Elucidating the genetic contributions to Parkinson's disease aetiology across diverse ancestries is a critical priority for the development of targeted therapies in a global context. We conducted the largest sequencing characterization of potentially disease-causing, protein-altering and splicing mutations in 710 cases and 11 827 controls from genetically predicted African or African admixed ancestries. We explored copy number variants (CNVs) and runs of homozygosity in prioritized early onset and familial cases. Our study identified rare GBA1 coding variants to be the most frequent mutations among patients with Parkinson's disease, with a frequency of 4% in our case cohort. Of the 18 GBA1 variants identified, 10 were previously classified as pathogenic or likely pathogenic, four were novel and four were reported as of uncertain clinical significance. The most common known disease-associated GBA1 variants in the Ashkenazi Jewish and European populations, p.Asn409Ser, p.Leu483Pro, p.Thr408Met and p.Glu365Lys, were not identified among the screened Parkinson's disease cases of African and African admixed ancestry. Similarly, the European and Asian LRRK2 disease-causing mutational spectrum, including LRRK2 p.Gly2019Ser and p.Gly2385Arg genetic risk factors, did not appear to play a major role in Parkinson's disease aetiology among West African ancestry populations. However, we found three heterozygous novel missense LRRK2 variants of uncertain significance, with two (p.Glu268Ala and p.Arg1538Cys) displaying higher frequencies in the African ancestry population reference datasets. Structural variant analyses revealed the presence of PRKN CNVs with a frequency of 0.7% in African and African admixed cases, with 66% of CNVs detected being compound heterozygous or homozygous in early-onset cases, providing further insights into the genetic underpinnings in early-onset juvenile Parkinson's disease in these populations. Short tandem repeat analysis also identified ATXN3 CAG repeat expansions within the pathogenic range (CAGn > 45) in three patients with Parkinson's disease of African ancestry. Novel genetic variation among screened genes warrants further replication and functional prioritization to unravel their pathogenic potential. Here, we created the most comprehensive genetic catalogue of both known and novel coding and splicing variants potentially linked to Parkinson's disease aetiology in an underserved population and further conducted global and local ancestry analyses to further explore population-specific effects. Our study has the potential to guide the development of targeted therapies in the emerging era of precision medicine. By expanding genetics research to involve underrepresented populations, we hope that future Parkinson's disease treatments are not only effective but also inclusive, addressing the needs of diverse ancestral groups.

People with advanced Parkinson’s disease (aPD) frequently experience unpredictable “Off” time and debilitating motor fluctuations. Foslevodopa/foscarbidopa (LDp/CDp), a levodopa/carbidopa (LD/CD) prodrug, is delivered as a 24-h continuous subcutaneous infusion. This post hoc analysis evaluated the efficacy of LDp/CDp in achieving consistent motor symptom control and stable motor states in people with aPD. Diaries of people with aPD treated with LDp/CDp participating in a 12-week, phase 3, randomized controlled trial (RCT) were evaluated versus oral LD/CD, and in a 52-week open-label, single-arm trial (OLT) with LDp/CDp alone. Motor symptom control was assessed by frequency (30-min intervals) and duration (4-h blocks) of motor states (good “On” time [without dyskinesia or troublesome dyskinesia] or “Off” time) over a 16-h waking day. Motor state stability was evaluated by changes in daily motor fluctuations and extreme fluctuations (defined as transition from “Off” to “On” with troublesome dyskinesia, or vice versa). Outcomes were analyzed using adjusted regression models. Analysis included 47 (RCT) and 55 (OLT) people with aPD on LDp/CDp. In the RCT, LDp/CDp had an approximately 1-h gain in good “On” time in the mornings versus a quarter-hour gain for those on LD/CD (P = 0.001), with > 80

A role of the immune system in Parkinson's disease (PD) progression has long been suspected due to the increased frequency of activated glial cells and infiltrating T cells in the substantia nigra. It was previously reported that PD donors have increased T cell responses towards PINK1 and α-synuclein (α-syn), two Lewy body-associated proteins. Further, T cell reactivity towards α-syn was highest closer to disease onset, highlighting that autoreactive T cells might play a role in PD pathogenesis. However, whether T cell autoreactivity is present during prodromal PD is unknown. Here, we investigated T cell responses towards PINK1 and α-syn in donors at high risk of developing PD (i.e. prodromal PD: genetic risk, hyposmia, and or REM sleep behavior disorder), in comparison to PD and healthy control donors. T cell reactivity to these two autoantigens was detected in prodromal PD at levels comparable to those detected in individuals with clinically diagnosed PD. Aligned with the increased incidence of PD in males, we found that males with PD, but not females, had elevated T cell reactivity compared to healthy controls. However, among prodromal PD donors, males and females had elevated T cell responses. These differing trends in reactivity highlights the need for further studies of the impact of biological sex on neuroinflammation and PD progression.

OBJECTIVE:Stereotactic radiosurgery (SRS) is an effective treatment for refractory tremor. However, the lack of reliable patient-specific targeting biomarkers leads to varying outcomes. Although connectomic-based targeting is commonly used in deep brain stimulation, its application in SRS is limited. This study aimed to develop a new targeting approach by using patient-specific structural connectivity to improve outcomes after SRS. METHODS:The authors performed a retrospective study of patients in a prospective trial for frameless virtual-cone SRS on a linear accelerator for essential tremor or tremor-dominant Parkinson disease. The primary endpoint was percentage improvement in Fahn-Tolosa-Marin tremor rating scale scores contralateral to the treatment side. Probabilistic tractography assessed connectivity from each thalamic voxel to the primary motor cortex (M1), primary sensory cortex (S1), and supplemental motor area/premotor cortex (SMA/PMC). Group-level comparisons were conducted to evaluate the relationship between the sweet spot for maximum contralateral tremor improvement and areas maximally connected to M1, S1, and SMA/PMC. Multiple regression analysis assessed the relationship between the lesion centerpoint coordinates and the maximally connected voxel to M1, S1, and SMA/PMC at the individual level. RESULTS:The analysis included 27 patients with a mean follow-up of 17.9 ± 11.1 months. The sweet spot for maximal contralateral tremor improvement at the group level was in the region most connected to M1 cortex. Smaller y-distances (anterior-posterior) from the lesion center to the M1 maximally connected voxel significantly correlated with tremor improvement at the single-subject level (p < 0.001). However, the authors found no significant correlation between the lesion y-coordinate and the maximally connected voxel to SMA/PMC and S1, nor between the x-distances from the lesions to the SMA/PMC, M1, and S1 voxels (p > 0.07). CONCLUSIONS:This study demonstrates that patient-specific connectivity between the treatment target and M1 correlates with treatment outcomes. The authors' approach provides a practical targeting method for SRS thalamotomy for tremor.

BACKGROUND:As Parkinson's disease (PD) progresses, managing symptoms becomes increasingly difficult. Foslevodopa/foscarbidopa (LDp/CDp), a 24-hour/day continuous subcutaneous infusion of levodopa/carbidopa (LD/CD) prodrugs, improves motor complications. The feasibility and sustainability of LDp/CDp monotherapy warrants investigation. OBJECTIVE:The aim was to report the efficacy and safety of LDp/CDp monotherapy and combination therapy. METHODS:This post hoc analysis assessed patients with PD and ≥2.5 "Off" hours/day receiving LDp/CDp monotherapy or combination therapy in 3 trials: a 12-week randomized active-controlled trial (RCT) comparing LDp/CDp with oral immediate-release LD/CD (NCT04380142), a 52-week open-label trial of LDp/CDp (NCT03781167), and its 96-week open-label extension study (OLE; NCT04379050). Monotherapy was defined as receiving LDp/CDp without concomitant PD medications; combination therapy was defined as receiving LDp/CDp with other PD medications. RESULTS:In the RCT, 74 of 141 patients received LDp/CDp. The 52-week trial enrolled 244 patients; 129 entered the OLE. Of LDp/CDp-treated patients, 19 of 74 (25.7%) in the RCT, 49 of 244 (20.1%) in the 52-week trial, and 46 of 129 (35.7%) in the OLE received monotherapy. In the RCT, mean (standard deviation) change from baseline to week 12 in "Off" time was -4.5 (4.4) and -3.0 (3.5) hours for monotherapy and combination therapy, respectively; +4.1 (3.7) and +3.1 (3.6) hours for "On" time without troublesome dyskinesia; and +4.0 (3.6) and +4.0 (3.9) hours for "On" time without dyskinesia. Efficacy was similar in open-label trials. Improvements in the Movement Disorder Society-Unified Parkinson's Disease Rating Scale Part II, 39-item Parkinson's Disease Questionnaire, Parkinson's Disease Sleep Scale-2 scores, and overall safety were comparable between monotherapy and combination therapy groups. CONCLUSIONS:LDp/CDp monotherapy treatment may be suitable for up to 96 weeks.

ObjectiveTo examine if immune cell changes are present in early stages of Dementia with Lewy Bodies (DLB).BackgroundEvidence for inflammation in synucleinopathies has been building. An extensive number of studies have documented inflammatory changes in Parkinson’s disease (PD), but much less is known about DLB. Post-mortem DLB brains show T-cell infiltration, and flow cytometry and cytokine/chemokine measures in DLB subjects have suggested the presence of inflammatory responses in DLB. However, there is limited understanding if immune cell changes are present at the earliest stages of DLB.MethodsWe recruited a small, exploratory cohort of nine subjects with Mild Cognitive Impairment—Lewy Bodies (MCI-LB) as part of the broader Alabama Udall cohort study, which is focused on the role of inflammation in early PD. The MCI-LB cohort was compared to subjects with de novo PD (n = 64) and healthy controls (n = 70) from the larger Alabama Udall cohort. Subjects underwent clinical assessments, including Movement Disorder Society-United Parkinson’s Disease rating scale (MDS-UPDRS), and comprehensive cognitive assessment. Blood was obtained for flow cytometry and cytokine/chemokine analyses.ResultsDemographics and medical history were comparable between groups. Significant differences in University of Pennsylvania Smell Identification Test, Schwab and England Activities of Daily Living, and MDS-UPDRS scores were observed between the groups. MCI-LB subjects had poorer cognitive composite scores compared to PD participants. MCI-LB subjects demonstrated a robust 60% reduction in mature neutrophils compared to healthy controls.ConclusionOur data show changes in innate immune cells in MCI-LB compared to healthy controls in this small exploratory study. A larger cohort study is needed to validate these findings.

Objective To understand what Parkinson’s Disease (PD) patients report in their own words about their mood and anxiety problems using the Parkinson’s Disease Patient Report of Problems (PD-PROP). Methods Patient-reported data from the PD-PROP (reporting most bothersome problems due to PD in their own words), Geriatric Depression Scale, MDS-UPDRS II, and the Euro-Q0L from the Fox Insight research database https://foxinsight.michaeljfox.org/ were examined using cross-sectional comparisons and logistic regression analyses to characterize non-depressive mood symptoms and anxiety. Results We identified 21,487 participants who completed at least one PD-PROP questionnaire. Four categories of non-depressive mood symptoms (Anxiety/Worry, Loneliness/Isolation, Negative Emotions NOS (Not Otherwise Specified), Death/Suicidal Ideation) were identified. Women were much more likely than men to report non-depressive mood symptoms as a bothersome PD-related problem. The frequency of Anxiety/Worry reporting decreased with longer duration of PD while Loneliness/Isolation increased. More severe PD motor impairment, as measured by the MDS-UPDRS II, was associated with increased reporting of Negative Emotions and Loneliness/Isolation. Higher Euro-QoL, indicating better quality of life, was associated with decreased reporting of Loneliness/Isolation. Death/Suicidal Ideation was only reported by a small number of participants (<0.5%). Conclusions Women were more likely than men with PD to identify Anxiety/Worry, Negative Emotions, and Loneliness/Isolation as problems. This finding and the higher prevalence of bothersome loneliness/isolation as PD duration increases can guide monitoring for these issues.

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. Parkinson’s diseases and other synucleinopathies are on the verge of a major paradigm shift toward being defined and staged by their biology, rather than symptoms; this Perspective offers context on progress, needs and opportunities toward this goal.

Growing evidence indicates that persons with Parkinson disease (PD), have a unique composition of indigenous gut microbes. Given the long prodromal or pre-diagnosed period, longitudinal studies of the human and rodent gut microbiome before symptomatic onset and for the duration of the disease are currently lacking. PD is partially characterized by the accumulation of the protein α-synuclein (α-syn) into insoluble aggregates, in both the central and enteric nervous systems. As such, several experimental rodent and non-human primate models of α-syn overexpression recapitulate some of the hallmark pathophysiologies of PD. These animal models provide an opportunity to assess how the gut microbiome changes with age under disease-relevant conditions. Here, we used a transgenic mouse strain, which overexpress wild-type human α-syn to test how the gut microbiome composition responds in this model of PD pathology during aging. Using shotgun metagenomics, we find significant, age and genotype-dependent bacterial taxa whose abundance becomes altered with age. We reveal that α-syn overexpression can drive alterations to the gut microbiome composition and suggest that it limits diversity through age. Taxa that were most affected by genotype-age interaction were Lactobacillus and Bifidobacteria. In a mouse model, we showed direct link between alpha synuclein geneotype (hallmark of PD), a dysbiotic and low-diversity gut microbiome, and dysbiotic levels of Bifidobacteria and Lactobacillus (most robust features of PD microbiome). Given emerging data on the potential contributions of the gut microbiome to PD pathologies, our data provide an experimental foundation to understand how the PD-associated microbiome may arise as a trigger or co-pathology to disease.

PURPOSE OF REVIEW:to review recent progress in the development and use of continuous levodopa therapies in Parkinson disease (PD). RECENT FINDINGS:Levodopa/Carbidopa intestinal gel (LCIG) is a continuous levodopa therapy which is widely used in the United States, Europe and other countries and is effective at reducing 'off' time. Recent work has shown that LCIG can be useful in managing dyskinesias and can improve nonmotor symptoms and quality of life. Several studies have shown good long-term effectiveness of LCIG. Recent data support the cost-effectiveness of this treatment strategy. Subcutaneous (SC) delivery of levodopa is a newer strategy that avoids the need for a surgically placed gastric tube. Two different products enabling SC delivery of levodopa are in development: ND0612 and foslevodopa/foscarbidopa. Both have recently been shown to reduce 'off' time in randomized, double-blind trials. Adverse effects of SC levodopa are primarily related to skin reactions at the infusion site. SUMMARY:Continuous levodopa therapies can be used to treat Parkinson disease motor fluctuations that cannot be managed with standard oral therapies. They may also improve nonmotor symptoms, and improve overall quality of life in patients with advanced PD.

Parkinson’s disease (PD) carries substantial psychosocial burden. Using a database of responses by people with PD reporting up to five “most bothersome problems,” we identified 225 fear-based verbatims, which were organized using the framework method into 26 categories. Commonly-reported fears included uncertainty of progression ( n = 60, 26.7%), fear of future cognitive impairment ( n = 24, 10.7%) and fear of becoming a burden on others ( n = 23, 10.2%). Fears in PD are wide-ranging and can constitute the most bothersome aspect of the condition. These data can be used to design interventions to lessen the psychosocial burden of PD.

Background: Early identification of subjective cognitive complaints (SCC) in Parkinson's disease (PD) may improve patient care if it predicts cognition-related functional impairment (CFI). Objectives: The aim was to determine the cross-sectional and longitudinal association between SCC and CFI in PD. Methods: Data were obtained from Fox Insight, an online longitudinal study that collects PD patient-reported outcomes. Participants completed a PD Patient Report of Problems that asked participants for their five most bothersome disease problems. SCCs were placed into eight categories through human-in-the-loop curation and classification. CFI had a Penn Parkinson's Daily Activities Questionnaire (PDAQ-15) score <= 49. Cox proportional hazards models and Kaplan-Meier survival analyses determined if baseline SCC was associated with incident CFI. Results: The PD-PROP cohort (N = 21,160) was 55.8% male, mean age was 65.9 years, and PD duration was 4.8 years. At baseline, 31.9% (N = 6750) of participants reported one or more SCCs among their five most bothersome problems, including memory (13.2%), language/word finding (12.5%), and concentration/attention (9.6%). CFI occurred in 34.7% (N = 7332) of participants. At baseline, SCC was associated with CFI (P-value <0.001). SCC at baseline was associated with incident CFI (hazard ratio [HR] = 1.58 [95% confidence interval: 1.45, 1.72], P-value <0.001), as did cognitive impairment not otherwise specified (HR = 2.31), executive abilities (HR = 1.97), memory (HR = 1.85), and cognitive slowing (HR = 1.77) (P-values <0.001). Kaplan-Meier curves showed that by year 3 an estimated 45% of participants with any SCC at baseline developed new-onset CFI. Conclusions :Self-reported bothersome cognitive complaints are associated with new-onset CFI in PD. Remote electronic assessment can facilitate widespread use of patient self-report at population scale. (c) 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Altered interaction between striatonigral dopaminergic (DA) inputs and local acetylcholine (ACh) in striatum has long been hypothesized to play a central role in the pathophysiology of dystonia and dyskinesia. Indeed, previous research using several genetic mouse models of human isolated dystonia identified a shared endophenotype with paradoxical excitation of striatal cholinergic interneuron (ChIs) activity in response to activation of dopamine D2 receptors (D2R). These mouse models lack a dystonic motor phenotype, which leaves a critical gap in comprehending the role of DA and ACh transmission in the manifestations of dystonia. To tackle this question, we used a combination of ex vivo slice physiology and in vivo monitoring of striatal ACh dynamics in the inducible, phenotypically penetrant, transgenic mouse model of paroxysmal non-kinesiogenic dyskinesia (PNKD), an animal with both dystonic and dyskinetic features. We found that, similarly to genetic models of isolated dystonia, the PNKD mouse displays D2R-induced paradoxical excitation of ChI firing in ex vivo striatal brain slices. In vivo, caffeine triggers dystonic symptoms while reversing the D2R-mediated excitation of ChIs and desynchronizing ACh release in PNKD mice. In WT littermate controls, caffeine stimulates spontaneous locomotion through a similar but reversed mechanism involving an excitatory switch of the D2R control of ChI activity, associated with enhanced synchronization of ACh release. These observations suggest that the “paradoxical excitation” of cholinergic interneurons described in isolated dystonia models could represent a compensatory or protective mechanism that prevents manifestation of movement abnormalities and that phenotypic dystonia is possible only when this is absent. These findings also suggest that D2Rs may play an important role in synchronizing the ChI network leading to rhythmic ACh release during heightened movement states. Dysfunction of this interaction and corresponding desynchrony of ACh release may contribute to aberrant movements.

Basic Science is crucial for the advancement of clinical care for Movement Disorders. Here, we provide brief updates on how basic science is important for understanding disease mechanisms, disease prevention, disease diagnosis, development of novel therapies and to establish the basis for personalized medicine. We conclude the viewpoint by a call to action to further improve interactions between clinician and basic scientists. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Background LRRK2-targeting therapeutics that inhibit LRRK2 kinase activity have advanced to clinical trials in idiopathic Parkinson's disease (iPD). LRRK2 phosphorylates Rab10 on endolysosomes in phagocytic cells to promote some types of immunological responses. The identification of factors that regulate LRRK2-mediated Rab10 phosphorylation in iPD, and whether phosphorylated-Rab10 levels change in different disease states, or with disease progression, may provide insights into the role of Rab10 phosphorylation in iPD and help guide therapeutic strategies targeting this pathway.Methods Capitalizing on past work demonstrating LRRK2 and phosphorylated-Rab10 interact on vesicles that can shed into biofluids, we developed and validated a high-throughput single-molecule array assay to measure extracellular pT73-Rab10. Ratios of pT73-Rab10 to total Rab10 measured in biobanked serum samples were compared between informative groups of transgenic mice, rats, and a deeply phenotyped cohort of iPD cases and controls. Multivariable and weighted correlation network analyses were used to identify genetic, transcriptomic, clinical, and demographic variables that predict the extracellular pT73-Rab10 to total Rab10 ratio.Results pT73-Rab10 is absent in serum from Lrrk2 knockout mice but elevated by LRRK2 and VPS35 mutations, as well as SNCA expression. Bone-marrow transplantation experiments in mice show that serum pT73-Rab10 levels derive primarily from circulating immune cells. The extracellular ratio of pT73-Rab10 to total Rab10 is dynamic, increasing with inflammation and rapidly decreasing with LRRK2 kinase inhibition. The ratio of pT73-Rab10 to total Rab10 is elevated in iPD patients with greater motor dysfunction, irrespective of disease duration, age, sex, or the usage of PD-related or anti-inflammatory medications. pT73-Rab10 to total Rab10 ratios are associated with neutrophil degranulation, antigenic responses, and suppressed platelet activation.Conclusions The extracellular serum ratio of pT73-Rab10 to total Rab10 is a novel pharmacodynamic biomarker for LRRK2-linked innate immune activation associated with disease severity in iPD. We propose that those iPD patients with higher serum pT73-Rab10 levels may benefit from LRRK2-targeting therapeutics that mitigate associated deleterious immunological responses.

L -DOPA-induced dyskinesia (LID) is a debilitating motor side effect arising from chronic dopamine (DA) replacement therapy with L -DOPA for the treatment of Parkinson ' s disease. LID is associated with supersensitivity of striatal dopaminergic signaling and fl uctuations in synaptic DA following each L -DOPA dose, shrinking the therapeutic window. The heterogeneous composition of the striatum, including subpopulations of medium spiny output neurons (MSNs), interneurons, and supporting cells, complicates the identi fi cation of cell(s) underlying LID. We used single -nucleus RNA sequencing (snRNA-seq) to establish a comprehensive striatal transcriptional pro fi le during LID development. Male hemiparkinsonian mice were treated with vehicle or L -DOPA for 1, 5, or 10 d, and striatal nuclei were processed for snRNA-seq. Analyses indicated a limited population of DA D1 receptor - expressing MSNs (D1-MSNs) formed three subclusters in response to L -DOPA treatment and expressed cellular markers of activation. These activated D1-MSNs display similar transcriptional changes previously associated with LID; however, their prevalence and transcriptional behavior were differentially in fl uenced by L -DOPA experience. Differentially expressed genes indicated acute upregulation of plasticity -related transcription factors and mitogen-activated protein kinase signaling, while repeated L -DOPA-induced synaptic remodeling, learning and memory, and transforming growth factor - (3 (TGF- (3 ) signaling genes. Notably, repeated L -DOPA sensitized Inhba , an activin subunit of the TGF- (3 superfamily, in activated D1-MSNs, and its pharmacological inhibition impaired LID development, suggesting that activin signaling may play an essential role in LID. These data suggest distinct subsets of D1-MSNs become differentially L -DOPA-responsive due to aberrant induction of molecular mechanisms necessary for neuronal entrainment, similar to processes underlying hippocampal learning and memory.