Abstract Functional brain imaging studies of normal aging typically show age-related under- and overactivations during episodic memory tasks. Older individuals also undergo nonuniform gray matter ...volume (GMv) loss. Thus, age differences in functional brain activity could at least in part result from local atrophy. We conducted a series of voxel-based blood oxygen level-dependent (BOLD)-GMv analyses to highlight whether age-related under- and overrecruitment was accounted for by GMv changes. Occipital GMv loss accounted for underrecruitment at encoding. Efficiency reduction of sensory-perceptual mechanisms underpinned by these areas may partly be due to local atrophy. At retrieval, local GMv loss accounted for age-related overactivation of left dorsolateral prefrontal cortex, but not of left dorsomedial prefrontal cortex. Local atrophy also accounted for age-related overactivation in left lateral parietal cortex. Activity in these frontoparietal regions correlated with performance in the older group. Atrophy in the overrecruited regions was modest in comparison with other regions as shown by a between-group voxel-based morphometry comparison. Collectively, these findings link age-related structural differences to age-related functional under- as well as overrecruitment.
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.
The impact of prediabetes and diabetes on cognitive decline and the potential underlying mechanisms remain unclear. We investigated whether prediabetes and diabetes accelerate cognitive decline and ...brain aging, and the initial pathological changes linked to microvascular processes.
Nine-year longitudinal data from the Swedish National Study on Aging and Care-Kungsholmen (n = 2746, age ≥60 years) and the magnetic resonance imaging subsample (n = 455) were used. Cognitive function was assessed with Mini-Mental State Examination. Brain magnetic resonance imaging markers included total brain tissue, white matter, gray matter, white matter hyperintensities, and hippocampal volumes.
Compared with diabetes-free status, prediabetes and diabetes were independently associated with accelerated cognitive decline. Prediabetes was cross-sectionally associated with smaller total brain tissue volume (P < .01), particularly smaller white matter volume. Diabetes was associated with larger white matter hyperintensities volume. Longitudinally, diabetes was associated with faster white matter hyperintensities accumulation. No associations between prediabetes or diabetes and hippocampal volume were found.
Diabetes and prediabetes accelerate cognitive decline and might predict microvascular lesions among dementia-free older adults.
•Higher iron load was linked to lower D1-like receptor availability across the adult lifespan.•The interplay between high iron, low D1DR and older age explained lower task-related brain ...response.•Lower brain response was related to deficient task performance.•The iron-DA coupling can help progress the understanding of the mechanisms behind DA-related neurodegeneration.
Brain iron overload and decreased integrity of the dopaminergic system have been independently reported as brain substrates of cognitive decline in aging. Dopamine (DA), and iron are co-localized in high concentrations in the striatum and prefrontal cortex (PFC), but follow opposing age-related trajectories across the lifespan. DA contributes to cellular iron homeostasis and the activation of D1-like DA receptors (D1DR) alleviates oxidative stress-induced inflammatory responses, suggesting a mutual interaction between these two fundamental components. Still, a direct in-vivo study testing the iron-D1DR relationship and their interactions on brain function and cognition across the lifespan is rare. Using PET and MRI data from the DyNAMiC study (n=180, age=20-79, %50 female), we showed that elevated iron content was related to lower D1DRs in DLPFC, but not in striatum, suggesting that dopamine-rich regions are less susceptible to elevated iron. Critically, older individuals with elevated iron and lower D1DR exhibited less frontoparietal activations during the most demanding task, which in turn was related to poorer working-memory performance. Together, our findings suggest that the combination of elevated iron load and reduced D1DR contribute to disturbed PFC-related circuits in older age, and thus may be targeted as two modifiable factors for future intervention.
Abstract With age, the brain undergoes both structural and functional alterations, probably resulting in reported cognitive declines. Relatively few investigations have sought to identify those areas ...that remain intact with aging, or undergo the least deterioration, which might underlie cognitive preservations. Our aim here was to establish a comprehensive profile of both structural and functional changes in the aging brain, using up-to-date voxel-based methodology (i.e. optimized voxel-based morphometry (VBM) procedure; resting-state18 FDG-PET with correction for partial volume effects (PVE)) in 45 optimally healthy subjects aged 20–83 years. Negative and positive correlations between age and both gray matter (GM) volume and18 FDG uptake were assessed. The frontal cortex manifested the greatest deterioration, both structurally and functionally, whereas the anterior hippocampus, the thalamus and (functionally) the posterior cingulate cortex were the least affected. Our results support the developmental theory which postulates that the first regions to emerge phylogenetically and ontogenetically are the most resistant to age effects, and the last ones the most vulnerable. Furthermore, the lesser affected anterior hippocampal region, together with the lesser functional alteration of the posterior cingulate cortex, appear to mark the parting of the ways between normal aging and Alzheimer's disease, which is characterized by early and prominent deterioration of both structures.
Ageing is associated with excessive free brain iron, which may induce oxidative stress and neuroinflammation, likely causing cognitive deficits. Lack of dopamine may be a factor behind the increase ...of iron with advancing age, as it has an important role in cellular iron homoeostasis. We investigated the effect of
Val 158 Met (rs4680), a polymorphism crucial for dopamine degradation and proxy for endogenous dopamine, on iron accumulation and working memory in a longitudinal lifespan sample (
= 208, age 20-79 at baseline, mean follow-up time = 2.75 years) using structural equation modelling. Approximation of iron content was assessed using quantitative susceptibility mapping in striatum and dorsolateral prefrontal cortex (DLPFC). Iron accumulated in both striatum and DLPFC during the follow-up period. Greater iron accumulation in DLPFC was associated with more deleterious change in working memory. Older (age 50-79) Val homozygotes (with presumably lower endogenous dopamine) accumulated more iron than older Met carriers in both striatum and DLPFC, no such differences were observed among younger adults (age 20-49). In conclusion, individual differences in genetic predisposition related to low dopamine levels increase iron accumulation, which in turn may trigger deleterious change in working memory. Future studies are needed to better understand how dopamine may modulate iron accumulation across the human lifespan.
Olfactory function, and specifically semantic olfactory memory (i.e., odor identification), has frequently been shown to predict cognitive functioning across multiple domains in old age. This ...observation suggests that olfactory function can serve as a marker for the integrity of temporolimbic cortical networks, but a clear delineation of this association is still missing. To address this issue, the present study employed voxel-based morphometry in a region of interest-based design to determine the extent to which gray matter volumes of core olfactory and memory areas are associated with olfactory memory performance in an aging population free from neurodegenerative disease. We further aimed to determine potential overlap in structural anatomical correlates, and differences in association strength, for semantic and episodic olfactory memory. Structural magnetic resonance imaging (MRI), episodic and semantic odor memory and episodic and semantic verbal memory data were collected in 422 participants from the Swedish National Study on Aging and Care in Kungsholmen (SNAC-K), all aged ≥ 60 years. Controlling for age and education, semantic, but not episodic, olfactory memory was positively related to gray matter volume in a cluster extending from the anterior hippocampus and amygdala into the posterior piriform cortex. The observed associations remained even when verbal memory performance was controlled for, supporting a link between the olfactory memory domain and cortical volume over and above more generalized memory abilities. As such, our data provide evidence for distinct functional-structural associations for semantic odor memory, supporting the idea of temporolimbic integrity as a neurobiological substrate linking olfactory function to cognitive health in old age.
•Olfactory semantic memory performance was linked to frontotemporal gray matter volume.•Associations remained significant when verbal memory performance was controlled for.•No significant correlates of olfactory episodic memory were found.
Resting-state spontaneous fluctuations have revealed individual differences in the functional architecture of brain networks. Previous research indicates that the striatal network shows alterations ...in neurological conditions but also in normal aging. However, the neurobiological mechanisms underlying individual differences in striatal resting-state networks (RSNs) have been less explored. One candidate that may account for individual differences in striatal spontaneous activity is the level of local iron accumulation. Excessive iron in the striatum has been linked to a loss of structural integrity and reduced brain activity during task performance in aging. Using independent component analysis in a sample of 42 younger and older adults, we examined whether higher striatal iron content, quantified using relaxometry, underlies individual differences in spontaneous fluctuations of RSNs in general, and of the striatum in particular. Higher striatal iron content was linked to lower spontaneous coherence within both caudate and putamen RSNs regardless of age. No such links were observed for other RSNs. Moreover, the number of connections between the putamen and other RSNs was negatively associated with iron content, suggesting that iron modulated the degree of cross-talk between the striatum and cerebral cortex. Importantly, these associations were primarily driven by the older group. Finally, a positive association was found between coherence in the putamen and motor performance, suggesting that this spontaneous activity is behaviorally meaningful. A follow-up mediation analysis also indicated that functional connectivity may mediate the link between striatal iron and motor performance. Our preliminary findings suggest that striatal iron potentially accounts for individual differences in spontaneous striatal fluctuations, and might be used as a locus of intervention.
•Striatal iron was associated with functional connectivity in RSNs.•Higher iron content was linked to lower within-network connectivity in caudate and putamen.•Within-network connectivity of the putamen was associated with motor performance.•Iron modulated between-network connectivity of the putamen to the rest of the brain.•Functional connectivity is a potential mediator between striatal iron and motor performance.
We investigated the association of load and accumulation of white matter hyperintensities (WMHs) with rate of cognitive decline. This population-based study included 510 dementia-free people (age ...≥60 years) who had repeated measures of global and regional (lobar, deep, periventricular) WMHs up to 6 years (from 2001–2003 to 2007–2010) and repeated measures of cognitive function (episodic memory, semantic memory, category fluency, letter fluency, executive function, perceptual speed) up to 15 years (from 2001–2004 to 2016–2019). We found that greater baseline loads of global and regional WMHs were associated with faster decline in letter fluency, perceptual speed, and global cognition. Furthermore, faster accumulation of global, deep, and periventricular WMHs was related to accelerated cognitive decline, primarily in perceptual speed. These data show that WMHs are associated with decline in perceptual speed rather than episodic or semantic memory and that cognitive change is more vulnerable to WMH accumulations in deep and periventricular regions.
Spontaneous mental activity is characterized by dynamic alterations of discrete and stabile brain states called functional microstates that are thought to represent distinct steps of human ...information processing. Electroencephalography (EEG) directly reflects functioning of brain synapses with a uniquely high temporal resolution, necessary for investigation of brain network dynamics. Since synaptic dysfunction is an early event and best correlate of cognitive status and decline in patients along Alzheimer's disease (AD) continuum, EEG microstates might serve as valuable early markers of AD. The present study investigated differences in EEG microstate topographies and parameters (duration, occurrence and contribution) between a large cohort of healthy elderly (n = 308) and memory clinic patients: subjective cognitive decline (SCD, n = 210); mild cognitive impairment (MCI, n = 230) and AD (n = 197) and how they correlate to conventional cerebrospinal fluid (CSF) markers of AD. Four most representative microstate maps assigned as classes A, B (asymmetrical), C and D (symmetrical) were computed from the resting state EEGs since it has been shown previously that this is sufficient to explain most of the resting state EEG data. Statistically different topography of microstate maps were found between the controls and the patient groups for microstate classes A, C and D. Changes in the topography of microstate class C were associated with the CSF A beta 42 levels, whereas changes in the topography of class B were linked with the CSF p-tau levels. Gradient-like increase in the contribution of asymmetrical (A and B) and gradient-like decrease in the contribution of symmetrical (C and D) maps were observed with the more severe stage of cognitive impairment. Our study demonstrated extensive relationship of resting state EEG microstates topographies and parameters with the stage of cognitive impairment and AD biomarkers. Resting state EEG microstates might therefore serve as functional markers of early disruption of neurocognitive networks in patients along AD continuum.
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