Recent advances in the diagnosis and prognosis of amyotrophic lateral sclerosis

Goutman, Stephen A.; Hardiman, Orla; Al‐Chalabi, Ammar; Chiò, Adriano; Savelieff, Masha G.; Kiernan, Matthew C.; Feldman, Eva L.

doi:10.1016/s1474-4422(21)00465-8

Cited by 191 publications

(146 citation statements)

References 109 publications

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“… 39 However, because these likely reflect neurodegeneration in an unspecific way, rather than being specific to ALS or FTD, none of them is definitive. 40 , 41 The next step is now to harness these newly discovered TDP‐43‐dependent cryptic splicing events and validate them in ALS and FTD patient tissue and biofluids (e.g., cerebrospinal fluid [CSF], blood urine) (Figure 2B ). Because some of the cryptic exon splicing events also result in the production of cryptic proteins and peptides, it is highly likely that the levels of these proteins will reflect the extent of TDP‐43 dysfunction in the brain.…”

Section: Cryptic Exons As Novel Biomarker Candidatesmentioning

confidence: 99%

“…In ALS, several candidate fluid biomarkers have been reported, such as vascular endothelial growth factor (VEGF), 37 neurofilament light chain protein (NfL) 38 and urinary p75 ECD 39 . However, because these likely reflect neurodegeneration in an unspecific way, rather than being specific to ALS or FTD, none of them is definitive 40,41 . The next step is now to harness these newly discovered TDP‐43‐dependent cryptic splicing events and validate them in ALS and FTD patient tissue and biofluids (e.g., cerebrospinal fluid [CSF], blood urine) (Figure 2B).…”

Section: Cryptic Exons As Novel Biomarker Candidatesmentioning

confidence: 99%

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Cracking the cryptic code in amyotrophic lateral sclerosis and frontotemporal dementia: Towards therapeutic targets and biomarkers

Akiyama

Koike

Petrucelli

et al. 2022

Clinical & Translational Med

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Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two devastating human neurodegenerative diseases. A hallmark pathological feature of both diseases is the depletion of the RNA‐binding protein TDP‐43 from the nucleus in the brain and spinal cord of patients. A major function of TDP‐43 is to repress the inclusion of cryptic exons during RNA splicing. When it becomes depleted from the nucleus in disease, this function is lost, and recently, several key cryptic splicing targets of TDP‐43 have emerged, including STMN2 , UNC13A , and others. UNC13A is a major ALS/FTD risk gene, and the genetic variations that increase the risk for disease seem to do so by making the gene more susceptible to cryptic exon inclusion when TDP‐43 function is impaired. Here, we discuss the prospects and challenges of harnessing these cryptic splicing events as novel therapeutic targets and biomarkers. Deciphering this new cryptic code may be a touchstone for ALS and FTD diagnosis and treatment.

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Section: Cryptic Exons As Novel Biomarker Candidatesmentioning

confidence: 99%

Section: Cryptic Exons As Novel Biomarker Candidatesmentioning

confidence: 99%

Cracking the cryptic code in amyotrophic lateral sclerosis and frontotemporal dementia: Towards therapeutic targets and biomarkers

Akiyama

Koike

Petrucelli

et al. 2022

Clinical & Translational Med

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“…Careful outcome measure selection is necessary to leverage psychometric and statistical advantages while also capturing clinically meaningful results that are relevant to the mechanism of the therapeutic agent of interest [ 5 ]. The use of ALS prediction algorithms and statistical enrichment techniques can serve as a valuable tool to improve trial efficiency and ability to detect a treatment effect [ 6 , 7 ]. Continued development and validation of biofluid biomarkers will serve as a valuable and necessary adjunct to clinical outcome measures by assessing target engagement, and the importance of biomarker incorporation into early phase clinical trials is increasingly recognized [ 8 , 9 ].…”

Section: Introductionmentioning

confidence: 99%

“…effect [6,7]. Continued development and validation of biofluid biomarkers will serve as a valuable and necessary adjunct to clinical outcome measures by assessing target engagement, and the importance of biomarker incorporation into early phase clinical trials is increasingly recognized [8,9].…”

Section: Introductionmentioning

confidence: 99%

Considerations for Amyotrophic Lateral Sclerosis (ALS) Clinical Trial Design

Fournier

2022

Neurotherapeutics

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Thoughtful clinical trial design is critical for efficient therapeutic development, particularly in the field of amyotrophic lateral sclerosis (ALS), where trials often aim to detect modest treatment effects among a population with heterogeneous disease progression. Appropriate outcome measure selection is necessary for trials to provide decisive and informative results. Investigators must consider the outcome measure’s reliability, responsiveness to detect change when change has actually occurred, clinical relevance, and psychometric performance. ALS clinical trials can also be performed more efficiently by utilizing statistical enrichment techniques. Innovations in ALS prediction models allow for selection of participants with less heterogeneity in disease progression rates without requiring a lead-in period, or participants can be stratified according to predicted progression. Statistical enrichment can reduce the needed sample size and improve study power, but investigators must find a balance between optimizing statistical efficiency and retaining generalizability of study findings to the broader ALS population. Additional progress is still needed for biomarker development and validation to confirm target engagement in ALS treatment trials. Selection of an appropriate biofluid biomarker depends on the treatment mechanism of interest, and biomarker studies should be incorporated into early phase trials. Inclusion of patients with ALS as advisors and advocates can strengthen clinical trial design and study retention, but more engagement efforts are needed to improve diversity and equity in ALS research studies. Another challenge for ALS therapeutic development is identifying ways to respect patient autonomy and improve access to experimental treatment, something that is strongly desired by many patients with ALS and ALS advocacy organizations. Expanded access programs that run concurrently to well-designed and adequately powered randomized controlled trials may provide an opportunity to broaden access to promising therapeutics without compromising scientific integrity or rushing regulatory approval of therapies without adequate proof of efficacy. Supplementary Information The online version contains supplementary material available at 10.1007/s13311-022-01271-2.

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“…Amyotrophic lateral sclerosis (ALS) is the most frequent adult-onset motor neuron disease, characterized by progressive pareses. 1 , 2 Despite the emphasis on the motor neurons, ALS has evolved to be regarded as a multisystem disorder, 3 given that it affects several brain regions in a distinctive propagation pattern. 4 In the clinical diagnostic processes, neuroimaging with magnetic resonance imaging (MRI) has an essential role in the exclusion of other etiologies of the clinical presentation.…”

Section: Introductionmentioning

confidence: 99%

Relaxation-weighted ²³Na magnetic resonance imaging maps regional patterns of abnormal sodium concentrations in amyotrophic lateral sclerosis

Müller

Nagel

Keidel

et al. 2022

Therapeutic Advances in Chronic Disease

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Objectives: Multiparametric magnetic resonance imaging (MRI) is established as a technical instrument for the characterisation of patients with amyotrophic lateral sclerosis (ALS). The contribution of relaxation-weighted sodium (23NaR) MRI remains to be defined. The aim of this study is to apply 23NaR MRI to investigate brain sodium homeostasis and map potential alterations in patients with ALS as compared with healthy controls. Materials and Methods: Seventeen patients with ALS (mean age 61.1 ± 11.4 years, m/f = 9/8) and 10 healthy control subjects (mean age 60.3 ± 15.3 years, m/f = 6/4) were examined by 23NaR MRI at 3 T. Regional sodium maps were obtained by the calculation of the weighted difference from two image data sets with different echo times (TE1 = 0.3 ms, TE2 = 25 ms). Voxel-based analysis of the relaxation-weighted maps, together with 23Na concentration maps for comparison, was performed. Results: ROI-based analyses of relaxation-weighted brain sodium concentration maps demonstrated increased sodium concentrations in the upper corticospinal tracts and in the frontal lobes in patients with ALS; no differences between ALS patients and controls were found in reference ROIs, where no involvement in ALS-associated neurodegeneration could be anticipated. Conclusion: 23NaR MRI mapped regional alterations within disease-relevant areas in ALS which correspond to the stages of the central nervous system (CNS) pathology, providing evidence that the technique is a potential biological marker of the cerebral neurodegenerative process in ALS.

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Recent advances in the diagnosis and prognosis of amyotrophic lateral sclerosis

Cited by 191 publications

References 109 publications

Cracking the cryptic code in amyotrophic lateral sclerosis and frontotemporal dementia: Towards therapeutic targets and biomarkers

Cracking the cryptic code in amyotrophic lateral sclerosis and frontotemporal dementia: Towards therapeutic targets and biomarkers

Considerations for Amyotrophic Lateral Sclerosis (ALS) Clinical Trial Design

Relaxation-weighted ²³Na magnetic resonance imaging maps regional patterns of abnormal sodium concentrations in amyotrophic lateral sclerosis

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Recent advances in the diagnosis and prognosis of amyotrophic lateral sclerosis

Cited by 191 publications

References 109 publications

Cracking the cryptic code in amyotrophic lateral sclerosis and frontotemporal dementia: Towards therapeutic targets and biomarkers

Cracking the cryptic code in amyotrophic lateral sclerosis and frontotemporal dementia: Towards therapeutic targets and biomarkers

Considerations for Amyotrophic Lateral Sclerosis (ALS) Clinical Trial Design

Relaxation-weighted 23Na magnetic resonance imaging maps regional patterns of abnormal sodium concentrations in amyotrophic lateral sclerosis

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Relaxation-weighted ²³Na magnetic resonance imaging maps regional patterns of abnormal sodium concentrations in amyotrophic lateral sclerosis