Amyotrophic lateral sclerosis: a long preclinical period?

Abstract

The onset of amyotrophic lateral sclerosis (ALS) is conventionally considered as commencing with the recognition of clinical symptoms. We propose that, in common with other neurodegenerations, the pathogenic mechanisms culminating in ALS phenotypes begin much earlier in life. Animal models of genetically determined ALS exhibit pathological abnormalities long predating clinical deficits. The overt clinical ALS phenotype may develop when safety margins are exceeded subsequent to years of mitochondrial dysfunction, neuroinflammation or an imbalanced environment of excitation and inhibition in the neuropil. Somatic mutations, the epigenome and external environmental influences may interact to trigger a metabolic cascade that in the adult eventually exceeds functional threshold. A long preclinical and subsequent presymptomatic period pose a challenge for recognition, since it offers an opportunity for protective and perhaps even preventive therapeutic intervention to rescue dysfunctional neurons. We suggest, by analogy with other neurodegenerations and from SOD1 ALS mouse studies, that vulnerability might be induced in the perinatal period.

Does dysfunction of the mirror neuron system contribute to symptoms in amyotrophic lateral sclerosis?

“…A significant difficulty in identifying impairment of the MNS in ALS, and other neurodegenerative diseases, is the slowly progressive nature of these disorders, and their prolonged preclinical period (Eisen et al , 2014a, Thomsen et al , 2014. This presumably enables a degree of adaption, masking subtle abnormalities in the MNS, which might otherwise induce clinical deficits.…”

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

“…Assessment of asymptomatic familial Alzheimer gene carriers has highlighted the added sensitivity of functional neuroimaging [Chhatwal et al, 2013] in keeping with the age‐dependent impact of APOE ε4 status on both fMRI [Filippini et al, 2011] and MEG [Cuesta et al, 2015] in the task‐free state. 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.…”

“…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]. …”

Transcranial Magnetic Stimulation for the Assessment of Neurodegenerative Disease

“…In addition, identification of subclinical upper motor neuron dysfunction in predominantly lower motor neuron ALS phenotypes, such as the flail arm and flail leg variants, has enabled a more definite diagnosis at an earlier stage in the disease process [97,98]. Incorporation of the TMS technique in future ALS diagnostic criteria as an objective tool for assessing upper motor neuron function may hasten ALS diagnosis and thereby enable earlier recruitment into clinical trials, perhaps during the therapeutic window period [158], where neurorecovery therapies may be more effective.…”