Digging into the intrinsic capacity concept: Can it be applied to Alzheimer's disease?

Historically, aging research has largely centered on disease pathology rather than promoting healthy aging. The World Health Organization's (WHO) policy framework (2015-2030) underscores the significance of fostering the contributions of older individuals to their families, communities, and economies. The WHO has introduced the concept of intrinsic capacity (IC) as a key metric for healthy aging, encompassing five primary domains: locomotion, vitality, sensory, cognitive, and psychological. Past AD research, constrained by methodological limitations, has focused on single outcome measures, sidelining the complexity of the disease. Our current scientific milieu, however, is primed to adopt the IC concept. This is due to three critical considerations: (I) the decline in IC is linked to neurocognitive disorders, including AD, (II) cognition, a key component of IC, is deeply affected in AD, and (III) the cognitive decline associated with AD involves multiple factors and pathophysiological pathways. Our study explores the application of the IC concept to AD patients, offering a comprehensive model that could revolutionize the disease's diagnosis and prognosis. There is a dearth of information on the biological characteristics of IC, which are a result of complex interactions within biological systems. Employing a systems biology approach, integrating omics technologies, could aid in unraveling these interactions and understanding IC from a holistic viewpoint. This comprehensive analysis of IC could be leveraged in clinical settings, equipping healthcare providers to assess AD patients' health status more effectively and devise personalized therapeutic interventions in accordance with the precision medicine paradigm. We aimed to determine whether the IC concept could be extended from older individuals to patients with AD, thereby presenting a model that could significantly enhance the diagnosis and prognosis of this disease.

Omics sciences for systems biology in Alzheimer's disease: State-of-the-art of the evidence.

Alzheimer's disease (AD) is characterized by non-linear, genetic-driven pathophysiological dynamics with high heterogeneity in biological alterations and disease spatial-temporal progression. Human in-vivo and post-mortem studies point out a failure of multi-level biological networks underlying AD pathophysiology, including proteostasis (amyloid-ß and tau), synaptic homeostasis, inflammatory and immune responses, lipid and energy metabolism, oxidative stress. Therefore, a holistic, systems-level approach is needed to fully capture AD multi-faceted pathophysiology. Omics sciences - genomics, epigenomics, transcriptomics, proteomics, metabolomics, lipidomics - embedded in the systems biology (SB) theoretical and computational framework can generate explainable readouts describing the entire biological continuum of a disease. Such path in Neurology is encouraged by the promising results of omics sciences and SB approaches in Oncology, where stage-driven pathway-based therapies have been developed in line with the precision medicine paradigm. Multi-omics data integrated in SB network approaches will help detect and chart AD upstream pathomechanistic alterations and downstream molecular effects occurring in preclinical stages. Finally, integrating omics and neuroimaging data - i.e., neuroimaging-omics - will identify multi-dimensional biological signatures essential to track the clinical-biological trajectories, at the subpopulation or even individual level.

Comparative efficacy and safety of Verbascox® - a proprietary herbal extract capable of inhibiting human cyclooxygenase-2 - and celecoxib for knee osteoarthritis.

The aim of this randomized, single-blind, active-controlled pilot study was to investigate the clinical efficacy of oral supplementation with Verbascox®, a proprietary herbal extract capable of inhibiting human cyclooxygenase-2 (COX-2), in patients with mild-to-moderate osteoarthritis (OA) of the knee. Patients in the control group (n = 50) did not undergo any treatment (watchful waiting). Patients in the Verbascox® group (n = 50) received oral supplementation (800 mg/day) with the herbal extract for 2 weeks. The final study group consisted of patients (n = 50) who received celecoxib, a known pharmacological inhibitor of COX-2, 200 mg/day for 2 weeks. Examining physicians and laboratory personnel were blinded to group assignment, whereas patients were unblinded. All participants were evaluated using standard measures of pain relief and improvement in functional capacity at baseline, after 1 week, and at the end of the 2-week treatment course. Moreover, serum levels of substance P (SP), a member of the tachykinin family of neuropeptides involved in pain perception, were measured at the three time points. Both Verbascox® and celecoxib reduced pain, improved functional capacity, and lowered serum SP levels at 2 weeks compared with baseline, without significant inter-arm differences. Both Verbascox® and celecoxib showed a limited number of treatment-emergent adverse events. In summary, oral supplementation with Verbascox® (800 mg/day) in patients with mild-to-moderate OA of the knee is as effective and safe as a standard therapeutic dose of celecoxib in terms of pain relief and improvement in functional capacity after a 2-week treatment course.

A proprietary herbal extract titred in verbascoside and aucubin suppresses lipopolysaccharide-stimulated expressions of cyclooxygenase-2 in human neutrophils.

INTRODUCTION: Bacterial lipopolysaccharide (LPS) initiates several major cellular responses that play a crucial role in the pathogenesis of inflammation, including activation of neutrophils and production of prostaglandin E2 (PGE2) by cyclooxygenase-2 (COX-2). MATERIAL AND METHODS: Recent years have witnessed a growing interest in natural compounds as promising alternatives to synthetic COX-2 inhibitors. In this study, we sought to investigate the effect of a proprietary herbal extract from Lippia citriodora and Plantago lanceolata, titred in verbascoside (≥ 5%) and aucubin (≥ 2%), against LPS-stimulated expressions of COX-2 in human neutrophils using both reverse transcription-polymerase chain reaction (RT-PCR) and a PGE2 immunoassay. RESULTS: Our main results indicated that: 1. The proprietary herbal extract titred in verbascoside and aucubin is not significantly cytotoxic as shown by the MTT assay; 2. The extract does not significantly inhibit COX-1, whereas it is able to suppress LPS-elicited COX-2 hyperexpression at the mRNA level in human neutrophils; and 3. The effect of the extract at 5% concentration was comparable to that elicited celecoxib 1%, although, in terms of absolute and relative reduction of COX-2 mRNA expression and production of PGE2 in human neutrophils, the drug significantly outperformed the extract. CONCLUSIONS: In general, these results suggest that the proprietary herbal extract titred in verbascoside and aucubin is safe and may possess significant anti-inflammatory and analgesic effects by acting as a specific COX-2 inhibitor. Further studies are required to confirm the clinical efficacy of the extract.

Supplements with purported effects on muscle mass and strength.

PURPOSE: Several supplements are purported to promote muscle hypertrophy and strength gains in healthy subjects, or to prevent muscle wasting in atrophying situations (e.g., ageing or disuse periods). However, their effectiveness remains unclear. METHODS: This review summarizes the available evidence on the beneficial impacts of several popular supplements on muscle mass or strength. RESULTS: Among the supplements tested, nitrate and caffeine returned sufficient evidence supporting their acute beneficial effects on muscle strength, whereas the long-term consumption of creatine, protein and polyunsaturated fatty acids seems to consistently increase or preserve muscle mass and strength (evidence level A). On the other hand, mixed or unclear evidence was found for several popular supplements including branched-chain amino acids, adenosine triphosphate, citrulline, ß-Hydroxy-ß-methylbutyrate, minerals, most vitamins, phosphatidic acid or arginine (evidence level B), weak or scarce evidence was found for conjugated linoleic acid, glutamine, resveratrol, tribulus terrestris or ursolic acid (evidence level C), and no evidence was found for other supplements such as ornithine or α-ketoglutarate (evidence D). Of note, although most supplements appear to be safe when consumed at typical doses, some adverse events have been reported for some of them (e.g., caffeine, vitamins, α-ketoglutarate, tribulus terrestris, arginine) after large intakes, and there is insufficient evidence to determine the safety of many frequently used supplements (e.g., ornithine, conjugated linoleic acid, ursolic acid). CONCLUSION:  In summary, despite their popularity, there is little evidence supporting the use of most supplements, and some of them have been even proven ineffective or potentially associated with adverse effects.

Comparative effects of a fixed Polypodium leucotomos/Pomegranate combination versus Polypodium leucotomos alone on skin biophysical parameters.

OBJECTIVES: Polypodium leucotomos extract is a commonly used systemic photoprotective agent. In an exploratory fashion, the current study aimed to compare the effects of oral supplementation with a fixed Polypodium leucotomos/pomegranate combination (PPmix®) versus Polypodium leucotomos alone (Fernblock®) on skin biophysical parameters of Caucasian adults. METHODS: Forty healthy adult volunteers (20 males and 20 females; mean age: 37.2±5.5 years) were randomized in a 1:1 fashion to a fixed Polypodium leucotomos/pomegranate combination (480 mg/day; n=20) or Polypodium leucotomos alone (480 mg/day; n=20) for 3 months. Six skin biophysical parameters (skin sebum content, hydration, transepidermal water loss [TEWL], erythema index, melanin index, and elasticity) were measured at baseline and after 3 months by personnel blinded to participant allocation. RESULTS: At the end of the study, hydration and elasticity were significantly improved and TEWL was reduced in both groups, without significant intergroup differences. The erythema index was decreased by both treatments, although the fixed Polypodium leucotomos/pomegranate combination was significantly more effective. Finally, melanin index and skin sebum content were reduced by the fixed Polypodium leucotomos/pomegranate combination, whereas Polypodium leucotomos alone did not affect them. CONCLUSIONS: Our results suggest that a fixed Polypodium leucotomos/pomegranate combination provides a greater improvement of skin biophysical parameters compared to Polypodium leucotomos alone in adult Caucasians. Our findings may have implications for optimizing systemic skin photoprotection and beautification strategies.

Upper versus lower limb exercise training in patients with intermittent claudication: a systematic review.

Lower extremity (LE) exercise training has been shown to contribute to improvements in Maximum Walking Distance (MWD), Claudication Distance (CD), peak oxygen uptake (VO2peak) and Quality of Life (QoL) in patients with intermittent claudication (IC). However, little is known regarding the efficacy of upper extremity (UE) exercise training in comparison to the widely used LE training. The objective of this systematic literature review is to identify and synthesize the available literature on the effects of UE versus LE exercises using the International Classification of Functioning (ICF) conceptual framework. A total of 6 randomized controlled trials comparing UE to LE exercises were included in this study. Two of the articles were considered to be of high quality using the PEDro grading list. Both UE and LE training groups demonstrated significant improvements in MWD, CD, VO2peak and QoL in comparison to the control group but LE was not better than UE training. This supports the use of UE training as an alternative to LE, which could provide symptomatic relief to patients with IC without the discomfort caused during the LE training.

A Systematic Review and Meta-Analysis of Ginkgo biloba in Neuropsychiatric Disorders: From Ancient Tradition to Modern-Day Medicine.

Ginkgo biloba (Gb) has demonstrated antioxidant and vasoactive properties as well as clinical benefits in several conditions such as ischemia, epilepsy, and peripheral nerve damage. Additionally, Gb is supposed to act as potential cognitive enhancer in dementia. So far, several trials have been conducted to investigate the potential effectiveness of Gb in neuropsychiatric conditions. However, the results of these studies remain controversial. We conducted a systematic review and a meta-analysis of three randomised controlled trials in patients with schizophrenia and eight randomised controlled trials in patients with dementia. Gb treatment reduced positive symptoms in patients with schizophrenia and improved cognitive function and activities of daily living in patients with dementia. No effect of Gb on negative symptoms in schizophrenic patients was found. The general lack of evidence prevents drawing conclusions regarding Gb effectiveness in other neuropsychiatric conditions (i.e., autism, depression, anxiety, attention-deficit hyperactivity disorder, and addiction). Our data support the use of Gb in patients with dementia and as an adjunctive therapy in schizophrenic patients.

Soluble RAGE-modulating drugs: state-of-the-art and future perspectives for targeting vascular inflammation.

The expression of the Receptor for Advanced Glycation Endproducts (RAGE) is upregulated at sites of vascular inflammation and plays a crucial role in vessel homeostasis. Soluble RAGE (sRAGE), a truncated soluble form of the receptor, acts as a decoy and prevents the inflammatory response mediated by RAGE activation. sRAGE has recently emerged as a biomarker in several RAGE-mediated vascular disorders, including coronary artery disease, hypertension, diabetic vasculopathy and Kawasaki disease. Given the pivotal role played by RAGE and sRAGE in numerous vascular disorders, there is a growing need to understand how drugs can modulate the RAGE axis in different disease conditions. In this regard, there is evidence to suggest that traditional cardiovascular drugs (statins, thiazolidinediones, ACE-inhibitors, AT-1 receptor antagonists) as well as nutraceuticals (grape seed proanthocyanidin extract) could modulate RAGE expression and circulating sRAGE levels in cardiovascular disease states characterized by enhanced RAGE activation. Additionally, the production of genetically engineered sRAGE may hold promise for targeting the activation of RAGE by proinflammatory ligands in the setting of vascular inflammation. The present review considers current vascular drugs as modulators of the RAGE axis, and highlights future directions in the context of RAGE-directed therapy in cardiovascular disease.

Behavioral effects of omega-3 fatty acid supplementation in young adults with severe autism: an open label study.

BACKGROUND: Pilot findings seem to suggest a potential beneficial effect of omega-3 fatty acid (FA) supplementation on behavioral alterations in children with autism. However, data on the potential benefits of omega-3 supplements in young adults with severe autism are lacking. In the present study, we sought to explore this issue in an open label study. METHODS: Nineteen young adults with severe autism (CARS >40), aged 18-40 years, received two fish oil capsules per day [0.93 g of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) plus 5 mg of vitamin E to avoid lipid peroxidation] for 6 weeks. Subjects were assessed with an ad hoc caregiver questionnaire, the Rossago Behavioral Checklist, for the assessment of behavioral anomalies. RESULTS: No significant improvements were observed with regard to the severity and frequency of problematic behaviors either during the active treatment period or during the post-treatment 6-week observation period. Moreover, no effect on the number of episodes and severity of behavior aberrations was observed. CONCLUSIONS: Our negative findings do not point toward a major effect of omega-3 FA supplementation on behavioral abnormalities in adults with severe autism. Further studies on larger sample sizes are warranted to shed more light on this important issue.

Aggressive dogs are characterized by low omega-3 polyunsaturated fatty acid status.

Canine aggressive behaviour is one of the most common problems being reported by dog owners. However, the biochemical basis of this phenomenon remains unclear. In humans, alterations in omega-3 plasma polyunsatured fatty acids and elevated omega6/omega-3 ratio have been linked to behavioural alterations, including aggression. Thus far, however, the relationship between plasma polyunsatured fatty acid status and aggression has not been investigated in the dog. In the present study we sought to investigate whether polyunsatured fatty acid status could be altered in plasma of pathologically aggressive Canis familiaris. Eighteen adult male German Shepherd dogs, aged 4.9 +/- 0.9 years, showing no clinical signs but aggression, were investigated. Eighteen healthy male dogs, aged 4.8 +/- 0.7 years, with a negative history of behavioural and neurological disorders served as controls. Baseline fasting plasma polyunsatured fatty acid composition was determined by gas chromatography. Compared to normal dogs, aggressive dogs showed lower docosahexaenoic acid (22:6 n-3) concentrations and a higher omega6/omega-3 ratio. In addition, they showed reduced cholesterol and bilirubin concentrations compared to their normally behaving counterparts. Altogether, our results suggest that low omega-3 fatty acids may adversely impact behaviour in dogs, resulting in greater propensity to aggression. However, given the cross-sectional design of our study, we cannot claim any causal relationship between the presence of alterations in fatty acid status and canine aggressiveness. Whether omega-3 fatty acids supplementation may be useful to reduce aggressive behaviour in the dog deserves further investigation.

Effect of long-term interactive music therapy on behavior profile and musical skills in young adults with severe autism.

BACKGROUND: Data on the potential behavioral effects of music therapy in autism are scarce. OBJECTIVE: The aim of this study was to investigate whether a musical training program based on interactive music therapy sessions could enhance the behavioral profile and the musical skills of young adults affected by severe autism. METHODOLOGY: Young adults (N = 8) with severe (Childhood Autism Rating Scale >30) autism took part in a total of 52 weekly active music therapy sessions lasting 60 minutes. Each session consisted of a wide range of different musical activities including singing, piano playing, and drumming. Clinical rating scales included the Clinical Global Impression (CGI) scale and the Brief Psychiatric Rating Scale (BPRS). Musical skills-including singing a short or long melody, playing the C scale on a keyboard, music absorption, rhythm reproduction, and execution of complex rhythmic patterns-were rated on a 5-point Likert-type scale ranging from "completely/entirely absent" to "completely/entirely present." RESULTS: At the end of the 52-week training period, significant improvements were found on both the CGI and BPRS scales. Similarly, the patients' musical skills significantly ameliorated as compared to baseline ratings. CONCLUSIONS: Our pilot data seem to suggest that active music therapy sessions could be of aid in improving autistic symptoms, as well as personal musical skills in young adults with severe autism.