Combined omega-3 fatty acids, aerobic exercise and cognitive stimulation prevents decline in gray matter volume of the frontal, parietal and cingulate cortex in patients with mild cognitive impairment.

Previous studies in older adults suggested beneficial effects of omega-3 fatty acid (FA) supplementation, aerobic exercise, or cognitive stimulation on brain structure and function. However, combined effects of these interventions in patients suffering from mild cognitive impairment (MCI) are unknown. Using a randomized interventional design, we evaluated the effect of combined omega-3 FA supplementation, aerobic exercise and cognitive stimulation (target intervention) versus omega-3 FA supplementation and non-aerobic exercise (control intervention) on cognitive function and gray matter volume in patients with MCI. Moreover, we analyzed potential vascular, metabolic or inflammatory mechanisms underlying these effects. Twenty-two MCI patients (8 females; 60-80years) successfully completed six months of omega-3 FA intake, aerobic cycling training and cognitive stimulation (n=13) or omega-3 FA intake and non-aerobic stretching and toning (n=9). Before and after the interventions, cognitive performance, magnetic resonance imaging of the brain at 3T (n=20), intima-media thickness of the internal carotid artery and serum markers of glucose control, lipid and B-vitamin metabolism, and inflammation were assessed. Intervention-related changes in gray matter volume of Alzheimer's disease (AD)-related brain regions, i.e., frontal, parietal, temporal and cingulate cortex were examined using voxel-based morphometry of high resolution T1-weighted images. After the intervention period, significant differences emerged in brain structure between groups: Gray matter volume decreased in the frontal, parietal and cingulate cortex of patients in the control intervention, while gray matter volume in these areas was preserved or even increased after the target intervention. Decreases in homocysteine levels in the target intervention group were associated with increases in gray matter volume in the middle frontal cortex (p=0.010). No significant differences in cognitive performance or other vascular, metabolic and inflammatory parameters were observed between groups. This pilot study provides preliminary evidence that omega-3 FA intake combined with aerobic exercise and cognitive stimulation prevents atrophy in AD-related brain regions in MCI patients, compared to omega-3 FA intake plus the control condition of stretching and toning. These promising findings should now be validated in a larger interventional trial.

MPTP-induced hippocampal effects on serotonin, dopamine, neurotrophins, adult neurogenesis and depression-like behavior are partially influenced by fluoxetine in adult mice.

In Parkinson's disease the loss of dopamine induces motor impairment but also leads to non-motor symptoms such as cognitive impairment, anxiety and depression. Selective serotonine reuptake inhibitors (SSRI) are so far first line therapy for mood alterations in PD and have also been shown to influence cognition, however with often insufficient results due to yet not fully understood underlying pathomechanisms of the symptoms. Deficits in the generation and maturation of new neurons in the adult hippocampus seem to be key mechanisms of major depression and cognitive decline and are robustly influenced by serotonergic pharmacotherapy. In this study we analyzed the effects of a short- and long-term treatment with the SSRI fluoxetine on changes of hippocampal precursor maturation, neurotransmitter-receptor mRNA-expression, neurotrophin levels and clinical symptoms in the MPTP-mouse model for PD. The generation of neuronal precursors as well as the absolute numbers of endogenous immature neurons increased following MPTP and were further elevated by fluoxetine. Net neurogenesis however, impaired after MPTP, remained unchanged by fluoxetine treatment. Fluoxetine induced microenvironmental changes in the hippocampus that might be involved in enhanced precursor generation involved increased contents of the neurotrophins VEGF and BDNF and decreased hippocampal expression of the 5HT1a receptor mRNA and the D2 receptor mRNA. Clinically, we were not able to detect any differences in anxiety or depressive behavior in MPTP animals compared to controls which is in line with previous studies indicating that neuropsychiatric symptoms in PD are difficult to assess in rodents due to their clinical characteristics and involvement of several brain regions. Taken together, we show that fluoxetine partially enhances brain's capacity to counteract MPTP-induced neurodegeneration by increasing the endogenous pool of immature neurons and upregulating neural precursor cell generation. The mechanisms underlying this phenomenon and the link to the clinical use of fluoxetine in PD remain to be further elucidated.