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.

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.

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.

Braak and others have proposed that Lewy body pathology LBP in Parkinson disease PD may arise not only in the brain but alternatively from an initial site in the gastrointestinal GI tract with subsequent passage to the central nervous system CNS through the vagus nerve or other routes. We tested this hypothesis by using both immunohistochemistry IHC and RT QuIC a form of alpha synuclein seed amplification assay SAA to detect alpha synuclein LBP in samples from selected brain regions and 10 GI tract sites taken from autopsies of 50 PD subjects and 128 elderly subjects without parkinsonism or dementia including 34 with IHC identified CNS incidental Lewy body disease ILBD and 94 with no Lewy body IHC pathology detected NLB. A positive SAA or IHC result was restricted to the GI tract in only 2 subjects while LBP by either SAA or IHC was restricted to the brain in 11 subjects. To fairly compare GI only with brain only synucleinopathy however we would have to do SAA on brain samples from all ILBD and NLB cases in at least 4 critical brain regions olfactory bulb medulla pons and amygdala. Further SAA of brain regions is estimated based on the proportional results to date to potentially identify 21 additional brain only LBP subjects total of 32 if it were done on all of the NLB subjects. From this brain only LBP is estimated to be 16 times more common than GI only LBP. To assess the clinical impact of SAA positive GI sites we found that the number of positive sites per subject is significantly correlated with UPDRS motor score and SCOPA AUT GI related scores including those for salivation straining constipation and bowel movement.

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.

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.

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

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.

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.

BackgroundEffective, measurable, and non-invasive treatments for motor symptoms, gait and balance difficulties, and associated non-motor burden in Parkinsons disease (PD) remain limited. We aimed to assess the usability, safety/tolerability, and clinical efficacy of CUE1+, a wearable cueing and vibrotactile stimulation non-invasive device, in people with PD. MethodsThis 12-week, double-blind, randomised controlled trial was conducted at two UK sites in adults with idiopathic PD. Participants were randomly assigned (1:1) to receive either an active CUE1+ device or a sham device, worn on the sternum for 8 hours daily. Participants, investigators, and assessors were blinded to treatment allocation. The primary outcomes were usability and safety/tolerability of CUE1+. Secondary outcomes, including Movement Disorder Society-sponsored revision of the Unified PD Rating Scale (MDS-UPDRS) Part III, were assessed in the ON-medication state at baseline and week 13. FindingsFifty participants were randomised to sham stimulation (Group A; n=25) or active CUE1+ stimulation (Group B; n=25). Median age was 70.0 years (IQR 65.0-75.5) in Group A and 68.0 years (62.0-75.0) in Group B. Group A included 14 (56%) men; Group B, 13 (52%) men. Four participants (8.0%) discontinued: three (6.3%) from Group A, one (2.0%) from Group B. Compliance to allocated intervention was equally excellent in both groups. Mild, transient skin irritation occurred in two participants (4.2%). MDS-UPDRS Part III scores improved by -4.5 points (95%CI: -8.7, -0.4; p=0.043), in Group A and -15.6 points (95%CI: - 20.3, -10.9; p<0.0001) in Group B, with a between-group difference of 11.08 points (95%CI: 4.85-17.31; p=0.002). InterpretationCUE1+ is a safe and well-tolerated non-invasive device that improves motor and non-motor outcomes in PD. These findings suggest a potential therapeutic benefit and support further evaluation in large-scale RCTs and consideration for integration into health care pathways. FundingUKRI Knowledge Transfer Partnership, 2021-2022, round 4 and Charco Neurotech Ltd.

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.

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.

BackgroundProgressive supranuclear palsy (PSP) is a rare, disabling, neurodegenerative disease. There are limited studies on the spectrum of PSP predominance-types and their clinico-demographic features among Asian patients. We prospectively characterized the clinical features, disease severity, and caregiver burden in a multi-ethnic Asian PSP cohort. MethodsConsecutively-recruited patients with PSP (n=104, 64.4% male; 67.3% Chinese, 21.2% Indians, 9.6% Malays) were extensively phenotyped by a movement disorders neurologist using the MDS-PSP clinical diagnostic criteria and PSP-Clinical Deficits Scale (PSP-CDS). Caregiver burden was measured using the modified Zarit Burden Interview (ZBI). Investigations were reviewed to help rule out potential PSP mimics. ResultsThere were 104 patients, consisting of 48.1% Richardson syndrome (PSP-RS), 37.5% parkinsonian phenotype (PSP-P), and 10.6% progressive gait freezing phenotype (PSP-PGF). Mean age at motor onset was 66.3{+/-}7.7 years, with no significant differences between the PSP phenotypes. Interestingly, REM-sleep behaviour disorder (RBD) symptoms and visual hallucinations (considered rare in PSP) were reported in 23.5% and 22.8% of patients, respectively, and a family history of possible neurodegenerative or movement disorder in 20.4%. PSP-CDS scores were highest (worst) in PSP-RS; and correlated moderately with disease duration (rs=0.45, P<0.001) and weakly with caregiver burden (rs=0.22, P=0.029) in the overall cohort. Three of 48 (6.3%) patients who had whole-exome sequencing harboured pathogenic/likely pathogenic GBA variants. ConclusionsThis prospective characterization of a relatively large cohort of Asian PSP patients depicts significant heterogeneity in clinical features and disease burden. Unexpectedly high rates of RBD symptoms, visual hallucinations, and familial involvement warrant further study.

Skin biopsies of patients with parkinsonism, mild cognitive impairment or dementia might offer a simple and relatively non-invasive means to determine whether -synuclein aggregates might be the underlying pathology. Accurate biomarkers are critically needed for Lewy body disease (LBD) clinical trials but currently there are none that have undergone full regulatory scrutiny. We sought to simulate the rigor of a diagnostic study done with regulatory oversight in this study of the accuracy of skin biopsies processed by -synuclein seeding amplification assays (SAA) in predicting the clinical diagnoses of Parkinson disease (PD), PD with dementia (PDD) and dementia with Lewy bodies (DLB). Our study design utilized parallel blinded performances of assays in two independent, experienced SAA assay laboratories. For control subjects without clinical LBD, we used a clinically heterogeneous set, simulating a cross-section of elderly, in comparison with previous studies that have mainly used cases and controls that have been prescreened to accentuate group differences. Subjects clinically diagnosed with PD, PDD and DLB as well as those without a suspected LBD were recruited from three sites, including the Mayo Clinic Arizona, Barrow Neurological Institute and Banner Sun Health Research Institute (BSHRI), all located in metropolitan Phoenix, Arizona. The LBD group was designated as Group 1 while the non-LBD groups were divided between a Group 2 and a Group 3, based on the absence (Group 2) or presence (Group 3) of potential clinical risk factors for LBD, including mild cognitive impairment, dementia, REM sleep behavior disorder and hyposmia. Skin punch biopsies were collected from the posterior cervical area and three biopsies were analyzed by SAA between the two labs. Sensitivity across assays ranged between 50.0% and 60.0% while specificity ranged between 69.6% and 100%. Comparisons of Group 1, with the highest clinical diagnostic confidence for the presence of an LBD, versus Group 2, with no clinical indicators of relevant abnormalities, produced the greatest specificities, between 77.3% and 100%, while sensitivities were less variable, ranging between 50% and 60% on group comparisons. Specificities were lower when Group 3 subjects, with potential LBD risk factors, were included in the calculations. Pairwise agreement between biopsy assays ranged from excellent, with a kappa of 0.816, to moderate, between 0.47 and 0.67. Agreement may have been affected by differing protocols, as substrate and testing strategies were different between the two laboratories. Also, it might be possible that variability in -synuclein seed concentrations within different skin biopsies might have contributed to differences in the outcome of the testing by the two labs. The greater agreement for Biopsy 3 was perhaps to be expected given that a single biopsy was analyzed by both labs and the homogenates were prepared by a single lab (Lab 2) and then shared between labs; homogenates for Biopsies 1 and 2 were separately prepared and separately assayed in Labs 1 and 2. A separate analysis of subjects diagnosed with PDD or DLB indicated that skin SAA may have a greater sensitivity for clinically advanced LBD. Nine of these eleven subjects had at least one positive assay, for a sensitivity of 81.82%, substantially better than the 57.1% sensitivity for probable PD subjects without dementia. This suggests that skin SAA may have greater utility as a diagnostic and progression biomarker of Lewy body dementias, as compared with PD subjects without dementia.

ObjectiveParkinsons disease (PD) is a neurodegenerative disorder characterized by motor and non-motor symptoms. Visual impairments, such as strabismus (misalignment of the eyes during gaze holding), affect up to two-thirds of PD patients, impacting their quality of life. Conventional treatments offer limited relief, prompting exploration of alternatives like deep brain stimulation (DBS) of subthalamic nucleus (STN). This pilot study aims to assess whether STN DBS can alleviate PD-related strabismus and identify specific STN regions associated with favorable outcomes. We hypothesize that STN DBS improves strabismus by modulating subthalamic connectivity with the cerebellum, hence volume of activate tissue (VTA) generated with DBS will be in dorsal STN. MethodsWe studied 12 PD patients with bilateral STN DBS and five healthy controls. Clinical assessments, eye movement measurements using high-resolution eye tracking, and patient-specific DBS models were employed. Analysis included the VTA models, revealing distinct effects based on the location within the STN. ResultsWe found significant strabismus in 66% of PD patients. STN DBS improved strabismus in 75% of cases. The improvement was associated with dorsal STN stimulation. STN DBS exacerbated strabismus in 25% of PD patients. The VTA in these participants were located in the ventral aspect of the STN. DiscussionThe findings highlight the significant effects of STN DBS on strabismus in PD, further offering insights into the complex interplay between neurodegeneration and control of eye alignment. This approach, combining clinical assessments, advanced eye tracking, and DBS computational modeling, contributes valuable knowledge towards targeted interventions for visual impairments in PD.

Background: Freezing of gait (FOG) is a disabling and often underrecognized feature of Parkinsons disease (PD). Objective gait analysis may improve characterization of this motor symptom. Objective: To compare quantitative 3D gait parameters in PD with FOG (PDF) and PD without FOG (PDNF) in a routine clinical cohort. Methods: We retrospectively analyzed a sequential sample of 180 patients with PD referred for motion analysis between 2020 and 2024. All patients underwent 3D motion capture in the off-medication state. Eighteen gait outcomes spanning pace, rhythm, postural control, variability, and asymmetry domains were derived from steady-state walking tasks. FOG status was determined using physician documentation and Movement Disorder Society Unified Parkinsons Disease Rating Scale (MDS-UPDRS) items. Group differences between PDF (n=99) and PDNF (n=81) were evaluated using independent samples t-tests, with outcomes adjusted for disease duration and corrected for multiple comparisons. A secondary analysis among PDF compared those in Hoehn and Yahr (H&Y) stage [&ge;]III to those in H&Y [&le;]II. Results: PDF had longer disease duration, higher OFF MDS-UPDRS III scores, and higher Hoehn and Yahr stage than PDNF but were similar in age and sex. After adjusting for disease duration and multiplicity, PDF demonstrated reduced step length, stride length, and forward velocity, and greater cadence variability, while most postural control, and asymmetry measures were comparable between groups. Among PDF, advanced H&Y stage was associated with impaired pace and rhythm, similar to previous reports among PD in general. Conclusion: In this large, sequential, clinically referred cohort, FOG was associated with more advanced PD and specific impairments in pace and gait variability. These findings support comprehensive 3D gait analysis as an objective tool to better delineate FOG-related gait abnormalities and identify features that may predict FOG, informing targeted interventions.