Deep spatial profiling of human COVID-19 brains reveals neuroinflammation with distinct microanatomical microglia-T-cell interactions.

COVID-19 can cause severe neurological symptoms, but the underlying pathophysiological mechanisms are unclear. Here, we interrogated the brain stems and olfactory bulbs in postmortem patients who had COVID-19 using imaging mass cytometry to understand the local immune response at a spatially resolved, high-dimensional, single-cell level and compared their immune map to non-COVID respiratory failure, multiple sclerosis, and control patients. We observed substantial immune activation in the central nervous system with pronounced neuropathology (astrocytosis, axonal damage, and blood-brain-barrier leakage) and detected viral antigen in ACE2-receptor-positive cells enriched in the vascular compartment. Microglial nodules and the perivascular compartment represented COVID-19-specific, microanatomic-immune niches with context-specific cellular interactions enriched for activated CD8+ T cells. Altered brain T-cell-microglial interactions were linked to clinical measures of systemic inflammation and disturbed hemostasis. This study identifies profound neuroinflammation with activation of innate and adaptive immune cells as correlates of COVID-19 neuropathology, with implications for potential therapeutic strategies.

The importance of brain banking for dementia practice: the first experience of Turkey.

This study reports the results of the first brain tissue banking experience of Turkey in the Unit for Aging Brain and Dementia at Dokuz Eylul University, Department of Geriatric Medicine, Izmir. Here, we have briefly described our efforts on brain banking in our country, which consist of six brains from autopsies that had at least two years of clinical follow-up in the 2015-2017 period. The evaluation led to the diagnosis of two Alzheimer's disease (AD) with cerebral amyloid angiopathy, one AD with dementia with Lewy bodies, one corticobasal degeneration, one multiple system atrophy, one vascular dementia. We believe that the study is of a special importance because of its potential of becoming a brain banking center in the region and because of its contributing to the international knowledge of the neuropathological features of dementia, while characterizing the epidemiology of these diseases in the region.

Unique cell tropism of HHV-6B in an infantile autopsy case of primary HHV-6B encephalitis.

Human herpes virus 6 (HHV-6) is known to cause primary encephalitis in the frontal lobes/cerebral hemisphere or reactivated encephalitis in the hippocampus, but the pathogenesis remains unclear. HHV-6B has also been detected in hippocampal samples in patients with mesial temporal lobe epilepsy. A 1 year and 3 months old female, who had been clinically diagnosed with exanthema subitum and febrile convulsion, was found dead on the third day after onset. Macroscopic findings showed massive brain edema. Microscopic examination revealed gemistocytic astrocytes and ballooned oligodendrocytes in the frontal white matter, along with neuronal cell death with microglial infiltration in the frontal cortex. Polymerase chain reaction detected HHV-6B in the cerebrospinal fluid and necropsy brain samples. The hippocampus showed a 4-5-fold increase in virus copy number of HHV-6B compared to samples from other brain sites. Immunostaining indicated that HHV-6B had infected vascular endothelial cells, neurons and oligodendrocytes but not astrocytes or microglia. Hippocampal neurons were infected with highly concentrated HHV-6B, but the hippocampus had neither neuronal loss nor reactive glial response. Silent and abundant HHV-6B infection in the hippocampus might be associated with latent infection, reactivation and some hippocampus-oriented disorders, including mesial temporal lobe epilepsy.

Neuropathologic differences by race from the National Alzheimer's Coordinating Center.

INTRODUCTION: Compared to Caucasians, African Americans (AAs) have higher dementia prevalence, different genetic markers, and higher vascular risk factors. However, pathologic underpinnings are unknown. METHODS: We used neuropathologic and clinical data on 110 AA and 2500 Caucasians who were demented before death. The groups were compared regarding demographics, cognition, apolipoprotein E (APOE) genotype, comorbidities, and clinical and neuropathologic characteristics. RESULTS: AA and Caucasians differed in their demographics, cognition at the last visit before death, APOE genotype, presence of hypertension, primary clinical diagnoses, and AD, cerebrovascular disease (CVD), and other neuropathologies such as Lewy body disease (LBD). DISCUSSION: AD, LBD, and CVD pathology were more common and TDP and frontotemporal lobar degeneration-tau less common in AA than in Caucasians. APOE accounted for most of the AD neuropathologic differences. If replicated, the observed differences in underlying neuropathology by race will be important for public health policy and recruitment for and interpreting of clinical trials.

[The autopsy of the brain and spinal cord in the diagnosis of neurodegenerative diseases - a practical approach to optimize the examination]. / Pitva mozku a míchy pri diagnóze neurodegenerativního onemocnení - praktický postup pro optimalizaci vysetrení.

Brain and spinal cord autopsies aimed at neuropathological diagnosis of the causes of dementia and motor abnormalities are of increasing importance. Neuropathological brain examination is often the only diagnostic modality capable of definitive diagnosis of a neurodegenerative disease and thus serves as invaluable feedback for clinicians and biochemical and imaging diagnostics. The brain and spinal cord autopsy is performed following a standardized protocol and its goal is to sample all diagnostically relevant structures. Subsequent diagnostics are then done using standard and special histologic stainings, however state-of-the-art diagnostics can be achieved only using immunohistochemical methods. The purpose of the article is to provide the pathologists with a brief and practical guideline for brain and spinal cord autopsy when diagnosis of a neurodegenerative disease is suspected.

Survival, but not the severity of hypoxic-ischemic encephalopathy, is associated with higher mean arterial blood pressure after cardiac arrest: a retrospective cohort study.

Background: This study investigates the association between the mean arterial blood pressure (MAP), vasopressor requirement, and severity of hypoxic-ischemic encephalopathy (HIE) after cardiac arrest (CA). Methods: Between 2008 and 2017, we retrospectively analyzed the MAP 200 h after CA and quantified the vasopressor requirements using the cumulative vasopressor index (CVI). Through a postmortem brain autopsy in non-survivors, the severity of the HIE was histopathologically dichotomized into no/mild and severe HIE. In survivors, we dichotomized the severity of HIE into no/mild cerebral performance category (CPC) 1 and severe HIE (CPC 4). We investigated the regain of consciousness, causes of death, and 5-day survival as hemodynamic confounders. Results: Among the 350 non-survivors, 117 had histopathologically severe HIE while 233 had no/mild HIE, without differences observed in the MAP (73.1 vs. 72.0 mmHg, pgroup = 0.639). Compared to the non-survivors, 211 patients with CPC 1 and 57 patients with CPC 4 had higher MAP values that showed significant, but clinically non-relevant, MAP differences (81.2 vs. 82.3 mmHg, pgroup < 0.001). The no/mild HIE non-survivors (n = 54), who regained consciousness before death, had higher MAP values compared to those with no/mild HIE (n = 179), who remained persistently comatose (74.7 vs. 69.3 mmHg, pgroup < 0.001). The no/mild HIE non-survivors, who regained consciousness, required fewer vasopressors (CVI 2.1 vs. 3.6, pgroup < 0.001). Independent of the severity of HIE, the survivors were weaned faster from vasopressors (CVI 1.0). Conclusions: Although a higher MAP was associated with survival in CA patients treated with a vasopressor-supported MAP target above 65 mmHg, the severity of HIE was not. Awakening from coma was associated with less vasopressor requirements. Our results provide no evidence for a MAP target above the current guideline recommendations that can decrease the severity of HIE.

Neuropathological findings in COVID-19 vs. non-COVID-19 acute respiratory distress syndrome-A case-control study.

Acute brain injury (ABI) and neuroinflammation is reported in COVID-19 and acute respiratory distress syndrome (ARDS). It remains unclear if COVID-19 plays an independent role in development of ABI compared to those with non-COVID-19 ARDS. We aimed to evaluate if COVID-19 ARDS is associated with higher risk and specific patterns of ABI compared to non-COVID-19 ARDS. We conducted an age and sex matched case-control autopsy study at a tertiary academic center. Ten patients with COVID-19 ARDS were matched to 20 non-COVID-19 ARDS patients. Baseline demographics were comparable between the two groups including severity of ARDS (p = 0.3). The frequency of overall ABI (70 vs. 60%), infratentorial ABI (40 vs. 25%), ischemic infarct (40 vs. 25%), intracranial hemorrhage (30 vs. 35%), and hypoxic-ischemic brain injury (30 vs. 35%) was similar between COVID-19 and non-COVID-19 ARDS patients, respectively (p > 0.05). Intracapillary megakaryocytes were exclusively seen in 30% of COVID-19 patients. Overall, frequency and pattern of ABI in COVID-19 ARDS was comparable to non-COVID-19.

Chronic Traumatic Encephalopathy in a Routine Neuropathology Service in Australia.

Chronic traumatic encephalopathy (CTE) is a neuropathological diagnosis defined by a unique pattern of hyperphosphorylated tau (p-tau) accumulation that begins in neocortical regions of the brain. It is associated with a range of neuropsychological symptoms, but a definitive diagnosis can only be made by postmortem brain examination. In 2018, we instituted CTE screening for all autopsy brains as part of our routine departmental protocol by performing p-tau immunohistochemistry on a restricted set of 3 neocortical blocks (frontal, temporal, and parietal). This strategy allowed us to identify 4 cases of low-stage CTE from 180 consecutive autopsies. Two of the 4 cases had a documented history of brain injury; for the remaining 2 cases, there was a long history of treatment-resistant tonic/clonic epilepsy suggesting that undocumented brain injuries may have occurred. Our experience indicates that 3-block CTE screening is useful in identifying CTE in routine practice. The results of this study further support the association between prior head injuries and CTE and demonstrate that, albeit uncommon, CTE does occur in the general population. Our findings suggest that p-tau screening should be routinely pursued in brain autopsy, particularly where there is a documented or likely history of traumatic brain injury.

COVID-19 - neuropathological point of view, pathobiology, and dilemmas after the first year of the pandemic struggle.

This article constitutes a summary of the knowledge on the involvement of the nervous system in COVID-19, concerning its general pathobiology, clinical presentation and neuropathological features as well as the future directions of investigation. Variable definitions, selection bias, mainly retrospective analyses of hospitalized patients and different methodologies are implemented in the research of this new disease. Central nervous system (CNS) pathology presents most frequently features of non-specific neuroinflammation with microglial activation and lymphoid infiltrations, ischemic/hypoxic encephalopathy, acute cerebrovascular disease, and microthrombi. Some brain specimens remain unaffected or show only non-specific changes of the critical status. Interpretations of the neuropathological findings are not always balanced in a clinical context and discrepant in consequence. Designing of longitudinal neuropathological studies, more frequent autopsies, and building of COVID-19 brain banks, together with neuroimaging analyses is essential. Genetic predispositions or immunological factors corresponding to the disease profile as well as cerebrospinal fluid (CSF) or serum biomarkers of COVID-19, the impact of different virus variants and influence of the therapy need to be identified. The mechanisms causing neuroCOVID and cognitive impairment - whether they are infectious, toxic, vascular or metabolic - create other aspects under research. There are also many existential questions about post-COVID and delayed sequelae of the infection. The fight with pandemic is a challenge for the global society, with neuropathologists and neuroscientists as important allies in struggle for understanding and conquering COVID-19.

Neuropathology and Inflammatory Cell Characterization in 10 Autoptic COVID-19 Brains.

COVID-19 presents with a wide range of clinical neurological manifestations. It has been recognized that SARS-CoV-2 infection affects both the central and peripheral nervous system, leading to smell and taste disturbances; acute ischemic and hemorrhagic cerebrovascular disease; encephalopathies and seizures; and causes most surviving patients to have long lasting neurological symptoms. Despite this, typical neuropathological features associated with the infection have still not been identified. Studies of post-mortem examinations of the cerebral cortex are obtained with difficulty due to laboratory safety concerns. In addition, they represent cases with different neurological symptoms, age or comorbidities, thus a larger number of brain autoptic data from multiple institutions would be crucial. Histopathological findings described here are aimed to increase the current knowledge on neuropathology of COVID-19 patients. We report post-mortem neuropathological findings of ten COVID-19 patients. A wide range of neuropathological lesions were seen. The cerebral cortex of all patients showed vascular changes, hyperemia of the meninges and perivascular inflammation in the cerebral parenchyma with hypoxic neuronal injury. Perivascular lymphocytic inflammation of predominantly CD8-positive T cells mixed with CD68-positive macrophages, targeting the disrupted vascular wall in the cerebral cortex, cerebellum and pons were seen. Our findings support recent reports highlighting a role of microvascular injury in COVID-19 neurological manifestations.

Persistent Brainstem Dysfunction in Long-COVID: A Hypothesis.

Long-COVID is a postviral illness that can affect survivors of COVID-19, regardless of initial disease severity or age. Symptoms of long-COVID include fatigue, dyspnea, gastrointestinal and cardiac problems, cognitive impairments, myalgia, and others. While the possible causes of long-COVID include long-term tissue damage, viral persistence, and chronic inflammation, the review proposes, perhaps for the first time, that persistent brainstem dysfunction may also be involved. This hypothesis can be split into two parts. The first is the brainstem tropism and damage in COVID-19. As the brainstem has a relatively high expression of ACE2 receptor compared with other brain regions, SARS-CoV-2 may exhibit tropism therein. Evidence also exists that neuropilin-1, a co-receptor of SARS-CoV-2, may be expressed in the brainstem. Indeed, autopsy studies have found SARS-CoV-2 RNA and proteins in the brainstem. The brainstem is also highly prone to damage from pathological immune or vascular activation, which has also been observed in autopsy of COVID-19 cases. The second part concerns functions of the brainstem that overlap with symptoms of long-COVID. The brainstem contains numerous distinct nuclei and subparts that regulate the respiratory, cardiovascular, gastrointestinal, and neurological processes, which can be linked to long-COVID. As neurons do not readily regenerate, brainstem dysfunction may be long-lasting and, thus, is long-COVID. Indeed, brainstem dysfunction has been implicated in other similar disorders, such as chronic pain and migraine and myalgic encephalomyelitis or chronic fatigue syndrome.

Pembrolizumab-Induced Meningoencephalitis: A Brain Autopsy Case.

Encephalitis is very rare, but often fatal immune-related adverse event (irAE) of immune checkpoint inhibitors (ICIs). A 65-year-old Japanese woman was admitted to our hospital because of general fatigue, chillness and high-grade fever for 4 days, 8 months after the initiation of the first-line pembrolizumab monotherapy for metastatic pulmonary adenocarcinoma. On the hospital day 3, she suddenly presented delirium and uncontrollable impaired consciousness. Although the magnetic resonance imaging (MRI) did not suggest a diagnosis of encephalitis and meningitis, the spinal fluid showed abnormally elevated levels of protein (317.6 mg/L) and cell count (197 cells/µL) with increased mononuclear cells (93%). An empirical and intravenous administration of acyclovir in doses of 10 mg/kg body weight every 8 h and steroid pulse therapy in dose of 1 g/body/day from the hospital day 5 until her death failed to improve her conditions. She died on the hospital day 8. The postmortem autopsy showed viable cancer cells in the metastatic tumor in the left occipital lobe and in the spinal fluids. However, many inflammatory cells infiltration in the meninges and perivascular cuffing were prominent especially in the brain stem and medial part of the temporal lobe. Infiltrating lymphocytes in the meninges and parenchyma of the brain stem were mainly composed of cluster of differentiation (CD)8-positive lymphocytes. For irAE encephalitis, early recognition of early signs and symptoms and subsequent early therapeutic intervention are necessary. It is important for oncologists to keep in mind of the possible adverse effects of immunotherapies on the nervous system.

Antigen-Dependent T Cell Response to Neural Peptides After Human Ischemic Stroke.

Ischemic stroke causes brain tissue damage and may release central nervous system (CNS)-specific peptides to the periphery. Neural antigen presentation in the lymphoid tissue could prime immune cells and result in adaptive immune response. However, autoimmune responses against neural antigens are not commonly uncovered after stroke. We studied the brain tissue of nine fatal stroke cases and the blood of a cohort of 13 patients and 11 controls. Flow cytometry carried out in three of the brain samples showed CD8 and CD4 T cells in the cerebrospinal fluid (CSF) of the ventricles in the patient deceased 1 day poststroke, T cells with an activated phenotype in the CSF of the patient that died at day 6, and T cells in the ischemic brain tissue in the patient deceased 140 days after stroke onset. Immunohistochemistry showed higher T cell numbers in the core of the lesion of the patient deceased 18 days post-stroke than in the patients deceased from 1 to 5 days post-stroke. In blood samples, we studied whether lymphocytes were primed in the periphery against neural antigens at sequential times (on admission, day 5, and day 90) after stroke. T lymphocytes of stroke patients produced IFN-γ and TNF-α and responded to MBP peptides by increasing their production of TNF-α and IL-10 at admission, but not at later time points. In contrast, IL-4 producing T cells showed progressive increases. Higher percentages of TNF-α producing T lymphocytes at admission were independently associated with poorer outcomes at 90 days. However, we did not detect T cell responses to neural-antigen stimulation 90 days post-stroke. Altogether the results suggest acute T cell priming in the periphery in acute stroke, T cell trafficking from the CSF to the ischemic brain tissue, and the existence of active mechanisms preventing autoreactivity.

The Brain Donation Program in South Korea.

PURPOSE: Obtaining brain tissue is critical to definite diagnosis and to furthering understanding of neurodegenerative diseases. The present authors have maintained the National Neuropathology Reference and Diagnostic Laboratories for Dementia in South Korea since 2016. We have built a nationwide brain bank network and are collecting brain tissues from patients with neurodegenerative diseases. We are aiming to facilitate analyses of clinic-pathological and image-pathological correlations of neurodegenerative disease and to broaden understanding thereof. MATERIALS AND METHODS: We recruited participants through two routes: from memory clinics and the community. As a baseline evaluation, clinical interviews, a neurological examination, laboratory tests, neuropsychological tests, and MRI were undertaken. Some patients also underwent amyloid PET. RESULTS: We recruited 105 participants, 70 from clinics and 35 from the community. Among them, 11 died and were autopsied. The clinical diagnoses of the autopsied patients included four with Alzheimer's disease (AD), two with subcortical vascular dementia, two with non-fluent variant primary progressive aphasia, one with leukoencephalopathy, one with frontotemporal dementia (FTD), and one with Creutzfeldt-Jakob disease (CJD). Five patients underwent amyloid PET: two with AD, one with mixed dementia, one with FTD, and one with CJD. CONCLUSION: The clinical and neuropathological information to be obtained from this cohort in the future will provide a deeper understanding of the neuropathological mechanisms of cognitive impairment in Asia, especially Korea.

A critical view of the quest for brain structural markers of Albert Einstein's special talents (a pot of gold under the rainbow).

Assertions regarding attempts to link glial and macrostructural brain events with cognitive performance regarding Albert Einstein, are critically reviewed. One basic problem arises from attempting to draw causal relationships regarding complex, delicately interactive functional processes involving finely tuned molecular and connectivity phenomena expressed in cognitive performance, based on highly variable brain structural events of a single, aged, formalin fixed brain. Data weaknesses and logical flaws are considered. In other instances, similar neuroanatomical observations received different interpretations and conclusions, as those drawn, e.g., from schizophrenic brains. Observations on white matter events also raise methodological queries. Additionally, neurocognitive considerations on other intellectual aptitudes of A. Einstein were simply ignored.