Summary Amyotrophic lateral sclerosis is a progressive adult-onset neurodegenerative disease that primarily affects upper and lower motor neurons, but also frontotemporal and other regions of the ...brain. The extent to which each neuronal population is affected varies between individuals. The subsequent patterns of disease progression form the basis of diagnostic criteria and phenotypic classification systems, with considerable overlap in the clinical terms used. This overlap can lead to confusion between diagnosis and phenotype. Formal classification systems such as the El Escorial criteria and the International Classification of Diseases are systematic approaches but they omit features that are important in clinical management, such as rate of progression, genetic basis, or functional effect. Therefore, many neurologists use informal classification approaches that might not be systematic, and could include, for example, anatomical descriptions such as flail-arm syndrome. A new strategy is needed to combine the benefits of a systematic approach to classification with the rich and varied phenotypic descriptions used in clinical practice.
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease predominantly affecting upper and lower motor neurons. The disease leads to relentlessly progressive weakness of voluntary muscles, ...with death typically resulting from diaphragmatic failure within 2-5 years. Since the discovery of mutations in SOD1, which account for ∼2% of ALS cases, increasing efforts have been made to understand the genetic component of ALS risk, with the expectation that this insight will not only aid diagnosis and classification, but also guide personalized treatment and reveal the mechanisms that cause motor neuron death. In this Review, we outline previous and current efforts to characterize genes that are associated with ALS, describe current knowledge about the genetic architecture of ALS - including the relevance of family history - and the probable nature of future gene discoveries, and explore how our understanding of ALS genetics affects present and future clinical decisions. We observe that many gene variants associated with ALS have effect sizes between those of mutations that greatly increase risk and those of common variants that have a small effect on risk, and combine this observation with insights from next-generation sequencing to explore the implications for genetic counselling.
Objective
Clinical trials in amyotrophic lateral sclerosis (ALS) continue to rely on survival or functional scales as endpoints, despite the emergence of quantitative biomarkers. Neuroimaging‐based ...biomarkers in ALS have been shown to detect ALS‐associated pathology in vivo, although anatomical patterns of disease spread are poorly characterized. The objective of this study is to simulate disease propagation using network analyses of cerebral magnetic resonance imaging (MRI) data to predict disease progression.
Methods
Using brain networks of ALS patients (n = 208) and matched controls across longitudinal time points, network‐based statistics unraveled progressive network degeneration originating from the motor cortex and expanding in a spatiotemporal manner. We applied a computational model to the MRI scan of patients to simulate this progressive network degeneration. Simulated aggregation levels at the group and individual level were validated with empirical impairment observed at later time points of white matter and clinical decline using both internal and external datasets.
Results
We observe that computer‐simulated aggregation levels mimic true disease patterns in ALS patients. Simulated patterns of involvement across cortical areas show significant overlap with the patterns of empirically impaired brain regions on later scans, at both group and individual levels. These findings are validated using an external longitudinal dataset of 30 patients.
Interpretation
Our results are in accordance with established pathological staging systems and may have implications for patient stratification in future clinical trials. Our results demonstrate the utility of computational models in ALS to predict disease progression and underscore their potential as a prognostic biomarker. ANN NEUROL 2020;87:725–738
Summary Two decades after the discovery that 20% of familial amyotrophic lateral sclerosis (ALS) cases were linked to mutations in the superoxide dismutase-1 ( SOD1 ) gene, a substantial proportion ...of the remainder of cases of familial ALS have now been traced to an expansion of the intronic hexanucleotide repeat sequence in C9orf72 . This breakthrough provides an opportunity to re-evaluate longstanding concepts regarding the cause and natural history of ALS, coming soon after the pathological unification of ALS with frontotemporal dementia through a shared pathological signature of cytoplasmic inclusions of the ubiquitinated protein TDP-43. However, with profound clinical, prognostic, neuropathological, and now genetic heterogeneity, the concept of ALS as one disease appears increasingly untenable. This background calls for the development of a more sophisticated taxonomy, and an appreciation of ALS as the breakdown of a wider network rather than a discrete vulnerable population of specialised motor neurons. Identification of C9orf72 repeat expansions in patients without a family history of ALS challenges the traditional division between familial and sporadic disease. By contrast, the 90% of apparently sporadic cases and incomplete penetrance of several genes linked to familial cases suggest that at least some forms of ALS arise from the interplay of multiple genes, poorly understood developmental, environmental, and age-related factors, as well as stochastic events.
Individuals who are diagnosed with amyotrophic lateral sclerosis (ALS) today face the same historically intransigent problem that has existed since the initial description of the disease in the 1860s ...- a lack of effective therapies. In part, the development of new treatments has been hampered by an imperfect understanding of the biological processes that trigger ALS and promote disease progression. Advances in our understanding of these biological processes, including the causative genetic mutations, and of the influence of environmental factors have deepened our appreciation of disease pathophysiology. The consequent identification of pathogenic targets means that the introduction of effective therapies is becoming a realistic prospect. Progress in precision medicine, including genetically targeted therapies, will undoubtedly change the natural history of ALS. The evolution of clinical trial designs combined with improved methods for patient stratification will facilitate the translation of novel therapies into the clinic. In addition, the refinement of emerging biomarkers of therapeutic benefits is critical to the streamlining of care for individuals. In this Review, we synthesize these developments in ALS and discuss the further developments and refinements needed to accelerate the introduction of effective therapeutic approaches.
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of motor neurons leading to death from respiratory failure within about 3 years of symptom onset. A family history of ALS is ...obtained in about 5 % but the distinction between familial and apparently sporadic ALS is artificial and genetic factors play a role in all types. For several years, only one gene was known to have a role in ALS pathogenesis,
SOD1
. In the last few years there has been a rapid advance in our genetic knowledge of the causes of ALS, and the relationship of the genetic subtypes with pathological subtypes and clinical phenotype. Mutations in the gene for TDP-43 protein,
TARDBP
, highlight this, with pathology mimicking closely that found in other types of ALS, and a phenotypic spectrum that includes frontotemporal dementia. Mutations in the
FUS
gene, closely related to TDP-43, lead to a similar clinical phenotype but distinct pathology, so that the three pathological groups represented by
SOD1
,
TARDBP
, and
FUS
are distinct. In this review, we explore the genetic architecture of ALS, highlight some of the genes implicated in pathogenesis, and describe their phenotypic range and overlap with other diseases.
Amyotrophic lateral sclerosis (ALS) is a debilitating neurodegenerative disorder with complex biology and significant clinical heterogeneity. Many preclinical and early phase ALS clinical trials have ...yielded promising results that could not be replicated in larger phase 3 confirmatory trials. One reason for the lack of reproducibility may be ALS biological and clinical heterogeneity. Therefore, in this review, we explore sources of ALS heterogeneity that may reduce statistical power to evaluate efficacy in ALS trials. We also review efforts to manage clinical heterogeneity, including use of validated disease outcome measures, predictive biomarkers of disease progression, and individual clinical risk stratification. We propose that personalized prognostic models with use of predictive biomarkers may identify patients with ALS for whom a specific therapeutic strategy may be expected to be more successful. Finally, the rapid application of emerging clinical and biomarker strategies may reduce heterogeneity, increase trial efficiency, and, in turn, accelerate ALS drug development.
Cerebral organoids are 3D stem cell-derived models that can be utilized to study the human brain. The current consensus is that cerebral organoids consist of cells derived from the neuroectodermal ...lineage. This limits their value and applicability, as mesodermal-derived microglia are important players in neural development and disease. Remarkably, here we show that microglia can innately develop within a cerebral organoid model and display their characteristic ramified morphology. The transcriptome and response to inflammatory stimulation of these organoid-grown microglia closely mimic the transcriptome and response of adult microglia acutely isolated from post mortem human brain tissue. In addition, organoid-grown microglia mediate phagocytosis and synaptic material is detected inside them. In all, our study characterizes a microglia-containing organoid model that represents a valuable tool for studying the interplay between microglia, macroglia, and neurons in human brain development and disease.
...the study duration was short, comprising 24 weeks in total, preceded by a 12-week observation period. ...while it is biologically plausible that sub-cohorts of patients might respond ...differentially to targeted therapies, how to select such patients remains a conundrum, as at present there are no reliable markers of pathobiology. ...although the side-effect profile does not suggest toxicity, the treatment regimen of intravenous infusions for 10-14 days each month is inconvenient and potentially costly, and the longer term efficacy of the drug and patient adherence to the intravenous treatment has not been established.
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