Oskarsson, Björn

Objective The primary lateral sclerosis ( PLS ) consensus diagnostic criteria and functional rating scale ( PLSFRS ) were recently established to facilitate and optimize future PLS clinical trials. We examined the trajectory of the PLSFRS and other functional outcome measures and biomarkers in the PLS Natural History Study ( PLS NHS ) to understand their performance in this prospective cohort. Methods The PLS NHS is a prospective, longitudinal, multicenter study of people living with PLS in different diagnostic categories: early (disease duration <2 years); probable (2–4 years); and definite PLS (4–15 years). PLSFRS scores and other functional outcome measures were collected at baseline, 3‐, 6‐, 9‐, and 12‐month follow‐up visits. Baseline characteristics were compared between the groups. The slopes of the PLSFRS and other functional outcome measures over 12 months were examined in the overall cohort and subgroups using linear mixed‐effect models. The associations between baseline characteristics and the rate of PLSFRS decline were analyzed with linear regression models. Results A total of 76 participants were included: early (n = 6); probable (n = 26); and definite (n = 44) PLS . Baseline PLSFRS total scores were highest in the early PLS group, followed by the probable and definite PLS groups. In the overall cohort, the PLSFRS total score declined by 0.33 points/month (95% confidence interval [0.27–0.39], adjusted p < 0.05). The rate of decline was steepest in the early PLS group, followed by the probable and definite PLS groups. Baseline neurofilament light chain level was associated with the rate of PLSFRS decline over 1 year ( p = 0.001). Interpretation In PLS, the rate of functional decline, as measured by the PLSFRS total score, is faster during the early phase of the disease. Neurofilament light might serve as a prognostic biomarker in PLS. ANN NEUROL 2026;99:418–428

ABSTRACTIntroduction/AimsMuscle cramps are a common symptom in amyotrophic lateral sclerosis (ALS). Ameliorating muscle cramps may improve quality of life in devastating diseases like ALS. A traditional Japanese medicine (Kampo, TJ‐68) is widely prescribed in Japan for muscle cramps. However, it is not available in the USA. This study evaluated the safety, tolerability, and efficacy of TJ‐68 in ALS.MethodsThis study was a double‐blind, randomized, placebo‐controlled crossover trial, consisting of four periods, conducted at three centers in the USA. Safety was evaluated using multiple measures. The primary efficacy outcome was the Visual Analog Scale for Muscle Cramps Affecting Overall Daily Activity (item #5 of the Muscle Cramp Scale (MCS)). The secondary outcomes included the remaining items of the MCS and the Clinical Global Impression of Changes (CGIC), among others. The study was planned to enroll 22 participants with ALS within 2 years.ResultsThe enrollment was slow and was completed with 11 participants. There were no serious safety issues and TJ‐68 was well tolerated. Although the primary outcome measure did not reach statistical significance (p = 0.35), several secondary measures showed significant results: MCS #1 triggering of cramps (p = 0.01), MCS #2 cramp frequency (p = 0.03), MCS Additional 1 change of motor behaviors (p = 0.02), and CGIC assessed by the evaluator (p = 0.009). Other outcome measures did not reach statistical significance.DiscussionThe study revealed that N‐of‐1 trial design can detect changes in a small sample size, and TJ‐68 appeared to be safe. Larger studies are needed to confirm the efficacy of TJ‐68.

Abstract Mass spectrometry (MS) is a technique widely employed for the identification and characterization of proteins, with personalized medicine, systems biology, and biomedical applications. The application of MS-based proteomics advances our understanding of protein function, cellular signaling, and complex biological systems. MS data analysis is a critical process that includes identifying and quantifying proteins and peptides and then exploring their biological functions in downstream analyses. To address the complexities associated with MS data analysis, we developed ProtPipe to streamline and automate the processing and analysis of high-throughput proteomics and peptidomics datasets with DIA-NN preinstalled. The pipeline facilitates data quality control, sample filtering, and normalization, ensuring robust and reliable downstream analyses. ProtPipe provides downstream analyses, including protein and peptide differential abundance identification, pathway enrichment analysis, protein–protein interaction analysis, and major histocompatibility complex (MHC)–peptide binding affinity analysis. ProtPipe generates annotated tables and visualizations by performing statistical post-processing and calculating fold changes between predefined pairwise conditions in an experimental design. It is an open-source, well-documented tool available at https://github.com/NIH-CARD/ProtPipe, with a user-friendly web interface.

Functional loss of TDP-43, an RNA binding protein genetically and pathologically linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), leads to the inclusion of cryptic exons in hundreds of transcripts during disease. Cryptic exons can promote the degradation of affected transcripts, deleteriously altering cellular function through loss-of-function mechanisms. Here, we show that mRNA transcripts harboring cryptic exons generated de novo proteins in TDP-43–depleted human iPSC–derived neurons in vitro, and de novo peptides were found in cerebrospinal fluid (CSF) samples from patients with ALS or FTD. Using coordinated transcriptomic and proteomic studies of TDP-43–depleted human iPSC–derived neurons, we identified 65 peptides that mapped to 12 cryptic exons. Cryptic exons identified in TDP-43–depleted human iPSC–derived neurons were predictive of cryptic exons expressed in postmortem brain tissue from patients with TDP-43 proteinopathy. These cryptic exons produced transcript variants that generated de novo proteins. We found that the inclusion of cryptic peptide sequences in proteins altered their interactions with other proteins, thereby likely altering their function. Last, we showed that 18 de novo peptides across 13 genes were present in CSF samples from patients with ALS/FTD spectrum disorders. The demonstration of cryptic exon translation suggests new mechanisms for ALS/FTD pathophysiology downstream of TDP-43 dysfunction and may provide a potential strategy to assay TDP-43 function in patient CSF.

Genetic variation at the transmembrane protein 106B gene ( TMEM106B) has been linked to risk of frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) through an unknown mechanism. We found that presence of the TMEM106B rs3173615 protective genotype was associated with longer survival after symptom onset in a postmortem FTLD-TDP cohort, suggesting a slower disease course. The seminal discovery that filaments derived from TMEM106B is a common feature in aging and, across a range of neurodegenerative disorders, suggests that genetic variants in TMEM106B could modulate disease risk and progression through modulating TMEM106B aggregation. To explore this possibility and assess the pathological relevance of TMEM106B accumulation, we generated a new antibody targeting the TMEM106B filament core sequence. Analysis of postmortem samples revealed that the TMEM106B rs3173615 risk allele was associated with higher TMEM106B core accumulation in patients with FTLD-TDP. In contrast, minimal TMEM106B core deposition was detected in carriers of the protective allele. Although the abundance of monomeric full-length TMEM106B was unchanged, carriers of the protective genotype exhibited an increase in dimeric full-length TMEM106B. Increased TMEM106B core deposition was also associated with enhanced TDP-43 dysfunction, and interactome data suggested a role for TMEM106B core filaments in impaired RNA transport, local translation, and endolysosomal function in FTLD-TDP. Overall, these findings suggest that prevention of TMEM106B core accumulation is central to the mechanism by which the TMEM106B protective haplotype reduces disease risk and slows progression.

AbstractIntroduction/AimsMost persons with amyotrophic lateral sclerosis (ALS) live at home with support of family caregivers, with escalating complexity of care over the trajectory of the disease requiring resources and support to mitigate negative physical, social, and emotional outcomes.MethodsThis scoping review identifies the home health/home care needs of persons with ALS and their caregivers as a basis for creating a home health medical standard. We used the PRISMA Extension for Scoping Reviews (PRISMA‐ScR) to examine studies describing home care needs published between 2011 and 2021.ResultsOur search yielded 481 articles, of which 44 were included with a total of 3592 (9–273) participants. Most studies used a cross‐sectional design and 20 (45%) were rated as high quality. We grouped the needs identified as emotional/psychological, assistive devices and technology, information and education, and human resources and professional services. Most studies demonstrated persistent unmet needs and that available interventions were helpful while needs generally were not met proactively, despite the predictable trajectory.DiscussionThis review describes biopsychosocial and equipment interventions over the trajectory of ALS with implications for anticipatory planning by clinicians, as well as policy for coverage of necessary services and supports. Interdisciplinary expert teams could develop consensus around needs across the trajectory and recommended services and supports. To make knowledge more accessible, encourage availability of services, and clarify the need for coverage of services, we aim to develop an expert consensus‐based ALS home health medical standard guidance document in collaboration with the American Association of Neuromuscular and Electrodiagnostic Medicine.

Abstract Objectives Mutations in VCP, HNRNPA2B1, HNRNPA1 , and SQSTM1 , encoding RNA‐binding proteins or proteins in quality‐control pathways, cause multisystem proteinopathies (MSP). They share pathological findings of protein aggregation and clinical combinations of inclusion body myopathy (IBM), neurodegeneration [motor neuron disorder (MND)/frontotemporal dementia (FTD)], and Paget disease of bone (PDB). Subsequently, additional genes were linked to similar but not full clinical‐pathological spectrum (MSP‐like disorders). We aimed to define the phenotypic‐genotypic spectrum of MSP and MSP‐like disorders at our institution, including long‐term follow‐up features. Methods We searched the Mayo Clinic database (January 2010–June 2022) to identify patients with mutations in MSP and MSP‐like disorders causative genes. Medical records were reviewed. Results Thirty‐one individuals (27 families) had pathogenic mutations in: VCP ( n = 17), SQSTM1 + TIA1 ( n = 5), TIA1 ( n = 5), MATR3, HNRNPA1, HSPB8 , and TFG ( n = 1, each). Myopathy occurred in all but 2 VCP ‐MSP patients with disease onset at age 52 (median). Weakness pattern was limb‐girdle in 12/15 VCP ‐MSP and HSPB8 patient, and distal‐predominant in other MSP and MSP‐like disorders. Twenty/24 muscle biopsies showed rimmed vacuolar myopathy. MND and FTD occurred in 5 (4 VCP , 1 TFG ) and 4 (3 VCP , 1 SQSTM1 + TIA1 ) patients, respectively. PDB manifested in 4 VCP ‐MSP. Diastolic dysfunction occurred in 2 VCP ‐MSP. After 11.5 years (median) from symptom onset, 15 patients ambulated without gait‐aids; loss of ambulation ( n = 5) and death ( n = 3) were recorded only in VCP ‐MSP. Interpretation VCP ‐MSP was the most common disorder; rimmed vacuolar myopathy was the most frequent manifestation; distal‐predominant weakness occurred frequently in non‐ VCP ‐MSP; and cardiac involvement was observed only in VCP ‐MSP.

Abstract Introduction/Aims: Muscle cramps are a common and often disabling symptom in Amyotrophic Lateral Sclerosis (ALS), a devastating and incurable neurodegenerative disorder. To date, there are no medications specifically approved for the treatment of muscle cramps. Ameliorating muscle cramps in this patient population may sustain quality of life longer. A traditional Japanese medicine, shakuyakukanzoto (TJ-68) is widely prescribed in Japan for managing muscle cramps in a variety of conditions. The Japanese ALS Management Guideline mentions TJ-68 for difficult muscle cramps in ALS. Therefore, this clinical trial is designed to test the safety and efficacy of TJ-68 in participants with ALS reporting serious muscle cramps using a personalized N-of-1 approach. If successful, we can introduce TJ-68 for muscle cramps in ALS to Western medicine. Methods: With FDA-IND approval, we are conducting a two-site, double-blind, randomized personalized N-of-1 early clinical trial with TJ-68. At least 22 participants with ALS and daily muscle cramps will receive drug or placebo for 2 weeks (one treatment period) followed by a 1-week washout in a four-period cross-over design. While the primary objective is to evaluate the safety of TJ-68, the study was sized to detect a one-point shift on the Columbia Muscle Cramp Scale (MCS) item #5 with 85% power under a four-period crossover design.The secondary assessment includes the full MCS score, a Cramp Diary, Clinical Global Impression of Changes, Goal Attainment Scale, quality of life scale and ALS functional rating scale-revised (ALSFRS-R). Discussion: The study is underway. A personalized N-of-1 trial design is an efficient approach to testing medications that alleviate MCS in rare disorders. If TJ-68 proves safe and efficacious, we will work to introduce this product to Western medicine for treatment of patients with ALS and disabling muscle cramps. Trial Registration: This clinical trial has been registered with ClinicalTrials.gov (NCT04998305).

Frontotemporal dementia and amyotrophic lateral sclerosis (FTD-ALS) are associated with both a repeat expansion in the C9orf72 gene and mutations in the TANK-binding kinase 1 ( TBK1 ) gene. We found that TBK1 is phosphorylated in response to C9orf72 poly(Gly-Ala) [poly(GA)] aggregation and sequestered into inclusions, which leads to a loss of TBK1 activity and contributes to neurodegeneration. When we reduced TBK1 activity using a TBK1-R228H (Arg 228 →His) mutation in mice, poly(GA)-induced phenotypes were exacerbated. These phenotypes included an increase in TAR DNA binding protein 43 (TDP-43) pathology and the accumulation of defective endosomes in poly(GA)-positive neurons. Inhibiting the endosomal pathway induced TDP-43 aggregation, which highlights the importance of this pathway and TBK1 activity in pathogenesis. This interplay between C9orf72 , TBK1 , and TDP-43 connects three different facets of FTD-ALS into one coherent pathway.