Disability trajectories and mortality in older adults with different cognitive and physical profiles.

BACKGROUND: Cognitive and physical deficits independently raise the risk for negative events in older adults. Less is known about whether their co-occurrence constitutes a distinct risk profile. This study quantifies the association between cognitive impairment, no dementia (CIND), slow walking speed (WS) and their combination and disability and mortality. METHODS: We examined 2546 dementia-free people aged ≥ 60 years, part of the Swedish National study on Aging and Care in Kungsholmen (SNAC-K) up to 12 years. The following four profiles were created: (1) healthy profile; (2) isolated CIND (scoring 1.5 SD below age-specific means on at least one cognitive domain); (3) isolated slow WS (< 0.8 m/s); (4) CIND+ slow WS. Disability was defined as the sum of impaired activities of daily living and trajectories of disability were derived from mixed-effect linear regression models. Piecewise proportional hazard models were used to estimate mortality rate [hazard ratios (HRs)]. Population attributable risks of death were calculated. RESULTS: Participants with both CIND and slow WS had the worst prognosis, especially in the short-term period. They experienced the steepest increase in disability and five times the mortality rate (HR 5.1; 95% CI 3.5-7.4) of participants free from these conditions. Similar but attenuated results were observed for longer follow-ups. Co-occurring CIND and slow WS accounted for 30% of short-term deaths. CONCLUSIONS: Co-occurring cognitive and physical limitations constitute a distinct risk profile in older people, and account for a large proportion of short-term deaths. Assessing cognitive and physical function could enable early identification of people at high risk for adverse events.

Association of Vitamin B12, Folate, and Sulfur Amino Acids With Brain Magnetic Resonance Imaging Measures in Older Adults: A Longitudinal Population-Based Study.

IMPORTANCE: Vitamin B12, folate, and sulfur amino acids may be modifiable risk factors for structural brain changes that precede clinical dementia. OBJECTIVE: To investigate the association of circulating levels of vitamin B12, red blood cell folate, and sulfur amino acids with the rate of total brain volume loss and the change in white matter hyperintensity volume as measured by fluid-attenuated inversion recovery in older adults. DESIGN, SETTING, AND PARTICIPANTS: The magnetic resonance imaging subsample of the Swedish National Study on Aging and Care in Kungsholmen, a population-based longitudinal study in Stockholm, Sweden, was conducted in 501 participants aged 60 years or older who were free of dementia at baseline. A total of 299 participants underwent repeated structural brain magnetic resonance imaging scans from September 17, 2001, to December 17, 2009. MAIN OUTCOMES AND MEASURES: The rate of brain tissue volume loss and the progression of total white matter hyperintensity volume. RESULTS: In the multi-adjusted linear mixed models, among 501 participants (300 women [59.9%]; mean [SD] age, 70.9 [9.1] years), higher baseline vitamin B12 and holotranscobalamin levels were associated with a decreased rate of total brain volume loss during the study period: for each increase of 1 SD, ß (SE) was 0.048 (0.013) for vitamin B12 (P < .001) and 0.040 (0.013) for holotranscobalamin (P = .002). Increased total homocysteine levels were associated with faster rates of total brain volume loss in the whole sample (ß [SE] per 1-SD increase, -0.035 [0.015]; P = .02) and with the progression of white matter hyperintensity among participants with systolic blood pressure greater than 140 mm Hg (ß [SE] per 1-SD increase, 0.000019 [0.00001]; P = .047). No longitudinal associations were found for red blood cell folate and other sulfur amino acids. CONCLUSIONS AND RELEVANCE: This study suggests that both vitamin B12 and total homocysteine concentrations may be related to accelerated aging of the brain. Randomized clinical trials are needed to determine the importance of vitamin B12 supplementation on slowing brain aging in older adults.

The dimensionality of between-person differences in white matter microstructure in old age.

Between-person differences in white matter microstructure may partly generalize across the brain and partly play out differently for distinct tracts. We used diffusion-tensor imaging and structural equation modeling to investigate this issue in a sample of 260 adults aged 60-87 years. Mean fractional anisotropy and mean diffusivity of seven white matter tracts in each hemisphere were quantified. Results showed good fit of a model positing that individual differences in white matter microstructure are structured according to tracts. A general factor, although accounting for variance in the measures, did not adequately represent the individual differences. This indicates the presence of a substantial amount of tract-specific individual differences in white matter microstructure. In addition, individual differences are to a varying degree shared between tracts, indicating that general factors also affect white matter microstructure. Age-related differences in white matter microstructure were present for all tracts. Correlations among tract factors did not generally increase as a function of age, suggesting that aging is not a process with homogenous effects on white matter microstructure across the brain. These findings highlight the need for future research to examine whether relations between white matter microstructure and diverse outcomes are specific or general.

Onset and rate of cognitive change before dementia diagnosis: findings from two Swedish population-based longitudinal studies.

We used data from two population-based longitudinal studies to estimate time of onset and rate of accelerated decline across cognitive domains before dementia diagnosis. The H70 includes an age-homogeneous sample (127 cases and 255 non-cases) initially assessed at age 70 with 12 follow-ups over 30 years. The Kungsholmen Project (KP) includes an age-heterogeneous sample (279 cases and 562 non-cases), with an average age of 82 years at initial assessment, and 4 follow-ups spanning 13 years. We fit mixed linear models to the data and determined placement of change points by a profile likelihood method. Results demonstrated onset of accelerated decline for fluid (speed, memory) versus crystallized (verbal, clock reading) abilities occurring approximately 10 and 5 years before diagnosis, respectively. Although decline before change points was greater for fluid abilities, acceleration was more pronounced for crystallized abilities after the change points. This suggests that onset and rate of acceleration vary systematically along the fluid-crystallized ability continuum. There is early onset in fluid abilities, but these changes are difficult to detect due to substantial age-related decline. Onset occurred later and acceleration was greater in crystallized abilities, suggesting that those markers may provide more valid identification of cases in later stages of the prodromal phase.

Differential verbal fluency deficits in the preclinical stages of Alzheimer's disease and vascular dementia.

We examined patterns of early and late word generation in category and letter fluency among persons in the preclinical stages of Alzheimer's disease (AD) and vascular dementia (VaD). The sample consisted of 20 preclinical VaD persons, 66 preclinical AD persons, and 267 control persons, sampled from the community. Persons in the preclinical phase of AD and VaD were similarly impaired in letter fluency, although the preclinical VaD group outperformed their AD counterparts in category fluency. This pattern of results is consistent with the notion that category fluency is relatively more dependent on the medial-temporal lobe, whereas letter fluency relies more on frontal regions. The patterns of fluency impairment in preclinical AD and VaD generalized across early and late word retrieval.

Cognitive impairment in preclinical Alzheimer's disease: a meta-analysis.

To determine the size of the impairment across different cognitive domains in preclinical Alzheimer's disease (AD), a meta-analysis based on 47 studies involving 9,097 controls and 1,207 preclinical AD cases was conducted. There were marked preclinical deficits in global cognitive ability, episodic memory, perceptual speed, and executive functioning; somewhat smaller deficits in verbal ability, visuospatial skill, and attention; and no preclinical impairment in primary memory. Younger age (< 75 years) and shorter follow-up intervals (< 3 years) were associated with larger effect sizes for both global cognitive ability and episodic memory. For global cognitive ability, studies that used population-based sampling yielded larger effect sizes; for episodic memory, larger differences were seen in studies that preidentified groups in terms of baseline cognitive impairment. Within episodic memory, delayed testing and recall-based assessment resulted in the largest effect sizes. The authors conclude that deficits in multiple cognitive domains are characteristic of AD several years before clinical diagnosis. The generalized nature of the deficit is consistent with recent observations that multiple brain structures and functions are affected long before the AD diagnosis.

A preclinical phase in vascular dementia: cognitive impairment three years before diagnosis.

Alzheimer's disease (AD) and vascular dementia (VaD) patients exhibit similar patterns of deficits in many cognitive tasks in the early clinical stages. Considering that preclinical cognitive deficits are well documented in AD, the purpose of the present study was to investigate if such deficits are also present in VaD. The cognitive outcome measure was the Mini-Mental State Examination (MMSE). The sample was taken from a population-based study and consisted of 699 persons who were nondemented at baseline, but out of whom 35 persons were diagnosed with VaD and 170 with AD at a 3-year follow-up. Both the incident VaD and AD cases exhibited baseline deficits on the total score of the MMSE and three of the subscales: orientation to time, orientation to place, and delayed memory. Further, both dementia groups exhibited precipitous decline on most MMSE subscales during the 3-year follow-up period. Logistic regression analyses showed that all subscales that revealed deficits at baseline predicted dementia status at follow-up. Delayed memory was the best predictor in both preclinical VaD and preclinical AD. Thus, these results demonstrate preclinical cognitive deficits in VaD in a measure of global cognitive functioning, which closely resemble those observed in AD. This observation suggests that circulatory disturbance is associated with cognitive problems several years before the actual VaD diagnosis.

Cognitive functioning in preclinical vascular dementia: a 6-year follow-up.

BACKGROUND AND PURPOSE: Recent studies have shown that cognitive deficits are present during the years preceding a diagnosis of vascular dementia (VaD). The aims of this study were to (1) extend previous research by examining whether cognitive deficits are already present 6 years before diagnosis, and (2) examine the strength of the association between cognitive performance and a future VaD diagnosis after controlling for previous vascular disorders. METHODS: Subjects from a population-based study of very old persons (> or =75) were examined with a test of global cognitive functioning (the Mini-Mental State Examination [MMSE]) at 3 occasions over a 6-year period. The study sample was nondemented the first 2 measurement times. On the last occasion, 22 individuals were diagnosed with VaD, and 450 persons remained nondemented. RESULTS: The preclinical VaD group showed no MMSE deficits 6 years before diagnosis (P>0.10) compared with the controls. However, 3 years before diagnosis, poor cognitive performance was significantly associated with forthcoming VaD after controlling for demographic factors and prior vascular disorders (odds ratio, 2.55; 95% CI, 1.67 to 3.89). CONCLUSIONS: This study extends previous findings on preclinical cognitive deficits in VaD and suggests that cognitive measures can be useful in the process of recognizing individuals at risk for developing VaD to initiate early treatment.

Similar patterns of cognitive deficits in the preclinical phases of vascular dementia and Alzheimer's disease.

We investigated whether (1) cognitive deficits are present among persons who will be diagnosed with vascular dementia (VaD) 3 years later, and (2) the pattern of such deficits is similar to that observed in preclinical Alzheimer's disease (AD). The VaD diagnosis was a diagnosis of post-stroke dementia. Population-based samples of 15 incident VaD cases, 43 incident AD cases, and 149 normal controls were compared on tests of episodic and short-term memory, verbal fluency, and visuospatial skill. Both dementia groups showed preclinical impairment relative controls on tasks assessing episodic memory 3 years before diagnosis, and there were no differences between these groups on any cognitive measure. The existence of a preclinical phase in the present VaD cases suggests that circulatory disturbance may affect cognitive performance before the occurrence of stroke that leads to clinical VaD. These results extend previous findings of similar patterns of cognitive deficits in the early clinical phases of AD and VaD to the preclinical phases of these diseases.

Cognitive deficits in preclinical Alzheimer's disease.

We review the literature on cognitive functioning during the transition from normal aging to clinical Alzheimer's disease (AD). There is ample empirical evidence that deficits across multiple cognitive domains are apparent years to decades before the AD diagnosis, with impairments in episodic memory representing a common cognitive manifestation of the preclinical phase of the disease. Interestingly, the magnitude of the preclinical cognitive deficits appears to be relatively stable until a few years before clinical diagnosis. The behavioural deficits associated with preclinical AD are consistent with the neural changes that appear many years before eventual diagnosis. In addition to increasing our theoretical understanding of AD development, research on cognition in preclinical AD contributes to the identification of persons at risk of developing AD for purposes of intervention.

Influences of preclinical dementia and impending death on the magnitude of age-related cognitive deficits.

The authors examined the influence of preclinical dementia and impending death on the cross-sectional relationship between age and performance in tasks assessing episodic memory, visuospatial skill, and verbal fluency. Increasing age was associated with a general decrease in cognitive performance. In addition, those who were to be diagnosed with dementia or had died by a 3-year follow-up, were older, and performed at a lower level than the remaining sample across all cognitive tasks at baseline. Nevertheless, removal of the preclinical dementia and impending death groups from the original sample affected the cross-sectional age-cognition relations relatively little. This pattern of findings suggests that the biological aging process exerts negative influences on cognitive functioning beyond those resulting from disease and mortality.