Publications by authors named "Douglas I Katz"

52 Publications

Neurorehabilitation.

Semin Neurol 2021 Apr 8;41(2):109-110. Epub 2021 Apr 8.

Department of Neurology, Boston University School of Medicine, Boston, Massachusetts.

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http://dx.doi.org/10.1055/s-0041-1726458DOI Listing
April 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

Prevalence of Drinking within Low-Risk Guidelines during the First Two Years Following Inpatient Rehabilitation for Moderate or Severe Traumatic Brain Injury.

Am J Phys Med Rehabil 2021 Mar 24. Epub 2021 Mar 24.

Institute for Behavioral Health, Heller School for Social Policy and Management, Brandeis University, Waltham, MA Veterans Health Administration, Rocky Mountain Mental Illness Research Education and Clinical Center, 1700 N Wheeling Street, Aurora, CO, 80045 Traumatic Brain Injury Model Systems, National Data and Statistical Center, Craig Hospital, Englewood, CO James A. Haley Veterans Hospital, Defense and Veterans Brain Injury Center, Tampa, FL Department of Neurology, Boston University School of Medicine, Boston, MA Department of Physical Medicine & Rehabilitation, Wexner Medical Center, The Ohio State University, Columbus, OH.

Abstract: The objective of this retrospective, longitudinal study was to investigate the prevalence of drinking within the recommended limits (i.e., low-risk drinking) following moderate/severe traumatic brain injury (TBI). Data were drawn from the National Institute on Disability, Independent Living, and Rehabilitation Research TBI Model Systems National Database (TBIMS), a longitudinal dataset closely representative of the U.S. adult population requiring inpatient rehabilitation for TBI. The sample included 6,348 adults with moderate or severe TBI (injured October 2006 - May 2016) who received inpatient rehabilitation at a civilian TBIMS center and completed the alcohol consumption items for pre-injury, and 1- and 2-year post-injury. National Institute on Alcohol Abuse and Alcoholism (NIAAA) guidelines define low-risk drinking as no more than 4 drinks per day for men or 3 drinks per day for women, and no more than 14 drinks per week for men, or no more than 7 drinks per week for women. Low-risk drinking was common both before and after TBI, with more than 30% drinking in the low-risk level pre- injury, and more than 25% at 1- and 2-years post-injury. Post-injury, the majority of drinkers consumed alcohol in the low-risk level regardless of pre-injury drinking level. Definitive research on the long-term outcomes of low-risk alcohol consumption following more severe TBI should be a high priority.
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http://dx.doi.org/10.1097/PHM.0000000000001753DOI Listing
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

Clinical Neurorehabilitation: Using Principles of Neurological Diagnosis, Prognosis, and Neuroplasticity in Assessment and Treatment Planning.

Semin Neurol 2021 Apr 4;41(2):111-123. Epub 2021 Mar 4.

Department of Neurology, Boston University School of Medicine, Boston, Massachusetts.

Neurorehabilitation aspires to restore a person to his or her fullest potential after incurring neurological dysfunction. In medical rehabilitation, diagnosis involves assessment of medical conditions and their effects on functioning. It is usually a team effort that involves an amalgam of diagnostic assessments by multiple disciplines, leading to a collection of rehabilitative treatment plans and goals. This article discusses a clinical neurological paradigm, using rigorous clinical assessment of neuropathological and clinical diagnosis, along with prognostication of natural history and recovery. In the context of the role of neuroplasticity in recovery, this paradigm can add significant value to rehabilitation team management and planning. It contributes to enhanced understanding of neurological impairments and syndromes as they relate to functional disability, aiding in targeting deficits and setting treatment goals. Rehabilitation strategies and goals should be informed by natural history and prognosis, and viewed in the framework of the stage of recovery. Prognostic formulations should suggest an emphasis on restorative versus compensatory strategies for functional problems. Treatment planning should be informed by evidence on how interventions modulate brain reorganization in promoting recovery. Strategies that promote adaptive neuroplasticity should be favored, especially with restorative efforts, and evidence supporting optimal techniques, timing, and dosing of rehabilitation should be considered in treatment planning.
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http://dx.doi.org/10.1055/s-0041-1725132DOI Listing
April 2021

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

Clinical Reasoning: A 33-Year-Old Patient With Left-Sided Hemiparesis and Anarthria.

Neurology 2021 01 10;96(3):128-133. Epub 2020 Sep 10.

From the Beth Israel Deaconess Medical Center (S.S.), Boston; Boston University School of Medicine (D.I.K.); and Massachusetts General Hospital (D.J.L.), Boston.

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http://dx.doi.org/10.1212/WNL.0000000000010809DOI Listing
January 2021

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

Post-traumatic Confusional State: A Case Definition and Diagnostic Criteria.

Arch Phys Med Rehabil 2020 11 29;101(11):2041-2050. Epub 2020 Jul 29.

Mary Free Bed Rehabilitation Hospital, Grand Rapids, Michigan.

In response to the need to better define the natural history of emerging consciousness after traumatic brain injury and to better describe the characteristics of the condition commonly labeled posttraumatic amnesia, a case definition and diagnostic criteria for the posttraumatic confusional state (PTCS) were developed. This project was completed by the Confusion Workgroup of the American Congress of Rehabilitation Medicine Brain Injury Interdisciplinary Special Interest group. The case definition was informed by an exhaustive literature review and expert opinion of workgroup members from multiple disciplines. The workgroup reviewed 2466 abstracts and extracted evidence from 44 articles. Consensus was reached through teleconferences, face-to-face meetings, and 3 rounds of modified Delphi voting. The case definition provides detailed description of PTCS (1) core neurobehavioral features, (2) associated neurobehavioral features, (3) functional implications, (4) exclusion criteria, (5) lower boundary, and (6) criteria for emergence. Core neurobehavioral features include disturbances of attention, orientation, and memory as well as excessive fluctuation. Associated neurobehavioral features include emotional and behavioral disturbances, sleep-wake cycle disturbance, delusions, perceptual disturbances, and confabulation. The lower boundary distinguishes PTCS from the minimally conscious state, while upper boundary is marked by significant improvement in the 4 core and 5 associated features. Key research goals are establishment of cutoffs on assessment instruments and determination of levels of behavioral function that distinguish persons in PTCS from those who have emerged to the period of continued recovery.
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http://dx.doi.org/10.1016/j.apmr.2020.06.021DOI Listing
November 2020

Minimum Competency Recommendations for Programs That Provide Rehabilitation Services for Persons With Disorders of Consciousness: A Position Statement of the American Congress of Rehabilitation Medicine and the National Institute on Disability, Independent Living and Rehabilitation Research Traumatic Brain Injury Model Systems.

Arch Phys Med Rehabil 2020 06 20;101(6):1072-1089. Epub 2020 Feb 20.

Concussion Care Centre of Virginia and Tree of life Services, Henrico, VA; Virginia Commonwealth University, Department of Physical Medicine and Rehabilitation, Richmond, VA.

Persons who have disorders of consciousness (DoC) require care from multidisciplinary teams with specialized training and expertise in management of the complex needs of this clinical population. The recent promulgation of practice guidelines for patients with prolonged DoC by the American Academy of Neurology, American Congress of Rehabilitation Medicine (ACRM), and National Institute on Disability, Independent Living, and Rehabilitation Research (NIDILRR) represents a major advance in the development of care standards in this area of brain injury rehabilitation. Implementation of these practice guidelines requires explication of the minimum competencies of clinical programs providing services to persons who have DoC. The Brain Injury Interdisciplinary Special Interest Group of the ACRM, in collaboration with the Disorders of Consciousness Special Interest Group of the NIDILRR-Traumatic Brain Injury Model Systems convened a multidisciplinary panel of experts to address this need through the present position statement. Content area-specific workgroups reviewed relevant peer-reviewed literature and drafted recommendations which were then evaluated by the expert panel using a modified Delphi voting process. The process yielded 21 recommendations on the structure and process of essential services required for effective DoC-focused rehabilitation, organized into 4 categories: diagnostic and prognostic assessment (4 recommendations), treatment (11 recommendations), transitioning care/long-term care needs (5 recommendations), and management of ethical issues (1 recommendation). With few exceptions, these recommendations focus on infrastructure requirements and operating procedures for the provision of DoC-focused neurorehabilitation services across subacute and postacute settings.
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http://dx.doi.org/10.1016/j.apmr.2020.01.013DOI Listing
June 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

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

Contact sport participation and chronic traumatic encephalopathy are associated with altered severity and distribution of cerebral amyloid angiopathy.

Acta Neuropathol 2019 09 10;138(3):401-413. Epub 2019 Jun 10.

Alzheimer's Disease and CTE Center, Boston University School of Medicine, Boston University, Boston, MA, 02118, USA.

Cerebral amyloid angiopathy (CAA) consists of beta-amyloid deposition in the walls of the cerebrovasculature and is commonly associated with Alzheimer's disease (AD). However, the association of CAA with repetitive head impacts (RHI) and with chronic traumatic encephalopathy (CTE) is unknown. We evaluated the relationship between RHI from contact sport participation, CTE, and CAA within a group of deceased contact sport athletes (n = 357), a community-based cohort (n = 209), and an AD cohort from Boston University AD Center (n = 241). Unsupervised hierarchal cluster analysis demonstrated a unique cluster (n = 11) with increased CAA in the leptomeningeal vessels compared to the intracortical vessels (p < 0.001) comprised of participants with significantly greater frequencies of CTE (7/11) and history of RHI. Overall, participants with CTE (n = 251) had more prevalent (p < 0.001) and severe (p = 0.010) CAA within the frontal leptomeningeal vessels compared to intracortical vessels. Compared to those with AD, participants with CTE had more severe CAA in frontal than parietal lobes (p < 0.001) and more severe CAA in leptomeningeal than intracortical vessels (p = 0.002). The overall frequency of CAA in participants with CTE was low, and there was no significant association between contact sport participation and the presence of CAA. However, in those with CAA, a history of contact sports was associated with increased CAA severity in the frontal leptomeningeal vessels (OR = 4.01, 95% CI 2.52-6.38, p < 0.001) adjusting for AD, APOE ε4 status, and age. Participants with CAA had increased levels of sulcal tau pathology and decreased levels of the synaptic marker PSD-95 (p's < 0.05), and CAA was a predictor of dementia (OR = 1.75, 95% CI 1.02-2.99, p = 0.043) adjusting for age, sex, and comorbid pathology. Overall, contact sport participation and CTE were associated with more severe frontal and leptomeningeal CAA, and CAA was independently associated with worse pathological and clinical outcomes.
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http://dx.doi.org/10.1007/s00401-019-02031-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6689453PMC
September 2019

Postconcussion syndrome.

Handb Clin Neurol 2018 ;158:163-178

Department of Neurology, Boston University School of Medicine, Boston, MA, United States. Electronic address:

Postconcussion syndrome (PCS) is a heterogeneous condition comprised of a set of signs and symptoms in somatic, cognitive, and emotional domains. PCS is a controversial concept because of differing consensus criteria, variability in presentation, and lack of specificity to concussion. Whereas symptoms of concussion resolve in most individuals over days to weeks, a minority of individuals experience symptoms persisting months to years. The clinical consequences of concussion may be best conceptualized as two multidimensional disorders: (1) a constellation of acute symptoms termed early-phase posttraumatic disorder (commonly headache, dizziness, imbalance, fatigue, sleep disruption, impaired cognition, photo- and phonophobia); and (2) late-phase posttraumatic disorder, consisting of somatic, emotional, and cognitive symptoms. This phase is highly influenced by various psychosocial factors and is much less specific to the brain injury itself. Risk factors for development of a late-phase disorder include a high early symptom burden (e.g., headache, fatigue), a history of multiple concussions, psychiatric conditions (anxiety, depression), longer duration of unconsciousness or amnesia, and younger age. Successful treatment requires thoughtful differential diagnosis, including consideration of comorbid and premorbid conditions and other possible contributing factors. Treatment should include a hierarchic, sequential approach to management of treatable symptoms that impact functioning, such as depression, anxiety, insomnia, headache, musculoskeletal pain, and vertigo. A guided prescription of aerobic exercise is beneficial for early- and late-phase disorders after concussion.
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http://dx.doi.org/10.1016/B978-0-444-63954-7.00017-3DOI Listing
March 2019

Variation in TMEM106B in chronic traumatic encephalopathy.

Acta Neuropathol Commun 2018 11 4;6(1):115. Epub 2018 Nov 4.

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

The genetic basis of chronic traumatic encephalopathy (CTE) is poorly understood. Variation in transmembrane protein 106B (TMEM106B) has been associated with enhanced neuroinflammation during aging and with TDP-43-related neurodegenerative disease, and rs3173615, a missense coding SNP in TMEM106B, has been implicated as a functional variant in these processes. Neuroinflammation and TDP-43 pathology are prominent features in CTE. The purpose of this study was to determine whether genetic variation in TMEM106B is associated with CTE risk, pathological features, and ante-mortem dementia. Eighty-six deceased male athletes with a history of participation in American football, informant-reported Caucasian, and a positive postmortem diagnosis of CTE without comorbid neurodegenerative disease were genotyped for rs3173615. The minor allele frequency (MAF = 0.42) in participants with CTE did not differ from previously reported neurologically normal controls (MAF = 0.43). However, in a case-only analysis among CTE cases, the minor allele was associated with reduced phosphorylated tau (ptau) pathology in the dorsolateral frontal cortex (DLFC) (AT8 density, odds ratio [OR] of increasing one quartile = 0.42, 95% confidence interval [CI] 0.22-0.79, p = 0.008), reduced neuroinflammation in the DLFC (CD68 density, OR of increasing one quartile = 0.53, 95% CI 0.29-0.98, p = 0.043), and increased synaptic protein density (β = 0.306, 95% CI 0.065-0.546, p = 0.014). Among CTE cases, TMEM106B minor allele was also associated with reduced ante-mortem dementia (OR = 0.40, 95% CI 0.16-0.99, p = 0.048), but was not associated with TDP-43 pathology. All case-only models were adjusted for age at death and duration of football play. Taken together, variation in TMEM106B may have a protective effect on CTE-related outcomes.
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http://dx.doi.org/10.1186/s40478-018-0619-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6215686PMC
November 2018

Comprehensive Systematic Review Update Summary: Disorders of Consciousness: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology; the American Congress of Rehabilitation Medicine; and the National Institute on Disability, Independent Living, and Rehabilitation Research.

Arch Phys Med Rehabil 2018 09 8;99(9):1710-1719. Epub 2018 Aug 8.

Department of Neurology, University of Florida College of Medicine, Gainesville.

Objective: To update the 1995 American Academy of Neurology (AAN) practice parameter on persistent vegetative state and the 2002 case definition for the minimally conscious state (MCS) by reviewing the literature on the diagnosis, natural history, prognosis, and treatment of disorders of consciousness lasting at least 28 days.

Methods: Articles were classified per the AAN evidence-based classification system. Evidence synthesis occurred through a modified Grading of Recommendations Assessment, Development and Evaluation process. Recommendations were based on evidence, related evidence, care principles, and inferences according to the AAN 2011 process manual, as amended.

Results: No diagnostic assessment procedure had moderate or strong evidence for use. It is possible that a positive EMG response to command, EEG reactivity to sensory stimuli, laser-evoked potentials, and the Perturbational Complexity Index can distinguish MCS from vegetative state/unresponsive wakefulness syndrome (VS/UWS). The natural history of recovery from prolonged VS/UWS is better in traumatic than nontraumatic cases. MCS is generally associated with a better prognosis than VS (conclusions of low to moderate confidence in adult populations), and traumatic injury is generally associated with a better prognosis than nontraumatic injury (conclusions of low to moderate confidence in adult and pediatric populations). Findings concerning other prognostic features are stratified by etiology of injury (traumatic vs nontraumatic) and diagnosis (VS/UWS vs MCS) with low to moderate degrees of confidence. Therapeutic evidence is sparse. Amantadine probably hastens functional recovery in patients with MCS or VS/UWS secondary to severe traumatic brain injury over 4 weeks of treatment. Recommendations are presented separately.
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http://dx.doi.org/10.1016/j.apmr.2018.07.002DOI Listing
September 2018

Practice Guideline Update Recommendations Summary: Disorders of Consciousness: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology; the American Congress of Rehabilitation Medicine; and the National Institute on Disability, Independent Living, and Rehabilitation Research.

Arch Phys Med Rehabil 2018 09 8;99(9):1699-1709. Epub 2018 Aug 8.

Department of Neurology, University of Florida College of Medicine, Gainesville.

Objective: To update the 1995 American Academy of Neurology (AAN) practice parameter on persistent vegetative state and the 2002 case definition on minimally conscious state (MCS) and provide care recommendations for patients with prolonged disorders of consciousness (DoC).

Methods: Recommendations were based on systematic review evidence, related evidence, care principles, and inferences using a modified Delphi consensus process according to the AAN 2011 process manual, as amended.

Recommendations: Clinicians should identify and treat confounding conditions, optimize arousal, and perform serial standardized assessments to improve diagnostic accuracy in adults and children with prolonged DoC (Level B). Clinicians should counsel families that for adults, MCS (vs vegetative state [VS]/ unresponsive wakefulness syndrome [UWS]) and traumatic (vs nontraumatic) etiology are associated with more favorable outcomes (Level B). When prognosis is poor, long-term care must be discussed (Level A), acknowledging that prognosis is not universally poor (Level B). Structural MRI, SPECT, and the Coma Recovery Scale-Revised can assist prognostication in adults (Level B); no tests are shown to improve prognostic accuracy in children. Pain always should be assessed and treated (Level B) and evidence supporting treatment approaches discussed (Level B). Clinicians should prescribe amantadine (100-200 mg bid) for adults with traumatic VS/UWS or MCS (4-16 weeks post injury) to hasten functional recovery and reduce disability early in recovery (Level B). Family counseling concerning children should acknowledge that natural history of recovery, prognosis, and treatment are not established (Level B). Recent evidence indicates that the term chronic VS/UWS should replace permanent VS, with duration specified (Level B). Additional recommendations are included.
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September 2018

Practice guideline update recommendations summary: Disorders of consciousness: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology; the American Congress of Rehabilitation Medicine; and the National Institute on Disability, Independent Living, and Rehabilitation Research.

Neurology 2018 09 8;91(10):450-460. Epub 2018 Aug 8.

From the Department of Physical Medicine and Rehabilitation (J.T.G.), Spaulding Rehabilitation Hospital and Harvard Medical School; Department of Psychiatry (J.T.G.), Massachusetts General Hospital, Boston; Department of Neurology (D.I.K.), Boston University School of Medicine; Braintree Rehabilitation Hospital (D.I.K.), MA; Department of Neurology and Neuroscience (N.D.S.), Weill Cornell Medical College, New York, NY; Moss Rehabilitation Research Institute (J.W.), Elkins Park, PA; Bronson Neuroscience Center (E.J.A.), Bronson Methodist Hospital, Kalamazoo, MI; Department of Pediatrics, Division of Child Neurology (S.A.), Loma Linda University School of Medicine, CA; Department of Neurology (R.B.), University of Rochester Medical Center, NY; Indiana University Department of Physical Medicine & Rehabilitation (F.M.H.), University of Indiana School of Medicine, Indianapolis; Coma Science Group-GIGA Research and Department of Neurology (S.L.), Sart Tillman Liège University & University Hospital, Liège, Belgium; Department of Neurology (G.S.F.L.), Uniformed Services University of Health Sciences, Bethesda; Department of Neurology (G.S.F.L.), Johns Hopkins University, Baltimore, MD; James A. Haley Veterans' Hospital (R.N.-R.), US Department of Veterans Affairs, Tampa, FL; Crawford Research Institute (R.T.S.), Shepherd Center, Atlanta, GA; Center for Rehabilitation Science and Engineering, Department of Physical Medicine & Rehabilitation (R.T.S.), Virginia Commonwealth University School of Medicine, Richmond; Division of Physical Medicine & Rehabilitation (S.Y.), University of Mississippi School of Medicine; Brain Injury Program (S.Y.), Methodist Rehabilitation Center, Jackson, MS; Heart Rhythm Society (T.S.D.G.), Washington, DC; Department of Neurology (G.S.G.), University of Kansas Medical Center, Kansas City; and Department of Neurology (M.J.A.), University of Florida College of Medicine, Gainesville.

Objective: To update the 1995 American Academy of Neurology (AAN) practice parameter on persistent vegetative state and the 2002 case definition on minimally conscious state (MCS) and provide care recommendations for patients with prolonged disorders of consciousness (DoC).

Methods: Recommendations were based on systematic review evidence, related evidence, care principles, and inferences using a modified Delphi consensus process according to the AAN 2011 process manual, as amended.

Recommendations: Clinicians should identify and treat confounding conditions, optimize arousal, and perform serial standardized assessments to improve diagnostic accuracy in adults and children with prolonged DoC (Level B). Clinicians should counsel families that for adults, MCS (vs vegetative state [VS]/unresponsive wakefulness syndrome [UWS]) and traumatic (vs nontraumatic) etiology are associated with more favorable outcomes (Level B). When prognosis is poor, long-term care must be discussed (Level A), acknowledging that prognosis is not universally poor (Level B). Structural MRI, SPECT, and the Coma Recovery Scale-Revised can assist prognostication in adults (Level B); no tests are shown to improve prognostic accuracy in children. Pain always should be assessed and treated (Level B) and evidence supporting treatment approaches discussed (Level B). Clinicians should prescribe amantadine (100-200 mg bid) for adults with traumatic VS/UWS or MCS (4-16 weeks post injury) to hasten functional recovery and reduce disability early in recovery (Level B). Family counseling concerning children should acknowledge that natural history of recovery, prognosis, and treatment are not established (Level B). Recent evidence indicates that the term chronic VS/UWS should replace permanent VS, with duration specified (Level B). Additional recommendations are included.
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http://dx.doi.org/10.1212/WNL.0000000000005926DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6139814PMC
September 2018

Comprehensive systematic review update summary: Disorders of consciousness: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology; the American Congress of Rehabilitation Medicine; and the National Institute on Disability, Independent Living, and Rehabilitation Research.

Neurology 2018 09 8;91(10):461-470. Epub 2018 Aug 8.

From the Department of Physical Medicine and Rehabilitation (J.T.G.), Spaulding Rehabilitation Hospital and Harvard Medical School; Department of Psychiatry (J.T.G.), Massachusetts General Hospital, Boston; Department of Neurology (D.I.K.), Boston University School of Medicine; Braintree Rehabilitation Hospital (D.I.K.), MA; Department of Neurology and Neuroscience (N.D.S.), Weill Cornell Medical College, New York, NY; Moss Rehabilitation Research Institute (J.W.), Elkins Park, PA; Bronson Neuroscience Center (E.J.A.), Bronson Methodist Hospital, Kalamazoo, MI; Department of Pediatrics, Division of Child Neurology (S.A.), Loma Linda University School of Medicine, CA; Department of Neurology (R.B.), University of Rochester Medical Center, NY; Indiana University Department of Physical Medicine & Rehabilitation (F.M.H.), University of Indiana School of Medicine, Indianapolis; Coma Science Group-GIGA Research and Department of Neurology (S.L.), Sart Tillman Liège University & University Hospital, Liège, Belgium; Department of Neurology (G.S.F.L.), Uniformed Services University of Health Sciences, Bethesda; Department of Neurology (G.S.F.L.), Johns Hopkins University, Baltimore, MD; James A. Haley Veterans' Hospital (R.N.-R.), US Department of Veterans Affairs, Tampa, FL; Crawford Research Institute (R.T.S.), Shepherd Center, Atlanta, GA; Center for Rehabilitation Science and Engineering, Department of Physical Medicine & Rehabilitation (R.T.S.), Virginia Commonwealth University School of Medicine, Richmond; Division of Physical Medicine & Rehabilitation (S.Y.), University of Mississippi School of Medicine; Brain Injury Program (S.Y.), Methodist Rehabilitation Center, Jackson, MS; Heart Rhythm Society (T.S.D.G.), Washington, DC; Department of Neurology (G.S.G.), University of Kansas Medical Center, Kansas City; and Department of Neurology (M.J.A.), University of Florida College of Medicine, Gainesville.

Objective: To update the 1995 American Academy of Neurology (AAN) practice parameter on persistent vegetative state and the 2002 case definition for the minimally conscious state (MCS) by reviewing the literature on the diagnosis, natural history, prognosis, and treatment of disorders of consciousness lasting at least 28 days.

Methods: Articles were classified per the AAN evidence-based classification system. Evidence synthesis occurred through a modified Grading of Recommendations Assessment, Development and Evaluation process. Recommendations were based on evidence, related evidence, care principles, and inferences according to the AAN 2011 process manual, as amended.

Results: No diagnostic assessment procedure had moderate or strong evidence for use. It is possible that a positive EMG response to command, EEG reactivity to sensory stimuli, laser-evoked potentials, and the Perturbational Complexity Index can distinguish MCS from vegetative state/unresponsive wakefulness syndrome (VS/UWS). The natural history of recovery from prolonged VS/UWS is better in traumatic than nontraumatic cases. MCS is generally associated with a better prognosis than VS (conclusions of low to moderate confidence in adult populations), and traumatic injury is generally associated with a better prognosis than nontraumatic injury (conclusions of low to moderate confidence in adult and pediatric populations). Findings concerning other prognostic features are stratified by etiology of injury (traumatic vs nontraumatic) and diagnosis (VS/UWS vs MCS) with low to moderate degrees of confidence. Therapeutic evidence is sparse. Amantadine probably hastens functional recovery in patients with MCS or VS/UWS secondary to severe traumatic brain injury over 4 weeks of treatment. Recommendations are presented separately.
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http://dx.doi.org/10.1212/WNL.0000000000005928DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6139817PMC
September 2018

Lewy Body Pathology and Chronic Traumatic Encephalopathy Associated With Contact Sports.

J Neuropathol Exp Neurol 2018 09;77(9):757-768

Department of Neurology.

Traumatic brain injury has been associated with increased risk of Parkinson disease and parkinsonism, and parkinsonism and Lewy body disease (LBD) can occur with chronic traumatic encephalopathy (CTE). To test whether contact sports and CTE are associated with LBD, we compared deceased contact sports athletes (n = 269) to cohorts from the community (n = 164) and the Boston University Alzheimer disease (AD) Center (n = 261). Participants with CTE and LBD were more likely to have β-amyloid deposition, dementia, and parkinsonism than CTE alone (p < 0.05). Traditional and hierarchical clustering showed a similar pattern of LBD distribution in CTE compared to LBD alone that was most frequently neocortical, limbic, or brainstem. In the community-based cohort, years of contact sports play were associated with neocortical LBD (OR = 1.30 per year, p = 0.012), and in a pooled analysis a threshold of >8 years of play best predicted neocortical LBD (ROC analysis, OR = 6.24, 95% CI = 1.5-25, p = 0.011), adjusting for age, sex, and APOE ɛ4 allele status. Clinically, dementia was significantly associated with neocortical LBD, CTE stage, and AD; parkinsonism was associated with LBD pathology but not CTE stage. Contact sports participation may increase risk of developing neocortical LBD, and increased LBD frequency may partially explain extrapyramidal motor symptoms sometimes observed in CTE.
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http://dx.doi.org/10.1093/jnen/nly065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6097837PMC
September 2018

Age of first exposure to tackle football and chronic traumatic encephalopathy.

Ann Neurol 2018 05;83(5):886-901

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

Objective: To examine the effect of age of first exposure to tackle football on chronic traumatic encephalopathy (CTE) pathological severity and age of neurobehavioral symptom onset in tackle football players with neuropathologically confirmed CTE.

Methods: The sample included 246 tackle football players who donated their brains for neuropathological examination. Two hundred eleven were diagnosed with CTE (126 of 211 were without comorbid neurodegenerative diseases), and 35 were without CTE. Informant interviews ascertained age of first exposure and age of cognitive and behavioral/mood symptom onset.

Results: Analyses accounted for decade and duration of play. Age of exposure was not associated with CTE pathological severity, or Alzheimer's disease or Lewy body pathology. In the 211 participants with CTE, every 1 year younger participants began to play tackle football predicted earlier reported cognitive symptom onset by 2.44 years (p < 0.0001) and behavioral/mood symptoms by 2.50 years (p < 0.0001). Age of exposure before 12 predicted earlier cognitive (p < 0.0001) and behavioral/mood (p < 0.0001) symptom onset by 13.39 and 13.28 years, respectively. In participants with dementia, younger age of exposure corresponded to earlier functional impairment onset. Similar effects were observed in the 126 CTE-only participants. Effect sizes were comparable in participants without CTE.

Interpretation: In this sample of deceased tackle football players, younger age of exposure to tackle football was not associated with CTE pathological severity, but predicted earlier neurobehavioral symptom onset. Youth exposure to tackle football may reduce resiliency to late-life neuropathology. These findings may not generalize to the broader tackle football population, and informant-report may have affected the accuracy of the estimated effects. Ann Neurol 2018;83:886-901.
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http://dx.doi.org/10.1002/ana.25245DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6367933PMC
May 2018

Dementia After Moderate-Severe Traumatic Brain Injury: Coexistence of Multiple Proteinopathies.

J Neuropathol Exp Neurol 2018 Jan;77(1):50-63

Department of Neurology; Department of Pathology, F. Edward Hébert School of Medicine; Center for Neuroscience and Regenerative Medicine (CNRM), Uniformed Services University of the Health Sciences (USUHS), Bethesda, Maryland; The Henry M. Jackson Foundation for the Advancement of Military Research (HJF); Center for Neurotechnology and Neurorecovery, Department of Neurology, Massachusetts General Hospital, Boston Massachusetts; Department of Radiology, Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts; Department of Neurology; Alzheimer's Disease Center and CTE Program, Boston University School of Medicine, Boston, Massachusetts; Department of Neurology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania;Department of Rehabilitation Medicine; Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, New York; Radiological Sciences Laboratory, Department of Radiology, Stanford University, Stanford, California; Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Boston, Massachusetts; VA Boston Healthcare System, Boston, Massachusetts; and Department of Pathology, Boston University School of Medicine, Boston, Massachusetts.

We report the clinical, neuroimaging, and neuropathologic characteristics of 2 patients who developed early onset dementia after a moderate-severe traumatic brain injury (TBI). Neuropathological evaluation revealed abundant β-amyloid neuritic and cored plaques, diffuse β-amyloid plaques, and frequent hyperphosphorylated-tau neurofibrillary tangles (NFT) involving much of the cortex, including insula and mammillary bodies in both cases. Case 1 additionally showed NFTs in both the superficial and deep cortical layers, occasional perivascular and depth-of-sulci NFTs, and parietal white matter rarefaction, which corresponded with decreased parietal fiber tracts observed on ex vivo MRI. Case 2 additionally showed NFT predominance in the superficial layers of the cortex, hypothalamus and brainstem, diffuse Lewy bodies in the cortex, amygdala and brainstem, and intraneuronal TDP-43 inclusions. The neuropathologic diagnoses were atypical Alzheimer disease (AD) with features of chronic traumatic encephalopathy and white matter loss (Case 1), and atypical AD, dementia with Lewy bodies and coexistent TDP-43 pathology (Case 2). These findings support an epidemiological association between TBI and dementia and further characterize the variety of misfolded proteins that may accumulate after TBI. Analyses with comprehensive clinical, imaging, genetic, and neuropathological data are required to characterize the full clinicopathological spectrum associated with dementias occurring after moderate-severe TBI.
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http://dx.doi.org/10.1093/jnen/nlx101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5939622PMC
January 2018

Clinicopathological Evaluation of Chronic Traumatic Encephalopathy in Players of American Football.

JAMA 2017 07;318(4):360-370

Boston University Alzheimer's Disease and CTE Center, Boston University School of Medicine, Boston, Massachusetts2Department of Neurology, Boston University School of Medicine, Boston, Massachusetts4VA Boston Healthcare System, US Department of Veteran Affairs, Boston, Massachusetts5Department of Veterans Affairs Medical Center, Bedford, Massachusetts12Department of Pathology, Boston University School of Medicine, Boston, Massachusetts23Boston University School of Medicine, Boston, Massachusetts.

Importance: Players of American football may be at increased risk of long-term neurological conditions, particularly chronic traumatic encephalopathy (CTE).

Objective: To determine the neuropathological and clinical features of deceased football players with CTE.

Design, Setting, And Participants: Case series of 202 football players whose brains were donated for research. Neuropathological evaluations and retrospective telephone clinical assessments (including head trauma history) with informants were performed blinded. Online questionnaires ascertained athletic and military history.

Exposures: Participation in American football at any level of play.

Main Outcomes And Measures: Neuropathological diagnoses of neurodegenerative diseases, including CTE, based on defined diagnostic criteria; CTE neuropathological severity (stages I to IV or dichotomized into mild [stages I and II] and severe [stages III and IV]); informant-reported athletic history and, for players who died in 2014 or later, clinical presentation, including behavior, mood, and cognitive symptoms and dementia.

Results: Among 202 deceased former football players (median age at death, 66 years [interquartile range, 47-76 years]), CTE was neuropathologically diagnosed in 177 players (87%; median age at death, 67 years [interquartile range, 52-77 years]; mean years of football participation, 15.1 [SD, 5.2]), including 0 of 2 pre-high school, 3 of 14 high school (21%), 48 of 53 college (91%), 9 of 14 semiprofessional (64%), 7 of 8 Canadian Football League (88%), and 110 of 111 National Football League (99%) players. Neuropathological severity of CTE was distributed across the highest level of play, with all 3 former high school players having mild pathology and the majority of former college (27 [56%]), semiprofessional (5 [56%]), and professional (101 [86%]) players having severe pathology. Among 27 participants with mild CTE pathology, 26 (96%) had behavioral or mood symptoms or both, 23 (85%) had cognitive symptoms, and 9 (33%) had signs of dementia. Among 84 participants with severe CTE pathology, 75 (89%) had behavioral or mood symptoms or both, 80 (95%) had cognitive symptoms, and 71 (85%) had signs of dementia.

Conclusions And Relevance: In a convenience sample of deceased football players who donated their brains for research, a high proportion had neuropathological evidence of CTE, suggesting that CTE may be related to prior participation in football.
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http://dx.doi.org/10.1001/jama.2017.8334DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5807097PMC
July 2017

Cognitive Reserve as a Modifier of Clinical Expression in Chronic Traumatic Encephalopathy: A Preliminary Examination.

J Neuropsychiatry Clin Neurosci 2017 19;29(1):6-12. Epub 2016 Aug 19.

From Boston University Alzheimer's Disease and CTE Center, Boston University School of Medicine, Boston (MLA, JM, NWK, TDS, LEG, RCC, TMS, PTK, LM, BA, DD, PHM, CJN, RAS, ACM); the Department of Neurology, Boston University School of Medicine, Boston (MLA, JM, NWK, TDS, LEG, DIK, TMS, PTK, LM, BA, DD, PHM, RAS, ACM); Internal Medicine Department, North Shore Medical Center (DD); the VA Boston Healthcare System, U.S. Department of Veteran Affairs, Boston (NWK, TDS, ACM); the Departments of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston (NWK, TDS, ACM); the Department of Veterans Affairs Medical Center, Bedford, Mass. (TDS, ACM); the Departments of Psychiatry and Ophthalmology, Boston University School of Medicine, Boston (LEG); the Departments of Biomedical, Electrical & Computer Engineering, Boston University College of Engineering, Boston (LEG); the Concussion Legacy Foundation (RCC, CJN); the Department of Neurosurgery, Boston University School of Medicine, Boston (RAS); the Department of Neurosurgery, Emerson Hospital, Concord, Mass. (RCC); Braintree Rehabilitation Hospital, Braintree, Mass. (DIK); and the Department of Anatomy and Neurobiology, Boston University School of Medicine, Boston (PHM, RAS).

This study conducted a preliminary examination on cognitive reserve (CR) as a modifier of symptom expression in subjects with autopsy-confirmed chronic traumatic encephalopathy (CTE). The sample included 25 former professional football players neuropathologically diagnosed with CTE stage III or IV. Next of kin interviews ascertained age at cognitive and behavioral/mood symptom onset and demographic/athletic characteristics. Years of education and occupational attainment defined CR. High occupational achievement predicted later age at cognitive (p=0.02) and behavioral/mood (p=0.02) onset. Education was not an individual predictor. These preliminary findings suggest that CR may forestall the clinical manifestation of CTE.
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http://dx.doi.org/10.1176/appi.neuropsych.16030043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5288278PMC
April 2017

Individuals With Traumatic Brain Injury and Their Significant Others' Perceptions of Information Given About the Nature and Possible Consequences of Brain Injury: Analysis of a National Survey.

Prof Case Manag 2016 Jan-Feb;21(1):22-33; quiz E3-4

Rosette C. Biester, PhD, is Clinical Associate Professor in Physical Medicine and Rehabilitation at the University of Pennsylvania School of Medicine and senior Polytrauma Neuropsychologist at the Michael Crescentz Veteran's Affairs Medical Center. Dr Biester's expertise and contributions to the field of brain injury rehabilitation are recognized nationally, with more than 28 years of experience in clinical care, research, and teaching/training areas. Her current clinical focus is on evaluation and specialized treatment of veterans with dual diagnoses of traumatic brain injury (TBI) and posttraumatic stress disorder. Her research has focused on assessment of cognitive functioning in mild TBI, outcomes associated with blast-related injuries, challenges in communicating diagnostic and prognostic TBI information, and the association between neuroradiological and neurocognitive outcomes. David Krych, MS-CCC-SLP, CBIS, is a speech and language pathologist who has served people with brain injuries for the past 35 years. Dave's contributions to the field of brain injury rehabilitation-particularly post-acute rehabilitation-are numerous, and his pioneering and ongoing accomplishments have been widely recognized by his alma mater and professional associations to which he has dedicated many years of service. Currently, Dave serves on the Executive Team at ReMed Recovery Care Centers. Dave has presented extensively in the United States and abroad and has published on a number of brain injury-related topics. M.J. Schmidt, MA, CBIS, is both a family member of someone with a brain injury and a professional with more than 25 years of experience in the field. Schmidt has worked in acute and post-acute rehabilitation, as a researcher, and most recently with individuals who are incarcerated. Schmidt is a graduate of Southern Illinois University, with a master's degree in Rehabilitation Administration and Services. She is a certified brain injury specialist and chairs the Council on B

Purpose Of The Study: An online survey was developed to assess how well individuals with brain injuries and family/friends of those with traumatic brain injury (TBI) (significant others) felt they were informed about the nature and consequences of brain injury.

Participants: A total of 117 significant others completed the survey. They were primarily female (84.6%), white (94.9%), and well educated (81.2%). A total of 149 individuals with brain injuries completed the survey and again were primarily female (63.8%), white (88.2%), and well educated (82.9%).

Results: More than half of the significant other respondents indicated that they were not provided enough information about TBI (53.5%). Up to 53.8% of the respondents with TBI felt that they were not provided enough information, with 43% reporting dissatisfaction with services. Female survivors and those with mild brain injuries were significantly more likely to feel that they were not provided sufficient rehabilitation or information. Increased satisfaction with services was correlated with decreased time since injury (r = -0.165, p = .049). Qualitative analysis revealed key themes about prognostic information and the adequacy of discharge planning and resources.

Implications For Case Management Practice: Given that more than half of all surveyed indicated that they were not well-informed about brain injury and its possible effects, it is evident that case managers and their teams need to be aware of and invested in their efforts to educate both individuals with brain injuries and their significant others (family and friends) about both the nature and consequences of brain injury. Specific recommendations for practice are included.
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http://dx.doi.org/10.1097/NCM.0000000000000121DOI Listing
January 2017

Assessing clinicopathological correlation in chronic traumatic encephalopathy: rationale and methods for the UNITE study.

Alzheimers Res Ther 2015 Oct 12;7(1):62. Epub 2015 Oct 12.

Alzheimer's Disease Center, Boston University School of Medicine, 72 East Concord Street, B-7800, Boston, MA, 02118, USA.

Introduction: Chronic traumatic encephalopathy (CTE) is a progressive neurodegeneration associated with repetitive head impacts. Understanding Neurologic Injury and Traumatic Encephalopathy (UNITE) is a U01 project recently funded by the National Institute of Neurological Disorders and Stroke and the National Institute of Biomedical Imaging and Bioengineering. The goal of the UNITE project is to examine the neuropathology and clinical presentation of brain donors designated as "at risk" for the development of CTE based on prior athletic or military exposure. Here, we present the rationale and methodology for UNITE.

Methods: Over the course of 4 years, we will analyze the brains and spinal cords of 300 deceased subjects who had a history of repetitive head impacts sustained during participation in contact sports at the professional or collegiate level or during military service. Clinical data are collected through medical record review and retrospective structured and unstructured family interviews conducted by a behavioral neurologist or neuropsychologist. Blinded to the clinical data, a neuropathologist conducts a comprehensive assessment for neurodegenerative disease, including CTE, using published criteria. At a clinicopathological conference, a panel of physicians and neuropsychologists, blinded to the neuropathological data, reaches a clinical consensus diagnosis using published criteria, including proposed clinical research criteria for CTE.

Results: We will investigate the validity of these clinical criteria and sources of error by using recently validated neuropathological criteria as a gold standard for CTE diagnosis. We also will use statistical modeling to identify diagnostic features that best predict CTE pathology.

Conclusions: The UNITE study is a novel and methodologically rigorous means of assessing clinicopathological correlation in CTE. Our findings will be critical for developing future iterations of CTE clinical diagnostic criteria.
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http://dx.doi.org/10.1186/s13195-015-0148-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4601147PMC
October 2015

Mild traumatic brain injury.

Handb Clin Neurol 2015 ;127:131-56

Concussion/TBI Program, Beth Israel Deaconess Medical Center, Boston, MA, USA; Spaulding Hospital Cambridge, Cambridge, MA, USA; Department of Neurology, Harvard Medical School, Boston, MA, USA.

Mild traumatic brain injury (TBI) is common but accurate diagnosis and defining criteria for mild TBI and its clinical consequences have been problematic. Mild TBI causes transient neurophysiologic brain dysfunction, sometimes with structural axonal and neuronal damage. Biomarkers, such as newer imaging technologies and protein markers, are promising indicators of brain injury but are not ready for clinical use. Diagnosis relies on clinical criteria regarding depth and duration of impaired consciousness and amnesia. These criteria are particularly difficult to confirm at the least severe end of the mild TBI continuum, especially when relying on subjective, retrospective accounts. The postconcussive syndrome is a controversial concept because of varying criteria, inconsistent symptom clusters and the evidence that similar symptom profiles occur with other disorders, and even in a proportion of healthy individuals. The clinical consequences of mild TBI can be conceptualized as two multidimensional disorders: (1) a constellation of acute symptoms that might be termed early phase post-traumatic disorder (e.g., headache, dizziness, imbalance, fatigue, sleep disruption, impaired cognition), that typically resolve in days to weeks and are largely related to brain trauma and concomitant injuries; (2) a later set of symptoms, a late phase post-traumatic disorder, evolving out of the early phase in a minority of patients, with a more prolonged (months to years), sometimes worsening set of somatic, emotional, and cognitive symptoms. The later phase disorder is highly influenced by a variety of psychosocial factors and has little specificity for brain injury, although a history of multiple concussions seems to increase the risk of more severe and longer duration symptoms. Effective early phase management may prevent or limit the later phase disorder and should include education about symptoms and expectations for recovery, as well as recommendations for activity modifications. Later phase treatment should be informed by thoughtful differential diagnosis and the multiplicity of premorbid and comorbid conditions that may influence symptoms. Treatment should incorporate a hierarchical, sequential approach to symptom management, prioritizing problems with significant functional impact and effective, available interventions (e.g., headache, depression, anxiety, insomnia, vertigo).
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http://dx.doi.org/10.1016/B978-0-444-52892-6.00009-XDOI Listing
August 2016

Clinical subtypes of chronic traumatic encephalopathy: literature review and proposed research diagnostic criteria for traumatic encephalopathy syndrome.

Alzheimers Res Ther 2014 24;6(5):68. Epub 2014 Sep 24.

Department of Anatomy and Neurobiology, Boston University School of Medicine, 72 East Concord Street, Boston 02118, MA, USA ; BU Alzheimer's Disease Center, Boston University School of Medicine, 72 East Concord Street, Boston 02118, MA, USA ; Department of Neurology, Boston University School of Medicine, 72 East Concord Street, Boston 02118, MA, USA ; Department of Neurosurgery, Boston University School of Medicine, 73 East Concord Street, Boston 02118, MA, USA.

The long-term consequences of repetitive head impacts have been described since the early 20th century. Terms such as punch drunk and dementia pugilistica were first used to describe the clinical syndromes experienced by boxers. A more generic designation, chronic traumatic encephalopathy (CTE), has been employed since the mid-1900s and has been used in recent years to describe a neurodegenerative disease found not just in boxers but in American football players, other contact sport athletes, military veterans, and others with histories of repetitive brain trauma, including concussions and subconcussive trauma. This article reviews the literature of the clinical manifestations of CTE from 202 published cases. The clinical features include impairments in mood (for example, depression and hopelessness), behavior (for example, explosivity and violence), cognition (for example, impaired memory, executive functioning, attention, and dementia), and, less commonly, motor functioning (for example, parkinsonism, ataxia, and dysarthria). We present proposed research criteria for traumatic encephalopathy syndrome (TES) which consist of four variants or subtypes (TES behavioral/mood variant, TES cognitive variant, TES mixed variant, and TES dementia) as well as classifications of 'probable CTE' and 'possible CTE'. These proposed criteria are expected to be modified and updated as new research findings become available. They are not meant to be used for a clinical diagnosis. Rather, they should be viewed as research criteria that can be employed in studies of the underlying causes, risk factors, differential diagnosis, prevention, and treatment of CTE and related disorders.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4288217PMC
January 2015

Common resting brain dynamics indicate a possible mechanism underlying zolpidem response in severe brain injury.

Elife 2013 Nov 19;2:e01157. Epub 2013 Nov 19.

Department of Neurology and Neuroscience, Weill Cornell Medical College, New York, United States.

Zolpidem produces paradoxical recovery of speech, cognitive and motor functions in select subjects with severe brain injury but underlying mechanisms remain unknown. In three diverse patients with known zolpidem responses we identify a distinctive pattern of EEG dynamics that suggests a mechanistic model. In the absence of zolpidem, all subjects show a strong low frequency oscillatory peak ∼6-10 Hz in the EEG power spectrum most prominent over frontocentral regions and with high coherence (∼0.7-0.8) within and between hemispheres. Zolpidem administration sharply reduces EEG power and coherence at these low frequencies. The ∼6-10 Hz activity is proposed to arise from intrinsic membrane properties of pyramidal neurons that are passively entrained across the cortex by locally-generated spontaneous activity. Activation by zolpidem is proposed to arise from a combination of initial direct drug effects on cortical, striatal, and thalamic populations and further activation of underactive brain regions induced by restoration of cognitively-mediated behaviors. DOI: http://dx.doi.org/10.7554/eLife.01157.001.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3833342PMC
November 2013