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Importance: Parkinsonism is associated with traumatic brain injury and chronic traumatic encephalopathy (CTE), a neurodegenerative disease associated with repetitive head impact (RHI) exposure, but the neuropathologic substrates that underlie parkinsonism in individuals with CTE are yet to be defined., Objective: To evaluate the frequency of parkinsonism in individuals with CTE and the association of RHI and neuropathologic substrates with parkinsonism in these individuals., Design, Setting, and Participants: This cross-sectional study included brain donors with neuropathologically diagnosed CTE without other significant neurodegenerative disease and with information on parkinsonism from the Understanding Neurologic Injury and Traumatic Encephalopathy brain bank between July 2015 and May 2022., Exposure: Years of contact sports participation as a proxy for RHI., Main Outcomes and Measures: The main outcomes were frequency of parkinsonism in individuals with CTE and associations between (1) RHI with substantia nigra (SN) Lewy bodies (LBs) and neurofibrillary tangles (NFTs); (2) LBs, NFTs, and arteriolosclerosis with SN neuronal loss; and (3) SN neuronal loss, LBs, NFTs, and arteriolosclerosis with parkinsonism, tested by age-adjusted logistic regressions., Results: Of 481 male brain donors with neuropathologically diagnosed CTE, parkinsonism occurred frequently in individuals with CTE (119 [24.7%]; 362 [75.3%] did not have parkinsonism). Participants with parkinsonism had a higher mean (SD) age at death (71.5 [13.0] years) than participants without parkinsonism (54.1 [19.3] years) (P < .001) and higher rates of dementia (104 [87.4%] vs 105 [29.0%]), visual hallucinations (45 [37.8%] vs 51 [14.1%]), and probable rapid eye movement sleep behavior disorder (52 [43.7%] vs 58 [16.0%]) (P < .001 for all). Participants with parkinsonism had a more severe CTE stage (eg, stage IV: 35 [29.4%] vs 39 [10.8%]) and nigral pathology than those without parkinsonism (NFTs: 50 of 117 [42.7%] vs 103 of 344 [29.9%]; P = .01; neuronal loss: 61 of 117 [52.1%] vs 59 of 344 [17.1%]; P < .001; and LBs: 28 of 116 [24.1%] vs 20 of 342 [5.8%]; P < .001). Years of contact sports participation were associated with SN NFTs (adjusted odds ratio [AOR], 1.04; 95% CI, 1.00-1.07; P = .03) and neuronal loss (AOR, 1.05; 95% CI, 1.01-1.08; P = .02). Nigral neuronal loss (AOR, 2.61; 95% CI, 1.52-4.47; P < .001) and LBs (AOR, 2.29; 95% CI, 1.15-4.57; P = .02) were associated with parkinsonism. However, SN neuronal loss was associated with SN LBs (AOR, 4.48; 95% CI, 2.25-8.92; P < .001), SN NFTs (AOR, 2.51; 95% CI, 1.52-4.15; P < .001), and arteriolosclerosis (AOR, 2.27; 95% CI, 1.33-3.85; P = .002). In American football players, regression analysis demonstrated that SN NFTs and neuronal loss mediated the association between years of play and parkinsonism in the context of CTE (β, 0.012; 95% CI, 0.001-0.038)., Conclusions and Relevance: In this cross-sectional study of contact sports athletes with CTE, years of contact sports participation were associated with SN tau pathology and neuronal loss, and these pathologies were associated with parkinsonism. Repetitive head impacts may incite neuropathologic processes that lead to symptoms of parkinsonism in individuals with CTE.

Repetitive head impacts (RHIs) from football are associated with the neurodegenerative tauopathy chronic traumatic encephalopathy (CTE). It is unclear whether a history of traumatic brain injury (TBI) is sufficient to precipitate CTE neuropathology. We examined the association between TBI and CTE neuropathology in 580 deceased individuals exposed to RHIs from football. TBI history was assessed using a modified version of the Ohio State University TBI Identification Method Short Form administered to informants. There were 22 donors who had no TBI, 213 who had at least one TBI without loss of consciousness (LOC), 345 who had TBI with LOC, and, of those with a history of TBI with LOC, 36 who had at least one moderate-to-severe TBI (msTBI, LOC >30 min). CTE neuropathology was diagnosed in 405. There was no association between CTE neuropathology status or severity and TBI with LOC (odds ratio [OR] = 0.95, 95% confidence interval [CI] = 0.64-1.41; OR = 1.22, 95% CI = 0.71-2.09) or msTBI (OR = 0.70, 95% CI = 0.33-1.50; OR = 1.01, 95% CI = 0.30-3.41). There were no associations with other neurodegenerative or cerebrovascular pathologies examined. TBI with LOC and msTBI were not associated with CTE neuropathology in this sample of brain donors exposed to RHIs from American football.

Down syndrome (DS) is the most common chromosomal disorder in humans. DS is associated with increased prevalence of several ocular sequelae, including characteristic blue-dot cerulean cataract. DS is accompanied by age-dependent accumulation of Alzheimer's disease (AD) amyloid-β (Aβ) peptides and amyloid pathology in the brain and comorbid early-onset Aβ amyloidopathy and colocalizing cataracts in the lens. Quasi-elastic light scattering (QLS) is an established optical technique that noninvasively measures changes in protein size distributions in the human lens in vivo. In this cross-sectional study, lenticular QLS correlation time was decreased in adolescent subjects with DS compared to age-matched control subjects. Clinical QLS was consistent with alterations in relative particle hydrodynamic radius in lenses of adolescents with DS. These correlative results suggest that noninvasive QLS can be used to evaluate molecular changes in the lenses of individuals with DS., Competing Interests: Declaration of competing interest Goldstein (Cognoptix, Rebion); Hunter (Rebion, Luminopia). None of the reported entities contributed financial support for or had access to results from this study. No other disclosures were reported., (Copyright © 2024. Published by Elsevier Ltd.)

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease caused by repetitive head impacts (RHI) and pathologically defined as neuronal phosphorylated tau aggregates around small blood vessels and concentrated at sulcal depths. Cross-sectional studies suggest that tau inclusions follow a stereotyped pattern that begins in the neocortex in low stage disease, followed by involvement of the medial temporal lobe and subcortical regions with significant neocortical burden in high stage CTE. Here, we define a subset of brain donors with high stage CTE and with a low overall cortical burden of tau inclusions (mean semiquantitative value ≤1) and classify them as cortical-sparing CTE (CSCTE). Of 620 brain donors with pathologically diagnosed CTE, 66 (11%) met criteria for CSCTE. Compared to typical high stage CTE, those with CSCTE had a similar age at death and years of contact sports participation and were less likely to carry apolipoprotein ε4 (p < 0.05). CSCTE had less overall tau pathology severity, but a proportional increase of disease burden in medial temporal lobe and brainstem regions compared to the neocortex (p's < 0.001). CSCTE also had lower prevalence of comorbid neurodegenerative disease. Clinically, CSCTE participants were less likely to have dementia (p =  0.023) and had less severe cognitive difficulties (as reported by informants using the Functional Activities Questionnaire (FAQ); p < 0.001, meta-cognitional index T score; p = 0.002 and Cognitive Difficulties Scale (CDS); p < 0.001,) but had an earlier onset age of behavioral (p = 0.006) and Parkinsonian motor (p = 0.013) symptoms when compared to typical high stage CTE. Other comorbid tauopathies likely contributed in part to these differences: when cases with concurrent Alzheimer dementia or frontal temporal lobar degeneration with tau pathology were excluded, differences were largely retained, but only remained significant for FAQ (p = 0.042), meta-cognition index T score (p = 0.014) and age of Parkinsonian motor symptom onset (p = 0.046). Overall, CSCTE appears to be a distinct subtype of high stage CTE with relatively greater involvement of subcortical and brainstem regions and less severe cognitive symptoms., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease characterized by hyperphosphorylated tau (p-tau) accumulation. The clinical features associated with CTE pathology are unclear. In brain donors with autopsy-confirmed CTE, we investigated the association of CTE p-tau pathology density and location with cognitive, functional, and neuropsychiatric symptoms., Methods: In 364 brain donors with autopsy confirmed CTE, semi-quantitative p-tau severity (range: 0-3) was assessed in 10 cortical and subcortical regions. We summed ratings across regions to form a p-tau severity global composite (range: 0-30). Informants completed standardized scales of cognition (Cognitive Difficulties Scale, CDS; BRIEF-A Metacognition Index, MI), activities of daily living (Functional Activities Questionnaire), neurobehavioral dysregulation (BRIEF-A Behavioral Regulation Index, BRI; Barratt Impulsiveness Scale, BIS-11), aggression (Brown-Goodwin Aggression Scale), depression (Geriatric Depression Scale-15, GDS-15), and apathy (Apathy Evaluation Scale, AES). Ordinary least squares regression models examined associations between global and regional p-tau severity (separate models for each region) with each clinical scale, adjusting for age at death, racial identity, education level, and history of hypertension, obstructive sleep apnea, and substance use treatment. Ridge regression models that incorporated p-tau severity across all regions in the same model assessed which regions showed independent effects., Results: The sample was predominantly American football players (333; 91.2%); 140 (38.5%) had low CTE and 224 (61.5%) had high CTE. Global p-tau severity was associated with higher (i.e., worse) scores on the cognitive and functional scales: MI ([Formula: see text] standardized  = 0.02, 95%CI = 0.01-0.04), CDS ([Formula: see text] standardized  = 0.02, 95%CI = 0.01-0.04), and FAQ ([Formula: see text] standardized  = 0.03, 95%CI = 0.01-0.04). After false-discovery rate correction, p-tau severity in the frontal, inferior parietal, and superior temporal cortex, and the amygdala was associated with higher CDS ([Formula: see text] s standardized  = 0.17-0.29, ps < 0.01) and FAQ ([Formula: see text] s standardized  = 0.21-0.26, ps < 0.01); frontal and inferior parietal cortex was associated with higher MI ([Formula: see text] s standardized  = 0.21-0.29, ps < 0.05); frontal cortex was associated with higher BRI ([Formula: see text] standardized  = 0.21, p < 0.01). Regions with effects independent of other regions included frontal cortex (CDS, MI, FAQ, BRI), inferior parietal cortex (CDS) and amygdala (FAQ). P-tau explained 13-49% of variance in cognitive and functional scales and 6-14% of variance in neuropsychiatric scales., Conclusion: Accumulation of p-tau aggregates, especially in the frontal cortex, are associated with cognitive, functional, and certain neurobehavioral symptoms in CTE., (© 2023. The Author(s).)

Background: Chronic traumatic encephalopathy (CTE) is a neurodegenerative tauopathy more frequently found in deceased former football players. CTE has heterogeneous clinical presentations with multifactorial causes. Previous literature has shown substance use (alcohol/drug) can contribute to Alzheimer's disease and related tauopathies pathologically and clinically., Objective: To examine the association between substance use and clinical and neuropathological endpoints of CTE., Methods: Our sample included 429 deceased male football players. CTE was neuropathologically diagnosed. Informant interviews assessed features of substance use and history of treatment for substance use to define indicators: history of substance use treatment (yes vs no, primary variable), alcohol severity, and drug severity. Outcomes included scales that were completed by informants to assess cognition (Cognitive Difficulties Scale, BRIEF-A Metacognition Index), mood (Geriatric Depression Scale-15), behavioral regulation (BRIEF-A Behavioral Regulation Index, Barratt Impulsiveness Scale-11), functional ability (Functional Activities Questionnaire), as well as CTE status and cumulative p-tau burden. Regression models tested associations between substance use indicators and outcomes., Results: Of the 429 football players (mean age = 62.07), 313 (73%) had autopsy confirmed CTE and 100 (23%) had substance use treatment history. Substance use treatment and alcohol/drug severity were associated with measures of behavioral regulation (FDR-p-values<0.05, ΔR2 = 0.04-0.18) and depression (FDR-p-values<0.05, ΔR2 = 0.02-0.05). Substance use indicators had minimal associations with cognitive scales, whereas p-tau burden was associated with all cognitive scales (p-values <0.05). Substance use treatment had no associations with neuropathological endpoints (FDR-p-values>0.05)., Conclusions: Among deceased football players, substance use was common and associated with clinical symptoms.

Plasma-to-autopsy studies are essential for validation of blood biomarkers and understanding their relation to Alzheimer's disease (AD) pathology. Few such studies have been done on phosphorylated tau (p-tau) and those that exist have made limited or no comparison of the different p-tau variants. This study is the first to use immunoprecipitation mass spectrometry (IP-MS) to compare the accuracy of eight different plasma tau species in predicting autopsy-confirmed AD. The sample included 123 participants (AD = 69, non-AD = 54) from the Boston University Alzheimer's disease Research Center who had an available ante-mortem plasma sample and donated their brain. Plasma samples proximate to death were analyzed by targeted IP-MS for six different tryptic phosphorylated (p-tau-181, 199, 202, 205, 217, 231), and two non-phosphorylated tau (195-205, 212-221) peptides. NIA-Reagan Institute criteria were used for the neuropathological diagnosis of AD. Binary logistic regressions tested the association between each plasma peptide and autopsy-confirmed AD status. Area under the receiver operating curve (AUC) statistics were generated using predicted probabilities from the logistic regression models. Odds Ratio (OR) was used to study associations between the different plasma tau species and CERAD and Braak classifications. All tau species were increased in AD compared to non-AD, but p-tau217, p-tau205 and p-tau231 showed the highest fold-changes. Plasma p-tau217 (AUC = 89.8), p-tau231 (AUC = 83.4), and p-tau205 (AUC = 81.3) all had excellent accuracy in discriminating AD from non-AD brain donors, even among those with CDR < 1). Furthermore, p-tau217, p-tau205 and p-tau231 showed the highest ORs with both CERAD (OR p-tau217  = 15.29, OR p-tau205  = 5.05 and OR p-tau231  = 3.86) and Braak staging (OR p-tau217  = 14.29, OR p-tau205  = 5.27 and OR p-tau231  = 4.02) but presented increased levels at different amyloid and tau stages determined by neuropathological examination. Our findings support plasma p-tau217 as the most promising p-tau species for detecting AD brain pathology. Plasma p-tau231 and p-tau205 may additionally function as markers for different stages of the disease., (© 2023. The Author(s).)

Introduction: This study examined plasma glial fibrillary acidic protein (GFAP) as a biomarker of cognitive impairment due to Alzheimer's disease (AD) with and against plasma neurofilament light chain (NfL), and phosphorylated tau (p-tau) 181+231 ., Methods: Plasma samples were analyzed using Simoa platform for 567 participants spanning the AD continuum. Cognitive diagnosis, neuropsychological testing, and dementia severity were examined for cross-sectional and longitudinal outcomes., Results: Plasma GFAP discriminated AD dementia from normal cognition (adjusted mean difference = 0.90 standard deviation [SD]) and mild cognitive impairment (adjusted mean difference = 0.72 SD), and demonstrated superior discrimination compared to alternative plasma biomarkers. Higher GFAP was associated with worse dementia severity and worse performance on 11 of 12 neuropsychological tests. Longitudinally, GFAP predicted decline in memory, but did not predict conversion to mild cognitive impairment or dementia., Discussion: Plasma GFAP was associated with clinical outcomes related to suspected AD and could be of assistance in a plasma biomarker panel to detect in vivo AD., Competing Interests: The authors MA, MAS, TKK, HJA, BF, YT, BM, JNP, EGS, IS, LAF, GRJ, KWT, AEB, MKO, LEG, NWK, RK, TDS, ACM, WQ, and JM have no competing interests to declare. HZ has served on scientific advisory boards and/or as a consultant for Abbvie, Acumen, Alector, Alzinova, ALZPath, Annexon, Apellis, Artery Therapeutics, AZTherapies, CogRx, Denali, Eisai, Nervgen, Novo Nordisk, Passage Bio, Pinteon Therapeutics, Prothena, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave; has given lectures in symposia sponsored by Cellectricon, Fujirebio, Alzecure, Biogen, and Roche; and is a co‐founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). KB has served as a consultant, on advisory boards, or on data monitoring committees for Abcam, Axon, BioArctic, Biogen, JOMDD/Shimadzu. Julius Clinical, Lilly, MagQu, Novartis, Ono Pharma, Pharmatrophix, Prothena, Roche Diagnostics, and Siemens Healthineers, and is a co‐founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program, outside the work presented in this paper. NJA has given lectures in symposia sponsored by Eli‐Lily. AEB has served as a consultant or on advisory boards for Eli Lilly and Roche Pharmaceuticals and has received grant monies from Cumulus Neuroscience, VoxNeuro, Bristol Myers Squibb, and Cyclerion. He receives publishing royalties from Elsevier and Oxford University Press. RA serves on the scientific advisory board of Signant Health, as consultant to Biogen, and has given a lecture in a symposium sponsored by Eisai. RAS has served as a consultant to Biogen and Lundbeck. He receives royalties for published neuropsychological tests from Psychological Assessment Resources, Inc. MLA has received honorarium from the Michael J. Fox Foundation for services unrelated to this study. He receives royalties from Oxford University Press., (© 2023 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

Importance: Young contact sport athletes may be at risk for long-term neuropathologic disorders, including chronic traumatic encephalopathy (CTE)., Objective: To characterize the neuropathologic and clinical symptoms of young brain donors who were contact sport athletes., Design, Setting, and Participants: This case series analyzes findings from 152 of 156 brain donors younger than 30 years identified through the Understanding Neurologic Injury and Traumatic Encephalopathy (UNITE) Brain Bank who donated their brains from February 1, 2008, to September 31, 2022. Neuropathologic evaluations, retrospective telephone clinical assessments, and online questionnaires with informants were performed blinded. Data analysis was conducted between August 2021 and June 2023., Exposures: Repetitive head impacts from contact sports., Main Outcomes and Measures: Gross and microscopic neuropathologic assessment, including diagnosis of CTE, based on defined diagnostic criteria; and informant-reported athletic history and informant-completed scales that assess cognitive symptoms, mood disturbances, and neurobehavioral dysregulation., Results: Among the 152 deceased contact sports participants (mean [SD] age, 22.97 [4.31] years; 141 [92.8%] male) included in the study, CTE was diagnosed in 63 (41.4%; median [IQR] age, 26 [24-27] years). Of the 63 brain donors diagnosed with CTE, 60 (95.2%) were diagnosed with mild CTE (stages I or II). Brain donors who had CTE were more likely to be older (mean difference, 3.92 years; 95% CI, 2.74-5.10 years) Of the 63 athletes with CTE, 45 (71.4%) were men who played amateur sports, including American football, ice hockey, soccer, rugby, and wrestling; 1 woman with CTE played collegiate soccer. For those who played football, duration of playing career was significantly longer in those with vs without CTE (mean difference, 2.81 years; 95% CI, 1.15-4.48 years). Athletes with CTE had more ventricular dilatation, cavum septum pellucidum, thalamic notching, and perivascular pigment-laden macrophages in the frontal white matter than those without CTE. Cognitive and neurobehavioral symptoms were frequent among all brain donors. Suicide was the most common cause of death, followed by unintentional overdose; there were no differences in cause of death or clinical symptoms based on CTE status., Conclusions and Relevance: This case series found that young brain donors exposed to repetitive head impacts were highly symptomatic regardless of CTE status, and the causes of symptoms in this sample are likely multifactorial. Future studies that include young brain donors unexposed to repetitive head impacts are needed to clarify the association among exposure, white matter and microvascular pathologic findings, CTE, and clinical symptoms.

Chronic traumatic encephalopathy (CTE) is a neurodegenerative tauopathy associated with repetitive head impacts (RHI), but the components of RHI exposure underlying this relationship are unclear. We create a position exposure matrix (PEM), composed of American football helmet sensor data, summarized from literature review by player position and level of play. Using this PEM, we estimate measures of lifetime RHI exposure for a separate cohort of 631 football playing brain donors. Separate models examine the relationship between CTE pathology and players' concussion count, athletic positions, years of football, and PEM-derived measures, including estimated cumulative head impacts, linear accelerations, and rotational accelerations. Only duration of play and PEM-derived measures are significantly associated with CTE pathology. Models incorporating cumulative linear or rotational acceleration have better model fit and are better predictors of CTE pathology than duration of play or cumulative head impacts alone. These findings implicate cumulative head impact intensity in CTE pathogenesis., (© 2023. The Author(s).)

American football players and other individuals exposed to repetitive head impacts can exhibit a constellation of later-life cognitive and neuropsychiatric symptoms. While tau-based diseases such as chronic traumatic encephalopathy can underpin certain symptoms, contributions from non-tau pathologies from repetitive head impacts are increasingly recognized. We examined cross-sectional associations between myelin integrity using immunoassays for myelin-associated glycoprotein and proteolipid protein 1 with risk factors and clinical outcomes in brain donors exposed to repetitive head impacts from American football. Immunoassays for myelin-associated glycoprotein and proteolipid protein 1 were conducted on dorsolateral frontal white matter tissue samples of 205 male brain donors. Proxies of exposure to repetitive head impacts included years of exposure and age of first exposure to American football play. Informants completed the Functional Activities Questionnaire, Behavior Rating Inventory of Executive Function-Adult Version (Behavioral Regulation Index), and Barratt Impulsiveness Scale-11. Associations between myelin-associated glycoprotein and proteolipid protein 1 with exposure proxies and clinical scales were tested. Of the 205 male brain donors who played amateur and professional football, the mean age was 67.17 (SD = 16.78), and 75.9% ( n = 126) were reported by informants to be functionally impaired prior to death. Myelin-associated glycoprotein and proteolipid protein 1 correlated with the ischaemic injury scale score, a global indicator of cerebrovascular disease ( r = -0.23 and -0.20, respectively, P s < 0.01). Chronic traumatic encephalopathy was the most common neurodegenerative disease ( n = 151, 73.7%). Myelin-associated glycoprotein and proteolipid protein 1 were not associated with chronic traumatic encephalopathy status, but lower proteolipid protein 1 was associated with more severe chronic traumatic encephalopathy ( P = 0.03). Myelin-associated glycoprotein and proteolipid protein 1 were not associated with other neurodegenerative disease pathologies. More years of football play was associated with lower proteolipid protein 1 [beta = -2.45, 95% confidence interval (CI) [-4.52, -0.38]] and compared with those who played <11 years of football ( n = 78), those who played 11 or more years ( n = 128) had lower myelin-associated glycoprotein (mean difference = 46.00, 95% CI [5.32, 86.69]) and proteolipid protein 1 (mean difference = 24.72, 95% CI [2.40, 47.05]). Younger age of first exposure corresponded to lower proteolipid protein 1 (beta = 4.35, 95% CI [0.25, 8.45]). Among brain donors who were aged 50 or older ( n = 144), lower proteolipid protein 1 (beta = -0.02, 95% CI [-0.047, -0.001]) and myelin-associated glycoprotein (beta = -0.01, 95% CI [-0.03, -0.002]) were associated with higher Functional Activities Questionnaire scores. Lower myelin-associated glycoprotein correlated with higher Barratt Impulsiveness Scale-11 scores (beta = -0.02, 95% CI [-0.04, -0.0003]). Results suggest that decreased myelin may represent a late effect of repetitive head impacts that contributes to the manifestation of cognitive symptoms and impulsivity. Clinical-pathological correlation studies with prospective objective clinical assessments are needed to confirm our findings., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background T1-weighted MRI and quantitative longitudinal relaxation rate (R1) mapping have been used to evaluate gadolinium retention in the brain after gadolinium-based contrast agent (GBCA) administration. Whether MRI measures accurately reflect gadolinium regional distribution and concentration in the brain remains unclear. Purpose To compare gadolinium retention in rat forebrain measured with in vivo quantitative MRI R1 and ex vivo laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) mapping after gadobenate, gadopentetate, gadodiamide, or gadobutrol administration. Materials and Methods Adult female Sprague-Dawley rats were randomly assigned to one of five groups (eight per group) and administered gadobenate, gadopentetate, gadodiamide, gadobutrol (2.4 mmol/kg per week for 5 weeks), or saline (4.8 mL/kg per week for 5 weeks). MRI R1 mapping was performed at baseline and 1 week after the final injection to determine R1 and ΔR1. Postmortem brains from the same rats were analyzed with LA-ICP-MS elemental mapping to determine regional gadolinium concentrations. Student t tests were performed to compare results between GBCA and saline groups. Results Rats that were administered gadobenate showed gadolinium-related MRI ΔR1 in 39.5% of brain volume (ΔR1 = 0.087 second -1 ± 0.051); gadopentetate, 20.6% (ΔR1 = 0.069 second -1 ± 0.018); gadodiamide, 5.4% (ΔR1 = 0.055 second -1 ± 0.019); and gadobutrol, 2.2% (ΔR1 = 0.052 second -1 ± 0.041). Agent-specific gadolinium-related ΔR1 was detected in multiple forebrain regions (neocortex, hippocampus, dentate gyrus, thalamus, and caudate-putamen) in rats treated with gadobenate or gadopentetate, whereas rats treated with gadodiamide showed gadolinium-related ΔR1 in caudate-putamen. By contrast, LA-ICP-MS elemental mapping showed a similar regional distribution pattern of heterogeneous retained gadolinium in the forebrain of rats treated with gadobenate, gadopentetate, or gadodiamide, with the average gadolinium concentration of 0.45 μg · g -1 ± 0.07, 0.50 μg · g -1 ± 0.10, and 0.60 μg · g -1 ± 0.11, respectively. Low levels (0.01 μg · g -1 ± 0.00) of retained gadolinium were detected in the forebrain of gadobutrol-treated rats. Conclusion Differences in in vivo MRI longitudinal relaxation rate versus ex vivo elemental mass spectrometry measures of retained gadolinium in rat forebrains suggest that some forms of retained gadolinium may escape detection with MRI. © RSNA, 2022 Online supplemental material is available for this article.

Electronic cigarettes (e-cigarettes) have been used widely as an alternative to conventional cigarettes and have become particularly popular among young adults. A growing body of evidence has shown that e-cigarettes are associated with acute lung injury and adverse effects in multiple other organs. Previous studies showed that high emissions of aldehydes (formaldehyde and acetaldehyde) in aerosols were associated with increased usage of the same e-cigarette coils. However, the impact on lung function of using aged coils has not been reported. We investigated the relationship between coil age and acute lung injury in mice exposed to experimental vaping for 1 h (2 puffs/min, 100 ml/puff). The e-liquid contains propylene glycol and vegetable glycerin (50:50, vol) only. The concentrations of formaldehyde and acetaldehyde in the vaping aerosols increased with age of the nichrome coils starting at 1200 puffs. Mice exposed to e-cigarette aerosols produced from 1800, but not 0 or 900, puff-aged coils caused acute lung injury, increased lung wet/dry weight ratio, and induced lung inflammation (IL-6, TNF-α, IL-1β, MIP-2). Exposure to vaping aerosols from 1800 puff-aged coils decreased heart rate, respiratory rate, and oxygen saturation in mice compared to mice exposed to air or aerosols from new coils. In conclusion, we observed that the concentration of aldehydes (formaldehyde and acetaldehyde) increased with repeated and prolonged usage of e-cigarette coils. Exposure to high levels of aldehyde in vaping aerosol was associated with acute lung injury in mice. These findings show significant risk of lung injury associated with prolonged use of e-cigarette devices., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Blood-based biomarkers such as tau phosphorylated at threonine 181 (phosphorylated-tau181) represent an accessible, cost-effective and scalable approach for the in vivo detection of Alzheimer's disease pathophysiology. Plasma-pathological correlation studies are needed to validate plasma phosphorylated-tau181 as an accurate and reliable biomarker of Alzheimer's disease neuropathological changes. This plasma-to-autopsy correlation study included participants from the Boston University Alzheimer's Disease Research Center who had a plasma sample analysed for phosphorylated-tau181 between 2008 and 2018 and donated their brain for neuropathological examination. Plasma phosphorelated-tau181 was measured with single molecule array technology. Of 103 participants, 62 (60.2%) had autopsy-confirmed Alzheimer's disease. Average time between blood draw and death was 5.6 years (standard deviation = 3.1 years). Multivariable analyses showed higher plasma phosphorylated-tau181 concentrations were associated with increased odds for having autopsy-confirmed Alzheimer's disease [AUC = 0.82, OR = 1.07, 95% CI = 1.03-1.11, P < 0.01; phosphorylated-tau standardized (z-transformed): OR = 2.98, 95% CI = 1.50-5.93, P < 0.01]. Higher plasma phosphorylated-tau181 levels were associated with increased odds for having a higher Braak stage (OR = 1.06, 95% CI = 1.02-1.09, P < 0.01) and more severe phosphorylated-tau across six cortical and subcortical brain regions (ORs = 1.03-1.06, P < 0.05). The association between plasma phosphorylated-tau181 and Alzheimer's disease was strongest in those who were demented at time of blood draw (OR = 1.25, 95%CI = 1.02-1.53), but an effect existed among the non-demented (OR = 1.05, 95% CI = 1.01-1.10). There was higher discrimination accuracy for Alzheimer's disease when blood draw occurred in years closer to death; however, higher plasma phosphorylated-tau181 levels were associated with Alzheimer's disease even when blood draw occurred >5 years from death. Ante-mortem plasma phosphorylated-tau181 concentrations were associated with Alzheimer's disease neuropathology and accurately differentiated brain donors with and without autopsy-confirmed Alzheimer's disease. These findings support plasma phosphorylated-tau181 as a scalable biomarker for the detection of Alzheimer's disease., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Neuropathological hallmarks of Alzheimer's disease (AD) include pathogenic accumulation of amyloid-β (Aβ) peptides and age-dependent formation of amyloid plaques in the brain. AD-associated Aβ neuropathology begins decades before onset of cognitive symptoms and slowly progresses over the course of the disease. We previously reported discovery of Aβ deposition, β-amyloidopathy, and co-localizing supranuclear cataracts (SNC) in lenses from people with AD, but not other neurodegenerative disorders or normal aging. We confirmed AD-associated Aβ molecular pathology in the lens by immunohistopathology, amyloid histochemistry, immunoblot analysis, epitope mapping, immunogold electron microscopy, quantitative immunoassays, and tryptic digest mass spectrometry peptide sequencing. Ultrastructural analysis revealed that AD-associated Aβ deposits in AD lenses localize as electron-dense microaggregates in the cytoplasm of supranuclear (deep cortex) fiber cells. These Aβ microaggregates also contain αB-crystallin and scatter light, thus linking Aβ pathology and SNC phenotype expression in the lenses of people with AD. Subsequent research identified Aβ lens pathology as the molecular origin of the distinctive cataracts associated with Down syndrome (DS, trisomy 21), a chromosomal disorder invariantly associated with early-onset Aβ accumulation and Aβ amyloidopathy in the brain. Investigation of 1249 participants in the Framingham Eye Study found that AD-associated quantitative traits in brain and lens are co-heritable. Moreover, AD-associated lens traits preceded MRI brain traits and cognitive deficits by a decade or more and predicted future AD. A genome-wide association study of bivariate outcomes in the same subjects identified a new AD risk factor locus in the CTNND2 gene encoding δ-catenin, a protein that modulates Aβ production in brain and lens. Here we report identification of AD-related human Aβ (hAβ) lens pathology and age-dependent SNC phenotype expression in the Tg2576 transgenic mouse model of AD. Tg2576 mice express Swedish mutant human amyloid precursor protein (APP-Swe), accumulate hAβ peptides and amyloid pathology in the brain, and exhibit cognitive deficits that slowly progress with increasing age. We found that Tg2576 trangenic (Tg + ) mice, but not non-transgenic (Tg - ) control mice, also express human APP, accumulate hAβ peptides, and develop hAβ molecular and ultrastructural pathologies in the lens. Tg2576 Tg + mice exhibit age-dependent Aβ supranuclear lens opacification that recapitulates lens pathology and SNC phenotype expression in human AD. In addition, we detected hAβ in conditioned medium from lens explant cultures prepared from Tg + mice, but not Tg - control mice, a finding consistent with constitutive hAβ generation in the lens. In vitro studies showed that hAβ promoted mouse lens protein aggregation detected by quasi-elastic light scattering (QLS) spectroscopy. These results support mechanistic (genotype-phenotype) linkage between Aβ pathology and AD-related phenotypes in lens and brain. Collectively, our findings identify Aβ pathology as the shared molecular etiology of two age-dependent AD-related cataracts associated with two human diseases (AD, DS) and homologous murine cataracts in the Tg2576 transgenic mouse model of AD. These results represent the first evidence of AD-related Aβ pathology outside the brain and point to lens Aβ as an optically-accessible AD biomarker for early detection and longitudinal monitoring of this devastating neurodegenerative disease., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: We examined the ability of plasma hyperphosphorylated tau (p-tau) 181 to detect cognitive impairment due to Alzheimer's disease (AD) independently and in combination with plasma total tau (t-tau) and neurofilament light (NfL)., Methods: Plasma samples were analyzed using the Simoa platform for 235 participants with normal cognition (NC), 181 with mild cognitive impairment due to AD (MCI), and 153 with AD dementia. Statistical approaches included multinomial regression and Gaussian graphical models (GGMs) to assess a network of plasma biomarkers, neuropsychological tests, and demographic variables., Results: Plasma p-tau 181 discriminated AD dementia from NC, but not MCI, and correlated with dementia severity and worse neuropsychological test performance. Plasma NfL similarly discriminated diagnostic groups. Unlike plasma NfL or t-tau, p-tau 181 had a direct association with cognitive diagnosis in a bootstrapped GGM., Discussion: These results support plasma p-tau 181 for the detection of AD dementia and the use of blood-based biomarkers for optimal disease detection., (© 2021 the Alzheimer's Association.)

Importance: Repetitive head impact (RHI) exposure is the chief risk factor for chronic traumatic encephalopathy (CTE). However, the occurrence and severity of CTE varies widely among those with similar RHI exposure. Limited evidence suggests that the APOEε4 allele may confer risk for CTE, but previous studies were small with limited scope., Objective: To test the association between APOE genotype and CTE neuropathology and related endophenotypes., Design, Setting, and Participants: This cross-sectional genetic association study analyzed brain donors from February 2008 to August 2019 from the Veterans Affairs-Boston University-Concussion Legacy Foundation Brain Bank. All donors had exposure to RHI from contact sports or military service. All eligible donors were included. Analysis took place between June 2020 and April 2022., Exposures: One or more APOEε4 or APOEε2 alleles., Main Outcomes and Measures: CTE neuropathological status, CTE stage (0-IV), semiquantitative phosphorylated tau (p-tau) burden in 11 brain regions (0-3), quantitative p-tau burden in the dorsolateral frontal lobe (log-transformed AT8+ pixel count per mm2), and dementia., Results: Of 364 consecutive brain donors (100% male; 53 [14.6%] self-identified as Black and 311 [85.4%] as White; median [IQR] age, 65 [47-77] years) 20 years or older, there were 294 individuals with CTE and 70 controls. Among donors older than 65 years, APOEε4 status was significantly associated with CTE stage (odds ratio [OR], 2.34 [95% CI, 1.30-4.20]; false discovery rate [FDR]-corrected P = .01) and quantitative p-tau burden in the dorsolateral frontal lobe (β, 1.39 [95% CI, 0.83-1.94]; FDR-corrected P = 2.37 × 10-5). There was a nonsignificant association between APOEε4 status and dementia (OR, 2.64 [95% CI, 1.06-6.61]; FDR-corrected P = .08). Across 11 brain regions, significant associations were observed for semiquantitative p-tau burden in the frontal and parietal cortices, amygdala, and entorhinal cortex (OR range, 2.45-3.26). Among football players, the APOEε4 association size for CTE stage was similar to playing more than 7 years of football. Associations were significantly larger in the older half of the sample. There was no significant association for CTE status. Association sizes were similar when donors with an Alzheimer disease neuropathological diagnosis were excluded and were reduced but remained significant after adjusting for neuritic and diffuse amyloid plaques. No associations were observed for APOEε2 status. Models were adjusted for age at death and race., Conclusions and Relevance: APOEε4 may confer increased risk for CTE-related neuropathological and clinical outcomes among older individuals with RHI exposure. Further work is required to validate these findings in an independent sample.

Exposure to military blast and repetitive head impacts (RHI) in contact sports is associated with increased risk of long-term neurobehavioral sequelae and cognitive deficits, and the neurodegenerative disease chronic traumatic encephalopathy (CTE). At present, the exact pathogenic mechanisms of RHI and CTE are unknown, and no targeted therapies are available. Astrocytes have recently emerged as key mediators of the multicellular response to head trauma. Here, we investigated interface astrogliosis in blast and impact neurotrauma, specifically in the context of RHI and early stage CTE. We compared postmortem brain tissue from former military veterans with a history of blast exposure with and without a neuropathological diagnosis of CTE, former American football players with a history of RHI with and without a neuropathological diagnosis of CTE, and control donors without a history of blast, RHI exposure or CTE diagnosis. Using quantitative immunofluorescence, we found that astrogliosis was higher at the grey-white matter interface in the dorsolateral frontal cortex, with mixed effects at the subpial surface and underlying cortex, in both blast and RHI donors with and without CTE, compared to controls. These results indicate that certain astrocytic alterations are associated with both impact and blast neurotrauma, and that different astroglial responses take place in distinct brain regions., (© 2022. The Author(s).)

Background: Cerebrospinal fluid (CSF) tau and beta-amyloid levels in chronic traumatic encephalopathy (CTE), a disease which can be clinically indistinguishable from Alzheimer's disease (AD), are largely unknown. We examined postmortem CSF analytes among participants with autopsy confirmed CTE and AD., Methods: In this cross-sectional study 192 participants from the Boston University AD Research Center, VA-BU-CLF Center, and Framingham Heart Study (FHS) had post-mortem CSF collected at autopsy. Participants were divided into pathological groups based on AD and CTE criteria, with 61 CTE participants (18 low, 43 high stage), 79 AD participants (23 low, 56 intermediate to high), 11 participants with CTE combined with AD, and 41 participants lacking both CTE and AD neuropathology. The Meso Scale Discovery immunoassay system was utilized to measure amyloid-beta (Aβ 1-40, Aβ 1-42 ) , total tau (t-tau), and phosphorylated tau (p-tau 181 and p-tau 231 ). CSF analytes were then compared across the pathological groups: no CTE/no AD (control), Low CTE, Low AD, High CTE, Intermediate/High AD, and AD+CTE., Results: Among the Low disease state groups, the Low CTE group had significantly higher levels of p-tau 231 versus the control group and compared to the Low AD group. The Low CTE group was also found to have significantly lower levels of Aβ 1-42 compared to the control group. The high CTE group had higher levels of p-tau 231 and lower levels of Aβ 1-42 compared to Intermediate/High AD group., Conclusions: Importantly, p-tau 231 and Aβ 1-42 were predictors of diagnosis of CTE vs. control and CTE vs. AD. Increased CSF p-tau 231 is a promising potentially sensitive biomarker of CTE, and CSF Aβ 1-42 needs further investigation in CTE., (© 2022. The Author(s).)

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., (© 2021. The Author(s).)