Amyloid PET across the cognitive spectrum in former professional and college American football players: findings from the DIAGNOSE CTE Research Project.

BACKGROUND: Exposure to repetitive head impacts (RHI) in American football players can lead to cognitive impairment and dementia due to neurodegenerative disease, particularly chronic traumatic encephalopathy (CTE). The pathognomonic lesion of CTE consists of perivascular aggregates of hyper-phosphorylated tau in neurons at the depths of cortical sulci. However, it is unclear whether exposure to RHI accelerates amyloid-ß (Aß) plaque formation and increases the risk for Alzheimer's disease (AD). Although the Aß neuritic plaques characteristic of AD are observed in a minority of later-stage CTE cases, diffuse plaques are more common. This study examined whether former professional and college American football players, including those with cognitive impairment and dementia, have elevated neuritic Aß plaque density, as measured by florbetapir PET. Regardless of cognitive and functional status, elevated levels of florbetapir uptake were not expected. METHODS: We examined 237 men ages 45-74, including 119 former professional (PRO) and 60 former college (COL) football players, with and without cognitive impairment and dementia, and 58 same-age men without a history of contact sports or TBI (unexposed; UE) and who denied cognitive or behavioral symptoms at telephone screening. Former players were categorized into four diagnostic groups: normal cognition, subjective memory impairment, mild cognitive impairment, and dementia. Positive florbetapir PET was defined by cortical-cerebellar average SUVR of ≥ 1.10. Multivariable linear regression and analysis of covariance (ANCOVA) compared florbetapir average SUVR across diagnostic and exposure groups. Multivariable logistic regression compared florbetapir positivity. Race, education, age, and APOE4 were covariates. RESULTS: There were no diagnostic group differences either in florbetapir average SUVR or the proportion of elevated florbetapir uptake. Average SUVR means also did not differ between exposure groups: PRO-COL (p = 0.94, 95% C.I. = [- 0.033, 0.025]), PRO-UE (p = 0.40, 95% C.I. = [- 0.010, 0.029]), COL-UE (p = 0.36, 95% CI = [0.0004, 0.039]). Florbetapir was not significantly associated with years of football exposure, cognition, or daily functioning. CONCLUSIONS: Cognitive impairment in former American football players is not associated with PET imaging of neuritic Aß plaque deposition. These findings are inconsistent with a neuropathological diagnosis of AD in individuals with substantial RHI exposure and have both clinical and medico-legal implications. TRIAL REGISTRATION: NCT02798185.

Decreased Deposition of Beta-Amyloid 1-38 and Increased Deposition of Beta-Amyloid 1-42 in Brain Tissue of Presenilin-1 E280A Familial Alzheimer's Disease Patients.

Familial Alzheimer's Disease (FAD) caused by Presenilin-1 (PS1) mutations is characterized by early onset, cognitive impairment, and dementia. Impaired gamma secretase function favors production of longer beta-amyloid species in PS1 FAD. The PS1 E280A mutation is the largest FAD kindred under study. Here, we studied beta-amyloid deposits in PS1 E280A FAD brains in comparison to sporadic Alzheimer's disease (SAD). We analyzed cortices and cerebellum from 10 FAD and 10 SAD brains using immunohistochemistry to determine total beta-amyloid, hyperphosphorylated tau (pTau), and specific beta-amyloid peptides 1-38, 1-40, 1-42, and 1-43. Additionally, we studied beta-amyloid subspecies by ELISA, and vessel pathology was detected with beta-amyloid 1-42 and truncated pyroglutamylated beta-amyloid antibodies. There were no significant differences in total beta-amyloid signal between SAD and FAD. Beta-amyloid 1-38 and 1-43 loads were increased, and 1-42 loads were decreased in frontal cortices of SAD when compared to FAD. Beta-amyloid species assessment by ELISA resembled our findings by immunohistochemical analysis. Differences in beta-amyloid 1-38 and 1-42 levels between SAD and FAD were evidenced by using beta-amyloid length-specific antibodies, reflecting a gamma secretase-dependent shift in beta-amyloid processing in FAD cases. The use of beta-amyloid length-specific antibodies for postmortem assessment of beta-amyloid pathology can differentiate between SAD and PS1 FAD cases and it can be useful for identification of SAD cases potentially affected with gamma secretase dysfunction.

Structural and functional connectivity of ascending reticular activating system in a patient with impaired consciousness after a cardiac arrest: A case report.

RATIONALE: Diffusion tensor imaging (DTI), diffusion tensor tractography (DTT), as well as resting-state-functional magnetic resonance imaging (rsfMRI) are promising methods for assessing patients with disorders of consciousness (DOCs). PATIENT CONCERNS: This work describes the main findings using DTI, DTT, and rsfMRI in a patient with a DOC secondary to an anoxic encephalopathy who had a fatal outcome. She was an 85-year-old woman who presented a cardiac arrest and underwent cardiopulmonary resuscitation for 20 minutes then returning to spontaneous circulation. After sedation withdrawal, 2 days after the event, she remained with a Glasgow Coma Scale score of 3/15 and with an absence of brainstem reflexes. DIAGNOSES: DOC secondary to an anoxic encephalopathy after cardiovascular resuscitation. INTERVENTIONS: A complete brain MRI scan was performed 72 hours after the initial event, including DTI, DTT, and rsfMRI. DTT demonstrated disruption of both ventral and dorsal tegmental tracts bilaterally. DTI showed a reduction of fractional anisotropic level in the mesencephalic nuclei. Moreover, changes in the number of fiber tracts were not evidenced in any portions of the ascending reticular activating system (ARAS). Finally, an increase in the anticorrelated and correlated association among the nuclei in the ARAS and the cortex was evidenced. OUTCOMES: Patient deceased. LESSONS: Neuroimaging demonstrated low FA values in the ARAS, destruction of dorsal and ventral tegmental tracts, as well as hyper-connective (highly correlated or anti-correlated) association among ARAS and cortical nuclei compared with 3 healthy control subjects.