The effect of exercise on blood concentrations of angiogenesis markers in older adults: A systematic review and meta-analysis.

Impaired angiogenesis is associated with cognitive decline in older adults. While exercise has been broadly associated with increased angiogenesis, the relevant mechanisms in older adults are not clear. Here, we present a systematic review and meta-analysis on the relationship between exercise and specific blood angiogenesis markers in older adults to better understand the relevant mechanisms. MEDLINE, Embase, and Cochrane CENTRAL were searched for original reports of angiogenesis markers' concentrations in blood before and after exercise in older adults (≥50 years). Heterogeneity was investigated using sub-group analyses and meta-regressions. Of the 44 articles included in the review, 38 were included in the meta-analyses for five markers: vascular endothelial growth factor (VEGF), e-selectin (CD62E), endostatin, fibroblast growth factor 2, and matrix metallopeptidase-9. VEGF levels were higher (SMD[95%CI]= 0.18[0.03, 0.34], and CD62E levels were lower (SMD[95%CI]= -0.72[-1.42, -0.03], p = 0.04) after exercise. No other markers were altered. Although more studies are needed, changes in angiogenesis markers may help explain the beneficial effects of exercise on angiogenesis in older adults.

The effect of exercise on blood concentrations of angiogenesis markers in older adults: a systematic review and meta-analysis.

Background: Physical exercise has positive impacts on health and can improve angiogenesis, which is impaired during aging, but the underlying mechanisms of benefit are unclear. This meta-analysis and systematic review investigated the effects of exercise on several peripheral angiogenesis markers in older adults to better understand the relationship between exercise and angiogenesis. Methods: MEDLINE, Embase, and Cochrane CENTRAL were searched for original, peer-reviewed reports of peripheral concentrations of angiogenesis markers before and after exercise interventions in older adults (> 50 years). The risk of bias was assessed with standardized criteria. Standardized mean differences (SMD) with 95% confidence intervals (CIs) were calculated from random-effects models. Publication bias was assessed with Egger's test, funnel plots, and trim-and-fill. A priori subgroup analyses and meta-regressions were performed to investigate heterogeneity where possible. Results: Of the 44 articles included in the review, 38 were included in meta-analyses for five proteins. Vascular endothelial growth factor (VEGF) was found to be higher after exercise (SMD[95%CI] = 0.18[0.03, 0.34], p = 0.02), and e-selectin (CD62E) was found to be lower after exercise (SMD[95%CI]= -0.72[-1.42, -0.03], p = 0.04). Endostatin (SMD[95%CI] = 0.28[-0.56, 1.11], p = 0.5), fibroblast growth factor 2 (SMD[95%CI] = 0.03[-0.18, 0.23], p = 0.8), and matrix metallopeptidase-9 (SMD[95%CI] = -0.26[-0.97, 0.45], p = 0.5) levels did not change after exercise. Conclusions: Of the five angiogenesis blood markers evaluated in this meta-analysis, only VEGF and CD62E changed with exercise. Although more studies are needed, changes in angiogenesis markers may explain the beneficial effects of exercise on angiogenesis and health in older adults.

Risks and benefits of current and novel drugs to treat agitation in Alzheimer's disease.

INTRODUCTION: At present, no pharmacological interventions have been approved for the treatment of agitation in Alzheimer's disease (AD), an important neuropsychiatric symptom that has been linked to increased mortality and greater caregiver burden. Antipsychotics offer some benefit, but increase the risk of adverse events such as falls, extrapyramidal symptoms, stroke, and mortality. Over the past 10 years, several new and repurposed medications have shown promise for treating AD-associated agitation. AREAS COVERED: We review the risks and benefits of emerging therapies for agitation in AD, which include newer atypical antipsychotics, selective serotonin reuptake inhibitors, cannabinoids, and dextromethorphan combination products. Other drugs such as mirtazapine, prazosin, and lithium are also discussed. Clinicaltrials.gov, PubMed/MEDLINE, EMBASE and Cochrane Central databases were searched for relevant studies from 1 January 2012 to 1 May 2022. EXPERT OPINION: At the present time, there are no pharmacological interventions for the treatment of agitation in AD whose benefits clearly outweigh their potential safety concerns. Therefore, management of agitation in AD should primarily be based on non-pharmacological approaches. When medications are considered necessary, they should only be initiated with the caregiver's appreciation of their risks and benefits and with careful and ongoing assessment of their safety.

Endosomal-Lysosomal and Autophagy Pathway in Alzheimer's Disease: A Systematic Review and Meta-Analysis.

BACKGROUND: The endosomal-lysosomal and autophagy (ELA) pathway may be implicated in the progression of Alzheimer's disease (AD); however, findings thus far have been inconsistent. OBJECTIVE: To systematically summarize differences in endosomal-lysosomal and autophagy proteins in the cerebrospinal fluid (CSF) of people with AD and healthy controls (HC). METHODS: Studies measuring CSF concentrations of relevant proteins in the ELA pathway in AD and healthy controls were included. Standardized mean differences (SMD) with 95% confidence intervals (CI) between AD and healthy controls in CSF concentrations of relevant proteins were meta-analyzed using random-effects models. RESULTS: Of 2,471 unique studies, 43 studies were included in the systematic review and meta-analysis. Differences in ELA protein levels in the CSF between AD and healthy controls were observed, particularly in lysosomal membrane (LAMP-1: NAD/NHC = 348/381, SMD [95% CI] = 0.599 [0.268, 0.930], I2 = 72.8%; LAMP-2: NAD/NHC = 401/510, SMD [95% CI] = 0.480 [0.134, 0.826], I2 = 78.7%) and intra-lysosomal proteins (GM2A: NAD/NHC = 390/420, SMD [95% CI] = 0.496 [0.039, 0.954], I2 = 87.7%; CTSB: NAD/NHC = 485/443, SMD [95% CI] = 0.201 [0.029, 0.374], I2 = 28.5%; CTSZ: NAD/NHC = 535/820, SMD [95% CI] = -0.160 [-0.305, -0.015], I2 = 24.0%) and in proteins involved in endocytosis (AP2B1:NAD/NHC = 171/205, SMD [95% CI] = 0.513 [0.259, 0.768], I2 = 27.4%; FLOT1: NAD/NHC = 41/45, SMD [95% CI] = -0.489 [-0.919, -0.058], I2 <0.01). LC3B, an autophagy marker, also showed a difference (NAD/NHC = 70/59, SMD [95% CI] = 0.648 [0.180, 1.116], I2 = 38.3%)), but overall there was limited evidence suggesting differences in proteins involved in endosomal function and autophagy. CONCLUSION: Dysregulation of proteins in the ELA pathway may play an important role in AD pathogenesis. Some proteins within this pathway may be potential biomarkers for AD.

Exercise priming with transcranial direct current stimulation: a study protocol for a randomized, parallel-design, sham-controlled trial in mild cognitive impairment and Alzheimer's disease.

BACKGROUND: Transcranial direct current stimulation (tDCS) is a non-invasive type of brain stimulation that uses electrical currents to modulate neuronal activity. A small number of studies have investigated the effects of tDCS on cognition in patients with Mild Cognitive Impairment (MCI) and Alzheimer's disease (AD), and have demonstrated variable effects. Emerging evidence suggests that tDCS is most effective when applied to active brain circuits. Aerobic exercise is known to increase cortical excitability and improve brain network connectivity. Exercise may therefore be an effective, yet previously unexplored primer for tDCS to improve cognition in MCI and mild AD. METHODS: Participants with MCI or AD will be randomized to receive 10 sessions over 2 weeks of either exercise primed tDCS, exercise primed sham tDCS, or tDCS alone in a blinded, parallel-design trial. Those randomized to an exercise intervention will receive individualized 30-min aerobic exercise prescriptions to achieve a moderate-intensity dosage, equivalent to the ventilatory anaerobic threshold determined by cardiopulmonary assessment, to sufficiently increase cortical excitability. The tDCS protocol consists of 20 min sessions at 2 mA, 5 times per week for 2 weeks applied through 35 cm2 bitemporal electrodes. Our primary aim is to assess the efficacy of exercise primed tDCS for improving global cognition using the Montreal Cognitive Assessment (MoCA). Our secondary aims are to evaluate the efficacy of exercise primed tDCS for improving specific cognitive domains using various cognitive tests (n-back, Word Recall and Word Recognition Tasks from the Alzheimer's Disease Assessment Scale-Cognitive subscale) and neuropsychiatric symptoms (Neuropsychiatric Inventory). We will also explore whether exercise primed tDCS is associated with an increase in markers of neurogenesis, oxidative stress and angiogenesis, and if changes in these markers are correlated with cognitive improvement. DISCUSSION: We describe a novel clinical trial to investigate the effects of exercise priming before tDCS in patients with MCI or mild AD. This proof-of-concept study may identify a previously unexplored, non-invasive, non-pharmacological combination intervention that improves cognitive symptoms in patients. Findings from this study may also identify potential mechanistic actions of tDCS in MCI and mild AD. TRIAL REGISTRATION: Clinicaltrials.gov, NCT03670615 . Registered on September 13, 2018.