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Brain and Spinal Cord Trauma as a Risk Factor for Amyotrophic Lateral Sclerosis: A Mini-Review

march 2013


Trauma to the central nervous system (CNS) has been investigated as a risk factor for amyotrophic lateral sclerosis (ALS) despite conflicting epidemiological reports. Studies have suggested a link between ALS and traumatic axonal injury which complements the “dying back” theory of ALS. The theory suggests that neuronal dysfunction first occurs at the neuromuscular junction, and subsequent axonal impairment leads to dysfunction of the cell body. A pathological link has been shown between CNS trauma and ALS, further supporting this relationship. Another proposed hypothesis is that differences in “molecular thresholds” based on individual genetic backgrounds could explain some individuals developing ALS or ALS-like pathology subsequent to trauma, as well as elucidate the seemingly increased risk for ALS associated with multiple traumas. However, it is still unclear how trauma to the CNS might directly or indirectly trigger ALS. The current mini-review re-examines the relationship between CNS trauma and risk of developing ALS or an ALS-like pathology, and explores potential explanations for discrepant study results.


TDP-43 proteinopathy and motor neuron disease in chronic traumatic encephalopathy.

September 2010


Epidemiological evidence suggests that the incidence of amyotrophic lateral sclerosis is increased in association with head injury. Repetitive head injury is also associated with the development of chronic traumatic encephalopathy (CTE), a tauopathy characterized by neurofibrillary tangles throughout the brain in the relative absence of β-amyloid deposits. We examined 12 cases of CTE and, in 10, found a widespread TAR DNA-binding protein of approximately 43kd (TDP-43) proteinopathy affecting the frontal and temporal cortices, medial temporal lobe, basal ganglia, diencephalon, and brainstem. Three athletes with CTE also developed a progressive motor neuron disease with profound weakness, atrophy, spasticity, and fasciculations several years before death. In these 3 cases, there were abundant TDP-43-positive inclusions and neurites in the spinal cord in addition to tau neurofibrillary changes, motor neuron loss, and corticospinal tract degeneration. The TDP-43 proteinopathy associated with CTE is similar to that found in frontotemporal lobar degeneration with TDP-43 inclusions, in that widespread regions of the brain are affected. Akin to frontotemporal lobar degeneration with TDP-43 inclusions, in some individuals with CTE, the TDP-43 proteinopathy extends to involve the spinal cord and is associated with motor neuron disease. This is the first pathological evidence that repetitive head trauma experienced in collision sports might be associated with the development of a motor neuron disease.