Richard J O'Brien

Duke University, Durham, North Carolina, United States

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Publications (106)931.15 Total impact

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    ABSTRACT: The pathophysiological processes underlying Alzheimer's disease (AD) are hypothesized to begin years to decades before clinical symptom onset, while individuals are still cognitively normal. Although many studies have examined the effect of biomarkers of amyloid pathology on measures of cognitive performance, less is known about the effect of tau pathology on cognitive performance. The present study examined the association between cerebrospinal fluid (CSF) biomarkers of AD pathology (amyloid, total tau (t-tau), and phosphorylated tau (p-tau)) and cognition in a large sample of cognitively normal middle-aged and older adults. Associations were examined with multivariate regressions, in which either amyloid and t-tau or amyloid and p-tau were included as simultaneous predictors of cognitive performance. Cognitive performance was measured with three composite scores assessing working memory, verbal episodic memory, and visuospatial episodic memory. In their respective models, CSF measures of both t-tau and p-tau were associated with the visuospatial episodic memory composite score (p < .001 and p=.02, respectively), but not with the other measures of cognition. In contrast, CSF amyloid was not significantly associated with cognitive performance, raising the possibility that measures of tau pathology have a more direct relationship with cognition in cognitively normal individuals. These results also suggest that tau pathology may have effects on visuospatial episodic memory during preclinical AD that precede alterations in other cognitive domains.
    Full-text · Article · Sep 2015 · Neuropsychologia
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    ABSTRACT: Understanding how midlife risk factors influence age at onset (AAO) of Alzheimer's disease (AD) may provide clues to delay disease expression. Although midlife adiposity predicts increased incidence of AD, it is unclear whether it affects AAO and severity of Alzheimer's neuropathology. Using a prospective population-based cohort, Baltimore Longitudinal Study of Aging (BLSA), this study aims to examine the relationships between midlife body mass index (BMI) and (1) AAO of AD (2) severity of Alzheimer's neuropathology and (3) fibrillar brain amyloid deposition during aging. We analyzed data on 1394 cognitively normal individuals at baseline (8643 visits; average follow-up interval 13.9 years), among whom 142 participants developed incident AD. In two subsamples of BLSA, 191 participants underwent autopsy and neuropathological assessment, and 75 non-demented individuals underwent brain amyloid imaging. Midlife adiposity was derived from BMI data at 50 years of age. We find that each unit increase in midlife BMI predicts earlier onset of AD by 6.7 months (P=0.013). Higher midlife BMI was associated with greater Braak neurofibrillary but not CERAD (Consortium to Establish a Registry for Alzheimer's Disease) neuritic plaque scores at autopsy overall. Associations between midlife BMI and brain amyloid burden approached statistical significance. Thus, higher midlife BMI was also associated with greater fibrillar amyloid measured by global mean cortical distribution volume ratio (P=0.075) and within the precuneus (left, P=0.061; right, P=0.079). In conclusion, midlife overweight predicts earlier onset of AD and greater burden of Alzheimer's neuropathology. A healthy BMI at midlife may delay the onset of AD.Molecular Psychiatry advance online publication, 1 September 2015; doi:10.1038/mp.2015.129.
    No preview · Article · Sep 2015 · Molecular Psychiatry
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    ABSTRACT: Data from both humans and animal models suggest that most recovery from motor impairment after stroke occurs in a sensitive period that lasts only weeks and is mediated, in part, by an increased responsiveness to training. Here, we used a mouse model of focal cortical stroke to test 2 hypotheses. First, we investigated whether responsiveness to training decreases over time after stroke. Second, we tested whether fluoxetine, which can influence synaptic plasticity and stroke recovery, can prolong the period over which large training-related gains can be elicited after stroke. Mice were trained to perform a skilled prehension task to an asymptotic level of performance after which they underwent stroke induction in the caudal forelimb area. The mice were then retrained after a 1- or 7-day delay with and without fluoxetine. Recovery of prehension after a caudal forelimb area stroke was complete if training was initiated 1 day after stroke but incomplete if it was delayed by 7 days. In contrast, if fluoxetine was administered at 24 hours after stroke, then complete recovery of prehension was observed even with the 7-day training delay. Fluoxetine seemed to mediate its beneficial effect by reducing inhibitory interneuron expression in intact premotor cortex rather than through effects on infarct volume or cell death. There is a gradient of diminishing responsiveness to motor training over the first week after stroke. Fluoxetine can overcome this gradient and maintain maximal levels of responsiveness to training even 7 days after stroke. © 2015 American Heart Association, Inc.
    No preview · Article · Aug 2015 · Stroke

  • No preview · Article · Jul 2015
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    ABSTRACT: Older adults with intact cognition before death and substantial Alzheimer disease (AD) lesions at autopsy have been termed "asymptomatic AD subjects" (ASYMAD). We previously reported hypertrophy of neuronal cell bodies, nuclei, and nucleoli in the CA1 of the hippocampus (CA1), anterior cingulate gyrus, posterior cingulate gyrus, and primary visual cortex of ASYMAD versus age-matched Control and mild cognitive impairment (MCI) subjects. However, it was unclear whether the neuronal hypertrophy could be attributed to differences in the severity of AD pathology. Here, we performed quantitative analyses of the severity of β-amyloid (Aβ) and phosphorylated tau (tau) loads in the brains of ASYMAD, Control, MCI, and AD subjects (n = 15 per group) from the Baltimore Longitudinal Study of Aging. Tissue sections from CA1, anterior cingulate gyrus, posterior cingulate gyrus, and primary visual cortex were immunostained for Aβ and tau; the respective loads were assessed using unbiased stereology by measuring the fractional areas of immunoreactivity for each protein in each region. The ASYMAD and MCI groups did not differ in Aβ and tau loads. These data confirm that ASYMAD and MCI subjects have comparable loads of insoluble Aβ and tau in regions vulnerable to AD pathology despite divergent cognitive outcomes. These findings imply that cognitive impairment in AD may be caused or modulated by factors other than insoluble forms of Aβ and tau.
    Full-text · Article · Mar 2014
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    ABSTRACT: This paper examines morphometry of MRI biomarkers derived from the network of temporal lobe structures including the amygdala, entorhinal cortex and hippocampus in subjects with preclinical Alzheimer's disease (AD). Based on template-centered population analysis, it is demonstrated that the structural markers of the amygdala, hippocampus and entorhinal cortex are statistically significantly different between controls and those with preclinical AD. Entorhinal cortex is the most strongly significant based on the linear effects model (p < .0001) for the high-dimensional vertex- and Laplacian-based markers corresponding to localized atrophy. The hippocampus also shows significant localized high-dimensional change (p < .0025) and the amygdala demonstrates more global change signaled by the strength of the low-dimensional volume markers. The analysis of the three structures also demonstrates that the volume measures are only weakly discriminating between preclinical and control groups, with the average atrophy rates of the volume of the entorhinal cortex higher than amygdala and hippocampus. The entorhinal cortex thickness also exhibits an atrophy rate nearly a factor of two higher in the ApoE4 positive group relative to the ApoE4 negative group providing weak discrimination between the two groups.
    Preview · Article · Dec 2013 · Clinical neuroimaging
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    ABSTRACT: To develop targeted intervention strategies for the treatment of Alzheimer's disease, we first need to identify early markers of brain changes that occur before the onset of cognitive impairment. Here, we examine changes in resting-state brain function in humans from the Baltimore Longitudinal Study of Aging. We compared longitudinal changes in regional cerebral blood flow (rCBF), assessed by (15)O-water PET, over a mean 7 year period between participants who eventually developed cognitive impairment (n = 22) and those who remained cognitively normal (n = 99). Annual PET assessments began an average of 11 years before the onset of cognitive impairment in the subsequently impaired group, so all participants were cognitively normal during the scanning interval. A voxel-based mixed model analysis was used to compare groups with and without subsequent impairment. Participants with subsequent impairment showed significantly greater longitudinal rCBF increases in orbitofrontal, medial frontal, and anterior cingulate regions, and greater longitudinal decreases in parietal, temporal, and thalamic regions compared with those who maintained cognitive health. These changes were linear in nature and were not influenced by longitudinal changes in regional tissue volume. Although all participants were cognitively normal during the scanning interval, most of the accelerated rCBF changes seen in the subsequently impaired group occurred within regions thought to be critical for the maintenance of cognitive function. These changes also occurred within regions that show early accumulation of pathology in Alzheimer's disease, suggesting that there may be a connection between early pathologic change and early changes in brain function.
    No preview · Article · Nov 2013 · The Journal of Neuroscience : The Official Journal of the Society for Neuroscience
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    ABSTRACT: The aging-suppressor gene klotho encodes a single-pass transmembrane protein that is predominantly secreted by the choroid plexus of the brain and in the kidney. Klotho-deficient mice develop multiple aging phenotypes, including impaired cognition. Klotho concentrations have not been described in the CSF of humans. We measured klotho in the CSF of 20 older adults with Alzheimer's disease and in 20 older and 20 younger adults with normal cognition. In 10 adults, aged 38-87 years, CSF klotho measurements were made at baseline and every 6hours up to 18-30hours later. Mean (95% Confidence Interval [C.I.]) CSF klotho in men versus women were 899 (814, 983) and 716 (632, 801) pg/mL, respectively (P=0.002). Mean (95%C.I.) CSF klotho in older adults with and without Alzheimer's disease were 664 (603, 725) and 776 (705, 828) pg/mL, respectively (P=0.02), adjusting for sex. Mean (95%C.I.) klotho in older versus younger adults were 766 (658, 874) and 992 (884, 1100) pg/mL, respectively (P=0.005), adjusting for sex. In the longitudinal study of CSF klotho, no significant circadian fluctuations were found in CSF klotho levels. This study suggests that CSF klotho concentrations are lower in females compared with males, in Alzheimer's disease, and in older versus younger adults.
    No preview · Article · Nov 2013 · Neuroscience Letters
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    ABSTRACT: This study evaluated longitudinal CSF biomarker measures collected when participants were cognitively normal to determine the magnitude and time course of biomarker changes before the onset of clinical symptoms in subjects with mild cognitive impairment (MCI). Longitudinal CSF collection and cognitive assessments were performed on a cohort of 265 participants who were cognitively normal at their baseline assessment and subsequently developed MCI or dementia. CSF β-amyloid 1-42 (Aβ1-42), total tau (t-tau), and phosphorylated tau (p-tau) were determined longitudinally. Consensus diagnoses were completed annually. Cox regression analyses were performed, with baseline CSF values and time-dependent rate of change in CSF values as covariates (adjusted by baseline age, race, and education), in relation to time to onset of mild cognitive symptoms. The mean time from baseline to onset of mild cognitive symptoms was 5.41 years. Increased risk of progressing from normal cognition to onset of clinical symptoms was associated with baseline values of Aβ1-42, p-tau, and the ratios of p-tau/Aβ1-42 and t-tau/Aβ1-42 (p < 0.002). Additionally, the rate of change in the ratios of t-tau/Aβ1-42 (p < 0.004) and p-tau/Aβ1-42 (p < 0.02) was greater among participants who were subsequently diagnosed with MCI. Baseline differences in CSF values were predictive of clinical symptoms that were a harbinger of a diagnosis of MCI more than 5 years before symptom onset, and continue to show longitudinal changes as cognitive symptoms develop, demonstrating that baseline and longitudinal changes in CSF biomarkers are evident during the preclinical phase of Alzheimer disease.
    No preview · Article · Oct 2013 · Neurology
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    ABSTRACT: The APOE ε4 allele increases the risk of developing Alzheimer's disease, whereas the APOE ε2 allele reduces risk. We examined whether cognitive reserve (CR), as measured by an index consisting of education, reading, and vocabulary, modifies these associations. CR was measured at baseline in 257 cognitively normal individuals (mean age 57.2 years) who have been followed for up to 17 years (mean follow-up = 9.2 years). Cox regression models showed that CR and APOE ε4 independently affected the risk of progressing from normal cognition to onset of clinical symptoms: CR reduced risk by about 50% in both ε4 carriers and non-carriers, while ε4 increased risk by about 150%. In contrast, APOE ε2 interacted with CR, such that CR was more protective in ε2 carriers than non-carriers. This suggests that individuals with an ε2 genotype may disproportionately benefit from lifetime experiences that enhance cognition.
    Full-text · Article · Aug 2013 · Cognitive neuroscience
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    ABSTRACT: The levels of β-amyloid (Aβ) and phosphorylated tau (p-tau), as measured in cerebrospinal fluid, have been associated with the risk of progressing from normal cognition to onset of clinical symptoms during preclinical Alzheimer's disease. We examined whether cognitive reserve (CR) modifies this association. Cerebrospinal fluid was obtained at baseline from 239 participants (mean age, 57.2 years) who had been followed for up to 17 years with clinical and cognitive assessments (mean follow-up, 8 years). A composite score based on the National Adult Reading Test, vocabulary, and years of education at baseline was used as an index of CR. Cox regression models showed that the increased risk of progressing from normal cognition to symptom onset was associated with lower CR, lower baseline Aβ, and higher baseline p-tau. There was no interaction between CR and Aβ, suggesting that the protective effects of higher CR are equivalent across the observed range of amyloid levels. In contrast, both tau and p-tau interacted with CR, indicating that CR was more protective at lower levels of tau and p-tau.
    Full-text · Article · Aug 2013 · Neurobiology of aging
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    ABSTRACT: IMPORTANCE Peripheral glucose homeostasis has been implicated in the pathogenesis of Alzheimer disease (AD). The relationship among diabetes mellitus, insulin, and AD is an important area of investigation. However, whether cognitive impairment seen in those with diabetes is mediated by excess pathological features of AD or other related abnormalities, such as vascular disease, remains unclear. OBJECTIVE To investigate the association between serial measures of glucose intolerance and insulin resistance and in vivo brain β-amyloid burden, measured with carbon 11-labeled Pittsburgh Compound B (11C-PiB), and AD pathology at autopsy. DESIGN Scores calculated from the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) and Braak criteria were correlated with measures of hyperglycemia, hyperinsulinemia, glucose intolerance, and insulin resistance in 197 participants who underwent autopsy after death and who had undergone 2 or more oral glucose tolerance tests (OGTT) using grouped analyses and a continuous mixed-models analysis. The same measures of glucose intolerance and insulin resistance were also correlated with brain 11C-PiB retention in an additional 53 living subjects from the Baltimore Longitudinal Study of Aging neuroimaging study. SETTING Prospective, serially assessed cohort of community-dwelling subjects. PARTICIPANTS Cohort 1 consisted of 197 participants enrolled in the Baltimore Longitudinal Study of Aging who had 2 or more OGTTs during life and a complete brain autopsy after death. Cohort 2 consisted of 53 living subjects who had 2 or more OGTTs and underwent brain 11C-PiB positron emission tomography. EXPOSURES Autopsy and 11C-PiB positron emission tomography. MAIN OUTCOMES AND MEASURES The correlation of brain markers of AD, including CERAD score, Braak score, and 11C-PiB retention, with serum markers of glucose homeostasis using grouped and continuous mixed-models analyses. RESULTS We found no significant correlations between measures of brain AD pathology or 11C-PiB β-amyloid load and glucose intolerance or insulin resistance in subjects who had a mean (SD) of 6.4 (3.2) OGTTs during 22.1 (8.0) years of follow-up. Thirty subjects with frank diabetes mellitus who received medications also had AD pathology scores that were similar to those of the cohort as a whole. CONCLUSIONS AND RELEVANCE In this prospective cohort with multiple assessments of glucose intolerance and insulin resistance, measures of glucose and insulin homeostasis are not associated with AD pathology and likely play little role in AD pathogenesis. Long-term therapeutic trials are important to elucidate this issue.
    No preview · Article · Jul 2013
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    ABSTRACT: Background: We examine whether broad factors and specific facets of personality are associated with increased risk of incident Alzheimer's disease (AD) in a long-run longitudinal study and a meta-analysis of published studies. Methods: Participants (n = 1671) were monitored for up to 22 years from a baseline personality assessment. The meta-analysis pooled results from up to five prospective studies (n = 5054). Results: Individuals with scores in the top quartile of neuroticism (hazard ratio = 3.1; 95% confidence interval = 1.6-6.0) or the lowest quartile of conscientiousness (hazard ratio = 3.3; 95% confidence interval = 1.4-7.4) had a threefold increased risk of incident AD. Among the components of these traits, self-discipline and depression had the strongest associations with incident AD. The meta-analysis confirmed the associations of neuroticism (P = 2 × 10(-9)) and conscientiousness (P = 2 × 10(-6)), along with weaker effects for openness and agreeableness (P < .05). Conclusions: The current study and meta-analysis indicate that personality traits are associated with increased risk of AD, with effect sizes similar to those of well-established clinical and lifestyle risk factors.
    Full-text · Article · May 2013 · Alzheimer's & dementia: the journal of the Alzheimer's Association
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    ABSTRACT: We investigated whether individuals with impaired glucose tolerance (IGT) in midlife subsequently show regionally specific longitudinal changes in regional cerebral blood flow (rCBF) relative to those with normal glucose tolerance (NGT). Sixty-four cognitively normal participants in the neuroimaging substudy of the Baltimore Longitudinal Study of Aging underwent serial (15)O-water positron emission tomography scans (age at first scan, 69.6 ± 7.5 years) and oral glucose tolerance tests 12 years earlier (age at first oral glucose tolerance test, 57.2 ± 11.1 years). Using voxel-based analysis, we compared changes in rCBF over an 8-year period between 15 participants with IGT in midlife and 49 with NGT. Significant differences were observed in longitudinal change in rCBF between the IGT and NGT groups. The predominant pattern was greater rCBF decline in the IGT group in the frontal, parietal, and temporal cortices. Some brain regions in the frontal and temporal cortices also showed greater longitudinal increments in rCBF in the IGT group. Our findings suggest that IGT in midlife is associated with subsequent longitudinal changes in brain function during aging even in cognitively normal older individuals.
    No preview · Article · Apr 2013 · Neurobiology of aging
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    ABSTRACT: To confirm associations of apolipoprotein E (ApoE) ε4 carrier status, sex, and time-dependent cognitive status with mortality risk and to investigate these joint effects of these associations in a cohort of community-dwelling U.S. adults. Prospective cohort study. The Baltimore Longitudinal Study of Aging (BLSA). Of 3,047 BLSA participants aged 17 to 98 at first visit (60.1% male), 1,704 with complete ApoE genotype data were included, of whom 1,461 aged 50 and older with one or more visits were eligible. Time to death from all, cardiovascular, and noncardiovascular causes. Probability of survival was lower for ApoE ε4 carriers, particularly those who were older. A Cox proportional hazards model for all-cause mortality yielded a hazard ratio (HR) for ApoE ε4 carrier versus noncarriers of 1.31 (95% confidence interval (CI) = 1.02-1.68). This association was also found for cardiovascular mortality. Time-dependent all-cause dementia (HR = 1.73, 95% CI = 1.33-2.26) and mild cognitive impairment (HR = 1.95, 95% CI = 1.42-2.67) increased all-cause mortality risk, associations that were also detected for noncardiovascular mortality. When individuals were free of cognitive impairment, a dose-response relationship with ε4 alleles was found for all-cause mortality (HR = 1.40, 95% CI = 0.94-2.07 for 1 ε4; HR = 2.61, 95% CI = 1.12-6.07 for 2 ε4). After onset of Alzheimer's disease (AD), carrying only one ε4 allele resulted in an approximately 77% greater all-cause mortality risk than in noncarriers. ApoE ε4 carrier status increased all-cause mortality risk in men and interacted with time-dependent AD to increase the risk of this outcome (relative excess risk due to interaction = 2.15, 95% CI = 1.22-3.07). ApoE ε4 carrier status was found to increase all-cause and cardiovascular mortality risks and interacted with sex and time-dependent AD status to affect all-cause mortality.
    Full-text · Article · Apr 2013 · Journal of the American Geriatrics Society
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    ABSTRACT: Background and purpose: Motor recovery after ischemic stroke in primary motor cortex is thought to occur in part through training-enhanced reorganization in undamaged premotor areas, enabled by reductions in cortical inhibition. Here we used a mouse model of focal cortical stroke and a double-lesion approach to test the idea that a medial premotor area (medial agranular cortex [AGm]) reorganizes to mediate recovery of prehension, and that this reorganization is associated with a reduction in inhibitory interneuron markers. Methods: C57Bl/6 mice were trained to perform a skilled prehension task to an asymptotic level of performance after which they underwent photocoagulation-induced stroke in the caudal forelimb area. The mice were then retrained and inhibitory interneuron immunofluorescence was assessed in prechosen, anatomically defined neocortical areas. Mice then underwent a second photocoagulation-induced stroke in AGm. Results: Focal caudal forelimb area stroke led to a decrement in skilled prehension. Training-associated recovery of prehension was associated with a reduction in parvalbumin, calretinin, and calbindin expression in AGm. Subsequent infarction of AGm led to reinstatement of the original deficit. Conclusions: We conclude that with training, AGm can reorganize after a focal motor stroke and serve as a new control area for prehension. Reduced inhibition may represent a marker for reorganization or it is necessary for reorganization to occur. Our mouse model, with all of the attendant genetic benefits, may allow us to determine at the cellular and molecular levels how behavioral training and endogenous plasticity interact to mediate recovery.
    No preview · Article · Jan 2013 · Stroke
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    ABSTRACT: Background and purpose: Although vascular risk factors have been implicated in the development of all-cause dementia and Alzheimer disease (AD), few studies have examined the association between subclinical atherosclerosis and prospective risk of dementia. Methods: Participants from the Baltimore Longitudinal Study of Aging (n=364; age, 60-95 years; median age, 73; 60% male; 82% white) underwent initial carotid atherosclerosis assessment and subsequently were assessed for dementia and AD annually for up to 14 years (median, 7.0). Cox proportional hazards models predicting all-cause dementia and AD were adjusted for age, sex, race, education, blood pressure, cholesterol, cardiovascular disease, diabetes mellitus, and smoking. Results: Sixty participants developed dementia, with 53 diagnosed as AD. Raw rates of future dementia and AD among individuals initially in the upper quintile of carotid intimal medial thickness or with bilateral carotid plaque were generally double the rates of individuals with intimal medial thickness in the lower quintiles or no plaque at baseline. Adjusted proportional hazards models revealed >2.5-fold increased risk of dementia and AD among individuals in the upper quintile of carotid intimal medial thickness, and approximately 2.0-fold increased risk of dementia among individuals with bilateral plaque. Conclusions: Multiple measures of carotid atherosclerosis are associated with prospective risk of dementia. Individuals in the upper quintile of carotid intimal medial thickness or bilateral carotid plaque were at greatest risk. These findings underscore the possibility that early intervention to reduce atherosclerosis may help delay or prevent onset of dementia and AD.
    Preview · Article · Oct 2012 · Stroke
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    ABSTRACT: Alzheimer's disease (AD) neuropathology is found at autopsy in approximately 30% of cognitively normal older individuals. We examined whether personality traits are associated with such resilience to clinical dementia in individuals with AD neuropathology. Broad factors and specific facets of personality were assessed up to 28 years (mean 11 ± 7 years) before onset of dementia and up to 30 years (mean 15 ± 7 years) before death in a cohort (n = 111) evaluated for AD neuropathology at autopsy. Individuals with higher baseline scores on vulnerability to stress, anxiety, and depression (neuroticism: odds ratio, 2.0; 95% confidence interval, 1.2-3.5), or lower scores on order and competence (conscientiousness: odds ratio, 0.4; 95% confidence interval, 0.2-0.9) were less likely to remain asymptomatic in the presence of AD neuropathology. Neuroticism (r = 0.26), low agreeableness (r = -0.34), and some facets were also significantly associated with advanced stages of neurofibrillary tangles, but the associations between personality traits and risk of clinical dementia were mostly unchanged by controlling for the extent of neurofibrillary tangles and Aβ neuritic plaques. In sum, a resilient personality profile is associated with lower risk or delay of clinical dementia even in persons with AD neuropathology.
    Full-text · Article · Oct 2012 · Neurobiology of aging
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    ABSTRACT: Although magnetic resonance imaging (MRI)-detected white matter disease has been correlated with cognitive decline in the elderly individuals, it is unclear whether white matter disease is primarily responsible for the cognitive deterioration or whether another process is common to both white matter disease and dementia. We examined the relationship between Alzheimer-type brain pathology at autopsy and MRI-detected cerebral white matter disease in 50 participants from the Baltimore Longitudinal Study of Aging Autopsy Program, a prospective study of aging that includes detailed cognitive assessments. White matter disease was quantitated in pre- and postmortem MRI scans using the Cardiovascular Health Study (CHS) criteria in a blinded manner. We found that several measures of Alzheimer's disease (AD) pathology, including the Consortium to Establish a Registry for Alzheimer's Disease score, Braak score, and a composite AD pathology score, along with hypertension, were significantly associated with CHS white matter score using univariate and multivariate ordinal regression. In contrast, amyloid angiopathy was not independently associated with CHS score. Although a clinical diagnosis of dementia was associated with CHS score in univariate analysis, the association disappeared after accounting for AD pathology. AD pathology at autopsy is associated with MRI-detected cerebral white matter disease. This relationship may explain, in part, the association between cerebral white matter disease and cognitive decline in the elderly individuals.
    No preview · Article · Oct 2012 · Alzheimer's & dementia: the journal of the Alzheimer's Association
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    Abhay Moghekar · Richard J O'Brien
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    ABSTRACT: The development of late-onset Alzheimer's disease is believed to be influenced by genetic, socioeconomic, and lifestyle factors. Recently, converging research in animal and human studies has found that beta-amyloid (Aβ) levels in cerebrospinal fluid are modulated by sleep-wake cycles. This raises the possibility that chronic sleep loss causes brain amyloid accumulation over time and leads to the development of Alzheimer's disease. The observation that circadian rhythm modulates Aβ levels has not yet been replicated by other groups, and subject selection and methodologies are potential explanations for this. While acute suppression of sleep may raise Aβ levels, it is not known whether chronic sleep loss has the same effect. It is conceivable that altered circadian rhythms are a manifestation of a disrupted sleep network because of preclinical disease, as has been observed in other neurodegenerative disorders. The findings that circadian variation in Aβ levels in cerebrospinal fluid is a direct result of sleep-wake cycles and that altering normal rhythms increases the risk for brain amyloid accumulation need to be replicated in larger cohorts. Prospective studies are needed to decipher whether circadian rhythm dysfunction is a cause, or a result of, amyloid accumulation.
    Preview · Article · Aug 2012 · Alzheimer's Research and Therapy

Publication Stats

9k Citations
931.15 Total Impact Points

Institutions

  • 2015
    • Duke University
      Durham, North Carolina, United States
  • 1997-2014
    • Johns Hopkins University
      • • Department of Neurology
      • • Department of Pathology
      • • Department of Medicine
      Baltimore, Maryland, United States
  • 2001-2013
    • Johns Hopkins Medicine
      • Department of Neurology
      Baltimore, Maryland, United States
  • 2005-2009
    • Foundation for Innovative New Diagnostics
      Genève, Geneva, Switzerland
  • 2008
    • World Health Organization WHO
      Genève, Geneva, Switzerland
  • 2006
    • McGill University
      • Department of Epidemiology, Biostatistics and Occupational Health
      Montréal, Quebec, Canada
  • 2002
    • Global Alliance for TB Drug Development
      New York, New York, United States
  • 2000
    • Georgetown University
      Washington, Washington, D.C., United States
    • Unité Inserm U1077
      Caen, Lower Normandy, France
  • 1998-1999
    • Howard Hughes Medical Institute
      Ashburn, Virginia, United States
  • 1987-1992
    • Centers for Disease Control and Prevention
      • Division of Tuberculosis Elimination
      Атланта, Michigan, United States