Katherine A. Gifford

The source of cognitive complaints predicts diagnostic conversion differentially among nondemented older adults.

The objective of this study was to compare whether different sources of cognitive complaint (i.e., subjective and informant) predict diagnostic conversion in nondemented older adults.

Blood pressure and cognition among older adults: a meta-analysis.

Hypertension has adverse effects on cognition, can alter cerebral vasculature integrity, and is associated with the pathogenesis of dementia. Using meta-analysis, we correlated blood pressure to multiple cognitive domains among older adults free of clinical stroke and dementia. We identified 230 studies indexed in PubMed and PsycINFO relating blood pressure and cognition. After applying exclusion criteria, we selected n = 12 articles with n = 4,076 participants (age range 43-91 years). Meta-analysis yielded an association between blood pressure and episodic memory (r = -.18, p < .001) and between blood pressure and global cognition (r = -.07, p < .001). When limiting analyses to studies adjusting for vascular covariates (n = 8, n = 2,141), blood pressure was modestly related to global cognition (r = -.11, p < .001), attention (r = .14, p = .002), and episodic memory (r = -.20, p < .001) with a trend for language (r = -.22, p = .07). Findings underscore the need to manage blood pressure as a key prevention method in minimizing abnormal cognitive aging prior to the onset of clinical dementia.

Adverse Vascular Risk is Related to Cognitive Decline in Older Adults

BACKGROUND Cardiovascular disease (CVD) and related risk factors are associated with Alzheimers disease (AD). This association is less well-defined in normal cognition (NC) or prodromal AD (mild cognitive impairment, MCI). OBJECTIVE Cross-sectionally and longitudinally relate a vascular risk index to cognitive outcomes among elders free of clinical dementia. METHODS 3,117 MCI (74 ± 8 years, 56% female) and 6,603 NC participants (72 ± 8 years, 68% female) were drawn from the National Alzheimers Coordinating Center. A composite measure of vascular risk was defined using the Framingham Stroke Risk Profile (FSRP) score (i.e., age, systolic blood pressure, anti-hypertensive medication, diabetes, cigarette smoking, CVD history, atrial fibrillation). Ordinary linear regressions and generalized linear mixed models related baseline FSRP to cross-sectional and longitudinal cognitive outcomes, separately for NC and MCI, adjusting for age, gender, race, education, and follow-up time (in longitudinal models). RESULTS In NC participants, increasing FSRP was related to worse baseline global cognition, information processing speed, and sequencing abilities (p-values <0.0001) and a worse longitudinal trajectory on all cognitive measures (p-values <0.0001). In MCI, increasing FSRP correlated with worse longitudinal delayed memory (p = 0.004). In secondary models using an age-excluded FSRP score, associations persisted in NC participants for global cognition, naming, information processing speed, and sequencing abilities. CONCLUSIONS An adverse vascular risk profile is associated with worse cognitive trajectory, especially global cognition, naming, and information processing speed, among NC elders. Future studies are needed to understand how effective management of CVD and related risk factors can modify cognitive decline to identify the ideal timeframe for primary prevention implementation.

Inclusion of an informant yields strong associations between cognitive complaint and longitudinal cognitive outcomes in non-demented elders.

BACKGROUND The relation between the source of cognitive complaint and objective cognitive performance is not well understood. OBJECTIVE Examine self and informant cognitive complaint as predictors of objective cognitive and functional trajectory in non-demented elders. METHODS Participants from the National Alzheimers Coordinating Center had a baseline diagnosis of normal cognition (NC; n = 6133, 72±8 years, 68% female) or mild cognitive impairment (MCI; n = 3010, 74±8 years, 55% female). Four independent groups defined cognitive complaint: no complaint, self-only complaint, informant-only complaint, or mutual complaint (both self and informant complaint). Linear mixed model regression analyses related complaint status (referent was no complaint) to cognitive and functional trajectories, adjusting for age, sex, race, education, and follow-up period. RESULTS Among NC participants, mutual complaint related to faster decline in global cognition (p < 0.0001), language (all p-values <0.0001), processing speed (p = 0.0002), and executive functioning (p = 0.0006). Informant-only complaint related to faster decline in global cognition (p = 0.0001) and processing speed (p = 0.0001). Self-only complaint related to greater decline in immediate (p < 0.0001) and delayed (p = 0.0005) episodic memory. In MCI, mutual complaint related to faster decline in global cognition (p < 0.0001), verbal episodic memory (all p-values <0.0001), language (all p-values <0.0001), and processing speed(all p-values <0.0006). Informant-only or self-only complaint associations with cognitive trajectory did not survive correction factor for multiple comparisons.Conclusion: Cognitive complaint appears to have clinical significance, as it is related to declines in objective cognitive performance over time. Mutual complaint was associated with the worst cognitive trajectory in both NC and MCI elders, highlighting the importance of incorporating an informant into evaluation of elders whenever feasible.

Stroke risk interacts with Alzheimer's disease biomarkers on brain aging outcomes.

Alzheimers disease (AD) biomarkers and stroke risk factors independently predict cognitive impairment, likely through independent disease pathways. However, limited work has sought to describe the dynamic interplay between these important risk factors. This article evaluated the interaction between stroke risk and AD biomarkers on hippocampal volume and cognitive performance. We first evaluated the interaction between stroke risk factors and AD biomarkers using data from the Alzheimers Disease Neuroimaging Initiative (ADNI, n = 1202). We then extended our findings to an independent autopsy data set from the National Alzheimers Coordinating Center (NACC, n = 1122) using measures of AD pathology. Stroke risk was quantified using the Framingham Stroke Risk Profile. In ADNI, stroke risk interacted with tau and amyloid levels in relation to baseline and longitudinal cognitive performance. Similarly, in NACC, stroke risk interacted with amyloid and tau positivity on cognitive performance. The effect of stroke risk factors on cognition was strongest in the absence of AD biomarkers or neuropathology, providing additional evidence that AD biomarkers and stroke risk factors relate to cognition through independent pathways.

Subjective Memory Complaint Only Relates to Verbal Episodic Memory Performance in Mild Cognitive Impairment

BACKGROUND A cognitive concern from the patient, informant, or clinician is required for the diagnosis of mild cognitive impairment (MCI); however, the cognitive and neuroanatomical correlates of complaint are poorly understood. OBJECTIVE We assessed how self-complaint relates to cognitive and neuroimaging measures in older adults with MCI. METHOD MCI participants were drawn from the Alzheimers Disease Neuroimaging Initiative and dichotomized into two groups based on the presence of self-reported memory complaint (no complaint n = 191, 77 ± 7 years; complaint n = 206, 73 ± 8 years). Cognitive outcomes included episodic memory, executive functioning, information processing speed, and language. Imaging outcomes included regional lobar volumes (frontal, parietal, temporal, cingulate) and specific medial temporal lobe structures (hippocampal volume, entorhinal cortex thickness, parahippocampal gyrus thickness). RESULTS Linear regressions, adjusting for age, gender, race, education, Mini-Mental State Examination score, mood, and apolipoprotein E4 status, found that cognitive complaint related to immediate (β = -1.07, p < 0.001) and delayed episodic memory performances assessed on a serial list learning task (β = -1.06, p = 0.001) but no other cognitive measures or neuroimaging markers. CONCLUSIONS Self-reported memory concern was unrelated to structural neuroimaging markers of atrophy and measures of information processing speed, executive functioning, or language. In contrast, subjective memory complaint related to objective verbal episodic learning performance. Future research is warranted to better understand the relation between cognitive complaint and surrogate markers of abnormal brain aging, including Alzheimers disease, across the cognitive aging spectrum.

Lower cardiac index levels relate to lower cerebral blood flow in older adults

Objective: To assess cross-sectionally whether lower cardiac index relates to lower resting cerebral blood flow (CBF) and cerebrovascular reactivity (CVR) among older adults. Methods: Vanderbilt Memory & Aging Project participants free of stroke, dementia, and heart failure were studied (n = 314, age 73 ± 7 years, 59% male, 39% with mild cognitive impairment). Cardiac index (liters per minute per meter squared) was quantified from echocardiography. Resting CBF (milliliters per 100 grams per minute) and hypercapnia-induced CVR were quantified from pseudo-continuous arterial spin-labeling MRI. Linear regressions with ordinary least-square estimates related cardiac index to regional CBF, with adjustment for age, education, race/ethnicity, Framingham Stroke Risk Profile score (systolic blood pressure, antihypertensive medication use, diabetes mellitus, current cigarette smoking, left ventricular hypertrophy, prevalent cardiovascular disease [CVD], atrial fibrillation), APOE ε4 status, cognitive diagnosis, and regional tissue volume. Results: Lower cardiac index corresponded to lower resting CBF in the left (β = 2.4, p = 0.001) and right (β = 2.5, p = 0.001) temporal lobes. Results were similar when participants with prevalent CVD and atrial fibrillation were excluded (left temporal lobe β = 2.3, p = 0.003; right temporal lobe β = 2.5, p = 0.003). Cardiac index was unrelated to CBF in other regions assessed (p > 0.25) and CVR in all regions (p > 0.05). In secondary cardiac index × cognitive diagnosis interaction models, cardiac index and CBF associations were present only in cognitively normal participants and affected a majority of regions assessed with effects strongest in the left (p < 0.0001) and right (p < 0.0001) temporal lobes. Conclusions: Among older adults without stroke, dementia, or heart failure, systemic blood flow correlates with cerebral CBF in the temporal lobe, independently of prevalent CVD, but not CVR.

Asymptomatic Alzheimer disease: Defining resilience

Objective: To define robust resilience metrics by leveraging CSF biomarkers of Alzheimer disease (AD) pathology within a latent variable framework and to demonstrate the ability of such metrics to predict slower rates of cognitive decline and protection against diagnostic conversion. Methods: Participants with normal cognition (n = 297) and mild cognitive impairment (n = 432) were drawn from the Alzheimer’s Disease Neuroimaging Initiative. Resilience metrics were defined at baseline by examining the residuals when regressing brain aging outcomes (hippocampal volume and cognition) on CSF biomarkers. A positive residual reflected better outcomes than expected for a given level of pathology (high resilience). Residuals were integrated into a latent variable model of resilience and validated by testing their ability to independently predict diagnostic conversion, cognitive decline, and the rate of ventricular dilation. Results: Latent variables of resilience predicted a decreased risk of conversion (hazard ratio < 0.54, p < 0.0001), slower cognitive decline (β > 0.02, p < 0.001), and slower rates of ventricular dilation (β < −4.7, p < 2 × 10−15). These results were significant even when analyses were restricted to clinically normal individuals. Furthermore, resilience metrics interacted with biomarker status such that biomarker-positive individuals with low resilience showed the greatest risk of subsequent decline. Conclusions: Robust phenotypes of resilience calculated by leveraging AD biomarkers and baseline brain aging outcomes provide insight into which individuals are at greatest risk of short-term decline. Such comprehensive definitions of resilience are needed to further our understanding of the mechanisms that protect individuals from the clinical manifestation of AD dementia, especially among biomarker-positive individuals.

The Vanderbilt Memory & Aging Project: Study Design and Baseline Cohort Overview

BACKGROUND Vascular health factors frequently co-occur with Alzheimers disease (AD). A better understanding of how systemic vascular and cerebrovascular health intersects with clinical and pathological AD may inform prevention and treatment opportunities. OBJECTIVE To establish the Vanderbilt Memory & Aging Project, a case-control longitudinal study investigating vascular health and brain aging, and describe baseline methodology and participant characteristics. METHODS From September 2012 to November 2014, 335 participants age 60- 92 were enrolled, including 168 individuals with mild cognitive impairment (MCI, 73±8 years, 41% female) and 167 age-, sex-, and race-matched cognitively normal controls (NC, 72±7 years, 41% female). At baseline, participants completed a physical and frailty examination, fasting blood draw, neuropsychological assessment, echocardiogram, cardiac MRI, and brain MRI. A subset underwent 24-hour ambulatory blood pressure monitoring and lumbar puncture for cerebrospinal fluid (CSF) collection. RESULTS As designed, participant groups were comparable for age (p = 0.31), sex (p = 0.95), and race (p = 0.65). MCI participants had greater Framingham Stroke Risk Profile scores (p = 0.008), systolic blood pressure values (p = 0.008), and history of left ventricular hypertrophy (p = 0.04) than NC participants. As expected, MCI participants performed worse on all neuropsychological measures (p-values < 0.001), were more likely to be APOEɛ4 carriers (p = 0.02), and had enhanced CSF biomarkers, including lower Aβ42 (p = 0.02), higher total tau (p = 0.004), and higher p-tau (p = 0.02) compared to NC participants. CONCLUSION Diverse sources of baseline and longitudinal data will provide rich opportunities to investigate pathways linking vascular and cerebrovascular health, clinical and pathological AD, and neurodegeneration contributing to novel strategies to delay or prevent cognitive decline.

Development of a subjective cognitive decline questionnaire using item response theory: A pilot study

Subjective cognitive decline (SCD) may indicate unhealthy cognitive changes, but no standardized SCD measurement exists. This pilot study aimed to identify reliable SCD questions.