BackgroundMitochondrial membrane protein–associated neurodegeneration (MPAN) from the neurodegeneration with brain iron accumulation (NBIA) family is a rare neurodegenerative disease marked by α‐synuclein aggregation, brain iron accumulation, and midbrain dopaminergic neuron degeneration.ObjectiveThe mechanisms driving neuron vulnerability remain unclear. Our study aimed to develop a patient‐derived disease model replicating key pathologies of patient brains.MethodsWe generated induced pluripotent stem cell–derived midbrain dopaminergic neurons from MPAN patients and examined ultrastructural and biochemical markers of pathology.ResultsMPAN patient neurons displayed α‐synuclein aggregation, axonal swellings, iron accumulation, and severe membrane destruction. In addition, levels of the major histocompatibility complex class I (MHC‐I), linked to cellular stress and neurodegenerative processes, were elevated in patient neurons. Treatment with acetyl‐leucine, a potentially neuroprotective compound, decreased MHC‐I.ConclusionsThis first patient‐derived neuronal model of MPAN provides a useful tool for further research aimed at unraveling the complexities of this disease and developing potential therapeutic interventions. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

BackgroundPhase‐amplitude coupling (PAC) in the beta‐gamma range has emerged as a promising electrophysiological biomarker of Parkinson's disease (PD).ObjectiveThis study aims to investigate how levodopa and locomotion modulate cortical (central electroencephalogram [cEEG]) and corticomuscular (cEEG‐gEMG [gastrocnemius electromyography]) beta‐gamma PAC in patients with PD.MethodsThirty patients with PD underwent simultaneous cEEG and gEMG recordings during sitting, standing, and free walking in both off and on dopaminergic states. Spectral features and PAC analyses were conducted to assess the effects of levodopa, locomotion, and their associations with motor symptoms.ResultsIn the off levodopa state, patients showed prolonged gait cycle intervals and shorter step lengths, correlating with higher Movement Disorder Society–revised Unified Parkinson's Disease Rating Scale Part III (UPDRS‐III) scores. The cEEG beta‐gamma PAC during sitting and standing, and cEEG‐gEMG beta‐gamma PAC during walking, positively correlated with UPDRS‐III in the off levodopa state. The cEEG alpha/low beta‐gamma and cEEG‐gEMG low beta‐gamma PAC increased from on to off levodopa while walking, with the latter correlating with reduced step length. Step event–related PAC analysis unveiled a dynamic enhancement of alpha/beta cEEG‐gamma gEMG PAC around heel strikes in on levodopa compared with off.ConclusionsBoth cortical and corticomuscular beta‐gamma PACs are modulated by levodopa and locomotion, with low beta‐gamma corticomuscular PAC specifically linked to gait dysfunction. Moreover, the levodopa‐related enhancement of alpha/beta–gamma PAC during heel strikes highlights the functional relevance of dopaminergic modulation during gait. These findings highlight the potential of PAC as a biomarker for PD, particularly in the development of gait phase‐locked adaptive deep brain stimulation strategies for patients with PD guided by noninvasive PAC monitoring. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

BackgroundDigital‐motor outcomes promise better responsiveness than clinician‐reported outcomes in ataxia trials. However, their patient meaningfulness and sensitivity to change remain to be demonstrated, particularly in the upper limb domain.ObjectivesValidation of quantitative motor (Q‐Motor) assessment for upper limb ataxia against patient‐reported outcomes and regarding sensitivity to both longitudinal and treatment‐induced change, the latter in n‐of‐1 treatment settings.MethodsSingle‐center longitudinal assessment of finger tapping, diadochokinesia, grip‐lift, spiral drawing, and target reaching in (1) 36 cross‐genotype ataxia patients and 20 controls, validating digital measures for correlations with patient‐reported outcome measure (PROM)‐ataxia, 2‐weeks test–retest reliability, and sensitivity to change within a trial‐relevant 1‐year follow‐up, anchored in Patient Global Impression of Change (PGI‐C); and (2) two patients with spinocerebellar ataxia type 27B (SCA27B) on versus off treatment with 4‐aminopyridine.ResultsTwenty‐four digital measures correlated with the PROM‐ataxia upper‐limb composite (|ρ| = 0.4–0.7) and had excellent test–retest reliability (ICC = 0.91–0.99). Correlations to individual PROM‐ataxia items were specific for functional impairment the respective measure was hypothesized to capture. Speed of finger tapping and diadochokinesia, and smoothness of target reaching (spectral arc length of movement in three dimensions [SPARC3D]) captured 1‐year progression in ataxia patients (|rprb| = 0.38–0.51), and specifically in patients with worsening PGI‐C. Estimated sample sizes to detect longitudinal change were lower for digital than clinical outcomes (SPARC3D: n = 33, Scale for the Assessment and Rating of Ataxia (SARA): n = 79, nine‐hole peg‐test: n = 214). Speed of diadochokinesia, stability of grip‐lift, and variability of target reaching captured treatment responses to 4‐aminopyridine in SCA27B, exceeding minimal detectable and minimal important change.ConclusionDigital upper limb measures capture patient‐meaningful 1‐year longitudinal and treatment‐induced change, and are therefore promising outcomes for upcoming ataxia trials. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

BackgroundImpaired glymphatic clearance may contribute to pathological accumulations in Parkinson's (PD), but how it interacts with other processes causing dementia remains unclear. Diffusion tensor image analysis along the perivascular space (DTI‐ALPS) has been proposed as an indirect proxy for glymphatic clearance.ObjectivesTo clarify DTI‐ALPS' relationship with cognition in PD, and its relationship with established imaging markers.MethodsWe assessed DTI‐ALPS in 98 PD patients (31 PD poor outcomes: dementia, mild cognitive impairment, frailty, or death within a 3‐year follow‐up; 67 PD good outcomes) and 28 controls. We assessed DTI‐ALPS' relationship to cognition, white matter (fiber cross‐section), cortical thickness, iron accumulation (quantitative susceptibility mapping [QSM]), and plasma markers [phosphorylated tau‐181 (p‐tau181 and neurofilament light (NfL)] cross‐sectionally and longitudinally).ResultsDTI‐ALPS was lower in PD‐poor outcomes compared with PD good outcomes and controls (P = 0.005) with further longitudinal reductions only in PD poor outcomes (group × time interaction: β = −0.013, P = 0.021). Lower DTI‐ALPS was associated with lower fiber cross‐section in PD, at baseline and longitudinally but with different spatial distribution from white matter changes relating to PD cognition. There was no correlation between baseline DTI‐ALPS and plasma p‐tau181 (P = 0.642), NFL (P = 0.448), or baseline cortical thickness. Lower DTI‐ALPS was associated with accelerated cortical thinning within left precentral gyrus and changes in brain iron distribution.ConclusionsPD patients who develop poor outcomes show lower DTI‐ALPS, potentially reflecting impaired glymphatic clearance. DTI‐ALPS correlated with white matter integrity and brain iron accumulation. However, both showed different spatial distribution than that seen in PD dementia, suggesting DTI‐ALPS captures a distinct contribution to cognitive decline. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

BackgroundThe differentiation between multiple system atrophy (MSA) and Parkinson's disease (PD) based on clinical diagnostic criteria can be challenging, especially at an early stage. Leveraging deep learning methods and magnetic resonance imaging (MRI) data has shown great potential in aiding automatic diagnosis.ObjectiveThe aim was to determine the feasibility of a three‐dimensional convolutional neural network (3D CNN)–based approach using multimodal, multicentric MRI data for differentiating MSA and its variants from PD.MethodsMRI data were retrospectively collected from three MSA French reference centers. We computed quantitative maps of gray matter density (GD) from a T1‐weighted sequence and mean diffusivity (MD) from diffusion tensor imaging. These maps were used as input to a 3D CNN, either individually (“monomodal,” “GD” or “MD”) or in combination (“bimodal,” “GD‐MD”). Classification tasks included the differentiation of PD and MSA patients. Model interpretability was investigated by analyzing misclassified patients and providing a visual interpretation of the most activated regions in CNN predictions.ResultsThe study population included 92 patients with MSA (50 with MSA‐P, parkinsonian variant; 33 with MSA‐C, cerebellar variant; 9 with MSA‐PC, mixed variant) and 64 with PD. The best accuracies were obtained for the PD/MSA (0.88 ± 0.03 with GD‐MD), PD/MSA‐C&PC (0.84 ± 0.08 with MD), and PD/MSA‐P (0.78 ± 0.09 with GD) tasks. Patients misclassified by the CNN exhibited fewer and milder image alterations, as found using an image‐based z score analysis. Activation maps highlighted regions involved in MSA pathophysiology, namely the putamen and cerebellum.ConclusionsOur findings hold promise for developing an efficient, MRI‐based, and user‐independent diagnostic tool suitable for differentiating parkinsonian syndromes in clinical practice. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

BackgroundGlial cell line–derived neurotrophic factor (GDNF) is required for development and survival of dopaminergic neurons. A previous trial evaluating lower‐dose adeno‐associated virus serotype 2–GDNF (AAV2‐GDNF) bilateral intraputaminal infusion in participants with advanced Parkinson's disease (PD) achieved 26% mean putaminal coverage and was associated with stable motor features with no unexpected adverse events (AEs) over 60 months.ObjectiveWe assessed safety and preliminary clinical outcomes of optimized bilateral intraputaminal infusion of a single, higher dose of AAV2‐GDNF (product code AB‐1005) for PD after 18 months.MethodsThis phase 1b single‐arm, open‐label clinical trial enrolled participants with mild (Movement Disorder Society–revised Unified Parkinson's Disease Rating Scale [MDS‐UPDRS] Part III off score ≤ 32) and moderate (MDS‐UPDRS Part III off score of 33–60) PD. The primary outcome was safety. Clinical outcomes were assessed using PD‐specific clinical measures.ResultsEleven participants were enrolled (n = 6 mild; n = 5 moderate). Mean (±SE) putaminal coverage of AAV2‐GDNF was 63% (±2%). All participants experienced treatment‐emergent AEs (63 events); most were transient and perioperative. Six serious AEs in three participants were unrelated to AAV2‐GDNF. At 18 months posttreatment, the mild cohort exhibited numerically stable MDS‐UPDRS, motor diary, Unified Dyskinesia Rating Scale (UDysRS) scores, and levodopa equivalent daily dose (LEDD). The moderate cohort demonstrated numerical improvements in mean (±SE) MDS‐UPDRS Part III off scores (−20.4 [±4.5]), motor diary off time (−1.7 [±1.1] hours), and UDysRS scores (−2.2 [±1.9]) and reduced LEDD (−257.6 [±162.2] mg).ConclusionsBilateral intraputaminal AAV2‐GDNF gene therapy was well tolerated and associated with numerical stability (mild cohort) and improvement (moderate cohort) in clinical assessments at 18 months posttreatment. © 2025 AskBio Inc and The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Long‐read sequencing methodologies provide powerful capacity to identify all types of genomic variations in a single test. Long‐read platforms such as Oxford Nanopore and PacBio have the potential to revolutionize molecular diagnostics by reaching unparalleled accuracies in genetic discovery and long‐range phasing. In the field of dystonia, promising results have come from recent pilot studies showing improved detection of disease‐causing structural variants and repeat expansions. Increases in throughput and ongoing reductions in cost will facilitate the incorporation of long‐read approaches into mainstream diagnostic practice. Although these developments are likely to transform clinical care, there is currently a discrepancy between the potential benefits of long‐read sequencing and the application of this technique to dystonia. In this review we highlight current opportunities and limitations of adopting long‐read sequencing methods for the investigation of patients with dystonia. We provide examples of long‐read sequencing integration into diagnostic evaluation and the study of pathomechanisms in individuals with dystonic disorders. The goal of this article is to stimulate research into the application and optimization of long‐read analysis strategies in dystonia, thus enabling more precise understanding of the underlying etiology in the future. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

BackgroundThe aim was to investigate if glymphatic function is impaired in patients with Huntington's disease (HD) and its clinical relevance.MethodsForty‐nine subjects carrying mutant Huntingtin (mHTT), comprising 35 manifest (mHD) and 14 pre‐manifest (PreHD), and 35 healthy controls (HC) were recruited in this study. The diffusion along perivascular spaces (ALPS) index and the percentage of perivascular space in the basal ganglia (pPVS_BG) were obtained in different groups. The discrimination effects of ALPS index were detected using receiver operating characteristic (ROC) analysis, and the correlations of ALPS index with clinical features of HD were further analyzed.ResultsALPS index was decreased in mHTT carriers compared to HCs, and it was lower in mHD compared to PreHD patients. ROC analysis showed that the ALPS index could discriminate mHTT from HC (AUC [area under the curve] = 0.903), mHD from PreHD (AUC = 0.886), and PreHD from controls (AUC = 0.755). Lower ALPS index correlated with greater disease burden, severity of the disease, lager pPVS_BG, and lower brain volume and thickness of cortices. Regression analysis showed that ALPS index could predict the performance of motor and cognitive functions. Mediation analysis revealed that ALPS partially mediated the effects of CAG repeat and age on the cognitive decline in HD.ConclusionsThis study demonstrated that the impairment of the glymphatic system, especially in the paraventricular white matter and BG, was correlated with the clinical manifestations, disease burden, and brain structural changes in mHTT carriers. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

BackgroundLittle is known about the prognostic value of plasma biomarkers in mild cognitive impairment with Lewy bodies (MCI‐LB).ObjectivesTo investigate the association of four plasma biomarkers with disease progression in MCI.MethodsPlasma amyloid‐beta (Aβ)42/40, glial fibrillary acidic protein (GFAP), neurofilament light (NfL), and phosphorylated tau 181 (pTau181) were measured at baseline in a longitudinal MCI cohort (n = 131).ResultsBaseline plasma NfL was associated with increased risk of dementia/death in the entire cohort. In MCI‐LB, baseline plasma NfL, GFAP, and pTau181 were associated with increased risk of dementia/death and increased cognitive decline measured by the Addenbrooke's Cognitive Examination‐Revised.ConclusionspTau181, GFAP, and NfL are associated with more rapid disease progression in MCI‐LB and, with further validation, could be useful to support prognosis and stratification for clinical practice and treatment trials. Further work, including clinicopathological studies, is needed to understand the biological correlates of these markers in MCI‐LB. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.