Poor Corticospinal Motor Neuron Health Is Associated with Increased Symptom Severity in the Acute Phase Following Repetitive Mild TBI and Predicts Early ALS Onset in Genetically Predisposed Rodents

Abstract

Traumatic brain injury (TBI) is a well-established risk factor for several neurodegenerative disorders including Alzheimer’s disease and Parkinson’s disease, however, a link between TBI and amyotrophic lateral sclerosis (ALS) has not been clearly elucidated. Using the SOD1G93A rat model known to recapitulate the human ALS condition, we found that exposure to mild, repetitive TBI lead ALS rats to experience earlier disease onset and shortened survival relative to their sham counterparts. Importantly, increased severity of early injury symptoms prior to the onset of ALS disease symptoms was linked to poor health of corticospinal motor neurons and predicted worsened outcome later in life. Whereas ALS rats with only mild behavioral injury deficits exhibited no observable changes in corticospinal motor neuron health and did not present with early onset or shortened survival, those with more severe injury-related deficits exhibited alterations in corticospinal motor neuron health and presented with significantly earlier onset and shortened lifespan. While these studies do not imply that TBI causes ALS, we provide experimental evidence that head injury is a risk factor for earlier disease onset in a genetically predisposed ALS population and is associated with poor health of corticospinal motor neurons.

Repetitive mild TBI causes pTau aggregation in nigra without altering preexisting fibril induced Parkinson’s-like pathology burden

“…Next, we wanted to determine how many mild injuries were necessary to cause detectable pathology similar to what is seen on neuroimaging in patients with a history of TBI where regional encephalomalacia or brain thinning can be detected [ 30 ]. Published focal injury models and mTBI models requiring preparatory surgery ranged from 2 to 10 injuries, some occurring seconds apart while others are weeks apart [ 50 – 53 ]. Initial experiments were performed with 4 injuries separated 14 days apart to allow for full recovery and to test for residual long lasting effects in the second week after injury.…”

Increased Risk of Aging-Related Neurodegenerative Disease after Traumatic Brain Injury

“…There is conflicting evidence of whether TBI accelerates or worsens disease in the most common animal model of ALS, which overexpresses a mutant form of human SOD1 (G93A) associated with a small number of human ALS patients. One group found that a single controlled cortical impact TBI did not affect disease onset or survival [ 123 ], but that repeated mild TBI caused earlier onset of motor symptoms, chronic motor deficits, and decreased cortical thickness in mutant SOD1 rodents [ 124 , 125 ]. However, another group found that a mild stab-wound injury to the motor cortex did not affect disease onset or progression in three different genetic rodent ALS models (SOD1, TAR DNA binding protein 43 (TDP-43), and fused in sarcoma (FUS)) [ 126 ].…”

B Cells in Neuroinflammation: New Perspectives and Mechanistic Insights

“…The evidence supporting a role for B cells in MS, PD, and AD is strong, while in other neurological diseases such as amyotrophic lateral sclerosis (ALS), it may be a contributing factor in disease progression rather than a disease initiator. ALS is a motor neuron disease with a number of known genetic risk factors including C9orf72 repeat expansion [ 114 , 115 ]. Evidence for an inflammatory involvement includes a high expression of C9orf72 in myeloid cells, including microglia, and an increase in pro-inflammatory factors found in the spinal cords of ALS models, like the mutant Superoxide dismutase 1 gene (SOD1) mice [ 116 ].…”