Incidence, Progression, and Patterns of Multimorbidity in Community-Dwelling Middle-Aged Men and Women.

Background: Determining the incidence, progression, and patterns of multimorbidity are important for the prevention, management, and treatment of concurrence of multiple conditions. This study aimed to analyze major multimorbidity patterns and the association of the onset of a primary condition or combinations of a primary and a secondary condition with the progression to subsequent conditions. Methods: We included 53,867 participants aged 45-64 years from the 45 and Up Study who were free of 10 predefined chronic conditions at baseline (2006-2009). The incidence of multimorbidity (coexistence of ≥2, ≥3, and ≥4 conditions) was identified using the claims database until December 31, 2016. The primary, secondary, tertiary, and quaternary condition for each participant was defined according to its temporal order of onset. Results: During a mean 9-years follow-up, the cumulative incidence of primary, secondary, tertiary, and quaternary conditions was 49.6, 23.7, 9.0, and 2.9%, respectively. The time to develop a subsequent condition decreased with the accumulation of conditions (P < 0.0001). Two concurrent cardiometabolic disorders (CMDs, 30.4%) and CMDs clustered with musculoskeletal disorders (15.2%), mental disorders (13.5%), asthma (12.0%), or cancer (8.7%) were the five most common multimorbidity patterns. CMDs tended to occur prior to mental or musculoskeletal disorders but after the onset of cancers or asthma. Compared with all participants who developed cancer as a primary condition, individuals who experienced mental disorders/neurodegenerative disorders and a comorbidity as cardiovascular disease, hypertension, dyslipidemia, diabetes, asthma, or osteoarthritis were 3.36-10.87 times more likely to develop cancer as a tertiary condition. Individuals with neurodegenerative disorders and a comorbidity as hypertension, dyslipidemia, osteoarthritis, or asthma were 5.14-14.15 times more likely to develop mental disorders as a tertiary condition. Conclusions: A high incidence of multimorbidity in middle-aged adults was observed and CMDs were most commonly seen in multimorbidity patterns. There may be accelerated aging after a primary condition occurs. Our findings also reveal a potential preventative window to obviate the development of secondary or tertiary conditions.

Mid-life predictors of late-life depressive symptoms; determining risk factors spanning two decades in the Women's Heathy Ageing Project.

BACKGROUND: Data available from longitudinal studies of adequate duration to explore midlife risk factors for late life higher depressive symptom scores in women is lacking. This study examines midlife (mean ages 50 years and 60 years) predictors of late life (mean age 70 years) depressive symptom scores to enrich our understanding of the role of changing risk factors across the lifespan. METHODS: This investigation was an assessment of the long-term impact of lifestyle and health variables on depressive symptoms. Data were drawn from an epidemiological prospective study of women's healthy ageing spanning two decades. Variables included assessment of mood, demographics, physical health, smoking status, attitudes towards ageing and menopause, alcohol consumption and employment. Analysis was conducted to determine the set of strongest predictors assessed in 1992 (mean age 50 years) and in 2002 (mean age 60 years) in relation to higher CESD-SF scores measured in 2012 (mean aged 70 years (n = 249)). A cross-sectional analysis determining concurrent associations at mean age 70 years was also conducted. RESULTS: An increase in positive mood at 50 and 60 years was associated with a 0.3 (95% CI 0.1-0.5) and 0.4 (95%CI 0.1-0.8) point reduction in CESD score at 70 years respectively. An increase in Hassles score at age 50 was associated with a 0.18-point increase in CESD (95% CI 0.01-0.05) 20 years later. However, no relationship was observed between Hassles score at 60 and CESD 10 years later. Analysis of concurrent risk factors demonstrated that bothersome symptom frequency and higher anxiety were associated with higher depressive symptom scores when women were 70 years. CONCLUSION: Low levels of positive mood were consistently associated with depressive symptoms scores 10 and 20 years later, suggesting clinical interventions aimed at improving positive affect may be particularly useful across the midlife.

Incidence of Medication-Treated Depression and Anxiety Associated with Long-Term Cancer, Cardiovascular Disease, Diabetes and Osteoarthritis in Community-dwelling Women and Men.

BACKGROUND: Long-term cancer, cardiovascular disease, diabetes and osteoarthritis may increase the risk of mental disorders, but which was more harmful and whether the associations differed between genders is unclear. METHODS: We included 115,094 participants (54.3% women) aged 45-64 years from the 45 and Up Study who were free of depression, anxiety, and Parkinson's disease at baseline (2006-2009). The incidence of depression and anxiety was identified using claim databases during follow-up until December 2016. Cox regression models were used to examine the association of cancer, cardiovascular disease, diabetes, and osteoarthritis at baseline with incident depression and anxiety. FINDINGS: During a mean eight-year follow-up (958,785 person-year), the cumulative incidence of depression and anxiety was 12.5% and 5.9% in the healthy population. Hazard ratios ([HRs] (95% CI) versus healthy population) for incident depression associated with long-term cancer, cardiovascular disease, diabetes, and osteoarthritis were 1.19 (95% CI: 1.13-1.25), 1.08 (1.00-1.16)), 1.18 (1.09-1.28), and 1.94 (1.80-2.10), respectively. The corresponding HRs (95% CIs) for incident anxiety were 1.11 (1.03-1.20), 1.26 (1.14-1.39), 1.10 (0.98-1.24), and 2.01 (1.80-2.23), respectively. The positive association between cancer and incident depression was more evident in men (HR (95% CI): 1.24 (1.13-1.35) than in women (1.14 (1.07-1.21). Long-term diabetes was an independent risk factor for incident anxiety in men (1.21 (1.02-1.44) but not in women (1.09 (0.93-1.28)). INTERPRETATION: Long-term osteoarthritis, cardiovascular disease, and cancer were independent risk factors for incident depression and anxiety in both genders with osteoarthritis having the highest relative risk.

Cohort profile: Women's Healthy Ageing Project (WHAP) - a longitudinal prospective study of Australian women since 1990.

BACKGROUND: The cohort was commenced to examine women's health from midlife (45-55 years) before the menopausal transition and into ageing. METHODS: Randomised selection and assessment of 2,001 women living in the Melbourne metropolitan area was conducted by the Roy Morgan Centre in 1990/91. Of the 779 women who met the entry criteria for the longitudinal follow-up (aged 45-55 years, menstruating, having a uterus and at least one ovary and not taking hormone therapy) 438 agreed to be seen annually across the menopausal transition from 1992 to 1999. Longitudinal prospective follow-up since 2000 has continued intermittently (2002/03, 2004/05, 2012/13, 2014/15). Data collection has included fasting biomarkers in each year since 1992, clinical assessment, lifestyle and quality of life data, physical measures and validated questionnaire data. Participants have consented to data linkage and, to date, mammogram and BioGrid data have been accessed. Biobank storage including serum, deoxyribonucleic acid (DNA) storage and PAXgene tubes are maintained. DISCUSSION: The WHAP has contributed to over 200 published research findings, several books, and book chapters in a variety of areas, including: health and wellbeing; mental and cognitive health; bone health; lifestyle, vascular risk and prevention; women's health and hormonal transition; and cross-cultural research.With all participants now aged over 70 years, the cohort is ideally placed to answer key questions of healthy ageing in women. With more than 25 years of longitudinal prospective follow-up this Australian dataset is unique in its duration, breadth and detail of measures including clinical review and specialized disease-specific testing and biomarkers. Ongoing follow-up into older ages for this long-running cohort will enable the association between mid to late-life factors and healthy ageing to be determined. This is particularly valuable for the examination of chronic diseases which have a 20-30 year prodrome and to provide knowledge on multiple morbidities. The dataset has a unique opportunity to improve our understanding of temporal relationships and the interactions between risk factors and comorbidities.

Oestrogen alpha-receptor variant and two-year memory decline in midlife Australian women.

OBJECTIVE: To prospectively examine the influence of the oestrogen-α receptor (ESR1)PvuII polymorphism on changes in memory performance over a 2-year period among 80 midlife postmenopausal Australian women. METHODS: Healthy women aged 56-67 years were administered a battery of four memory (verbal and non-verbal) tasks at baseline and 2 years later. RESULTS: Carriers of the ESR1 p allele had significantly greater declines in logical memory compared to participants with the PP genotype, independent of demographic characteristics (e.g. age), chronic illness (e.g. hypertension), sleep aid usage, hormone levels, apolipoprotein E e4 status and prospective changes in mood, smoking and alcohol consumption. CONCLUSION: These findings provide preliminary evidence for larger and longer prospective trials that will be able to determine if the p allele of the ESR1PvuII polymorphism is a potential biomarker of logical memory decline among aging women.

Protocol for a randomized controlled trial evaluating the effect of physical activity on delaying the progression of white matter changes on MRI in older adults with memory complaints and mild cognitive impairment: the AIBL Active trial.

BACKGROUND: Older adults free of dementia but with subjective memory complaints (SMC) or mild cognitive impairment (MCI) are considered at increased risk of cognitive decline. Vascular risk factors (VRF), including hypertension, heart disease, smoking, hypercholesterolemia and lack of physical activity (PA) have been identified as modifiable risk factors contributing to cognitive decline, and white matter hyperintensities (WMH) are associated with VRF, SMC and cognitive impairment. Findings from a growing number of clinical trials with older adults are providing strong evidence for the benefits of physical activity for maintaining cognitive function, but few studies are investigating these benefits in high-risk populations. The aim of AIBL Active is to determine whether a 24-month physical activity program can delay the progression of white matter changes on magnetic resonance imaging (MRI). METHODS/DESIGN: This single-blind randomized controlled trial (RCT) is offered to 156 participants, aged 60 and older, in the Melbourne arm of the Australian Imaging Biomarkers and Lifestyle Flagship Study of Aging (AIBL). Participants must have SMC with or without MCI and at least one VRF. The PA intervention is a modification of the intervention previously trialed in older adults with SMC and MCI (Fitness for the Ageing Brain Study). It comprises 24 months of moderate, home-based PA (150 minutes per week) and a behavioral intervention package. The primary outcome measure will be change in WMH after 24 months on MRI. Cognition, quality of life, functional fitness, level of physical activity, plasma biomarkers for cerebrovascular disease and amyloid positron emission tomography (PET) imaging comprise secondary measures. DISCUSSION: Currently, there is no effective pharmacological treatment available to delay cognitive decline and dementia in older adults at risk. Should our findings show that physical activity can slow down the progression of WMH, this RCT would provide an important proof of concept. Since imbedded in AIBL this RCT will also be able to investigate the interaction between vascular and Alzheimer's disease pathologies. TRIAL REGISTRATION: Australia New Zealand Clinical Trials Registry ACTRN12611000612910.

Stronger effect of amyloid load than APOE genotype on cognitive decline in healthy older adults.

OBJECTIVE: Although the APOE ε4 allele is associated with more rapid decline in memory in healthy older adults, the significance of elevated cerebral ß-amyloid (Aß) load for longitudinal changes in cognition is unclear. METHODS: Healthy and cognitively normal older adults (n = 141; mean age 76 years) underwent PET neuroimaging for cerebral Aß, APOE genotyping, and cognitive assessment as part of their baseline assessment in the Australian Imaging Biomarkers and Lifestyle study. Cognitive function was reassessed 18 months later. RESULTS: Linear mixed-model analyses adjusted for baseline cognitive function indicated that, relative to individuals with low cerebral Aß, individuals with high cerebral Aß showed significantly greater decline in working memory and verbal and visual episodic memory at 18 months. Compared with noncarriers, APOE ε4 carriers showed a greater decline in visual memory at the 18-month assessment. No interaction between APOE ε4 and cerebral Aß load was observed for any measure of cognitive function. CONCLUSIONS: In this prospective study of healthy older adults, high cerebral Aß load was associated with greater decline in episodic and working memory over 18 months. The APOE ε4 genotype was also associated with a decline in visual memory, although the effect was less than that observed for cerebral Aß load.

Blood-based protein biomarkers for diagnosis of Alzheimer disease.

OBJECTIVE: To identify plasma biomarkers for the diagnosis of Alzheimer disease (AD). DESIGN: Baseline plasma screening of 151 multiplexed analytes combined with targeted biomarker and clinical pathology data. SETTING: General community-based, prospective, longitudinal study of aging. PARTICIPANTS: A total of 754 healthy individuals serving as controls and 207 participants with AD from the Australian Imaging Biomarker and Lifestyle study (AIBL) cohort with identified biomarkers that were validated in 58 healthy controls and 112 individuals with AD from the Alzheimer Disease Neuroimaging Initiative (ADNI) cohort. RESULTS: A biomarker panel was identified that included markers significantly increased (cortisol, pancreatic polypeptide, insulinlike growth factor binding protein 2, ß(2) microglobulin, vascular cell adhesion molecule 1, carcinoembryonic antigen, matrix metalloprotein 2, CD40, macrophage inflammatory protein 1α, superoxide dismutase, and homocysteine) and decreased (apolipoprotein E, epidermal growth factor receptor, hemoglobin, calcium, zinc, interleukin 17, and albumin) in AD. Cross-validated accuracy measures from the AIBL cohort reached a mean (SD) of 85% (3.0%) for sensitivity and specificity and 93% (3.0) for the area under the receiver operating characteristic curve. A second validation using the ADNI cohort attained accuracy measures of 80% (3.0%) for sensitivity and specificity and 85% (3.0) for area under the receiver operating characteristic curve. CONCLUSIONS: This study identified a panel of plasma biomarkers that distinguish individuals with AD from cognitively healthy control subjects with high sensitivity and specificity. Cross-validation within the AIBL cohort and further validation within the ADNI cohort provides strong evidence that the identified biomarkers are important for AD diagnosis.

Hormone levels and cognitive function in postmenopausal midlife women.

Gonadal hormones may influence cognitive function. Postmenopausal midlife women in the population-based Melbourne Women's Midlife Health Project cohort were administered a comprehensive battery of neuropsychological tests on two occasions 2 years apart. Participants (n = 148, mean age 60 years) had undergone natural menopause and were not using hormone therapy. Estrone, total and free estradiol, and total and free testosterone levels were measured at time of the first testing. Principal-component analysis identified four cognitive factors. In multiple linear regression analyses, better semantic memory performance was associated with higher total (p = 0.02) and free (p = 0.03) estradiol levels and a lower ratio of testosterone to estradiol (p = 0.007). There were trends for associations between better verbal episodic memory and lower total testosterone (p = 0.08) and lower testosterone/estradiol ratio (p = 0.06). Lower free testosterone levels were associated with greater 2-year improvement on verbal episodic memory (p = 0.04); higher testosterone/estradiol predicted greater semantic memory improvement (p = 0.03). In postmenopausal midlife women, endogenous estradiol and testosterone levels and the testosterone/estradiol ratio are associated with semantic memory and verbal episodic memory abilities.

Hormone levels and cognitive function in postmenopausal midlife women.

Gonadal hormones may influence cognitive function. Postmenopausal midlife women in the population-based Melbourne Women's Midlife Health Project cohort were administered a comprehensive battery of neuropsychological tests on two occasions 2 years apart. Participants (n = 148, mean age 60 years) had undergone natural menopause and were not using hormone therapy. Estrone, total and free estradiol, and total and free testosterone levels were measured at time of the first testing. Principal-component analysis identified four cognitive factors. In multiple linear regression analyses, better semantic memory performance was associated with higher total (p = 0.02) and free (p = 0.03) estradiol levels and a lower ratio of testosterone to estradiol (p = 0.007). There were trends for associations between better verbal episodic memory and lower total testosterone (p = 0.08) and lower testosterone/estradiol ratio (p = 0.06). Lower free testosterone levels were associated with greater 2-year improvement on verbal episodic memory (p = 0.04); higher testosterone/estradiol predicted greater semantic memory improvement (p = 0.03). In postmenopausal midlife women, endogenous estradiol and testosterone levels and the testosterone/estradiol ratio are associated with semantic memory and verbal episodic memory abilities.

Effects of anticholinergic drugs on cognitive function in older Australians: results from the AIBL study.

BACKGROUND/AIMS: The nature and extent of adverse cognitive effects due to the prescription of anticholinergic drugs in older people with and without dementia is unclear. METHODS: We calculated the anticholinergic load (ACL) of medications taken by participants of the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of ageing, a cohort of 211 Alzheimer's disease (AD) patients, 133 mild cognitive impairment (MCI) patients and 768 healthy controls (HC) all aged over 60 years. The association between ACL and cognitive function was examined for each diagnostic group (HC, MCI, AD). RESULTS: A high ACL within the HC group was associated with significantly slower response speeds for the Stroop color and incongruent trials. No other significant relationships between ACL and cognition were noted. CONCLUSION: In this large cohort, prescribed anticholinergic drugs appeared to have modest effects upon psychomotor speed and executive function, but not on other areas of cognition in healthy older adults.

Executive functions in recently postmenopausal women: absence of strong association with serum gonadal steroids.

It is controversial to what extent endogenous gonadal hormone exposures influence executive functions in midlife women. Participants in the population-based Melbourne Women's Midlife Health Project were administered a battery of neuropsychological tests on two occasions 2 years apart. Tests of executive functions were the Trail Making Test (Part B), Tower of London (administered at baseline only), Symbol Digit Modalities Test, Digit Span Backward, and Letter-Number Sequencing. Estrone, free estradiol, and free testosterone levels were measured at the time of the first testing, and analyses were restricted to 147 women aged 56-64 years who had recently undergone natural menopause (mean age of menopause 53 years) and were not using hormone therapy. In multiple linear regression analyses, 2 of 20 baseline associations were significant at an alpha level of 0.05. Estrone concentrations were positively associated with Tower of London performance (p=0.02), and the ratio of free testosterone to free estradiol was positively associated with scores on the Symbol Digit Modalities Test score (p=0.04). No hormone measure was significantly predictive of 2-year change in executive functions performance. Significance levels in these exploratory analyses were unadjusted for multiple comparisons, and observed associations could be due to unique psychometric properties of these particular tasks or due to chance. Sex hormone binding globulin concentrations were unrelated to executive function scores. In recently postmenopausal women not receiving hormone therapy, serum concentrations of estrone, estradiol and testosterone, and the testosterone/estradiol ratio are not strongly associated with executive functions.

Association between temporal lobe P-glycoprotein expression and seizure recurrence after surgery for pharmacoresistant temporal lobe epilepsy.

Surgery is recommended for pharmacoresistant temporal lobe epilepsy (TLE), but seizures recur in approximately one third of patients postsurgery. P-glycoprotein is an efflux multidrug transporter that is overexpressed in a range of epileptogenic pathologies. We hypothesized that increased expression of P-glycoprotein in the epileptogenic temporal lobe might be a marker for recurrence of pharmacoresistant seizures postsurgery. We performed immunohistochemistry on temporal lobe tissues resected from 69 patients who underwent anterior temporal lobectomy for pharmacoresistant TLE with histopathological proven hippocampal sclerosis. P-glycoprotein expression was rated by three pathologists independently. Patients with seizure recurrence (n=22) had greater number of positively stained capillaries (p=0.001) and higher P-glycoprotein immunoreactive score in capillaries (p=0.002) in the white matter of resected temporal lobe. The differences remained significant in multivariate analysis (p=0.002 and 0.006, respectively). The results suggest that P-glycoprotein expression in temporal lobe may be associated with seizure recurrence after surgery for pharmacoresistant TLE.

The Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging: methodology and baseline characteristics of 1112 individuals recruited for a longitudinal study of Alzheimer's disease.

BACKGROUND: The Australian Imaging, Biomarkers and Lifestyle (AIBL) flagship study of aging aimed to recruit 1000 individuals aged over 60 to assist with prospective research into Alzheimer's disease (AD). This paper describes the recruitment of the cohort and gives information about the study methodology, baseline demography, diagnoses, medical comorbidities, medication use, and cognitive function of the participants. METHODS: Volunteers underwent a screening interview, had comprehensive cognitive testing, gave 80 ml of blood, and completed health and lifestyle questionnaires. One quarter of the sample also underwent amyloid PET brain imaging with Pittsburgh compound B (PiB PET) and MRI brain imaging, and a subgroup of 10% had ActiGraph activity monitoring and body composition scanning. RESULTS: A total of 1166 volunteers were recruited, 54 of whom were excluded from further study due to comorbid disorders which could affect cognition or because of withdrawal of consent. Participants with AD (211) had neuropsychological profiles which were consistent with AD, and were more impaired than participants with mild cognitive impairment (133) or healthy controls (768), who performed within expected norms for age on neuropsychological testing. PiB PET scans were performed on 287 participants, 100 had DEXA scans and 91 participated in ActiGraph monitoring. CONCLUSION: The participants comprising the AIBL cohort represent a group of highly motivated and well-characterized individuals who represent a unique resource for the study of AD. They will be reassessed at 18-month intervals in order to determine the predictive utility of various biomarkers, cognitive parameters and lifestyle factors as indicators of AD, and as predictors of future cognitive decline.

A prospective study of the association between endogenous hormones and depressive symptoms in postmenopausal women.

OBJECTIVE: Across a woman's lifetime, variations in hormone levels are known to influence mood and well-being. Whether absolute or changes in hormone levels over time are associated with depression among postmenopausal women remains unclear. METHODS: The Melbourne Women's Midlife Health Project is a longitudinal population-based study of women who were followed through the menopausal transition. This analysis is based on data collected from 138 postmenopausal women in years 11 and 13 of the study, who were assessed for the presence of depressive symptoms using the Center for Epidemiological Studies Depression Scale. Logistic regression models were developed to determine whether absolute or changes in hormone levels were associated with depression. RESULTS: No significant associations were found between depressive symptoms and the absolute levels of sex hormone-binding globulin, testosterone, free androgen index, estradiol, free estradiol, or follicle-stimulating hormone (FSH). On the other hand, women with a decline in total serum estradiol over the 2-year period had a more than threefold increased risk of depressive symptoms (odds ratio, 3.5; 95% CI, 1.2-9.9). A large increase in FSH levels over this period was also associated with depressive symptoms (odds ratio, 2.6; 95% CI, 1.0-6.7). These associations remained even after adjustment for initial depression score, as well as a range of potential confounding factors. CONCLUSIONS: Changes in estradiol and, to a lesser extent, in FSH levels are associated with an increased risk of depressive symptoms in postmenopausal women. These results further support a role for fluctuating rather than absolute hormone levels in depression in later life.