Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative disease found in individuals with a history of repetitive head injury (RHI) received through playing contact sports. Currently, CTE can only be diagnosed after death through the identification of perivascular neuronal hyperphosphorylated tau (pTau) pathology, found at the depth of the cortical sulcus. Although the pathognomonic lesion is found among all cases, pTau deposition is patchy and heterogeneous among individuals. To determine whether the heterogeneity of CTE masks more subtle ordering or additional disease variants, we applied the unsupervised machine learning algorithm subtype and stage inference (SuStaIn) on fully quantitative pTau density data from 26 brain regions in 207 CTE cases and 75 control cases. SuStaIn identified three distinct pathological progression subtypes: 93 cases were classified as Subtype 1 (cortical predominant) and showed dense, rapidly progressing cortical pTau akin to the classically described CTE neuropathology; Subtype 2 (cortical sparing–hippocampal enhanced) had 105 cases that exhibited a reduced cortical pTau burden that progressed slower, but also had pronounced hippocampal involvement in a CTE-specific pattern; and Subtype 3 (copathology altered) consisted of 28 older cases with higher CTE stage, was enriched for comorbid pathologies (pTDP43, Aβ, hippocampal sclerosis, and arteriolosclerosis), and had enhanced pTau in regions highly related to those additional pathologies. Clinically, impaired performance in the Functional Activities Questionnaire (FAQ) correlated with pTau regional burden and severity only in cases with Subtype 1 pathology, suggesting the enhanced cortical pTau pathology was linked to greater functional decline. Overall, these findings help characterize the heterogeneity in CTE progression, validate key pathological variants, and will be crucial for refining diagnostic criteria and advancing in-life diagnosis.

Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative disease associated with repeated head injuries (RHI) commonly experienced by contact sport athletes, military personnel, and domestic abuse victims. Despite growing recognition of CTE, the molecular mechanisms underlying disease progression remain poorly understood. This study aims to identify proteomic alterations associated with CTE pathology and clinical features to elucidate key biological pathways involved in disease pathogenesis. SomaScan 7k high-throughput proteomics was performed on 204 dorsolateral prefrontal cortex samples from the Boston University CTE Center Brain Bank. We identified differentially expressed proteins associated with CTE, hyperphosphorylated tau (ptau) pathology, duration of contact sports play, dementia status, and Cognitive Difficulty Scale (CDS) scores. Gene set enrichment analysis revealed that proteasome subunit proteins and related pathways were strongly associated with CTE progression and correlated with years of contact sports play. Reduction in ribosomal proteins and pathways was closely associated with ptau burden. Additionally, multiple models demonstrated significant alterations in MAPK-related cell signaling pathways. These findings advance our understanding of CTE progression and identify mechanisms correlated with key pathological features of the disease. Validation of these results could inform the development of diagnostics and treatments for CTE.

Repetitive head impacts (RHI), primarily through contact sports play and military service, are a recognized risk factor for cognitive and behavioral symptoms, as well as progressive neurodegenerative diseases such as chronic traumatic encephalopathy. While altered DNA methylation has been linked to environmental exposures and neurodegeneration, its association with RHI remains unknown. In this study, we investigated whether duration of contact sports play in a community-based aging cohort is associated with altered DNA methylation patterns. Reduced representation bisulfite sequencing on human dorsolateral frontal cortex identified 461 genome-wide significant CpG sites associated with duration of contact sports play, spanning 13 genes of which the majority were hypomethylated. The hypomethylation pattern was largely replicated in an independent cohort. Notably, CAMK2B, B4GALT6, and TLR2, were hypomethylated and upregulated in the cortical sulcus of the DLFC in individuals with RHI exposure from contact sports. Furthermore, alterations of CAMK2B and B4GALT6 were observed in CTE cases. Together, these findings reveal distinct, region-specific epigenetic changes associated with contact sports exposure and provide new insights into the molecular mechanisms underlying RHI-related sequalae.

BackgroundRetinal thickness has been associated with neurocognitive conditions such as Alzheimer's disease (AD).ObjectiveRetinal cell layer thickness was evaluated for associations with neurodegenerative protein biomarkers glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) in plasma, vitreous humor, and aqueous humor.MethodsThis cross-sectional study included 50 patients who underwent vitrectomy and optical coherence tomography imaging of the inner macular ring (IM) and outer macular ring (OM). Associations between inner retinal cell layer thicknesses and GFAP or NfL levels were evaluated with linear regression adjusted for demographic and clinical factors. p-values less than 0.05 and with a false discovery rate less than 10% were considered significant.ResultsHigher plasma GFAP levels were significantly associated with a thinner retinal nerve fiber layer at the superior, nasal, and inferior OM as well as a thinner ganglion cell layer at the superior IM, inferior IM, temporal IM, nasal OM, and temporal OM. Plasma GFAP was also associated with a thinner inner plexiform layer at the nasal IM, inferior IM, temporal IM, nasal OM, and temporal OM. Plasma NfL was negatively associated with GCL thickness only in the superior IM.ConclusionsHigher plasma GFAP levels were associated with thinner inner cell layers, whereas plasma NfL levels showed a more limited association. These findings suggest that systemic astroglial activation may be associated with retinal structural changes.

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease caused by repetitive head impacts (RHI). However, individuals with similar RHI exposure can show differing pathology, suggesting a role for genetic variation. A common Transmembrane Protein 106B ( TMEM106B ) risk variant is associated with greater CTE severity, though its mechanism remains unclear. To determine whether TMEM106B alters the inflammatory response to pathology in CTE, we examined associations between microglia, via immunohistochemistry, and inflammatory cytokines, via immunoassay, in brain donors with CTE with and without the risk genotype ( rs3173615) . We analyzed 323 RHI-exposed brain donors: 55 without pathology (controls) and 268 with CTE. Regression models tested associations between TMEM106B risk and CTE presence, CTE stage, TDP-43, and dementia in those < = 65 and > 65 years of age. Within a subset of 122 brain donors, we examined associations between microglia, cytokines, and pathology stratified by TMEM106B genotype. Among donors > 65 years old, the TMEM106B risk genotype was associated with increased CTE stage (OR = 2.748 [95% CI 1.183–6.383], p = 0.019), comparable to the effect of playing > 8 years of contact sports, and with greater odds of having TDP-43 inclusions (OR = 3.649 [95% CI 1.278–10.422], p = 0.016). In donors < = 65, TMEM106B risk was associated with higher odds of dementia (OR = 6.912 [95% CI 2.015–23.705], p = 0.002). TMEM106B gene variation had a significant effect on associations between inflammatory markers and CTE-related pathology. In the protective genotype, IL-8 and IL-6 demonstrated positive associations with CD68, TREM2, and tau pathology within the dorsolateral prefrontal cortex. In the risk genotype, IFN-γ, IL-4, TNF-α, TNF-β, and IL-10 demonstrated negative associations with TREM2 ( p ’s < 0.05), and TNF-α was negatively associated with cortical tau ( p = 0.003). These results suggest that the microglial production of TREM2-associated cytokines and their association with pathology is aberrant in the TMEM106B risk genotype in CTE. Overall, TMEM106B rs3173615 is associated with an increased risk of developing higher stage CTE and TDP-43 pathology, potentially via impaired microglial activation and aberrant cytokine production.

Repetitive head impacts that occur in contact/collision sports, military service, and physical violence are associated with TDP-43 pathology, and TDP-43 inclusions are frequently present in the hippocampus and frontal cortex in chronic traumatic encephalopathy (CTE). Individuals with CTE and TDP-43 inclusions are more likely to show severe cognitive impairment; however, the underlying mechanism is unknown. In amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP), TDP-43 inclusions are associated with widespread gene mis-splicing and cryptic exon expression. We hypothesized that TDP-43 pathology in CTE similarly contributes to gene mis-splicing, leading to selective protein loss and neurodegeneration. A total of 212 brain donors with a history of repetitive head impacts were examined for CTE and the presence and distribution of TDP-43 inclusions. Clinical outcomes, including measures of cognitive impairment, were obtained from informants and medical records. Bulk RNA sequencing and SomaScan 7K aptamer-based proteomics were performed on the dorsolateral prefrontal cortex. After excluding those with AD, FTLD-TDP, or ALS, variable splicing events were determined using LeafCutter in those with CTE and TDP-43 inclusions in the hippocampus or frontal cortex (CTE-TDP) compared to CTE without TDP-43 in those regions (CTE). Out of 142 with CTE, 72 (51%) had TDP-43 inclusions within the hippocampus, frontal cortex, or both (CTE-TDP). Differential analysis revealed altered splicing within 836 genes in CTE-TDP compared to CTE with a false discovery rate <0.01. Of these, 23 overlapped with previously identified mis-spliced genes in ALS and FTLD-TDP. Seven of these genes had protein levels measured with SomaScan proteomics, including CAMK2B, DLGAP4, EPB41L1, NCAM1, PTPRD, RAP1GAP, and SH3KBP1. Notably, protein levels of erythrocyte membrane protein band 4.1 like 1 (EPB41L1) and RAP1 GTPase-activating protein (RAP1GAP) were significantly reduced in CTE-TDP frontal cortex compared to CTE ( p 's <0.01) and negatively correlated with both amygdala and hippocampal TDP-43 inclusions. Furthermore, decreased levels of EPB41L1 and RAP1GAP were associated with dementia adjusting for age ( p 's <0.05). Both EPB41L1 and RAP1GAP are involved in synaptic plasticity and signaling. Mis-splicing and decreased protein expression of these synapse-related genes may partially underlie the neurodegeneration and cognitive impairments in CTE with TDP-43 inclusions.

BackgroundDiabetes has been linked to increased prevalence of dementia, but the link between diabetic retinopathy (DR) and Alzheimer's disease (AD) remains unclear.ObjectiveThis study aimed to evaluate potential associations between DR and AD-related protein biomarkers in plasma and ocular fluid.MethodsA prospective, cross-sectional study collected human blood, vitreous, aqueous, and tear samples and measured amyloid-β (Aβ40, Aβ42), total-tau (t-tau), phosphorylated-tau (ptau181), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL) by digital immunoassays.ResultsThe study included 79 eyes (79 patients) [41 females (59.4%); mean (SD) age 57.1 (12.2) years] of which DR was present in 44 (55.7%). All six biomarkers were significantly higher in plasma in participants with DR compared to those without DR [Aβ40 p = 0.002, Aβ42 p = 0.002, t-tau = 0.013, ptau181 p = 0.005, GFAP p = 0.010, and NfL p < 0.001]. Within vitreous, DR participants had significantly elevated t-tau (p = 0.002), ptau181 (p = 0.049), and NfL (p = 0.006); and within aqueous, higher NfL (p = < 0.001). Neuropsychological testing scores were lower in participants with DR than those without but did not reach statistical significance (Montreal-Cognitive-Assessment: p = 0.070; Mini-Mental-State-Exam: p = 0.057).ConclusionsThis study showed significant increases of AD associated protein biomarkers in plasma, vitreous, and aqueous in patients with DR. These results support a potential biological link between DR and AD pathology and suggest that DR, which tends to occur in younger individuals, may be a predictive factor for AD.

Ocular imaging and fluid protein levels are emerging as biomarkers for neurodegenerative disease. Elevated levels of plasma glial fibrillary acidic protein (GFAP), a marker of astrogliosis, have been demonstrated early in the course of Alzheimer’s Disease. In this study, we measured GFAP levels in the aqueous and vitreous humors and plasma of 79 participants undergoing vitrectomy surgery for retinal disease and correlated them with subject Mini Mental Status Exam (MMSE) and Trail Making Test part b (TMT-b) scores. Measured GFAP concentrations were higher in vitreous and aqueous than in plasma. Levels of GFAP within the aqueous and vitreous were correlated (r = 0.6; p < 0.0001); however, there was no association between GFAP levels in either ocular fluid and plasma. There was no significant correlation between GFAP levels in any of the measured ocular fluids and cognition as measured by MMSE and TMT-b scores. In plasma, higher GFAP levels were associated with lower TMT-b, but not MMSE, scores. Given that elevated GFAP levels are associated with a variety of vitreoretinal diseases, future studies evaluating its use as a potential biomarker for dementias should concentrate on recruiting subjects without a history of ocular disease.

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 (beta, 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.

Protein biomarkers have been broadly investigated in cerebrospinal fluid and blood for the detection of neurodegenerative diseases, yet a clinically useful diagnostic test to detect early, pre-symptomatic Alzheimer’s disease (AD) remains elusive. We conducted this study to quantify Aβ40, Aβ42, total Tau (t-Tau), hyperphosphorylated Tau (ptau181), glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) in eye fluids relative to blood. In this cross-sectional study we collected vitreous humor, aqueous humor, tear fluid and plasma in patients undergoing surgery for eye disease. All six biomarkers were quantitatively measured by digital immunoassay. Spearman and Bland–Altman correlation analyses were performed to assess the agreement of levels between ocular fluids and plasma. Seventy-nine adults underwent pars-plana vitrectomy in at least one eye. Of the 79, there were 77 vitreous, 67 blood, 56 tear fluid, and 51 aqueous samples. All six biomarkers were quantified in each bio-sample, except GFAP and NfL in tear fluid due to low sample volume. All six biomarkers were elevated in vitreous humor compared to plasma samples. T-Tau, ptau181, GFAP and NfL were higher in aqueous than in plasma, and t-Tau and ptau181 concentrations were higher in tear fluid than in plasma. Significant correlations were found between Aβ40 in plasma and tears (r = 0.5; p = 0.019), t-Tau in plasma and vitreous (r = 0.4; p = 0.004), NfL in plasma and vitreous (r = 0.3; p = 0.006) and plasma and aqueous (r = 0.5; p = 0.004). No significant associations were found for Aβ42, ptau181 and GFAP among ocular fluids relative to plasma. Bland–Altman analysis showed aqueous humor had the closest agreement to plasma across all biomarkers. Biomarker levels in ocular fluids revealed statistically significant associations between vitreous and aqueous for t-Tau (r = 0.5; p = 0.001), GFAP (r = 0.6; p < 0.001) and NfL (r = 0.7; p < 0.001). AD biomarkers are detectable in greater quantities in eye fluids than in plasma and show correlations with levels in plasma. Future studies are needed to assess the utility of ocular fluid biomarkers as diagnostic and prognostic markers for AD, especially in those at risk with eye disease.

Neurodegeneration is a seminal feature of many neurological disorders. Chronic traumatic encephalopathy (CTE) is caused by repetitive head impacts (RHI) and is characterized by sulcal tau pathology. However, quantitative assessments of regional neurodegeneration in CTE have not been described. In this study, we quantified three key neurodegenerative measures, including cortical thickness, neuronal density, and synaptic proteins, in contact sport athletes (n = 185) and non-athlete controls (n = 52) within the sulcal depth, middle, and gyral crest of the dorsolateral frontal cortex. Cortical thickness and neuronal density were decreased within the sulcus in CTE compared to controls (p’s < 0.05). Measurements of synaptic proteins within the gyral crest showed a reduction of α-synuclein with CTE stage (p = 0.002) and variable changes in PSD-95 density. After adjusting for age, multiple linear regression models demonstrated a strong association between the duration of contact sports play and cortical thinning (p = 0.001) and neuronal loss (p = 0.032) within the sulcus. Additional regression models, adjusted for tau pathology, suggest that within the sulcus, the duration of play was associated with neuronal loss predominantly through tau pathology. In contrast, the association of duration of play with cortical thinning was minimally impacted by tau pathology. Overall, CTE is associated with cortical atrophy and a predominant sulcal neurodegeneration. Furthermore, the duration of contact sports play is associated with measures of neurodegeneration that are more severe in the cortical sulcus and may occur through tau-dependent and independent mechanisms.

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease linked to repetitive head impacts (RHI) and characterized by perivascular hyperphosphorylated tau (p-tau) deposits. The role of vascular injury, blood-brain barrier leakage, and neuroinflammation in CTE pathogenesis is not well understood. We performed quantitative immunoassays for intercellular adhesion molecule 1 (ICAM1), vascular cellular adhesion molecule 1 (VCAM1), and C-reactive protein (CRP) within the postmortem dorsolateral frontal cortex of participants with and without a history of RHI and CTE (n = 156), and tested for associations with RHI, microgliosis, and tau pathology measures. Levels of vascular injury-associated markers ICAM1, VCAM1, and CRP were increased in CTE compared to RHI-exposed and -naïve controls. ICAM1 and CRP increased with RHI exposure duration (p < 0.01) and were associated with increased microglial density (p < 0.001) and tau pathology (AT8, p-tau396, p-tau202; p < 0.05). Histologically, there was significantly increased ICAM1 staining of the microvasculature, extracellular space, and astrocytes at the sulcal depths in high stage CTE compared to both low stage CTE and controls. Multifocal perivascular immunoreactivity for serum albumin was present in all RHI-exposed individuals. These findings demonstrate that vascular injury markers are associated with RHI exposure, duration, and microgliosis, are elevated in CTE, and increase with disease severity.

Identification of blood-based biomarkers that are indicative of Alzheimer’s disease (AD) pathology may help with early detection. We generated proteome data for ∼7,000 proteins in both antemortem plasma and postmortem brain tissue from 103 participants of the Boston University Alzheimer’s Disease Research Center. All participants completed comprehensive neuropsychological evaluations and dementia severity was measured by global cognitive dementia rating (CDR) scores. A pathological AD diagnosis was established using NIA Reagan criteria. We conducted association tests with dementia (i.e., CDR ≥1 for dementia, CDR <1 for control) and autopsy-confirmed AD status as binary outcomes. Plasma proteins significantly associated with clinical or pathological AD (P<0.05) were tested for association with quantitative cognitive tests and AD-related neuropathological traits in which outcomes were rank-transformed after adjusting for sex and either age at last antemortem exam or death. Of the 103 brain donors, 43 were diagnosed with dementia and 55 had autopsy-confirmed AD. Five proteins (ACES, AURKB, CBARP, G45IP, and MMP-8) measured in plasma were significantly associated with both pathological AD and dementia, while 252 plasma proteins were associated with either diagnosis (P<0.05). MMP-8 was the only protein that was significantly associated in both plasma and brain with autopsy-confirmed AD (P plasma = 0.005, P brain = 0.001) and dementia (P plasma = 0.01, P brain = 9×10 −5 ). ACES and AURKB levels in plasma and brain were significantly associated with dementia (P<0.05). Levels of these. Increased MMP-8 level in plasma was associated with decreased animals (P = 0.03) and scores (P = 0.04), which both assess verbal fluency. Dementia and pathologically confirmed AD were associated with lower AURKB and elevated ACES levels in plasma. Decreased plasma ACES level was associated with executive function (TrailsB: P = 0.01) and language (Boston Naming Test: P = 0.02) impairment, and the reduced plasma AURKB level was associated with memory impairment (Logical Memory Immediate Recall score: P = 0.03). MMP-8, a neutrophil collagenase and member of the matrix metalloproteinase family, is a potential blood-based biomarker for dementia and underlying AD pathology and is associated predominantly with impaired verbal fluency.

BACKGROUND:Our understanding of the molecular underpinnings of chronic traumatic encephalopathy (CTE) and its associated pathology in post-mortem brain is incomplete. Factors including years of play and genetic risk variants influence the extent of tau pathology associated with disease expression, but how these factors affect gene expression, and whether those effects are consistent across the development of disease, is unknown. METHODS:To address these questions, we conducted an analysis of the largest post-mortem brain CTE mRNASeq whole-transcriptome dataset available to date. We examined the genes and biological processes associated with disease by comparing individuals with CTE with control individuals with a history of repetitive head impacts that lack CTE pathology. We then identified genes and biological processes associated with total years of play as a measure of exposure, amount of tau pathology present at time of death, and the presence of APOE and TMEM106B risk variants. Samples were stratified into low and high pathology groups based on McKee CTE staging criteria to model early versus late changes in response to exposure, and the relative effects associated with these factors were compared between these groups. RESULTS:Substantial gene expression changes were associated with severe disease for most of these factors, primarily implicating diverse, strongly involved neuroinflammatory and neuroimmune processes. In contrast, low pathology groups had many fewer genes and processes implicated and show striking differences for some factors when compared with severe disease. Specifically, gene expression associated with amount of tau pathology showed a nearly perfect inverse relationship when compared between these two groups. CONCLUSIONS:Together, these results suggest the early CTE disease process may be mechanistically different than what occurs in late stages, that total years of play and tau pathology influence disease expression differently, and that related pathology-modifying risk variants may do so via distinct biological pathways.

Hippocampal sclerosis (HS) is associated with advanced age as well as transactive response DNA-binding protein with 43 kDa (TDP-43) deposits. Both hippocampal sclerosis and TDP-43 proteinopathy have also been described in chronic traumatic encephalopathy (CTE), a neurodegenerative disease linked to exposure to repetitive head impacts (RHI). However, the prevalence of HS in CTE, the pattern of TDP-43 pathology, and associations of HS and TDP-43 with RHI are unknown. A group of participants with a history of RHI and CTE at autopsy (n = 401) as well as a group with HS-aging without CTE (n = 33) was examined to determine the prevalence of HS and TDP-43 inclusions in CTE and to compare the clinical and pathological features of HS and TDP-43 inclusions in CTE to HS-aging. In CTE, HS was present in 23.4%, and TDP-43 inclusions were present in 43.3% of participants. HS in CTE occurred at a relatively young age (mean 77.0 years) and was associated with a greater number of years of RHI than CTE without HS adjusting for age (p = 0.029). In CTE, TDP-43 inclusions occurred frequently in the frontal cortex and occurred both with and without limbic TDP-43. Additionally, structural equation modeling demonstrated that RHI exposure years were associated with hippocampal TDP-43 inclusions (p < 0.001) through increased CTE stage (p < 0.001). Overall, RHI and the development of CTE pathology may contribute to TDP-43 deposition and hippocampal sclerosis.

BACKGROUND:Multiple studies have reported brain lipidomic abnormalities in Alzheimer's disease (AD) that affect glycerophospholipids, sphingolipids, and fatty acids. However, there is no consensus regarding the nature of these abnormalities, and it is unclear if they relate to disease progression. OBJECTIVE:Monogalactosyl diglycerides (MGDGs) are a class of lipids which have been recently detected in the human brain. We sought to measure their levels in postmortem human brain and determine if these levels correlate with the progression of the AD-related traits. METHODS:We measured MGDGs by ultrahigh performance liquid chromatography tandem mass spectrometry in postmortem dorsolateral prefrontal cortex gray matter and subcortical corona radiata white matter samples derived from three cohorts of participants: the Framingham Heart Study, the Boston University Alzheimer's Disease Research Center, and the Arizona Study of Aging and Neurodegenerative Disorders/Brain and Body Donation Program (total n = 288). RESULTS:We detected 40 molecular species of MGDGs (including diacyl and alkyl/acyl compounds) and found that the levels of 29 of them, as well as total MGDG levels, are positively associated with AD-related traits including pathologically confirmed AD diagnosis, clinical dementia rating, Braak and Braak stage, neuritic plaque score, phospho-Tau AT8 immunostaining density, levels of phospho-Tau396 and levels of Aβ40. Increased MGDG levels were present in both gray and white matter, indicating that they are widespread and likely associated with myelin-producing oligodendrocytes-the principal cell type of white matter. CONCLUSIONS:Our data implicate the MGDG metabolic defect as a central correlate of clinical and pathological progression in AD.

Parkinsonism has been shown to be more frequent in those with a history of traumatic brain injury, repetitive head impacts (RHI), and chronic traumatic encephalopathy (CTE), a disease characterized by tau pathology. However, the underlying pathological associations with parkinsonism in this context are not well known. Autopsy participants with a history of RHI exposure through contact sports participation and neuropathologically diagnosed with CTE (n = 481) were examined for pathology in the substantia nigra. Based on review of next-of-kin interviews and medical records, expert clinicians judged whether symptoms of parkinsonism, including bradykinesia, resting tremor, rigidity, micrographia, and shuffling gait, were present. The total number of consecutive years of contact sports play was used as a proxy for RHI exposure. Neuropathological diagnoses were made using established criteria. Pathology in the substantia nigra was quantified for alpha-synuclein-positive Lewy bodies, neurofibrillary tangles (NFTs), and neuronal loss. Of a total of 481 male CTE participants, 119 (24.7%) had symptoms of parkinsonism during life. Comparison of clinical characteristics of CTE participants with (n = 119) and without (n = 362) parkinsonism showed those with parkinsonism had an older age of death, and a larger proportion had symptoms of dementia, probable REM sleep behavior disorder, and visual hallucinations than participants without parkinsonism (p’s <0.00001). Of those with CTE and parkinsonism, the majority (70%) did not have Lewy bodies within the substantia nigra, suggesting other pathologies may also contribute to motor symptoms. In fact, those with parkinsonism were more likely to have nigral NFTs and neuronal loss ( Figure ), adjusting for age as well as when restricting to those age >65 (p’s<0.001). Years of contact sports play was associated with NFTs (p = 0.03) and neuronal loss (p = 0.016), but not Lewy bodies in the substantia nigra. Both nigral NFTs (p = 0.001) and Lewy bodies (p<0.001) were associated with nigral neuronal loss. Parkinsonism was associated with neuronal loss (p<0.001) and Lewy bodies (p = 0.027) in the substantia nigra. Overall, these findings suggest that RHI contributes to tau pathology and neuronal loss in the substantia nigra. Those susceptible to Lewy body pathology may be further at risk for parkinsonism in CTE.

Repetitive head impacts (RHI) and traumatic brain injuries are risk factors for the neurodegenerative diseases chronic traumatic encephalopathy (CTE) and amyotrophic lateral sclerosis (ALS). ALS and CTE are distinct disorders, yet in some instances, share pathology, affect similar brain regions, and occur together. The pathways involved and biomarkers for diagnosis of both diseases are largely unknown. MicroRNAs (miRNAs) involved in gene regulation may be altered in neurodegeneration and be useful as stable biomarkers. Thus, we set out to determine associations between miRNA levels and disease state within the prefrontal cortex in a group of brain donors with CTE, ALS, CTE + ALS and controls. Of 47 miRNAs previously implicated in neurological disease and tested here, 28 (60%) were significantly different between pathology groups. Of these, 21 (75%) were upregulated in both ALS and CTE, including miRNAs involved in inflammatory, apoptotic, and cell growth/differentiation pathways. The most significant change occurred in miR-10b, which was significantly increased in ALS, but not CTE or CTE + ALS. Overall, we found patterns of miRNA expression that are common and unique to CTE and ALS and that suggest shared and distinct mechanisms of pathogenesis.

Alzheimer disease (AD) is a chronic neurodegenerative disease with a multitude of contributing genetic factors, many of which are related to inflammation. The apolipoprotein E (APOE) ε 4 allele is the most common genetic risk factor for AD and is related to a pro-inflammatory state. To test the hypothesis that microglia and AD-implicated cytokines were differentially associated with AD pathology based on the presence of APOE ε4, we examined the dorsolateral frontal cortex from deceased participants within a community-based aging cohort ( n = 154). Cellular density of Iba1, a marker of microglia, was positively associated with tau pathology only in APOE ε4 positive participants ( p = 0.001). The cytokines IL-10, IL-13, IL-4, and IL-1α were negatively associated with tau pathology, independent of Aβ 1–42 levels, only in APOE ε4 negative participants. Overall, the association of mostly anti-inflammatory cytokines with less tau pathology suggests a protective effect in APOE ε4 negative participants. These associations are largely absent in the presence of APOE ε4 where tau pathology was significantly associated with increased microglial cell density. Taken together, these results suggest that APOE ε4 mediates an altered inflammatory response and increased tau pathology independent of Aβ 1–42 pathology.