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.

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.

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.

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.

Moderate Intensity Functional Training as Adjuvant Treatment in Patients With Peripheral Arterial Disease: A Case Report.

BACKGROUND: Traditional aerobic training and muscle resistance ("strength") training have been shown to be effective for improving functional and health-related quality of life (HRQoL) outcomes in peripheral arterial disease (PAD). However, the transfer of the current resistance exercise modes proposed to other activities of daily living (ADLs) is questionable. Moderate intensity functional training (MIFT) has emerged with the aim of achieving cardiovascular and neuromuscular adaptations simultaneously with functional exercises typical of ADLs. The effect of MIFT in patients with PAD is not yet known. Our purpose is to verify the influence of the combination of intermittent treadmill walking exercise with MIFT on functional capacity and HRQoL in patients with PAD. METHODS: Three patients with PAD participated in a novel supervised exercise therapy program of 6 weeks duration based on intermittent treadmill walking exercise and MIFT. RESULTS: After the training period, the 3 patients showed high adherence to the program (95%) and they improved total distance (TD) (25%, 9%, and 21%), claudication onset distance (COD) (56%, 19%, and 151%), total number of repetitions (33%, 24%, and 33%) and total work capacity (80%, 79%, and 72%). Also, physical component in Short Form-36 Health Survey (SF-36) and Vascular Quality of Life Questionnaire-6 (VascuQol-6) showed increases in the patients. CONCLUSIONS: The 6-week intervention in patients with PAD, based on intermittent treadmill walking exercise and MIFT, seems to improve their functional status and total work capacity in functional exercises as well as their HRQoL.

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.

Corrigendum: Blood Flow Restriction Exercise: Considerations of Methodology, Application, and Safety.

[This corrects the article DOI: 10.3389/fphys.2019.00533.].

Blood Flow Restriction Exercise: Considerations of Methodology, Application, and Safety.

The current manuscript sets out a position stand for blood flow restriction (BFR) exercise, focusing on the methodology, application and safety of this mode of training. With the emergence of this technique and the wide variety of applications within the literature, the aim of this position stand is to set out a current research informed guide to BFR training to practitioners. This covers the use of BFR to enhance muscular strength and hypertrophy via training with resistance and aerobic exercise and preventing muscle atrophy using the technique passively. The authorship team for this article was selected from the researchers focused in BFR training research with expertise in exercise science, strength and conditioning and sports medicine.

El papel del ejercicio aeróbico en la prevención y manejo de la fibrilación auricular. ¿Amigo o enemigo? / The role of aerobic exercise in the prevention and management of auricular fibrillation. Friend or foe?

La fibrilación auricular es la arritmia que presenta mayor prevalencia en la población a nivel mundial. De hecho, la bibliografía científica existente parece mostrar también una elevada prevalencia en deportistas de resistencia. Sin embargo, actualmente la relación entre la fibrilación auricular y el ejercicio aeróbico resulta controvertida. Por un lado, el ejercicio aeróbico puede considerarse una herramienta de prevención primaria para el desarrollo de enfermedades cardiovasculares, incluidas las arritmias. Por otro, realizar actividades de alta intensidad de manera regular con grandes volúmenes, ha sido identificada por algunos autores como un factor de riesgo. Actualmente, se desconoce el mecanismo exacto por el cual el ejercicio aérobico podría incrementar el riesgo de fibrilación auricular, pero podría estar relacionado con cambios anatómicos y funcionales a nivel cardíaco. Esta revisión pretende realizar una actualización del efecto que presenta el ejercicio aérobico sobre la fibrilación auricular para establecer una pauta de prescripción. Los resultados del presente trabajo, según la evidencia actual, parecen mostrar al ejercicio aérobico como una estrategia no farmacológica útil tanto para la prevención, como para el tratamiento de la fibrilación auricular. El efecto preventivo del ejercicio aeróbico en la fibrilación auricular parece estar relacionado con la disminución de factores de riesgo asociados. Aunque no existe consenso sobre la carga de ejercicio, se considera que el ejer-cicio aeróbico debería practicarse regularmente y a una intensidad moderada-vigorosa para alcanzar los mayores beneficios. Se requieren más investigaciones para determinar los mejores parámetros de ejercicio aeróbico en la fibrilación auricular

Atrial fibrillation is the arrhythmia with the highest prevalence world-wide. In fact, scientific literature seems to show a high prevalence of atrial fibrillation in endurance athletes too. However, currently the relationship between atrial fibrillation and aerobic exercise is controversial. On the one hand, aerobic exercise could be defined as a useful tool to be used as primary prevention strategy for the development of cardiovascular diseases, including arrhythmias. On the other hand, some authors identify it as a risk factor, specifically if it is performed at high intensity with large regular volumes. But the exact mechanism by which aerobic exercise might increase the risk of atrial fibrillation is unknown, although it could be related to anatomical and functional changes at the cardiac level. This review aims to update the knowledge about the effect of aerobic exercise on atrial fibrillation to establish a prescription pattern. The results of the present work, according to the current evidence, show the aerobic exercise as a non-pharmacological strategy, both for the primary and secondary prevention of atrial fibri-llation. The preventive effect of aerobic exercise on atrial fibrillation seems to be related to the reduction of associated risks. Although there is no consensus on the exercise load, it is considered that aerobic exercise should be practiced often and at a moderate-vigorous intensity to get the greatest benefits. More research is required to determine the best parameters of aerobic exercise in atrial fibrillation

Tool for filtering PubMed search results by sample size.

Objective: The most used search engine for scientific literature, PubMed, provides tools to filter results by several fields. When searching for reports on clinical trials, sample size can be among the most important factors to consider. However, PubMed does not currently provide any means of filtering search results by sample size. Such a filtering tool would be useful in a variety of situations, including meta-analyses or state-of-the-art analyses to support experimental therapies. In this work, a tool was developed to filter articles identified by PubMed based on their reported sample sizes. Materials and Methods: A search engine was designed to send queries to PubMed, retrieve results, and compute estimates of reported sample sizes using a combination of syntactical and machine learning methods. The sample size search tool is publicly available for download at http://ihealth.uemc.es. Its accuracy was assessed against a manually annotated database of 750 random clinical trials returned by PubMed. Results: Validation tests show that the sample size search tool is able to accurately (1) estimate sample size for 70% of abstracts and (2) classify 85% of abstracts into sample size quartiles. Conclusions: The proposed tool was validated as useful for advanced PubMed searches of clinical trials when the user is interested in identifying trials of a given sample size.

Syncope Episodes and Blood Flow Restriction Training.

The combination of low-load resistance training [or more recently, neuromuscular electrical stimulation (NMES)] with a moderate local blood flow restriction (BFR) is becoming a widespread training and rehabilitation method. Scientific data indicate the overall safety of BFR, at least in healthy young people. However, it has been associated with side effects, usually minor, and further research is warranted regarding the safety and efficacy of this technique, especially in clinical populations. We found 3 syncope/presyncopal episodes among 21 healthy people (9 men), all occurring in men and during familiarization sessions (in which BFR was applied alone) but not thereafter (BFR sessions combined with NMES): 1 subject experienced a brief syncope and 2 other subjects exhibited presyncopal symptoms (sweating, lightheadedness, and pallor). Our cases are evidence that cardiovascular complications may emerge during BFR. Caution is thus needed in the application of BFR, and gentle familiarization with this training modality is also recommended.

Adaptation of Perceptual Responses to Low-Load Blood Flow Restriction Training.

Martín-Hernández, J, Ruiz-Aguado, J, Herrero, AJ, Loenneke, JP, Aagaard, P, Cristi-Montero, C, Menéndez, H, and Marín, PJ. Adaptation of perceptual responses to low-load blood flow restriction training. J Strength Cond Res 31(3): 765-772, 2017-The purpose of this study was to determine the adaptive response of ratings of perceived exertion (RPE) and pain over 6 consecutive training sessions. Thirty subjects were assigned to either a blood flow restriction training (BFRT) group or a high-intensity resistance training (HIT) group. Blood flow-restricted training group performed 4 sets (30 + 15 + 15 + 15, respectively) of unilateral leg extension at an intensity of 20% one repetition maximum (1RM) while a restrictive cuff was applied to the most proximal part of the leg. The HIT group performed 3 sets of 8 repetitions with 85% 1RM. Ratings of perceived exertion and pain were assessed immediately after each exercise set along the 6 training sessions and were then averaged to obtain the overall RPE and pain per session. Statistical analyses showed significant main effects for group (p ≤ 0.05) and time (p < 0.001). Ratings of perceived exertion values dropped from session 1 to session 6 in both BFRT (8.12 ± 1.3 to 5.7 ± 1.1, p < 0.001) and HIT (8.5 ± 1.2 to 6.40 ± 1.2, p < 0.001). Similar results were observed regarding pain ratings (BFRT: 8.12 ± 1.3 to 5.90 ± 1.55, p < 0.001; HIT: 6.22 ± 1.7 to 5.14 ± 1.42, p < 0.01). Our results indicate that RPE was higher after HIT, whereas differences did not reach significance regarding pain. These perceptual responses were attenuated over time, and the time course of this adaptive response was similar between BFRT and HIT. In summary, BFRT induces a marked perceptual response to training, comparable with that observed with HIT. However, this response becomes attenuated with continuous practice, leading to moderate values of RPE and pain. Perceptual responses may not limit the application of BFRT to highly motivated individuals.

Cerebral versus Ocular Visual Impairment: The Impact on Developmental Neuroplasticity.

Cortical/cerebral visual impairment (CVI) is clinically defined as significant visual dysfunction caused by injury to visual pathways and structures occurring during early perinatal development. Depending on the location and extent of damage, children with CVI often present with a myriad of visual deficits including decreased visual acuity and impaired visual field function. Most striking, however, are impairments in visual processing and attention which have a significant impact on learning, development, and independence. Within the educational arena, current evidence suggests that strategies designed for individuals with ocular visual impairment are not effective in the case of CVI. We propose that this variance may be related to differences in compensatory neuroplasticity related to the type of visual impairment, as well as underlying alterations in brain structural connectivity. We discuss the etiology and nature of visual impairments related to CVI, and how advanced neuroimaging techniques (i.e., diffusion-based imaging) may help uncover differences between ocular and cerebral causes of visual dysfunction. Revealing these differences may help in developing future strategies for the education and rehabilitation of individuals living with visual impairment.

Influence of isolated or simultaneous application of electromyostimulation and vibration on leg blood flow.

PURPOSE: The aim of this study was to analyze the acute effects of isolated or simultaneously applied whole-body vibration (WBV) and electromyostimulation (ES) on the popliteal arterial blood velocity and skin temperature (ST) of the calf. METHODS: Thirteen healthy males were assessed in five different sessions. After a familiarization session, four interventions were applied in random order; WBV, ES, simultaneous WBV and ES (WBV+ES), and 30 s of WBV followed by 30 s of ES (WBV30/ES30). Each intervention consisted of 10 sets × 1 min ON + 1 min OFF. The subject was standing on the vibration platform (squat position, 30° knee flexion, 26 Hz, 5 mm peak-to-peak), and ES was applied on the gastrocnemius of both the legs (8 Hz, 400 µs). RESULTS: The WBV+ES intervention was the only one that maintained the mean blood velocity (MBV) elevated above baseline during the 10 sets, from set-1 (134.6 % p < 0.01) to set-10 (112.6 % p < 0.05). The combined interventions were the only ones that maintained the peak blood velocity (PBV) elevated above baseline during all the sets, from set-1 (113.5 % p < 0.001) to set-10 (88.8 % p < 0.01) and from set-1 (58.4 % p < 0.01) to set-10 (49.1 % p < 0.05) for WBV+ES and WBV30/ES30, respectively. CONCLUSION: The simultaneous application of WBV and ES produced a general greater increase in MBV and PBV than the application of each method alone or consecutive. This novel methodological proposal could be interesting in different fields such as sports or the rehabilitation process of different pathologies, to achieve an enhanced peripheral blood flow.