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Search Results: 1 - 10 of 224584 matches for " Neill R. Graff-Radford "
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Can aerobic exercise protect against dementia?
Neill R Graff-Radford
Alzheimer's Research & Therapy , 2011, DOI: 10.1186/alzrt65
Abstract: In 2005, in the US, 36 million persons were over 65. Strong evidence indicates that memory and other cognitive tasks start declining at age 50 [1]. Furthermore, in the US, the prevalence of dementia ranges from 5% to 10% [2,3] and that of mild cognitive impairment (MCI) ranges from 12% to 18% [4,5]. Cognitive decline is common in persons over 70 and has an important impact on quality of life. To improve the quality of life for older persons, it is imperative that we begin to understand which factors contribute to cognitive decline and brain atrophy. Furthermore, we need to determine which biomarkers or neurological measures can be used to predict these conditions and what therapeutic interventions can improve an individual's brain health. Recently, moderate exercise and improved fitness were shown to enhance cognition in cognitively normal older persons as well as in individuals who complain of memory difficulty [6].Additionally, fitness correlates with brain volume in persons who are cognitively normal [7] and in those with Alzheimer's disease (AD) [8]. In this paper, we shall discuss the following:1. The causes of cognitive decline in older persons and why exercise could be a broad-spectrum intervention for dementia.2. After this, we shall present epidemiological evidence that exercise may slow cognitive decline and decrease the chance of dementia.3. Then we shall discuss the randomized control trials that provide evidence that exercise has a positive effect on improving cognition.4. Following that, the paper will report the animal studies showing that exercise may be protective of the brain.5. Lastly, we shall discuss biomarkers, starting with imaging and moving onto telomeres, plasma measures, cerebrospinal fluid (CSF) measures, and inflammatory biomarkers.The three most common forms of dementia are AD, Lewy body disease (LBD), and vascular dementia (VaD) [9] and all contribute to cognitive decline and brain atrophy. Noting that mixed dementia (having overlappin
Evaluation of the Role of SNCA Variants in Survival without Neurological Disease
Michael G. Heckman, Alexandra I. Soto-Ortolaza, Nancy N. Diehl, Minerva M. Carrasquillo, Ryan J. Uitti, Zbigniew K. Wszolek, Neill R. Graff-Radford, Owen A. Ross
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0042877
Abstract: Background A variety of definitions of successful aging have been proposed, many of which relate to longevity, freedom from disease and disability, or preservation of high physical and cognitive function. Many behavioral, biomedical, and psychological factors have been linked with these various measures of successful aging, however genetic predictors are less understood. Parkinson's disease (PD) is an age-related neurodegenerative disorder, and variants in the α-synuclein gene (SNCA) affect susceptibility to PD. This exploratory study examined whether SNCA variants may also promote successful aging as defined by survival without neurological disease. Methods We utilized 769 controls without neurological disease (Mean age: 79 years, Range: 33–99 years) and examined the frequency of 20 different SNCA variants across age groups using logistic regression models. We also included 426 PD cases to assess the effect of these variants on PD risk. Results There was a significant decline in the proportion of carriers of the minor allele of rs10014396 as age increased (P = 0.021), from 30% in controls younger than 60 to 14% in controls 90 years of age or older. Findings were similar for rs3775439, where the proportion of carriers of the minor allele declined from 32% in controls less than 60 years old to 19% in those 90 or older (P = 0.025). A number of SNCA variants, not including rs10014396 or rs3775439, were significantly associated with susceptibility to PD. Conclusions In addition to its documented roles in PD and α-synucleinopathies, our results suggest that SNCA has a role in survival free of neurological disease. Acknowledging that our findings would not have withstood correction for multiple testing, validation in an independent series of aged neurologically normal controls is needed.
Altered microRNA expression in frontotemporal lobar degeneration with TDP-43 pathology caused by progranulin mutations
Jannet Kocerha, Naomi Kouri, Matt Baker, NiCole Finch, Mariely DeJesus-Hernandez, John Gonzalez, Kumaravel Chidamparam, Keith A Josephs, Bradley F Boeve, Neill R Graff-Radford, Julia Crook, Dennis W Dickson, Rosa Rademakers
BMC Genomics , 2011, DOI: 10.1186/1471-2164-12-527
Abstract: Using miRNA array profiling, we identified the 20 miRNAs that showed greatest evidence (unadjusted P < 0.05) of dysregulation in frontal cortex of eight FTLD-TDP patients carrying PGRN mutations when compared to 32 FTLD-TDP patients with no apparent genetic abnormalities. Quantitative real-time PCR (qRT-PCR) analyses provided technical validation of the differential expression for 9 of the 20 miRNAs in frontal cortex. Additional qRT-PCR analyses showed that 5 out of 9 miRNAs (miR-922, miR-516a-3p, miR-571, miR-548b-5p, and miR-548c-5p) were also significantly dysregulated (unadjusted P < 0.05) in cerebellar tissue samples of PGRN mutation carriers, consistent with a systemic reduction in PGRN levels. We developed a list of gene targets for the 5 candidate miRNAs and found 18 genes dysregulated in a reported FTLD mRNA study to exhibit anti-correlated miRNA-mRNA patterns in affected cortex and cerebellar tissue. Among the targets is brain-specific angiogenesis inhibitor 3, which was recently identified as an important player in synapse biology.Our study suggests that miRNAs may contribute to the pathogenesis of FTLD-TDP caused by PGRN mutations and provides new insight into potential future therapeutic options.Frontotemporal lobar degeneration (FTLD) is the second most common cause of early-onset dementia after Alzheimer's Disease (AD) [1]. FTLD patients are clinically characterized by personality changes and disinhibited behaviour, often combined with a gradual and progressive language dysfunction [2]. Memory impairment is typically preserved in the early phase of disease, which distinguishes them from patients with AD. Pathologically, around 40% of FTLD patients present with neuronal and/or glial tau aggregates (FTLD-tau), whereas the majority of FTLD patients show ubiquitin-immunoreactive cytoplasmic and intranuclear inclusions historically referred to as FTLD-U (FTLD with ubiquitin-positive inclusions) [3]. More recently, it was shown that hyperphosphorylated and
Rare Variants in APP, PSEN1 and PSEN2 Increase Risk for AD in Late-Onset Alzheimer's Disease Families
Carlos Cruchaga, Sumitra Chakraverty, Kevin Mayo, Francesco L. M. Vallania, Robi D. Mitra, Kelley Faber, Jennifer Williamson, Tom Bird, Ramon Diaz-Arrastia, Tatiana M. Foroud, Bradley F. Boeve, Neill R. Graff-Radford, Pamela St. Jean, Michael Lawson, Margaret G. Ehm, Richard Mayeux, Alison M. Goate, for the NIA-LOAD/NCRAD Family Study Consortium
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0031039
Abstract: Pathogenic mutations in APP, PSEN1, PSEN2, MAPT and GRN have previously been linked to familial early onset forms of dementia. Mutation screening in these genes has been performed in either very small series or in single families with late onset AD (LOAD). Similarly, studies in single families have reported mutations in MAPT and GRN associated with clinical AD but no systematic screen of a large dataset has been performed to determine how frequently this occurs. We report sequence data for 439 probands from late-onset AD families with a history of four or more affected individuals. Sixty sequenced individuals (13.7%) carried a novel or pathogenic mutation. Eight pathogenic variants, (one each in APP and MAPT, two in PSEN1 and four in GRN) three of which are novel, were found in 14 samples. Thirteen additional variants, present in 23 families, did not segregate with disease, but the frequency of these variants is higher in AD cases than controls, indicating that these variants may also modify risk for disease. The frequency of rare variants in these genes in this series is significantly higher than in the 1,000 genome project (p = 5.09×10?5; OR = 2.21; 95%CI = 1.49–3.28) or an unselected population of 12,481 samples (p = 6.82×10?5; OR = 2.19; 95%CI = 1.347–3.26). Rare coding variants in APP, PSEN1 and PSEN2, increase risk for or cause late onset AD. The presence of variants in these genes in LOAD and early-onset AD demonstrates that factors other than the mutation can impact the age at onset and penetrance of at least some variants associated with AD. MAPT and GRN mutations can be found in clinical series of AD most likely due to misdiagnosis. This study clearly demonstrates that rare variants in these genes could explain an important proportion of genetic heritability of AD, which is not detected by GWAS.
Replication of EPHA1 and CD33 associations with late-onset Alzheimer's disease: a multi-centre case-control study
Minerva M Carrasquillo, Olivia Belbin, Talisha A Hunter, Li Ma, Gina D Bisceglio, Fanggeng Zou, Julia E Crook, V Pankratz, Sigrid B Sando, Jan O Aasly, Maria Barcikowska, Zbigniew K Wszolek, Dennis W Dickson, Neill R Graff-Radford, Ronald C Petersen, Peter Passmore, Kevin Morgan, for the Alzheimer's Research UK (ARUK) consortium, Steven G Younkin
Molecular Neurodegeneration , 2011, DOI: 10.1186/1750-1326-6-54
Abstract: We found no significant evidence of series heterogeneity. Associations with LOAD were successfully replicated for EPHA1 (rs11767557; OR = 0.87, p = 5 × 10-4) and CD33 (rs3865444; OR = 0.92, p = 0.049), with odds ratios comparable to those previously reported. Although the two ARID5B variants (rs2588969 and rs494288) showed significant association with LOAD in meta-analysis of our dataset (p = 0.046 and 0.008, respectively), the associations did not survive adjustment for covariates (p = 0.30 and 0.11, respectively). We had insufficient evidence in our data to support the association of the CD2AP variant (rs9349407, p = 0.56).Our data overwhelmingly support the association of EPHA1 and CD33 variants with LOAD risk: addition of our data to the results previously reported (total n > 42,000) increased the strength of evidence for these variants, providing impressive p-values of 2.1 × 10-15 (EPHA1) and 1.8 × 10-13 (CD33).Following the identification of the APOE ε4 allele as a risk factor for late-onset Alzheimer's disease (LOAD) in 1993 [1], consistent replication of subsequently identified candidates was not achieved until 2009, when two genome-wide association studies (GWAS) [2,3] identified associations of variants in or near CLU, PICALM , and CR1 with LOAD, which were consistently replicated in multiple large, independent case-control studies [4-17]. Subsequently, a variant near BIN1 was reported [4] to achieve genome-wide significant association in a later GWAS published in 2010 that also replicated well in follow-up studies [14-19]. These results demonstrate the utility of the hypothesis-free GWAS approach for identifying loci that associate with LOAD and the necessity of pooling samples and data from multiple centers to obtain resources with sufficient statistical power (GWAS typically > 14,000, follow-up typically total > 28,000) to detect the modest ORs (e.g. 0.8/1.2) associated with these variants in GWAS and follow-up studies.Two recently published companion s
Linking Protective GAB2 Variants, Increased Cortical GAB2 Expression and Decreased Alzheimer’s Disease Pathology
Fanggeng Zou, Olivia Belbin, Minerva M. Carrasquillo, Oliver J. Culley, Talisha A. Hunter, Li Ma, Gina D. Bisceglio, Mariet Allen, Dennis W. Dickson, Neill R. Graff-Radford, Ronald C. Petersen, the Genetic and Environmental Risk for Alzheimer’s disease (GERAD1) Consortium , Kevin Morgan, Steven G. Younkin
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0064802
Abstract: GRB-associated binding protein 2 (GAB2) represents a compelling genome-wide association signal for late-onset Alzheimer’s disease (LOAD) with reported odds ratios (ORs) ranging from 0.75–0.85. We tested eight GAB2 variants in four North American Caucasian case-control series (2,316 LOAD, 2,538 controls) for association with LOAD. Meta-analyses revealed ORs ranging from (0.61–1.20) with no significant association (all p>0.32). Four variants were hetergeneous across the populations (all p<0.02) due to a potentially inflated effect size (OR = 0.61–0.66) only observed in the smallest series (702 LOAD, 209 controls). Despite the lack of association in our series, the previously reported protective association for GAB2 remained after meta-analyses of our data with all available previously published series (11,952-22,253 samples; OR = 0.82–0.88; all p<0.04). Using a freely available database of lymphoblastoid cell lines we found that protective GAB2 variants were associated with increased GAB2 expression (p = 9.5×10?7?9.3×10?6). We next measured GAB2 mRNA levels in 249 brains and found that decreased neurofibrillary tangle (r = ?0.34, p = 0.0006) and senile plaque counts (r = ?0.32, p = 0.001) were both good predictors of increased GAB2 mRNA levels albeit that sex (r = ?0.28, p = 0.005) may have been a contributing factor. In summary, we hypothesise that GAB2 variants that are protective against LOAD in some populations may act functionally to increase GAB2 mRNA levels (in lymphoblastoid cells) and that increased GAB2 mRNA levels are associated with significantly decreased LOAD pathology. These findings support the hypothesis that Gab2 may protect neurons against LOAD but due to significant population heterogeneity, it is still unclear whether this protection is detectable at the genetic level.
LRRTM3 Interacts with APP and BACE1 and Has Variants Associating with Late-Onset Alzheimer’s Disease (LOAD)
Sarah Lincoln, Mariet Allen, Claire L. Cox, Louise P. Walker, Kimberly Malphrus, Yushi Qiu, Thuy Nguyen, Christopher Rowley, Naomi Kouri, Julia Crook, V. Shane Pankratz, Samuel Younkin, Linda Younkin, Minerva Carrasquillo, Fanggeng Zou, Samer O. Abdul-Hay, Wolfdieter Springer, Sigrid B. Sando, Jan O. Aasly, Maria Barcikowska, Zbigniew K. Wszolek, Jada M. Lewis, Dennis Dickson, Neill R. Graff-Radford, Ronald C. Petersen, Elizabeth Eckman, Steven G. Younkin, Nilüfer Ertekin-Taner
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0064164
Abstract: Leucine rich repeat transmembrane protein 3 (LRRTM3) is member of a synaptic protein family. LRRTM3 is a nested gene within α-T catenin (CTNNA3) and resides at the linkage peak for late-onset Alzheimer’s disease (LOAD) risk and plasma amyloid β (Aβ) levels. In-vitro knock-down of LRRTM3 was previously shown to decrease secreted Aβ, although the mechanism of this is unclear. In SH-SY5Y cells overexpressing APP and transiently transfected with LRRTM3 alone or with BACE1, we showed that LRRTM3 co-localizes with both APP and BACE1 in early endosomes, where BACE1 processing of APP occurs. Additionally, LRRTM3 co-localizes with APP in primary neuronal cultures from Tg2576 mice transduced with LRRTM3-expressing adeno-associated virus. Moreover, LRRTM3 co-immunoprecipitates with both endogenous APP and overexpressed BACE1, in HEK293T cells transfected with LRRTM3. SH-SY5Y cells with knock-down of LRRTM3 had lower BACE1 and higher CTNNA3 mRNA levels, but no change in APP. Brain mRNA levels of LRRTM3 showed significant correlations with BACE1, CTNNA3 and APP in ~400 humans, but not in LRRTM3 knock-out mice. Finally, we assessed 69 single nucleotide polymorphisms (SNPs) within and flanking LRRTM3 in 1,567 LOADs and 2,082 controls and identified 8 SNPs within a linkage disequilibrium block encompassing 5′UTR-Intron 1 of LRRTM3 that formed multilocus genotypes (MLG) with suggestive global association with LOAD risk (p = 0.06), and significant individual MLGs. These 8 SNPs were genotyped in an independent series (1,258 LOADs and 718 controls) and had significant global and individual MLG associations in the combined dataset (p = 0.02–0.05). Collectively, these results suggest that protein interactions between LRRTM3, APP and BACE1, as well as complex associations between mRNA levels of LRRTM3, CTNNA3, APP and BACE1 in humans might influence APP metabolism and ultimately risk of AD.
Novel Mutations in TARDBP (TDP-43) in Patients with Familial Amyotrophic Lateral Sclerosis
Nicola J. Rutherford,Yong-Jie Zhang,Matt Baker,Jennifer M. Gass,NiCole A. Finch,Ya-Fei Xu,Heather Stewart,Brendan J. Kelley,Karen Kuntz,Richard J. P. Crook,Jemeen Sreedharan,Caroline Vance,Eric Sorenson,Carol Lippa,Eileen H. Bigio,Daniel H. Geschwind,David S. Knopman,Hiroshi Mitsumoto,Ronald C. Petersen,Neil R. Cashman,Mike Hutton,Christopher E. Shaw,Kevin B. Boylan,Bradley Boeve,Neill R. Graff-Radford,Zbigniew K. Wszolek,Richard J. Caselli,Dennis W. Dickson,Ian R. Mackenzie,Leonard Petrucelli,Rosa Rademakers
PLOS Genetics , 2008, DOI: 10.1371/journal.pgen.1000193
Abstract: The TAR DNA-binding protein 43 (TDP-43) has been identified as the major disease protein in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin inclusions (FTLD-U), defining a novel class of neurodegenerative conditions: the TDP-43 proteinopathies. The first pathogenic mutations in the gene encoding TDP-43 (TARDBP) were recently reported in familial and sporadic ALS patients, supporting a direct role for TDP-43 in neurodegeneration. In this study, we report the identification and functional analyses of two novel and one known mutation in TARDBP that we identified as a result of extensive mutation analyses in a cohort of 296 patients with variable neurodegenerative diseases associated with TDP-43 histopathology. Three different heterozygous missense mutations in exon 6 of TARDBP (p.M337V, p.N345K, and p.I383V) were identified in the analysis of 92 familial ALS patients (3.3%), while no mutations were detected in 24 patients with sporadic ALS or 180 patients with other TDP-43–positive neurodegenerative diseases. The presence of p.M337V, p.N345K, and p.I383V was excluded in 825 controls and 652 additional sporadic ALS patients. All three mutations affect highly conserved amino acid residues in the C-terminal part of TDP-43 known to be involved in protein-protein interactions. Biochemical analysis of TDP-43 in ALS patient cell lines revealed a substantial increase in caspase cleaved fragments, including the ~25 kDa fragment, compared to control cell lines. Our findings support TARDBP mutations as a cause of ALS. Based on the specific C-terminal location of the mutations and the accumulation of a smaller C-terminal fragment, we speculate that TARDBP mutations may cause a toxic gain of function through novel protein interactions or intracellular accumulation of TDP-43 fragments leading to apoptosis.
Brain Expression Genome-Wide Association Study (eGWAS) Identifies Human Disease-Associated Variants
Fanggeng Zou equal contributor,High Seng Chai equal contributor,Curtis S. Younkin equal contributor,Mariet Allen equal contributor,Julia Crook,V. Shane Pankratz,Minerva M. Carrasquillo,Christopher N. Rowley,Asha A. Nair,Sumit Middha,Sooraj Maharjan,Thuy Nguyen,Li Ma,Kimberly G. Malphrus,Ryan Palusak,Sarah Lincoln,Gina Bisceglio,Constantin Georgescu,Naomi Kouri,Christopher P. Kolbert,Jin Jen,Jonathan L. Haines,Richard Mayeux,Margaret A. Pericak-Vance,Lindsay A. Farrer,Gerard D. Schellenberg,Alzheimer's Disease Genetics Consortium,Ronald C. Petersen,Neill R. Graff-Radford,Dennis W. Dickson,Steven G. Younkin,Nilüfer Ertekin-Taner
PLOS Genetics , 2012, DOI: 10.1371/journal.pgen.1002707
Abstract: Genetic variants that modify brain gene expression may also influence risk for human diseases. We measured expression levels of 24,526 transcripts in brain samples from the cerebellum and temporal cortex of autopsied subjects with Alzheimer's disease (AD, cerebellar n = 197, temporal cortex n = 202) and with other brain pathologies (non–AD, cerebellar n = 177, temporal cortex n = 197). We conducted an expression genome-wide association study (eGWAS) using 213,528 cisSNPs within ±100 kb of the tested transcripts. We identified 2,980 cerebellar cisSNP/transcript level associations (2,596 unique cisSNPs) significant in both ADs and non–ADs (q<0.05, p = 7.70×10?5–1.67×10?82). Of these, 2,089 were also significant in the temporal cortex (p = 1.85×10?5–1.70×10?141). The top cerebellar cisSNPs had 2.4-fold enrichment for human disease-associated variants (p<10?6). We identified novel cisSNP/transcript associations for human disease-associated variants, including progressive supranuclear palsy SLCO1A2/rs11568563, Parkinson's disease (PD) MMRN1/rs6532197, Paget's disease OPTN/rs1561570; and we confirmed others, including PD MAPT/rs242557, systemic lupus erythematosus and ulcerative colitis IRF5/rs4728142, and type 1 diabetes mellitus RPS26/rs1701704. In our eGWAS, there was 2.9–3.3 fold enrichment (p<10?6) of significant cisSNPs with suggestive AD–risk association (p<10?3) in the Alzheimer's Disease Genetics Consortium GWAS. These results demonstrate the significant contributions of genetic factors to human brain gene expression, which are reliably detected across different brain regions and pathologies. The significant enrichment of brain cisSNPs among disease-associated variants advocates gene expression changes as a mechanism for many central nervous system (CNS) and non–CNS diseases. Combined assessment of expression and disease GWAS may provide complementary information in discovery of human disease variants with functional implications. Our findings have implications for the design and interpretation of eGWAS in general and the use of brain expression quantitative trait loci in the study of human disease genetics.
Glutathione S-transferase omega genes in Alzheimer and Parkinson disease risk, age-at-diagnosis and brain gene expression: an association study with mechanistic implications
Mariet Allen, Fanggeng Zou, High Chai, Curtis S Younkin, Richard Miles, Asha A Nair, Julia E Crook, V Pankratz, Minerva M Carrasquillo, Christopher N Rowley, Thuy Nguyen, Li Ma, Kimberly G Malphrus, Gina Bisceglio, Alexandra I Ortolaza, Ryan Palusak, Sumit Middha, Sooraj Maharjan, Constantin Georgescu, Debra Schultz, Fariborz Rakhshan, Christopher P Kolbert, Jin Jen, Sigrid B Sando, Jan O Aasly, Maria Barcikowska, Ryan J Uitti, Zbigniew K Wszolek, Owen A Ross, Ronald C Petersen, Neill R Graff-Radford, Dennis W Dickson, Steven G Younkin, Nilüfer Ertekin-Taner
Molecular Neurodegeneration , 2012, DOI: 10.1186/1750-1326-7-13
Abstract: We found that rs156697 minor allele associates with significantly increased risk (odds ratio = 1.14, p = 0.038) in the older ADs with age-at-diagnosis > 80 years. The minor allele of GSTO1 rs4925 associates with decreased risk in familial PD (odds ratio = 0.78, p = 0.034). There was no other association with disease risk or age-at-diagnosis. The minor alleles of both GSTO SNPs associate with lower brain levels of GSTO2 (p = 4.7 × 10-11-1.9 × 10-27), but not GSTO1. Pathway analysis of significant genes in our brain expression GWAS, identified significant enrichment for glutathione metabolism genes (p = 0.003).These results suggest that GSTO locus variants may lower brain GSTO2 levels and consequently confer AD risk in older age. Other glutathione metabolism genes should be assessed for their effects on AD and other chronic, neurologic diseases.Glutathione S-Transferase (GST) family of genes have been implicated in multiple neuropsychiatric [1-4] and neurodegenerative diseases [5-11]; where altered levels or function of these enzymes is thought to impact levels of oxidative stress and/or inflammation in a way that contributes to disease susceptibility. A linkage locus on chromosome 10q that has been implicated in both Alzheimer's (AD)[11-13] and Parkinson's disease (PD)[13] harbors two GST genes of the omega class: GSTO1 and GSTO2, which are approximately 75 kb apart.GSTOs have enzymatic activities as thioltransferases and dehydroascorbate reductases that promote antioxidant activity and can also function in metabolism of drugs and toxins[14]. Additionally, GSTO1 was shown to promote activation of the pro-inflammatory cytokine, interleukin-1β (IL-1β) by post-translational processing[15]. Given their location and function, they have been studied as candidate genes in AD and PD[5,6,9,11,14,16-18]. Li et al. compared hippocampal gene expression levels in 6 AD vs. 2 control brains and identified significantly lower GSTO1 levels in the AD hippocampi[5]. This group studied
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