Normal Aging Research Articles

A Review of the Comparison of Working Memory Performance, Cognitive Function, and Behavioral, and Psychological Symptoms across Normal Aging, Mild Cognitive Impairment, and Alzheimer's Disease

A Review of the Comparison of Working Memory Performance, Cognitive Function, and Behavioral, and Psychological Symptoms across Normal Aging, Mild Cognitive Impairment, and Alzheimer's Disease

Brain activations elicited during task-switching generalize beyond the task: A partial least squares correlation approach to combine fMRI signals and cognition.

An underlying hypothesis for broad transfer from cognitive training is that the regional brain signals engaged during the training task are related to the transfer tasks. However, it is unclear whether the brain activations elicited from a specific cognitive task can generalize to performance of other tasks, esp. in normal aging where cognitive training holds much promise. In this large dual-site functional magnetic resonance imaging (fMRI) study, we aimed to characterize the neurobehavioral correlates of task-switching in normal aging and examine whether the task-switching-related fMRI-blood-oxygen-level-dependent (BOLD) signals, engaged during varieties of cognitive control, generalize to other tasks of executive control and general cognition. We therefore used a hybrid blocked and event-related fMRI task-switching paradigm to investigate brain regions associated with multiple types of cognitive control on 129 non-demented older adults (65-85 years). This large dataset provided a unique opportunity for a data-driven partial least squares-correlation approach to investigate the generalizability of multiple fMRI-BOLD signals associated with task-switching costs to other tasks of executive control, general cognition, and demographic characteristics. While some fMRI signals generalized beyond the scanned task, others did not. Results indicate right middle frontal brain activation as detrimental to task-switching performance, whereas inferior frontal and caudate activations were related to faster processing speed during the fMRI task-switching, but activations of these regions did not predict performance on other tasks of executive control or general cognition. However, BOLD signals from the right lateral occipital cortex engaged during the fMRI task positively predicted performance on a working memory updating task, and BOLD signals from the left post-central gyrus that were disengaged during the fMRI task were related to slower processing speed in the task as well as to lower general cognition. Together, these results suggest generalizability of these BOLD signals beyond the scanned task. The findings also provided evidence for the general slowing hypothesis of aging as most variance in the data were explained by low processing speed and global low BOLD signal in older age. As processing speed shared variance with task-switching and other executive control tasks, it might be a possible basis of generalizability between these tasks. Additional results support the dedifferentiation hypothesis of brain aging, as right middle frontal activations predicted poorer task-switching performance. Overall, we observed that the BOLD signals related to the fMRI task not only generalize to the performance of other executive control tasks, but unique brain predictors of out-of-scanner performance can be identified.

Association of Arterial Stiffness Index and Brain Structure in the UK Biobank: A 10-Year Retrospective Analysis.

Arterial stiffening and changes in brain structure both occur with normal aging and can be exacerbated via acquired health conditions. While cross-sectional associations exist, the longitudinal relationship between arterial stiffness and brain structure remains unclear. In this study, we investigated 1) associations between baseline arterial stiffness index (ASI) and brain structure (global and regional grey matter volumes (GMV), white matter hyperintensities (WMH)) 10-years post-baseline (10.4±0.8 years) and 2) associations between the 10-year change in ASI from baseline and brain structure 10-years post-baseline in 650 healthy middle- to older-aged adults (53.4±7.5 years) from the UK Biobank. We observed significant associations between baseline ASI and GMV (p<0.001) and WMH (p=0.0036) 10-years post-baseline. No significant associations between 10-year change in ASI and brain structure (global GMV p=0.24; WMH volume p=0.87) were observed. There were significant associations of baseline ASI in 2 of 60 regional brain volumes analyzed (right posterior superior temporal gyrus p=0.001; left superior lateral occipital cortex p<0.001). Strong associations with baseline ASI, but not changes in ASI over 10-years, suggest arterial stiffness at the entry point of older adulthood is more impactful on brain structure 10-years later compared to age-related stiffening. Based on these associations, we suggest clinical monitoring and potential intervention for reducing arterial stiffness should occur in midlife to reduce vascular contributions to structural changes in the brain, supporting a healthy trajectory of brain aging. Our findings also support use of ASI as a surrogate for gold standard measures in showing overall relationships between arterial stiffness and brain structure.

Immunoglobulin G glycosylation and its alterations in aging-related diseases.

Immunoglobulin G (IgG) is an important serum glycoprotein and a major component of antibodies. Glycans on IgG affect the binding of IgG to the Fc receptor or complement C1q, which in turn affects the biological activity and biological function of IgG. Altered glycosylation patterns on IgG emerge as important biomarkers in the aging process and age-related diseases. Key aging-related alterations observed in IgG glycosylation include reductions in galactosylation and sialylation, alongside increases in agalactosylation, and bisecting GlcNAc. Understanding the role of IgG glycosylation in aging-related diseases offers insights into disease mechanisms and provides opportunities for the development of diagnostic and therapeutic strategies. This review summarizes five aspects of IgG: an overview of IgG, IgG glycosylation, IgG glycosylation with inflammation mediation, IgG glycan changes with normal aging, as well as the relevance of IgG glycan changes to aging-related diseases. This review provides a reference for further investigation of the regulatory mechanisms of IgG glycosylation in aging-related diseases, as well as for evaluating the potential of IgG glycosylation changes as markers of aging and aging-related diseases.

VoiceAD: A multilingual speech based classifier for early detection of Alzheimers disease

Alzheimer's Disease (AD) causes memory decline beyond normal aging and is the most common cause of dementia. Early detection and intervention can delay the progression of AD and alleviate symptoms. However, high expense, insensitivity, and inconvenience are among various deterrents to traditional diagnosis methods. Dementia impacts more than 55 million people globally, with this number set to double every 20 years. Much of this increase will be in low- and middle-income countries which often lack the resources for early diagnosis. Recently speech has emerged as an effective digital biomarker for AD detection. However, most studies in this area are limited to English speech due to lack of suitable data in other languages. This study aims to construct a speech-based classifier (VoiceAD) that can be trained on English data and still maintain its performance on other languages. Acoustic features were extracted from English, Spanish, and Greek data from DementiaBank with the eGeMAPS v2.0 feature set. Subsequently, an Extra Trees model was employed for classification. VoiceADs performance for English and Greek surpassed that of the baseline model and model incorporating only demographic data while the Spanish performance was lower due to task effect. In addition, VoiceADs satisfactory generalizability and interpretability positions it as a promising candidate for clinical applications. It can be implemented as a free screening tool such as a mobile application to monitor AD risk. VoiceADs crosslingual applicability can its enable worldwide deployment, especially in settings where traditional methods of diagnosis are less attainable.

Aging drives cerebrovascular network remodeling and functional changes in the mouse brain

Aging is frequently associated with compromised cerebrovasculature and pericytes. However, we do not know how normal aging differentially impacts vascular structure and function in different brain areas. Here we utilize mesoscale microscopy methods and in vivo imaging to determine detailed changes in aged murine cerebrovascular networks. Whole-brain vascular tracing shows an overall ~10% decrease in vascular length and branching density with ~7% increase in vascular radii in aged brains. Light sheet imaging with 3D immunolabeling reveals increased arteriole tortuosity of aged brains. Notably, vasculature and pericyte densities show selective and significant reductions in the deep cortical layers, hippocampal network, and basal forebrain areas. We find increased blood extravasation, implying compromised blood-brain barrier function in aged brains. Moreover, in vivo imaging in awake mice demonstrates reduced baseline and on-demand blood oxygenation despite relatively intact neurovascular coupling. Collectively, we uncover regional vulnerabilities of cerebrovascular network and physiological changes that can mediate cognitive decline in normal aging.

Response to Replication Stress and Maintenance of Genome Stability by WRN, the Werner Syndrome Protein.

Werner syndrome (WS) is an autosomal recessive disease caused by loss of function of WRN. WS is a segmental progeroid disease and shows early onset or increased frequency of many characteristics of normal aging. WRN possesses helicase, annealing, strand exchange, and exonuclease activities and acts on a variety of DNA substrates, even complex replication and recombination intermediates. Here, we review the genetics, biochemistry, and probably physiological functions of the WRN protein. Although its precise role is unclear, evidence suggests WRN plays a role in pathways that respond to replication stress and maintain genome stability particularly in telomeric regions.

Neuronal expression of human amyloid-β and Tau drives global phenotypic and multi-omic changes in C. elegans.

Alzheimer's disease (AD) and Alzheimer's related diseases (ADRD) are prevalent age-related neurodegenerative disorders characterized by the accumulation of amyloid-β (Aβ) plaques and Tau neurofibrillary tangles. The nematode Caenorhabditis elegan s ( C. elegans ) serves as an invaluable model organism in diseases of old age-due to its rapid aging. Here we performed an unbiased systems analysis of a C. elegans strain expressing both Aβ and Tau proteins within neurons. We set out to determine if there was a phenotypic interaction between Aβ and Tau. In addition, we were interested in determining the temporal order of the phenotypic and multi-omic (geromic) outcomes. At an early stage of adulthood, we observed reproductive impairments and mitochondrial dysfunction consistent with disruptions in mRNA transcript abundance, protein solubility, and metabolite levels. Notably, the expression of these neurotoxic proteins exhibited a synergistic effect, leading to accelerated aging. Our findings shed light on the close relationship between normal aging and ADRD. Specifically, we demonstrate alterations to metabolic functions preceding age-related neurotoxicity, offering a resource for the development of new therapeutic strategies.

Population-based reference values for kidney function and kidney function decline in 25- to 95-year-old Germans without and with diabetes

Understanding normal aging of kidney function is pivotal to help distinguish individuals at particular risk for chronic kidney disease. Glomerular filtration rate (GFR) is typically estimated via serum creatinine (eGFRcrea) or cystatin C (eGFRcys). Since population-based age-group-specific reference values for eGFR and eGFR-decline are scarce, we aimed to provide such reference values from population-based data of a wide age range. In four German population-based cohorts (KORA-3, KORA-4, AugUR, DIACORE), participants underwent medical exams, interview, and blood draw up to five times within up to 25 years. We analyzed eGFRcrea and eGFRcys cross-sectionally and longitudinally (12,000 individuals, age 25-95 years). Cross-sectionally, we found age-group-specific eGFRcrea to decrease approximately linearly across the full age range, for eGFRcys up to the age of 60 years. Within age-groups, there was little difference by sex or diabetes status. Longitudinally, linear mixed models estimated an annual eGFRcrea decline of -0.80 [95% confidence interval -0.82, -0.77], -0.79 [-0.83, -0.76], and -1.20 mL/min/1.73m2 [-1.33, -1.08] for the general population, “healthy” individuals, or individuals with diabetes, respectively. Reference values for eGFR using cross-sectional data were shown as percentile curves for “healthy” individuals and for individuals with diabetes. Reference values for eGFR-decline using longitudinal data were presented as 95% prediction intervals for “healthy” individuals and for individuals with diabetes, obesity, and/or albuminuria. Thus, our results can help clinicians to judge eGFR values in individuals seen in clinical practice according to their age and to understand the expected range of annual eGFR-decline based on their risk profile.

Decoding molecular mechanisms: brain aging and Alzheimer's disease.

The complex morphological, anatomical, physiological, and chemical mechanisms within the aging brain have been the hot topic of research for centuries. The aging process alters the brain structure that affects functions and cognitions, but the worsening of such processes contributes to the pathogenesis of neurodegenerative disorders, such as Alzheimer's disease. Beyond these observable, mild morphological shifts, significant functional modifications in neurotransmission and neuronal activity critically influence the aging brain. Understanding these changes is important for maintaining cognitive health, especially given the increasing prevalence of age-related conditions that affect cognition. This review aims to explore the age-induced changes in brain plasticity and molecular processes, differentiating normal aging from the pathogenesis of Alzheimer's disease, thereby providing insights into predicting the risk of dementia, particularly Alzheimer's disease.

Functional disability among the older adult population in Kedah, Malaysia

BackgroundFunctional disability, defined as acquired difficulty in performing basic daily tasks or more complex tasks needed for independent living. Functional assessment among community dwelling elderly is critical due to the changes taking place during the normal aging process, acute illness, worsening chronic illness, and hospitalization which compromises their performances necessary to live independently. Measuring their functional ability can provide objective data to assist with targeting individualized care plan for older adults being the highest consumers of medications due to greater burden of medical conditions in addition to being vulnerable to the effects of medications. It is crucial for the pharmacists to be aware of the geriatric functional disability as pharmacies are often the first point-of-care this elderly group may encounter in community settings. MethodsThis study was conducted to estimate the prevalence of functional disability and the common difficulties in the daily task performance among elderly from a state in the Northern region of Malaysia. Besides, the differences in terms of functional disability in both genders were also explored. Among a total of 266 elderly participants. ResultsAround 42 % was estimated to face at least one difficulty with Activities of Daily Living while more than half, 57 %, had at least one difficulty with Instrumental Activities of Daily Living. The most common difficulties reported with Activities of Daily Living and Instrumental Activities of Daily Living were transferring (22 %) and transportation (33 %), respectively. ConclusionIn order to deliver effective pharmaceutical care plan emphatically, both senior-friendly pharmacy curricula and pharmacy settings are imperative to address the most common difficulties faced by this vulnerable group.

Age and familiarity effects on musical memory.

A common complaint in older adults is trouble with their memory, especially for new information. Current knowledge about normal aging and changes in memory identify a divide between memory tasks that are unaffected by aging and those that are. Among the unaffected are recognition tasks. These memory tasks rely on accessing well-known information, often include environmental support, and tend to be automatic. Negative age effects on memory are often observed at both encoding and during recall. Older adults often have difficulty with recall tasks, particularly those that require effortful self-initiated processing, episodic memory, and retention of information about contextual cues. Research in memory for music in healthy aging suggests a skill-invariance hypothesis: that age effects dominate when general-purpose cognitive mechanisms are needed to perform the musical task at hand, while experience effects dominate when music-specific knowledge is needed to perform the task [1]. The goals of this pair of studies were to investigate the effects of age and familiarity on musical memory in the context of real pieces of music, and to compare a live concert experimental setting with a lab-based experimental setting. Participants' task was to click a button (or press the spacebar) when they heard the target theme in three pieces of music. One was Mozart's Eine Kleine Nachtmusik and the others were original pieces commissioned for this study, one tonal and one atonal. Participants heard the relevant theme three times before listening to a piece of music. The music was performed by the Newfoundland Symphony Orchestra; participants either attended the concert, or watched a recording of the concert in the lab. Participants also completed two short cognitive tests and filled out a questionnaire collecting demographic information and a hearing abilities self-assessment. We find a significant effect of familiarity and setting but not of age or musical training on recognition performance as measured by d'. More specifically, performance is best for the familiar, tonal piece, moderate for the unfamiliar tonal piece and worst for the unfamiliar atonal piece. Performance was better in the live setting than the lab setting. The absence of an age effect provides encouraging evidence that music's diverse cues may encourage cognitive scaffolding, in turn improving encoding and subsequent recognition. Better performance in an ecological versus lab setting supports the expansion of ecological studies in the field.

Age-associated myeloid malignancies - the role of STAT3 and STAT5 in myelodysplastic syndrome and acute myeloid leukemia.

In the last few decades, the increasing human life expectancy has led to the inflation of the elderly population and consequently the escalation of age-related disorders. Biological aging has been associated with the accumulation of somatic mutations in the Hematopoietic Stem Cell (HSC) compartment, providing a fitness advantage to the HSCs leading to clonal hematopoiesis, that includes non-malignant and malignant conditions (i.e. Clonal Hematopoiesis of Indeterminate Potential, Myelodysplastic Syndrome and Acute Myeloid Leukemia). The Janus Kinase-Signal Transducer and Activator of Transcription (JAK-STAT) pathway is a key player in both normal and malignant hematopoiesis. STATs, particularly STAT3 and STAT5, are greatly implicated in normal hematopoiesis, immunity, inflammation, leukemia, and aging. Here, the pleiotropic functions of JAK-STAT pathway in age-associated hematopoietic defects and of STAT3 and STAT5 in normal hematopoiesis, leukemia, and inflammaging are reviewed. Even though great progress has been made in deciphering the role of STATs, further research is required to provide a deeper understanding of the molecular mechanisms of leukemogenesis, as well as novel biomarkers and therapeutic targets for improved management of age-related disorders.

Optimal Social Security with Loss Aversion

This article characterizes optimal social security in economies with agents who exhibit loss aversion. Two forms of loss aversion are explored. In the first, workers have a fixed retirement age and are loss averse over private savings. This motivates a more generous social security program. In the second, workers do no private savings but can choose their retirement age, exhibiting loss aversion over the foregone leisure time from delayed retirement. Social security benefits consequently rise steeper with retirement age and an earlier normal retirement age is optimal. In both cases, optimal policy is highly sensitive to the introduction of loss averse preferences.

MRI-informed machine learning-driven brain age models for classifying mild cognitive impairment converters.

Brain age model, including estimated brain age and brain-predicted age difference (brain-PAD), has shown great potentials for serving as imaging markers for monitoring normal ageing, as well as for identifying the individuals in the pre-diagnostic phase of neurodegenerative diseases. This study aimed to investigate the brain age models in normal ageing and mild cognitive impairments (MCI) converters and their values in classifying MCI conversion. Pre-trained brain age model was constructed using the structural magnetic resonance imaging (MRI) data from the Cambridge Centre for Ageing and Neuroscience (Cam-CAN) project (N = 609). The tested brain age model was built using the baseline, 1-year and 3-year follow-up MRI data from normal ageing (NA) adults (n = 32) and MCI converters (n = 22) drew from the Open Access Series of Imaging Studies (OASIS-2). The quantitative measures of morphometry included total intracranial volume (TIV), gray matter volume (GMV) and cortical thickness. Brain age models were calculated based on the individual's morphometric features using the support vector machine (SVM) algorithm. With comparable chronological age, MCI converters showed significant increased TIV-based (Baseline: P = 0.021; 1-year follow-up: P = 0.037; 3-year follow-up: P = 0.001) and left GMV-based brain age than NA adults at all time points. Higher brain-PAD scores were associated with worse global cognition. Acceptable classification performance of TIV-based (AUC = 0.698) and left GMV-based brain age (AUC = 0.703) was found, which could differentiate the MCI converters from NA adults at the baseline. This is the first demonstration that MRI-informed brain age models exhibit feature-specific patterns. The greater GMV-based brain age observed in MCI converters may provide new evidence for identifying the individuals at the early stage of neurodegeneration. Our findings added value to existing quantitative imaging markers and might help to improve disease monitoring and accelerate personalized treatments in clinical practice.

Myelin dystrophy impairs signal transmission and working memory in a multiscale model of the aging prefrontal cortex.

Normal aging leads to myelin alterations in the rhesus monkey dorsolateral prefrontal cortex (dlPFC), which are positively correlated with degree of cognitive impairment. It is hypothesized that remyelination with shorter and thinner myelin sheaths partially compensates for myelin degradation, but computational modeling has not yet explored these two phenomena together systematically. Here, we used a two-pronged modeling approach to determine how age-related myelin changes affect a core cognitive function: spatial working memory. First, we built a multicompartment pyramidal neuron model fit to monkey dlPFC empirical data, with an axon including myelinated segments having paranodes, juxtaparanodes, internodes, and tight junctions. This model was used to quantify conduction velocity (CV) changes and action potential (AP) failures after demyelination and subsequent remyelination. Next, we incorporated the single neuron results into a spiking neural network model of working memory. While complete remyelination nearly recovered axonal transmission and network function to unperturbed levels, our models predict that biologically plausible levels of myelin dystrophy, if uncompensated by other factors, can account for substantial working memory impairment with aging. The present computational study unites empirical data from ultrastructure up to behavior during normal aging, and has broader implications for many demyelinating conditions, such as multiple sclerosis or schizophrenia.

Ethnic identity centrality across the adult lifespan: Aging, cohort, and period effects among majority and minority group members.

Ethnic identity is a major area of study across many disciplines including psychology, sociology, anthropology, and political science. Yet, little is known about changes in ethnic identity across the adult lifespan, and whether such changes are driven by normal aging processes (aging effects), unique societal influences linked with one's formative years (cohort effects), or social changes during a specific time frame (period effects). We address these key oversights by utilizing 13 annual waves of longitudinal panel data from a nationwide random sample of both ethnic majority (N = 49,660) and Indigenous ethnic minority (N = 8,325) group members in New Zealand to examine changes in ethnic identity centrality using cohort-sequential latent growth modeling. This approach helps to identify changes in mean levels of ethnic identity centrality over time and whether such changes are driven by aging, cohort, and/or period effects. Our data reveal that, among both ethnic majority and ethnic minority individuals, changes in ethnic identity centrality were informed by a combination of normative aging processes, societal circumstances that reflected the unique historical context in which people grew to maturity, and societal changes during the 13 annual assessments of our study. Collectively, these results demonstrate for the first time that ethnic identity centrality in adulthood is subject to lifelong changes. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Altered Endogenous Pain-Inhibitory Function in Older Adults With Chronic Pain Is Associated With Disruptions in Functional Connectivity During Resting State

Increasing research points to a decline in the ability to internally regulate pain as a contributing factor to the increased pain susceptibility in aging. This study investigated the connection between pain regulation and resting-state functional connectivity (rsFC) in older adults with chronic pain. We compared functional magnetic resonance imaging rsFC of 30 older adults with chronic pain (69.5 ± 6.58 years, 14 males), 29 pain-free older (70.48 ± 4.60, 15 males), and 30 younger adults (20.0 ± 1.58, 15 males). Pain inhibition and facilitatory capabilities were assessed using conditioned pain modulation (CPM) and temporal summation. Older adults with chronic pain displayed lower pain inhibition during the CPM than pain-free older and younger adults. rsFC analysis showed that older adults with chronic pain, in comparison with younger participants, displayed an abnormal hyperconnectivity between right dorsolateral prefrontal cortex and left amygdala, which was significantly correlated with lower pain inhibition during the CPM. Older adults with chronic pain displayed higher connectivity between the primary somatosensory cortex and nucleus accumbens than pain-free older adults. Finally, both older adult groups displayed reduced connectivity between brain structures involved in pain inhibition and processing in comparison with younger adults. Altogether, our results suggest that suffering from pain during aging leads to a dysfunction of pain-inhibitory processes, which significantly surpass those caused by normal aging. Furthermore, our results point to a key role of emotional and motivational brain areas, and their interaction with executive and somatosensory areas, in the reduced inhibitory capacity and likely the maintenance of chronic pain in aging. PerspectiveThis study examines the link between reduced pain-inhibition capacity and increased resting-state connectivity between affective, sensory, and executive brain structures in older adults with chronic pain. These findings could inform new pain assessment and treatment programs for this population.

Histomorphology and Histomorphometrics of the retina in Juvenile and Adult African Giant Rats (Cricetomys gambianus)

Aging is accompanied with various forms of functional ultrastructural and morphological changes in the eye, including the retina, leading to vision deterioration. However, age related retinal degenerative changes requires further elucidation especially as all previous studies on age-related change of the retina were done in mutant mouse strain models of hereditary retinal degenerations. The potential of using African giant rats (AGRs) as models for ageing in the eye, especially retina, was explored in this study. A total of 14 AGRs divided into two age groups (juvenile and adult) were used to study the histomorphology and histomorphometrics of the retina as well as retinal astrocyte morphology and heterogeneity. Histological findings included retinal atrophy and hypoplasia, with cellular swellings of neuronal cell populations and astrocytes soma and ramifications in the retina of adult compared to juvenile AGR. We suggest that AGR be used as animal model for translational research into normal aging process of the retina, as well as to elucidate the process of age-related neuronal cells loss.

Blood-Brain Barrier Permeability Is Associated With Cognitive Functioning in Normal Aging and Neurodegenerative Diseases.

The purpose of this study was to investigate the relationship between blood-brain barrier (BBB) permeability and cognitive functioning in healthy older adults and individuals with neurodegenerative diseases. A total of 124 participants with Alzheimer disease, cerebrovascular disease, or a mix Alzheimer's and cerebrovascular diseases and 55 controlparticipants underwent magnetic resonance imaging and neuropsychological testing. BBB permeability was measured with dynamic contrast-enhanced magnetic resonance imaging and white matter injury was measured using a quantitative diffusion-tensor imaging marker of white matter injury. Structural equation modeling was used to examine the relationships between BBB permeability, vascular risk burden, white matter injury, and cognitive functioning. Vascular risk burden predicted BBB permeability (r=0.24, P<0.05) and white matter injury (r=0.38, P<0.001). BBB permeability predicted increased white matter injury (r=0.34, P<0.001) and increased white matter injury predicted lower cognitive functioning (r=-0.51, P<0.001). The study provides empirical support for a vascular contribution to white matter injury and cognitive impairment, directly or indirectly via BBB permeability. This highlights the importance of targeting modifiable vascular risk factors to help mitigate future cognitive decline.