Movement Disorders

ObjectiveTo investigate the genetic etiology of dystonia-parkinsonism among individuals with parkinsonism who have dopamine transporter (DAT) SPECT scans without evidence of dopaminergic deficits (SWEDD). MethodsData for this case-control study were from the Parkinsons Progression Markers Initiative (PPMI) cohort, a multisite observational study. The sample analyzed included participants with whole genome sequencing (WGS) who were diagnosed as Parkinsons disease (PD, n=421), SWEDD (n=64) or healthy controls (HC, n=196). WGS data were analyzed to identify rare pathogenic variants in 30 dystonia-parkinsonism genes. Rare variants were prioritized for those present in individuals with SWEDD, but not in HC, reported pathogenicity in the literature and genetic databases, and with data from programs analyzing variant conservation and effect on protein function. For each SWEDD case with predicted or reported pathogenic variant(s), demographic, clinical, and imaging data were reviewed. ResultsEight of the 64 SWEDD participants (12.5%) had a pathogenic variant in one or more dystonia-parkinsonism genes, including PRKRA, SGCE, GLB1, ADCY5, SLC6A3, and GCDH. Notably, one case had a heterozygous variant in SGCE, p.R263H, which is predicted pathogenic but currently classified as a variant of uncertain significance due to insufficient evidence. ConclusionsPathogenic variants in parkinsonism-dystonia genes occurred in more than 10% of SWEDD cases in the PPMI cohort, supporting the importance of considering dystonia disorders in the differential diagnosis of PD, particularly in the case of participants with normal DAT SPECT scans. Analysis of genetic variants in parkinsonism-dystonia genes in SWEDD cases can provide information which will improve clinical diagnosis and management. KEY MESSAGESO_ST_ABSWhat is already known on this topicC_ST_ABSIndividuals with parkinsonism with scans without evidence of dopamine deficiency (SWEDD) constitute up to 16% of subjects with early parkinsonism referred for inclusion in multicenter observational studies and randomized clinical trials; however, the majority of these individuals do not have Parkinsons disease. Dystonic disorders are high on the list of differential diagnoses for individuals with parkinsonism and SWEDD, and an increasing number of studies support genetic etiologies for dystonic disorders. What proportion of individuals with parkinsonism and SWEDD referred for research studies might carry pathogenic variants in dystonia-parkinsonism related genes is not known. What this study addsThis study identified predicted or reported pathogenic variants in dystonia-parkinsonism related genes in more than 10% of SWEDD cases in the PPMI cohort, supporting the utility of evaluating dystonia-parkinsonism related genetic etiology in SWEDD cases. How this study might affect research, practice, or policyThis study supports the importance of genetic analyses in SWEDD cases which could improve clinical diagnosis and patient management.

Parkinsonism is a feature of several neurodegenerative disorders, including Parkinsons disease (PD), progressive supranuclear palsy (PSP), corticobasal degeneration syndrome (CBS) and multiple system atrophy (MSA). Neuroimaging studies have yielded insights into parkinsonism; however it remains unclear whether there is a common neural substrate amongst disorders. The aim of the present meta-analysis was to identify consistent brain alterations in parkinsonian disorders (PD, PSP, CBS, MSA) both individually, and combined, to elucidate the shared substrate of parkinsonism. 33,505 studies were systematically screened following searches of MEDLINE Complete and Embase databases. A series of whole-brain activation likelihood estimation meta-analyses were performed on 126 neuroimaging studies (64 PD; 25 PSP; 18 CBS; 19 MSA) utilizing anatomical MRI, perfusion or metabolism positron emission tomography and single photon emission computed tomography. Abnormality of the caudate, thalamus, middle frontal and temporal gyri was common to all parkinsonian disorders. Localizations of commonly affected brain regions in individual disorders aligned with current diagnostic imaging markers, localizing the midbrain in PSP, putamen in MSA-parkinsonian variant and brainstem in MSA-cerebellar variant. Regions of the basal ganglia and precuneus were most commonly affected in PD, while CBS was characterized by caudate abnormality. To our knowledge, this is the largest meta-analysis of neuroimaging studies in parkinsonian disorders. Findings support the notion that parkinsonism may share a common neural substrate, independent of the underlying disease process, while also highlighting characteristic patterns of brain abnormality in each disorder.

Introduction: GCH1 has been implicated in Parkinson's disease (PD), but its risks variants and associations are not well defined. Objectives: To investigate the clinical relevance and PD risk associated with the GCH1 p.Ser80Asn variant. Methods: We first identified a segregating GCH1 p.Ser80Asn variant in a Malaysian Chinese PD family via whole genome sequencing (WGS). We assessed its risk association using multi-ancestry WGS data from the Global Parkinson's Genetics Program (GP2) (n=22,372PD vs n=8,826Controls) and meta-analysis of East Asian (EAS) cohorts (n=4,712PD vs 38,733Controls). Clinico-demographic details of affected variant carriers were collated. Results: The GCH1 p.Ser80Asn variant was enriched in GP2 EAS PD populations (n=9/2,757; 0.33%) but not detected in other ancestries. Meta-analysis revealed increased PD risk in EAS populations (odds ratio:5.1; 95%CI:2.3-10.7; p=2.89x10-5). Affected carriers (mean age at onset:56.3+-12.5 years) had additional occurrence of dystonia, while dementia was rare. Conclusions: The GCH1 p.Ser80Asn variant is a rare, EAS-enriched risk variant for PD.

BackgroundParkinsons disease (PD) and Essential Tremor (ET) are heterogeneous, yet distinct disorders. At the same time, PD and ET show overlapping features such as phenotypes with predominant tremor. These heterogeneities and overlaps pose challenges for clinical management and research and may indicate transdiagnostic, shared mechanisms for tremor. ObjectivesTo test the hypothesis that MRI may reveal structural brain changes related to tremor phenotypes rather than diagnoses in PD and ET patients. For this, we compared regional brain volumes between three patient groups with overlapping phenotypes and distinct diagnoses: ET, PD with tremor-dominant phenotype (PD-T), and PD with non-tremor-dominant phenotype (PD-nT). MethodsWe studied 164 patients (18 ET, 38 PD-T, 108 PD-nT) who were evaluated for deep brain stimulation. All patients underwent structural MRI, and standardized assessment of motor symptoms. We compared regional brain volumes between groups. ResultsVolumes of the thalamus, pallidum, and pre-cerebellar and upper brainstem (midbrain, pons, superior cerebellar peduncle) differed across groups and were smallest in ET, intermediate in PD-T, and largest in PD-nT. Differences reached significance when comparing ET or PD-T with PD-nT but not ET with PD-T. Thalamic and brainstem volumes correlated with more severe and less levodopa-responsive tremor in PD. In contrast to the subcortical findings, cortical thickness in frontal and parietal regions was thinner in PD-nT compared to PD-T patients. ConclusionsWe identified tremor-related volume loss in cerebellothalamic and interconnected regions (pallidum), potentially suggesting shared mechanisms of tremor in PD and ET and pointing towards a transdiagnostic structural brain signature of tremor.

Objectives: X-linked dystonia-parkinsonism is a neurodegenerative movement disorder with predominant striatal pathology in affected males, who frequently show hyperechogenicity of the lentiform nucleus on transcranial sonography. We aim to investigate female mutation carriers and female healthy controls using transcranial sonography to identify potential abnormalities in the striatum, substantia nigra, and ventricular system. Methods: We examined 81 participants (35 female mutation carriers and 46 female controls) using transcranial sonography to assess the presence of hyperechogenicity of the lentiform nucleus, the area of substantia nigra hyperechogenicity, and the widths of the lateral and third ventricles. Clinical evaluation focused on dystonic and parkinsonian symptoms, and we determined genotypes relevant for four X-linked dystonia-parkinsonism genetic modifiers. Results: Female mutation carriers showed more subtle parkinsonian signs compared with controls. The prevalence of hyperechogenicity of the lentiform nucleus was higher in female mutation carriers and was associated with a more unfavorable genetic modifier profile. No relevant abnormalities were observed in the substantia nigra or the ventricular system. Imbalanced X-chromosome inactivation in favor of the wildtype allele expression was not significantly associated with clinical severity or hyperechogenicity of the lentiform nucleus frequency, although female mutation carriers with such an imbalance showed no parkinsonian signs and only rarely hyperechogenicity of the lentiform nucleus (1/8, 13%). Conclusions: Women carrying the X-linked dystonia-parkinsonism-causing variant display subtle parkinsonian signs and frequently exhibit hyperechogenicity of the lentiform nucleus, supporting hyperechogenicity of the lentiform nucleus as a sensitive imaging marker of early neurodegenerative change, especially in those with higher genetic risk.

Glucocerebrosidase (GCase) deficiency due to mutations of the glucosidase acid beta (GBA) gene causes autosomal-recessive Gauchers disease, the most frequent lysosomal storage disorder. Over the past two decades, GBA mutations have been established as the most frequent genetic risk factor to develop Parkinsons Disease. In dystonia, the underlying aetiology in a relevant proportion of cases remains unknown, hampering the development of causative treatment strategies. Here, we explored the possible role of lysosomal dysfunction in clinical (n=130) and post mortem (n=10) patients with dystonia. As part of extensive diagnostic evaluations (screening for structural, acquired and degenerative causes of dystonia), lysosomal enzyme activity was measured in n=79 retrospectively collected cases of patients with combined dystonia and n=51 prospectively collected cases of patients with cervical dystonia using a clinically validated, fluorescence-based assay. Clinical information on all cases was extensively reviewed and an alternative aetiology of dystonia was identified in n=14 cases on follow-up. Of the remaining n=116 cases of dystonia of unknown origin, complete Sanger Sequencing of GBA exons 1-11 was performed using an established protocol in all n=97 of cases with available DNA. Where there was suspicion based on clinical examination or family history, nigro-striatal degeneration was excluded in n=19 (17.2%) cases with dystonia of unknown origin. Furthermore, lysosomal enzyme activity was measured in different brain regions of age-, sex- and post-mortem delay-matched cases with dystonia of unknown origin (n=10) and healthy controls (n=10) from the Queen Square brain bank. Among cases with dystonia of unknown origin, decreased white cell Glucocerebrosidase activity was measured in a range typical for homozygous (n=2; 1.7%) or heterozygous (n=23; 19.8%) GBA mutation carriers. The frequency of GBA mutations (5/80=6.25%) was significantly higher in patients than in controls (3/257=1.17%) of a historical control group from the same ethnic background (P=0.02; Odds Ratio=5.64, 95% Confidence Interval=1.44 - 21.58) - known pathogenic mutations E326K, T369M and N370S were found. We also identified lower Glucocerebrosidase activity in the cerebellar dentate nucleus (P=0.048) of dystonia patients than healthy controls. This study provides evidence for peripheral and central lysosomal dysfunction in a significant proportion and across the clinical spectrum of dystonia. As in Parkinsons disease, this was found irrespective of GBA mutation status, indicating a possible role of lysosomal dysfunction as a more general disease mechanism in dystonia.

BackgroundExcessive daytime sleepiness (EDS) is a disabling symptom of Lewy body disorders (LBD). The hypothalamus is a key sleep-wake regulator, but its contribution to EDS in LBD remains unclear. ObjectivesUse diffusion MRI to evaluate the relationship of hypothalamic microstructure to EDS symptoms in LBD. MethodsWe studied 102 patients with clinically-defined LBD (Parkinsons disease, n=93; Parkinsons disease dementia, n=4; and dementia with Lewy bodies, n=5) and Epworth Sleepiness Scale (ESS) within 2 years of MRI. Mean diffusivity (MD) was compared between EDS+ (ESS[&ge;]10, n=37) and EDS- (ESS<10, n=65) groups in the whole hypothalamus and three subregions, covarying for age and sex. Secondary analyses tested correlations between subregion MD and continuous ESS, global cognition, and motor scores; and between subregion volume and continuous ESS. ResultsMD was increased in EDS+ compared to EDS-only in the inferior tuberal subregion (Cohens d=0.43, p=0.043, {beta}=0.117{+/-}0.057), with trend level differences in the whole hypothalamus (Cohens d=0.39, p=0.064, {beta}=0.070{+/-}0.037) and superior tuberal subregion (Cohens d=0.38, p=0.073, {beta}=0.063{+/-}0.035). No difference was seen in the posterior subregion (Cohens d=0.1, p=0.628, {beta}=0.019{+/-}0.038). Significant correlations with continuous ESS were seen in MD of whole hypothalamus (r2=0.074, p=0.0057), superior tuberal (r2=0.081, p=0.0038), and inferior tuberal (r2=0.073, p=0.0059) subregions. There was no correlation of hypothalamic MD with global cognition or motor scores, and no correlation of whole/subregional hypothalamic volumes with ESS. ConclusionsDaytime sleepiness associates with increased MD in the inferior tuberal hypothalamus in an LBD cohort. This suggests degeneration within this region could contribute to EDS symptoms.

Biallelic pathogenic expansions of the RFC1 gene are the genetic cause of cerebellar ataxia, neuropathy, and bilateral vestibular areflexia syndrome. Sensory neuropathy is the most common symptom, but the clinical impairments and gateways to RFC1-related diseases are extremely variable. We genotyped patients with parkinsonism to test the hypothesis that this condition is another such gateway. We screened four cohorts of patients with parkinsonism (n = 2037) for pathogenic expansions in the RFC1 gene. In patients bearing two pathogenic expansions, we excluded the possibility of other pathogenic variants by exome sequencing. We detected 10/2037 (0.5%) biallelic (AAGGG)n RFC1 expansions. The initial diagnosis was Parkinsons disease in five patients, multiple system atrophy in three and atypical parkinsonism in two. Phenotypes perfectly mimicking Parkinsons disease and multiple system atrophy defined according to the international diagnostic criteria may serve as gateways to some RFC1-related disorders. These results could modify the diagnostic and management of these two diseases. The diagnosis and follow-up of patients with parkinsonism should include searches for typical features evocative of a RFC1-relative disease, such as sensory neuropathy or chronic cough. Nerve conduction studies should be conducted in patients with unexplained symptoms of neuropathic pain or sensory neuropathy. We also suggest that RFC1 screening should be performed in patients with atypical parkinsonism or multiple system atrophy with a long survival. Trial Registration Information: The PREDISTIM cohort is registered with ClinicalTrials.gov: NCT02360683 Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=143 SRC="FIGDIR/small/25332961v1_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@89b54borg.highwire.dtl.DTLVardef@dd503aorg.highwire.dtl.DTLVardef@1be1faaorg.highwire.dtl.DTLVardef@110fcd9_HPS_FORMAT_FIGEXP M_FIG C_FIG MSA = multiple system atrophy; PD = Parkinsons disease; RFC1 = replication factor C subunit 1

BackgroundParkinsonian tremor usually starts unilaterally. The mid-term prognosis of this lateralized tremor is unknown, as is the development of tremor in the contralateral arm. ObjectiveTo investigate the emergence of contralateral tremor in the Parkinson-Progression-Marker-Initiative database, with data available for 7 years. MethodsTremor Amenable for surgery (TAS) was defined as any rest, postural or kinetic tremor with amplitude >1 cm (MDS-UPDRS score [&ge;]2) as this criterion is commonly accepted for inclusion in surgical studies. Tremor was analyzed by side mainly in the off-medication state. ResultsAt baseline, 348 (87.7%) of the 397 patients with Parkinsons disease had tremor at least on one side of the body. 183 (46%) had only mild tremors but 165 (41.6%) had TAS. 159 patients (40.1%) had lateralized TAS and 6 (1.6%) had bilateral TAS. Among patients with unilateral TAS, 40 patients (25.8%) developed contralateral TAS at 3 years, 49 patients (30.8%) at 5 years, and 61 patients (39%) at 7 years. The side more affected by tremor was also more affected by other cardinal symptoms. In 159 patients with initially unilateral TAS, tremor severity did not increase on the tremor-dominant side over the 7-year period. However, there was an increase in tremor on the contralateral side. This was associated with a clear increase in bradykinesia and rigidity on both sides. ConclusionThe study findings may prove beneficial in counselling patients with TAS, and may also provide an explanation as to why the worsening of tremor is not correlated with overall disease progression.

Background: Dystonia frequently co-exists with Parkinson's disease (PD), yet the extent of genetic overlap remains insufficiently explored. Objective: To examine whether rare variants in dystonia-related genes are associated with PD or early-onset PD (EOPD). Methods: We curated 44 dystonia-related genes using OMIM and the updated Movement Disorder Society report on hereditary dystonia. Whole-genome sequencing data from 5,315 PD patients, including 300 with EOPD, and 36,902 controls across the Accelerating Medicines Partnership-PD and UK Biobank cohorts were analyzed. For each gene, we evaluated rare variants (minor allele frequency <1%) in four pre-specified variant classes: exonic, nonsynonymous, CADD score [&ge;]20 and loss-of-function. For the rare variant burden analysis, SKAT-O was performed, followed by meta-analysis with MetaSKAT. Results: In analyses of all PD cases, several genes showed nominal associations in meta-analysis: SQSTM1 (Ploss-of-function = 5.52 x 10-3), AOPEP (Pexonic = 6.96 x 10-3; Pnonsynonymous = 0.017), KCNA4 (Pexonic = 0.017), SPR (Pexonic = 0.029), SLC30A10 (PCADD[&ge;]20 = 0.046), and ACTB (Pexonic = 0.047). However, none remained significant after multiple-testing correction. In exploratory EOPD analyses, five genes reached significance after multiple test correction (ATP5MC3, DNAJC12, KMT2B, TBC1D24, TMEM151A). These signals were driven by small numbers of variants and were not robust to leave-one-variant-out analyses. GCH1 was nominally significant in the meta-analysis of EOPD (Pnonsynonymous = 4.36 x 10-3, PFDR = 0.062). Conclusions: Rare variants in dystonia-related genes do not appear to make a major contribution to PD risk overall. Signals observed in the EOPD subset were based on small numbers of variant carriers and require replication in larger cohorts.

Background: Pathogenic variants in GCH1 have been associated with Parkinson's disease (PD), but the clinical phenotype and longitudinal disease course of GCH1-associated PD remain incompletely characterized. Objectives: To characterize the genetic spectrum, clinical phenotype, and longitudinal progression of GCH1-associated PD across multiple populations. Methods: Whole-genome sequencing (WGS) and clinical exome sequencing (CES) data from the Global Parkinson Genetics Program (GP2) were analyzed together with unpublished and published GCH1-associated PD patients. Variant pathogenicity was classified according to ACMG criteria. Demographic, clinical, and longitudinal features were compared between GCH1 P/LP variant carriers and non-carrier PD patients; individuals with known pathogenic variants in PD-associated genes were excluded from both groups. Results: In the GP2 cohort (PD, n=22,825; controls, n=4,453), 16 pathogenic or likely pathogenic (P/LP) GCH1 variants were identified in 58 individuals, including 54 PD patients, one control, and three individuals with other neurodegenerative phenotypes (two with progressive supranuclear palsy and one with dementia with Lewy bodies). In the pooled-ancestry WGS analysis, GCH1 P/LP variants were enriched in PD patients versus controls (0.267% vs 0.023%; OR=11.854; 95% CI=1.620-86.699; p=0.0006). Variant frequencies in PD patients ranged from 0.121% to 0.714% across ancestries. In the CES cohort, P/LP variants were identified in 0.201% of PD patients. After integrating GP2 with additional unpublished and published datasets, 119 GCH1-associated PD patients were analyzed. Compared with noncarriers, carriers of P/LP GCH1 variants had an earlier age at onset (mean [SD], 53.7 [14.8] vs 59.2 [11.7] years; P < .001), lower levodopa equivalent daily dose requirements (mean [SD , 467.5 [331.7] vs 680.3 [466.4] mg/d; P < .001), and a higher frequency of a family history of Parkinson disease (47.6% vs 19.9%; P < .001). Adjusted Cox models showed significant delayed progression to motor fluctuations (HR=0.32, 95% CI=0.16-0.62) and levodopa-induced dyskinesias (HR=0.51, 95% CI=0.30-0.87). Conclusion: GCH1 pathogenic variants were associated with a clinically distinct phenotype characterized by earlier disease onset and slower progression of motor complications. These findings suggest that GCH1 genetic variants may serve as genetic biomarkers for patient stratification and prognosis in PD.

BackgroundThere is a need to establish the role of lipid-lowering agents as a therapeutic option for Parkinsons Disease (PD), but its associations remain elusive. This study investigated genetic variants proxying lipid-lowering agents through HMGCR, NPC1L1, and PCSK9 inhibitors to determine casual associations with PD risk. MethodsWe utilized a two-sample Mendelian randomization (MR) framework, where low-density lipoprotein (LDL) was the outcome of interest. Genetic associations with LDL were extracted from the Global Lipids Genetics Consortium. Summary statistics for PD were extracted from two GWAS datasets, consistent of 1,843 PD cases and 216,630 control in the first dataset and 1,570 PD cases and 1,259 controls in the second dataset. Instrumental variables (IV) were optimized with positive control analyses on cardiovascular and metabolic outcomes. IV-exposure associations from LDL GWAS data were integrated with IV-outcome associations from the PD GWAS data. The inverse variance weighted method was applied. Bayesian colocalization analysis identified target gene regions for LDL and PD. ResultsGenetic variations in HMGCR were significantly associated with a reduced risk of PD (odds ratio [OR] = 0.54, 95% CI 0.34-0.86). However, variation in HMGCR was associated with an increased risk of the tremor-dominant (TD) subtype compared to the postural instability/gait difficulty (PIGD) subtype (OR = 8.43, 95% CI 2.12-33.52). There were trends with increased risk for the TD subtype in NPC1L1 and a decreased risk in PCSK9 but these findings did not meet the Bonferroni threshold. We identified two single nucleotide polymorphisms (SNPs) in HMGCR within the same genomic region of close proximity, with rs12916 as the leading SNP associated with LDL and rs10942735 as the leading SNP associated with PD. ConclusionA casual association between HMGCR inhibition and reduced overall PD risk was identified, but there were increased the risks of tremor-dominant subtypes.

BackgroundThe genetic architecture of Parkinsons disease (PD) varies considerably across ancestries, yet most genetic studies have focused on individuals of European descent, limiting insights into the genetic landscape of PD at a global scale. MethodsWe conducted a large-scale, multi-ancestry investigation of causal and risk variants in PD-related genes. Using genetic datasets from the Global Parkinsons Genetics Program (GP2), we analyzed sequencing and genotyping data from 105,588 individuals, including 63,837 affected and 41,751 unaffected, from eleven different ancestries. Approximately 29% of individuals included were from underrepresented populations. FindingsOur findings revealed shared and ancestry-specific patterns in the prevalence and variant spectrum. Overall, [~]2% of PD individuals carried a causative variant, with substantial variations across ancestries ranging from [~]0{middle dot}5% in African to [~]7% in Middle Eastern and >10% Ashkenazi Jewish ancestries. Including disease-associated GBA1 and LRRK2 risk variants raised the yield to 13{middle dot}6%, largely driven by GBA1, except in East Asians, where LRRK2 risk variants dominated. GBA1 variants were most frequent globally, albeit with substantial differences in frequencies and variant spectra. While GBA1 variants were identified across all ancestries, frequencies ranged from [~]5% in Middle Eastern and South Asian to [~]52% in African ancestry. Similarly, LRRK2 variants showed ancestry-specific enrichment, with p.G2019S most frequently seen in Middle Eastern and Ashkenazi Jewish populations, and risk variants predominating in East Asians. Notably, clinical trials targeting specific genetic variants are currently primarily based in Europe and North America. Another globally PD-relevant gene was PRKN, with variant carriers identified across almost all ancestries. InterpretationThis large-scale, multi-ancestry assessment offers crucial insights into the population-specific genetic architecture of PD. It underscores the critical need for increased ancestral diversity in PD research to improve diagnostic accuracy, enhance our understanding of disease mechanisms across populations, and ensure equitable development and application of emerging precision therapies. FundingAligning Science Across Parkinsons (ASAP) Global Parkinsons Genetics Program (GP2)

Background and ObjectivesClinical heterogeneity of patients with Parkinsons disease is well recognized. Parkinsons disease with rapid eye movement (REM) sleep behavior disorder (RBD) is a more malignant phenotype with faster motor progression and higher non-motor symptom burden. However, the neural mechanisms underlying this clinical divergence concerning disbalances in neurotransmitter systems remain elusive. MethodsCombining magnetic resonance (MR) spectroscopy and 11C-ABP688 positron emission tomography (PET) on PET/MR hybrid system, we simultaneously investigated two different mechanisms of glutamate signaling in patients with Parkinsons disease. Thirty-three patients were grouped according to their RBD status in overnight video-polysomnography and compared to 15 age- and sex-matched healthy control (HC) subjects. Total volumes of distribution (VT) of 11C-ABP688 were estimated with metabolite-corrected plasma concentrations during steady-state conditions between minutes 45 to 60 of the scan following a bolus-infusion protocol. Glutamate, glutamine, and glutathione levels were investigated with single voxel STEAM MR spectroscopy of the left putamen. ResultsWe measured globally elevated VT of 11C-ABP688 in patients with Parkinsons disease and RBD compared to patients without RBD and HC subjects (F(2,45) = 5.579, p = 0.007). Conversely, glutamatergic metabolites did not differ between groups and did not correlate with the regional VT of 11C-ABP688. VT of 11C-ABP688 correlated with the amount of REM sleep without atonia (F(1,42) = 5.600, p = 0.023), and with dopaminergic treatment response in Parkinsons disease patients (F(1,30) = 5.823, p = 0.022). ConclusionOur results suggest that patients with Parkinsons disease and RBD exhibit altered glutamatergic signaling indicated by higher VT of 11C-ABP688 despite unaffected glutamate metabolism. The disbalance of glutamate receptors and neurotransmitter might indicate a novel mechanism contributing to the heterogeneity of Parkinsons disease and warrants further investigation of drugs targeting mGluR5.

IntroductionParkinsonism encompasses neurodegenerative disorders characterized by rigidity, tremor, and bradykinesia, with Parkinsons disease (PD) accounting for most cases. Emerging evidence suggests that metabolic dysfunction, including insulin resistance and neuroinflammation, may contribute to PD pathogenesis. Glucagon-like peptide-1 receptor agonists (GLP-1RAs), approved for type 2 diabetes (T2D) and obesity, demonstrate neuroprotective effects in preclinical PD models. However, real-world evidence in individuals without T2D is limited. This study evaluated whether GLP-1RA use among adults with obesity or overweight is associated with the risk of PD and Parkinsonian disorders. MethodsWe conducted a retrospective cohort study using 2014-2024 electronic health record data from the OneFlorida+ Network. Adults with obesity (BMI [&ge;]30 kg/m2), overweight (BMI 25-29.9 kg/m2) with a weight-related comorbidity, or an obesity diagnosis were eligible. Exclusions included age <50 years, <30 days of follow-up, baseline PD or Parkinsonism, anti-Parkinson medication use, or T2D. GLP-1RA users were matched 1:1 to non-users using time-conditional propensity scores. Outcomes were a composite of (1) PD/Parkinsonism and (2) any Parkinsonian-related disorder, including PD, Parkinsonism, Lewy body dementias, and multiple system atrophy. Cox proportional hazards models estimated hazard ratios (HRs) and 95% confidence intervals (CIs). ResultsThe matched cohort included 11,683 GLP-1RA users and 11,683 non-users with balanced characteristics and a median follow-up of 286 days. GLP-1RA use was not associated with reduced risk of PD or Parkinsonism (22 vs. 33 events; HR 0.70, 95% CI 0.41-1.22) or any Parkinsonian-related disorder (98 vs. 108 events; HR 0.96, 95% CI 0.73-1.27). Findings were consistent in subgroup and sensitivity analyses. ConclusionAmong adults with obesity or overweight with a weight related condition, there was no difference in the risk of PD or Parkinsonian disorders between GLP-1 RA users and non-users. Longer follow-up and clinical trials are needed to clarify potential neuroprotective effects across populations.

BackgroundThe relationship between essential tremor (ET) and Parkinsons disease (PD) remains controversial. Beyond viewing ET as a discrete risk factor for PD, recent frameworks propose that an ET phenotype may represent a clinical presentation of prodromal PD (pPD), consistent with the current reconceptualization of ET as a syndrome. Whether co-occurring subtle motor signs alter pPD probability in ET remains unknown. MethodsUsing the MDS research criteria, we calculated pPD probability in a large cohort of ET patients with and without subtle motor signs (rest tremor, hypomimia, isolated rigidity, reduced arm swing, altered repetitive movements, global slowing). Multivariable regression was used to identify independent predictors of pPD probability. ResultsAmong 599 ET patients (median disease duration: 12 years), only 6 (1.0%) met criteria for probable pPD. Although ET patients with subtle motor signs exhibited higher continuous pPD probability scores than those without, the frequency of possible or probable pPD did not differ significantly between groups. In multivariable regression, neither ET nor individual subtle motor signs, but hypomimia, were independent predictors of pPD probability, which was primarily driven by older age and male sex. ConclusionsLong-standing ET, whether isolated or accompanied by subtle motor signs, is not associated with pPD, with the possible exception of co-occurring hypomimia.

Freezing of gait (FOG) is a major cause of falling and leads to loss of independence in Parkinsons disease (PD). The pathophysiology of FOG is poorly understood - although there is a hypothesized link with NE systems. PD-FOG can present in levodopa-responsive and unresponsive forms. We examined NE transporter (NET) binding via brain positron emission tomography (PET) to evaluate changes in NET density associated with FOG using the high affinity selective NET antagonist radioligand [11C]MeNER (2S,3S)(2-[-(2-methoxyphenoxy)benzyl]morpholine) in N=52 parkinsonian patients. We used a rigorous levodopa challenge paradigm to characterize patients as non-freezing PD (NO-FOG, N=16), levodopa responsive freezing (OFF-FOG, N=10), levodopa-unresponsive freezing (ONOFF-FOG, N=21), and primary progressive freezing of gait (PP-FOG, N=5). Linear mixed models identified significant reductions in whole brain NET binding in the OFF-FOG group compared to the NO-FOG group (-16.8%, P=0.021). Additional contrasts tested post-hoc identified trends toward increased NET expression in ONOFF-FOG vs. OFF-FOG ({approx}10%; P=0.123). Linear mixed models with interaction terms identified significantly reduced NET binding in right thalamus in the OFF-FOG group (P=0.038). A linear regression analysis identified an association between reduced NET binding and more severe NFOG-Q score only in the OFF-FOG group (P=0.022). This is the first study to examine brain noradrenergic innervation using NET-PET in PD patients with and without FOG. Based on the normal regional distribution of noradrenergic innervation and pathological studies in the thalamus of PD patients, the implications of our findings suggest that noradrenergic limbic pathways may play a key role in OFF-FOG in PD. This finding could have implications for clinical subtyping of FOG as well as development of therapies.

BackgroundMelanocortin 1 receptor (MC1R) is a key regulator of pigmentation. Previous studies have linked MC1R loss-of-function variants to increased risk for Parkinsons disease (PD); however, whether they are associated with PD progression remains unknown. Using data from the Parkinsons Progression Markers Initiative (PPMI) cohort, we aimed to test whether MC1R loss-of-function variants, especially those previously associated with an increased risk of PD, are associated with PD progression and phenoconversion. MethodsWe analyzed PD progression in 802 PPMI participants (n=185 sporadic PD, 220 MC1R PD (139 heterozygotes, 64 compound heterozygotes, 17 homozygotes), 84 LRRK2 PD, 43 GBA PD, 187 MC1R + LRRK2 PD, and 83 MC1R + GBA PD) with 13 years of motor, non-motor, and cognitive assessments alongside 5 years of dopamine transporter imaging using linear mixed-effects models adjusted for potential confounders. Additionally, we explored risk of phenoconversion in 45 prodromal participants (n=16 sporadic, 29 MC1R) using time-to-event survival analysis. ResultsParticipants with MC1R PD exhibited a 23% faster rate of motor decline (p=0.035) than participants with sporadic PD. The R160W variant (n=43 carriers), previously associated with an increased risk of PD, exhibited the strongest association with motor decline (p=0.023). High penetrance variants exhibited a stronger association with motor decline than low penetrance variants. Further, stratifying by genotype revealed that homozygotes exhibited a stronger association with motor decline than heterozygotes. Participants with MC1R PD also exhibited a non-statistically significant 24% faster rate of non-motor decline (p=0.070) than participants with sporadic PD. The rate of change in MoCA and DAT-SPECT SBR was minimal in all groups. Although not statistically significant, prodromal participants with MC1R loss-of-function variants exhibited a 3.81-fold increased risk of phenoconversion compared to noncarriers (p=0.059). InterpretationMC1R loss-of-function variants are associated with accelerated PD motor decline in the PPMI cohort. Together with previous biological findings from our group and others, these results highlight the potential role of MC1R in PD prognosis, warranting further validation and investigation into whether MC1R-targeted interventions may modify PD progression.

BackgroundPRKN biallelic pathogenic variants are the most common cause of autosomal recessive early-onset Parkinsons disease (PD). However, the variants responsible for suspected PRKN-PD individuals are not always identified with standard genetic testing. ObjectivesIdentify the genetic cause in two siblings with a PRKN-PD phenotype using long-read sequencing (LRS). MethodsThe genetic investigation involved standard testing using successively multiple ligation probe amplification (MLPA), Sanger sequencing, targeted sequencing, whole-exome sequencing and LRS. ResultsMLPA and targeted sequencing identified one copy of exon four in PRKN but no other variants were identified. Subsequently, LRS unveiled a large deletion encompassing exon 3 to 4 on one allele and a duplication of exon 3 on the second allele; explaining the siblings phenotype. MLPA could not identify the balanced rearrangement of exon 3. ConclusionsThis study highlights the potential utility of long-read sequencing in the context of unsolved typical PRKN-PD individuals.

BackgroundPRKN mutations are the most common cause of young onset and autosomal recessive Parkinsons disease (PD). PRKN is located in FRA6E which is one of the common fragile sites in the human genome, making this region prone to structural variants. However, complex structural variants such as inversions of PRKN are seldom reported, suggesting that there are potentially unrevealed complex pathogenic PRKN structural variants. ObjectivesTo identify complex structural variants in PRKN using long-read sequencing. MethodsWe investigated the genetic cause of monozygotic twins presenting with a young onset dystonia-parkinsonism using targeted sequencing, whole exome sequencing, multiple ligation probe amplification, and long-read. We assessed the presence and frequency of complex inversions overlapping PRKN using whole-genome sequencing data of AMP-PD and UK-Biobank datasets. ResultsMultiple ligation probe amplification identified a heterozygous exon 3 deletion in PRKN and long-read sequencing identified a large novel inversion spanning over 7Mb, including a large part of the coding DNA sequence of PRKN. We could diagnose the affected subjects as compound heterozygous carriers of PRKN. We analyzed whole genome sequencing data of 43,538 participants of the UK-Biobank and 4,941 participants of the AMP-PD datasets. Nine inversions in the UK-Biobank and two in AMP PD were identified and were considered potentially damaging and likely to affect PRKN isoforms. ConclusionsThis is the first report describing a large 7Mb inversion involving breakpoints outside of PRKN. This study highlights the importance of using long-read whole genome sequencing for structural variant analysis in unresolved young-onset PD cases.