Randomized Trial of Marine n-3 Polyunsaturated Fatty Acids for the Prevention of Cerebral Small Vessel Disease and Inflammation in Aging (PUFA Trial): Rationale, Design and Baseline Results.

Vascular risk factors for age-related cognitive decline are significant, and their management may ultimately prove the most successful strategy for reducing risk and sustaining cognitive health. This randomized, double-blinded, placebo-controlled trial with parallel group allocation to either marine n-3 polyunsaturated fatty acids (n-3 PUFA) or soybean oil placebo assesses the effects on the total volume of accumulation in cerebral white matter hyperintensities (WMH), a potentially modifiable neurovascular component of age-related cognitive decline. Total WMH accumulation over 3 years is the primary endpoint. The safety and efficacy of n-3 PUFA is evaluated in older adults with significant WMH and suboptimum plasma n-3 PUFA as inclusion criteria. One hundred and two non-demented older adults were enrolled with a mean age of 81.1 (±4.4) years, WMH of 19.4 (±16.1) cm³, and a plasma n-3 PUFA of 86.64 (±29.21) µg/mL. 61% were female, 28% were apolipoprotein E epsilon 4 carriers, and the mean mini-mental state exam (MMSE) was 27.9 (±1.7). This trial provides an initial evaluation of n-3 PUFA effects on WMH, a reproducible and valid risk biomarker for cognitive decline, as well as on inflammatory biomarkers thought to play a role in WMH accumulation. We present the baseline results and operational experience of enriching a study population on advanced age, blood n-3 PUFA, and magnetic resonance imaging (MRI) derived WMH with biomarker outcomes (WMH, inflammation markers) in a dementia prevention paradigm.

Current limitations of neuropsychological tests and assessment procedures.

OBJECTIVE: Neuropsychological tests are used for a wide variety of purposes: assessing basic cognitive abilities or disabilities; determining cognitive patterns associated with brain disorders or injury; exploring brain-behavior relationships; and, in some cases, addressing psycho-legal issues. This paper will focus on the limitations of current neuropsychological tests for these purposes. METHOD: Current limits of neuropsychological tests and assessment procedures are reviewed and recommendations for improvements are made. The relationship between the conceptual basis of neuropsychological tests and modern theories of brain functional organization is discussed. In addition, psycho-legal concerns are briefly outlined. CONCLUSIONS: Existing tests and techniques can be improved. Normative data for some neuropsychological tests are based on small samples or have limited validity or reliability data. A variety of neuropsychological tests are available but particular cognitive domains are underrepresented, particularly those involving high-level cognitive skills and social skills. Progress is being made in the availability of tests in multiple languages, but the restricted range of languages and cultural influences demands more attention. Standard test procedures often deviate from real-world activities. In this modern age, some tests have become too familiar because of the Internet. Understanding of complex neural networks activated by cognitive tasks is only beginning to be appreciated. Procedures for determining psycho-legal issues need improvements in some areas.

Pathologies Underlying Longitudinal Cognitive Decline in the Oldest Old.

BACKGROUND: Understanding contributions of different brain pathologies to domain-specific cognitive trajectories in the oldest old is crucial to guide future intervention studies. METHODS: Two-hundred-twenty Oregon Alzheimer's Disease Center research participants who were cognitively intact at entry were followed on average for 7.3 years with annual neuropsychological testing until death (mean age, 93.7 y) and autopsy. Mixed effects models examined the relationship between trajectories in memory, verbal fluency, and mini-mental state examination (MMSE) and pathology (neurofibrillary tangles, neuritic plaques, gross infarcts, hippocampal sclerosis, Lewy bodies, APOE genotype, age at death, and years of education). The association between the MMSE trajectory and pathologic variables were examined using a Poisson model with MMSE errors as outcomes given the nonlinear distribution of MMSE scores. RESULTS: Memory trajectory was associated with the APOε4 allele (P=0.006). Verbal fluency trajectory was associated with gross infarcts (P=0.008). MMSE trajectory was associated with high Braak scores (P=0.03), gross infarcts (P<0.0001), hippocampal sclerosis (P=0.003), moderate neuritic plaques (P=0.04), and the APOε4 allele (P=0.02). CONCLUSIONS: The association between trajectory of decline in global cognitive scores and multiple brain pathologies highlights the importance of accounting for comorbid pathologies in therapeutic trials aimed at one specific pathology in the oldest old. Only the APOε4 allele showed an association with memory decline, despite accounting for Alzheimer's disease pathology, suggesting that APOE may be involved in mechanisms beyond amyloid metabolism in its role in memory. Further studies are needed to examine the role of APOE in brain aging.

Embedded Online Questionnaire Measures Are Sensitive to Identifying Mild Cognitive Impairment.

BACKGROUND/AIMS: Early changes in cognitively demanding daily activities occur between normal cognition and the development of mild cognitive impairment (MCI). These real-world functional changes as early signals of cognitive change form a prime target for meaningful early detection of dementia. We examined whether passive aspects of responding to a remotely monitored weekly online questionnaire discriminated between older adults with and without MCI. METHODS: Participants were 83 independent, community-dwelling older adults enrolled in a longitudinal study of in-home monitoring technologies, which included completion of a short weekly online questionnaire of health and life events. RESULTS: In longitudinal analyses, time to complete the online questionnaire decreased over 1 year in both MCI and cognitively intact participants (P<0.01). MCI and intact participants did not differ in the time of day they submitted their questionnaires initially; however, over the course of 1 year MCI participants began to submit their questionnaires progressively later in the day and they needed greater assistance from staff as compared with intact participants (P<0.05). The online questionnaire performance measures were significantly correlated to conventional cognitive test scores (P<0.05) across the spectrum of normal cognition to MCI. CONCLUSIONS: Ambiently assessed, passive performance measures embedded within an online questionnaire are able to discriminate between normal cognition and MCI. Remote monitoring of cognitively demanding routine daily activities is a promising approach for ecologically valid real-world cognitive assessment.

Memory Complaints in Older Adults: Prognostic Value and Stability in Reporting over Time.

OBJECTIVE: The purpose of this longitudinal study was to examine the prognostic value of subjective memory complaints in 156 cognitively intact community-dwelling older adults with a mean age of 83 years. METHODS: Participants were assessed for subjective memory complaints, cognitive performance, functional status, and mood at annual evaluations with a mean follow-up of 4.5 years. RESULTS: Subjective memory complaint at entry (n=24) was not associated with impaired memory performance and did not predict memory decline or progression to incipient dementia. Memory complaints were inconsistent across examinations for 62% of participants who reported memory problems. CONCLUSIONS: Memory complaints by older adults are inconsistent over time. Memory complaint's value as a research criterion for selecting people at risk for dementia is weak among community dwelling older adults. Age, length of follow-up, and other population characteristics may affect the implication of self-reported memory problems.

The impact of sleep on neuropsychological performance in cognitively intact older adults using a novel in-home sensor-based sleep assessment approach.

The relationship between recent episodes of poor sleep and cognitive testing performance in healthy cognitively intact older adults is not well understood. In this exploratory study we examined the impact of recent sleep disturbance, sleep duration, and sleep variability on cognitive performance in 63 cognitively intact older adults using a novel unobtrusive in-home sensor-based sleep assessment methodology. Specifically, we examined the impact of sleep the night prior, the week prior, and the month prior to a neuropsychological evaluation on cognitive performance. Results showed that mildly disturbed sleep the week prior and month prior to cognitive testing was associated with reduced working memory on cognitive evaluation. One night of mild sleep disturbance was not associated with decreased cognitive performance the next day. Sleep duration was unrelated to cognition. In-home, unobtrusive, sensor monitoring technologies provide a novel method for objective, long-term, and continuous assessment of sleep behavior and other everyday activities that might contribute to decreased or variable cognitive performance in healthy older adults.

Cognitive Skills and the Aging Brain: What to Expect.

Whether it's a special episode on the PBS series, "The Secret Life of the Brain" or an entire issue dedicated to the topic in the journal Science, a better understanding of the aging brain is viewed as a key to an improved quality of life in a world where people live longer. Despite dementia and other neurobiological disorders that are associated with aging, improved imaging has revealed that even into our seventies, our brains continue producing new neurons. Our author writes about how mental health functions react to the normal aging process, including why an aging brain may even form the basis for wisdom.

Computer mouse movement patterns: A potential marker of mild cognitive impairment.

INTRODUCTION: Subtle changes in cognitively demanding activities occur in MCI but are difficult to assess with conventional methods. In an exploratory study, we examined whether patterns of computer mouse movements obtained from routine home computer use discriminated between older adults with and without MCI. METHODS: Participants were 42 cognitively intact and 20 older adults with MCI enrolled in a longitudinal study of in-home monitoring technologies. Mouse pointer movement variables were computed during one week of routine home computer use using algorithms that identified and characterized mouse movements within each computer use session. RESULTS: MCI was associated with making significantly fewer total mouse moves (p<.01), and making mouse movements that were more variable, less efficient, and with longer pauses between movements (p<.05). Mouse movement measures were significantly associated with several cognitive domains (p's<.01-.05). DISCUSSION: Remotely monitored computer mouse movement patterns are a potential early marker of real-world cognitive changes in MCI.

Neuropathologic basis of white matter hyperintensity accumulation with advanced age.

OBJECTIVE: To determine which vascular pathology measure most strongly correlates with white matter hyperintensity (WMH) accumulation over time, and whether Alzheimer disease (AD) neuropathology correlates with WMH accumulation. METHODS: Sixty-six older persons longitudinally followed as part of an aging study were included for having an autopsy and >1 MRI scan, with last MRI scan within 36 months of death. Mixed-effects models were used to examine the associations between longitudinal WMH accumulation and the following neuropathologic measures: myelin pallor, arteriolosclerosis, microvascular disease, microinfarcts, lacunar infarcts, large-vessel infarcts, atherosclerosis, neurofibrillary tangle rating, and neuritic plaque score. Each measure was included one at a time in the model, adjusted for duration of follow-up and age at death. A final model included measures showing an association with p < 0.1. RESULTS: Mean age at death was 94.5 years (5.5 SD). In the final mixed-effects models, arteriolosclerosis, myelin pallor, and Braak score remained significantly associated with increased WMH accumulation over time. In post hoc analysis, we found that those with Braak score 5 or 6 were more likely to also have high atherosclerosis present compared with those with Braak score 1 or 2 (p = 0.003). CONCLUSION: Accumulating white matter changes in advanced age are likely driven by small-vessel ischemic disease. Additionally, these results suggest a link between AD pathology and white matter integrity disruption. This may be due to wallerian degeneration secondary to neurodegenerative changes. Alternatively, a shared mechanism, for example ischemia, may lead to both vascular brain injury and neurodegenerative changes of AD. The observed correlation between atherosclerosis and AD pathology supports the latter.

Neuropathologic basis of age-associated brain atrophy.

IMPORTANCE: While brain volume changes are used as surrogate markers for Alzheimer disease neuropathology in clinical studies, the extent to which these changes are due to pathologic features of Alzheimer disease in the aging brain is not well established. This study aims to clarify the neuropathologic correlates of longitudinal brain atrophy. OBJECTIVE: To examine the association between brain atrophy during life and neuropathology in an elderly population. DESIGN: Autopsy study of a cohort of elderly individuals. SETTING: Community-based population. PARTICIPANTS: Seventy-one healthy elderly individuals were selected from participants of the Oregon Brain Aging Study for having an autopsy, more than 1 magnetic resonance imaging scan, and the last magnetic resonance imaging scan within 36 months of death. MAIN OUTCOMES AND MEASURES: The associations between brain volume trajectories (ventricular, total brain, and hippocampal) and time interaction terms for neurofibrillary tangles, neuritic plaques, gross infarcts, microinfarcts, amyloid angiopathy, Lewy bodies, APOE ε4 presence, and clinical diagnosis (no cognitive impairment, mild cognitive impairment, or dementia as time-varying covariates) were examined in mixed-effects models, adjusting for duration of follow-up and age at death. RESULTS: Ventricular volume trajectory was significantly associated with age, presence of infarcts, neurofibrillary tangle and neuritic plaque scores, APOE ε4 allele presence, and dementia diagnosis. Total brain volume trajectory was significantly associated with age and mild cognitive impairment diagnosis. Hippocampal volume trajectory was significantly associated with amyloid angiopathy. CONCLUSIONS AND RELEVANCE: Ventricular volume trajectory is more sensitive than total brain and hippocampal volume trajectories as a marker of accruing Alzheimer disease and vascular pathology in elderly individuals. The association between brain volume trajectories and cognitive impairment (mild cognitive impairment and dementia) remained after controlling for the degree of neuropathology and other covariates. This suggests that there may be other factors not measured in this study that could be contributing to brain atrophy in those with cognitive impairment.

Measurement of reaction time in the home for people with dementia: a feasibility study.

BACKGROUND: Cognitive decline is the cardinal symptom of dementia. Accurate measurement of changes in cognition, while essential for testing interventions to slow cognitive decline, can be challenging in people with dementia (PWD). For example, the laboratory environment may cause anxiety and negatively affect performance. MATERIAL AND METHOD: In healthy people, researchers measure one aspect of cognition, attention, via assessing reaction times in a laboratory environment. This repeated-measures study investigated the feasibility of reaction time measurement in participants' homes using the computerized psychomotor vigilance task (PVT) for PWD. Research questions were (a) Can laboratory controls be replicated in the home? (b) Where do PWD perform PVT trials optimally? and (c) What are the preferences of PWD and their caregivers? Two groups that differed by sequence of testing location completed 12 reaction time assessments over 2 days. Caregiver and person with dementia dyad preferences were examined in a follow-up phone interview. RESULTS: Complete data were collected from 14 dyads. Although there were slight differences in lighting between settings, the time of day, temperature, and sound did not differ. There were no significant differences in PVT performance between the two locations, but the group who tested in the home on Day 1 performed better than the group who tested in the lab on Day 1. All participants preferred home examination. DISCUSSION: It is feasible to measure reaction times in the home. Home testing contributes to optimal performance and participants preferred the home.

Plasma omega-3 PUFA and white matter mediated executive decline in older adults.

INTRODUCTION: Cross-sectional studies have identified long chain omega-3 polyunsaturated fatty acids (eicosapentaenoic acid 20:5n-3 and docosahexaenoic acid 22:6n-3 (O3PUFA) in association with fewer white matter lesions and better executive function in older adults. We hypothesized that O3PUFA are associated with less executive decline over time and that total white matter hyperintensity volume (WMH) mediates this association. METHODS: Eighty-six non-demented older adults were followed over 4 years after measurement of plasma O3PUFA with annual evaluations of cognitive function. A subset of these participants also had brain MRI of total WMH available to conduct a formal mediation analysis of a putative relationship between O3PUFA and cognitive function. RESULTS: Mean age at baseline was 86, 62% were female and 11% carried the APOE4 allele. Each 100 µg/ml increase in plasma O3PUFA associated with 4 s less change in executive decline per year of aging (p = 0.02, fully adjusted model). O3PUFA was not associated with verbal memory or global cognitive changes. The significance of the association between O3PUFA and better executive function was lost once WMH was added to the regression model. CONCLUSION: Executive decline with age appears to be a cognitive domain particularly sensitive to plasma O3PUFA in longitudinal examination. O3PUFA may modulate executive functioning by mechanisms underlying the development of WMH, a biologically plausible hypothesis that warrants further investigation.

Ginkgo biloba does not improve cognitive function in MS: a randomized placebo-controlled trial.

OBJECTIVE: To determine whether Ginkgo biloba extract (ginkgo) improves cognitive function in persons with multiple sclerosis (MS). METHODS: Persons with MS from the Seattle and Portland VA clinics and adjacent communities who scored 1 SD or more below the mean on one of 4 neuropsychological tests (Stroop Test, California Verbal Learning Test II [CVLT-II], Controlled Oral Word Association Test [COWAT], and Paced Auditory Serial Addition Task [PASAT]) were randomly assigned to receive either one 120-mg tablet of ginkgo (EGb-761; Willmar Schwabe GmbH & Co, Germany) or one placebo tablet twice a day for 12 weeks. As the primary outcome, we compared the performance of the 2 groups on the 4 tests at exit after adjusting for baseline performance. RESULTS: Fifty-nine subjects received placebo and 61 received ginkgo; 1 participant receiving placebo and 3 receiving ginkgo were lost to follow-up. Two serious adverse events (AEs) (myocardial infarction and severe depression) believed to be unrelated to the treatment occurred in the ginkgo group; otherwise, there were no significant differences in AEs. The differences (ginkgo - placebo) at exit in the z scores for the cognitive tests were as follows: PASAT -0.2 (95% confidence interval [CI] -0.5 to 0.1); Stroop Test -0.5 (95% CI -0.9 to -0.1); COWAT 0.0 (95% CI -0.2 to 0.3); and CVLT-II 0.0 (95% CI -0.3 to 0.3); none was statistically significant. CONCLUSIONS: Treatment with ginkgo 120 mg twice a day did not improve cognitive performance in persons with MS. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that treatment with ginkgo 120 mg twice a day for 12 weeks does not improve cognitive performance in people with MS.

Executive function predicts risk of falls in older adults without balance impairment.

BACKGROUND: Executive dysfunction has previously been found to be a risk factor for falls. The aim of this study is to investigate the association between executive dysfunction and risk of falling and to determine if this association is independent of balance. METHODS: Participants were 188 community-dwelling individuals aged 65 and older. All participants underwent baseline and annual evaluations with review of health history, standardized neurologic examination, neuropsychological testing, and qualitative and quantitative assessment of motor function. Falls were recorded prospectively using weekly online health forms. RESULTS: During 13 months of follow-up, there were 65 of 188 participants (34.6%) who reported at least one fall. Univariate analysis showed that fallers were more likely to have lower baseline scores in executive function than non-fallers (p = 0.03). Among participants without balance impairment we found that higher executive function z-scores were associated with lower fall counts (p = 0.03) after adjustment for age, sex, health status and prior history of falls using negative binomial regression models. This relationship was not present among participants with poor balance. CONCLUSIONS: Lower scores on executive function tests are a risk factor for falls in participants with minimal balance impairment. However, this effect is attenuated in individuals with poor balance where physical or more direct motor systems factors may play a greater role in fall risk.

Serial position effects in mild cognitive impairment.

Mild cognitive impairment (MCI) is often associated with the preclinical phase of Alzheimer's disease (AD). Special scoring of word-list recall data for serial position has been suggested to improve discrimination of normal aging from dementia. We examined serial position effects in word-list recall for MCI participants compared to Alzheimer patients and controls. Individuals with MCI, like Alzheimer patients, had a diminished primacy effect in recalling words from a list. No alternative scoring system was better than standard scoring of word-list recall in distinguishing MCI patients from controls. Retention weighted scoring improved the discrimination of MCI and AD groups.

The trajectory of gait speed preceding mild cognitive impairment.

OBJECTIVES: To compare the trajectory of motor decline, as measured by gait speed and finger-tapping speed, between elderly people who developed mild cognitive impairment (MCI) and those who remained cognitively intact. We also sought to determine the approximate time at which the decline in motor function accelerated in persons who developed MCI. DESIGN: Longitudinal cohort study. PARTICIPANTS: Participants were 204 healthy seniors (57.8% women) from the Oregon Brain Aging Study evaluated for up to 20 years using annual neurologic, neuropsychological, and motor examinations. MAIN OUTCOME MEASURES: The pattern of motor decline with aging was compared using a mixed-effects model with an interaction term for age and a clinical diagnosis of MCI. The time before diagnosis of MCI, when the change in gait or finger-tapping speed accelerates, was assessed using a mixed-effects model with a change point for men and women, separately and combined, who developed MCI. RESULTS: The rates of change, with aging, in gait speed (P < .001) and finger-tapping speed in the dominant hand (P = .003) and nondominant hand (P < .001) were significantly different between participants who developed MCI (converters) and those who did not (nonconverters). Using a change point analysis for MCI converters, the decrease in gait speed accelerated by 0.023 m/s/y (P < .001), occurring 12.1 years before the onset of MCI. An acceleration in gait speed decline occurred earlier in men than women. For tapping speed, the change point occurred after the onset of MCI for both dominant and nondominant hands when men and women were combined. CONCLUSIONS: Motor decline as indexed by gait speed accelerates up to 12 years before MCI. Longitudinal changes in motor function may be useful in the early detection of dementia during preclinical stages, when the utility of disease-modifying therapies would be greatest.

Cognitive impairment risk: white matter hyperintensity progression matters.

OBJECTIVE: To determine whether white matter hyperintensity (WMH) progression rate is a better predictor of cognitive impairment risk than baseline WMH volume in healthy elderly individuals. METHOD: Ninety-eight cognitively intact elderly subjects were followed in the Oregon Brain Aging Study. Forty-nine had at least 3 brain MRIs and annual cognitive and neurologic assessments until diagnosed with persistent cognitive impairment (PCI). Brain, ventricular CSF (vCSF), intracranial volume (ICV), hippocampus, total WMH, periventricular (PV) WMH, and subcortical WMH volumes were measured. Cox proportional hazards survival analyses were used to assess cognitive impairment risk. RESULTS: After adjusting for age, apolipoprotein E4 status, incident hypertension, ICV, entry Mini-Mental State Examination, baseline hippocampus, and both baseline vCSF volume and rate of vCSF volume change, increased progression of total WMH volume (hazard ratio [HR] 1.84, 95% confidence interval [CI] 1.3-2.7, p = 0.0007) and PV WMH volume (HR 1.94, 95% CI 1.3-3.1, p = 0.001) conferred higher risk of PCI, whereas baseline WMH volumes did not. Every 1 mL/y increase in PV WMH volume was associated with a 94% increased risk of PCI. CONCLUSION: Progression of total and periventricular (PV) white matter hyperintensity (WMH) volumes are better predictors of persistent cognitive impairment (PCI) than baseline WMH burden. Greater PV WMH burden progression is associated with the development of PCI, a potential precursor to Alzheimer or vascular dementia. Identification of factors that decrease WMH accumulation over time is needed to maintain cognitive health in our growing elderly population.

Wechsler Memory Scale-III Faces test performance in patients with mild cognitive impairment and mild Alzheimer's disease.

Little is known about the sensitivity of the Wechsler Memory Scale-Third Edition (WMS-III) Faces subtest to memory impairment associated with mild cognitive impairment (MCI). In this study, Faces performance was examined in 24 MCI patients, 46 mild Alzheimer's disease (AD) patients, and 98 elderly controls. We hypothesized that participants with diagnoses of MCI or AD would be impaired relative to controls on Faces. Analyses showed that AD participants performed significantly worse than MCI and intact participants, although there were no significant differences between MCI and intact participants. Data suggest that brain areas specialized for face recognition memory may be less affected by MCI and mild AD than regions specialized for verbal memory.