Although chronic traumatic encephalopathy (CTE) garners substantial attention in the media and there have been marked scientific advances in the last few years, much remains unclear about the role of genetic risk in CTE. Two athletes with comparable contact-sport exposure may have varying amounts of CTE neuropathology, suggesting that other factors, including genetics, may contribute to CTE risk and severity. In this review, we explore reasons why genetics may be important for CTE, concepts in genetic study design for CTE (including choosing controls, endophenotypes, gene by environment interaction, and epigenetics), implicated genes in CTE (including APOE, MAPT, and TMEM106B), and whether predictive genetic testing for CTE should be considered.

Background: Gadolinium retention after repeated gadolinium-based contrast agent (GBCA) exposure has been reported in subcortical gray matter. However, gadolinium retention in the cerebral cortex has not been systematically investigated. Purpose: To determine whether and where gadolinium is retained in rat and human cerebral cortex. Materials and Methods: The cerebral cortex in Sprague-Dawley rats treated with gadopentetate dimeglumine (three doses over 4 weeks; cumulative gadolinium dose, 7.2 mmol per kilogram of body weight; n = 6) or saline (n = 6) was examined with antemortem MRI. Two human donors with repeated GBCA exposure (three and 15 doses; 1 and 5 months after exposure), including gadopentetate dimeglumine, and two GBCA-naive donors were also evaluated. Elemental brain maps (gadolinium, phosphorus, zinc, copper, iron) for rat and human brains were constructed by using laser ablation inductively coupled plasma mass spectrometry. Results: Gadopentetate dimeglumine-treated rats showed region-, subregion-, and layer-specific gadolinium retention in the neocortex(anterior cingulate cortex: mean gadolinium concentration, 0.28 mu g.g(-1)+/- 0.04 [standard error of the mean]) that was comparable (P >.05) to retention in the allocortex (mean gadolinium concentration, 0.33 mu g. g(-1)+/- 0.04 in piriform cortex, 0.24 mu g.g(-1)+/- 0.04 in dentate gyrus, 0.17 mu g.g(-1)+/- 0.04 in hippocampus) and subcortical structures (0.47 mu g.g(-1)+/- 0.10 in facial nucleus, 0.39 mu g.g(-1)+/- 0.10 in choroid plexus, 0.29 mu g.g(-1)+/- 0.05 in caudate-putamen, 0.26 mu g.g(-1)+/- 0.05 in reticular nucleus of the thalamus, 0.24 mu g.g(-1)+/- 0.04 in vestibular nucleus) and significantly greater than that in the cerebellum (0.17 mu g.g(-1)+/- 0.03, P =.01) and white matter tracts (anterior commissure: 0.05 mu g.g(-1)+/- 0.01, P =.002; corpus callosum: 0.05 mu g.g(-1)+/- 0.02, P =.001; cranial nerve: 0.02 mu g.g(-1)+/- 0.01, P =.004). Retained gadolinium colocalized with parenchymal iron. T1-weightedMRI signal intensification was not observed. Gadolinium retention was detected in the cerebral cortex, pia mater, and pia-ensheathed leptomeningeal vessels in two GBCA-exposed human brains but not in two GBCA-naive human brains. Conclusion: Repeated gadopentetate dimeglumine exposure is associated with gadolinium retention in specific regions, subregions, and layers of cerebral cortex that are critical for higher cognition, affect, and behavior regulation, sensorimotor coordination, and executive function. (C) RSNA, 2019

This chapter reviews fundamental principles of genetics and genomics as well as many of the analytic tools available to conduct genetic research. Information is presented in the context of genetic research on well-understood adult cognitive disorders. Specifically, this chapter utilizes Huntington’s disease to explain concepts related to diseases with Mendelian inheritance patterns, and it uses Alzheimer’s disease to discuss topics related to diseases with complex inheritance patterns. An array of topics are covered, including how genetic information is inherited, linkage analysis, genome-wide association, missing heritability, next-generation sequencing, epistasis, gene–environment interaction, and epigenetics. Although not fully comprehensive, the chapter does provide sufficient background that the clinician and clinical researcher can begin to competently review the human genetics literature and can effectively communicate with their genetics colleagues.

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease that can currently only be diagnosed through neuropathological examination. It cannot be diagnosed during life at this time due in part to the lack of validated in vivo biomarkers. Structural magnetic resonance imaging (MRI) is an integral component of the clinical evaluation and diagnosis of neurodegenerative diseases. Yet, structural MRI patterns in CTE are unknown. The objective of this study was to characterize the structural MRI patterns of CTE by comparing visually-rated macrostructural features on clinical MRIs between deceased individuals with autopsy-confirmed CTE and cognitively normal participants. The sample included 35 deceased individuals neuropathologically diagnosed with CTE and 50 cognitively normal participants from the Boston University Alzheimer's Disease Center Registry. Participants were ³60 years. Clinical MRIs were obtained through medical record requests. Three radiologists (two neuroradiologists) used established five-point (0=absent, 4=severe) visual rating scales to rate regional atrophy on T1 sequences and microvascular disease on T2-FLAIR. Presence of cavum septum pellucidum (CSP) was rated. Raters were trained on the scales using two practice sets and were blinded to case/control status during test ratings. Majority consensus rating was used; in the absence of majority, median was used. All p-values were false discovery rate (FDR)-corrected. All participants with CTE were American football players (Table 1). Table 2 provides a summary of results. Ordinal regressions showed those with CTE had significantly increased odds for more severe frontal and temporal lobe atrophy, larger lateral and third ventricles, as well as thinner genu and splenium of the corpus callosum. Binary logistic regression showed those with CTE had a 9.96X (95% CI=1.60-62.20) increased odds for having an anterior CSP. There were no statistically significant effects for parietooccipital regions.

The genetic basis of chronic traumatic encephalopathy (CTE) is poorly understood. Variation in transmembrane protein 106B ( TMEM106B ) has been associated with enhanced neuroinflammation during aging and with TDP-43-related neurodegenerative disease, and rs3173615, a missense coding SNP in TMEM106B , has been implicated as a functional variant in these processes. Neuroinflammation and TDP-43 pathology are prominent features in CTE. The purpose of this study was to determine whether genetic variation in TMEM106B is associated with CTE risk, pathological features, and ante-mortem dementia. Eighty-six deceased male athletes with a history of participation in American football, informant-reported Caucasian, and a positive postmortem diagnosis of CTE without comorbid neurodegenerative disease were genotyped for rs3173615 . The minor allele frequency (MAF = 0.42) in participants with CTE did not differ from previously reported neurologically normal controls (MAF = 0.43). However, in a case-only analysis among CTE cases, the minor allele was associated with reduced phosphorylated tau (ptau) pathology in the dorsolateral frontal cortex (DLFC) (AT8 density, odds ratio [OR] of increasing one quartile = 0.42, 95% confidence interval [CI] 0.22–0.79, p = 0.008), reduced neuroinflammation in the DLFC (CD68 density, OR of increasing one quartile = 0.53, 95% CI 0.29–0.98, p = 0.043), and increased synaptic protein density (β = 0.306, 95% CI 0.065–0.546, p = 0.014). Among CTE cases, TMEM106B minor allele was also associated with reduced ante-mortem dementia (OR = 0.40, 95% CI 0.16–0.99, p = 0.048), but was not associated with TDP-43 pathology. All case-only models were adjusted for age at death and duration of football play. Taken together, variation in TMEM106B may have a protective effect on CTE-related outcomes.

Traumatic brain injury has been associated with increased risk of Parkinson disease and parkinsonism, and parkinsonism and Lewy body disease (LBD) can occur with chronic traumatic encephalopathy (CTE). To test whether contact sports and CTE are associated with LBD, we compared deceased contact sports athletes (n = 269) to cohorts from the community (n 164) and the Boston University Alzheimer disease (AD) Center (n = 261). Participants with CTE and LBD were more likely to have 3-amyloid deposition, dementia, and parkinsonism than CTE alone (p < 0.05). Traditional and hierarchical clustering showed a similar pattern of LBD distribution in CTE compared to LBD alone that was most frequently neocortical, limbic, or brainstem. In the community-based cohort, years of contact sports play were associated with neocortical LBD (OR = 1.30 per year, p = 0.0112), and in a pooled analysis a threshold of >8 years of play best predicted neocortical LBD (ROC analysis, OR = 6.24, 95% CI = 1.5 25, p = 0.011), adjusting for age, sex, and APOE allele status. Clinically, dementia was significantly associated with neocortical LBD, CTE stage, and AD; parkinsonism was associated with LBD pathology but not CTE stage. Contact sports participation may increase risk of developing neocortical LBD, and increased LBD frequency may partially explain extrapyramidal motor symptoms sometimes observed in CTE.