C9ORF72 hexanucleotide expansion is the most common genetic cause of familial amyotrophic lateral sclerosis (ALS)/fronto-temporal dementia (FTD) disease spectrum. Even though three major mechanisms of disease pathogenesis have been proposed, we lack detailed understanding of the factors that influence disease onset and progression. We sought to characterize cerebrospinal fluid and sera of C9ORF72 patients via a multiplex assay of 41 chemokines and cytokines in comparison to neurological controls and sporadic ALS patients. We found an increase in synthesis of pro-inflammatory chemokines and cytokines in disease samples and particularly in C9ORF72 patients in comparison to controls. We provide evidence that a CSF pro-inflammatory signature is a feature of C9ORF72–mediated disease.

Introduction/Aims: Expanded access protocols (EAPs) allow individuals ineligible for clinical trials to receive investigational products. EAP data can be collected in parallel to randomized clinical trials (RCTs) and serve as a source of evidence in clinical practice. Here, we present the results of a National Institutes of Health (NIH)‐funded EAP for amyotrophic lateral sclerosis (ALS). Methods: Participants received trehalose, a drug studied in a parallel RCT, for up to 24 weeks; clinical and biomarker data were collected throughout the study. Results: Seventy participants were enrolled at 20 study centers across the United States. Treatment with trehalose did not affect the levels of neurofilament light chain [estimated flat slope per month was −0.005, SE = 0.0078; 95% CI (−0.021, 0.011)] or disease progression [estimated least square mean change of the ALS Functional Rating Scale—Revised total score and slow vital capacity (percent predicted) from baseline to Week 24 were −5.6 (0.67); 95% CI (−7.0, −4.3) and −4.53 (4.308); 95% CI (−13.55, 4.48)], respectively. No unexpected treatment‐related risks were identified. Serious adverse events were deemed not related to trehalose (20 occurrences in 13 [18.6%] participants with eight deaths). Discussion: This EAP establishes a framework for implementing multi‐center EAPs that complement data collected from RCTs. Additional NIH‐funded EAPs are currently underway. Data and additional serum samples collected in this study are available to the research community for further study. Trial Registration: ClinicalTrials.gov: NCT05597436

Background and Objectives: Neuropathy is a debilitating disorder characterized by peripheral nerve dysfunction and damage to sensory, motor, and autonomic neurons and their axons. While homozygous mutations in DNAJB2/HSJ1 have been linked to early-onset neuropathy, a heterozygous DNAJB2 c.823+6C>T was discovered in an adult patient with severe sensory–motor polyneuropathy. This mutation is predicted to affect both isoforms of the protein. DNAJB2 (HSP40), a key member of the heat shock protein family, plays a critical role in cellular protection and stress, including response to heat shock. DNAJB2 traffics unfolded proteins to another heat shock protein, HSP70, and activates its ATPase activity to result in a correctly folded protein(s). In this study, we aimed to investigate the effects of the heterozygous DNAJB2 c.823+6C>T mutation on the stress response of DNAJB2 in fibroblasts obtained from the neuropathy patient. Methods: The fibroblasts were subjected to one hour of heat shock at 42 °C, and the time course of expression levels of DNAJB2 was established. Additionally, we evaluated the therapeutic efficacy of Cystamine, which has been shown to modulate DNAJB2 levels in cellular and animal models of Huntington’s disease. Results: Our results revealed reduced baseline levels of DNAJB2 between the mutant and control fibroblasts. Importantly the mutant cells exhibited a diminished response to heat shock. Thus, the mutation affects the upregulation of DNAJB2 under stress, possibly contributing to the pathogenesis of sensory–motor polyneuropathy. A 48-h pretreatment with 150 μM of Cystamine increased the levels of DNAJB2 in both the control and patient’s fibroblasts. Conclusions: To the best of our knowledge, this is the first study to explore this mutant form of DNAJB2 in neuropathy. The study demonstrated that the heterozygous DNAJB2 c.823+6C>T mutation leads to impaired DNAJB2 response to heat shock in the fibroblasts. Cystamine showed promise in restoring DNAJB2 expression, highlighting the need for further research into targeted therapeutic strategies for DNAJB2-related disorders.

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive and fatal neurological disease that leads to death within 2-5 years of diagnosis for more than 80% of people living with ALS (PLWALS). The American Academy of Neurology (AAN) developed practice parameters-general principles to guide clinicians in managing ALS-encouraging multidisciplinary care (MDC) but does not recommend specific healthcare delivery models. Three healthcare delivery models have evolved: a traditional model, a triage model, and a non-triage model. This study aims to describe preferences for and satisfaction with various models, among PLWALS and their caregivers (CALS), along with their perceptions of how their care aligns with AAN guidelines. A cross-sectional observational study utilizing a web-based survey was distributed via email to PLWALS and CALS. Three multi-assessment questionnaires were developed and tailored for PLWALS, CALS, and former CALS. Best-worst scaling (object case) data were analyzed using a best-minus-worst approach and descriptive statistics were calculated from means, t-tests and chi-square. The combined sample included 378 respondents: 254 PLWALS (67.20%) and 124 CALS (32.80%; composed of 79 current caregivers [20.90%] and 45 former caregivers [11.90%]). The mean respondent age was 61.09 years (SD 11.1). The majority of the sample was white (92.86%), insured by Medicare (61.11%), and married/partnered (79.10%). Respondents preferred a non-triage model the most and a traditional model the least; 88.20% (CI: 84.92-91.49) were extremely likely to choose a non-triage model if given the choice and 83.12% (CI: 79.29-86.92) of respondents ranked non-triage as most preferred. A traditional model was ranked as the least preferred model in 75.28% (CI: 70.78-79.78) of respondents. The most important factors driving respondent preferences were ALS expertise and team-based care. Overall, respondents are satisfied with their care teams. PLWALS utilizing non-triage MDC models reported more adherence to quality care measures compared with those utilizing triage and traditional models. Respondent preference for non-triage models is consistent with the importance they place on the features of non-triage models. However, these findings should be understood in the context of our sample in which a large majority of respondents were receiving care via a non-triage model. To ensure ALS care delivery is patient-centered, practice parameters that aim to guide clinicians in managing ALS should provide more guidance to MDCs to deliver care aligned with patient preferences and values. Efforts should focus on sustainable financial models that can better facilitate non-triage models of care.