Naftali Raz

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.

The cognitive correlates of white matter abnormalities in normal aging: a quantitative review.

Cerebral white matter of asymptomatic people frequently exhibits circumscribed areas of hyperintensity on magnetic resonance (MR) images and hypodensity on computed tomography scans. However, behavioral implications of this phenomenon remain unclear. In this meta-analysis, the authors examine cumulative evidence regarding the cognitive sequelae of white matter abnormalities in adults without dementia. The influence of potential moderator variables, such as neuroimaging technique, location of the lesions, rating scale, and demographic characteristics of the sample on the association between the burden of white matter hyperintensities and cognitive performance was also examined. Results indicate that white matter abnormalities observed on MR images are associated with attenuated performance on tasks of processing speed, immediate and delayed memory, executive functions, and indices of global cognitive functioning. There was no significant link between the white matter hyperintensities and psychometric indices of intelligence or fine motor performance.

Differential effects of aging on memory for content and context: a meta-analysis.

The authors reviewed the evidence of age differences in episodic memory for content of a message and the context associated with it. Specifically, the authors tested a hypothesis that memory for context is more vulnerable to aging than memory for content. In addition, the authors inquired whether effort at encoding and retrieval and type of stimulus material moderate the magnitude of age differences in both memory domains. The results of the meta-analysis of 46 studies confirmed the main hypothesis: Age differences in context memory are reliably greater than those in memory for content. Tasks that required greater effort during retrieval yielded larger age differences in content but not in context memory. The greatest magnitude of age differences in context memory was observed for those contextual features that were more likely to have been encoded independently from content. Possible mechanisms that may underlie age differences in context memory-attentional deficit, reduced working memory capacity, and failure of inhibitory processing are discussed.

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.

Neuroanatomical correlates of cognitive aging: Evidence from structural magnetic resonance imaging.

To examine putative brain substrates of cognitive functions differentially affected by age the authors measured the volume of cortical regions and performance on tests of executive functions, working memory, explicit memory, and priming in healthy adults (18-77 years old). The results indicate that shrinkage of the prefrontal cortex mediates age-related increases in perseveration. The volume of visual processing areas predicted performance on nonverbal working memory tasks. Contrary to the hypotheses, in the examined age range, the volume of limbic structures was unrelated to any of the cognitive functions; verbal working memory, verbal explicit memory, and verbal priming were independent of cortical volumes. Nevertheless, among the participants aged above 60, reduction in the volume of limbic structures predicted declines in explicit memory. Chronological age adversely influenced all cognitive indices, although its effects on priming were only indirect, mediated by declines in verbal working memory.

High Consistency of Regional Cortical Thinning in Aging across Multiple Samples

Cross-sectional magnetic resonance imaging (MRI) studies of cortical thickness and volume have shown age effects on large areas, but there are substantial discrepancies across studies regarding the localization and magnitude of effects. These discrepancies hinder understanding of effects of aging on brain morphometry, and limit the potential usefulness of MR in research on healthy and pathological age-related brain changes. The present study was undertaken to overcome this problem by assessing the consistency of age effects on cortical thickness across 6 different samples with a total of 883 participants. A surface-based segmentation procedure (FreeSurfer) was used to calculate cortical thickness continuously across the brain surface. The results showed consistent age effects across samples in the superior, middle, and inferior frontal gyri, superior and middle temporal gyri, precuneus, inferior and superior parietal cortices, fusiform and lingual gyri, and the temporo-parietal junction. The strongest effects were seen in the superior and inferior frontal gyri, as well as superior parts of the temporal lobe. The inferior temporal lobe and anterior cingulate cortices were relatively less affected by age. The results are discussed in relation to leading theories of cognitive aging.

Neuroanatomical correlates of selected executive functions in middle-aged and older adults: a prospective MRI study.

Neuroanatomical substrates of age-related differences in working memory and perseverative behavior were examined in a sample of healthy adults (50-81 years old). The participants, who were screened for history of neurological, psychiatric, and medical conditions known to be linked to poor cognitive performance, underwent magnetic resonance imaging (MRI) and were administered tests of working memory and perseveration. Regional brain volumes and the volume of white matter hyperintensities (WMH) were measured on magnetic resonance images. The analyses indicate that the volume of the prefrontal cortex (PFC) and the volume of white matter hyperintensities in the prefrontal region are independently associated with age-related increases in perseverative errors on the Wisconsin Card Sorting Test (WCST). When participants taking antihypertensive medication were excluded from the analysis, both the volume of the prefrontal cortex and the frontal white matter hyperintensities (FWMH) still predicted increases in perseveration. Neither reduced volume of the prefrontal cortex nor the FWMH volume was linked to age-associated declines in working memory. The volumes of the fusiform gyrus (FG) and the temporal white matter hyperintensities (TWMH) were unrelated to cognitive performance.

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.

Multiple shifts in the representation of a motor sequence during the acquisition of skilled performance.

When do learning-related changes in performance occur? Here we show that the knowledge of a sequence of movements evolves through several distinctive phases that depend on two critical factors: the amount of practice as well as the passage of time. Our results show the following. (i) Within a given session, large performance gains constituted a signature for motor novelty. Such gains occurred only for newly introduced conditions irrespective of the absolute level of performance. (ii) A single training session resulted in both immediate but also time-dependent, latent learning hours after the termination of practice. Time in sleep determined the time of expression of these delayed gains. Moreover, the delayed gains were sequence-specific, indicating a qualitative change in the representation of the task within 24 h posttraining. (iii) Prolonged training resulted in additional between-session gains that, unlike the effects of a single training session, were confined to the trained hand. Thus, the effects of multisession training were qualitatively different than the immediate and time-dependent effects of a single session. Altogether, our results indicate multiple time-dependent shifts in the representation of motor experience during the acquisition of skilled performance.

Aging white matter and cognition: Differential effects of regional variations in diffusion properties on memory, executive functions, and speed

Disruption of cerebral white matter has been proposed as an explanation for age-related cognitive declines. However, the role of specific regions in specific cognitive declines remains unclear. We used diffusion tensor imaging to examine the associations between regional microstructural integrity of the white matter and performance on age-sensitive cognitive tasks in a sample of healthy adults (N=52, age 19-81 years). White matter integrity was assessed by fractional anisotropy (FA) and apparent diffusion coefficient (ADC) in multiple regions of interest (genu and splenium of corpus callosum, internal capsule limbs, prefrontal, temporal, superior/posterior parietal, occipital white matter) and related to processing speed, working memory, inhibition, task switching, and episodic memory. We found that age and regional white matter integrity differentially influenced cognitive performance. Age-related degradation in anterior brain areas was associated with decreased processing speed and poorer working memory, whereas reduced inhibition and greater task switching costs were linked to decline in posterior areas. Poorer episodic memory was associated with age-related differences in central white matter regions. The observed multiple dissociations among specific age-sensitive cognitive skills and their putative neuroanatomical substrates support the view that age-related cognitive declines are unlikely to stem from a single cause.