Background: Clinical trials for rare diseases pose unique challenges warranting alternative approaches in demonstrating treatment efficacy. Such trials face challenges including small patient populations, variable onset of symptoms and rate of disease progression, and ethical considerations, particularly in neurodegenerative diseases. In this study, we present the retrospective clinical global impression (RCGI) severity and change (RCGI-S/C) scale on 27 patients with GM1 gangliosidosis, a post hoc clinician-rated outcome measure to evaluate natural history study participants as historical controls for comparisons with treated patients in a clinical trial. Methods: We conducted a systematic chart review of 27 GM1 gangliosidosis natural history participants across 95 total visits. RCGI-S was assessed at the first visit and rated 1 (normal) to 7 (among the most extremely ill). Each subsequent follow-up was rated on the RCGI-C scale from 1 (very much improved) to 7 (very much worse). We demonstrate scoring guidelines of both scales with examples and justifications for this pilot in GM1 gangliosidosis natural history participants. The convergent validity of the RCGI scales was explored through correlations with magnetic resonance imaging (MRI) and the Vineland Adaptive Behavioral Scales. Results: We found strong association between the RCGI-S scores with gray matter volume (r(14) = −0.81; 95% CI [−0.93, −0.51], p < 0.001), and RCGI-C scores significantly correlated with increases in ventricular volume (χ²(1) = 18.6, p < 0.001). Baseline RCGI-S scores also strongly correlated with Vineland adaptive behavioral composite scores taken at the same visit (r(14) = −0.72; 95% CI [−0.93, −0.17], p = 0.02). Conclusion: RCGI-S/C scales, which use the clinical evaluation to assess the severity of disease of each patient visit over time, were consolidated into a single quantitative metric in this study. Longitudinal RCGI-C scores allowed us to quantify disease progression in our late-infantile and juvenile GM1 patients. We suggest that the retrospective CGI may be an important tool in evaluating historical data for comparison with changes in disease progression/mitigation following therapeutic interventions.

Transcranial magnetic stimulation (TMS) is a treatment procedure for some neuropsychiatric disorders, and it has been used for brain mapping, as well as diagnosis and treatment of neuromuscular dysfunctions. There is a disconnect between TMS modeling and clinical data: several groups have reported the simulated induced electric field and measured resting motor threshold (RMT) with inconsistent results in the relationship between RMT and brain scalp distance. This necessitates the use of simulation parameters that further account for individual differences in neuroanatomy. We recruited ten healthy subjects and obtained empirical RMT, magnetic resonance imaging (MRI), and diffusion tensor imaging (DTI). We developed anatomically accurate brain models from MRI and simulated TMS to determine the percent depolarized volume of gray matter (DVG) from TMS-induced electric fields. Corticospinal fiber tracts were extracted from the primary motor cortex from DTI to obtain fiber tract surface areas (FTSAs) for each participant. Linear mixed-effects models were used to evaluate the effect of DVG and FTSA on RMT. We report that DVG correlates with RMT when accounting for corticospinal FTSA.

The dual rAAVrh8-HEXA and rAAVrh8-HEXB vector can restore central nervous system hexosaminidase (Hex) enzyme activity, decrease GM2 levels in cerebrospinal fluid and rescue phenotypic consequences of GM2 gangliosidosis, Tay-Sachs and Sandhoff diseases in animal models following simultaneous bi-thalamic (BiT) injections. Following up on an n = 2 expanded access trial, we initiated a phase 1/2, single-dose, dose-escalation of combined BiT, intra-cisterna magna and intrathecal infusion in children with Tay-Sachs and Sandhoff diseases (six infantile, three juvenile). The BiT injection volume and vector dose were doubled between four cohorts, with the lowest dose matching the earlier expanded access trial. Cerebrospinal fluid HexA enzyme activity, serum total Hex activity and GM2 levels showed a dose-dependent biochemical correction of the disease. Serum Hex activity surpassed 40 nmol h^-1 ml^-1, two times the lower limit of normal, and neuroimaging demonstrated increased fiber tracts. Correction was greatest at 12 weeks, but in decline by 24 weeks postdosing. Infantile patients experienced global clinical stabilization and prolonged oral feeding without aspiration until 3-3.5 years. Seizures had a later onset, were less frequent, less severe and more responsive to anti-convulsant medication. Adverse events were rare in infantile patients, but worsening dystonia was observed in juvenile patients, who were excluded from ongoing enrollment. ClinicalTrials.gov registration: NCT04669535 and NCT06614569 .

Transcranial magnetic stimulation (TMS) is a non-invasive treatment protocol for treating several psychiatric conditions, including depression, migraine, smoking cessation, and obsessive-compulsive disorder. Past research suggests that TMS treatment outcomes vary based on neuroanatomy, functional connectivity, and tractography-based structural connectivity. In a previous study, 26 mild to moderate traumatic brain injury (mTBI) patients underwent repetitive transcranial magnetic stimulation (rTMS) and showed improvements in depression, post-concussive symptoms, and sleep dysfunction. The present study was a secondary analysis of that data. Anatomically accurate head models were derived from magnetic resonance imaging (MRI), and finite element analysis simulations were performed to mimic empirical data collection. This allowed for examination of the roles that age, brain scalp distance (BSD), gray matter volume (GMV), site-specific electrical field strength (EFS), and depolarized gray matter volume (DGMV) had on resting motor threshold (RMT) at the precentral gyrus (PreCG). We also investigated how EFS simulated at the dorsolateral prefrontal cortex (DLPFC) and RMT influenced rTMS treatment outcomes. Linear regression showed BSD was associated with EFS, RMT, and DGMV supporting efforts to derive accurate parameters from MRI-based modeling. Furthermore, linear mixed effects modeling showed RMT was associated with EFS and DGMV at the PreCG when age and individual neuroanatomy was accounted for suggesting MRI based anatomy and simulated EFS potentially determine TMS dosage. We did not observe any significant relationship between any of the measures from this study on empirically collected rTMS outcomes in mTBI suggesting further investigations into the mechanisms behind these outcomes are needed.

Background: Volumetric analysis and segmentation of magnetic resonance imaging (MRI) data is an important tool for evaluating neurological disease progression and neurodevelopment. Fully automated segmentation pipelines offer faster and more reproducible results. However, since these analysis pipelines were trained on or run based on atlases consisting of neurotypical controls, it is important to evaluate how accurate these methods are for neurodegenerative diseases. In this study, we compared five fully automated segmentation pipelines, including FSL, Freesurfer, volBrain, SPM12, and SimNIBS, with a manual segmentation process in GM1 gangliosidosis patients and neurotypical controls. Methods: We analyzed 45 MRI scans from 16 juvenile GM1 gangliosidosis patients, 11 MRI scans from 8 late-infantile GM1 gangliosidosis patients, and 19 MRI scans from 11 neurotypical controls. We compared the results for seven brain structures, including volumes of the total brain, bilateral thalamus, ventricles, bilateral caudate nucleus, bilateral lentiform nucleus, corpus callosum, and cerebellum. Results: We found volBrain’s vol2Brain pipeline to have the strongest correlations with the manual segmentation process for the whole brain, ventricles, and thalamus. We also found Freesurfer’s recon-all pipeline to have the strongest correlations with the manual segmentation process for the caudate nucleus. For the cerebellum, we found a combination of volBrain’s vol2Brain and SimNIBS’ headreco to have the strongest correlations, depending on the cohort. For the lentiform nucleus, we found a combination of recon-all and FSL’s FIRST to give the strongest correlations, depending on the cohort. Lastly, we found segmentation of the corpus callosum to be highly variable. Conclusions: Previous studies have considered automated segmentation techniques to be unreliable, particularly in neurodegenerative diseases. However, in our study, we produced results comparable to those obtained with a manual segmentation process. While manual segmentation processes conducted by neuroradiologists remain the gold standard, we present evidence to the capabilities and advantages of using an automated process that includes the ability to segment white matter throughout the brain or analyze large datasets, which pose feasibility issues to fully manual processes. Future investigations should consider the use of artificial intelligence-based segmentation pipelines to determine their accuracy in GM1 gangliosidosis, lysosomal storage disorders, and other neurodegenerative diseases.

GM1 gangliosidosis, caused by biallelic variants in GLB1, results from deficiency of lysosomal β-galactosidase, which degrades GM1 ganglioside. This fatal neurodegenerative disease currently has no effective therapy. In a phase 1-2, open-label, dose-escalation study, we assessed immunosuppression and a single intravenous infusion of adeno-associated virus serotype 9 (AAV9) encoding β-galactosidase in children with type II GM1 gangliosidosis with late-infantile or juvenile onset. The primary end point was safety. Secondary end points included changes from baseline in the cerebrospinal fluid (CSF) GM1 ganglioside concentration and β-galactosidase activity, clinical assessments (including the Clinical Global Impression-Improvement [CGI-I] score, assessed on a scale from 1 [very much improved] to 7 [very much worse]), and neuroimaging patterns. Nine participants were enrolled. Over a 3-year period, 124 adverse events occurred, 30 of which (8 gastrointestinal events, 21 laboratory abnormalities associated with inflammation, and 1 tachycardia event) were deemed by the investigator as being possibly, probably, or definitely related to the gene therapy. Five serious adverse events occurred, including vomiting that led to hospitalization in one participant, which was attributed to the gene therapy. Serum aspartate and alanine aminotransferase levels increased in all participants and returned to baseline levels by 18 months. In all participants, the CSF β-galactosidase level increased and CSF GM1 ganglioside level decreased. Expressive communication and gross motor scores appeared stable, but fine motor and receptive communication scores decreased. The median CGI-I score was 3 (indicating minimal improvement) at 2 years and 4 (indicating no change) at 3 years; in historical controls, scores have been shown to increase (indicating worsening) over time. Neuroimaging showed patterns consistent with reduced rates of cerebral atrophy and favorable changes in myelination as compared with baseline. In this study involving nine participants with type II GM1 gangliosidosis, a single infusion of AAV9 encoding β-galactosidase was associated with adverse events, including severe vomiting in one participant and elevated liver-enzyme levels in all participants. Secondary end-point results suggested improvements in biochemical markers and neuroimaging patterns and stable or reduced rates of developmental deterioration in some measures. (Funded by the National Human Genome Research Institute and others; ClinicalTrials.gov number, NCT03952637.).