BackgroundCare management of Parkinson's disease (PD) patients currently remains symptomatic, mainly because diagnosis relying on the expression of the cardinal motor symptoms is made too late. ...Earlier detection of PD therefore represents a key step for developing therapies able to delay or slow down its progression.MethodsWe investigated metabolic markers in 3 different animal models of PD, mimicking different phases of the disease assessed by behavioral and histological evaluation, and in 3 cohorts of de novo PD patients and matched controls (n = 129). Serum and brain tissue samples were analyzed by nuclear magnetic resonance spectroscopy and data submitted to advanced multivariate statistics.ResultsOur translational strategy reveals common metabolic dysregulations in serum of the different animal models and PD patients. Some of them were mirrored in the tissue samples, possibly reflecting pathophysiological mechanisms associated with PD development. Interestingly, some metabolic dysregulations appeared before motor symptom emergence and could represent early biomarkers of PD. Finally, we built a composite biomarker with a combination of 6 metabolites. This biomarker discriminated animals mimicking PD from controls, even from the first, nonmotor signs and, very interestingly, also discriminated PD patients from healthy subjects.ConclusionFrom our translational study, which included 3 animal models and 3 de novo PD patient cohorts, we propose a promising biomarker exhibiting a high accuracy for de novo PD diagnosis that may possibly predict early PD development, before motor symptoms appear.FundingFrench National Research Agency (ANR), DOPALCOMP, Institut National de la Santé et de la Recherche Médicale, Université Grenoble Alpes, Association France Parkinson.
The gene encoding apolipoprotein E (APOE) on chromosome 19 is the only confirmed susceptibility locus for late-onset Alzheimer's disease. To identify other risk loci, we conducted a large genome-wide ...association study of 2,032 individuals from France with Alzheimer's disease (cases) and 5,328 controls. Markers outside APOE with suggestive evidence of association (P < 10−5) were examined in collections from Belgium, Finland, Italy and Spain totaling 3,978 Alzheimer's disease cases and 3,297 controls. Two loci gave replicated evidence of association: one within CLU (also called APOJ), encoding clusterin or apolipoprotein J, on chromosome 8 (rs11136000, OR = 0.86, 95% CI 0.81-0.90, P = 7.5 × 10−9 for combined data) and the other within CR1, encoding the complement component (3b/4b) receptor 1, on chromosome 1 (rs6656401, OR = 1.21, 95% CI 1.14-1.29, P = 3.7 × 10−9 for combined data). Previous biological studies support roles of CLU and CR1 in the clearance of β amyloid (Aβ) peptide, the principal constituent of amyloid plaques, which are one of the major brain lesions of individuals with Alzheimer's disease.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
The progranulin gene (PGRN) encodes a pleiotropic molecule with anti-inflammatory actions and neuronal protective effects. Accordingly, PGRN-deficient mice have been demonstrated to develop enhanced ...inflammation and progressive neurodegeneration. Loss of function mutations of the PGRN gene have been also reported to cause frontotemporal lobar degeneration (FTLD), a neurodegenerative disease leading to dementia generally in the presenium. Since neurodegeneration might be negatively impacted by chronic inflammation, the possible influence of PGRN defects on inflammatory pathways appears to be of great relevance for the understanding of neurodegeneration pathogenic processes in those patients. However, no data about the inflammatory profile of PGRN-defective subjects have been so far provided.In this study, we analyzed serum levels of the pro-inflammatory mediators IL-6, TNF-α and IL-18 in FTLD patients with or without PGRN mutations, at both pre-symptomatic and symptomatic stages. We provide evidence that circulating IL-6 is increased in PGRN-mutated FTLD patients, as compared to both PGRN non-mutated FTLD patients and controls. In contrast, levels of IL-6 were not altered in asymptomatic subjects carrying the PGRN mutations. Finally, TNF-α and IL-18 serum levels did not differ among all groups of included subjects.We conclude that the profile of circulating pro-inflammatory cytokines is altered in PGRN-related symptomatic FTLD. Thus, our findings point to IL-6 as a possible specific mediator and a potential therapeutic target in this monogenic disease, suggesting that an enhanced inflammatory response might be indeed involved in its progression.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Late onset Alzheimer's disease is the most common form of dementia for which about 30 susceptibility loci have been reported. The aim of the current study is to identify novel genes associated with ...Alzheimer's disease using the largest up-to-date reference single nucleotide polymorphism (SNP) panel, the most accurate imputation software and a novel gene-based analysis approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 million genotypes from 17,008 Alzheimer's cases and 37,154 controls. In addition to earlier reported genes, we detected three novel gene-wide significant loci PPARGC1A (p = 2.2 × 10-6), RORA (p = 7.4 × 10-7) and ZNF423 (p = 2.1 × 10-6). PPARGC1A and RORA are involved in circadian rhythm; circadian disturbances are one of the earliest symptoms of Alzheimer's disease. PPARGC1A is additionally linked to energy metabolism and the generation of amyloid beta plaques. RORA is involved in a variety of functions apart from circadian rhythm, such as cholesterol metabolism and inflammation. The ZNF423 gene resides in an Alzheimer's disease-specific protein network and is likely involved with centrosomes and DNA damage repair.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Homotaurine is a potential therapeutic compound for treatment of Alzheimer's disease (AD), but its efficacy is still under investigation. Emerging data have shown that other than neuroprotective, ...homotaurine is endowed with anti-inflammatory activities, though with still unclear underlying mechanisms. Inflammation plays a critical role in the pathogenesis of AD and we previously suggested that homotaurine supplementation in patients with amnestic mild cognitive impairment (MCI) plays beneficial effects associated to a decrease in the circulating levels of the pro-inflammatory cytokine IL-18. Here we report that MCI patients supplemented with homotaurine for 12 months show elevated serum levels of IL-10 and IL-33, as compared to baseline, in addition to the described IL-18 decrease. Furthermore, we observed a significant positive correlation between IL-10 and IL-33 levels after treatment but not at the baseline, underlining the effectiveness of the compound in modulating both cytokines in an inter-related fashion and in regulating the pro/anti-inflammation balance. Furthermore, the elevation of both IL-10 and IL-33 is significantly associated with an improvement of episodic memory of treated patients, as measured by the Delayed Verbal Ray Test. In conclusion, our results confirm that homotaurine treatment exerts an overall anti-inflammatory action in MCI patients, based not only on the down-regulation of pro-inflammatory IL-18, but also on up-regulation of the anti-inflammatory IL-33 and IL-10 cytokines, which in turn are associated with an amelioration of patient's cognitive functions. Future studies should be addressed to investigate the molecular mechanisms of homotaurine anti-inflammatory activity and its therapeutic exploitation in early AD.
Amnestic mild cognitive impairment (aMCI) and sporadic Alzheimer's disease (AD) are multifactorial conditions resulting from a complex crosstalk among multiple molecular and biological processes. The ...present study investigates the association of variants localized in genes and miRNAs with aMCI and AD, which may represent susceptibility, prognostic biomarkers or multi-target treatment options for such conditions. We included 371 patients (217 aMCI and 154 AD) and 503 healthy controls, which were genotyped for a panel of 120 single nucleotide polymorphisms (SNPs) and, subsequently, analyzed by statistical, bioinformatics and machine-learning approaches. As a result, 21 SNPs were associated with aMCI and 13 SNPs with sporadic AD. Interestingly, a set of variants shared between aMCI and AD displayed slightly higher Odd Ratios in AD with respect to aMCI, highlighting a specific risk trajectory linking aMCI to AD. Some of the associated genes and miRNAs were shown to interact within the signaling pathways of APP (Amyloid Precursor Protein), ACE2 (Angiotensin Converting Enzyme 2), miR-155 and PPARG (Peroxisome Proliferator Activated Receptor Gamma), which are known to contribute to neuroinflammation and neurodegeneration. Overall, results of this study increase insights concerning the genetic factors contributing to the neuroinflammatory and neurodegenerative mechanisms underlying aMCI and sporadic AD. They have to be exploited to develop personalized approaches based on the individual genetic make-up and multi-target treatments.
The present study investigated the association of SNPs involved in the regulation of immune response, cellular degenerative and neuroinflammatory pathways with the susceptibility and progression of ...idiopathic Parkinson's Disease (PD). In particular, 342 PD patients were subjected to a genotyping analysis of a panel of 120 SNPs by Open Array Technology. As control group, 503 samples representative of the European general population were utilized. The genetic analysis identified 26 SNPs associated with PD susceptibility. Of them, 12 SNPs were described as significant expression Quantitative Loci (eQTL) variants in different brain regions associated with motor and non-motor PD phenomenology. Moreover, the study highlighted 11 novel susceptibility genes for PD, which may alter multiple signaling pathways critically involved in peripheral immune response, neuroinflammation, neurodegeneration and dopaminergic neurons wiring. The study of miRNA-target genes highlighted a possible role of miR-499a, miR-196a2, and miR-29a in the modulation of multiple neuroinflammatory and neurodegenerative mechanisms underlying PD physiopathology. The study described a network of interconnected genes (
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Cytokines and receptors of the IL-1 family are key mediators in innate immune and inflammatory reactions in physiological defensive conditions, but are also significantly involved in immune-mediated ...inflammatory diseases. Here, we will address the role of cytokines of the IL-1 superfamily and their receptors in neuroinflammatory and neurodegenerative diseases, in particular Multiple Sclerosis and Alzheimer's disease. Notably, several members of the IL-1 family are present in the brain as tissue-specific splice variants. Attention will be devoted to understanding whether these molecules are involved in the disease onset or are effectors of the downstream degenerative events. We will focus on the balance between the inflammatory cytokines IL-1β and IL-18 and inhibitory cytokines and receptors, in view of future therapeutic approaches.
Abstract Recent genome-wide association studies have identified 5 loci ( BIN1 , CLU , CR1 , EXOC3L2 , and PICALM ) as genetic determinants of Alzheimer's disease (AD). We attempted to confirm the ...association between these genes and the AD risk in 3 contrasting European populations (from Finland, Italy, and Spain). Because CLU and CR1 had already been analyzed in these populations, we restricted our investigation to BIN1 , EXO2CL3 , and PICALM . In a total of 2816 AD cases and 2706 controls, we unambiguously replicated the association of rs744373 (for BIN1 ) and rs541458 (for PICALM ) polymorphisms with the AD risk (odds ratio OR = 1.26, 95% confidence interval CI 1.15–1.38, p = 2.9 × 10−7 , and OR = 0.80, 95% CI 0.74–0.88, p = 4.6 × 10−7 , respectively). In a meta-analysis, rs597668 ( EXOC3L2 ) was also associated with the AD risk, albeit to a lesser extent (OR = 1.19, 95% CI 1.06–1.32, p = 2.0 × 10−3 ). However, this signal did not appear to be independent of APOE . In conclusion, we confirmed that BIN1 and PICALM are genetic determinants of AD, whereas the potential involvement of EXOC3L2 requires further investigation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
The subventricular zone (SVZ) is a region that lies immediately beneath the ependymal layer on the lateral wall of the lateral ventricles, and is separated from the caudate nucleus by a layer of ...myelin. It contains multipotent neural stem cells. The aim of this study was to investigate the tissue around the SVZ, with the hypothesis that multimodal MRI is able to highlight the progressive disruption of tissue caused by the neurodegenerative disease in this area. We combined volumetric and diffusion tensor (DTI) imaging using a 3
T imager in a cross-sectional study including 30 patients with amnestic-mild cognitive impairment (a-MCI), 30 patients with Alzheimer's disease (AD) and 30 age- and gender-matched healthy controls (HC). Our data indicate that mean diffusivity (MD) values increase continuously from HC through a-MCI to AD in the bilateral SVZ, where most of the proliferating stem cells in the adult brain are located. This result was specific for the SVZ and could not be observed in other periventricular areas. Multimodal MRI, being able to highlight structural changes of microscopic tissue in humans in vivo, could represent a precious tool to complement histological studies of neurogenesis.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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