Karen M. Rodrigue

Differential aging of the brain: Patterns, cognitive correlates and modifiers

Deciphering the secret of successful aging depends on understanding the patterns and biological underpinnings of cognitive and behavioral changes throughout adulthood. That task is inseparable from comprehending the workings of the brain, the physical substrate of behavior. In this review, we summarize the extant literature on age-related differences and changes in brain structure, including postmortem and noninvasive magnetic resonance imaging (MRI) studies. Among the latter, we survey the evidence from volumetry, diffusion-tensor imaging, and evaluations of white matter hyperintensities (WMH). Further, we review the attempts to elucidate the mechanisms of age-related structural changes by measuring metabolic markers of aging through magnetic resonance spectroscopy (MRS). We discuss the putative links between the pattern of brain aging and the pattern of cognitive decline and stability. We then present examples of activities and conditions (hypertension, hormone deficiency, aerobic fitness) that may influence the course of normal aging in a positive or negative fashion. Lastly, we speculate on several proposed mechanisms of differential brain aging, including neurotransmitter systems, stress and corticosteroids, microvascular changes, calcium homeostasis, and demyelination.

Aging, sexual dimorphism, and hemispheric asymmetry of the cerebral cortex: replicability of regional differences in volume.

We examined age-, sex-, and hemisphere-related differences in the cerebral cortex. Volumes of the cerebral hemispheres and 13 regions of interest (ROIs) were measured on magnetic resonance images of 200 healthy adults. The strength of association between age and volume differed across ROIs. The lateral prefrontal cortex exhibited the greatest age-related differences, whereas significantly weaker associations were observed in the prefrontal white matter, sensory-motor, and visual association regions. The hippocampal shrinkage was significant in people in their mid-fifties. The primary visual, anterior cingulate, the inferior parietal cortices, and the parietal white matter showed no age-related differences. The pattern of age-related regional differences replicated the findings previously obtained on an independent sample drawn from the same population. Men evidenced larger volumes in all ROIs except the inferior parietal lobule, even after sexual dimorphism in body size was statistically controlled. In some regions (hippocampus and fusiform gyrus) men exhibited steeper negative age-related trends than women. Although a typical pattern of global hemispheric asymmetry was observed, the direction and magnitude of regional volumetric asymmetry was as inconsistent as in the previous reports. Thus, a pattern of age-related shrinkage suggesting increased vulnerability of the lateral prefrontal cortex to aging appears stable and replicable, whereas little consistency exists in sex-related and hemispheric differences in regional cortical volumes.

Differential aging of the medial temporal lobe A study of a five-year change

Objective: To test the hypothesis that entorhinal cortex (EC) volume decreases at a slower rate than the hippocampal (HC) volume in healthy adults, and to examine whether the rate of shrinkage increases with age. Methods: Volumes of the HC and EC were measured twice on MRI scans of 54 healthy adults (aged 26 to 82 years), with an average interval of 5 years. Results: Markedly different age trends were noted in the examined regions. The EC showed no age-related differences on both occasions and only minimal age-related change (0.33%/y). By contrast, the HC exhibited significant age-related differences at baseline and at follow-up evaluation and decreased at a faster pace of 0.86%/y. Older participants (aged ≥50 years) showed increased annual shrinkage of the HC (1.18%) and EC shrinkage (0.53%/y). The rate of HC volume loss significantly exceeded that of the EC. No EC shrinkage and modest HC volume reduction were observed in people aged <50 years. Conclusions: Age-related shrinkage occurs in the medial temporal lobes of healthy adults, with significant hippocampal decline and minimal entorhinal changes. In both regions, the rate of decline accelerates with age, although the role of pathologic factors in age-related increase of volume loss merits further investigation.

Trajectories of brain aging in middle-aged and older adults: regional and individual differences.

The human brain changes with age. However, the rate and the trajectories of change vary among the brain regions and among individuals, and the reasons for these differences are unclear. In a sample of healthy middle-aged and older adults, we examined mean volume change and individual differences in the rate of change in 12 regional brain volumes over approximately 30 months. In addition to the baseline assessment, there were two follow-ups, 15 months apart. We observed significant average shrinkage of the hippocampus, entorhinal cortex, orbital-frontal cortex, and cerebellum in each of the intervals. Shrinkage of the hippocampus accelerated with time, whereas shrinkage of the caudate nucleus, prefrontal subcortical white matter, and corpus callosum emerged only at the second follow-up. Throughout both assessment intervals, the mean volumes of the lateral prefrontal and primary visual cortices, putamen, and pons did not change. Significant individual differences in shrinkage rates were observed in the lateral prefrontal cortex, the cerebellum, and all the white matter regions throughout the study, whereas additional regions (medial-temporal structures, the insula, and the basal ganglia) showed significant individual variation in change during the second follow-up. No individual variability was noted in the change of orbital frontal and visual cortices. In two white matter regions, we were able to identify factors associated with individual differences in brain shrinkage. In corpus callosum, shrinkage rate was greater in persons with hypertension, and in the pons, women and carriers of the ApoEepsilon4 allele exhibited declines not noted in the whole sample.

Hypertension and the brain: vulnerability of the prefrontal regions and executive functions.

Untreated hypertension negatively affects brain anatomy and cognitive functions, but the effects of medically treated hypertension are unclear. The authors compared 40 middle-age and older adults diagnosed with essential hypertension to demographically matched normotensive peers. Volumes of 7 brain regions and deep and periventricular white-matter hyperintensities (WMH) were measured on magnetic resonance imaging scans. Performance in 4 cognitive domains (perseveration, working memory, fluid reasoning, and vocabulary knowledge) was evaluated. Persons with hypertension had smaller prefrontal cortex and underlying white matter volumes and increased frontal WMH. No group differences were found in other examined brain regions. Among examined cognitive variables, hypertensive patients committed significantly more perseverative errors. Thus, even controlled hypertension may be associated with deficits in brain structure and cognition, warranting further study.

Vascular health and longitudinal changes in brain and cognition in middle-aged and older adults.

The impact of vascular health on the relations between structural brain changes and cognition was assessed in a longitudinal study of 46 adults, 23 of whom remained healthy for 5 years and 23 of whom had hypertension at baseline or acquired vascular problems during follow-up. At both measurement occasions, the volume of white matter hyperintensities (WMH) and regional brain volumes correlated with age. In 5 years, WMH volume more than doubled in the vascular risk group but did not increase in healthy participants. The frontal lobes had the highest WMH load at baseline and follow-up; the parietal WMH showed the greatest rate of expansion. In the vascular risk group, systolic blood pressure at follow-up correlated with posterior WMH volume. The fastest cortical shrinkage was observed in the prefrontal cortex and the hippocampus. Fluid intelligence correlated with WMH burden and declined along with faster WMH progression. In the vascular risk group, WMH progression and shrinkage of the fusiform cortex correlated with decline in working memory. Thus, poor vascular health contributes to age-related declines in brain and cognition, and some of the age-related declines may be limited to persons with elevated vascular risk.

Shrinkage of the Entorhinal Cortex over Five Years Predicts Memory Performance in Healthy Adults

Lesions in the hippocampus (HC), the entorhinal cortex (EC), and the prefrontal cortex (PFC) are associated with impairment of episodic memory; reduced HC volume is linked to memory declines in dementia; and decline in EC volume predicts progression from mild cognitive impairment to dementia. However, in healthy adults, the relationship between memory and regional volumes is unclear, and no data are available on the relationship of longitudinal regional shrinkage to memory performance in a cognitively intact population. The objective of this study was to examine whether shrinkage of the EC, HC, and PFC over a 5 year period can predict declarative memory performance in healthy adults. The volumes of three brain regions were measured on magnetic resonance images that were acquired twice, 5 years apart. Multiple measures of episodic memory were administered at follow-up. Results indicated that the volume of HC and PFC (but not EC) correlated with age at baseline and follow-up. However, after age differences in memory were taken into account, none of the regional volumes was associated with memory performance at follow-up. In contrast, greater annual rate of shrinkage in EC (but not HC or PFC) predicted poorer memory performance. Thus, in a healthy and educated population, even mild age-related shrinkage of the EC may be a sensitive predictor of memory decline.

β-Amyloid burden in healthy aging Regional distribution and cognitive consequences

Objective: Several lines of evidence suggest that pathologic changes underlying Alzheimer disease (AD) begin years prior to the clinical expression of the disease, underscoring the need for studies of cognitively healthy adults to capture these early changes. The overall goal of the current study was to map the cortical distribution of &bgr;-amyloid (A&bgr;) in a healthy adult lifespan sample (aged 30–89), and to assess the relationship between elevated amyloid and cognitive performance across multiple domains. Methods: A total of 137 well-screened and cognitively normal adults underwent A&bgr; PET imaging with radiotracer 18F-florbetapir. A&bgr; load was estimated from 8 cortical regions. Participants were genotyped for APOE and tested for processing speed, working memory, fluid reasoning, episodic memory, and verbal ability. Results: A&bgr; deposition is distributed differentially across the cortex and progresses at varying rates with age across cortical brain regions. A subset of cognitively normal adults aged 60 and over show markedly elevated deposition, and also had a higher rate of APOE ε4 (38%) than nonelevated adults (19%). A&bgr; burden was linked to poorer cognitive performance on measures of processing speed, working memory, and reasoning. Conclusions: Even in a highly selected lifespan sample of adults, A&bgr; deposition is apparent in some adults and is influenced by APOE status. Greater amyloid burden was related to deleterious effects on cognition, suggesting that subtle cognitive changes accrue as amyloid progresses. GLOSSARY: A&bgr;: &bgr;-amyloid AD: Alzheimer disease DLBS: Dallas Lifespan Brain Study DLPFC: dorsolateral prefrontal cortex ETS: Educational Testing Service FWHM: full width at half maximum GLM: general linear model MCI: mild cognitive impairment OFC: orbital-frontal cortex ROI: region of interest SUVR: standardized uptake value ratio WAIS: Wechsler Adult Intelligence Scale

Age-related differences in regional brain volumes: A comparison of optimized voxel-based morphometry to manual volumetry

Regional manual volumetry is the gold standard of in vivo neuroanatomy, but is labor-intensive, can be imperfectly reliable, and allows for measuring limited number of regions. Voxel-based morphometry (VBM) has perfect repeatability and assesses local structure across the whole brain. However, its anatomic validity is unclear, and with its increasing popularity, a systematic comparison of VBM to manual volumetry is necessary. The few existing comparison studies are limited by small samples, qualitative comparisons, and limited selection and modest reliability of manual measures. Our goal was to overcome those limitations by quantitatively comparing optimized VBM findings with highly reliable multiple regional measures in a large sample (N=200) across a wide agespan (18-81). We report a complex pattern of similarities and differences. Peak values of VBM volume estimates (modulated density) produced stronger age differences and a different spatial distribution from manual measures. However, when we aggregated VBM-derived information across voxels contained in specific anatomically defined regions (masks), the patterns of age differences became more similar, although important discrepancies emerged. Notably, VBM revealed stronger age differences in the regions bordering CSF and white matter areas prone to leukoaraiosis, and VBM was more likely to report nonlinearities in age-volume relationships. In the white matter regions, manual measures showed stronger negative associations with age than the corresponding VBM-based masks. We conclude that VBM provides realistic estimates of age differences in the regional gray matter only when applied to anatomically defined regions, but overestimates effects when individual peaks are interpreted. It may be beneficial to use VBM as a first-pass strategy, followed by manual measurement of anatomically defined regions.

Brain Aging and Its Modifiers: Insights from in Vivo Neuromorphometry and Susceptibility Weighted Imaging

Abstract:  Aging is marked by individual differences and differential vulnerability of cognitive operations and their neural substrates. Cross‐sectional studies of brain volume reveal greater age‐related shrinkage of the prefrontal cortex (PFC) and the hippocampus than in the entorhinal and primary visual cortex. Longitudinal studies of regional brain shrinkage indicate that when individual differences are controlled, larger and broader shrinkage estimates are evident, with most polymodal cortices affected to the same extent. The mechanisms of age‐related shrinkage are unclear. Vascular risk factors may exacerbate brain aging and account for some of the observed declines as both the PFC and the hippocampus show elevated vulnerability to hypertension. MRI techniques that are sensitive to small vessels function, tissue oxygenation, and perfusion may be especially well suited to study brain aging and its vascular modifiers. We present an example of one such technique, susceptibility weighted imaging (SWI), that allows direct measurement of T2* values that reflect deoxy‐ to oxyhemoglobin fraction in blood vessels and iron deposits in cerebral tissue. The T2* shortening is associated with advanced age, but the effect is significantly stronger in the PFC and the hippocampus than the entorhinal and visual cortices. Moreover, T2* is shorter in hypertensive participants than in their matched normotensive counterparts, and the difference is especially prominent in the hippocampus, thus mirroring the findings of the neuromorphometric studies. Future research on brain aging would benefit from combining structural and metabolic techniques in a longitudinal design, as such studies will allow examination of leading–trailing effects of those factors.