Alireza Salami

Longitudinal evidence for diminished frontal cortex function in aging

Cross-sectional estimates of age-related changes in brain structure and function were compared with 6-y longitudinal estimates. The results indicated increased sensitivity of the longitudinal approach as well as qualitative differences. Critically, the cross-sectional analyses were suggestive of age-related frontal overrecruitment, whereas the longitudinal analyses revealed frontal underrecruitment with advancing age. The cross-sectional observation of overrecruitment reflected a select elderly sample. However, when followed over time, this sample showed reduced frontal recruitment. These findings dispute inferences of true age changes on the basis of age differences, hence challenging some contemporary models of neurocognitive aging, and demonstrate age-related decline in frontal brain volume as well as functional response.

Age-related white matter microstructural differences partly mediate age-related decline in processing speed but not cognition☆

Aging is associated with declining cognitive performance as well as structural changes in brain gray and white matter (WM). The WM deterioration contributes to a disconnection among distributed brain networks and may thus mediate age-related cognitive decline. The present diffusion tensor imaging (DTI) study investigated age-related differences in WM microstructure and their relation to cognition (episodic memory, visuospatial processing, fluency, and speed) in a large group of healthy subjects (n=287) covering 6 decades of the human life span. Age related decreases in fractional anisotropy (FA) and increases in mean diffusivity (MD) were observed across the entire WM skeleton as well as in specific WM tracts, supporting the WM degeneration hypothesis. The anterior section of the corpus callosum was more susceptible to aging compared to the posterior section, lending support to the anterior-posterior gradient of WM integrity in the corpus callosum. Finally, and of critical interest, WM integrity differences were found to mediate age-related reductions in processing speed but no significant mediation was found for episodic memory, visuospatial ability, or fluency. These findings suggest that compromised WM integrity is not a major contributing factor to declining cognitive performance in normal aging. This article is part of a Special Issue entitled: Imaging Brain Aging and Neurodegenerative disease.

Elevated hippocampal resting-state connectivity underlies deficient neurocognitive function in aging

Significance Aging is accompanied by disruptive alterations in large-scale brain systems, such as the default mode network (DMN) and the associated hippocampus (HC) subsystem, which support higher cognitive functions. However, the exact form of DMN–HC alterations and concomitant memory deficits is largely unknown. We identified age-related decrements in resting-state functional connectivity of the cortical DMN, whereas elevated connectivity between the bilateral HC was found along with attenuated HC–cortical connectivity. Critically, elevated HC at rest restricts the degree to which HC interacts with other brain regions during memory tasks, and thus results in memory deficits. This study provides empirical evidence of how the relationship between the DMN and HC breaks down in aging and how such alterations underlie deficient mnemonic processing. The brain is not idle during rest. Functional MRI (fMRI) studies have identified several resting-state networks, including the default mode network (DMN), which contains a set of cortical regions that interact with a hippocampus (HC) subsystem. Age-related alterations in the functional architecture of the DMN and HC may influence memory functions and possibly constitute a sensitive biomarker of forthcoming memory deficits. However, the exact form of DMN–HC alterations in aging and concomitant memory deficits is largely unknown. Here, using both task and resting data from 339 participants (25–80 y old), we have demonstrated age-related decrements in resting-state functional connectivity across most parts of the DMN, except for the HC network for which age-related elevation of connectivity between left and right HC was found along with attenuated HC–cortical connectivity. Elevated HC connectivity at rest, which was partly accounted for by age-related decline in white matter integrity of the fornix, was associated with lower cross-sectional episodic memory performance and declining longitudinal memory performance over 20 y. Additionally, elevated HC connectivity at rest was associated with reduced HC neural recruitment and HC–cortical connectivity during active memory encoding, which suggests that strong HC connectivity restricts the degree to which the HC interacts with other brain regions during active memory processing revealed by task fMRI. Collectively, our findings suggest a model in which age-related disruption in cortico–hippocampal functional connectivity leads to a more functionally isolated HC at rest, which translates into aberrant hippocampal decoupling and deficits during mnemonic processing.

Opposing Effects of Aging on Large-Scale Brain Systems for Memory Encoding and Cognitive Control

Episodic memory declines with advancing age. Neuroimaging studies have associated such decline to age-related changes in general cognitive-control networks as well as to changes in process-specific encoding or retrieval networks. To assess the specific influence of aging on encoding and retrieval processes and associated brain systems, it is vital to dissociate encoding and retrieval from each other and from shared cognitive-control processes. We used multivariate partial-least-squares to analyze functional magnetic resonance imaging data from a large population-based sample (n = 292, 25–80 years). The participants performed a face-name paired-associates task and an active baseline task. The analysis revealed two significant network patterns. The first reflected a process-general encoding-retrieval network that included frontoparietal cortices and posterior hippocampus. The second pattern dissociated encoding and retrieval networks. The anterior hippocampus was differentially engaged during encoding. Brain scores, representing whole-brain integrated measures of how strongly an individual recruited a brain network, were correlated with cognitive performance and chronological age. The scores from the general cognitive-control network correlated negatively with episodic memory performance and positively with age. The encoding brain scores, which strongly reflected hippocampal functioning, correlated positively with episodic memory performance and negatively with age. Univariate analyses confirmed that bilateral hippocampus showed the most pronounced activity reduction in older age, and brain structure analyses found that the activity reduction partly related to hippocampus atrophy. Collectively, these findings suggest that age-related structural brain changes underlie age-related reductions in the efficient recruitment of a process-specific encoding network, which cascades into upregulated recruitment of a general cognitive-control network.

Effects of vascular risk factors and APOE ε4 on white matter integrity and cognitive decline

Objective: To investigate the effects of vascular risk factors and APOE status on white matter microstructure, and subsequent cognitive decline among older people. Methods: This study included 241 participants (age 60 years and older) from the population-based Swedish National Study on Aging and Care in Kungsholmen in central Stockholm, Sweden, who were free of dementia and stroke at baseline (2001–2004). We collected data through interviews, clinical examinations, and laboratory tests. We measured fractional anisotropy (FA) and mean diffusivity (MD) on diffusion tensor imaging, and estimated volume of white matter hyperintensities using automatic segmentation. We assessed global cognitive function with the Mini-Mental State Examination at baseline and at 3- and/or 6-year follow-up. We analyzed the data using multivariate linear regression and linear mixed models. Results: Heavy alcohol consumption, hypertension, and diabetes were significantly associated with lower FA or higher MD (p < 0.05). When aggregating heavy alcohol consumption, hypertension, and diabetes together with current smoking, having an increasing number of these 4 factors concurrently was associated with decreasing FA and increasing MD (ptrend < 0.01), independent of white matter hyperintensities. Vascular risk factors and APOE ε4 allele interacted to negatively affect white matter microstructure; having multiple (≥2) vascular factors was particularly detrimental to white matter integrity among APOE ε4 carriers. Lower tertile of FA and upper tertile of MD were significantly associated with faster Mini-Mental State Examination decline. Conclusions: Vascular risk factors are associated with reduced white matter integrity among older adults, which subsequently predicted faster cognitive decline. The detrimental effects of vascular risk factors on white matter microstructure were exacerbated among APOE ε4 carriers.

Changes in perceptual speed and white matter microstructure in the corticospinal tract are associated in very old age

The integrity of the brains white matter is important for neural processing and displays age-related differences, but the contribution of changes in white matter to cognitive aging is unclear. We used latent change modeling to investigate this issue in a sample of very old adults (aged 81-103 years) assessed twice with a retest interval of 2.3 years. Using diffusion-tensor imaging, we probed white matter microstructure by quantifying mean fractional anisotropy and mean diffusivity of six major white matter tracts. Measures of perceptual speed, episodic memory, letter fluency, category fluency, and semantic memory were collected. Across time, alterations of white matter microstructure in the corticospinal tract were associated with decreases of perceptual speed. This association remained significant after statistically controlling for changes in white matter microstructure in the entire brain, in the other demarcated tracts, and in the other cognitive abilities. Changes in brain volume also did not account for the association. We conclude that white matter microstructure is a potent correlate of changes in sensorimotor aspects of behavior in very old age, but that it is unclear whether its impact extends to higher-order cognition.

Neuroplasticity in response to cognitive behavior therapy for social anxiety disorder.

Patients with anxiety disorders exhibit excessive neural reactivity in the amygdala, which can be normalized by effective treatment like cognitive behavior therapy (CBT). Mechanisms underlying the brain’s adaptation to anxiolytic treatments are likely related both to structural plasticity and functional response alterations, but multimodal neuroimaging studies addressing structure–function interactions are currently missing. Here, we examined treatment-related changes in brain structure (gray matter (GM) volume) and function (blood–oxygen level dependent, BOLD response to self-referential criticism) in 26 participants with social anxiety disorder randomly assigned either to CBT or an attention bias modification control treatment. Also, 26 matched healthy controls were included. Significant time × treatment interactions were found in the amygdala with decreases both in GM volume (family-wise error (FWE) corrected PFWE=0.02) and BOLD responsivity (PFWE=0.01) after successful CBT. Before treatment, amygdala GM volume correlated positively with anticipatory speech anxiety (PFWE=0.04), and CBT-induced reduction of amygdala GM volume (pre–post) correlated positively with reduced anticipatory anxiety after treatment (PFWE⩽0.05). In addition, we observed greater amygdala neural responsivity to self-referential criticism in socially anxious participants, as compared with controls (PFWE=0.029), before but not after CBT. Further analysis indicated that diminished amygdala GM volume mediated the relationship between decreased neural responsivity and reduced social anxiety after treatment (P=0.007). Thus, our results suggest that improvement-related structural plasticity impacts neural responsiveness within the amygdala, which could be essential for achieving anxiety reduction with CBT.

Dopamine D2 receptor availability is linked to hippocampal–caudate functional connectivity and episodic memory

Significance Cognitive functioning depends in part on dopamine neurotransmission in the brain. Research implicates the dopamine D1 receptor family in cognitive functions linked to the prefrontal cortex, such as working memory. The dopamine D2 receptor family has also been linked to cognition, but it remains unclear to which cognitive functions it is specifically related. We examined the relation of D2 receptors to episodic memory, working memory, and speed of processing. D2 receptors in the caudate and hippocampus were related to episodic memory and modulated caudate–hippocampal functional connections. These findings link the dopamine D2 system to hippocampus-based cognitive functions. D1 and D2 dopamine receptors (D1DRs and D2DRs) may contribute differently to various aspects of memory and cognition. The D1DR system has been linked to functions supported by the prefrontal cortex. By contrast, the role of the D2DR system is less clear, although it has been hypothesized that D2DRs make a specific contribution to hippocampus-based cognitive functions. Here we present results from 181 healthy adults between 64 and 68 y of age who underwent comprehensive assessment of episodic memory, working memory, and processing speed, along with MRI and D2DR assessment with [11C]raclopride and PET. Caudate D2DR availability was positively associated with episodic memory but not with working memory or speed. Whole-brain analyses further revealed a relation between hippocampal D2DR availability and episodic memory. Hippocampal and caudate D2DR availability were interrelated, and functional MRI-based resting-state functional connectivity between the ventral caudate and medial temporal cortex increased as a function of caudate D2DR availability. Collectively, these findings indicate that D2DRs make a specific contribution to hippocampus-based cognition by influencing striatal and hippocampal regions, and their interactions.

Genetics and Functional Imaging: Effects of APOE, BDNF, COMT, and KIBRA in Aging

Increasing evidence from cross-sectional and longitudinal molecular-genetic studies suggests that effects of common genetic variations on cognitive functioning increase with aging. We review the influence of candidate genes on brain functioning in old age, focusing on four genetic variations that have been extensively investigated: APOE, BDNF, COMT, and KIBRA. Similar to the behavioral evidence, there are reports from age-comparative studies documenting stronger genetic effects on measures of brain functioning in older adults compared to younger adults. This pattern suggests disproportionate impairments of neural processing among older individuals carrying disadvantageous genotypes. We discuss various factors, including gene-gene interactions, study population characteristics, lifestyle factors, and diseases, that need to be considered in future studies and may help understand inconsistent findings in the extant literature.

BOLD Variability is Related to Dopaminergic Neurotransmission and Cognitive Aging

Dopamine (DA) losses are associated with various aging-related cognitive deficits. Typically, higher moment-to-moment brain signal variability in large-scale patterns of voxels in neocortical regions is linked to better cognitive performance and younger adult age, yet the physiological mechanisms regulating brain signal variability are unknown. We explored the relationship among adult age, DA availability, and blood oxygen level-dependent (BOLD) signal variability, while younger and older participants performed a spatial working memory (SWM) task. We quantified striatal and extrastriatal DA D1 receptor density with [(11)C]SCH23390 and positron emission tomography in all participants. We found that BOLD variability in a neocortical region was negatively related to age and positively related to SWM performance. In contrast, BOLD variability in subcortical regions and bilateral hippocampus was positively related to age and slower responses, and negatively related to D1 density in caudate and dorsolateral prefrontal cortex. Furthermore, BOLD variability in neocortical regions was positively associated with task-related disengagement of the default-mode network, a network whose activation needs to be suppressed for efficient SWM processing. Our results show that age-related DA losses contribute to changes in brain signal variability in subcortical regions and suggest a potential mechanism, by which neocortical BOLD variability supports cognitive performance.