G protein-coupled estrogen receptor (GPER) in the dorsal hippocampus regulates memory consolidation in gonadectomized male mice, likely via different signaling mechanisms than in female mice.

Studies in ovariectomized (OVX) female rodents suggest that G protein-coupled estrogen receptor (GPER) is a key regulator of memory, yet little is known about its importance to memory in males or the cellular mechanisms underlying its mnemonic effects in either sex. In OVX mice, bilateral infusion of the GPER agonist G-1 into the dorsal hippocampus (DH) enhances object recognition and spatial memory consolidation in a manner dependent on rapid activation of c-Jun N-terminal kinase (JNK) signaling, cofilin phosphorylation, and actin polymerization in the DH. However, the effects of GPER on memory consolidation and DH cell signaling in males are unknown. Thus, the present study first assessed effects of DH infusion of G-1 or the GPER antagonist G-15 on object recognition and spatial memory consolidation in gonadectomized (GDX) male mice. As in OVX mice, immediate post-training bilateral DH infusion of G-1 enhanced, whereas G-15 impaired, memory consolidation in the object recognition and object placement tasks. However, G-1 did not increase levels of phosphorylated JNK (p46, p54) or cofilin in the DH 5, 15, or 30 min after infusion, nor did it affect phosphorylation of ERK (p42, p44), PI3K, or Akt. Levels of phospho-cAMP-responsive element binding protein (CREB) were elevated in the DH 30 min following G-1 infusion, indicating that GPER in males activates a yet unknown signaling mechanism that triggers CREB-mediated gene transcription. Our findings show for the first time that GPER in the DH regulates memory consolidation in males and suggests sex differences in underlying signaling mechanisms.

Could motor blocks be a therapeutic option for treatment-resistant functional dystonia? A case series of three patients.

The diagnosis of functional dystonia is challenging because it is difficult to distinguish functional dystonia from other types of dystonia. After diagnostic explanation, multidisciplinary care is recommended, but some patients are resistant to treatments. We used motor blocks in three patients with severe resistant functional dystonia of the upper limbs to test (i) whether joint contracture was present and (ii) whether motor blocks have a therapeutic effect on functional dystonia. Patient 1 showed a good and sustained therapeutic response, Patient 2 experienced a resolution of the dystonic posture that lasted for 10 days, and Patient 3 experienced no effect. Motor blocks may be a useful therapeutic option in chronic treatment-resistant functional dystonia. The treatment effect might be achieved through the experience of normal positioning and functioning of the limb.

Association between carpal tunnel syndrome and the five-year incidence of anxiety disorder and depression in adults followed in general practices in Germany.

OBJECTIVE: Little is known about the longitudinal relationship between carpal tunnel syndrome (CTS) and mental health. Therefore, this retrospective cohort study investigated the association between CTS and the five-year incidence of anxiety disorder and depression in adults from Germany. METHODS: Data from the Disease Analyzer database (IQVIA) were used for the present study. Patients aged ≥18 years diagnosed for the first time with CTS in one of 1284 general practices in Germany in 2005-2020 were included (index date). Individuals without CTS were matched to those with CTS using a propensity score based on age, sex, the mean number of consultations per year during the follow-up, and the index year. In people without CTS, the index date was a randomly selected consultation in 2005-2020. RESULTS: There were 75,135 patients with and 75,135 patients without CTS included in the study (mean [SD] age 57.2 [16.5] years; 59.7% women). Within five years of the index date, the incidence of anxiety disorder was 3.9% and 3.6% in the group with and the group without CTS, respectively (log-rank p-value<0.001), while figures for depression were 14.8% and 11.5% (log-rank p-value<0.001). These findings were corroborated in the Cox regression analyses adjusted for multiple physical conditions, as CTS was associated with anxiety disorder (HR = 1.14, 95% CI = 1.08-1.21) and depression (HR = 1.29, 95% CI = 1.25-1.33) in the overall sample. CONCLUSION: CTS was associated with an increased incidence of anxiety disorder and depression in Germany. Further research should identify the mediators involved in these relationships.

Role of age and sex in the association between BMI and functional limitations in stroke patients: Cross-sectional analysis in three European and US cohorts.

BACKGROUND: A U- or J-shaped association between BMI and different post-stroke outcomes is suggested. Thus, the aim is to evaluate the association between BMI with ADL, IADL and mobility limitations in the ageing post-stroke population at different ages, as well as the differences in this association by sex. METHODS: A total of 5,468 participants with stroke and 21,872 without stroke over 50 years of age were assessed for the number of limitations in basic or instrumental activities of daily living (ADL/IADL) as well as mobility tasks. The association between BMI at the interview (continuous time-dependent variable) and the level of limitations was assessed using a linear mixed model stratified by sex and stroke status. RESULTS: The association between BMI and ADL/IADL and mobility limitations were found to be significant in both men and women regardless of stroke status (p<0.001 for all). The association differs between those who have suffered a stroke and those who have not (p<0.001 for all). In ADL/IADL limitations, men with stroke showed a transition from an inverted J-shape to a U-shape association with age. In women, the BMI showed a less pronounced association between BMI and ADL/IADL limitations compared to men but with similar trends. A effect of sex was observed in the association between BMI and mobility, with women with and without stroke showing a linear association that differed from the inverted J-shaped or U-shaped association of men. CONCLUSION: Our results suggest that BMI is associated with limitations in ADL, IADL and mobility in stroke patients. In addition, this association differs between men and women and is also influenced by age.

Chronic Low Back Pain and Incident Transient Ischemic Attack and Stroke in General Practices in Germany.

The aim was to investigate the association between chronic low back pain (CLBP) and incident transient ischemic attack (TIA) and stroke in Germany. The present retrospective cohort study included adults aged ≥18 years who were diagnosed for the first time with CLBP in one of 1198 general practices in Germany in 2005-2019 (index date). Patients without CLBP were matched to those with CLBP (1:1) using a propensity score based on age, sex, the index year, the number of medical consultations per year during the follow-up, and the number of years of follow-up. In patients without CLBP, the index date was a randomly selected visit date. Both groups were followed for up to 10 years. There were 159,440 patients included in the study (mean (SD) age: 52.1 (16.5) years; 51.5% women). Within 10 years of the index date, 6.5% and 5.9% of patients with and without CLBP were diagnosed with TIA or stroke, respectively (log-rank p-value < 0.001). The Cox regression analysis corroborated these results, as there was a significant association between CLBP and incident TIA or stroke (HR = 1.28, 95% CI = 1.22-1.35). CLBP was positively and significantly associated with incident TIA and stroke in Germany. More research is warranted to better understand this relationship.

Dual-task versus single-task gait rehabilitation after stroke: the protocol of the cognitive-motor synergy multicenter, randomized, controlled superiority trial (SYNCOMOT).

BACKGROUND: Gait disorders and cognitive impairments are prime causes of disability and institutionalization after stroke. We hypothesized that relative to single-task gait rehabilitation (ST GR), cognitive-motor dual-task (DT) GR initiated at the subacute stage would be associated with greater improvements in ST and DT gait, balance, and cognitive performance, personal autonomy, disability, and quality of life in the short, medium and long terms after stroke. METHODS: This multicenter (n=12), two-arm, parallel-group, randomized (1:1), controlled clinical study is a superiority trial. With p<0.05, a power of 80%, and an expected loss to follow-up rate of 10%, the inclusion of 300 patients will be required to evidence a 0.1-m.s-1 gain in gait speed. Trial will include adult patients (18-90 years) in the subacute phase (0 to 6 months after a hemispheric stroke) and who are able to walk for 10 m (with or without a technical aid). Registered physiotherapists will deliver a standardized GR program (30 min three times a week, for 4 weeks). The GR program will comprise various DTs (phasic, executive function, praxis, memory, and spatial cognition tasks during gait) in the DT (experimental) group and gait exercises only in the ST (control) group. The primary outcome measure is gait speed 6 months after inclusion. The secondary outcomes are post-stroke impairments (National Institutes of Health Stroke Scale and the motor part of the Fugl-Meyer Assessment of the lower extremity), gait speed (10-m walking test), mobility and dynamic balance (timed up-and-go test), ST and DT cognitive function (the French adaptation of the harmonization standards neuropsychological battery, and eight cognitive-motor DTs), personal autonomy (functional independence measure), restrictions in participation (structured interview and the modified Rankin score), and health-related quality of life (on a visual analog scale). These variables will be assessed immediately after the end of the protocol (probing the short-term effect), 1 month thereafter (the medium-term effect), and 5 months thereafter (the long-term effect). DISCUSSION: The main study limitation is the open design. The trial will focus on a new GR program applicable at various stages after stroke and during neurological disease. TRIAL REGISTRATION: NCT03009773 . Registered on January 4, 2017.

Association between prolonged exposure to long working hours and stroke subtypes in the CONSTANCES cohort.

BACKGROUND: Though there is increasing evidence on the effect of long working hours (LWH) and stroke, few studies have distinguished stroke subtypes. We examined the associations between LWH and ischaemic or haemorrhagic stroke after adjusting for cardiovascular risk factors. METHODS: From a national population-based cohort CONSTANCES, baseline questionnaires and initial health examinations were used to retrieve sociodemographic and cardiovascular risk factors from 2012 to 2018. LWH were defined as self-reported working time≥10 hours daily for at least 50 days per year. Incident cases of stroke were collected using International Classification of Disease codes recorded in the National Health Data System. Associations between LWH and stroke were investigated using multinomial models adjusted for cardiovascular risk factors. RESULTS: Among the 160 751 participants who were free from stroke at baseline, exposure to LWH≥10 years was reported by 20 723 participants, and 190 incident cases of stroke were identified, including 134 ischaemic and 56 haemorrhagic. Exposure to LWH was associated with an elevated odds of ischaemic stroke (OR=1.61 (1.04-2.49)) and haemorrhagic stroke (OR=2.50 (1.38-4.53)) in unadjusted models. In adjusted multivariable models, only the LWH association with haemorrhagic stroke remained significant (aOR=1.92 (1.01-3.09)). CONCLUSIONS: LWH were associated with stroke, though it remained significant for haemorrhagic stroke only after adjustments. Differences in direct and indirect biological pathways and lack of power in the ischaemic subgroup may explain these results and further studies on the impact of mediating and effect measure modifying factors are needed. Nevertheless, policies that attenuate effects of both LWH and cardiovascular risks factor are warranted.

[Excess mortality in nursing homes during the first wave of the Covid-19 pandemic]. / Surmortalité dans les Ehpad pendant la première vague de la pandémie de la Covid-19.

Overall mortality in France is 147 568 deaths since the first wave. Although accounting for nearly 20% of deaths in France, the excess mortality in long-term care facilities compared to previous years has not been fully studied. The Covid-19 pandemic has highlighted the vulnerability of residents in long-term care facilities, with highly dependent elderly patients being the most exposed to the risk of death, with deleterious effects linked to the effects of confinement, which in Ehpad has resulted in major isolation of residents and the appearance by care teams of cognitive disorders appearing or deteriorating in residents, as well as a significant loss of autonomy.

International Recommendations to Manage Poststroke Equinovarus Foot Deformity Validated by a Panel of Experts Using Delphi.

OBJECTIVE: To establish international recommendations for the management of spastic equinovarus foot deformity. DESIGN: Delphi method. SETTING: International study. PARTICIPANTS: A total of 24 international experts (N=24) in neuro-orthopedic deformities, from different specialties (Physical and Rehabilitation Medicine physicians, neurologists, geriatricians, orthopedic surgeons, neurosurgeons, plastic surgeons). INTERVENTIONS: Experts answered 3 rounds of questions related to important aspects of diagnosis, assessment, and treatment of spastic equinovarus foot deformity. MAIN OUTCOME MEASURES: A consensus was established when at least 80% of experts agreed on a statement RESULTS: A total of 52 items reached consensus. Experts recommend assessing effect of the deformity on functional activities before treatment. Before treatment, it is crucial to differentiate spastic muscle overactivity from soft tissue contractures, identify which muscles are involved in the deformity, and evaluate the activity of antagonist muscles. Motor nerve blocks, 2-dimensional video analysis, and radiologic examinations are often required to complement a clinical examination. The treatment of equinovarus foot depends on the correctability of the deformity and the patient's ability to stand or walk. The preoperative assessment should include an interdisciplinary consultation that must finalize a formal agreement between physicians and the patient, which will define personalized attainable goals before surgery. CONCLUSION: The establishment of guidelines on managing equinovarus foot will help physicians and surgeons, specialists, and nonspecialists to diagnoses and assess the deformity and direct patients to a network of experts to optimize patient functional recovery and improve their autonomy.

The role of age, sex, and multimorbidity in 7-year change in prevalence of limitations in adults 60-94 years.

Recent data suggest a temporal trend in decline in functional limitations in older adults but whether this trend extends to the period after the 8th decade of life remains unclear. We examined change in prevalence of limitations in activities and instrumental activities of daily living (ADL and IADL) between 2008 and 2015 among adults of 60-94 years and the role of age, sex, multimorbidity; we also examined changes in severity of limitations. Data were drawn from two nationally representative surveys in 2008 (n = 13,593) and 2015 (n = 13,267). The 6-item scales of ADL and IADL were each categorized first as ≥ 1 limitations, and then to examine severity as 0, 1-2, and ≥ 3 limitations. Weighted logistic and multinomial regressions were used to estimate prevalence of limitations; the difference between surveys were extracted every 5 years between 60 and 90 years. The prevalence of ≥ 1 ADL declined between 2008 and 2015, from age 75 (- 1.2%; 95%CI = - 2.0, - 0.4%) to age 90 (- 8.8%; 95%CI = - 12.7, - 5.0%). This decline was more pronounced in men than women (p-value for interaction = 0.05) and observed primarily in those with multimorbidity (p-value for interaction = 0.06). Up to 2 ADL limitations declined from age 75 (- 1.0; 95%CI = - 1.7, - 0.3) to 90 (- 6.7; 95%CI = - 9.9, - 3.6) and from age 80 (- 0.6; 95%CI = - 1.1, 0.1) to 85 (- 1.2; 95%CI = - 2.2, - 0.1) for ≥ 3 ADL limitations. There was no substantial change in IADL limitations. These data from a high-income country with universal health care show improvement in ADL even after the 8th decade of life despite increase in multimorbidity.

AbobotulinumtoxinA Doses in Upper and Lower Limb Spasticity: A Systematic Literature Review.

Disabling limb spasticity can result from stroke, traumatic brain injury or other disorders causing upper motor neuron lesions such as multiple sclerosis. Clinical studies have shown that abobotulinumtoxinA (AboBoNT-A) therapy reduces upper and lower limb spasticity in adults. However, physicians may administer potentially inadequate doses, given the lack of consensus on adjusting dose according to muscle volume, the wide dose ranges in the summary of product characteristics or cited in the published literature, and/or the high quantity of toxin available for injection. Against this background, a systematic literature review based on searches of MEDLINE and Embase (via Ovid SP) and three relevant conferences (2018 to 2020) was conducted in November 2020 to examine AboBoNT-A doses given to adults for upper or lower limb muscles affected by spasticity of any etiology in clinical and real-world evidence studies. From the 1781 unique records identified from the electronic databases and conference proceedings screened, 49 unique studies represented across 56 publications (53 full-text articles, 3 conference abstracts) were eligible for inclusion. Evidence from these studies suggested that AboBoNT-A dose given per muscle in clinical practice varies considerably, with only a slight trend toward a relationship between dose and muscle volume. Expert-based consensus is needed to inform recommendations for standardizing AboBoNT-A treatment initiation doses based on muscle volume.

Pre-stroke Disability and Long-Term Functional Limitations in Stroke Survivors: Findings From More of 12 Years of Follow-Up Across Three International Surveys of Aging.

Background: Almost 50% of the post-stroke disabled population already have a premorbid disability before stroke. These patients may be offered a different care pathway in the acute and subacute phase than those without pre-morbid disability. Therefore, the aim of this study was to assess the association of the severity of premorbid disability with change of limitations in basic and instrumental activities of daily living (ADL/IADL) 1 year after stroke and over the following decade. Methods: Among 3,432 participants from HRS, SHARE and ELSA cohorts with a first stroke, ADL/IADL limitations were measured at 1-2 years prior to stroke, at 1 year post-stroke, and during the chronic phase. Modified Ranking Scale (P-mRS) was used to categorize the participants by level of premorbid disability (1-2 years pre-stroke). Change in ADL/IADL limitations by P-mRS level (0-1, 2-3, and 4-5) was assessed using a piecewise linear mixed model with a breakpoint set at 1 year post-stroke, stratified by median age groups. Results: Increase in ADL limitations at 1 year post-stroke was less pronounced in P-mRS ≥2 (p < 0.005). After years of relative stability, limitations of ADL increased for all P-mRS levels (p = 0.003). In those aged ≥75 years at stroke event, the increase was similar irrespective of P-mRS (p = 0.090). There were no significant differences in IADL trajectories between P-mRS levels (p ≥ 0.127). Conclusion: These results suggest similar trajectories of functional limitations between P-mRS levels up to 9 years post-stroke, highlighting the possible benefit of including patients with pre-morbid disability to certain treatments during the acute phase.

Determinants of disability at 6 months after stroke: The GRECogVASC Study.

BACKGROUND AND PURPOSE: The aim of this study was to determine the contributions of background disorders responsible for participation restriction as indexed by a structured interview for the modified Rankin Scale (mRS-SI). METHODS: A subset of 256 patients was assessed at 6 months after stroke using the National Institutes of Health Stroke Scale (NIHSS), gait score, comprehensive cognitive battery (yielding a global cognitive Z-score), behavioral dysexecutive disorders (DDs), anxiety and depressive symptoms, epilepsy, and headache. Following bivariate analyses, determinants of participation restriction were selected using ordinal regression analysis with partial odds. RESULTS: Poststroke participation restriction (mRS-SI score > 1) was observed in 59% of the patients. In bivariate analyses, mRS-SI score was associated with prestroke mRS-SI score, 6-month NIHSS score, gait score, global cognitive Z-score, behavioral DDs, and presence of anxiety and depression (all: p = 0.0001; epilepsy: p =0.3; headache: p = 0.7). After logistic regression analysis, NIHSS score was associated with increasing mRS-SI score (p = 0.00001). Prestroke mRS-SI score (p = 0.00001), behavioral DDs (p = 0.0008) and global cognitive Z-score (p = 0.01) were associated with both mRS-SI score > 1 and mRS-SI score > 2. In addition, gait score was associated with mRS-SI score > 2 (p = 0.00001). This model classified 85% of mRS-SI scores correctly (p = 0.001). Structural equation modeling showed the contributions of gait limitation (standardized coefficient [SC]: 0.68; p = 0.01), prestroke mRS-SI (SC: 0.41; p = 0.01), severity of neurological impairment (SC: 0.16; p = 0.01), global cognitive Z-score (SC: -0.14; p = 0.05), and behavioral DDs (SC: 0.13; p = 0.01). CONCLUSION: These results provide a statistical model of weights of determinants responsible for poststroke participation restriction and highlight a new independent determinant: behavioral DDs.

Long-Term Evolution of Functional Limitations in Stroke Survivors Compared With Stroke-Free Controls: Findings From 15 Years of Follow-Up Across 3 International Surveys of Aging.

BACKGROUND AND PURPOSE: In the chronic phase 2 to 5 years poststroke, limitations in activities of daily living (ADL) and instrumental ADL (IADL) initially plateau before steady increasing. However, the impact of age and differences in initial levels of disability on the evolution of these limitations remains unclear. As such, this study aims to evaluate differences in long-term evolution of ADL/IADL limitations between stroke survivors and stroke-free population, and how limitations differ by initial level of disability for stroke survivors. METHODS: Thirty-three thousand six hundred sixty participants (5610 first-ever stroke cases with no recurrence during follow-up and 28 050 stroke-free controls) aged ≥50 from the Health and Retirement Study, Survey of Health, Ageing and Retirement in Europe, and English Longitudinal Study of Ageing were assessed for number of ADL/IADL limitations during the poststroke chronic phase (for cases) and over follow-up years 1996 to 2018 (for controls). Three thousand seven hundred eighteen stroke cases were additionally categorized by disability level using the modified Rankin Scale score of 1 to 2 years poststroke. Evolution of ADL/IADL limitations was assessed in stroke cases and controls and by modified Rankin Scale score (0-1, 2-3, 4-5) using linear mixed models. Models were stratified by age group (50-74 and ≥75 years) and adjusted for baseline characteristics, health behaviors, BMI, and comorbidities. RESULTS: Findings showed relative stability of ADL/IADL limitations during 3 to 6 years poststroke followed by an increase for both populations, which was faster for younger stroke cases, suggesting a differential age-effect (P<0.001). Disability level at 1 to 2 years poststroke influenced the evolution of limitations over time, especially for severe disability (modified Rankin Scale score, 4-5) associated with a reduction in limitations at 5 to 6 years poststroke. CONCLUSIONS: Our findings showed that during the poststroke chronic phase functional limitations first plateau and then increase and the evolution differs by disability severity. These results highlight the importance of adaptive long-term health and social care measures for stroke survivors.

Association between osteoarthritis and the incidence of Parkinson's disease in the United Kingdom.

BACKGROUND: Little is known on the potential relationship between osteoarthritis and Parkinson's disease. OBJECTIVE: Therefore, the objective of this retrospective cohort study was to analyze the association between osteoarthritis and the incidence of Parkinson's disease in patients followed up for up to 10 years in general practices in the United Kingdom. METHODS: This study included patients diagnosed for the first time with osteoarthritis in one of 256 general practices in the United Kingdom between 2000 and 2016 (index date). Patients without osteoarthritis were matched (1:1) to those with osteoarthritis using propensity scores based on sex, age and index year. In individuals without osteoarthritis, index date corresponded to a randomly selected visit date. The outcome of this study was the 10-year cumulative incidence of Parkinson's disease in patients with and without osteoarthritis. Cox regression analyses were adjusted for common comorbidities. RESULTS: This study included 260,224 patients (62.0% women; mean [SD] age 66.4 [12.7] years). The 10-year cumulative incidence of Parkinson's disease was 1.2% in patients with osteoarthritis and 0.6% in their counterparts without osteoarthritis (log-rank p-value < 0.001). The adjusted Cox regression model further showed a positive and significant association between osteoarthritis and the incidence of Parkinson's disease (HR = 1.82, 95% CI: 1.63-2.02). Similar results were obtained in all sex and age subgroups. CONCLUSIONS: In this retrospective cohort study conducted in the United Kingdom, there was a positive association between osteoarthritis and the incidence of Parkinson's disease. More research is warranted to confirm or refute these findings in other settings and countries.

Sexual Orientation and Functional Limitations: Cross-sectional Analyses From the Adult Psychiatric Morbidity Survey.

OBJECTIVE: To assess the association between sexual orientation and functional limitations in a large representative sample of the English population. DESIGN: Cross-sectional. SETTING: Data were from the 2007 Adult Psychiatric Morbidity Survey. PARTICIPANTS: A total of 7403 adults aged 16-95 years (51.4% female; mean age, 46.3±18.6y) were included in the present study. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Sexual orientation was assessed using 2 items adapted from the Kinsey scale and was dichotomized into heterosexual and sexual minority orientation. Functional limitations were assessed using 7 activities of daily living (ADL) and instrumental activities of daily living (IADL). Functional limitations were defined as at least 1 difficulty in 1 of 7 ADL and IADL. Adjusted logistic regression analyses were conducted to investigate the association between sexual orientation (independent variable) and functional limitations (dependent variable). RESULTS: The level of sexual minority orientation and prevalence of functional limitations in the sample was 7.1% and 32.9%, respectively. After adjusting for several potential confounders, sexual minority orientation was positively and significantly associated with functional limitations (odds ratio, 1.51; 95% confidence interval, 1.18-1.95; reference group: heterosexual orientation). CONCLUSIONS: Based on the findings of this study, interventions aiming to prevent against and/or manage/reduce functional limitations in sexual minorities are needed. More research is also warranted to better understand mediators (eg, obesity, cognitive complaints, psychiatric disorders) involved in the sexual orientation-functional limitation relationship.

The association of APOE ε4 with cognitive function over the adult life course and incidence of dementia: 20 years follow-up of the Whitehall II study.

BACKGROUND: Approximately 25% of the general population carries at least one ε4 allele of the Apolipoprotein E (APOE ε4), the strongest genetic risk factor for late onset Alzheimer's disease. Beyond its association with late-onset dementia, the association between APOE ε4 and change in cognition over the adult life course remains uncertain. This study aims to examine whether the association between Apolipoprotein E (APOE) ε4 zygosity and cognition function is modified between midlife and old age. METHODS: A cohort study of 5561 participants (mean age 55.5 (SD = 5.9) years, 27.1% women) with APOE genotyping and repeated cognitive tests for reasoning, memory, and semantic and phonemic fluency, during a mean (SD) follow-up of 20.2 (2.8) years (the Whitehall II study). We used joint models to examine the association of APOE genotype with cognitive function trajectories between 45 and 85 years taking drop-out, dementia, and death into account and Fine and Gray models to examine associations with dementia. RESULTS: Compared to non-carriers, heterozygote (prevalence 25%) and homozygote (prevalence 2%) APOE ε4 carriers had increased risk of dementia, sub-distribution hazard ratios 2.19 (95% CI 1.73, 2.77) and 5.97 (95% CI 3.85, 9.28) respectively. Using data spanning 45-85 years with non-ε4 carriers as the reference, ε4 homozygotes had poorer global cognitive score starting from 65 years; ε4 heterozygotes had better scores between 45 and 55 years, then no difference until poorer cognitive scores from 75 years onwards. In analysis of individual cognitive tests, better cognitive performance in the younger ε4 heterozygotes was primarily attributable to executive function. CONCLUSIONS: Both heterozygous and homozygous ε4 carriers had poorer cognition and greater risk of dementia at older ages. Our findings show some support for a complex antagonist pleiotropic effect of APOE ε4 heterozygosity over the adult life course, characterized by cognitive advantage in midlife.

Healthy behaviors at age 50 years and frailty at older ages in a 20-year follow-up of the UK Whitehall II cohort: A longitudinal study.

BACKGROUND: Frailty is associated with increased risk of various health conditions, disability, and death. Health behaviors are thought to be a potential target for frailty prevention, but the evidence from previous studies is based on older populations with short follow-ups, making results susceptible to reverse causation bias. We examined the associations of healthy behaviors at age 50, singly and in combination, as well as 10-year change in the number of healthy behaviors over midlife with future risk of frailty. METHODS AND FINDINGS: In this prospective cohort study of 6,357 (29.2% women; 91.7% white) participants from the British Whitehall II cohort, healthy behaviors-nonsmoking, moderate alcohol consumption, ≥2.5 hours per week of moderate to vigorous physical activity, and consumption of fruits or vegetables at least twice a day-were measured at age 50, and change in behaviors was measured between 1985 (mean age = 44.4) and 1997 (mean age = 54.8). Fried's frailty phenotype was assessed in clinical examinations in 2002, 2007, 2012, and 2015. Participants were classified as frail if they had ≥3 of the following criteria: slow walking speed, low grip strength, weight loss, exhaustion, and low physical activity. An illness-death model accounting for both competing risk of death and interval censoring was used to examine the association between healthy behaviors and risk of frailty. Over an average follow-up of 20.4 years (standard deviation, 5.9), 445 participants developed frailty. Each healthy behavior at age 50 was associated with lower risk of incident frailty: hazard ratio (HR) after adjustment for other health behaviors and baseline characteristics 0.56 (95% confidence interval [CI] 0.44-0.71; p < 0.001) in nonsmokers, 0.73 (95% CI 0.61-0.88; p < 0.001) for moderate alcohol consumption, 0.66 (95% CI 0.54-0.81; p < 0.001) for ≥2.5 hours of physical activity per week, and 0.76 (95% CI 0.59-0.98; p = 0.03) for consumption of fruits or vegetables at least twice a day. A greater number of healthy behaviors was associated with reduced risk of frailty, with the HR for each additional healthy behavior being 0.69 (95% CI 0.62-0.76; p < 0.001) and the HR for having all versus no healthy behaviors at age 50 being 0.28 (95% CI 0.15-0.52; p < 0.001). Among participants with no or 1 healthy behavior in 1985, those who increased the number of healthy behaviors by 1997 were at a lower risk of frailty (mean follow-up = 16 years) compared with those with no such increase: the HR was 0.64 (95% CI 0.44-0.94; p = 0.02) for change to 2 healthy behaviors and 0.57 (95% CI 0.38-0.87; p < 0.001) for change to 3-4 healthy behaviors in 1997. The primary limitation of this study is potential selection bias during the follow-up due to missing data on frailty components. CONCLUSIONS: Our findings suggest that healthy behaviors at age 50, as well as improvements in behaviors over midlife, are associated with a lower risk of frailty later in life. Their benefit accumulates so that risk of frailty decreases with greater number of healthy behaviors. These results suggest that healthy behaviors in midlife are a good target for frailty prevention.

Social inequalities in multimorbidity, frailty, disability, and transitions to mortality: a 24-year follow-up of the Whitehall II cohort study.

BACKGROUND: Social inequalities in mortality persist in high-income countries with universal health care, and the mechanisms by which these inequalities are generated remain unclear. We aimed to examine whether social inequalities were present before or after the onset of adverse health conditions (multimorbidity, frailty, and disability). METHODS: Our analysis was based on data from the ongoing Whitehall II cohort study, which enrolled British civil servants aged 35-55 years in 1985-88. Participants were assessed for three indicators of socioeconomic status (education, occupational position, and literacy) at age 50 years. Participants underwent clinical examinations (in 2002-04, 2007-09, 2012-13, and 2015-16) for assessment of frailty (two or more of low physical activity, slow walking speed, poor grip strength, weight loss, and exhaustion) and disability (two or more difficulties in bathing, dressing, going to the toilet, transferring, feeding, and walking). In addition, electronic health records were used to assess the incidence of multimorbidity (two or more of diabetes, coronary heart disease, stroke, chronic obstructive pulmonary disease, depression, arthritis, cancer, dementia, and Parkinson's disease) and mortality. In analyses adjusted for sociodemographic factors, we used multistate models to examine social inequalities in transitions from healthy state to adverse health conditions and subsequently to mortality. FINDINGS: Of 10 308 individuals in the Whitehall II study cohort, 6425 had relevant data available at 50 years and to the end of follow-up on Aug 31, 2017, and were included in our analysis. Participants were followed up for a median of 23·6 years (IQR 19·6-28·9). 1694 (26·4%) of 6425 participants developed multimorbidity, 1733 (27·0%) became frail, 692 (10·8%) had a disability, and 611 (9·5%) died. Multimorbidity (hazard ratio [HR] 4·12 [95% CI 3·41-4·98]), frailty (HR 2·38 [95% CI 1·93-2·93]), and disability (HR 1·73 [95% CI 1·34-2·22]) were associated with increased risk of mortality; these associations were not modified by socioeconomic status. In multistate models, occupation was the socioeconomic status indicator that was most strongly associated with inequalities in the transition from healthy state to multimorbidity (HR 1·54 [95% CI 1·37-1·73]), to frailty (HR 2·08 [95% CI 1·85-2·33]), and to disability (HR 1·44 [95% CI 1·18-1·74]). Socioeconomic status indicators did not affect transitions to mortality in those with multimorbidity, frailty, or disability. INTERPRETATION: Socioeconomic status affects the risk of multimorbidity, frailty, and disability, but does not affect the risk of mortality after the onset of these adverse health conditions. Therefore, primary prevention is key to reducing social inequalities in mortality. Of the three adverse health conditions, multimorbidity had the strongest association with mortality, making it a central target for improving population health. FUNDING: UK Medical Research Council; National Institute on Aging, National Institutes of Health; British Heart Foundation.