Publications by authors named "Yorghos Tripodis"

120 Publications

Exposure to Repetitive Head Impacts Is Associated With Corpus Callosum Microstructure and Plasma Total Tau in Former Professional American Football Players.

J Magn Reson Imaging 2021 Jun 16. Epub 2021 Jun 16.

Psychiatry Neuroimaging Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

Background: Exposure to repetitive head impacts (RHI) is associated with an increased risk of later-life neurobehavioral dysregulation and neurodegenerative disease. The underlying pathomechanisms are largely unknown.

Purpose: To investigate whether RHI exposure is associated with later-life corpus callosum (CC) microstructure and whether CC microstructure is associated with plasma total tau and neuropsychological/neuropsychiatric functioning.

Study Type: Retrospective cohort study.

Population: Seventy-five former professional American football players (age 55.2 ± 8.0 years) with cognitive, behavioral, and mood symptoms.

Field Strength/sequence: Diffusion-weighted echo-planar MRI at 3 T.

Assessment: Subjects underwent diffusion MRI, venous puncture, neuropsychological testing, and completed self-report measures of neurobehavioral dysregulation. RHI exposure was assessed using the Cumulative Head Impact Index (CHII). Diffusion MRI measures of CC microstructure (i.e., free-water corrected fractional anisotropy (FA), trace, radial diffusivity (RD), and axial diffusivity (AD)) were extracted from seven segments of the CC (CC1-7), using a tractography clustering algorithm. Neuropsychological tests were selected: Trail Making Test Part A (TMT-A) and Part B (TMT-B), Controlled Oral Word Association Test (COWAT), Stroop Interference Test, and the Behavioral Regulation Index (BRI) from the Behavior Rating Inventory of Executive Function, Adult version (BRIEF-A).

Statistical Tests: Diffusion MRI metrics were tested for associations with RHI exposure, plasma total tau, neuropsychological performance, and neurobehavioral dysregulation using generalized linear models for repeated measures.

Results: RHI exposure was associated with increased AD of CC1 (correlation coefficient (r) = 0.32, P < 0.05) and with increased plasma total tau (r = 0.34, P < 0.05). AD of the anterior CC1 was associated with increased plasma total tau (CC1: r = 0.30, P < 0.05; CC2: r = 0.29, P < 0.05). Higher trace, AD, and RD of CC1 were associated with better performance (P < 0.05) in TMT-A (trace, r = 0.33; AD, r = 0.31; and RD, r = 0.28) and TMT-B (trace, r = 0.31; RD, r = 0.34). Higher FA and AD of CC2 were associated with better performance (P < 0.05) in TMT-A (FA, r = 0.36; AD, r = 0.28), TMT-B (FA, r = 0.36; AD, r = 0.27), COWAT (FA, r = 0.36; AD, r = 0.32), and BRI (AD, r = 0.29).

Data Conclusion: These results suggest an association among RHI exposure, CC microstructure, plasma total tau, and clinical functioning in former professional American football players.

Level Of Evidence:  3 Technical Efficacy Stage: 1.
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http://dx.doi.org/10.1002/jmri.27774DOI Listing
June 2021

Tau isoforms are differentially expressed across the hippocampus in chronic traumatic encephalopathy and Alzheimer's disease.

Acta Neuropathol Commun 2021 05 12;9(1):86. Epub 2021 May 12.

VA Boston Healthcare System, 150 S. Huntington Ave, Boston, MA, 02130, USA.

Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative disease, characterized by hyperphosphorylated tau, found in individuals with a history of exposure to repetitive head impacts. While the neuropathologic hallmark of CTE is found in the cortex, hippocampal tau has proven to be an important neuropathologic feature to examine the extent of disease severity. However, the hippocampus is also heavily affected in many other tauopathies, such as Alzheimer's disease (AD). How CTE and AD differentially affect the hippocampus is unclear. Using immunofluorescent analysis, a detailed histologic characterization of 3R and 4R tau isoforms and their differential accumulation in the temporal cortex in CTE and AD was performed. CTE and AD were both observed to contain mixed 3R and 4R tau isoforms, with 4R predominating in mild disease and 3R increasing proportionally as pathological severity increased. CTE demonstrated high levels of tau in hippocampal subfields CA2 and CA3 compared to CA1. There were also low levels of tau in the subiculum compared to CA1 in CTE. In contrast, AD had higher levels of tau in CA1 and subiculum compared to CA2/3. Direct comparison of the tau burden between AD and CTE demonstrated that CTE had higher tau densities in CA4 and CA2/3, while AD had elevated tau in the subiculum. Amyloid beta pathology did not contribute to tau isoform levels. Finally, it was demonstrated that higher levels of 3R tau correlated to more severe extracellular tau (ghost tangles) pathology. These findings suggest that mixed 3R/4R tauopathies begin as 4R predominant then transition to 3R predominant as pathological severity increases and ghost tangles develop. Overall, this work demonstrates that the relative deposition of tau isoforms among hippocampal subfields can aid in differential diagnosis of AD and CTE, and might help improve specificity of biomarkers for in vivo diagnosis.
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http://dx.doi.org/10.1186/s40478-021-01189-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8114683PMC
May 2021

Validity of the 2014 traumatic encephalopathy syndrome criteria for CTE pathology.

Alzheimers Dement 2021 Apr 7. Epub 2021 Apr 7.

Boston University Alzheimer's Disease and CTE Centers, Boston University School of Medicine, Boston, Massachusetts, USA.

Introduction: Validity of the 2014 traumatic encephalopathy syndrome (TES) criteria, proposed to diagnose chronic traumatic encephalopathy (CTE) in life, has not been assessed.

Methods: A total of 336 consecutive brain donors exposed to repetitive head impacts from contact sports, military service, and/or physical violence were included. Blinded to clinical information, neuropathologists applied National Institute on Neurological Disorders and Stroke/National Institute of Biomedical Imaging and Bioengineering CTE criteria. Blinded to neuropathological information, clinicians interviewed informants and reviewed medical records. An expert panel adjudicated TES diagnoses.

Results: A total of 309 donors were diagnosed with TES; 244 donors had CTE pathology. TES criteria demonstrated sensitivity and specificity of 0.97 and 0.21, respectively. Cognitive (odds ratio [OR] = 3.6; 95% confidence interval [CI]: 1.2-5.1), but not mood/behavior or motor symptoms, were significantly associated with CTE pathology. Having Alzheimer's disease (AD) pathology was significantly associated with reduced TES accuracy (OR = 0.27; 95% CI: 0.12-0.59).

Discussion: TES criteria provided good evidence to rule out, but limited evidence to rule in, CTE pathology. Requiring cognitive symptoms in revised criteria and using AD biomarkers may improve CTE pathology prediction.
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http://dx.doi.org/10.1002/alz.12338DOI Listing
April 2021

Variation in HIV care and treatment outcomes by facility in South Africa, 2011-2015: A cohort study.

PLoS Med 2021 Mar 31;18(3):e1003479. Epub 2021 Mar 31.

Department of Global Health, Boston University School of Public Health, BA, United States of America.

Background: Despite widespread availability of HIV treatment, patient outcomes differ across facilities. We propose and evaluate an approach to measure quality of HIV care at health facilities in South Africa's national HIV program using routine laboratory data.

Methods And Findings: Data were extracted from South Africa's National Health Laboratory Service (NHLS) Corporate Data Warehouse. All CD4 counts, viral loads (VLs), and other laboratory tests used in HIV monitoring were linked, creating a validated patient identifier. We constructed longitudinal HIV care cascades for all patients in the national HIV program, excluding data from the Western Cape and very small facilities. We then estimated for each facility in each year (2011 to 2015) the following cascade measures identified a priori as reflecting quality of HIV care: median CD4 count among new patients; retention 12 months after presentation; 12-month retention among patients established in care; viral suppression; CD4 recovery; monitoring after an elevated VL. We used factor analysis to identify an underlying measure of quality of care, and we assessed the persistence of this quality measure over time. We then assessed spatiotemporal variation and facility and population predictors in a multivariable regression context. We analyzed data on 3,265 facilities with a median (IQR) annual size of 441 (189 to 988) lab-monitored HIV patients. Retention 12 months after presentation increased from 42% to 47% during the study period, and viral suppression increased from 66% to 79%, although there was substantial variability across facilities. We identified an underlying measure of quality of HIV care that correlated with all cascade measures except median CD4 count at presentation. Averaging across the 5 years of data, this quality score attained a reliability of 0.84. Quality was higher for clinics (versus hospitals), in rural (versus urban) areas, and for larger facilities. Quality was lower in high-poverty areas but was not independently associated with percent Black. Quality increased by 0.49 (95% CI 0.46 to 0.53) standard deviations from 2011 to 2015, and there was evidence of geospatial autocorrelation (p < 0.001). The study's limitations include an inability to fully adjust for underlying patient risk, reliance on laboratory data which do not capture all relevant domains of quality, potential for errors in record linkage, and the omission of Western Cape.

Conclusions: We observed persistent differences in HIV care and treatment outcomes across South African facilities. Targeting low-performing facilities for additional support could reduce overall burden of disease.
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http://dx.doi.org/10.1371/journal.pmed.1003479DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8012100PMC
March 2021

National Institute of Neurological Disorders and Stroke Consensus Diagnostic Criteria for Traumatic Encephalopathy Syndrome.

Neurology 2021 05 15;96(18):848-863. Epub 2021 Mar 15.

From the Boston University CTE Center (D.I.K.), Department of Neurology, Boston University School of Medicine, Boston; Brain Injury Program (D.I.K.), Encompass Health Braintree Rehabilitation Hospital, Braintree, MA; University of Washington Memory & Brain Wellness Clinic (C.B.), Department of Neurology, University of Washington School of Medicine, Seattle; Department of Neurology (D.W.D., C.H.A.), Mayo Clinic, Scottsdale, AZ; Boston University CTE Center (J.M., M.L.A.), Boston University Alzheimer's Disease Center, Department of Neurology, Boston University School of Medicine; Boston University CTE Center (M.L.M.), Boston University School of Medicine, MA; Departments of Neurology (L.J.B.), Ophthalmology, and Population Health, New York University Grossman School of Medicine; Departments of Neurosciences and Psychiatry University of California San Diego (S.J.B.), La Jolla; Departments of Neurology and Psychiatry (W.B.B.), New York University Grossman School of Medicine; Center for Neuroscience and Regenerative Medicine (D.L.B.), Uniformed Services University of the Health Sciences, Department of Neurology, F. Edward Hebert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD; Boston University CTE Center (R.C.C.), Boston University Alzheimer's Disease Center, Departments of Neurology and Neurosurgery, Boston University School of Medicine, MA; Departments of Rehabilitation Medicine and Neurology (K.D.-O.C.), Icahn School of Medicine, Mount Sinai, New York; Department of Neurology (Y.E.G.), Barrow Neurological Institute, Phoenix, AZ; Rancho Los Amigos National Rehabilitation Center (B.D.J.), Downey, CA; Department of Neurology (B.D.J.), Keck School of Medicine of USC. Los Angeles, CA; Departments of Psychiatry and Neurology (T.W.M.), Indiana University School of Medicine, Indianapolis; Veterans Affairs Northwest Mental Illness (E.R.P.), Research, Education, and Clinical Center, VA Puget Sound Health Care System, Seattle, WA; Department of Psychiatry and Behavioral Sciences (E.R.P.), University of Washington School of Medicine, Seattle; Mayo Clinic Alzheimer's Disease Research Center (R.C.P.), Mayo Clinic, Rochester, MN; Department of Psychiatry and Psychology (J.V.W.), Mayo Clinic, Scottsdale, AZ; Department of Physical Medicine and Rehabilitation (R.D.Z.), Spaulding Rehabilitation Hospital, Massachusetts General Hospital, Brigham and Women's Hospital, Harvard Medical School, Boston; Faculty of Psychology and Neuroscience (É.M.F.), Maastricht University, the Netherlands, Department of Psychiatry, University of Cambridge, United Kingdom; National Institute of Neurological Disorders and Stroke (D.J.B.), National Institutes of Health; National Institute of Neurological Disorders and Stroke (W.J.K.), Bethesda, MD; Boston University CTE Center (Y.T.), Boston University Alzheimer's Disease Center, Boston University School of Medicine, Department of Biostatistics, Boston University School of Public Health; Boston University CTE Center (A.C.M.), Boston University Alzheimer's Disease Center, Departments of Neurology and Pathology & Laboratory Medicine, Boston University School of Medicine; VA Boston Healthcare System (A.C.M.), US Department of Veteran Affairs, MA; Psychiatry Neuroimaging Laboratory (M.E.S.), Departments of Psychiatry and Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Chambers-Grundy Center for Transformative Neuroscience (J.L.C.), Department of Brain Health, University of Nevada School of Integrated Health Sciences; Cleveland Clinic Lou Ruvo Center for Brain Health (J.L.C.), Las Vegas, NV; Banner Alzheimer's Institute (E.M.R.), Arizona State University; Department of Psychiatry (E.M.R.), University of Arizona, Phoenix, AZ; and Boston University CTE Center (R.A.S.), Boston University Alzheimer's Disease Center, Departments of Neurology, Neurosurgery, and Anatomy & Neurobiology, Boston University School of Medicine, MA.

Objective: To develop evidence-informed, expert consensus research diagnostic criteria for traumatic encephalopathy syndrome (TES), the clinical disorder associated with neuropathologically diagnosed chronic traumatic encephalopathy (CTE).

Methods: A panel of 20 expert clinician-scientists in neurology, neuropsychology, psychiatry, neurosurgery, and physical medicine and rehabilitation, from 11 academic institutions, participated in a modified Delphi procedure to achieve consensus, initiated at the First National Institute of Neurological Disorders and Stroke Consensus Workshop to Define the Diagnostic Criteria for TES April, 2019. Before consensus, panelists reviewed evidence from all published cases of CTE with neuropathologic confirmation, and they examined the predictive validity data on clinical features in relation to CTE pathology from a large clinicopathologic study (n = 298).

Results: Consensus was achieved in 4 rounds of the Delphi procedure. Diagnosis of TES requires (1) substantial exposure to repetitive head impacts (RHIs) from contact sports, military service, or other causes; (2) core clinical features of cognitive impairment (in episodic memory and/or executive functioning) and/or neurobehavioral dysregulation; (3) a progressive course; and (4) that the clinical features are not fully accounted for by any other neurologic, psychiatric, or medical conditions. For those meeting criteria for TES, functional dependence is graded on 5 levels, ranging from independent to severe dementia. A provisional level of certainty for CTE pathology is determined based on specific RHI exposure thresholds, core clinical features, functional status, and additional supportive features, including delayed onset, motor signs, and psychiatric features.

Conclusions: New consensus diagnostic criteria for TES were developed with a primary goal of facilitating future CTE research. These criteria will be revised as updated clinical and pathologic information and in vivo biomarkers become available.
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http://dx.doi.org/10.1212/WNL.0000000000011850DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8166432PMC
May 2021

Age at First Exposure to Tackle Football is Associated with Cortical Thickness in Former Professional American Football Players.

Cereb Cortex 2021 Jun;31(7):3426-3434

cBRAIN, Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Ludwig-Maximilians-Universität, 80337 Munich, Germany.

Younger age at first exposure (AFE) to repetitive head impacts while playing American football increases the risk for later-life neuropsychological symptoms and brain alterations. However, it is not known whether AFE is associated with cortical thickness in American football players. Sixty-three former professional National Football League players (55.5 ± 7.7 years) with cognitive, behavioral, and mood symptoms underwent neuroimaging and neuropsychological testing. First, the association between cortical thickness and AFE was tested. Second, the relationship between clusters of decreased cortical thickness and verbal and visual memory, and composite measures of mood/behavior and attention/psychomotor speed was assessed. AFE was positively correlated with cortical thickness in the right superior frontal cortex (cluster-wise P value [CWP] = 0.0006), the left parietal cortex (CWP = 0.0003), and the occipital cortices (right: CWP = 0.0023; left: CWP = 0.0008). A positive correlation was found between cortical thickness of the right superior frontal cortex and verbal memory (R = 0.333, P = 0.019), and the right occipital cortex and visual memory (R = 0.360, P = 0.012). In conclusion, our results suggest an association between younger AFE and decreased cortical thickness, which in turn is associated with worse neuropsychological performance. Furthermore, an association between younger AFE and signs of neurodegeneration later in life in symptomatic former American football players seems likely.
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http://dx.doi.org/10.1093/cercor/bhab021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8196248PMC
June 2021

The Second NINDS/NIBIB Consensus Meeting to Define Neuropathological Criteria for the Diagnosis of Chronic Traumatic Encephalopathy.

J Neuropathol Exp Neurol 2021 Feb;80(3):210-219

VA Boston Healthcare System, Boston, Massachusetts.

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disorder associated with exposure to head trauma. In 2015, a panel of neuropathologists funded by the NINDS/NIBIB defined preliminary consensus neuropathological criteria for CTE, including the pathognomonic lesion of CTE as "an accumulation of abnormal hyperphosphorylated tau (p-tau) in neurons and astroglia distributed around small blood vessels at the depths of cortical sulci and in an irregular pattern," based on review of 25 tauopathy cases. In 2016, the consensus panel met again to review and refine the preliminary criteria, with consideration around the minimum threshold for diagnosis and the reproducibility of a proposed pathological staging scheme. Eight neuropathologists evaluated 27 cases of tauopathies (17 CTE cases), blinded to clinical and demographic information. Generalized estimating equation analyses showed a statistically significant association between the raters and CTE diagnosis for both the blinded (OR = 72.11, 95% CI = 19.5-267.0) and unblinded rounds (OR = 256.91, 95% CI = 63.6-1558.6). Based on the challenges in assigning CTE stage, the panel proposed a working protocol including a minimum threshold for CTE diagnosis and an algorithm for the assessment of CTE severity as "Low CTE" or "High CTE" for use in future clinical, pathological, and molecular studies.
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http://dx.doi.org/10.1093/jnen/nlab001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7899277PMC
February 2021

Does Parental Report of Having a Medical Home Attenuate the Negative Association Between Unmet Basic Needs and Health for Low-Income Children?

Glob Pediatr Health 2020 28;7:2333794X20985805. Epub 2020 Dec 28.

Boston University School of Medicine, Boston Medical Center, Boston, MA, USA.

It is unknown whether the medical home reduces the impact of adverse social determinants on low-income child health. To examine whether the medical home attenuates the association between unmet basic needs and health for low-income children. . Secondary data analysis of the 2011-12 NSCH restricted to <200% FPL children (n = 26 974). Multivariable logistic regression modeled child health with unmet basic needs to examine the effect modification of the medical home. Low-income children with unmet needs had lower odds of "excellent/very good" health compared to children without unmet needs, regardless of the medical home [aOR = 0.78 (0.61-0.99) vs aOR = 0.77 (0.63-0.94),  = .01), respectively]. The medical home did not modify the negative association between unmet basic needs and "excellent/very good" child health ( = .97). . Having a medical home per parental report did not attenuate the negative relationship between unmet basic needs and lowincome child health.
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http://dx.doi.org/10.1177/2333794X20985805DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7783885PMC
December 2020

Evaluating the validity of self-report as a method for quantifying heading exposure in male youth soccer.

Res Sports Med 2020 Dec 6:1-13. Epub 2020 Dec 6.

cBRAIN, Department of Child and Adolescent Psychiatry, Psychosomatic, and Psychotherapy, Ludwig-Maximilian-University, Munich, Germany.

Assessing heading exposure in football is important when exploring the association between heading and brain alterations. To this end, questionnaires have been developed for use in adult populations. However, the validity of self-report in adolescents remains to be elucidated. Male youth soccer players (n = 34) completed a questionnaire on heading exposure after a two-week period, which included matches and training sessions. Self-reported numbers were compared to observation (considered reference). In total, we observed 157 training sessions and 64 matches. Self-reported heading exposure correlated with observed heading exposure (Spearman's rho 0.68; p < 0.001). Players systematically overestimated their heading exposure by a factor of 3 with the random error of 46%. Area under the curve was 0.87 (95% CI 0.67-1) utilizing self-report for identifying players from high- and low-exposure groups. Thus, in this study, self-reported data could be used to group youth players into high and low heading exposure groups, but not to quantify individual heading exposure.
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http://dx.doi.org/10.1080/15438627.2020.1853541DOI Listing
December 2020

CCL2 is associated with microglia and macrophage recruitment in chronic traumatic encephalopathy.

J Neuroinflammation 2020 Dec 5;17(1):370. Epub 2020 Dec 5.

Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, MA, USA.

Background: Neuroinflammation has been implicated in the pathogenesis of chronic traumatic encephalopathy (CTE), a progressive neurodegenerative disease association with exposure to repetitive head impacts (RHI) received though playing contact sports such as American football. Past work has implicated early and sustained activation of microglia as a potential driver of tau pathology within the frontal cortex in CTE. However, the RHI induced signals required to recruit microglia to areas of damage and pathology are unknown.

Methods: Postmortem brain tissue was obtained from 261 individuals across multiple brain banks. Comparisons were made using cases with CTE, cases with Alzheimer's disease (AD), and cases with no neurodegenerative disease and lacked exposure to RHI (controls). Recruitment of Iba1+ cells around the CTE perivascular lesion was compared to non-lesion vessels. TMEM119 staining was used to characterize microglia or macrophage involvement. The potent chemoattractant CCL2 was analyzed using frozen tissue from the dorsolateral frontal cortex (DLFC) and the calcarine cortex. Finally, the amounts of hyperphosphorylated tau (pTau) and Aβ were compared to CCL2 levels to examine possible mechanistic pathways.

Results: An increase in Iba1+ cells was found around blood vessels with perivascular tau pathology compared to non-affected vessels in individuals with RHI. TMEM119 staining revealed the majority of the Iba1+ cells were microglia. CCL2 protein levels in the DLFC were found to correlate with greater years of playing American football, the density of Iba1+ cells, the density of CD68+ cells, and increased CTE severity. When comparing across multiple brain regions, CCL2 increases were more pronounced in the DLFC than the calcarine cortex in cases with RHI but not in AD. When examining the individual contribution of pathogenic proteins to CCL2 changes, pTau correlated with CCL2, independent of age at death and Aβ in AD and CTE. Although levels of Aβ were not correlated with CCL2 in cases with CTE, in males in the AD group, Aβ trended toward an inverse relationship with CCL2 suggesting possible gender associations.

Conclusion: Overall, CCL2 is implicated in the pathways recruiting microglia and the development of pTau pathology after exposure to RHI, and may represent a future therapeutic target in CTE.
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http://dx.doi.org/10.1186/s12974-020-02036-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7718711PMC
December 2020

Revised Framingham Stroke Risk Profile: Association with Cognitive Status and MRI-Derived Volumetric Measures.

J Alzheimers Dis 2020 ;78(4):1393-1408

Boston University Alzheimer's Disease Center and CTE Center, Boston University School of Medicine, Boston, MA, USA.

Background: The Framingham Stroke Risk Profile (FSRP) was created in 1991 to estimate 10-year risk of stroke. It was revised in 2017 (rFSRP) to reflect the modern data on vascular risk factors and stroke risk.

Objective: This study examined the association between the rFSRP and cognitive and brain aging outcomes among participants from the National Alzheimer's Coordinating Center (NACC) Uniform Data Set (UDS).

Methods: Cross-sectional rFSRP was computed at baseline for 19,309 participants (mean age = 72.84, SD = 8.48) from the NACC-UDS [9,697 (50.2%) normal cognition, 4,705 (24.4%) MCI, 4,907 (25.4%) dementia]. Multivariable linear, logistic, or ordinal regressions examined the association between the rFSRP and diagnostic status, neuropsychological test performance, CDR® Sum of Boxes, as well as total brain volume (TBV), hippocampal volume (HCV), and log-transformed white matter hyperintensities (WMH) for an MRI subset (n = 1,196). Models controlled for age, sex, education, racial identity, APOEɛ4 status, and estimated intracranial volume for MRI models.

Results: The mean rFSRP probability was 10.42% (min = 0.50%, max = 95.71%). Higher rFSRP scores corresponded to greater CDR Sum of Boxes (β= 0.02, p = 0.028) and worse performance on: Trail Making Test A (β= 0.05, p < 0.001) and B (β= 0.057, p < 0.001), and Digit Symbol (β= -0.058, p < 0.001). Higher rFSRP scores were associated with increased odds for a greater volume of log-transformed WMH (OR = 1.02 per quartile, p = 0.015). No associations were observed for diagnosis, episodic memory or language test scores, HCV, or TBV.

Conclusion: These results support the rFSRP as a useful metric to facilitate clinical research on the associations between cerebrovascular disease and cognitive and brain aging.
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http://dx.doi.org/10.3233/JAD-200803DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7887636PMC
January 2020

Association of probable REM sleep behavior disorder with pathology and years of contact sports play in chronic traumatic encephalopathy.

Acta Neuropathol 2020 12 17;140(6):851-862. Epub 2020 Sep 17.

Boston University Alzheimer's Disease and CTE Center, Boston University School of Medicine, Boston, MA, USA.

Probable rapid eye movement (REM) sleep behavior disorder (pRBD) is a synucleinopathy-associated parasomnia in which loss of REM sleep muscle atonia results in motor behavior during REM sleep, including dream enactment. Traumatic brain injury is independently associated with increased risk of pRBD and Lewy body disease, and both pRBD and Lewy body disease are often observed in chronic traumatic encephalopathy (CTE). However, the frequency and pathological substrate of pRBD in CTE have not been formally studied and remain unknown. Of the total sample of 247 men, age at death of 63.1 ± 18.8 years (mean ± SD), 80 [32%] were determined by informant report to have symptoms of pRBD. These participants had played more years of contact sports (18.3 ± 11.4) than those without pRBD (15.1 ± 6.5; P = 0.02) and had an increased frequency of Lewy body disease (26/80 [33%] vs 28/167 [17%], P = 0.005). Of the 80 participants with pRBD, 54 [68%] did not have Lewy body disease; these participants were more likely to have neurofibrillary tangles and pretangles in the dorsal and median raphe (41 of 49 [84%] non-LBD participants with pRBD symptoms vs 90 of 136 [66%] non-LBD participants without pRBD symptoms, P = 0.02), brainstem nuclei with sleep regulatory function. Binary logistic regression modeling in the total study sample showed that pRBD in CTE was associated with dorsal and median raphe nuclei neurofibrillary tangles (OR = 3.96, 95% CI [1.43, 10.96], P = 0.008), Lewy body pathology (OR = 2.36, 95% CI [1.18, 4.72], P = 0.02), and years of contact sports participation (OR = 1.04, 95% CI [1.00, 1.08], P = 0.04). Overall, pRBD in CTE is associated with increased years of contact sports participation and may be attributable to Lewy body and brainstem tau pathologies.
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http://dx.doi.org/10.1007/s00401-020-02206-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7669574PMC
December 2020

Hippocampal Resting-State Functional Connectivity Patterns are More Closely Associated with Severity of Subjective Memory Decline than Whole Hippocampal and Subfield Volumes.

Cereb Cortex Commun 2020 28;1(1):tgaa019. Epub 2020 May 28.

Department of Anatomy & Neurobiology, Boston University School of Medicine, Boston, MA 02118, USA.

The goal of this study was to examine whether hippocampal volume or resting-state functional connectivity (rsFC) patterns are associated with subjective memory decline (SMD) in cognitively normal aged adults. Magnetic resonance imaging data from 53 participants (mean age: 71.9 years) of the Boston University Alzheimer's Disease Center registry were used in this cross-sectional study. Separate analyses treating SMD as a binary and continuous variable were performed. Subfield volumes were generated using FreeSurfer v6.0, and rsFC strength between the head and body of the hippocampus and the rest of the brain was calculated. Decreased left whole hippocampal volume and weaker rsFC strength between the right body of the hippocampus and the default mode network (DMN) were found in SMD+. Cognitive Change Index score was not correlated with volumetric measures but was inversely correlated with rsFC strength between the right body of the hippocampus and 6 brain networks, including the DMN, task control, and attentional networks. These findings suggest that hippocampal rsFC patterns reflect the current state of SMD in cognitively normal adults and may reflect subtle memory changes that standard neuropsychological tests are unable to capture.
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http://dx.doi.org/10.1093/texcom/tgaa019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7463163PMC
May 2020

Characterizing tau deposition in chronic traumatic encephalopathy (CTE): utility of the McKee CTE staging scheme.

Acta Neuropathol 2020 10 11;140(4):495-512. Epub 2020 Aug 11.

Department of Neurology, Boston University Alzheimer's Disease and CTE Centers, Boston University School of Medicine, Boston, USA.

Chronic traumatic encephalopathy (CTE) is a tauopathy associated with repetitive head impacts (RHI) that has been neuropathologically diagnosed in American football players and other contact sport athletes. In 2013, McKee and colleagues proposed a staging scheme for characterizing the severity of the hyperphosphorylated tau (p-tau) pathology, the McKee CTE staging scheme. The staging scheme defined four pathological stages of CTE, stages I(mild)-IV(severe), based on the density and regional deposition of p-tau. The objective of this study was to test the utility of the McKee CTE staging scheme, and provide a detailed examination of the regional distribution of p-tau in CTE. We examined the relationship between the McKee CTE staging scheme and semi-quantitative and quantitative assessments of regional p-tau pathology, age at death, dementia, and years of American football play among 366 male brain donors neuropathologically diagnosed with CTE (mean age 61.86, SD 18.90). Spearman's rho correlations showed that higher CTE stage was associated with higher scores on all semi-quantitative and quantitative assessments of p-tau severity and density (p's < 0.001). The severity and distribution of CTE p-tau followed an age-dependent progression: older age was associated with increased odds for having a higher CTE stage (p < 0.001). CTE stage was independently associated with increased odds for dementia (p < 0.001). K-medoids cluster analysis of the semi-quantitative scales of p-tau across 14 regions identified 5 clusters of p-tau that conformed to increasing CTE stage (stage IV had 2 slightly different clusters), age at death, dementia, and years of American football play. There was a predilection for p-tau pathology in five regions: dorsolateral frontal cortex (DLF), superior temporal cortex, entorhinal cortex, amygdala, and locus coeruleus (LC), with CTE in the youngest brain donors and lowest CTE stage restricted to DLF and LC. These findings support the usefulness of the McKee CTE staging scheme and demonstrate the regional distribution of p-tau in CTE.
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http://dx.doi.org/10.1007/s00401-020-02197-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7914059PMC
October 2020

Late contributions of repetitive head impacts and TBI to depression symptoms and cognition.

Neurology 2020 08 26;95(7):e793-e804. Epub 2020 Jun 26.

From the Departments of Neurology (M.L.A., J.M., O.H., S.C., A.C.M., R.A.S.), Pathology & Laboratory Medicine (T.D.S., A.C.M.), Boston University Alzheimer's Disease Center and CTE Center (Y.T., B.M.), and Departments of Neurosurgery (R.A.S.) and Anatomy and Neurobiology (R.A.S.), Boston University School of Medicine; Department of Biostatistics (Y.T., Z.H.B.), Biostatistics and Epidemiology Data Analytics Center (B.M.), and Department of Environmental Health (M.M.), Boston University School of Public Health, MA; VA Boston Healthcare System (T.D.S., A.C.M.); Department of Veterans Affairs Medical Center (T.D.S., A.C.M.), Bedford, MA; Departments of Psychiatry (R.N., S.M., M.W.W.), Radiology (M.W.W.), Biomedical Imaging (M.W.W.), Medicine (M.W.W.), and Neurology (M.W.W.), University of California, San Francisco; and Department of Veterans Affairs Medical Center (R.N., S.M., M.W.W.), Center for Imaging and Neurodegenerative Diseases, San Francisco, CA.

Objective: To test the hypothesis that repetitive head impacts (RHIs), like those from contact sport play and traumatic brain injury (TBI) have long-term neuropsychiatric and cognitive consequences, we compared middle-age and older adult participants who reported a history of RHI and/or TBI with those without this history on measures of depression and cognition.

Methods: This cross-sectional study included 13,323 individuals (mean age, 61.95; 72.5% female) from the Brain Health Registry who completed online assessments, including the Ohio State University TBI Identification Method, the Geriatric Depression Scale (GDS-15), and the CogState Brief Battery and Lumos Labs NeuroCognitive Performance Tests. Inverse propensity-weighted linear regressions accounting for age, sex, race/ethnicity, and education tested the effects of RHI and TBI compared to a non-RHI/TBI group.

Results: A total of 725 participants reported RHI exposure (mostly contact sport play and abuse) and 7,277 reported TBI (n = 2,604 with loss of consciousness [LOC]). RHI (β, 1.24; 95% CI, 0.36-2.12), TBI without LOC (β, 0.43; 95% CI, 0.31-0.54), and TBI with LOC (β, 0.75; 95% CI, 0.59-0.91) corresponded to higher GDS-15 scores. While TBI with LOC had the most neuropsychological associations, TBI without LOC had a negative effect on CogState Identification (β, 0.004; 95% CI, 0.001-0.01) and CogState One Back Test (β, 0.004; 95% CI, 0.0002-0.01). RHI predicted worse CogState One Back Test scores (β, 0.02; 95% CI, -0.01 to 0.05). There were RHI × TBI interaction effects on several neuropsychological subtests, and participants who had a history of both RHI and TBI with LOC had the greatest depression symptoms and worse cognition.

Conclusions: RHI and TBI independently contributed to worse mid- to later-life neuropsychiatric and cognitive functioning.
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http://dx.doi.org/10.1212/WNL.0000000000010040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7605500PMC
August 2020

A longitudinal examination of plasma neurofilament light and total tau for the clinical detection and monitoring of Alzheimer's disease.

Neurobiol Aging 2020 10 29;94:60-70. Epub 2020 May 29.

Boston University Alzheimer's Disease Center and CTE Center, Boston University School of Medicine, Boston, MA, USA; Department of Neurology, Boston University School of Medicine, Boston, MA, USA. Electronic address:

We examined baseline and longitudinal associations between plasma neurofilament light (NfL) and total tau (t-tau), and the clinical presentation of Alzheimer's disease (AD). A total of 579 participants (238, normal cognition [NC]; 185, mild cognitive impairment [MCI]; 156, AD dementia) had baseline blood draws; 82% had follow-up evaluations. Plasma samples were analyzed for NfL and t-tau using Simoa technology. Baseline plasma NfL was higher in AD dementia than MCI (standardized mean difference = 0.55, 95% CI: 0.37-0.73) and NC (standardized mean difference = 0.68, 95% CI: 0.49-0.88), corresponded to Clinical Dementia Rating scores (OR = 1.94, 95% CI: 1.35-2.79]), and correlated with all neuropsychological tests (r's = 0.13-0.42). Longitudinally, NfL did not predict diagnostic conversion but predicted decline on 3/10 neuropsychological tests. Baseline plasma t-tau was higher in AD dementia than NC with a small effect (standardized mean difference = 0.33, 95% CI: 0.10-0.57) but not MCI. t-tau did not statistically significant predict any longitudinal outcomes. Plasma NfL may be useful for the detection of AD dementia and monitoring of disease progression. In contrast, there was minimal evidence in support of plasma t-tau.
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http://dx.doi.org/10.1016/j.neurobiolaging.2020.05.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7484086PMC
October 2020

Temporal trends in pharmacologic prophylaxis for venous thromboembolism after hip and knee replacement in older adults.

Vasc Med 2020 10 9;25(5):450-459. Epub 2020 Jun 9.

Section of General Internal Medicine, Boston University Medical Center, Boston University School of Medicine, Boston, MA, USA.

Trends in prescription for venous thromboembolism (VTE) prophylaxis following total hip (THR) and knee replacement (TKR) since the approval of direct oral anticoagulants (DOACs) and the 2012 guideline endorsement of aspirin are unknown, as are the risks of adverse events. We examined practice patterns in the prescription of prophylaxis agents and the risk of adverse events during the in-hospital period (the 'in-hospital sample') and 90 days following discharge (the 'discharge sample') among adults aged ⩾ 65 undergoing THR and TKR in community hospitals in the Institute for Health Metrics database over a 30-month period during 2011 to 2013. Eligible medications included fondaparinux, DOACs, low molecular weight heparin (LMWH), other heparin products, warfarin, and aspirin. Outcomes were validated by physician review of source documents: VTE, major hemorrhage, cardiovascular events, and death. The in-hospital and the discharge samples included 10,503 and 5722 adults from 65 hospitals nationwide, respectively (mean age 73, 74 years; 61%, 63% women). Pharmacologic prophylaxis was near universal during the in-hospital period (93%) and at discharge (99%). DOAC use increased substantially and was the prophylaxis of choice for nearly a quarter (in-hospital) and a third (discharge) of the patients. Aspirin was the sole discharge prophylactic agent for 17% and 19% of patients undergoing THR and TKR, respectively. Warfarin remained the prophylaxis agent of choice for patients aged 80 years and older. The overall risk of adverse events was low, at less than 1% for both the in-hospital and discharge outcomes. The low number of adverse events precluded statistical comparison of prophylaxis regimens.
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http://dx.doi.org/10.1177/1358863X20927096DOI Listing
October 2020

In Vivo Quasi-Elastic Light Scattering Eye Scanner Detects Molecular Aging in Humans.

J Gerontol A Biol Sci Med Sci 2020 09;75(9):e53-e62

Molecular Aging & Development Laboratory, Boston University School of Medicine, Massachusetts.

The absence of clinical tools to evaluate individual variation in the pace of aging represents a major impediment to understanding aging and maximizing health throughout life. The human lens is an ideal tissue for quantitative assessment of molecular aging in vivo. Long-lived proteins in lens fiber cells are expressed during fetal life, do not undergo turnover, accumulate molecular alterations throughout life, and are optically accessible in vivo. We used quasi-elastic light scattering (QLS) to measure age-dependent signals in lenses of healthy human subjects. Age-dependent QLS signal changes detected in vivo recapitulated time-dependent changes in hydrodynamic radius, protein polydispersity, and supramolecular order of human lens proteins during long-term incubation (~1 year) and in response to sustained oxidation (~2.5 months) in vitro. Our findings demonstrate that QLS analysis of human lens proteins provides a practical technique for noninvasive assessment of molecular aging in vivo.
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http://dx.doi.org/10.1093/gerona/glaa121DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7494032PMC
September 2020

Evolution of neuronal and glial tau isoforms in chronic traumatic encephalopathy.

Brain Pathol 2020 09 2;30(5):913-925. Epub 2020 Jul 2.

Neuropathology Brain Bank & Research CoRE, Department of Pathology, Nash Family Department of Neuroscience, Ronald M. Loeb Center for Alzheimer's Disease, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY.

Chronic traumatic encephalopathy (CTE) is a neurodegenerative tauopathy characterized by accumulation of hyperphosphorylated tau (p-tau) in perivascular aggregates in neurons and glia at the depths of neocortical sulci and progresses to diffuse neocortical, allocortical and brainstem structures. The strongest risk factor is exposure to repetitive head impacts acquired most commonly through contact sports and military service. Given that CTE can only be definitively diagnosed after death, a better understanding of the cellular and molecular changes in CTE brains may lead to identification of mechanisms that could be used for novel biomarkers, monitoring progression or therapeutic development. Disruption of alternative pre-mRNA splicing of tau mRNA plays a pathogenic role in tauopathy, with multiple characteristic patterns of isoform accumulation varying among tauopathies. Limited data are available on CTE, particularly at early stages. Using biochemical and histological approaches, we performed a detailed characterization of tau isoform signatures in post-mortem human brain tissue from individuals with a range of CTE stages (n = 99). In immunoblot analyses, severity was associated with decreased total monomeric tau and increased total oligomeric tau. Immunoblot with isoform-specific antisera revealed that oligomeric tau with three and four microtubule binding domain repeats (3R and 4R) also increased with CTE severity. Similarly, immunohistochemical studies revealed p-tau accumulation consisting of both 3R and 4R in perivascular lesions. When the ratio of 4R:3R was analyzed, there was mixed expression throughout CTE stages, although 4R predominated in early CTE stages (I-II), a 3R shift was observed in later stages (III-IV). While neurons were found to contain both 3R and 4R, astrocytes only contained 4R. These 4R-positive cells were exclusively neuronal at early stages. Overall, these findings demonstrate that CTE is a mixed 4R/3R tauopathy. Furthermore, histologic analysis reveals a progressive shift in tau isoforms that correlates with CTE stage and extent of neuronal pathology.
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http://dx.doi.org/10.1111/bpa.12867DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7484331PMC
September 2020

Impact of an On-Site Versus Remote Patient Navigator on Pediatricians' Referrals and Families' Receipt of Resources for Unmet Social Needs.

J Prim Care Community Health 2020 Jan-Dec;11:2150132720924252

Boston Medical Center, Boston, MA, USA.

Patient navigation is increasingly being used by pediatric health care delivery systems to address patients' unmet social needs. However, it is not known whether navigators working remotely can be as effective at linking families to community resources as on-site navigators. The aim of this study was to assess whether a patient navigator located on-site versus remotely is more likely to receive referrals from clinicians, successfully follow-up with patients, and assist families with enrollment in social needs resources. A patient navigator worked on-site and remotely as she divided her time between 4 federally qualified health centers (FQHCs) from May 2015 to June 2019. We conducted a 1-sample test of proportion comparing the proportion of on-site referrals made with the proportion of the week spent in each FQHC. To assess the impact of on-site versus remote referrals on number of contacts with a family, we conducted a 2-sample t test. We used chi-square testing to assess the effect of on-site versus remote status on resource enrollment. Of the referrals (N = 414) made to the patient navigator, the majority were made through the electronic health record (83%) versus in person (17%) ( < .0001). When the navigator was on-site, significantly more referrals were made than expected (45% vs 29%, < .0001). Between remote and on-site referral groups, there was no significant difference in number of contact points (1.0 vs 1.1 points, = .32) or in the proportion of families who received a resource (4.6% vs 5.1%, = .31). Our results indicate that clinicians were significantly more likely to refer families to patient navigation if the navigator was on-site. The likelihood of having contact with the navigator and enrolling in a resource, however, did not differ between families referred when the patient navigator was on-site compared with remote.
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http://dx.doi.org/10.1177/2150132720924252DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7249580PMC
May 2020

False Memories: The Other Side of Forgetting.

J Int Neuropsychol Soc 2020 07 28;26(6):545-556. Epub 2020 Feb 28.

Center for Translational Cognitive Neuroscience, VA Boston Healthcare System, Boston, MA02130, USA.

Objective: To measure caregivers' and clinicians' perception of false memories in the lives of patients with memory loss due to Alzheimer's disease (AD) and mild cognitive impairment (MCI) using a novel false memories questionnaire. Our hypotheses were that false memories are occurring as often as forgetting according to clinicians and family members.

Method: This prospective, questionnaire-based study consisting of 20 false memory questions paired with 20 forgetting questions had two forms: one for clinicians and the other for family members of older subjects. In total, 226 clinicians and 150 family members of 49 patients with AD, 44 patients with MCI, and 57 healthy older controls (OCs) completed the questionnaire.

Results: False memories occurred nearly as often as forgetting according to clinicians and family members of patients with MCI and AD. Family members of OCs and patients with MCI reported fewer false memories compared to those of the AD group. As Mini-Mental State Examination scores decreased, the mean score increased for both forgetting and false memories. Among clinicians, correlations were observed between the dementia severity of patients seen with both forgetting and false memories questionnaire scores as well as with the impact of forgetting and false memories on daily life.

Conclusion: Patients with AD experience false memories almost as frequently as they do forgetting. Given how common false memories are in AD patients, additional work is needed to understand the clinical implications of these false memories on patients' daily lives. The novel false memories questionnaire developed may be a valuable tool.
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http://dx.doi.org/10.1017/S1355617720000016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7319895PMC
July 2020

Mild traumatic brain injury impacts associations between limbic system microstructure and post-traumatic stress disorder symptomatology.

Neuroimage Clin 2020 22;26:102190. Epub 2020 Jan 22.

Psychiatry Neuroimaging Laboratory, Department of Psychiatry, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States; Department of Child and Adolescent Psychiatry, Psychosomatic, and Psychotherapy, Ludwig-Maximilian University, Munich, Germany. Electronic address:

Background: Post-traumatic stress disorder (PTSD) is a psychiatric disorder that afflicts many individuals, yet the neuropathological mechanisms that contribute to this disorder remain to be fully determined. Moreover, it is unclear how exposure to mild traumatic brain injury (mTBI), a condition that is often comorbid with PTSD, particularly among military personnel, affects the clinical and neurological presentation of PTSD. To address these issues, the present study explores relationships between PTSD symptom severity and the microstructure of limbic and paralimbic gray matter brain regions, as well as the impact of mTBI comorbidity on these relationships.

Methods: Structural and diffusion MRI data were acquired from 102 male veterans who were diagnosed with current PTSD. Diffusion data were analyzed with free-water imaging to quantify average CSF-corrected fractional anisotropy (FA) and mean diffusivity (MD) in 18 limbic and paralimbic gray matter regions. Associations between PTSD symptom severity and regional average dMRI measures were examined with repeated measures linear mixed models. Associations were studied separately in veterans with PTSD only, and in veterans with PTSD and a history of military mTBI.

Results: Analyses revealed that in the PTSD only cohort, more severe symptoms were associated with higher FA in the right amygdala-hippocampus complex, lower FA in the right cingulate cortex, and lower MD in the left medial orbitofrontal cortex. In the PTSD and mTBI cohort, more severe PTSD symptoms were associated with higher FA bilaterally in the amygdala-hippocampus complex, with higher FA bilaterally in the nucleus accumbens, with lower FA bilaterally in the cingulate cortex, and with higher MD in the right amygdala-hippocampus complex.

Conclusions: These findings suggest that the microstructure of limbic and paralimbic brain regions may influence PTSD symptomatology. Further, given the additional associations observed between microstructure and symptom severity in veterans with head trauma, we speculate that mTBI may exacerbate the impact of brain microstructure on PTSD symptoms, especially within regions of the brain known to be vulnerable to chronic stress. A heightened sensitivity to the microstructural environment of the brain could partially explain why individuals with PTSD and mTBI comorbidity experience more severe symptoms and poorer illness prognoses than those without a history of brain injury. The relevance of these microstructural findings to the conceptualization of PTSD as being a disorder of stress-induced neuronal connectivity loss is discussed.
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http://dx.doi.org/10.1016/j.nicl.2020.102190DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7026283PMC
March 2021

Relationships Between Material Hardship, Resilience, and Health Care Use.

Pediatrics 2020 02 16;145(2). Epub 2020 Jan 16.

Division of General Pediatrics, Department of Pediatrics, School of Medicine, New York University and New York City Health and Hospitals/Bellevue, New York, New York; and.

Background: Material hardship has been associated with adverse health care use patterns for children with special health care needs (CSHCN). In this study, we assessed if resilience factors were associated with lower emergency department (ED) visits and unmet health care needs and if they buffered associations between material hardship and health care use for CSHCN and children without special health care needs.

Methods: A cross-sectional study using the 2016 National Survey of Children's Health, restricted to low-income participants (<200% federal poverty level). Separately, for CSHCN and children without special health care needs, weighted logistic regression was used to measure associations between material hardship, 2 resilience factors (family resilience and neighborhood cohesion), and 2 measures of use. Moderation was assessed using interaction terms. Mediation was assessed using structural equation models.

Results: The sample consisted of 11 543 children (weighted: = 28 465 581); 26% were CSHCN. Material hardship was associated with higher odds of ED visits and unmet health care needs for all children. Resilience factors were associated with lower odds of unmet health care needs for CSHCN (family resilience adjusted odds ratio: 0.58; 95% confidence interval: 0.36-0.94; neighborhood cohesion adjusted odds ratio: 0.53; 95% confidence interval: 0.32-0.88). For CSHCN, lower material hardship mediated associations between resilience factors and unmet health care needs. Neighborhood cohesion moderated the association between material hardship and ED visits (interaction term: = .02).

Conclusions: Among low-income CSHCN, resilience factors may buffer the effects of material hardship on health care use. Future research should evaluate how resilience factors can be incorporated into programs to support CSHCN.
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http://dx.doi.org/10.1542/peds.2019-1975DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6993324PMC
February 2020

Interactive Effects of Racial Identity and Repetitive Head Impacts on Cognitive Function, Structural MRI-Derived Volumetric Measures, and Cerebrospinal Fluid Tau and Aβ.

Front Hum Neurosci 2019 20;13:440. Epub 2019 Dec 20.

Boston University Alzheimer's Disease Center and Boston University CTE Center, Boston University School of Medicine, Boston, MA, United States.

Background: Factors of increased prevalence among individuals with Black racial identity (e.g., cardiovascular disease, CVD) may influence the association between exposure to repetitive head impacts (RHI) from American football and later-life neurological outcomes. Here, we tested the interaction between racial identity and RHI on neurobehavioral outcomes, brain volumetric measures, and cerebrospinal fluid (CSF) total tau (t-tau), phosphorylated tau (p-tau), and Aβ in symptomatic former National Football League (NFL) players.

Methods: 68 symptomatic male former NFL players (ages 40-69; = 27 Black, = 41 White) underwent neuropsychological testing, structural MRI, and lumbar puncture. FreeSurfer derived estimated intracranial volume (eICV), gray matter volume (GMV), white matter volume (WMV), subcortical GMV, hippocampal volume, and white matter (WM) hypointensities. Multivariate generalized linear models examined the main effects of racial identity and its interaction with a cumulative head impact index (CHII) on all outcomes. Age, years of education, Wide Range Achievement Test, Fourth Edition (WRAT-4) scores, CVD risk factors, and ε4 were included as covariates; eICV was included for MRI models. -values were false discovery rate adjusted.

Results: Compared to White former NFL players, Black participants were 4 years younger ( = 0.04), had lower WRAT-4 scores (mean difference = 8.03, = 0.002), and a higher BMI (mean difference = 3.09, = 0.01) and systolic blood pressure (mean difference = 8.15, = 0.03). With regards to group differences on the basis of racial identity, compared to White former NFL players, Black participants had lower GMV (mean adjusted difference = 45649.00, = 0.001), lower right hippocampal volume (mean adjusted difference = 271.96, = 0.02), and higher p-tau/t-tau ratio (mean adjusted difference = -0.25, = 0.01). There was not a statistically significant association between the CHII with GMV, right hippocampal volume, or p-tau/t-tau ratio. However, there was a statistically significant Race x CHII interaction for GMV ( = 2206.29, = 0.001), right hippocampal volume ( = 12.07, = 0.04), and p-tau/t-tau ratio concentrations ( = -0.01, = 0.004).

Conclusion: Continued research on racial neurological disparities could provide insight into risk factors for long-term neurological disorders associated with American football play.
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http://dx.doi.org/10.3389/fnhum.2019.00440DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6933867PMC
December 2019

The Relationship Between Social Risks and the Mental Health of School-Age Children in Primary Care.

Acad Pediatr 2020 03 18;20(2):208-215. Epub 2019 Nov 18.

Department of Pediatrics, Boston University School of Medicine, Boston Medical Center (WG Adams and A Garg), Boston, Mass.

Background And Objective: The study's goal was to measure the association between social risks and the mental health of school-age children in primary care.

Methods: We conducted a cross-sectional study in an urban safety-net hospital-based pediatric clinic using data collected from 2 standardized screening tools administered at well-child care visits for children age 6 to 11. Psychosocial dysfunction was measured with the Pediatric Symptom Checklist-17 (PSC-17), and 6 social risks (caregiver education, employment, child care, housing, food security, and household heat) were measured with the WE CARE screener. Multivariable linear and logistic regression analyses were conducted to measure the association between scores while controlling for sociodemographic characteristics.

Results: Among N = 943 patients, cumulative social risks were significantly associated with a positive PSC-17 total score (adjusted odds ratio [aOR] 1.2; 95% confidence interval [CI] 1.1-1.5; P = .02), indicating psychosocial dysfunction. Children with ≥3 social risks were 2.4 times more likely to have a positive PSC-17 total score compared to children with <3 social risks (95% CI 1.5-3.9; P < .001). Of the individual social risks measured, only food insecurity significantly predicted a positive PSC-17 total score (aOR 1.9; 95% CI 1.1-3.2; P = .02) and attention score (aOR 1.9; 95% CI 1.1-3.4; P = .03).

Conclusion: Number of risks on a social risk screener was associated with psychosocial dysfunction in school-age children. Food insecurity was the only individual risk associated with psychosocial dysfunction, in particular attention problems. Screening tools for social risks could be used to identify at-risk children whose mental health may be adversely impacted by their social conditions.
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http://dx.doi.org/10.1016/j.acap.2019.11.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7036330PMC
March 2020

Duration of American Football Play and Chronic Traumatic Encephalopathy.

Ann Neurol 2020 01 23;87(1):116-131. Epub 2019 Nov 23.

Boston University Alzheimer's Disease and Chronic Traumatic Encephalopathy Center, Boston University School of Medicine, Boston, MA.

Objective: Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with exposure to contact and collision sports, including American football. We hypothesized a dose-response relationship between duration of football played and CTE risk and severity.

Methods: In a convenience sample of 266 deceased American football players from the Veterans Affairs-Boston University-Concussion Legacy Foundation and Framingham Heart Study Brain Banks, we estimated the association of years of football played with CTE pathological status and severity. We evaluated the ability of years played to classify CTE status using receiver operating characteristic curve analysis. Simulation analyses quantified conditions that might lead to selection bias.

Results: In total, 223 of 266 participants met neuropathological diagnostic criteria for CTE. More years of football played were associated with having CTE (odds ratio [OR] = 1.30 per year played, 95% confidence interval [CI] = 1.19-1.41; p = 3.8 × 10 ) and with CTE severity (severe vs mild; OR = 1.14 per year played, 95% CI = 1.07-1.22; p = 3.1 × 10 ). Participants with CTE were 1/10th as likely to have played <4.5 years (negative likelihood ratio [LR] = 0.102, 95% CI = 0.100-0.105) and were 10 times as likely to have played >14.5 years (positive LR = 10.2, 95% CI = 9.8-10.7) compared with participants without CTE. Sensitivity and specificity were maximized at 11 years played. Simulation demonstrated that years played remained adversely associated with CTE status when years played and CTE status were both related to brain bank selection across widely ranging scenarios.

Interpretation: The odds of CTE double every 2.6 years of football played. After accounting for brain bank selection, the magnitude of the relationship between years played and CTE status remained consistent. ANN NEUROL 2020;87:116-131.
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http://dx.doi.org/10.1002/ana.25611DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6973077PMC
January 2020

Variability in Informed Consent Practices for Non-Emergent Procedures in Pediatric Emergency Departments.

Clin Pediatr (Phila) 2019 Dec 26;58(14):1509-1514. Epub 2019 Sep 26.

Boston University, School of Medicine, Boston, MA, USA.

Although informed consent is a cornerstone of medical ethics, it is unclear if the practice for obtaining informed consent is consistent among pediatric emergency departments. This study's goal is to describe the current practice for written informed consent in academic pediatric emergency departments for non-emergent procedures. A questionnaire distributed to pediatric emergency medicine fellowship directors queried whether written informed consent was standard of care for 15 procedures and assessed departmental consent policies and use of "blanket" consent-to-treat forms. Response rate was 80% (n = 64). Institutions obtained written consent for a mean of 4.4 procedures. Written informed consent was most commonly obtained for procedural sedation (82.5%), blood transfusion (72.9%), and lumbar puncture (66.5%). Twenty-one institutions (32.8%) had policies specifying procedures requiring written consent. Thirty-five institutions (54.7%) used "blanket" consent-to-treat forms. Our results suggest that there is variability in the use of written informed consent for non-emergent procedures among academic pediatric emergency departments.
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http://dx.doi.org/10.1177/0009922819877873DOI Listing
December 2019

Gender Differences in Social and Behavioral Determinants of Health in Aging Adults.

J Gen Intern Med 2019 11;34(11):2310-2312

Department of Pediatrics, Boston Medical Center, Boston, MA, USA.

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http://dx.doi.org/10.1007/s11606-019-05225-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6848471PMC
November 2019

Association of White Matter Rarefaction, Arteriolosclerosis, and Tau With Dementia in Chronic Traumatic Encephalopathy.

JAMA Neurol 2019 Nov;76(11):1298-1308

Boston University Alzheimer's Disease Center and CTE Center, Department of Neurology, Boston University School of Medicine, Boston, Massachusetts.

Importance: Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with repetitive head impacts, including those from US football, that presents with cognitive and neuropsychiatric disturbances that can progress to dementia. Pathways to dementia in CTE are unclear and likely involve tau and nontau pathologic conditions.

Objective: To investigate the association of white matter rarefaction and cerebrovascular disease with dementia in deceased men older than 40 years who played football and had CTE.

Design, Setting, And Participants: This cross-sectional study involves analyses of data from the ongoing Understanding Neurologic Injury and Traumatic Encephalopathy (UNITE) Study, which is conducted via and included brain donors from the Veterans Affairs-Boston University-Concussion Legacy Foundation brain bank between 2008 and 2017. An original sample of 224 men who had played football and were neuropathologically diagnosed with CTE was reduced after exclusion of those younger than 40 years and those missing data.

Exposures: The number of years of football play as a proxy for repetitive head impacts.

Main Outcomes And Measures: Neuropathological assessment of white matter rarefaction and arteriolosclerosis severity (on a scale of 0-3, where 3 is severe); number of infarcts, microinfarcts, and microbleeds; and phosphorylated tau accumulation determined by CTE stage and semiquantitative rating of dorsolateral frontal cortex (DLFC) neurofibrillary tangles (NFTs) (none or mild vs moderate or severe). Informant-based retrospective clinical interviews determined dementia diagnoses via diagnostic consensus conferences.

Results: A total of 180 men were included. The mean (SD) age of the sample at death was 67.9 (12.7) years. Of 180, 120 [66.7%]) were found to have had dementia prior to death. Moderate to severe white matter rarefaction (84 of 180 [46.6%]) and arteriolosclerosis (85 of 180 [47.2%]) were common; infarcts, microinfarcts, and microbleeds were not. A simultaneous equations regression model controlling for age and race showed that more years of play was associated with more severe white matter rarefaction (β, 0.16 [95% CI, 0.02-0.29]; P = .03) and greater phosphorylated tau accumulation (DLFC NFTs: β, 0.15 [95% CI, 0.004-0.30]; P = .04; CTE stage: β, 0.27 [95% CI, 0.14-0.41]; P < .001). White matter rarefaction (β, 0.16 [95% CI, 0.02-0.29]; P = .03) and DLFC NFTs (β, 0.16 [95% CI, 0.03-0.28]; P = .01) were associated with dementia. Arteriolosclerosis and years of play were not associated, but arteriolosclerosis was independently associated with dementia (β, 0.21 [95% CI, 0.07-0.35]; P = .003).

Conclusions And Relevance: Among older men who had played football and had CTE, more years of football play were associated with more severe white matter rarefaction and greater DLFC NFT burden. White matter rarefaction, arteriolosclerosis, and DLFC NFTs were independently associated with dementia. Dementia in CTE is likely a result of neuropathologic changes, including white matter rarefaction and phosphorylated tau, associated with repetitive head impact and pathologic changes not associated with head trauma, such as arteriolosclerosis.
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http://dx.doi.org/10.1001/jamaneurol.2019.2244DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6686769PMC
November 2019

Independent effects of white matter hyperintensities on cognitive, neuropsychiatric, and functional decline: a longitudinal investigation using the National Alzheimer's Coordinating Center Uniform Data Set.

Alzheimers Res Ther 2019 07 27;11(1):64. Epub 2019 Jul 27.

Boston University Alzheimer's Disease Center and CTE Center, Boston University School of Medicine, 72 E. Concord Street, Suite B7800, Boston, MA, 02118, USA.

Background: Longitudinal investigations are needed to improve understanding of the contributions of cerebral small vessel disease to the clinical manifestation of Alzheimer's disease, particularly in the early disease stages. This study leveraged the National Alzheimer's Coordinating Center Uniform Data Set to longitudinally examine the association between white matter hyperintensities and neuropsychological, neuropsychiatric, and functional decline among participants with normal cognition.

Methods: The sample included 465 participants from the National Alzheimer's Coordinating Center Uniform Data Set who had quantitated volume of white matter hyperintensities from fluid-attenuated inversion recovery MRI, had normal cognition at the time of their MRI, and were administered the National Alzheimer's Coordinating Center Uniform Data Set neuropsychological test battery within 1 year of study evaluation and had at least two post-MRI time points of clinical data. Neuropsychiatric status was assessed by the Geriatric Depression Scale-15 and Neuropsychiatric Inventory-Questionnaire. Clinical Dementia Rating Sum of Boxes defined functional status. For participants subsequently diagnosed with mild cognitive impairment (MCI) or dementia, their impairment must have been attributed to Alzheimer's disease (AD) to evaluate the relationships between WMH and the clinical presentation of AD.

Results: Of the 465 participants, 56 converted to MCI or AD dementia (average follow-up = 5 years). Among the 465 participants, generalized estimating equations controlling for age, sex, race, education, APOE ε4, and total brain and hippocampal volume showed that higher baseline log-white matter hyperintensities predicted accelerated decline on the following neuropsychological tests in rank order of effect size: Trails B (p < 0.01), Digit Symbol Coding (p < 0.01), Logical Memory Immediate Recall (p = 0.02), Trail Making A (p < 0.01), and Semantic Fluency (p < 0.01). White matter hyperintensities predicted increases in Clinical Dementia Rating Sum of Boxes (p < 0.01) and Geriatric Depression Scale-15 scores (p = 0.01). Effect sizes were comparable to total brain and hippocampal volume. White matter hyperintensities did not predict diagnostic conversion. All effects also remained after including individuals with non-AD suspected etiologies for those who converted to MCI or dementia.

Conclusions: In this baseline cognitively normal sample, greater white matter hyperintensities were associated with accelerated cognitive, neuropsychiatric, and functional decline independent of traditional risk factors and MRI biomarkers for Alzheimer's disease.
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http://dx.doi.org/10.1186/s13195-019-0521-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6661103PMC
July 2019