Journal of Parkinson's Disease

Background: Reliable biomarkers for Parkinson's disease (PD) pathology detection are essential for research. The alpha-synuclein (aSyn) seed amplification assay (SAA) is a validated biomarker for misfolded aSyn. Objectives: To assess the association between aSyn SAA and LRRK2-related PD (LRRK2-PD) and its link to mitochondrial genetic burden. Methods: We included N=76 LRRK2 p.Gly2019Ser variant carriers (N=22 affected, N=54 unaffected), N=714 patients with idiopathic PD (iPD), and N=411 controls from Norway. We analyzed cerebrospinal fluid (CSF)-based aSyn SAA in N=10 PD patients and N=30 unaffected LRRK2 p.Gly2019Ser carriers, alongside N=6 controls and N=56 iPD patients. A mitochondrial polygenic score (MGS) was derived from genotyping data, using PPMI as an additional cohort (iPD: N=355, LRRK2-PD: N=118). Results: Seeding was observed in 80% of patients with LRRK2-PD, and in one unaffected variant carrier (AUC=0.97, CI 0.92-1.00). In a meta-analysis across two PD cohorts, higher MGS was associated with increased aSyn seeding (pooled beta=0.38, p=0.028). Conclusions: CSF-based aSyn SAA can discriminate between LRRK2-PD and unaffected carriers. Our findings support an association with mitochondrial burden and aSyn seeding.

Background: Gait variability is a hallmark of Parkinson's disease (PD) and has been linked to cognitive deficits and fall risk. Rapid eye movement sleep behavior disorder (RBD) is a strong predictor of synucleinopathies, yet evidence for gait changes in RBD is inconsistent. Performing a dual task increases gait variability, an effect that can be quantified using a cost function. Objective: Determine the degree to which dual task cost differs between control, RBD, and PD participants at baseline, and between RBD converters versus non-converters at follow-up. Methods: 46 RBD, 23 control, and 14 PD participants completed standardized gait analysis at baseline. Parameters chosen for analysis included enhanced gait variability index (eGVI), functional ambulation performance (FAP), velocity, step length, cadence, base of support, and double support time. Medical records were surveilled for 3 years following participant enrollment, determining that 6 RBD participants converted to PD or dementia. Baseline gait indices and dual task costs were compared between control, RBD, and PD groups at enrollment, and between RBD stable and RBD converters at follow-up. Results: The PD group had greater eGVI, as well as greater dual task cost for FAP, cadence, width, and double support time. No differences in gait variability were identified between RBD and control groups at baseline. Compared to the stable group, RBD converters had greater dual task cost for FAP, velocity, cadence, and double support time. Conclusions: Increased gait variability during dual task may identify RBD patients at imminent risk of phenoconversion.

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.

Background Neuropsychiatric fluctuations in Parkinson's disease (PD) often accompany motor fluctuations, but their temporal relationship during the acute levodopa response remains unclear. Objectives To determine whether motor and neuropsychiatric responses occur synchronously during the OFF-to-ON transition. Methods Nineteen fluctuating PD patients underwent a high-resolution levodopa challenge with repeated assessments every 10 minutes for 60 minutes after levodopa administration. Motor symptoms (akinesia, rigidity) and neuropsychiatric fluctuations were quantified. Transition times (t25%-t50%-t75%-t100%) and response profiles were analyzed using correlation and clustering approaches. Results Motor and neuropsychiatric transition times were not correlated at any threshold (all FDR-corrected p>0.05; Bayes factors <1), supporting temporal dissociation. Among 18 patients with complete data, clustering revealed synchronous (6/18), neuropsychiatric-preceding (7/18), and motor-preceding (3/18) profiles. Conclusion Motor and neuropsychiatric responses to levodopa during PD fluctuations are partly independent and follow heterogeneous, patient-specific temporal profiles, supporting the search for distinct biomarkers and future individualized adaptative therapies

Background: PD GENEration (NCT04057794, NCT04994015), sponsored by the Parkinson's Foundation in partnership with Aligning Science Across Parkinson's (ASAP) through the Global Parkinson's Genetics Program (GP2), is an international, observational, clinical research study that offers genetic testing and counseling to people living with Parkinson's disease (PwP) at no cost. PD GENEration has aimed to empower PwP and their clinicians with knowledge of their genetic status, to accelerate recruitment into precision medicine trials, and to advance research through data sharing. Since its launch in 2019, the study has expanded to enroll over 32,000 PwP (as of March 31, 2026), from 10 countries across North, Central, and South America, the Caribbean, and Israel. Methods: Over the course of 6 years, PD GENEration has evolved to accommodate the growing scientific and research needs of the Parkinson's community while also increasing the ability to return genetic test results to PwP at a greater scale. Participants with a diagnosis of Parkinson's disease (PD) may enroll in-person or virtually where informed consent and blood sample collection can occur. Samples are analyzed at a College of American Pathologists/Clinical Laboratory Improvement Amendments (CAP/CLIA)-certified laboratory using whole genome sequencing, with variants curated for a primary panel of seven PD-associated genes. Results are disclosed during a genetic counseling visit, where further testing is offered for two optional additional gene panels. Those who consent undergo analysis of additional genes, and results are returned during a genetic counseling visit for those that test positive for a variant. In addition to returning genetic results to PwP, a central pillar of the study design has been the open sharing of genomic data to advance discovery in PD research in partnership with ASAP and GP2. Discussion: PD GENEration applies a flexible framework, allowing for country specific considerations and the integration of multiple site models, evolving based on participant needs and the prioritization of equity and accessibility. We summarize PD GENEration's implementation and scaling, highlight key accomplishments and lessons learned, and provide guidance for those interested in implementing large-scale clinical genetic testing studies across other diseases and therapeutic domains.

Background: Parkinson's disease (PD) has a prolonged prodromal phase during which non-motor symptoms (NMS) may emerge years before the appearance of classical motor signs. This makes NMS a promising and clinically accessible source of information for early risk stratification. Objective: In this study, we investigated whether NMS alone can serve as reliable predictors of PD risk using clinical data from the Parkinson's Progression Markers Initiative (PPMI) cohort. Methods: We developed a stacked ensemble machine learning framework that integrates feature-level modelling, a global multivariate model, and a patient-similarity component to capture complementary patterns within NMS profiles. The model was trained using leakage-controlled patient-level validation and evaluated on an independent held-out test set. Results: The final ensemble achieved strong predictive performance, with an area under the ROC curve of 0.955, sensitivity of 0.929, and specificity of 0.900. Explainability analysis further showed that olfactory dysfunction, gastrointestinal symptoms, urinary and other autonomic features, and selected cognitive measures were among the most influential predictors. These findings support the hypothesis that NMS are not merely associated features of PD, but can function as meaningful predictors of disease risk even without imaging or biomarker inputs. Additionally, the final validated model is implemented as a web-based research prototype to demonstrate real-time translational feasibility. Conclusion: Overall, this study highlights the predictive value of NMS for PD risk assessment and supports their use in research-oriented early screening frameworks.

In both preclinical and clinical studies, transfusions of plasma from young individuals have been reported to ameliorate aspects of neurodegeneration. This study was designed as a preliminary test of the hypothesis that plasma transfusions from young donors might benefit Parkinson's patients. 19 patients were allocated to receive either 2-liters of plasma from young donors, in two doses spaced two days apart, or two doses of placebo. For the next 24 weeks, this double-blind study evaluated changes on a modified MDS-UPDRS scale, along with blood tests and other observations. Adverse events possibly related to transfusion were mild rise in blood pressure and urticaria. A t-test on the changes in the sum of UPDRS subscales 1-3 showed that the plasma patients did better than the placebo patients (p = 0.03*). For patients given yFFP (young Fresh Frozen Plasma), the estimated decrease in the sum of scales 1-3 was 7.1 (95% conf. interval 4.3 to 9.9). Our results give a preliminary indication that young plasma transfusions reduce Parkinson's symptoms and have a place in treatment of these patients. (NCT 04202757).

Introduction. The cerebellum is increasingly recognized as a key contributor to cognitive reserve and network adaptation in Parkinsons disease (PD). However, how cerebellocortical and cerebellobasal ganglia connectivity reorganizes across disease duration and cognitive status remains incompletely understood. Methods. Resting state fMRI data from the Parkinsons Progression Markers Initiative were analyzed in 172 individuals with PD. We investigated cerebellobasal ganglia and cerebellocortical connectivity using ROI to ROI and seed to voxel pipelines respectively, providing novel insights into both subcortical and cortical effects. Effects of age, disease duration, cognitive status, motor symptom severity, and dopaminergic medication were assessed. Results. Across all participants, cerebellar lobule VI and vermis VI showed robust positive connectivity with the pallidum, along with high intracerebellar coupling. When controlling for dopaminergic medication, lobule V connectivity with the primary motor cortex was reduced. Age was associated with lower cerebellobasal ganglia connectivity widespread across nodes, evident across medication states. Disease duration showed region specific effects: in cognitively normal PD, longer duration corresponded to stronger lobule V and temporal cortex connectivity as well as higher Crus I and precentral gyrus connectivity than PD with cognitive dysfunction. Motor symptom severity was not related to connectivity. Conclusions. Cerebellar connectivity patterns in PD are linked to disease duration and cognitive preservation. Enhanced cerebellocortical coupling in cognitively normal PD may reflect compensatory network recruitment that diminishes with cognitive decline.

Freezing of gait is a disabling episodic symptom of Parkinson's disease, typically emerging during complex locomotor tasks such as turning, obstacle negotiation, and gait initiation. These tasks require effective motor planning and proactive visual search of the intended walking route. Current evidence suggests that people with Parkinson's disease and freezing of gait show different patterns of visual search compared to those without freezing of gait and healthy older adults. However, existing reports are based on relatively simple tasks that lack common triggers for freezing of gait and do not adequately control for other factors likely to influence visual search, such as motor symptom severity and balance ability. This study examined visual search behaviour in 24 healthy older adults and 37 people with Parkinson's disease (21 with freezing of gait, 16 without) during a complex walking task requiring repeated turning and navigation through narrow spaces. Visual search characteristics were compared between people with Parkinson's disease and healthy controls, and relationships between visual search, freezing of gait, motor symptom severity, and balance ability were explored within the Parkinson's disease group. Compared with healthy controls, people with Parkinson's disease showed significantly fewer fixations toward areas outside the walking path, longer average fixation durations, and reduced saccade amplitudes, with no differences in proactive visual planning of the intended route. No relationship was found between visual search outcomes and freezing of gait. Reduced fixations to outside-path areas were associated with poorer functional balance independently of motor symptom severity. These findings indicate that restricted visual sampling in Parkinson's disease is primarily associated with balance impairment rather than freezing of gait or motor symptom severity.

PurposeParkinsons disease (PD) is a neurodegenerative disease that affects motor control but can also influence sensory perception. Changes in vision and proprioception are well-documented but less is known about how PD alters auditory perception, particularly perception of speech acoustic properties. The current study examined perception of speech rate and intensity in PD and the relationship of auditory perception to disease severity. MethodPeople with PD were compared to age- and hearing-matched controls using perceptual tasks focused on discrimination and learning of speech rate and intensity. For rate discrimination, speech, non-speech, and visual stimuli were included to determine whether performance differences for PD participants and controls were specific to speech. Disease severity was assessed using the MDS-Unified Parkinsons Disease Rating Scale (MDS-UPDRS) and the relationship to performance on perceptual discrimination and learning tasks was evaluated. ResultsPeople with PD performed significantly worse than controls in the rate discrimination task for all types of stimuli. There were no significant group differences for intensity discrimination. However, participants with greater PD disease severity demonstrated significantly poorer intensity discrimination accuracy. Performance on learning tasks utilizing rate and intensity manipulations did not differ between PD and control participants and was unrelated to PD disease severity. ConclusionsPeople with PD had difficulty discriminating rate differences across speech, non-speech, and visual stimuli, indicating that challenges with rate perception are not limited to speech. The relationship between intensity discrimination and disease severity suggests common dopaminergic networks between motor symptoms and auditory perception in PD.

Aldehyde dehydrogenase 1A1-positive (ALDH1A1+) dopaminergic neurons (DANs) are preferentially vulnerable in Parkinsons disease (PD), yet how their activity is modulated by presynaptic inputs remains poorly defined. Here we investigated the role of glutamatergic input by conditionally deleting Grin1, which encodes a critical NMDA receptor (NMDAR) subunit, in ALDH1A1+ DANs. Grin1 conditional knockout (cKO) mice displayed normal locomotion and motor learning; however, females exhibited enhanced operant reward acquisition and excessive feeding with transient weight gain following food restriction. To determine regional contributions, Grin1 was selectively knocked down in ALDH1A1+ DANs of either the ventral tegmental area (VTA) or substantia nigra pars compacta (SNc). VTA-specific knockdown in females was sufficient to reproduce the post-restriction feeding and weight gain phenotype. Bulk whole-brain mRNA sequencing revealed pronounced sex-dependent transcriptional changes, primarily in female Grin1 cKO mice after food restriction. Many differentially expressed genes were associated with mitochondrial function, energy metabolism, and synaptic signaling. Together, these findings reveal a sex-specific role for NMDAR-mediated glutamatergic input to ALDH1A1+ VTA DANs in regulating feeding behavior, providing mechanistic insight into how dysfunction of this vulnerable subpopulation may contribute to PD-associated compulsive eating disorders. Key FindingDisrupted NMDA receptor-mediated glutamatergic input to ALDH1A1+ DANs drives sex-specific feeding abnormalities relevant to PD-associated compulsive eating disorders.

Background: The clinical applicability of large language models (LLMs) in Parkinson's disease (PD) management remains insufficiently characterized, particularly in generative responses to clinical vignette scenarios. Objective: To evaluate the quality of clinical assessments and management plans generated by a general-purpose LLM (Gemini 1.5 Pro) and a medically specialized LLM (OpenEvidence), and to compare their performance. Methods: Models generated free-text responses to 45 open clinical queries, focused on assessment of the situation, and recommended management plan. Two movement disorders fellows rated outputs using 5-point Likert scales, dichotomized into clinically appropriate ([&ge;]4) versus inappropriate ([&le;]3). Discrepancies were adjudicated by a senior movement disorders specialist. Paired comparisons used McNemar's test; qualitative analysis examined severe errors. Results: Gemini 1.5 Pro and OpenEvidence showed high rates of clinically appropriate assessments (80.0% vs. 86.7%) but lower performance in management plans (48.9% vs. 57.8%). Cases in which both assessment and plan were clinically appropriate occurred in 46.7% and 55.6% of cases, respectively. None of these differences reached statistical significance. Severe errors were uncommon in assessments (6.7% vs. 8.9%) but more frequent in plans (26.7% in both), predominantly reflecting treatment strategy errors. Conclusions: In generative clinical reasoning tasks involving Parkinson's disease management vignettes, LLMs demonstrated reasonable performance in assessment, but consistent limitations in plan generation. The medically specialized LLM demonstrated several qualitative advantages but no statistically significant performance benefit over the general-purpose model. Therefore, these tools should be used with appropriate caution in Parkinson's disease management, particularly regarding treatment recommendations.

Huntingtons disease (HD) is a neurodegenerative disorder caused by CAG repeat expansion in the huntingtin (HTT) gene, with longer repeats linked to earlier onset. Somatic CAG expansion, particularly in the striatum, contributes to disease progression and is influenced by HTT biology and genetic modifiers. Modulating somatic expansion is emerging as a promising approach to slow or prevent HD, and mouse models have been crucial for preclinical testing of different therapeutic strategies. The BAC-CAG model, developed on the FVB strain, has been used to study somatic expansion of human expanded HTT. However, comparisons with other key HD mouse models have been limited by differences in genetic background, as many other models are on the C57BL/6 strain. The BAC-CAG model has now been developed on a C57BL/6 background. To determine whether the C57BL/6 BAC-CAG model can be used to study and modulate somatic expansion, we compared CAG expansion in mice on C57BL/6 or FVB backgrounds, with and without intraventricular divalent small interfering RNAs (siRNA) targeting HD modifiers MutS homolog 3 (MSH3) and HTT. Both strains exhibited robust, comparable somatic expansion over two months, which was blocked by MSH3-, but not HTT-, targeted siRNA. RNA sequencing identified gene expression differences primarily in pseudogenes, with no differences in endogenous Htt, human HTT, or mismatch repair genes. These results demonstrate that BAC-CAG mice on a C57BL/6 background exhibit somatic CAG expansion comparable to the validated FVB strain, providing a model to study and preclinically test therapies targeting somatic expansion in HD.

BackgroundAmyotrophic lateral sclerosis (ALS) is characterized by profound metabolic reprogramming, yet the lack of biomarkers for specific druggable targets remains a major hurdle for precision medicine. We hypothesized that peripheral lipid biosynthetic signatures could serve as both prognostic indicators and a roadmap for identifying novel disease-modifying targets. MethodsWe assessed serum fatty acid (FA) metabolic pathways in two independent longitudinal cohorts (n = 37 and n = 38) using high-dimensional CoxBoost modeling. Primary outcomes were survival and functional staging milestones, including non-invasive ventilation and gastrostomy. The biological relevance of the identified candidate was further assessed through correlation with plasma neurofilament light-chain (NfL) levels. Causality and therapeutic potential were validated in Drosophila melanogaster models of TDP-43 proteinopathy via genetic ablation and pharmacological inhibition. ResultsOur multi-parametric model, comprising two clinical variables and the estimated ELOVL6 (elongation of very long-chain fatty acids protein 6) activity, demonstrated robust prognostic accuracy (Unos C 0.69) across both cohorts; ELOVL6 activity served as a strong independent predictor of mortality and functional decline. Notably, high ELOVL6 activity significantly correlated with elevated plasma NfL levels (p < 0.01), linking peripheral elongation imbalances to central axonal damage. In Drosophila, ELOVL6 overactivation was identified as a conserved pathological consequence of TDP-43 dysfunction, characterized by an increased C18:0/C16:0 ratio in both loss-of-function and gain-of-function models. Inhibition of ELOVL6, either genetically or pharmacologically, rescued neuromuscular junction integrity, prolonged survival, and significantly reduced pathological TDP-43 phosphorylation in glial models. ConclusionThese findings position ELOVL6 as a promising modifiable metabolic node with potential for disease-modifying intervention in ALS. Beyond its potential utility for identifying high-risk metabolic profiles and assisting in prognostic counseling, ELOVL6 bridges systemic lipid dysregulation with TDP-43 proteinopathy. Targeting this pathway offers a dual opportunity: as a biological marker to supplement clinical staging and as a druggable enzymatic target to ameliorate motor neuron degeneration. HIGHLIGHTSO_LISystemic ELOVL6 activity is a robust independent predictor of ALS survival. C_LIO_LIHigh ELOVL6 levels correlate with plasma NfL and functional decline. C_LIO_LIInhibition of ELOVL6 rescues NMJ integrity and survival in Drosophila models. C_LIO_LIPharmacological targeting of ELOVL6 reduces glial TDP-43 phosphorylation. C_LIO_LIELOVL6 represents a druggable metabolic node linking lipids to proteinopathy. C_LI

Parkinsons disease (PD) is a neurodegenerative disorder characterized by a prolonged prodromal stage that culminates in motor deficits. Current PD therapies primarily alleviate symptoms, underscoring the need for disease-modifying strategies. Glucagon-like peptide-1 (GLP-1) analogs showed early promise as candidate disease modifiers, but recent clinical results have been inconsistent, and their mechanism of action remains poorly defined. Here, we employed our SncaG51D/G51D knock-in mouse model to investigate the effects of subcutaneously administered GLP-1 analogs, semaglutide and lixisenatide. Both analogs reversed motor and non-motor deficits and reduced gliosis and detergent-insoluble -synuclein. Bulk and single-nuclei transcriptomics together with CellChat-based intercellular communication analysis revealed that GLP-1 analogs normalize early striatal mitochondrial and inflammatory dysregulation and restore neuregulin (NRG) and neurexin (NRXN) signaling networks to wild-type levels. Treatment was effective when initiated either before or shortly after symptom onset, defining an early therapeutic window for GLP-1 analog therapy in PD.

CLN3 disease is an inherited neurodegenerative disease, typically with childhood onset, and characterized by vision loss, seizures, cognitive decline, and difficulties. The CLN3 Staging System (CLN3SS) characterizes disease progression. Our aim was to assess differences in cognitive test scores in relation to CLN3SS among individuals with CLN3 disease. We evaluated the relationship between cognitive test performance and the CLN3SS in individuals with genetically confirmed CLN3 disease. Participants completed tasks of verbal reasoning, vocabulary knowledge, attention, fund of information, and ability to recite the alphabet. One-way ANOVA testing assessed differences in mean cognitive test score among CLN3SS score groups, and Chi-square testing was used to compare the proportion in each CLN3SS group that could recite the alphabet. Data were evaluated from a sample of 85 individuals with a total 245 CLN3SS assessments conducted within 6 months of their cognitive testing, A significant decrease in test scores was found between CLN3SS Stages 1 (vision loss present) and 2 (vision loss and seizures present) for each of the cognitive tests. The proportion of participants able to recite the alphabet also decreased from Stage 1 to Stage 2 (X2=12.1, p<.01). Cognitive ability declines with advanced disease severity in CLN3 disease, though motor disability in Stage 3 likely contributes to difficulty participating in cognitive assessment at this later disease stage. Understanding the relationship between cognition and CLN3 disease stage may help guide decision making, i.e., determining who could or should undergo cognitive assessment for clinical care or for group stratification in disease modifying clinical trials.

BackgroundVascular cells are emerging as active players in Parkinsons disease (PD), yet their molecular contribution to -Synuclein (-Syn) pathology remains undefined. Here, we show that human brain pericytes respond in a distinct manner to unique -Syn strains, with systematic validation identifying BCL-XL as a potential regulator of the neurovascular unit in PD. MethodsPrimary human brain-derived pericytes were exposed to five recombinant -Syn strains (Fibrils, Fibrils-65, Fibrils-91, Fibrils-110, and Ribbons). Transcriptomic profiling identified differentially expressed genes (DEGs), which were validated at the protein level using multiplex immunocytochemistry and in situ labelling of post-mortem middle temporal gyrus (MTG) tissue microarrays from PD (n = 24) and neurologically normal (n = 24) cases. Results-Syn strain exposure produced 300 DEGs with limited overlap between strains. BCL-XL and CSNK1D were upregulated in -Syn-treated pericytes. In post-mortem PD tissue BCL-XL showed marked pericyte-specific elevation in the MTG and increased pericytic and microglial expression in the substantia nigra. ConclusionBCL-XL emerges as a potential regulator of pericyte and microglial resilience in PD, linking acute -Syn strain-specific responses in pericytes to broader neurovascular alterations. Its upregulation likely represents a generalised compensatory response to chronic -Syn-associated stress beyond individual strain effects, identifying BCL-XL as a possible therapeutic target within the neurovascular unit.

Parkinsons disease (PD) is associated with motor impairment and cortical synaptic dysfunction, which involve altered glutamate receptor trafficking, yet the underlying mechanisms remain incompletely understood. VPS26B, a component of the retromer complex, regulates GluA1 recycling in the trans-entorhinal cortex region. However, its role in the primary motor cortex (M1) under Parkinsonian conditions has not been explored. Here, we show that VPS26B levels are reduced in the M1 of an MPTP-induced PD mouse model, accompanied by decreased surface GluA1 and synaptic protein levels. VPS26B overexpression partially attenuated these alterations. In the accelerating rotarod test, VPS26B-deficient mice exhibited unstable motor performance following MPTP administration, whereas VPS26B overexpression was associated with improved performance in both wild-type and knockout mice. These findings suggest that cortical VPS26B may contribute to maintaining glutamate receptor surface expression and synaptic protein levels, especially under Parkinsonian conditions, with potential implications for motor learning.

Abstract Objectives: Amyotrophic lateral sclerosis (ALS) is a clinically heterogeneous neurodegenerative disease requiring reliable biomarkers to improve patient stratification and trial design. While serum neurofilament light chain (sNfL) reflects neuroaxonal stress and disease aggressiveness, troponin T (TnT) may capture complementary aspects of neuromuscular involvement. We assessed the associations of TnT and sNfL with D50-derived measures of disease aggressiveness (D50) and disease accumulation (rD50) in ALS. Material and Methods: In this retrospective observation, TnT and sNfL levels from ALS patients in two independent German cohorts were analyzed using the D50 disease progression model; discovery cohort (Essen, n =433) and validation cohort (Bonn, n =185). Results: In both cohorts TnT demonstrated a robust correlation with rD50-defined phases across all aggressiveness subgroups (p<0.001). There was no consistent pattern regarding sNfL and the rD50 phases. sNfL concentrations demonstrated a significant and inverse correlation with D50 applied for all disease aggressiveness subgroups (p<0.001). Correlations of TnT levels with D50 disease aggressiveness groups were generally less strong and inconsistent between the two cohorts. In the discovery cohort only low aggressiveness subgroups correlated significantly (p<0.001), intermediate aggressiveness subgroups showed only a weak correlation (p<0.05) with TnT levels. High disease aggressiveness subgroups showed no significant correlation with TnT. Conclusion: In application of the D50 disease progression model, TnT was strongly associated with disease accumulation (rD50) across all disease phases, independent of disease aggressiveness (D50), whereas sNfL robustly reflected disease aggressiveness but not overall disease burden. These complementary biomarker profiles highlight the value of an integrated approach for refined disease stratification in ALS. Combining TnT and sNfL may enhance clinical decision-making, improve monitoring of disease progression and treatment response, and support optimized clinical trial design.

Objectives: X-linked dystonia-parkinsonism is a neurodegenerative movement disorder with predominant striatal pathology in affected males, who frequently show hyperechogenicity of the lentiform nucleus on transcranial sonography. We aim to investigate female mutation carriers and female healthy controls using transcranial sonography to identify potential abnormalities in the striatum, substantia nigra, and ventricular system. Methods: We examined 81 participants (35 female mutation carriers and 46 female controls) using transcranial sonography to assess the presence of hyperechogenicity of the lentiform nucleus, the area of substantia nigra hyperechogenicity, and the widths of the lateral and third ventricles. Clinical evaluation focused on dystonic and parkinsonian symptoms, and we determined genotypes relevant for four X-linked dystonia-parkinsonism genetic modifiers. Results: Female mutation carriers showed more subtle parkinsonian signs compared with controls. The prevalence of hyperechogenicity of the lentiform nucleus was higher in female mutation carriers and was associated with a more unfavorable genetic modifier profile. No relevant abnormalities were observed in the substantia nigra or the ventricular system. Imbalanced X-chromosome inactivation in favor of the wildtype allele expression was not significantly associated with clinical severity or hyperechogenicity of the lentiform nucleus frequency, although female mutation carriers with such an imbalance showed no parkinsonian signs and only rarely hyperechogenicity of the lentiform nucleus (1/8, 13%). Conclusions: Women carrying the X-linked dystonia-parkinsonism-causing variant display subtle parkinsonian signs and frequently exhibit hyperechogenicity of the lentiform nucleus, supporting hyperechogenicity of the lentiform nucleus as a sensitive imaging marker of early neurodegenerative change, especially in those with higher genetic risk.