Cerebrovascular CO2 reactivity and dynamic cerebral autoregulation through the eighth decade of life and their implications for cognitive decline.

Aging is accompanied by a decrease in cerebral blood flow (CBF), especially in the presence of preclinical cognitive decline. The role of cerebrovascular physiology including regulatory mechanisms of CBF in processes underlying aging and subclinical cognitive decline is, however, not fully understood. We explored changes in cerebrovascular CO2 reactivity and dynamic cerebral autoregulation (dCA) through the eighth decade of life, and their relation with early cognitive decline. After 10.9 years, twenty-eight (age, 80.0 ± 3.5 years; 46% female) out of forty-eight healthy older adults who had participated in a previous study (age at baseline, 70 ± 4 years; 42% female), underwent repeated transcranial Doppler assessments. Linear mixed-model analyses revealed small reductions in cerebrovascular CO2 reactivity with aging (-0.37%/mmHg, P = 0.041), whereas dCA was modestly enhanced (gain: -0.009 cm/s/mmHg, P = 0.038; phase: +8.9 degrees, P = 0.004). These changes were more pronounced in participants who had developed subjective memory complaints at follow-up. Our observations confirm that dCA is not impaired in aging, despite lower cerebral perfusion and cerebrovascular reactivity. Altogether, this unique longitudinal study highlights the involvement of cerebrovascular health in preclinical cognitive decline, which is of clinical relevance in the development of dementia management strategies.

A decade of aging in healthy older adults: longitudinal findings on cerebrovascular and cognitive health.

Research suggests an association between cerebrovascular health and cognitive decline, but previous work is limited by its cross-sectional nature or short (< 1-2 years) follow-up. Our aim was to examine, across 10 years of follow-up in healthy older adults, changes in cerebrovascular health and their relationship with subjective memory complaints as an early marker of cognitive decline. Between 2008 and 2010, twenty-eight healthy older adults (69 ± 4 years) underwent baseline blood pressure and transcranial Doppler measurements to assess middle cerebral artery blood velocity (MCAv), cerebrovascular resistance index (CVRi), and measures of cerebral autoregulation (CA). After 9-12 years of follow-up, these measurements were repeated, and presence of memory complaints was evaluated. Linear mixed-model analyses explored effects of aging on cerebrovascular parameters and whether memory complaints were associated with cerebrovascular changes. Across a median follow-up of 10.9 years, no changes in MCAv, CVRi, or CA were found. At baseline, these parameters were not different between subjects with (n = 15) versus without (n = 13) memory complaints. During follow-up, subjects with memory complaints showed larger decreases in MCAv (- 10% versus + 9%, P = 0.041) and increases in CVRi (+ 26% versus - 9%, P = 0.029) compared to other peers without memory complaints, but no distinct changes in CA parameters (P > 0.05). Although a decade of aging does not lead to deterioration in cerebral blood flow or autoregulation, our findings suggest that reductions in cerebral blood flow and increases in cerebrovascular resistance are associated with early subjective cognitive decline.

Dynamic Regulation of Cerebral Blood Flow in Patients With Alzheimer Disease.

Cerebral autoregulation and baroreflex sensitivity are key mechanisms that maintain cerebral blood flow. This study assessed whether these control mechanisms are affected in patients with dementia and mild cognitive impairment due to Alzheimer disease, as this would increase the risks of antihypertensive treatment. We studied 53 patients with dementia (73.1 years [95% confidence interval (CI), 71.4-74.8]), 37 patients with mild cognitive impairment (69.2 years [95% CI, 66.4-72.0]), and 47 controls (69.4 years [95% CI, 68.3-70.5]). Beat-to-beat blood pressure (photoplethysmography), heart rate, and cerebral blood flow velocity (transcranial Doppler) were measured during 5-minute rest (sitting) and 5 minutes of orthostatic challenges, using repeated sit-to-stand maneuvers. Cerebral autoregulation was assessed using transfer function analysis and the autoregulatory index. Baroreflex sensitivity was estimated with transfer function analysis and by calculating the heart rate response to blood pressure changes during the orthostatic challenges. Dementia patients had the lowest cerebral blood flow velocity (P=0.004). During rest, neither transfer function analysis nor the autoregulatory index indicated impairments in cerebral autoregulation. During the orthostatic challenges, higher autoregulatory index (P=0.011) and lower transfer function gain (P=0.017), indicating better cerebral autoregulation, were found in dementia (4.56 arb. unit [95% CI, 4.14-4.97]; 0.59 cm/s per mm Hg [95% CI, 0.51-0.66]) and mild cognitive impairment (4.59 arb. unit [95% CI, 4.04-5.13]; 0.51 cm/s per mm Hg [95% CI, 0.44-0.59]) compared with controls (3.71 arb. unit [95% CI, 3.35-4.07]; 0.67 cm/s per mm Hg [95% CI, 0.59-0.74]). Baroreflex sensitivity measures did not differ between groups. In conclusion, the key mechanisms to control blood pressure and cerebral blood flow are not reduced in 2 stages of Alzheimer disease compared with controls, both in rest and during orthostatic changes that reflect daily life challenges.

Improvements in fitness are not obligatory for exercise training-induced improvements in CV risk factors.

The purpose of this study was to assess whether changes in physical fitness relate to changes in cardiovascular risk factors following standardized, center-based and supervised exercise training programs in subjects with increased cardiovascular risk. We pooled data from exercise training studies of subjects with increased cardiovascular risk (n = 166) who underwent 8-52 weeks endurance training. We determined fitness (i.e., peak oxygen uptake) and traditional cardiovascular risk factors (body mass index, blood pressure, total cholesterol, high-density lipoprotein cholesterol), before and after training. We divided subjects into quartiles based on improvement in fitness, and examined whether these groups differed in terms of risk factors. Associations between changes in fitness and in cardiovascular risk factors were further tested using Pearson correlations. Significant heterogeneity was apparent in the improvement of fitness and individual risk factors, with nonresponder rates of 17% for fitness, 44% for body mass index, 33% for mean arterial pressure, 49% for total cholesterol, and 49% for high-density lipoprotein cholesterol. Neither the number, nor the magnitude, of change in cardiovascular risk factors differed significantly between quartiles of fitness change. Changes in fitness were not correlated with changes in cardiovascular risk factors (all P > 0.05). Our data suggest that significant heterogeneity exists in changes in peak oxygen uptake after training, while improvement in fitness did not relate to improvement in cardiovascular risk factors. In subjects with increased cardiovascular risk, improvements in fitness are not obligatory for training-induced improvements in cardiovascular risk factors.

Association of Fitness Level With Cardiovascular Risk and Vascular Function in Older Nonexercising Individuals.

It is currently unknown whether differences in physical fitness in older, nonexercising individuals affect cardiovascular risk profile and vascular function. To examine this, 40 healthy older individuals (age 69 ± 4 years) who were classified as nonexercising for the past 5-10 years were allocated to a lower physical fitness (LF; VO2max 20.7 ± 2.4 mlO2/min/kg) or higher physical fitness group (HF; VO2max 29.1 ± 2.8 mlO2/ min/kg, p < .001). Cardiovascular risk profile was calculated using the Lifetime Risk Score (LRS). Vascular function was examined using the gold standard venous occlusion plethysmography to assess blood flow changes in response to intra-arterial infusion of acetylcholine, sodium nitroprusside, and L-NNMA. Daily life activity level of the HF group was higher compared with the LF group (p = .04). LRS was higher (p < .001) and blood flow ratio response to acetylcholine was lower (p = .04) in the LF group. This study shows that a higher physical fitness level is associated with better cardiovascular health and vascular function in nonexercising older individuals.

Assessment of dynamic cerebral autoregulation and cerebrovascular CO2 reactivity in ageing by measurements of cerebral blood flow and cortical oxygenation.

With ageing, cerebral blood flow velocity (CBFV) decreases; however, to what extent dynamic cerebral autoregulation and cerebrovascular CO2 reactivity are influenced by ageing is unknown. The aim was to examine the dynamic responses of CBFV and cortical oxygenation to changes in blood pressure (BP) and arterial CO2 across different ages. Fifty-eight participants in three age groups were included, as follows: young (n = 20, 24 ± 2 years old), elderly (n = 20, 66 ± 1 years old), and older elderly (n = 18, 78 ± 3 years old). The CBFV was measured using transcranial Doppler ultrasound, simultaneously with oxyhaemoglobin (O2Hb) using near-infrared spectroscopy and beat-to-beat BP measurements using Finapres. Postural manoeuvres were performed to induce haemodynamic fluctuations. Cerebrovascular CO2 reactivity was tested with hyperventilation and CO2 inhalation. With age, CBFV decreased (young 59 ± 12 cm s(-1), elderly 48 ± 7 cm s(-1) and older elderly 42 ± 9 cm s(-1), P < 0.05) and cerebrovascular resistance increased (1.46 ± 0.58, 1.81 ± 0.36 and 1.98 ± 0.52 mmHg cm(-1) s(-1), respectively, P < 0.05). Normalized gain (autoregulatory damping) increased with age for BP-CBFV (0.88 ± 0.18, 1.31 ± 0.30 and 1.06 ± 0.34, respectively, P < 0.05) and CBFV-O2Hb (0.10 ± 0.09, 0.12 ± 0.04 and 0.17 ± 0.08, respectively, P < 0.05) during the repeated sit-stand manoeuvre at 0.05 Hz. Even though the absolute changes in CBFV and cerebrovascular resistance index during the cerebrovascular CO2 reactivity were higher in the young group, the percentage changes in CBFV, cerebrovascular resistance index and O2Hb were similar in all age groups. In conclusion, there was no decline in dynamic cerebral autoregulation and cerebrovascular CO2 reactivity with increasing age up to 86 years. Despite the decrease in cerebral blood flow velocity and increase in cerebrovascular resistance with advancing age, CBFV and cortical oxygenation were not compromised in these elderly humans during manoeuvres that mimic daily life activities.

Impact of physical fitness and daily energy expenditure on sleep efficiency in young and older humans.

BACKGROUND: Physical activity is known to influence sleep efficiency. Relatively little is known about the relationship between physical activity and sleep efficiency in young and older humans and the impact of exercise training on sleep efficiency in healthy older individuals. OBJECTIVES: To determine the relationship between physical fitness and daily energy expenditure with sleep efficiency in young and older subjects, and assess the effect of 12-month exercise training on sleep efficiency in healthy older participants. METHODS: The relationship between physical fitness (maximal cycling test) and daily energy expenditure (accelerometry) with sleep efficiency (accelerometry) was examined cross-sectionally in 12 healthy young adults (27 ± 5 years) and 21 healthy older participants (69 ± 3 years). Subsequently, the effect of 12-month exercise training (n = 11) or control period (n = 10) on sleep efficiency in older participants was examined using a randomized controlled trial. RESULTS: Daily energy expenditure and sleep efficiency did not differ between young and older subjects. A significant correlation was found between energy expenditure and sleep efficiency (r = 0.627, p = 0.029) in young adults, but not in older participants (r = -0.158, p = 0.49). Physical fitness did not correlate with sleep efficiency in either group. Exercise training significantly improved physical fitness (15.0%, p < 0.001), but failed to alter sleep characteristics such as sleep efficiency, sleep onset latency and awakenings. CONCLUSIONS: We found that young adults with higher daily energy expenditure have greater sleep efficiency, whilst this relationship is diminished with advanced age. In contrast, we found no correlation between physical fitness and sleep characteristics in healthy young or older participants, which may explain the lack of improvement in sleep characteristics in older participants with 12-month exercise training. Exercise training may be more successful in subjects with existing sleep disturbances to improve sleep characteristics rather than in healthy older subjects.

The effect of an advanced glycation end-product crosslink breaker and exercise training on vascular function in older individuals: a randomized factorial design trial.

Aging leads to accumulation of irreversible advanced glycation end-products (AGEs), contributing to vascular stiffening and endothelial dysfunction. When combined with the AGE-crosslink breaker Alagebrium, exercise training reverses cardiovascular aging in experimental animals. This study is the first to examine the effect of Alagebrium, with and without exercise training, on endothelial function, arterial stiffness and cardiovascular risk in older individuals. Forty-eight non-exercising individuals (mean age 70 ± 4 years) without manifest diseases or use of medication were allocated into 4 groups for a 1-year intervention: Exercise training & Alagebrium (200 mg/day); exercise training & placebo; no exercise training & Alagebrium (200 mg/day); and no exercise training & placebo. We performed a maximal exercise test (VO2max) and measured endothelial function using venous occlusion plethysmography and intra-arterial infusion of acetylcholine, sodium nitroprusside and NG-monomethyl-l-arginine. Arterial stiffness was measured using pulse wave velocity. Cardiovascular risk was calculated using the Lifetime Risk Score (LRS). In the exercise training groups, LRS and VO2max improved significantly (23.9 ± 4.5 to 27.2 ± 4.6mLO2/min/kg, p < 0.001). Endothelial response to the vasoactive substances did not change, nor did arterial stiffness in any of the four groups. In conclusion, one year of exercise training significantly improved physical fitness and lifetime risk for cardiovascular disease without affecting endothelial function or arterial stiffness. The use of the AGE-crosslink breaker Alagebrium had no independent effect on vascular function, nor did it potentiate the effect of exercise training. Despite the clinical benefits of exercise training for older individuals, neither exercise training nor Alagebrium (alone or in combination) was able to reverse the vascular effects of decades of sedentary aging.