Microglial immunophenotype in dementia with Alzheimer's pathology.

BACKGROUND: Genetic risk factors for Alzheimer's disease imply that inflammation plays a causal role in development of the disease. Experimental studies suggest that microglia, as the brain macrophages, have diverse functions, with their main role in health being to survey the brain parenchyma through highly motile processes. METHODS: Using the Medical Research Council Cognitive Function and Ageing Studies resources, we have immunophenotyped microglia to investigate their role in dementia with Alzheimer's pathology. Cerebral cortex obtained at post-mortem from 299 participants was analysed by immunohistochemistry for cluster of differentiation (CD)68 (phagocytosis), human leukocyte antigen (HLA)-DR (antigen-presenting function), ionized calcium-binding adaptor molecule (Iba1) (microglial motility), macrophage scavenger receptor (MSR)-A (plaque-related phagocytosis) and CD64 (immunoglobulin Fcγ receptor I). RESULTS: The presence of dementia was associated positively with CD68 (P < 0.001), MSR-A (P = 0.010) and CD64 (P = 0.007) and negatively with Iba1 (P < 0.001). Among participants without dementia, the cognitive function according to the Mini-Mental State Examination was associated positively with Iba1 (P < 0.001) and negatively with CD68 (P = 0.033), and in participants with dementia and Alzheimer's pathology, positively with all microglial markers except Iba1. Overall, in participants without dementia, the relationship with Alzheimer's pathology was negative or not significant, and positive in participants with dementia and Alzheimer's pathology. Apolipoprotein E (APOE) ε2 allele was associated with expression of Iba1 (P = 0.001) and MSR-A (P < 0.001) and APOE ε4 with CD68, HLA-DR and CD64 (P < 0.001). CONCLUSIONS: Our findings raise the possibility that in dementia with Alzheimer's pathology, microglia lose motility (Iba-1) necessary to support neurons. Conversely, other microglial proteins (CD68, MSR-A), the role of which is clearance of damaged cellular material, are positively associated with Alzheimer's pathology and impaired cognitive function. In addition, our data imply that microglia may respond differently to Aβ and tau in participants with and without dementia so that the microglial activity could potentially influence the likelihood of developing dementia, as supported by genetic studies, highlighting the complexity and diversity of microglial responses

Postnatal development of the primate prefrontal cortex (areas 9 and 46): maturation of pyramidal neurons and serotonergic innervation in layer 3

The dorsolateral prefrontal cortex (DLPFC) of the monkey brain exhibits a unique combination of intraareal and interareal connections, as well as distinctive neuronal properties, which correlate with diverse cognitive and mnemonic behaviours. Many of these attributes are found in the homologous region of the human brain. This thesis describes and compares the developmental time courses of two important components of the cortical circuitry in the monkey DLPFC: pyramidal neurons providing extensive, elaborately-patterned intrinsic connections in the superficial layers and the serotonin (5-HT) innervation in the same region. We hope that the results from these studies will contribute to a model of the human DLPFC; aiding the understanding of complex interactions within the DLPFC during postnatal development. The layer 3 pyramidal neurons providing intrinsic lattice connectivity within layers 1-3, are also the sources and targets for efferent and afferent corticocortical connections between the DLPFC and the rest of the brain. The postnatal time course of maturation for layer 3 pyramidal neurons was quantified by means of the changes in the relative density of their dendritic spines, which represent the postsynaptic sites of excitatory (asymmetric) synapses. We compared the developmental sequence for dendritic spines to the time courses of maturation for other components of layer 3 circuitry, e.g. asymmetric synapses, inhibitory parvalbumin-immunoreactive (PV-IR) cartridges, dopaminergic (DAergic) axons and we comment on possible implications for observed temporal similarities or differences between them. Layer 3 is also the site of a dense 5-HTergic axon innervation, which originates from the mid-brain raphe nuclei and comprises 2 classes of axon fibres ("thick" and "thin"). We examined the time-scale of postnatal development for 5-HTergic axons in layer 3 and attempted to find temporal correlation's between 5-HT axon maturation and pyramidal neuron dendritic spine development, as well as with previously examined layer 3 components, including DAergic axons and 5-HT tissue concentration. Findings included the demonstration of concurrent time courses of maturation for dendritic spines and PV-IR cartridges; synchrony between rates of spine and excitatory synapse production in the first 2 postnatal months and a subsequent plateau phase, but different time periods of decline (from 1.5 and 3.0 years, respectively) and complex relationships between the stages of spine maturation and changes in density of DAergic axons coinciding with the rise (birth-2 months) and fall (1.5-4.6 years) of spine numbers. We also demonstrated temporal interrelations between 5-HTergic axon development and that of other neuropil components, including modulatory interaction between the density of 5-HTergic axons and dendritic spines as well as strong reciprocal correlation's between the 5-HTergic and DAergic axon innervations

TREM2 expression in the human brain:: a marker of monocyte recruitment?

Mutation in the triggering receptor expressed on myeloid cells (TREM) 2 gene has been identified as a risk factor for several neurodegenerative diseases including Alzheimer’s disease (AD). Experimental studies using animal models of AD have highlighted a number of functions associated with TREM2 and its expression by microglial cells. It has therefore been assumed that this is also the case in humans. However, there is very limited information concerning the cellular expression of TREM2 in the human brain. As part of investigations of microglia using post-mortem resources provided by the Medical Research Council Cognitive Function and Ageing Studies (MRC-CFAS), we immunostained the cerebral cortex of 299 participants for TREM2 using the Sigma antibody HPA010917 and compared with the macrophage/microglial markers Iba1 and CD68. As expected, Iba1 and CD68 labelled microglia and perivascular macrophages. However, in most cases (284/299), the TREM2 antibody labelled monocytes within vascular lumens, but not microglia or perivascular macrophages. In contrast, in 5 out of 6 cases with acute infarcts, TREM2 immunoreaction identified cells within the brain parenchyma interpreted as recruited monocytes. Six cases with old infarcts contained phagocytic foamy macrophages which were CD68-positive but TREM2 negative. Our observations, using the HPA010917 anti-TREM2 antibody, suggest that TREM2 is not expressed by microglia but instead seems to be a marker of recruited monocytes in the human brain. This finding has implications with regards to the role of TREM2 as a risk factor, emphasizing the importance of systemic immune responses in the development and progression of Alzheimer’s disease

Metaflammasome components in the human brain: a role in dementia with Alzheimer’s pathology?

Epidemiological and genetic studies have identified metabolic disorders and inflammation as risk factors for Alzheimer’s disease (AD). Evidence in obesity and type-2 diabetes suggests a role for a metabolic inflammasome (“metaflammasome”) in mediating chronic inflammation in peripheral organs implicating IKK? (inhibitor of nuclear factor kappa-B kinase subunit beta), IRS1 (insulin receptor substrate 1), JNK (c-jun N-terminal kinase), and PKR (double-stranded RNA protein kinase). We hypothesized that these proteins are expressed in the brain in response to metabolic risk factors in AD. Neocortex from 299 participants from the MRC Cognitive Function and Ageing Studies was analysed by immunohistochemistry for the expression of the phosphorylated (active) form of IKK? [pSer176/180], IRS1 [pS312], JNK [pThr183/Tyr185] and PKR [pT451]. The data were analysed to investigate whether the proteins were expressed together and in relation with metabolic disorders, dementia, Alzheimer’s pathology and APOE genotype. We observed a change from a positive to a negative association between the proteins and hypertension according to the dementia status. Type-2 diabetes was negatively related with the proteins among participants without dementia; whereas participants with dementia and AD pathology showed a positive association with JNK. A significant association between IKK? and JNK in participants with dementia and AD pathology was observed, but not in those without dementia. Otherwise, weak to moderate associations were observed among the protein loads. The presence of dementia was significantly associated with JNK and negatively associated with IKK? and IRS1. Cognitive scores showed a significant positive relationship with IKK? and a negative with IRS1, JNK and PKR. The proteins were significantly associated with pathology in Alzheimer’s participants with the relationship being inverse or not significant in participants without dementia. Expression of the proteins was not related to APOE genotype. These findings highlight a role for these proteins in AD pathophysiology but not necessarily as a complex

The Hemophilia Joint Health Score version 2.1 Validation in Adult Patients Study: A multicenter international study

BACKGROUND: The Hemophilia Joint Health Score (HJHS) was developed and validated to detect arthropathy in children. Additional evidence is required to show validity in adults. We studied the convergent and discriminant construct validity of the HJHS version 2.1(HJHSv2.1) in adults with hemophilia. A secondary aim was to define age-related normative adult HJHSv2.1 reference values. METHODS: We studied 192 adults with hemophilia, and 120 healthy adults in four age-matched groups-18 to 29, 30 to 40, 41 to 50, and >50 years-at nine centers. Trained physiotherapists scored the HJHS and World Federation of Hemophilia (WFH) joint score. Health history, the Functional Independence Scale of Hemophilia (FISH), Hemophilia Activities List (HAL), and Short-Form McGill Pain Questionnaire (SF-MPQ) were also collected. RESULTS: The median age was 35.0 years. Of participants with hemophilia, 68% had severe, 14% moderate, and 18% mild disease. The HJHS correlated strongly with WFH score (Spearman's rho [rs ] = .95, P < .001). Moderate correlations were seen between the FISH (rs = .50, P < .001) and SF-MPQ Present Pain Intensity (rs = .50, P < .001), while a modest correlation was found with the HAL (rs = -.37, P < .001). The HJHS significantly differentiated between age groups (Kruskal-Wallis T = 35.02, P < .001) and disease severity in participants with hemophilia. The HJHS had high internal reliability (Cronbach's α = .88). We identified duration of swelling as a redundant item in the HJHS. CONCLUSIONS: The HJHS shows evidence of strong convergent and discriminant construct validity to detect arthropathy in adults with hemophilia and is well suited for use in this population