Objective: To determine, using a systematic review of case-control studies, whether head injury is a significant risk factor for Alzheimer's disease. We sought to replicate the findings of the meta-analysis of Mortimer et al (1991). Methods: A predefined inclusion criterion specified case-control studies eligible for inclusion. A comprehensive and systematic search of various electronic databases, up to August 2001, was undertaken. Two independent reviewers screened studies for eligibility. Fifteen case-control studies were identified that met the inclusion criteria, of which seven postdated the study of Mortimer et al. The most convincing evidence to date in support of an association between head injury and Alzheimer's disease is the meta-analysis by Mortimer et al of seven case-control studies conducted before 1991. 5 In this study, the raw data for each case-control study were collected directly from the original authors. Mortimer et al reported a relative risk of 1.82 (95% confidence interval (CI) 1.26 to 2.67) for head injury with a loss of consciousness. 5 The relative risk, when adjusted for a family history of dementing illness, education, and alcohol consumption, remained significant but was only true for males (2.67, 95% CI 1.64 to 4.41) and not females (0.85, 95% CI 0.43 to 1.70).In view of the equivocal findings from Mortimer et al's study, 5 and knowing that further case-control studies have been reported, we aimed to replicate the findings of Mortimer et al using a systematic review of case-control studies conducted in the past 10 years. We also sought to review the evidence for a relation between APOE status and head injury as risk factors for Alzheimer's disease. We have primarily relied on the data presented in published papers and, consequently, were unable to analyse covariate risk factors such as alcohol consumption, family history of dementing illness, and education. METHODS Inclusion criteriaThis study identified case-control studies that reported on head injury, or the interaction between head injury and APOE status, as risk factors for Alzheimer's disease. The inclusion criteria were developed on the basis of a comprehensive review of the literature, and consideration of the criteria used by Mortimer et al, 5 in order to identify the major sources of potential bias and the measures taken in an attempt to minimise such bias. Seven factors were identified as essential requirements for entry into this study:(1) Head injury with loss of consciousness: We were interested in head injury of a severity that occurs infrequently and that is likely to produce neurological effect. Therefore, we required that studies defined head trauma in terms of the presence of loss of consciousness. By excluding lesser head injuries, studies should be less exposed to recall bias and less likely to find an association that merely reflects a consequence of the prodrome of the dementia. No time restriction was placed on the period of unconsciousness.(2) Matching of case and control subjects: Two different types o...

Alpha-synuclein (αSyn Agg) are pathological hallmarks of Parkinson's disease (PD) and other synucleinopathies that induce microglial activation and immune-mediated neurotoxicity, but the molecular mechanisms of αSyn Agg-induced immune activation are poorly defined. We performed quantitative proteomics by mass spectrometry coupled with PCR, immunohistochemical and functional validations studies to define the molecular characteristics of alpha synuclein mediated microglial activation. In mouse microglia, αSyn Agg induced robust pro-inflammatory activation (increased expression of 864 genes including Irg1, Ifit1, and Pyhin) and increased nuclear proteins involved in RNA synthesis, splicing, and anti-viral defense mechanisms. Conversely, αSyn Agg decreased expression several proteins (including Cdc123, Sod1, and Grn), which were predominantly cytosolic and involved in metabolic, proteasomal and lysosomal mechanisms. Pathway analyses and confirmatory in vitro studies suggested that αSyn Agg partly mediates its effects via Stat3 activation. As predicted by our proteomic findings, we verified that αSyn Agg induces mitochondrial dysfunction in microglia. Twenty-six proteins differentially expressed by αSyn Agg were also identified as PD risk genes in genome-wide association studies (upregulated: Brd2, Clk1, Siglec1; down-regulated: Memo1, Arhgap18, Fyn, and Pgrn/Grn). We validated progranulin (PGRN) as a lysosomal PD-associated protein that is downregulated by αSyn Agg in microglia in-vivo and is expressed by microglia in post-mortem PD brain, congruent with our in vitro findings. Conclusion: Together, proteomics approach both reveals novel molecular insights into αSyn-mediated neuroinflammation in PD and other synucleinopathies.

Background The etiology of sporadic Parkinson’s disease (PD) remains uncertain, but genetic, epidemiological, and physiological overlap between PD and inflammatory bowel disease suggests that gut inflammation could promote dysfunction of dopamine-producing neurons in the brain. Mechanisms behind this pathological gut-brain effect and their interactions with sex and with environmental factors are not well understood but may represent targets for therapeutic intervention. Methods We sought to identify active inflammatory mechanisms which could potentially contribute to neuroinflammation and neurological disease in colon biopsies and peripheral blood immune cells from PD patients. Then, in mouse models, we assessed whether dextran sodium sulfate-mediated colitis could exert lingering effects on dopaminergic pathways in the brain and whether colitis increased vulnerability to a subsequent exposure to the dopaminergic neurotoxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). We assessed the involvement of inflammatory mechanisms identified in the PD patients in colitis-related neurological dysfunction in male and female mice, utilizing mice lacking the Regulator of G-Protein Signaling 10 (RGS10)—an inhibitor of nuclear factor kappa B (NFκB)—to model enhanced NFκB activity, and mice in which CD8+ T-cells were depleted. Results High levels of inflammatory markers including CD8B and NFκB p65 were found in colon biopsies from PD patients, and reduced levels of RGS10 were found in immune cells in the blood. Male mice that experienced colitis exhibited sustained reductions in tyrosine hydroxylase but not in dopamine as well as sustained CD8+ T-cell infiltration and elevated Ifng expression in the brain. CD8+ T-cell depletion prevented colitis-associated reductions in dopaminergic markers in males. In both sexes, colitis potentiated the effects of MPTP. RGS10 deficiency increased baseline intestinal inflammation, colitis severity, and neuropathology. Conclusions This study identifies peripheral inflammatory mechanisms in PD patients and explores their potential to impact central dopaminergic pathways in mice. Our findings implicate a sex-specific interaction between gastrointestinal inflammation and neurologic vulnerability that could contribute to PD pathogenesis, and they establish the importance of CD8+ T-cells in this process in male mice. Graphical abstract

Inflammation in the aging brain increases risk for neurodegenerative disease. In humans, the Regulator of G-protein Signaling (RGS) 10 locus has been associated with age-related maculopathy. Chronic peripheral administration of lipopolysaccharide in the RGS10-null mice induces nigral dopaminergic (DA) degeneration, suggesting that RGS10 modulates neuroimmune interactions and may influence susceptibility to neurodegeneration. Since age is the strongest risk factor for neurodegenerative disease, we assessed whether RGS10 expression changes with age and whether aged RGS10-null mice have altered immune cell profiles. Loss of RGS10 in aged mice does not alter the regulation of nigral DA neurons but does alter B cell, monocyte, microglial and CD4+ T cell populations and inflammatory cytokine levels in the cerebrospinal fluid. These results suggest that loss of RGS10 is associated with an age-dependent dysregulation of peripheral and central immune cells rather than dysregulation of dopaminergic neuron function.