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Research suggests that frailty is associated with higher inflammation levels. We investigated the longitudinal association between chronic inflammation and frailty progression. Participants of the Lothian Birth Cohort 1936, aged 70 at baseline were tested four times over 12 years (wave 1: n = 1091, wave 4: n = 550). Frailty was assessed by; the Frailty Index at waves 1–4 and Fried phenotype at waves 1, 3 and 4. Two blood-based inflammatory biomarkers were measured at wave 1: Fibrinogen and C-reactive protein (CRP). Fully-adjusted, linear mixed effects models showed higher Fibrinogen was significantly associated with higher wave 1 Frailty Index score (β = 0.011, 95% CI[0.002,0.020], p <.05). Over 12 year follow-up, higher wave 1 CRP (β = 0.001, 95% CI[0.000,0.002], p <.05) and Fibrinogen (β = 0.004, 95% CI[0.001,0.007], p <.05) were significantly associated with increased Frailty Index change. For the Fried phenotype, wave 1 Pre-frail and Frail participants had higher CRP and Fibrinogen than Non-frail participants (p <.001). Logistic regression models calculated risk of worsening frailty over follow-up and we observed no significant association of CRP or Fibrinogen in minimally-adjusted nor fully-adjusted models. Findings showed a longitudinal association of higher wave 1 CRP and Fibrinogen on worsening frailty in the Frailty Index, but not Fried Phenotype. A possible explanation for this disparity may lie in the conceptual differences between frailty measures (a biopsychosocial vs physical approach). Future research, which further explores different domains of frailty, as well the associations between improving frailty and inflammation levels, may elucidate the pathway through which inflammation influences frailty progression. This may improve earlier identification of those at high frailty risk. • Research exploring inflammation and frailty change over time is lacking. • Inflammation is associated with frailty over time when measured by a Frailty Index. • Understanding this association may help improve frailty interventions. • Results differ according to the tool used to measure frailty. • Future research should continue to compare different ways of measuring frailty. [ABSTRACT FROM AUTHOR]

11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) is an intracellular enzyme that catalyses conversion of cortisone into cortisol; correspondingly, 11β-HSD1 inhibitors inhibit this conversion. This systematic review focuses on the use of 11β-HSD1 inhibitors in diseases known to be associated with abnormalities in hypothalamic pituitary adrenal (HPA) axis function. The databases screened for suitable papers were: MedLine, EMBASE, Web of Science, ClinicalTrials.gov , and Cochrane Central. 1925 papers were identified, of which 29 were included in the final narrative synthesis. 11β-HSD1 and its inhibitors have been studied in diabetes, obesity, metabolic syndrome (MetS), and Alzheimer's disease (AD). Higher expression of 11β-HSD1 is seen in obesity and MetS, but has not yet been described in obesity or AD. Genetic studies identify 11β-HSD1 SNPs of interest in populations with diabetes, MetS, and AD. One phase II trial successfully reduced HbA1c in a diabetic population, however trials in MetS, obesity, and AD have not met primary endpoints. Translation of this research from preclinical studies has proved challenging so far, however this is a growing area of research and more studies should focus on understanding the complex relationships between 11β-HSD1 and disease pathology, especially given the therapeutic potential of 11β-HSD1 inhibitors in development. • 11ßHSD1 is an enzyme that converts cortisone (inactive) to cortisol (active). • High 11ßHSD1 activity is found in obesity and metabolic syndrome. • 11ßHSD1 genes are associated with diabetes, obesity and Alzheimer's. • Emerging treatments are targeting 11ßHSD1 in these diseases. [ABSTRACT FROM AUTHOR]

The Mediterranean diet (MedDiet) has been associated with better brain health and reduced incidence of dementia. Few studies have compared the effects of the MedDiet in early Alzheimer's disease or compared the effects of the diet within and outside of the Mediterranean region. The Mediterranean diet adherence screener (MEDAS) and MEDAS continuous scores were calculated at the baseline visit of the European Prevention of Alzheimer's Dementia Longitudinal Cohort Study (n = 1625). The scores were included in linear regression models to test for associations with hippocampal volume, log-transformed white matter lesion volume, cerebrospinal fluid pTau 18 , and Aβ 42. Higher MEDAS scores were associated with lower log-transformed white matter lesion volume (β: −0.07, standard error [SE]: 0.02, p < 0.001). This association was only seen in the Mediterranean region (β: −0.12, SE: 0.03, p < 0.001). In the non-Mediterranean region, higher MEDAS continuous scores were associated with lower cerebrospinal fluid Aβ 42 (β: −68.30, SE: 14.32, p < 0.001). More research is needed to understand the differences in the associations seen with the MedDiet and Alzheimer's disease biomarkers in different European regions. • Mediterranean diet (MedDiet) has been associated with lower incidence of dementia. • Higher MedDiet scores were associated with lower white matter lesion volume. • This finding was only significant in the Mediterranean region. • In the non-Mediterranean, higher MedDiet scores were associated with lower Aβ 42. • There are different effects of MedDiet on brain health by biogeographical region. [ABSTRACT FROM AUTHOR]

Using a large longitudinal sample of adults from the Midlife in the United States (MIDUS) study, the present study extended a recently developed hierarchical model to determine how best to model the accumulation of stressors, and to determine whether the rate of change in stressors or traditional composite scores of stressors are stronger predictors of health outcomes. We used factor analysis to estimate a stress-factor score and then, to operationalize the accumulation of stressors we examined five approaches to aggregating information about repeated exposures to multiple stressors. The predictive validity of these approaches was then assessed in relation to different health outcomes. The prediction of chronic conditions, body mass index, difficulty with activities of daily living, executive function, and episodic memory later in life was strongest when the accumulation of stressors was modeled using total area under the curve (AUC) of estimated factor scores, compared to composite scores that have traditionally been used in studies of cumulative stress, as well as linear rates of change. Like endogenous, biological markers of stress reactivity, AUC for individual trajectories of self-reported stressors shows promise as a data reduction technique to model the accumulation of stressors in longitudinal studies. Overall, our results indicate that considering different quantitative models is critical to understanding the sequelae and predictive power of psychosocial stressors from midlife to late adulthood. • Five approaches to creating composite scores of cumulative stress were examined. • The strength of these approaches to predict different health outcomes was tested. • Area under the curve with respect to ground outperformed alternative approaches. • The effects of cumulative stress varied across age groups and health outcomes. [ABSTRACT FROM AUTHOR]

• Functional connectivity changes are present in individuals with AD-risk factors. • The topography shows an overlap with regions characteristic for AD. • Less consensus on the directionality of functional connectivity changes. Functional brain connectivity of the resting-state networks has gained recent attention as a possible biomarker of Alzheimer's Disease (AD). In this paper, we review the literature of functional connectivity differences in young adults and middle-aged cognitively intact individuals with non-modifiable risk factors of AD (n = 17). We focus on three main intrinsic resting-state networks: The Default Mode network, Executive network, and the Salience network. Overall, the evidence from the literature indicated early vulnerability of functional connectivity across different at-risk groups, particularly in the Default Mode Network. While there was little consensus on the interpretation on directionality, the topography of the findings showed frequent overlap across studies, especially in regions that are characteristic of AD (i.e., precuneus, posterior cingulate cortex, and medial prefrontal cortex areas). We conclude that while resting-state functional connectivity markers have great potential to identify at-risk individuals, implementing more data-driven approaches, further longitudinal and cross-validation studies, and the analysis of greater sample sizes are likely to be necessary to fully establish the effectivity and utility of resting-state network-based analyses. [ABSTRACT FROM AUTHOR]

Cerebral small vessel disease (SVD) and inflammation are increasingly recognized as key contributors to Alzheimer's disease (AD), although the timing, trajectory, and relation between them early in the disease process is unclear. Therefore, to investigate very early-stage changes, we compared 158 healthy midlife adults with and without inherited AD predisposition (APOE4 carriership (38% positive), parental family history (FH) of dementia (54% positive)) on markers of SVD (white matter hyperintensities (WMH), cerebral microbleeds), and inflammation (C-reactive protein (CRP), fibrinogen), cross-sectionally and longitudinally over two years. While WMH severity was comparable between groups at baseline, longitudinal progression of WMH was greater in at-risk groups (APOE4+ and FH+). Topographically, APOE4 was associated exclusively with deep, but not periventricular, WMH progression after adjusting for FH. Conversely, APOE4 carriers displayed lower CRP levels than noncarriers, but not fibrinogen. Furthermore, interaction analysis showed that FH moderated the effect of SVD and inflammation on reaction time, an early feature of SVD, but not episodic memory or executive function. Findings suggest that vascular and inflammatory changes could occur decades before dementia onset, and may be of relevance in predicting incipient clinical progression. • Heritable risk factors related to SVD progression, despite lower levels of inflammation. • SVD progression had more pronounced adverse effects on reaction time in at-risk individuals. • Association between SVD and inflammation was stronger in those at-risk. [ABSTRACT FROM AUTHOR]

Further understanding of the associations between personality traits and allostatic load (AL) may be important for predicting, addressing, and optimizing health outcomes. This review synthesized the existing literature reporting the association between the Big Five personality traits and AL in adults to identify the generalizability and robustness of relationships, potential mechanisms underlying the associations, and study characteristics that may be contributing to inconsistencies in the field. Published and unpublished empirical reports were included if at least one of the Big Five traits was examined and an AL index was constructed using at least two biomarkers in a sample of adults. The methodological plan and standardized coding guide were pre-registered and reported (https://osf.io/rxw5a). Based on 11 studies that met eligibility, meta-analysis of correlation coefficients indicated a small but significant positive association between neuroticism and AL, and small but significant inverse associations between both conscientiousness and openness with AL. This review identifies strengths and limitations within the field, as well as several avenues for future research. • Meta-analytic results suggest that individuals higher in conscientiousness are lower in allostatic load (AL). • Meta-analytic results suggest that individuals higher in neuroticism are higher in AL. • Meta-analytic results suggest that individuals higher in openness are lower in AL. • There are extensive between-study differences in AL algorithm computation approaches. • Future research should examine perceived stress as a pathway linking traits and AL. [ABSTRACT FROM AUTHOR]

Previous studies have demonstrated an association between adherence to the Mediterranean diet (MedDiet) and better cognitive performance, lower incidence of dementia and lower Alzheimer's disease biomarker burden. The aim of this systematic review was to evaluate the evidence base for MedDiet associations with hippocampal volume and white matter hyperintensity volume (WMHV). We searched systematically for studies reporting on MedDiet and hippocampal volume or WMHV in MedLine, EMBASE, CINAHL and PsycInfo. Searches were initially carried out on 21st July 2021 with final searches run on 23rd November 2022. Risk of bias was assessed using the NIH Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies. Of an initial 112 papers identified, seven papers were eligible for inclusion in the review reporting on 21,933 participants. Four studies reported on hippocampal volume, with inconclusive or no associations seen with MedDiet adherence. Two studies found a significant association between higher MedDiet adherence and lower WMHV, while two other studies found no significant associations. Overall these results highlight a gap in our knowledge about the associations between the MedDiet and AD and cerebrovascular related structural neuroimaging findings. • Adherence to a Mediterranean diet was not associated with hippocampal volume. • Limited evidence of association between Mediterranean diet and white matter disease • Future research should focus on novel imaging methods and detailed dietary data. [ABSTRACT FROM AUTHOR]

Very few studies looking at slow gait speed as early marker of cognitive decline investigated the competing risk of death. The current study examines associations between slow gait speed and transitions between cognitive states and death in later life. We performed a coordinated analysis of three longitudinal studies with 9 to 25 years of follow-up. Data were used from older adults participating in H70 (Sweden; n = 441; aged ≥70 years), InCHIANTI (Italy; n = 955; aged ≥65 years), and LASA (the Netherlands; n = 2824; aged ≥55 years). Cognitive states were distinguished using the Mini-Mental State Examination. Slow gait speed was defined as the lowest sex-specific quintile at baseline. Multistate models were performed, adjusted for age, sex and education. Most effect estimates pointed in the same direction, with slow gait speed predicting forward transitions. In two cohort studies, slow gait speed predicted transitioning from mild to severe cognitive impairment (InCHIANTI: HR = 2.08, 95%CI = 1.40–3.07; LASA: HR = 1.33, 95%CI = 1.01–1.75) and transitioning from a cognitively healthy state to death (H70: HR = 3.30, 95%CI = 1.74–6.28; LASA: HR = 1.70, 95%CI = 1.30–2.21). Screening for slow gait speed may be useful for identifying older adults at risk of adverse outcomes such as cognitive decline and death. However, once in the stage of more advanced cognitive impairment, slow gait speed does not seem to predict transitioning to death anymore. • There has been an increasing interest in slow gait speed as risk factor for cognitive decline. • Very few studies have investigated the competing risk of death. • This study shows that slow gait speed predicts transitions into cognitive impairment and death. • Once in the stage of more advanced cognitive impairment, slow gait does not predict death anymore. [ABSTRACT FROM AUTHOR]