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Background The loss of noradrenergic neurones of the locus coeruleus is a major feature of Alzheimer's disease (AD). Dopamine β-hydroxylase (DBH) catalyses the conversion of dopamine to noradrenaline. Interactions have been reported between the low-activity -1021T allele (rs1611115) of DBH and polymorphisms of the pro-inflammatory cytokine genes, IL1A and IL6, contributing to the risk of AD. We therefore examined the associations with AD of the DBH -1021T allele and of the above interactions in the Epistasis Project, with 1757 cases of AD and 6294 elderly controls. Methods We genotyped eight single nucleotide polymorphisms (SNPs) in the three genes, DBH, IL1A and IL6. We used logistic regression models and synergy factor analysis to examine potential interactions and associations with AD. Results We found that the presence of the -1021T allele was associated with AD: odds ratio = 1.2 (95% confidence interval: 1.06-1.4, p = 0.005). This association was nearly restricted to men < 75 years old: odds ratio = 2.2 (1.4-3.3, 0.0004). We also found an interaction between the presence of DBH -1021T and the -889TT genotype (rs1800587) of IL1A: synergy factor = 1.9 (1.2-3.1, 0.005). All these results were consistent between North Europe and North Spain. Conclusions Extensive, previous evidence (reviewed here) indicates an important role for noradrenaline in the control of inflammation in the brain. Thus, the -1021T allele with presumed low activity may be associated with misregulation of inflammation, which could contribute to the onset of AD. We suggest that such misregulation is the predominant mechanism of the association we report here.

© 2015, Elsevier Inc. All rights reserved. Background: Late-onset Alzheimer's disease (AD) is heritable with 20 genes showing genome-wide association in the International Genomics of Alzheimer's Project (IGAP). To identify the biology underlying the disease, we extended these genetic data in a pathway analysis. Methods: The ALIGATOR and GSEA algorithms were used in the IGAP data to identify associated functional pathways and correlated gene expression networks in human brain. Results: ALIGATOR identified an excess of curated biological pathways showing enrichment of association. Enriched areas of biology included the immune response (P = 3.27 × 10-12 after multiple testing correction for pathways), regulation of endocytosis (P = 1.31 × 10-11), cholesterol transport (P = 2.96 × 10-9), and proteasome-ubiquitin activity (P = 1.34 × 10-6). Correlated gene expression analysis identified four significant network modules, all related to the immune response (corrected P =.002-.05). Conclusions: The immune response, regulation of endocytosis, cholesterol transport, and protein ubiquitination represent prime targets for AD therapeutics., Medical Research Council, Alzheimer’s Research UK, and theWelsh Assembly Government. ADGC and CHARGE were supported by the National Institutes of Health, National Institute on Aging (NIH-NIA). CHARGE was also supported by Erasmus Medical Center and Erasmus University. IGAP was funded by the French National Foundation on Alzheimer’s Disease and Related Disorders, the Centre National de Genotypage and the Institut Pasteur de Lille, Inserm, FRC (Fondation pour la Recherche sur le Cerveau), and Rotary. This work has been developed and supported by the LABEX (Laboratory of Excellence Program Investment for the Future) DISTALZ grant (Development of Innovative Strategies for a Transdisciplinary approach to ALZheimer’s disease).

Resumen Introduccion Describir el espectro de las infecciones causadas por Rothia mucilaginosa. Metodos Estudio retrospectivo de 20 casos de infeccion por R. mucilaginosa entre los anos 2009 y 2012. Resultados La infeccion pulmonar fue la forma clinica mas frecuente (n = 14; 70%): bronquiectasias sobreinfectadas (10), empiema pleural (2), neumonia (1) y bronquitis aguda (1). Dos episodios fueron digestivos: colangitis bacteriemica y peritonitis secundaria. Dos bacteriemias afectaron a pacientes con neoplasia hematologica. Hubo una infeccion bacteriemica de herida quirurgica y otra infeccion urinaria bacteriemica en portador de nefrostomia. Discusion R. mucilaginosa puede ser responsable de infecciones de vias respiratorias bajas en pacientes con bronquiectasias pulmonares.

Epistasis between interleukin-10 (IL10) and aromatase gene polymorphisms has previously been reported to modify the risk of Alzheimer's disease (AD). However, although the main effects of aromatase variants suggest a sex-specific effect in AD, there has been insufficient power to detect sex-specific epistasis between these genes to date. Here we used the cohort of 1757 AD patients and 6294 controls in the Epistasis Project. We replicated the previously reported main effects of aromatase polymorphisms in AD risk in women, for example, adjusted odds ratio of disease for rs1065778 GG = 1.22 (95% confidence interval: 1.01-1.48, P=0.03). We also confirmed a reported epistatic interaction between IL10 rs1800896 and aromatase (CYP19A1) rs1062033, again only in women: adjusted synergy factor = 1.94 (1.16-3.25, 0.01). Aromatase, a rate-limiting enzyme in the synthesis of estrogens, is expressed in AD-relevant brain regions,and is downregulated during the disease. IL-10 is an anti-inflammatory cytokine. Given that estrogens have neuroprotective and anti-inflammatory activities and regulate microglial cytokine production, epistasis is biologically plausible. Diminishing serum estrogen in postmenopausal women, coupled with suboptimal brain estrogen synthesis, may contribute to the inflammatory state, that is a pathological hallmark of AD.

Item does not contain fulltext Iron overload may contribute to the risk of Alzheimer's disease (AD). In the Epistasis Project, with 1757 cases of AD and 6295 controls, we studied 4 variants in 2 genes of iron metabolism: hemochromatosis (HFE) C282Y and H63D, and transferrin (TF) C2 and -2G/A. We replicated the reported interaction between HFE 282Y and TF C2 in the risk of AD: synergy factor, 1.75 (95% confidence interval, 1.1-2.8, p = 0.02) in Northern Europeans. The synergy factor was 3.1 (1.4-6.9; 0.007) in subjects with the APOEepsilon4 allele. We found another interaction, between HFE 63HH and TF -2AA, markedly modified by age. Both interactions were found mainly or only in Northern Europeans. The interaction between HFE 282Y and TF C2 has now been replicated twice, in altogether 2313 cases of AD and 7065 controls, and has also been associated with increased iron load. We therefore suggest that iron overload may be a causative factor in the development of AD. Treatment for iron overload might thus be protective in some cases. 01 januari 2012

Objective The aim of this study was to analyze cerebral perfusion and glucose metabolism in patients with cognitive impairment using cerebral blood flow 99m Tc-HMPAO SPECT and 18 F-FDG PET/CT scans. Material and methods Twenty-two patients with cognitive impairment were included: 4 subjective memory complaints (SMC), 8 amnestic mild cognitive impairment (MCI), 5 prodromic Alzheimer's disease (AD) and 5 AD. In each clinical group, 99m Tc-HMPAO SPECT and 18 F-FDG PET/CT scans were performed. Results 99m Tc-HMPAO SPECT showed regions of cerebral hypoperfusion in 15 patients and was normal in 7 of the 22 patients. 18 F-FDG PET/CT scan showed cerebral regional hypometabolism in 19 patients and was normal in the other 3 patients. The distribution of abnormalities on 99m Tc-HMPAO SPECT and 18 F-FDG PET/CT scans was similar in 9 patients (2 SMC, 2 amnestic MCI, 2 prodromic AD, and 3 AD). In 6 patients (1 amnestic MCI, 2 prodromic AD, and 3 AD), FDG hypometabolism was more extensive than the cerebral hypoperfusion. Four patients (1 SMC, 3 amnestic MCI) had an abnormal 18 F-FDG PET/CT scan and normal 99m Tc-HMPAO SPECT. There were 3 patients (1 SMC, 2 amnestic MCI) with normal 99m Tc-HMPAO SPECT and 18 F-FDG PET/CT scans. Conclusion 99m Tc-HMPAO SPECT and 18 F-FDG PET/CT scans showed cerebral hypoperfusion and hypometabolism in patients with cognitive impairment, even in patients with clinical diagnosis of SMC. In patients with a normal cerebral blood flow SPECT, brain glucose cerebral hypometabolism can be detected. In some patients, the extension of FDG hypometabolism is more pronounced than that corresponding to the hypoperfusion area.

Oxidative stress, which plays a critical role in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease (AD), is intimately linked to aging, the best established risk factor for AD. Studies in neuronal cells subjected to oxidative stress, mimicking such stress in AD brains, are therefore of great interest. PLA2G3 is the most overexpressed gene in a human neuronal model of oxidative stress induced by the free radical-generating xanthine/xanthine oxidase (X-XOD) system, which provokes apoptotic cell death. In this work, we describe that PLA2G3 gene silencing produced a marked inhibition of X-XOD induced cell death, and that PLA2G3 polymorphisms are associated with AD in a Spanish case-control sample. The capacity to respond to oxidative stress may therefore modulate the risk of AD, and PLA2G3 is a potential target to regulate neuronal damage induced by free radicals.

We sought to identify new susceptibility loci for Alzheimer's disease through a staged association study (GERAD+) and by testing suggestive loci reported by the Alzheimer's Disease Genetic Consortium (ADGC) in a companion paper. We undertook a combined analysis of four genome-wide association datasets (stage 1) and identified ten newly associated variants with P ĝ‰Currency sign 1 × 10 -5. We tested these variants for association in an independent sample (stage 2). Three SNPs at two loci replicated and showed evidence for association in a further sample (stage 3). Meta-analyses of all data provided compelling evidence that ABCA7 (rs3764650, meta P = 4.5 × 10 -17; including ADGC data, meta P = 5.0 × 10 -21) and the MS4A gene cluster (rs610932, meta P = 1.8 × 10 -14; including ADGC data, meta P = 1.2 × 10 -16) are new Alzheimer's disease susceptibility loci. We also found independent evidence for association for three loci reported by the ADGC, which, when combined, showed genome-wide significance: CD2AP (GERAD+, P = 8.0 × 10 -4; including ADGC data, meta P = 8.6 × 10 -9), CD33 (GERAD+, P = 2.2 × 10 -4; including ADGC data, meta P = 1.6 × 10 -9) and EPHA1 (GERAD+, P = 3.4 × 10 -4; including ADGC data, meta P = 6.0 × 10 -10). © 2011 Nature America, Inc. All rights reserved.

Objective – Glycogen synthase kinase-3β (GSK-3β) and cyclin-dependent kinase 5 (CDK5) have been implicated as two major protein kinases involved in the abnormal hyperphosphorylation of tau in Alzheimer’s disease (AD) brain, and the development of neurofibrillary tangles. CDK5 regulatory subunit 1 (CDK5R1) encodes for p35, a protein required for activation of CDK5. As both CDK5R1 and GSK-3β genes are related to phosphorylation of tau, we examined the combined contribution of these genes to the susceptibility for AD. Methods – In a case–control study in 283 AD patients and 263 healthy controls, we examined the combined effects between CDK5R1 (3′-UTR, rs735555) and GSK-3β (−50, rs334558) polymorphisms on susceptibility to AD. Results – Subjects carrying both the CDK5R1 (3′-UTR, rs735555) AA genotype and the GSK-3β (−50, rs334558) CC genotype had a 12.5-fold decrease in AD risk (adjusted by age, sex and APOE status OR = 0.08, 95% CI = 0.01–0.76, P = 0.03), suggesting synergistic effects (epistasis) between both genes. Conclusion – These data support a role for tau phosphorylation regulating genes in risk for AD.

Apolipoprotein E (APOE) epsilon4 allele is the strongest hitherto known risk factor for sporadic Alzheimer's disease (AD). Liver X receptor-beta (LXRbeta) is a transcription factor that controls expression of genes involved in brain cholesterol metabolism, and one of the main LXRbeta targets is APOE. To evaluate the relationship between LXRbeta genetic variants and AD, independently or in concert with the APOE epsilon4 allele, we examined three LXRbeta polymorphisms located in introns 2 (rs 2695121), 5 (rs 1052533), and 7 (rs 1405655), in 414 Spanish AD patients and 447 controls. The current study does not demonstrate an association between LXRbeta genotypes or haplotypes and AD, neither in the total sample nor when the populations were stratified for the presence or absence of the APOE epsilon4 allele.

Oxidative stress plays a role in tau hyperphosphorylation and the development of neurofibrillary tangles (NFT). In Alzheimer’s disease (AD) brain, accumulation of hyperphosphorylated tau in NFT is associated with the induction of heme oxygenase-1 (HO-1), a potent antioxidant that downregulates the production of tau. In a case-control study of 300 AD patients and 360 healthy controls, we examined whether the combined gene effects between HO-1 (–413, rs2071746) and tau (5′ of exon 1, rs242557) polymorphisms might be responsible for susceptibility to AD. Subjects carrying both the HO-1 (–413) TT and the tau (5′ of exon 1) AA genotypes had a more than 6.5-time higher risk of developing AD than subjects without these risk genotypes (OR = 6.65, 95% CI 1.12–39.29; p = 0.037). These data support a role for tau-related genes in the risk of AD.

Excessive release of proinflammatory cytokines by activated microglia surrounding senile plaques might contribute to the neurodegeneration associated with Alzheimer’s disease (AD). Poly(ADP-ribose) polymerase 1 (PARP-1) is a nuclear protein recently implicated in the initial inflammatory response by modulating expression of inflammation-related genes, like interleukin 1 (IL-1). As PARP-1 overactivity has been shown in the AD brain, we tested the hypothesis that the PARP-1 –410 and –1672 polymorphisms would predispose people to AD due to overexpression of the PARP-1 gene, independently or in concert with the proinflammatory IL-1A –889 polymorphism. So, we performed a case-control study in 263 Spanish AD patients and 293 healthy controls. PARP-1 –410 and PARP-1 –1672 haplotypes were associated with an increased risk for AD (global haplotype association p value = 0.019), and, in addition, PARP-1 haplotypes increased the risk of AD by interaction with the IL-1A –889 allele 2.

Objective Only a small percentage of patients with acute stroke receive thrombolytic therapy, mainly due to late hospital arrival. Factors excluding those who arrive within 3 h after stroke onset are less well known. Patients and methods During the first year after implementing a protocol for stroke thrombolysis, we prospectively evaluated all patients with stroke admitted to our center within 3 h from onset. Within-hospital time intervals were calculated and the reasons for exclusion from thrombolysis were analyzed. Results Ninety-six patients (representing 16% of all stroke patients admitted) arrived in less than 3 h, and 25 of them (representing 7.5% of all patients with ischemic stroke) received thrombolytic therapy, with a door-to-needle interval of 51 min (range, 33–121). The reasons that accounted for 75% of therapy exclusions were non-modifiable (a too mild or improving deficit, and intracranial hemorrhage), except for a time window exceeded, which would probably require increasing public awareness about stroke. Conclusions Most reasons for not applying thrombolysis to patients who arrive early enough are non-modifiable. Minimizing the door-to-needle time could compensate for late hospital arrival, which continues to be the main reason for not applying this therapy to stroke patients throughout the world.

Aberrant phosphorylated tau is the major component of the neurofibrillary tangles in Alzheimer’s disease (AD) brains. Glycogen synthase kinase-3β (GSK-3β) phosphorylates tau protein, and increased GSK-3β expression has been associated with neurofibrillary tangles. Saitohin (STH) is a recently identified protein that shares tissue expression pattern with tau, and previous evidence in the Spanish population indicated that a polymorphism at codon 7 (Q7R) of the STH gene was associated with late-onset AD. Since both GSK-3β and STH are related to tau, we examined the association between a polymorphism in the promoter region (–50) of the GSK-3β gene and AD, either through an independent effect or through interaction with the STH (Q7R) polymorphism, in a well-defined group of 333 sporadic AD patients and 307 control subjects from Spain. The current study reveals that GSK-3β (–50) TT genotype is associated with an increased risk (OR 1.99, p = 0.003) for late-onset (after the age of 72 years) AD. Our results indicate that both the GSK-3β (–50) and STH (Q7R) polymorphisms increase the risk of late-onset (subjects >72 years) AD, although they appear to be independent and thus not to interact synergistically.

Cholesterol regulates the production of amyloid beta (Abeta), which is central to the pathogenesis of Alzheimer's disease (AD), with high cellular cholesterol promoting and low cellular cholesterol reducing Abeta in vitro and in vivo. High density lipoprotein (HDL) plays a central role in the removal of excess cholesterol from cells, and cholesteryl ester transfer protein (CETP) is a crucial protein involved in the regulation of HDL levels. Two common polymorphisms in the promoter region (C-629A) and exon 14 I405V of the CETP gene are associated with CETP activity and HDL levels. To investigate if these sequence variants in CETP might be of importance in mediating susceptibility to AD, independently or in concert with apolipoprotein E (APOE) epsilon4 allele, we studied a sample of 286 Spanish AD patients and 315 healthy controls. In APOE epsilon4 carriers, homozygous for the CETP (-629) A allele had approximately a three times lower risk of developing AD (odds ratio 2.33, 95% CI 1.01-5.37), than homozygous and heterozygous carriers of the CETP (-629) C allele (odds ratio 7.12, 95% CI 4.51-11.24, P for APOE epsilon4/CETP (-629) AA genotype interaction0.001). Our data suggest that CETP behaves as a modifier gene of the AD risk associated with the APOE epsilon4 allele, possibly through modulation of brain cholesterol metabolism.

Introduction – One of the main features of Friedreich's ataxia (FA) is phenotypic variability that can now be explained by the molecular mechanism (GAA expansion) underlying the disease. Materials and methods – We have analyzed genotype-phenotype correlations in a group of 40 patients homozygous for the GAA expansion. Results – The smaller GAA expansion (GAA1 allele) size correlated with age at onset and progression disease rate, but we found no correlation between the larger GAA expansion (GAA2 allele) size and these clinical parameters. The frequency of pes cavus, scoliosis, axonal sensory neuropathy and areflexia increased with the size of GAA1, whereas some signs such as sphincter disturbances, cerebellar atrophy on MRI, amyotrophy, dysarthria and decreased vibration sense were associated with increased duration of the disease. Conclusion – GAA1 size is the main determinant of FA phenotype and GAA2 size is a poor predictor of clinical variation. Some clinical features are independent of GAA1 and GAA2 sizes and are determined by the duration of the disease.

Clinical, electrophysiologic and molecular studies were performed on at-risk members of 14 families with hereditary neuropathy with liability to pressure palsies (HNPP), in order to detect asymptomatic carriers of the 17p11.2 deletion. Sporadic cases due to de novo deletion accounted for 21% of the investigated HNPP families. Approximately one half of deletion carriers were asymptomatic and did not display significant signs on clinical examination. The electrophysiologic hallmark in both symptomatic and asymptomatic deletion carriers was the presence of a nonuniform sensorimotor demyelinating polyneuropathy with conduction abnormalities preferentially located at common entrapment sites and distal nerve segments. A perfect correlation was found between the molecular and electrophysiologic analyses. A reliable screening method to detect clinically unaffected carriers of the deletion in families with HNPP was the evaluation of motor conduction in at least two nerves across usual entrapment sites, especially the ulnar nerve at the elbow, and evaluation of sensory conduction in the sural nerve. In sporadic cases due to a de novo deletion, electrophysiologic studies were suggestive but not sufficient for the diagnosis, and molecular analysis represented the most sensitive diagnostic tool.

Mateo I, Infante J, Sanchez-Juan P, Garcia-Gorostiaga I, Rodriguez-Rodriguez E, Vazquez-Higuera JL, Berciano J, Combarros O. Serum heme oxygenase-1 levels are increased in Parkinson’s disease but not in Alzheimer’s disease. Acta Neurol Scand: 2010: 121: 136–138. © 2009 The Authors Journal compilation © 2009 Blackwell Munksgaard. Objective – Oxidative stress is implicated in Parkinson’s disease (PD) and Alzheimer’s disease (AD), and heme oxygenase-1 (HO-1) is a potent antioxidant overexpressed in PD substantia nigra and AD cerebral cortex and hippocampus, indicating a possible up-regulation of antioxidant defenses in both neurodegenerative diseases. The role of HO-1 in peripheral blood of PD and AD patients remains unresolved. Methods – We measured serum HO-1 levels in 107 patients with PD, 105 patients with AD, 104 controls for PD and 120 controls for AD. Results – The median serum concentration of HO-1 was significantly higher in PD patients (2.04 ng/ml) compared with that of PD controls (1.69 ng/ml, P = 0.016), with PD patients predominating over controls in the upper tertile of serum HO-1 levels, whereas there was more PD controls than PD patients in the lower tertile (P = 0.006). Median serum levels of HO-1 did not differ significantly between AD patients and AD controls. Conclusion – The increase of serum HO-1 levels in PD patients could indicate a systemic antioxidant reaction related to a chronic oxidative stress state in PD brain.

Background: Oxidative stress is a central factor in the pathogenesis of Parkinson’s disease (PD). Heme oxygenase-1 (HO-1) is an antioxidant protein expressed in response to oxidative challenge, and its expression levels are inversely correlated with glycogen synthase kinase-3β (GSK3β) activity. Underexpression of HO-1 in concert with an upregulation of GSK3β would result in a less effective antioxidant response and might increase the risk of PD. Methods: We examined two functional polymorphism in the promoter regions of HO-1 (−413, rs2071746) and GSK3β (−157, rs6438552) in a group of 251 Spanish patients with PD and 234 controls. Results: Subjects carrying both the HO-1 (−413, rs2071746) TT genotype and the GSK3β (−157, rs6438552) TT genotype had a four times higher risk of developing PD than subjects without these genotypes (adjusted by age and sex OR = 4.12; 95% CI = 1.45–11.71; Bonferroni corrected P = 0.024). Conclusions: Considering synergistic effects between polymorphisms in oxidative stress-related genes may help in determining the risk profile for PD.

Sirs, A chronic inflammatory process with activation of microglial cells contribute to the neurodegeneration associated with Alzheimer’s disease (AD) [9]. NF-jB, a major transcription factor controlling inflammation, is activated in AD brains [5], and genes encoding several different proinflammatory cytokines, such as interleukin-6 (IL-6), are induced by NF-jB in activated microglia surrounding senile plaques [4]. In contrast with the majority of CARD proteins described to date that activate NF-jB, CARD8 potently suppresses NF-jB activation and reduces the inflammatory process [8]. A biallelic (T/A) polymorphism located at the third nucleotide of codon 10 of CARD8 (rs2043211) generates a premature stop codon (allele A) that severely truncates CARD8 protein giving rise to a small N-terminal peptide unable to regulate the NF-jB signaling pathway; in contrast, the full-length protein (allele T) represses the activity of NF-jB and limits the induction of inflammatory mediators [3]. CARD8 (rs2043211) polymorphism has been associated with chronic inflammatory diseases, such as Crohn’s disease [6] and rheumatoid arthritis [3]. A biallelic (G/C) polymorphism in the promoter region (-174, rs1800795) of the IL-6 gene was found to be associated with susceptibility for AD [1, 7]. The postulated common pathway of CARD8 and IL-6 in the cerebral inflammatory response (CARD8 suppressing the NF-jB activity in the context of proinflammatory signals) prompted us to examine the combined contribution of both genes to the susceptibility for AD. The study included 239 AD patients (66% women; mean age at the time of study 75.6 years; SD 7.8; range 50– 97 years; mean age at onset 72.4 years; SD 7.9; range 48– 94 years) who met NINCDS/ADRDA criteria for probable AD. All AD cases were defined as sporadic because their family history did not mention any first-degree relative with dementia; this information was obtained by direct interviews with relatives. Control subjects consisted of 165 unrelated individuals (69% women; mean age 80.8 years; SD 7.1; range 63–98 years) who had complete neurological and medical examinations establishing that they were free of significant illness and all had MMSE scores of 28 or more. Control subjects were randomly selected from a nursing home, and they arose from the same base population as the cases. The AD and control samples were Caucasians originating from a homogeneous population in a limited geographical area in Northern Spain. All patients and control subjects were ascertained to have parents and grandparents born in Northern Spain to ensure ethnicity; consequently, possible confounding effects of the inclusion in the study of members of different ethnic groups have been minimized. Blood samples were taken after written informed consent had been obtained from the subjects or their representatives. The study was approved by the ethical committee of the University Hospital ‘‘Marques de Valdecilla’’. The CARD8 (rs2043211) and IL-6 (-174, rs1800795) polymorphisms were determined as described A. Fontalba O. Gutierrez J. L. Fernandez-Luna Unidad de Genetica Molecular, ‘‘Marques de Valdecilla’’ University Hospital, Santander, Spain

For the first time, the multilocus approach by the set-association method has been applied for the analysis of a cluster of five genes [tumor necrosis factor alpha (TNF-alpha), interleukin 6 (IL-6), IL-8, IL-1alpha and IL-10] involved in the brain neuroinflammatory pathway in Parkinson's disease (PD), in a well-defined group of 197 PD patients and 173 control subjects from Spain. Set-association analysis did not reveal an independent or an interactive effect of these inflammatory genes on the PD risk.

A chronic inflammatory process with activation of microglial cells contribute to the neurodegeneration associated with Alzheimer's disease (AD). CD14 and LXRβ are receptors involved in the regulation of inflammatory responses of microglia in response to bacterial infection or lipopolysaccharide stimulation. In a case–control study in 266 AD patients and 273 healthy controls, we examined whether the combined gene effects between CD14 (− 260) polymorphism and LXRβ (intron 5) polymorphism might be responsible for susceptibility to AD. Subjects carrying both the CD14 (− 260) C/C and the LXRβ (intron 5) G/G genotypes had a six times lower risk of developing AD than subjects without these risk genotypes (OR 0.16, 95% CI 0.04–0.67, p = 0.01). These data support a role for innate immune response genes in risk for AD.

Objective – As vascular endothelial growth factor (VEGF) determines important neurotrophic and neuroprotective actions, we postulated serum VEGF levels could be abnormally low in patients with Alzheimer's disease (AD). Methods – We measured serum VEGF levels (VEGF165 isoform by ELISA) in 51 patients with AD by National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorder Association criteria and compared with 66 age- and gender-matched non-demented controls. Patients with AD were stratified into levels of dementia severity by the Clinical Dementia Rating scale. Serum VEGF levels were stratified into upper (>309 pg/ml), middle (207–309 pg/ml), and lower (

A number of studies suggest that brain cholesterol metabolism may play a role in Alzheimer's disease (AD) development, probably through modulation of amyloid beta production. The discovery that apolipoprotein E (APOE) e4 allele is a risk factor for sporadic AD raises the possibility that the receptors to which APOE binds on the surface of neurons are also involved in the neurodegenerative process. To evaluate the relationship between low density lipoprotein receptor (LDLR) genetic variant and AD, independently or in concert with the APOE e4 allele, we examined three LDLR polymorphisms located in exons 8 (rs 11669576), 10 (rs 5930), and 13 (rs 5925), in a large group of 322 Spanish AD patients and 314 controls. The current study does not demonstrate an association between LDLR genotypes or haplotypes and AD, neither in the total sample nor when the populations were stratified for the presence or absence of the APOE e4 allele. © 2006 Wiley-Liss, Inc.

To describe the spectrum of infections caused by Rothia mucilaginosa.Retrospective study of 20 cases diagnosed with R. mucilaginosa from 2009 to 2012.Pulmonary infection was the most frequent clinical presentation (n=14, 70%): bronchiectasis infected (10), followed by pleural empyema (2), pneumonia (1) and acute bronchitis (1). Two episodes were of gastrointestinal origin: cholangitis secondary to biliary drainage and secondary peritonitis. Two episodes included bacteremia in patients with hematological malignancy. One patient had a surgical wound infection with bacteremia, and another had a bacteremic urinary tract infection in a patient with nephrostomy.R. mucilaginosa may be responsible for infections of the lower respiratory tract in predisposed patients.

Aside from APOE, the genetic factors that influence the progression from mild cognitive impairment (MCI) to Alzheimer’s disease (AD) remain largely unknown. We assessed whether a genetic risk score (GRS), based on eight non-APOE genetic variants previously associated with AD risk in genome-wide association studies, is associated with either risk of conversion or with rapid progression from MCI to AD. Among 288 subjects with MCI, follow-up (mean 26.3 months) identified 118 MCI-converters to AD and 170 MCI-nonconverters. We genotyped ABCA7 rs3764650, BIN1 rs744373, CD2AP rs9296559, CLU rs1113600, CR1 rs1408077, MS4A4E rs670139, MS4A6A rs610932, and PICALM rs3851179. For each subject we calculated a cumulative GRS, defined as the number of risk alleles (range 0–16) with each allele weighted by the AD risk odds ratio. GRS was not associated with risk of conversion from MCI to AD. However, MCI-converters to AD harboring six or more risk alleles (second and third GRS tertiles) progressed twofold more rapidly to AD when compared with those with less than six risk alleles (first GRS tertile). Our GRS is a first step toward development of prediction models for conversion from MCI to AD that incorporate aggregate genetic factors.

The ocular ischemic syndrome represents a serious blinding condition due to retinal ischemia secondary to hemodynamically significant carotid artery stenosis. However, this condition has received little attention in the neurological literature and is likely underdiagnosed. We here describe a patient with bilateral severe carotid stenosis and progressive visual loss due to ocular ischemia. The best management for this condition remains controversial and should be established by including these patients into randomized trials of carotid surgery.

Common genetic variants (rs5848 and rs646776) have been reported as regulators of blood progranulin (GRN) levels in healthy individuals.To assess the influence of rs5848 and rs646776 polymorphisms in both serum GRN level and risk for common neurodegenerative diseases, we studied 304 patients with Parkinson's disease (PD), 217 individuals with Alzheimer's disease, 131 subjects with mild cognitive impairment, and 126 controls.The mean concentration of GRN in the serum of patients with PD (319.6 ng/ml) was significantly lower than that of controls (371.5 ng/ml; P = 0.009), whereas there were no significant differences between other groups. Rs646776 minor allele carriers had lower serum GRN levels in each of the four subgroups. There was no correlation between rs5848 genotypes and serum GRN concentrations. Genotype frequencies of both polymorphisms did not differ between groups.Reduced circulating GRN levels might be associated with PD risk by pathogenic factors different from rs5848 and rs646776 polymorphisms.

Recently, several genome-wide association studies (GWASs) have led to the discovery of nine new loci of genetic susceptibility in Alzheimer’s disease (AD). However, the landscape of the AD genetic susceptibility is far away to be complete and in addition to single-SNP (single-nucleotide polymorphism) analyses as performed in conventional GWAS, complementary strategies need to be applied to overcome limitations inherent to this type of approaches. We performed a genome-wide haplotype association (GWHA) study in the EADI1 study (n = 2025 AD cases and 5328 controls) by applying a sliding-windows approach. After exclusion of loci already known to be involved in AD (APOE, BIN1 and CR1), 91 regions with suggestive haplotype effects were identified. In a second step, we attempted to replicate the best suggestive haplotype associations in the GERAD1 consortium (2820 AD cases and 6356 controls) and observed that 9 of them showed nominal association. In a third step, we tested relevant haplotype associations in a combined analysis of five additional case– control studies (5093 AD cases and 4061 controls). We consistently replicated the association of a haplotype within FRMD4A on Chr.10p13 in all the data set analyzed (OR: 1.68; 95% CI: (1.43–1.96); P= 1.11010). We finally searched for association between SNPs within the FRMD4A locus and Ab plasma concentrations in three independent non-demented populations (n = 2579). We reported that polymorphisms were associated with plasma Ab42/Ab40 ratio (best signal, P = 5.4107). In conclusion, combining both GWHA study and a conservative three-stage replication approach, we characterised FRMD4A as a new genetic risk factor of AD.

Background: Tau abnormal hyperphosphorylation and the formation of neurofibrillary tangles in AD brain is the result of upregulation of tau kinases and downregulation of tau phosphatases. Methods. In a group of 729 Spanish late-onset Alzheimer's disease (AD) patients and 670 healthy controls, we examined variations into a set of candidate genes (PPP2CA, PPP2R2A, ANP32A, LCMT1, PPME1 and PIN1) in the tau protein phosphatase-2A (PP2A) pathway, to address hypotheses of genetic variation that might influence AD risk. Results: There were no differences in the genotypic, allelic or haplotypic distributions between cases and controls in the overall analysis or after stratification by age, gender or APOE 4 allele. Conclusion: Our negative findings in the Spanish population argue against the hypothesis that genetic variation in the tau protein phosphatase-2A (PP2A) pathway is causally related to AD risk. © 2011 Combarros et al; licensee BioMed Central Ltd., CIEN Foundation (PI019/09) and CIBERNED (CB06/07/0037).

Background Mild cognitive impairment (MCI) is a heterogeneous clinical entity that comprises the prodromal phase of Alzheimer's disease (Pr-AD). New biomarkers are useful in detecting Pr-AD, but they are not universally available. We aimed to investigate baseline clinical and neuropsychological variables that might predict progression from MCI to AD dementia. Methods All patients underwent a complete clinical and neuropsychological evaluation at baseline and every 6 months during a two-year follow-up period, with 54 out of 109 MCI patients progressing to dementia (50 of them progressed to AD dementia), and 55 remaining as stable MCI (S-MCI). Results A combination of MMSE and California Verbal Learning Test Long Delayed Total Recall (CVLT-LDTR) constituted the best predictive model: subjects scoring above 26/30 on MMSE and 4/16 on CVLT-LDTR had a negative predictive value of 93.93% at 2 years, whereas those subjects scoring below both of these cut-off scores had a positive predictive value of 80.95%. Conclusions Pr-AD might be distinguished from S-MCI at baseline using the combination of MMSE and CVLT-LDTR. These two neuropsychological predictors are relatively brief and may be readily completed in non-specialist clinical settings.

Background Dementia in Parkinson disease (PD) causes nursing home placement, caregiver distress, higher health care burden, and increased mortality. Objective To determine whether the microtubule-associated protein tau ( MAPT ) H1 haplotype and MAPT subhaplotypes play a role in the risk of PD and Parkinson disease–dementia (PDD) complex. Design Case-control genetic analysis. Setting Movement Disorders and Memory Units, Hospital de Sant Pau, Barcelona, Spain. Participants Two hundred two patients with PD (48 of whom developed dementia >2 years after disease onset), 41 patients with Lewy body dementia (LBD, pathologically confirmed in 17), 164 patients with Alzheimer disease (AD), and 374 controls. Methods The MAPT haplotype was determined by testing for a 238-base pair deletion between exons 9 and 10, which is characteristic of the H2 haplotype. Haploview was used to visualize linkage disequilibrium relationships between all genetic variants (5 single-nucleotide polymorphisms and the del-In9 variant) within and surrounding the MAPT region. Results The H1 haplotype was significantly overrepresented in PD patients compared with controls ( P = .001). Stratifying the PD sample by the presence of dementia revealed a stronger association in PDD patients (sex- and age-adjusted odds ratio, 3.73; P = .002) than in PD patients without dementia (sex- and age-adjusted odds ratio, 1.89; P = .04). Examination of specific subhaplotypes showed that a rare version of the H1 haplotype (named H1p) was overrepresented in PDD patients compared with controls (2.3% vs 0.1%; P = .003). No positive signals for any of the MAPT variants or H1 subhaplotypes were found in AD or LBD. Conclusions Our data confirm that MAPT H1 is associated with PD and has a strong influence on the risk of dementia in PD patients. Our results also suggest that none of the MAPT subhaplotypes play a significant role in other neurodegenerative diseases, such as LBD or AD.

Tau abnormal hyperphosphorylation and the formation of neurofibrillary tangles in the Alzheimer's disease (AD) brain is the result of upregulation of tau kinases. In a group of 729 Spanish late-onset AD patients and 670 healthy controls, we examined variations into a set of 20 candidate genes of kinases involved in tau phosphorylation at AD-related sites (PRKACB; CAMK2A; MARK1, 2, 3 and 4; CSNK1D; CDC2; RPS6KB1 and 2; p38α and β; IB1; JNK1, 2 and 3; MEK1 and 2; ERK1 and 2), to address hypotheses of genetic variation that might influence both AD risk and age at disease onset. There was an increased frequency of RPS6KB2 (intron 2, rs917570) minor allele in patients (50%) versus controls (39%) (OR = 1.52; 95% CI 1.30-1.77; p = 1.24 × 10 -5 Bonferroni corrected), and the presence of this minor allele was significantly (p = 4.2 × 10 -5) associated with a 3-years later onset of AD (mean age 74.1 years) when compared to age at onset of non-minor allele carriers (mean age 71.1 years). In APOE non-ε4 allele carriers, the combined effect of AD-associated risk alleles from the genes of CDC2, RPS6KB1 and 2, p38α, JNK (1, 2 and 3), MEK2, and ERK2 was significantly (p = 0.002) associated with a late-onset (>76 years) of AD. The CDC2 AGC haplotype derived from SNPs in introns 3 (rs2448347), 5 (rs2456772), and 7 (rs1871447) showed a protective effect against AD in APOE non-ε4 allele carriers (permutation p = 1.0 × 10 -4) with a frequency of 9% in cases and 15% in controls. Common genetic variation in the tau kinases pathway does underlie individual differences not only in susceptibility to AD but also in disease phenotype (age at disease onset)., This study was supported by grants from CIEN Foundation (PI019/09) and CIBERNED (CB06/07/0037).

Recent genome-wide association studies have identified 5 loci (BIM, 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 CRI 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 [Cl] [1.15-1.38], p = 2.9 X 10(-7), and OR = 0.80, 95% CI [0.74-0.88], p = 4.6 X 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% Cl [1.06-1.32], p = 2.0 X 10(-3)). However, this signal did not appear to be independent of APOE. In conclusion, we confirmed that BIN! and PICALM are genetic determinants of AD, whereas the potential involvement of EXOC3L2 requires further investigation. (C) 2011 Elsevier Inc. All rights reserved.

There has been a lot of interest in the detection of predictors of conversion from mild cognitive impairment (MCI) to Alzheimer’s disease (AD) using neuroimaging methods, CSF biomarkers and cognitive tests [2]. Despite the many genetic studies of AD, there has been little research directed toward determining the influence of genetic variation on progression from MCI to AD [1, 4]. Variation in the caspase-1 (CASP1) gene has been evaluated in both cognitive function in elderly individuals with normal cognition [5] and in predisposition to AD [6], but no previous study has specifically explored the association between genetic variation in CASP1 and progression from MCI to AD. As a primary goal in this study, we investigate APOE e4 allele and CASP1 (rs580253) polymorphisms in order to predict MCI individuals likely to convert to AD in a relatively short follow-up period. Between 2007 and 2009, we examined 84 consecutive patients who attended the Department of Neurology of University Hospital ‘‘Marques de Valdecilla’’ (Santander, Spain) and that fulfilled the Petersen criteria for amnestic MCI [3]. Patients with MCI were longitudinally assessed at 6-month intervals (mean duration of follow-up 26.5 months; SD 8.1; range 7–37 months). According to their Clinical Dementia Rating (CDR) scores during the follow-up period, 50 MCI patients whose global CDR score changed from CDR = 0.5 to CDR = 1 were diagnosed as MCI-converters to AD (70% women; mean age 76.3 years; SD 5.7; range 60–85 years), and two additional MCI patients converted to dementia with Lewy bodies and vascular dementia, respectively; 32 MCI whose global CDR score remained stable were classified as MCI-nonconverters to AD (63% women; mean age 74.8 years; SD 7.0; range 60–86 years). Except one MCI-converter to AD patient with a minimal follow-up period of 7 months, the rest of our patients were followed up for at least 1 year to avoid the risk to label as MCI-non-converter to AD subjects who will develop dementia over time. We selected the CASP1 gene (rs580253) polymorphism that had been previously related to cognitive function [5]. Blood samples were taken after written informed consent had been obtained from the subjects or their representatives. The study was approved by the ethical committee of the University Hospital ‘‘Marques de Valdecilla’’. Kaplan–Meier curves and Cox regression model (including APOE status, age and gender) were used to assess whether timeto-conversion was associated with CASP1 (rs580253) polymorphism. Kaplan–Meier survival analysis (Fig. 1), shows the effect of APOE e4 allele and CASP1 (rs580253) T allele on the time-to-conversion to AD in patients with MCI. Survival function estimates did not differ significantly between APOE e4 allele carriers and non-carriers. Conversely, the mean time of conversion from MCI to AD was 25.2 months (SD 9.1) in people with CASP1 (rs580253) T allele (CT and TT genotypes) versus 31.7 months (SD 7.4) in CASP1 (rs580253) T allele non-carriers (CC genotype); thus, CASP1 (rs580253) T allele accelerated the progression from MCI to AD by an average of 6.5 months (P = 0.009). The risk factors of conversion from MCI to AD were analyzed simultaneously with a multivariate Cox A. Pozueta J. L. Vazquez-Higuera P. Sanchez-Juan E. Rodriguez-Rodriguez C. Sanchez-Quintana I. Mateo J. Berciano O. Combarros (&) Neurology Service and CIBERNED, University Hospital ‘‘Marques de Valdecilla’’ (University of Cantabria), 39008 Santander, Spain e-mail: combarro@unican.es

Cathepsin D (catD) is an intracellular aspartyl protease that exhibits beta and gamma secretase-like activity to cleave amyloid precursor protein into beta amyloid peptide. The T-allele of a biallelic (alleles C and T) polymorphism in the exon 2 of the catD gene has been found to be associated with increased risk of Alzheimer disease (AD) in two independent German populations. Other groups have been unable to replicate this association in Caucasian American and Northern Ireland populations. Moreover, a small and no significant tendency for the T-allele to be protective for AD has been demonstrated in Caribbean Hispanics. A case control study utilizing a clinically well-defined group of 311 sporadic AD patients and 346 control subjects was performed to test this association in an ethnically homogeneous population from Spain. We did not observe any association between the T-allele of the catD gene and the disease. Furthermore, catD was not predictive of AD in an interactive fashion when considering apolipoprotein E, age, or gender.

The only established genetic determinant of non-Mendelian forms of Alzheimer's disease (AD) is the epsilon 4 allele of the apolipoprotein E gene (APOE). Recently, it has been reported that the P86L polymorphism of the calcium homeostasis modulator 1 gene (CALHM1) is associated with the risk of developing AD. In order to independently assess this association, we performed a meta-analysis of 7,873 AD cases and 13,274 controls of Caucasian origin (from a total of 24 centers in Belgium, Finland, France, Italy, Spain, Sweden, the UK, and the USA). Our results indicate that the CALHM1 P86L polymorphism is likely not a genetic determinant of AD but may modulate age of onset by interacting with the effect of the epsilon 4 allele of the APOE gene.

Elevated cerebral levels of amyloid beta-protein (Aβ) occur in Alzheimer's disease (AD), yet only a few patients show evidence of increased Aβ production. This observation suggests that many, perhaps most, cases of AD are caused by faulty clearance of Aβ. Megalin, which plays an important role in mediating Aβ clearance, is an attractive candidate gene for genetic association with AD. To investigate this hypothesis, we analyzed the megalin gene in a population of 2,183 subjects. Genetic analysis indicated that the rs3755166 (G/A) polymorphism located in the megalin promoter associated with risk for AD, dependently of apolipoprotein E genotype. The rs3755166 AA genotype frequency was significantly greater in AD patients than in control subjects. Furthermore, the luciferase reporter assay indicated that the rs3755166 A variant has 20% less transcriptional activity than the rs3755166 G variant. This study provides strong evidence that this megalin polymorphism confers a greater risk for AD, and supports a biological role for megalin in the neurodegenerative processes involved in AD, This work was supported by grants from Fondo de Investigación Sanitaria (FIS) (CP04/00179, PI060155), Fundación Investigación Médica Mutua Madrileña (2006.125), CIBERNED, Obra Social Caja Madrid, Comunidad Autónoma de Madrid (GR/SAL/0783/2004). We thank Drs. P. Gil, P. Coria, and A. Labad-Alquézar for their cooperation in the generation of the case–control samples