Repeated Passive Mobilization to Stimulate Vascular Function in Individuals of Advanced Age Who Are Chronically Bedridden: A Randomized Controlled Trial.

BACKGROUND: Vascular dysfunction and associated disorders are major side effects of chronic bed rest, yet passive mobilization as a potential treatment has only been theorized so far. This study investigated the effects of passive mobilization treatment on vascular function in older, chronically bedridden people. METHOD: The study sample was 45 chronically bedridden people of advanced age (mean age: 87 years; 56% female; mean bed rest: 4 years) randomly assigned to a treatment (n = 23) or a control group (CTRL, n = 22). The treatment group received passive mobilization twice daily (30 minutes, 5 times/wk) for 4 weeks. A kinesiologist performed passive mobilization by passive knee flexion/extension at 1 Hz in one leg (treated leg [T-leg] vs control leg [Ctrl-leg]). The CTRL group received routine treatment. The primary outcome was changes in peak blood flow (∆peak) as measured with the single passive leg movement test at the common femoral artery. RESULTS: ∆Peak was increased in both legs in the Treatment group (+90.9 mL/min, p < .001, in T-leg and +25.7 mL/min, p = .039 in Ctrl-leg). No difference in peak blood flow after routine treatment was found in the CTRL group. CONCLUSION: Improvement in vascular function after 4 weeks of passive mobilization was recorded in the treatment group. Passive mobilization may be advantageously included in standard clinical practice as an effective strategy to treat vascular dysfunction in persons with severely limited mobility.

Exercise training improves vascular function in patients with Alzheimer's disease.

PURPOSE: Vascular dysfunction has been demonstrated in patients with Alzheimer's disease (AD). Exercise is known to positively affect vascular function. Thus, the aim of our study was to investigate exercise-induced effects on vascular function in AD. METHODS: Thirty-nine patients with AD (79 ± 8 years) were recruited and randomly assigned to exercise training (EX, n = 20) or control group (CTRL, n = 19). All subjects performed 72 treatment sessions (90 min, 3 t/w). EX included moderate-high-intensity aerobic and strength training. CTRL included cognitive stimuli (visual, verbal, auditive). Before and after the 6-month treatment, the vascular function was measured by passive-leg movement test (PLM, calculating the variation in blood flow: ∆peak; and area under the curve: AUC) tests, and flow-mediated dilation (FMD, %). A blood sample was analyzed for vascular endothelial growth factor (VEGF). Arterial blood flow (BF) and shear rate (SR) were measured during EX and CTRL during a typical treatment session. RESULTS: EX group has increased FMD% (+ 3.725%, p < 0.001), PLM ∆peak (+ 99.056 ml/min, p = 0.004), AUC (+ 37.359AU, p = 0.037) and VEGF (+ 8.825 pg/ml, p = 0.004). In the CTRL group, no difference between pre- and post-treatment was found for any variable. Increase in BF and SR was demonstrated during EX (BF + 123%, p < 0.05; SR + 134%, p < 0.05), but not during CTRL treatment. CONCLUSION: Exercise training improves peripheral vascular function in AD. These ameliorations may be due to the repetitive increase in SR during exercise which triggers NO and VEGF upregulation. This approach might be included in standard AD clinical practice as an effective strategy to treat vascular dysfunction in this population.

The Vascular Side of Chronic Bed Rest: When a Therapeutic Approach Becomes Deleterious.

The interplay between chronic constraint and advanced aging on blood flow, shear-rate, vascular function, nitric oxide (NO)-bioavailability, microcirculation, and vascular inflammation factors is still a matter of debate. Ninety-eight individuals (Young, n=28, 23±3yrs; Old, n=36, 85±7yrs; Bedridden, n=34, 88±6yrs) were included in the study. The bedridden group included old individuals chronically confined to bed (3.8±2.3yrs). A blood sample was collected and analyzed for plasma nitrate, and vascular inflammatory markers. Hyperemic response (∆peak) during the single passive leg movement (sPLM) test was used to measure vascular function. Skeletal muscle total hemoglobin was measured at the vastus lateralis during the sPLM test, by means of near infrared spectroscopy (NIRS). Bedridden subjects revealed a depletion of plasma nitrates compared with Old (-23.8%) and Young (-31.1%). Blood flow was lower in the Bedridden in comparison to Old (-20.1%) and Young (-31.7%). Bedridden presented lower sPLM ∆peak compared Old (-72.5%) and the Young (-83.3%). ∆peak of NIRS total hemoglobin was lower in the Bedridden compared to that in the Young (-133%). All vascular inflammatory markers except IL-6 were significantly worse in the Bedridden compared to Old and Young. No differences were found between the Old and Young in inflammatory markers. Results of this study confirm that chronic physical constraint induces an exacerbation of vascular disfunction and differential regulation of vascular-related inflammatory markers. The mechanisms involved in these negative adaptations seems to be associated with endothelial dysfunction and consequent diminished NO-bioavailability likely caused by the reduced shear-rate consequential to long-term reduction of physical activity.

Corrigendum: Skeletal Muscle Fiber Size and Gene Expression in the Oldest-Old With Differing Degrees of Mobility.

[This corrects the article DOI: 10.3389/fphys.2019.00313.].

An Indoor Therapeutic Garden for Behavioral Symptoms in Alzheimer's Disease: A Randomized Controlled Trial.

BACKGROUND: Behavioral and psychological symptoms of dementia (BPSD) affect 60-90% of patients with Alzheimer's disease (AD). OBJECTIVE: To determine if environmental therapy is an effective strategy to reduce BPSD, we tested 163 patients with AD with Neuropsychiatric Inventory (NPI) before and after 6 months of an indoor therapeutic garden (TG) or standard environment. METHODS: A single-blind randomized controlled trial on AD patients with BPSD. Participants were randomized to an indoor TG (N = 82), or standard environment (control, N = 81) for 6 months. PRIMARY OUTCOME: change in the NPI score from baseline (T0) to end of treatment (T1). SECONDARY OUTCOMES: change in use of quetiapine, cognition, activities of daily living, salivary cortisol, blood pressure from T0 to T1. RESULTS: NPI score significantly ameliorated (TG versus control: -31.8 points), quetiapine dosage (-150 mg), blood pressure (-2.6 mm Hg), and salivary cortisol (-6.4 to -2.1 Nmol/l) were significantly reduced, the Mini-Mental State Examination significantly improved (1.8 points) in the TG versus control arm at T1 (p < 0.001). No adverse events were reported. CONCLUSION: The indoor TG seems safe and may reduce BPSD, medication intake, and cortisol levels in AD.

Comparison between physical and cognitive treatment in patients with MCI and Alzheimer's disease.

Cognitive and physical activity treatments (CT and PT) are two non-pharmacological approaches frequently used in patients with Mild Cognitive Impairment (MCI) and Alzheimer's Disease (AD). The aim of this study was to compare CT and PT in these diseases. Eighty-seven patients were randomly assigned to CT (n=30), PT (n=27) or control group (CTRL; n=30) for 6 months. The global cognitive function was measured by Mini Mental State Examination (MMSE). Specific neuropsychological tests explored attention, memory, executive functions, behavioral disorders. Cardiovascular risk factors (CVD) were collected. All measures were performed before (T0), after treatments (T1), and at three-months follow-up (T2). MMSE did not change from T0 to T1 and T2 in patients assigned to PT and CT, while CTRL patients showed a decline MCI: -11.8%, AD: -16.2%). Between group differences (MCI vs AD) were not found at T1 and T2. Significant worsening was found for CTRL in MCI (T0- T1: P=.039; T0-T2: P<.001) and AD (T0-T1: P<.001; T0-T2: P<.001), and amelioration was found for CT in AD (T0-T2: P<.001). Attention, executive functions and behavioral disorders were unaffected by either PT or CT. Memory was increased in patients with MCI assigned to PT (+6.9%) and CT (+8.5%).. CVD were ameliorated in the PT group. CTRL patients of both groups, revealed significant decline in all functions and no between groups differences were detected. PT appear to ameliorate CVD. Although between groups differences were not found, results suggest a major retention in MCI compared with AD, suggesting that the latter might benefit better of constant rather than periodic treatments. This study confirms the positive effects of CT and PT in mitigating the cognitive decline in MCI and AD patients, and it is the first to demonstrate their similar effectiveness on maintaining cognitive function.

Skeletal Muscle Fiber Size and Gene Expression in the Oldest-Old With Differing Degrees of Mobility.

The oldest-old, in the ninth and tenth decades of their life, represent a population characterized by neuromuscular impairment, which often implies a loss of mobility and independence. As recently documented by us and others, muscle atrophy and weakness are accompanied by an unexpected preservation of the size and contractile function of skeletal muscle fibers. This suggests that, while most fibers are likely lost with their respective motoneurons, the surviving fibers are well preserved. Here, we investigated the mechanisms behind this fiber preservation and the relevance of physical activity, by comparing a group of 6 young healthy controls (YG: 22-28 years) with two groups of oldest-old (81-96 years), one able to walk (OW: n = 6, average 86 years) and one confined to a wheelchair (ONW n = 9, average 88 years). We confirmed previous results of fiber preservation and, additionally, observed a shift in fiber type, toward slow predominance in OW and fast predominance in ONW. Myonuclear density was increased in muscles of ONW, compared to YG and OW, potentially indicative of an ongoing atrophy process. We analyzed, by RT-qPCR, the expression of genes relevant for fiber size and type regulation in a biopsy sample from the vastus lateralis. In all oldest-old both myostatin and IGF-1 expression were attenuated compared to YG, however, in ONW two specific IGF-1 isoforms, IGF-1EA and MGF, demonstrated a further significant decrease compared to OW. Surprisingly, atrogenes (MURF1 and atrogin) expression was also significantly reduced compared to YG and this was accompanied by a close to statistically significantly attenuated marker of autophagy, LC3. Among the determinants of the metabolic fiber type, PGC1α was significantly reduced in both OW and ONW compared to YG, while AMPK was down-regulated only in ONW. We conclude that, in contrast to the shift of the balance in favor of pro-atrophy factors found by other studies in older adults (decreased IGF-1, increase of myostatin, increase of atrogenes), in the oldest-old the pro-atrophy factors also appear to be down-regulated, allowing a partial recovery of the proteostasis balance. Furthermore, the impact of muscle activity, as a consequence of lost or preserved walking ability, is limited.

Non-Aß-Dependent Factors Associated with Global Cognitive and Physical Function in Alzheimer's Disease: A Pilot Multivariate Analysis.

Recent literature highlights the importance of identifying factors associated with mild cognitive impairment (MCI) and Alzheimer's Disease (AD). Actual validated biomarkers include neuroimaging and cerebrospinal fluid assessments; however, we investigated non-Aß-dependent factors associated with dementia in 12 MCI and 30 AD patients. Patients were assessed for global cognitive function (Mini-Mental state examination-MMSE), physical function (Physical Performance Test-PPT), exercise capacity (6-min walking test-6MWT), maximal oxygen uptake (VO2max), brain volume, vascular function (flow-mediated dilation-FMD), inflammatory status (tumor necrosis factor-α ,TNF- α, interleukin-6, -10 and -15) and neurotrophin receptors (p75NTR and Tropomyosin receptor kinase A -TrkA). Baseline multifactorial information was submitted to two separate backward stepwise regression analyses to identify the variables associated with cognitive and physical decline in demented patients. A multivariate regression was then applied to verify the stepwise regression. The results indicated that the combination of 6MWT and VO2max was associated with both global cognitive and physical function (MMSE = 11.384 + (0.00599 × 6MWT) - (0.235 × VO2max)); (PPT = 1.848 + (0.0264 × 6MWT) + (19.693 × VO2max)). These results may offer important information that might help to identify specific targets for therapeutic strategies (NIH Clinical trial identification number NCT03034746).

Impact of Nitric Oxide Bioavailability on the Progressive Cerebral and Peripheral Circulatory Impairments During Aging and Alzheimer's Disease.

Advanced aging, vascular dysfunction, and nitric oxide (NO) bioavailability are recognized risk factors for Alzheimer's disease (AD). However, the contribution of AD, per se, to this putative pathophysiological mechanism is still unclear. To better answer this point, we quantified cortical perfusion with arterial spin labeling (PVC-CBF), measured ultrasound internal carotid (ICA), and femoral (FA) artery blood flow in a group of patients with similar age (~78 years) but different cognitive impairment (i.e., mild cognitive impairment MCI, mild AD-AD1, moderate AD-AD2, and severe AD-AD3) and compared them to young and healthy old (aged-matched) controls. NO-metabolites and passive leg-movement (PLM) induced hyperemia were used to assess systemic vascular function. Ninety-eight individuals were recruited for this study. PVC-CBF, ICA, and FA blood flow were markedly (range of 9-17%) and significantly (all p < 0.05) reduced across the spectrum from YG to OLD, MCI, AD1, AD2, AD3 subjects. Similarly, plasma level of nitrates and the values of PLM were significantly reduced (range of 8-26%; p < 0.05) among the six groups. Significant correlations were retrieved between plasma nitrates, PLM and PVC-CBF, CA, and FA blood flow. This integrative and comprehensive approach to vascular changes in aging and AD showed progressive changes in NO bioavailability and cortical, extracranial, and peripheral circulation in patients with AD and suggested that they are directly associated with AD and not to aging. Moreover, these results suggest that AD-related impairments of circulation are progressive and not confined to the brain. The link between cardiovascular and the central nervous systems degenerative processes in patients at different severity of AD is likely related to the depletion of NO.

Exercise Training on Locomotion in Patients with Alzheimer's Disease: A Feasibility Study.

BACKGROUND: Although current literature has shown that patients with Alzheimer's disease (AD) have worse locomotion compared with healthy counterparts, no studies have focused on the efficacy of exercise training in improving gait abnormalities including biomechanics and metabolic aspects, in this population. OBJECTIVE: To verify the effectiveness of exercise training (ET) on gait parameters (i.e., speed, step and stride length, single and double support, and energy cost of walking (Cw)) in patients with AD with respect to a standard cognitive treatment (CT). METHODS: In this study, we included a small portion of data belonging to a larger study (ClinicalTrials.gov number, NCT03034746). Patients with AD (Mini-Mental State Examination 22±5) were included in the study. Gait parameters and Cw were assessed at baseline and after 6 months (72 treatment sessions) of treatment. ET included 90 min of aerobic and strength training. CT included 90 min of cognitive stimuli. RESULTS: The 16 patients assigned to ET exhibited significant improvement of Cw (-0.9±0.1 J/kg·m-1), while differences in gait parameters were negligible. The effect on gait parameters were undetectable in the 18 patients assigned to CT (-0.2±0.5 J/kg·m-1). CONCLUSIONS: Data from this study showed that ET program seems effective in improving Cw in patients with AD. Interestingly, the positive effect of ET on Cw was not coupled with ameliorations of patient's gait parameters, suggesting that the gain of metabolic aspects of locomotion were the main factors responsible for this positive result.

Effectiveness of Exercise- and Cognitive-Based Treatments on Salivary Cortisol Levels and Sundowning Syndrome Symptoms in Patients with Alzheimer's Disease.

Sundowning syndrome (SDS) in patients with Alzheimer's disease (AD) is characterized by the intensification of behavioral disorders at sunset. Despite SDS etiology being unclear, a strong relationship between high cortisol levels and SDS has been reported. Aerobic exercise (AE) and cognitive training (CT) can reduce cortisol levels. However, whether SDS would benefit from AE and CT is still unknown. Therefore, the aim of this study was to investigate whether AE and CT treatments are effective in reducing SDS via downregulation of cortisol levels. The possible additive effects of combined AE+CT were also assessed. Eighty AD patients were randomly assigned to AE (n = 20), CT (n = 20), AE+CT (n = 20), and standard therapy (no treatment, NT; n = 20). Treatments were administered for 3 months, 5 days/week, 1 hour before sunset. Before and after treatments, salivary cortisol levels were sampled at 7, 11, 15, at sunset, and 20 (time of day). Blind assessment of behavioral disorders (neuropsychiatric inventory, NPI) and agitation (agitated behavior scale, ABS) were also performed. After interventions, cortisol levels were reduced in AE and AE+CT by ∼26%. In the same groups, NPI and ABS decreased by ∼50%. By contrast, cortisol and behavioral disorders were similar to baseline in CT and NT. Changes in NPI and ABS were significantly correlated with the reduction in cortisol levels. AE or AE+CT effects on SDS and cortisol levels and the lack of effect of CT alone indicate the effectiveness of an exercise-based treatment on SDS, suggesting a possible hypothalamic-pituitary-adrenal axis dysregulation underpinning SDS.

Possible Predictors of Involuntary Weight Loss in Patients with Alzheimer's Disease.

Loss in body mass (∆BM) is a common feature in patients with Alzheimer's disease (AD). However, the etiology of this phenomenon is unclear. The aim of this cohort study was to observe possible ∆BM in AD patients following a standard institutionalized diet. Secondary objective was to identify possible predictors of ∆BM. To this end, 85 AD patients (age: 76±4 yrs; stature: 165±3 cm; BM: 61.6±7.4 kg; mean±standard deviation) and 86 controls (CTRL; age: 78±5 yrs; stature: 166±4 cm; BM: 61.7±6.4 kg) were followed during one year of standard institutionalized diet (~1800 kcal/24h). BM, daily energy expenditure, albuminemia, number of medications taken, and cortisolism, were recorded PRE and POST the observation period. Potential predictors of ∆BM in women (W) and men (M) with AD were calculated with a forward stepwise regression model. After one year of standard institutionalized diet, BM decreased significantly in AD (-2.5 kg; p < 0.01), while in CTRL remained unchanged (-0.4 kg; p = 0.8). AD patients and CTRL exhibited similar levels of daily energy expenditure (~1625 kcal/24h). The combination of three factors, number of medications taken, albuminemia, and cortisolism, predicted ∆BM in W with AD. At contrary, the best predictor of ∆BM in M with AD was the cortisolism. Despite a controlled energy intake and similar energy expenditure, both W and M with AD suffered of ∆BM. Therefore, controlled diet did not prevent this phenomenon. The assessments of these variables may predict W and M with AD at risk of weight loss.

Limitations to exercise in female centenarians: evidence that muscular efficiency tempers the impact of failing lungs.

Centenarians are an outstanding model of successful aging, with genetics and healthy lifestyle certainly being key factors responsible for their longevity. Exercise capacity has been identified to play an important role in healthy aging, but a comprehensive assessment of the limitations to maximal exercise in this population is lacking. Following, health histories, lung function, and anthropometric measures, eight female centenarians (98-102 years old) and eight young females (18-22 years old) performed a series of graded maximal exercise tests on a cycle ergometer that facilitated absolute and relative work rate comparisons. Centenarians revealed a dramatically attenuated lung function, as measured by spirometry (forced expiratory volume in 1 s (FEV1/forced vital capacity (FVC), 55 ± 10%) compared to the young (FEV1/FVC, 77 ± 5%). During exercise, although the centenarians relied heavily on respiratory rate which yielded ~50% higher dead space/tidal volume, minute ventilation was similar to that of the young at all but maximal exercise, and alveolar PO2 was maintained in both groups. In contrast, peak WR and VO2 were significantly reduced in the centenarians (33 ± 4 vs 179 ± 24 W; 7.5 ± 1.2 vs 39.6 ± 3.5 ml min(-1) kg(-1)). Arterial PO2 of the centenarians fell steadily from the normal range of both groups to yield a large A-a gradient (57 ± 6 mmHg). Metabolic cost of a given absolute work rate was consistently lower, ~46% less than the young at maximal effort. Centenarians have significant limitations to gas exchange across the lungs during exercise, but this limited oxygen transport is tempered by improved skeletal muscle mechanical efficiency that may play a vital role in maintaining physical function and therefore longevity in this population.

Positive effects of physical training in activity of daily living-dependent older adults.

The goal of this study was to determinate the effects of physical training in older adults with mobility limitations. Thirty frail women (84 +/- 6 years) were randomly assigned to a training or control group for 12 weeks of upper body physical training (UBT) performed sitting on wheelchairs. Trained subjects showed a significant improvement in arms strength (+29%), and shoulder flexibility (+10 cm) but did not improve in arms circumference. The activities of daily living (ADLs) were improved (+77%), cognitive function as defined by the Mini-Mental State Examination (MMSE) was maintained in the trained group (+3%) and declined in the control group (-21%). These results demonstrate that UBT in dependent older women with mobility limitations can increase strength and improve ADLs.