Digital technologies hold promise for transforming healthcare by enhancing personalized treatments and offer valuable opportunities to improve patient care. Here, we evaluated several novel, self-administered, home-based, digital endpoints for their association with corresponding conventional standard clinical measures (primary) in people living with Amyotrophic Lateral Sclerosis (ALS). This was a longitudinal study in people with ALS who were followed up to 9 months. A total of 33 participants were enrolled in the study. At each of six visits, participants were evaluated with a battery of conventional standard measurements to determine ALS disease progression and quality of life. Between visits, participants performed weekly home-based self-assessments with digital health technologies (DHT) and self-administered ALSFRS-R. Cross-sectional analysis of DHTs anchored to ALSFRS-R and longitudinal analyses were performed and compared to standard clinical measures. Of the 33 participants, 20 completed the study, and 13 discontinued before completing the planned 9-month follow-up mainly due to disease progression. The distribution of various digital metrics in home-based assessments corresponded well with the sub-scores of ALSFRS-R in the cross-sectional analyses, with the strongest construct validity for digital speaking rate. In the longitudinal analysis, a weak but significant trend in most metrics was observed, with the strongest trend in the duration of the Timed Up and Go (high variability between participants). The findings from this study provide insights into the potential of digital endpoints to evaluate people living with ALS with the goal of reducing the burden of study participation and improving the efficiency of ALS clinical trials.

The present study investigated problematic internet use (PIU) among 61 patients with frontotemporal dementia (FTD) compared to a cohort of 354 patients with mild cognitive impairment (MCI) and Alzheimer's dementia. PIU was identified in 22.9% of FTD patients compared to only 0.8% of AD patients (p < 0.001). Behaviors included compulsive social media use, gaming, and online shopping. These findings suggest that PIU may represent an emerging behavioral feature associated with FTD, significantly more prevalent than in MCI and Alzheimer's dementia. Recognizing these digital behaviors could provide valuable clinical insights for diagnosis and management in the digital age.

Variants in SLC6A1, encoding the GABA transporter 1 (GAT-1), cause epilepsy, autism spectrum disorder, and developmental delay via loss of GABA uptake, impaired trafficking, and ER retention. We previously found that 4-Phenylbutyrate (PBA), an FDA-approved drug, restores GABA uptake and reduces seizures in SLC6A1-related disorders, prompting a phase I clinical trial (NCT04937062) primarily designed to evaluate safety and tolerability of Ravicti (PBA). However, its exact mechanism, pharmacochaperoning or histone deacetylase (HDAC) inhibition, remains unclear. This study compares PBA with pharmacochaperones and HDAC inhibitors to determine how it restores GAT-1 function in the cell and mouse models. We evaluated the function for 32 SLC6A1 variants and two representative mouse models at baseline and various treatment options using 3H GABA uptake assays. We evaluated the effect of PBA in comparison with other chaperone inducers or HDAC inhibitors on the mutant and the wild-type GAT-1 expression. Importantly, we evaluated the effect of chaperone inducers and HDAC inhibitors on GAT-1 function and seizures in two representative knock-in mouse models, Slc6a1+/A288V and Slc6a1+/S295L, with EEG recordings. PBA restored GABA uptake and GAT-1 surface expression across all variants, and TUDCA mimicked the effects of PBA. HDAC inhibitors exhibited modest rescue invitro but failed to restore GAT-1 function or mitigate seizures in the knockin mice. PBA acts as a pharmacochaperone, not an HDAC inhibitor, to restore GAT-1 function and reduce seizure burden in the diseased mice, supporting pharmacochaperoning as the major mechanism for rescuing SLC6A1-related disorders.

Autoimmune autonomic ganglionopathy (AAG) is a rare but potentially treatable cause of severe autonomic failure. Evidence guiding long-term immunotherapy, treatment sequencing, and residual autonomic impairment is limited. We evaluated long-term treatment response, residual autonomic dysfunction, and relapse patterns in patients with seropositive AAG. Patients with seropositive AAG undergoing longitudinal follow-up with repeated quantitative autonomic assessments before and after immunotherapy were included. Residual autonomic impairment was assessed using cardiovascular, pupillary, and urinary autonomic biomarkers, need for anti-hypotensive medications or catheterisation, and patient-reported symptoms measured by the COMPASS-31 questionnaire. Of 18 patients with seropositive AAG, 16 had longitudinal quantitative autonomic testing, antibody titres, COMPASS-31 scores, and documented medication and catheter use before and after immunotherapy. At baseline, all 16 had widespread autonomic failure. All received plasma exchange, 10 received intravenous immunoglobulins, and 11 were treated with oral prednisolone followed by steroid-sparing agents. Treatment was associated with significant improvements in cardiovascular autonomic markers, antibody titres, and pupillary light responses, with non-significant improvements in COMPASS-31 scores. Four patients discontinued catheterisation. Two patients were refractory to plasma exchange and intravenous immunoglobulins but responded to prednisolone. Two patients relapsed while receiving steroid-sparing immunotherapy. High antibody titres correlated with the severity of cardiovascular and urinary dysfunction at disease onset, but not during follow-up. Prolonged stepwise immunosuppression in seropositive AAG is associated with sustained objective autonomic improvement, although residual impairment and relapse remain common. These findings support individualised, biomarker-guided immunotherapy and highlight the need for ongoing supportive management of autonomic complications.

Peripheral neutrophil levels in amyotrophic lateral sclerosis (ALS) inversely correlate with survival, suggesting a role for neutrophils in disease progression. Here, we characterize markers of several neutrophil activation pathways and evaluate their associations with survival to identify potential mechanisms of disease. Blood samples were obtained from participants at the University of Michigan ALS Clinic or from healthy controls. Exvivo neutrophil extracellular trap (NET) formation was quantified via image analysis of primary neutrophils. Neutrophil function markers of general activation (calprotectin), migration (matrix-metalloproteinase 9 [MMP9]), and degranulation (neutrophil gelatinase-associated lipocalin [NGAL]) were then quantified in plasma via ELISA; NET formation (double-stranded DNA [dsDNA]) was assessed via fluorescence assay. These markers were then associated with ALS survival using Cox proportional hazard regression models, and analyses were stratified by sex. Spontaneous exvivo NET formation (N = 20 controls, 66 ALS) was increased in ALS (1.0% vs. 9.7%; p = 0.017). In plasma (N = 233 controls, 178 ALS), calprotectin (294 vs. 372 ng/mL; p < 0.001), MMP9 (106 vs. 152 ng/mL; p < 0.001), and NGAL (61 vs. 66 ng/mL; p = 0.01) were elevated in ALS. Calprotectin, MMP9, and NGAL levels were not associated with ALS survival; however, dsDNA was associated with poorer ALS survival but only in females (HR = 1.77 [95% CI, 1.20-2.61]; p = 0.004). Neutrophil function is altered in ALS, and NET formation is a potential mechanism by which neutrophils contribute to ALS, particularly in females.

SRPK3/TTN-digenic myopathy was recently established as a skeletal muscle myopathy caused by digenic inheritance. This study characterizes the early clinical presentation of SRPK3/TTN-digenic myopathy in one previously reported and seven newly identified pediatric patients. Next generation sequencing and deep clinical phenotyping provide detailed genetic, clinical, imaging, and histopathological characterization of SRPK3/TTN-digenic myopathy. From the cohort of eight male patients (5-19 years at last evaluation), five presented prenatally with reduced fetal movements. At the time of birth, five had hypotonia, two had contractures, and two had respiratory distress. All patients demonstrated motor delay and muscle weakness within the first 15 months of life. Independent ambulation was achieved in six patients (ages 1.5-4 years); three could run. Variable respiratory compromise was documented as early as 5 years of age, with one patient requiring non-invasive nocturnal ventilation support. Cardiac evaluation was normal in all except one patient who had left ventricular non-compaction cardiomyopathy. Muscle MRI demonstrated mild, slowly progressive fibroadipose replacement of muscle with striking early selective involvement of the semitendinosus muscle. Histopathologic and ultrastructural features mimicked TTN-related myopathy (titinopathy), showing abnormal fiber size variation, increased internally placed nuclei, type 1 fiber predominance, and cores/minicores. This work highlights the early clinical manifestations of SRPK3/TTN-digenic myopathy and demonstrates early muscle imaging patterns and histopathological features that are indistinct from those observed in monogenic biallelic titinopathy cases. These features could help with the potentially challenging interpretation of digenic SRPK3 and TTN variants to allow for a confident clinical diagnosis of this novel congenital myopathy.

To clarify the clinical relevance of dopamine transporter single-photon emission computed tomography (DAT-SPECT) abnormalities in amyotrophic lateral sclerosis (ALS), with a prespecified focus on sex-stratified associations with disease progression and short-term prognosis. Fifty-eight consecutive patients with ALS were prospectively enrolled and underwent 123I-ioflupane DAT-SPECT, and DAT-SPECT data from 30 patients with essential tremor were analyzed as a reference group. We quantified the specific binding ratio (SBR) and the caudate-to-putamen binding ratio (BR-C/P) as age-adjusted Z-scores. Associations with functional decline (ΔALSFRS-R), respiratory function (forced vital capacity), neuropsychiatric measures, and a 6-month composite endpoint of death or ventilator support were examined using correlation and logistic regression analyses, with prespecified sex-stratified evaluation. A significant sex difference in BR-C/P Z-scores prompted sex-stratified analyses. SBR Z-scores were not associated with clinical or neuropsychiatric variables in either sex. In women, lower BR-C/P Z-scores correlated with faster functional decline and were independently associated with a higher risk of death or ventilator support within 6 months (odds ratio per 1-unit increase, 0.31; 95% confidence interval, 0.12-0.83). In men, BR-C/P Z-scores correlated with forced vital capacity and respiratory decline. Exploratory voxel-based morphometry suggested limbic and striatal gray matter correlates in women with lower BR-C/P Z-scores. Regional dopaminergic imbalance captured by BR-C/P, rather than global SBR, demonstrated sex-stratified associations with disease progression in ALS. These findings support sex-specific interpretation of dopaminergic imaging biomarkers and suggest that BR-C/P may complement clinical measures for identifying higher-risk trajectories, particularly in women. Validation in larger, longitudinal cohorts is required.

To characterize the demographic, clinical, and laboratory features of the Chinese patients of genetic Creutzfeldt-Jakob disease with T188K variant (T188K-gCJD), the most common subtype of genetic prion diseases (gPrDs) in China. In this nationwide retrospective study, data from 98 genetically confirmed T188K-gCJD patients were collected via Chinese National Surveillance for CJD (CNS-CJD) from 2007 to 2025. The features of demography, clinical manifestations, MRI and EEG, cerebrospinal fluid (CSF) tests (14-3-3, CaM, RT-QuIC) and PRNP sequencing were comprehensively analyzed. The onset ages of 98 Chinese T188K-gCJD patients ranged from 40 to 80 years old (y) (median: 61 years), with a male-to-female ratio of 1:0.85. The geographic distribution of T188K-gCJD patients showed a significant north-south disparity (cumulative incidence: 0.1217 vs. 0.0534 per million, p = 0.0227). Clinical phenotype of T188K-gCJD resembled closely that of sporadic CJD (sCJD), but positive rates of periodic sharp wave complexes (PSWC) on EEG (29.9%) and CSF RT-QuIC (53.2%) were relatively low. Majority of the patients progressed rapidly with the median survival of 5.0 months, which was associated only with a shorter onset-to-report interval. The phenotype of T188K-gCJD is extremely similar to that of sCJD, underscoring the critical importance of PRNP sequencing for accurate diagnosis.

We examined relationships between metabolic factors, microvascular complications, and brain health in adults with type 1 diabetes. Fifty-one adults were assessed for metabolic risk factors, microvascular complications, and cognitive function, with a subset completing brain MRI. Compared to normative data, participants showed reduced fluid cognition (p = 0.01) but elevated crystallized cognition (p = 0.0001). Microvascular complications and metabolic risk factors (including obesity, diabetes duration, and HbA1c) were not consistently linked to brain health outcomes. These exploratory findings suggest subtle cognitive changes in adults with type 1 diabetes, though larger longitudinal studies are needed to clarify how metabolic and microvascular factors influence brain health.

This post hoc analysis examined the impact of prior immunosuppressants on the long-term efficacy and safety of inebilizumab, a cluster of differentiation 19+ B-cell-depleting monoclonal antibody, in participants with aquaporin-4-seropositive neuromyelitis optica spectrum disorder from the N-MOmentum trial (NTC02200770). Inebilizumab treatment resulted in a sustained low annualized attack rate relative to the pretrial annualized attack rate and a high probability of remaining attack-free for up to 4 years among participants with and without prior immunosuppressant use. Based on modeling data, inebilizumab had greater long-term efficacy than historical immunosuppressants. Inebilizumab was well tolerated regardless of prior immunosuppressant use.