Despite the success of combination antiretroviral therapy (ART) in suppressing systemic HIV replication, neurocognitive impairment (NCI) remains common among people with HIV (PWH). In the pre‐ART era, severe forms such as HIV‐associated dementia (HAD) were prevalent and characterized by distinct neuropathological features, including multinucleated giant cells, microglial nodules, and extensive neuronal loss. In the ART era, milder forms of NCI are more frequent; however, the underlying histopathology remains poorly understood. These milder impairments are primarily associated with synaptodendritic damage and neuronal dysregulation, typically in the absence of productive infection in neurons. Instead, microglia and macrophages are implicated as key drivers of neuroinflammation and neuronal injury. In this study, we investigated the neuropathological features of brain tissue from PWH with and without symptomatic cognitive impairment. Immunohistochemical analysis revealed microglial nodules with active neuronal phagocytosis, which was associated with dendritic loss and neuronal damage. Complementary in vitro studies demonstrated that HIV‐infected microglia demonstrated enhanced phagocytic activity, supporting their direct role in neurodegeneration beyond cytokine‐mediated mechanisms. Together, these findings highlight microglial phagocytosis as one of the critical contributors of HIV‐associated NCI in the ART era.

There is a paucity of autopsy‐based studies providing detailed neuropathological characteristics of fatal hypothermia cases, particularly in trauma‐associated cases. Hence, this study investigated 2054 serial autopsy cases in which histopathological examination of all organs, including the brain, could be performed. We identified 168 cases (75 female and 93 male patients) of fatal hypothermia and examined the clinical and neuropathological characteristics in these cases. Patients aged ≥65 years constituted 80% of the cohort (135 cases). Cognitive impairment (CI) was identified in 39% of cases with available clinical histories, and approximately half of these cases were presumed to have developed hypothermia while wandering, based on clinical history and the circumstances of discovery. Alzheimer's disease was the most commonly identified pathology, affecting 40% of the total and approximately two‐thirds of patients aged ≥80 years. CI caused by multiple pathologies, especially two, was more frequently observed than by a single pathology. The most common manner of exposure to cold temperatures was accidents (120 cases), including 35 cases with multiple traumatic injuries, most likely resulting from falls. In these cases, the trauma was considered the primary cause of immobility, leading to subsequent exposure to cold environments. Importantly, 30 (86%) of these trauma‐associated cases showed one or more neuropathological conditions, and CI was documented in 13, with four presumed to have fallen while wandering. Notable neuropathological manifestations were also observed in eight of the 33 cases of patients aged less than 65 years. Our results demonstrate that neurodegenerative diseases, especially Alzheimer's disease, are underlying conditions in fatal hypothermia in the elderly and in relatively younger individuals, suggesting that they may contribute to its onset. These findings highlight the necessity for comprehensive neuropathological examination in all forensic autopsy cases of hypothermia.

This study leverages x‐ray phase‐contrast tomography (XPCT) for detailed analysis of neurodegenerative diseases, focusing on the three‐dimensional (3D) visualization and quantification of neuropathological features within fixed human postmortem tissue. XPCT with synchrotron radiation offers micrometer and even sub‐micron resolution, enabling us to examine intra‐ and extraneuronal aggregates and inclusions such as Lewy bodies (LBs), granulovacuolar degeneration (GvD), Hirano bodies (HBs), neurofibrillary tangles (NFTs), β‐amyloid plaques, and vascular amyloid deposits in three dimensions. In the reconstructions, we identified the highest electron densities in Hirano and LBs, while NFTs exhibited no significant increase in XPCT contrast. Using cutting‐edge high‐resolution x‐ray synchrotron beamlines, we were now able to detect even detect subcellular differences in electron densities found in GvD. Small‐scale inhomogeneities of the electron density were also detected in LBs, potentially relating to inclusions of organelles. Additionally, we reveal here a peculiar 3D geometry of HBs and demonstrate the co‐occurrence with GvD in the same neuron. These findings underscore the potential of XPCT as a powerful, label‐free tool for spatially resolved neuropathological investigations, opening new avenues for the systematic 3D characterization of inclusions and aggregates in neurodegeneration.

Glycosylation is the most common form of post‐translational modification in the brain and becomes significantly altered in the context of neurodegeneration. One notable alteration is an enrichment of terminal sialic acid (SA) modifications. Previous studies provide evidence of increased sialylation on microglia, the innate immune cell of the brain, in Alzheimer's disease (AD), particularly near amyloid beta plaques. Yet, there is little understanding of the relationship between SA and other amyloid beta‐related diseases like Cerebral Amyloid Angiopathy (CAA). Nearly half of all AD cases have CAA; thus, it is critical to understand the relationship between amyloid pathology and SA modifications. The present study aimed to overcome this gap in knowledge by investigating sialylation patterns in AD cases with CAA compared with CAA‐negative AD cases and amyloid‐negative control cases. The localization of SA modifications was investigated in the frontal cortex of 30 post‐mortem cases with or without diagnoses of AD and/or CAA. Quantitative digital pathology analyses were used to determine regional SA differences in parenchymal and leptomeningeal blood vessels. First, we found no difference in intravascular amyloid‐beta levels between the parenchymal and leptomeningeal vessels of AD with CAA cases, suggesting no regional differences in this amyloid aggregation. Next, there was a visual increase in microglia sialylation surrounding parenchymal blood vessels in the CAA cases. Notably, there were significant differences in intravascular SA levels across the three comparison groups. AD cases with CAA had significantly greater sialylation levels in both the parenchymal and leptomeningeal vessels compared with the AD‐only and control groups. This is a novel finding that supports the consideration of glycosylation changes that contribute to worse pathological outcomes in AD with CAA.

Vasculitic neuropathy remains challenging to diagnose and monitor because of its heterogeneous clinical and laboratory presentation. Blood‐based biomarkers indicating nerve damage could serve as an additional diagnostic tool to ensure early diagnosis, precise therapeutic monitoring, and a more targeted anti‐inflammatory treatment. A potential marker for this purpose is neurofilament light chain (NfL), a marker of neuroaxonal damage that is used as a biomarker in several diseases of the central and peripheral nervous system. NfL has also been suggested to reflect disease activity in patients with vasculitic neuropathy. However, its biodynamics and link to degeneration of peripheral nerve tissue remain unconfirmed. To investigate the usefulness of NfL as a marker of peripheral nerve damage in this context, we retrospectively assembled a cohort of 35 patients undergoing sural nerve biopsies (including patients with vasculitic neuropathy and other neuropathies). We then measured NfL in serum samples cryoarchived at the time of biopsy and correlated NfL levels with histological parameters. For our histological analysis, we quantified parameters of acute axonal degeneration and chronic axonal loss using a combination of manual, threshold‐based, and supervised learning‐based analyses. We found a significant positive correlation between parameters of acute axonal degeneration and serum‐NfL levels that persisted after adjusting for age and concomitant central nervous system disease. We did not find a similar correlation with parameters of chronic axonal loss quantified in nerve biopsies. These findings support the value of NfL as a marker for acute axonal degeneration in patients with vasculitic neuropathy.

Nitro‐oleic acid (OA‐NO2) is an endogenous peroxisome proliferator‐activated receptor‐γ (PPARγ) ligand and can activate this receptor under both physiological and pathological conditions. In this study, we explore the role and molecular mechanisms of OA‐NO2 in maintaining blood–brain barrier (BBB) integrity and enhancing neurovascular function during ischemic stroke, with a particular emphasis on the activation of endothelial PPARγ signaling pathways. Endothelial cell‐selective PPARγ conditional knockout (EC‐PPARγ cKO) and wild‐type (WT) mice underwent 1 h middle cerebral artery occlusion (MCAO) with 1–7 days of reperfusion. Mice were treated with oleic acid (OA) or OA‐NO2 (5 mg/kg) via tail vein 2 h after MCAO. Neurobehavioral deficits were assessed on days 3, 5, and 7 after MCAO. Neuroinflammation and BBB function were assessed on days 1 or 2 after MCAO by immunohistochemistry, RT‐qPCR, or Western blot analysis. Compared to OA controls, intravenous administration of OA‐NO2 led to reduced BBB leakage in ischemic brains, as indicated by a significant decrease in the extravasation of BBB tracers. This reduction in BBB leakage was also almost abolished in the EC‐PPARγ cKO mice. Furthermore, OA‐NO2 treatment reduced brain infarction in stroke mice, but this protective effect was completely reversed in the EC‐PPARγ cKO mice. Interestingly, OA‐NO2 treatment promoted a shift towards an anti‐inflammatory microglial phenotype (M2) in the peri‐infarct regions of WT mice, but not in EC‐PPARγ cKO mice. Mechanistically, OA‐NO2 increased levels of major endothelial tight junction proteins in WT mice but not in EC‐PPARγ cKO mice following ischemic stroke. These findings suggest that OA‐NO2 activation of endothelial PPARγ signaling cascade attenuates neurovascular injury after ischemic stroke.

Pediatric low‐grade gliomas (pLGG) comprise 35% of all brain tumors. Despite favorable survival, patients experience significant morbidity from disease and treatments. A deeper understanding of pLGG biology is essential to identify novel, more effective, and less toxic therapies. We utilized single‐cell RNA sequencing (scRNA‐seq), spatial transcriptomics, and cytokine analyses to characterize and understand tumor and immune cell heterogeneity of pilocytic astrocytoma (PA) and ganglioglioma (GG). scRNA‐seq revealed tumor and immune cells within the tumor microenvironment (TME). Tumor cell subsets include both progenitor and mature cell populations. Immune cells included myeloid and lymphocytic cells. There was a significant difference between the prevalence of two major myeloid subclusters between PA and GG. Bulk and single‐cell cytokine analyses evaluated the immune cell signaling cascade with distinct immune phenotypes among tumor samples. KIAA1549‐BRAF tumors appeared more immunogenic, secreting higher levels of immune cell activators and chemokines, compared to BRAF V600E tumors. Spatial transcriptomics revealed the differential gene expression of these chemokines and their location within the TME. A multi‐pronged analysis demonstrated the complexity of the PA and GG TME and differences between genetic drivers that may influence their response to immunotherapy. Further investigation of immune cell infiltration and tumor‐immune interactions is warranted.

A key role for inflammation in amyotrophic lateral sclerosis/motor neuron disease (ALS/MND) has been identified. It is vital to assess which central nervous system structures are most affected and which inflammatory processes are responsible in humans. The inflammatory transcriptome was characterized in the cervical spinal cord and motor cortex in post‐mortem frozen and formalin‐fixed paraffin‐embedded specimens from human sporadic ALS/MND and control cases using the nCounter® Neuroinflammation Panel. Archival data were reanalyzed and compared with the nCounter data. Immunohistochemistry was used to examine the inflammatory response in the spinal cord and motor cortex and validate changes found during transcriptomic analyses. In the spinal cord, marked inflammation was observed, while less inflammation was detected in the motor cortex. Examination of differentially expressed genes in the spinal cord highlighted TREM2, TYROBP, APOE, and CD163, as well as phagocytic pathways. In sporadic ALS/MND spinal cord, significant microglial reactivity and involvement of TREM2, ApoE (encoded by APOE), and TYROBP were confirmed, suggesting the involvement of the disease‐associated microglial (DAM) phenotype. The corticospinal tracts showed greater inflammation than the ventral horns. The precentral gyrus of ALS/MND again showed less immune reactivity to disease when compared to controls. Finally, in the largest cohort assessed to date, we demonstrate an association between the APOE variant and ALS/MND risk, age of onset, and survival. We find confirmed associations between APOE ε3/ε3 and disease and between ε2/ε2 and absence of disease. Further, ε4/ε4 appears to be associated with earlier disease onset and a more aggressive course. We conclude that while there is widespread inflammation in the CNS in sporadic ALS/MND, this is more marked in the spinal cord, especially the corticospinal tract. The specific markers stress the DAM phenotype as having a key role together with a possible influx of somatic macrophages. In addition, APOE function and genotype may be relevant in ALS/MND.

Brain Pathology is the official journal of the International Society of Neuropathology.It is a peer-reviewed, bi-monthly, Open Access journal that includes original research, review articles and symposia focuses on the pathogenesis of neurological disease. Aims and ScopeThe official journal of the ISN is intended to be a forum for recent progress in the science and practice of neuropathology, with a strong emphasis on disease mechanisms.It will be broad in scope, encompassing advances in neighboring disciplines, including cell biology, molecular genetics, immunology and virology.Although primarily directed to pathologists, Brain Pathology addresses all members of the scientific community interested in diseases of the nervous system