorder Society.

BACKGROUND:The pathological hallmarks of multiple system atrophy and Parkinson's disease are, respectively, misfolded-α-synuclein-laden glial cytoplasmic inclusions and Lewy bodies. CSF-soluble misfolded α-synuclein aggregates (seeds) are readily detected in people with Parkinson's disease by α-synuclein seed amplification assay (synSAA), but identification of seeds associated with multiple system atrophy for diagnostic purposes has proven elusive. We aimed to assess whether a novel synSAA could reliably distinguish seeds from Lewy bodies and glial cytoplasmic inclusions. METHODS:In this multicentre cohort study, a novel synSAA that multiplies and detects seeds by fluorescence was used to analyse masked CSF and brain samples from participants with either clinically diagnosed or pathology-confirmed multiple system atrophy, Parkinson's disease, dementia with Lewy bodies, isolated rapid eye movement sleep behaviour disorder (IRBD), disorders that were not synucleinopathies, or healthy controls. Participants were from eight available cohorts from seven medical centres in four countries: New York Brain Bank, New York, USA (NYBB); University of Pennsylvania, Philadelphia, PA, USA (UPENN); Paracelsus-Elena-Klinik, Kassel, Germany (DeNoPa and KAMSA); Hospital Clinic Barcelona, Spain (BARMSA); Universität Tübingen, Tübingen, Germany (EKUT); Göteborgs Universitet, Göteborgs, Sweden (UGOT); and Karolinska Institutet, Stockholm, Sweden (KIMSA). Clinical cohorts were classified for expected diagnostic accuracy as either research (longitudinal follow-up visits) or real-life (single visit). Sensitivity and specificity were estimated according to pathological (gold standard) and clinical (reference standard) diagnoses. FINDINGS/RESULTS:In 23 brain samples (from the NYBB cohort), those containing Lewy bodies were synSAA-positive and produced high fluorescence amplification patterns (defined as type 1); those containing glial cytoplasmic inclusions were synSAA-positive and produced intermediate fluorescence (defined as type 2); and those without α-synuclein pathology produced below-threshold fluorescence and were synSAA-negative. In 21 pathology-confirmed CSF samples (from the UPENN cohort), those with Lewy bodies were synSAA-positive type 1; those with glial cytoplasmic inclusions were synSAA-positive type 2; and those with four-repeat tauopathy were synSAA-negative. In the DeNoPa research cohort (which had no samples from people with multiple system atrophy), the novel synSAA had sensitivities of 95% (95% CI 88-99) for 80 participants with Parkinson's disease and 95% (76-100) for 21 participants with IRBD, and a specificity of 95% (86-99) for 60 healthy controls. Overall (combining BARMSA, EKUT, KAMSA, UGOT, and KIMSA cohorts that were enriched for cases of multiple system atrophy), the novel synSAA had 87% sensitivity for multiple system atrophy (95% CI 80-93) and specificity for type 2 seeds was 77% (67-85). For participants with multiple system atrophy just in research cohorts (BARMSA and EKUT), the novel synSAA had a sensitivity of 84% (95% CI 71-92) and a specificity for type 2 seeds of 87% (74-95), whereas cases from real-life cohorts (KAMSA, KIMSA, and UGOT) had a sensitivity of 91% (95% CI 80-97) but a decreased specificity for type 2 seeds of 68% (53-81). INTERPRETATION/CONCLUSIONS:The novel synSAA produced amplification patterns that enabled the identification of underlying α-synuclein pathology, showing two levels of fluorescence that corresponded with different pathological hallmarks of synucleinopathy. The synSAA might be useful for early diagnosis of synucleinopathies in clinical trials, and potentially for clinical use, but additional formal validation work is needed. FUNDING/BACKGROUND:Michael J Fox Foundation for Parkinson's Research, Amprion.

The development of disease-modifying therapies (DMTs) for neurological disorders is an important goal in modern neurology, and the associated challenges are similar in many chronic neurological conditions. Major advances have been made in the multiple sclerosis (MS) field, with a range of DMTs being approved for relapsing MS and the introduction of the first DMTs for progressive MS. By contrast, people with Parkinson disease (PD) still lack such treatment options, relying instead on decades-old therapeutic approaches that provide only symptomatic relief. To address this unmet need, an in-person symposium was held in Toronto, Canada, in November 2022 for international researchers and experts in MS and PD to discuss strategies for advancing DMT development. In this Roadmap article, we highlight discussions from the symposium, which focused on therapeutic targets and preclinical models, disease spectra and subclassifications, and clinical trial design and outcome measures. From these discussions, we propose areas for novel or deeper exploration in PD using lessons learned from therapeutic development in MS. In addition, we identify challenges common to the PD and MS fields that need to be addressed to further advance the discovery and development of effective DMTs.

BACKGROUND:Long-term use of levodopa for Parkinson's disease (PD) treatment is often hindered by development of motor complications, including levodopa-induced dyskinesia (LID). The substantia nigra pars reticulata (SNr) and globus pallidus internal segment (GPi) are the output nuclei of the basal ganglia. Dysregulation of SNr and GPi activity contributes to PD pathophysiology and LID. OBJECTIVE:The objective of this study was to determine whether direct modulation of SNr GABAergic neurons and SNr projections to the pedunculopontine nucleus (PPN) regulates PD symptoms and LID in a mouse model. METHODS:We expressed Cre-recombinase activated channelrhodopsin-2 (ChR2) or halorhodopsin adeno-associated virus-2 (AAV2) vectors selectively in SNr GABAergic neurons of Vgat-IRES-Cre mice in a 6-hydroxydopamine model of PD to investigate whether direct optogenetic modulation of SNr neurons or their projections to the PPN regulates PD symptoms and LID expression. The forepaw stepping task, mouse LID rating scale, and open-field locomotion were used to assess akinesia and LID to test the effect of SNr modulation. RESULTS:Akinesia was improved by suppressing SNr neuron activity with halorhodopsin. LID was significantly reduced by increasing SNr neuronal activity with ChR2, which did not interfere with the antiakinetic effect of levodopa. Optical stimulation of ChR2 in SNr projections to the PPN recapitulated direct SNr stimulation. CONCLUSIONS:Modulation of SNr GABAergic neurons alters akinesia and LID expression in a manner consistent with the rate model of basal ganglia circuitry. Moreover, the projections from SNr to PPN likely mediate the antidyskinetic effect of increasing SNr neuronal activity, identifying a potential novel role for the PPN in LID. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

INTRODUCTION/BACKGROUND:Impaired autophagy is a pathogenic mechanism in the synucleinopathies. Sirolimus, a potent mTOR inhibitor and autophagy activator, had no beneficial effects in a randomized placebo-controlled trial in patients with multiple system atrophy (MSA). Whether sirolimus effectively inhibited brain mTOR activity was unknown. We aimed to evaluate if patients with MSA treated with sirolimus had evidence of inhibited brain mTOR pathways by measuring neuron-derived serum extracellular vesicles (NEVs). METHODS:Serum samples were collected from participants of the sirolimus-MSA trial, which randomized patients to sirolimus (2-6 mg/day) or placebo for 48 weeks. NEVs were immunoprecipitated with three antibodies-against neurons. Brain mTOR engagement was quantified as the change in the NEV phosphorylated mTOR (p-mTOR) to total-mTOR (tot-mTOR) ratio after 48 weeks of sirolimus. RESULTS:Samples from 27 patients [mean (±SD) age, 59.2±7 years, 15 (55.5%) men] were analyzed (19 sirolimus, 8 placebo). Treated- and placebo-patients had similar p-mTOR:tot-mTOR ratio at 24 (placebo: 0.248 ± 0.03, sirolimus: 0.289 ± 0.02; P = 0.305) and 48 weeks (placebo: 0.299 ± 0.05, sirolimus: 0.261 ± 0.03; P = 0.544). The tot-mTOR, p-mTOR, or their ratio levels were not associated with Unified MSA Rating Scale (UMSARS) worsening. DISCUSSION/CONCLUSIONS:These results are consistent with no brain mTOR engagement by oral sirolimus up to 6 mg/day. NEV-based biomarkers are a rational approach to investigating target engagement in clinical trials of brain-targeted therapeutics.

BACKGROUND:To date, no medication has slowed the progression of Parkinson's disease (PD). Preclinical, epidemiological, and experimental data on humans all support many benefits of endurance exercise among persons with PD. The key question is whether there is a definitive additional benefit of exercising at high intensity, in terms of slowing disease progression, beyond the well-documented benefit of endurance training on a treadmill for fitness, gait, and functional mobility. This study will determine the efficacy of high-intensity endurance exercise as first-line therapy for persons diagnosed with PD within 3 years, and untreated with symptomatic therapy at baseline. METHODS:This is a multicenter, randomized, evaluator-blinded study of endurance exercise training. The exercise intervention will be delivered by treadmill at 2 doses over 18 months: moderate intensity (4 days/week for 30 min per session at 60-65% maximum heart rate) and high intensity (4 days/week for 30 min per session at 80-85% maximum heart rate). We will randomize 370 participants and follow them at multiple time points for 24 months. The primary outcome is the Movement Disorders Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) motor score (Part III) with the primary analysis assessing the change in MDS-UPDRS motor score (Part III) over 12 months, or until initiation of symptomatic antiparkinsonian treatment if before 12 months. Secondary outcomes are striatal dopamine transporter binding, 6-min walk distance, number of daily steps, cognitive function, physical fitness, quality of life, time to initiate dopaminergic medication, circulating levels of C-reactive protein (CRP), and brain-derived neurotrophic factor (BDNF). Tertiary outcomes are walking stride length and turning velocity. DISCUSSION/CONCLUSIONS:SPARX3 is a Phase 3 clinical trial designed to determine the efficacy of high-intensity, endurance treadmill exercise to slow the progression of PD as measured by the MDS-UPDRS motor score. Establishing whether high-intensity endurance treadmill exercise can slow the progression of PD would mark a significant breakthrough in treating PD. It would have a meaningful impact on the quality of life of people with PD, their caregivers and public health. TRIAL REGISTRATION/BACKGROUND:ClinicalTrials.gov NCT04284436 . Registered on February 25, 2020.

Non-motor symptoms of Parkinson's disease (PD) such as dysautonomia and REM sleep behavior disorder (RBD) are recognized to be important prodromal symptoms that may also indicate clinical subtypes of PD with different pathogenesis. Unbiased clustering analyses showed that subjects with dysautonomia and RBD symptoms, as well as early cognitive dysfunction, have faster progression of the disease. Through analysis of the Parkinson's Progression Markers Initiative (PPMI) de novo PD cohort, we tested the hypothesis that symptoms of dysautonomia and RBD, which are readily assessed by standard questionnaires in an ambulatory care setting, may help to independently prognosticate disease progression. Although these two symptoms associate closely, dysautonomia symptoms predict severe progression of motor and non-motor symptoms better than RBD symptoms across the 3-year follow-up period. Autonomic system involvement has not received as much attention and may be important to consider for stratification of subjects for clinical trials and for counseling patients.