Movement Disorders

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.

BackgroundVariants in the GBA1 gene are the commonest genetic risk factor for Parkinson disease (PD). Genotype- phenotype correlations exist but with conflicting data, particularly in the cognitive domain. ObjectivesComparing clinical phenotypes in a multicentre, international cohort incorporating GBA-PD and idiopathic PD (iPD) patients. MethodsPatients underwent a comprehensive assessment of motor and non-motor functions. Two-group (GBA- PD vs iPD) and multiple-group comparisons (iPD, risk, mild, and severe variant GBA-PD) were performed. ResultsThree hundred eleven PD patients were recruited: 183 iPD, 39 severe GBA-PD, 24 mild GBA-PD, 55 risk GBA-PD, and 10 patients carrying variants of unknown significance. Groups were matched for sex, education, disease duration and medications. Mild and severe GBA-PD were younger and developed PD earlier. Severe GBA-PD had worse depression, cognitive impairment, hyposmia, and motor complications. ConclusionsOnly severe variant GBA-PD have a distinctive, more severe clinical profile.

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 [≥]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.

BackgroundMutations and multiplications in the gene encoding for alpha-synuclein are associated with Parkinsons disease (PD). However, not all individuals with alpha-synuclein variants develop PD, suggesting that additional factors are involved. We hypothesized that increased alpha-synuclein might alter epigenetic regulation of PD pathways. ObjectivesTo identify genome-wide DNA methylation and hydroxymethylation changes induced by overexpression of two alpha-synuclein variants in human dopaminergic neurons, and to relate these to the corresponding transcriptome. MethodsWe assessed DNA methylation and hydroxymethylation at >850,000 CpGs using the EPIC BeadChip in LUHMES cells differentiated to dopaminergic neurons. Control LUHMES neurons, LUHMES neurons overexpressing wild type alpha-synuclein, and LUHMES neurons overexpressing A30P alpha-synuclein were compared. We used SMITE network analysis to identify functionally related genes with altered DNA methylation, DNA hydroxymethylation, and/or gene expression, incorporating LUHMES H3K4me1 ChIP-seq to delineate enhancers in addition to the default promoter and gene body regions. ResultsUsing stringent statistical thresholds, we found that increased expression of wild type or A30P mutant alpha-synuclein induced DNA methylation changes at thousands of CpGs and DNA hydroxymethylation changes at hundreds of CpGs. Differentially methylated sites in both genotypes were enriched for several processes including movement-associated pathways and glutamate signaling. For glutamate and other signaling pathways (i.e. PDGF, insulin), this differential DNA methylation was also associated with transcriptional changes. ConclusionsOur results indicated that alpha-synuclein altered the DNA methylome of dopaminergic neurons, influencing regulation of pathways involved in development, signaling, and metabolism. This supports a role for alpha-synuclein in the epigenetic etiology of PD.

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.

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.

BackgroundFalls are a major source of morbidity in Parkinsons disease (PD), yet their evolution over time remains unclear. ObjectivesTo compare fall risk and outcomes among PD, prodromal alpha-synucleinopathy, (PAS) and healthy controls (HC); estimate fall frequency across PD progression; and characterize clinical features of PD faller subgroups. MethodsWe analyzed fall-related outcomes in the Parkinsons Progression Markers Initiative. Yearly rates of rare and frequent falls were estimated by time since diagnosis. Unique PD participants were grouped as never, rare, or frequent fallers. Clinical variables included motor, cognitive, behavioral, sleep, and autonomic measures. Outcomes included injuries and healthcare utilization. Regression models adjusted for age, sex, and disease duration, with Benjamini-Hochberg correction. ResultsAcross 6,977 visits from 3,100 participants (937 PD, 1,926 PAS, 237 HC), PD participants had higher odds of falling than PAS (OR=1.66, 95% CI [1.46-1.87]) and HC (OR=4.03, 95% CI [3.14-5.23]). PD participants were also more likely to report fall-related injuries and healthcare use than PAS (OR=1.70, 1.71) and HC (OR=3.26, 3.81). Falls occurred in 15.5% of visits at diagnosis and 69.2% after 14 years, increasing across Neuronal Synuclein Disease-Integrated Staging System (NSD-ISS) stages. Frequent fallers had longer disease duration, higher NSD-ISS, and worse clinical profiles. Women were more likely to fall than men (46.1% vs 34.9%, p=0.002) despite milder symptoms. ConclusionFalls and related morbidity increase with disease duration and NSD-ISS. Risk reflects sex and motor and non-motor factors, supporting a multifactorial model. Fall frequency may represent a practical marker of progression and guide prevention strategies in PD.

ObjectiveREM sleep behavior disorder (RBD) is a prodromal synucleinopathy, reported in a subset of Parkinsons disease (PD) patients, and associated with neuropsychiatric symptoms in PD. We aimed to compare the genetic background of PD patients with probable RBD (PD+RBD) and PD patients without probable RBD (PD-RBD). Furthermore, we examined genetic correlations and potential causal associations between multiple neuropsychiatric traits and PD+RBD. MethodsWe performed a genome-wide association study (GWAS) including 5,403 PD+RBD and 13,020 PD-RBD. To test for genetic correlations and potential causal associations between neuropsychiatric traits and PD+RBD, we used linkage disequilibrium score regression and Mendelian randomization. ResultsThe SNCA locus was associated with PD+RBD compared to PD-RBD (rs10005233, OR=1.21, 95% CI=1.16-1.27, p=1.81e-15). Further examination of known genetic loci associated with PD from the most recent PD GWAS in Europeans and Asians identified additional variants associated with reduced risk for PD+RBD: two in the SNCA locus (rs5019538-G, OR=0.85, 95% CI=0.81-0.89, p=2.46E-10; rs356182-G, OR=0.89, 95% CI=0.84-0.95, p=0.0001), and one in the LRRK2 locus (rs34637584, p.G2019S, OR=0.41, 95% CI=0.28-0.61, p=1.04E-5). We found a potential genetic correlation between attention deficit hyperactivity disorder (ADHD) and PD+RBD, which was not statistically significant after correction for multiple comparisons. No causative association emerged between PD and neuropsychiatric traits. InterpretationGenetic variants contribute to the occurrence of RBD in PD, further distinguishing between the PD+RBD and PD-RBD subtypes. Understanding the mechanisms underlying these genetic associations could contribute to the development of subtype-specific treatments.

IntroductionParkinsons Disease (PD) features debilitating motor symptoms, particularly gait and balance impairments inadequately managed by current therapies. Bassoon (BSN), a presynaptic active-zone organizer, has been implicated in various neurological disorders. Here, we evaluate the impact of rare BSN mutations on motor symptoms in PD patients. MethodsOur study included 110 PD patients carrying BSN mutations and 558 PD controls from a South Asian early-onset PD cohort (onset <50 years). Variants with mean allele frequency (MAF) <0.1% were classified as "rare" (n=44). Clinical motor features were compared between variant carriers and non-carriers. Computational tools (CADD, PolyPhen-2, I-Mutant2.0, ConSurf) predicted deleteriousness, while GeneMANIA and STRING elucidated Bassoons functional interactions. ResultsPatients carrying BSN variants exhibited significantly increased freezing of gait (FOG, p=0.026, Carmers V=0.118), shuffling gait (SG, p=0.041, Carmers V=0.111), and falls (p=0.028, Carmers V=0.117). Rare BSN mutations clustered in the Bassoon C-terminal region (aa 3500- 3800), threefold above expected frequency. Computational predictions identified seven likely pathogenic variants (P171L, A852T, P988A, R1015H, R2561H, R3400W, L3561P), with highest confidence for P171L (confirmed by AlphaMissense). Functional analyses implicated Bassoon in axonal transport, presynaptic proteostasis, and neurotransmitter release in dopaminergic/cholinergic neurons. ConclusionOur findings identify BSN mutations as a genetic risk factor for PD-related gait and balance dysfunction, highlighting Bassoons role in neurotransmission. The link with Progressive Supranuclear Palsy phenotypes suggests Bassoon dysfunction could represent a convergence point between synucleinopathies and tauopathies.

BackgroundSeveral lysosomal genes are associated with Parkinsons disease (PD), yet the association between PD and ARSA, which encodes for the enzyme arylsulfatase A, remains controversial. ObjectivesTo evaluate the association between rare ARSA variants and PD. MethodsTo study possible association of rare variants (minor allele frequency<0.01) in ARSA with PD, we performed burden analyses in six independent cohorts with a total of 5,801 PD patients and 20,475 controls, using optimized sequence Kernel association test (SKAT-O), followed by a meta-analysis. ResultsWe found evidence for an association between functional ARSA variants and PD in four independent cohorts (P[&le;]0.05 in each) and in the meta-analysis (P=0.042). We also found an association between loss-of-function variants and PD in the UKBB cohort (P=0.005) and in the meta-analysis (P=0.049). However, despite replicating in four independent cohorts, these results should be interpreted with caution as no association survived correction for multiple comparisons. Additionally, we describe two families with potential co-segregation of the ARSA variant p.E384K and PD. ConclusionsRare functional and loss-of-function ARSA variants may be associated with PD. Further replication in large case-control cohorts and in familial studies is required to confirm these associations.

BackgroundVariants in GBA1 are important genetic risk factors for synucleinopathies, including Parkinsons disease (PD). While several GBA1 variants are established risk or severity modifiers, the role of the p.E427K variant remains unclear. ObjectiveTo determine whether the GBA1 p.E427K variant is associated with risk of synucleinopathies. MethodsWe performed a meta-analysis of case-control studies reporting the frequency of GBA1 p.E427K (p.E388K) in PD and related synucleinopathies. Data were obtained from published studies, open-access resources, and large cohorts, including in-house datasets. Odds ratios (ORs) were calculated for each cohort and pooled using a random-effects model. ResultsAcross 67,484 patients and 124,079 controls, GBA1 p.E427K was associated with increased disease risk (pooled OR = 1.87, 95% CI 1.28-2.72, P = 0.001). Enzymatic data showed reduced glucocerebrosidase activity in carriers. ConclusionsThe GBA1 p.E427K variant is a risk factor for synucleinopathies and should be considered in genetic studies and clinical trials.

ObjectiveTo determine whether established parameters of cardiac autonomic function are associated with incident Parkinsons disease, independent of clinical characteristics, and established autonomic prodromal features. Methods Population-based cohortstudy of UK Biobank participants who performed a standardized bicycle exercise test (2009-2013), followed until November 2022, and analyzed in January 2024. Heart rate increase from rest to exercise, and the decrease in heart rate from peak exercise to recovery were extracted and associated with incident Parkinsons disease. Associations were adjusted using multivariable models consisting of clinical characteristics only and combined with prodromal autonomic features. Results69,288 eligible participants (male 48%, mean age 56.8 [SD 8.2]) were followed for 12.5 years (median; IQR 0.3): 319 (0.5%) developed Parkinsons disease. Median lag time to diagnosis was 9.3 years (IQR 4.4). Both heart rate increase (37.5 [SD 11.5] vs 40.8 [SD 12.4] beats/min, p < 0.001) and recovery (23.4 [SD 8.8] vs. 27.8 [SD 10.3] beats/min, p < 0.001) were significantly lower in incident cases compared to controls. After adjusting for prodromal clinical and autonomic features, heart rate recovery was independently associated with incident Parkinsons disease, while heart rate increase was not. Specifically, a blunted heart rate lowering during recovery was associated with a 30% higher risk of incident Parkinsons disease (HR: 1.3; 95% CI 1.1-1.4; p < 0.001 per 10 beats less recovery) InterpretationThese findings suggest that cardiac autonomic dysfunction precedes clinically manifest Parkinsons disease, and that heart rate recovery might serve as a quantitative prodromal marker.

ObjectiveTo identify genetic factors that may modify the effects of the MAPT locus in Parkinsons disease (PD). MethodsWe used data from the International Parkinsons Disease Genomics Consortium (IPDGC) and the UK biobank (UKBB). We stratified the IPDGC cohort for carriers of the H1/H1 genotype (PD patients n=8,492 and controls n=6,765) and carriers of the H2 haplotype (with either H1/H2 or H2/H2 genotypes, patients n=4,779 and controls n=4,849) to perform genome-wide association studies (GWASs). Then, we performed replication analyses in the UKBB data. To study the association of rare variants in the new nominated genes, we performed burden analyses in two cohorts (Accelerating Medicines Partnership - Parkinson Disease and UKBB) with a total sample size PD patients n=2,943 and controls n=18,486. ResultsWe identified a novel locus associated with PD among MAPT H1/H1 carriers near EMP1 (rs56312722, OR=0.88, 95%CI= 0.84-0.92, p= 1.80E-08), and a novel locus associated with PD among MAPT H2 carriers near VANGL1 (rs11590278, OR=1.69 95%CI=1.40-2.03, p= 2.72E-08). Similar analysis of the UKBB data did not replicate these results and rs11590278 near VANGL1 did have similar effect size and direction in carriers of H2 haplotype, albeit not statistically significant (OR= 1.32, 95%CI= 0.94-1.86, p=0.17). Rare EMP1 variants with high CADD scores were associated with PD in the MAPT H2 stratified analysis (p=9.46E-05), mainly driven by the p.V11G variant. InterpretationWe identified several loci potentially associated with PD stratified by MAPT haplotype and larger replication studies are required to confirm these associations.

BackgroundPathogenic mutations in the leucine-rich repeat kinase-2 (LRRK2) gene are the most common cause of familial Parkinsons disease (PD). LRRK2 shows incomplete penetrance, yet the biological factors influencing disease expression remain unknown. ObjectivesTo investigate whether genetic variants in aquaporin-4 (AQP4), key in glymphatic system functioning, are associated with the penetrance of PD in LRRK2 carriers. MethodsWe analyzed baseline data from 302 LRRK2 carriers from the Parkinsons Progression Markers Initiative. Fourteen AQP4 single nucleotide polymorphisms, previously implicated in PD, Alzheimers disease, or other neurodegenerative-related processes were tested for association with PD manifestation using logistic regression models adjusted for age and sex. Recessive, dominant, and additive genetic models were explored. Sensitivity analyses were conducted in G2019S carriers (n=273). ResultsOne hundred twenty-seven (42%) LRRK2 carriers were asymptomatic, and 174 (58%) had PD. There were no differences between groups in age (63.5[9.5] vs. 62.2[7.5]) or number of women (52.0% vs. 55.7%). Homozygosity for the minor allele of rs9951307 was associated with reduced likelihood of PD (OR=0.28, 95% CI 0.10-0.64, p=0.005), whereas rs335930 homozygosity was associated with increased likelihood (OR=4.2, 95% CI 1.41-15.6, p=0.016). Additive models supported these associations, though rs335930 did not surpass the adjusted threshold. Results were consistent in the G2019S subgroup. ConclusionsAQP4 polymorphisms may contribute to the variable penetrance of LRRK2 mutations, potentially though modulation of glymphatic clearance. These findings support the glymphatic system as a relevant pathway in familial PD and highlight AQP4 as a candidate therapeutic target.

BackgroundThe leucine-rich repeat kinase 2 (LRRK2) gene harbors both rare highly damaging missense variants (e.g. p.G2019S) and common non-coding variants (e.g. rs76904798) with lower effect sizes that are associated with Parkinsons disease risk. ObjectivesThis study aimed to investigate in a large meta-analysis whether the LRRK2 GWAS signal represented by rs76904798 is independently associated with Parkinsons disease risk from LRRK2 coding variation, and whether complex linkage disequilibrium structures with p.G2019S and the 5 non-coding haplotype account for the association of LRRK2 coding variants. MethodsWe performed a meta-analysis using imputed genotypes from 17,838 cases, 13,404 proxy-cases and 173,639 healthy controls of European ancestry. We excluded carriers of p.G2019S and/or rs76904798 to clarify the role of LRRK2 coding variation in mediating disease risk, and excluded carriers of relatively rare LRRK2 coding variants to assess the independence of rs76904798. We also investigated the co-inheritance of LRRK2 coding variants with p.G2019S, rs76904798 and p.N2081D. ResultsLRRK2 rs76904798 remained significantly associated with Parkinsons disease after excluding carriers of relatively rare LRRK2 coding variants. LRRK2 p.R1514Q and p.N2081D were frequently co-inherited with rs76904798 and the allele distribution of p.S1647T significantly changed among cases after removing rs76904798 carriers. ConclusionsThese data suggest that the LRRK2 coding variants previously linked to Parkinsons disease (p.N551K, p.R1398H, p.M1646T and p.N2081D) do not drive the 5 non-coding GWAS signal. These data, however, do not preclude the independent association of the haplotype p.N551K-p.R1398H and p.M1646T with altered disease risk.

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.

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.

BackgroundParkinsons disease (PD) affects millions of people worldwide, but only 5-10% of patients suffer from a monogenic form of the disease with Mendelian inheritance. SNCA, the gene encoding for the protein alpha-synuclein (aSyn), was the first to be associated with familial forms of PD and, since then, several missense variants and multiplications of the SNCA gene have been established as rare causes of autosomal dominant forms of PD. Aim and methodsA patient carrying aSyn missense mutation and his family members were studied. We present the clinical features, genetic testing - whole exome sequencing (WES), and neuropathological findings. The functional consequences of this aSyn variant were extensively investigated using biochemical, biophysical, and cellular assays. ResultsThe patient exhibited a complex neurodegenerative disease that included generalized myocloni, bradykinesia, dystonia of the left arm and apraxia. WES identified a novel heterozygous SNCA variant (cDNA 40G>A; protein G14R). Neuropathological examination showed extensive atypical aSyn pathology with frontotemporal lobar degeneration (FTLD) and nigral degeneration pattern with abundant ring-like neuronal inclusions, and few oligodendroglial inclusions. Sanger sequencing confirmed the SNCA variant in the healthy, elderly parent of the patient patient suggesting incomplete penetrance. NMR studies suggest that the G14R mutation induces a local structural alteration in aSyn, and lower thioflavin T binding in in vitro fibrillization assays. Interestingly, the G14R aSyn fibers display different fibrillar morphologies as revealed by cryo-electron microscopy. Cellular studies of the G14R variant revealed increased inclusion formation, enhanced membrane association, and impaired dynamic reversibility of serine-129 phosphorylation. SummaryThe atypical neuropathological features observed, which are reminiscent of those observed for the G51D aSyn variant, suggest a causal role of the SNCA variant with a distinct clinical and pathological phenotype, which is further supported by the properties of the mutant aSyn, compatible with the strain hypothesis of proteinopathies.

BackgroundThe abnormalities of subcortical structures, such as putamen and caudate, play a key role in the occurrence of Parkinsons disease (PD); however, whether and how imaging-derived phenotypes (IDPs) in subcortical structures are causally associated with the risk of PD remain poorly understood. MethodsThe causal associations between subcortical IDPs from UK biobank and risk of PD were evaluated with bidirectional two-sample Mendelian randomization (MR) studies. ResultsTotally five subcortical IDPs were found to be causally associated with the risk of PD. Among these IDPs, IDP 168 (Global volume of subcortical gray matter, OR = 1.38 [1.16, 1.63], P = 1.82 x 10-4), IDP 214 (Right putamen volume, OR = 1.31 [1.15, 1.50], P = 7.71 x 10-5) and IDP 1441 (T2* signal in right caudate, OR = 1.21 [1.09, 1.35], P = 5.23 x 10-4) were found to be associated with increased risk of PD. In contrast, IDP 1358 (Mean intensity in right caudate, OR = 0.72 [0.62, 0.85), P = 6.77 x 10-5) and IDP 1344 (Mean intensity in left caudate, OR = 0.76 [0.65, 0.88], P = 3.23 x 10-4) were associated with reduced risk of PD. ConclusionsThe specific imaging features of the caudate and putamen are causally associated with altered risk of developing PD, thereby providing new insights into the development of novel predictive imaging biomarkers and therapies for PD patients.

BackgroundLRRK2-Parkinsons disease (LRRK2-PD) is biologically heterogeneous with approximately 30% lacking aggregated alpha synuclein (Syn) in cerebrospinal fluid by seed amplification assay (SAA). Prior work has suggested slower progression in LRRK2-PD compared to sporadic PD (sPD). ObjectiveWe aimed to assess how LRRK2-PD with Syn aggregates on SAA (S+ LRRK2-PD) compares to S+ sPD. MethodsData from the Parkinsons Progression Markers Initiative were used to compare S+ LRRK2-PD and S+ sPD cohorts propensity score-matched on age, disease duration, sex and levodopa equivalent dose (N = 79 per cohort). Baseline clinical and biological features and 4-year longitudinal features were assessed. ResultsAt baseline, S+ LRRK2-PD participants had lower motor scores and dopaminergic deficit. Among measures showing within group progression, longitudinal trajectories did not differ significantly between groups. ConclusionsLongitudinal clinical progression of S+ LRRK2-PD and sPD in the PPMI study is similar despite differences in baseline features.