Theresa Köbe

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 Alzheimers 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.

Vitamin B-12 concentration, memory performance, and hippocampal structure in patients with mild cognitive impairment

BACKGROUND Low-normal concentrations of vitamin B-12 (VitB12) may be associated with worse cognition. However, previous evidence has been mixed, and the underlying mechanisms remain unclear. OBJECTIVE We determined whether serum VitB12 concentrations within the normal range were linked to memory functions and related neuronal structures in patients with mild cognitive impairment (MCI). DESIGN In a cross-sectional design, we assessed 100 amnestic MCI patients (52 women; age range: 50-80 y) with low- and high-normal VitB12 concentration (median split: 304 pmol/L) for memory functions with the use of the Auditory Verbal Learning Test. MRI was performed at 3 tesla (n= 86) for the estimation of the volume and microstructure of the hippocampus and its subfields as indicated by the mean diffusivity on diffusion-weighted images. With the use of a mediation analysis, we examined whether the relation between VitB12 and memory performance was partially explained by volume or microstructure. RESULTS MCI patients with low-normal VitB12 showed a significantly poorer learning ability (P= 0.014) and recognition performance (P= 0.008) than did patients with high-normal VitB12. Also, the microstructure integrity of the hippocampus was lower in patients with low-normal VitB12, mainly in the cornu ammonis 4 and dentate gyrus region (P= 0.029), which partially mediated the effect of VitB12 on memory performance (32-48%). Adjustments for age, sex, education, apolipoprotein E e4 status, and total homocysteine, folate, and creatinine did not attenuate the effects. CONCLUSIONS Low VitB12 concentrations within the normal range are associated with poorer memory performance, which is an effect that is partially mediated by the reduced microstructural integrity of the hippocampus. Future interventional trials are needed to assess whether supplementation of VitB12 may improve cognition in MCI patients even in the absence of clinically manifested VitB12 deficiency. This trial was registered at clinicaltrials.gov as NCT01219244.

Impact of Resveratrol on Glucose Control, Hippocampal Structure and Connectivity, and Memory Performance in Patients with Mild Cognitive Impairment

In healthy older adults, resveratrol supplementation has been shown to improve long-term glucose control, resting-state functional connectivity (RSFC) of the hippocampus, and memory function. Here, we aimed to investigate if these beneficial effects extend to individuals at high-risk for dementia, i.e., patients with mild cognitive impairment (MCI). In a randomized, double-blind interventional study, 40 well-characterized patients with MCI (21 females; 50–80 years) completed 26 weeks of resveratrol (200 mg/d; n = 18) or placebo (1,015 mg/d olive oil; n = 22) intake. Serum levels of glucose, glycated hemoglobin A1c and insulin were determined before and after intervention. Moreover, cerebral magnetic resonance imaging (MRI) (3T) (n = 14 vs. 16) was conducted to analyze hippocampus volume, microstructure and RSFC, and neuropsychological testing was conducted to assess learning and memory (primary endpoint) at both time points. In comparison to the control group, resveratrol supplementation resulted in lower glycated hemoglobin A1c concentration with a moderate effect size (ANOVARM p = 0.059, Cohens d = 0.66), higher RSFC between right anterior hippocampus and right angular cortex (p < 0.001), and led to a moderate preservation of left anterior hippocampus volume (ANOVARM p = 0.061, Cohens d = 0.68). No significant differences in memory performance emerged between groups. This proof-of-concept study indicates for the first-time that resveratrol intake may reduce glycated hemoglobin A1c, preserves hippocampus volume, and improves hippocampus RSFC in at-risk patients for dementia. Larger trials with longer intervention time should now determine if these benefits can be validated and extended to cognitive function.

Impact of KIBRA polymorphism on memory function and the hippocampus in older adults

The single nucleotide polymorphism rs17070145 within the KIBRA gene (kidney and brain expressed protein) has been associated with variations in memory functions and related brain areas. However, previous studies yielded conflicting results, which might be due to divergent sample characteristics or task-specific effects. Therefore, we aimed to determine the impact of KIBRA genotype on learning and memory formation, and volume, microstructural integrity and functional connectivity (FC) of the hippocampus and its subfields in a well-characterized cohort of healthy older adults. One-hundred and forty subjects (72 women, age 50–80) were KIBRA genotyped and memory was tested using the Auditory Verbal Learning Task. Also, subjects underwent structural and resting-state functional magnetic resonance imaging at 3T. Subfields were delineated using automated segmentation (FreeSurfer software). Microstructural integrity was measured using mean diffusivity (MD) derived from diffusion tensor images. Seed-based analyses were used to assess FC patterns of the hippocampus. KIBRA T-allele carriers showed a trend for better memory performance, and in the hippocampus significantly higher volumes and partly lower MD, indicative for better microstructure, compared with non-T-allele carriers in the cornu ammonis (CA)2/3 and CA4/dentate gyrus subfields (all P⩽0.008, Bonferroni corrected). Also, T-allele carriers exhibited lower FC of the left hippocampus with areas outside the synchronized HC network. In sum, we could show for the first time that older T-allele carriers exhibited larger volumes and better microstructure within those hippocampus subfields that are implicated in long-term potentiation and neurogenesis, key features of memory processes. Moreover, T-allele carriers showed a more selective FC network of the hippocampus.

Genetic variants of the FADS gene cluster are associated with erythrocyte membrane LC PUFA levels in patients with mild cognitive impairment

BackgroundLong-chain (> 20 C-atoms) polyunsaturated fatty acids (LC PUFAs) of both the omega-6 (n-6) and omega-3 (n-3) series are important for the functional integrity of brain and thereby cognition, memory and mood. Clinical studies observed associations between altered LC PUFA levels and neurodegenerative diseases such as Alzheimer´s disease and its prodromal stage, mild cognitive impairment (MCI).MethodsThe present study examined the LC PUFA status of MCI patients with specific view on the relative LC n-3 PUFA levels of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in erythrocyte membranes (omega-3 index). 12 single nucleotide polymorphisms (SNPs) of the FADS1, FADS2, and FADS3 gene clusters were genotyped in 111 MCI patients and evaluated associations with PUFA levels in erythrocyte membranes (primary outcome). In addition, the associations between FADS SNPs and LC PUFA levels with serum lipid levels as well as depressive symptoms were examined (secondary outcomes).ResultsMinor allele carrier of rs174546, rs174548 (FADS1), rs3834458, rs1535, rs174574, rs174575, rs174576, and rs174578 (FADS2) showed significant higher n-6 and n-3 precursor PUFA levels (linoleic acid, and alpha-linolenic acid, respectively) and lower arachidonic acid (AA) levels in erythrocyte membranes compared to the major allele carriers. Differences in EPA and DHA levels were not significant. Minor allele carriers of rs174574, rs174576 and rs174578 (FADS2) and rs174455 (FADS3) exhibited significant higher triglyceride levels, whereas minor allele carriers for rs174449 and rs174455 (FADS3) exhibited significant higher total- and LDL-cholesterol levels compared to the more common variant. The mean omega-3 index of the study cohort was 6.19 ± 1.55 %. In more than 85 % of the patients, the omega-3 index was below 8 % and in 23 % below 5 %. Moreover, it was shown that a low DHA status and omega-3 index was associated with depressive symptoms (Beck’s depression-inventory).Discussion and conclusionThese findings indicate an association between several FADS genotypes for higher n-6 and n-3 precursor PUFA and lower AA levels in erythrocyte membranes in minor compared to major allele carriers. To what extent FADS genotypes and a lower conversion of LA and ALA to biologically important LC PUFAs such as AA, EPA and DHA contributes to cognitive decline should be investigated in further trials. Nevertheless, the omega-3 index in this cohort of MCI patients can be classified as insufficient.

Divergent regional patterns of cerebral hypoperfusion and gray matter atrophy in mild cognitive impairment patients.

Reductions of cerebral blood flow and gray matter structure have been implicated in early pathogenesis of Alzheimer’s disease, potentially providing complementary information. The present study evaluated regional patterns of cerebral hypoperfusion and atrophy in patients with mild cognitive impairment and healthy older adults. In each participant, cerebral perfusion and gray matter structure were extracted within selected brain regions vulnerable to Alzheimer’s disease using magnetic resonance imaging. Measures were compared between diagnostic groups with/without adjustment for covariates. In mild cognitive impairment patients, cerebral blood flow was significantly reduced in comparison with healthy controls in temporo-parietal regions and the basal ganglia in the absence of local gray matter atrophy. By contrast, gray matter structure was significantly reduced in the hippocampus in the absence of local hypoperfusion. Both, cerebral perfusion and gray matter structure were significantly reduced in the entorhinal and isthmus cingulate cortex in mild cognitive impairment patients compared with healthy older adults. Our results demonstrated partly divergent patterns of temporo-parietal hypoperfusion and medial-temporal atrophy in mild cognitive impairment patients, potentially indicating biomarker sensitivity to dissociable pathological mechanisms. The findings support applicability of cerebral perfusion and gray matter structure as complementary magnetic resonance imaging-based biomarkers in early Alzheimer’s disease detection, a hypothesis to be further evaluated in longitudinal studies.

Impact of leptin on memory function and hippocampal structure in mild cognitive impairment

Metabolic changes have been suggested to contribute to dementia and its precursor mild cognitive impairment (MCI), yet previous results particularly for the “satiety hormone” leptin are mixed. Therefore, we aimed to determine if MCI patients show systematic differences in leptin, independent of sex, adipose mass, age, and glucose and lipid metabolism, and whether leptin levels correlated with memory performance and hippocampal integrity. Forty MCI patients (20 females, aged 67 years ± 7 SD) were compared to 40 healthy controls (HC) that were pair‐wise matched for sex, age, and body fat. Memory performance was assessed using the auditory verbal learning test. Volume and microstructure of the hippocampus were determined using 3T‐neuroimaging. Fasting serum markers of leptin, glucose and lipid metabolism, and other confounding factors were assayed. MCI patients, compared with HC, showed lower serum leptin, independent of sex, age, and body fat (P < 0.001). Glucose and lipid markers did not attenuate these results. Moreover, MCI patients exhibited poorer memory and lower volume and microstructural integrity within hippocampal subfields. While leptin and memory were not significantly correlated, mediation analyses indicated that lower leptin contributed to poorer memory through its negative effect on right hippocampus volume and left hippocampus microstructure. We demonstrated that MCI is associated with lower serum leptin independent of sex, age, body fat, glucose, and lipid metabolism. Our data further suggest that inefficient leptin signaling could partly contribute to decreases in memory performance through changes in hippocampus structure, a hypothesis that should now be verified in longitudinal studies. Hum Brain Mapp 37:4539–4549, 2016.

Using resting-state fMRI to assess the effect of aerobic exercise on functional connectivity of the DLPFC in older overweight adults

&NA; Cardiovascular fitness is thought to exert beneficial effects on brain function and might delay the onset of cognitive decline. Empirical evidence of exercise‐induced cognitive enhancement, however, has not been conclusive, possibly due to short intervention times in clinical trials. Resting‐state functional connectivity (RSFC) has been proposed as an early indicator for intervention‐induced changes. Here, we conducted a study in which healthy older overweight subjects took either part in a moderate aerobic exercise program over 6 months (AE group; n = 11) or control condition of non‐aerobic stretching and toning (NAE group; n = 18). While cognitive and gray matter volume changes were rather small (i.e., appeared only in certain sub‐scores without Bonferroni correction for multiple comparisons or using small volume correction), we found significantly increased RSFC after training between dorsolateral prefrontal cortex and superior parietal gyrus/precuneus in the AE compared to the NAE group. This intervention study demonstrates an exercise‐induced modulation of RSFC between key structures of the executive control and default mode networks, which might mediate an interaction between task‐positive and task‐negative brain activation required for task switching. Results further emphasize the value of RSFC as a sensitive biomarker for detecting early intervention‐related cognitive improvements in clinical trials.

P57. Safety and tolerability of spermidine supplementation: A translational study in mice and older adults with subjective cognitive decline

Background Supplementation of spermidine, an autophagy-inducing agent, has been shown to protect against neurodegeneration and memory impairment in aged animal models. We report a translational study aiming to determine safety and tolerability of a wheat germ extract containing enhanced spermidine concentrations in murine model and a human cohort of older adults with subjective cognitive decline (SCD), a risk factor of dementia. Methods In murine model, safety of various dosing strategies was assessed using a sub-chronic, oral administration scenario. Post mortem examination of mice included macroscopic inspection of organs, organ weighing and neoplastic examination after 28 days of spermidine supplementation at various concentrations. In addition, animal behavior and animal bodyweight were controlled during the treatment to detect any negative effects. In the human cohort, a randomized, placebo-controlled, double-blind Phase II study was carried out over 3 months to assess safety and tolerability of spermidine supplementation. Safety assessments included vital signs, weight, clinical chemistry and hematological parameters of safety, as well as self-reported health status at the end of intervention. Frequency, duration and severity of adverse event was monitored throughout the trial. Results In the preclinical toxicity study, spermidine supplementation did not result in morbidities or changes in behavior in BALBc/Rj mice during the 28-days repeated-dose tolerance study. Post mortem examination of the mice organs showed no significant increase in tumorigenic and fibrotic events. In the human cohort, no differences were observed between spermidine and placebo-treated groups in vital signs, weight, clinical chemistry and hematological parameters of safety, as well as in self-reported health status at the end of intervention. Compliance rates were above 85% and indicated excellent tolerability. Conclusion Findings of this translational study demonstrate that spermidine supplementation using a spermidine-rich plant extract is safe and well-tolerated in mice and older adults. These findings call for longer-term intervention studies in humans to investigate the impact of spermidine treatment on memory function and brain integrity.

P79. The effect of cognitive reserve in a subcohort of the EMPIR project NeuroMet ‘Innovative measurements for improved diagnosis and management of neurodegenerative diseases’

Background One of the most common neurodegenerative diseases is Alzheimer’s disease (AD). Maintaining a healthy life style can reduce the risk of AD due to cognitive and brain reserve, but the influence of reserve is often difficult to measure. In this ongoing study, we use 7 T high resolution MRI data from the EMPIR project NeuroMet to explore cognitive reserve in more detail. In NeuroMet, the diverse expertise of various national measurement institutes, including both clinicians and academics, joined together to improve accurate diagnostic and thereby approach better therapy. We present an overview of the project, which aims to (1) develop improved magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) methods, (2) understand bias and uncertainty of immunoassays and digital PCR methods for neurodegenerative disease protein and miRNA biomarkers, (3) develop reference methods for tau, and (4) improve cognitive assessment questionnaire for early diagnosis of Alzheimer’s disease. Methods In this project, a total of 90 participants are being recruited (30 Healthy Control, 30 Mild Cognitive Impairment and 30 AD patients). All subjects are undergoing a battery of neuropsychological tests. With a focus on reserve, the relationship between memory scores and hippocampal volumetric data obtained from T1 weighted MRI images of a 7T MRI scanner (Siemens Magnetom, Erlangen, Germany) will be analyzed. Additionally, participants are being asked to fill in a self-administered lifestyle questionnaire which assesses current physical activity and nutrition. The influence of lifestyle factors will be investigated and preliminary results will be presented. For general blood count and APOE genotyping, blood samples are being drawn. Immunoassays (Meso Scale Discovery) are being developed to overcome matrix effects and achieve duplexed detection of As40 and As42 within human plasma. Available cerebrospinal fluid (CSF) samples are being tested performing digital PCR for a panel of proteins and miRNA biomarkers, all of which might be used to obtain further insights into cognitive reserve. Furthermore, liquid chromatography mass spectrometry (LC-MS, triple quadrupole and quadrupole time of flight) is performed on blood and CSF samples, to investigate concentrations of the mentioned biomarkers. This diversity of different cutting-edge measures, like ultra-high field MRI and MRS, LC-MS, miRNA assays, new immunoassays, and digital PCR methods, will provide anatomical, functional, and metabolic information in order to improve sensitivity, resolution and delineation for volume, connectivity, and metabolite quantification. Conclusion The NeuroMet project aims to improve diagnostic measurements for AD, which are important to better understand the effects of cognitive and brain reserve in detail.