Floeter, Mary Kay

ABSTRACT Background Primary lateral sclerosis (PLS) is an ultrarare upper motor neuron syndrome with a prognosis unique from classical ALS. The study of PLS is complicated by its rarity and the difficulty distinguishing PLS from ALS. We present data from a 1‐year prospective follow‐up study on PLS and efforts to distinguish it from ALS. Methods Seventy‐six PLS participants enrolled in this prospective natural history study. EMG studies, blood neurofilament light chain levels (NfLs), and demographic characteristics were obtained at baseline. At 1‐year follow‐up, repeat EMG studies were conducted to determine which participants fulfilled criteria for ALS. Baseline characteristics were then compared to determine features that predict reclassification. Results Seventy participants completed 1‐year follow‐up. Five of the 70 were reclassified to ALS (7.1%). Those reclassified had higher trends in baseline blood NfL levels (91.4 vs. 34.0 pg/mL, p = 0.13) and shorter symptom duration (39 vs. 69 months in the PLS group, p = 0.15). Reclassification was noted in both probable and definite PLS participants. All cases with a symptomatic duration of less than 2 years retained the PLS phenotype (5 of 5). NfL levels over 90 pg/mL predicted reclassification with 94% specificity and 60% sensitivity. No other features predicted reclassification to ALS. Conclusions In our population, reclassification of PLS to ALS occurred at a low frequency at 1 year follow‐up (7.1%). Baseline NfL was the strongest predictor in differentiating UMN dominant ALS from PLS at 1‐year follow‐up. Based on our data, we propose EMG and NfL criteria for enrollment in future PLS trials.

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

Abstract Significant progress has been made in understanding the pre-symptomatic phase of amyotrophic lateral sclerosis. While much is still unknown, advances in other neurodegenerative diseases offer valuable insights. Indeed, it is increasingly clear that the well-recognized clinical syndromes of Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, spinal muscular atrophy and frontotemporal dementia are also each preceded by a pre-symptomatic or prodromal period of varying duration, during which the underlying disease process unfolds, with associated compensatory changes and loss of inherent system redundancy. Key insights from these diseases highlight opportunities for discovery in amyotrophic lateral sclerosis. The development of biomarkers reflecting amyloid and tau has led to a shift in defining Alzheimer’s disease based on inferred underlying histopathology. Parkinson’s disease is unique among neurodegenerative diseases in the number and diversity of non-genetic biomarkers of pre-symptomatic disease, most notably REM sleep behaviour disorder. Huntington’s disease benefits from an ability to predict the likely timing of clinically manifest disease based on age and CAG-repeat length alongside reliable neuroimaging markers of atrophy. Spinal muscular atrophy clinical trials have highlighted the transformational value of early therapeutic intervention, and studies in frontotemporal dementia illustrate the differential role of biomarkers based on genotype. Similar advances in amyotrophic lateral sclerosis would transform our understanding of key events in pathogenesis, thereby dramatically accelerating progress towards disease prevention. Deciphering the biology of pre-symptomatic amyotrophic lateral sclerosis relies on a clear conceptual framework for defining the earliest stages of disease. Clinically manifest amyotrophic lateral sclerosis may emerge abruptly, especially among those who harbour genetic mutations associated with rapidly progressive amyotrophic lateral sclerosis. However, the disease may also evolve more gradually, revealing a prodromal period of mild motor impairment preceding phenoconversion to clinically manifest disease. Similarly, cognitive and behavioural impairment, when present, may emerge gradually, evolving through a prodromal period of mild cognitive impairment or mild behavioural impairment before progression to amyotrophic lateral sclerosis. Biomarkers are critically important to studying pre-symptomatic amyotrophic lateral sclerosis and essential to efforts to intervene therapeutically before clinically manifest disease emerges. The use of non-genetic biomarkers, however, presents challenges related to counselling, informed consent, communication of results and limited protections afforded by existing legislation. Experiences from pre-symptomatic genetic testing and counselling, and the legal protections against discrimination based on genetic data, may serve as a guide. Building on what we have learned—more broadly from other pre-symptomatic neurodegenerative diseases and specifically from amyotrophic lateral sclerosis gene mutation carriers—we present a road map to early intervention, and perhaps even disease prevention, for all forms of amyotrophic lateral sclerosis.

AbstractIntroductionOur research aim was to develop a novel clinimetric scale sensitive enough to detect disease progression in primary lateral sclerosis (PLS).MethodsA prototype of the PLS Functional Rating Scale (PLSFRS) was generated. Seventy‐seven participants with PLS were enrolled and evaluated at 21 sites that comprised the PLSFRS study group. Participants were assessed using the PLSFRS, Neuro‐Quality of Life (QoL), Schwab‐England Activities of Daily Living (ADL), and the Clinical Global Impression of Change scales. Participants completed telephone assessments at 12, 24, and 48 weeks after enrollment.ResultsThe PLSFRS demonstrated internal consistency as well as intrarater, interrater, telephone test‐retest reliability, and construct validity. Significant changes in disease progression were detected at 6 and 12 months; changes measured by the PLSFRS vs the ALSFRS‐R were significantly higher.DiscussionThe PLSFRS is a valid tool to assess the natural history of PLS in a shorter study period.

As potential treatments for C9ORF72‐associated amyotrophic lateral sclerosis (c9ALS) approach clinical trials, the identification of prognostic biomarkers for c9ALS becomes a priority. We show that levels of phosphorylated neurofilament heavy chain (pNFH) in cerebrospinal fluid (CSF) predict disease status and survival in c9ALS patients, and are largely stable over time. Moreover, c9ALS patients exhibit higher pNFH levels, more rapid disease progression, and shorter survival after disease onset than ALS patients without C9ORF72 expansions. These data support the use of CSF pNFH as a prognostic biomarker for clinical trials, which will increase the likelihood of successfully developing a treatment for c9ALS. Ann Neurol 2017;82:139–146

Poly(GP) proteins are a promising pharmacodynamic marker for developing and testing therapeutics for treating C9ORF72 -associated amyotrophic lateral sclerosis.