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Chronic traumatic encephalopathy (CTE) is a tauopathy associated with repetitive mild head impacts characterized by perivascular hyperphosphorylated tau (p-tau) in neurofibrillary tangles (NFTs) and neurites in the depths of the neocortical sulci. In moderate to advanced CTE, NFTs accumulate in the hippocampus, potentially overlapping neuroanatomically with primary age-related tauopathy (PART), an age-related tauopathy characterized by Alzheimer disease-like tau pathology in the hippocampus devoid of amyloid plaques. We measured p-tau burden using positive-pixel counts on immunohistochemically stained and neuroanatomically segmented hippocampal tissue. Subjects with CTE had a higher total p-tau burden than PART subjects in all sectors (p = 0.005). Within groups, PART had significantly higher total p-tau burden in CA1/subiculum compared to CA3 (p = 0.02) and CA4 (p = 0.01) and total p-tau burden in CA2 trended higher than CA4 (p = 0.06). In CTE, total p-tau burden in CA1/subiculum was significantly higher than in the dentate gyrus; and CA2 also trended higher than dentate gyrus (p = 0.01, p = 0.06). When controlling for p-tau burden across the entire hippocampus, CA3 and CA4 had significantly higher p-tau burden in CTE than PART (p

Primary age-related tauopathy (PART) is a neurodegenerative pathology with features distinct from but also overlapping with Alzheimer disease (AD). While both exhibit Alzheimer-type temporal lobe neurofibrillary degeneration alongside amnestic cognitive impairment, PART develops independently of amyloid-β (Aβ) plaques. The pathogenesis of PART is not known, but evidence suggests an association with genes that promote tau pathology and others that protect from Aβ toxicity. Here, we performed a genetic association study in an autopsy cohort of individuals with PART (n = 647) using Braak neurofibrillary tangle stage as a quantitative trait. We found some significant associations with candidate loci associated with AD (SLC24A4, MS4A6A, HS3ST1) and progressive supranuclear palsy (MAPT and EIF2AK3). Genome-wide association analysis revealed a novel significant association with a single nucleotide polymorphism on chromosome 4 (rs56405341) in a locus containing three genes, including JADE1 which was significantly upregulated in tangle-bearing neurons by single-soma RNA-seq. Immunohistochemical studies using antisera targeting JADE1 protein revealed localization within tau aggregates in autopsy brains with four microtubule-binding domain repeats (4R) isoforms and mixed 3R/4R, but not with 3R exclusively. Co-immunoprecipitation in post-mortem human PART brain tissue revealed a specific binding of JADE1 protein to four repeat tau lacking N-terminal inserts (0N4R). Finally, knockdown of the Drosophila JADE1 homolog rhinoceros (rno) enhanced tau-induced toxicity and apoptosis in vivo in a humanized 0N4R mutant tau knock-in model, as quantified by rough eye phenotype and terminal deoxynucleotidyl transferase dUTP nick end-labeling (TUNEL) in the fly brain. Together, these findings indicate that PART has a genetic architecture that partially overlaps with AD and other tauopathies and suggests a novel role for JADE1 as a modifier of neurofibrillary degeneration.

Embryonal rhabdomyosarcoma (eRMS) is one of the most common soft tissue sarcomas in children and adolescents. Parameningeal eRMS is a variant that is often more difficult to treat than eRMS occurring at other sites. A 14-year-old female with persistent headaches and rapid weight loss was diagnosed with parameningeal eRMS. She progressed and died despite chemotherapy with vincristine, actinomycin-D, and cyclophosphamide plus 50.4 Gy radiation therapy to the primary tumor site. Tumor specimens were acquired by rapid autopsy and tumor tissue was transplanted into immunodeficient mice to create a patient-derived xenograft (PDX) animal model. As autopsy specimens had an ALK R1181C mutation, PDX tumor bearing animals were treated with the pan-kinase inhibitor lestaurtinib but demonstrated no decrease in tumor growth, suggesting that single agent kinase inhibitor therapy may be insufficient in similar cases. This unique parameningeal eRMS PDX model is publicly available for preclinical study.

The extracellular matrix (ECM) of the brain comprises unique glycan "sulfation codes" that influence neurological function. Perineuronal nets (PNNs) are chondroitin sulfate‐glycosaminoglycan (CS‐GAG) containing matrices that enmesh neural networks involved in memory and cognition, and loss of PNN matrices is reported in patients with neurocognitive and neuropsychiatric disorders including Alzheimer's disease (AD). Using liquid chromatography tandem mass spectrometry (LC‐MS/MS), we show that patients with a clinical diagnosis of AD‐related dementia undergo a re‐coding of their PNN‐associated CS‐GAGs that correlates to Braak stage progression, hyperphosphorylated tau (p‐tau) accumulation, and cognitive impairment. As these CS‐GAG sulfation changes are detectable prior to the regional onset of classical AD pathology, they may contribute to the initiation and/or progression of the underlying degenerative processes and implicate the brain matrix sulfation code as a key player in the development of AD clinicopathology. [ABSTRACT FROM AUTHOR]

Background: T2‐weighted white matter hyperintensities (WMH) are ubiquitous with age, and associated mild cognitive impairment and dementia. Recent studies have demonstrated altered microstructural integrity and perfusion within the normal appearing white matter (NAWM) surrounding WMHs, the "WMH penumbra", indicating more widespread WM tissue damage than is commonly observed on routine MRI. While common pathological features associated with in vivo WMH burden have been described, histochemical (HC) features obtained by directly targeting the WMH core and surrounding NAWM remain largely uncharacterized. Method: Post mortem (PM) 7T MRI was obtained on 6 brain hemispheres from Oregon Alzheimer's Disease Research Center subjects (Table 1). Fifty‐three WMH and NAWM penumbra regions of interest (ROI) were identified from 11 brain regions and targeted for HC analysis (Table 2). Tissue samples were stained with hematoxylin & eosin‐luxol fast blue (HELFB), aquaporin‐1 (AQP1), and vimentin and scanned for quantitative ROI analysis. WMHs were segmented on T2‐weighted images, and WMH masks were dilated by 1mm increments to define a 5 mm NAWM penumbra and coregistered to IHC images (Figure 1). Digitalized IHC mages were assessed quantitatively using mean pixel saturation (AQP1,Vimentin) or thresholded area coverage (HELFB). Mixed effects models were used to examine mean differences in IHC staining between WMH and the NAWM penumbra and change in HC staining within the NAWM with distance from WMHs. Analyses were adjusted for global WMH burden, and individual slide effects to account for potential differences in staining. Result: WMHs demonstrated increased vimentin, and decreased AQP1 and HELFB staining, compared with the NAWM penumbra. Within the NAWM penumbra, there was an increase in vimentin and a decrease in AQP1 and myelin content with closer proximity to WMHs (Figure 2). Conclusion: The MRI‐identified NAWM region surrounding WMHs show a gradient of demyelination and astrocytopathy with distance from WMHs. Findings confirm the presence of the WMH penumbra consisting of damaged tissue that is likely vulnerable to further injury over time that could be a target for intervention in life. Results suggest that MRI visible WMHs are a state marker of more widespread tissue degeneration that may contribute to cognitive decline in older individuals. [ABSTRACT FROM AUTHOR]

Neurocysticercosis is a parasitic brain disease caused by the larval form (Cysticercus cellulosae) of Taenia solium and is the leading cause of preventable epilepsy worldwide. However, the pathophysiology and relation to the wide range of clinical features remains poorly understood. Axonal swelling is emerging as an important early pathological finding in multiple neurodegenerative diseases and as a cause of brain injury, but has not been well described in neurocysticercosis. Histological analysis was performed on human, rat and porcine NCC brain specimens to identify axonal pathology. Rat infection was successfully carried out via two routes of inoculation: direct intracranial injection and oral feeding. Extensive axonal swellings, in the form of spheroids, were observed in both humans and rats and to a lesser extent in pigs with NCC. Spheroids demonstrated increased immunoreactivity to amyloid precursor protein and neurofilament indicating probable impairment of axonal transport. These novel findings demonstrate that spheroids are present in NCC which is conserved across species. Not only is this an important contribution toward understanding the pathogenesis of NCC, but it also provides a model to analyze the association of spheroids with specific clinical features and to investigate the reversibility of spheroid formation with antihelminthic treatment. [ABSTRACT FROM AUTHOR]

Background: The existence of individuals who remain cognitively intact despite presenting histopathological signs of Alzheimer's disease (AD), here referred to as "Non demented with AD neuropathology" (NDAN), suggests that some unknown mechanisms are triggered to resist cognitive impairment. Synaptic dysfunction has been identified as one of the major AD causes and it is established that microglia, attracted to plaques, engulf damaged synapses. In this context, exposed phosphatidylserine (ePS) represents a neuronal "eat‐me" signal involved in microglial‐mediated phagocytosis of damaged synapses. A possible candidate mediator of this process is represented by TREM2, a microglial surface receptor activated by ligands including PS. Based on TREM2 role in the scavenging function of microglia, we hypothesize that an efficient microglial phagocytosis of damaged synapses underlies synaptic resilience in NDAN, thus protecting from memory deficits. Method: Using immunofluorescence microscopy, a comparative study of human post‐mortem frontal cortices of aged‐matched individuals, AD and NDAN individuals has been performed. The distribution of activated microglia (IBA1 and IBA1/CD68 positive cells) and the expression of phagocytic microglia‐related proteins (TREM2 and DAP12) were evaluated. To test the efficacy of microglia in removing debris and damaged synapses, preservation of synapses around plaques was assessed using MAP2 and tubulin βIII as dendritic and axonal markers respectively, and PSD95 as a post synaptic marker. Furthermore, taking advantage of flow cytometry techniques, a study of the ePS using Annexin V assay has been performed. Result: Immunofluorescence analyses indicate higher microglial activation and TREM2 expression in NDAN individuals, as well as preserved axonal and dendritic structure around plaques vs. AD. High levels of PSD95 around NDAN plaques and the colocalization of PSD95 and CD68 may suggest a prompt removal of damaged synapses by hyperactive phagocytic microglia. Annexin V assay on synaptosomes isolated from aged‐matched, AD and NDAN individuals indicates changes in the ePS in NDAN individuals, confirming the engulfment of damaged synapses. Conclusion: Our results suggest a higher efficiency of TREM2‐induced phagocytic microglia in removing damaged synapses, underlying synaptic resilience in NDAN individuals. [ABSTRACT FROM AUTHOR]

The extracellular matrix (ECM) of the brain comprises unique glycan "sulfation codes" that influence neurological function. Perineuronal nets (PNNs) are chondroitin sulfate-glycosaminoglycan (CS-GAG) containing matrices that enmesh neural networks involved in memory and cognition, and loss of PNN matrices is reported in patients with neurocognitive and neuropsychiatric disorders including Alzheimer's disease (AD). Using liquid chromatography tandem mass spectrometry (LC-MS/MS), we show that patients with a clinical diagnosis of AD-related dementia undergo a re-coding of their PNN-associated CS-GAGs that correlates to Braak stage progression, hyperphosphorylated tau (p-tau) accumulation, and cognitive impairment. As these CS-GAG sulfation changes are detectable prior to the regional onset of classical AD pathology, they may contribute to the initiation and/or progression of the underlying degenerative processes and implicate the brain matrix sulfation code as a key player in the development of AD clinicopathology., (© 2021 the Alzheimer's Association.)

Introduction: The pathogenesis of vascular cognitive impairment (VCI) is not fully understood. GPR39, an orphan G-protein coupled receptor, is implicated in neurological disorders but its role in VCI is unknown., Methods: We performed GPR39 immunohistochemical analysis in post mortem brain samples from mild cognitive impairment (MCI) and control subjects. DNA was analyzed for GPR39 single nucleotide polymorphisms (SNPs), and correlated with white matter hyperintensity (WMH) burden on pre mortem magnetic resonance imaging., Results: GPR39 is expressed in aged human dorsolateral prefrontal cortex, localized to microglia and peri-capillary cells resembling pericytes. GPR39-capillary colocalization, and density of GPR39-expressing microglia was increased in aged brains compared to young. SNP distribution was equivalent between groups; however, homozygous SNP carriers were present only in the MCI group, and had higher WMH volume than wild-type or heterozygous SNP carriers., Discussion: GPR39 may play a role in aging-related VCI, and may serve as a therapeutic target and biomarker for the risk of developing VCI., Competing Interests: NJA is co‐inventor of GPR39‐targeting compounds that have been licensed to a company with a commercial interest in the results; in the past 36 months, NJA co‐founded, then sold shares in, a company (Vasocardea) that was formed to develop GPR39‐targeting drugs and diagnostic probes. He is also founder of another company (NeuvaRx), formed to develop GPR39‐targeting drugs and diagnostic probes for central nervous system disorders. This potential conflict of interest has been reviewed and managed by OHSU. NJA has received royalties for a co‐invention ([18F]FNDP for PET Imaging of Soluble Epoxide Hydrolase), licensed to Precision Molecular. NJA has also received compensation from National Institutes of Health for grant reviews, and honoraria from academic universities for invited lectures. NJA has one patent issued (WO2017192854A1: Radiofluorinated FNDP for PET imaging of soluble epoxide hydrolase [sEH]), and two other provisional patents are pending (Use of GPR39 probes and ligands for the diagnosis and treatment of cardiovascular disease, and biomarkers for detection of coronary artery disease and its management). KG has received consultant fees from OHSU for coding tools. Other authors have declared that no conflict of interest exists., (© 2021 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

Although manganese is an essential trace metal, little is known about its transport and homeostatic regulation. Here we have identified a cohort of patients with a novel autosomal recessive manganese transporter defect caused by mutations in SLC39A14. Excessive accumulation of manganese in these patients results in rapidly progressive childhood-onset parkinsonism-dystonia with distinctive brain magnetic resonance imaging appearances and neurodegenerative features on post-mortem examination. We show that mutations in SLC39A14 impair manganese transport in vitro and lead to manganese dyshomeostasis and altered locomotor activity in zebrafish with CRISPR-induced slc39a14 null mutations. Chelation with disodium calcium edetate lowers blood manganese levels in patients and can lead to striking clinical improvement. Our results demonstrate that SLC39A14 functions as a pivotal manganese transporter in vertebrates.