Angela L. Jefferson

Trail Making Test Errors in Normal Aging, Mild Cognitive Impairment, and Dementia

The objective of the present study was to provide normative data for Trail Making Test (TMT) time to completion and performance errors among cognitively normal older adults, and to examine TMT error rates in conjunction with time scores for pre-clinical and clinical Alzheimers disease (AD) diagnostic decision-making. A sample of 526 individuals was classified into three diagnostic groups (normal controls, N=269; mild cognitive impairment, MCI, N=200; AD, N=57) by a multidisciplinary consensus conference. Results indicated that performance differed among the three groups for TMT A and B time scores as well as TMT B error rate. Diagnostic classification accuracy (i.e., sensitivity, specificity, and positive and negative predictive powers) is described for various combinations of the diagnostic groups. The findings show that TMT B time and errors are independently meaningful scores, and both therefore have clinical utility in assessing individuals referred for dementia evaluations.

Inflammatory biomarkers are associated with total brain volume The Framingham Heart Study

Background: Systemic inflammation is associated with ischemia and Alzheimer disease (AD). We hypothesized that inflammatory biomarkers would be associated with neuroimaging markers of ischemia (i.e., white matter hyperintensities [WMH]) and AD (i.e., total brain volume [TCB]). Methods: MRI WMH and TCB were quantified on 1,926 Framingham Offspring participants free from clinical stroke, TIA, or dementia (mean age 60 ± 9 years; range 35 to 85 years; 54% women) who underwent measurement of a circulating inflammatory marker panel, including CD40 ligand, C-reactive protein, interleukin-6 (IL-6), soluble intracellular adhesion molecule-1, monocyte chemoattractant protein-1, myeloperoxidase, osteoprotegerin (OPG), P-selectin, tumor necrosis factor-alpha (TNFα), and tumor necrosis factor receptor II. To account for head size, both TCB (TCBV) and WMH (WMH/TCV) were divided by total cranial volume. We used multivariable linear regression to relate 10 log-transformed inflammatory biomarkers to brain MRI measures. Results: In multivariable models, inflammatory markers as a group were associated with TCBV (p < 0.0001) but not WMH/TCV (p = 0.28). In stepwise models adjusted for clinical covariates with backwards elimination of markers, IL-6 and OPG were inversely associated with TCBV; TNFα was inversely related to TCBV in a subset of 1,430 participants. Findings were similar in analyses excluding individuals with prevalent cardiovascular disease. The relations between TCBV and inflammatory markers were modified by both sex and age, and generally were more pronounced in men and in older individuals. Conclusions: Although our observational cross-sectional data cannot establish causality, they are consistent with the hypothesis that higher inflammatory markers are associated with greater atrophy than expected for age.

Cardiac Index Is Associated With Brain Aging The Framingham Heart Study

Background— Cardiac dysfunction is associated with neuroanatomic and neuropsychological changes in aging adults with prevalent cardiovascular disease, theoretically because systemic hypoperfusion disrupts cerebral perfusion, contributing to subclinical brain injury. We hypothesized that cardiac function, as measured by cardiac index, would be associated with preclinical brain magnetic resonance imaging (MRI) and neuropsychological markers of ischemia and Alzheimer disease in the community. Methods and Results— Brain MRI, cardiac MRI, neuropsychological, and laboratory data were collected on 1504 Framingham Offspring Cohort participants free of clinical stroke, transient ischemic attack, or dementia (age, 61±9 years; 54% women). Neuropsychological and brain MRI variables were related to cardiac MRI–assessed cardiac index (cardiac output/body surface area). In multivariable-adjusted models, cardiac index was positively related to total brain volume (P=0.03) and information processing speed (P=0.02) and inversely related to lateral ventricular volume (P=0.048). When participants with clinically prevalent cardiovascular disease were excluded, the relation between cardiac index and total brain volume remained (P=0.02). Post hoc comparisons revealed that participants in the bottom cardiac index tertile (values <2.54) and middle cardiac index tertile (values between 2.54 and 2.92) had significantly lower brain volumes (P=0.04) than participants in the top cardiac index tertile (values >2.92). Conclusions— Although observational data cannot establish causality, our findings are consistent with the hypothesis that decreasing cardiac function, even at normal cardiac index levels, is associated with accelerated brain aging.

Characterization of activities of daily living in individuals with mild cognitive impairment.

OBJECTIVE To determine whether participants with mild cognitive impairment (MCI) differ from cognitively normal (NC) older adults on traditional and novel informant-based measures of activities of daily living (ADL) and to identify cognitive correlates of ADLs among participants with MCI. DESIGN Cross-sectional. SETTING University medical setting. PARTICIPANTS Seventy-seven participants (NC: N = 39; MCI: N = 38), 60 to 90 years old (73.5 +/- 6.6 years; 53% female). MEASUREMENTS Neuropsychological and ADL measures. METHODS Neuropsychological tests were administered to NC and MCI participants. Informants completed the Lawton and Brody Instrumental Activities of Daily Living and Physical Self-Maintenance Scale, including instrumental (IADL) and basic ADL (BADL) scales, as well as the Functional Capacities for Activities of Daily Living (FC-ADL), an error-based ADL measure. RESULTS No statistically or clinically significant between-group differences emerged for the BADL or IADL subscales. However, a robust difference was noted for the FC-ADL scale (MCI errors > NC errors; F((1,75))= 13.6, p <0.001; d = 0.84). Among MCI participants, correlations revealed that a measure of verbal learning was the only neuropsychological correlate of FC-ADL total score (r = -0.39, df = 36, p = 0.007). No neuropsychological measures were significantly associated with the IADL or BADL subscale score. CONCLUSION Traditional measures assessing global ADLs may not be sensitive to early functional changes related to MCI; however, error-based measures may capture the subtle evolving functional decline associated with MCI. Among MCI participants, early functional difficulties are associated with verbal learning performance, possibly secondary to the hallmark cognitive impairment associated with this cohort.

Conceptual and measurement challenges in research on cognitive reserve.

Cognitive reserve, broadly conceived, encompasses aspects of brain structure and function that optimize individual performance in the presence of injury or pathology. Reserve is defined as a feature of brain structure and/or function that modifies the relationship between injury or pathology and performance on neuropsychological tasks or clinical outcomes. Reserve is challenging to study for two reasons. The first is: reserve is a hypothetical construct, and direct measures of reserve are not available. Proxy variables and latent variable models are used to attempt to operationalize reserve. The second is: in vivo measures of neuronal pathology are not widely available. It is challenging to develop and test models involving a risk factor (injury or pathology), a moderator (reserve) and an outcome (performance or clinical status) when neither the risk factor nor the moderator are measured directly. We discuss approaches for quantifying reserve with latent variable models, with emphasis on their application in the analysis of data from observational studies. Increasingly latent variable models are used to generate composites of cognitive reserve based on multiple proxies. We review the theoretical and ontological status of latent variable modeling approaches to cognitive reserve, and suggest research strategies for advancing the field.

Endothelial function and white matter hyperintensities in older adults with cardiovascular disease.

Background and Purpose— The presence of white matter hyperintensities on brain MRI is common among elderly individuals. Previous research suggests that cardiovascular risk factors are associated with increased white matter hyperintensities. Examining the role of direct physiological measures of vascular function will help to clarify the vascular mechanisms related to white matter hyperintensities. The aim of the present study was to examine the association between endothelial-dependent and endothelial-independent vasodilatation and white matter hyperintensity volume. Methods— Twenty-five older adults with a range of cardiovascular diseases underwent brain MRI and completed assessments of blood vessel integrity using endothelial-dependent and independent flow-mediated dilation of the brachial artery. A semi-automated pixel-based method was used to quantify total brain volume and white matter hyperintensity volume, with white matter hyperintensity volume corrected for total brain volume. The association between measures of flow-mediated dilation and log-transformed white matter hyperintensities was examined. Results— Correlation analysis revealed that endothelial-dependent vasodilatation was significantly and inversely associated with white matter hyperintensity volume. In contrast, endothelial-independent vasodilatation was not associated with white matter hyperintensities. Neither endothelial-dependent nor endothelial-independent vasodilatation was associated with total brain volume. Conclusions— These data provide preliminary evidence that the integrity of the vascular endothelium is associated with white matter hyperintensities in older adults with cardiovascular disease. Impaired vascular function may be one mechanism that contributes to the development of white matter hyperintensities in the brain. Additional longitudinal research combining measures of vessel function, neuroimaging and cognition will be helpful in clarifying this potential mechanism.

A Life Course Model of Cognitive Activities, Socioeconomic Status, Education, Reading Ability, and Cognition

OBJECTIVES: To cross‐sectionally quantify the contribution of proxy measures of cognitive reserve reflective of the lifespan, such as education, socioeconomic status (SES), reading ability, and cognitive activities, in explaining late‐life cognition.

Lower Cardiac Output Is Associated with Greater White Matter Hyperintensities in Older Adults with Cardiovascular Disease

OBJECTIVES: To preliminarily examine the association between cardiac output, a measure of systemic blood flow, and structural brain magnetic resonance imaging indices of white matter hyperintensities (WMHs).

Vascular and cognitive functions associated with cardiovascular disease in the elderly.

This study examines the relationship between systemic vascular function, neurocognitive performance, and structural brain abnormalities on magnetic resonance imaging (MRI) among geriatric outpatients with treated, stable cardiovascular disease and no history of neurological illness (n = 88, ages 56–85 years). Vascular function was assessed by cardiac ejection fraction and output, sequential systolic and diastolic blood pressures, flow mediated brachial artery reactivity (BAR), and carotid intima media thickness (IMT). White matter hyperintensities (WMH) on MRI were quantified and examined relative to cognitive and vascular function. Principal component analysis revealed two primary vascular components: one associated with cardiac function, the other with atherosclerotic burden/endothelial dysfunction. Both factors were significantly associated with cognitive function and WMH volume. Reduced systolic variability and increased IMT were most strongly related to reduced attention, executive function, and information-processing speed. These findings suggest the possibility that systemic vascular indices may provide proxy measures of cerebrovascular dysfunction and reinforce the importance of achieving greater understanding of interaction between systemic vascular disease and brain dysfunction among elderly people with cardiovascular disease.

Clock drawing errors in dementia: neuropsychological and neuroanatomical considerations.

Objectives:A clock drawing test scoring system is presented to explore the neuropsychological/neuroanatomic components underlying clock drawing in patients initially diagnosed with Alzheimer disease, ischemic vascular dementia associated with white matter alterations, and Parkinson disease. Methods:Fourteen clock drawing test errors were scored to create 4 clock drawing test subscales that assess different underlying cognitive operations. Results:In the command condition, errors on the Time subscale were correlated with impairment on executive control measures. In the copy condition, errors on the Perseveration/Pull to Stimulus subscale was also correlated with executive control measures. Patients presenting with mild (low) magnetic resonance imaging white matter alterations, significant (high) white matter alterations, and Parkinson disease were compared. In the command condition, the low white matter alterations group made fewer total errors than the Parkinson disease group. In the copy condition, the low white matter alterations group made fewer errors on the Time, Spatial Layout, and Perseveration/Pull to Stimulus clock drawing test subscales than the high white matter alterations or Parkinson disease groups. Few differences were noted between the high white matter alterations and Parkinson disease groups. Discussion:Our data suggest that heavy demands on executive control associated with the interruption of large-scale cortical–subcortical neural networks underlie impairment in clock drawing in mild dementia.