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.

Processed foods and diet quality in pregnancy may affect child neurodevelopment disorders: a narrative review.

OBJECTIVE: To review the evidence on the association between maternal exposure to ultra-processed food (UPF) categories, UPF diet items, and overall diet quality, as assessed by recognized dietary indices, and neurodevelopmental outcomes in offspring. METHODS: PubMed, MEDLINE, EMBASE, Scopus, Ovid, and Scholar databases were searched for original articles on female gestational exposure to UPF categories, individual elements of the UPF diet, or indices of diet quality, in relation to outcomes regarding their offspring's neurocognitive development, according to neuropsychometric and behavioral scales, anthropometric/psychomotor indices, and symptoms/diagnosis of neurodevelopmental disorders (NDDs). RESULTS: Fourteen articles were selected and underwent the quantitative analysis. Six of these examined diet quality, and eight exposure to UPF categories or specific UPF foods. The maternal population was adult (18+). Child cognitive development was negatively impacted by a diet featuring many processed foods, saturated fats, and sugars. Conversely, a Med-diet led to better neurodevelopment, particularly verbal intelligence and executive functions, in middle childhood. DISCUSSION: A maternal diet with many UPFs, saturated fats, and total sugars (especially those added or hidden in packaged carbonated beverages) can adversely affect a child's cognitive development. Knowledge needs to be further extended and managed from a prevention perspective in light of the well-known negative effects of UPFs on human health in all age groups.

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.

NIR ICG-Enhanced Fluorescence: A Quantitative Evaluation of Bowel Microperfusion and Its Relation to Central Perfusion in Colorectal Surgery.

BACKGROUND: To date, no standardized protocols nor a quantitative assessment of the near-infrared fluorescence angiography with indocyanine green (NIR-ICG) are available. The aim of this study was to evaluate the timing of fluorescence as a reproducible parameter and its efficacy in predicting anastomotic leakage (AL) in colorectal surgery. METHODS: A consecutive cohort of 108 patients undergoing minimally invasive elective procedures for colorectal cancer was prospectively enrolled. The difference between macro and microperfusion (ΔT) was obtained by calculating the timing of fluorescence at the level of iliac artery division and colonic wall, respectively. RESULTS: Subjects with a ΔT ≥ 15.5± 0.5 s had a higher tendency to develop an AL (p < 0.01). The ΔT/heart rate interaction was found to predict AL with an odds ratio of 1.02 (p < 0.01); a cut-off threshold of 832 was identified (sensitivity 0.86, specificity 0.77). Perfusion parameters were also associated with a faster bowel motility resumption and a reduced length of hospital stay. CONCLUSIONS: The analysis of the timing of fluorescence provides a quantitative, easy evaluation of tissue perfusion. A ΔT/HR interaction ≥832 may be used as a real-time parameter to guide surgical decision making in colorectal surgery.

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.

Olive Oil Polyphenols Improve HDL Cholesterol and Promote Maintenance of Lipid Metabolism: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

In 2011, the European Food Safety Authority (EFSA) accorded a health claim to olive oil polyphenols in that they protected LDL particles from oxidative damage. However, limited scientific evidence has so far failed to confer any claim of function on the maintenance of normal lipid metabolism. We performed a systematic review and meta-analysis of human RCTs, evaluating the effect of olive oil polyphenol administration on lipid profiles. Previous literature was acquired from six electronic databases until June 2023. A total of 75 articles were retrieved and screened for inclusion criteria, which resulted in the selection of 10 RCTs that evaluated the effect of daily exposure to olive oil polyphenols on serum lipids in adults. Meta-analyses were built by tertiles of outcomes, as follows: low (0-68 mg/kg), medium (68-320 mg/kg), and high (320-600 mg/kg) polyphenols for HDL and LDL cholesterol (HDL-C and LDL-C, respectively), and low (0-59.3 mg/kg), medium (59.3-268 mg/kg), and high (268-600 mg/kg) polyphenols for total cholesterol (TC). The study protocol was registered on PROSPERO (registration code: CRD42023403383). The study design was predominantly cross-over (n = 8 of 10) but also included parallel (n = 2 of 10). The study population was predominantly European and healthy. Daily consumption of olive oil polyphenols did not affect TC levels and only slightly significantly reduced LDL-C, with WMD statistically significant only for high daily consumption of olive oil polyphenols (WMD -4.28, 95%CI -5.78 to -2.77). Instead, our data found a statistically significant HDL-C enhancing effect (WMD pooled effect model: 1.13, 95%CI 0.45; 1.80, heterogeneity 38%, p = 0.04) with WMD by daily exposure level showing a statistically significant improvement effect for low (WMD 0.66, 95%CI 0.10-1.23), medium (WMD 1.36, 95%CI 0.76-1.95), and high (WMD 1.13, 95%CI 0.45-1.80) olive oil polyphenol consumptions. Olive oil polyphenols contribute toward maintaining lipid metabolism. Thus, food labeling regulations should stress this health feature of olive oil, whereby a declaration of the olive oil polyphenol content should be added to products on the market. Consumers need to be aware of the quality and possible health effects of any products they consume, and enforcement of nutrition labels offers the best way of providing this information.

Discovering the Individualized Factors Associated with Sarcopenia and Sarcopenic Obesity Phenotypes-A Machine Learning Approach.

The literature shows how sarcopenia often occurs along with different phenotypes based either on the concomitant presence of adipose tissue excess (i.e., sarcopenic obesity, SO), or osteopenia/osteoporosis (osteosarcopenia, OS), or the combination of the two conditions, so-called osteosarcopenic obesity (OSO). This research aimed to assess the prevalence of sarcopenia phenotypes (SO, OS, OSO), their associated risk factors and their health impact in a population of out- and inpatients living in the North of Italy. Male and female subjects aged ≥18 years were enrolled for the study. A blood sample was collected to measure targeted blood makers. A comprehensive anthropometric clinical assessment (height, weight, Body Mass Index, BMI and Dual Energy X-ray Absorptiometry, DXA) was performed to measure ponderal, bone, fat, and muscle status. A total of 1510 individuals participated to the study (females, n = 1100; 72.85%). Sarcopenia was the most prevalent phenotype (17%), followed by osteosarcopenia (14.7%) and sarcopenic obesity. Only 1.9% of the sample was affected by OSO. According to logistic regression analysis, sarcopenia was associated with age, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) (positively) and BMI, Iron (Fe), Total Cholesterol, albumin (%), albumin (g), and gamma proteins (negatively). Sarcopenic obesity was associated with age, ferritin, ESR, CRP (positively) and BMI, Fe, and albumin (%) (negatively). Osteosarcopenia was associated with age, ESR (positively) and BMI, Total Cholesterol, albumin (%), albumin (g), and Ca (negatively). Osteosarcopenic obesity was associated with glycemia and gamma-glutamyl transferase (gGT) (positively). According to random forest analysis, a higher BMI was the most important protective factor for sarcopenia, for sarcopenic obesity (along with Iron) and for osteosarcopenia (along with albumin). Moreover, osteosarcopenic obesity was positively associated with GgT and glycaemia. The possibility of gaining such information, especially in the younger population, could help to prevent the onset of such diseases and best fit the patient's needs, according to a precision-medicine approach.

Scientific evidence supporting the newly developed one-health labeling tool "Med-Index": an umbrella systematic review on health benefits of mediterranean diet principles and adherence in a planeterranean perspective.

BACKGROUND: Med-Index is a one-health front-of-pack (FOP) label, based on Mediterranean diet (MedDiet) principles, developed to summarize information about the nutritional properties and related-health benefits of any food as well as its sustainable production processes, and the associated food company's social responsibility parameters in a new "Planeterranean" perspective. Thus, Med-Index can be adopted in and by any European region and authority as well as worldwide; this is achieved by consumption and cooking of locally available and sourced foods that respect MedDiet principles, both in terms of healthy nutrition and sustainable production. The huge body of scientific evidence about the health benefits of the MedDiet model and principles requires a comprehensive framework to encompass the scientific reliability and robustness of this tool. A systematic review was carried out to examine the association between human health and adherence to MedDiet patterns upon which the "Med-Index" tool was subsequently developed. METHODS: MEDLINE and PubMed databases were searched for eligible publications from 1990 to April 2023. Systematic literature reviews, with or without meta-analysis, of clinical trials and observational studies were screened by two independent investigators for eligibility, data extraction, and quality assessment. English language and the time interval 1990-2023 were applied. A registry code CRD42023464807 was generated on PROSPERO and approved for this search protocol. The corrected covered area (CCA), calculated to quantify the degree of overlap between reviews, gave a slight overlap (CCA = 4%). RESULTS: A total of 84 systematic reviews out of 6681 screened records were selected. Eligible reviews included studies with predominantly observational designs (61/84, 72.6%%), of which 26/61 referenced studies of mixed observational and RCT designs, while 23/84 (27.4%) were RCT-only systematic reviews. Seventy-nine different entries were identified for health outcomes, clustered into 10 macro-categories, each reporting a statistically significant association with exposure to the MedDiet. Adherence to MedDiet was found to strongly benefit age-related chronic diseases (21.5%), neurological disorders (19%), and obesity-related metabolic features (12.65), followed by CVDs (11.4%), cancer (10.1%), diabetes (7.5%), liver health (6.3%), inflammation (5%), mortality (5%), and renal health (1.2%). The quality of the studies was moderate to high. CONCLUSION: In the context of a "Planeterranean" framework and perspective that can be adopted in any European region and worldwide, MedDiet represents a healthy and sustainable lifestyle model, able to prevent several diseases and reduce premature mortality. In addition, the availability of a FOP, such as Med-Index, might foster more conscious food choices among consumers, paying attention both to human and planetary health.

The Relationship between Oral Health-Related Quality of Life and Body Mass Index in an Older Population from Southern Italy: The Salus in Apulia Study.

BACKGROUND: The assessment of oral health-related quality of life (OHRQoL) evaluated the impact of an individual's oral health on the patient's physical and psychosocial status. We evaluated the association between subjective OHRQoL, measured with the Oral Health Impact Profile-14 (OHIP-14) questionnaire, and unfavorable body mass index (BMI) (i.e., too high or too low) in a large population-based study on older adults from Southern Italy. Moreover, we assessed which of the seven OHIP-14 domains was the most strongly associated with an unfavorable BMI. METHODS: We used data on a subpopulation of the Salus in Apulia Study, including 216 older adults. BMI < 18.4 kg/m2 and >30 kg/m2 were classified as unfavorable, while values between 18.5 and 30 kg/m2 were classified as ideal. RESULTS: A higher OHIP-14 total score increased the risk of an unfavorable BMI (odds ratio (OR): 1.08, 95% confidence interval (CI): 1.01-1.15). In the model adjusted for age, sex, education, hypertension, carbohydrate consumption, and alcohol consumption, this finding was confirmed with a higher OHIP-14 total score increasing the risk of an unfavorable BMI (OR: 1.10, 95% CI: 1.01-1.22), and higher age linked to a decreased risk of an unfavorable BMI (OR: 0.89, 95% CI: 0.82-0.97). In a random forest regression model, the most important predictive domains/sub-scales of OHIP-14 in the mean decrease in the Gini coefficient for unfavorable BMI were, in order of decreasing importance, physical pain, functional limitation, psychological discomfort, physical disability, social disability, psychological disability, and handicap. CONCLUSIONS: In older age, negative OHRQoL, particularly linked to the physical pain domain, increased the risk of being underweight or overweight and obesity.

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.

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.

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.

Corrigendum: Associations between serum biomarkers and non-alcoholic liver disease: results of a clinical study of Mediterranean patients with obesity.

[This corrects the article DOI: 10.3389/fnut.2022.1002669.].

Prevalence of Sarcopenia in Liver Cirrhosis: A Systematic Review and Meta-Analysis.

INTRODUCTION: Chronic liver disease is often combined with a morbidity burden that strongly affects the functional domain. In liver cirrhosis (LC), qualitative and quantitative muscle wasting, known as sarcopenia, poses an added clinical burden, together with comorbidities and a poor quality of life. METHODS: We conducted a systematic review and meta-analysis of the prevalence of sarcopenia in LC. The literature was screened through 6 electronic databases from the study's inception to January 2023. No exclusion criteria were applied to language, operative tools for diagnosing sarcopenia, population age, general health status, country, and study setting (cohort or cross-sectional). Two independent researchers applied the inclusion criteria in parallel to evaluate the eligibility of the 44 retrieved articles; only 36 met the eligibility requirements. RESULTS: The total sample (N = 8,821) was slightly dominated by men (N = 4,941). The cross-sectional design predominated over the longitudinal, and the hospital setting was prevalent. The pooled prevalence of sarcopenia across the selected studies was 33% (95% confidence interval [CI] 0.32-0.34), with high heterogeneity ( I2 = 96%). A further meta-analysis using the Child-Pugh (CP) score to stage LC was conducted on 24 entries, and the results showed that for the LC populations classified with the CP-A, CP-B, and CP-C staging, respectively, the overall mean prevalence was 33% (95% CI 0.31-0.35), 36% (95% CI 0.34-0.39) and 46% (95% CI 0.43-0.50). The risk of bias was moderate. In LC, 1 in 3 patients suffers sarcopenia. DISCUSSION: Poor management of muscle mass loss plays a role in the prognosis of death and quality of life of patients with LC. Clinicians in the field are recommended, when screening for sarcopenia, to pay close attention by carefully assessing body composition as part of the monitoring scheme.

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.].

A Machine-Learning Approach to Target Clinical and Biological Features Associated with Sarcopenia: Findings from Northern and Southern Italian Aging Populations.

Epidemiological and public health resonance of sarcopenia in late life requires further research to identify better clinical markers useful for seeking proper care strategies in preventive medicine settings. Using a machine-learning approach, a search for clinical and fluid markers most associated with sarcopenia was carried out across older populations from northern and southern Italy. A dataset of adults >65 years of age (n = 1971) made up of clinical records and fluid markers from either a clinical-based subset from northern Italy (Pavia) and a population-based subset from southern Italy (Apulia) was employed (n = 1312 and n = 659, respectively). Body composition data obtained by dual-energy X-ray absorptiometry (DXA) were used for the diagnosis of sarcopenia, given by the presence of either low muscle mass (i.e., an SMI < 7.0 kg/m2 for males or <5.5 kg/m2 for females) and of low muscle strength (i.e., an HGS < 27 kg for males or <16 kg for females) or low physical performance (i.e., an SPPB ≤ 8), according to the EWGSOP2 panel guidelines. A machine-learning feature-selection approach, the random forest (RF), was used to identify the most predictive features of sarcopenia in the whole dataset, considering every possible interaction among variables and taking into account nonlinear relationships that classical models could not evaluate. Then, a logistic regression was performed for comparative purposes. Leading variables of association to sarcopenia overlapped in the two population subsets and included SMI, HGS, FFM of legs and arms, and sex. Using parametric and nonparametric whole-sample analysis to investigate the clinical variables and biological markers most associated with sarcopenia, we found that albumin, CRP, folate, and age ranked high according to RF selection, while sex, folate, and vitamin D were the most relevant according to logistics. Albumin, CRP, vitamin D, and serum folate should not be neglected in screening for sarcopenia in the aging population. Better preventive medicine settings in geriatrics are urgently needed to lessen the impact of sarcopenia on the general health, quality of life, and medical care delivery of the aging population.