TDP-43 Proteinopathy and Motor Neuron Disease in Chronic Traumatic Encephalopathy

Abstract

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 43 kd (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.

Mind the gaps—advancing research into short-term and long-term neuropsychological outcomes of youth sports-related concussions

“…In severe cases, the cerebral cortex and medial temporal lobes seem most profoundly affected, 81,82 with pathology characterized by neurofibrillary tangles composed of phosphorylated tau 79 and, in some cases, TAR DNA-binding protein 43 pathology. 83 CTE is also associated with marked atrophy, notably in the frontal cortex and medial temporal lobe, as well as in the mammillary bodies, thalamus and hypothalamus. 79 Confirmed clinical diagnosis of CTE remains autopsy-based.…”

A role for calpain-dependent cleavage of TDP-43 in amyotrophic lateral sclerosis pathology

“…It is also observed in various neurological diseases, including Alzheimer's disease 39 and traumatic brain injury 40 , and in the CNS of animals exposed to various adverse conditions, including sciatic axotomies 41 and brain ischaemia 42 . In addition, mislocalization of TDP-43 from the nucleus to the cytoplasm is observed in the cortical neurons of normal elderly people 43 and motor neurons of aged mice 44 .…”

Lifelong behavioral and neuropathological consequences of repetitive mild traumatic brain injury

“…However, a subset of this population demonstrates persisting neurocognitive dysfunction and non‐neurological disorders that cannot be considered mild 3. Notably, it is now well documented that the adverse effects of r‐mTBI in participants of contact sports and in former military personnel may continue for many years after the original event,4, 5, 6, 7, 8 with brain trauma being a risk factor for the development of neurodegenerative disease,9 in particular chronic traumatic encephalopathy (CTE); for review see Smith et al 10…”