The development of biomarkers capable of reliably detecting pathologic forms of α-synuclein (aSyn) in vivo marks a significant step forward in the field of neurodegeneration. Over the recent years, CSF aSyn seed amplification assays (aSyn-SAA) and skin biopsy phospho-aSyn immunofluorescence (skin aSyn-IF) testing were developed that detect pathologic aSyn seeds and phosphorylated aSyn aggregates, respectively, in patients with synucleinopathies, which include Parkinson disease, dementia with Lewy bodies, and also multiple system atrophy. High rates of positivity have also been documented in research participants at a risk of developing future aSyn-related disease (e.g., hyposmia and REM sleep behavior disorder), as well as other contexts. These assays have numerous potential applications in research settings and clinical care. Here, we review the currently published evidence supporting CSF aSyn-SAA and skin aSyn-IF testing and discuss their potential research applications in clinical trials. As CSF aSyn-SAA and skin aSyn-IF testing is now commercially available to clinicians in nonresearch settings, we also explore their current utility and limitations as diagnostic tools and call for the development of a formal clinical use guidelines. We also highlight where critical knowledge gaps remain and explore emerging developments related to these assays.

Kidney function declines with age, largely due to chronic low-grade inflammation. Mesenchymal stem cells (MSCs) have demonstrated immunomodulatory effects in certain immune-mediated kidney diseases, but their role in preserving renal function in aging individuals without chronic kidney disease (CKD) remains unclear. This study presents secondary outcome findings from a randomized clinical trial in Parkinson’s disease (PD), evaluating the impact of allogeneic human bone marrow-derived MSCs (allo-hMSCs) on kidney function in an aging population with PD with preserved renal function. Subjects with PD aged 50–79 years with baseline estimated glomerular filtration rate (eGFR) > 60 mL/min/1.73 m2 were randomized to receive either three allo-hMSC infusions, one placebo followed by two allo-hMSC infusions, or three placebo infusions at 18-week intervals. Kidney function was assessed using eGFR, serum creatinine (SCr), and blood urea nitrogen (BUN) at baseline, 9 weeks after the first two infusions, and at weeks 40 and 88. eGFR was calculated using the 2021 CKD-EPI equation. A Bayesian modeling approach was used to estimate posterior probabilities (PP) of treatment effects. Of 45 randomized patients, 44 were analyzed; 43 completed infusions, and 40 completed the 88-week follow-up. The three-infusion group (N = 16) showed an average annual eGFR increase of 3.29 mL/min/1.73 m2, versus declines of –1.46 and –2.92 in the two-infusion (N = 14) and placebo (N = 15) groups. SCr decreased by –0.12 mg/dL at both weeks 40 (PP: 93.9 https://clinicaltrials.gov/study/NCT04506073

Rapid-eye-movement sleep behavior disorder (RBD) is a parasomnia causing motor behaviors and vocalizations during sleep, which can lead to injuries in patients and their bed partners. Adult-onset RBD generally precedes a neurodegenerative synucleinopathy, while other cases can be associated with antidepressant use, neurotrauma and narcolepsy. The management of RBD relies on the systematic identification of etiologic and contributing factors, implementation of safety measures, appropriate pharmacotherapy and counseling, which should be patient-centered. In this manuscript, we summarize the evidence on the management of RBD. We summarize the evidence supporting the use of clonazepam, melatonin, rivastigmine, and pramipexole, the four agents currently recommended by the American Academy of Sleep Medicine. For each agent and for alternative therapies, we discuss efficacy, dosing, adverse effects and indications. We integrate the current knowledge on therapies in RBD in treatment algorithms that can guide providers in choosing the most appropriate initial therapy, and alternative options based on the course of symptoms and comorbidities. There is a large need for additional, well tolerated therapies for reducing RBD symptoms. The last section of this manuscript discusses current challenges and unmet needs, as well as future directions in developing therapies and improving the care of patients with RBD.

BACKGROUND:Neuroinflammation contributes to Parkinson's disease (PD) progression and motor dysfunction. Allogeneic human mesenchymal stem cells (allo-hMSCs) may reduce neuroinflammation and improve motor symptoms. OBJECTIVES:To evaluate the efficacy of repeated intravenous doses of 10 × 106/kg allo-hMSCs in improving motor symptoms in patients with PD (PwP). METHODS:In this phase 2, randomized, placebo-controlled trial (November 2020-July 2023), mild-to-moderate PwP received either three allo-hMSC infusions, one placebo followed by two allo-hMSC infusions, or three placebo infusions at 18-week intervals. Follow-up lasted 88 weeks. The primary outcome was a >70% posterior probability (PP) of a difference in the proportion of participants with ≥5-point improvement in OFF-medication Movement Disorder Society Sponsored Revision of the Unified Parkinson's Disease Rating Scale-Part III (MDS-UPDRS-III) at week 62. Bayesian analysis was conducted using R v4.2.0. RESULTS:Forty-five PwP were enrolled. A larger proportion of subjects achieved a ≥5-point improvement in MDS-UPDRS-III in the three-infusion arm compared with placebo at week 62 (mean difference [MD]: 5.0%, PP = 93.7%), translating to a 16.9-point improvement in MDS-UPDRS-III in the three-infusion arm compared with a 14.6-point improvement in the placebo arm. Conversely, fewer subjects in the two-infusion arm compared with placebo showed ≥5-point improvement at week 62 (MD: -62.4%, PP ≥ 99.9%), translating to only a 3.9-point improvement in MDS-UPDRS-III in the two-infusion arm. However, improvement in MDS-UPDRS-III was seen across all treatment arms. Adverse events were mild and transient. CONCLUSIONS:Three infusions of 10 × 106 allo-hMSCs/kg improved motor function in mild-to-moderate PwP, while two infusions showed less improvement than placebo. To address this discrepancy, future studies should conduct functional potency assays to understand batch-to-batch variability affecting clinical efficacy. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Deep brain stimulation (DBS) advances enable the recording of local field potentials (LFP) in real-world settings. LFP recordings from the subthalamic nucleus (STN) and globus pallidus internus (GPi) in people with Parkinson's disease (PwPD) have illuminated the role of oscillatory synchronization in parkinsonian motor symptoms [ [1] van Wijk B.C.M. de Bie R.M.A. Beudel M. A systematic review of local field potential physiomarkers in Parkinson's disease: from clinical correlations to adaptive deep brain stimulation algorithms. J. Neurol. 2022; Google Scholar , [2] Yin Z. Zhu G. Zhao B. et al. Local field potentials in Parkinson's disease: a frequency-based review. Neurobiol. Dis. 2021; 155105372 Crossref PubMed Scopus (42) Google Scholar ].

•Early differentiation between PD and atypical parkinsonism is challenging.•Variability in diagnosis can weaken statistical power in trials.•Precise diagnostic tools are needed for trial population homogeneity.•This patient initially diagnosed with PD, was diagnosed with MSA via CSF αSyn-SAA.•Adding αSyn-SAA to inclusion criteria could enhance subject selection in trials.

Background and purpose The intestinal microbiome plays a primary role in the pathogenesis of neurodegenerative disorders and may provide an opportunity for disease modification. We performed a pilot clinical study looking at the safety of fecal microbiota transplantation (FMT), its effect on the microbiome, and improvement of symptoms in Parkinson's disease. Methods This was a randomized, double-blind placebo-controlled pilot study, wherein orally administered lyophilized FMT product or matching placebo was given to 12 subjects with mild to moderate Parkinson's disease with constipation twice weekly for 12 weeks. Subjects were followed for safety and clinical improvement for 9 additional months (total study duration 12 months). Results Fecal microbiota transplantation caused non-severe transient upper gastrointestinal symptoms. One subject receiving FMT was diagnosed with unrelated metastatic cancer and was removed from the trial. Beta diversity (taxa) of the microbiome, was similar comparing placebo and FMT groups at baseline, however, for subjects randomized to FMT, it increased significantly at 6 weeks ( p = 0.008) and 13 weeks ( p = 0.0008). After treatment with FMT, proportions of selective families within the phylum Firmicutes increased significantly, while proportion of microbiota belonging to Proteobacteria were significantly reduced. Objective motor findings showed only temporary improvement while subjective symptom improvements were reported compared to baseline in the group receiving FMT. Constipation, gut transient times (NS), and gut motility index ( p = 0.0374) were improved in the FMT group. Conclusions Subjects with Parkinson's disease tolerated multi-dose-FMT, and experienced increased diversity of the intestinal microbiome that was associated with reduction in constipation and improved gut transit and intestinal motility. Fecal microbiota transplantation administration improved subjective motor and non-motor symptoms. Clinical trial registration ClinicalTrial.gov , identifier: NCT03671785.

Objective: To determine the association of real-world local field potential (LFP) recordings in patients with Parkinson's disease (PD) with mobility quality of life (m-QoL), patient demographics, interhemispheric recordings, and stimulation parameters. Background: LFPs are associated with various symptoms in PD and are considered a biomarker of interest for deep brain stimulation (DBS). However, real-world LFP data is limited. Design/Methods: Twenty-seven patients (age: 63.7±9.4-years, Sex: 18-male, Disease Duration: 12.9±7.3-years) with PD and bilateral subthalamic nucleus DBS (STN-DBS) were included. Recordings occurred during routine clinic visits, OFF stimulation. Raw LFP data was processed to identify spectral peaks and frequency band power in the alpha, beta, and gamma ranges. M-QoL was assessed using the EuroQol-5 Dimensions (EQ-5D) question 1. Due to non-normally distributed data, non-parametric tests were used for all analyses with significance set at p<0.05. Results: Peaks were detected in 42(77.8%) of 54 STNs with 18(66.7%) patients demonstrating bilateral peaks and 6(22%) demonstrating unilateral peaks. No significant differences were found in LFP characteristics between hemispheres (p>0.05). Interhemispheric peak frequency (rho=0.46, p=0.06) and amplitude (rho=0.34, p=0.162) demonstrated non-significant interhemispheric correlations. Interhemispheric band power demonstrated a significant correlation in the low-beta (rho=0.43, p=0.027) and high-beta (rho=0.42, p=0.031) ranges. Those with worse m-QoL demonstrated increased low- (Z=−2.47, p=0.012, eta squared=0.23) and high-beta (Z=−2.26, p=0.023, eta squared=0.20) band power. No sex differences were noted across peak characteristics and beta band power averages (p>0.05). Peak characteristics and beta band power primarily demonstrated non-significant correlations with age, disease duration, and stimulation amplitude (p>0.05). Conclusions: LFP peaks were readily detected in real-world, clinical settings. Elevated STN low- and high-beta band power of patients with PD may be linked to worse m-QoL. This information, along with other significant findings related to STN LFPs, may guide further treatment of patients with PD and improve our understanding of PD pathophysiology. Disclosure: Dr. Morelli has received personal compensation for serving as an employee of Medtronic. Alexa Singer has received personal compensation for serving as an employee of Medtronic. Mrs. Sannelli has received personal compensation for serving as an employee of Medtronic GmbH. Mrs. Sannelli has stock in Metronic Inc.. Hideo Mure has nothing to disclose. The institution of Dr. Martinez has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Merz. The institution of Dr. Martinez has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biohaven. The institution of Dr. Martinez has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Amgen/Novartis. The institution of Dr. Martinez has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Abbott. The institution of Dr. Martinez has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Abbvie/Allergan. The institution of Dr. Martinez has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Abbvie/Allergan. The institution of Dr. Martinez has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Merz. The institution of Dr. Martinez has received research support from Medtronic. The institution of Dr. Martinez has received research support from Boston Scientific. The institution of Dr. Martinez has received research support from Abbvie/Allergan. Dr. Oyama has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Medtronic. Dr. Oyama has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Boston Scientific. Dr. Oyama has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Otsuka Pharmaceutical Co. Ltd.. Dr. Oyama has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Sumitomo Dainippon Pharma Co. Ltd.. Dr. Oyama has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Eisai Co., Ltd.. Dr. Oyama has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Takeda Pharmaceutical Company LTD.. Dr. Oyama has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Kyowa Hakko Kirin Co. Ltd.. Dr. Oyama has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for AbbVie, Inc. The institution of Dr. Oyama has received research support from AbbVie, Inc. The institution of Dr. Oyama has received research support from GLORY LTD. The institution of Dr. Oyama has received research support from Kirin Company LTD. The institution of Dr. Oyama has received research support from Mitsubishi UFJ Lease & Finance Company LTD. The institution of Dr. Oyama has received research support from Sunwels Co., Ltd. The institution of Dr. Oyama has received research support from Ohara Pharmaceutical Co.,Ltd.. The institution of Dr. Oyama has received research support from PARKINSON Laboratories Co., Ltd.. Mr. Falowski has received personal compensation in the range of $50,000-$99,999 for serving as a Consultant for Medtronic. Mr. Falowski has received personal compensation in the range of $100,000-$499,999 for serving as a Consultant for Abbott. Sarah Bick has nothing to disclose. Dr. Schiess has nothing to disclose. Dr. Farrokhi has nothing to disclose. Dr. Witt has nothing to disclose.

Background Tremor affects up to 45% of patients with Multiple Sclerosis (PwMS). Current understanding is based on insights from other neurological disorders, thus, not fully addressing the distinctive aspects of MS pathology. Objective To characterize the brain white matter (WM) correlates of MS-related tremor using diffusion tensor imaging (DTI). Methods In a prospective case-control study, PwMS with tremor were assessed for tremor severity and underwent MRI scans including DTI. PwMS without tremor served as matched controls. After tract selection and segmentation, the resulting diffusivity measures were used to calculate group differences and correlations with tremor severity. Results This study included 72 PwMS. The tremor group (n = 36) exhibited significant changes in several pathways, notably in the right inferior longitudinal fasciculus (Cohen's d = 1.53, q < 0.001) and left corticospinal tract ( d = 1.32, q < 0.001), compared to controls (n = 36). Furthermore, specific tracts showed a significant correlation with tremor severity, notably in the left medial lemniscus (Spearman's coefficient [ r s p] = −0.56, p < 0.001), and forceps minor of corpus callosum ( r s p = -0.45, p < 0.01). Conclusion MS-related tremor is associated with widespread diffusivity changes in WM pathways and its severity correlates with commissural and sensory projection pathways, which suggests a role for proprioception or involvement of the dentato-rubro-olivary circuit.

Objective: To identify the lowest mean and standard deviation of susceptibility in two reference regions, lateral ventricle (LV) and white matter (WM) and compare them to choroid plexus (CP) and putamen (PUT), two areas of known iron accumulation. Background: Quantitative Susceptibility Mapping (QSM) is a promising non-invasive approach for investigating Parkinson9s Disease, as several studies have reported a correlation of magnetic susceptibility with brain iron concentrations in vivo. Since QSM measures susceptibility relative to a reference value, a suitable reference region must be chosen to compare patients and the stages of the disease. Some studies using non-PD patients suggest LV as a reference with a low susceptibility of cerebrospinal fluid (CSF) that is closest to water, while others use white matter. Design/Methods: 44 PD patients underwent baseline QSM as part of a phase II mesenchymal stem cell trial assessing a disease-modifying therapy for PD. We compared the regional mean and standard deviation of susceptibility in parts per billion in left (LH) and right hemisphere (RH) LV, WM, CP and PUT after image processing in QSMxT. Results: WM had the lowest susceptibility (LH mean −1.044 std 0.939, RH −1.053 std 0.950), followed by LV (LH mean 3.181 std 1.654, RH 3.167 std 1.555). The two iron-accumulating regions had higher susceptibility, with CP (LH mean 5.205 std 4.214, RH mean 6.316 std 4.404) followed by PUT (LH mean 7.069 std 4.068, RH 7.301 std 4.247). Notably, both left, and right LV susceptibility were significantly higher than left and right hemisphere WM (LH LV vs. LH WM t(43)=14.44, p<0.001; RH LV vs. RH WM t(43)=13.91, p<0.001). Conclusions: WM is a more suitable QSM reference region than LV in PD. However, elevated susceptibility of LV CSF may be promising for future QSM analysis in PD as a correlation of iron CSF levels with disease duration has been reported. Disclosure: The institution of Prof. Ellmore has received research support from NIMH. Dr. Suescun has nothing to disclose. The institution of Dr. Shahnawaz has received research support from American Parkinson Disease Association. The institution of Dr. Shahnawaz has received research support from NIH. The institution of Dr. Shahnawaz has received research support from Texas Alzheimer's Research & Care Consortium . Dr. Shahnawaz has received intellectual property interests from a discovery or technology relating to health care. Dr. Schiess has nothing to disclose.

The neurodegenerative synucleinopathies, including Parkinson’s disease and dementia with Lewy bodies, are characterized by a typically lengthy prodromal period of progressive subclinical motor and non-motor manifestations. Among these, idiopathic REM sleep behaviour disorder is a powerful early predictor of eventual phenoconversion, and therefore represents a critical opportunity to intervene with neuroprotective therapy. To inform the design of randomized trials, it is essential to study the natural progression of clinical markers during the prodromal stages of disease in order to establish optimal clinical end points. In this study, we combined prospective follow-up data from 28 centres of the International REM Sleep Behavior Disorder Study Group representing 12 countries. Polysomnogram-confirmed REM sleep behaviour disorder subjects were assessed for prodromal Parkinson’s disease using the Movement Disorder Society criteria and underwent periodic structured sleep, motor, cognitive, autonomic and olfactory testing. We used linear mixed-effect modelling to estimate annual rates of clinical marker progression stratified by disease subtype, including prodromal Parkinson’s disease and prodromal dementia with Lewy bodies. In addition, we calculated sample size requirements to demonstrate slowing of progression under different anticipated treatment effects. Overall, 1160 subjects were followed over an average of 3.3 ± 2.2 years. Among clinical variables assessed continuously, motor variables tended to progress faster and required the lowest sample sizes, ranging from 151 to 560 per group (at 50% drug efficacy and 2-year follow-up). By contrast, cognitive, olfactory and autonomic variables showed modest progression with higher variability, resulting in high sample sizes. The most efficient design was a time-to-event analysis using combined milestones of motor and cognitive decline, estimating 117 per group at 50% drug efficacy and 2-year trial duration. Finally, while phenoconverters showed overall greater progression than non-converters in motor, olfactory, cognitive and certain autonomic markers, the only robust difference in progression between Parkinson’s disease and dementia with Lewy bodies phenoconverters was in cognitive testing. This large multicentre study demonstrates the evolution of motor and non-motor manifestations in prodromal synucleinopathy. These findings provide optimized clinical end points and sample size estimates to inform future neuroprotective trials.

Objective: To present the design, baseline data and initial safety of subjects enrolled in an ongoing Phase II randomized, double-blind, placebo-controlled trial of mesenchymal stem cells (MSCs) as a disease-modifying therapy for idiopathic Parkinson's disease (PD). Background: Neuroinflammation plays a vital role in the pathogenesis of PD, thus supporting the rationale for using an immunomodulatory therapy such as MSCs for restoring homeostasis to the neuronal-glial microenvironment. Design/Methods: A total of 45 subjects were enrolled and randomized to 1 of the three treatment arms. 14 patients were randomized to arm 0, 15 were assigned to arm 1, and 16 were allocated to arm 2. The study design includes 3 treatment arms: a) 2 infusions of 10 X 10 6 MSC/kg and 1 placebo; b) 3 infusions of 10 X 106 MSC/kg; and c) 3 infusions of placebo. All subjects have received 3 infusions at 4-month intervals and have entered a 1-year follow-up. The last subject is projected to complete the study in August 2023. Results: All treatment‐related adverse events have been mild/moderate and temporary. There were no significant changes in CBC and CMP one month after the last infusion. Only one patient had a positive transient immunogenic reaction that could be related to the treatment. All Baseline characteristics appeared similar across groups. Subjects had a mean age of 66, an average modified H&Y of 2, a disease duration between 2 and 9 years, and mean total MDS-UPDRS total score of 64.9, and a mean MDS-UPDRS-III of 36.3. All patients used dopaminergic medications before baseline evaluation. Conclusions: This study is the first FDA-approved mesenchymal stem cell study for PD. Preliminary findings showed that repeated doses of intravenous infusion of allogeneic bone marrow-derived MSCs are safe and well-tolerated in PD. Efficacy and preliminary mechanism of action data will be reported in December 2023. Disclosure: Dr. Schiess has nothing to disclose. The institution of Prof. Ellmore has received research support from NIMH. The institution of Dr. Shahnawaz has received research support from American Parkinson Disease Association. The institution of Dr. Shahnawaz has received research support from NIH. The institution of Dr. Shahnawaz has received research support from Texas Alzheimer's Research & Care Consortium . Dr. Shahnawaz has received intellectual property interests from a discovery or technology relating to health care. Marie-Francoise Doursout has nothing to disclose. Dr. Adams has stock in Medtronic. Dr. Tharp has nothing to disclose. Dr. Suescun has nothing to disclose.