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1.  Neuropathologic basis of white matter hyperintensity accumulation with advanced age 
Neurology  2013;81(11):977-983.
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.
doi:10.1212/WNL.0b013e3182a43e45
PMCID: PMC3888199  PMID: 23935177
2.  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.
doi:10.3389/fnagi.2013.00092
PMCID: PMC3863786  PMID: 24379780
omega-3 fatty acids; white matter hyperintensity; cognitive decline; memory; hypertension
3.  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.
doi:10.1080/13803395.2010.516742
PMCID: PMC3058855  PMID: 21128149
4.  Executive function predicts risk of falls in older adults without balance impairment 
BMC Geriatrics  2011;11:74.
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.
doi:10.1186/1471-2318-11-74
PMCID: PMC3226437  PMID: 22070602
5.  Physical Activity and the Risk of Dementia in Oldest Old 
Journal of aging and health  2007;19(2):242-259.
Objective
This study evaluated the protective role of physical activity (PA) against cognitive impairment (CI) in the oldest old (age ≥ 85).
Method
Prospective data on 66 optimally healthy, oldest old adults (mean age 88.5) were analyzed using survival analysis.
Results
In all, 12 men and 11 women reported exercising > 4 hours per week, and 38 participants developed CI (mean onset age 93; mean follow-up 4.7 years). The effect of exercise was modified by gender. In more active women (> 4 hours/week), the risk of CI was reduced by 88% (95% confidence interval 0.03, 0.41) compared to those less active. Less active women had 2 times the incidence rate of CI compared to less active men and almost 5 times the rate compared to active women.
Discussion
This study demonstrates the beneficial effects of exercise on healthy brain aging even in the oldest old and emphasizes the importance of increasing PA in older women.
doi:10.1177/0898264307299299
PMCID: PMC3110722  PMID: 17413134
oldest old; physical activity; exercise; dementia; cognitive impairment
6.  Cognitive impairment risk 
Neurology  2009;73(2):120-125.
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.
GLOSSARY
= Alzheimer disease;
= Dementia Rating Scale;
= confidence interval;
= hazard ratio;
= hippocampal sclerosis;
= hypertension;
= intracranial volume;
= mild cognitive impairment;
= Mini-Mental State Examination;
= not applicable;
= not significant;
= persistent cognitive impairment;
= periventricular;
= socioeconomic status;
= echo time;
= repetition time;
= ventricular CSF;
= volume;
= white matter hyperintensity.
doi:10.1212/WNL.0b013e3181ad53fd
PMCID: PMC2713187  PMID: 19597134
7.  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.
doi:10.1080/13803390802484763
PMCID: PMC2829111  PMID: 19037811
Wechsler Memory Scale–Third Edition; Face recognition; Face memory; Mild cognitive impairment; Alzheimer’s disease

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