We report on a measurement of the energy resolution that can be attained in liquid xenon when recording only the scintillation light. Our setup is optimized to maximize light collection and uses state-of-the-art, high-PDE (photodetection efficiency), VUV-sensitive silicon photomultipliers. We find a value of 3.7%±0.4% at 511 keV, once saturation effects are corrected for, a result close to the Poissonian resolution that we expect in our setup (2.8%±0.4% at 511 keV). Our results in the intrinsic resolution (2.3%±0.8%) are compatible, within errors, at 511 keV, with those found by theoretical estimations that have been standing for the last 20 years, 1.8%. Our work opens possibilities for apparatus based on liquid xenon and using scintillation only. In particular, it suggests that modular scintillation detectors using liquid xenon can be very competitive as building blocks in segmented calorimeters, with applications to Positron Emission Tomography technology.

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.

The unique lesion of chronic traumatic encephalopathy (CTE) is the perivascular deposition of hyperphosphorylated tau at the depth of the cortical sulci. The distribution and molecular composition of p-tau is distinct from Alzheimer’s disease (AD), but differential diagnostic challenges remain. Understanding disease differences in regional density of p-tau will inform differential diagnosis and interpretation of in vivo biomarkers. Here, we compared autopsy-confirmed CTE and AD across cortical and subcortical measurements of p-tau density. The sample included 109 brain donors with stage III/IV CTE, and 109 age (+/- 3 years) and sex similar brain donors with autopsy-confirmed AD. While the original sample was similar, there is missing data across regions due to older cases not having AT8 stains. CTE was neuropathologically diagnosed using published criteria. NIA-Reagan was used for AD. Neuropathologists used semi-quantitative rating scales (0=none, 3=severe) to evaluate p-tau severity in the dorsolateral frontal cortex (DLFC), inferior orbital frontal cortex (IFC), superior temporal cortex (STC), inferior parietal cortex (IPC), CA1, CA2, and CA4, entorhinal cortex (EC), and amygdala. Digital slide scanning of AT8 tissue was done for quantitative assessment of p-tau density in the DLFC, STC, IPC, CA1, CA2/3, CA4, and calcarine cortex. Regression and analysis of variance models compared disease groups on each outcome, controlling for age. On the semi-quantitative rating scales, those with autopsy-confirmed CTE had greater p-tau severity in the CA4-hippocampus compared with AD (OR=4.43, p=0.003); in contrast, AD had greater p-tau severity in the CA1-hippocampus (OR=0.07), EC (OR=0.10), and amygdala (OR=0.24) (ps<0.05). There were no differences for the CA2-hippocampus. Regarding cortical regions, those with AD had greater p-tau severity on the DLFC, IFC, STC, and IPC (ORs=0.03-0.16, ps<0.05). A similar pattern was found for the quantitative p-tau density data: CTE had greater p-tau density in CA4- (marginal mean difference=7.45) and CA2/3 (marginal mean difference=9.86) (ps<0.01) and AD had higher density of p-tau across the other regions (i.e., DLFC, IPC, STC, calcarine). Compared with AD, CA4-hippocampus was most affected in CTE. AD had greater p-tau density across cortical regions. Findings inform neuropathological differential diagnosis and interpretation of in vivo biomarkers in CTE and AD.

Chronic traumatic encephalopathy (CTE) is a progressive brain disease linked to repetitive head impacts (RHI), often incurred from contact sports, and can lead to dementia. Here, we investigated the association between RHI and white matter/vascular neuropathologies and their relative contribution to dementia status in deceased men 50 + years old with and without exposure to RHI from various types of contact and collision sports. Our sample included two RHI groups from the UNITE brain bank: (1) American Football players (RHI-AF, n = 79), and (2) non-AF contact and collision sport athletes (e.g., boxing, rugby; RHI-CCS, n = 49). Controls included similarly aged (± 5 years) male brain donors without RHI. A modified ischemic injury scale (mIIS) served as a global measure of white matter and vascular neuropathologies, encompassing nine subcomponents. Dementia was determined through diagnostic consensus conference based on interviews with families. Using linear regression models controlling for age at death, mIIS was different in RHI-AF versus non-RHI only (p = 0.036). Subsequent logistic regression of each mIIS subcomponent, controlling for age at death, demonstrated that worse white matter rarefaction (RHI-AF; Beta = 1.42, [95

Repetitive head impacts (RHI) sustained from contact sports are the largest risk factor for chronic traumatic encephalopathy (CTE). Currently, CTE can only be diagnosed after death and the multicellular cascade of events that trigger initial hyperphosphorylated tau (p-tau) deposition remain unclear. Further, the symptoms endorsed by young individuals with early disease are not fully explained by the extent of p-tau deposition, severely hampering development of therapeutic interventions. Here, we show that RHI exposure associates with a multicellular response in young individuals (<51 years old) prior to the onset of CTE p-tau pathology that correlates with number of years of RHI exposure. Leveraging single nucleus RNA sequencing of tissue from 8 control, 9 RHI-exposed, and 11 low stage CTE individuals, we identify SPP1+ inflammatory microglia, angiogenic and inflamed endothelial cell profiles, reactive astrocytes, and altered synaptic gene expression in excitatory and inhibitory neurons in all individuals with exposure to RHI. Surprisingly, we also observe a significant loss of cortical sulcus layer 2/3 neurons in contact sport athletes compared to controls independent of p-tau pathology. Finally, we identify TGFB1 as a potential signal mediating microglia-endothelial cell cross talk through ligand-receptor analysis. These results provide robust evidence that multiple years of RHI exposure is sufficient to induce lasting cellular alterations that may underlie p-tau deposition and help explain the early pathogenesis in young former contact sport athletes. Furthermore, these data identify specific cellular responses to repetitive head impacts that may direct future identification of diagnostic and therapeutic strategies for CTE.

The traditional semiquantitative (SQ) scoring system for neuropathologic assessment, although widely used, is prone to variability among assessors and does not capture the full spectrum of pathological changes. To address these limitations, digital pathology-based strategies like positive pixel quantitation or advanced artificial intelligence (AI) techniques have been developed. However, a comprehensive comparison of these measures has never been performed. Using 1412 cases from Boston University brain banks, human-driven SQ scoring was compared with computer-driven percent area-stained measures and AI-driven cellular density quantitation of tau pathology in the dorsolateral frontal cortex. When comparing each measure directly in all cases, we observed general agreement between measures. Because the full dataset included a large range of different neuropathologies, to reduce noise we performed a subanalysis in cases with the neurodegenerative disease chronic traumatic encephalopathy (CTE) and examined correlations with clinical and neuropathologic variables. While all methods demonstrated significant ability to predict CTE neuropathology, inconsistent background, noncellular elements, and artifacts increased variability for the positive pixel method. Thus, the AI-driven method was better at identifying pathological changes associated with sparse pathology. Overall, our results demonstrate important differences among neuropathologic assessment techniques and highlight the need for careful consideration when selecting analysis methods.

This work explores the combination of liquid xenon as a scintillating medium and silicon photomultipliers as a readout in Positron Emission Tomography (PET) for enhanced Time-Of-Flight resolution. We present the results of our first prototype optimized to maximize light collection using high photodetection efficiency (PDE), VUV-sensitive sensors and to minimize time fluctuations. We report a coincidence time resolution of 281±2 ps FWHM, obtained using a Na22 calibration source. This result is competitive with the current state-of-the-art PET scanners and represents a significant step forward in the development of liquid xenon as a viable alternative to conventional scintillators in PET technology.

The cerebrovasculature is responsible for supplying oxygenated blood and nutrients to the brain and removing neurotoxic buildup. With age, trauma, and disease, the structural constituents of cerebral arteries including the extracellular matrix and smooth muscle cells are subject to remodeling and degradation. Cerebrovascular dysfunction can have detrimental impacts on the brain and is closely associated with cognitive impairment. Clinical studies have found that cerebrovascular dysfunction is correlated with cognitive decline in neurodegenerative diseases including Alzheimer’s disease (AD) and chronic traumatic encephalopathy (CTE). However, cerebrovascular changes during the progression of neurological disorders remain to be understood. Using matched and parallel studies of cerebrovasculature and brain tissue, this study set out to determine the temporal development of cerebrovascular remodeling and neurodegenerative disease progression. We examined changes to human anterior cerebral arteries (ACAs) from subjects with various degrees of AD and CTE neuropathology. Using biaxial inflation-extension testing, histological staining, and multiphoton imaging, we examined changes to the mechanical response and to the ACA wall structure. We found circumferential stiffening of the ACA with age. Furthermore, a minor relationship was reported between ACA stiffening and elevated levels of tau-based neuropathologies including neurofibrillary tangles, characteristic of both AD and CTE. Histological and multiphoton structural studies of the ACAs revealed smooth muscle cell atrophy at the media-adventitia interface and disorganization and straightening of adventitial collagen with age and disease. Our study reveals changes to the extracellular and cellular components of cerebral arteries that help describe the functional alterations of cerebrovasculature. Results from this study shed light on the complex relationship between cerebrovascular remodeling and neurodegenerative disease progression.

Repetitive head impacts (RHIs) sustained from contact sports are the largest risk factor for chronic traumatic encephalopathy (CTE)1-4. Currently, CTE can only be diagnosed after death and the events that trigger initial hyperphosphorylated tau (p-tau) deposition remain unclear2. Furthermore, the symptoms endorsed by young individuals are not fully explained by the extent of p-tau deposition2, severely hampering therapeutic interventions. Here we observed a multicellular response prior to the onset of CTE p-tau pathology that correlates with number of years of RHI exposure in young people (less than 51 years of age) with RHI exposure, the majority of whom played American football. Leveraging single-nucleus RNA sequencing of tissue from 8 control individuals, 9 RHI-exposed individuals and 11 individuals with low-stage CTE, we identify SPP1-expressing inflammatory microglia, angiogenic and inflamed endothelial cells, astrocytosis and altered synaptic gene expression in those exposed to RHI. We also observe a significant loss of cortical sulcus layer 2/3 neurons independent of p-tau pathology. Finally, we identify TGFβ1 as a potential signal that mediates microglia-endothelial cell cross talk. These results provide robust evidence that multiple years of RHI is sufficient to induce lasting cellular alterations that may underlie p-tau deposition and help explain the early pathogenesis in young former contact sport athletes. Furthermore, these data identify specific cellular responses to RHI that may direct future identification of diagnostic and therapeutic strategies for CTE.

Chronic traumatic encephalopathy (CTE) is a neurodegenerative tauopathy associated with repetitive head impact (RHI) exposure. Genetic variation in the 17q21.31 region, containing microtubule-associated protein tau (MAPT), has been implicated in tauopathies but has not been investigated in CTE. The region includes a megabase-long inversion (H1/H2) and copy-number variations, including α, β, and γ segments, which can be characterized as nine segregating structural haplotypes. We leveraged array SNP data and a reference panel across the 17q21.31 region to impute structural haplotypes and test their association with CTE endophenotypes in 447 European ancestry brain donors with RHI exposure. The H1β1γ1 haplotype was significantly associated with dementia and semi-quantitative tau burden in multiple cortical and medial temporal regions commonly affected in CTE. H1β1γ1 differential expression analyses in dorsolateral frontal cortex implicated cis-acting genes and inflammatory pathways. Taken together, the H1β1γ1 haplotype may help explain CTE heterogeneity among those with similar RHI exposure.

The molecular pathology of stress-related disorders remains elusive. Our brain multiregion, multiomic study of posttraumatic stress disorder (PTSD) and major depressive disorder (MDD) included the central nucleus of the amygdala, hippocampal dentate gyrus, and medial prefrontal cortex (mPFC). Genes and exons within the mPFC carried most disease signals replicated across two independent cohorts. Pathways pointed to immune function, neuronal and synaptic regulation, and stress hormones. Multiomic factor and gene network analyses provided the underlying genomic structure. Single nucleus RNA sequencing in dorsolateral PFC revealed dysregulated (stress-related) signals in neuronal and non-neuronal cell types. Analyses of brain-blood intersections in >50,000 UK Biobank participants were conducted along with fine-mapping of the results of PTSD and MDD genome-wide association studies to distinguish risk from disease processes. Our data suggest shared and distinct molecular pathology in both disorders and propose potential therapeutic targets and biomarkers.

Postmortem human brain tissue is a critical resource for studying neurodegenerative disease, providing critical insights into cellular morphology, pathology, and network connectivity. To improve standard microscopy and enable high-resolution, three-dimensional (3D) images of tissues at the subcellular level, tissue-clearing methods have been developed. These 3D images allow for the analysis of large regions of interest and can be used to study structural and spatial changes that occur during neurodegeneration. Additionally, 3D imaging facilitates the visualization of whole-cell morphology, especially in cells with long processes that would otherwise be truncated in single-plane images. Human brain tissue is especially challenging for tissue clearing due to the abundance of lipids in myelin and the need for optimal fixation and low postmortem intervals. Formaldehyde-based fixatives, commonly used in preserving tissue, hinder antibody binding by crosslinking important antibody epitopes, and fluorescent microscopy requires the incorporation of fluorescent labels through passive diffusion or electrophoresis. Recent studies have focused on optimally fixed human brain tissue with short postmortem intervals, limiting the general applicability of these methods. To address these challenges, we developed SHARD (SHIELD, antigen retrieval, and delipidation), a simple and widely applicable method for clearing and labeling human brain tissue, which can be applied to long-term banked human brain tissue preserved in formaldehyde. SHARD is a novel addition to the SHIELD tissue clarification method, combining antigen retrieval, tissue clearing, and staining of 200-μm sections from long-term banked human brain tissue. The SHARD method is effective for postmortem intervals (PMIs) ranging from 10 to 72 h in multiple neurodegenerative diseases and control samples. In this study, we demonstrate that the SHARD method significantly enhances the immunostaining of glial fibrillary acidic protein (GFAP), an astrocytic cytoskeletal marker. Overall, the combination of antigen retrieval and tissue delipidation holds great potential for achieving detailed 3D immunostaining in long-term formaldehyde-fixed postmortem human brain tissue, opening new avenues for research and discovery.

ImportanceChronic traumatic encephalopathy (CTE) is a neurodegenerative tauopathy associated with repetitive head impacts (RHIs). Prior research suggests a dose-response association between American football play duration and CTE risk and severity, but this association has not been studied for ice hockey. ObjectiveTo investigate associations of duration of ice hockey play with CTE diagnosis and severity, functional status, and dementia. Design, Setting, and ParticipantsThis cross-sectional study was conducted among male brain donors in the Understanding Neurological Injury and Traumatic Encephalopathy and Framingham Heart Study Brain Banks whose primary RHI exposure was from ice hockey. Donors died, brains were donated, and data were collected between July 1997 and January 2023. Data analysis was conducted from January 2023 to May 2024. ExposuresIce hockey years played as an RHI proxy. Main Outcomes and MeasuresCTE neuropathological diagnosis, cumulative phosphorylated tau (ptau) burden across 11 brain regions commonly affected in CTE, informant-reported Functional Activities Questionnaire (FAQ) score at death, and consensus dementia diagnosis were assessed. ResultsAmong 77 male donors (median [IQR] age, 51 [33-73] years), 42 individuals (54.5%) had CTE, including 27 of 28 professional players (96.4%). CTE was found in 5 of 26 donors (19.2%) who played fewer than 13 years, 14 of 27 donors (51.9%) who played 13 to 23 years, and 23 of 24 donors (95.8%) who played more than 23 years of hockey. Increased years played was associated with increased odds for CTE (odds ratio [OR] per 1-year increase, 1.34; 95% CI, 1.15-1.55; P < .001) and with increased ptau burden (SD increase per 1-year increase = 0.037; 95% CI, 0.017-0.057; P < .001) after adjusting for age at death, other contact sports played, age of first hockey exposure, concussion count, and hockey position. Simulation demonstrated that years played remained associated with CTE when years played and CTE were both associated with brain bank selection across widely ranging scenarios (median [full range] OR across all simulations, 1.34 [1.29-1.40]). Increased ptau burden was associated with FAQ score (beta standardized = 0.045; 95% CI, 0.021-0.070; P < .001) and dementia (OR per SD increase, 1.12; 95% CI, 1.01-1.26; P = .04) after adjusting for age at death, other contact sports played, hockey years played, enforcer status, age of first hockey exposure, concussion count, and hockey position. Conclusions and RelevanceIn this study of male former ice hockey players, a dose-response association was observed between hockey years played and risk and severity of CTE. Simulation suggested that brain bank selection may not bias the magnitude of outcomes in the association.

Abstract The NEXT-White detector, a high-pressure gaseous xenon time projection chamber, demonstrated the excellence of this technology for future neutrinoless double beta decay searches using photomultiplier tubes (PMTs) to measure energy and silicon photomultipliers (SiPMs) to extract topology information. This analysis uses 83mKr data from the NEXT-White detector to measure and understand the energy resolution that can be obtained with the SiPMs, rather than with PMTs. The energy resolution obtained of (10.9 ± 0.6)%, full-width half-maximum, is slightly larger than predicted based on the photon statistics resulting from very low light detection coverage of the SiPM plane in the NEXT-White detector. The difference in the predicted and measured resolution is attributed to poor corrections, which are expected to be improved with larger statistics. Furthermore, the noise of the SiPMs is shown to not be a dominant factor in the energy resolution and may be negligible when noise subtraction is applied appropriately, for high-energy events or larger SiPM coverage detectors. These results, which are extrapolated to estimate the response of large coverage SiPM planes, are promising for the development of future, SiPM-only, readout planes that can offer imaging and achieve similar energy resolution to that previously demonstrated with PMTs.

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.

Abstract 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 ( $$\beta$$ β standardized = 0.02, 95%CI = 0.01–0.04), CDS ( $$\beta$$ β standardized = 0.02, 95%CI = 0.01–0.04), and FAQ ( $$\beta$$ β 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 ( $$\beta$$ β sstandardized = 0.17–0.29, ps < 0.01) and FAQ ( $$\beta$$ β sstandardized = 0.21–0.26, ps < 0.01); frontal and inferior parietal cortex was associated with higher MI ( $$\beta$$ β sstandardized = 0.21–0.29, ps < 0.05); frontal cortex was associated with higher BRI ( $$\beta$$ β 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.

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

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.

Abstract Noble element time projection chambers are a leading technology for rare event detection in physics, such as for dark matter and neutrinoless double beta decay searches. Time projection chambers typically assign event position in the drift direction using the relative timing of prompt scintillation and delayed charge collection signals, allowing for reconstruction of an absolute position in the drift direction. In this paper, alternate methods for assigning event drift distance via quantification of electron diffusion in a pure high pressure xenon gas time projection chamber are explored. Data from the NEXT-White detector demonstrate the ability to achieve good position assignment accuracy for both high- and low-energy events. Using point-like energy deposits from $$^{83\textrm{m}}$$ 83 m Kr calibration electron captures ( $$E\sim 45$$ E ∼ 45 keV), the position of origin of low-energy events is determined to 2 cm precision with bias $$< 1~$$ < 1 mm. A convolutional neural network approach is then used to quantify diffusion for longer tracks ( $$E\ge ~1.5$$ E ≥ 1.5 MeV), from radiogenic electrons, yielding a precision of 3 cm on the event barycenter. The precision achieved with these methods indicates the feasibility energy calibrations of better than 1% FWHM at Q $$_{\beta \beta }$$ β β in pure xenon, as well as the potential for event fiducialization in large future detectors using an alternate method that does not rely on primary scintillation.