A critical appraisal of blood-based biomarkers for Alzheimer's disease.

Biomarkers that predict the clinical onset of Alzheimer's disease (AD) enable the identification of individuals in the early, preclinical stages of the disease. Detecting AD at this point may allow for more effective therapeutic interventions and optimized enrollment for clinical trials of novel drugs. The current biological diagnosis of AD is based on the AT(N) classification system with the measurement of brain deposition of amyloid-ß (Aß) ("A"), tau pathology ("T"), and neurodegeneration ("N"). Diagnostic cut-offs for Aß1-42, the Aß1-42/Aß1-40 ratio, tau and hyperphosphorylated-tau concentrations in cerebrospinal fluid have been defined and may support AD clinical diagnosis. Blood-based biomarkers of the AT(N) categories have been described in the AD continuum. Cross-sectional and longitudinal studies have shown that the combination of blood biomarkers tracking neuroaxonal injury (neurofilament light chain) and neuroinflammatory pathways (glial fibrillary acidic protein) enhance sensitivity and specificity of AD clinical diagnosis and improve the prediction of AD onset. However, no international accepted cut-offs have been identified for these blood biomarkers. A kit for blood Aß1-42/Aß1-40 is commercially available in the U.S.; however, it does not provide a diagnosis, but simply estimates the risk of developing AD. Although blood-based AD biomarkers have a great potential in the diagnostic work-up of AD, they are not ready for the routine clinical use.

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.

Monitoring synaptic pathology in Alzheimer's disease through fluid and PET imaging biomarkers: a comprehensive review and future perspectives.

Alzheimer's disease (AD) is currently constrained by limited clinical treatment options. The initial pathophysiological event, which can be traced back to decades before the clinical symptoms become apparent, involves the excessive accumulation of amyloid-beta (Aß), a peptide comprised of 40-42 amino acids, in extraneuronal plaques within the brain. Biochemical and histological studies have shown that overaccumulation of Aß instigates an aberrant escalation in the phosphorylation and secretion of tau, a microtubule-binding axonal protein. The accumulation of hyperphosphorylated tau into intraneuronal neurofibrillary tangles is in turn correlated with microglial dysfunction and reactive astrocytosis, culminating in synaptic dysfunction and neurodegeneration. As neurodegeneration progresses, it gives rise to mild clinical symptoms of AD, which may eventually evolve into overt dementia. Synaptic loss in AD may develop even before tau alteration and in response to possible elevations in soluble oligomeric forms of Aß associated with early AD. These findings largely rely on post-mortem autopsy examinations, which typically involve a limited number of patients. Over the past decade, a range of fluid biomarkers such as neurogranin, α-synuclein, visinin-like protein 1 (VILIP-1), neuronal pentraxin 2, and ß-synuclein, along with positron emission tomography (PET) markers like synaptic vesicle glycoprotein 2A, have been developed. These advancements have facilitated the exploration of how synaptic markers in AD patients correlate with cognitive impairment. However, fluid biomarkers indicating synaptic loss have only been validated in cerebrospinal fluid (CSF), not in plasma, with the exception of VILIP-1. The most promising PET radiotracer, [11C]UCB-J, currently faces significant challenges hindering its widespread clinical use, primarily due to the necessity of a cyclotron. As such, additional research geared toward the exploration of synaptic pathology biomarkers is crucial. This will not only enable their extensive clinical application, but also refine the optimization process of AD pharmacological trials.

Winners do what they fear: exercise and peripheral arterial disease-an umbrella review.

AIMS: This systematic review aims to evaluate and summarize findings from published meta-analyses on the effects of regular exercise in patients with peripheral arterial disease (PAD). The review will assess the impact of exercise on functional parameters, health-related quality of life, haemodynamic parameters, physical activity levels, adverse events, and mortality. METHODS AND RESULTS: A systematic search was performed in PubMed, Web of Science, Scopus, and Cochrane Library databases (up to May 2023) to identify meta-analyses including randomized controlled trials that examined the effects of regular exercise in patients with PAD. Sixteen studies, with a total of 198 meta-analyses, were identified. Results revealed with strong evidence that patients with PAD who exercised improved functional and health-related quality of life parameters. Specifically, supervised aerobic exercise (i.e. walking to moderate-maximum claudication pain) improves maximum walking distance [mean difference (MD): 177.94 m, 95% confidence interval (CI) 142.29-213.60; P < 0.00001; I2: 65%], pain-free walking distance (fixed MD: 68.78 m, 95% CI 54.35-83.21; P < 0.00001; I2: 67%), self-reported walking ability [i.e. distance score (MD: 9.22 points, 95% CI 5.74-12.70; P < 0.00001; I2: 0%), speed score (MD: 8.71 points, 95% CI 5.64-11.77; P < 0.00001, I2: 0%), stair-climbing score (MD: 8.02 points, 95% CI 4.84-11.21; P < 0.00001, I2: 0%), and combined score (MD: 8.76 points, 95% CI 2.78-14.74; P < 0.0001, I2: 0%)], aerobic capacity (fixed MD: 0.62 mL/kg/min, 95% CI 0.47-0.77, P < 0.00001, I2: 64%), and pain score (MD: 7.65, 95% CI 3.15-12.15; P = 0.0009; I2: 0%), while resistance exercise improves lower limb strength (standardized mean difference: 0.71, 95% CI 0.29-1.13, P = 0.0009; I2: 0%]. Regarding other outcomes, such as haemodynamic parameters, no significant evidence was found, while physical activity levels, adverse events, and mortality require further investigation. CONCLUSION: Synthesis of the currently available meta-analyses suggests that regular exercise may be beneficial for a broad range of functional tasks improving health-related quality of life in patients with PAD. Supervised aerobic exercise is the best type of exercise to improve walking-related outcomes and pain, while resistance exercise is more effective to improve lower limb strength.

Regular exercise is beneficial for a wide range of functional capacity-related outcomes that seem to improve health-related quality of life in patients with peripheral arterial disease (PAD). Supervised aerobic exercise (i.e. walking to moderate­maximum claudication pain) is the best type of exercise to improve walking-related outcomes and pain. Resistance exercise improves lower limb strength.

Integrative metabolomics science in Alzheimer's disease: Relevance and future perspectives.

Alzheimer's disease (AD) is determined by various pathophysiological mechanisms starting 10-25 years before the onset of clinical symptoms. As multiple functionally interconnected molecular/cellular pathways appear disrupted in AD, the exploitation of high-throughput unbiased omics sciences is critical to elucidating the precise pathogenesis of AD. Among different omics, metabolomics is a fast-growing discipline allowing for the simultaneous detection and quantification of hundreds/thousands of perturbed metabolites in tissues or biofluids, reproducing the fluctuations of multiple networks affected by a disease. Here, we seek to critically depict the main metabolomics methodologies with the aim of identifying new potential AD biomarkers and further elucidating AD pathophysiological mechanisms. From a systems biology perspective, as metabolic alterations can occur before the development of clinical signs, metabolomics - coupled with existing accessible biomarkers used for AD screening and diagnosis - can support early disease diagnosis and help develop individualized treatment plans. Presently, the majority of metabolomic analyses emphasized that lipid metabolism is the most consistently altered pathway in AD pathogenesis. The possibility that metabolomics may reveal crucial steps in AD pathogenesis is undermined by the difficulty in discriminating between the causal or epiphenomenal or compensatory nature of metabolic findings.

Effects of physical exercise on physical function in older adults in residential care: a systematic review and network meta-analysis of randomised controlled trials.

BACKGROUND: Physical exercise is effective at attenuating ageing-related physical decline in general, but evidence of its benefits for older adults in residential care, who often have functional dependency, multimorbidity, and polypharmacy, is inconclusive. We aimed to establish the effects of exercise interventions on the physical function of this population. METHODS: For this systematic review and network meta-analysis, we searched PubMed, Web of Science, Cochrane Library, Rehabilitation & Sports Medicine Source, and SPORTDiscus to identify randomised controlled trials assessing the effects of exercise interventions (vs usual care) on physical function (ie, functional independence, physical performance, and other related measures, such as muscle strength, balance, or flexibility) in adults aged 60 years or older living in residential care. Relevant studies published in English or Spanish up to Jan 12, 2023, were included in the systematic review. The quality of studies was assessed using the Tool for the Assessment of Study Quality and Reporting in Exercise (TESTEX) score. A network meta-analysis was performed for physical function-related outcomes reported in at least ten studies, with subanalyses for specific intervention (ie, exercise type, training volume, and study duration) and participant (eg, having cognitive impairment or dementia, pre-frail or frail status, and being functionally dependent) characteristics. The study protocol was registered on PROSPERO (CRD42021247809). FINDINGS: 147 studies (11 609 participants, with mean ages ranging from 67 years [SD 9] to 92 years [2]) were included in the systematic review, and were rated as having overall good quality (median TESTEX score 9 [range 3-14]). In the meta-analysis (including 105 studies, n=7759 participants), exercise interventions were associated with significantly improved overall physical function, with a standardised mean difference [SMD] of 0·13 (95% credible interval [CrI] 0·04-0·21), which was confirmed in all analysed subpopulations. The strongest association was observed with 110-225 min per week of exercise, and the greatest improvements were observed with 170 min per week (SMD 0·36 [95% CrI 0·20-0·52]). No significant differences were found between exercise types. Subanalyses showed significant improvements for almost all analysed physical function-related outcomes (Barthel index, five-times sit-to-stand test, 30-s sit-to-stand test, knee extension, hand grip strength, bicep curl strength, Short Physical Performance Battery, 6-min walking test, walking speed, Berg balance scale, and sit-and-reach test). Large heterogeneity was found between and within studies in terms of population and intervention characteristics. INTERPRETATION: Exercise interventions are associated with improved physical function in older adults in residential care, and should, therefore, be routinely promoted in long-term care facilities. FUNDING: None. TRANSLATION: For the Spanish translation of the abstract see Supplementary Materials section.

Validation and Determination of Physical Activity Intensity GT3X+ Cut-Points in Children and Adolescents with Physical Disabilities: Preliminary Results in a Cerebral Palsy Population.

BACKGROUND: Children and adolescents with disabilities engage in low levels of moderate-to-vigorous intensity physical activity (MVPA), which may create the onset of a sedentary lifestyle. In light of this, MVPA levels must be quantified with a valid tool such as accelerometry. This study aimed to: (i) analyze the accuracy of Evenson cut-points by estimating MVPA and sedentary behavior (SB) in children and adolescents with disabilities; (ii) define new equations to estimate energy expenditure (EE) with the GT3X+ accelerometer in this population and particularly in those with cerebral palsy (CP); (iii) define specific GT3X+ cut-points to estimate MVPA in those with CP. METHODS: A total of 23 children and adolescents with disabilities (10 ± 3 years; 44%females) participated in the study. GT3X+-counts and oxygen uptake (VO2) were measured in four laboratory walking conditions. RESULTS: (i) Evenson cut-points were accurate; (ii) new equations were defined to effectively predict EE; (iii) specific GT3X+ cut-points (VM ≥ 702 counts·min-1; Y-Axis ≥ 360 counts·min-1) were defined for estimating MVPA levels in children and adolescents with CP. CONCLUSIONS: The use of specific cut-points for ActiGraph GT3X+ seems to be accurate to estimate MVPA levels in children and adolescents with disabilities and, particularly, in those with CP, at least in laboratory conditions.

Physical Exercise and the Hallmarks of Breast Cancer: A Narrative Review.

Growing evidence suggests that, among the different molecular/cellular pathophysiological mechanisms associated with cancer, there are 14 hallmarks that play a major role, including: (i) sustaining proliferative signaling, (ii) evading growth suppressors, (iii) activating invasion and metastasis, (iv) enabling replicative immortality, (v) inducing angiogenesis, (vi) resisting cell death, (vii) reprogramming energy metabolism, (viii) evading immune destruction, (ix) genome instability and mutations, (x) tumor-promoting inflammation, (xi) unlocking phenotypic plasticity, (xii) nonmutational epigenetic reprogramming, (xiii) polymorphic microbiomes, and (xiv) senescent cells. These hallmarks are also associated with the development of breast cancer, which represents the most prevalent tumor type in the world. The present narrative review aims to describe, for the first time, the effects of physical activity/exercise on these hallmarks. In summary, an active lifestyle, and particularly regular physical exercise, provides beneficial effects on all major hallmarks associated with breast cancer, and might therefore help to counteract the progression of the disease or its associated burden.

Acute effects of electrostimulation and blood flow restriction on muscle thickness and fatigue in the lower body.

Neuromuscular electrical stimulation (NMES) in combination with blood flow restriction (BFR) enhances muscle hypertrophy and force-generating capacity. The present study aimed to investigate the acute effects of BFR and NMES, both in isolation and in combination, on muscle thickness (MT) and fatigue in the lower body of 20 young healthy subjects. Different stimuli were applied for 25 min, defined by the combination of BFR with high- and low-frequency NMES, and also isolated BFR or NMES. Changes in MT were then evaluated by ultrasound of the rectus femoris (RF) and vastus lateralis (VL) muscles at the end of the session (POST) and 15 min later (POST 15'). Lower limb fatigue was evaluated indirectly by strength performance. Results showed that RF MT was higher under the combined protocol (BFR + NMES) or isolated BFR than under NMES - regardless of the frequency - both at POST (p ≤ 0.018) and POST 15' (p ≤ 0.016). No significant changes in MT were observed under isolated NMES or BFR at POST 15' when compared with basal values (p ≥ 0.067). No significant differences were observed for VL MT between conditions (p = 0.322) or for fatigue between conditions (p ≥ 0.258). Our results indicate that a combination of BFR and NMES acutely increases MT in sedentary subjects. Also, although not significantly, BFR conditions had a greater tendency to induce fatigue than isolated NMES.HighlightsThe combination of blood flow restriction (BFR) and neuromuscular electrical stimulation (NMES) produces higher acute cell swelling than the isolated application of either NMES or BFR.BFR in isolation appears to produce greater cell swelling than NMES, regardless of the frequency used.BFR conditions had a greater tendency to induce fatigue than isolated NMES.

Effects of physical activity and exercise interventions on Alzheimer's disease: an umbrella review of existing meta-analyses.

INTRODUCTION: During the last decade, physical activity (PA) (or "exercise") has been identified as one of the main modifiable factors that influence the development of Alzheimer's disease (AD) pathophysiology. We performed an umbrella review to summarize the evidence on the association between PA/exercise and the risk of developing AD risk, and the effect of exercise interventions on the progression of AD. METHODS: A systematic search was performed in PubMed, SportDiscus, Cochrane Library and Web of Science (March 2022) to identify meta-analyses assessing the association between PA and the incidence of AD, and assessing the effect of exercise interventions on patients with AD. RESULTS: Twenty-one studies were included. The results with strongest evidence revealed the positive effects of PA on AD risk. Specifically, meeting the WHO recommendations for PA was associated with a lower risk of AD. They also revealed positive effects of exercise on cognitive function, physical performance, and functional independence. CONCLUSIONS: There is strong evidence of a protective effect of regular PA against AD risk; however, the dose-response association remains unclear. Physical exercise seems to improve several dimensions in patients with AD, although research is warranted to elucidate the exercise characteristics that promote the greatest benefits.

Exercise and the hallmarks of peripheral arterial disease.

Peripheral arterial disease (PAD) is a prevalent cardiovascular disease. The main hallmarks of this condition are atherosclerosis and myopathy in the lower limbs, with progressive deterioration of the functional capacity and quality of life of affected individuals. There is evidence supporting physical exercise as an effective alternative for the treatment of PAD. In this context, unraveling the biological mechanisms by which exercise intervention might improve the clinical manifestation of PAD can help gain insight into the pathophysiology of this condition, as well as explore new treatment and preventive approaches. In this review, we thus describe the different mechanisms by which exercise could impact the different hallmarks of PAD. Physical exercise positively modulates pathways related to inflammation and the atherosclerotic process and can attenuate the progression of lower-limb myopathy, with subsequent improvements in patients' functional capacity and health-related quality of life. At the whole-body level, these improvements translate into a better functional status and wellbeing.

Defining and assessing intrinsic capacity in older people: A systematic review and a proposed scoring system.

INTRODUCTION: The World Health Organization has introduced the term 'intrinsic capacity' (IC) as a marker of healthy ageing. However, controversy exists on the definition and assessment of IC. We aimed to review the definitions and methods used for the assessment of IC in older adults. In addition, we proposed a new IC scoring method. METHODS: A systematic search was performed in PubMed, Web of Science, Cochrane Library, Scopus and SPORTDiscus (up to February 10th, 2022) for studies assesing IC in older adults (>60 years). RESULTS: Thirty-three studies were included. There is overall consensus on the definition of IC as well as on its different dimensions, that is: locomotion, vitality, sensory, cognition and psychological. However, the methods for assessing each of these five dimensions differ substantially across studies and there is no consensus on the best method to compute an eventual global compound score to evaluate IC taking into account all its different dimensions. CONCLUSIONS: The IC represents a highly relevant clinical concept that has been unfortunately underutilized. We propose a standardization for the assessment of each dimension of IC, with a global 0 (worst) to 10 (highest) score.

Exercise interventions in Alzheimer's disease: A systematic review and meta-analysis of randomized controlled trials.

AIMS: To assess the potential multi-domain benefits of exercise interventions on patients with Alzheimer's disease (AD), as well as to determine the specific effects of different exercise modalities (aerobic, strength, or combined training). METHODS: A systematic search was conducted in PubMed and Web of Science until March 2021 for randomized controlled trials assessing the effect of exercise interventions (compared with no exercise) on patients with AD. Outcomes included cognitive function (mini-mental state examination [MMSE] test), physical function (e.g., 6-minute walking test [6MWT]), functional independence (Barthel index), and neuropsychiatric symptoms (Neuropsychiatric Inventory [NPI]). A random-effects meta-analysis was conducted. RESULTS: 28 studies (total n = 1337 participants, average age 79-90 years) were included in the systematic review, of which 21 could be meta-analyzed. Although considerable heterogeneity was found, exercise interventions induced several significant benefits, including in Barthel index (n = 147 patients, mean difference [MD]=8.36 points, 95% confidence interval [CI]=0.63-16.09), 6MWT (n = 369, MD=84 m, 95% CI=44-133)), and NPI (n = 263, MD=-4.4 points, 95% CI=-8.42 to -0.38). Benefits were also found in the MMSE test, albeit significance was only reached for aerobic exercise (n = 187, MD=2.31 points, 95% CI 0.45-4.27). CONCLUSIONS: Exercise interventions appear to exert multi-domain benefits in patients with AD.

Physical Exercise and Alzheimer's Disease: Effects on Pathophysiological Molecular Pathways of the Disease.

Alzheimer's disease (AD), the most common form of neurodegenerative dementia in adults worldwide, is a multifactorial and heterogeneous disorder characterized by the interaction of genetic and epigenetic factors and the dysregulation of numerous intracellular signaling and cellular/molecular pathways. The introduction of the systems biology framework is revolutionizing the study of complex diseases by allowing the identification and integration of cellular/molecular pathways and networks of interaction. Here, we reviewed the relationship between physical activity and the next pathophysiological processes involved in the risk of developing AD, based on some crucial molecular pathways and biological process dysregulated in AD: (1) Immune system and inflammation; (2) Endothelial function and cerebrovascular insufficiency; (3) Apoptosis and cell death; (4) Intercellular communication; (5) Metabolism, oxidative stress and neurotoxicity; (6) DNA damage and repair; (7) Cytoskeleton and membrane proteins; (8) Synaptic plasticity. Moreover, we highlighted the increasingly relevant role played by advanced neuroimaging technologies, including structural/functional magnetic resonance imaging, diffusion tensor imaging, and arterial spin labelling, in exploring the link between AD and physical exercise. Regular physical exercise seems to have a protective effect against AD by inhibiting different pathophysiological molecular pathways implicated in AD.

Incidence of Atrial Fibrillation in Elite Athletes.

Importance: Vigorous exercise (particularly endurance sports) might increase the risk of atrial fibrillation (AF), but there is variability in the reported frequency of this condition among elite athletes. The underlying pathophysiologic source remains unclear. Objective: To determine AF incidence in a large cohort of elite athletes and its association with potential risk factors. Design, Setting, and Participants: Retrospective observational cohort of all Spanish athletes (N = 6813) referred to a single center was used to determine AF incidence from January 1, 1997, to December 31, 2017, and cross-sectional analysis was conducted to compare athletes with and without reported AF. The cohort covered most sports disciplines, and the studied athletes were on national teams and competed in major international events. Cardiologists responsible for echocardiographic assessment were not blinded to the condition (AF or no AF) of the athletes. Exposures: All participants underwent at least 1 cardiologic evaluation, including assessment at time of AF diagnosis in those with this condition. Main Outcomes and Measures: Diagnosis of AF based on resting and/or exercise electrocardiogram, and/or 24-hour Holter monitoring and echocardiography-assessed atrial dimensions. Results: A total of 6813 Spanish elite athletes (2385 [35.0%] women) were referred for cardiac evaluation during the study period. Mean (SD) age was 22 (7) years, and mean (SD) time of competition was 8 (5) years. Only 21 athletes (1 woman), participating in different types of sports, had AF (ie, paroxysmal [n = 18], persistent [n = 1], or long-standing persistent [n = 2]) during the 20-year study. In multivariate analysis, increasing values of age (odds ratio [OR], 1.07; 95% CI, 1.00-1.14), years of competition (OR, 1.14; 95% CI, 1.07-1.22), and left atrial anteroposterior diameter (OR, 1.21; 95% CI, 1.10-1.32) were associated with higher AF risk. Conclusions and Relevance: The incidence of AF is low among young Spanish elite athletes, even when considering only endurance athletes. Yet, potential contributors (particularly atrial remodeling) need to be monitored.