Oscar L Lopez

University of Pittsburgh, Pittsburgh, Pennsylvania, United States

Are you Oscar L Lopez?

Claim your profile

Publications (344)1828.64 Total impact

  • [show abstract] [hide abstract]
    ABSTRACT: IMPORTANCE Recent studies show that cerebral β-amyloid (Aβ) deposition is associated with blood pressure and measures of arterial stiffness in nondemented individuals. OBJECTIVE To examine the association between measures of arterial stiffness and change in Aβ deposition over time. DESIGN, SETTING, AND PARTICIPANTS Deposition of Aβ was determined in a longitudinal observational study of aging by positron emission tomography using the Pittsburgh compound B twice 2 years apart in 81 nondemented individuals 83 years and older. Arterial stiffness was measured with a noninvasive and automated waveform analyzer at the time closest to the second positron emission tomography scan. All measures were performed under standardized conditions. Pulse wave velocity (PWV) was measured in the central (carotid-femoral and heart-femoral PWV), peripheral (femoral-ankle PWV), and mixed (brachial-ankle PWV) vascular beds. MAIN OUTCOMES AND MEASURES The change in Aβ deposition over 2 years was calculated from the 81 individuals with repeat Aβ-positron emission tomography. RESULTS The proportion of Aβ-positive individuals increased from 48% at baseline to 75% at follow-up. Brachial-ankle PWV was significantly higher among Aβ-positive participants at baseline and follow-up. Femoral-ankle PWV was only higher among Aβ-positive participants at follow-up. Measures of central stiffness and blood pressure were not associated with Aβ status at baseline or follow-up, but central stiffness was associated with a change in Aβ deposition over time. Each standard deviation increase in central stiffness (carotid-femoral PWV, P = .001; heart-femoral PWV, P = .004) was linked with increases in Aβ deposition over 2 years. CONCLUSIONS AND RELEVANCE This study showed that Aβ deposition increases with age in nondemented individuals and that arterial stiffness is strongly associated with the progressive deposition of Aβ in the brain, especially in this age group. The association between Aβ deposition changes over time and generalized arterial stiffness indicated a relationship between the severity of subclinical vascular disease and progressive cerebral Aβ deposition.
    JAMA neurology. 03/2014;
  • [show abstract] [hide abstract]
    ABSTRACT: ABSTRACT Background: TAR DNA-binding protein 43 (TDP-43) has been identified as a major disease protein in frontotemporal lobar degeneration. More recently, TDP-43 proteinopathy has also been observed in Alzheimer's disease (AD) with a characteristic distribution of TDP-43 predominantly in the mesial temporal lobe, and to a lesser degree in the neocortical areas. AD subjects with psychotic symptoms (AD+P) represent a subgroup characterized by greater impairment of frontal cortex-dependent cognitive functions and more severe frontal cortical neuropathology. The aim of this study is to determine whether there is an association between TDP-43 pathology and AD+P. We hypothesized that TDP-43 pathology would be more frequent in AD+P than in AD without psychosis. Methods: We studied the presence and distribution of TDP-43 pathology by immunohistochemistry in the dentate gyrus (DG) and prefrontal cortex (FC) of postmortem brain specimens from 68 subjects with a primary neuropathologic diagnosis of AD as determined by the Neuropathology Core of the University of Pittsburgh Alzheimer's Disease Research Center. Results: Forty-five (66%) subjects were classified as AD+P. Fourteen (20.6%) subjects had TDP-43 pathology in DG, eight (11.8%) had TDP-43 pathology in FC, and six (8.8%) had TDP-43 pathology in both regions. TDP-43 in DG was not significantly associated with AD+P. However, TDP-43 in FC demonstrated a trend toward reduced likelihood of psychosis (p = 0.068). TDP-43 pathology in DG, but not FC, was significantly associated with greater age at death and longer duration of illness. Conclusions: Our findings indicate that there was no association between concomitant TDP-43 pathology in DG or FC and AD+P.
    International Psychogeriatrics 03/2014; · 2.19 Impact Factor
  • [show abstract] [hide abstract]
    ABSTRACT: Objectives To determine the association between interleukin-6 (IL-6), IL-6 soluble receptor (sR), and soluble tumor necrosis factor receptor-1 (sTNF-R1) and cognitive status in the oldest-old women.DesignTwenty-year longitudinal cohort study.SettingFour clinical sites in the United States.ParticipantsWomen from the Study of Osteoporotic Fractures (N = 905; mean age 88.3 ± 2.8 at cognitive status adjudication).MeasurementsAt Year 20, cognitive status was adjudicated as normal, mild cognitive impairment (MCI), or dementia. Inflammatory markers were measured from blood serum at Years 10 and 16 in a random sample of women.ResultsOver 10 years, 199 (22.0%) women developed MCI and 145 (16.0%) dementia. There were no significant associations between IL-6 or sTNF-R1 and cognitive status. High IL-6-sR (≥37,401.36 pg/mL, highest tertile) at Year 16 was significantly associated with lower risk of dementia (odds ratio (OR) = 0.54, 95% confidence interval (CI) = 0.30–0.97) than in women with lower levels (<37,401.36 pg/mL, lower two tertiles). Women with high IL-6-sR at both time points (OR = 0.39, 95% CI = 0.17–0.89) or who transitioned to a high level (OR = 0.35, 95% CI = 0.14–0.88) had a lower risk of dementia.Conclusion In this cohort of white, high-functioning oldest-old women, a consistently high or an increasing level of IL-6-sR was associated with lower risk of dementia. Compared with other studies of younger-old adults, this suggests that the effect of inflammation on dementia may differ in younger-old and the oldest-old individuals. Understanding these differences will be crucial in interpreting results from ongoing clinical trials and in targeting therapeutic strategies to the oldest-old individuals.
    Journal of the American Geriatrics Society 03/2014; · 3.98 Impact Factor
  • Source
    [show abstract] [hide abstract]
    ABSTRACT: Amyloid beta (Aβ) peptides are the major components of senile plaques, one of the main pathological hallmarks of Alzheimer disease (AD). However, Aβ peptides' functions are not fully understood and seem to be highly pleiotropic. We hypothesized that plasma Aβ peptides concentrations could be a suitable endophenotype for a genome-wide association study (GWAS) designed to (i) identify novel genetic factors involved in amyloid precursor protein metabolism and (ii) highlight relevant Aβ-related physiological and pathophysiological processes. Hence, we performed a genome-wide association meta-analysis of four studies totaling 3 528 healthy individuals of European descent and for whom plasma Aβ1-40 and Aβ1-42 peptides levels had been quantified. Although we did not observe any genome-wide significant locus, we identified 18 suggestive loci (P<1 × 10-5). Enrichment-pathway analyses revealed canonical pathways mainly involved in neuronal functions, for example, axonal guidance signaling. We also assessed the biological impact of the gene most strongly associated with plasma Aβ1-42 levels (cortexin 3, CTXN3) on APP metabolism in vitro and found that the gene protein was able to modulate Aβ1-42 secretion. In conclusion, our study results suggest that plasma Aβ peptides levels are valid endophenotypes in GWASs and can be used to characterize the metabolism and functions of APP and its metabolites.
    Molecular psychiatry 02/2014; · 15.05 Impact Factor
  • Oscar L Lopez, James T Becker
    American Journal of Psychiatry 02/2014; 171(2):227-8. · 14.72 Impact Factor
  • Source
    [show abstract] [hide abstract]
    ABSTRACT: The Australian National University AD Risk Index (ANU-ADRI, http://anuadri.anu.edu.au) is a self-report risk index developed using an evidence-based medicine approach to measure risk of Alzheimer's disease (AD). We aimed to evaluate the extent to which the ANU-ADRI can predict the risk of AD in older adults and to compare the ANU-ADRI to the dementia risk index developed from the Cardiovascular Risk Factors, Aging and Dementia (CAIDE) study for middle-aged cohorts. This study included three validation cohorts, i.e., the Rush Memory and Aging Study (MAP) (n = 903, age ≥53 years), the Kungsholmen Project (KP) (n = 905, age ≥75 years), and the Cardiovascular Health Cognition Study (CVHS) (n = 2496, age ≥65 years) that were each followed for dementia. Baseline data were collected on exposure to the 15 risk factors included in the ANU-ADRI of which MAP had 10, KP had 8 and CVHS had 9. Risk scores and C-statistics were computed for individual participants for the ANU-ADRI and the CAIDE index. For the ANU-ADRI using available data, the MAP study c-statistic was 0·637 (95% CI 0·596-0·678), for the KP study it was 0·740 (0·712-0·768) and for the CVHS it was 0·733 (0·691-0·776) for predicting AD. When a common set of risk and protective factors were used c-statistics were 0.689 (95% CI 0.650-0.727), 0.666 (0.628-0.704) and 0.734 (0.707-0.761) for MAP, KP and CVHS respectively. Results for CAIDE ranged from c-statistics of 0.488 (0.427-0.554) to 0.595 (0.565-0.625). A composite risk score derived from the ANU-ADRI weights including 8-10 risk or protective factors is a valid, self-report tool to identify those at risk of AD and dementia. The accuracy can be further improved in studies including more risk factors and younger cohorts with long-term follow-up.
    PLoS ONE 01/2014; 9(1):e86141. · 3.73 Impact Factor
  • Nature 01/2014; 505(7484):550-554. · 38.60 Impact Factor
  • [show abstract] [hide abstract]
    ABSTRACT: A rare amyloid precursor protein gene variant, A673T (rs63750847) was recently reported to protect against Alzheimer's disease and age-related cognitive decline among Icelanders and the same rare variant was observed also in Finnish, Norwegian, and Swedish populations. We investigated this variant in 1674 late-onset Alzheimer's disease cases and 2644 elderly control subjects, all North American Whites (US Whites). We did not observe any example of the A673T variant in our large sample. Our findings suggest that this rare variant could be specific to the individuals of the origin from the Nordic countries.
    Neurobiology of aging 01/2014; · 5.94 Impact Factor
  • [show abstract] [hide abstract]
    ABSTRACT: Background. Dementia and cardiovascular disease (CVD) are frequently comorbid. The presence of dementia may have an effect on how CVD is treated. Objective. To examine the effect of dementia on the use of four medications recommended for secondary prevention of ischemic heart disease (IHD): angiotensin-converting enzyme inhibitors, beta-blockers, lipid-lowering medications, and antiplatelet medications. Design. Retrospective analysis of data from the Cardiovascular Health Study: Cognition Study. Setting and Subjects. 1,087 older adults in four US states who had or developed IHD between 1989 and 1998. Methods. Generalized estimating equations to explore the association between dementia and the use of guideline-recommended medications for the secondary prevention of IHD. Results. The length of follow-up for the cohort was 8.7 years and 265 (24%) had or developed dementia during the study. Use of medications for the secondary prevention of IHD for patients with and without dementia increased during the study period. In models, subjects with dementia were not less likely to use any one particular class of medication but were less likely to use two or more classes of medications as a group (OR, 0.60; 95% CI, 0.36-0.99). Conclusions. Subjects with dementia used fewer guideline-recommended medications for the secondary prevention of IHD than those without dementia.
    Journal of aging research 01/2014; 2014:897671.
  • [show abstract] [hide abstract]
    ABSTRACT: Objective: Postmortem and genetic studies of clinically diagnosed Frontotemporal dementia (FTD) patients suggest that a number of clinically diagnosed FTD patients are actually "frontal variants" of Alzheimer's disease (fvAD). The purpose of this study was to evaluate this hypothesis by combining neuropathological data, genetic association studies of APOE, phenotype-APOE genotype correlations and discriminant analysis techniques. Methods: Neuropathological information on 24 FTD cases, genetic association studies of APOE (168 FTD, 3083 controls and 2528 AD), phenotype-genotype correlations and discriminant techniques (LDA, logistic regression and decision trees) were combined to identify fvAD patients within a clinical FTD series. Results: Four of 24 FTLD patients (16.6%) met criteria for definite AD. By comparing allele and genotype frequencies of APOE in controls, FTD and AD groups and by applying the Hardy-Weinberg equilibrium law (HWE), we inferred a consistent (17.2%) degree of AD contamination in clinical FTD. A penetrance analysis for APOE ε4 genotype in the FTD series identified 14 features for discrimination analysis. These features were compared between clinical AD (n=332) and clinical FTD series (n=168) and classifiers were constructed usinglinear discriminant analysis logistic regression or decision tree techniques. The classifier had 92.8% sensitivity to FTD and 93.4% sensitivity to AD relative to neuropathology (global AUC=0.939, p<0.001). We identified 30 potential fvAD cases (17.85%) in the clinical FTD sample. Conclusion: The APOE locus association in clinical FTD might be entirely explained by the existence of "hidden" fvAD cases within an FTD sample. The degree of fvAD contamination can be inferred from APOE genotypes.
    Current Alzheimer research 12/2013; · 4.97 Impact Factor
  • [show abstract] [hide abstract]
    ABSTRACT: Psychosis occurs in 40-60% of Alzheimer's disease (AD) subjects, is heritable, and indicates a more rapidly progressive disease phenotype. Neuroimaging and postmortem evidence support an exaggerated prefrontal cortical synaptic deficit in AD with psychosis. Microtubule-associated protein tau is a key mediator of amyloid-β-induced synaptotoxicity in AD, and differential mechanisms of progressive intraneuronal phospho-tau accumulation and interneuronal spread of tau aggregates have recently been described. We hypothesized that psychosis in AD would be associated with greater intraneuronal concentration of phospho-tau and greater spread of tau aggregates in prefrontal cortex. We therefore evaluated prefrontal cortex phospho-tau in a cohort of 45 AD cases with and without psychosis. Intraneuronal phospho-tau concentration was higher in subjects with psychosis, while a measure of phospho-tau spread, volume fraction, was not. Across groups both measures were associated with lower scores on the Mini-Mental State Examination and Digit Span Backwards test. These novel findings indicate that tau phosphorylation may be accelerated in AD with psychosis, indicating a more dynamic, exaggerated pathology in AD with psychosis.
    Journal of Alzheimer's disease: JAD 11/2013; · 4.17 Impact Factor
  • [show abstract] [hide abstract]
    ABSTRACT: To determine arterial stiffness and β-amyloid (Aβ) deposition in the brain of dementia-free older adults. We studied a cohort of 91 dementia-free participants aged 83-96 years. In 2009, participants completed brain MRI and PET imaging using Pittsburgh compound B (PiB; a marker of amyloid plaques in human brain). In 2011, we measured resting blood pressure (BP), mean arterial pressure (MAP), and arterial stiffness by pulse wave velocity (PWV) in the central, peripheral, and mixed (e.g., brachial ankle PWV [baPWV]) vascular beds, using a noninvasive and automated waveform analyzer. A total of 44/91 subjects were Aβ-positive on PET scan. Aβ deposition was associated with mixed PWV, systolic BP, and MAP. One SD increase in baPWV resulted in a 2-fold increase in the odds of being Aβ-positive (p = 0.007). High white matter hyperintensity (WMH) burden was associated with increased central PWV, systolic BP, and MAP. Compared to Aβ-negative individuals with low WMH burden, each SD increase in PWV was associated with a 2-fold to 4-fold increase in the odds of being Aβ-positive and having high WMH. Arterial stiffness was associated with Aβ plaque deposition in the brain, independent of BP and APOE ε4 allele. The associations differed by type of brain abnormality and vascular bed measured (e.g., WMH with central stiffness and Aβ deposition and mixed stiffness). Arterial stiffness was highest in individuals with both high Aβ deposition and WMH, which has been suggested to be a "double hit" contributing to the development of symptomatic dementia.
    Neurology 10/2013; · 8.25 Impact Factor
  • [show abstract] [hide abstract]
    ABSTRACT: Interventions directed at the mental health of family dementia caregivers may have limited impact when focused on caregivers who have provided care for years and report high burden levels. We sought to evaluate the mental health effects of problem-solving therapy (PST), designed for caregivers of individuals with a recent diagnosis of Mild Cognitive Impairment (MCI) or early dementia. Seventy-three (43 MCI and 30 early dementia) family caregivers were randomly assigned to receive PST or a comparison condition (nutritional education). Depression, anxiety, and problem-solving orientation were assessed at baseline and at 1, 3, 6, and 12 months post intervention. In general, the PST caregiver intervention was feasible and acceptable to family caregivers of older adults with a new cognitive diagnosis. Relative to nutritional education, PST led to significantly reduced depression symptoms, particularly among early dementia caregivers. PST also lowered caregivers' anxiety levels, and led to lessening of negative problem orientation. Enhanced problem-solving skills, learned early after a loved one's cognitive diagnosis (especially dementia), results in positive mental health outcomes among new family caregivers.
    The American journal of geriatric psychiatry: official journal of the American Association for Geriatric Psychiatry 10/2013; · 3.35 Impact Factor
  • [show abstract] [hide abstract]
    ABSTRACT: Cholesterol is implicated in the development of late-onset Alzheimer's disease (AD). We sought to determine the associations between beta amyloid (Aβ) plaque deposition in vivo using Pittsburgh compound B (PiB) and several indices of cholesterol homeostasis (i.e., total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, apolipoprotein E (ApoE), clusterin, oxysterol metabolites of cholesterol, and previously reported genes associated with late-onset AD) in 175 nondemented elderly subjects. High Aβ deposition was associated significantly with a lower Mini-Mental State Examination score (<27 points, p = 0.04), high systolic blood pressure (p = 0.04), carrying the apolipoprotein E epsilon 4 allele (p < 0.01), and lower plasma ApoE levels (p = 0.02), and variation in the ABCA7 (p = 0.02) and EPHA1 genes (p = 0.02). Cholesterol measures were not related to Aβ deposition in this cohort of nondemented elderly adults. However, plasma and genetic factors relating to cholesterol transport were associated with Aβ deposition in the brain. A better understanding of cholesterol transport mechanisms may lead to the design of potential targets for the prevention of Aβ deposition in the brain.
    Neurobiology of aging 10/2013; · 5.94 Impact Factor
  • Source
    Nature Genetics 10/2013; · 35.21 Impact Factor
  • [show abstract] [hide abstract]
    ABSTRACT: OBJECTIVE The authors sought to determine the effects of conventional and atypical antipsychotic use on time to nursing home admission and time to death in a group of outpatients with mild to moderate probable Alzheimer's disease. METHOD The authors examined time to nursing home admission and time to death in 957 patients with the diagnosis of probable Alzheimer's disease who had at least one follow-up evaluation (mean follow-up time, 4.3 years [SD=2.7]; range, 0.78-18.0 years) using Cox proportional hazard models adjusted for age, gender, education level, dementia severity, hypertension, diabetes mellitus, heart disease, extrapyramidal signs, depression, psychosis, aggression, agitation, and dementia medication use. RESULTS A total of 241 patients (25%) were exposed to antipsychotics at some time during follow-up (conventional, N=138; atypical, N=95; both, N=8). Nursing home admission (63% compared with 23%) and death (69% compared with 34%) were more frequent in individuals taking conventional than atypical antipsychotics. In a model that included demographic and cognitive variables, hypertension, diabetes mellitus, heart disease, incident strokes, and extrapyramidal signs, only conventional antipsychotic use was associated with time to nursing home admission. However, the association was no longer significant after adjustment for psychiatric symptoms. Psychosis was strongly associated with nursing home admission and time to death, but neither conventional nor atypical antipsychotics were associated with time to death. CONCLUSIONS The use of antipsychotic medications, both conventional and atypical, was not associated with either time to nursing home admission or time to death after adjustment for relevant covariates. Rather, it was the presence of psychiatric symptoms, including psychosis and agitation, that was linked to increased risk of institutionalization and death after adjustment for exposure to antipsychotics.
    American Journal of Psychiatry 07/2013; · 14.72 Impact Factor
  • [show abstract] [hide abstract]
    ABSTRACT: Objective White matter hyperintensity (WMH) confers increased mortality risk in patients with cardiovascular diseases. However, little is known about differences in survival times among adults 65 years and older who have WMH and live in the community. To characterize the factors that may reduce mortality risk in the presence of WMH, measures of race, sex, apolipoprotein E4, neuroimaging, and cardiometabolic, physiological, and psychosocial characteristics were examined, with a particular focus on information processing as measured by the Digit Symbol Substitution Test (DSST).Methods Cox proportional models were used to estimate mortality risks in a cohort of 3513 adults (74.8 years, 58% women, 84% white) with WMH (0-9 points), DSST (0-90 points), risk factor assessment in 1992 to 1994, and data on mortality and incident stroke in 2009 (median follow-up [range] = 14.2 [0.5-18.1] years).ResultsWMH predicted a 48% greater mortality risk (age-adjusted hazard ratio [HR; 95% confidence interval {CI}] for WMH >3 points = 1.48 [1.35-1.62]). This association was attenuated after adjustment for DSST (HR [CI] = 1.38 [1.27-1.51]) or lacunar infarcts (HR [CI] = 1.37 [1.25,1.50]) but not after adjustment for other factors. The interaction between DSST and WMH was significant (p = .011). In fully adjusted models stratified by WMH of 3 or higher, participants with DSST greater than or equal to median had a 34% lower mortality risk among those with WMH of 3 or higher (n = 532/1217) and a 28% lower mortality risk among those with WMH lower than 3 (n = 1364/2296), compared with participants with DSST less than median (HR [95% CI] = 0.66 [0.55-0.81] and 0.72 [0.62-0.83], respectively).ConclusionsWMH is associated with increased long-term mortality risk in community-dwelling adults 65 years and older. The increased risk is attenuated for those with higher DSST. Assessment of cognitive function with DSST may improve risk stratification of individuals with WMH.
    Psychosomatic Medicine 07/2013; · 4.08 Impact Factor
  • [show abstract] [hide abstract]
    ABSTRACT: To identify loci associated with Alzheimer disease, we conducted a three-stage analysis using existing genome-wide association studies (GWAS) and genotyping in a new sample. In Stage I, all suggestive single-nucleotide polymorphisms (at P<0.001) in a previously reported GWAS of seven independent studies (8082 Alzheimer's disease (AD) cases; 12 040 controls) were selected, and in Stage II these were examined in an in silico analysis within the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium GWAS (1367 cases and 12904 controls). Six novel signals reaching P<5 × 10-6 were genotyped in an independent Stage III sample (the Fundació ACE data set) of 2200 sporadic AD patients and 2301 controls. We identified a novel association with AD in the adenosine triphosphate (ATP) synthase, H+ transporting, mitochondrial F0 (ATP5H)/Potassium channel tetramerization domain-containing protein 2 (KCTD2) locus, which reached genome-wide significance in the combined discovery and genotyping sample (rs11870474, odds ratio (OR)=1.58, P=2.6 × 10-7 in discovery and OR=1.43, P=0.004 in Fundació ACE data set; combined OR=1.53, P=4.7 × 10-9). This ATP5H/KCTD2 locus has an important function in mitochondrial energy production and neuronal hyperpolarization during cellular stress conditions, such as hypoxia or glucose deprivation.
    Molecular psychiatry 07/2013; · 15.05 Impact Factor
  • Source
    [show abstract] [hide abstract]
    ABSTRACT: Clinico-pathological correlation studies and positron emission tomography amyloid imaging studies have shown that some individuals can tolerate substantial amounts of Alzheimer's pathology in their brains without experiencing dementia. Few details are known about the neuropathological phenotype of these unique cases that might prove relevant to understanding human resilience to Alzheimer's pathology. We conducted detailed quantitative histopathological and biochemical assessments on brains from non-demented individuals before death whose brains were free of substantial Alzheimer's pathology, non-demented individuals before death but whose post-mortem examination demonstrated significant amounts of Alzheimer's changes ('mismatches'), and demented Alzheimer's cases. Quantification of amyloid-β plaque burden, stereologically-based counts of neurofibrillary tangles, neurons and reactive glia, and morphological analyses of axons were performed in the multimodal association cortex lining the superior temporal sulcus. Levels of synaptic integrity markers, and soluble monomeric and multimeric amyloid-β and tau species were measured. Our results indicate that some individuals can accumulate equivalent loads of amyloid-β plaques and tangles to those found in demented Alzheimer's cases without experiencing dementia. Analyses revealed four main phenotypic differences among these two groups: (i) mismatches had striking preservation of neuron numbers, synaptic markers and axonal geometry compared to demented cases; (ii) demented cases had significantly higher burdens of fibrillar thioflavin-S-positive plaques and of oligomeric amyloid-β deposits reactive to conformer-specific antibody NAB61 than mismatches; (iii) strong and selective accumulation of hyperphosphorylated soluble tau multimers into the synaptic compartment was noted in demented cases compared with controls but not in mismatches; and (iv) the robust glial activation accompanying amyloid-β and tau pathologies in demented cases was remarkably reduced in mismatches. Further biochemical measurements of soluble amyloid-β species-monomers, dimers and higher molecular weight oligomers-in total brain homogenates and synaptoneurosomal preparations failed to demonstrate significant differences between mismatches and demented cases. Together, these data suggest that amyloid-β plaques and tangles do not inevitably result in neural system derangement and dementia in all individuals. We identified distinct phenotypic characteristics in the profile of brain fibrillar and soluble amyloid-β and tau accrual and in the glial response that discriminated demented and non-demented individuals with high loads of Alzheimer's pathology. Amyloid-β deposition in the form of fibrillar plaques and intimately related oligomeric amyloid-β assemblies, hyperphosphorylated soluble tau species localized in synapses, and glial activation emerged in this series as likely mediators of neurotoxicity and altered cognition, providing further insight into factors and pathways potentially involved in human susceptibility or resilience to Alzheimer's pathological changes.
    Brain 07/2013; · 9.92 Impact Factor
  • [show abstract] [hide abstract]
    ABSTRACT: OBJECTIVE: To determine whether a high prevalence (55%) of Aβ deposition in a cohort of individuals remaining dementia-free into their 9th and 10th decades is associated with cognitive decline prior to imaging. METHODS: A total of 194 participants (mean age 85.5 years, range 82-95) who completed the Ginkgo Evaluation of Memory Study (GEMS) and remained dementia-free subsequently completed Pittsburgh compound B-PET imaging. We examined cross-sectional associations between Aβ status and performance on a broad neuropsychological test battery completed at GEMS entry 7-9 years prior to neuroimaging. We also longitudinally examined cognition over annual evaluations using linear mixed models. RESULTS: At GEMS screening (2000-2002), participants who were Aβ-positive in 2009 had lower performance on the Stroop test (p < 0.01) and Raven's Progressive Matrices (p = 0.05), with trend level difference for Block Design (p = 0.07). Longitudinal analyses showed significant slope differences for immediate and delayed recall of the Rey-Osterrieth figure, semantic fluency, and Trail-Making Test parts A and B, indicating greater performance decline prior to neuroimaging for Aβ-positive relative to Aβ-negative participants (ps < 0.05). CONCLUSIONS: Highly prevalent Aβ deposition in oldest-older adults is associated with cognitive decline in visual memory, semantic fluency, and psychomotor speed beginning 7-9 years prior to neuroimaging. Mean differences in nonmemory domains, primarily executive functions, between Aβ-status groups may be detectable 7-9 years before neuroimaging.
    Neurology 03/2013; · 8.25 Impact Factor

Publication Stats

8k Citations
1,828.64 Total Impact Points

Institutions

  • 1990–2014
    • University of Pittsburgh
      • • Department of Neurology
      • • Department of Psychiatry
      • • Department of Pathology
      • • Department of Epidemiology
      • • School of Medicine
      • • Center for Alzheimer Disease Research
      Pittsburgh, Pennsylvania, United States
  • 2013
    • Wake Forest University
      • Department of Internal Medicine
      Winston-Salem, North Carolina, United States
  • 2008–2013
    • National Institute on Aging
      • Laboratory of Epidemiology, Demography and Biometry (LEDB)
      Baltimore, MD, United States
  • 2012
    • University Hospital Vall d'Hebron
      • Department of Psychiatry
      Barcino, Catalonia, Spain
    • Inha University Hospital
      Sinhyeon, South Gyeongsang, South Korea
    • University of Pennsylvania
      Philadelphia, Pennsylvania, United States
  • 2011
    • Carnegie Mellon University
      • Department of Statistics
      Pittsburgh, PA, United States
    • University of Texas Health Science Center at Houston
      • Brown Foundation Institute of Molecular Medicine
      Houston, TX, United States
    • Université du Québec à Montréal
      Montréal, Quebec, Canada
  • 2005–2011
    • University of California, Los Angeles
      • • Department of Neurology
      • • Laboratory of Neuro Imaging
      Los Angeles, CA, United States
    • University of Washington Seattle
      • Department of Medicine
      Seattle, WA, United States
  • 2010
    • National Institutes of Health
      • Laboratory of Epidemiology, Demography, and Biometry (LEDB)
      Bethesda, MD, United States
  • 2006–2010
    • University of California, San Francisco
      • Department of Psychiatry
      San Francisco, CA, United States
    • Institut Marqués, Spain, Barcelona
      Barcino, Catalonia, Spain
  • 2009
    • Boston Children's Hospital
      • Department of Radiology
      Boston, MA, United States
    • Beth Israel Medical Center
      New York City, New York, United States
  • 2007
    • Pennsylvania State University
      University Park, Maryland, United States
  • 2006–2007
    • University of California, Davis
      • • Center for Neuroscience
      • • Department of Neurology
      Davis, CA, United States
  • 2001
    • University of Malaga
      • Departamento de Medicina y Dermatología
      Málaga, Andalusia, Spain
  • 1999
    • Institut d'Assistència Sanitaria
      Girona, Catalonia, Spain
  • 1996
    • Western Psychiatric Institute and Clinic
      Pittsburgh, Pennsylvania, United States
  • 1994
    • New York State
      New York City, New York, United States
  • 1992
    • IMSA Amsterdam
      Amsterdamo, North Holland, Netherlands