Chronic Traumatic Encephalopathy (CTE) is a progressive neurodegenerative disease arising from repeated mild traumatic brain injuries, such as concussions and subconcussive impacts. It is defined by the accumulation of hyperphosphorylated tau (p-tau) protein within brain tissue, which ultimately causes nerve cell death.
CTE is currently diagnosed only posthumously through neuropathological examination to identify the specific pattern of tau deposits.
Researchers use a four-stage system to describe the sequential progression of this tau pathology, which generally correlates with the severity of clinical symptoms observed during life. This framework helps understand how the disease spreads throughout the brain.
Stage I Early Mild Symptoms
Stage I is characterized by minimal pathological changes and often presents with subtle or absent clinical symptoms. Pathologically, it involves the sparse, focal deposition of p-tau protein in isolated clusters.
These clusters are typically found in the superior frontal cortex and around small blood vessels in the brain’s sulci. The brain tissue still appears grossly normal, with no visible atrophy or shrinkage.
Clinically, individuals may experience only mild, non-specific symptoms such as occasional short-term memory deficits or slight disorientation. Subtle changes in mood, including mild depression, may also be present, but these signs are often dismissed, making Stage I difficult to detect.
Stage II Behavioral and Mood Changes
In Stage II, the tau pathology becomes more established and spreads beyond the initial focal points. Multiple epicenters of p-tau deposits are visible, affecting various regions of the cerebral cortex, including the frontal, temporal, and parietal lobes.
Crucially, the medial temporal lobe, which houses memory structures like the hippocampus, is typically spared at this point.
The clinical presentation is marked by the emergence of significant behavioral and mood disturbances. These changes can include heightened irritability, severe depression, impulsive behavior, and uncontrollable rage, often leading to social instability. While memory issues may become more noticeable, the defining feature of Stage II is behavioral dysregulation.
Stage III Cognitive Impairment Begins
Stage III represents a significant escalation in both the extent of the tau pathology and the severity of the clinical symptoms. Pathologically, the p-tau protein becomes widespread throughout the cerebral cortex, concentrated heavily in the frontal and temporal lobes.
This stage is defined by the spread of neurofibrillary pathology into the medial temporal lobe, affecting the hippocampus and the amygdala. These structures are critical for memory formation and emotional regulation. Grossly, the brain may show early signs of atrophy, including reduced brain weight and mild enlargement of the ventricles.
Clinically, the primary concern shifts from mood to the onset of frank cognitive impairment. Individuals struggle with executive functions, such as planning and problem-solving, and major memory deficits impede their ability to manage daily tasks.
Stage IV Severe Dementia and Motor Issues
The final stage of Chronic Traumatic Encephalopathy is characterized by the most devastating and widespread pathological changes throughout the brain.
The p-tau pathology is globally distributed, affecting nearly all regions of the cerebral cortex, the medial temporal lobe, the basal ganglia, and extending into the brainstem and cerebellum. Severe brain atrophy is evident upon gross examination, resulting in a dramatic reduction in brain weight.
Clinically, this stage is defined by profound dementia, leading to a complete loss of independence and severe disorientation. In addition to advanced cognitive decline and personality changes, patients often develop significant motor symptoms. These can include features resembling Parkinsonism, such as gait issues, tremors, and slowed movement, or sometimes a progressive motor neuron disease.