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  • Mez, Jesse  (200)
  • 1
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    Associations of Sex, Race, and Apolipoprotein E Alleles With Multiple Domains of Cognition Among Older Adults
    American Medical Association (AMA) ; 2023
    In:  JAMA Neurology Vol. 80, No. 9 ( 2023-09-01), p. 929-
    Details
    In: JAMA Neurology, American Medical Association (AMA), Vol. 80, No. 9 ( 2023-09-01), p. 929-
    Abstract: Sex differences are established in associations between apolipoprotein E ( APOE ) ε4 and cognitive impairment in Alzheimer disease (AD). However, it is unclear whether sex-specific cognitive consequences of APOE are consistent across races and extend to the APOE ε2 allele. Objective To investigate whether sex and race modify APOE ε4 and ε2 associations with cognition. Design, Setting, and Participants This genetic association study included longitudinal cognitive data from 4 AD and cognitive aging cohorts. Participants were older than 60 years and self-identified as non-Hispanic White or non-Hispanic Black (hereafter, White and Black). Data were previously collected across multiple US locations from 1994 to 2018. Secondary analyses began December 2021 and ended September 2022. Main Outcomes and Measures Harmonized composite scores for memory, executive function, and language were generated using psychometric approaches. Linear regression assessed interactions between APOE ε4 or APOE ε2 and sex on baseline cognitive scores, while linear mixed-effect models assessed interactions on cognitive trajectories. The intersectional effect of race was modeled using an APOE  × sex × race interaction term, assessing whether APOE  × sex interactions differed by race. Models were adjusted for age at baseline and corrected for multiple comparisons. Results Of 32 427 participants who met inclusion criteria, there were 19 007 females (59%), 4453 Black individuals (14%), and 27 974 White individuals (86%); the mean (SD) age at baseline was 74 years (7.9). At baseline, 6048 individuals (19%) had AD, 4398 (14%) were APOE ε2 carriers, and 12 538 (38%) were APOE ε4 carriers. Participants missing APOE status were excluded (n = 9266). For APOE ε4, a robust sex interaction was observed on baseline memory (β = −0.071, SE = 0.014; P  = 9.6 × 10 −7 ), whereby the APOE ε4 negative effect was stronger in females compared with males and did not significantly differ among races. Contrastingly, despite the large sample size, no APOE ε2 × sex interactions on cognition were observed among all participants. When testing for intersectional effects of sex, APOE ε2, and race, an interaction was revealed on baseline executive function among individuals who were cognitively unimpaired (β = −0.165, SE = 0.066; P  = .01), whereby the APOE ε2 protective effect was female-specific among White individuals but male-specific among Black individuals. Conclusions and Relevance In this study, while race did not modify sex differences in APOE ε4, the APOE ε2 protective effect could vary by race and sex. Although female sex enhanced ε4-associated risk, there was no comparable sex difference in ε2, suggesting biological pathways underlying ε4-associated risk are distinct from ε2 and likely intersect with age-related changes in sex biology.
    Type of Medium: Online Resource
    ISSN: 2168-6149
    URL: Article
    DOI: 10.1001/jamaneurol.2023.2169
    Language: English
    Publisher: American Medical Association (AMA)
    Publication Date: 2023
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  • 2
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    Associations between near end-of-life flortaucipir PET and postmortem CTE-related tau neuropathology in six former American football players
    Springer Science and Business Media LLC ; 2023
    In:  European Journal of Nuclear Medicine and Molecular Imaging Vol. 50, No. 2 ( 2023-01), p. 435-452
    Details
    In: European Journal of Nuclear Medicine and Molecular Imaging, Springer Science and Business Media LLC, Vol. 50, No. 2 ( 2023-01), p. 435-452
    Abstract: Flourine-18-flortaucipir tau positron emission tomography (PET) was developed for the detection for Alzheimer’s disease. Human imaging studies have begun to investigate its use in chronic traumatic encephalopathy (CTE). Flortaucipir-PET to autopsy correlation studies in CTE are needed for diagnostic validation. We examined the association between end-of-life flortaucipir PET and postmortem neuropathological measurements of CTE-related tau in six former American football players. Methods Three former National Football League players and three former college football players who were part of the DIAGNOSE CTE Research Project died and agreed to have their brains donated. The six players had flortaucipir (tau) and florbetapir (amyloid) PET prior to death. All brains from the deceased participants were neuropathologically evaluated for the presence of CTE. On average, the participants were 59.0 (SD = 9.32) years of age at time of PET. PET scans were acquired 20.33 (SD = 13.08) months before their death. Using Spearman correlation analyses, we compared flortaucipir standard uptake value ratios (SUVRs) to digital slide-based AT8 phosphorylated tau (p-tau) density in a priori selected composite cortical, composite limbic, and thalamic regions-of-interest (ROIs). Results Four brain donors had autopsy-confirmed CTE, all with high stage disease ( n  = 3 stage III, n  = 1 stage IV). Three of these four met criteria for the clinical syndrome of CTE, known as traumatic encephalopathy syndrome (TES). Two did not have CTE at autopsy and one of these met criteria for TES. Concomitant pathology was only present in one of the non-CTE cases (Lewy body) and one of the CTE cases (motor neuron disease). There was a strong association between flortaucipir SUVRs and p-tau density in the composite cortical ( ρ  = 0.71) and limbic ( ρ  = 0.77) ROIs. Although there was a strong association in the thalamic ROI ( ρ  = 0.83), this is a region with known off-target binding. SUVRs were modest and CTE and non-CTE cases had overlapping SUVRs and discordant p-tau density for some regions. Conclusions Flortaucipir-PET could be useful for detecting high stage CTE neuropathology, but specificity to CTE p-tau is uncertain. Off-target flortaucipir binding in the hippocampus and thalamus complicates interpretation of these associations. In vivo biomarkers that can detect the specific p-tau of CTE across the disease continuum are needed.
    Type of Medium: Online Resource
    ISSN: 1619-7070 , 1619-7089
    URL: Article
    DOI: 10.1007/s00259-022-05963-x
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2023
    detail.hit.zdb_id: 2098375-X
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  • 3
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    Developing methods to detect and diagnose chronic traumatic encephalopathy during life: rationale, design, and methodology for the DIAGNOSE CTE Research Project
    Springer Science and Business Media LLC ; 2021
    In:  Alzheimer's Research & Therapy Vol. 13, No. 1 ( 2021-12)
    Details
    In: Alzheimer's Research & Therapy, Springer Science and Business Media LLC, Vol. 13, No. 1 ( 2021-12)
    Abstract: Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease that has been neuropathologically diagnosed in brain donors exposed to repetitive head impacts, including boxers and American football, soccer, ice hockey, and rugby players. CTE cannot yet be diagnosed during life. In December 2015, the National Institute of Neurological Disorders and Stroke awarded a seven-year grant (U01NS093334) to fund the “Diagnostics, Imaging, and Genetics Network for the Objective Study and Evaluation of Chronic Traumatic Encephalopathy (DIAGNOSE CTE) Research Project.” The objectives of this multicenter project are to: develop in vivo fluid and neuroimaging biomarkers for CTE; characterize its clinical presentation; refine and validate clinical research diagnostic criteria (i.e., traumatic encephalopathy syndrome [TES]); examine repetitive head impact exposure, genetic, and other risk factors; and provide shared resources of anonymized data and biological samples to the research community. In this paper, we provide a detailed overview of the rationale, design, and methods for the DIAGNOSE CTE Research Project. Methods The targeted sample and sample size was 240 male participants, ages 45–74, including 120 former professional football players, 60 former collegiate football players, and 60 asymptomatic participants without a history of head trauma or participation in organized contact sports. Participants were evaluated at one of four U.S. sites and underwent the following baseline procedures: neurological and neuropsychological examinations; tau and amyloid positron emission tomography; magnetic resonance imaging and spectroscopy; lumbar puncture; blood and saliva collection; and standardized self-report measures of neuropsychiatric, cognitive, and daily functioning. Study partners completed similar informant-report measures. Follow-up evaluations were intended to be in-person and at 3 years post-baseline. Multidisciplinary diagnostic consensus conferences are held, and the reliability and validity of TES diagnostic criteria are examined. Results Participant enrollment and all baseline evaluations were completed in February 2020. Three-year follow-up evaluations began in October 2019 . However, in-person evaluation ceased with the COVID-19 pandemic, and resumed as remote, 4-year follow-up evaluations (including telephone-, online-, and videoconference-based cognitive, neuropsychiatric, and neurologic examinations, as well as in-home blood draw) in February 2021. Conclusions Findings from the DIAGNOSE CTE Research Project should facilitate detection and diagnosis of CTE during life, and thereby accelerate research on risk factors, mechanisms, epidemiology, treatment, and prevention of CTE. Trial registration NCT02798185
    Type of Medium: Online Resource
    ISSN: 1758-9193
    URL: Article
    DOI: 10.1186/s13195-021-00872-x
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
    detail.hit.zdb_id: 2506521-X
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  • 4
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    Advanced Brain Age in Former American Football Players
    Elsevier BV ; 2023
    In:  Brain and Spine Vol. 3 ( 2023), p. 101892-
    Details
    In: Brain and Spine, Elsevier BV, Vol. 3 ( 2023), p. 101892-
    Type of Medium: Online Resource
    ISSN: 2772-5294
    URL: Article
    DOI: 10.1016/j.bas.2023.101892
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2023
    detail.hit.zdb_id: 3102718-0
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  • 5
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    Evolution of neuronal and glial tau isoforms in chronic traumatic encephalopathy
    Wiley ; 2020
    In:  Brain Pathology Vol. 30, No. 5 ( 2020-09), p. 913-925
    Details
    In: Brain Pathology, Wiley, Vol. 30, No. 5 ( 2020-09), p. 913-925
    Abstract: Chronic traumatic encephalopathy (CTE) is a neurodegenerative tauopathy characterized by accumulation of hyperphosphorylated tau (p‐tau) in perivascular aggregates in neurons and glia at the depths of neocortical sulci and progresses to diffuse neocortical, allocortical and brainstem structures. The strongest risk factor is exposure to repetitive head impacts acquired most commonly through contact sports and military service. Given that CTE can only be definitively diagnosed after death, a better understanding of the cellular and molecular changes in CTE brains may lead to identification of mechanisms that could be used for novel biomarkers, monitoring progression or therapeutic development. Disruption of alternative pre‐mRNA splicing of tau mRNA plays a pathogenic role in tauopathy, with multiple characteristic patterns of isoform accumulation varying among tauopathies. Limited data are available on CTE, particularly at early stages. Using biochemical and histological approaches, we performed a detailed characterization of tau isoform signatures in post‐mortem human brain tissue from individuals with a range of CTE stages (n = 99). In immunoblot analyses, severity was associated with decreased total monomeric tau and increased total oligomeric tau. Immunoblot with isoform‐specific antisera revealed that oligomeric tau with three and four microtubule binding domain repeats (3R and 4R) also increased with CTE severity. Similarly, immunohistochemical studies revealed p‐tau accumulation consisting of both 3R and 4R in perivascular lesions. When the ratio of 4R:3R was analyzed, there was mixed expression throughout CTE stages, although 4R predominated in early CTE stages (I‐II), a 3R shift was observed in later stages (III‐IV). While neurons were found to contain both 3R and 4R, astrocytes only contained 4R. These 4R‐positive cells were exclusively neuronal at early stages. Overall, these findings demonstrate that CTE is a mixed 4R/3R tauopathy. Furthermore, histologic analysis reveals a progressive shift in tau isoforms that correlates with CTE stage and extent of neuronal pathology.
    Type of Medium: Online Resource
    ISSN: 1015-6305 , 1750-3639
    URL: Issue
    URL: Article
    DOI: 10.1111/bpa.v30.5
    DOI: 10.1111/bpa.12867
    Language: English
    Publisher: Wiley
    Publication Date: 2020
    detail.hit.zdb_id: 2029927-8
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  • 6
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    Clinicopathological Evaluation of Chronic Traumatic Encephalopathy in Players of American Football
    American Medical Association (AMA) ; 2017
    In:  JAMA Vol. 318, No. 4 ( 2017-07-25), p. 360-
    Details
    In: JAMA, American Medical Association (AMA), Vol. 318, No. 4 ( 2017-07-25), p. 360-
    Type of Medium: Online Resource
    ISSN: 0098-7484
    URL: Article
    DOI: 10.1001/jama.2017.8334
    RVK:
    XA 10000
    Language: English
    Publisher: American Medical Association (AMA)
    Publication Date: 2017
    detail.hit.zdb_id: 2958-0
    detail.hit.zdb_id: 2018410-4
    SSG: 5,21
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  • 7
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    Football Years Played Has A Dose-response Relationship With Odds Of Having Chronic Traumatic Encephalopathy And Severity Of Disease : 2828 Board #289 May 29 9:30 AM - 11:00 AM
    Ovid Technologies (Wolters Kluwer Health) ; 2020
    In:  Medicine & Science in Sports & Exercise Vol. 52, No. 7S ( 2020-7), p. 784-784
    Details
    In: Medicine & Science in Sports & Exercise, Ovid Technologies (Wolters Kluwer Health), Vol. 52, No. 7S ( 2020-7), p. 784-784
    Type of Medium: Online Resource
    ISSN: 1530-0315 , 0195-9131
    URL: Article
    DOI: 10.1249/01.mss.0000683764.23963.2e
    RVK:
    ZX 1000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2020
    detail.hit.zdb_id: 2031167-9
    SSG: 31
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  • 8
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    Multimodal deep learning for Alzheimer’s disease dementia assessment
    Springer Science and Business Media LLC ; 2022
    In:  Nature Communications Vol. 13, No. 1 ( 2022-06-20)
    Details
    In: Nature Communications, Springer Science and Business Media LLC, Vol. 13, No. 1 ( 2022-06-20)
    Abstract: Worldwide, there are nearly 10 million new cases of dementia annually, of which Alzheimer’s disease (AD) is the most common. New measures are needed to improve the diagnosis of individuals with cognitive impairment due to various etiologies. Here, we report a deep learning framework that accomplishes multiple diagnostic steps in successive fashion to identify persons with normal cognition (NC), mild cognitive impairment (MCI), AD, and non-AD dementias (nADD). We demonstrate a range of models capable of accepting flexible combinations of routinely collected clinical information, including demographics, medical history, neuropsychological testing, neuroimaging, and functional assessments. We then show that these frameworks compare favorably with the diagnostic accuracy of practicing neurologists and neuroradiologists. Lastly, we apply interpretability methods in computer vision to show that disease-specific patterns detected by our models track distinct patterns of degenerative changes throughout the brain and correspond closely with the presence of neuropathological lesions on autopsy. Our work demonstrates methodologies for validating computational predictions with established standards of medical diagnosis.
    Type of Medium: Online Resource
    ISSN: 2041-1723
    URL: Article
    DOI: 10.1038/s41467-022-31037-5
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
    detail.hit.zdb_id: 2553671-0
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  • 9
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    Amyloid PET across the cognitive spectrum in former professional and college American football players: findings from the DIAGNOSE CTE Research Project
    Springer Science and Business Media LLC ; 2023
    In:  Alzheimer's Research & Therapy Vol. 15, No. 1 ( 2023-10-05)
    Details
    In: Alzheimer's Research & Therapy, Springer Science and Business Media LLC, Vol. 15, No. 1 ( 2023-10-05)
    Abstract: 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-β (Aβ) plaque formation and increases the risk for Alzheimer’s disease (AD). Although the Aβ 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 Aβ 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 Aβ 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.
    Type of Medium: Online Resource
    ISSN: 1758-9193
    URL: Article
    DOI: 10.1186/s13195-023-01315-5
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2023
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  • 10
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    CCL2 is associated with microglia and macrophage recruitment in chronic traumatic encephalopathy
    Springer Science and Business Media LLC ; 2020
    In:  Journal of Neuroinflammation Vol. 17, No. 1 ( 2020-12)
    Details
    In: Journal of Neuroinflammation, Springer Science and Business Media LLC, Vol. 17, No. 1 ( 2020-12)
    Abstract: Neuroinflammation has been implicated in the pathogenesis of chronic traumatic encephalopathy (CTE), a progressive neurodegenerative disease association with exposure to repetitive head impacts (RHI) received though playing contact sports such as American football. Past work has implicated early and sustained activation of microglia as a potential driver of tau pathology within the frontal cortex in CTE. However, the RHI induced signals required to recruit microglia to areas of damage and pathology are unknown. Methods Postmortem brain tissue was obtained from 261 individuals across multiple brain banks. Comparisons were made using cases with CTE, cases with Alzheimer’s disease (AD), and cases with no neurodegenerative disease and lacked exposure to RHI (controls). Recruitment of Iba1+ cells around the CTE perivascular lesion was compared to non-lesion vessels. TMEM119 staining was used to characterize microglia or macrophage involvement. The potent chemoattractant CCL2 was analyzed using frozen tissue from the dorsolateral frontal cortex (DLFC) and the calcarine cortex. Finally, the amounts of hyperphosphorylated tau (pTau) and Aβ 42 were compared to CCL2 levels to examine possible mechanistic pathways. Results An increase in Iba1+ cells was found around blood vessels with perivascular tau pathology compared to non-affected vessels in individuals with RHI. TMEM119 staining revealed the majority of the Iba1+ cells were microglia. CCL2 protein levels in the DLFC were found to correlate with greater years of playing American football, the density of Iba1+ cells, the density of CD68+ cells, and increased CTE severity. When comparing across multiple brain regions, CCL2 increases were more pronounced in the DLFC than the calcarine cortex in cases with RHI but not in AD. When examining the individual contribution of pathogenic proteins to CCL2 changes, pTau correlated with CCL2, independent of age at death and Aβ 42 in AD and CTE. Although levels of Aβ 42 were not correlated with CCL2 in cases with CTE, in males in the AD group, Aβ 42 trended toward an inverse relationship with CCL2 suggesting possible gender associations. Conclusion Overall, CCL2 is implicated in the pathways recruiting microglia and the development of pTau pathology after exposure to RHI, and may represent a future therapeutic target in CTE.
    Type of Medium: Online Resource
    ISSN: 1742-2094
    URL: Article
    DOI: 10.1186/s12974-020-02036-4
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2020
    detail.hit.zdb_id: 2156455-3
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