Amyotrophic lateral sclerosis: Origins traced to impaired balance between neural excitation and inhibition in the neonatal period

Kiernan, Matthew C.; Ziemann, Ulf; Eisen, Andrew

doi:10.1002/mus.26617

Cited by 29 publications

(20 citation statements)

References 41 publications

(67 reference statements)

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“…A multistep process would provide an elegant explanation for the notion that the seeds for developing ALS occur during the neonatal period. 6,20 The mechanism by which neonatal events trigger the development of ALS later in life remains hypothetical, although there is precedence with other neurobiological diseases. 21 During embryogenesis, synchronized and complex neuronal activity evolves with brain development, which is essential for neurogenesis, development of neuronal circuitry, cell migration and differentiation, programmed cell death, as well establishment of axonal connections.…”

Section: Pathophysiologic Mechanisms Underlying Alsmentioning

confidence: 99%

ALS is a multistep process in South Korean, Japanese, and Australian patients

Vucic¹,

Higashihara²,

Sobue³

et al. 2020

Neurology

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ObjectiveTo establish whether amyotrophic lateral sclerosis (ALS) is a multistep process in South Korean and Japanese populations when compared to Australian cohorts.MethodsWe generated incident data by age and sex for Japanese (collected between April 2009 and March 2010) and South Korean patients with ALS (collected between January 2011 and December 2015). Mortality rates were provided for Australian patients with ALS (collected between 2007 and 2016). We regressed the log of age-specific incidence against the log of age with least squares regression for each ALS population.ResultsWe identified 11,834 cases of ALS from the 3 populations, including 6,524 Australian, 2,264 Japanese, and 3,049 South Korean ALS cases. We established a linear relation between the log incidence and log age in the 3 populations: Australia r2 = 0.99, Japan r2 = 0.99, South Korea r2 = 0.99. The estimate slopes were similar across the 3 populations, being 5.4 (95% confidence interval [CI], 4.8–5.5) in Japanese, 5.4 (95% CI, 5.2–5.7) in Australian, and 4.4 (95% CI, 4.2–4.8) in South Korean patients.ConclusionsThe linear relationship between log age and log incidence is consistent with a multistage model of disease, with slope estimated suggesting that 6 steps were required in Japanese and Australian patients with ALS while 5 steps were needed in South Korean patients. Identification of these steps could identify novel therapeutic strategies.

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Section: Pathophysiologic Mechanisms Underlying Alsmentioning

confidence: 99%

ALS is a multistep process in South Korean, Japanese, and Australian patients

Vucic¹,

Higashihara²,

Sobue³

et al. 2020

Neurology

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“…In theory, such a loss of PV+ interneurons would lead to a reduction in cortical inhibition, which could have excitotoxic consequences for the pyramidal projection neurons onto which they synapse (Kiernan et al, 2019). In support of this proposal, patients with mutations in C9orf72, the most common genetic cause of ALS and FTD, have been found to demonstrate cortical hyperexcitability (Geevasinga et al, 2014).…”

Section: Discussionmentioning

confidence: 96%

MRI-guided histology of TDP-43 knock-in mice implicates parvalbumin interneuron loss, impaired neurogenesis and aberrant neurodevelopment in ALS-FTD

Lin

Kim

Ahmed

et al. 2020

Preprint

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Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are overlapping neurodegenerative diseases that are increasingly understood to have long prodromal periods.Investigation of these early stages promises to yield valuable biomarkers of disease and will be key to understanding mechanisms underlying the genesis of ALS-FTD. Here, we use in vivo magnetic resonance imaging (MRI), histology and computed tomography to identify structural and cellular readouts of early stage disease in the TDP-43 Q331K knock-in mouse model of ALS-FTD. Adult mutant mice demonstrated parenchymal volume reductions affecting the frontal lobe and entorhinal cortex in a manner reminiscent of ALS-FTD. Subcortical, cerebellar and brain stem regions were also affected in line with observations in presymptomatic carriers of mutations in C9orf72, the commonest genetic cause of both ALS and FTD. Volume loss, as measured by MRI, was also observed in the dentate gyrus (DG) of the hippocampus, along with ventricular enlargement. Guided by these imaging findings, detailed post-mortem brain tissue analysis revealed reduced parvalbumin-positive (PV+) interneurons as a potential cellular correlate of MRI changes in mutant mice. By contrast, microglia were in a disease activated state even in the absence of brain volume loss. A reduction in immature neurons was found in the DG, indicative of impaired adult neurogenesis, while a paucity of PV+ interneurons in juvenile mutant mice (P14) suggests that TDP-43 Q331K disrupts neurodevelopment. Computerised tomography imaging also showed altered skull morphology in mutants, further suggesting a role for TDP-43 Q331K in development. Finally, analysis of human post-mortem prefrontal cortices confirmed a paucity of PV+ interneurons in the prefrontal cortex in cases with both sporadic ALS and ALS linked to C9orf72 mutations. This study suggests an important role for PV+ interneurons in regional brain vulnerability associated with ALS-FTD, and identifies novel MRI and histological biomarkers that will be of value in assessing the efficacy of putative therapeutics in TDP-43 Q331K knock-in mice.

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“…We know from literature that both impaired cognitive function 31 and white matter alterations 32 may be linked to early CNS development. Accordingly, it may be speculated that the cognitive and structural changes in C9orf72 carriers may not only be preclinical signs of ALS, but might be indicative of a general developmental disorder in C9orf72 carriers as suggested previously.…”

Section: Discussionmentioning

confidence: 99%

Deficits in verbal fluency in presymptomatic C9orf72 mutation gene carriers—a developmental disorder

Lulé

Müller

Finsel

et al. 2020

J Neurol Neurosurg Psychiatry

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BackgroundA mutation in C9orf72 constitute a cross-link between amyotrophic lateral sclerosis (ALS) and fronto-temporal dementia (FTD). At clinical manifestation, both patient groups may present with either cognitive impairment of predominantly behaviour or language (in FTD) or motor dysfunctions (in ALS).MethodsIn total, 36 non-symptomatic mutation carriers from ALS or FTD families were examined, including 21 subjects with C9orf72 and 15 with SOD1 mutations. Data were compared with 91 age-matched, education-matched and gender-matched healthy subjects (56 were first-degree relatives from ALS or FTD families, 35 with no known family history of ALS/FTD). MRI scanning for diffusion tensor imaging was performed to map fractional anisotropy (FA). Subjects performed an extensive neuropsychological assessment to address verbal fluency, language, executive, memory and visuospatial function. Measurements were repeated after 12 months.ResultsC9orf72 expansion carriers performed significantly worse in verbal fluency and non-verbal memory and presented with distinct alterations in structural white matter integrity indicated by lower FA values in inferior and orbitofrontal cortical areas compared with carriers of SOD1 mutations or healthy subjects. Loss of structural integrity was associated with decreased verbal fluency performance. White matter alterations and cognitive performance showed no changes over 12 months in all subjects.DiscussionReduced verbal fluency performance seems to be a distinct clinical feature of C9orf72 carriers before symptomatic disease onset without evidence for change over time in our cohort. The results support the emerging hypothesis of a general disorder in development in addition to neurodegeneration in C9orf72 carriers.

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Amyotrophic lateral sclerosis: Origins traced to impaired balance between neural excitation and inhibition in the neonatal period

Cited by 29 publications

References 41 publications

ALS is a multistep process in South Korean, Japanese, and Australian patients

ALS is a multistep process in South Korean, Japanese, and Australian patients

MRI-guided histology of TDP-43 knock-in mice implicates parvalbumin interneuron loss, impaired neurogenesis and aberrant neurodevelopment in ALS-FTD

Deficits in verbal fluency in presymptomatic C9orf72 mutation gene carriers—a developmental disorder

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