Introduction Later-life brain alterations in former tackle football players are poorly understood, particularly regarding their relationship with repetitive head impacts (RHIs) and clinical function. We examined white matter signal abnormalities (WMSAs) and their association with RHIs and clinical function in former National Football League (NFL) players. Methods Eighty-six clinically symptomatic former NFL players and 23 same-age reportedly asymptomatic controls without head trauma exposure underwent magnetic resonance imaging and neuropsychological testing. FreeSurfer calculated WMSAs. A cumulative head impact index quantified RHIs. Results In former NFL players, increased volume of WMSAs was associated with higher cumulative head impact index scores ( P = .043) and worse psychomotor speed and executive function ( P = .015). Although former NFL players had greater WMSA volume than controls ( P = .046), these findings are inconclusive due to recruitment of controls based on lack of clinical symptoms and head trauma exposure. Discussion In former NFL players, WMSAs may reflect long-term microvascular and nonmicrovascular pathologies from RHIs that negatively impact cognition.

Background Longitudinal investigations are needed to improve understanding of the contributions of cerebral small vessel disease to the clinical manifestation of Alzheimer’s disease, particularly in the early disease stages. This study leveraged the National Alzheimer’s Coordinating Center Uniform Data Set to longitudinally examine the association between white matter hyperintensities and neuropsychological, neuropsychiatric, and functional decline among participants with normal cognition. Methods The sample included 465 participants from the National Alzheimer’s Coordinating Center Uniform Data Set who had quantitated volume of white matter hyperintensities from fluid-attenuated inversion recovery MRI, had normal cognition at the time of their MRI, and were administered the National Alzheimer’s Coordinating Center Uniform Data Set neuropsychological test battery within 1 year of study evaluation and had at least two post-MRI time points of clinical data. Neuropsychiatric status was assessed by the Geriatric Depression Scale-15 and Neuropsychiatric Inventory-Questionnaire. Clinical Dementia Rating Sum of Boxes defined functional status. For participants subsequently diagnosed with mild cognitive impairment (MCI) or dementia, their impairment must have been attributed to Alzheimer’s disease (AD) to evaluate the relationships between WMH and the clinical presentation of AD. Results Of the 465 participants, 56 converted to MCI or AD dementia (average follow-up = 5 years). Among the 465 participants, generalized estimating equations controlling for age, sex, race, education, APOE ε4 , and total brain and hippocampal volume showed that higher baseline log-white matter hyperintensities predicted accelerated decline on the following neuropsychological tests in rank order of effect size: Trails B ( p < 0.01), Digit Symbol Coding ( p < 0.01), Logical Memory Immediate Recall ( p = 0.02), Trail Making A ( p < 0.01), and Semantic Fluency ( p < 0.01). White matter hyperintensities predicted increases in Clinical Dementia Rating Sum of Boxes ( p < 0.01) and Geriatric Depression Scale-15 scores ( p = 0.01). Effect sizes were comparable to total brain and hippocampal volume. White matter hyperintensities did not predict diagnostic conversion. All effects also remained after including individuals with non-AD suspected etiologies for those who converted to MCI or dementia. Conclusions In this baseline cognitively normal sample, greater white matter hyperintensities were associated with accelerated cognitive, neuropsychiatric, and functional decline independent of traditional risk factors and MRI biomarkers for Alzheimer’s disease.

Background Chronic traumatic encephalopathy (CTE), a neurodegenerative tauopathy, cannot currently be diagnosed during life. Atrophy patterns on magnetic resonance imaging could be an effective in vivo biomarker of CTE, but have not been characterized. Mechanisms of neurodegeneration in CTE are unknown. Here, we characterized macrostructural magnetic resonance imaging features of brain donors with autopsy-confirmed CTE. The association between hyperphosphorylated tau (p-tau) and atrophy on magnetic resonance imaging was examined. Methods Magnetic resonance imaging scans were obtained by medical record requests for 55 deceased symptomatic men with autopsy-confirmed CTE and 31 men (n = 11 deceased) with normal cognition at the time of the scan, all >60 years Three neuroradiologists visually rated regional atrophy and microvascular disease (0 [none]–4 [severe]), microbleeds, and cavum septum pellucidum presence. Neuropathologists rated tau severity and atrophy at autopsy using semi-quantitative scales. Results Compared to unimpaired males, donors with CTE (45/55=stage III/IV) had greater atrophy of the orbital-frontal (mean diff.=1.29), dorsolateral frontal (mean diff.=1.31), superior frontal (mean diff.=1.05), anterior temporal (mean diff.=1.57), and medial temporal lobes (mean diff.=1.60), and larger lateral (mean diff.=1.72) and third (mean diff.=0.80) ventricles, controlling for age at scan (ps<0.05). There were no effects for posterior atrophy or microvascular disease. Donors with CTE had increased odds of a cavum septum pellucidum (OR = 6.7, p < 0.05). Among donors with CTE, greater tau severity across 14 regions corresponded to greater atrophy on magnetic resonance imaging (beta = 0.68, p < 0.01). Conclusions These findings support frontal-temporal atrophy as a magnetic resonance imaging finding of CTE and show p-tau accumulation is associated with atrophy in CTE.

Background and Objectives:Cerebrovascular disease (CBVD) is frequently co-morbid with autopsy-confirmed Alzheimer’s disease (AD), but it’s contribution to the clinical presentation of AD remains unclear. We leveraged the National Alzheimer’s Coordinating Center (NACC) uniform and neuropathology data sets to compare the cognitive and functional trajectories of AD+/CBVD+ and AD+/CBVD- brain donors.Methods:The sample included NACC brain donors with autopsy-confirmed AD (Braak stage ≥ 3, CERAD ≥ 2) and complete Uniform Data Set (UDS) evaluations between 2005 and 2019, and most recent UDS evaluation within two years of autopsy. CBVD was defined as moderate to severe arteriosclerosis or atherosclerosis. We employed propensity score weighting to isolate the effects of co-morbid AD and CBVD. This method improved the balance of covariates between AD+/CBVD+ and AD+/CBVD- groups. Longitudinal mixed-effects models were assessed with robust Bayesian estimation. UDS neuropsychological tests and the Clinical Dementia Rating Scale Sum of Boxes (CDR®-SB) were primary outcomes.Results:Of 2,423 brain donors, 1,476 were classified as AD+/CBVD+. Compared with AD+/CVBD- donors, the AD+/CBVD+ group had accelerated decline (i.e., group x time effects) on measures of processing speed (β = -0.93, 95%CI [-1.35, -0.51], Bayes factor [BF] = 130.75), working memory (β = 0.05, 95%CI [0.02, 0.07], BF = 3.59), verbal fluency (β = 0.10, 95%CI [0.04, 0.15], BF = 1.28), naming (β = 0.09, 95%CI [0.03, 0.16], BF = 0.69), and CDR®-SB (β = -0.08, 95%CI [-0.12, -0.05], BF = 18.11). Effects ranged from weak (BFs < 3.0) to strong (BFs < 150). We also found worse performance in the AD+/CBVD+ group across time on naming, β = -1.04, 95%CI [-1.83, -0.25], BF = 2.52, and verbal fluency, β = -0.73, 95%CI [-1.30, -0.15], BF = 1.34, and more impaired CDR®-SB scores, β = 0.45, 95%CI [0.01, 0.89], BF = 0.33.Discussion:In brain donors with autopsy confirmed AD, comorbid CBVD was associated with an accelerated functional and cognitive decline, particularly on neuropsychological tests of attention, psychomotor speed, and working memory. CBVD magnified effects of AD neuropathology on semantic-related neuropsychological tasks. Findings support a prominent additive and more subtle synergistic effect for co-morbid CBVD neuropathology in AD.