Olfactory impairment is a potential marker for prodromal dementia, but the underlying mechanisms are poorly understood. This population‐based study included 4214 dementia‐free participants (age ≥65 ...years). Olfaction was assessed using the 16‐item Sniffin’ Sticks identification test. In the subsamples, we measured plasma amyloid beta (Aβ)40, Aβ42, total tau, and neurofilament light chain (NfL; n = 1054); and quantified hippocampal, entorhinal cortex, and white matter hyperintensity (WMH) volumes, and Alzheimer's disease (AD)‐signature cortical thickness (n = 917). Data were analyzed with logistic and linear regression models. In the total sample, mild cognitive impairment (MCI) was diagnosed in 1102 persons (26.2%; amnestic MCI, n = 931; non‐amnestic MCI, n = 171). Olfactory impairment was significantly associated with increased likelihoods of MCI, amnestic MCI, and non‐amnestic MCI. In the subsamples, anosmia was significantly associated with higher plasma total tau and NfL concentrations, smaller hippocampal and entorhinal cortex volumes, and greater WMH volume, and marginally with lower AD‐signature cortical thickness. These results suggest that cerebral neurodegenerative and microvascular lesions are common neuropathologies linking anosmia with MCI in older adults.
Prospective memory (PM) denotes the ability to remember to perform actions in the future. It has been argued that standard laboratory paradigms fail to capture core aspects of PM.
We combined ...functional MRI, virtual reality, eye-tracking and verbal reports to explore the dynamic allocation of neurocognitive processes during a naturalistic PM task where individuals performed errands in a realistic model of their residential town. Based on eye movement data and verbal reports, we modeled PM as an iterative loop of five sustained and transient phases: intention maintenance before target detection (TD), TD, intention maintenance after TD, action, and switching, the latter representing the activation of a new intention in mind. The fMRI analyses revealed continuous engagement of a top-down fronto-parietal network throughout the entire task, likely subserving goal maintenance in mind. In addition, a shift was observed from a perceptual (occipital) system while searching for places to go, to a mnemonic (temporo-parietal, fronto-hippocampal) system for remembering what actions to perform after TD. Updating of the top-down fronto-parietal network occurred at both TD and switching, the latter likely also being characterized by frontopolar activity.
Taken together, these findings show how brain systems complementary interact during real-world PM, and support a more complete model of PM that can be applied to naturalistic PM tasks and that we named PROspective MEmory DYnamic (PROMEDY) model because of its dynamics on both multi-phase iteration and the interactions of distinct neurocognitive networks.
To identify brain magnetic resonance imaging (MRI) signatures characterizing people with different patterns of decline in cognition and motor function.
In the Swedish National Study on Aging and Care ...in Kungsholmen, Stockholm, 385 participants had available repeated brain MRI examinations, where markers of brain volumes and white matter integrity were assessed. The speed of cognitive and motor decline was estimated as the rate of a Mini-Mental State Examination and gait speed decline over 12 years (linear mixed models), and further dichotomized into the upper (25% fastest rate of decline) versus the lower quartiles. Participants were grouped in slow/no decliners (reference), isolated motor decliners, isolated cognitive decliners, and cognitive and motor decliners. We estimated the associations between changes in brain markers (linear mixed models) and baseline diffusion tensor imaging measures (linear regression model) and the 4 decline patterns.
Individuals with concurrent cognitive and motor decline (n = 51) experienced the greatest loss in the total brain (β: -12.3; 95% confidence interval CI: -18.2; -6.38) and hippocampal (β: -0.25; 95% CI: -0.34; -0.16) volumes, the steepest accumulation of white matter hyperintensities (β: 1.61; 95% CI: 0.54; 2.68), and the greatest ventricular enlargement (β: 2.07; 95% CI: 0.67; 3.47). Compared to the reference, those only experiencing cognitive decline presented with steeper hippocampal volume loss, whereas those exhibiting only motor decline displayed a greater white matter hyperintensities burden. Lower microstructural white matter integrity was associated with concurrent cognitive and motor decline.
Concurrent cognitive and motor decline is accompanied by rapidly evolving and complex brain pathology involving both gray and white matter. Isolated cognitive and motor declines seem to exhibit brain damage with different qualitative features.
► Taking tests enhance learning. ► FMRI was used to investigate the neurocognitive mechanisms of this testing effect. ► The findings indicate that testing boosts systems-level consolidation.
The ...“testing effect” refers to the beneficial effects on memory performance from being tested, a phenomenon of potentially substantial implications in educational settings. While the effect itself is firmly established in previous research, little is known of related brain changes. Here we used fMRI and a parametric design to show that repeated successful retrieval during a memory acquisition phase leads to higher brain activity in the anterior cingulate cortex (ACC) at a subsequent test phase. The extent of ACC activity increase correlated across individuals with memory performance 5 months later. In relation to recent research that associates the ACC with memory consolidation processes, the present results suggest that the testing effect may operate at the systems level by enhancing consolidation of memory representations.
Concomitant exploration of structural, functional, and neurochemical brain mechanisms underlying age‐related cognitive decline is crucial in promoting healthy aging. Here, we present the DopamiNe, ...Age, connectoMe, and Cognition (DyNAMiC) project, a multimodal, prospective 5‐year longitudinal study spanning the adult human lifespan. DyNAMiC examines age‐related changes in the brain’s structural and functional connectome in relation to changes in dopamine D1 receptor availability (D1DR), and their associations to cognitive decline. Critically, due to the complete lack of longitudinal D1DR data, the true trajectory of one of the most age‐sensitive dopamine systems remains unknown. The first DyNAMiC wave included 180 healthy participants (20–80 years). Brain imaging included magnetic resonance imaging assessing brain structure (white matter, gray matter, iron), perfusion, and function (during rest and task), and positron emission tomography (PET) with the 11CSCH23390 radioligand. A subsample (n = 20, >65 years) was additionally scanned with 11Craclopride PET measuring D2DR. Age‐related variation was evident for multiple modalities, such as D1DR; D2DR, and performance across the domains of episodic memory, working memory, and perceptual speed. Initial analyses demonstrated an inverted u‐shaped association between D1DR and resting‐state functional connectivity across cortical network nodes, such that regions with intermediate D1DR levels showed the highest levels of nodal strength. Evident within each age group, this is the first observation of such an association across the adult lifespan, suggesting that emergent functional architecture depends on underlying D1DR systems. Taken together, DyNAMiC is the largest D1DR study worldwide, and will enable a comprehensive examination of brain mechanisms underlying age‐related cognitive decline.
This study presents the DopamiNe, Age, connectoMe, and Cognition (DyNAMiC) project, a multimodal, prospective 5‐year longitudinal study of the adult human lifespan. DyNAMiC examines age‐related differences in the brain’s structural and functional connectomes in relation to the dopaminergic (DA) D1 receptor system, and their associations to cognition in aging. Initial findings demonstrate an inverted u‐shaped effect of DA D1 receptor availability on functional connectivity across cortical network nodes.
INTRODUCTION
We quantified the association of mild (ie, involving one or two body systems) and complex (ie, involving ≥3 systems) multimorbidity with structural brain changes in older adults.
METHODS
...We included 390 dementia‐free participants aged 60+ from the Swedish National Study on Aging and Care in Kungsholmen who underwent brain magnetic resonance imaging at baseline and after 3 and/or 6 years. Using linear mixed models, we estimated the association between multimorbidity and changes in total brain tissue, ventricular, hippocampal, and white matter hyperintensities volumes.
RESULTS
Compared to non‐multimorbid participants, those with complex multimorbidity showed the steepest reduction in total brain (β*time −0.03, 95% CI −0.05, −0.01) and hippocampal (β*time −0.05, 95% CI −0.08, −0.03) volumes, the greatest ventricular enlargement (β*time 0.03, 95% CI 0.01, 0.05), and the fastest white matter hyperintensities accumulation (β*time 0.04, 95% CI 0.01, 0.07).
DISCUSSION
Multimorbidity, particularly when involving multiple body systems, is associated with accelerated structural brain changes, involving both neurodegeneration and vascular pathology.
Highlights
Multimorbidity accelerates structural brain changes in cognitively intact older adults
These brain changes encompass both neurodegeneration and cerebrovascular pathology
The complexity of multimorbidity is associated with the rate of brain changes’ progression
•EEG microstate topographies differ between controls and memory clinic patients.•Microstate parameters differ in a gradient-like manner in SCD, MCI and AD patients.•Changes in topography of ...microstate class C correlate with CSF Aβ42 levels.•Changes in topography of microstate class B correlate with CSF p-tau levels.•EEG microstates detect early disruption of neurocognitive networks in AD.
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 Aβ42 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.
Evidence from neuroimaging studies suggests a critical role of hippocampus and inferior frontal gyrus (IFG) in associative relative to item encoding. Here, we investigated similarities and ...differences in functional brain correlates for associative and item memory as a function of encoding instruction. Participants received either incidental (animacy judgments) or intentional encoding instructions while fMRI was employed during the encoding of associations and items. In a subsequent recognition task, memory performance of participants receiving intentional encoding instructions was higher compared with those receiving incidental encoding instructions. Furthermore, participants remembered more items than associations, regardless of encoding instruction. Greater brain activation in the left anterior hippocampus was observed for intentionally compared with incidentally encoded associations, although activity in this region was not modulated by the type of instruction for encoded items. Furthermore, greater activity in the left anterior hippocampus and left IFG was observed during intentional associative compared with item encoding. The same regions were related to subsequent memory of intentionally encoded associations and were thus task relevant. Similarly, connectivity of the anterior hippocampus to the right superior temporal lobe and IFG was uniquely linked to subsequent memory of intentionally encoded associations. Our study demonstrates the differential involvement of anterior hippocampus in intentional relative to incidental associative encoding. This finding likely reflects that the intent to remember triggers a specific binding process accomplished by this region.
We investigated the association of cognitive reserve (CR) with transitions across cognitive states and death.
This population-based cohort study included 2631 participants (age ≥60 years) who were ...dementia-free at baseline and regularly examined up to 15 years. Data were analyzed using the Markov multistate models.
Each 1-point increase in the composite CR score (range: -4.25 to 3.46) was significantly associated with lower risks of transition from normal cognition to cognitive impairment, no dementia (CIND) (multivariable-adjusted hazards ratio = 0.78; 95% confidence interval = 0.72-0.85) and death (0.85; 0.79-0.93), and from CIND to death (0.82; 0.73-0.91), but not from CIND to normal cognition or dementia. A greater composite CR score was associated with a lower risk of transition from CIND to death in people aged 60-72 but not in those aged ≥ 78 years.
CR contributes to cognitive health by delaying cognitive deterioration in the prodromal phase of dementia.
We use Markov multistate model to examine the association between cognitive reserve and transitions across cognitive states and death. A great cognitive reserve contributes to cognitive health by delaying cognitive deterioration in the prodromal phase of dementia. A great cognitive reserve is associated with a lower risk of transition from cognitive impairment, no dementia to death in people at the early stage of old age, but not in those at the late stage of old age.
Abstract Accumulating evidence suggests that engagement in leisure activities is associated with favorable trajectories of cognitive aging, but little is known about brain changes related to both ...activities and cognition. White matter microstructure shows experience-dependent plasticity and declines in aging. Therefore, we investigated the role of change in white matter microstructure in the activities-cognition link. We used repeated assessments of engagement, perceptual speed, and white matter microstructure (probed with diffusion tensor imaging) in a population-based sample of individuals over 80 years without dementia ( n = 442, Mage = 85.1; n = 70 for diffusion tensor imaging; 2 occasions 3 years apart). Using multivariate latent change modeling, we observed positive correlations among changes in predominantly social activities, white matter microstructure, and perceptual speed. Interindividual differences in change in white matter microstructure statistically accounted for the association between change in leisure activities and change in perceptual speed. However, as analyses are based on observational data from 2 measurement occasions, causality remains unclear.
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