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Aerobic exercise (AE) has recently received increasing attention in the prevention of Alzheimer's disease (AD). There is some evidence that it can improve neurocognitive function in elderly individuals. However, the mechanism of these improvements is not completely understood. In this prospective clinical trial, thirty amnestic mild cognitive impairment participants were enrolled into two groups and underwent 12 months of intervention. One group (n = 15) performed AE training (8M/7F, age = 66.4 years), whereas the other (n = 15) performed stretch training (8M/7F, age = 66.1 years) as a control intervention. Both groups performed 25-30 minutes training, 3 times per week. Frequency and duration were gradually increased over time. Twelve-month AE training improved cardiorespiratory fitness (p = 0.04) and memory function (p = 0.004). Cerebral blood flow (CBF) was measured at pre- and post-training using pseudo-continuous-arterial-spin-labeling MRI. Relative to the stretch group, the AE group displayed a training-related increase in CBF in the anterior cingulate cortex (p = 0.016). Furthermore, across individuals, the extent of memory improvement was associated with CBF increases in anterior cingulate cortex and adjacent prefrontal cortex (voxel-wise p < 0.05). In contrast, AE resulted in a decrease in CBF of the posterior cingulate cortex, when compared to the stretch group (p = 0.01). These results suggest that salutary effects of AE in AD may be mediated by redistribution of blood flow and neural activity in AD-sensitive regions of brain.

Cerebral white matter (WM) represents the structural substrate of neuronal communications which is damaged by Alzheimer's disease (AD). Aerobic exercise training (AET) may improve WM integrity in cognitively normal older adults, but its efficacy remains unknown in patients with amnestic mild cognitive impairment (MCI), a prodromal phase of AD dementia. Therefore, we conducted a proof-of-concept study that randomized 70 amnestic MCI patients to a 1-year program of AET or a non-aerobic stretching and toning (SAT), active control group. Thirty-six patients completed both baseline and follow-up MRI scans, and cerebral WM integrity was measured by WM lesion volume and diffusion characteristics using fluid-attenuated-inversion-recovery and diffusion tensor imaging respectively. Peak oxygen uptake (VO2peak) and neuropsychological function were also measured. At baseline and 1-year follow-up, WM lesion volume and diffusion characteristics were similar between the AET and SAT groups, although VO2peak significantly improved after AET. The AET group showed slight improvement in neuropsychological performance. When analyzing individual data, tract-based spatial statistics demonstrated that VO2peak improvements are associated with attenuated elevations in mean and axial diffusivities, particularly the anterior WM fiber tracts (e.g., genu of corpus callosum). In patients with amnestic MCI, we found that although AET intervention did not improve WM integrity at group level analysis, individual cardiorespiratory fitness gains were associated with improved WM tract integrity of the prefrontal cortex.

Background: The current evidence is inconclusive to support the benefits of aerobic exercise training (AET) for preventing neurocognitive decline in patients with amnestic mild cognitive impairment (aMCI)., Objective: To examine the effect of a progressive, moderate-to-high intensity AET program on memory and executive function, brain volume, and cortical amyloid-β (Aβ) plaque deposition in aMCI patients., Methods: This is a proof-of-concept trial that randomized 70 aMCI patients to 12 months of AET or stretching and toning (SAT, active control) interventions. Primary neuropsychological outcomes were assessed by using the California Verbal Learning Test-second edition (CVLT-II) and the Delis-Kaplan Executive Function System (D-KEFS). Secondary outcomes were the global and hippocampal brain volumes and the mean cortical and precuneus Aβ deposition., Results: Baseline cognitive scores were similar between the groups. Memory and executive function performance improved over time but did not differ between the AET and SAT groups. Brain volume decreased and precuneus Aβ plaque deposition increased over time but did not differ between the groups. Cardiorespiratory fitness was significantly improved in the AET compared with SAT group. In amyloid positive patients, AET was associated with reduced hippocampal atrophy when compared with the SAT group., Conclusion: The AET and SAT groups both showed evidence of slightly improved neuropsychological scores in previously sedentary aMCI patients. However, these interventions did not prevent brain atrophy or increases in cortical Aβ deposition over 12 months. In amyloid positive patients, AET reduced hippocampal atrophy when compared with the SAT group.

Background: Mounting evidence showed the self-reported levels of physical activity are positively associated with white matter (WM) integrity and cognitive performance in normal adults and patients with mild cognitive impairment (MCI). However, the objective measure of cardiorespiratory fitness (CRF) was not used in these studies., Objective: To determine the associations of CRF measured by maximal oxygen uptake (VO2max) with WM fiber integrity and neurocognitive performance in older adults with MCI., Methods: Eighty-one participants (age = 65±7 years, 43 women), including 26 cognitively normal older adults and 55 amnestic MCI patients, underwent VO2max test to measure CRF, diffusion tensor imaging (DTI) to assess WM fiber integrity, and neurocognitive assessment focused on memory and executive function. DTI data were analyzed by the tract-based spatial statistics and region-of-interest approach., Results: Cognitively normal older adults and MCI patients were not different in global WM fiber integrity and VO2max. VO2max was associated positively with DTI metrics of fractional anisotropy in ∼54% WM fiber tracts, and negatively with mean and radial diffusivities in ∼46% and ∼56% of the WM fiber tracts. The associations of VO2max with DTI metrics remained statistically significant after adjustment of age, sex, body mass index, WM lesion burden, and MCI status. The DTI metrics obtained from the area that correlated to VO2max were associated with executive function performance in MCI patients., Conclusions: Higher levels of CRF are associated with better WM fiber integrity, which in turn is correlated with better executive function performance in MCI patients.

Amnestic mild cognitive impairment represents an early stage of Alzheimer's disease, and characterization of physiological alterations in mild cognitive impairment is an important step toward accurate diagnosis and intervention of this condition. To investigate the extent of neurodegeneration in patients with mild cognitive impairment, whole-brain cerebral metabolic rate of oxygen in absolute units of µmol O 2 /min/100 g was quantified in 44 amnestic mild cognitive impairment and 28 elderly controls using a novel, non-invasive magnetic resonance imaging method. We found a 12.9% reduction ( p = 0.004) in cerebral metabolic rate of oxygen in mild cognitive impairment, which was primarily attributed to a reduction in the oxygen extraction fraction, by 10% ( p = 0.016). Global cerebral blood flow was not found to be different between groups. Another aspect of vascular function, cerebrovascular reactivity, was measured by CO 2 -inhalation magnetic resonance imaging and was found to be equivalent between groups. Therefore, there seems to be a global, diffuse diminishment in neural function in mild cognitive impairment, while their vascular function did not show a significant reduction.