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On page 1 showing 1 ~ 20 papers out of 22 papers

Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease.

  • Denise Harold‎ et al.
  • Nature genetics‎
  • 2009‎

We undertook a two-stage genome-wide association study (GWAS) of Alzheimer's disease (AD) involving over 16,000 individuals, the most powerful AD GWAS to date. In stage 1 (3,941 cases and 7,848 controls), we replicated the established association with the apolipoprotein E (APOE) locus (most significant SNP, rs2075650, P = 1.8 x 10(-157)) and observed genome-wide significant association with SNPs at two loci not previously associated with the disease: at the CLU (also known as APOJ) gene (rs11136000, P = 1.4 x 10(-9)) and 5' to the PICALM gene (rs3851179, P = 1.9 x 10(-8)). These associations were replicated in stage 2 (2,023 cases and 2,340 controls), producing compelling evidence for association with Alzheimer's disease in the combined dataset (rs11136000, P = 8.5 x 10(-10), odds ratio = 0.86; rs3851179, P = 1.3 x 10(-9), odds ratio = 0.86).


Apolipoprotein E levels in cerebrospinal fluid and the effects of ABCA1 polymorphisms.

  • Suzanne E Wahrle‎ et al.
  • Molecular neurodegeneration‎
  • 2007‎

Animal studies suggest that brain apolipoprotein E (apoE) levels influence amyloid-beta (Abeta) deposition and thus risk for Alzheimer's disease (AD). We have previously demonstrated that deletion of the ATP-binding cassette A1 transporter (ABCA1) in mice causes dramatic reductions in brain and cerebrospinal fluid (CSF) apoE levels and lipidation. To examine whether polymorphisms in ABCA1 affect CSF apoE levels in humans, we measured apoE in CSF taken from 168 subjects who were 43 to 91 years old and were either cognitively normal or who had mild AD. We then genotyped the subjects for ten previously identified ABCA1 single nucleotide polymorphisms (SNPs).


Association of Functional Impairments and Co-Morbid Conditions with Driving Performance among Cognitively Normal Older Adults.

  • David B Carr‎ et al.
  • PloS one‎
  • 2016‎

To examine the relationship between key functional impairments, co-morbid conditions and driving performance in a sample of cognitively normal older adults.


The effects of white matter hyperintensities and amyloid deposition on Alzheimer dementia.

  • Brian A Gordon‎ et al.
  • NeuroImage. Clinical‎
  • 2015‎

Elevated levels of amyloid deposition as well as white matter damage are thought to be risk factors for Alzheimer Disease (AD). Here we examined whether qualitative ratings of white matter damage predicted cognitive impairment beyond measures of amyloid.


Novel Simulation Model of Non-Muscle Invasive Bladder Cancer: A Platform for a Virtual Randomized Trial of Conservative Therapy vs. Cystectomy in BCG Refractory Patients.

  • Sanjay Patel‎ et al.
  • Bladder cancer (Amsterdam, Netherlands)‎
  • 2015‎

Introduction: There have been no randomized controlled trials (RCTs) evaluating the clinical or economic benefit of mitomycin C intravesical therapy vs. radical cystectomy in patients with high-risk non-muscle invasive bladder cancer (NMIBC). We used the Archimedes computational model to simulate RCT comparing radical cystectomy versus intravesical mitomycin C (MMC) therapy to evaluate the clinical and economic outcomes for BCG-refractory NMIBC as well demonstrate the utility of computer based models to simulate a clinical trial. Methods: The Archimedes model was developed to generate a virtual population using the Surveillance Epidemiology and End Results database, other clinical trials, and expert opinions. Patients selected were diagnosed with NMIBC (


SNPs associated with cerebrospinal fluid phospho-tau levels influence rate of decline in Alzheimer's disease.

  • Carlos Cruchaga‎ et al.
  • PLoS genetics‎
  • 2010‎

Alzheimer's Disease (AD) is a complex and multifactorial disease. While large genome-wide association studies have had some success in identifying novel genetic risk factors for AD, case-control studies are less likely to uncover genetic factors that influence progression of disease. An alternative approach to identifying genetic risk for AD is the use of quantitative traits or endophenotypes. The use of endophenotypes has proven to be an effective strategy, implicating genetic risk factors in several diseases, including anemia, osteoporosis and heart disease. In this study we identify a genetic factor associated with the rate of decline in AD patients and present a methodology for identification of other such factors. We have used an established biomarker for AD, cerebrospinal fluid (CSF) tau phosphorylated at threonine 181 (ptau(181)) levels as an endophenotype for AD, identifying a SNP, rs1868402, in the gene encoding the regulatory sub-unit of protein phosphatase B, associated with CSF ptau(181) levels in two independent CSF series (P(combined) = 1.17 x 10(-05)). We show no association of rs1868402 with risk for AD or age at onset, but detected a very significant association with rate of progression of disease that is consistent in two independent series (P(combined) = 1.17 x 10(-05)). Our analyses suggest that genetic variants associated with CSF ptau(181) levels may have a greater impact on rate of progression, while genetic variants such as APOE4, that are associated with CSF Aβ(42) levels influence risk and onset but not the rate of progression. Our results also suggest that drugs that inhibit or decrease tau phosphorylation may slow cognitive decline in individuals with very mild dementia or delay the appearance of memory problems in elderly individuals with low CSF Aβ(42) levels. Finally, we believe genome-wide association studies of CSF tau/ptau(181) levels should identify novel genetic variants which will likely influence rate of progression of AD.


Exome-sequencing confirms DNAJC5 mutations as cause of adult neuronal ceroid-lipofuscinosis.

  • Bruno A Benitez‎ et al.
  • PloS one‎
  • 2011‎

We performed whole-exome sequencing in two autopsy-confirmed cases and an elderly unaffected control from a multigenerational family with autosomal dominant neuronal ceroid lipofuscinosis (ANCL). A novel single-nucleotide variation (c.344T>G) in the DNAJC5 gene was identified. Mutational screening in an independent family with autosomal dominant ANCL found an in-frame single codon deletion (c.346_348 delCTC) resulting in a deletion of p.Leu116del. These variants fulfill all genetic criteria for disease-causing mutations: they are found in unrelated families with the same disease, exhibit complete segregation between the mutation and the disease, and are absent in healthy controls. In addition, the associated amino acid substitutions are located in evolutionarily highly conserved residues and are predicted to functionally affect the encoded protein (CSPα). The mutations are located in a cysteine-string domain, which is required for membrane targeting/binding, palmitoylation, and oligomerization of CSPα. We performed a comprehensive in silico analysis of the functional and structural impact of both mutations on CSPα. We found that these mutations dramatically decrease the affinity of CSPα for the membrane. We did not identify any significant effect on palmitoylation status of CSPα. However, a reduction of CSPα membrane affinity may change its palmitoylation and affect proper intracellular sorting. We confirm that CSPα has a strong intrinsic aggregation propensity; however, it is not modified by the mutations. A complementary disease-network analysis suggests a potential interaction with other NCLs genes/pathways. This is the first replication study of the identification of DNAJC5 as the disease-causing gene for autosomal dominant ANCL. The identification of the novel gene in ANCL will allow us to gain a better understanding of the pathological mechanism of ANCLs and constitutes a great advance toward the development of new molecular diagnostic tests and may lead to the development of potential therapies.


Multi-germ layer lineage central nervous system repair: nerve and vascular cell generation by embryonic stem cells transplanted in the injured brain.

  • Sudhakar Vadivelu‎ et al.
  • Journal of neurosurgery‎
  • 2005‎

To restore proper function to a damaged central nervous system (CNS) through transplantation, it is necessary to replace both neural and nonneural elements that arise from different germ layers in the embryo. Mounting evidence indicates the importance of signals related to vasculogenesis in governing neural proliferation and differentiation in early CNS development. Here, the authors examined whether embryonic stem cell (ESC)-derived progenitors can selectively generate both neural and endothelial cells after transplantation in the damaged CNS.


Reduction of Leukocyte Microvascular Adherence and Preservation of Blood-Brain Barrier Function by Superoxide-Lowering Therapies in a Piglet Model of Neonatal Asphyxia.

  • Jacob B Ruden‎ et al.
  • Frontiers in neurology‎
  • 2019‎

Background: Asphyxia is the most common cause of brain damage in newborns. Substantial evidence indicates that leukocyte recruitment in the cerebral vasculature during asphyxia contributes to this damage. We tested the hypothesis that superoxide radical ( O 2 ⋅ _ ) promotes an acute post-asphyxial inflammatory response and blood-brain barrier (BBB) breakdown. We investigated the effects of removing O 2 ⋅ _ by superoxide dismutase (SOD) or C3, the cell-permeable SOD mimetic, in protecting against asphyxia-related leukocyte recruitment. We also tested the hypothesis that xanthine oxidase activity is one source of this radical. Methods: Anesthetized piglets were tracheostomized, ventilated, and equipped with closed cranial windows for the assessment of post-asphyxial rhodamine 6G-labeled leukocyte-endothelial adherence and microvascular permeability to sodium fluorescein in cortical venules. Asphyxia was induced by discontinuing ventilation. SOD and C3 were administered by cortical superfusion. The xanthine oxidase inhibitor oxypurinol was administered intravenously. Results: Leukocyte-venular adherence significantly increased during the initial 2 h of post-asphyxial reperfusion. BBB permeability was also elevated relative to non-asphyxial controls. Inhibition of O 2 ⋅ _ production by oxypurinol, or elimination of O 2 ⋅ _ by SOD or C3, significantly reduced rhodamine 6G-labeled leukocyte-endothelial adherence and improved BBB integrity, as measured by sodium fluorescein leak from cerebral microvessels. Conclusion: Using three different strategies to either prevent formation or enhance elimination of O 2 ⋅ _ during the post-asphyxial period, we saw both reduced leukocyte adherence and preserved BBB function with treatment. These findings suggest that agents which lower O 2 ⋅ _ in brain may be attractive new therapeutic interventions for the protection of the neonatal brain following asphyxia.


Amyloid Imaging, Cerebrospinal Fluid Biomarkers Predict Driving Performance Among Cognitively Normal Individuals.

  • Catherine M Roe‎ et al.
  • Alzheimer disease and associated disorders‎
  • 2017‎

Postmortem brain studies of older drivers killed in car accidents indicate that many had Alzheimer disease (AD) neuropathologic changes. We examined whether AD biomarkers are related to driving performance among cognitively normal older adults. Individuals with normal cognition, aged 65+ years, and driving at least once per week, were recruited. Participants (N=129) took part in clinical assessments, a driving test, and positron emission tomography imaging with Pittsburgh compound B (PIB) and/or cerebrospinal fluid (CSF) collection. General linear models tested whether the number of driving errors differed as a function of each of the biomarker variables (mean cortical binding potential for PIB, and CSF Aβ42, tau, ptau181, tau/Aβ42, ptau181/Aβ42). Higher ratios of CSF tau/Aβ42, ptau181/Aβ42, and PIB mean cortical binding potential, were associated with more driving errors (P<0.05). Preclinical AD may have subtle cognitive and functional effects, which alone may go unnoticed. However, when combined, these changes may impact complex behaviors such as driving.


Identification and validation of novel cerebrospinal fluid biomarkers for staging early Alzheimer's disease.

  • Richard J Perrin‎ et al.
  • PloS one‎
  • 2011‎

Ideally, disease modifying therapies for Alzheimer disease (AD) will be applied during the 'preclinical' stage (pathology present with cognition intact) before severe neuronal damage occurs, or upon recognizing very mild cognitive impairment. Developing and judiciously administering such therapies will require biomarker panels to identify early AD pathology, classify disease stage, monitor pathological progression, and predict cognitive decline. To discover such biomarkers, we measured AD-associated changes in the cerebrospinal fluid (CSF) proteome.


Preclinical Alzheimer's disease and longitudinal driving decline.

  • Catherine M Roe‎ et al.
  • Alzheimer's & dementia (New York, N. Y.)‎
  • 2017‎

Links between preclinical AD and driving difficulty onset would support the use of driving performance as an outcome in primary and secondary prevention trials among older adults (OAs). We examined whether AD biomarkers predicted the onset of driving difficulties among OAs.


Haplotype-based association analysis of the MAPT locus in late onset Alzheimer's disease.

  • Odity Mukherjee‎ et al.
  • BMC genetics‎
  • 2007‎

Late onset Alzheimer's disease (LOAD) is a common sporadic form of the illness, affecting individuals above the age of 65 yrs. A prominent hypothesis for the aetiopathology of Alzheimer's disease is that in the presence of a beta-amyloid load, individuals expressing a pathogenic form of tau protein (MAPT) are at increased risk for developing the disease. Genetic studies in this pursuit have, however, yielded conflicting results. A recent study showed a significant haplotype association (H1c) with AD. The current study is an attempt to replicate this association in an independently ascertained cohort.


The ideological divide in confidence in science and participation in medical research.

  • Matthew Gabel‎ et al.
  • Scientific reports‎
  • 2021‎

In the United States, the wide ideological divergence in public confidence in science poses a potentially significant problem for the scientific enterprise. We examine the behavioral consequences of this ideological divide for Americans' contributions to medical research. Based on a mass survey of American adults, we find that engagement in a wide range of medical research activities is a function of a latent propensity to participate. The propensity is systematically higher among liberals than among conservatives. A substantial part of this ideological divide is due to conservative Americans' lower confidence in science. These findings raise important issues for the recruitment of subjects for medical studies and the generalizability of results from such studies.


Evaluation of Naturalistic Driving Behavior Using In-Vehicle Monitoring Technology in Preclinical and Early Alzheimer's Disease.

  • Jennifer D Davis‎ et al.
  • Frontiers in psychology‎
  • 2020‎

Cognitive impairment is a significant risk factor for hazardous driving among older drivers with Alzheimer's dementia, but little is known about how the driving behavior of mildly symptomatic compares with those in the preclinical, asymptomatic phase of Alzheimer's disease (AD). This study utilized two in-car technologies to characterize driving behavior in symptomatic and preclinical AD. The goals of this pilot study were to (1) describe unsafe driving behaviors in individuals with symptomatic early AD using G-force triggered video capture and (2) compare the driving habits of these symptomatic AD drivers to two groups of cognitively normal drivers, those with and those without evidence of cerebral amyloidosis (CN/A+ and CN/A-) using a global positioning system (GPS) datalogger. Thirty-three drivers (aged 60+ years) were studied over 3 months. G-force triggered video events captured instances of near-misses/collisions, traffic violations, risky driver conduct, and driving fundamentals. GPS data were sampled every 30 s and all instances of speeding, hard braking, and sudden acceleration were recorded. For the early AD participants, video capture identified driving unbelted, late response, driving too fast for conditions, traffic violations, poor judgment, and not scanning intersections as the most frequently occurring safety errors. When evaluating driving using the GPS datalogger, hard breaking events occurred most frequently on a per trip basis across all three groups. The CN/A+ group had the lowest event rate across all three event types with lower instances of speeding. Slower psychomotor speed (Trail Making Part A) was associated with fewer speeding events, more hard acceleration events, and more overall events. GPS tracked instances of speeding were correlated with total number of video-captured near-collisions/collisions and driving fundamentals. Results demonstrate the utility of electronic monitoring to identify potentially unsafe driving events in symptomatic and preclinical AD. Results suggest that drivers with preclinical AD may compensate for early, subtle cognitive changes by driving more slowly and cautiously than healthy older drivers or those with cognitive impairment. Self-regulatory changes in driving behavior appear to occur in the preclinical phase of AD, but safety concerns may not arise until symptoms of cognitive impairment emerge and the ability to self-monitor declines.


Neuropathology of nondemented aging: presumptive evidence for preclinical Alzheimer disease.

  • Joseph L Price‎ et al.
  • Neurobiology of aging‎
  • 2009‎

To determine the frequency and possible cognitive effect of histological Alzheimer's disease (AD) in autopsied older nondemented individuals.


Fine mapping of genetic variants in BIN1, CLU, CR1 and PICALM for association with cerebrospinal fluid biomarkers for Alzheimer's disease.

  • John S K Kauwe‎ et al.
  • PloS one‎
  • 2011‎

Recent genome-wide association studies of Alzheimer's disease (AD) have identified variants in BIN1, CLU, CR1 and PICALM that show replicable association with risk for disease. We have thoroughly sampled common variation in these genes, genotyping 355 variants in over 600 individuals for whom measurements of two AD biomarkers, cerebrospinal fluid (CSF) 42 amino acid amyloid beta fragments (Aβ(42)) and tau phosphorylated at threonine 181 (ptau(181)), have been obtained. Association analyses were performed to determine whether variants in BIN1, CLU, CR1 or PICALM are associated with changes in the CSF levels of these biomarkers. Despite adequate power to detect effects as small as a 1.05 fold difference, we have failed to detect evidence for association between SNPs in these genes and CSF Aβ(42) or ptau(181) levels in our sample. Our results suggest that these variants do not affect risk via a mechanism that results in a strong additive effect on CSF levels of Aβ(42) or ptau(181).


A Systematic Review Examining Associations between Cardiovascular Conditions and Driving Outcomes among Older Drivers.

  • Ganesh M Babulal‎ et al.
  • Geriatrics (Basel, Switzerland)‎
  • 2020‎

There is a vast literature on stroke as a cardiovascular disease and driving outcomes, however little is known about other cardiovascular conditions and driving. The purpose of this review is to examine the literature for studies assessing the effect of non-stroke, vascular conditions on daily driving, reported crash risk and driving decline in older adult drivers as captured by naturalistic methodologies. A systematic review of Embase, Ovid and Scopus Plus examined articles on driving and vascular conditions among older adults. A search yielded 443 articles and, following two screenings, no articles remained that focused on non-stroke, vascular conditions and naturalistic driving. As a result, this review examined non-stroke, vascular conditions in nine driving studies of older adults that used road testing, driving simulators and self-report measures. These studies fell into three categories-heart failure, vascular dementia and white matter hyperintensities/leukoaraiosis. The combined findings of the studies suggest that heart failure, vascular dementia and white matter hyperintensities (WMH) negatively impact driving performance and contribute to driving cessation among older adults. Future research should examine cardiovascular risk factors like hypertension, hypercholesterolemia, myocardial infraction or atherosclerosis using naturalistic driving measurement, as well as traditional measures, in order to more fully characterize how these conditions impact older adult driving.


Cerebrospinal fluid tau and ptau(181) increase with cortical amyloid deposition in cognitively normal individuals: implications for future clinical trials of Alzheimer's disease.

  • Anne M Fagan‎ et al.
  • EMBO molecular medicine‎
  • 2009‎

Alzheimer's disease (AD) pathology is estimated to develop many years before detectable cognitive decline. Fluid and imaging biomarkers may identify people in early symptomatic and even preclinical stages, possibly when potential treatments can best preserve cognitive function. We previously reported that cerebrospinal fluid (CSF) levels of amyloid-beta(42) (Abeta(42)) serve as an excellent marker for brain amyloid as detected by the amyloid tracer, Pittsburgh compound B (PIB). Using data from 189 cognitively normal participants, we now report a positive linear relationship between CSF tau/ptau(181) (primary constituents of neurofibrillary tangles) with the amount of cortical amyloid. We observe a strong inverse relationship of cortical PIB binding with CSF Abeta(42) but not for plasma Abeta species. Some individuals have low CSF Abeta(42) but no cortical PIB binding. Together, these data suggest that changes in brain Abeta(42) metabolism and amyloid formation are early pathogenic events in AD, and that significant disruptions in CSF tau metabolism likely occur after Abeta(42) initially aggregates and increases as amyloid accumulates. These findings have important implications for preclinical AD diagnosis and treatment.


Lack of association between acute stroke, post-stroke dementia, race, and β-amyloid status.

  • Lauren N Koenig‎ et al.
  • NeuroImage. Clinical‎
  • 2021‎

Stroke and Alzheimer disease share risk factors and often co-occur, and both have been reported to have a higher prevalence in African Americans as compared to non-Hispanic whites. However, their interaction has not been established. The objective of this study was to determine if preclinical Alzheimer disease is a risk factor for stroke and post-stroke dementia and whether racial differences moderate this relationship.


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