Global rural health disparities in Alzheimer's disease and related dementias: State of the science.

INTRODUCTION: Individuals living in rural communities are at heightened risk for Alzheimer's disease and related dementias (ADRD), which parallels other persistent place-based health disparities. Identifying multiple potentially modifiable risk factors specific to rural areas that contribute to ADRD is an essential first step in understanding the complex interplay between various barriers and facilitators. METHODS: An interdisciplinary, international group of ADRD researchers convened to address the overarching question of: "What can be done to begin minimizing the rural health disparities that contribute uniquely to ADRD?" In this state of the science appraisal, we explore what is known about the biological, behavioral, sociocultural, and environmental influences on ADRD disparities in rural settings. RESULTS: A range of individual, interpersonal, and community factors were identified, including strengths of rural residents in facilitating healthy aging lifestyle interventions. DISCUSSION: A location dynamics model and ADRD-focused future directions are offered for guiding rural practitioners, researchers, and policymakers in mitigating rural disparities. HIGHLIGHTS: Rural residents face heightened Alzheimer's disease and related dementia (ADRD) risks and burdens due to health disparities. Defining the unique rural barriers and facilitators to cognitive health yields insight. The strengths and resilience of rural residents can mitigate ADRD-related challenges. A novel "location dynamics" model guides assessment of rural-specific ADRD issues.

Differential associations between simple physical performance tests with global and specific cognitive functions in cognitively normal and mild cognitive impairment: a cross-sectional cohort study of Asian community-dwelling older adults.

BACKGROUND: Physical performance declines and executive dysfunctions are predictors of dementia. However, their associations are not well understood in Asian older adults without dementia (cognitively normal [CN] and mild cognitive impairment [MCI]), especially in a single study. OBJECTIVE: Examine the associations between physical performance measures with executive function (EF)-based and non-EF-based neurocognitive tests and whether preclinical dementia cognitive status i.e., CN and MCI, moderated these associations. METHODS: We examined cross-sectional cohort of 716 community-dwelling older adults without dementia (CN = 562 and MCI = 154) using multivariable linear regression models. We associated three simple physical performance measures, namely timed-up-and-go (TUG), fast gait speed (FGS), and 30-s chair stand test (30 s-CST), with a comprehensive neurocognitive test battery measuring EF and non-EF cognitive functions. Moderating effects of cognitive status on the associations were examined. In all models, we controlled for pertinent covariates, including age, education, medical and psychiatric status. RESULTS: Upon controlling for covariates, TUG was most strongly and positively associated with multiple EF-based neurocognitive tests, followed by FGS, with 30 s-CST having the weakest associations. For all physical performance measures, no significant associations with non-EF-based neurocognitive tests were detected. Cognitive status significantly moderated the associations between all physical measures and several neurocognitive tests, with stronger associations in the MCI than CN. CONCLUSION: Compared to FGS and 30 s-CST, TUG had the most robust associations with multiple EF-based cognitive functions. Given their differential associations with global and detailed neurocognitive tests and significant moderating effects of cognitive status, findings highlight a need to carefully consider the choices of simple physical performance tests when using these tests with a heterogenous group of community-dwelling older adults without dementia.

Decreased Serum Brain-Derived Neurotrophic Factor (BDNF) Levels in Patients with Alzheimer's Disease (AD): A Systematic Review and Meta-Analysis.

Findings from previous studies reporting the levels of serum brain-derived neurotrophic factor (BDNF) in patients with Alzheimer's disease (AD) and individuals with mild cognitive impairment (MCI) have been conflicting. Hence, we performed a meta-analysis to examine the aggregate levels of serum BDNF in patients with AD and individuals with MCI, in comparison with healthy controls. Fifteen studies were included for the comparison between AD and healthy control (HC) (n = 2067). Serum BDNF levels were significantly lower in patients with AD (SMD: -0.282; 95% confidence interval [CI]: -0.535 to -0.028; significant heterogeneity: I² = 83.962). Meta-regression identified age (p < 0.001) and MMSE scores (p < 0.001) to be the significant moderators that could explain the heterogeneity in findings in these studies. Additionally, there were no significant differences in serum BDNF levels between patients with AD and MCI (eight studies, n = 906) and between MCI and HC (nine studies, n = 5090). In all, patients with AD, but not MCI, have significantly lower serum BDNF levels compared to healthy controls. This meta-analysis confirmed the direction of change in serum BDNF levels in dementia. This finding suggests that a significant change in peripheral BDNF levels can only be detected at the late stage of the dementia spectrum. Molecular mechanisms, implications on interventional trials, and future directions for studies examining BDNF in dementia were discussed.

Cognitive and physical age gaps in relation to mild cognitive impairment and behavioral phenotypes.

We can study how fast our biological aging clocks tick by calculating the difference (i.e., age gaps) between machine learning estimations of biological age and chronological age. While this approach has been increasingly used to study various aspects of aging, few had applied this approach to study cognitive and physical age gaps; not much is known about the behavioral and neurocognitive factors associated with these age gaps. In the present study, we examined these age gaps in relation to behavioral phenotypes and mild cognitive impairment (MCI) among community-dwelling older adults. Participants (N = 822, Agemean = 67.6) were partitioned into equally-sized training and testing samples. Cognitive and physical age-prediction models were fitted using nine cognitive and eight physical fitness test scores, respectively, within the training samples, and subsequently used to estimate cognitive and physical age gaps for each subject in the testing sample. These age gaps were then compared among those with and without MCI and correlated with 17 behavioral phenotypes in the domains of lifestyle, well-being, and attitudes. Across 5000 random train-test split iterations, we showed that older cognitive age gaps were significantly associated with MCI (versus cognitively normal) and worse outcomes across several well-being and attitude-related measures. Both age gaps were also significantly correlated with each other. These results suggest accelerated cognitive and physical aging were linked to worse well-being and more negative attitudes about the self and others and reinforce the link between cognitive and physical aging. Importantly, we have also validated the use of cognitive age gaps in the diagnosis of MCI.

LFC study: Protocol for a longitudinal follow-up cohort study on ageing and mental health in community-dwelling older adults in Singapore.

The rapid pace of population ageing worldwide has prompted the need to better understand the ageing process. The current study, titled the Longitudinal Follow-up of the CHI (LFC) study, was a 3-year follow-up study of an earlier study titled the Community Health and Intergenerational (CHI) study. The LFC study looked to examine longitudinal changes in their cognitive functioning and psychosocial outcomes across the 3-year period. Additionally, the current study built upon the earlier CHI study by collecting neuroimaging data and exploring the long-term effects of non-pharmacological interventions, which were not examined in the prior study. A total of 653 community-dwelling participants from the baseline CHI study cohort were invited to take part in the LFC study, where they underwent a battery of neuropsychological assessments, psychosocial questionnaires, a Magnetic Resonance Imaging scan and a voice recording segment. The current study would holistically track longitudinal changes in cognitive functioning and psychosocial outcomes in the ageing population in Singapore. Unique associations between linguistics and neuroimaging data alongside cognitive and psychosocial outcomes would be explored. This study also serves to guide the development of new interventions for older adults and assist in improving the well-being of the local and global ageing population.

Reversal of the concreteness effect can be detected in the natural speech of older adults with amnestic, but not non-amnestic, mild cognitive impairment.

INTRODUCTION: Patients with Alzheimer's disease present with difficulty in lexical retrieval and reversal of the concreteness effect in nouns. Little is known about the phenomena before the onset of symptoms. We anticipate early linguistic signs in the speech of people who suffer from amnestic mild cognitive impairment (MCI). Here, we report the results of a corpus-linguistic approach to the early detection of cognitive impairment. METHODS: One hundred forty-eight English-speaking Singaporeans provided natural speech data, on topics of their choice; 74 were diagnosed with single-domain MCI (38 amnestic, 36 non-amnestic), 74 cognitively healthy. The recordings yield 267,310 words, which are tagged for parts of speech. We calculate the per-minute word counts and concreteness scores of all tagged words, nouns, and verbs in the dataset. RESULTS: Compared to controls, subjects with amnestic MCI produce fewer but more abstract nouns. Verbs are not affected. DISCUSSION: Slower retrieval of nouns and the reversal of the concreteness effect in nouns are manifested in natural speech and can be detected early through corpus-based analysis. Highlights: Reversal of the concreteness effect is manifested in patients with Alzheimer's disease (AD) and semantic dementia.The paper reports a corpus-based analysis of natural speech by people with amnestic and non-amnestic mild cognitive impairment (MCI) and cognitively healthy controls.People with amnestic MCI produce fewer and more abstract nouns than people with non-amnestic MCI and healthy controls. Verbs appear to be unaffected.The imageability problem can be detected in natural everyday speech by people with amnestic MCI, which carries a higher risk of conversion to AD.

Sex differences in the mediating role of chronic inflammation on the association between social isolation and cognitive functioning among older adults in the United States.

BACKGROUND: Previous research has reported the association between social isolation and cognitive impairment. However, biological mechanisms underlying this association are understudied. It is also unclear whether there are sex differences in these biological mechanisms. OBJECTIVES: To examine whether chronic inflammation biomarkers are potential mediators of the association between social isolation and cognitive functioning among older men and women. METHODS: Data were the National Health and Nutrition Examination Survey 1999-2002. A total of 2535 older adults aged 60 and older were included. Chronic inflammation was measured by C-reactive protein (CRP), plasma fibrinogen, and serum albumin. Cognitive functioning was assessed by the Digit Symbol Substitution Test (DSST). Social isolation was defined using a 4-point composite index of items pertaining to the strength of social network and support. Linear regression models and formal mediation analysis were applied. RESULTS: Social isolation was associated with lower DSST scores [ß (SE) = -2.445 (1.180), p < 0.01 for men; ß (SE) = -5.478 (1.167), p < 0.001 for women]. For older men, social isolation was associated with higher levels of CRP (ß [SE] = 0.226 (0.110), p < 0.05) and fibrinogen (ß [SE] = 0.058 (0.026), p < 0.05). In mediation analyses, among older men, CRP mediated 6.1% and fibrinogen mediated 12.0% of the association of social isolation with DSST. CONCLUSION: Social isolation was associated with poorer cognitive functioning partially via heightened inflammatory responses in older men. Defining these associations' mechanisms in sex-specific contexts could inform preventive and therapeutic strategies for cognitive impairment in older adults.

Gut-brain axis through the lens of gut microbiota and their relationships with Alzheimer's disease pathology: Review and recommendations.

Alzheimer's disease (AD) is a neurodegenerative disorder that affects millions of people worldwide. Growing evidence suggests that the gut microbiome (GM) plays a pivotal role in the pathogenesis of AD through the microbiota-gut-brain axis (MGB). Alterations in GM composition and diversity have been observed in both animal models and in human patients with AD. GM dysbiosis has been implicated in increased intestinal permeability, blood-brain barrier (BBB) impairment, neuroinflammation and the development of hallmarks of AD. Further elucidation of the role of GM in AD could pave way for the development of holistic predictive methods for determining AD risk and progression of disease. Furthermore, accumulating evidence suggests that GM modulation could alleviate adverse symptoms of AD or serve as a preventive measure. In addition, increasing evidence shows that Type 2 Diabetes Mellitus (T2DM) is often comorbid with AD, with common GM alterations and inflammatory response, which could chart the development of GM-related treatment interventions for both diseases. We conclude by exploring the therapeutic potential of GM in alleviating symptoms of AD and in reducing risk. Furthermore, we also propose future directions in AD research, namely fecal microbiota transplantation (FMT) and precision medicine.

The association between isometric strength and cognitive function in adults with cerebral palsy.

Background: The literature supports quantifying the maximum force/tension generated by one's forearm muscles such as the hand grip strength (HGS) to screen for physical and cognitive frailty in older adults. Thus, we postulate that individuals with cerebral palsy (CP), who are at higher risk for premature aging, could benefit from tools that objectively measure muscle strength as a functional biomarker to detect frailty and cognitive decline. This study assesses the clinical relevancy of the former and quantifies isometric muscle strength to determine its association with cognitive function in adults with CP. Methods: Ambulatory adults with CP were identified from a patient registry and were enrolled into this study. Peak rate of force development (RFD) and maximum voluntary isometric contraction of the quadriceps were measured using a commercial isokinetic machine, while HGS was collected with a clinical dynamometer. Dominant and non-dominant side were identified. Standardized cognitive assessments, including the Wechsler Memory and Adult Intelligence Scales IV, Short Test of Mental Status, and the Patient-Reported Outcomes Measurement Information System (PROMIS®) were used to evaluate cognitive function. Results: A total of 57 participants (32 females; mean age 24.3 [SD 5.3]; GMFCS levels I-IV) were included in the analysis. Although dominant and non-dominant RFD and HGS measures were associated with cognitive function, non-dominant peak RFD showed the strongest associations with cognitive function. Conclusion: RFD capacity may reflect age-related neural and physical health and could be a better health indicator than HGS in the CP population.

Modifications of Traditional Formulas to Estimate and Project Dependency Ratios and Their Implications in a Developing Country, Bangladesh.

Traditional dependency ratios based on the United Nations' old age definition (≥ 65 years) appear to be an inappropriate indicator for many developing countries, including Bangladesh. Bangladesh, with a retirement age of 59 in many sectors, defines old age as ≥ 60 years, whereas the United Nations documents 60-64 years as working age. This study offers two modifications to the traditional formulas of dependency ratios and compares the modified measures against the traditional measures from 1975 to 2100. Using data from the United Nations and the World Bank, (i) we moved the cut-off for 'old age' to 60 instead of 65 years, considering 15-59 years as 'potentially working', and (ii) we used the economically active population instead of the entire working-age population. Using our modified calculations, the growth rate of older adults (≥ 60 years) will be at its peak (4.6%) between 2020 and 2030 and continue to increase until 2085, though we will observe a negative population growth after 2055, and 2020-2040 appears to be the best time for reaping the highest demographic dividend. Compared to our modification, the traditional formula undercounted the older adults substantially, predicting a much lower demographic and financial burden. The modifications and associated estimates are important in advancing our understanding of dependency ratios in Bangladesh and have policy and practical implications in preventing the inaccurate representation of demographic and financial issues, and they are useful for planning for geriatric care, social safety nets, and healthy aging. The modified formulas may also be applicable in other countries which adopt ≥ 60 years as an old-age threshold. Supplementary Information: The online version contains supplementary material available at 10.1007/s11113-022-09720-8.

Associations of Circulating Insulin-Growth Factor-1 With Cognitive Functions and Quality of Life Domains in Ambulatory Young Adults With Cerebral Palsy: A Pilot Study.

Objective: Adults with cerebral palsy (CP) often have impaired cognitive functions. CP also has deteriorations in multiple quality-of-life (QoL) domains. The bio-psycho-social health psychology model posits that biological factor interacts with social and psychological functions. However, the biological determinant of psycho-social and functional outcomes in CP has been scarcely examined. Circulating Insulin-like growth factor-1 (IGF-1) is associated with cognitive deficits in older adults, we thus aimed to examine the associations of circulating IGF-1 with: (1) objectively measured cognitive functions, (2) self-reported cognitive functions, and (3) QoL measures in adults diagnosed with CP. Methods: Seventy-two adults with CP and varying degrees of cognitive functions were recruited from an accredited clinical motion analysis laboratory at a regional Children's Hospital. Circulating IGF-1 was measured using post-fasting serum. The Wechsler Adult Intelligence Scale (WAIS) tests were administered to assess multiple cognitive functions, whereas the Patient-Reported Outcomes Measurement Information System (PROMIS) was used to measure multiple domains of self-reported health, including cognitive complaints and eight QoL domains. Results: Sixty-eight participants had complete data [mean age = 25 (SD = 5.3), female = 52.8%]. Controlling for covariates, circulating IGF-1 was associated with multiple cognitive domains, including positively with declarative memory and executive function and inversely with visual-spatial and motor skills, and processing speed, while no association with subjective memory complaint was detected. Circulating IGF-1 was also inversely associated with four QoL domains, including depressive symptoms, executive function, physical function, and social roles and activities. Conclusions: In CP, circulating IGF-1 might be a useful biological determinant of objective cognitive functions and several quality-of-life domains commonly impaired in CP.

Plasma acylcarnitines as metabolic signatures of declining health-related quality of life measure in community-dwelling older adults: a combined cross-sectional and longitudinal pilot study.

BACKGROUND: Health-related quality of life (HRQoL) measures are predictors of adverse health outcomes in older adults. Studies have demonstrated cross-sectional associations between HRQoL measures and blood-based biochemical markers. Acylcarnitines (ACs) are a class of metabolites generated in the mitochondria and are predictive of multiple geriatric syndromes. Changes in ACs reflect alterations in central carbon metabolic pathways. However, the prospective relationship between plasma acylcarnitines and declining HRQoL has not been examined. This study aimed to investigate both cross-sectional and longitudinal associations of baseline ACs with baseline and declining EuroQol-5 Dimension/ EuroQol Visual Analogue Scale (EQ-5D/ EQ-VAS) in community-dwelling older adults. METHODS: 120 community-dwelling older adults with EQ-5D/ EQ-VAS measurements at baseline and follow-up were included. We quantified ACs at baseline using targeted plasma metabolomics profiling. Multivariate regressions were performed to examine cross-sectional and longitudinal associations between the measures. RESULTS: Cross-sectionally, ACs showed no significant associations with either EQ-5D index or EQ-VAS scores. Longitudinally, multiple baseline short-chain ACs were significantly and inversely associated with declining EQ-5D index score, explaining up to 8.5% of variance in the decline. CONCLUSIONS: Within a cohort of community-dwelling older adults who had high HRQoL at baseline, we showed that short-chain acylcarnitines are independent predictors of declining HRQoL. These findings reveal a novel association between central carbon metabolic pathways and declining HRQoL. Notably, dysregulation in mitochondrial central carbon metabolism could be detected prior to clinically important decline in HRQoL, providing the first evidence of objective biomarkers as novel predictors to monitor HRQoL in non-pharmacological interventions and epidemiology.

A 5-year community program in Singapore to prevent cognitive decline.

INTRODUCTION: There is a scarcity of naturalistic follow-up studies on cognitive stimulating activities (CSAs), particularly in a real-world setting and over long-term. We thus investigated a pooled novel CSA intervention to prevent cognitive decline amongst community-dwelling older adults without dementia. METHODS: Nested within a community-based longitudinal follow-up cohort study of community-dwelling and multi-ethnic older adults (N = 991), a subset of the cohort (n = 264) underwent four single-blinded randomized controlled trials involving four novel CSAs, including mindfulness, horticulture, art therapy, and choral singing. At the cohort's 5-year follow-up, we examined if involvements in the CSAs improved cognition, compared to controls (n = 727). The primary outcomes were changes in global cognition and specific cognitive domain scores measured by the mini-mental state examination (MMSE). Exploratory subgroup analyses stratified by baseline cognitive status and the number of CSAs were also conducted. RESULTS: Compared to the control group, there was a small improvement in the CSA group on the total MMSE score (d = 0.108) and MMSE-immediate recall score (d = 0.199). Furthermore, subgroup analyses revealed medium effect sizes of improvements (d = 0.420) in cognitive domains in mild cognitive impairment (MCI) (vs. cognitively healthy) and those involved in two CSAs (vs. one CSA). DISCUSSION: In summary, a CSA intervention improved cognition. MCI and those involved in two CSAs gained greater benefits from the CSAs. These sustained improvements in cognitive functions could have a significant impact on delaying or preventing dementia.

Research priorities for measuring biologic age: summary and future directions from the Research Centers Collaborative Network Workshop.

Biologic aging reflects the genetic, molecular, and cellular changes underlying the development of morbidity and mortality with advancing chronological age. As several potential mechanisms have been identified, there is a growing interest in developing robust measures of biologic age that can better reflect the underlying biology of aging and predict age-related outcomes. To support this endeavor, the Research Centers Collaborative Network (RCCN) conducted a workshop in January 2022 to discuss emerging concepts in the field and identify opportunities to move the science forward. This paper presents workshop proceedings and summarizes the identified research needs, priorities, and recommendations for measuring biologic age. The highest priorities identified were the need for more robust measures, longitudinal studies, multidisciplinary collaborations, and translational approaches.

Effects of Mindful Awareness Practice (MAP) on Subclinical Depressive and Anxiety Symptoms and General Cognitive Function in Older Adults with Mild Cognitive Impairment: A 5-Year Follow-Up of the MAP-Randomized Controlled Trial.

BACKGROUND: Few randomized controlled trials (RCTs) investigated the effects of mindfulness intervention on affective and cognitive symptoms in older adults with mild cognitive impairment (MCI). Furthermore, no RCTs on mindfulness followed participants beyond two years. OBJECTIVE: To examine the longitudinal effects of a mindful awareness practice (MAP) intervention on depressive, anxiety, and cognitive symptoms in MCI. METHODS: In this parallel-arm and assessor-blinded RCT, 55 community-dwelling older adults with MCI were randomized into the MAP or active control, i.e., health education program (HEP). Intervention sessions were conducted weekly for three months and monthly for the subsequent six months. Assessments and follow-up were conducted at baseline, 3-month, 9-month, and 5-year time points. Depressive, anxiety, and cognitive symptoms were measured using the Geriatric Depression Scale-15 (GDS-15), Geriatric Anxiety Inventory-20 (GAI-20), and Mini-Mental State Examination (MMSE), respectively. Linear-mixed models, following the intention-to-treat principle, were used for data analyses. RESULTS: A total of 55 participants aged 60 to 86 (Mean age: 71.3±6 years old) was recruited, with n = 28 allocated to the MAP arm and n = 27 allocated to the HEP arm. Compared to HEP, GDS-15, GAI-20, and MMSE scores did not differ significantly in MAP during follow-ups. CONCLUSION: Compared to HEP, MAP did not improve affective symptoms nor delay deteriorations in general cognition in community-dwelling older adults with MCI. Compared to our previous findings showing domain-specific improvements in MAP over HEP in attention and memory up to 9 months, this study highlights the importance of examining domain-specificity using detailed cognitive measures in non-pharmacological intervention with MCI.

Novel metabolomics markers are associated with pre-clinical decline in hand grip strength in community-dwelling older adults.

BACKGROUND: Hand grip strength (HGS) has been proposed as a robust predictor for frailty and sarcopenia. Hence, identifying biomarkers for declining HGS accompanying aging could deepen our understanding of the biological underpinnings, informing pre-emptive intervention. Acylcarnitines (ACs) are metabolites generated by fatty acid metabolism in the mitochondria and are dysregulated in multiple disorders affecting the musculature. However, they have not been comprehensively profiled and examined regarding their utility in predicting variability in declining HGS, longitudinally. Thus, we aimed to: 1) validate previous findings on insignificant cross-sectional association between ACs and HGS, and 2) examine whether baseline ACs were associated with both decline and variability in HGS over 18 months, in community-dwelling older adults. METHODS: We included participants who had HGS measured with dynamometer longitudinally (N = 121). We quantified ACs by targeted plasma metabolomics profiling. Multivariable linear regressions were then performed. RESULTS: Cross-sectionally, ACs were not significantly associated with HGS. Longitudinally, baseline short-chain dicarboxylic and hydroxylated acylcarnitines (AC-DC/-OH) levels were inversely associated with and significantly explained the variability in 18-month decline in HGS. A specific AC species, the C4-OH, accounted for most of the variance explained. CONCLUSIONS: We showed novel biomarkers for declining HGS, furthering molecular understanding and informing nutritional pre-emptive programs.

Association between housing type and accelerated biological aging in different sexes: moderating effects of health behaviors.

INTRODUCTION: Despite associated with multiple geriatric disorders, whether housing type, an indicator of socioeconomic status (SES) and environmental factors, is associated with accelerated biological aging is unknown. Furthermore, although individuals with low-SES have higher body mass index (BMI) and are more likely to smoke, whether BMI and smoking status moderate the association between SES and biological aging is unclear. We examined these questions in urbanized low-SES older community-dwelling adults. METHODS: First, we analyzed complete blood count data using the cox proportional hazards model and derived measures for biological age (BA) and biological age acceleration (BAA, the higher the more accelerated aging) (N = 376). Subsequently, BAA was regressed on housing type, controlling for covariates, including four other SES indicators. Interaction terms between housing type and BMI/smoking status were separately added to examine their moderating effects. Total sample and sex-stratified analyses were performed. RESULTS: There were significant differences between men and women in housing type and BAA. Compared to residents in ≥3 room public or private housing, older adults resided in 1-2 room public housing had a higher BAA. Furthermore, BMI attenuated the association between housing type and BAA. In sex-stratified analyses, the main and interaction effects were only significant in women. In men, smoking status instead aggravated the association between housing type and BAA. CONCLUSION: Controlling for other SES indicators, housing type is an independent socio-environmental determinant of BA and BAA in a low-SES urbanized population. There were also sex differences in the moderating effects of health behaviors on biological aging.

Social connectedness as a mediator for horticultural therapy's biological effect on community-dwelling older adults: Secondary analyses of a randomized controlled trial.

BACKGROUND: Elevated levels of inflammatory marker and a lack of social connectedness are two prominent risk factors for developing dementia and depression. Horticultural therapy (HT) has been shown to improve social connectedness and inflammatory markers. However, the underpinning mechanisms of HT remained unknown. Within this study, we hypothesized that improved social connectedness mediates the effects of HT on IL-6 levels. METHODS: The present study is a secondary analysis of a randomized controlled trial investigating the bio-psycho-social effects of HT. Social connectedness was operationalized as positive relationships with others (PRWO), a sub-scale of the Ryff's scale of psychological well-being. IL-6 was quantified using a commercial ELISA kit. Outcomes were assessed at baseline, 3-month and 6-month post-intervention. Mediation analyses with bootstrapping were run to investigate our primary hypothesis. All analyses were controlled for covariates. RESULTS: We recruited 59 participants (78% women; 67.10 ± 4.31 years). 29 participants partook in HT and 30 participants were included in the waitlist control group. At baseline, social connectedness was significantly correlated with IL-6 levels (ß = -0.12, 95% CI = -0.21 to -0.03, p = 0.008). Furthermore, social connectedness at 3-month significantly mediated the effects of HT on IL-6 levels at 6-month (ß = 0.32, 95% CI = 0.09 to 0.54, p = 0.005; ß = -0.25, 95% CI = -0.45 to -0.05, p = 0.016). CONCLUSIONS: These findings highlight the critical roles of social connectedness as a social determinant of health in eliciting HT's biological effects. When administering HT, interventionalists should consider social connectedness as a modifiable factor for ameliorating increased inflammation in older adults.

Increased plasma brain-derived neurotrophic factor (BDNF) as a potential biomarker for and compensatory mechanism in mild cognitive impairment: a case-control study.

BACKGROUND: Previous meta-analyses examining the continuum of Alzheimer's disease (AD) concluded significantly decreased peripheral brain-derived neurotrophic factor (BDNF) in AD. However, across different meta-analyses, there remain inconsistent findings on peripheral BDNF levels in individuals with mild cognitive impairment (MCI). This issue has been attributed to the highly heterogenous clinical and laboratory factors. Thus, BDNF's level, discriminative accuracy for identifying all-cause MCI and its subtypes, and its associations with other biomarkers and neurocognitive domains, remain largely unknown. METHODS: To address this heterogeneity, we compared a healthy control cohort (n=56, 45 female) to an MCI cohort (n=40, 28 female), to determine whether plasma BDNF, hs-CRP, and DHEA-S can differentiate healthy from MCI individuals, including two MCI subtypes (amnestic [aMCI] and non-amnestic [non-aMCI]). The associations between BDNF with other biomarkers and neurocognitive tests were examined. Adults with cerebral palsy were included as sensitivity analyses. RESULTS: Compared to healthy controls, BDNF was significantly higher in all-cause MCI, aMCI, and non-aMCI. Furthermore, BDNF had good (AUC=0.84, 95% CI=0.74 to 0.95, p<0.001) and excellent discriminative accuracies (AUC=0.92, 95% CI=0.84 to 1.00, p<0.001) for all-cause MCI and non-amnestic MCI, respectively. BDNF was significantly and positively associated with plasma hs-CRP (ß=0.26, 95% CI=0.02 to 0.50, p=0.038), despite attenuated association upon controlling for BMI (ß=0.15, 95% CI=-0.08 to 0.38, p=0.186). Multiple inverse associations between BDNF and detailed neurocognitive tests were also detected. CONCLUSIONS: These findings suggest BDNF is increased as a compensatory mechanism in preclinical dementia, supporting the neurotrophic and partially the inflammatory hypotheses of cognitive impairment.

Effect of mindfulness intervention versus health education program on salivary Aß-42 levels in community-dwelling older adults with mild cognitive impairment: A randomized controlled trial.

BACKGROUND: Few randomized controlled trials have investigated the effects of mindfulness intervention on older adults diagnosed with mild cognitive impairment (MCI). Specifically, scarce literature exists on the potential benefits of mindfulness intervention on biomarkers representing AD hallmarks. Our previous studies showed the potential of Mindful Awareness Practice (MAP) in improving multiple biomarkers of gut microbiota, systemic inflammation, and synaptic functions. Extending these findings, in this study, we conducted analysis on bio-banked saliva samples, examining whether MAP improved salivary amyloid beta-42 (Aß-42) levels in community-dwelling older adults diagnosed with MCI. We also explored the moderating role of education level, an indicator of cognitive reserve, on intervention effect. METHODS: A total of 55 community-dwelling older adults diagnosed with MCI were randomized into either the treatment arm, MAP, or the active control arm, the health education program (HEP). Interventions were performed for a total of nine months. Field and laboratory investigators who were blinded to the treatment allocations collected saliva samples at baseline, 3-month, and 9-month follow-ups. Salivary Aß-42 levels were quantified using a commercial assay. Linear-mixed models were used to examine the effect of MAP on salivary Aß-42 levels. RESULTS: Compared to the HEP arm, MAP participants had no significantly modified Aß-42 levels throughout the 9-month intervention period, regardless of subgroup analyses stratified by either sex or MCI-subtypes (amnestic and non-amnestic). Exploring the moderating effect of education, participants in the HEP arm with higher education levels had significantly lower salivary Aß-42 at 3-month time-point. DISCUSSION: Taken together with our previous findings and other mindfulness interventional studies failing to find a significant effect on peripheral Aß-42, we conclude the non-significant effects of mindfulness intervention on ameliorating peripheral Aß-42 levels. Conversely, participants in the HEP arm with higher cognitive reserve had significantly improved salivary Aß-42, highlighting the role of cognitive reserve in moderating treatment response in MCI.