The patient was a 74 year-old man at the time of death with a past medical history positive for atrial fibrillation and AD (clinically diagnosed at age 67). His initial symptoms included an inability to compute simple percentage discounts at his furniture store, followed by a gradual progression with variable response to Aricept/memantine, eventually becoming aphasic. Additional neurological history is significant for head trauma in the following instances: breech delivery (as an infant), diving accident (as a child), bicycle accident, warehouse fall (age 60), high school and college football starter with numerous concussions sustained while participating, and two falls while in the nursing home.
The brain weighed 1336 grams. The leptomeninges were fibrotic, including at the base of the brain; there were no exudates. There was no cerebral edema, and no evidence of contusions at the base of the brain. The brain demonstrated evidence of diffuse cerebral cortical atrophy involving the frontal and temporal lobes as well as the cingulate gyrus. The arteries of the circle of Willis demonstrated mild atherosclerosis. The brainstem and cerebellum had a normal external appearance. Serial coronal sectioning revealed the usual internal architectural features without infarcts or mass lesions. The caudate nuclei, however, were flattened bilaterally. The remainder of the basal ganglia and thalamus, and mammillary bodies bilaterally were of normal size, color, and consistency. There was, however, bilateral hippocampal and amygdalae atrophy. The ventricular system was moderately dilated (posteriorly > anteriorly). In addition, a cavum septum pellucidum was found and was most prominent ventrally. Serial sections of the brainstem and cerebellum revealed no lesions with the substantia nigra being well pigmented. However, the pontine locus ceruleus was pale. There was mild superior vermal atrophy in the cerebellum.
The H&E and Bielschowsky silver stains revealed numerous amyloid plaques of both the diffuse as well as neuritic type in all neocortical areas (Figure 3). In addition, there were numerous neurofibrillary tangles seen, particularly in the neocortical pyramidal neurons of layers 3 and 5, but no cortical Lewy bodies were found. The tangles were both laminar in distribution with some punctate perivascular positive staining. The sensory motor-strip and temporal tip showed Congo red positive cortical blood vessels for cerebral amyloid angiopathy. There was pallor of the white matter with numerous hyalinized barrel-shaped small blood vessels. The caudate and putamen contain diffuse plaques, evidence of gliosis, and numerous hyalinized barrel-shaped small blood vessels. Neurofibrillary tangles were also noted in the ventral striatum. The hippocampus and amygdala contained numerous amyloid plaques and neurofibrillary tangles, particularly in the CA1 field. In addition, the amygdala contained Lewy bodies evidenced by positive alpha-synuclein. The thalamus contained neurofibrillary tangles in the midline nuclei. The substantia nigra was gliotic with neuronal drop out with some remaining neurons containing neurofibrillary tangles, but no Lewy bodies were indentified. The pons contained tangles in the locus ceruleus and raphe nuclei. The cerebellum contained diffuse plaques in the molecular layer.
PHF-1 tau staining revealed numerous positive neurofibrillary tangles and neuritic plaques as well as a laminar distribution of neuritic neuropil changes consistent with typical AD as described above. However, there were significant PHF-1 tau tangles and neuritic changes in the following areas: the pontine tegmentum outside the locus ceruleus and raphe, the substantia nigra both laterally and medially, and the lateral thalamic nuclei and pulvinar. Additionally, characteristic of CTE, perivascular PHF was seen at the depths of the sulci in cortical white matter and the indusium griseum (Figures 4 and 5). The neuropathologic findings were consistent with AD neuropathologic change (high level) by the NIA Consensus Criteria . Each category of scoring - Abetaplaque distribution (A score-3), neurofibrillary tangles extent (B score-3), and number of neuritic plaques (C score-3) - received a high grade (A3 B3 C3). When cognitive impairment and behavioral change is apparent clinically, an intermediate or high grade of neuropathologic change strongly substantiates AD as the main disease. The finding of cerebral amyloid angiopathy was typical, as it is rather common in cases with a significant degree of Abeta plaques. The finding of Lewy bodies in the amygdala (Lewy body disease, amygdala-predominant) is also typical for AD, as Lewy body disease in the amygdala typically occurs along with high grade AD neuropathologic change. There was both small and large vessel disease present. Cerebrovascular disease is thought to be a comorbid factor.
Additional abnormal tau findings in the reticular activating system of the pons, the entire substantia nigra, lateral thalamic nuclei, the pulvinar, and in the perivascular subcortical white matter, suggest a concomitant diagnosis of CTE. CTE has a clinical picture of mood, personality, cognitive change, behavioral change, and motor symptomatology, as described above. Associated histopathologic changes are considered due to an extensive accumulation of phosphorylated tau protein, seen as neurofibrillary and astrocytic tangles. With or without the specific label of CTE, football players with a history of TBI have a higher risk of chronic mood, behavioral, and cognitive issues. AD clearly played a significant role in the neurological morbidity but may have been exacerbated by CTE. The deceased patient competed in contact sports at a high level for many years, experiencing multiple concussive events, along with head injuries acquired outside of athletics. Therefore, it is important to consider CTE, in addition to AD, as a separate and/or concomitant contributor in his neurological decline.