About

Rephael Stern is a faculty member at Boston University School of Law. The provided page text does not include specific details about his research focus, background, or key contributions. Therefore, a detailed biography cannot be extracted from the available information.

Research topics

• Medicine
• Psychology
• Psychiatry
• Internal medicine
• Pathology
• Biology
• Neuroscience
• Bioinformatics
• Genetics
• Pediatrics
• Political Science
• Audiology
• Oncology
• Physical therapy
• Nuclear medicine
• Gerontology
• Surgery
• Medical emergency
• Chemistry
• Emergency medicine
• Physical medicine and rehabilitation
• Clinical psychology

Selected publications

• A Video series to explain the Crust and Sedimentary Basins beneath the United States: A progress report

  Abstracts with programs - Geological Society of America · 2025-01-01

  article
  PublisherDOI

• Sex differences on tau, astrocytic, and neurodegenerative plasma biomarkers

  Journal of Alzheimer s Disease · 2025-03-28 · 11 citations

  articleOpen access

  Background Sex differences have consistently been identified on autopsy, neuroimaging, and cerebrospinal fluid outcomes related to Alzheimer's disease (AD), but the exact mechanisms for these associations are unclear. Blood-based biomarkers are practical alternatives for the investigation of mechanisms of AD, in addition to accurate disease detection and monitoring. Objective The objective of this study was to examine sex differences across a panel of blood-based plasma biomarkers in participants with and without cognitive impairment due to AD. Methods Plasma samples were collected from 567 participants from across the AD diagnostic continuum (i.e., normal cognition (NC), mild cognitive impairment (MCI), and dementia) and analyzed for glial fibrillary acidic protein (GFAP), neurofilament light (NfL), phosphorylated tau at threonine 181 (p-tau 181 ), and total tau (t-tau). Baseline and longitudinal analyses evaluated for any significant associations between sex and AD-related plasma biomarkers. Results Females were found to have higher plasma GFAP compared to males at baseline regardless of cognitive diagnosis. Among those with AD dementia, females were also found to have higher NfL levels compared to males. Longitudinal analyses found that higher plasma NfL at baseline was associated with an increased risk of worsening AD dementia status only in females. No significant findings were observed for p-tau 181 or t-tau. Conclusions This study found significant sex differences in plasma biomarkers of GFAP and NfL. Further research is needed to better understand the underlying mechanisms mediating these differences.

  PublisherOA PDFDOI

• 18F-MK-6240 tau PET in patients at-risk for chronic traumatic encephalopathy

  Molecular Neurodegeneration · 2025-02-25 · 4 citations

  articleOpen access

  Abstract Background Molecular biomarkers of chronic traumatic encephalopathy (CTE) are lacking. We evaluated 18 F-MK-6240 tau PET as a biomarker for CTE. Two studies were done: (1) 3 H-MK-6240 autoradiography and an in-vitro brain homogenate binding studies on postmortem CTE tissue, (2) an in-vivo 18 F-MK-6240 tau PET study in former American football players. Methods Autoradiography and in-vitro binding studies were done using 3 H-MK-6240 on frozen temporal and frontal cortex tissue from six autopsy cases with stage III CTE compared to Alzheimer’s disease. Thirty male former National Football League (NFL) players with cognitive concerns (mean age = 58.9, SD = 7.8) completed tau ( 18 F-MK-6240) and Aβ ( 18 F-Florbetapir) PET. Controls included 39 Aβ-PET negative, cognitively normal males (mean age = 65.7, SD = 6.3). 18 F-MK-6240 SUVr images were created using 70–90 min post-injection data with inferior cerebellar gray matter as the reference. We compared SUVr between players and controls using voxelwise and region-of-interest approaches. Correlations between 18 F-MK-6240 SUVr and cognitive scores were tested. Results All six CTE stage III cases had Braak NFT stage III but no neuritic plaques. Two had Thal Phase 1 for Aβ; one showed a laminar pattern of 3 H-MK-6240 autoradiography binding in the superior temporal cortex and less so in the dorsolateral frontal cortex, corresponding to tau-immunoreactive lesions detected using the AT8 antibody (pSer202/pThr205 tau) in adjacent tissue sections. The other CTE cases had low frequencies of cortical tau-immunoreactive deposits and no well-defined autoradiography binding. In-vitro 3 H-MK-6240 binding studies to CTE brain homogenates in the case with autoradiography signal indicated high binding affinity (K D = 2.0 ± 0.9 nM, B max = 97 ± 24 nM, n = 3). All NFL players had negative Aβ-PET. There was variable, low-to-intermediate intensity 18 F-MK-6240 uptake across participants: 16 had no cortical signal, 7 had medial temporal lobe (MTL) uptake, 2 had frontal uptake, and 4 had MTL and frontal uptake. NFL players had higher SUVr in the entorhinal cortex (d = 0.86, p = 0.001), and the parahippocampal gyrus (d = 0.39, p = 0.08). Voxelwise regressions showed increased uptake in NFL players in two bilateral anterior MTL clusters ( p < 0.05 FWE). Higher parahippocampal and frontal–temporal SUVrs correlated with worse memory ( r = -0.38, r = -0.40) and semantic fluency ( r = -0.38, r = -0.48), respectively. Conclusion We present evidence of 3 H-MK-6240 in-vitro binding to post-mortem CTE tissue homogenates and in vivo 18 F-MK-6240 PET binding in the MTL among a subset of participants. Additional studies in larger samples and PET-to-autopsy correlations are required to further elucidate the potential of 18 F-MK-6240 to detect tau pathology in CTE.

  PublisherOA PDFDOI

• Catecholamine Dysregulation in Former American Football Players

  Neurology · 2025-04-21 · 2 citations

  articleOpen accessSenior author

  BACKGROUND AND OBJECTIVES: Disturbances in brain catecholamine activity may be associated with symptoms after exposure to repetitive head impacts (RHIs) or related chronic traumatic encephalopathy (CTE). In this article, we studied CSF catecholamines in former professional and college American football players and examined the relationship with football proxies of RHI exposure, CTE probability, cognitive performance, neuropsychiatric symptoms, and parkinsonism. METHODS: In this observational cross-sectional study, we examined male former American football players, professional ("PRO") or college ("COL") level, and asymptomatic unexposed male ("UE") individuals from the DIAGNOSE CTE Research Project. Catecholamines-norepinephrine (NE) and its metabolite, 3,4-dihydroxyphenylglycol (DHPG), and dopamine (DA) and its precursor, 3,4-dihydroxyphenylalanine (l-DOPA), and metabolite, 3,4-dihydroxyphenylacetic acid (DOPAC)-were measured in CSF with high-performance liquid chromatography and compared across groups with analysis of covariance. Multivariable linear regression models tested the relationship between CSF catecholamines and proxies of RHI exposure (e.g., total years of playing American football), factor scores for cognition, and neurobehavioral dysregulation (explosivity, emotional dyscontrol, impulsivity, affective lability), as well as depressive/anxiety symptoms, measured with the Beck Depression/Anxiety Inventories. CTE probability and parkinsonism were assessed using the National Institute of Neurological Disorders and Stroke consensus diagnostic criteria for traumatic encephalopathy syndrome (TES), and biomarkers were compared among different diagnostic groups. RESULTS: The cohort consisted of 120 former American football players (85 PRO players, 35 COL players) and 35 UE participants (age 45-75). Former players had significantly lower levels of NE (mean difference = -0.114, 95% CI -0.190 to -0.038), l-DOPA (-0.121, 95% CI -0.109 to -0.027), and DOPAC (-0.116, 95% CI -0.177 to -0.054) than UE participants. For NE and DOPAC, these overall group differences were primarily due to differences between the PRO and UE cohorts. No significant differences were found across TES-CTE probability subgroups or TES-parkinsonism diagnostic groups. Within the COL cohort, tested as post hoc analyses, higher CSF NE and l-DOPA were associated with higher neurobehavioral dysregulation factor scores, BAI total score, and worse executive functioning and processing speed. CSF DHPG and DOPAC were associated with impulsivity only in this subgroup. DISCUSSION: We observed reduced CSF catecholamine concentrations in former elite American football players, although the relationship with degree of RHI exposure and the clinical impact needs further study.

  PublisherDOI

• A structural haplotype in the 17q21.31 MAPT region is associated with increased risk for chronic traumatic encephalopathy endophenotypes

  Cell Reports Medicine · 2025-04-15 · 3 citations

  articleOpen access

  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. • 17q21.31 structural haplotypes include a 1 Mb inversion (H) and duplications (α, β, γ) • H1β1γ1 was associated with CTE neuropathological and clinical endophenotypes • Among football players, H1β1γ1 effect was similar to effect of playing 9.6 years • In DGE analysis, H1β1γ1 showed up-regulation of immune-related genes and pathways Han et al. identify H1β1γ1, a structural haplotype in the 17q21.31 region that contains MAPT , as a genetic risk factor for CTE neuropathological and clinical endophenotypes. H1β1γ1 DGE analyses in the dorsolateral frontal cortex implicate cis -acting genes and inflammatory pathways. H1β1γ1 may help explain CTE risk beyond repetitive head impact exposure.

  PublisherDOI

• Chronic traumatic encephalopathy: State-of-the-science update and narrative review

  The Clinical Neuropsychologist · 2025-01-20 · 3 citations

  reviewOpen access

  OBJECTIVE: The long-recognized association of brain injury with increased risk of dementia has undergone significant refinement and more detailed study in recent decades. Chronic traumatic encephalopathy (CTE) is a specific neurodegenerative tauopathy related to prior exposure to repetitive head impacts (RHI). We aim to contextualize CTE within a historical perspective and among emerging data which highlights the scientific and conceptual evolution of CTE-related research in parallel with the broader field of neurodegenerative disease and dementia. METHODS: We provide a narrative state-of-the-science update on CTE neuropathology, clinical manifestations, biomarkers, different types and patterns of head impact exposure relevant for CTE, and the complicated influence of neurodegenerative co-pathology on symptoms. CONCLUSIONS: Now almost 20 years since the initial case report of CTE in a former American football player, the field of CTE continues evolving with increasing clarity but also several ongoing controversies. Our understanding of CTE neuropathology outpaces that of disease-specific clinical correlates or the development of in-vivo biomarkers. Diagnostic criteria for symptoms attributable to CTE are still being validated, but leveraging increasingly available biomarkers for other conditions like Alzheimer's disease may be helpful for informing the CTE differential diagnosis. As diagnostic refinement efforts advance, clinicians should provide care and/or referrals to providers best suited to treat an individual patient's clinical symptoms, many of which have evidence-based behavioral treatment options that are etiologically agnostic. Several ongoing research initiatives and the gradual accrual of gold standard clinico-pathological data will pay dividends for advancing the many existing gaps in the field of CTE.

  PublisherOA PDFDOI

• 116. CANNABIS AND AGING: THE IMPLICATIONS OF LEGALIZATION FOR OLDER ADULTS

  American Journal of Geriatric Psychiatry · 2025-07-15 · 1 citations

  article
  PublisherDOI

• Dispersion-based cognitive intra-individual variability in former American football players: Association with traumatic encephalopathy syndrome, repetitive head impacts, and biomarkers

  The Clinical Neuropsychologist · 2025-01-26 · 3 citations

  articleOpen access

  d-CIIV is linked to RHI exposure and TES diagnosis in former football players, with associated changes in CSF biomarkers and white matter integrity.

  PublisherOA PDFDOI

• Shape analysis of the amygdala, hippocampus and thalamus in former American football players

  Brain Communications · 2025-01-01 · 1 citations

  articleOpen access

  Abstract Repetitive head impacts are common in contact and collision sports and are linked to structural brain changes and an elevated risk of neurodegenerative diseases such as Chronic Traumatic Encephalopathy. Identifying early in vivo structural markers remains challenging. Although diagnosis currently requires post-mortem confirmation, clinical symptoms, including cognitive impairment and behavioural changes, are reflected in the diagnosis of Traumatic Encephalopathy Syndrome. These symptoms align with dysfunction in key brain regions—amygdala, hippocampus and thalamus—which support memory, emotion and behaviour and commonly show tau pathology in Chronic Traumatic Encephalopathy. This study uses shape analysis to examine structural differences in these regions between former American football players and unexposed asymptomatic controls and evaluates the influence of age, head impact exposure and clinical diagnosis on brain structure. We analyzed brain morphology in former American football players (n = 163) and unexposed, asymptomatic controls (n = 53). Structural segmentation was performed with FreeSurfer 7.1, and the shape analysis pipeline was used to generate subregional reconstructions. Vertex-level morphometry, based on the logarithm of the Jacobian determinant and radial distance, quantified local surface area dilation and thickness. Group differences were examined with covariate-adjusted linear regression models contrasting football players and controls, as well as participants with and without a Traumatic Encephalopathy Syndrome diagnosis. Partial correlations examined the influence of age, age of first football exposure and cumulative head impact index metrics, including frequency, linear acceleration and rotational force. Models were adjusted accordingly for age, body mass index, education, race, imaging site, apolipoprotein ϵ4 status and total intracranial volume. Former football players exhibited bilateral surface area contractions in the hippocampus and amygdala, along with reduced amygdala thickness, compared to controls. Older age was associated with widespread surface contractions and thinning across all regions, except for preserved thickness in the left hippocampus. An earlier age of first exposure to football correlated with surface contractions in the thalamus and left hippocampus. Greater cumulative linear acceleration was linked to bilateral hippocampal surface contractions and reduced thickness in the left thalamus, while greater rotational force exposure was associated with hippocampal thinning. No significant structural differences were found between players with and without a diagnosis of Traumatic Encephalopathy Syndrome. These findings extend volume-based research by revealing localized alterations in surface area dilation and thickness and emphasize the roles of age and repetitive head impact exposure in long-term brain changes.

  PublisherDOI

• Sulcal morphology in former American football players

  Brain Communications · 2025-01-01 · 2 citations

  articleOpen access

  Abstract Repetitive head impacts are associated with structural brain changes and an increased risk for chronic traumatic encephalopathy, a progressive neurodegenerative disease that can only be diagnosed after death. Chronic traumatic encephalopathy is defined by the abnormal accumulation of phosphorylated tau protein, particularly at the depths of the superior frontal sulci, suggesting that sulcal morphology may serve as a relevant structural biomarker. Contact sport athletes, such as former football players, are at elevated risk due to their prolonged exposure to repetitive head impacts. Cortical atrophy linked to underlying tau accumulation may result in shallower and wider sulci, potentially making sulcal morphology an imaging marker for identifying individuals at risk for this disease. This study investigated sulcal morphological differences in former football players and examined associations with age, football-related exposure, clinical diagnosis of traumatic encephalopathy syndrome, levels of certainty for chronic traumatic encephalopathy pathology, neuropsychological performance, and positron emission tomography imaging using flortaucipir. We analysed structural magnetic resonance imaging data from 169 male former football players (mean age 57.2 (8.2) years, range 45–74) and 54 age-matched, unexposed asymptomatic male controls (mean age 59.4 (8.5) years, range 45–74). Sulcal depth and width were quantified using the CalcSulc, focusing on two regions in each hemisphere commonly affected by chronic traumatic encephalopathy pathology: the superior frontal and occipitotemporal sulci. Generalized least squares models were used to assess group differences and interactions with age and football exposure variables, including age of first exposure, total years played, and cumulative head impact exposure. An analysis of covariance evaluated relationships between sulcal morphology, clinical measures, and flortaucipir uptake, adjusting for age, race, body mass index, education, imaging site, apolipoprotein E4 status, and total intracranial volume. Former football players demonstrated significantly shallower sulcal depth in the left superior frontal sulcus compared to unexposed controls. Earlier age of first exposure and longer football careers were associated with greater widening of the left occipitotemporal sulcus. Higher cumulative head impact exposure was linked to reduced sulcal depth in the left superior frontal region. However, sulcal morphology was not associated with clinical diagnosis, levels of certainty, neuropsychological test performance, or flortaucipir imaging. These findings suggest that sulcal morphology may reflect cumulative exposure to repetitive head impacts, particularly in brain regions vulnerable to chronic traumatic encephalopathy pathology. Future ante- and post-mortem validation studies are needed to determine whether sulcal morphology can serve as a reliable in vivo biomarker of risk.

  PublisherDOI

Recent grants

• NIH Grant R56NS078337

  NIH · $786k · 2016

• Chronic Traumatic Encephalopathy: Detection, Diagnosis, Course, and Risk Factors

  NIH · $17.0M · 2015–2023

• NIH Grant P50MH033127

  NIH · $1.5M · 1997

• NIH Grant R01MH080295

  NIH · $3.1M · 2014

• NIH Grant R01GM046765

  NIH · $762k · 1997

Frequent coauthors

• Keith A. Johnson

  Massachusetts General Hospital

  771 shared

• D. Cheng

  567 shared

• Joseph C. Wu

  486 shared

• Steven E. Arnold

  Harvard University

  422 shared

• Marcelo F. Di Carli

  Harvard University

  405 shared

• Carl K. Hoh

  University of California, San Diego

  405 shared

• Monte S. Buchsbaum

  University of California, Irvine

  405 shared

• Andrew J. Saykin

  Indiana University

  404 shared

Labs

• Rephael Stern LabPI