Comparing the Pathology, Clinical, and Demographic Characteristics of Younger and Older-Onset Multiple Sclerosis.

OBJECTIVE: Older people with multiple sclerosis (MS) have a less active radiological and clinical presentation, but many still attain significant levels of disability; but what drives worsening disability in this group? METHODS: We used data from the UK MS Register to characterize demographics and clinical features of late-onset multiple sclerosis (LOMS; symptom onset at ≥50 years), compared with adult-onset MS (AOMS; onset 18-49 years). We performed a pathology study of a separate MS cohort with a later onset (n = 18, mean age of onset 54 years) versus AOMS (n = 23, mean age of onset 29 years). RESULTS: In the Register cohort, there were 1,608 (9.4%) with LOMS. When compared with AOMS, there was a lower proportion of women, a higher proportion of primary progressive MS, a higher level of disability at diagnosis (median MS impact scale 36.7 vs. 28.3, p < 0.001), and a higher proportion of gait-related initial symptoms. People with LOMS were less likely to receive a high efficacy disease-modifying treatment and attained substantial disability sooner. Controlling for age of death and sex, neuron density in the thalamus and pons decreased with onset-age, whereas actively demyelinating lesions and compartmentalized inflammation was greatest in AOMS. Only neuron density, and not demyelination or the extent of compartmentalized inflammation, correlated with disability outcomes in older-onset MS patients. INTERPRETATION: The more progressive nature of older-onset MS is associated with significant neurodegeneration, but infrequent inflammatory demyelination. These findings have implications for the assessment and treatment of MS in older people. ANN NEUROL 2024;95:471-486.

Complement Activation and Up-Regulated Expression of Anaphylatoxin C3a/C3aR in Glioblastoma: Deciphering the Links with TGF-ß and VEGF.

The complement (C) innate immune system has been shown to be activated in the tumor microenvironment of various cancers. The C may support tumor growth by modulating the immune response and promoting angiogenesis through the actions of C anaphylatoxins (e.g., C5a, C3a). The C has important double-edged sword functions in the brain, but little is known about its role in brain tumors. Hence, we analyzed the distribution and the regulated expression of C3a and its receptor C3aR in various primary and secondary brain tumors. We found that C3aR was dramatically upregulated in Grade 4 diffuse gliomas, i.e., glioblastoma multiforme, IDH-wildtype (GBM) and astrocytoma, IDH-mutant, Grade 4, and was much less expressed in other brain tumors. C3aR was observed in tumor-associated macrophages (TAM) expressing CD68, CD18, CD163, and the proangiogenic VEGF. Robust levels of C3a were detected in the parenchyma of GBM as a possible result of Bb-dependent C activation of the alternative C pathway. Interestingly, in vitro models identified TGF-ß1 as one of the most potent growth factors that upregulate VEGF, C3, and C3aR in TAM (PMA-differentiated THP1) cell lines. Further studies should help to delineate the functions of C3a/C3aR on TAMs that promote chemotaxis/angiogenesis in gliomas and to explore the therapeutic applications of C3aR antagonists for brain tumors.

Complement activation and increased anaphylatoxin receptor expression are associated with cortical grey matter lesions and the compartmentalised inflammatory response of multiple sclerosis.

Background: The extent of cortical pathology is an important determinant of multiple sclerosis (MS) severity. Cortical demyelination and neurodegeneration are related to inflammation of the overlying leptomeninges, a more inflammatory CSF milieu and with parenchymal microglia and astroglia activation. These are all components of the compartmentalised inflammatory response. Compartmentalised inflammation is a feature of progressive MS, which is not targeted by disease modifying therapies. Complement is differentially expressed in the MS CSF and complement, and complement receptors, are associated with demyelination and neurodegeneration. Methods: To better understand if complement activation in the leptomeninges is associated with underlying cortical demyelination, inflammation, and microglial activation, we performed a neuropathological study of progressive MS (n = 22, 14 females), neuroinflammatory (n = 8), and non-neurological disease controls (n = 10). We then quantified the relative extent of demyelination, connective tissue inflammation, complement, and complement receptor positive microglia/macrophages. Results: Complement was elevated at the leptomeninges, subpial, and within and around vessels of the cortical grey matter. The extent of complement C1q immunoreactivity correlated with connective tissue infiltrates, whilst activation products C4d, Bb, and C3b associated with grey matter demyelination, and C3a receptor 1+ and C5a receptor 1+ microglia/macrophages closely apposed C3b labelled cells. The density of C3a receptor 1+ and C5a receptor 1+ cells was increased at the expanding edge of subpial and leukocortical lesions. C5a receptor 1+ cells expressed TNFα, iNOS and contained puncta immunoreactive for proteolipid protein, neurofilament and synaptophysin, suggesting their involvement in grey matter lesion expansion. Interpretation: The presence of products of complement activation at the brain surfaces, their association with the extent of underlying pathology and increased complement anaphylatoxin receptor positive microglia/macrophages at expanding cortical grey matter lesions, could represent a target to modify compartmentalised inflammation and cortical demyelination.

The association between neurodegeneration and local complement activation in the thalamus to progressive multiple sclerosis outcome.

The extent of grey matter demyelination and neurodegeneration in the progressive multiple sclerosis (PMS) brains at post-mortem associates with more severe disease. Regional tissue atrophy, especially affecting the cortical and deep grey matter, including the thalamus, is prognostic for poor outcomes. Microglial and complement activation are important in the pathogenesis and contribute to damaging processes that underlie tissue atrophy in PMS. We investigated the extent of pathology and innate immune activation in the thalamus in comparison to cortical grey and white matter in blocks from 21 cases of PMS and 10 matched controls. Using a digital pathology workflow, we show that the thalamus is invariably affected by demyelination and had a far higher proportion of active inflammatory lesions than forebrain cortical tissue blocks from the same cases. Lesions were larger and more frequent in the medial nuclei near the ventricular margin, whilst neuronal loss was greatest in the lateral thalamic nuclei. The extent of thalamic neuron loss was not associated with thalamic demyelination but correlated with the burden of white matter pathology in other forebrain areas (Spearman r = 0.79, p < 0.0001). Only thalamic neuronal loss, and not that seen in other forebrain cortical areas, correlated with disease duration (Spearman r = -0.58, p = 0.009) and age of death (Spearman r = -0.47, p = 0.045). Immunoreactivity for the complement pattern recognition molecule C1q, and products of complement activation (C4d, Bb and C3b) were elevated in thalamic lesions with an active inflammatory pathology. Complement regulatory protein, C1 inhibitor, was unchanged in expression. We conclude that active inflammatory demyelination, neuronal loss and local complement synthesis and activation in the thalamus, are important to the pathological and clinical disease outcomes of PMS.

Persistent neuropathological effects 14 years following amyloid-ß immunization in Alzheimer's disease.

We performed a 15-year post-mortem neuropathological follow-up of patients in the first trial of amyloid-ß immunotherapy for Alzheimer's disease. Twenty-two participants of a clinical trial of active amyloid-ß42 immunization (AN1792, Elan Pharmaceuticals) or placebo were studied. Comprehensive post-mortem neuropathological assessments were performed from 4 months to 15 years after the trial. We analysed the relationships between the topographical distribution of amyloid-ß removal from the cerebral cortex and tau pathology, cerebrovascular territories, plasma anti-AN1792 antibody titres and late cognitive status. Seventeen of 22 (77%) participants had Alzheimer's neuropathological change, whereas 5 of 22 (23%) had alternative causes for dementia (progressive supranuclear palsy = 1, Lewy body disease = 1, vascular brain injury = 1, and frontotemporal lobar degeneration = 2). Nineteen of the 22 participants had received the active agent, three the placebo. Fourteen of 16 (88%) patients with Alzheimer's disease receiving the active agent had evidence of plaque removal (very extensive removal = 5, intermediate = 4, very limited = 5, no removal = 2). Of particular note, two Alzheimer's patients who died 14 years after immunization had only very sparse or no detectable plaques in all regions examined. There was a significant inverse correlation between post-vaccination peripheral blood anti-AN1792 antibody titres and post-mortem plaque scores (ρ = - 0.664, P = 0.005). Cortical foci cleared of plaques contained less tau than did cortex with remaining plaques, but the overall distribution of tangles was extensive (Braak V/VI). In conclusion, patients with Alzheimer's disease actively immunized against amyloid-ß can remain virtually plaque-free for 14 years. The extent of plaque removal is related to the immune response. This long duration of efficacy is important in support of active immunization protocols as therapy for, or potentially prevention of, neurodegeneration-associated protein accumulations. Inclusion of patients without Alzheimer's disease in Alzheimer's therapy trials is a problem for assessing the efficacy of treatment. Despite modification of Alzheimer's pathology, most patients had progressed to severe dementia, notably including the five with very extensive plaque removal, possibly due to continued tau propagation. Neuropathology follow-up of patients in therapeutic trials provides valuable information on the causes of dementia and effects of treatment.

Meningeal inflammation and cortical demyelination in acute multiple sclerosis.

OBJECTIVE: Cortical gray matter (GM) pathology, involving demyelination and neurodegeneration, associated with meningeal inflammation, could be important in determining disability progression in multiple sclerosis (MS). However, we need to know more about how cortical demyelination, neurodegeneration, and meningeal inflammation contribute to pathology at early stages of MS to better predict long-term outcome. METHODS: Tissue blocks from short disease duration MS (n = 12, median disease duration = 2 years), progressive MS (n = 21, disease duration = 25 years), non-diseased controls (n = 11), and other neurological inflammatory disease controls (n = 6) were quantitatively analyzed by immunohistochemistry, immunofluorescence, and in situ hybridization. RESULTS: Cortical GM demyelination was extensive in some cases of acute MS (range = 1-48% of total cortical GM), and subpial lesions were the most common type (62%). The numbers of activated (CD68+ ) microglia/macrophages were increased in cases with subpial lesions, and the density of neurons was significantly reduced in acute MS normal appearing and lesion GM, compared to controls (p < 0.005). Significant meningeal inflammation and lymphoid-like structures were seen in 4 of 12 acute MS cases. The extent of meningeal inflammation correlated with microglial/macrophage activation (p < 0.05), but not the area of cortical demyelination, reflecting the finding that lymphoid-like structures were seen adjacent to GM lesions as well as areas of partially demyelinated/remyelinated, cortical GM. INTERPRETATION: Our findings demonstrate that cortical demyelination, neuronal loss, and meningeal inflammation are notable pathological hallmarks of acute MS and support the need to identify early biomarkers of this pathology to better predict outcome. Ann Neurol 2018;84:829-842.

CD93 regulates central nervous system inflammation in two mouse models of autoimmune encephalomyelitis.

Microglia and non-professional immune cells (endothelial cells, neurons) participate in the recognition and removal of pathogens and tissue debris in the injured central nervous system through major pro-inflammatory processes. However, the mechanisms involved in regulating these responses remain ill-characterized. We herein show that CD93, also known as complement C1qRp/AA4 stem cell marker, has an important role in the regulation of inflammatory processes. The role of CD93 was evaluated in two models of neuroinflammation. We used the MOG-experimental autoimmune encephalomyelitis (EAE) model and the antibody-dependent EAE (ADEAE), which were induced in wild-type and CD93 knockout mice. We found that CD93 was highly expressed by neurons, endothelial cells and microglia (ramified >> amoeboid). Astrocytes and oligodendrocytes did not to express CD93. We further observed that CD93-deficient (CD93-/- ) mice presented a more robust brain and spinal cord inflammation in EAE and ADEAE. Encephalitis in CD93-/- was characterized by increased numbers of infiltrating M1 macrophages (CD11c+ CD206- ) and amoeboid microglia exhibiting a more activated phenotype (Tomato Lectinhigh Cox2high ). Damage to and leakage through the blood-brain barrier was increased in CD93-/- animals and was associated with a more robust neuronal injury when compared with wild-type EAE mice. We propose that CD93 is an important neuro-immune regulator to control central nervous system inflammation.

Tissue microarray methodology identifies complement pathway activation and dysregulation in progressive multiple sclerosis.

The complement pathway has potential contributions to both white (WM) and grey matter (GM) pathology in Multiple Sclerosis (MS). A quantitative assessment of complement involvement is lacking. Here we describe the use of Tissue MicroArray (TMA) methodology in conjunction with immunohistochemistry to investigate the localization of complement pathway proteins in progressive MS cortical GM and subcortical WM. Antibodies targeting complement proteins C1q, C3b, regulatory proteins C1 inhibitor (C1INH, complement receptor 1 (CR1), clusterin, factor H (FH) and the C5a anaphylatoxin receptor (C5aR) were utilised alongside standard markers of tissue pathology. All stained slides were digitised for quantitative analysis. We found that numbers of cells immunolabelled for HLA-DR, GFAP, C5aR, C1q and C3b were increased in WM lesions (WML) and GM lesions (GML) compared to normal appearing WM (NAWM) and GM (NAGM), respectively. The complement regulators C1INH, CR1, FH and clusterin were more abundant in WM lesions, while the number of C1q+ neurons were increased and the number of C1INH+, clusterin+, FH+ and CR1+ neurons decreased in GM lesions. The number of complement component positive cells (C1q, C3b) correlated with complement regulator expression in WM, but there was no statistical association between complement activation and regulator expression in the GM. We conclude that TMA methodology and quantitative analysis provides evidence of complement dysregulation in MS GML, including an association of the numerical density of C1q+ cells with tissue lesions. Our work confirms that complement activation and dysregulation occur in all cases of progressive MS and suggest that complement may provide potential biomarkers of the disease.

Mixed pathologies including chronic traumatic encephalopathy account for dementia in retired association football (soccer) players.

In retired professional association football (soccer) players with a past history of repetitive head impacts, chronic traumatic encephalopathy (CTE) is a potential neurodegenerative cause of dementia and motor impairments. From 1980 to 2010, 14 retired footballers with dementia were followed up regularly until death. Their clinical data, playing career, and concussion history were prospectively collected. Next-of-kin provided consent for six to have post-mortem brain examination. Of the 14 male participants, 13 were professional and 1 was a committed amateur. All were skilled headers of the ball and had played football for an average of 26 years. Concussion rate was limited in six cases to one episode each during their careers. All cases developed progressive cognitive impairment with an average age at onset of 63.6 years and disease duration of 10 years. Neuropathological examination revealed septal abnormalities in all six post-mortem cases, supportive of a history of chronic repetitive head impacts. Four cases had pathologically confirmed CTE; concomitant pathologies included Alzheimer's disease (N = 6), TDP-43 (N = 6), cerebral amyloid angiopathy (N = 5), hippocampal sclerosis (N = 2), corticobasal degeneration (N = 1), dementia with Lewy bodies (N = 1), and vascular pathology (N = 1); and all would have contributed synergistically to the clinical manifestations. The pathological diagnosis of CTE was established in four individuals according to the latest consensus diagnostic criteria. This finding is probably related to their past prolonged exposure to repetitive head impacts from head-to-player collisions and heading the ball thousands of time throughout their careers. Alzheimer's disease and TDP-43 pathologies are common concomitant findings in CTE, both of which are increasingly considered as part of the CTE pathological entity in older individuals. Association football is the most popular sport in the world and the potential link between repetitive head impacts from playing football and CTE as indicated from our findings is of considerable public health interest. Clearly, a definitive link cannot be established in this clinico-pathological series, but our findings support the need for further systematic investigation, including large-scale case-control studies to identify at risk groups of footballers which will justify for the implementation of protective strategies.

Complement is activated in progressive multiple sclerosis cortical grey matter lesions.

BACKGROUND: The symptoms of multiple sclerosis (MS) are caused by damage to myelin and nerve cells in the brain and spinal cord. Inflammation is tightly linked with neurodegeneration, and it is the accumulation of neurodegeneration that underlies increasing neurological disability in progressive MS. Determining pathological mechanisms at play in MS grey matter is therefore a key to our understanding of disease progression. METHODS: We analysed complement expression and activation by immunocytochemistry and in situ hybridisation in frozen or formalin-fixed paraffin-embedded post-mortem tissue blocks from 22 progressive MS cases and made comparisons to inflammatory central nervous system disease and non-neurological disease controls. RESULTS: Expression of the transcript for C1qA was noted in neurons and the activation fragment and opsonin C3b-labelled neurons and glia in the MS cortical and deep grey matter. The density of immunostained cells positive for the classical complement pathway protein C1q and the alternative complement pathway activation fragment Bb was significantly increased in cortical grey matter lesions in comparison to control grey matter. The number of cells immunostained for the membrane attack complex was elevated in cortical lesions, indicating complement activation to completion. The numbers of classical (C1-inhibitor) and alternative (factor H) pathway regulator-positive cells were unchanged between MS and controls, whilst complement anaphylatoxin receptor-bearing microglia in the MS cortex were found closely apposed to cortical neurons. Complement immunopositive neurons displayed an altered nuclear morphology, indicative of cell stress/damage, supporting our finding of significant neurodegeneration in cortical grey matter lesions. CONCLUSIONS: Complement is activated in the MS cortical grey matter lesions in areas of elevated numbers of complement receptor-positive microglia and suggests that complement over-activation may contribute to the worsening pathology that underlies the irreversible progression of MS.

Complement activation in multiple sclerosis plaques: an immunohistochemical analysis.

INTRODUCTION: Inflammation and complement activation are firmly implicated in the pathology of multiple sclerosis; however, the extent and nature of their involvement in specific pathological processes such as axonal damage, myelin loss and disease progression remains uncertain. This study aims to bring clarity to these questions. RESULTS: We describe a detailed immunohistochemical study to localise a strategically selected set of complement proteins, activation products and regulators in brain and spinal cord tissue of 17 patients with progressive multiple sclerosis and 16 control donors, including 9 with central nervous system disease. Active, chronic active and chronic inactive multiple sclerosis plaques (35 in total) and non-plaque areas were examined.Multiple sclerosis plaques were consistently positive for complement proteins (C3, factor B, C1q), activation products (C3b, iC3b, C4d, terminal complement complex) and regulators (factor H, C1-inhibitor, clusterin), suggesting continuing local complement synthesis, activation and regulation despite the absence of other evidence of ongoing inflammation. Complement staining was most apparent in plaque and peri-plaque but also present in normal appearing white matter and cortical areas to a greater extent than in control tissue. C1q staining was present in all plaques suggesting a dominant role for the classical pathway. Cellular staining for complement components was largely restricted to reactive astrocytes, often adjacent to clusters of microglia in close apposition to complement opsonised myelin and damaged axons. CONCLUSIONS: The findings demonstrate the ubiquity of complement involvement in multiple sclerosis, suggest a pathogenic role for complement contributing to cell, axon and myelin damage and make the case for targeting complement for multiple sclerosis monitoring and therapy.

Inflammatory components in human Alzheimer's disease and after active amyloid-ß42 immunization.

Inflammatory processes are important in the pathogenesis of Alzheimer's disease and in response to amyloid-ß immunotherapy. We investigated the expression of multiple inflammatory markers in the brains of 28 non-immunized patients with Alzheimer's disease and 11 patients with Alzheimer's disease immunized against amyloid-ß42 (AN1792): microglial ionized calcium-binding adaptor Iba-1, lysosome marker CD68, macrophage scavenger receptor A, Fcγ receptors I (CD64) and II (CD32); and also immunoglobulin IgG, complement C1q and the T lymphocyte marker CD3 using immunohistochemistry. The data were analysed with regard to amyloid-ß and phospho-tau pathology, severity of cerebral amyloid angiopathy and cortical microhaemorrhages. In non-immunized Alzheimer's disease cases, amyloid-ß42 correlated inversely with CD32 and Iba-1, whereas phospho-tau correlated directly with all microglial markers, IgG, C1q and the number of T cells. In immunized Alzheimer's disease cases, amyloid-ß42 load correlated directly with macrophage scavenger receptor A-positive clusters and inversely with C1q. The severity of cerebral amyloid angiopathy and microhaemorrhages did not relate to any of the analysed markers. Overall, the levels of CD68, macrophage scavenger receptor A, CD64, CD32 and the number of macrophage scavenger receptor A-positive plaque-related clusters were significantly lower in immunized than non-immunized cases, although there was no significant difference in Iba-1 load, number of Iba-1-positive cells, IgG load, C1q load or number of T cells. Our findings indicate that different microglial populations co-exist in the Alzheimer's disease brain, and that the local inflammatory status within the grey matter is importantly linked with tau pathology. After amyloid-ß immunization, the microglial functional state is altered in association with reduced amyloid-ß and tau pathology. The results suggest that, in the long term, amyloid-ß immunotherapy results in downregulation of microglial activation and potentially reduces the inflammation-mediated component of the neurodegeneration of Alzheimer's disease.

How does the brain limit the severity of inflammation and tissue injury during bacterial meningitis?

The most devastating CNS bacterial infection, bacterial meningitis, has both acute and long-term neurologic consequences. The CNS defends itself against bacterial invasion through a combination of physical barriers (i.e. blood-brain barrier, meninges, and ependyma), which contain macrophages that express a range of pattern-recognition receptors that detect pathogens before they gain access to the CNS and cerebrospinal fluid. This activates an antipathogen response consisting of inflammatory cytokines, complement, and chemoattractants. Regulation of the antipathogen inflammatory response is essential for preventing irreversible brain injury and protecting stem cell populations in the ventricle wall. The severity of brain inflammation is regulated by the clearance of apoptotic inflammatory cells and neurons. Death signaling pathways are expressed by glia to stimulate apoptosis of neutrophils, lymphocytes, and damaged neurons and to regulate in flammation and remove necrotic cells. The emerging group of neuroimmunoregulatory molecules adjusts the balance of the anti-inflammatory and proinflammatory response to provide optimal conditions for effective clearance of pathogens and apoptotic cells but reduce the severity of the inflammatory response to prevent injury to brain cells, including stem cell populations. The neuroimmunoregulatory molecules and other CNS anti-inflammatory pathways represent potential therapeutic targets capable of reducing brain injury caused by bacterial infection.

Recent advances in the genetics of the ALS-FTLD complex.

There is a clinical and pathological overlap between amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). A number of autosomal-dominant genes have been described that primarily cause ALS or FTLD such as progranulin (GRN), valosin-containing protein (VCP), and TAR DNA-Binding Protein (TARDBP), and for each of these conditions there are a small number of cases with both ALS and FTLD. Two major genes were described in 2011, which cause FTLD and/or ALS within extended kindreds. Ubiquilin2 (UBQLN2) is responsible for X-linked FTLD/ALS. A hexanucleotide repeat expansion in C9ORF72 causes chromosome 9p linked FTLD/ALS and is the most common cause of familial ALS accounting for about 40 % of familial cases. Both UBQLN2 and C9ORF72 mutations lead to TDP-43 positive neuropathology, and C9ORF72-positive cases have p62/ubiquitin-positive pathology, which is not stained by TDP-43 antibodies. Ubiquilin2 is one of a family of proteins thought to be important in targeting abnormal proteins for degradation via lysosomal and proteasomal routes. The pathogenic mechanism of the C9ORF72 expansion is unknown but may involve partial haploinsufficiency of C9ORF72 and/or the formations of toxic RNA inclusions. The identification of mutations in these genes represents an important step forward in our understanding of the clinical, pathological, and genetic spectrum of ALS/FTLD diseases.

C3-dependent mechanism of microglial priming relevant to multiple sclerosis.

Microglial priming predisposes the brain to neurodegeneration and affects disease progression. The signal to switch from the quiescent to the primed state is unknown. We show that deleting the C3 convertase regulator complement receptor 1-related protein y (Crry) induces microglial priming. Mice that were double-knockout for Crry and either C3 or factor B did not show priming, demonstrating dependence on alternative pathway activation. Colocalization of C3b/iC3b and CR3 implicated the CR3/iC3b interaction in priming. Systemic lipopolysaccharide challenge overactivated primed microglia with florid expression of proinflammatory molecules, which were blocked by complement inhibition. Relevance for neurodegenerative disease is exemplified by human multiple sclerosis (MS) and by experimental autoimmune encephalomyelitis (EAE), a model of MS. In human MS, microglial priming was evident in perilesional white matter, in close proximity to C3b/iC3b deposits. EAE was accelerated and exacerbated in Crry-deficient mice, and was dependent on C activation. In summary, C3-dependent microglial priming confers susceptibility to other challenges. Our observations are relevant to progression in MS and other neurological diseases exacerbated by acute insults.

Familial early onset frontotemporal dementia caused by a novel S356T MAPT mutation, initially diagnosed as schizophrenia.

Autosomal dominant frontotemporal dementia (FTD) due to mutations in the MAPT gene is referred to as FTD with parkinsonism linked to chromosome 17 with tau pathology (FTDP-17T). Typically the disease begins in the sixth decade of life. We report a novel exon 12 mutation in MAPT (S356T), in a family with an exceptionally early age at onset (27 and 29 years), causing familial behavioural variant frontotemporal dementia. Both the proband and the proband's father were initially diagnosed as having schizophrenia. Pathological examination showed frontotemporal lobar degeneration with extensive neuronal and glial tau deposition. This mutation is one of a small group of MAPT mutations (including P301S, G335V and S352L) that cause very early onset FTDP-17T. It is likely that the early age at onset reflects a marked pathogenic effect of the mutation involving a disturbance of microtubule binding, tau phosphorylation or a major acceleration of tau aggregation.

Reduction of aggregated Tau in neuronal processes but not in the cell bodies after Abeta42 immunisation in Alzheimer's disease.

Alzheimer's disease (AD) pathology is characterised by aggregation in the brain of amyloid-beta (Abeta) peptide and hyperphosphorylated tau (phospho-tau), although how these proteins interact in disease pathogenesis is unclear. Abeta immunisation results in removal of Abeta from the brain but cognitive decline continues to progress, possibly due to persistent phospho-tau. We quantified phospho-tau and Abeta42 in the brains of 10 AD patients (iAD) who were actively immunised with Abeta42 (AN1792, Elan Pharmaceuticals) compared with 28 unimmunised AD cases (cAD). The phospho-tau load was lower in the iAD than the cAD group in the cerebral cortex (cAD 1.08% vs. iAD 0.72%, P = 0.048), CA1 hippocampus (cAD 2.26% vs. iAD 1.05%; P = 0.001), subiculum (cAD 1.60% vs. iAD 0.31%; P = 0.001) and entorhinal cortex (cAD 1.10% vs. iAD 0.18%; P < 0.001). Assessment of the localisation within neurons of phospho-tau indicated that the Abeta immunotherapy-associated reduction was confined to neuronal processes, i.e. neuropil threads and dystrophic neurites. However, the phospho-tau accumulation in the neuronal cell bodies, contributing to neurofibrillary tangles, appeared not to be affected. In showing that Abeta immunisation can influence phospho-tau pathology, we confirm the position of Abeta as a target for modifying tau accumulation in AD and demonstrate a link between these proteins. However, the continuing progression of cognitive decline in AD patients after Abeta immunisation may be explained by its lack of apparent effect on tangles.

The multiple roles of the innate immune system in the regulation of apoptosis and inflammation in the brain.

Central nervous system (CNS) tissues contain cells (i.e. glia and neurons) that have innate immune functions. These cells express a range of receptors that are capable of detecting and clearing apoptotic cells and regulating inflammatory responses. Phagocytosis of apoptotic cells is a nonphlogistic (i.e. noninflammatory) process that provides immune regulation through anti-inflammatory cytokines andregulatory T cells. Neurons and glia express cellular death signals, including CD95Fas/CD95L, FasL, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and tumor necrosis factor receptor 1 (TNFR), through which they can trigger apoptosis in T cells and other infiltrating cells. Microglia, astrocytes, ependymal cells, and neurons express defense collagens and scavenger and phagocytic receptors that recognize apoptotic cells displaying apoptotic cell-associated molecular patterns, which serve as markers of "altered self." Glia also express pentraxins and complement proteins (C1q, C3b, and iC3b) that opsonize apoptotic cells, making them targets for the phagocytic receptors CR3 and CR4. Immunoregulatory molecules such as the complement regulator CD46 are lost from apoptotic cells and stimulate phagocytosis, whereas the expression of CD47 and CD200 is upregulated during apoptosis; this inhibits proinflammatory microglial cytokine expression, thereby reducing the severity of inflammation. This review outlines the cellular pathways used for the detection and phagocytosis of apoptotic cells in vitro and in experimental models of CNS inflammation.