Publications by authors named "Victor E Alvarez"

47 Publications

Altered oligodendroglia and astroglia in chronic traumatic encephalopathy.

Acta Neuropathol 2021 May 21. Epub 2021 May 21.

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

Chronic traumatic encephalopathy (CTE) is a progressive tauopathy found in contact sport athletes, military veterans, and others exposed to repetitive head impacts. White matter rarefaction and axonal loss have been reported in CTE but have not been characterized on a molecular or cellular level. Here, we present RNA sequencing profiles of cell nuclei from postmortem dorsolateral frontal white matter from eight individuals with neuropathologically confirmed CTE and eight age- and sex-matched controls. Analyzing these profiles using unbiased clustering approaches, we identified eighteen transcriptomically distinct cell groups (clusters), reflecting cell types and/or cell states, of which a subset showed differences between CTE and control tissue. Independent in situ methods applied on tissue sections adjacent to that used in the single-nucleus RNA-seq work yielded similar findings. Oligodendrocytes were found to be most severely affected in the CTE white matter samples; they were diminished in number and altered in relative proportions across subtype clusters. Further, the CTE-enriched oligodendrocyte population showed greater abundance of transcripts relevant to iron metabolism and cellular stress response. CTE tissue also demonstrated excessive iron accumulation histologically. In astrocytes, total cell numbers were indistinguishable between CTE and control samples, but transcripts associated with neuroinflammation were elevated in the CTE astrocyte groups compared to controls. These results demonstrate specific molecular and cellular differences in CTE oligodendrocytes and astrocytes and suggest that white matter alterations are a critical aspect of CTE neurodegeneration.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00401-021-02322-2DOI Listing
May 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/alz.12338DOI Listing
April 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/jnen/nlab001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7899277PMC
February 2021

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12974-020-02036-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7718711PMC
December 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00401-020-02206-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7669574PMC
December 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00401-020-02197-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7914059PMC
October 2020

Reply to "Chronic Traumatic Encephalopathy and Primary Age-Related Tauopathy".

Ann Neurol 2020 11 22;88(5):1052-1053. Epub 2020 Aug 22.

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

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ana.25858DOI Listing
November 2020

Neuropathological profile of long-duration amyotrophic lateral sclerosis in military Veterans.

Brain Pathol 2020 11 4;30(6):1028-1040. Epub 2020 Aug 4.

VA Boston Healthcare System, Boston, MA.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder affecting both the upper and lower motor neurons. Although ALS typically leads to death within 3 to 5 years after initial symptom onset, approximately 10% of patients with ALS live more than 10 years after symptom onset. We set out to determine similarities and differences in clinical presentation and neuropathology in persons with ALS with long vs. those with standard duration. Participants were United States military Veterans with a pathologically confirmed diagnosis of ALS (n = 179), dichotomized into standard duration (<10 years) and long-duration (≥10 years). The ALS Functional Rating Scale-Revised (ALSFRS-R) was administered at study entry and semi-annually thereafter until death. Microglial density was determined in a subset of participants. long-duration ALS occurred in 76 participants (42%) with a mean disease duration of 16.3 years (min/max = 10.1/42.2). Participants with long-duration ALS were younger at disease onset (P = 0.002), had a slower initial ALS symptom progression on the ALSFRS-R (P < 0.001) and took longer to diagnose (P < 0.002) than standard duration ALS. Pathologically, long-duration ALS was associated with less frequent TDP-43 pathology (P < 0.001). Upper motor neuron degeneration was similar; however, long-duration ALS participants had less severe lower motor neuron degeneration at death (P < 0.001). In addition, the density of microglia was decreased in the corticospinal tract (P = 0.017) and spinal cord anterior horn (P = 0.009) in long-duration ALS. Notably, many neuropathological markers of ALS were similar between the standard and long-duration groups and there was no difference in the frequency of known ALS genetic mutations. These findings suggest that the lower motor neuron system is relatively spared in long-duration ALS and that pathological progression is likely slowed by as yet unknown genetic and environmental modifiers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/bpa.12876DOI Listing
November 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/bpa.12867DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7484331PMC
September 2020

Alterations of transcriptome signatures in head trauma-related neurodegenerative disorders.

Sci Rep 2020 06 1;10(1):8811. Epub 2020 Jun 1.

Gong-Wu Genomic Medicine Institute, Seoul National University Bundang Hospital, Seongnam, 13605, Republic of Korea.

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease that is associated with repetitive traumatic brain injury (TBI). CTE is known to share similar neuropathological features with Alzheimer's disease (AD), but little is known about the molecular properties in CTE. To better understand the neuropathological mechanism of TBI-related disorders, we conducted transcriptome sequencing analysis of CTE including AD and CTE with AD (CTE/AD) post-mortem human brain samples. Through weighted gene co-expression network analysis (WGCNA) and principal component analysis (PCA), we characterized common and unique transcriptome signatures among CTE, CTE/AD, and AD. Interestingly, synapse signaling-associated gene signatures (such as synaptotagmins) were commonly down-regulated in CTE, CTE/AD, and AD. Quantitative real-time PCR (qPCR) and Western blot analyses confirmed that the levels of synaptotagmin 1 (SYT1) were markedly decreased in CTE and AD compared to normal. In addition, calcium/calmodulin-dependent protein kinase II (CaMKII), protein kinase A (PKA), protein kinase C (PKC), and AMPA receptor genes that play a pivotal role in memory function, were down-regulated in head trauma-related disorders. On the other hand, up-regulation of cell adhesion molecules (CAMs) associated genes was only found in CTE. Our results indicate that dysregulation of synaptic transmission- and memory function-related genes are closely linked to the pathology of head injury-related disorder and AD. Alteration of CAMs-related genes may be specific pathological markers for the CTE pathology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-020-65916-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7264177PMC
June 2020

Labyrinthine concussion: Historic otopathologic antecedents of a challenging diagnosis.

Laryngoscope Investig Otolaryngol 2020 Apr 16;5(2):267-277. Epub 2020 Mar 16.

Department of Otolaryngology Harvard Medical School Boston Massachusetts.

Objective: The term "labyrinthine concussion" has evolved to mean audiovestibular dysfunction in the absence of a temporal bone fracture (TBF). Despite a multitude of case descriptions of labyrinthine concussion, the precise pathophysiology remains poorly understood. Herein, we explore the historical otopathologic underpinnings of the diagnosis of labyrinthine concussion with a focus on the auditory pathway during the late 19th to the mid-20th centuries and conclude with a discussion of its contemporary relevance.

Methods And Data Sources: A review of primary and secondary medical sources written in English, German, and French on otopathology labyrinthine concussion studies from the late-19th to the mid-20th centuries.

Results: Around the turn of the 20th century, otopathologists identified histologic changes in the temporal bones of individuals that sustained head injury without TBFs. Based on these otopathologic findings in humans, early experiments investigating the pathophysiology of labyrinthine concussion were performed in animals through either the delivery of blows to the head or direct introduction of a pressure wave into the labyrinthine fluid. Collectively, otopathologists hypothesized that predominant mechanisms for labyrinthine concussion included inner ear hemorrhage, cochleovestibular nerve traction injury, direct damage from a labyrinthine fluid pressure wave, or vasomotor dysfunction.

Conclusion: Historical study shows a variety of inner ear pathologies potentially responsible for auditory dysfunction following head injury. Understanding the history and otopathology of labyrinthine concussion may help clinicians focus on new pathways toward novel research and improved patient care.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/lio2.360DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7178453PMC
April 2020

Associations between brain inflammatory profiles and human neuropathology are altered based on apolipoprotein E ε4 genotype.

Sci Rep 2020 02 19;10(1):2924. Epub 2020 Feb 19.

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

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

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-020-59869-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7031423PMC
February 2020

Nonhomogeneous Gadolinium Retention in the Cerebral Cortex after Intravenous Administration of Gadolinium-based Contrast Agent in Rats and Humans.

Radiology 2020 02 26;294(2):377-385. Epub 2019 Nov 26.

From the Departments of Radiology (O.M., N.H., N.L., A.Z.M., C.W.F., X.L., J.A.M., H.J., A.G., J.A.S., S.W.A., L.E.G.), Neurology (A.C.M., L.E.G.), Pathology and Laboratory Medicine (V.E.A., B.R.H., A.C.M., L.E.G.), Behavioral Neuroscience (S.E.C.), and Anatomy and Neurobiology (K.J.B.), Boston University School of Medicine, 670 Albany St, Boston, MA 02118; Boston University Alzheimer's Disease Center, Boston, Mass (O.M., N.H., P.T.K., L.E.E., S.E.C., J.A.M., V.E.A., B.R.H., A.C.M., L.E.G.); VA Boston Healthcare System, Jamaica Plain, Mass (A.M.H., V.E.A., B.R.H., A.C.M.); Stroke Branch, National Institute of Neurologic Diseases and Stroke, National Institutes of Health, Bethesda, Md (A.D.G., L.L.L.); Center for Neuroscience and Regenerative Medicine, Uniformed Services University, Bethesda, Md (A.D.G., L.L.L.); and Center for Biometals and Metallomics (O.M., N.L., J.A.M., L.E.G.), College of Engineering (E.S.F., A.C.M., S.W.A., L.E.G.), and Photonics Center (O.M., J.A.M., S.W.A., L.E.G.), Boston University, Boston, Mass.

Background Gadolinium retention after repeated gadolinium-based contrast agent (GBCA) exposure has been reported in subcortical gray matter. However, gadolinium retention in the cerebral cortex has not been systematically investigated. Purpose To determine whether and where gadolinium is retained in rat and human cerebral cortex. Materials and Methods The cerebral cortex in Sprague-Dawley rats treated with gadopentetate dimeglumine (three doses over 4 weeks; cumulative gadolinium dose, 7.2 mmol per kilogram of body weight; = 6) or saline ( = 6) was examined with antemortem MRI. Two human donors with repeated GBCA exposure (three and 15 doses; 1 and 5 months after exposure), including gadopentetate dimeglumine, and two GBCA-naive donors were also evaluated. Elemental brain maps (gadolinium, phosphorus, zinc, copper, iron) for rat and human brains were constructed by using laser ablation inductively coupled plasma mass spectrometry. Results Gadopentetate dimeglumine-treated rats showed region-, subregion-, and layer-specific gadolinium retention in the neocortex (anterior cingulate cortex: mean gadolinium concentration, 0.28 µg ∙ g ± 0.04 [standard error of the mean]) that was comparable ( > .05) to retention in the allocortex (mean gadolinium concentration, 0.33 µg ∙ g ± 0.04 in piriform cortex, 0.24 µg ∙ g ± 0.04 in dentate gyrus, 0.17 µg ∙ g ± 0.04 in hippocampus) and subcortical structures (0.47 µg ∙ g ± 0.10 in facial nucleus, 0.39 µg ∙ g ± 0.10 in choroid plexus, 0.29 µg ∙ g ± 0.05 in caudate-putamen, 0.26 µg ∙ g ± 0.05 in reticular nucleus of the thalamus, 0.24 µg ∙ g ± 0.04 in vestibular nucleus) and significantly greater than that in the cerebellum (0.17 µg ∙ g ± 0.03, = .01) and white matter tracts (anterior commissure: 0.05 µg ∙ g ± 0.01, = .002; corpus callosum: 0.05 µg ∙ g ± 0.02, = .001; cranial nerve: 0.02 µg ∙ g ± 0.01, = .004). Retained gadolinium colocalized with parenchymal iron. T1-weighted MRI signal intensification was not observed. Gadolinium retention was detected in the cerebral cortex, pia mater, and pia-ensheathed leptomeningeal vessels in two GBCA-exposed human brains but not in two GBCA-naive human brains. Conclusion Repeated gadopentetate dimeglumine exposure is associated with gadolinium retention in specific regions, subregions, and layers of cerebral cortex that are critical for higher cognition, affect, and behavior regulation, sensorimotor coordination, and executive function. © RSNA, 2019 See also the editorial by Kanal in this issue.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1148/radiol.2019190461DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6996690PMC
February 2020

Mid-life and late-life vascular risk factor burden and neuropathology in old age.

Ann Clin Transl Neurol 2019 12 5;6(12):2403-2412. Epub 2019 Nov 5.

Framingham Heart Study, Framingham, Massachusetts.

Objective: To determine whether vascular risk factor burden in mid- or late-life associates with postmortem vascular and neurodegenerative pathologies in a community-based sample.

Methods: We studied participants from the Framingham Heart Study who participated in our voluntary brain bank program. Overall vascular risk factor burden was calculated using the Framingham Stroke Risk Profile (FSRP). Mid-life FSRP was measured at 50 to 60 years of age. Following death, brains were autopsied and semi-quantitatively assessed by board-certified neuropathologists for cerebrovascular outcomes (cortical infarcts, subcortical infarcts, atherosclerosis, arteriosclerosis) and Alzheimer's disease pathology (Braak stage, cerebral amyloid angiopathy, and neuritic plaque score). We estimated adjusted odds ratios between vascular risk burden (at mid-life and before death) and neuropathological outcomes using logistic and proportional-odds logistic models.

Results: The median time interval between FSRP and death was 33.4 years for mid-life FSRP and 4.4 years for final FSRP measurement before death. Higher mid-life vascular risk burden was associated with increased odds of all cerebrovascular pathology, even with adjustment for vascular risk burden before death. Late-life vascular risk burden was associated with increased odds of cortical infarcts (OR [95% CI]: 1.04 [1.00, 1.08]) and arteriosclerosis stage (OR [95% CI]: 1.03 [1.00, 1.05]). Mid-life vascular risk burden was not associated with Alzheimer's disease pathology, though late-life vascular risk burden was associated with increased odds of higher Braak stage (OR [95% CI]: 1.03 [1.01, 1.05]).

Interpretation: Mid-life vascular risk burden was predictive of cerebrovascular but not Alzheimer's disease neuropathology, even after adjustment for vascular risk factors before death.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/acn3.50936DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6917310PMC
December 2019

[F]-AV-1451 binding profile in chronic traumatic encephalopathy: a postmortem case series.

Acta Neuropathol Commun 2019 10 28;7(1):164. Epub 2019 Oct 28.

MassGeneral Institute for Neurodegenerative Disease, Charlestown, MA, USA.

Introduction: Chronic traumatic encephalopathy (CTE) is a tauopathy associated to repetitive head trauma. There are no validated in vivo biomarkers of CTE and a definite diagnosis can only be made at autopsy. Recent studies have shown that positron emission tomography (PET) tracer AV-1451 (Flortaucipir) exhibits high binding affinity for paired helical filament (PHF)-tau aggregates in Alzheimer (AD) brains but relatively low affinity for tau lesions in other tauopathies like temporal lobal degeneration (FTLD)-tau, progressive supranuclear palsy (PSP) or corticobasal degeneration (CBD). Little is known, however, about the binding profile of this ligand to the tau-containing lesions of CTE.

Objective: To study the binding properties of [F]-AV-1451 on pathologically confirmed CTE postmortem brain tissue samples.

Methods: We performed [F]-AV-1451 phosphor screen and high resolution autoradiography, quantitative tau measurements by immunohistochemistry and Western blot and tau seeding activity assays in brain blocks containing hippocampus, superior temporal cortex, superior frontal cortex, inferior parietal cortex and occipital cortex from 5 cases of CTE, across the stages of disease: stage II-III (n = 1), stage III (n = 3), and stage IV (n = 1). Importantly, low or no concomitant classic AD pathology was present in these brains.

Results: Despite the presence of abundant tau aggregates in multiple regions in all CTE brains, only faint or no [F]-AV-1451 binding signal could be detected by autoradiography. The only exception was the presence of a strong signal confined to the region of the choroid plexus and the meninges in two of the five cases. Tau immunostaining and Thioflavin-S staining ruled out the presence of tau aggregates in those regions. High resolution nuclear emulsion autoradiography revealed the presence of leptomeningeal melanocytes as the histologic source of this off-target binding. Levels of abnormally hyperphosphorylated tau species, as detected by Western Blotting, and tau seeding activity were both found to be lower in extracts from cases CTE when compared to AD.

Conclusion: AV-1451 may have limited utility for in vivo selective and reliable detection of tau aggregates in CTE. The existence of disease-specific tau conformations may likely explain the differential binding affinity of this tracer for tau lesions in different tauopathies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s40478-019-0808-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6816221PMC
October 2019

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ana.25611DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6973077PMC
January 2020

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00401-019-02031-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6689453PMC
September 2019

Cortical degeneration in chronic traumatic encephalopathy and Alzheimer's disease neuropathologic change.

Neurol Sci 2019 Mar 18;40(3):529-533. Epub 2018 Dec 18.

Departments of Neurology and Pathology & Immunology, Washington University School of Medicine, Saint Louis, MO, 63110, USA.

Objectives: An observational study to compare the laminar distributions in frontal and temporal cortex of the tau-immunoreactive pathologies in chronic traumatic encephalopathy (CTE) and Alzheimer's disease neuropathologic change (ADNC).

Patients: Post-mortem material of (1) four cases of CTE without ADNC, (2) seven cases of CTE with ADNC (CTE/ADNC), and (3) seven cases of ADNC alone.

Results: In CTE and CTE/ADNC, neurofibrillary tangles (NFT), neuropil threads (NT), and dot-like grains (DLG) were distributed either in upper cortex or across all layers. Low densities of astrocytic tangles (AT) and abnormally enlarged neurons (EN) were not localized to any specific layer. Surviving neurons exhibited peaks of density in both upper and lower cortex, and vacuole density was greatest in superficial layers. In ADNC, neuritic plaques (NP) were more frequent, AT rare, NFT and NT were more widely distributed, NT affected lower layers more frequently, and surviving neurons were less frequently bimodal than in CTE and CTE/ADNC.

Conclusion: Tau pathology in CTE and CTE/ADNC consistently affected the upper cortex but was more widely distributed in ADNC. The presence of CTE may encourage the development of ADNC pathology later in the course of the disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10072-018-3686-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6433808PMC
March 2019

Co-occurrence of chronic traumatic encephalopathy and prion disease.

Acta Neuropathol Commun 2018 12 18;6(1):140. Epub 2018 Dec 18.

Department of Pathology, Case Western Reserve University, School of Medicine, Cleveland, OH, 44106, USA.

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with repetitive traumatic brain injury (TBI). CTE is generally found in athletes participating in contact sports and military personnel exposed to explosive blasts but can also affect civilians. Clinically and pathologically, CTE overlaps with post-traumatic stress disorder (PTSD), a term mostly used in a clinical context. The histopathology of CTE is defined by the deposition of hyperphosphorylated tau protein in neurons and astrocytes preferentially with perivascular distribution and at the depths of the cortical sulci. In addition to hyperphosphorylated tau, other pathologic proteins are deposited in CTE, including amyloid β (Aβ), transactive response (TAR) DNA-binding protein 43 kDa (TDP-43) and α-synuclein. However, the coexistence of prion disease in CTE has not been observed. We report three cases of histopathologically validated CTE with co-existing sporadic prion disease. Two were identified in a cohort of 55 pathologically verified cases of CTE submitted to the CTE Center of Boston University. One was identified among brain tissues submitted to the National Prion Disease Pathology Surveillance Center of Case Western Reserve University. The histopathological phenotype and properties of the abnormal, disease-related prion protein (PrP) of the three CTE cases were examined using lesion profile, immunohistochemistry, electrophoresis and conformational tests. Subjects with sporadic Creutzfeldt-Jakob disease (sCJD) matched for age, PrP genotype and PrP type were used as controls. The histopathology phenotype and PrP properties of the three CTE subjects showed no significant differences from their respective sCJD controls suggesting that recurring neurotrauma or coexisting CTE pathology did not detectably impact the prion disease phenotype and PrP conformational characteristics. Based on the reported incidence of sporadic prion disease, the detection of two cases with sCJD in the CTE Center series of 55 CTE cases by chance alone would be highly unlikely (p = 8.93*10). Nevertheless, examination of a larger cohort of CTE is required to conclusively determine whether the risk of CJD is significantly increased in patients with CTE.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s40478-018-0643-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6299534PMC
December 2018

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s40478-018-0619-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6215686PMC
November 2018

Reduced interleukin 1A gene expression in the dorsolateral prefrontal cortex of individuals with PTSD and depression.

Neurosci Lett 2019 01 23;692:204-209. Epub 2018 Oct 23.

National Center for PTSD at VA Boston Healthcare System, United States; Pathology and Laboratory Medicine, VA Boston Healthcare System, United States; Department of Neurology, Boston University School of Medicine, United States. Electronic address:

The inflammatory system has been implicated in the pathophysiology of a variety of psychiatric conditions. Individuals with PTSD, depression, and other fear- and anxiety-related disorders exhibit alterations in peripheral circulating inflammatory markers, suggesting dysregulation of the inflammatory system. The relationship between inflammation and PTSD has been investigated almost exclusively in the periphery, and has not been extensively explored in human postmortem brain tissue. Interleukins (ILs) represent a subtype of cytokines and are key signaling proteins in the immune and inflammatory systems. Based on prior research implicating IL signaling in PTSD and depression, we performed a preliminary investigation of IL gene expression in a region of the cortex involved in emotion regulation and PTSD, the dorsolateral prefrontal cortex (dlPFC), using tissue from the newly established VA National PTSD Brain Bank. Gene expression analyses were conducted on post-mortem tissue from the dlPFC from 50 donors: 13 controls, 12 PTSD cases, and 25 depressed cases. RNA was extracted from frozen dlPFC tissue, reverse transcribed to cDNA, and quantitative polymerase chain reaction (qPCR) was performed to assess gene expression of IL1A, IL1B, IL6, IL8, IL10, IL13, and IL15. We found a multiple-testing corrected significant decrease in IL1A expression in the dlPFC for PTSD and depression cases compared to controls (p < 0.005) with age at death, sex, race and RNA integrity number (RIN) included as covariates. To our knowledge this finding is the first demonstration of altered IL expression in brain tissue from deceased individuals with histories of PTSD and/or depression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neulet.2018.10.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6351202PMC
January 2019

Chronic Traumatic Encephalopathy Within an Amyotrophic Lateral Sclerosis Brain Bank Cohort.

J Neuropathol Exp Neurol 2018 12;77(12):1091-1100

VA Boston Healthcare System, Boston, Massachusetts.

Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative disorder linked to repetitive head impacts and has been associated with amyotrophic lateral sclerosis (ALS), a fatal, degenerative neuromuscular disorder. The Department of Veterans Affairs Biorepository Brain Bank (VABBB) is a tissue repository that collects antemortem disease progression data and postmortem central nervous system tissue from veterans with ALS. We set out to determine the frequency of co-morbid ALS and CTE in the VABBB cohort and to characterize the clinical, genetic, and pathological distinctions between participants with ALS only and those with both ALS and CTE (ALS+CTE). Of 155 participants, 9 (5.8%) had neuropathologically confirmed ALS+CTE. Participants with ALS+CTE were more likely to have a history of traumatic brain injury (p < 0.001), served during the first Persian Gulf War (p < 0.05), and to have more severe tau pathology within the frontal cortex and spinal cord (p < 0.05). The most common exposures to head impacts included contact sports (n = 5) and military service (n = 2). Clinically, participants with ALS+CTE were more likely to have bulbar onset ALS (p = 0.006), behavioral changes (p = 0.002), and/or mood changes (p < 0.001). Overall, compared with ALS in isolation, comorbid ALS+CTE is associated with a history of TBI and has a distinct clinical and pathological presentation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/jnen/nly092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6927868PMC
December 2018

Astrocytic degeneration in chronic traumatic encephalopathy.

Acta Neuropathol 2018 12 7;136(6):955-972. Epub 2018 Sep 7.

Department of Neurology, Washington University, St. Louis, MO, USA.

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with repeated head traumas. Using immunohistochemistry for glial fibrillary acidic protein as a marker, plus automated quantitative analysis, we examined the characteristics and extent of astrogliosis present in stage III and IV CTE, along with Alzheimer's disease (AD), and frontotemporal dementia (FTD) cases. Astrogliosis in CTE patients was more diffuse compared to that of AD and FTD patients, which was concentrated in the sulcal depths. Of 14 patients with CTE, 10 exhibited signs of a degenerating astrocyte pathology, characterized by beaded, broken astrocytic processes. This astrocytic degeneration was typically found to be diffuse throughout the white matter, although two cases demonstrated astrocytic degeneration in the gray matter. The degeneration was also observed in 2 of 3 AD and 2 of 3 FTD brains, with overall similar characteristics across diseases. There was minimal to no astrocytic degeneration in six age-matched controls with no neurodegenerative disease. We found that the extent of the white matter astrocytic degeneration was strongly correlated with the level of overall astrogliosis in both the white and gray matter. However, astrocytic degeneration was not correlated with the overall extent of tau pathology. Specifically, there was no correlation between levels of p-tau in the sulcal depths and astrocytic degeneration in the white matter adjacent to the sulcal depths. Thus, astrocytic degeneration and overall astrogliosis appear to represent distinct pathological features of CTE. Further investigation into these astroglial pathologies could provide new insights into underlying disease mechanisms and represent a potential target for in vivo assessment of CTE as well as other neurodegenerative disorders.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00401-018-1902-3DOI Listing
December 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/jnen/nly065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6097837PMC
September 2018

Concussion, microvascular injury, and early tauopathy in young athletes after impact head injury and an impact concussion mouse model.

Brain 2018 02;141(2):422-458

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

The mechanisms underpinning concussion, traumatic brain injury, and chronic traumatic encephalopathy, and the relationships between these disorders, are poorly understood. We examined post-mortem brains from teenage athletes in the acute-subacute period after mild closed-head impact injury and found astrocytosis, myelinated axonopathy, microvascular injury, perivascular neuroinflammation, and phosphorylated tau protein pathology. To investigate causal mechanisms, we developed a mouse model of lateral closed-head impact injury that uses momentum transfer to induce traumatic head acceleration. Unanaesthetized mice subjected to unilateral impact exhibited abrupt onset, transient course, and rapid resolution of a concussion-like syndrome characterized by altered arousal, contralateral hemiparesis, truncal ataxia, locomotor and balance impairments, and neurobehavioural deficits. Experimental impact injury was associated with axonopathy, blood-brain barrier disruption, astrocytosis, microgliosis (with activation of triggering receptor expressed on myeloid cells, TREM2), monocyte infiltration, and phosphorylated tauopathy in cerebral cortex ipsilateral and subjacent to impact. Phosphorylated tauopathy was detected in ipsilateral axons by 24 h, bilateral axons and soma by 2 weeks, and distant cortex bilaterally at 5.5 months post-injury. Impact pathologies co-localized with serum albumin extravasation in the brain that was diagnostically detectable in living mice by dynamic contrast-enhanced MRI. These pathologies were also accompanied by early, persistent, and bilateral impairment in axonal conduction velocity in the hippocampus and defective long-term potentiation of synaptic neurotransmission in the medial prefrontal cortex, brain regions distant from acute brain injury. Surprisingly, acute neurobehavioural deficits at the time of injury did not correlate with blood-brain barrier disruption, microgliosis, neuroinflammation, phosphorylated tauopathy, or electrophysiological dysfunction. Furthermore, concussion-like deficits were observed after impact injury, but not after blast exposure under experimental conditions matched for head kinematics. Computational modelling showed that impact injury generated focal point loading on the head and seven-fold greater peak shear stress in the brain compared to blast exposure. Moreover, intracerebral shear stress peaked before onset of gross head motion. By comparison, blast induced distributed force loading on the head and diffuse, lower magnitude shear stress in the brain. We conclude that force loading mechanics at the time of injury shape acute neurobehavioural responses, structural brain damage, and neuropathological sequelae triggered by neurotrauma. These results indicate that closed-head impact injuries, independent of concussive signs, can induce traumatic brain injury as well as early pathologies and functional sequelae associated with chronic traumatic encephalopathy. These results also shed light on the origins of concussion and relationship to traumatic brain injury and its aftermath.awx350media15713427811001.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/brain/awx350DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5837414PMC
February 2018

Gene Profiling of Nucleus Basalis Tau Containing Neurons in Chronic Traumatic Encephalopathy: A Chronic Effects of Neurotrauma Consortium Study.

J Neurotrauma 2018 06 5;35(11):1260-1271. Epub 2018 Apr 5.

1 Department of Neurobiology, Barrow Neurological Institute , Phoenix, Arizona.

Military personnel and athletes exposed to traumatic brain injury may develop chronic traumatic encephalopathy (CTE). Brain pathology in CTE includes intracellular accumulation of abnormally phosphorylated tau proteins (p-tau), the main constituent of neurofibrillary tangles (NFTs). Recently, we found that cholinergic basal forebrain (CBF) neurons within the nucleus basalis of Meynert (nbM), which provide the major cholinergic innervation to the cortex, display an increased number of NFTs across the pathological stages of CTE. However, molecular mechanisms underlying nbM neurodegeneration in the context of CTE pathology remain unknown. Here, we assessed the genetic signature of nbM neurons containing the p-tau pretangle maker pS422 from CTE subjects who came to autopsy and received a neuropathological CTE staging assessment (Stages II, III, and IV) using laser capture microdissection and custom-designed microarray analysis. Quantitative analysis revealed dysregulation of key genes in several gene ontology groups between CTE stages. Specifically, downregulation of the nicotinic cholinergic receptor subunit β-2 gene (CHRNB2), monoaminergic enzymes catechol-O-methyltransferase (COMT) and dopa decarboxylase (DDC), chloride channels CLCN4 and CLCN5, scaffolding protein caveolin 1 (CAV1), cortical development/cytoskeleton element lissencephaly 1 (LIS1), and intracellular signaling cascade member adenylate cyclase 3 (ADCY3) was observed in pS422-immunreactive nbM neurons in CTE patients. By contrast, upregulation of calpain 2 (CAPN2) and microtubule-associated protein 2 (MAP2) transcript levels was found in Stage IV CTE patients. These single-population data in vulnerable neurons indicate alterations in gene expression associated with neurotransmission, signal transduction, the cytoskeleton, cell survival/death signaling, and microtubule dynamics, suggesting novel molecular pathways to target for drug discovery in CTE.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1089/neu.2017.5368DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5962931PMC
June 2018

Characterization of Detergent Insoluble Proteome in Chronic Traumatic Encephalopathy.

J Neuropathol Exp Neurol 2018 Jan;77(1):40-49

Boston University Alzheimer's Disease and CTE Center; Department of Neurology, Boston University School of Medicine, Boston, Massachusetts; Center for Neurodegenerative Disease, Emory University School of Medicine; Department of Biochemistry, Emory University School of Medicine; Department of Neurology, Emory University School of Medicine, Atlanta, Georgia; Department of Anatomy and Neurobiology; Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, Massachusetts; VA Boston Healthcare System, Boston, Massachusetts; and Department of Veterans Affairs Medical Center, Bedford, Massachusetts.

Quantitative proteomics of postmortem human brain can identify dysfunctional proteins that contribute to neurodegenerative disorders like Alzheimer disease (AD) and frontotemporal dementia. Similar studies in chronic traumatic encephalopathy (CTE) are limited, therefore we hypothesized that proteomic sequencing of CTE frontal cortex brain homogenates from varying CTE pathologic stages may provide important new insights into this disorder. Quantitative proteomics of control, CTE and AD brains was performed to characterize differentially expressed proteins, and we identified over 4000 proteins in CTE brains, including significant enrichment of the microtubule associated protein tau. We also found enrichment and pathologic aggregation of RNA processing factors as seen previously in AD, supporting the previously recognized overlap between AD and CTE. In addition to these similarities, we identified CTE-specific enrichment of proteins which increase with increasing severity of CTE pathology. NADPH dehydrogenase quinone 1 (NQO1) was one of the proteins which showed significant enrichment in CTE and also correlated with increasing CTE stage. NQO1 demonstrated neuropathologic correlation with hyperphosphorylated tau in glial cells, mainly astrocytes. These results demonstrate that quantitative proteomic analysis of CTE postmortem human brain can identify disease relevant findings and novel cellular pathways involved in CTE pathogenesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/jnen/nlx100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5939631PMC
January 2018

SIRT3 deregulation is linked to mitochondrial dysfunction in Alzheimer's disease.

Aging Cell 2018 02 11;17(1). Epub 2017 Nov 11.

VA Boston Healthcare System, Boston, MA, 02130, USA.

Alzheimer's disease (AD) is the leading cause of dementia in the elderly. Despite decades of study, effective treatments for AD are lacking. Mitochondrial dysfunction has been closely linked to the pathogenesis of AD, but the relationship between mitochondrial pathology and neuronal damage is poorly understood. Sirtuins (SIRT, silent mating type information regulation 2 homolog in yeast) are NAD-dependent histone deacetylases involved in aging and longevity. The objective of this study was to investigate the relationship between SIRT3 and mitochondrial function and neuronal activity in AD. SIRT3 mRNA and protein levels were significantly decreased in AD cerebral cortex, and Ac-p53 K320 was significantly increased in AD mitochondria. SIRT3 prevented p53-induced mitochondrial dysfunction and neuronal damage in a deacetylase activity-dependent manner. Notably, mitochondrially targeted p53 (mito-p53) directly reduced mitochondria DNA-encoded ND2 and ND4 gene expression resulting in increased reactive oxygen species (ROS) and reduced mitochondrial oxygen consumption. ND2 and ND4 gene expressions were significantly decreased in patients with AD. p53-ChIP analysis verified the presence of p53-binding elements in the human mitochondrial genome and increased p53 occupancy of mitochondrial DNA in AD. SIRT3 overexpression restored the expression of ND2 and ND4 and improved mitochondrial oxygen consumption by repressing mito-p53 activity. Our results indicate that SIRT3 dysfunction leads to p53-mediated mitochondrial and neuronal damage in AD. Therapeutic modulation of SIRT3 activity may ameliorate mitochondrial pathology and neurodegeneration in AD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/acel.12679DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5771400PMC
February 2018

CCL11 is increased in the CNS in chronic traumatic encephalopathy but not in Alzheimer's disease.

PLoS One 2017 26;12(9):e0185541. Epub 2017 Sep 26.

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

CCL11, a protein previously associated with age-associated cognitive decline, is observed to be increased in the brain and cerebrospinal fluid (CSF) in chronic traumatic encephalopathy (CTE) compared to Alzheimer's disease (AD). Using a cohort of 23 deceased American football players with neuropathologically verified CTE, 50 subjects with neuropathologically diagnosed AD, and 18 non-athlete controls, CCL11 was measured with ELISA in the dorsolateral frontal cortex (DLFC) and CSF. CCL11 levels were significantly increased in the DLFC in subjects with CTE (fold change = 1.234, p < 0.050) compared to non-athlete controls and AD subjects with out a history of head trauma. This increase was also seen to correlate with years of exposure to American football (β = 0.426, p = 0.048) independent of age (β = -0.046, p = 0.824). Preliminary analyses of a subset of subjects with available post-mortem CSF showed a trend for increased CCL11 among individuals with CTE (p = 0.069) mirroring the increase in the DLFC. Furthermore, an association between CSF CCL11 levels and the number of years exposed to football (β = 0.685, p = 0.040) was observed independent of age (β = -0.103, p = 0.716). Finally, a receiver operating characteristic (ROC) curve analysis demonstrated CSF CCL11 accurately distinguished CTE subjects from non-athlete controls and AD subjects (AUC = 0.839, 95% CI 0.62-1.058, p = 0.028). Overall, the current findings provide preliminary evidence that CCL11 may be a novel target for future CTE biomarker studies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0185541PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5614644PMC
October 2017