To determine the effect of moderate-to-high-intensity aerobic exercise on cerebral blood flow in patients with Alzheimer’s disease (AD).An increasing number of studies report beneficial effect of physical activity on brain structure and function. As well, there has been an increasing focus in recent years on the relation between cerebrovascular health and Alzheimer’s disease. Studies suggest a modulating effect of exercise on both symptoms and neuropathology in patients with AD, but clarification of the underlying mechanism is needed. In non-demented elderly physical activity has been associated with a reduction in age-related decline in cerebral blood flow (CBF) as well as improved cognition^1,2. In patients with AD, a reduction in both global and focal CBF has been found compared to healthy controls^3,4,5, and an association has been found with cognitive functioning as measured by the Mini Mental State Examination⁶.

The ADEX study (NCT01681602) is a multicenter, single-blind, randomized, controlled trial which aimed to investigate whether a supervised aerobic exercise program could ameliorate symptoms of AD.

Participants

A total of 200 patients with mild to moderate AD were randomized to either an exercise group (60-minute exercise sessions 3 times a week for 16 weeks) or to a control group (usual care). Of these a subgroup of 51 patients underwent brain MRI at baseline and at 16 weeks⁷. Inclusion criteria were amongst others an age between 50 and 90, a score of ≥20 on the MMSE⁷.

Imaging protocol

The imaging protocol on 3T (Trio, Siemens, Erlangen, Germany) included T₁-weighed magnetization-prepared rapid gradient echo (MPRAGE) (TE 3.04ms, TR 1550ms, FoV read 256mm, FoV phase 100%, 192 slices), and pulsed arterial spin labeling (PASL) with flow-sensitive alternating inversion recovery (FAIR) labeling scheme and a 3D gradient-and-spin-echo (GRASE) multishot readout (TE=19ms, TR=3400ms, FOV=320x160, matrix=64x32, slices=26, slice-thickness=4mm, TI=2000ms).

Data processing

Whole brain CBF was calculated, and three regions were selected known to be involved in AD and/or the neuropsychological tests administered: the frontal lobe, anterior cingulate cortex (ACC), and superior parietal gyrus (SPG). The T₁-weighed images were segmented with Freesurfer^8,9. The PASL images were linearly registered to the MPRAGE space to select the areas for regional CBF analysis(https://surfer.nmr.mgh.harvard.edu/fswiki/). The absolute change in CBF (CBF_follow-up – CBF_baseline) and relative change in CBF ((CBF_follow-up – CBF_baseline)/CBF_baseline*100%) were calculated.

Cognitive and physical outcome measures

The Verbal Fluency test (VFT), Stroop test, the Symbol Digit Modalities Test (SDMT), and the Mini Mental State Examination (MMSE) were administrated at baseline and at 16-week follow-up. The peak oxygen uptake (VO_{2 peak}) was recorded at both time points.

Statistical analysis

Statistical analysis was carried out with R (R Foundation for Statistical Computing, Vienna, Austria). The non-parametric statistical tests Wilcoxon rank-sum test, Wilcoxon signed-rank test and Spearman’s correlation were used. Bonferroni correction was used for multiple comparisons.

There were no differences in between the baseline characteristics of the intervention and control group (see table 1). The effect of exercise was reflected in the peak oxygen uptake: the control group showed no change in VO_2peak, while it increased by 211 mL/min (p<0.01) on average in the intervention group. A significant change in CBF of on average -14 mL/100g/min was detected in the control group in the ACC (p < .05) whereas, no change in CBF was seen in the intervention group (figure 1). No differences were found for the absolute and relative CBF change between the control and intervention group for whole brain and regional measures. Finally, no correlation was found between the change in ACC perfusion and performance on the cognitive tasks both for all patients and within each group separately.CBF in the ACC was significantly lower at 16 weeks in the control group, but it remained unchanged in the intervention group. This could indicate that moderate-to-intense aerobic exercise can maintain regional CBF, and that through this it can as such counteract the decline in CBF typically seen in AD. This, however, was not reflected in changes in relevant neuropsychological tests in this study. Also, the lack of effect on whole brain CBF could indicate that either aerobic exercise affects specific brain areas, or that a 16-week period is too brief to see any global effects. Our results suggest that even brains affected by mild Alzheimer’s disease may still benefit from regular exercise.