Changes in the locus coeruleus during the course of Alzheimer's disease and their relationship to cortical pathology.

AIMS: In Alzheimer's disease (AD), the locus coeruleus (LC) undergoes early and extensive neuronal loss, preceded by abnormal intracellular tau aggregation, decades before the onset of clinical disease. Neuromelanin-sensitive MRI has been proposed as a method to image these changes during life. Surprisingly, human post-mortem studies have not examined how changes in LC during the course of the disease relate to cerebral pathology following the loss of the LC projection to the cortex. METHODS: Immunohistochemistry was used to examine markers for 4G8 (pan-Aß) and AT8 (ptau), LC integrity (neuromelanin, dopamine ß-hydroxylase [DßH], tyrosine hydroxylase [TH]) and microglia (Iba1, CD68, HLA-DR) in the LC and related temporal lobe pathology of 59 post-mortem brains grouped by disease severity determined by Braak stage (0-II, III-IV and V-VI). The inflammatory environment was assessed using multiplex assays. RESULTS: Changes in the LC with increasing Braak stage included increased neuronal loss (p < 0.001) and microglial Iba1 (p = 0.005) together with a reduction in neuromelanin (p < 0.001), DßH (p = 0.002) and TH (p = 0.041). Interestingly in LC, increased ptau and loss of neuromelanin were detected from Braak stage III-IV (p = 0.001). At Braak stage V/VI, the inflammatory environment was different in the LC vs TL, highlighting the anatomical heterogeneity of the inflammatory response. CONCLUSIONS: Here, we report the first quantification of neuromelanin during the course of AD and its relationship to AD pathology and neuroinflammation in the TL. Our findings of neuromelanin loss early in AD and before the neuroinflammatory reaction support the use of neuromelanin-MRI as a sensitive technique to identify early changes in AD.

Glial reactivity and T cell infiltration in frontotemporal lobar degeneration with tau pathology.

Frontotemporal lobar degeneration with tau (FTLD-tau) is a group of tauopathies that underlie ∼50% of FTLD cases. Identification of genetic risk variants related to innate/adaptive immunity have highlighted a role for neuroinflammation and neuroimmune interactions in FTLD. Studies have shown microglial and astrocyte activation together with T cell infiltration in the brain of THY-Tau22 tauopathy mice. However, this remains to be confirmed in FTLD-tau patients. We conducted a detailed post-mortem study of FTLD-tau cases including 45 progressive supranuclear palsy with clinical frontotemporal dementia, 33 Pick's disease, 12 FTLD-MAPT and 52 control brains to characterize the link between phosphorylated tau (pTau) epitopes and the innate and adaptive immunity. Tau pathology was assessed in the cerebral cortex using antibodies directed against: Tau-2 (phosphorylated and unphosphorylated tau), AT8 (pSer202/pThr205), AT100 (pThr212/pSer214), CP13 (pSer202), PHF1 (pSer396/pSer404), pThr181 and pSer356. The immunophenotypes of microglia and astrocytes were assessed with phenotypic markers (Iba1, CD68, HLA-DR, CD64, CD32a, CD16 for microglia and GFAP, EAAT2, glutamine synthetase and ALDH1L1 for astrocytes). The adaptive immune response was explored via CD4+ and CD8+ T cell quantification and the neuroinflammatory environment was investigated via the expression of 30 inflammatory-related proteins using V-Plex Meso Scale Discovery. As expected, all pTau markers were increased in FTLD-tau cases compared to controls. pSer356 expression was greatest in FTLD-MAPT cases versus controls (P < 0.0001), whereas the expression of other markers was highest in Pick's disease. Progressive supranuclear palsy with frontotemporal dementia consistently had a lower pTau protein load compared to Pick's disease across tau epitopes. The only microglial marker increased in FTLD-tau was CD16 (P = 0.0292) and specifically in FTLD-MAPT cases (P = 0.0150). However, several associations were detected between pTau epitopes and microglia, supporting an interplay between them. GFAP expression was increased in FTLD-tau (P = 0.0345) with the highest expression in Pick's disease (P = 0.0019), while ALDH1L1 was unchanged. Markers of astrocyte glutamate cycling function were reduced in FTLD-tau (P = 0.0075; Pick's disease: P < 0.0400) implying astrocyte reactivity associated with a decreased glutamate cycling activity, which was further associated with pTau expression. Of the inflammatory proteins assessed in the brain, five chemokines were upregulated in Pick's disease cases (P < 0.0400), consistent with the recruitment of CD4+ (P = 0.0109) and CD8+ (P = 0.0014) T cells. Of note, the CD8+ T cell infiltration was associated with pTau epitopes and microglial and astrocytic markers. Our results highlight that FTLD-tau is associated with astrocyte reactivity, remarkably little activation of microglia, but involvement of adaptive immunity in the form of chemokine-driven recruitment of T lymphocytes.

The mitochondrial protein TSPO in Alzheimer's disease: relation to the severity of AD pathology and the neuroinflammatory environment.

The 18kD translocator protein (TSPO) is used as a positron emission tomography (PET) target to quantify neuroinflammation in patients. In Alzheimer's disease (AD), the cerebellum is the pseudo-reference region for comparison with the cerebral cortex due to the absence of AD pathology and lower levels of TSPO. However, using the cerebellum as a pseudo-reference region is debated, with other brain regions suggested as more suitable. This paper aimed to establish the neuroinflammatory differences between the temporal cortex and cerebellar cortex, including TSPO expression. Using 60 human post-mortem samples encompassing the spectrum of Braak stages (I-VI), immunostaining for pan-Aß, hyperphosphorylated (p)Tau, TSPO and microglial proteins Iba1, HLA-DR and MSR-A was performed in the temporal cortex and cerebellum. In the cerebellum, Aß but not pTau, increased over the course of the disease, in contrast to the temporal cortex, where both proteins were significantly increased. TSPO increased in the temporal cortex, more than twofold in the later stages of AD compared to the early stages, but not in the cerebellum. Conversely, Iba1 increased in the cerebellum, but not in the temporal cortex. TSPO was associated with pTau in the temporal cortex, suggesting that TSPO positive microglia may be reacting to pTau itself and/or neurodegeneration at later stages of AD. Furthermore, the neuroinflammatory microenvironment was examined, using MesoScale Discovery assays, and IL15 only was significantly increased in the temporal cortex. Together this data suggests that the cerebellum maintains a more homeostatic environment compared to the temporal cortex, with a consistent TSPO expression, supporting its use as a pseudo-reference region for quantification in TSPO PET scans.

Clinical impact of anti-inflammatory microglia and macrophage phenotypes at glioblastoma margins.

Glioblastoma is a devastating brain cancer for which effective treatments are required. Tumour-associated microglia and macrophages promote glioblastoma growth in an immune-suppressed microenvironment. Most recurrences occur at the invasive margin of the surrounding brain, yet the relationships between microglia/macrophage phenotypes, T cells and programmed death-ligand 1 (an immune checkpoint) across human glioblastoma regions are understudied. In this study, we performed a quantitative immunohistochemical analysis of 15 markers of microglia/macrophage phenotypes (including anti-inflammatory markers triggering receptor expressed on myeloid cells 2 and CD163, and the low-affinity-activating receptor CD32a), T cells, natural killer cells and programmed death-ligand 1, in 59 human IDH1-wild-type glioblastoma multi-regional samples (n = 177; 1 sample at tumour core, 2 samples at the margins: the infiltrating zone and leading edge). Assessment was made for the prognostic value of markers; the results were validated in an independent cohort. Microglia/macrophage motility and activation (Iba1, CD68), programmed death-ligand 1 and CD4+ T cells were reduced, and homeostatic microglia (P2RY12) were increased in the invasive margins compared with the tumour core. There were significant positive correlations between microglia/macrophage markers CD68 (phagocytic)/triggering receptor expressed on myeloid cells 2 (anti-inflammatory) and CD8+ T cells in the invasive margins but not in the tumour core (P < 0.01). Programmed death-ligand 1 expression was associated with microglia/macrophage markers (including anti-inflammatory) CD68, CD163, CD32a and triggering receptor expressed on myeloid cells 2, only in the leading edge of glioblastomas (P < 0.01). Similarly, there was a positive correlation between programmed death-ligand 1 expression and CD8+ T-cell infiltration in the leading edge (P < 0.001). There was no relationship between CD64 (a receptor for autoreactive T-cell responses) and CD8+/CD4+ T cells, or between the microglia/macrophage antigen presentation marker HLA-DR and microglial motility (Iba1) in the tumour margins. Natural killer cell infiltration (CD335+) correlated with CD8+ T cells and with CD68/CD163/triggering receptor expressed on myeloid cells 2 anti-inflammatory microglia/macrophages at the leading edge. In an independent large glioblastoma cohort with transcriptomic data, positive correlations between anti-inflammatory microglia/macrophage markers (triggering receptor expressed on myeloid cells 2, CD163 and CD32a) and CD4+/CD8+/programmed death-ligand 1 RNA expression were validated (P < 0.001). Finally, multivariate analysis showed that high triggering receptor expressed on myeloid cells 2, programmed death-ligand 1 and CD32a expression at the leading edge were significantly associated with poorer overall patient survival (hazard ratio = 2.05, 3.42 and 2.11, respectively), independent of clinical variables. In conclusion, anti-inflammatory microglia/macrophages, CD8+ T cells and programmed death-ligand 1 are correlated in the invasive margins of glioblastoma, consistent with immune-suppressive interactions. High triggering receptor expressed on myeloid cells 2, programmed death-ligand 1 and CD32a expression at the human glioblastoma leading edge are predictors of poorer overall survival. Given substantial interest in targeting microglia/macrophages, together with immune checkpoint inhibitors in cancer, these data have major clinical implications.

Amyloid-related imaging abnormalities (ARIA): radiological, biological and clinical characteristics.

Excess accumulation and aggregation of toxic soluble and insoluble amyloid-ß species in the brain are a major hallmark of Alzheimer's disease. Randomized clinical trials show reduced brain amyloid-ß deposits using monoclonal antibodies that target amyloid-ß and have identified MRI signal abnormalities called amyloid-related imaging abnormalities (ARIA) as possible spontaneous or treatment-related adverse events. This review provides a comprehensive state-of-the-art conceptual review of radiological features, clinical detection and classification challenges, pathophysiology, underlying biological mechanism(s) and risk factors/predictors associated with ARIA. We summarize the existing literature and current lines of evidence with ARIA-oedema/effusion (ARIA-E) and ARIA-haemosiderosis/microhaemorrhages (ARIA-H) seen across anti-amyloid clinical trials and therapeutic development. Both forms of ARIA may occur, often early, during anti-amyloid-ß monoclonal antibody treatment. Across randomized controlled trials, most ARIA cases were asymptomatic. Symptomatic ARIA-E cases often occurred at higher doses and resolved within 3-4 months or upon treatment cessation. Apolipoprotein E haplotype and treatment dosage are major risk factors for ARIA-E and ARIA-H. Presence of any microhaemorrhage on baseline MRI increases the risk of ARIA. ARIA shares many clinical, biological and pathophysiological features with Alzheimer's disease and cerebral amyloid angiopathy. There is a great need to conceptually link the evident synergistic interplay associated with such underlying conditions to allow clinicians and researchers to further understand, deliberate and investigate on the combined effects of these multiple pathophysiological processes. Moreover, this review article aims to better assist clinicians in detection (either observed via symptoms or visually on MRI), management based on appropriate use recommendations, and general preparedness and awareness when ARIA are observed as well as researchers in the fundamental understanding of the various antibodies in development and their associated risks of ARIA. To facilitate ARIA detection in clinical trials and clinical practice, we recommend the implementation of standardized MRI protocols and rigorous reporting standards. With the availability of approved amyloid-ß therapies in the clinic, standardized and rigorous clinical and radiological monitoring and management protocols are required to effectively detect, monitor, and manage ARIA in real-world clinical settings.

Localized microglia dysregulation impairs central nervous system myelination in development.

Myelination of neuronal axons is a critical aspect of central nervous system development and function. However, the fundamental cellular and molecular mechanisms influencing human developmental myelination and its failure are not fully understood. Here, we used digital spatial transcriptomics of a rare bank of human developing white matter to uncover that a localized dysregulated innate immune response is associated with impeded myelination. We identified that poorly myelinating areas have a distinct signature of Type II interferon signalling in microglia/macrophages, relative to adjacent myelinating areas. This is associated with a surprising increase in mature oligodendrocytes, which fail to form myelin processes appropriately. We functionally link these findings by showing that conditioned media from interferon-stimulated microglia is sufficient to dysregulate myelin process formation by oligodendrocytes in culture. We identify the Type II interferon inducer, Osteopontin (SPP1), as being upregulated in poorly myelinating brains, indicating a potential biomarker. Our results reveal the importance of microglia-mature oligodendrocyte interaction and interferon signaling in regulating myelination of the developing human brain.

The spatiotemporal dynamics of microglia across the human lifespan.

Microglia, the brain's resident macrophages, shape neural development and are key neuroimmune hubs in the pathological signatures of neurodevelopmental disorders. Despite the importance of microglia, their development has not been carefully examined in the human brain, and most of our knowledge derives from rodents. We aimed to address this gap in knowledge by establishing an extensive collection of 97 post-mortem tissues in order to enable quantitative, sex-matched, detailed analysis of microglia across the human lifespan. We identify the dynamics of these cells in the human telencephalon, describing waves in microglial density across gestation, infancy, and childhood, controlled by a balance of proliferation and apoptosis, which track key neurodevelopmental milestones. These profound changes in microglia are also observed in bulk RNA-seq and single-cell RNA-seq datasets. This study provides a detailed insight into the spatiotemporal dynamics of microglia across the human lifespan and serves as a foundation for elucidating how microglia contribute to shaping neurodevelopment in humans.

Glioblastoma, IDH-wildtype: A New Association with IgM Paraproteinaemic Neuropathy?

It is well recognized that B-cell clonal disorders such as Waldenstrom's macroglobulinaemia may affect the central nervous system by direct infiltration of malignant B cells (Bing-Neel syndrome). However, there is no recognition in the current literature of a clear link between paraproteinaemia and primary brain tumours such as glioma. We present 3 cases of classical IgM paraproteinaemic neuropathy who developed glioblastoma in the course of their illness following treatment with chemoimmunotherapy (CIT). Due to the progressive symptomatic nature of their neuropathy, all 3 patients were treated with CIT. The patients presented with glioblastoma, IDH-wildtype at 9 months, 5 years, and 6 years following treatment completion. None of the patients had unequivocal evidence of known predisposing factors for glioblastoma. Both disorders are exceedingly rare and the chance of random association is less than one in a million. Potential common pathogenic mechanisms include the influence of paraproteins and circulating lymphoplasmacytic cells on blood-brain permeability and CNS immune micro-environment as well as raised circulating angiogenic cytokines such as vascular endothelial growth factor. In cases with anti-myelin-associated glycoprotein (MAG) antibodies, surface MAG on glial cells may act as a target releasing cells from growth inhibition. We suggest that all glioblastoma cases be screened at diagnosis for serum paraproteins and that such cases be reported to central registries to establish the frequency of the association more accurately.

Iron Deposition in the Brain After Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND: After aneurysmal subarachnoid hemorrhage (SAH), thrombus forms over the cerebral cortex and releases hemoglobin. When extracellular, hemoglobin is toxic to neurones. High local hemoglobin concentration overwhelms the clearance capacity of macrophages expressing the hemoglobin-haptoglobin scavenger receptor CD163. We hypothesized that iron is deposited in the cortex after SAH and would associate with outcome. METHODS: Two complementary cross-sectional studies were conducted. Postmortem brain tissue from 39 SAH (mean postictal interval of 9 days) and 22 control cases was studied with Perls' staining for iron and immunolabeling for CD163, ADAM17 (a disintegrin and metallopeptidase domain 17), CD68, and Iba1 (ionized calcium binding adaptor molecule 1). In parallel, to study the persistence of cortical iron and its relationship to clinical outcome, we conducted a susceptibility-weighted imaging study of 21 SAH patients 6 months postictus and 10 control individuals. RESULTS: In brain tissue from patients dying soon after SAH, the distribution of iron deposition followed a gradient that diminished with distance from the brain surface. Iron was located intracellularly (mainly in macrophages, and occasionally in microglia, neurones, and glial cells) and extracellularly. Microglial activation and motility markers were increased after SAH, with a similar inward diminishing gradient. In controls, there was a positive correlation between CD163 and iron, which was lost after SAH. In SAH survivors, iron-sensitive imaging 6 months post-SAH confirmed persistence of cortical iron, related to the size and location of the blood clot immediately after SAH, and associated with cognitive outcome. CONCLUSIONS: After SAH, iron deposits in the cortical gray matter in a pattern that reflects proximity to the brain surface and thrombus and is related to cognitive outcome. These observations support therapeutic manoeuvres which prevent the permeation of hemoglobin into the cortex after SAH.

Histopathological correlates of haemorrhagic lesions on ex vivo magnetic resonance imaging in immunized Alzheimer's disease cases.

Haemorrhagic amyloid-related imaging abnormalities on MRI are frequently observed adverse events in the context of amyloid ß immunotherapy trials in patients with Alzheimer's disease. The underlying histopathology and pathophysiological mechanisms of haemorrhagic amyloid-related imaging abnormalities remain largely unknown, although coexisting cerebral amyloid angiopathy may play a key role. Here, we used ex vivo MRI in cases that underwent amyloid ß immunotherapy during life to screen for haemorrhagic lesions and assess underlying tissue and vascular alterations. We hypothesized that these lesions would be associated with severe cerebral amyloid angiopathy. Ten cases were selected from the long-term follow-up study of patients who enrolled in the first clinical trial of active amyloid ß immunization with AN1792 for Alzheimer's disease. Eleven matched non-immunized Alzheimer's disease cases from an independent brain brank were used as 'controls'. Formalin-fixed occipital brain slices were imaged at 7 T MRI to screen for haemorrhagic lesions (i.e. microbleeds and cortical superficial siderosis). Samples with and without haemorrhagic lesions were cut and stained. Artificial intelligence-assisted quantification of amyloid ß plaque area, cortical and leptomeningeal cerebral amyloid angiopathy area, the density of iron and calcium positive cells and reactive astrocytes and activated microglia was performed. On ex vivo MRI, cortical superficial siderosis was observed in 5/10 immunized Alzheimer's disease cases compared with 1/11 control Alzheimer's disease cases (κ = 0.5). On histopathology, these areas revealed iron and calcium positive deposits in the cortex. Within the immunized Alzheimer's disease group, areas with siderosis on MRI revealed greater leptomeningeal cerebral amyloid angiopathy and concentric splitting of the vessel walls compared with areas without siderosis. Moreover, greater density of iron-positive cells in the cortex was associated with lower amyloid ß plaque area and a trend towards increased post-vaccination antibody titres. This work highlights the use of ex vivo MRI to investigate the neuropathological correlates of haemorrhagic lesions observed in the context of amyloid ß immunotherapy. These findings suggest a possible role for cerebral amyloid angiopathy in the formation of haemorrhagic amyloid-related imaging abnormalities, awaiting confirmation in future studies that include brain tissue of patients who received passive immunotherapy against amyloid ß with available in vivo MRI during life.

Immunisation with UB-312 in the Thy1SNCA mouse prevents motor performance deficits and oligomeric α-synuclein accumulation in the brain and gut.

Alpha synuclein has a key role in the pathogenesis of Parkinson's disease (PD), Dementia with Lewy Bodies (LBD) and Multiple System Atrophy (MSA). Immunotherapies aiming at neutralising toxic αSyn species are being investigated in the clinic as potential disease modifying therapies for PD and other synucleinopathies. In this study, the effects of active immunisation against αSyn with the UB-312 vaccine were investigated in the Thy1SNCA/15 mouse model of PD. Young transgenic and wild-type mice received an immunisation regimen over a period of 6 weeks, then observed for an additional 9 weeks. Behavioural assessment was conducted before immunisation and at 15 weeks after the first dose. UB-312 immunisation prevented the development of motor impairment in the wire test and challenging beam test, which was associated with reduced levels of αSyn oligomers in the cerebral cortex, hippocampus and striatum of Thy1SNCA/15 mice. UB-312 immunotherapy resulted in a significant reduction of theαSyn load in the colon, accompanied by a reduction in enteric glial cell reactivity in the colonic ganglia. Our results demonstrate that immunisation with UB-312 prevents functional deficits and both central and peripheral pathology in Thy1SNCA/15 mice.

CD8 T-cell-mediated cerebellitis directed against Purkinje cell antigen after ipilimumab for small cell lung cancer.

We report a rapidly progressive and fatal CD8 T-cell-mediated cerebellitis after ipilimumab (cytotoxic T-lymphocyte-associated protein 4 inhibitor) for small cell lung cancer. Clinical features and histopathology were consistent with an accelerated form of paraneoplastic cerebellar degeneration. A patchy CD8 T-cell infiltrate spatially corresponded to areas of Purkinje cell loss, with occasional CD8 polarisation towards Purkinje cells. CD20-positive B cells were sparse. CD8 T-cell-mediated cerebellitis after immune checkpoint inhibitor treatment may recapitulate the early stages of paraneoplastic cerebellar degeneration.

BRAIN UK: Accessing NHS tissue archives for neuroscience research.

The purpose of BRAIN UK (the UK BRain Archive Information Network) is to make the very extensive and comprehensive National Health Service (NHS) Neuropathology archives available to the national and international neuroscience research community. The archives comprise samples of tumours and a wide range of other neurological disorders, not only from the brain but also spinal cord, peripheral nerve, muscle, eye and other organs when relevant. BRAIN UK was founded after the recognition of the importance of this large tissue resource, which was not previously readily accessible for research use. BRAIN UK has successfully engaged the majority of the regional clinical neuroscience centres in the United Kingdom to produce a centralised database of the extensive autopsy and biopsy archive. Together with a simple application process and its broad ethical approval, BRAIN UK offers researchers easy access to most of the national archives of neurological tissues and tumours (http://www.brain-uk.org). The range of tissues available reflects the spectrum of disease in society, including many conditions not covered by disease-specific brain banks, and also allows relatively large numbers of cases of uncommon conditions to be studied. BRAIN UK has supported 141 studies (2010-2020) that have generated 70 publications employing methodology as diverse as morphometrics, genetics, proteomics and methylomics. Tissue samples that would otherwise have been unused have supported valuable neuroscience research. The importance of this unique resource will only increase as molecular techniques applicable to human tissues continue to develop and technical advances permit large-scale high-throughput studies.

Amyloid-ß and α-Synuclein Immunotherapy: From Experimental Studies to Clinical Trials.

Alzheimer's disease and Lewy body diseases are the most common causes of neurodegeneration and dementia. Amyloid-beta (Aß) and alpha-synuclein (αSyn) are two key proteins involved in the pathogenesis of these neurodegenerative diseases. Immunotherapy aims to reduce the harmful effects of protein accumulation by neutralising toxic species and facilitating their removal. The results of the first immunisation trial against Aß led to a small percentage of meningoencephalitis cases which revolutionised vaccine design, causing a shift in the field of immunotherapy from active to passive immunisation. While the vast majority of immunotherapies have been developed for Aß and tested in Alzheimer's disease, the field has progressed to targeting other proteins including αSyn. Despite showing some remarkable results in animal models, immunotherapies have largely failed final stages of clinical trials to date, with the exception of Aducanumab recently licenced in the US by the FDA. Neuropathological findings translate quite effectively from animal models to human trials, however, cognitive and functional outcome measures do not. The apparent lack of translation of experimental studies to clinical trials suggests that we are not obtaining a full representation of the effects of immunotherapies from animal studies. Here we provide a background understanding to the key concepts and challenges involved in therapeutic design. This review further provides a comprehensive comparison between experimental and clinical studies in Aß and αSyn immunotherapy and aims to determine the possible reasons for the disconnection in their outcomes.

Microglial morphology in Alzheimer's disease and after Aß immunotherapy.

Microglia are the brain immune cells and their function is highly dependent on cell motility. It was hypothesised that morphological variability leads to differences in motility, ultimately impacting on the microglial function. Here, we assessed microglial morphology in 32 controls, 44 Alzheimer's disease (AD) cases and 16 AD cases from patients immunised against Aß42 (iAD) using 2D and 3D approaches. Our 2D assessment showed an increased number of microglia in iAD vs. AD (P = 0.032) and controls (P = 0.018). Ramified microglia were fewer in AD vs. controls (P = 0.041) but increased in iAD compared to AD (P < 0.001) and controls (P = 0.006). 3D reconstructions highlighted larger cell bodies in AD vs. controls (P = 0.049) and increased total process length in iAD vs. AD (P = 0.032), with negative correlations detected for pan-Aß load with total process length (P < 0.001) in AD and number of primary processes (P = 0.043) in iAD. In summary, reactive/amoeboid microglia are the most represented population in the aged human brain. AD does not affect the number of microglia, but the ramified population is decreased adopting a more reactive morphology. Aß removal by immunotherapy leads to increased ramified microglia, implying that the cells retain plasticity in an aged disease brain meriting further investigation.

Immune environment of the brain in schizophrenia and during the psychotic episode: A human post-mortem study.

A causal relationship between immune dysregulation and schizophrenia has been supported by genome-wide association studies and epidemiological evidence. It remains unclear to what extent the brain immune environment is implicated in this hypothesis. We investigated the immunophenotype of microglia and the presence of perivascular macrophages and T lymphocytes in post-mortem brain tissue. Dorsal prefrontal cortex of 40 controls (22F:18M) and 37 (10F:27M) schizophrenia cases, of whom 16 had active psychotic symptoms at the time of death, was immunostained for seven markers of microglia (CD16, CD32a, CD64, CD68, HLA-DR, Iba1 and P2RY12), two markers for perivascular macrophages (CD163 and CD206) and T-lymphocytes (CD3). Automated quantification was blinded to the case designation and performed separately on the grey and white matter. 3D reconstruction of Iba1-positive microglia was performed in selected cases. An increased cortical expression of microglial Fcγ receptors (CD64 F = 7.92, p = 0.007; CD64/HLA-DR ratio F = 5.02, p = 0.029) highlights the importance of communication between the central and peripheral immune systems in schizophrenia. Patients in whom psychotic symptoms were present at death demonstrated an age-dependent increase of Iba1 and increased CD64/HLA-DR ratios relative to patients without psychotic symptoms. Microglia in schizophrenia demonstrated a primed/reactive morphology. A potential role for T-lymphocytes was observed, but we did not confirm the presence of recruited macrophages in the brains of schizophrenia patients. Taking in account the limitations of a post-mortem study, our findings support the hypothesis of an alteration of the brain immune environment in schizophrenia, with symptomatic state- and age-dependent effects.

Innate Immune Anti-Inflammatory Response in Human Spontaneous Intracerebral Hemorrhage.

Background and Purpose: Spontaneous intracerebral hemorrhage (sICH) is a common form of hemorrhagic stroke, with high mortality and morbidity. Pathophysiological mechanisms in sICH are poorly understood and treatments limited. Neuroinflammation driven by microglial-macrophage activation contributes to brain damage post-sICH. We aim to test the hypothesis that an anti-inflammatory (repair) process occurs in parallel with neuroinflammation in clinical sICH. Methods: We performed quantitative analysis of immunohistochemical markers for microglia and macrophages (Iba1, CD68, TMEM119, CD163, and CD206) in brain tissue biospecimens 1 to 12 days post-sICH and matched control cases. In a parallel, prospective group of patients, we assayed circulating inflammatory markers (CRP [C-reactive protein], total white cell, and monocyte count) over 1 to 12 days following sICH. Results: In 27 supratentorial sICH cases (n=27, median [interquartile range] age: 59 [52­80.5], 14F/13M) all microglia-macrophage markers increased post-sICH, relative to control brains. Anti-inflammatory markers (CD163 and CD206) were elevated alongside proinflammatory markers (CD68 and TMEM119). CD163 increased progressively post-sICH (15.0-fold increase at 7­12 days, P<0.001). CD206 increased at 3 to 5 days (5.2-fold, P<0.001) then returned to control levels at 7 to 12 days. The parenchymal immune response combined brain-derived microglia (TMEM119 positive) and invading monocyte-derived macrophages (CD206 positive). In a prospective sICH patient cohort (n=26, age 74 [66­79], National Institutes of Health Stroke Scale on admission: 8 [4­17]; 14F/12M) blood CRP concentration and monocyte density (but not white blood cell) increased post-sICH. CRP increased from 0 to 2 to 3 to 5 days (8.3-fold, P=0.020) then declined at 7 to 12 days. Monocytes increased from 0 to 2 to 3 to 5 days (1.8-fold, P<0.001) then declined at 7 to 12 days. Conclusions: An anti-inflammatory pathway, enlisting native microglia and blood monocytes, occurs alongside neuroinflammation post-sICH. This novel pathway offers therapeutic targets and a window of opportunity (3­5 days post-sICH) for delivery of therapeutics via invading monocytes.

Glial cells and adaptive immunity in frontotemporal dementia with tau pathology.

Neuroinflammation is involved in the aetiology of many neurodegenerative disorders including Alzheimer's disease, Parkinson's disease and motor neuron disease. Whether neuroinflammation also plays an important role in the pathophysiology of frontotemporal dementia is less well known. Frontotemporal dementia is a heterogeneous classification that covers many subtypes, with the main pathology known as frontotemporal lobar degeneration. The disease can be categorized with respect to the identity of the protein that causes the frontotemporal lobar degeneration in the brain. The most common subgroup describes diseases caused by frontotemporal lobar degeneration associated with tau aggregation, also known as primary tauopathies. Evidence suggests that neuroinflammation may play a role in primary tauopathies with genome-wide association studies finding enrichment of genetic variants associated with specific inflammation-related gene loci. These loci are related to both the innate immune system, including brain resident microglia, and the adaptive immune system through possible peripheral T-cell involvement. This review discusses the genetic evidence and relates it to findings in animal models expressing pathogenic tau as well as to post-mortem and PET studies in human disease. Across experimental paradigms, there seems to be a consensus regarding the involvement of innate immunity in primary tauopathies, with increased microglia and astrocyte density and/or activation, as well as increases in pro-inflammatory markers. Whilst it is less clear as to whether inflammation precedes tau aggregation or vice versa; there is strong evidence to support a microglial contribution to the propagation of hyperphosphorylated in tau frontotemporal lobar degeneration associated with tau aggregation. Experimental evidence-albeit limited-also corroborates genetic data pointing to the involvement of cellular adaptive immunity in primary tauopathies. However, it is still unclear whether brain recruitment of peripheral immune cells is an aberrant result of pathological changes or a physiological aspect of the neuroinflammatory response to the tau pathology.