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Walter A Kukull

Publications and source records attributed to Walter A Kukull.

At least 19 recordsLinked to original sources
PubMed2026

Genetic modifiers of APOE-ε4-associated cognitive decline.

The APOE-ε4 allele is the strongest genetic risk factor for late-onset Alzheimer's disease. However, APOE-ε4 is not deterministic, highlighting the need to identify additional genetic and environmental factors. APOE-ε4 has been linked to accelerated cognitive decline, so we sought to investigate genetic factors that modify APOE-ε4-associated cognitive decline. We conduct cross-ancestry APOE-ε4-stratified and interaction GWAS using harmonized cognitive data from 32,778 participants, including 29,354 non-Hispanic White and 3,424 non-Hispanic Black individuals. Our primary outcome is late-life cognition, measured using harmonized composite scores for memory, executive function, and language, modeled as continuous traits reflecting both normative cognitive aging and disease-related decline. We identify two genome-wide significant loci in APOE-ε4 carriers, reaching genome-wide significance for executive function. These loci also demonstrate nominal associations across the other domains, suggesting broad effects on cognition. In non-carriers, we identify a genome-wide significant association at ITGB8 restricted to executive function, and another locus associated with language. We further link these loci to SEMA6D, GRIN3A, and ITGB8 through expression and methylation databases. Post-GWAS analyses implicate additional genes including SLCO1A2, and DNAH11. Genetic correlation analyses reveal differences by APOE-ε4 status for immune-related traits, suggesting immune-related predispositions may exacerbate cognitive risk in APOE-ε4 carriers.

Humans↗
PubMed2025

The Consortium for Clarity in ADRD Research Through Imaging (CLARiTI): Overview of consortium sites and anticipated enrollment.

INTRODUCTION: The Consortium for Clarity in Alzheimer's disease related dementias (ADRD) Research Through Imaging (CLARiTI) is a study that aims to collect standardized imaging and plasma biomarkers on 2000 Clinical Core participants enrolled across all Alzheimer's Disease Research Centers (ADRC) sites. We sought to summarize the known heterogeneity across centers regarding scientific focus and initial enrollment plans for CLARiTI. METHODS: We developed and distributed a survey capturing information on the 36 CLARiTI site's theme/expertise, recruitment plans, and the intersection of CLARiTI with other ADRC imaging efforts. RESULTS: Anticipated CLARiTI enrollees spanned 11 different categories of suspected etiologies underlying impairment. A wide range of risk factors were endorsed across sites regarding the enrollment of unimpaired individuals. Variability also existed regarding site-level strategies in enrollment into CLARiTI versus other imaging efforts. DISCUSSION: We anticipate that the 2000 individuals that will enroll into CLARiTI will reflect the clinical heterogeneity already in place across the ADRC network. HIGHLIGHTS: The ADRC Consortium for Clarity in ADRD Research Through Imaging (CLARiTI) will leverage and contribute to the existing Alzheimer's Disease Research Centers (ADRC) program by supporting standardized imaging and plasma collection across all centers. We summarize the variation in scientific focus and enrollment plans across ADRC sites participating in CLARiTI. The anticipated CLARiTI cohort will reflect the clinical heterogeneity that already exists across the ADRC network. CLARiTI will contribute to scientific goals related to the detection of multi-etiological signatures relevant for Alzheimer's disease and related disorders (ADRDs).

Humans↗
PubMed2006

Gene expression profiles in anatomically and functionally distinct regions of the normal aged human brain.

In this article, we have characterized and compared gene expression profiles from laser capture microdissected neurons in six functionally and anatomically distinct regions from clinically and histopathologically normal aged human brains. These regions, which are also known to be differentially vulnerable to the histopathological and metabolic features of Alzheimer's disease (AD), include the entorhinal cortex and hippocampus (limbic and paralimbic areas vulnerable to early neurofibrillary tangle pathology in AD), posterior cingulate cortex (a paralimbic area vulnerable to early metabolic abnormalities in AD), temporal and prefrontal cortex (unimodal and heteromodal sensory association areas vulnerable to early neuritic plaque pathology in AD), and primary visual cortex (a primary sensory area relatively spared in early AD). These neuronal profiles will provide valuable reference information for future studies of the brain, in normal aging, AD and other neurological and psychiatric disorders.

Aged↗
PubMed2006

Calcium channel blockers and beta-blockers in relation to Parkinson's disease.

We investigated the risk of Parkinson's disease (PD) associated with calcium channel blockers (CCBs) and beta-blockers in a population-based case-control study of 206 men and women between ages 35 and 89 with a new diagnosis of idiopathic PD between 1992 and 2002, and 383 controls without PD or other neurodegenerative disorders who were frequency matched on age, sex, duration of GHC enrollment and clinic. The adjusted odds ratio associated with ever use was 0.85 (95% confidence interval [CI]: 0.43, 1.66) for CCBs, and 1.20 (95% CI: 0.71, 2.03) for beta-blockers. We observed no association with PD risk for either class of medication in terms of duration, dose, number of prescriptions or pattern of use. The weakness of these associations and the absence of additional influence of dose or duration of use argue against any causal interpretation.

Adrenergic beta-Antagonists↗
PubMed2006

Tumor necrosis factor alpha and interleukin 10 promoter region polymorphisms and risk of late-onset Alzheimer disease.

BACKGROUND: Functional polymorphisms in tumor necrosis factor alpha (TNF-alpha) and interleukin 10 (IL-10) can affect immune response, inflammation, tissue injury, and possibly the susceptibility to Alzheimer disease (AD). OBJECTIVE: To evaluate the association between promoter region polymorphisms in the TNF-alpha and IL-10 genes and risk of late-onset AD in older white subjects. DESIGN: Community-based case-control study. SETTING: Group Health Cooperative of Puget Sound. PARTICIPANTS: White subjects (n = 265) meeting criteria for probable or definite AD (cases) and white control subjects (n = 347) (controls). MAIN OUTCOME MEASURES: Genotyping results for TNF-alpha, IL-10, and apolipoprotein E (APOE) genotyping. RESULTS: The TNF-alpha -863 A allele was associated with reduced odds of developing AD, and the test for trend suggested that having 2 copies of the A allele further reduces the risk (odds ratios [C/C, reference], 0.66 for C/A and 0.58 for A/A; P = .04). Because of linkage disequilibrium in the TNF-alpha region, we constructed promoter region haplotypes as defined by single nucleotide polymorphisms at positions -863 and -308. Based on knowledge of TNF-alpha protein production, we ordered the haplotypes based on apparent increasing transcriptional activity. After adjusting for age, education, and the presence of the APOE epsilon4 genotype, the test for trend showed increasing odds of AD with increasing transcriptional activity (P = .02). The IL-10 -1082 and IL-10 -592 allele and genotype frequencies were not significantly different between cases and controls. CONCLUSION: Variation in the TNF-alpha promoter region, or possibly polymorphisms in nearby genes, could affect cerebral inflammatory response and the risk of late-onset AD.

Age of Onset↗
PubMed2006

Nonsteroidal anti-inflammatory drugs and risk of Parkinson's disease.

Inflammation and oxidative stress have been implicated as pathogenic mechanisms in Parkinson's disease (PD). Evidence from in vitro and animal studies suggests a possible protective role of nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin. We investigated the risk of PD associated with use of aspirin and nonaspirin NSAIDs in a population-based case-control study among enrollees of Group Health Cooperative, a health maintenance organization in the Seattle area. Subjects included 206 cases between ages 35 and 89 with a new diagnosis of idiopathic PD between 1992 and 2002, and 383 randomly selected controls frequency-matched by age, sex, duration of enrollment, and clinic. We obtained information on participants' age, smoking, and medical history from interview. Exposure to NSAIDs was ascertained from an automated pharmacy database. Medications filled within 5 years of the interview were excluded. After adjusting for age, sex, smoking, duration of enrollment, and clinic, the risk of PD among individuals who received nonaspirin NSAIDs between 1977 and 1992 was 0.90 (95% CI: 0.59-1.35) and 1.67 (95% CI: 0.60-4.60) between 1993 and 2002. Use of ibuprofen was not associated with PD (OR: 0.89; 95% CI: 0.60-1.32). The risk of PD associated with aspirin or aspirin-containing medications was 0.74 (95% CI: 0.49-1.12). We observed no trend in risk according to number of fills for these drugs. Our results provide only limited support for the hypothesis that use of aspirin may reduce the risk of this disease, and no indication of protection from other NSAIDs.

Adult↗
PubMed2005

Interrater reliability and accuracy in identifying ischemic strokes using computed tomography scans in people with dementia.

OBJECTIVES: To assess the reliability and interobserver agreement of stroke identification on neuroimaging in patients presenting with dementia. DESIGN: Comparison study between neurologists, radiology reports, and autopsy. SETTING: Dementia registry within a health maintenance organization. PARTICIPANTS: Dementia patients with computed tomography (CT) scans obtained near the time of diagnosis and postmortem neuropathological examinations (N=99). MEASUREMENTS: Three neurologists independently read CT scans for the presence and locations of strokes. Radiology reports from these scans were reviewed. The results from neurologists, radiologists, and autopsies were compared. RESULTS: The positive predictive value for CT-observed strokes compared with their presence on autopsy was 0.44 to 0.49, regardless of the specialty of the observer. Strokes were present at autopsy in 46 of 99 cases. Agreement between neurologists on the presence of strokes was fair to moderate (kappa=0.27-0.56). Less agreement was found between neurologists and radiologists (kappa=0.00-0.11). Results improved slightly when each case was evaluated as any stroke present versus no stroke on imaging (kappa=0.34-0.75) or for the presence of multiple strokes (kappa=0.17-0.69). CONCLUSION: There is only fair to moderate agreement between observers regarding the identification of strokes on CT scans in patients presenting with dementia. Furthermore, strokes identified on imaging were present on pathology only half the time.

Aged↗
PubMed2004

Active and passive cigarette smoking and risk of intracranial meningioma.

Motivated by prior studies, we examined associations between cigarette smoking and risk of intracranial meningioma in a population-based case-control study, including 200 cases and 2 controls matched to each case on age and sex. Subjects were asked to recall their history of active and passive cigarette smoking occurring 10 or more years before the date of meningioma surgery. Ever active smoking was associated with an increased risk of meningioma in men (OR = 2.1; 95% CI 1.1-4.2) but not in women (OR = 0.7; 95% CI 0.5-1.1). The statistical interaction by gender was significant (p = 0.01). In men, risk increased with increasing number of cigarettes smoked daily (p for trend = 0.04). In women, the trend was opposite (p for trend = 0.08). Among never active smokers, passive smoking from a spouse was associated with increased risk in both sexes (OR 2.0; 95% CI 1.1-3.5), and risk increased with increasing duration of exposure (p for trend = 0.02). Uncertain is whether these findings reflect a true biological phenomenon or result from chance or uncontrolled confounding.

Adolescent↗
PubMed2004

Survival after initial diagnosis of Alzheimer disease.

BACKGROUND: Alzheimer disease is an increasingly common condition in older people. Knowledge of life expectancy after the diagnosis of Alzheimer disease and of associations of patient characteristics with survival may help planning for future care. OBJECTIVE: To investigate the course of Alzheimer disease after initial diagnosis and examine associations hypothesized to correlate with survival among community-dwelling patients with Alzheimer disease. DESIGN: Prospective observational study. SETTING: An Alzheimer disease patient registry from a base population of 23 000 persons age 60 years and older in the Group Health Cooperative, Seattle, Washington. PATIENTS: 521 newly recognized persons with Alzheimer disease enrolled from 1987 to 1996 in an Alzheimer disease patient registry. MEASUREMENTS: Baseline measurements included patient demographic features, Mini-Mental State Examination score, Blessed Dementia Rating Scale score, duration since reported onset of symptoms, associated symptoms, comorbid conditions, and selected signs. Survival was the outcome of interest. RESULTS: The median survival from initial diagnosis was 4.2 years for men and 5.7 years for women with Alzheimer disease. Men had poorer survival across all age groups compared with females. Survival was decreased in all age groups compared with the life expectancy of the U.S. population. Predictors of mortality based on proportional hazards models included a baseline Mini-Mental State Examination score of 17 or less, baseline Blessed Dementia Rating Scale score of 5.0 or greater, presence of frontal lobe release signs, presence of extrapyramidal signs, gait disturbance, history of falls, congestive heart failure, ischemic heart disease, and diabetes at baseline. LIMITATIONS: The base population, although typical of the surrounding Seattle community, may not be representative of other, more diverse populations. CONCLUSIONS: In this sample of community-dwelling elderly persons who received a diagnosis of Alzheimer disease, survival duration was shorter than predicted on the basis of U.S. population data, especially for persons with onset at relatively younger ages. Features significantly associated with reduced survival at diagnosis were increased severity of cognitive impairment, decreased functional level, history of falls, physical examination findings of frontal release signs, and abnormal gait. The variables most strongly associated with survival were measures of disease severity at the time of diagnosis. These results should be useful to patients and families experiencing Alzheimer disease, other caregivers, clinicians, and policymakers when planning for future care needs.

Aged↗
PubMed2004

Footwear style and risk of falls in older adults.

OBJECTIVES: To determine how the risk of a fall in an older adult varies in relation to style of footwear worn. DESIGN: Nested case-control study. SETTING: Group Health Cooperative, a large health maintenance organization in Washington state. PARTICIPANTS: A total of 1,371 adults aged 65 and older were monitored for falls over a 2-year period; 327 qualifying fall cases were compared with 327 controls matched on age and sex. MEASUREMENTS: Standardized in-person examinations before fall occurrence, interviews about fall risk factors after the fall occurred, and direct examination of footwear were conducted. Questions for controls referred to the last time they engaged in an activity broadly similar to what the case was doing at the time of the fall. RESULTS: Athletic and canvas shoes (sneakers) were the styles of footwear associated with lowest risk of a fall. Going barefoot or in stocking feet was associated with sharply increased risk, even after controlling for measures of health status (adjusted odds ratio=11.2, 95% confidence interval (CI)=2.4-51.8). Relative to athletic/canvas shoes, other footwear was associated with a 1.3-fold increase in the risk of a fall (95% CI=0.9-1.9), varying somewhat by style. CONCLUSION: Contrary to findings from gait-laboratory studies, athletic shoes were associated with relatively low risk of a fall in older adults during everyday activities. Fall risk was markedly increased when participants were not wearing shoes.

Accidental Falls↗
PubMed2004

Biomechanical properties of shoes and risk of falls in older adults.

OBJECTIVES: To determine the relationships between the biomechanical properties of shoes worn in a cohort of healthy older adults and the risk of falling. DESIGN: Nested case-control study, comparing biomechanical measurements of shoes worn by those who reported a fall with measurements of shoes worn by age- and sex-matched nonfallers engaged in broadly similar activities. SETTING: On-site measurements where falls occurred. PARTICIPANTS: A cohort of 1,371 older adults, of whom 327 reported a fall and 327 served as age- and sex-matched controls. MEASUREMENTS: Shoe measurements related to lateral stability (heel height and width, critical tipping angle), foot position sense (heel-collar height, sole thickness, and sole flexibility), and the shoe/surface interface (foresole material, shoe-to-ground coefficient of friction, sole contact area). RESULTS: Greater heel height was associated with increased risk of a fall (P for trend=.03), whereas greater sole contact area was associated with reduced risk (P for trend=.005). Shoe characteristics related to foot position sense bore little apparent relation to fall risk. Coefficients of friction of 0.5 or greater were observed in 93% of shoes measured, indicating that very few were excessively slippery. CONCLUSION: Certain measurable properties of shoes were found to be significantly related to risk of falls in older adults. Wearing shoes with low heels and large contact area may help older adults reduce the risk of a fall in everyday settings and activities.

Accidental Falls↗
PubMed2004

Subjective memory deterioration and future dementia in people aged 65 and older.

OBJECTIVES: To study whether subjective memory deterioration is associated with future dementia in older people. DESIGN: A population-based prospective cohort study begun in 1994 with biennial follow-up interviews. SETTING: Community-based members of Group Health Cooperative, a large health maintenance organization in the Seattle area. PARTICIPANTS: A sample of 1,883 subjects, dementia free, aged 65 and older, who scored 91 or higher on the 100-point Cognitive Ability Screening Instrument (CASI) at study entry. MEASUREMENTS: Subjective memory was assessed by asking whether memory had changed on 5-point Likert scales (e.g., 1=definitely improved, 3=no change, 5=definitely deteriorated) with regard to five items: remembering names, faces, friends, and appointments and judging the time. The items were summed for a possible total score ranging from 5 to 25. Subjective memory deterioration was defined as present if the total score was 20 or above. Cognitive performance was measured using the CASI. Incident dementia cases were identified using Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria. RESULTS: Of 1,883 subjects, 126 developed dementia during 5 years of follow-up. Subjective memory deterioration was associated with cognitive decline and incident dementia. Age modified the association between subjective memory deterioration and future dementia. For persons reporting subjective memory deterioration at the ages of 70, 75, and 80, the hazard ratios of developing dementia were 6.0 (95% confidence interval (CI)=2.1-18), 3.2 (95% CI=1.6-6.2) and 1.6 (95% CI=0.86-3.1), respectively. CONCLUSION: Subjective memory deterioration was found to precede the development of dementia in older people with normal cognitive screening results. These findings suggest that a high level of subjective memory deterioration in persons with normal objective cognitive function may identify a subset of individuals at greater risk for developing dementia.

Aged↗
PubMed2004

Alcohol, gender, and cognitive performance: a longitudinal study comparing older Japanese and non-Hispanic white Americans.

BACKGROUND: Recent data demonstrate that moderate consumption of alcohol may be beneficial to cognition. DESIGN: Longitudinal growth curve analyses controlling for variables related to cognition were used to examine the relationship between alcohol consumption, ethnic differences, gender, and cognition over a 4-year-follow-up period. SAMPLE: The sample included 1,836 Japanese American and 2,581 Non-Hispanic White American community-dwelling adults age 65 and older who were cognitively intact at baseline and participated in at least one follow-up examination. MEASUREMENT: Cognitive performance was measured using the Cognitive Abilities Screening Instrument (CASI) and reaction time. RESULTS: Current drinkers scored significantly higher on CASI over time than past drinkers or abstainers. The same association between alcohol and CASI was observed in both genders and both ethnic groups. CONCLUSION: This study provides support regarding the potential beneficial outcomes associated with alcohol consumption and cognition and that these benefits were not modified by gender or ethnicity.

Acculturation↗
PubMed2003

Exercise plus behavioral management in patients with Alzheimer disease: a randomized controlled trial.

CONTEXT: Exercise training for patients with Alzheimer disease combined with teaching caregivers how to manage behavioral problems may help decrease the frailty and behavioral impairment that are often prevalent in patients with Alzheimer disease. OBJECTIVE: To determine whether a home-based exercise program combined with caregiver training in behavioral management techniques would reduce functional dependence and delay institutionalization among patients with Alzheimer disease. DESIGN, SETTING, AND PATIENTS: Randomized controlled trial of 153 community-dwelling patients meeting National Institute of Neurological and Communicative Diseases and Stroke/Alzheimer Disease and Related Disorders Association criteria for Alzheimer disease, conducted between June 1994 and April 1999. INTERVENTIONS: Patient-caregiver dyads were randomly assigned to the combined exercise and caregiver training program, Reducing Disability in Alzheimer Disease (RDAD), or to routine medical care (RMC). The RDAD program was conducted in the patients' home over 3 months. MAIN OUTCOME MEASURES: Physical health and function (36-item Short-Form Health Survey's [SF-36] physical functioning and physical role functioning subscales and Sickness Impact Profile's Mobility subscale), and affective status (Hamilton Depression Rating Scale and Cornell Depression Scale for Depression in Dementia). RESULTS: At 3 months, in comparison with the routine care patients, more patients in the RDAD group exercised at least 60 min/wk (odds ratio [OR], 2.82; 95% confidence interval [CI], 1.25-6.39; P =.01) and had fewer days of restricted activity (OR, 3.10; 95% CI, 1.08-8.95; P<.001). Patients in the RDAD group also had improved scores for physical role functioning compared with worse scores for patients in the RMC group (mean difference, 19.29; 95% CI, 8.75-29.83; P<.001). Patients in the RDAD group had improved Cornell Depression Scale for Depression in Dementia scores while the patients in the RMC group had worse scores (mean difference, -1.03; 95% CI, -0.17 to -1.91; P =.02). At 2 years, the RDAD patients continued to have better physical role functioning scores than the RMC patients (mean difference, 10.89; 95% CI, 3.62-18.16; P =.003) and showed a trend (19% vs 50%) for less institutionalization due to behavioral disturbance. For patients with higher depression scores at baseline, those in the RDAD group improved significantly more at 3 months on the Hamilton Depression Rating Scale (mean difference, 2.21; 95% CI, 0.22-4.20; P =.04) and maintained that improvement at 24 months (mean difference, 2.14; 95% CI, 0.14-4.17; P =.04). CONCLUSION: Exercise training combined with teaching caregivers behavioral management techniques improved physical health and depression in patients with Alzheimer disease.

Activities of Daily Living↗
PubMed2003

Depression as a risk factor for Alzheimer disease: the MIRAGE Study.

BACKGROUND: Depression symptoms may be associated with the development of Alzheimer disease (AD). OBJECTIVES: To evaluate the association between depression symptoms and risk of AD, and to explore the temporal aspects of this association. SETTING: Academic institutions with specialized memory clinics. DESIGN: Cross-sectional, family-based, case-control study with standardized self- and proxy questionnaires to collect information on depression symptoms and other risk factors. PARTICIPANTS: A total of 1953 subjects with AD and 2093 of their unaffected relatives enrolled in the Multi-institutional Research in Alzheimer's Genetic Epidemiology Study. MAIN OUTCOME MEASURES: Odds ratios (ORs) of AD were estimated with and without depression symptoms, adjusted for age, sex, education, history of head trauma, and apolipoprotein E status. RESULTS: There was a significant association between depression symptoms and AD (adjusted OR, 2.13; 95% confidence interval [CI], 1.71-2.67). In families where depression symptoms first occurred within 1 year before the onset of AD, the association was higher (OR, 4.57; 95% CI, 2.87-7.31), while in the families where the depression symptoms first occurred more than 1 year before the onset of AD, the association was lower (OR, 1.38; 95% CI, 1.03-1.85). In families where depression symptoms first occurred more than 25 years before the onset of AD, there was still a modest association (OR, 1.71; 95% CI, 1.03-2.82). CONCLUSIONS: Depression symptoms before the onset of AD are associated with the development of AD, even in families where first depression symptoms occurred more than 25 years before the onset of AD. These data suggest that depression symptoms are a risk factor for later development of AD.

Age of Onset↗
PubMed2002

Dementia and Alzheimer disease incidence: a prospective cohort study.

CONTEXT: Age-specific incidence rates for dementia and Alzheimer disease (AD) are important for research and clinical practice. Incidence estimates for the United States are few and vary with the population sampled and study design; we present data that will contribute to a consensus of these rates. OBJECTIVES: To provide age-specific incidence estimates for dementia and AD and to estimate the association of sex, educational level, and apolipoprotein E genotype with onset. DESIGN: Prospective cohort study; begun in 1994 with follow-up interviews every 2 years. SETTING: Members of community-based, large health maintenance organization with demographics consistent with the surrounding base population; diagnostic evaluation by university-based study clinicians. SUBJECTS: Random sample of subjects aged 65 years or older from the base population; dementia free, nonnursing home residents. Of 5422 who were eligible, 2581 were enrolled, and 2356 had at least 1 follow-up evaluation (10 591 person-years of observation). MAIN OUTCOME MEASURE: Dementia and Alzheimer disease diagnoses were based on standard criteria. Age-specific incidence rates were calculated using a person-years approach with Poisson distribution confidence intervals. Cox proportional hazards model analysis was used to examine other factors. RESULTS: Two hundred fifteen cases of dementia and 151 cases of AD were diagnosed. Incidence rates for dementia and AD increase across the 5-year age groups; AD rates rise from 2.8 per 1000 person-years (age group, 65-69 years) to 56.1 per 1000 person-years in the older than 90-year age group. The rates nearly triple from the 75-to-79-year and 80-to-84-year age groups, but the relative increase is much less thereafter. Sex was not associated with AD onset. Educational level (>15 years vs <12 years) was associated with a decreased risk of AD; however, the association was also dependent on the baseline cognitive screening test score. CONCLUSIONS: Our dementia and AD incidence rates are consistent with recent US and European cohort studies, providing clinicians and researchers new information concerning the reproducibility of incidence estimates across settings. Increased risk was associated with age and the apolipoprotein E genotype; also with a low baseline cognitive screening test score. Educational level was inversely associated with the risk of dementia and positively associated with the baseline cognitive test score; thus, detection of AD by the screening test could also be influenced by educational level.

Age Factors↗