Presymptomatic amyotrophic lateral sclerosis: from characterization to prevention

Abstract

Purpose of review Significant progress in characterizing presymptomatic amyotrophic lateral sclerosis (ALS) is ushering in an era of potential disease prevention. Although these advances have largely been based on cohorts of deep-phenotyped mutation carriers at an elevated risk for ALS, there are increasing opportunities to apply principles and insights gleaned, to the broader population at risk for ALS [and frontotemporal dementia (FTD)]. Recent findings The discovery that blood neurofilament light chain (NfL) level increases presymptomatically and may serve as a susceptibility biomarker, predicting timing of phenoconversion in some mutation carriers, has empowered the first-ever prevention trial in SOD1-ALS. Moreover, there is emerging evidence that presymptomatic disease is not uniformly clinically silent, with mild motor impairment (MMI), mild cognitive impairment (MCI), and/or mild behavioral impairment (MBI) representing a prodromal stage of disease. Structural and functional brain abnormalities, as well as systemic markers of metabolic dysfunction, have emerged as potentially even earlier markers of presymptomatic disease. Ongoing longitudinal studies will determine the extent to which these reflect an endophenotype of genetic risk. Summary The discovery of presymptomatic biomarkers and the delineation of prodromal states is yielding unprecedented opportunities for earlier diagnosis, treatment, and perhaps even prevention of genetic and apparently sporadic forms of disease.

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“…Given that the overlap of the neurodegenerative pathologies we see in MMC children are reported both in unimpaired and cognitively impaired older populations (Wakisaka et al, 2003;Kovacs et al, 2013;Boyle et al, 2018;Nag et al, 2018;Wennberg et al, 2019;Karanth et al, 2020;Robinson et al, 2023), early neurotoxic environmental factors must be identified, and preventive interventions executed in highly exposed populations. Moreover, early identification of pre-symptomatic stages, the definition of early progression and heterogeneity of the quadruple neurodegenerative hallmarks, and the contribution of brain structural changes to early neuropsychiatric symptoms need to be described (Benatar et al, 2023;Busy et al, 2023;Butler Pagnotti et al, 2023;Kapustin et al, 2023;Manca et al, 2023;Montero-Calle et al, 2023;Russell and Rohrer, 2023;Ulugut et al, 2023;Young et al, 2023).…”

The Spectrum of Cognitive Dysfunction in Amyotrophic Lateral Sclerosis: An Update

“…A significant elevation of the neurofilament light chain (NfL) in cerebrospinal fluid (CSF) and serum was found in ALS patients, compared to healthy controls. Increased values were found particularly in ALS patients with known mutations but have also been applied to sALS patients and may shorten the diagnostic delay by up to 3 months [20]. ALS is characterized by increased CSF and serum levels of NfL, a marker of neuroaxonal degeneration [216,217] that may be associated with CI [218].…”

“…There is emerging evidence that presymptomatic disease is not uniformly clinically silent with mild motor, cognitive and/or behavioral impairment, representing a prodromal stage of ALS [20]. In contrast to motor functioning that declines concomitantly with disease progression, cognitive deficits appear in early disease, are essentially present at the initial visit and usually do not substantially decline on follow-up [46].…”

“…During the last 10 years, radiological, humoral, neurophysiological and genetic biomarkers have been reported in ALS and some of them correlate to the CI of ALS patients. Early detection and careful monitoring of ALSci even at early disease stages are crucial for patient and caregiver and may not only have prognostic implications but may also be important for future clinical trials [20]. The present review is restricted to the neuroimaging and pathological bases of CI in ALS and its pathogenesis, without a specific discussion of FTLD.…”

Non-motor symptoms in patients with amyotrophic lateral sclerosis: current state and future directions

“…More to that, when the speed of diagnostic neuropsychological tests was adjusted for dysarthria, no significant difference between spinal and bulbar onset was found [ 224 ]. Detecting and monitoring CI in ALS early on is essential not just for prognostic reasons, but also because it could have significant implications for future clinical trials [ 229 ].…”