Dietary profiling of physical frailty in older age phenotypes using a machine learning approach: the Salus in Apulia Study.

PURPOSE: Growing awareness of the biological and clinical value of nutrition in frailty settings calls for further efforts to investigate dietary gaps to act sooner to achieve focused management of aging populations. We cross-sectionally examined the eating habits of an older Mediterranean population to profile dietary features most associated with physical frailty. METHODS: Clinical and physical examination, routine biomarkers, medical history, and anthropometry were analyzed in 1502 older adults (65 +). CHS criteria were applied to classify physical frailty, and a validated Food Frequency Questionnaire to assess diet. The population was subdivided by physical frailty status (frail or non-frail). Raw and adjusted logistic regression models were applied to three clusters of dietary variables (food groups, macronutrients, and micronutrients), previously selected by a LASSO approach to better predict diet-related frailty determinants. RESULTS: A lower consumption of wine (OR 0.998, 95% CI 0.997-0.999) and coffee (OR 0.994, 95% CI 0.989-0.999), as well as a cluster of macro and micronutrients led by PUFAs (OR 0.939, 95% CI 0.896-0.991), zinc (OR 0.977, 95% CI 0.952-0.998), and coumarins (OR 0.631, 95% CI 0.431-0.971), was predictive of non-frailty, but higher legumes intake (OR 1.005, 95%CI 1.000-1.009) of physical frailty, regardless of age, gender, and education level. CONCLUSIONS: Higher consumption of coffee and wine, as well as PUFAs, zinc, and coumarins, as opposed to legumes, may work well in protecting against a physical frailty profile of aging in a Mediterranean setting. Longitudinal investigations are needed to better understand the causal potential of diet as a modifiable contributor to frailty during aging.

Nutritional patterns as machine learning predictors of liver health in a population of elderly subjects.

BACKGROUND AND AIMS: Non-alcoholic hepatic steatosis affects 25% of adults worldwide and its prevalence increases with age. There is currently no definitive treatment for NAFLD but international guidelines recommend a lifestyle-based approach, including a healthy diet. The aim of this study was to investigate the interactions between eating habits and the risk of steatosis and/or hepatic fibrosis, using a machine learning approach, in a non-institutionalized elderly population. METHODS AND RESULTS: We recruited 1929 subjects, mean age 74 years, from the population-based Salus in Apulia Study. Dietary habits and the risk of steatosis and hepatic fibrosis were evaluated with a validated food frequency questionnaire, the Fatty Liver Index (FLI) and the FIB-4 score, respectively. Two dietary patterns associated with the risk of steatosis and hepatic fibrosis have been identified. They are both similar to a "western" diet, defined by a greater consumption of refined foods, with a rich content of sugars and saturated fats, and alcoholic and non-alcoholic calorie drinks. CONCLUSION: This study further supports the concept of diet as a factor that significantly influences the development of the most widespread liver diseases. However, longitudinal studies are needed to better understand the causal effect of the consumption of particular foods on fat accumulation in the liver.

Processed meat consumption and the risk of incident late-onset depression: a 12-year follow-up of the Salus in Apulia Study.

BACKGROUND: the possible relationship between dietary habits and the incidence of late-onset depression (LOD), defined as first depression onset at later age, is unclear. OBJECTIVE: to investigate the relationship between consumption of different food groups and incident LOD. DESIGN: longitudinal population-based study with a 12-year follow-up. SETTING: Castellana Grotte, Bari, Italy. SUBJECTS: five hundred and forty-six older subjects from the Salus in Apulia Study. METHODS: baseline data were recorded in 2003-06, and diagnostic data were recorded in 2013-18 at follow-up. Dietary intake was assessed with a food frequency questionnaire. Depressive disorders were assessed with the Structured Clinical Interview for DSM-IV Axis I Disorders. Subjects who already suffered from depression or other psychiatric disorders at baseline were excluded from the analysis. The association between LOD and single dietary determinants was examined by Cox regression analysis and then applying the hazard ratio (HR). RESULTS: subjects with incident LOD (n = 34) had lower global cognition and total cholesterol levels and a higher body mass index (BMI) at baseline. Only processed meat significantly increased the risk of incident LOD of about 10% by 5 g/day intake (HR adjusted for age, sex, education, multimorbidity and BMI: 1.13, 95% confidence intervals: 1.04-1.22). A similar relationship was found for single foods in the processed meat food group such as sausages, salami and mortadella and baked ham, but not for raw ham. CONCLUSIONS: in midlife, a higher intake of processed meat was not only associated with an increased risk of cardiovascular- and metabolic-related chronic diseases in older age but also with an increased risk of developing LOD.

Role of plant-based diet in late-life cognitive decline: results from the Salus in Apulia Study.

OBJECTIVES: Consistency among population-based studies investigating the relationship between diet and cognition in older inhabitants in the Mediterranean area is poor. The present study investigated whether diet changes over 12 years were associated with cognitive function in older people in Southern-Italy. METHODS: From the 'Salus in Apulia Study', that includes the MICOL and GreatAGE Studies, 584 participants were selected, firstly enrolled in MICOL3 (M3) and later in the GreatAGE Study (MICOL4, M4). Foods and micronutrients intake were recorded in both studies, and global cognitive function in M4, assessed with the Mini Mental State Examination. RESULTS: Plant-based foods, particularly coffee and vegetables, as well as vitamin A sources, were inversely associated to age-related cognitive impairment. Alcohol consumption showed a detrimental role on cognition, while red meat appeared to be beneficial in the present study, although its role is traditionally considered harmful for cognitive function. DISCUSSION: Our study confirmed that a traditional Mediterranean dietary pattern based on agricultural products and low alcohol consumption may help to prevent/delay age-related cognitive impairment.

Dietary Patterns Associated with Diabetes in an Older Population from Southern Italy Using an Unsupervised Learning Approach.

Dietary behaviour is a core element in diabetes self-management. There are no remarkable differences between nutritional guidelines for people with type 2 diabetes and healthy eating recommendations for the general public. This study aimed to evaluate dietary differences between subjects with and without diabetes and to describe any emerging dietary patterns characterizing diabetic subjects. In this cross-sectional study conducted on older adults from Southern Italy, eating habits in the "Diabetic" and "Not Diabetic" groups were assessed with FFQ, and dietary patterns were derived using an unsupervised learning algorithm: principal component analysis. Diabetic subjects (n = 187) were more likely to be male, slightly older, and with a slightly lower level of education than subjects without diabetes. The diet of diabetic subjects reflected a high-frequency intake of dairy products, eggs, vegetables and greens, fresh fruit and nuts, and olive oil. On the other hand, the consumption of sweets and sugary foods was reduced compared to non-diabetics (23.74 ± 35.81 vs. 16.52 ± 22.87; 11.08 ± 21.85 vs. 7.22 ± 15.96). The subjects without diabetes had a higher consumption of red meat, processed meat, ready-to-eat dishes, alcoholic drinks, and lower vegetable consumption. The present study demonstrated that, in areas around the Mediterranean Sea, older subjects with diabetes had a healthier diet than their non-diabetic counterparts.

Associations between nutritional frailty and 8-year all-cause mortality in older adults: The Salus in Apulia Study.

INTRODUCTION: Preventive nutritional management of frailty, a multidimensional intermediate status in the ageing process, may reduce the risk of adverse health-related outcomes. We investigated the ability of a measure combining physical frailty with nutritional imbalance, defined as nutritional frailty, to predict all-cause mortality over a period of up to 8 years. METHODS: We analysed data on 1,943 older adults from the population-based 'Salus in Apulia Study'. Physical frailty was operationalized using Cardiovascular Health Study criteria and cognitive frailty by combining physical frailty with cognitive impairment. A novel five-item construct was built to assess the extent of nutritional imbalance identified with a machine learning algorithm. Cox models and Kaplan-Meier survival probability analyses of physical frailty, nutritional imbalance (two or more of the following: low body mass index, low skeletal muscle index, ≥2.3 g/day sodium intake, <3.35 g/day potassium intake and <9.9 g/day iron intake), cognitive frailty and the novel nutritional frailty phenotype (physical frailty plus nutritional imbalance) were applied to assess all-cause mortality risk, adjusted for age, sex, education and multimorbidity. RESULTS: The overall prevalence of nutritional frailty was 4.52% (95% confidence interval, CI:3.55-5.44), being more frequent in males. Subjects with nutritional frailty were at higher risk for all-cause mortality [hazard ratio (HR):2.31; 95%CI:1.41-3.79] than those with physical frailty (HR:1.45,95% CI:1.0-2.02), nutritional imbalance (HR:1.39; 95%CI:1.05-1.83) and cognitive frailty (HR:1.06; 95%CI:0.56-2.01). CONCLUSIONS: Efforts to identify, manage and prevent frailty should include the nutritional domain. The nutritional frailty phenotype may highlight major nutritional determinants that could drive survival and health trajectories in older adults.

Physical and cognitive profiles in motoric cognitive risk syndrome in an older population from Southern Italy.

BACKGROUND AND PURPOSE: In older age, physical and cognitive declines have been shown to occur simultaneously or consequent to one another, and several operational definitions have been proposed to consider the co-presence of the two declines; for example, "Motoric cognitive risk syndrome" (MCR) has been proposed as a definition for the coexistence of slow gait plus subjective cognitive complaints. Given the increasing interest in MCR and its potential role as both biomarker and therapeutic target, we aimed to estimate its prevalence in a large cohort of non-demented older subjects, and to examine the associations between physical status, global cognitive dysfunction, and impairment in various cognitive domains in MCR. METHODS: A population-based sample of 1041 older people in Southern Italy (mean age 75.15 years) was enrolled. We defined MCR using slowness and a single question for subjective cognitive complaints. We also administered a comprehensive neuropsychological test battery, together with tests assessing physical function. RESULTS: The prevalence of MCR was 9.9% (95% confidence interval 8.2-11.9). MCR was associated with decreased processing speed and executive function after adjusting for all relevant confounders. However, we found no significant association of MCR with decreased global cognition and immediate/delayed free recall of verbal memory. MCR was also associated with increased exhaustion, low muscle strength, and low physical activity, and increased levels of C-reactive protein and interleukin-6. CONCLUSIONS: The present findings on MCR prevalence and associated cognitive and physical domains and inflammatory biomarkers may help to uncover altered pathways and therapeutic targets for intervention during the long preclinical phase of neurodegenerative dementia.

Healthy aging: the INTECMAN project.

Aging is associated not only with the reduction of psychophysical and sensory capacities but also with different types of neurodegenerative disorders up to dementia manifestations. Aging in health and self-sufficiency is strictly dependent on the prevention and correction of factors that may determine reduction of psychophysical capacities (e.g., cardiovascular, locomotor and neurodegenerative ones). To reach this goal, due to the dynamics of social and family changes and to the aging of the population, health professionals can be supported by technologies which provide noninvasive monitoring of physiologic parameters and rely on telemedicine, both instruments of support and care for better aging in the home setting. The authors, starting from the initial idea of a personalized monitoring of different psychophysical variables, defined a pilot study to assess the role of a 12-month individually tailored lifestyle counseling on parameters of mild cognitive impairment in a group of elderly subjects. Data derived from the applied approach appeared promising and may open the road to the possible implementation of individual counseling, based on multiparametric non-obtrusive technologies which take into consideration both psychological and physical aspects, to be followed in the home environment.

Immersive Virtual Environments and Wearable Haptic Devices in rehabilitation of children with neuromotor impairments: a single-blind randomized controlled crossover pilot study.

BACKGROUND: The past decade has seen the emergence of rehabilitation treatments using virtual reality. One of the advantages in using this technology is the potential to create positive motivation, by means of engaging environments and tasks shaped in the form of serious games. The aim of this study is to determine the efficacy of immersive Virtual Environments and weaRable hAptic devices (VERA) for rehabilitation of upper limb in children with Cerebral Palsy (CP) and Developmental Dyspraxia (DD). METHODS: A two period cross-over design was adopted for determining the differences between the proposed therapy and a conventional treatment. Eight children were randomized into two groups: one group received the VERA treatment in the first period and the manual therapy in the second period, and viceversa for the other group. Children were assessed at the beginning and the end of each period through both the Nine Hole Peg Test (9-HPT, primary outcome) and Kinesiological Measurements obtained during the performing of similar tasks in a real setting scenario (secondary outcomes). RESULTS: All subjects, not depending from which group they come from, significantly improved in both the performance of the 9-HPT and in the parameters of the kinesiological measurements (movement error and smoothness). No statistically significant differences have been found between the two groups. CONCLUSIONS: These findings suggest that immersive VE and wearable haptic devices is a viable alternative to conventional therapy for improving upper extremity function in children with neuromotor impairments. Trial registration ClinicalTrials, NCT03353623. Registered 27 November 2017-Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT03353623.

Activity Energy Expenditure Predicts Clinical Average Levels of Physical Activity in Older Population: Results from Salus in Apulia Study.

Self-report questionnaires are a valuable method of physical activity measurement in public health research; however, accuracy is often lacking. Resolving the differences between self-reported and objectively measured physical activity is an important surveillance challenge currently facing population health experts. The present work aims at providing the relationship between activity energy expenditure estimated from wrist-worn accelerometers and intensity of self-reported physical activity (InCHIANTI structured interview questionnaire) in a sub-cohort of a population-based study on aging in Southern Italy. Linear regression was used to test the association between measured and reported physical activity. We found that activity energy expenditure predicted clinical average levels of PA assessed through InCHIANTI classification.

A low-cost vision system based on the analysis of motor features for recognition and severity rating of Parkinson's Disease.

BACKGROUND: Assessment and rating of Parkinson's Disease (PD) are commonly based on the medical observation of several clinical manifestations, including the analysis of motor activities. In particular, medical specialists refer to the MDS-UPDRS (Movement Disorder Society - sponsored revision of Unified Parkinson's Disease Rating Scale) that is the most widely used clinical scale for PD rating. However, clinical scales rely on the observation of some subtle motor phenomena that are either difficult to capture with human eyes or could be misclassified. This limitation motivated several researchers to develop intelligent systems based on machine learning algorithms able to automatically recognize the PD. Nevertheless, most of the previous studies investigated the classification between healthy subjects and PD patients without considering the automatic rating of different levels of severity. METHODS: In this context, we implemented a simple and low-cost clinical tool that can extract postural and kinematic features with the Microsoft Kinect v2 sensor in order to classify and rate PD. Thirty participants were enrolled for the purpose of the present study: sixteen PD patients rated according to MDS-UPDRS and fourteen healthy paired subjects. In order to investigate the motor abilities of the upper and lower body, we acquired and analyzed three main motor tasks: (1) gait, (2) finger tapping, and (3) foot tapping. After preliminary feature selection, different classifiers based on Support Vector Machine (SVM) and Artificial Neural Networks (ANN) were trained and evaluated for the best solution. RESULTS: Concerning the gait analysis, results showed that the ANN classifier performed the best by reaching 89.4% of accuracy with only nine features in diagnosis PD and 95.0% of accuracy with only six features in rating PD severity. Regarding the finger and foot tapping analysis, results showed that an SVM using the extracted features was able to classify healthy subjects versus PD patients with great performances by reaching 87.1% of accuracy. The results of the classification between mild and moderate PD patients indicated that the foot tapping features were the most representative ones to discriminate (81.0% of accuracy). CONCLUSIONS: The results of this study have shown how a low-cost vision-based system can automatically detect subtle phenomena featuring the PD. Our findings suggest that the proposed tool can support medical specialists in the assessment and rating of PD patients in a real clinical scenario.

The epigenetics of frailty.

The conceptual change of frailty, from a physical to a biopsychosocial phenotype, expanded the field of frailty, including social and behavioral domains with critical interaction between different frailty models. Environmental exposures - including physical exercise, psychosocial factors and diet - may play a role in the frailty pathophysiology. Complex underlying mechanisms involve the progressive interactions of genetics with epigenetics and of multimorbidity with environmental factors. Here we review the literature on possible mechanisms explaining the association between epigenetic hallmarks (i.e., global DNA methylation, DNA methylation age acceleration and microRNAs) and frailty, considered as biomarkers of aging. Frailty could be considered the result of environmental epigenetic factors on biological aging, caused by conflicting DNA methylation age and chronological age.

The present narrative review describes the available evidence about epigenetic biological markers of frailty considered aging biomarkers, among others. Aging biomarkers can help in identifying frail and older individuals affected by multiple diseases to further increase the power of composite biomarker panels in the diagnostic and prognostic process. Among combined biomarkers, epigenetic regulators with different methylation patterns and small molecules such as microRNAs are included. Given that frailty involves multiple biological systems, it is possible to define it according to a novel model, including emotional and social domains and the influence of environmental factors, named the biopsychosocial phenotype. Different epigenetic biomarkers of frailty, from the first generation to the more specific and recent second-generation epigenetic aging biomarkers, may account for factors linked to different cellular types, such as heterogeneity, and a reverse causation process that requires integration with gene expression. A better understanding of the relationships among frailty, multimorbidity and overall mortality will help us to identify the best therapeutic targets.

Lessons learned from the failure of solanezumab as a prospective treatment strategy for Alzheimer's disease.

INTRODUCTION: In the last decade, the efforts conducted for discovering Alzheimer's Disease (AD) treatments targeting the best-known pathogenic factors [amyloid-ß (Aß), tau protein, and neuroinflammation] were mostly unsuccessful. Given that a systemic failure of Aß clearance was supposed to primarily contribute to AD development and progression, disease-modifying therapies with anti-Aß monoclonal antibodies (e.g. solanezumab, bapineuzumab, gantenerumab, aducanumab, lecanemab and donanemab) are ongoing in randomized clinical trials (RCTs) with contrasting results. AREAS COVERED: The present Drug Discovery Case History analyzes the failures of RCTs of solanezumab on AD. Furthermore, the authors review the pharmacokinetics, pharmacodynamics, and tolerability effect of solanezumab from preclinical studies with its analogous m266 in mice. Finally, they describe the RCTs with cognitive, cerebrospinal fluid and neuroimaging findings in mild-to-moderate AD (EXPEDITION studies) and in secondary prevention studies (A4 and DIAN-TU). EXPERT OPINION: Solanezumab was one of the first anti-Aß monoclonal antibodies to be tested in preclinical and clinical AD showing to reduce brain Aß level by acting on soluble monomeric form of Aß peptide without significant results on deposits. Unfortunately, this compound showed to accelerate cognitive decline in both asymptomatic and symptomatic trial participants, and this failure of solanezumab further questioned the Aß cascade hypothesis of AD.

Clinical, Biomechanical, and Self-reported Health Status After ACL Reconstruction With Meniscal Repair in Soccer Players: Results at Minimum 1-Year Follow-up.

Background: Performing meniscal repair with anterior cruciate ligament reconstruction (ACLR) has been shown to contribute to the long-term preservation of knee health and gait biomechanics. Purpose: To evaluate the role of meniscal repair in the performance of semiprofessional soccer players who returned to sport after ACLR. Study Design: Case series; Level of evidence, 4. Methods: This study included 51 male soccer players (mean ± SD age, 28.82 ± 5.33 years) who underwent ACLR at a single institution between July 2018 and July 2019. The players were divided into 3 groups according to surgery type: ACLR only (n = 30), ACLR with lateral meniscal repair (n = 9), and ACLR with medial meniscal repair (n = 12). Outcomes were evaluated through clinical examination, self-reported health questionnaires (Cincinnati Knee Rating System, Tegner activity score, Tegner Lysholm Knee Scoring Scale, Tampa Scale of Kinesiophobia, and ACL-Return to Sport After Injury), and biomechanical performance evaluations (balance, strength, coordination, and symmetry tests). Parametric and nonparametric tests were carried out for multiple comparisons. Results: The mean ± SD follow-up time was 20.75 ± 9.38 months. Although no significant differences emerged in clinical and self-reported health status, almost all the physical parameters tested resulted in lower performance in players treated with ACLR and meniscal repair. Moreover, patients with ACLR with lateral meniscal repair reported higher pain and fear of reinjury, with lower outcomes in terms of strength, symmetry, and coordination as compared with the other 2 groups. Balance abilities were significantly affected in players who underwent meniscal repair as compared with those who underwent ACLR only. Conclusion: The findings showed that biomechanical performance measures and fear of reinjury were significantly worse in soccer players with associated meniscal repair at a minimum 1-year follow-up, especially in those with a lateral meniscal tear.

The Impact of Apolipoprotein E (APOE) Epigenetics on Aging and Sporadic Alzheimer's Disease.

Sporadic Alzheimer's disease (AD) derives from an interplay among environmental factors and genetic variants, while epigenetic modifications have been expected to affect the onset and progression of its complex etiopathology. Carriers of one copy of the apolipoprotein E gene (APOE) ε4 allele have a 4-fold increased AD risk, while APOE ε4/ε4-carriers have a 12-fold increased risk of developing AD in comparison with the APOE ε3-carriers. The main longevity factor is the homozygous APOE ε3/ε3 genotype. In the present narrative review article, we summarized and described the role of APOE epigenetics in aging and AD pathophysiology. It is not fully understood how APOE variants may increase or decrease AD risk, but this gene may affect tau- and amyloid-mediated neurodegeneration directly or indirectly, also by affecting lipid metabolism and inflammation. For sporadic AD, epigenetic regulatory mechanisms may control and influence APOE expression in response to external insults. Diet, a major environmental factor, has been significantly associated with physical exercise, cognitive function, and the methylation level of several cytosine-phosphate-guanine (CpG) dinucleotide sites of APOE.

Ultra-processed food consumption and nutritional frailty in older age.

Frailty is a multidisciplinary public health issue and nutrition is key concern. Given the scientific consistency about inflammation as shared pathway to poor nutrition and frailty, food processing seems a suitable target to gain evidence in frailty prevention nutrition settings. This study aimed to assess diet in relation to nutritional frailty using the NOVA classification. Browsing the dataset of the Salus in Apulia, 2185 older adults were found to have completed the nutritional assessment, providing eligible data for this study goal. A validated construct, based on the co-presence of physical frailty by CHS criteria plus nutritional imbalance, was applied to characterize nutritional frailty phenotypes. Using the NOVA classification, daily food and beverage intakes from an 85-item self-administered FFQ were assigned to three categories, and effect sizes were tested among groups according to nutritional frailty status (presence/absence). Raw and adjusted logistic regression models were run to assess associations between NOVA food categories by quintiles of daily exposure (very-low, low, mild, moderate, high) and nutritional frailty. Nutritional frailty prevalence was 27%, being more frequent in males. Eating more unprocessed or minimally processed foods was inversely related to nutritional frailty, even after adjustment (OR: 0.10, 95%CI 0.07-0.16), showing a downward ORs behavior toward lower consumption quintiles. Listing in the quintile of moderate consumption of processed foods meant a nearly 50% increase in nutritional frailty probability (OR: 1.46, 95%CI 1.03-2.06), while the probability was double for the highest quintile against the lowest (OR: 3.22, 95%CI 2.27-4.58). A growing probability of nutritional frailty was found for increasing consumption of ultra-processed foods, but significance was lacking. The contribution of food processing to poor nutrition needs to be considered when promoting a better understanding of effective nutritional screening in aging. Therefore, food processing should be accounted for when composing diet guidelines for the older population within the framework of multidisciplinary efforts to ease the frailty healthcare burden.

Clinical development of passive tau-based immunotherapeutics for treating primary and secondary tauopathies.

INTRODUCTION: Tauopathies are clinicopathological entities with increased and pathological deposition in glia and/or neurons of hyperphosphorylated aggregates of the microtubule-binding protein tau. In secondary tauopathies, i.e. Alzheimer's disease (AD), tau deposition can be observed, but tau coexists with another protein (amyloid-ß). In the last 20 years, little progress has been made in developing disease-modifying drugs for primary and secondary tauopathies and available symptomatic drugs have limited efficacy. AREAS COVERED: The present review summarized recent advances about the development and challenges in treatments for primary and secondary tauopathies, with a focus on passive tau-based immunotherapy. EXPERT OPINION: Several tau-targeted passive immunotherapeutics are in development for treating tauopathies. At present, 14 anti-tau antibodies have entered clinical trials, and 9 of them are still in clinical testing for progressive supranuclear palsy syndrome and AD (semorinemab, bepranemab, E2814, JNJ-63733657, Lu AF87908, APNmAb005, MK-2214, PNT00, and PRX005). However, none of these nine agents have reached Phase III. The most advanced anti-tau monoclonal antibody for treating AD is semorinemab, while bepranemab is the only anti-tau monoclonal antibody still in clinical testing for treating progressive supranuclear palsy syndrome. Further evidence on passive immunotherapeutics for treating primary and secondary tauopathies will come from ongoing Phase I/II trials.

Corrigendum: Dietary customs and social deprivation in an aging population from Southern Italy: A machine learning approach.

[This corrects the article DOI: 10.3389/fnut.2022.811076.].

Depressive and Biopsychosocial Frailty Phenotypes: Impact on Late-life Cognitive Disorders.

In older age, frailty is a detrimental transitional status of the aging process featuring an increased susceptibility to stressors defined by a clinical reduction of homoeostatic reserves. Multidimensional frailty phenotypes have been associated with all-cause dementia, mild cognitive impairment (MCI), Alzheimer's disease (AD), AD neuropathology, vascular dementia, and non-AD dementias. In the present article, we reviewed current evidence on the existing links among depressive and biopsychosocial frailty phenotypes and late-life cognitive disorders, also examining common pathways and mechanisms underlying these links. The depressive frailty phenotype suggested by the construct of late-life depression (LLD) plus physical frailty is poorly operationalized. The biopsychosocial frailty phenotype, with its coexistent biological/physical and psychosocial dimensions, defines a biological aging status and includes motivational, emotional, and socioeconomic domains. Shared biological pathways/substrates among depressive and biopsychosocial frailty phenotypes and late-life cognitive disorders are hypothesized to be inflammatory and cardiometabolic processes, together with multimorbidity, loneliness, mitochondrial dysfunction, dopaminergic neurotransmission, specific personality traits, lack of subjective/objective social support, and neuroendocrine dysregulation. The cognitive frailty phenotype, combining frailty and cognitive impairment, may be a risk factor for LLD and vice versa, and a construct of depressive frailty linking physical frailty and LLD may be a good dementia predictor. Frailty assessment may enable clinicians to better target the pharmacological and psychological treatment of LLD. Given the epidemiological links of biopsychosocial frailty with dementia and MCI, multidomain interventions might contribute to delay the onset of late-life cognitive disorders and other adverse health-related outcomes, such as institutionalization, more frequent hospitalization, disability, and mortality.