Classification Of MeMory InTerventions: Rationale and developmental process of the COMMIT tool

Most people’s cognitive abilities decline with age, with significant and partly genetically driven, individual differences in rate of change. Although APOE ɛ4 and genetic scores for late-onset Alzheimer’s disease (LOAD) have been related to cognitive decline during preclinical stages of dementia, there is limited knowledge concerning genetic factors implied in normal cognitive aging. In the present study, we examined three potential genetic predictors of age-related cognitive decline as follows: (1) the APOE ɛ4 allele, (2) a polygenic score for general cognitive ability (PGS-cog), and (3) a polygenic risk score for late-onset AD (PRS-LOAD). We examined up to six time points of cognitive measurements in the longitudinal population-based Betula study, covering a 25-year follow-up period. Only participants that remained alive and non-demented until the most recent dementia screening (1–3 years after the last test occasion) were included (n = 1087). Individual differences in rate of cognitive change (composite score) were predicted by the PRS-LOAD and APOE ɛ4, but not by PGS-cog. To control for the possibility that the results reflected a preclinical state of Alzheimer’s disease in some participants, we re-ran the analyses excluding cognitive data from the last test occasion to model cognitive change up-until a minimum of 6 years before potential onset of clinical Alzheimers. Strikingly, the association of PRS-LOAD, but not APOE ɛ4, with cognitive change remained. The results indicate that PRS-LOAD predicts individual difference in rate of cognitive decline in normal aging, but it remains to be determined to what extent this reflects preclinical Alzheimer’s disease brain pathophysiology and subsequent risk to develop the disease.

IntroductionWhen we memorize simultaneous items, we not only store information about specific items and/or their locations but also how items are related to each other. Such relational information can be parsed into spatial (spatial configuration) and identity (object configuration) components. Both these configurations are found to support performance during a visual short‐term memory (VSTM) task in young adults. How the VSTM performance of older adults is influenced by object/spatial configuration is less understood, which this study investigated.MethodsTwenty‐nine young adults, 29 normally aging older adults, and 20 older adults with mild cognitive impairment (MCI) completed two yes–no memory‐recognition experiments for four simultaneously presented items (2.5 s). Test display items were presented either at the same locations as the memory items (Experiment 1) or were globally shifted (Experiment 2). One of the test display items (target) was highlighted with a square box; participants indicated whether this item was shown in the preceding memory display. Both experiments comprised four conditions where nontarget items changed as follows: (i) nontarget items remained the same; (ii) nontarget items were replaced by new items; (iii) nontarget items switched locations; (iv) nontarget items were replaced by square boxes.ResultsPerformance (% correct) in both older groups was significantly reduced than young adults in both experiments and each condition. For the MCI adults, significantly reduced performance (vs. normal older adults) was found only for Experiment 1.ConclusionVSTM for simultaneous items declines significantly in normal aging; the decline is not influenced differently by spatial/object configuration change. The ability of VSTM to differentiate MCI from normal cognitive aging is apparent only where the spatial configuration of stimuli is retained at original locations. Findings are discussed in terms of the reduced ability to inhibit irrelevant items and location priming (by repetition) deficits.

A sample of 704 cognitively intact individuals (M age = 63.7 years) performed a battery of cognitive tests on as many as three occasions, at approximately 3-year intervals. The authors used random effects models to analyze cross-sectional relationships between cognitive performance and state anxiety and longitudinal relationships between cognitive change and neuroticism, after controlling for gender, age, and education. Cross-sectionally, higher state anxiety was associated with poorer performance on Wechsler Adult Intelligence Scale Synonyms, WIT III Analogies, Koh's Block Design, two measures of visual learning (Names and Faces and Thurstone's Picture Memory), and, for men, CVB-Scales Digit Span Test and Card Rotations. In longitudinal models, the main effects for neuroticism were significant for Block Design, Symbol Digit, and Names and Faces, but there were no significant interactions among neuroticism, gender, and time. These results provide some support for Eysenck's processing efficiency theory but none for neuroticism as a risk factor for cognitive decline in normal aging.

Age-related changes in striatal function are potentially important for predicting declining memory performance over the adult life span. Here, we used fMRI to measure functional connectivity of caudate subfields with large-scale association networks and positron emission tomography to measure striatal dopamine transporter (DAT) density in 51 older adults (age 65-86 years) who received annual cognitive testing for up to 7 years (mean = 5.59, range 2-7 years). Analyses showed that cortical-caudate functional connectivity was less differentiated in older compared with younger adults (n = 63, age 18-32 years). Unlike in younger adults, the central lateral caudate was less strongly coupled with the frontal parietal control network in older adults. Older adults also showed less "decoupling" of the caudate from other networks, including areas of the default network (DN) and the hippocampal complex. Contrary to expectations, less decoupling between caudate and the DN was not associated with an age-related reduction of striatal DAT, suggesting that neurobiological changes in the cortex may drive dedifferentiation of cortical-caudate connectivity. Reduction of specificity in functional coupling between caudate and regions of the DN predicted memory decline over subsequent years at older ages. The age-related reduction in striatal DAT density also predicted memory decline, suggesting that a relation between striatal functions and memory decline in aging is multifaceted. Collectively, the study provides evidence highlighting the association of age-related differences in striatal function to memory decline in normal aging.

Loss of cerebral white matter structural integrity tracks the gray matter metabolic decline in normal aging

Decision letter for "The impact of stimulus configuration on visual short‐term memory decline in normal aging and mild cognitive impairment"

Decision letter for "The impact of stimulus configuration on visual short‐term memory decline in normal aging and mild cognitive impairment"

The brain of higher organisms, such as nonhuman primates, is particularly rich in lipids, with a gray to white matter ratio of approximately 40 to 60%. White matter primarily consists of lipids, and during normal aging, it undergoes significant degeneration due to myelin pathology, which includes structural abnormalities, like sheath splitting, and local inflammation. Cognitive decline in normal aging, without neurodegenerative diseases, is strongly linked to myelin pathology. Although the exact cause of myelin damage is unclear, older myelin differs from younger myelin, as shown by electron microscopy and altered expression of myelin-related RNAs. However, changes in lipid composition during brain aging remain poorly understood. This study assessed lipid profiles from the frontal lobe corpus callosum, an area where age-related myelin pathology is linked to cognitive decline. Results showed significant changes in lipids with age, revealing distinct age-related profiles. Some lipids that are enriched in myelin sheaths become more saturated, while important structural components, like ceramides, decrease. Disease-associated biomarkers such as cholesterol ester Che (22:6) and sulfatide ST (42:2) also change in older monkeys. Additionally, gene expression of lipid biosynthetic enzymes declines with age, while lipid peroxidation remains stable in the same brain region. This suggests that changes in lipid biosynthesis, rather than oxidative damage, likely account for the differences in lipid composition. Our findings indicate that myelin in the normal aging monkey brain shows diverse lipid changes, which may relate to age-related myelin pathology and could constitute targets for designing nutrient supplements or drugs to rejuvenate the brain's lipidome.

Background: Normal aging is associated with a decline in cognitive abilities, particularly in the domains of psychomotor speed and executive functioning. However, ‘aging,' per se, is not a cause of cognitive decline but rather a variable that likely captures multiple accumulating biological changes over time that collectively affect mental abilities. Recent work has focused on the role of cerebrovascular disease as one of the biological changes. In the current study, we examined whether lobar microbleeds - magnetic resonance imaging (MRI) signal voids due to hemosiderin deposits secondary to cerebral amyloid angiopathy - are associated with cognitive decline in normal aging. Previous studies that reported a relationship between the presence of lobar microbleeds and decreased cognitive abilities have been primarily cross-sectional. Here, we used a retrospective longitudinal design to examine whether the presence of lobar microbleeds is associated with the rate of cognitive decline among non-demented older adults. Methods: Participants came from an ongoing longitudinal community-based aging study, in which subjects are evaluated at 18-24 months intervals and received a full medical, neurological, and neuropsychological examination at each of the follow-up visits. Gradient echo MRI scans were available on 197 non-demented participants (mean age: 84.15 ± 5.02 years). Microbleeds were rated visually on axial view and divided into subcortical (basal ganglia, cerebellum) and lobar (frontal, temporal, parietal, occipital lobe) regions, and confirmed with coronal and sagittal views to exclude artifacts. Cognition was assessed with a neuropsychological battery, providing summary scores for memory, language, executive, and visuospatial abilities. Using general estimating equations (GEE), we compared cognition cross-sectionally between individuals with 2 or more (n = 11) and fewer than 2 (n = 186) lobar microbleeds and examined longitudinal cognitive change beginning 9.47 ± 3.13 years before the MRI scan. Results: Subjects with 2 or more lobar microbleeds had worse executive functioning at the visit closest to the MRI scan (β = -0.044; p < 0.001) and had a faster decline in executive function over time (β = -0.072; p = 0.012) than subjects with fewer than 2 lobar microbleeds. The two groups were similar in age at scan date, education, ethnicity, sex distribution, and cognitive performance at first visit. Conclusions: Lobar microbleeds, a marker of cerebral amyloid angiopathy, are associated with an accelerated rate of executive function decline. The presence of cerebral amyloid angiopathy may be an important source of cognitive decline in aging. Future work should examine how cerebral amyloid angiopathy interacts with neurodegenerative processes, such as Alzheimer's disease.

Older adults undergoing surgery are at risk of postoperative neurocognitive disorders, prompting the need for preoperative cognitive screening in this population. Traditionally, cognitive screening has been conducted in-person using brief assessment tools such as the Montreal Cognitive Assessment (MoCA) or the Mini-Mental State Examination (MMSE). More comprehensive test batteries, such as the Uniform Data Set (UDS) Neuropsychological Battery, and its remote testing version, the Uniform Data Set version 3 tele-adapted test battery (UDS v3.0 T-cog), have been developed to assess cognitive decline in normal aging and disease conditions, but have not been applied in the perioperative setting. We assessed the feasibility of using this remote UDS v3.0 T-cog battery for preoperative cognitive assessment in 81 older adults 65+ scheduled for lower extremity joint replacement surgery. Our results indicate that the UDS v3.0 T-cog achieves 99% completion rates and demonstrates high patient satisfaction. Further, we found 28% of subjects were cognitively impaired in this patient cohort. These findings suggest that the UDS v3.0 T-cog is a feasible tool for assessing cognitive function in the older adult perioperative population. To our knowledge, this is the first study to apply this comprehensive remote test battery in the preoperative setting.

Pick a PACC: Comparing domain-specific and general cognitive composites in Alzheimer disease research.

Theory-of-Mind (ToM) is critical to individual social competence and mental health across the lifespan (Frith, 2008). Though it is often discussed as one broad construct, ToM abilities can be viewed as following a developmental trajectory: from early emotion recognition and gaze following to more advanced inferences about others’ beliefs, perspectives, and intentions (Hutchins et al., 2012). Despite current literature suggesting that ToM abilities may be impaired in late adulthood, there is no consensus regarding whether ToM abilities are differentially affected by age. In this study, we examined younger adults (N=18, aged 19-30) and older adults (N=13, aged 58-76) on their ToM competence across three levels of ToM abilities: Early-ToM (e.g., recognizing a happy face), Basic-ToM (e.g., perspective-taking and false-belief reasoning), and Advanced-ToM (e.g., inferring second-order emotion and false belief). All participants completed a Theory-of-Mind Task Battery consisting of three subscales that assessed the three levels of ToM, where participants viewed vignettes and answered questions about the protagonists’ feelings and beliefs. Overall, younger adults outperformed older adults on the battery, F(1,29)=7.34, p=.011. However, a significant interaction between age and ToM levels (p=.010) revealed that Early and Advanced ToM (ps>.25) were not as affected by age as Basic ToM (p=.007). Older adults have difficulty in inferring others’ perspectives/beliefs while their attributions of emotion and higher-order false beliefs are relatively preserved compared to the younger adults. These findings provide important insights into the impact of age on various levels of ToM and could help inform early detection of ToM decline in normal aging.

Thirty-five young adult and 38 elderly cybernauts, matched for education, sex, alcohol consumption, and time/day of computer use were compared on a computerized simulation of professional activities of daily living (ADLs). The program quantified performance in terms of speed and accuracy on four major constructs: (1) planning (a 30-item office party script); (2) prospective memory (injections, sleep, phone); (3) working memory (PASAT, D2, and CES analogs); and (4) retrospective memory. Participants had to organize an office party, self inject insulin and go to bed at requisite times of day, do “office work” at unpredictable times of day, and answer the phone that blinked but did not ring (near threshold stimulus). The elderly were markedly and equally impaired on all four constructs (F = 24.3, p < .000). The elderly were also equally and markedly impaired on slave and central executive systems (c.f. Baddeley's model) and on event-based and time-based prospective memory (c.f. McDaniel's model)—findings arguing against a “frontal” model of cognitive decline. This supports Salthouse's concept of a “general factors” decline in normal aging due to diffuse deterioration of the brain. On the other hand, as expected from previous findings, the balance of omissiveness/commissiveness was significantly increased in the elderly sample's error profile. Furthermore, the balance of speed and accuracy was significantly increased in the elderly. This defines limits of the “general factors” model. The elderly also markedly underused a clock icon which had to be clicked on to get the virtual time of day necessary for integrating all the required actions. Prospective memory explained 11% of the aging variance despite partialing out of the three other constructs, making it appear as a golden standard of sensititivity to normal aging—though perhaps provided it be implemented in a distracting, multitask, strategically demanding context.

One possible contributing factor for cerebral blood flow (CBF) decline in normal aging is the increase in partial volume effects due to brain atrophy, as cortical thinning can exacerbate the contamination of gray-matter (GM) voxels by other tissue types. This work investigates CBF changes in normal aging of a large elderly cohort aged 54 to 84 and how correction for partial volume effects that would accommodate potential changes in GM might affect this. The study cohort consisted of 474 participants aged 54 to 84 years using pseudo-continuous arterial spin labeling MRI. A volumetric pipeline and a surface-based pipeline were applied to measure global and regional perfusion. Volumetric regions of interest (ROIs) included GM, cerebral white matter, vascular territories, and the brain atlas from the UK Biobank. The cortical parcellation was using Desikan-Killiany atlas. Non-partial volume effect correction (PVEc) and PVEc GM-CBF changes with aging were modeled using linear regressions. Global GM CBF decreased by 0.17 mL/100 g/min per year with aging before PVEc (p < 0.05) and was 0.18 mL/100 g/min after PVEc (p < 0.05). All cortical parcels exhibited CBF decreases with age before PVEc. After PVEc, seven parcels retained decreasing trends. However, GM CBF demonstrated increase with age after PVEc in three parcels. Although decreases in global perfusion are observed with aging before PVEc, perfusion variations appear to be more regionally selective after PVEc. This supports the understanding that variation in cerebral perfusion with age observed with imaging is influenced by regional changes in anatomy that can be accommodated with PVEc, but perfusion variation is still observable even after PVE is accounted for.

The prefrontal cortex and medial temporal lobe are particularly vulnerable to the effects of aging. The disconnection between them is suggested to be an important cause of cognitive decline in normal aging. Here, using multimodal intervention training, we investigated the functional plasticity in resting-state connectivity of these two regions in older adults. The multimodal intervention, comprised of cognitive training, Tai Chi exercise, and group counseling, was conducted to explore the regional connectivity changes in the default-mode network, as well as changes in prefrontal-based voxel-wise connectivity in the whole brain. Results showed that the intervention selectively affected resting-state functional connectivity between the medial prefrontal cortex and medial temporal lobe. Moreover, the strength of resting-state functional connectivity between these regions correlated with individual cognitive performance. Our results suggest that multimodal intervention could postpone the effects of aging and improve the function of the regions that are most heavily influenced by aging, as well as play an important role in preserving the brain and cognition during old age.