Journal of Parkinson's Disease

Variants in GBA1 are important genetic risk factors in Parkinsons disease (PD). GBA1 T369M has been linked to an [~]80% increased PD risk but the reports are conflicting and the relevance of GBA1 variants in different populations varies. A lack of association between T369M and PD in the Swedish population was recently reported but needs further validation. We therefore investigated T369M in 1,808 PD patients and 2,183 controls and our results support that T369M is not a risk factor for PD in the Swedish population.

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.

BackgroundA recent study identified a mutation in the SH3GL Interacting Endocytic Adaptor 1 (SGIP1) gene, located at 1p31.3, linked to early-onset Parkinsonism in 2 sisters in an Arab family with a history of young-onset Parkinson symptoms. SGIP1 had not been previously associated with Parkinsonism, a group of disorders including Parkinsons disease (PD), characterized by motor dysfunction and cognitive decline. SGIP1 plays a role in endocytosis, particularly clathrin-mediated synaptic vesicle recycling, essential for synaptic proteostasis. In a fruit fly model, SGIP1 deletion resulted in synaptic dysfunction, impaired protein recycling, and brain cell degeneration, which mirrors Parkinsonism. We aimed to explore the genetic association of SGIP1 in Parkinsons disease using data from the UK Biobank, specifically examining the nearby common intron variant rs7549881 at 1p31.3. MethodsThis study utilized data from the UK Biobank, a large biomedical database with genetic and health information from approximately 500,000 participants. We analyzed the association between rs7549881 and PD. The study included all participants with self-reported or ICD-diagnosed PD and restricted analysis to those with at least seven years of education. Genetic association analysis was performed using PLINK and SPSS, with logistic regression adjusting for covariates such as age, sex, and smoking. Additionally, a Phenome-Wide Association Study (PheWAS) was conducted to examine rs7549881 across a wide range of phenotypes. ResultsThe study analyzed data from 385,629 subjects, with PD patients having a mean age of 63 {+/-} 5 years. Among females, 26% of those homozygous for the rs7549881 GG allele had PD, compared to 22.2% who did not have PD (p = 0.004). This effect was not significant in males. Logistic regression revealed that male sex (OR 1.828, p < 0.001), age (OR 1.141 per year, p < 0.001), and constipation (OR 4.726, p = 0.001) increased PD risk, while cigarette smoking decreased it (OR 0.748, p < 0.001). The GG genotype was associated with increased PD risk when compared to the AA phenotype (OR 1.208, p = 0.015). PheWAS identified significant associations of rs7549881 with digestive disorders, including functional digestive disorders and non-infectious gastroenteritis. ConclusionThe study demonstrated an association between the rs7549881 variant and PD in females, highlighting the potential role of SGIP1 in neurodegeneration. Additionally, the PheWAS findings link this variant to gastrointestinal disorders, supporting the emerging concept of a gut-brain axis in PD. The results suggest that SGIP1 may influence both neuronal and gastrointestinal functions, providing a new avenue for understanding the genetic mechanisms underlying Parkinsons disease and its non-motor symptoms.

The aetiology of Parkinsons disease (PD) has been linked to the aggregation and spread of misfolded alpha-synuclein via the gut-brain axis. We previously reported the effects of a biological response modifier, beta-glucan, produced by the AFO-202 strain of Aureobasidium Pullulans, which improves clinical symptoms and controls gut Enterobacteriaceae associated with curli and amyloid-alpha-synuclein production. In this study, we report the effects of beta-glucan on PD. Eight patients with PD were recruited, five of whom completed the study. Each participant was administered 3 g of AFO-202 B-glucan orally daily for 90 days in addition to their regular prescription drugs. Pre- and post-study comparison revealed that the mean UPDRS decreased from 43.25 {+/-} 13.75 at baseline to 40 {+/-} 13.65 post intervention. Improvements in cognition, walking and balance, postural stability, and constipation scales were observed. The mean constipation severity score decreased from 3 {+/-} 1.73 to 1.75 {+/-} 0.43 post intervention. The serum creatinine kinase levels decreased and the blood glucose and lipid levels normalised. The MRI Parkinsons index (MRPI) improved in one patient. This safe AFO-202 B-glucan produced beneficial disease-modifying improvements in the UPDRS and MRI that were clinically significant in the short timeframe of 90 days. Further validation in larger, longer-term clinical trials will help confirm the use of beta-glucan as a potential adjuvant treatment for PD which may pave way for future evaluations of these beta-glucans in other synculeinopathies as well Lewy-body related pathogenesis.

A definitive diagnostic test for PD remains elusive, so identification of potential biomarkers may shed light on methods for diagnosis and facilitate early intervention. Excess sebum secretion and skin pathology are recognised symptoms of early PD. It is likely these result in a unique signature of volatile organic compounds that could be used to identify early stages of disease. Numerous medical conditions produce distinctive odours, and dogs have been trained to detect many of these. A single previous study, suggested that dogs can also be trained to detect Parkinsons Disease. In this study, two dogs were trained to distinguish sebum swabs obtained from drug naive, and medicated Parkinsons patients from swabs from control participants. After 38-53 weeks of training on 205 samples (90 target and 115 control), the dogs were tested in a double-blind trial using 60 control and 40 target samples from drug-naive patients. The dogs both showed high sensitivity (proportion of target samples found 70% and 80%) and specificity (proportion of control samples not alerted to 90% and 98%) of alerting response. This trial supports previous findings that dogs can be trained to reliably detect the odour of PD. We suggest there is a potential for dogs to achieve even higher accuracy with increased exposure and refined training methods and to detect early-stage PD, even prior to diagnosis, as well as hard to diagnose PD cases. Further exploration of the factors which affect dogs sensitivity and specificity and sample features which affect accuracy of discrimination are now required.

BackgroundAlthough levodopa remains the gold standard treatment for Parkinsons disease (PD), its chronic use is associated with levodopa-induced dyskinesia (LID), a motor complication that impacts prognosis, quality of life, and treatment costs. Most known LID-associated factors have been identified in European-descendant populations. ObjectivesTo describe the epidemiology of LID in Latin American and Caribbean (LATAM) countries and assess the relevance of known and novel LID-associated factors in this population. MethodsWe conducted a cross-sectional study using data from the Latin American Research consortium on the Genetics of Parkinsons Disease (LARGE-PD). We included PD patients with information on LID status and levodopa use from eight LATAM countries. LID prevalence was calculated overall and by country. Countries were compared on demographic and clinical variables. Logistic regression was used to identify associations with LID. ResultsA total of 3,695 PD patients (58.8% male) were included. Overall LID prevalence was 25.4% [95% CI: 24.06-26.87], ranging from 9.3% in Colombia to 45.1% in Puerto Rico. Prevalence increased progressively with longer disease duration. Country comparisons showed that not all known LID-associated factors explained prevalence differences. In logistic regression, fast disease progression was significantly associated with LID (OR: 1.55, 95%CI: 1.16-2.07), while sex was not (OR: 1.02, 95%CI: 0.87-1.18). ConclusionsThis is the largest study on LID epidemiology in LATAM. While some known risk factors remain relevant, others, like sex, do not, underscoring the need for population-specific studies. Future work should integrate environmental, clinical, and genetic data to better understand LID mechanisms.

BackgroundLevodopa-induced dyskinesia (LID) is a common motor complication of levodopa therapy in patients with Parkinsons disease (PD). Doxycycline is a widely used and inexpensive tetracycline with anti-inflammatory properties. ObjectiveEvaluate the efficacy and safety of doxycycline in patients with PD and LID. MethodsThis was an open-label, single-center, phase 2 proof-of-concept study in patients with PD with mild functional impact of dyskinesia, which used levodopa three times daily, in a movement disorders clinic in Brazil. Participants were treated with doxycycline 200 mg/day for 12 weeks, with evaluations in baseline, week 4, and week 12 of treatment. The primary outcome measure was the change from baseline in the Unified Dyskinesia Rating Scale (UDysRS) total score at week 12, evaluated by two blinded raters. Key secondary outcomes measures were OFF time and ON time with troublesome dyskinesia in the PD home diary. ResultsEight patients with PD were treated and evaluated. Doxycycline 200 mg/day reduced the UDysRS total score in week 12, compared with baseline (Friedmans X2 = 9.6, p = 0.008). Further, doxycycline reduced the ON time with troublesome dyskinesia (Friedmans X2 = 10.8, p = 0.004) without worsening parkinsonism. There were no severe adverse events, and dyspepsia was the commonest event. ConclusionsDoxycycline was effective in reducing LID and safe after a 12-week treatment. Further well-designed placebo-controlled clinical trials with a longer duration and a larger number of participants are needed.

BackgroundWhile summarized under the umbrella term "Parkinsonism", several subtypes with different etiologies exist, including Parkinsons Disease, Vascular Parkinsonism and Drug-induced Parkinsonism. However, evidence on their incidence and prevalence remains limited. ObjectivesTo evaluate secular trends of incidence and prevalence of parkinsonism, Parkinsons Disease, Vascular Parkinsonism, and Drug-induced Parkinsonism from 2007 to 2021 in the United Kingdom. MethodsWe used primary care data, Clinical Practice Research Datalink GOLD, from the United Kingdom. Individuals were included if they were registered from January 2007 to December 2021 with at least one year of prior observation. Incidence and prevalence were calculated on a yearly basis with 95% confidence intervals and then stratified by age and sex. ResultsFrom 2007 to 2019, the incidence of parkinsonism and Parkinsons Disease decreased, with Parkinsons Disease incidence dropping from 35.86 (95% confidence interval: 34.22 - 37.56) to 31.40 (29.40 - 33.50) per 100,000 person-years. The prevalence of parkinsonism and Parkinsons Disease increased from 0.22% (0.22% - 0.23%) and 0.21% (0.21% - 0.22%) in 2007 to peak in 2016 with 0.25% (0.25% - 0.26%) and 0.23% (0.23% - 0.24%) respectively. The number of Vascular Parkinsonism diagnoses have increased from 2010, whereas incidence and prevalence of Drug-induced Parkinsonism remained stable. Incidence and prevalence increased with age and were generally higher in males, except for Drug-induced Parkinsonism, which was slightly higher in females. ConclusionsGiven its association with aging, parkinsonism and these subtypes continue to present an increasing challenge to our aging society.

BackgroundThe role of blood uric acid and more recently bilirubin as biomarkers in symptomatic motor PD has been increasingly established in the literature. ObjectiveOur present study assessed the role of serum uric acid and total bilirubin as putative biomarkers in a prodromal PD cohort followed longitudinally. MethodsLongitudinal 5-year serum uric acid and total bilirubin measurement data of 65 Prodromal PD patients (including REM Sleep Behavior disorder (RBD), N=39 and Hyposmia, N=26) with an abnormal DATSCAN imaging were downloaded from the Parkinsons Progression Markers Initiative (PPMI) database. This cohort was compared with 423 de novo sporadic PD patients and 196 healthy controls enrolled in the same study. ResultsAfter adjusting for age, sex and Body Mass Index (BMI), baseline and 5-year longitudinal serum uric acid levels were higher in the Prodromal cohort and RBD subgroup as compared to the motor PD cohort. This was also true for longitudinal measurements in the Hyposmic subgroup. In contrast, baseline and longitudinal serum total bilirubin did not differ between each prodromal group and the PD cohort. ConclusionsOur results are indicative of a role of serum uric acid (but probably not of total bilirubin) as a marker of neuroprotection, in a certain subgroup of premotor patients exhibiting exclusively non motor features (hyposmia or RBD). It is possible that an inherent antioxidant resistance of a subset of RBD or hyposmia patients with high serum uric acid level delayed or precluded the emergence of a motor PD phenotype as opposed to the PD cohort.

There is evidence that transforming growth factor (TGF)-{beta} signaling participates in the pathology of Parkinsons disease (PD). Dampened TGF-{beta} signaling in Smad3- or T{beta}RII-deficient mice leads to the appearance of -synuclein inclusions in the brain, as well as dopaminergic, motor, and cognitive deficits. Accordingly, we hypothesized that genetic variants of TGFB/SMAD could be risk factors for PD in humans. Here, we present two independent case-control studies aimed at evaluating the association between genetic variants of six genes related to TGF-{beta} signaling (TGFB1, TGFB2, TGFBRI, TGFBRII, SMAD3 and SMAD2) and the development of sporadic PD. A total of 275 unrelated Spanish Caucasian individuals were included in the study (141 cases and 134 controls), with 132 individuals in the discovery phase and 143 individuals in the replication phase. Next-generation sequencing identified a total of 409 variants in the coding, splicing, and untranslated regions of these genes. Analysis of common variants in the discovery phase revealed an association between PD and the TGFB1 rs8179181 variant, which was further confirmed in the replication phase [odds ratio (OR) 0.48, 95% confidence interval (CI) 0.32-0.73, p = 0.00057). A weak association of the SMAD3 rs11556089 polymorphism with PD was also detected (OR 0.49, 95% CI 0.26-0.93, p = 0.0375). Seven haplotypes were identified; however, there were no significant differences in their frequencies between patients with PD and controls. In conclusion, both the discovery and replication phases of this study suggest that the rs8179181 variant of TGFB1 represents a novel susceptibility locus for PD. HIGHLIGHTSO_LIDeficient TGF-{beta} signalling via Smad3 induces the formation of -synuclein aggregates and a parkinsonian pathology in mice. C_LIO_LITGFB1, TGFB2, TGFBRI, TGFBRII, SMAD3 and SMAD2 genes were sequenced to search for associations of their allelic variants with idiopathic PD. C_LIO_LITwo independent case-control studies of Spanish Caucasian individuals identified 409 genetic variants in their coding, splicing and UTR regions. C_LIO_LIThe rs8179181 SNP in TGFB1 was reproducibly associated with idiopathic PD, representing a novel PD susceptibility locus. C_LI

Alpha-synuclein has been implicated in neurodegenerative diseases such as Parkinsons disease and Dementia with Lewy bodies, with A53T and A30P mutations shown to be disease-causing. It has been reported that transgenic mice with tyrosine hydroxylase promotor-driven expression of A53T / A30P mutant alpha-synuclein in dopamine neurons provide a useful preclinical model of these conditions by virtue of developing dopaminergic neuronal cell death and related behavioral deficits. Here, we report a lack of replication of this finding. Despite detecting robust overexpression of A53T / A30P mutant alpha-synuclein in dopamine neurons, we observed neither cell death or related behavioral deficits in these mice. Our results demonstrate that preclinical models of synucleinopathy need careful validation in the field.

We investigated whether people with Parkinson's disease who are dual GBA1+LRRK2 carriers have a milder, LRRK2-like phenotype as previously reported. This was accomplished by comparing clinical features and alpha-synuclein seed amplification assay (SAA) positivity rates between dual GBA1+LRRK2-PD(n=13), GBA1-PD(n=169) and LRRK2-PD(n=175) carriers in a cross-sectional retrospective study of Parkinson's Progression Markers Initiative (PPMI) data. Our results show that GBA1+LRRK2-PD rate(83%) is closer to GBA1-PD rate(87%) rather than LRRK2-PD rate (62%mp-value>0.05). GBA1+LRRK2-PD have both non-motor and motor phenotypic similarity of GBA1-PD(p-value>0.05). This small PPMI cohort indicates that dual GBA1+LRRK2-PD carriers' SAA positivity and phenotype are aligned with GBA1-PD.

Asymmetric arm swing reduction is a hallmark of early-stage Parkinsons disease (PD). We evaluated wrist sensor-based arm swing measures during free-living gait as digital progression biomarkers in 623 early-stage PD participants and 50 controls monitored continuously for one year (controls) or two years (PD). Biweekly measures were extracted from gait segments without other arm activities. Arm swing measures were reduced in PD, reduced on the most affected side, moderately correlated with clinical motor severity, and highly reliable. In unmedicated participants, most affected side measures declined over one year (standardized response means: -0.32 to -0.78) and two years (-0.51 to -1.10), exceeding an MDS-UPDRS Part III subscore at one year (-0.21) and matching it at two years (-0.83). In medicated participants, arm swing increased on the most affected side, which was associated with higher dopaminergic doses and dyskinesia. Overall, free-living arm swing measures are promising progression biomarkers in early, untreated PD.

BackgroundNilotinib, a tyrosine kinase Abelson inhibitor, exhibits neuroprotective effects in preclinical Parkinson disease (PD) models. MethodsThis Phase 2A double-blind placebo-controlled study in moderate/advanced PD randomized participants 1:1:1 to placebo:150:300 mg nilotinib in matching capsules once daily for 6 months. The primary outcomes were safety and tolerability, the latter defined as ability to complete the study on assigned dose. Secondary outcomes included change in PD disability (Movement Disorder Society Unified Parkinsons Disease Rating Scale (MDS-UPDRS), Part 3 OFF/ON). Additional exploratory outcomes included serum and cerebrospinal fluid (CSF) pharmacokinetic (PK) profile, and CSF dopamine metabolites. FindingsThe study screened 125 and enrolled 76 participants (39% screen failure) between November 2017 and December 2018 at 25 US sites. The last participant completed the study in September 2019. At baseline, mean (standard deviation) age was 64.6 years (7.5), disease duration 9.9 years (4.7), MDS-UPDRS Part 1-3 OFF score 66.4(19.3) and ON score 48.4(16.2), Montreal Cognitive Assessment (MoCA) score 27.1(2.2). Tolerability was 21(84%):19 (76%):20 (77%) in placebo:150:300 mg arm, respectively. Both active doses were safe. The most common reasons for drug suspension were elevations of amylase and/or lipase, which were dose-dependent. The 300 mg group had transitory worsening of MDS-UPDRS-3 ON at 1 month compared to placebo (p<0.01), which resolved by 6 months. There was no difference in the change of MDS-UPDRS-3 OFF from baseline to 6 months between the groups (p=0.17). CSF/serum PK ratio was 0.2-0.3%. There was no evidence of treatment-related elevation of any dopamine metabolites. InterpretationBoth doses of nilotinib were safe and tolerable in these participants, who were selected with strict inclusion/exclusion criteria. There was no evidence of any symptomatic benefit of nilotinib. The drug had low CSF exposure and failed to change dopamine metabolites. These findings do not warrant further testing of nilotinib in PD. FundingThe study was funded by Funded by Michael J Fox Foundation for Parkinsons Research / The Cure Parkinson Trust / Van Andel Institute. Clinicaltrials.gov NCT03205488

As the number of Parkinsons patients is expected to increase with the growth of the aging population there is a growing need to identify new diagnostic markers that can be used cheaply and routinely to monitor the population, stratify patients towards treatment paths and provide new therapeutic leads. Genetic predisposition and familial forms account for only around 10% of PD cases [1] leaving a large fraction of the population with minimal effective markers for identifying high risk individuals. The establishment of population-wide omics and longitudinal health monitoring studies provides an opportunity to apply machine learning approaches on these unbiased cohorts to identify novel PD markers. Here we present the application of three machine learning models to identify protein plasma biomarkers of PD using plasma proteomics measurements from 43,408 UK Biobank subjects as the training and test set and an additional 103 samples from Parkinsons Progression Markers Initiative (PPMI) as external validation. We identified a group of highly predictive plasma protein markers including known markers such as DDC and CALB2 as well as new markers involved in the JAK-STAT, PI3K-AKT pathways and hormonal signaling. We further demonstrate that these features are well correlated with UPDRS severity scores and stratify these to protective and adversarial features that potentially contribute to the pathogenesis of PD.

Background and Objectives: PD is the second most common neurodegenerative disorder and the fastest growing. Genetic factors account for [~]15% of cases. Despite some consistency in symptoms across idiopathic and genetic PD cases, tracking progression and treatment response remains an important challenge especially in the development of new therapies. There have been many traditional approaches to tracking including DaTscan imaging, cardiac 123I-MIBG scintigraphy, MRI, CSF analysis, and following clinical symptom progression. Methods: Our previous work showed that peripheral blood mononuclear cells (PBMCs) expressing dopamine transporter (DAT) and tyrosine hydroxylase (TH) in PD patients may correlate with disease progression and with the response to treatment with levodopa. We describe a single case longitudinal follow up of a 40-45-year-old woman with PD who carried a heterozygous TH mutation. We assessed her clinical features over 18 months with DaT scans and immunophenotyping of her PBMCs. Her data were compared with idiopathic PD (n=130 subjects, both sexes) and healthy controls (n=80, age/sex matched). Results: The results revealed a rise in DAT+ immune cells which occurred coincident to documented worsening of her UPDRS-III motor scores. Unlike idiopathic PD patients, following levodopa therapy, the TH+ immune cell levels remained elevated, despite UPDRS-III score improvement. Discussion: The longitudinal immunophenotyping in this PD patient with a TH mutation suggested that DAT+ and TH+ PBMCs could be candidate biomarkers for PD progression and possibly treatment effectiveness. This study provides proof of concept to explore this approach to investigate immunophenotyping in PD progression.

Transcranial alternating current stimulation (tACS) is a promising noninvasive intervention for modulating pathological brain oscillations in Parkinson's disease (PD). To evaluate its clinical and neurophysiological efficacy, we searched five databases (Web of Science, PubMed, Scopus, Google Scholar and APA PsycInfo) up to August 31, 2025, for trials employing tACS in patients with idiopathic PD. Risk of bias was assessed using the RoB 2 and ROBINS-I tools. Random-effects meta-analyses were used to calculate standardized (SMD) and unstandardized mean differences (MD) with 95% confidence intervals (CIs). We included 10 studies (184 patients with PD, mean age: 64.9, mean disease duration: 5.2 years) in the qualitative review and seven trials (146 patients with PD, mean age: 65.6, mean disease duration: 5 years) in the meta-analysis. No statistically significant differences favoring active tACS over control were found in overall motor severity (UPDRS: SMD = 0.21, 95% CI [-0.10, 0.52], p = 0.097), tremor (SMD = -0.40, 95% CI [-1.97, 1.17], p = 0.478), or a neurophysiological marker of inhibitory response, represented by short intracortical inhibition (MD = 0.00, 95% CI [-0.40, 0.41], p = 0.971). The prediction intervals indicated substantial uncertainty, and significant between-study heterogeneity was observed, particularly for tremor outcomes (I2 = 86.1%). This variability and limitation in evidence quality is largely driven by small sample sizes, highly heterogeneous stimulation protocols, and varying outcome assessments. Systematically, tACS was generally well-tolerated, with no serious adverse events reported across the included studies; however, formal safety assessment was beyond the scope of this review. Current exploratory evidence shows a lack of consistent improvements in motor symptoms or functions in PD largely due to protocol-level heterogeneity. Future studies should consistently assess the MDS-UPDRS III post-tACS and report its specific subscores alongside neurophysiological measures to enable robust meta-analyses.

IntroductionPrevious research has shown that inflammatory immune biomarkers including peripheral white blood cell subpopulations differ between Parkinsons disease (PD) patients and healthy controls (HC), with idiopathic PD exhibiting higher neutrophil to lymphocyte ratio (NLR). The aim of our present report was to assess the peripheral immune profile in patients or asymptomatic carriers harboring the p.A53T alpha-synuclein (SNCA) mutation. MethodsData regarding 31 p.A53T SNCA PD patients, 9 asymptomatic mutation carriers and 194 HCs were obtained from the database of the Parkinsons Progression Markers Initiative (PPMI). Focus was placed on peripheral immune blood cells subpopulations and clinical/imaging parameters during the initial study assessment. ResultsNLR, Absolute Neutrophil cell count and Neutrophil to total Leukocytes ratio were increased in the p.A53T SNCA PD group as compared to HCs [2,77 vs 2,18 (p<0.001), 4,32x10^3 cells/L vs 3,67x 10^3 cells/L (p=0.001), 65,67% vs 59,55% (p<0.001) respectively]. Differences in NLR were mainly driven by the male patient subgroup. The absolute Lymphocyte cell count showed a trend towards being decreased in p.A53T PD, and Lymphocyte to total leukocytes ratio was lower in p.A53T SNCA cohort as compared to HC [26,16% vs 30,02% (p=0.001)]. Monocyte to total Leukocytes ratio was lower in p.A53T PD 5,49% vs 6,74% (p=0.002). Finally, we observed a positive correlation between the absolute Lymphocyte count and the mean putamen DATSCAN signal. Asymptomatic carriers did not differ statistically from p.A53T SNCA PD or HC regarding leucocyte subpopulations counts. DiscussionOur current study provides evidence of a specific pattern of peripheral immune response in the p.A53T SNCA PD group which aligns well with literature data in idiopathic and other genetic PD forms. Furthermore, given former evidence that alpha-synuclein represents an immune target in PD, we can speculate a putative underlying inflammatory pathway in this archetypal form of genetic synucleinopathy.

BackgroundParkinsons disease (PD) is a progressive neurodegenerative disorder with complex pathophysiology. The potential of integrating biomarkers of neuronal injury, neuroinflammation, and modulators of Wnt signaling for PD diagnosis remains largely unexplored. ObjectiveThis study aimed to evaluate the diagnostic and clinical predictive value of a ten-biomarker serum panel encompassing markers of neuronal injury (NSE, UCHL1), neuroinflammation (GFAP, HMGB1), synaptic plasticity (BDNF), proteinopathy (-Synuclein, {beta}-Amyloid-42), and Wnt signaling (R-spondin-1, DKK1, Sclerostin), with a particular focus on chronic fatigue in PD. MethodsIn this case-control study, 90 PD patients and 45 healthy controls were enrolled. Serum biomarkers were quantified using ELISA. Clinical severity was assessed using the Movement Disorder Society-Unified Parkinsons Disease Rating Scale (MDS-UPDRS) and Fibro-Fatigue (FF) scales. Binary logistic regression and multiple linear regression analyses were used to evaluate the diagnostic and predictive value of biomarkers for PD diagnosis, psychiatric and motoric scores, and an FF score reflecting chronic fatigue syndrome (CFS) severity. ResultsA model incorporating NSE, DKK1, and {beta}-Amyloid-42 effectively discriminated PD patients from controls, yielding an area under the curve (AUC) of 0.932 and an overall accuracy of 83.0%. NSE and DKK1 emerged as the main predictors of overall disease severity, motor symptoms, and CFS severity. Regression analyses indicated that 41.3% of the variance in the FF score was explained by increased NSE, DKK1, {beta}-amyloid, and UCHL1, while 42.9% of the variance in psychiatric symptoms was explained by increased NSE, DKK1, and {beta}-amyloid. Increased GFAP levels were significantly associated with motor dysfunction. ConclusionThe combined presence of neuronal injury, Wnt signaling dysregulation, and amyloid pathology may represent a key pathophysiological component underlying PD, CFS-like fatigue, and psychiatric symptoms in PD. Targeting neuronal injury and Wnt signaling pathways may offer novel therapeutic strategies for managing fatigue and psychiatric manifestations in PD.

BackgroundThe definite diagnosis of Parkinsons disease (PD) is usually made by the detection of -synuclein aggregates in the brain post mortem with the rare exception of some genetic forms. Traces of -synuclein aggregates in extracerebral tissue biopsies may serve as an appropriate biomarker to confirm a clinical diagnosis in vivo. ObjectivesWe set out to determine whether the detection of -synuclein aggregates in submandibular gland biopsies is an effective means for diagnosing PD patients. MethodsWe examined submandibular gland biopsies from 25 patients with PD under investigation and 25 age-matched controls to detect -synuclein aggregates using real-time quaking induced conversion (RT-QuIC) as a seed amplification-assay and immunohistochemical -synuclein aggregate detection and paraffin-embedded tissue blot (PET-blot) as confirmatory methods. ResultsOur RT-QuIC assay detected -synuclein aggregates in submandibular gland biopsies with a sensitivity of 81,1%, which increased to 90% after a clinical follow-up, and a specificity of 100%. The PET-blot with mAb5C12 confirmed 50% of the RT-QuIC positives and offered a sensitivity of 45,8% (50% after clinical follow-up) and a specificity of 100%. Immunohistochemical detection using the same antibody confirmed 28% of the RT-QuIC positives, but found two of the controls to be positive and therefore provided a sensitivity of 26,1% (28,6% after clinical follow-up) and a specificity of 92%. ConclusionsThe RT-QuIC Assay demonstrated comparable sensitivity to the clinical diagnosis (when neuropathologic examination represents the gold standard) and exhibited a similar level of specificity as the PET-blot.