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Background: Individuals with subjective cognitive decline (SCD) are hypothesized to be the earliest along the cognitive continuum between healthy aging and Alzheimer’s disease (AD), although more research is needed on this topic. Given that treatment approaches may be most effective pre-clinically, a primary objective of emerging research is to identify biological markers of SCD using neuroimaging methods. Objective: The current review aimed to comprehensively present the neuroimaging studies on SCD to date. Methods: PubMed and PsycINFO databases were searched for neuroimaging studies of individuals with SCD. Quality assessments were completed using the Appraisal tool for Cross-Sectional Studies. Results: In total, 62 neuroimaging studies investigating differences between participants with SCD and healthy controls were identified. Specifically, the number of studies were as follows: 36 MRI, 6 PET, 8 MRI/PET, 4 EEG, 7 MEG, and 1 SPECT. Across neuroimaging modalities, 48 of the 62 included studies revealed significant differences in brain structure and/or function between groups. Conclusion: Neuroimaging methods can identify differences between healthy controls and individuals with SCD. However, inconsistent results were found within and between neuroimaging modalities. Discrepancies across studies may be best accounted for by methodological differences, notably variable criteria for SCD, and differences in participant characteristics and risk factors for AD. Clinic based recruitment and cross-sectional study design were common and may bias the literature. Future neuroimaging investigations of SCD should consistently incorporate the standardized research criteria for SCD (as recommended by the SCD-Initiative), include more details of their SCD sample and their symptoms, and examine groups longitudinally.

Lack of physical activity is a risk factor for dementia, however, the utility of interventional physical activity programs as a protective measure against brain atrophy and cognitive decline is uncertain. Here we present the effect of a randomized controlled trial of a 24-month physical activity intervention on global and regional brain atrophy as characterized by longitudinal voxel-based morphometry with T1-weighted MRI images. The study sample consisted of 98 participants at risk of dementia, with mild cognitive impairment or subjective memory complaints, and having at least one vascular risk factor for dementia, randomized into an exercise group and a control group. Between 0 and 24 months, there was no significant difference detected between groups in the rate of change in global, or regional brain volumes.

Digital biomarkers are defined as objective, quantifiable physiological and behavioral data that are collected and measured by means of digital devices. Their use has revolutionized clinical research by enabling high-frequency, longitudinal, and sensitive measurements. In the field of neurodegenerative diseases, an example of a digital biomarker-based technology is instrumental activities of daily living (iADL) digital medical application, a predictive biomarker of conversion from mild cognitive impairment (MCI) due to Alzheimer’s disease (AD) to dementia due to AD in individuals aged 55 + . Digital biomarkers show promise to transform clinical practice. Nevertheless, their use may be affected by variables such as demographics, genetics, and phenotype. Among these factors, sex is particularly important in Alzheimer’s, where men and women present with different symptoms and progression patterns that impact diagnosis. In this study, we explore sex differences in Altoida’s digital medical application in a sample of 568 subjects consisting of a clinical dataset (MCI and dementia due to AD) and a healthy population. We found that a biological sex-classifier, built on digital biomarker features captured using Altoida’s application, achieved a 75% ROC-AUC (receiver operating characteristic — area under curve) performance in predicting biological sex in healthy individuals, indicating significant differences in neurocognitive performance signatures between males and females. The performance dropped when we applied this classifier to more advanced stages on the AD continuum, including MCI and dementia, suggesting that sex differences might be disease-stage dependent. Our results indicate that neurocognitive performance signatures built on data from digital biomarker features are different between men and women. These results stress the need to integrate traditional approaches to dementia research with digital biomarker technologies and personalized medicine perspectives to achieve more precise predictive diagnostics, targeted prevention, and customized treatment of cognitive decline. RLH and IT were supported by Altoida Inc. JM was supported in this work by the Charles University Grant Agency (GA UK) project no. 436119 at Charles University, Second Faculty of Medicine, Prague, Czech Republic. Peer Reviewed "Article signat per 16 autors/es: Robbert L. Harms, Alberto Ferrari, Irene B. Meier, Julie Martinkova, Enrico Santus, Nicola Marino, Davide Cirillo, Simona Mellino, Silvina Catuara Solarz, Ioannis Tarnanas, Cassandra Szoeke, Jakub Hort, Alfonso Valencia, Maria Teresa Ferretti, Azizi Seixas & Antonella Santuccione Chadha "

White matter hyperintensities (WMHs) are a risk factor for cognitive decline. Physical activity (PA) is associated with lower WMH. Whether long-term exposure to PA programs has beneficial effects on WMH progression in older adults with memory complaints and comorbid conditions has had limited exploration. This study explored whether a 24-month moderate-intensity PA intervention can delay the progression of WMH and hippocampus loss in older adults at risk for cognitive decline. Data acquired on magnetic resonance imaging were used to measure the progression of WMH and hippocampus loss. The results of this study showed no effect of intervention on either the primary outcome measure "WMH" or the secondary outcome measure "hippocampal volume." In addition, neither beta amyloid status nor the adherence to the intervention had any effect on the outcome. In this cohort of subjective memory complaints and mild cognitive impairment participants with vascular risk factors, there was no effect of long-term moderate-intensity PA on WMH or hippocampal loss.

International audience; The Alzheimer's Association International Conference held its sixth Satellite Symposium in Sydney, Australia in 2019, highlighting the leadership of Australian researchers in advancing the understanding of and treatment developments for Alzheimer's disease (AD) and other dementias.This leadership includes the Australian Imaging, Biomarker, and Lifestyle Flagship Study of Ageing (AIBL), which has fueled the identification and development of many biomarkers and novel therapeutics. Two multimodal lifestyle intervention studies have been launched in Australia; and Australian researchers have played leadership roles in other global studies in diverse populations.Australian researchers have also played an instrumental role in efforts to understand mechanisms underlying vascular contributions to cognitive impairment and dementia; and through the Women's Healthy Aging Project have elucidated hormonal and other factors that contribute to the increased risk of AD in women. Alleviating the behavioral and psychological symptoms of dementia has also been a strong research and clinical focus in Australia.

Importance: Women represent two-thirds of patients with Alzheimer disease (AD), and sex differences might affect results of randomized clinical trials (RCTs). However, little information exists on differences in sex as reported in RCTs for AD. Objective: To assess the ratio of females to males and the reporting of sex-stratified data in large pharmaceutical RCTs for AD. Data Sources: A search for pharmaceutical RCTs for AD was conducted on September 4, 2019, using ClinicalTrials.gov with the key word Alzheimer disease, and articles related to those trials were identified using the PubMed, Scopus, and Google Scholar databases. Searches were conducted between September 4 and October 31, 2019, and between April 15 and May 31, 2020. Study Selection: Controlled RCTs that had more than 100 participants and tested the efficacy of drugs or herbal extracts were included. Of 1047 RCTs identified, 409 were published and therefore screened. A total of 77 articles were included in the final analysis, including 56 primary articles on AD, 13 secondary articles on AD, and 8 articles on mild cognitive impairment. Data Extraction and Synthesis: The location and date of publication; number, sex, and age of patients enrolled; disease severity; experimental or approved status of the drug; and whether the study included a sex-stratified analysis in the protocol, methods, or results were extracted by 1 reviewer for each article, and the meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline. Data were analyzed using a mixed-effects model. Main Outcomes and Measures: The mean proportion of women enrolled in the trials and the associations between prespecified variables were analyzed. The proportion of articles that included sex-stratified results and the temporal trends in the reporting of these results were also studied. Results: In this review of 56 RCTs for AD involving 39 575 participants, 23 348 women (59.0%) were included. The mean (SD) proportion of women in RCTs of approved drugs was 67.3% (6.9%), and in RCTs of experimental drugs was 57.9% (5.9%). The proportion of women in RCTs of experimental drugs was significantly lower than the proportion of women in the general population with AD in the US (62.1%; difference, -4.56% [95% CI, -6.29% to -2.87%]; P

© 2021 The Author(s)Background: Both physical activity (PA) and sedentary behavior (SB) are important factors for healthy ageing. This systematic review aimed to determine the association of objectively assessed (instrumented) PA and SB with global cognitive function in older adults. Methods: PubMed, Embase, the Cochrane Library (via Wiley), CINAHL, PsychINFO, and SPORTDiscus (via EBSCO) were searched from inception to June 21, 2020 for articles that described associations of objectively assessed PA/SB with global cognitive function in older adults aged 60 years and older. Results were synthesized using an effect direction heat map and albatross plots portrayed estimated effect sizes (standardized regression coefficients (βs)), which were summarized in boxplots. Results: In total, 45 articles were included representing a total of 15,817 older adults (mean/median age ranged from 65 to 88 years; 49.5% female). Longitudinal studies (n = 7) showed that higher moderate-to-vigorous and light PA (MVPA and LPA, respectively) and lower SB were associated with better global cognitive function. Standardized βs of cross-sectional studies (n = 38) showed that lower SB (median [IQR], β = 0.078 [0.004-0.184] and higher LPA (β = 0.096 [0.046-0.188]), activity counts (β = 0.131 [0.049-0.224]), number of steps (β = 0.155 [0.096-0.246]), MVPA (β = 0.163 [0.069-0.285]) and total PA (TPA) (β = 0.174 [0.147-0.255]) were associated with better global cognitive function. Conclusions: Higher PA and lower SB are associated with better global cognitive function in older adults. The greatest estimated effect sizes were found for moderate-to-vigorous and TPA, suggesting that greater duration of any PA, and high intensity PA could be most beneficial for global cognitive function.

Background In vivo measurement of hippocampal volume with magnetic resonance imaging (MRI) has become an important element in neuroimaging research. However, hippocampal volumetric findings and their relationship with cardiovascular risk factors and memory performance are still controversial and inconsistent for non-demented adults. Purpose To compare total and regional hippocampal volumes from manual tracing and automated Freesurfer segmentation methods and their relationship with mid-life clinical data and late-life verbal episodic memory performance in older women. Material and Methods This study used structural MRI datasets from 161 women who were scanned in 2012 and underwent neuropsychological assessments. Of these participants, 135 women had completed baseline measures of cardiovascular risk factors in 1992. Results Our results showed a significant correlation between manual tracing and automated Freesurfer output segmentations of total (r = 0.71), anterior (r = 0.65), and posterior (r = 0.38) hippocampal volumes. Mid-life Framingham Cardiovascular Risk Profile score is not associated with late-life hippocampal volumes, adjusted for intracranial volume, age, education, and apolipoprotein E gene ε4 status. Anterior hippocampal volume segmented either with manual tracing or automated Freesurfer software is sensitive to changes in mid-life high-density lipoprotein (HDL) cholesterol level, while posterior hippocampal volume is linked with verbal episodic memory performance in elderly women. Conclusion These findings support the use of Freesurfer automated segmentation measures for large datasets as being highly correlated with the manual tracing method. In addition, our results suggest intervention strategies that target mid-life HDL cholesterol level in women.

Background Depression is a major global health burden and psychiatry requires evidence-based primary prevention and treatment strategies. Evidence suggests that certain dietary patterns, in particular, components of the Mediterranean diet, possess key biological factors associated with abating depressive risk and disease progression. We sought to evaluate the existing evidence regarding the association between the Mediterranean diet and depressive symptoms by conducting a systematic review. Methods A search of published studies was conducted using the computer databases Medline, Embase, PsychINFO, Scopus and Google Scholar, for articles in the English language published from inception to April 2018. The search strategy applied the following subject headings and keywords: “Mediterranean diet” OR Mediterranean* AND “Major depressive disorder” OR Depress* OR “Negative mood” OR Mood. The NIH quality assessment tool was implemented by reviewers to determine study quality. Results Results from twenty observational studies and six intervention trials were qualitatively examined. The majority (85%) of observational studies support the evidence that the Mediterranean dietary pattern is associated with reductions in depressive incidence and all intervention studies echoed these findings. Limitations Methodological disparity in Mediterranean style diets limited comparisons but were overcome by specifying inclusion criteria and compressive appraisal of the data. Conclusions Modifying diet provides a potential treatment for depression which procures few side effects, lessens disease progression and demonstrates a cost-effective measure that can be implemented globally. Present research has found that more objective measures are necessary to define the Mediterranean diet and highlights the need for longitudinal studies and clinical trials for future research.

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. Keywords: Cardiovascular disease, Cancer, Diabetes, Osteoarthritis, Depression, Anxiety

Background: Previous studies have demonstrated that physical activity (PA) interventions can improve physical and cognitive outcomes in older adults, but most have been relatively short in duration (

OBJECTIVE: Robust norms for neuropsychological tests may offer superior clinical utility to conventional norms, in their ability to distinguish normal cognitive aging from prodromal dementia. However, the availability of robust norms from midlife, where cognitive changes in those at risk of disease may arise, is limited. This study presents demographically stratified robust norms for tests of verbal memory in Australian women. METHOD: Participants were from the population-based Women's Healthy Ageing Project. Baseline (1999 to 2002; n = 368; age range = 53-67years) and follow-up (2012 to 2014; n = 291; age range = 65-80years) measures of word-list and story recall were administered at least 10 years apart. Four samples were identified: conventional (derived from a cross-sectional sample), robust (derived from a longitudinal sample), mild cognitive impairment (MCI) or Alzheimer's disease (AD), and lost to follow-up. Area under the curve (AUC) values were generated to assess the diagnostic ability of conventional and robust norms using 1 standard deviation and 1.5 standard deviation cut-offs. RESULTS: There were differences between conventional Australian and American normative data for the Consortium to Establish a Registry for Alzheimer's Disease word-list recall. Individuals who declined to MCI/AD over the follow-up displayed poorer performance at baseline, however no differences in classification ability of robust (AUC range .54 to.64) and conventional (AUC range .51 to .65) norms were observed. CONCLUSION: Neuropsychological performance in midlife predicted clinical cognitive decline 1 decade later, but conventional and robust norms was similarly predictive of conversion to disease in this cohort. The use of country-specific, representative conventional norms remains a valuable tool for neuropsychologists to assess cognitive performance throughout midlife. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Background Depression's relationship with cerebral abnormalities and cognitive decline is temporally dynamic. Despite clear clinical utility, understanding depression's effect on cerebral structures, cognitive impairment and the interaction between these symptoms has had limited consideration. Methods This review summarised studies examining a clinical depression diagnosis or validated scales measuring depressive symptoms, data concerning amyloid-beta (Aβ) levels, brain structure and function focusing on hippocampal alterations, or white matter hyperintensities (WMH), and at least one validated neuropsychological test. Online database searches of: PsycINFO, EMBASE, MEDLINE, and Scopus were conducted to identify potential articles. Results While depression was consistently associated with cross-sectionally cognitive decline across multiple domains, the neuropathological basis of this dysfunction remained unclear. Hippocampal, frontal, and limbic dysfunction as well as cortical thinning, WMH, and Aβ burden all provide inconsistent findings, likely due to depression subtypes. The consistency of these findings additionally decreases when examining this relationship longitudinally, as these results are further confounded by pre-dementia states. The therapeutic interventions examined were more efficacious in the younger compared with the older samples, who were characterised by greater WMH and Aβ burden. Limitations The limited number of longitudinal and interventional studies in addition to the heterogeneity of the samples restricts their generalisability. Conclusions Symptomatological differences between early-onset and late-onset depression (EOD and LOD) appear crucial in understanding whether late-life depression is the primary or secondary source of cerebral pathology. Though severe cognitive impairments and clearer neuropathological underpinnings are more characteristic of LOD than EOD, the inconsistency of valid biomarkers remains problematic.

Cerebral amyloid-β (Aβ) plaques are the hallmark biomarker of Alzheimer’s disease (AD) and are detectable decades before clinical symptoms. Modifying risk factors associated with Aβ accrual offers an opportunity for AD prevention. While midlife vascular health is linked to AD; there is minimal longitudinal evidence regarding the effect of midlife lipids on Aβ. We examined the association between midlife lipids and Aβ 20 years later. One hundred and twenty-two women had serum lipid profiles in midlife (1992, 45–57 years), and cerebral imaging, genotyping, and cognition measured 20 years later (2012/13, 66–77 years). Imaging was performed in 2012/13 via F-18 Florbetaben positron emission tomography (PET) and standard uptake value ratios (SUVR) were calculated. Lipid profiles and other predictors of high PET-SUVR levels (>1.2) were evaluated using multivariable logistic regression. Increases in low-density lipoprotein (LDL) cholesterol in midlife were associated with Aβ, adjusting for age, education, cholesterol medication, and cognition (AdjOR1.81, 95% CI 1.08–3.01, p = 0.024), but attenuated on adjustment for apolipoprotein E4 (APOE ɛ4). Aβ risk increased in women with APOE ɛ4 and midlife cholesterol >6.2 mmol/L (AdjOR9.59, 95% CI 2.94–31.31, p 3.3 mmol/L (AdjOR9.00, 95% CI 2.89–28.03, p

The development of SARS-CoV-2 vaccines represents a significant breakthrough for managing the COVID-19 pandemic. However, their approval process has exposed a crucial limitation in clinical trial reports-that is, a disregard for sex differences in response to vaccines. Historically, males and females have shown different reactions to vaccines of many kinds, which have become apparent with the arrival of COVID-19 vaccines in late-2020. In this article, we review regulatory data from Phase III vaccine trials as well as peer-reviewed reports from vaccines administered to the general population, many of which failed to stratify results by sex. We also discuss the exclusion of pregnant and lactating persons in drug development and the regulatory guidelines for use of COVID-19 vaccines in such populations. We conclude by proposing some questions to stimulate discussion with the intent of advancing the field toward precision medicine.

Aim: The long-term effects of intimate partner violence (IPV) on physical health outcomes and health-related behaviors are underresearched in comparison to the effects on mental health and pregnancy. This systematic review examines the recent research in this area from 2012 through 2019. Methods: SCOPUS, PubMed, EBSCOhost, and gray literature were searched using the key words “intimate partner violence” and “health.” To meet inclusion criteria, studies needed to be original research and focus on IPV during adulthood and its effects on the physical health or health-related behaviors of women. Fifty-two studies were qualitatively analyzed, with results grouped into broad categories of effects, including cardiovascular, endocrine, infectious diseases, and health screening. Results: IPV was shown to have negative effects on physical health outcomes for women, including worsening the symptoms of menopause and increasing the risk of developing diabetes, contracting sexually transmitted infections, engaging in risk-taking behaviors including the abuse of drugs and alcohol, and developing chronic diseases and pain. It also has significant effects on human immunodeficiency virus outcomes, worsening CD4+ cell depletion. Results varied regarding the effects of IPV on cardiovascular health outcomes. Conclusion: The result of this review demonstrates that women who have experienced violence and abuse are at significantly increased risk of poor health outcomes in a variety of areas and so require specialized and tailored primary care. This review highlights significant gaps in this field of research, particularly in relation to cardiovascular disease, endocrine dysfunction, and neurological symptoms and conditions. It demonstrates a need for additional long-term studies in this field to better inform the health care of women who have experienced IPV and to establish the physiological mediators of these outcomes.

BackgroundOlder people are often admitted for rehabilitation to improve walking, yet not everyone improves. The aim of this study was to determine key factors associated with a positive response to hospital-based rehabilitation in older people.MethodsThis was a secondary data analysis from a multisite randomized controlled trial. Older people (n= 198, median age 80.9 years, IQR 76.6- 87.2) who were admitted to geriatric rehabilitation wards with a goal to improve walking were recruited. Participants were randomized to receive additional daily physical therapy focused on mobility (n = 99), or additional social activities (n = 99). Self-selected gait speed was measured on admission and discharge. Four participants withdrew. People who changed gait speed ≥0.1 m/s were classified as ‘responders’ (n = 130); those that changed ResultsResponding to rehabilitation was associated with the number of days in rehabilitation (OR 1.04; 95% CI 1.00 to 1.08; p = .039) and higher Mini Mental State Examination scores (OR 1.07, 95% CI 1.00 – 1.14; p = .048). No other factors were found to have association with responding to rehabilitation.ConclusionIn older people with complex health problems or multi-morbidities, better cognition and a longer stay in rehabilitation were associated with a positive improvement in walking speed. Further research to explore who best responds to hospital-based rehabilitation and what interventions improve rehabilitation outcomes is warranted.Trial registrationAustralian New Zealand Clinical Trials Registry ACTRN12613000884707; ClinicalTrials.gov IdentifierNCT01910740.

This chapter will focus on the sex hormone influence on cognition, cognitive decline, and the risk of dementia. We are only just beginning to look at the impact of reproductive aging on cognitive aging and a 2019 review showed how few aging studies have considered this ( Taylor, Pritschet, Yu, & Jacobs, 2019 ), yet it is clearly an important question for at least two-thirds of those with dementia. There are strong indicators that the sex hormones have a role in cognition, neural activity, performance, brain structure, function, and inflammation. Given more than 100 years of dementia research has yielded no disease-modifying therapy or cure, it is clear our understanding of this complex neurodegenerative disease is incomplete. A snapshot of dementia research shows a predominance of research on older individuals (well after the onset of early changes in working memory circuitry ( Jacobs et al., 2017 )), often excluding those with vascular pathology ( Ritchie, Terrera, & Quinn, 2015 ; Sperling et al., 2011 ) and there is an absence of reporting differences by sex, which then does not provide the opportunity to examine sex differences in results ( Laws, Irvine, & Gale, 2016 ). Yet two-thirds of all dementia cases are women ( Alzheimer Association, 2014 ), vascular risk and disease is a fundamental component of disease manifestation ( de la Torre, 2010a ; Harrison et al., 2014 ; Wiesmann, Kiliaan, & Claassen, 2013 )—itself an area with well documented sex differences ( Sobhani et al., 2018 )—and it takes three decades for the neuropathological changes characteristic of Alzheimer’s dementia to reach levels clinically matched with a diagnosis ( Villemagne et al., 2013 ). The menopausal transition occurs in the key window identified by dementia researchers as likely responsible for the chronic evolution of neurodegenerative processes from age 45 to manifestation of disease over 70 years.

Lack of physical activity is a risk factor for dementia, however, the utility of interventional physical activity programs as a protective measure against brain atrophy and cognitive decline is uncertain. Here we present the effect of a randomized controlled trial of a 24-month physical activity intervention on global and regional brain atrophy as characterized by longitudinal voxel-based morphometry with T1-weighted MRI images. The study sample consisted of 98 participants at risk of dementia, with mild cognitive impairment or subjective memory complaints, and having at least one vascular risk factor for dementia, randomized into an exercise group and a control group. Between 0 and 24 months, there was no significant difference detected between groups in the rate of change in global, or regional brain volumes.

After more than a century of research, we have failed to develop a pharmacological prevention or cure for dementia. There are strong indicators that sex hormones influence cognition. In this paper we discuss the role of these hormones at the intersection between vascular disease and dementia, in light of the mounting literature covering the shared risk factors, pathological features alongside the timeline of hormonal change with the evolution of vascular and neurodegenerative disease. Interactive risk factors and the role of inflammation over the duration of disease evolution are highlighted. Our summary tables assessing the impact of estrogen-based hormone therapy on cognition over the past 45 years illustrate the effort expended to determine the ideal age for intervention and the type, dose, administration, and duration of therapy that might improve or protect cognition as well as alleviate menopausal symptoms. As the prevalence of dementia is rising and is higher in women, it is crucial we advance our knowledge from the "inconclusive" position statement on menopausal hormone therapy of the US Preventive Services Task Force.

Questions: Among older people receiving inpatient rehabilitation, does additional supervised physical activity lead to faster self-selected gait speed at discharge? Does additional supervised physical activity lead to better mobility, function and quality of life at discharge and 6 months following discharge? Design: Multi-centre, parallel-group, randomised controlled trial with concealed allocation, assessor blinding, and intention-to-treat analysis. Participants: Older people (age > 60 years) from two Australian hospitals undergoing rehabilitation to improve mobility. Intervention: Participants received multidisciplinary care, including physiotherapy. During hospital rehabilitation, the experimental group (n = 99) spent additional time daily performing physical activities that emphasised upright mobility tasks; the control group (n = 99) spent equal time participating in social activities. Outcome measures: Self-selected gait speed was the primary outcome at discharge and a secondary outcome at the 6-month follow-up. Timed Up and Go, De Morton Mobility Index, Functional Independence Measure and quality of life were secondary outcomes at discharge and tertiary outcomes at the 6-month follow-up. Results: The experimental group received a median of 20 additional minutes per day (IQR 15.0 to 22.5) of upright activities for a median of 16.5 days (IQR 10.0 to 25.0). Gait speed did not differ between groups at discharge. Mean gait speed was 0.51 m/s (SD 0.29) in the experimental group and 0.56 m/s (SD 0.28) in the control group (effect size −0.06 m/s, 95% CI −0.12 to 0.01, p = 0.096). No significant differences were detected in other secondary measures. Conclusion: While substantial gains in mobility were achieved by older people receiving inpatient rehabilitation, additional physical activity sessions did not lead to better walking outcomes at discharge or 6 months. Trial registration: ACTRN12613000884707. [Said CM, Morris ME, McGinley JL, Szoeke C, Workman B, Liew D, Hill KD, Woodward M, Wittwer JE, Churilov L, Danoudis M, Bernhardt J (2018) Additional structured physical activity does not improve walking in older people (> 60 years) undergoing inpatient rehabilitation: a randomised trial. Journal of Physiotherapy 64: 237–244] Key words: Mobility limitation, Rehabilitation, Exercise therapy, Hospitalisation, Randomised controlled trial

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.

This systematic review aimed to synthesise multimorbidity profiling literature to identify replicable and clinically meaningful groupings of multimorbidity. We searched six electronic databases (Medline, EMBASE, PsycINFO, CINAHL, Scopus, and Web of Science) for articles reporting multimorbidity profiles. The identified profiles were synthesised with multidimensional scaling, stratified by type of statistical analysis used in the derivation of profiles. The 51 studies that met inclusion criteria reported results of 98 separate analyses of multimorbidity profiling, with a total of 407 multimorbidity profiles identified. The statistical techniques used to identify multimorbidity profiles were exploratory factor analysis, cluster analysis of diseases, cluster analysis of people, and latent class analysis. Reporting of methodological details of statistical methods was often incomplete. The discernible groupings of multimorbidity took the form of both discrete categories and continuous dimensions. Mental health conditions and cardio-metabolic conditions grouped along identifiable continua in the synthesised results of all four methods. Discrete groupings of chronic obstructive pulmonary disease with asthma, falls and fractures with sensory deficits and of Parkinson’s disease and cognitive decline where partially replicable (identifiable in the results of more than one method), while clustering of musculoskeletal conditions and clustering of reproductive systems were each observed only in one statistical approach. The two most replicable multimorbidity profiles were mental health conditions and cardio-metabolic conditions. Further studies are needed to understand aetiology and evolution of these multimorbidity groupings. Guidelines for strengthening the reporting of multimorbidity profiling studies are proposed.

The importance of diet for the maintenance of health during aging is attracting a growing body of research interest. Given dietary intakes, along with BMI, are substantial contributors to disease burden, this study aimed to investigate prospective changes in dietary patterns and nutrient intakes in a sample of mid to late-life women over 14 years.Participants were from the Women's Healthy Ageing Project (WHAP); a longitudinal cohort of Australian-born women within the Melbourne metropolitan area. 173 participants were included in this analysis, their mean age in 1998 was 55 years (range 51-62) and in 2012 was 70 years (range 66-76). Diet was assessed using the Dietary Questionnaire for Epidemiological Studies Version 2 in 1998 and 2012. Nutritional intakes, Dietary Inflammatory Index (DII®) scores, Mediterranean Diet (MD) scores, sociodemographic and physical measures were calculated for all participants at both time points.Energy intake was found to significantly decrease over time (p0.005). Energy-adjusted (i.e., energy density) total fat, saturated fat, monounsaturated fat and cholesterol intakes increased over time (all p0.002), while energy-adjusted and absolute carbohydrate intake decreased (p0.002). Adherence to the MD decreased over time (p0.001) whilst DII scores increased slightly over time, although this result was not significant.This study shows significant changes in the intake of energy and several nutrients in a cohort of aging Australian women in the Melbourne metropolitan area over a period of 14 years. Between 1998 and 2012, changes in indices reflecting overall diet were consistently in the direction of a poorer diet.

Globally our populations are ageing and with this trend, there is a rise in chronic disease. We know that lifestyle and environment are significant contributors to risk for disease, quality of life and function. Despite this representing an opportunity to improve health and quality of life in ageing, there is a paucity of research in this field. The social aspects of this period of development which have been most researched include employment, function and disability. Grand-parenting is one of the most popular sources of childcare in the world and therefore research investigating this role is of vital significance.

Background Abnormalities in brain structure and function can occur several decades prior to the onset of cognitive decline. It is in the preceding decades that an intervention is most likely to be effective, when informed by an understanding of factors contributing to the disease prodrome. Few studies, however, have sufficient longitudinal data on relevant risks to determine the optimum targets for interventions to improve cognition in aging. In this article we examine the timing and exposure of factors contributing to verbal memory performance in later life. Methods 387 participants from the population-based Women's Healthy Ageing Project, mean age at baseline of 49.6 years (range: 45–55 years), had complete neuropsychiatric assessments, clinical information, physical measures, and biomarkers collected at baseline, with at least three follow-up visits that included at least one cognitive reassessment. Mixed linear models were conducted to assess the significance of risk factors on later-life verbal memory. We explored the influence of early, contemporaneous, and cumulative exposures. Results Younger age and better education were associated with baseline memory test performance (CERAD). Over the 20 years of study follow-up, cumulative mid- to late-life physical activity had the strongest effect on better later life verbal memory (0.136 [0.058, 0.214]). The next most likely contributors to verbal memory in late life were the negative effect of cumulative hypertension (−0.033 [−0.047, −0.0.18] and the beneficial effect of HDL cholesterol (0.818 [0.042, 1.593]). Conclusions Findings suggest that midlife interventions focused on physical activity, hypertension control, and achieving optimal levels of HDL cholesterol will help maintain later-life verbal memory skills.

As social roles in later life are shaped by significant life events and changes occurring in the late-life transition, examining social engagement in midlife may provide a context for interpreting the ageing social identity. This is particularly important for women, who are heavily dependent on social relationships and are more influenced by social losses and change. Objective To examine major social changes occurring in the decade prior to late-life, starting from approximately 45–55 years of age. Study design The study accessed data from the longitudinal prospective Women’s Healthy Ageing Project (WHAP). Participants were 493 women who had completed at least one assessment in the first 12 years of the study. Results Living with a partner was common and stable amongst participants, while the proportion with children still at home decreased markedly (79–44%). Full-time employment also decreased as participants approached the average retirement age (40–13%). Volunteer work was popular throughout the study, increasing slightly with age, and minding grandchildren was common at the end of the study period (80%). Conclusions Taken together, these findings suggest a notable deficit in participants’ social lives as they transition into later life, but with some evidence of compensation by increasing other social activities.

Background: Physical chronic conditions may increase the risk of mental disorders but the findings are inconsistent between studies and whether the associations differed between genders is unclear. This study aimed to examine whether long-term cancer, cardiovascular disease, diabetes and osteoarthritis were associated with higher risks of incident depression and anxiety and these associations in women compared with men. 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. The hazard ratios ([HRs] (95% CI) VS 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)). Other associations were significant in men and women. 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. Depression screen deserves more concern in men with long-term cancer and anxiety screen in men with long-term diabetes. Funding Statement: Professor Mingguang He receives support from the University of Melbourne at Research Accelerator Program and the CERA Foundation. The Centre for Eye Research Australia (CERA) receives Operational Infrastructure Support from the Victorian State Government. The specific project is funded by Australia China Research Accelerator Program at CERA. Professor Mingguang He is also supported by the Fundamental Research Funds of the State Key Laboratory in Ophthalmology, National Natural Science Foundation of China (81420108008). The sponsor or funding organization had no role in the design or conduct of this research. Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: The study protocol was approved by the Royal Victorian Eye and Ear Hospital Human Research Ethics Committee. Participants provided consent to follow-up and link their data to routine health datasets.

Brain atrophy can occur several decades prior to onset of cognitive impairments. However, few longitudinal studies have examined the relationship between brain volume changes and cognition over a long follow-up period in healthy elderly women. In the present study we investigate the relationship between whole brain and hippocampal atrophy rates and longitudinal changes in cognition, including verbal episodic memory and executive function, in older women. We also examine whether baseline brain volume predicts subsequent changes in cognitive performance over a 10-year period. A total of 60 individuals from the population-based Women's Healthy Ageing Project with a mean age at baseline of 59 years underwent 3T MRI. Of these, 40 women completed follow-up cognitive assessments, 23 of whom had follow-up MRI scans. Linear regression analysis was used to examine the relationship between brain atrophy and changes in verbal episodic memory and executive function over a 10-year period. The results show that baseline measurements of frontal and temporal grey matter volumes predict changes in verbal episodic memory performance, whereas hippocampal volume at baseline is associated with changes in executive function performance over a 10-year period of follow-ups. In addition, higher whole brain and hippocampal atrophy rates are correlated with a decline in verbal episodic memory. These findings indicate that in addition to atrophy rate, smaller regional grey matter volumes even 10 years prior is associated with increased rates of cognitive decline. This study suggests useful neuroimaging biomarkers for the prediction of cognitive decline in healthy elderly women.