BackgroundExercise interventions to prevent dementia and delay cognitive decline have gained considerable attention in recent years. Human and animal studies have demonstrated that regular physical activity targets brain function by increasing cognitive reserve. There is also evidence of structural changes caused by exercise in preventing or delaying the genesis of neurodegeneration. Although initial studies indicate enhanced cognitive performance in patients with mild cognitive impairment (MCI) following an exercise intervention, little is known about the effect of an extensive, controlled and regular exercise regimen on the neuropathology of patients with MCI. This study aims to determine the effects of an extensive exercise programme on the progression of MCI.Methods/designThis randomised controlled clinical intervention study will take place across three European sites. Seventy-five previously sedentary patients with a clinical diagnosis of MCI will be recruited at each site. Participants will be randomised to one of three groups. One group will receive a standardised 1-year extensive aerobic exercise intervention (3 units of 45 min/week). The second group will complete stretching and toning (non-aerobic) exercise (3 units of 45 min/week) and the third group will act as the control group. Change in all outcomes will be measured at baseline (T0), after six months (T1) and after 12 months (T2). The primary outcome, cognitive performance, will be determined by a neuropsychological test battery (CogState battery, Trail Making Test and Verbal fluency). Secondary outcomes include Montreal Cognitive Assessment (MoCA), cardiovascular fitness, physical activity, structural changes of the brain, quality of life measures and measures of frailty. Furthermore, outcome variables will be related to genetic variations on genes related to neurogenesis and epigenetic changes in these genes caused by the exercise intervention programme.DiscussionThe results will add new insights into the prevailing notion that exercise may slow the rate of cognitive decline in MCI.Trial registrationClinicalTrials.gov NCT02913053

Exercise intervention studies in mild cognitive impairment (MCI), a prodromal stage of Alzheimer's disease (AD), have demonstrated inconsistent yet promising results. Addressing the limitations of previous studies, this trial investigated the effects of a 12-month structured exercise program on the progression of MCI. The NeuroExercise study is a multicenter randomized controlled trial across three European countries (Ireland, Netherlands, Germany). Hundred and eighty-three individuals with amnestic MCI were included and were randomized to a 12-month exercise intervention (3 units of 45 min) of either aerobic exercise (AE; n = 60), stretching and toning exercise (ST; n = 65) or to a non-exercise control group (CG; n = 58). The primary outcome, cognitive performance, was determined by an extensive neuropsychological test battery. For the primary complete case (CC) analyses, between-group differences were analyzed with analysis of covariance under two conditions: (1) the exercise group (EG = combined AE and ST groups) compared to the CG and (2) AE compared to ST. Primary analysis of the full cohort (n = 166, 71.5 years; 51.8% females) revealed no between-group differences in composite cognitive score [mean difference (95% CI)], 0.12 [(−0.03, 0.27), p = 0.13] or in any cognitive domain or quality of life. VO2 peak was significantly higher in the EG compared to the CG after 12 months [−1.76 (−3.39, −0.10), p = 0.04]. Comparing the two intervention groups revealed a higher VO2peak level in the aerobic exercise compared to the stretching and toning group, but no differences for the other outcomes. A 12-month exercise intervention did not change cognitive performance in individuals with amnestic MCI in comparison to a non-exercise CG. An intervention effect on physical fitness was found, which may be an important moderator for long term disease progression and warrants long-term follow-up investigations.Clinical Trial Registration:https://clinicaltrials.gov/ct2/show/NCT02913053, identifier: NCT02913053.

ObjectiveTo investigate the brain-derived neurotrophic factor (BDNF) and cognitive response to a short bout of high-intensity aerobic exercise in older adults with mild cognitive impairment (MCI).MethodsParticipants were randomised to one of two testing schedules, completing either a standardised exercise test (group A) or a resting control condition (group B). Blood sampling and cognitive measures (visuospatial learning and memory, sustained attention and executive function) were collected at baseline (T1) and postintervention (T2). An additional measurement of study outcomes was collected after exercise (T3) in group B only.Results64 participants (female 53.2%, mean age 70.5±6.3 years) with MCI were recruited. From T1 to T2, serum BDNF (sBDNF) concentration increased in group A (n=35) (median (Md) 4564.61±IQR 5737.23 pg/mL to Md 5173.27±5997.54 pg/mL) and decreased in group B (Md 4593.74±9558.29 pg/mL to Md 3974.66±3668.22 pg/mL) (between-group difference p=0.024, effect size r=0.3). The control group made fewer errors on the sustained attention task compared with the exercise group (p=0.025). Measures of visuospatial learning and memory or executive function did not change significantly between groups.ConclusionThis study is the first to show that a short bout of high-intensity aerobic exercise increases peripheral sBDNF in a population with MCI. However, acute exercise did not improve cognitive performance.

Prevention trials in subjects with mild cognitive impairment (MCI), especially lifestyle interventions, can be difficult to carry out, particularly the recruitment and retention of subjects. We experienced these challenges in our multi-site one-year exercise trial in MCI, NeuroExercise. Trial recruitment rates differed significantly across sites; the non-medical sport university site, providing free access to a range of group exercise in a sports environment, proved far more successful than memory clinics linked to hospitals. This suggests that non-medical settings and a non-medical research community facilitating physical activities may be important factors in recruitment of subjects with MCI for large prevention trials.

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