Researchers who have spent their careers studying schizophrenia and mood disorders might be forgiven a bit of “biomarker envy.” At long last, it seems that the neurologists and neuropsychiatrists have developed… Read More
When discussing the concept of cognitive impairment, many terms are used, including dementia, amnestic disorder, cognitive impairment not dementia (CIND), cognitive impairment associated with… Read More
In a presentation at the U.S. Psychiatric and Mental Health Congress in Las Vegas, Kevin Gray, MD, director of the Geriatric Neuropsychiatry Clinic, Veterans Affairs North Texas Health Care System, Dallas, gave a… Read More
The association between Paraoxonase 1 (PON1) gene polymorphisms (Q192R, L55M) and Alzheimer's disease (AD) risk has been reported inconsistent results. To assess the association between PON1 polymorphisms and AD risk, a meta-analysis was performed. Based on comprehensive searches of the PubMed, Embase, Web of Science, Weipu, and CBM databases, a total of 10 studies including 3081 AD cases and 3054 controls were identified. The pooled odds ratio (OR) with 95% confidence interval (95% CI) were performed. There was no significant association between PON1 Q192R polymorphism and AD risk in all comparison models (R vs. Q, OR=0.89, 95% CI=0.82-0.96; RR vs. QQ, OR=0.83, 95% CI=0.68-1.01; RR+RQ vs. QQ, OR=0.86, 95% CI=0.75-0.97; and RR vs. QR+QQ, OR=0.94, 95% CI=0.81-1.11). For the PON1 L55M polymorphism, lack of an association was also found (L vs. M, OR=0.95, 95% CI=0.86-1.05; LL vs. MM, OR=0.67, 95% CI=0.51-0.88; LL vs. ML+MM, OR=0.82, 95% CI=0.69-0.98; and LL+ML vs. MM, OR=0.75, 95% CI=0.58
Association studies of presenilin-2 (PSEN2) polymorphisms and sporadic Alzheimer's disease (AD) have yielded inconsistent results, possibly because single studies often lack sufficient statistical power. In this study, we performed a meta-analysis to evaluate the association of the two most extensively studied PSEN2 polymorphisms, rs8383 and 5'indel, with the risk of sporadic AD. We systematically reviewed relevant studies retrieved by Medline, Pubmed, Embase, AlzGene, and CNKI. Data were analyzed using the Stata (v11.0) software package. The fixed effects model or random-effects model were applied depending on between-study heterogeneity. Publication bias was evaluated using Egger's test and Begg's funnel plots. Overall, the meta-analysis included 6 case-control studies for each polymorphism with 2186 confirmed AD cases and 2507 healthy controls in total. Analysis suggested a significant association between SNP rs8383 polymorphism and AD risk with no evidence of between-study
Recent genome-wide association studies (GWAS) of late-onset Alzheimer disease (LOAD) identified 9 novel risk loci. Discovery of functional variants within genes at these loci is required to confirm their role in Alzheimer disease (AD). Single nucleotide polymorphisms that influence gene expression (eSNPs) constitute an important class of functional variants. We therefore investigated the influence of the novel LOAD risk loci on human brain gene expression.|We measured gene expression levels in the cerebellum and temporal cortex of autopsied AD subjects and those with other brain pathologies (400 total subjects). To determine whether any of the novel LOAD risk variants are eSNPs, we tested their cis-association with expression of 6 nearby LOAD candidate genes detectable in human brain (ABCA7, BIN1, CLU, MS4A4A, MS4A6A, PICALM) and an additional 13 genes 100 kb of these SNPs. To identify additional eSNPs that influence brain gene expression levels of the novel candidate LOAD genes,
The interassay variability and inconsistency of plasma -amyloid (A) measurements among centers are major factors precluding the interpretation of results and a substantial obstacle in the meta-analysis across studies of this biomarker. The goal of this investigation was to address these problems by improving the performance of the bioanalytical method.|We used the Luminex immunoassay platform with a multiplex microsphere-based reagent kit from Innogenetics. A robotic pipetting system was used to perform crucial steps of the procedure. The performance of this method was evaluated using two kit control samples and two quality control plasma samples from volunteer donors, and by retesting previously assayed patient samples in each run. This setup was applied to process 2454 patient plasma samples from the Alzheimer's Disease Neuroimaging Initiative study biofluid repository. We have additionally evaluated the correlations between our results and cerebrospinal fluid (CSF) biomarker
No consensus has been recently reached at the relationship between the 1-antichymotrypsin (ACT) signal peptide -15A/T polymorphism and Alzheimers disease (AD) risk. Thus, our study aimed to better assess this association by performing a meta-analysis, including 4,212 cases and 4,039 controls from 29 studies. Odds ratios (ORs) with the 95% confidence interval (CI) were used to assess the strength of relationship between ACT -15A/T polymorphism and AD risk. Overall, a borderline statistically significant association was detected under recessive model comparison in all subjects (AA vs. AT+TT: OR 1.12, 95% CI 1.01-1.25, P = 0.04). But in subgroup analysis by ethnicity, no significant association was found in Caucasians, Asians, or Africans. Moreover, after exclusion of one study which affect the heterogeneity, the ACT A allele and AA genotype were statistically associated with late-onset AD (LOAD) risk (AA vs. TT: OR 1.25, 95% CI 1.06-1.48, P = 0.007, A vs. T: OR 1.12, 95% CI
23363499 2013 01 31 2013 02 07 1533-4406 368 5 Jan 31 N. Engl. J. Med. 455-64 10.1056/NEJMra1106180 McAllister Heart Institute, and Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, USA. Willis Monte S MS
Alzheimer's disease is the world's most common dementing illness. Deposition of amyloid- peptide drives cerebral neuroinflammation by activating microglia. Indeed, amyloid- activation of the NLRP3 inflammasome in microglia is fundamental for interleukin-1 maturation and subsequent inflammatory events. However, it remains unknown whether NLRP3 activation contributes to Alzheimer's disease in vivo. Here we demonstrate strongly enhanced active caspase-1 expression in human mild cognitive impairment and brains with Alzheimer's disease, suggesting a role for the inflammasome in this neurodegenerative disease. Nlrp3(-/-) or Casp1(-/-) mice carrying mutations associated with familial Alzheimer's disease were largely protected from loss of spatial memory and other sequelae associated with Alzheimer's disease, and demonstrated reduced brain caspase-1 and interleukin-1 activation as well as enhanced amyloid- clearance. Furthermore, NLRP3 inflammasome deficiency skewed microglial cells
A practical diagnostic test is needed for early Alzheimer's disease (AD) detection. Immunosignaturing, a technology that employs antibody binding to a random-sequence peptide microarray, generates profiles that distinguish transgenic mice engineered with familial AD mutations (APPswe/PSEN1-dE9) from non-transgenic littermates. It can also detect an AD-like signature in humans. Here, we assess the changes in the immunosignature at different time points of the disease in mice and humans. We also evaluate the accuracy of the late-stage signature as a test to discriminate between young mice with familial AD mutations from non-transgenic littermates. Plasma samples from AD patients were assayed 3-12 months apart, while APPswe/PSEN1-dE9 and non-transgenic controls supplied plasma at monthly intervals until they reached 15 months of age. Microarrays with 10,000 random-sequence peptides were used to compare antibody binding patterns. These patterns gradually changed over the life-span of mice.
Immunotherapy has the potential to provide a possible treatment therapy to prevent or delay Alzheimer disease. In a clinical trial (AN1792) in which patients received this immunotherapy and received active A1-42 peptide immunizations, treatment was stopped when 6% of patients showed signs of meningoencephalitis. Follow up on these patients led to the conclusion that the antibody response was beneficial in removing A1-42 from brain but an accompanying inflammatory Th1 T cell response was harmful. As a safe alternative treatment targeting the same self protein, A1-42, in brain, we and others are working on a DNA A1-42 immunization protocol as the immune response to DNA immunizations differs in many aspects from immunizations with peptide antigens. Because the immune response to DNA vaccination has different kinetics and has a significantly lower antibody production, we evaluated two different prime boost regimens, A1-42 DNA prime/A1-42 peptide boost and A1-42 peptide
A number of widespread and devastating chronic diseases, including atherosclerosis, type 2 diabetes, and Alzheimer's disease, have a pathophysiologically important inflammatory component. In these diseases, the precise identity of the inflammatory stimulus is often unknown and, if known, is difficult to remove. Thus, there is interest in therapeutically targeting the inflammatory response. Although there has been success with anti-inflammatory therapy in chronic diseases triggered by primary inflammation dysregulation or autoimmunity, there are considerable limitations. In particular, the inflammatory response is critical for survival. As a result, redundancy, compensatory pathways, and necessity narrow the risk:benefit ratio of anti-inflammatory drugs. However, new advances in understanding inflammatory signaling and its links to resolution pathways, together with new drug development, offer promise in this area of translational biomedical research.
Five Steps to Improving Patient Access Judy Capko, May 21, 2013 Patient access is getting increased attention through reform initiatives. Here are five steps you can take to make sure patients get appropriate access to care in your office.