Lori L. Beason-Held

Longitudinal Changes in Cerebral Blood Flow in the Older Hypertensive Brain

Background and Purpose— Changes in patterns of regional cerebral blood flow (rCBF) were assessed over a period of 6 years in 14 treated hypertensive participants (HTNs) and 14 age-matched healthy older participants (healthy controls [HCs]) in the Baltimore Longitudinal Study of Aging. Methods— Resting-state PET scans collected at years 1, 3, 5, and 7 were used to determine differences in longitudinal patterns of rCBF change in HTNs relative to HCs. Pulse pressure, arterial pressure, systolic/diastolic blood pressure, and hypertension duration were also correlated with patterns of rCBF change in the HTN group. Results— Relative to HCs, the HTN group shows greater rCBF decreases in prefrontal, anterior cingulate, and occipital areas over time, suggesting that these regions are more susceptible to hypertension-related dysfunction with advancing age. The HTN group also fails to show preservation of function over time in motor regions and in the temporal cortex and hippocampus as observed in HC. Although pulse pressure, mean arterial pressure, and systolic and diastolic pressure all correlate similarly with longitudinal rCBF changes, increased duration of hypertension is associated with decreased rCBF in prefrontal and anterior cingulate areas of functional vulnerability observed in the HTN group. Conclusions— These results show that hypertension significantly affects resting brain function in older individuals and suggest that duration of hypertension contributes significantly to the patterns of change over time.

Subjective Cognitive Complaints and Longitudinal Changes in Memory and Brain Function

OBJECTIVE Subjective cognitive complaints are often used in the diagnosis of memory and other cognitive impairment. This study examined whether cognitive complaints are associated with longitudinal changes in cognition and cross-sectional differences in regional brain function during memory performance in 98 participants with a mean age of 75. METHOD The Cognitive Failures Questionnaire (CFQ) assessed cognitive complaints and mixed effects regression models were used to determine whether mean CFQ scores predicted rates of change in cognitive function over a period of 11.5 years. RESULTS Higher CFQ scores, reflecting increased subjective complaints, were associated with steeper rates of decline in immediate and delayed recall on the California Verbal Learning Test. Voxel-based regression analysis was used to determine the cross-sectional relationship between CFQ scores and regional cerebral blood flow measured by PET during a resting condition and during verbal and figural memory tasks. Higher levels of cognitive complaints were associated with increased activity in insular, lingual and cerebellar areas during memory tasks. CONCLUSIONS These findings offer some support for the validity of subjective cognitive complaints as markers of age related changes in memory and brain activity.

APOE ε4 Genotype and Longitudinal Changes in Cerebral Blood Flow in Normal Aging

OBJECTIVE To study differences in longitudinal changes in regional cerebral blood flow (rCBF) between apolipoprotein E (APOE) epsilon4 carriers and noncarriers in nondemented older adults from the Baltimore Longitudinal Study of Aging using positron emission tomography in order to determine whether there are regionally specific longitudinal changes in rCBF in APOE epsilon4 carriers that might be related to its well-established role as a genetic risk factor for Alzheimer disease. DESIGN, SETTING, AND PARTICIPANTS Using oxygen 15 ([(15)O])-labeled water positron emission tomography and voxel-based analysis, we compared changes in rCBF over an 8-year period between 29 nondemented APOE epsilon4 carriers and 65 noncarriers older than 55 years. Serial neuropsychological data were collected for all participants. RESULTS Widespread differences were observed in longitudinal change in rCBF between epsilon4 carriers and noncarriers. The predominant pattern was greater rCBF decline in epsilon4 carriers. These differences were observed in the frontal, parietal, and temporal cortices. The affected brain regions were those especially vulnerable to pathological changes in Alzheimer disease. Both epsilon4 carriers and noncarriers remained free of clinical diagnoses of dementia or mild cognitive impairment during the course of the study. CONCLUSIONS Our findings suggest that APOE epsilon4-mediated risk for Alzheimer disease is associated with widespread decline in rCBF over time that precedes the onset of dementia. Accelerated rates of decline in brain function in APOE epsilon4 carriers may contribute to an increased risk for Alzheimer disease and a younger age at onset.

Statins and serum cholesterol's associations with incident dementia and mild cognitive impairment

Background Statin use and serum cholesterol reduction have been proposed as preventions for dementia and mild cognitive impairment (MCI). Methods 1604 and 1345 eligible participants from the Baltimore Longitudinal Study of Aging (BLSA) were followed after age 50 for a median time of around 25 years, to examine the incidence of dementia (n=259) and MCI (n=138), respectively. Statin use (ever-use and time-dependent use), total cholesterol levels (TC; first visit and time-dependent), TC change trajectory from first visit and high-density lipoprotein (HDL-C):TC ratio (first visit and time-dependent) were the main exposures of interest. Cox proportional hazards models were used. Results Participants with incident dementia had a higher first-visit TC compared with participants who remained free of dementia and MCI, while first-visit TC was higher among statin ever-users compared with never-users (age-unadjusted associations). Statin users had a two- to threefold lower risk of developing dementia (HR=0.41; 95% CI 0.18 to 0.92), but not MCI, when considering time-dependent ‘statin use’ with propensity score model adjustment. This association remained significant independently of serum cholesterol exposures. An elevated first-visit TC was associated with reduced MCI risk (upper quartile (Q4) vs Q1: HR=0.51; 95% CI 0.29 to 0.90). Compared with the lowest quartile (Q1: 0.00–0.19), HDL-C:TC (time-dependent) in (Q2: 0.19–0.24) was associated with reduced MCI risk (HR=0.58; 95% CI 0.34 to 0.98). Among men only, TC decline from first visit was significantly associated with increased dementia risk (HR=4.21; 95% CI 1.28 to 13.85). Conclusions Statins may have multifactorial effects on dementia but not MCI risk. Future interventions may be warranted, and research should focus on optimal serum TC, HDL-C:TC ratio and TC change trajectories.

I. Longitudinal changes in aging brain function

Changes in brain activity over time were evaluated in a group of older adults in the Baltimore Longitudinal Study of Aging who maintained good physical and cognitive health. Participants underwent PET scans during rest and delayed verbal and figural recognition memory performance at year 1 baseline and at year 9. While memory performance remained stable over the 8 years, longitudinal changes in regional cerebral blood flow were observed within each scan condition. Further analyses revealed distinctive patterns of change related specifically to verbal or figural recognition, as well as longitudinal changes common to all scan conditions. These findings demonstrate that the older brain undergoes functional reorganization with increasing age in healthy, cognitively stable individuals. In view of the stable memory performance, the task-dependent results suggest that age-related changes in brain activity help maintain cognitive function with advancing age.

Alzheimer risk variant CLU and brain function during aging.

BACKGROUND We examined the effect of the novel Alzheimers disease (AD) risk variant rs11136000 single nucleotide polymorphism in the clusterin gene (CLU) on longitudinal changes in resting state regional cerebral blood flow (rCBF) during normal aging and investigated its influence on cognitive decline in presymptomatic stages of disease progression. METHODS Subjects were participants in the Baltimore Longitudinal Study of Aging. A subset of 88 cognitively normal older individuals had longitudinal (15)O-water positron emission tomography measurements of rCBF at baseline and up to eight annual follow-up visits. We also analyzed trajectories of cognitive decline among CLU risk carriers and noncarriers in individuals who remained cognitively normal (n = 599), as well as in those who subsequently converted to mild cognitive impairment or AD (n = 95). RESULTS Cognitively normal carriers of the CLU risk allele showed significant and dose-dependent longitudinal increases in resting state rCBF in brain regions intrinsic to memory processes. There were no differences in trajectories of memory performance between CLU risk carriers and noncarriers who remained cognitively normal. However, in cognitively normal individuals who eventually converted to mild cognitive impairment or AD, CLU risk carriers showed faster rates of decline in memory performance relative to noncarriers in the presymptomatic stages of disease progression. CONCLUSIONS The AD risk variant CLU influences longitudinal changes in brain function in asymptomatic individuals and is associated with faster cognitive decline in presymptomatic stages of disease progression. These results suggest mechanisms underlying the role of CLU in AD and may be important in monitoring disease progression in at-risk elderly.

Longitudinal Cerebral Blood Flow and Amyloid Deposition: An Emerging Pattern?

Although cerebral amyloid deposition may precede cognitive impairment by decades, the relationship between amyloid deposition and longitudinal change in neuronal function has not, to our knowledge, been studied. The aim of this article was to determine whether individuals without dementia with high and low amyloid burden show different patterns of longitudinal regional cerebral blood flow (rCBF) changes in the years preceding measurement of amyloid deposition. Methods: Twenty-eight participants without dementia (mean age ± SD, 82.5 ± 4.8 y; 6 mildly impaired) from the Baltimore Longitudinal Study of Aging underwent yearly resting-state 15O-H2O PET scans for up to 8 y. 11C-PIB images of amyloid deposition were acquired on average 10.8 ± 0.8 y after the first CBF scan. 11C-PIB distribution volume ratios of regions of interest were estimated by fitting a reference-tissue model to the measured time–activity curves. On the basis of mean cortical distribution volume ratios, participants were divided into groups with high or low 11C-PIB retention. Differences in longitudinal rCBF changes between high– and low–11C-PIB groups were investigated by voxel-based analysis. Results: Longitudinal rCBF changes differed significantly between high– (n = 10) and low– (n = 18) 11C-PIB groups (P ≤ 0.001). Greater longitudinal decreases in rCBF in the high–11C-PIB group than in the low–11C-PIB group were seen in right anterior to middle cingulate, right supramarginal gyrus, left thalamus, and midbrain bilaterally. Greater increases in rCBF over time in the high–11C-PIB group were found in left medial and inferior frontal gyri, right precuneus, left inferior parietal lobule, and left postcentral gyrus. Conclusion: In this group of older adults without dementia, those with high 11C-PIB show greater longitudinal declines in rCBF in certain areas, representing regions with greater decrements in neuronal function. Greater longitudinal increases in rCBF are also observed in those with higher amyloid load and may represent an attempt to preserve neuronal function in these regions.

PET reveals occipitotemporal pathway activation during elementary form perception in humans

To define brain regions involved in feature extraction or elementary form perception, regional cerebral blood flow (rCBF) was measured using positron emission tomography (PET) in subjects viewing two classes of achromatic textures. Textures composed of local features (e.g. extended contours and rectangular blocks) produced activation or increased rCBF along the occipitotemporal pathway relative to textures with the same mean luminance, contrast, and spatial-frequency content but lacking organized form elements or local features. Significant activation was observed in striate, extrastriate, lingual, and fusiform cortices as well as the hippocampus and brain stem. On a scan-by-scan basis, increases in rCBF shifted from the occipitotemporal visual cortices to medial temporal (hippocampus) and frontal lobes with increased exposure to only those textures containing local features. These results suggest that local feature extraction occurs throughout the occipitotemporal (ventral) pathway during extended exposure to visually salient stimuli, and may indicate the presence of similar receptive-field mechanisms in both occipital and temporal visual areas of the human brain.

The Impact of Magnetic Resonance Imaging-Detected White Matter Hyperintensities on Longitudinal Changes in Regional Cerebral Blood Flow

White matter hyperintensities are frequently detected on cranial magnetic resonance imaging (MRI) scans of older adults. Given the presumed ischemic contribution to the etiology of these lesions and the posited import of resting brain activity on cognitive function, we hypothesized that longitudinal changes in MRI-detected white matter disease, and its severity at a given time point, would be associated with changes in regional cerebral blood flow (rCBF) over time. We evaluated MRI scans and resting H215O positron emission tomographic rCBF at baseline and after an average of 7.7-year follow-up in Baltimore Longitudinal Study of Aging participants without dementia. Differences in patterns of rCBF were evident at baseline and at follow-up between the group of subjects showing increased white matter disease over the 8-year interval compared with the group with stable white matter ratings. Furthermore, longitudinal changes over time in rCBF also differed between the two groups. Specifically, the group with progressive white matter abnormalities showed greater increase in the right inferior temporal gyrus/fusiform gyrus, right anterior cingulate, and the rostral aspect of the left superior temporal gyrus. Regions of greater longitudinal decrease in this group were evident in the right inferior parietal lobule and at the right occipital pole. Changes in white matter disease over time and its severity at any given time are associated significantly with both cross-sectional and longitudinal patterns of rCBF. The longitudinal increases may reflect cortical compensation mechanisms for reduced efficacy of interregional neural communications that result from white matter deterioration.

Longitudinal study of chronic depressive symptoms and regional cerebral blood flow in older men and women

Late‐life depression is associated with alterations in regional cerebral blood flow (rCBF) and metabolism in a neural network that includes frontostriatal and limbic regions and the cerebellum. Prior studies suggest that clinical depression and subthreshold depressive symptoms (SDS) are associated with similar cognitive deficits and structural brain changes, but little is known about the relationship between SDS and patterns of brain activity. Additionally, the neural correlates of depression have not been fully explored in men and women separately. This study investigated cross‐sectional and longitudinal relationships between SDS and rCBF in older men and women.