Cortical influences drive amyotrophic lateral sclerosis

Area of Science:

• Neuroscience
• Neurology
• Pathology

Background:

• Early motor symptoms in sporadic amyotrophic lateral sclerosis (ALS) indicate failures in complex adaptive motor skills.
• These skills rely on the corticomotoneuronal system, which is highly developed in humans.

Purpose of the Study:

• To investigate the origins and spread of TDP-43 pathology in ALS.
• To understand the link between cortical hyperexcitability and early motor deficits in ALS.
• To explore ALS as a primary cortical neurodegenerative disorder.

Main Methods:

• Clinical neurophysiology using transcranial magnetic stimulation (TMS) to assess cortical excitability.
• Analysis of TDP-43 pathological signatures in cortical and subcortical brain regions.
• Review of clinical presentations and neuroimaging findings in ALS.

Main Results:

• Presymptomatic reduction or absence of short interval intracortical inhibition and increased intracortical facilitation indicate cortical hyperexcitability.
• TDP-43 pathology is primarily found in cortical areas and their direct subcortical targets.
• Early motor manifestations like gait disturbance and bulbar symptoms may stem from this corticomotoneuronal system failure.

Conclusions:

• Sporadic ALS may originate as a primary neurodegenerative disorder of the cerebral cortex.
• The spread of TDP-43 pathology along corticofugal projections explains multisystem degeneration.
• Cortical hyperexcitability and TDP-43 pathology are key features in understanding ALS pathogenesis and its relation to frontotemporal dementia.