Chronic traumatic encephalopathy (CTE) is a neurodegeneration characterized by the abnormal accumulation of hyperphosphorylated tau protein within the brain. Like many other neurodegenerative ...conditions, at present, CTE can only be definitively diagnosed by post-mortem examination of brain tissue. As the first part of a series of consensus panels funded by the NINDS/NIBIB to define the neuropathological criteria for CTE, preliminary neuropathological criteria were used by 7 neuropathologists to blindly evaluate 25 cases of various tauopathies, including CTE, Alzheimer’s disease, progressive supranuclear palsy, argyrophilic grain disease, corticobasal degeneration, primary age-related tauopathy, and parkinsonism dementia complex of Guam. The results demonstrated that there was good agreement among the neuropathologists who reviewed the cases (Cohen’s kappa, 0.67) and even better agreement between reviewers and the diagnosis of CTE (Cohen’s kappa, 0.78). Based on these results, the panel defined 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. The group also defined supportive but non-specific p-tau-immunoreactive features of CTE as: pretangles and NFTs affecting superficial layers (layers II–III) of cerebral cortex; pretangles, NFTs or extracellular tangles in CA2 and pretangles and proximal dendritic swellings in CA4 of the hippocampus; neuronal and astrocytic aggregates in subcortical nuclei; thorn-shaped astrocytes at the glial limitans of the subpial and periventricular regions; and large grain-like and dot-like structures. Supportive non-p-tau pathologies include TDP-43 immunoreactive neuronal cytoplasmic inclusions and dot-like structures in the hippocampus, anteromedial temporal cortex and amygdala. The panel also recommended a minimum blocking and staining scheme for pathological evaluation and made recommendations for future study. This study provides the first step towards the development of validated neuropathological criteria for CTE and will pave the way towards future clinical and mechanistic studies.
Haplodeficiency of the microglia gene TREM2 increases risk for late-onset Alzheimer’s disease (AD) but the mechanisms remain uncertain. To investigate this, we used high-resolution confocal and ...super-resolution (STORM) microscopy in AD-like mice and human AD tissue. We found that microglia processes, rich in TREM2, tightly surround early amyloid fibrils and plaques promoting their compaction and insulation. In Trem2- or DAP12-haplodeficient mice and in humans with R47H TREM2 mutations, microglia had a markedly reduced ability to envelop amyloid deposits. This led to an increase in less compact plaques with longer and branched amyloid fibrils resulting in greater surface exposure to adjacent neurites. This was associated with more severe neuritic tau hyperphosphorylation and axonal dystrophy around amyloid deposits. Thus, TREM2 deficiency may disrupt the formation of a neuroprotective microglia barrier that regulates amyloid compaction and insulation. Pharmacological modulation of this barrier could be a novel therapeutic strategy for AD.
•TREM2/DAP12 signaling regulates microglia process envelopment of amyloid plaques•Loss of microglia envelopment in TREM2/DAP12 deficiency reduces plaque compaction•STORM microscopy shows greater fibril branching and surface area in TREM2 deficiency•Human R47H TREM2 variant impairs the microglia barrier and worsens axonal dystrophy
Yuan, Condello, et al. demonstrate that haplodeficiency of the microglia-specific gene TREM2 markedly impairs the ability of microglia to compact and insulate amyloid deposits. Loss of this neuroprotective microglia function leads to marked axonal dystrophy, potentially contributing to the increased risk of dementia for carriers of TREM2 loss-of-function mutations.
Synaptic disturbances in excitatory to inhibitory (E/I) balance in forebrain circuits are thought to contribute to the progression of Alzheimer's disease (AD) and dementia, although direct evidence ...for such imbalance in humans is lacking. We assessed anatomical and electrophysiological synaptic E/I ratios in post-mortem parietal cortex samples from middle-aged individuals with AD (early-onset) or Down syndrome (DS) by fluorescence deconvolution tomography and microtransplantation of synaptic membranes. Both approaches revealed significantly elevated E/I ratios for AD, but not DS, versus controls. Gene expression studies in an independent AD cohort also demonstrated elevated E/I ratios in individuals with AD as compared to controls. These findings provide evidence of a marked pro-excitatory perturbation of synaptic E/I balance in AD parietal cortex, a region within the default mode network that is overly active in the disorder, and support the hypothesis that E/I imbalances disrupt cognition-related shifts in cortical activity which contribute to the intellectual decline in AD.
All significance levels based on the new p values are reported in the corrected figures and the statistical tests used are reported in the corresponding figure legends and in the experimental ...procedures section online.
Methods for quantifying gene expression
and chromatin accessibility
in single cells are well established, but single-cell analysis of chromatin regions with specific histone modifications has been ...technically challenging. In this study, we adapted the CUT&Tag method
to scalable nanowell and droplet-based single-cell platforms to profile chromatin landscapes in single cells (scCUT&Tag) from complex tissues and during the differentiation of human embryonic stem cells. We focused on profiling polycomb group (PcG) silenced regions marked by histone H3 Lys27 trimethylation (H3K27me3) in single cells as an orthogonal approach to chromatin accessibility for identifying cell states. We show that scCUT&Tag profiling of H3K27me3 distinguishes cell types in human blood and allows the generation of cell-type-specific PcG landscapes from heterogeneous tissues. Furthermore, we used scCUT&Tag to profile H3K27me3 in a patient with a brain tumor before and after treatment, identifying cell types in the tumor microenvironment and heterogeneity in PcG activity in the primary sample and after treatment.
Traumatic brain injury (TBI), particularly of greater severity (i.e., moderate to severe), has been identified as a risk factor for all-cause dementia and Parkinson’s disease, with risk for specific ...dementia subtypes being more variable. Among the limited studies involving neuropathological (postmortem) confirmation, the association between TBI and risk for neurodegenerative disease increases in complexity, with polypathology often reported on examination. The heterogeneous clinical and neuropathological outcomes associated with TBI are likely reflective of the multifaceted postinjury acute and chronic processes that may contribute to neurodegeneration. Acutely in TBI, axonal injury and disrupted transport influences molecular mechanisms fundamental to the formation of pathological proteins, such as amyloid-β peptide and hyperphosphorylated tau. These protein deposits may develop into amyloid-β plaques, hyperphosphorylated tau–positive neurofibrillary tangles, and dystrophic neurites. These and other characteristic neurodegenerative disease pathologies may then spread across brain regions. The acute immune and neuroinflammatory response involves alteration of microglia, astrocytes, oligodendrocytes, and endothelial cells; release of downstream pro- and anti-inflammatory cytokines and chemokines; and recruitment of peripheral immune cells. Although thought to be neuroprotective and reparative initially, prolongation of these processes may promote neurodegeneration. We review the evidence for TBI as a risk factor for neurodegenerative disorders, including Alzheimer’s dementia and Parkinson’s disease, in clinical and neuropathological studies. Further, we describe the dynamic interactions between acute response to injury and chronic processes that may be involved in TBI-related pathogenesis and progression of neurodegeneration.
Orbital neoplasms in adults may be categorized on the basis of location and histologic type. Imaging features of these lesions often reflect their tissue composition. Cavernous malformations (also ...known as cavernous hemangiomas), although not true neoplasms, are the most common benign adult orbital tumor. They typically appear as a well-circumscribed, ovoid intraconal mass on cross-sectional images. Lymphoma, which may be primary or secondary to systemic disease, is the most prevalent orbital neoplasm in older adults (≥60 years of age). Choroidal melanoma is the most common primary adult ocular malignancy. Melanin has intrinsic T1 and T2 shortening effects, classically manifesting with hyperintense signal on T1-weighted magnetic resonance (MR) images and with hypointense signal on T2-weighted images. However, amelanotic or mildly pigmented lesions of melanoma do not demonstrate these characteristic MR imaging features. Breast cancer is the most common malignancy to metastasize to the orbit, followed by prostate cancer, melanoma, and lung cancer. In women with bilateral enophthalmos, metastatic scirrhous breast cancer should be considered in the differential diagnosis. Neoplasms that arise from the optic nerve or its sheath include glioma and meningioma. At imaging, gliomas often cause fusiform expansion of the optic nerve, in which the nerve itself cannot be delineated from the lesion. In contrast, meningiomas classically have a "tram-track" configuration, whereby the contrast-enhancing tumor is seen alongside the optic nerve. Neoplasms that derive from peripheral nerves include schwannoma and neurofibroma, the latter of which is associated with neurofibromatosis type 1. MR imaging is particularly valuable for evaluation of orbital neoplasms, as it provides critical anatomic information about ocular structures involved, perineural spread, and intracranial extension.
IMPORTANCE: The late effects of traumatic brain injury (TBI) are of great interest, but studies characterizing these effects are limited. OBJECTIVE: To determine whether TBI with loss of ...consciousness (LOC) is associated with an increased risk for clinical and neuropathologic findings of Alzheimer disease (AD), Parkinson disease (PD), and other dementias. DESIGN, SETTING, AND PARTICIPANTS: This study analyzed data from the Religious Orders Study (ROS), Memory and Aging Project (MAP), and Adult Changes in Thought study (ACT). All ROS and MAP participants and a subset of ACT participants consent to autopsy. Studies performed annual (ROS and MAP) or biennial (ACT) cognitive and clinical testing to identify incident cases of dementia and AD. The 7130 participants included members of a Seattle-area health care delivery system (ACT), priests and nuns living in orders across the United States (ROS), and Chicago-area adults in retirement communities (MAP). Of these, 1589 underwent autopsy. Primary hypothesis was that TBI with LOC would be associated with increased risk for AD and neurofibrillary tangles. Data were accrued from 1994 to April 1, 2014. EXPOSURES: Self-reported TBI when the participant was free of dementia, categorized as no more than 1 vs more than 1 hour of LOC. MAIN OUTCOMES AND MEASURES: Clinical outcomes included incident all-cause dementia, AD, and PD in all studies and incident mild cognitive impairment and progression of parkinsonian signs in ROS and MAP. Neuropathologic outcomes included neurofibrillary tangles, neuritic plaques, microinfarcts, cystic infarcts, Lewy bodies, and hippocampal sclerosis in all studies. RESULTS: Of 7130 participants (2879 40.4% men; overall mean SD age, 79.9 6.9 years), 865 reported a history of TBI with LOC. In 45 190 person-years of follow-up, 1537 incident cases of dementia and 117 of PD were identified. No association was found between TBI with LOC and incident dementia (ACT: HR for TBI with LOC ≤1 hour, 1.03; 95% CI, 0.83-1.27; HR for TBI with LOC >1 hour, 1.18; 95% CI, 0.77-1.78; ROS and MAP: HR for TBI with LOC ≤1 hour, 0.87; 95% CI, 0.58-1.29; HR for TBI with LOC >1 hour, 0.84; 95% CI, 0.44-1.57) or AD (findings similar to those for dementia). Associations were found for TBI with LOC and incident PD in ACT (HR for TBI with LOC >1 hour, 3.56; 95% CI, 1.52-8.28) and progression of parkinsonian signs in ROS and MAP (odds ratio OR for TBI with LOC ≤1 hour, 1.65; 95% CI, 1.23-2.21; OR for TBI with LOC >1 hour, 2.23; 95% CI, 1.16-4.29). Traumatic brain injury with LOC was associated with Lewy bodies (any Lewy body in ACT: RR for TBI with LOC >1 hour, 2.64; 95% CI, 1.40-4.99; Lewy bodies in substantia nigra and/or locus ceruleus in ACT: RR for TBI with LOC >1 hour, 3.30; 95% CI, 1.71-6.38; Lewy bodies in frontal or temporal cortex in ACT: RR for TBI with LOC >1 hour, 5.73; 95% CI, 2.18-15.0; ROS and MAP: RR for TBI with LOC ≤1 hour, 1.64; 95% CI, 1.00-2.70; pooled RR for TBI with LOC ≤1 hour, 1.59; 95% CI, 1.06-2.39) and microinfarcts (any cortical microinfarct in ROS and MAP: RR for TBI with LOC >1 hour, 2.12; 95% CI, 1.12-4.01; pooled RR for TBI with LOC >1 hour, 1.58; 95% CI, 1.06-2.35). CONCLUSIONS AND RELEVANCE: Pooled clinical and neuropathologic data from 3 prospective cohort studies indicate that TBI with LOC is associated with risk for Lewy body accumulation, progression of parkinsonism, and PD, but not dementia, AD, neuritic plaques, or neurofibrillary tangles.
Abstract
The expanded HTT CAG repeat causing Huntington’s disease (HD) exhibits somatic expansion proposed to drive the rate of disease onset by eliciting a pathological process that ultimately ...claims vulnerable cells. To gain insight into somatic expansion in humans, we performed comprehensive quantitative analyses of CAG expansion in ~50 central nervous system (CNS) and peripheral postmortem tissues from seven adult-onset and one juvenile-onset HD individual. We also assessed ATXN1 CAG repeat expansion in brain regions of an individual with a neurologically and pathologically distinct repeat expansion disorder, spinocerebellar ataxia type 1 (SCA1). Our findings reveal similar profiles of tissue instability in all HD individuals, which, notably, were also apparent in the SCA1 individual. CAG expansion was observed in all tissues, but to different degrees, with multiple cortical regions and neostriatum tending to have the greatest instability in the CNS, and liver in the periphery. These patterns indicate different propensities for CAG expansion contributed by disease locus-independent trans-factors and demonstrate that expansion per se is not sufficient to cause cell type or disease-specific pathology. Rather, pathology may reflect distinct toxic processes triggered by different repeat lengths across cell types and diseases. We also find that the HTT CAG length-dependent expansion propensity of an individual is reflected in all tissues and in cerebrospinal fluid. Our data indicate that peripheral cells may be a useful source to measure CAG expansion in biomarker assays for therapeutic efforts, prompting efforts to dissect underlying mechanisms of expansion that may differ between the brain and periphery.
Progressive neuron loss in the frontal and temporal lobes of the cerebral cortex typifies frontotemporal lobar degeneration (FTLD). FTLD sub types are classified on the basis of neuronal aggregated ...protein deposits, typically containing either aberrantly phosphorylated TDP-43 or tau. Our recent work demonstrated that tau tubulin kinases 1 and 2 (TTBK1/2) robustly phosphorylate TDP-43 and co-localize with phosphorylated TDP-43 in human postmortem neurons from FTLD patients. Both TTBK1 and TTBK2 were initially identified as tau kinases and TTBK1 has been shown to phosphorylate tau epitopes commonly observed in Alzheimer's disease and other tauopathies.
To further elucidate how TTBK1/2 activity contributes to both TDP-43 and tau phosphorylation in the context of the neurodegeneration seen in FTLD, we examined the consequences of elevated human TTBK1/2 kinase expression in transgenic animal models of disease.
We show that C. elegans co-expressing tau/TTBK1 tau/TTBK2, or TDP-43/TTBK1 transgenes in combination exhibit synergistic exacerbation of behavioral abnormalities and increased pathological protein phosphorylation. We also show that C. elegans co-expressing tau/TTBK1 or tau/TTBK2 transgenes in combination exhibit aberrant neuronal architecture and neuron loss. Surprisingly, the TTBK2/TDP-43 transgenic combination showed no exacerbation of TDP-43 proteinopathy related phenotypes. Additionally, we observed elevated TTBK1/2 protein expression in cortical and hippocampal neurons of FTLD-tau and FTLD-TDP cases relative to normal controls.
Our findings suggest a possible etiology for the two most common FTLD subtypes through a kinase activation driven mechanism of neurodegeneration.
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