Advances in molecular pathology, diagnosis, and treatment of amyotrophic lateral sclerosis

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Abstract

Although the past two decades have produced exciting discoveries in the genetics and pathology of amyotrophic lateral sclerosis (ALS), progress in developing an effective therapy remains slow. This review summarizes the critical discoveries and outlines the advances in disease characterization, diagnosis, imaging, and biomarkers, along with the current status of approaches to ALS care and treatment. Additional knowledge of the factors driving disease progression and heterogeneity will hopefully soon transform the care for patients with ALS into an individualized, multi-prong approach able to prevent disease progression sufficiently to allow for a dignified life with limited disability.

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Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia.

Katya Rascovsky, John R. Hodges, David Knopman … (2011)

Based on the recent literature and collective experience, an international consortium developed revised guidelines for the diagnosis of behavioural variant frontotemporal dementia. The validation process retrospectively reviewed clinical records and compared the sensitivity of proposed and earlier criteria in a multi-site sample of patients with pathologically verified frontotemporal lobar degeneration. According to the revised criteria, 'possible' behavioural variant frontotemporal dementia requires three of six clinically discriminating features (disinhibition, apathy/inertia, loss of sympathy/empathy, perseverative/compulsive behaviours, hyperorality and dysexecutive neuropsychological profile). 'Probable' behavioural variant frontotemporal dementia adds functional disability and characteristic neuroimaging, while behavioural variant frontotemporal dementia 'with definite frontotemporal lobar degeneration' requires histopathological confirmation or a pathogenic mutation. Sixteen brain banks contributed cases meeting histopathological criteria for frontotemporal lobar degeneration and a clinical diagnosis of behavioural variant frontotemporal dementia, Alzheimer's disease, dementia with Lewy bodies or vascular dementia at presentation. Cases with predominant primary progressive aphasia or extra-pyramidal syndromes were excluded. In these autopsy-confirmed cases, an experienced neurologist or psychiatrist ascertained clinical features necessary for making a diagnosis according to previous and proposed criteria at presentation. Of 137 cases where features were available for both proposed and previously established criteria, 118 (86%) met 'possible' criteria, and 104 (76%) met criteria for 'probable' behavioural variant frontotemporal dementia. In contrast, 72 cases (53%) met previously established criteria for the syndrome (P < 0.001 for comparison with 'possible' and 'probable' criteria). Patients who failed to meet revised criteria were significantly older and most had atypical presentations with marked memory impairment. In conclusion, the revised criteria for behavioural variant frontotemporal dementia improve diagnostic accuracy compared with previously established criteria in a sample with known frontotemporal lobar degeneration. Greater sensitivity of the proposed criteria may reflect the optimized diagnostic features, less restrictive exclusion features and a flexible structure that accommodates different initial clinical presentations. Future studies will be needed to establish the reliability and specificity of these revised diagnostic guidelines.

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Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis.

M. Neumann, D. Sampathu, L K Kwong … (2006)

Ubiquitin-positive, tau- and alpha-synuclein-negative inclusions are hallmarks of frontotemporal lobar degeneration with ubiquitin-positive inclusions and amyotrophic lateral sclerosis. Although the identity of the ubiquitinated protein specific to either disorder was unknown, we showed that TDP-43 is the major disease protein in both disorders. Pathologic TDP-43 was hyper-phosphorylated, ubiquitinated, and cleaved to generate C-terminal fragments and was recovered only from affected central nervous system regions, including hippocampus, neocortex, and spinal cord. TDP-43 represents the common pathologic substrate linking these neurodegenerative disorders.

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Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS.

Mariely DeJesus-Hernandez, Ian R. Mackenzie, Bradley F. Boeve … (2011)

Several families have been reported with autosomal-dominant frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), genetically linked to chromosome 9p21. Here, we report an expansion of a noncoding GGGGCC hexanucleotide repeat in the gene C9ORF72 that is strongly associated with disease in a large FTD/ALS kindred, previously reported to be conclusively linked to chromosome 9p. This same repeat expansion was identified in the majority of our families with a combined FTD/ALS phenotype and TDP-43-based pathology. Analysis of extended clinical series found the C9ORF72 repeat expansion to be the most common genetic abnormality in both familial FTD (11.7%) and familial ALS (23.5%). The repeat expansion leads to the loss of one alternatively spliced C9ORF72 transcript and to formation of nuclear RNA foci, suggesting multiple disease mechanisms. Our findings indicate that repeat expansion in C9ORF72 is a major cause of both FTD and ALS. Copyright © 2011 Elsevier Inc. All rights reserved.

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Author and article information

Contributors

Hristelina Ilieva: Role: assistant professor of neurology and clinical director

Mithila Vullaganti: Role: associate professor

Justin Kwan: Role: associate research physician

Journal

Journal ID (nlm-ta): BMJ

Journal ID (iso-abbrev): BMJ

Journal ID (publisher-id): BMJ-US

Journal ID (hwp): bmj

Title: The BMJ

Publisher: BMJ Publishing Group Ltd.

ISSN (Print): 0959-8138

ISSN (Electronic): 1756-1833

Publication date Collection: 2023

Publication date (Electronic): 27 October 2023

Volume: 383

Electronic Location Identifier: e075037

Affiliations

[1 ]Jefferson Weinberg ALS Center, Thomas Jefferson University, Philadelphia, PA, USA

[2 ]Tufts University School of Medicine, Boston, Massachusetts, MA, USA

[3 ]National Institute of Neurological Disorders and Stroke, National Institute of Health, Bethesda, MD, USA

Author notes

Correspondence to: J Kwan justin.kwan@ 123456nih.gov

Article

Publisher ID: bmj-2023-075037.R1 Publisher ID: kwaj075037

DOI: 10.1136/bmj-2023-075037

PMC ID: 10603569

PubMed ID: 37890889

SO-VID: 1d261719-20f0-41e7-9401-5c8d1f7d1388

License:

This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

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Funding

Funded by: FundRef http://dx.doi.org/10.13039/100000002, National Institutes of Health;

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Advances in molecular pathology, diagnosis, and treatment of amyotrophic lateral sclerosis

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Most cited references 203

Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia.

Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis.

Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS.

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