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1.  Changes in Alcohol Intake and their Relation to Health Status over a 24 Year Follow-up Period in Community-Dwelling Older Adults 
Journal of the American Geriatrics Society  2013;61(8):10.1111/jgs.12366.
OBJECTIVES
To determine whether alcohol use changes over time in older adults, and whether alcohol intake is associated with common chronic diseases.
DESIGN
Longitudinal study spanning 24 years.
SETTING
Southern California community
PARTICIPANTS
1076 members of the Rancho Bernardo cohort, aged 50–89 years at baseline.
MEASUREMENTS
Participants completed two to six research visits at approximate four year intervals between 1984 and 2009. At each visit, participants completed standard questionnaires on alcohol use, chronic diseases, and behaviors. Mixed-effects linear models were used to examine changes in average weekly alcohol intake over time and in relation to health status.
RESULTS
Prevalence and frequency of alcohol use was high throughout the study with more than 60% of participants reporting weekly alcohol intake. The average amount consumed declined over time with advancing age, irrespective of the presence of any of the eight most common chronic diseases. Prevalence of drinking in excess of age and sex-specific low risk guidelines was high across all visits and did not vary by disease burden. At the final visit, 29% of participants drank in excess of low risk drinking guidelines; including 28% of those with hypertension and 31% of those with diabetes.
CONCLUSION
Prevalence and frequency of alcohol intake remained stable over a 24 year follow-up in this cohort of White, educated middle class older adults, although average amount consumed decreased over time with advanced age. Despite this decrease, a high proportion of older adults, including those with common chronic health conditions, drank in excess of current guidelines. Clinicians should provide more education on the importance of moderating alcohol intake in older patients.
doi:10.1111/jgs.12366
PMCID: PMC3819601  PMID: 23865905
aging; alcohol trajectories; drinking; hypertension; diabetes
2.  CETP polymorphisms associate with brain structure, atrophy rate, and Alzheimer’s disease risk in an APOE-dependent manner 
Brain imaging and behavior  2012;6(1):16-26.
Two alleles in cholesteryl ester transfer protein (CETP) gene polymorphisms have been disputably linked to enhanced cognition and decreased risk of Alzheimer’s disease (AD): the V and A alleles of I405V and C-629A. This study investigates whether these polymorphisms affect brain structure in 188 elderly controls and 318 AD or mild cognitive impairment (MCI) subjects from the Alzheimer’s Disease Neuroimaging Initiative cohort. Nominally signficant associations were dependent on APOE ε4 carrier status. In APOE ε4 carriers, the V and A alleles, both of which decrease CETP and increase HDL, associated with greater baseline cortical thickness and less 12-month atrophy in the medial temporal lobe. Conversely, in APOE ε4 non-carriers, the I allele, which increases CETP and decreases HDL, associated with greater baseline thickness, less atrophy and lower risk of dementia. These results suggest CETP may contribute to the genetic variability of brain structure and dementia susceptibility in an APOE-dependent manner.
doi:10.1007/s11682-011-9137-0
PMCID: PMC4305449  PMID: 21892657
Imaging genetics; Quantitative neuroimaging; CETP; Alzheimer’s disease; Dementia; APOE
3.  Enrichment and Stratification for Predementia Alzheimer Disease Clinical Trials 
PLoS ONE  2012;7(10):e47739.
The tau and amyloid pathobiological processes underlying Alzheimer disease (AD) progresses slowly over periods of decades before clinical manifestation as mild cognitive impairment (MCI), then more rapidly to dementia, and eventually to end-stage organ failure. The failure of clinical trials of candidate disease modifying therapies to slow disease progression in patients already diagnosed with early AD has led to increased interest in exploring the possibility of early intervention and prevention trials, targeting MCI and cognitively healthy (HC) populations. Here, we stratify MCI individuals based on cerebrospinal fluid (CSF) biomarkers and structural atrophy risk factors for the disease. We also stratify HC individuals into risk groups on the basis of CSF biomarkers for the two hallmark AD pathologies. Results show that the broad category of MCI can be decomposed into subsets of individuals with significantly different average regional atrophy rates. By thus selectively identifying individuals, combinations of these biomarkers and risk factors could enable significant reductions in sample size requirements for clinical trials of investigational AD-modifying therapies, and provide stratification mechanisms to more finely assess response to therapy. Power is sufficiently high that detecting efficacy in MCI cohorts should not be a limiting factor in AD therapeutics research. In contrast, we show that sample size estimates for clinical trials aimed at the preclinical stage of the disorder (HCs with evidence of AD pathology) are prohibitively large. Longer natural history studies are needed to inform design of trials aimed at the presymptomatic stage.
doi:10.1371/journal.pone.0047739
PMCID: PMC3474753  PMID: 23082203
4.  The role of clusterin in amyloid-β associated neurodegeneration 
JAMA neurology  2014;71(2):180-187.
Importance
Converging evidence indicates that clusterin, a chaperone glycoprotein, influences Alzheimer's disease (AD) neurodegeneration. However, the precise role of clusterin in AD pathogenesis is still not well understood.
Objective
To elucidate the relationship between clusterin, amyloid-β (Aβ), p-tau, and rate of brain atrophy over time among non-demented older individuals.
Design
A longitudinal cohort of cognitively normal older participants (HC) and individuals with mild cognitive impairment (MCI) assessed with baseline lumbar puncture and longitudinal structural MRI.
Setting
Research centers across the United States and Canada.
Participants
We examined 241 non-demented older individuals (91 participants with a Clinical Dementia Rating (CDR) of 0 and 150 individuals with a CDR of 0.5).
Main Outcome Measures
Using linear mixed effects models, we investigated interactions between CSF clusterin, CSF Aβ1-42 and CSF p-tau181p on atrophy rate of the entorhinal cortex and hippocampus.
Results
Across all participants, we found a significant interaction between CSF clusterin and CSF Aβ1-42 on entorhinal cortex atrophy rate, but not on hippocampal atrophy rate. CSF clusterin was associated with entorhinal cortex atrophy rate among CSF Aβ1-42 positive individuals, but not among CSF Aβ1-42 negative individuals. In secondary analyses, we found significant interactions between CSF Aβ1-42 and CSF clusterin and CSF Aβ1-42 and CSF p-tau181p on entorhinal cortex atrophy rate. We found similar results in subgroup analyses within the MCI and HC cohorts.
Conclusions and Relevance
In non-demented older individuals, Aβ-associated volume loss occurs in the presence of elevated clusterin. The effect of clusterin on Aβ-associated brain atrophy is not confounded or explained by p-tau. These findings implicate a potentially important role for clusterin in the earliest stages of the AD neurodegenerative process and suggest independent effects of clusterin and p-tau on Aβ-associated volume loss.
doi:10.1001/jamaneurol.2013.4560
PMCID: PMC4118752  PMID: 24378367
5.  Rates of Decline in Alzheimer Disease Decrease with Age 
PLoS ONE  2012;7(8):e42325.
Age is the strongest risk factor for sporadic Alzheimer disease (AD), yet the effects of age on rates of clinical decline and brain atrophy in AD have been largely unexplored. Here, we examined longitudinal rates of change as a function of baseline age for measures of clinical decline and structural MRI-based regional brain atrophy, in cohorts of AD, mild cognitive impairment (MCI), and cognitively healthy (HC) individuals aged 65 to 90 years (total n = 723). The effect of age was modeled using mixed effects linear regression. There was pronounced reduction in rates of clinical decline and atrophy with age for AD and MCI individuals, whereas HCs showed increased rates of clinical decline and atrophy with age. This resulted in convergence in rates of change for HCs and patients with advancing age for several measures. Baseline cerebrospinal fluid densities of AD-relevant proteins, Aβ1–42, tau, and phospho-tau181p (ptau), showed a similar pattern of convergence with advanced age across cohorts, particularly for ptau. In contrast, baseline clinical measures did not differ by age, indicating uniformity of clinical severity at baseline. These results imply that the phenotypic expression of AD is relatively mild in individuals older than approximately 85 years, and this may affect the ability to distinguish AD from normal aging in the very old. Our findings show that inclusion of older individuals in clinical trials will substantially reduce the power to detect disease-modifying therapeutic effects, leading to dramatic increases in required clinical trial sample sizes with age of study sample.
doi:10.1371/journal.pone.0042325
PMCID: PMC3410919  PMID: 22876315
6.  APOE ε4 does not modulate amyloid-β associated neurodegeneration in preclinical Alzheimer’s disease 
Background and Purpose
Among cognitively normal older individuals, the relationship between the two hallmark proteins of Alzheimer’s disease (AD), amyloid-β (Aβ) and tau, the ε4 allele of apolipoprotein E (APOE ε4), and neurodegeneration is not well understood.
Materials and Methods
We examined 107 cognitively healthy older adults who underwent longitudinal MR imaging and baseline lumbar puncture. Within the same linear mixed effects model, we concurrently investigated main and interactive effects between APOE ε4 genotype and CSF Aβ1-42, CSF phospo-tau (p-tau181p) and CSF Aβ1-42, and APOE ε4 genotype and CSF p-tau181p on entorhinal cortex atrophy rate. We also examined the relationship between APOE ε4, CSF p-tau181p, and CSF Aβ1-42 on atrophy rate of other AD-vulnerable neuroanatomic regions.
Results
The full model with main and interactive effects demonstrated a significant interaction only between CSF p-tau181p and CSF Aβ1-42 on entorhinal cortex atrophy rate indicating elevated atrophy over time in individuals with increased CSF p-tau181p and decreased CSF Aβ1-42. APOE ε4 genotype was significantly and specifically associated with CSF Aβ1-42. However, the interaction between APOE ε4 genotype and either CSF Aβ1-42 or CSF p-tau181p on entorhinal cortex atrophy rate was not significant. We found similar results in other AD-vulnerable regions.
Conclusions
Based upon our findings and building upon prior experimental evidence, we propose a model of the pathogenic cascade underlying preclinical AD where APOE ε4 primarily influences Alzheimer’s pathology via Aβ-related mechanisms and in turn, Aβ-associated neurodegeneration occurs only in the presence of phospho-tau.
doi:10.3174/ajnr.A3267
PMCID: PMC4041629  PMID: 22976236
preclinical AD; neurodegeneration; p-tau; amyloid-β; APOE
7.  White Matter Tracts Associated with Set-Shifting in Healthy Aging 
Neuropsychologia  2009;47(13):2835-2842.
Attentional set-shifting ability, commonly assessed with the Trail Making Test (TMT), decreases with increasing age in adults. Since set-shifting performance relies on activity in widespread brain regions, deterioration of the white matter tracts that connect these regions may underlie the age-related decrease in performance. We used an automated fiber tracking method to investigate the relationship between white matter integrity in several cortical association tracts and TMT performance in a sample of 24 healthy adults, 21 – 80 years. Diffusion tensor images were used to compute average fractional anisotropy (FA) for five cortical association tracts, the corpus callosum (CC), and the corticospinal tract (CST), which served as a control. Results showed that advancing age was associated with declines in set-shifting performance and with decreased FA in the CC and in association tracts that connect frontal cortex to more posterior brain regions, including the inferior fronto-occipital fasciculus (IFOF), uncinate fasciculus (UF), and superior longitudinal fasciculus (SLF). Declines in average FA in these tracts, and in average FA of the right inferior longitudinal fasciculus (ILF), were associated with increased time to completion on the set-shifting subtask of the TMT but not with the simple sequencing subtask. FA values in these tracts were strong mediators of the effect of age on set-shifting performance. Automated tractography methods can enhance our understanding of the fiber systems involved in performance of specific cognitive tasks and of the functional consequences of age-related changes in those systems.
doi:10.1016/j.neuropsychologia.2009.06.008
PMCID: PMC2749901  PMID: 19540862
8.  Higher Rates of Decline for Women and APOE ε4 Carriers 
Background and Purpose
Age and the ε4 allele of apolipoprotein E (APOE ε4) are well-known risk factors for Alzheimer disease (AD), but whether female sex is also a risk factor remains controversial. It is also unclear how these risk factors affect rates of structural brain and clinical decline across the spectrum of preclinical to clinical AD. Our objective is to estimate the effects of APOE ε4 and sex on age-specific rates of morphometric and clinical decline in late onset sporadic AD.
Materials and Methods
Using linear mixed effects models, we examined the effect of age, APOE ε4, and sex on longitudinal brain atrophy and clinical decline among cognitively normal older individuals, and individuals with mild cognitive impairment and AD (total = 688). We also evaluated the relationship between these effects and cerebrospinal fluid (CSF) biomarkers of AD pathology.
Results
APOE ε4 significantly accelerated rates of decline, and women in all cohorts experienced higher rates of decline than men. The magnitude of the sex effect on rates of decline were as large as those of ε4, yet their relationship to measures of CSF biomarkers were weaker.
Conclusion
These results indicate that in addition to APOE ε4 status, diagnostic and therapeutic strategies should take into account the effect of female sex on the Alzheimer disease process.
doi:10.3174/ajnr.A3601
PMCID: PMC3894062  PMID: 23828104
9.  Higher Education is Not Associated with Greater Cortical Thickness in Brain Areas Related to Literacy or Intelligence in Normal Aging or Mild Cognitive Impairment 
Education may reduce risk of dementia through passive reserve, by increasing neural substrate. We tested the hypotheses that education is associated with thicker cortex and reduced rates of atrophy in brain regions related to literacy and intellectual ability. Healthy older adults and those with mild cognitive impairment were categorized into High (≥18 yrs) and Low (≤13 yrs) education groups. Higher education was associated with thinner cortices in several areas, but one-year atrophy rates in these areas did not differ by education group. These results do not support a passive reserve model in which early life education protects against dementia by increasing cortical thickness. Connectivity and synaptic efficiency, or other lifestyle factors may more directly reflect cognitive reserve.
doi:10.1080/13803395.2012.702733
PMCID: PMC3488147  PMID: 22905705
Brain reserve; cortical thickness; education; hippocampal volume; literacy; Mild Cognitive Impairment (MCI); aging
10.  Heart fatty acid binding protein and Aβ-associated Alzheimer’s neurodegeneration 
Background
Epidemiological and molecular findings suggest a relationship between Alzheimer’s disease (AD) and dyslipidemia, although the nature of this association is not well understood.
Results
Using linear mixed effects models, we investigated the relationship between CSF levels of heart fatty acid binding protein (HFABP), a lipid binding protein involved with fatty acid metabolism and lipid transport, amyloid-β (Aβ), phospho-tau, and longitudinal MRI-based measures of brain atrophy among 295 non-demented and demented older individuals. Across all participants, we found a significant association of CSF HFABP with longitudinal atrophy of the entorhinal cortex and other AD-vulnerable neuroanatomic regions. However, we found that the relationship between CSF HABP and brain atrophy was significant only among those with low CSF Aβ1–42 and occurred irrespective of phospho-tau181p status.
Conclusions
Our findings indicate that Aβ-associated volume loss occurs in the presence of elevated HFABP irrespective of phospho-tau. This implicates a potentially important role for fatty acid binding proteins in Alzheimer’s disease neurodegeneration.
doi:10.1186/1750-1326-8-39
PMCID: PMC3850652  PMID: 24088526
Alzheimer’s disease; Fatty acids; Lipids; Amyloid; Tau; Brain atrophy
11.  Unbiased Comparison of Sample Size Estimates From Longitudinal Structural Measures in ADNI 
Human brain mapping  2011;33(11):2586-2602.
Structural changes in neuroanatomical subregions can be measured using serial magnetic resonance imaging scans, and provide powerful biomarkers for detecting and monitoring Alzheimer's disease. The Alzheimer's Disease Neuroimaging Initiative (ADNI) has made a large database of longitudinal scans available, with one of its primary goals being to explore the utility of structural change measures for assessing treatment effects in clinical trials of putative disease-modifying therapies. Several ADNI-funded research laboratories have calculated such measures from the ADNI database and made their results publicly available. Here, using sample size estimates, we present a comparative analysis of the overall results that come from the application of each laboratory's extensive processing stream to the ADNI database. Obtaining accurate measures of change requires correcting for potential bias due to the measurement methods themselves; and obtaining realistic sample size estimates for treatment response, based on longitudinal imaging measures from natural history studies such as ADNI, requires calibrating measured change in patient cohorts with respect to longitudinal anatomical changes inherent to normal aging. We present results showing that significant longitudinal change is present in healthy control subjects who test negative for amyloid-β pathology. Therefore, sample size estimates as commonly reported from power calculations based on total structural change in patients, rather than change in patients relative to change in healthy controls, are likely to be unrealistically low for treatments targeting amyloid-related pathology. Of all the measures publicly available in ADNI, thinning of the entorhinal cortex quantified with the Quarc methodology provides the most powerful change biomarker.
doi:10.1002/hbm.21386
PMCID: PMC3782292  PMID: 21830259
MCI; bias; biomarker; clinical trial; disease-specific effect; amyloid; aging; Alzheimer's disease; entorhinal cortex; hippocampus
12.  Long-Term and Within-Day Variability of Working Memory Performance and EEG in Individuals 
Clinical Neurophysiology  2011;123(7):1291-1299.
Objective
Assess individual-subject long-term and within-day variability of a combined behavioral and EEG test of working memory.
Methods
EEGs were recorded from 16 adults performing n-back working memory tasks, with 10 tested in morning and afternoon sessions over several years. Participants were also tested after ingesting non-prescription medications or recreational substances. Performance and EEG measures were analyzed to derive an Overall score and three constituent sub-scores characterizing changes in performance, cortical activation, and alertness from each individual’s baseline. Long-term and within-day variability were determined for each score; medication effects were assessed by reference to each individual’s normal day-to-day variability.
Results
Over the several year period, the mean Overall score and sub-scores were approximately zero with standard deviations less than one. Overall scores were lower and their variability higher in afternoon relative to morning sessions. At the group level, alcohol, diphenhydramine and marijuana produced significant effects, but there were large individual differences.
Conclusions
Objective working memory measures incorporating performance and EEG are stable over time and sensitive at the level of individual subjects to interventions that affect neurocognitive function.
Significance
With further research these measures may be suitable for use in individualized medical care by providing a sensitive assessment of incipient illness and response to treatment.
doi:10.1016/j.clinph.2011.11.004
PMCID: PMC3325329  PMID: 22154302
working memory; EEG; long-term variability; circadian variability; drug effects; individual differences
13.  Metabolic Syndrome and 16-year Cognitive Decline in Community-Dwelling Older Adults 
Annals of Epidemiology  2012;22(5):310-317.
PURPOSE
To determine whether metabolic syndrome is associated with accelerated cognitive decline in community-dwelling older adults.
METHODS
Longitudinal study of 993 adults (mean 66.8 ± 8.7 years) from the Rancho Bernardo Study. Metabolic syndrome components, defined by 2001 NCEP-ATP III criteria, were measured in 1984–87. Cognitive function was first assessed in 1988–92. Cognitive assessments were repeated approximately every four years, for a maximum 16-year follow-up. Mixed-effects models examined longitudinal rate of cognitive decline by metabolic syndrome status, controlling for factors plausibly associated with cognitive function (diabetes, inflammation).
RESULTS
Metabolic syndrome was more common in men than women (14% vs. 9%, p=0.01). In women, metabolic syndrome was associated with greater executive function and long term memory decline. These associations did not differ by inflammatory biomarker levels. Diabetes did not alter the association of metabolic syndrome with long-term recall but modified the association with executive function: metabolic syndrome was associated with accelerated executive function decline in diabetic women only. Metabolic syndrome was not related to rate of decline on any cognitive measure in men.
CONCLUSIONS
Metabolic syndrome was a risk factor for accelerated cognitive decline, but only in women. Prevention of metabolic syndrome may aid in maintenance of cognitive function with age.
doi:10.1016/j.annepidem.2011.12.003
PMCID: PMC3338905  PMID: 22285865
Aging; cognition; inflammation; diabetes; memory; executive function
14.  Age-related changes in the neurophysiology of language in adults: Relationship to regional cortical thinning and white matter microstructure 
Although reading skill remains relatively stable with advancing age in humans, neurophysiological measures suggest potential reductions in efficiency of lexical information processing. It is unclear whether these age-related changes are secondary to decreases in regional cortical thickness and/or microstructure of fiber tracts essential to language. Magnetoencephalography, volumetric MRI, and diffusion tensor imaging were performed in 10 young (18–33 years) and 10 middle-aged (42–64 years) human individuals to evaluate the spatiotemporal dynamics and structural correlates of age-related changes in lexical-semantic processing. Increasing age was associated with reduced activity in left temporal lobe regions from 250–350ms and in left inferior prefrontal cortex from 350–450ms (i.e., N400). Hierarchical regression indicated that age no longer predicted left inferior prefrontal activity after cortical thickness and fractional anisotropy (FA) of the uncinate fasciculus (UF) were considered. Interestingly, FA of the UF was a stronger predictor of the N400 response than cortical thickness. Age-related reductions in left-lateralization of language responses were observed between 250–350ms, and were associated with left temporal thinning and frontotemporal FA reductions. N400 reductions were not associated with poorer task performance. Rather, increasing age was associated with reduction in the left prefrontal N400, which in turn was also associated with slower response time. These results reveal that changes in the neurophysiology of language occur by middle age and appear to be partially mediated by structural brain loss. These neurophysiological changes may reflect an adaptive process that ensues as communication between left perisylvian regions declines.
doi:10.1523/JNEUROSCI.0136-12.2012
PMCID: PMC3475615  PMID: 22933802
N400; magnetoencepholography; language; semantic processing; cortical thickness; diffusion tensor imaging
15.  Biomarkers for the clinical evaluation of the cognitively impaired elderly: amyloid is not enough 
Imaging in medicine  2012;4(3):343-357.
The number of elderly patients seeking clinical treatment for memory problems will rise sharply in coming years as our population ages. These patients present a challenge for diagnosis and prognosis since cognitive problems in older patients can arise from many etiologies, some of which are curable. With the development of clinically available biomarkers for detecting Alzheimer’s disease pathology in living patients, evaluation of cognitively impaired elderly patients is about to undergo a major paradigm shift. This article describes the two classes of biomarkers available for assessing Alzheimer’s disease risk: those that indicate presence of amyloid pathology and those that provide evidence of neuronal injury and neurodegeneration. We argue that, currently, incorporation of biomarkers of neurodegeneration can help in patient prognosis whereas tests for amyloid, if used in isolation, have potential for harm. Amyloid tests are clinically useful only when evidence suggests progressive cognitive decline or neurodegeneration.
doi:10.2217/iim.12.27
PMCID: PMC3573528  PMID: 23420460
Alzheimer’s disease; amyloid imaging; biomarker; florbetapir; MCI; mild cognitive impairment; MRI; PET
16.  Relationship between regional atrophy rates and cognitive decline in mild cognitive impairment 
Neurobiology of aging  2010;33(2):242-253.
We investigated the relationship between regional atrophy rates and 2-year cognitive decline in a large cohort of patients with mild cognitive impairment (MCI; N=103) and healthy controls (N=90). Longitudinal MRIs were analyzed using high-throughput image analysis procedures. Atrophy rates were derived by calculating percent cortical volume loss between baseline and 24-month scans. Step-wise regressions were performed to investigate the contribution of atrophy rates to language, memory, and executive functioning decline, controlling for age, gender, baseline performances, and disease progression. In MCI, left temporal lobe atrophy rates were associated with naming decline, whereas bilateral temporal, left frontal, and left anterior cingulate atrophy rates were associated with semantic fluency decline. Left entorhinal atrophy rate was associated with memory decline and bilateral frontal atrophy rates were associated with executive function decline. These data provide evidence that regional atrophy rates in MCI contribute to domain-specific cognitive decline, which appears to be partially independent of disease progression. MRI measures of regional atrophy can provide valuable information for understanding the neural basis of cognitive impairment in MCI.
doi:10.1016/j.neurobiolaging.2010.03.015
PMCID: PMC2923665  PMID: 20471718
cortical thinning; cognitive deficits; naming; semantic fluency; verbal memory; executive dysfunction
17.  Amyloid-β associated volume loss occurs only in the presence of phospho-tau 
Annals of Neurology  2011;70(4):657-661.
The relationship between neurodegeneration and the two hallmark proteins of Alzheimer's disease, amyloid-β (Aβ) and tau, is still unclear. Here, we examined 286 non-demented participants (107 cognitively normal older adults and 179 memory impaired individuals) who underwent longitudinal MR imaging and lumbar puncture. Using mixed effects models, we investigated the relationship between longitudinal entorhinal cortex atrophy, CSF p-tau181p and CSF Aβ1-42. We found a significant relationship between elevated entorhinal cortex atrophy and decreased CSF Aβ1-42 only with elevated CSF p-tau181p. Our findings indicate that Aβ-associated volume loss occurs only in the presence of phospho-tauin humans at risk for dementia.
doi:10.1002/ana.22509
PMCID: PMC3368003  PMID: 22002658
18.  Sex Differences in the Association of Framingham Cardiac Risk Score with Cognitive Decline in Community-Dwelling Elders without Clinical Heart Disease 
Psychosomatic medicine  2011;73(8):683-689.
Objective
To investigate a possible link between cardiovascular risk factors and age-related cognitive decline, the association of the 1998 Framingham Cardiac Risk Score (FCRS) with the trajectory of cognitive function test (CFT) performance over 18 years was examined in adults 50 years and older without clinical heart disease at baseline.
Methods
Participants were 985 men and women who had assessments of cognitive function at three to four year intervals. The association of FCRS category with CFT score trajectory was examined using mixed effect models stratified by sex and controlling for age, education, and number of repeat cognitive assessments.
Results
At baseline, median FCRS corresponded to a 14% risk of a CHD event within 10 years for men and a 8% risk for women; 31% of men and 6% of women were at high (>20%) risk. In longitudinal analyses, women with FCRS risk >7% had a higher rate of decline on tests of verbal fluency (p’s <.05) and long term recall (p’s <.01) compared to low risk women; modest, but significant (p’s <.05), differences in the trajectory of MMSE and Trails B scores were also apparent. FCRS category was not related to the rate of decline in CFT performance in men.
Conclusions
For older women, very low levels of CHD risk were associated with preservation of cognitive function over 10 years, suggesting that maintenance of cardiovascular health may slow cognitive decline. The minimal association in men, who were at higher baseline risk, may be due to selective attrition of men with greater cognitive decline.
doi:10.1097/PSY.0b013e31822f9089
PMCID: PMC3188670  PMID: 21949428
aging; cardiovascular; cognitive function; prospective
19.  Amyloid-β associated clinical decline occurs only in the presence of elevated p-tau 
Archives of neurology  2012;69(6):709-713.
Objective
To elucidate the relationship between the two hallmark proteins of Alzheimer's disease (AD), amyloid-β (Aβ) and tau, and clinical decline over time among cognitively normal older individuals.
Design
A longitudinal cohort of clinically and cognitively normal older individuals assessed with baseline lumbar puncture and longitudinal clinical assessments.
Setting
Research centers across the United States and Canada.
Patients
We examined one hundred seven participants with a Clinical Dementia Rating (CDR) of 0 at baseline examination.
Main Outcome Measures
Using linear mixed effects models, we investigated the relationship between CSF p-tau181p, CSF Aβ1-42 and clinical decline as assessed using longitudinal change in global CDR, CDR-Sum of Boxes (CDR-SB), and the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog).
Results
We found a significant relationship between decreased CSF Aβ1-42 and longitudinal change in global CDR, CDR-SB, and ADAS-cog in individuals with elevated CSF p-tau181p. In the absence of CSF p-tau181p, the effect of CSF Aβ1-42 on longitudinal clinical decline was not significantly different from zero.
Conclusions
In cognitively normal older individuals, Aβ-associated clinical decline over a mean of three years may occur only in the presence of ongoing, “downstream” neurodegeneration.
doi:10.1001/archneurol.2011.3354
PMCID: PMC3423526  PMID: 22529247
20.  A cognitive and neurophysiological test of change from an individual’s baseline 
Objective
An automated cognitive neurophysiological test is presented that characterizes how an individual was affected by a drug or treatment. The test calculates sub-scores for working memory task performance, cortical activation, and alertness, and combines the sub-scores into an overall score.
Methods
The test was applied in a double-blind, placebo-controlled study of alcohol, caffeine, diphenhydramine, and sleep deprivation in 16 healthy adults.
Results
The between- and within-day variability of the sub-scores and overall scores for placebo were all near zero, suggesting that the scores are stable. All treatments affected the overall score, while differential effects on sub-scores highlighted the added value of EEG measures.
Conclusions
The test is sensitive to relatively mild alterations in cognitive function. Its automation makes it suitable for use in large-scale clinical trials.
Significance
By combining task performance with EEG brain function measures, the test may prove to have better sensitivity and specificity in detecting changes due to drugs or other treatments than comparable neuropsychological test batteries that do not directly measure brain function signals.
doi:10.1016/j.clinph.2010.06.010
PMCID: PMC2976786  PMID: 20619727
brain function; cognition; EEG; working memory; clinical trials
21.  A Method to Combine Cognitive and Neurophysiological Assessments of the Elderly 
Background
The development of better treatments for brain diseases of the elderly will necessitate more sensitive and efficient means of repeatedly assessing an individual's neurocognitive status.
Aim
To illustrate the development of an assessment combining episodic memory and working memory tasks with simultaneous electroencephalography and evoked potential (EP) brain function measures.
Methods
Data from matched groups of elderly subjects with mildly impaired episodic verbal memory on neuropsychological tests and those with no objective signs of impairment were used for scale development. An exploratory multivariate divergence analysis selected task performance and neurophysiological variables that best recognized impairment. Discriminant validity was then initially assessed on separate impaired and unimpaired groups.
Results
Decreased response accuracy and parietal late positive component EP amplitude in the episodic memory task best characterized impaired subjects. Sensitivity in recognizing impairment in the validation analysis was 89% with 79% specificity (area under the curve = 0.94). Retest reliability was 0.89 for the unimpaired and 0.74 for the impaired validation groups.
Conclusion
These promising initial results suggest that with further refinement and testing, an assessment combining cognitive task performance with simultaneous neurofunctional measures could eventually provide an important benefit for clinicians and researchers.
doi:10.1159/000322108
PMCID: PMC3019365  PMID: 21109739
Mild cognitive impairment; Neuropsychology; Neurophysiology; Neurocognitive; Electroencephalography; Evoked potential; Episodic memory; Working memory
22.  Quantitative structural MRI for early detection of Alzheimer’s disease 
Expert review of neurotherapeutics  2010;10(11):1675-1688.
Alzheimer’s disease (AD) is a common progressive neurodegenerative disorder that is not currently diagnosed until a patient reaches the stage of dementia. There is a pressing need to identify AD at an earlier stage, so that treatment, when available, can begin early. Quantitative structural MRI is sensitive to the neurodegeneration that occurs in mild and preclinical AD, and is predictive of decline to dementia in individuals with mild cognitive impairment. Objective evidence of ongoing brain atrophy will be critical for risk/benefit decisions once potentially aggressive, disease-modifying treatments become available. Recent advances have paved the way for the use of quantitative structural MRI in clinical practice, and initial clinical use has been promising. However, further experience with these measures in the relatively unselected patient populations seen in clinical practice is needed to complete translation of the recent enormous advances in scientific knowledge of AD into the clinical realm.
doi:10.1586/ern.10.162
PMCID: PMC3182103  PMID: 20977326
amyloid; biomarker; CSF; mild cognitive impairment; prodromal Alzheimer’s disease; quantitative neuroimaging; volumetric imaging
23.  Brain Atrophy in Healthy Aging Is Related to CSF Levels of Aβ1-42 
Cerebral Cortex (New York, NY)  2010;20(9):2069-2079.
Reduced levels of β-amyloid1-42 (Aβ1-42) and increased levels of tau proteins in the cerebrospinal fluid (CSF) are found in Alzheimer’s disease (AD), likely reflecting Aβ deposition in plaques and neuronal and axonal damage. It is not known whether these biomarkers are associated with brain atrophy also in healthy aging. We tested the relationship between CSF levels of Aβ1-42 and tau (total tau and tau phosphorylated at threonine 181) proteins and 1-year brain atrophy in 71 cognitively normal elderly individuals. Results showed that under a certain threshold value, levels of Aβ1-42 correlated highly with 1-year change in a wide range of brain areas. The strongest relationships were not found in the regions most vulnerable early in AD. Above the threshold level, Aβ1-42 was not related to brain changes, but significant volume reductions as well as ventricular expansion were still seen. It is concluded that Aβ1-42 correlates with brain atrophy and ventricular expansion in a subgroup of cognitively normal elderly individuals but that reductions independent of CSF levels of Aβ1-42 is common. Further research and follow-up examinations over several years are needed to test whether degenerative pathology will eventually develop in the group of cognitively normal elderly individuals with low levels of Aβ1-42.
doi:10.1093/cercor/bhp279
PMCID: PMC3025722  PMID: 20051356
aging; amyloid; cerebral cortex; CSF biomarkers; MRI
24.  Level of Executive Function Influences Verbal Memory in Amnestic Mild Cognitive Impairment and Predicts Prefrontal and Posterior Cingulate Thickness 
Cerebral Cortex (New York, NY)  2009;20(6):1305-1313.
This study aims to investigate the relationship between executive function and verbal memory and to explore the underlying neuroanatomical correlates in 358 individuals with amnestic mild cognitive impairment (MCI) and 222 healthy controls (HCs). The MCI participants were divided into 2 groups (high vs. low) based on executive function task performance. Results demonstrated that although both MCI groups were impaired on all memory measures relative to HCs, MCI individuals with higher executive function (HEF) demonstrated better verbal memory performance than those with lower executive function (LEF), particularly on measures of learning. The 2 MCI groups did not differ in mesial temporal morphometric measures, but the MCI LEF group showed significant thinning in dorsolateral prefrontal and posterior cingulate cortices bilaterally compared with the MCI HEF and HCs. Further, thickness in numerous regions of frontal cortex, and bilateral posterior cingulate, was significantly associated with memory performance in all MCI participants above and beyond the contribution of the mesial temporal regions known to be associated with episodic memory. Overall, these results demonstrate the importance of evaluating executive function in individuals with MCI to predict involvement of brain areas beyond the mesial temporal lobe.
doi:10.1093/cercor/bhp192
PMCID: PMC2912652  PMID: 19776343
Alzheimer's disease; clinical subtypes; cognition; longitudinal outcome; morphometry
25.  Brain substrates of learning and retention in mild cognitive impairment diagnosis and progression to Alzheimerâs disease 
Neuropsychologia  2009;48(5):1237-1247.
Understanding the underlying qualitative features of memory deficits in mild cognitive impairment (MCI) can provide critical information for early detection of Alzheimerâs disease (AD). This study sought to investigate the utility of both learning and retention measures in (a) the diagnosis of MCI, (b) predicting progression to AD, and (c) examining their underlying brain morphometric correlates. A total of 607 participants were assigned to three MCI groups (high learning-low retention; low learning-high retention; low learning-low retention) and one control group (high learning-high retention) based on scores above or below a 1.5 SD cutoff on learning and retention indices of the Rey Auditory Verbal Learning Test. Our results demonstrated that MCI individuals with predominantly a learning deficit showed a widespread pattern of gray matter loss at baseline, whereas individuals with a retention deficit showed more focal gray matter loss. Moreover, either learning or retention measures provided good predictive value for longitudinal clinical outcome over two years, although impaired learning had modestly better predictive power than impaired retention. As expected, impairments in both measures provided the best predictive power. Thus, the conventional practice of relying solely on the use of delayed recall or retention measures in studies of amnestic MCI misses an important subset of older adults at risk of developing AD. Overall, our results highlight the importance of including learning measures in addition to retention measures when making a diagnosis of MCI and for predicting clinical outcome.
doi:10.1016/j.neuropsychologia.2009.12.024
PMCID: PMC2851550  PMID: 20034503
Amnestic MCI; Early detection; Episodic memory; Longitudinal outcome; MR morphometry

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