Aggregation of neurologic and neuropsychiatric disease in amyotrophic lateral sclerosis kindreds: A population‐based case–control cohort study of familial and sporadic amyotrophic lateral sclerosis

Abstract

Medical histories from 9,684 first- and second-degree relatives of 172 ALS probands and 192 controls were obtained. Cause of death was verified in 2,494 cases. Sixteen percent (n=27) of ALS patients had a family history of ALS. The lifetime hazard ratio (HR) of developing ALS among first- and second-degree relatives was 34.3 (p<0.0001) in relatives of ALS patients with the C9orf72 repeat expansion, and 2.3 (p=0.019) in relatives of ALS patients without the expansion. The relatives of ALS patients also had an increased HR of developing a psychotic illness (HR=4.7, p=0.004, 95% confidence interval [CI]=1.6-12.3) and of suicide (HR=5.6, p<0.0001, 95% CI=2.4-12.9) INTERPRETATION: The true rate of familial ALS in Ireland is 16%. There is an overlap between ALS, FTD, and neuropsychiatric disease that is pronounced in kindreds with the C9orf72 repeat expansion, but is also present in kindreds of those without the C9orf72 expanded repeat.

Altered cortical beta‐band oscillations reflect motor system degeneration in amyotrophic lateral sclerosis

“…It remains an open question to what extent symptoms of ALS are preceded by temporally remote cellular abnormalities [Eisen et al, 2014]. Although animal models of ALS demonstrate abnormal neural architecture and function during embryonic stages [Martin et al, 2013; Vinsant et al, 2013], human epidemiological [Byrne et al, 2013; Schoder et al, 2010] and pathological [Proudfoot et al, 2014a] links to neurodevelopmental disorders remain sparse. Suggestions that ALS (or FTD) pathology might manifest in a behavioural prodrome long before diagnostic symptoms remain speculative [Eisen et al, 2014; Lule et al, 2008].…”

Amyotrophic Lateral Sclerosis Incidence and Previous Prescriptions of Drugs for the Nervous System

“…Several studies found associations of neurodegenerative and psychiatric disorders with ALS, but were not able to examine the temporal relation with ALS onset [11][12][13][14]19] . The type of analysis performed, that is, survival analysis, which considers the exposure to drugs as time-dependent variables, has allowed to classify correctly exposed and non-exposed periods at the individual level and to compute appropriately exposed and non-exposed person-years.…”

“…Recent studies showed an increased risk of psychotic manifestations and other neurodegenerative disorders associated in ALS patients and their family aggregates [11][12][13][14] , even if antipsychotic and antidepressant drugs have been hypothesized to be protective toward ALS onset [15] . On the basis of these data, and since no longitudinal studies have been conducted on the association between ALS onset and previous nervous system drugs consumption, the aim of the present study was to assess whether drugs acting on nervous system could have an effect on the development of ALS.…”

Defining the genetic connection linking amyotrophic lateral sclerosis (ALS) with frontotemporal dementia (FTD)

“…Mutations in the same genes can influence different phenotypic traits, such as cognitive impairment, parkinsonism, ataxia, and dementia. For example, patients carrying the C9orf72 expansion were shown to develop more often concomitant neuropsychiatric conditions, such as schizophrenia, psychotic illness, and suicidal behavior [45]. The pleiotropic nature of the expanded repeats in the C9orf72 made them difficult to identify clinically (because patients with parkinsonism or dementia were not included in the analysis), which has consequences for genetic counseling and for the development of new drugs [21].…”