Feasibility and first results of a group program to increase the frequency of cognitively stimulating leisure activities in people with mild cognitive impairment (AKTIVA–MCI)

AKTIVA-MCI is a program for patients with mild cognitive impairment (MCI) that aims to enhance participation in cognitively stimulating leisure activities. Participation in cognitively stimulating activities seems to be a potential strategy for people with MCI delaying cognitive decline for a while. In total, 35 MCI patients were enrolled in the pilot study of whom 29 completed the whole program (16 female, 71.1±7.5 years; Mini Mental Status Examination score: 28±2.2). Daily activity protocols were used to measure the frequency of participation in cognitively stimulating activities during the program (12 sessions). Additional standardized psychometric tests and questionnaires were used to assess cognition, mood, and subjective memory decline. Analyses of the daily activity protocols showed that during the intervention participants increased the frequency of several cognitively stimulating leisure activities. Comparison of pre-post data indicates no changes in cognitive status, mood, and subjective memory decline. These findings indicate that the program is suitable for patients with MCI

Negative affective burden is associated with higher resting-state functional connectivity in subjective cognitive decline

Publisher Copyright: © 2022, The Author(s).Subjective cognitive decline (SCD), as expressed by older adults, is associated with negative affect, which, in turn, is a likely risk factor for Alzheimer’s Disease (AD). This study assessed the associations between negative affective burden, cognitive functioning, and functional connectivity in networks vulnerable to AD in the context of SCD. Older participants (60–90 years) with SCD (n = 51) and healthy controls (n = 50) were investigated in a cross-sectional study. Subclinical negative affective burden, quantified through a composite of self-reported negative affective factors, was related to cognitive functioning (self-perceived and objective) and functional connectivity. Seed-to-voxel analyses were carried out in default mode network (DMN) and salience network (SAL) nodes using resting-state functional magnetic resonance imaging. Greater negative affective burden was associated with lower self-perceived cognitive functioning and lower between-network functional connectivity of DMN and SAL nodes in the total sample. In addition, there was a significant moderation of SCD status. Greater negative affective burden related to higher functional connectivity within DMN (posterior cingulate-to-precuneus) and within SAL (anterior cingulate-to-insula) nodes in the SCD group, whereas in controls the inverse association was found. We show that negative affective burden is associated with functional brain alterations in older adults, regardless of SCD status. Specifically in the SCD phenotype, greater negative affective burden relates to higher functional connectivity within brain networks vulnerable to AD. Our findings imply that negative affective burden should be considered a potentially modifiable target for early intervention.Peer reviewe

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, Cohen's 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, Cohen's 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

Effects of spermidine supplementation on cognition and biomarkers in older adults with subjective cognitive decline (SmartAge)—study protocol for a randomized controlled trial

Background: Given the global increase in the aging population and age-related diseases, the promotion of healthy aging is one of the most crucial public health issues. This trial aims to contribute to the establishment of effective approaches to promote cognitive and brain health in older individuals with subjective cognitive decline (SCD). Presence of SCD is known to increase the risk of objective cognitive decline and progression to dementia due to Alzheimer’s disease. Therefore, it is our primary goal to determine whether spermidine supplementation has a positive impact on memory performance in this at-risk group, as compared with placebo. The secondary goal is to examine the effects of spermidine intake on other neuropsychological, behavioral, and physiological parameters. Methods: The SmartAge trial is a monocentric, randomized, double-blind, placebo-controlled phase IIb trial. The study will investigate 12 months of intervention with spermidine-based nutritional supplementation (target intervention) compared with 12months of placebo intake (control intervention). We plan to recruit 100 cognitively normal older individuals with SCD from memory clinics, neurologists and general practitioners in private practice, and the general population. Participants will be allocated to one of the two study arms using blockwise randomization stratified by age and sex with a 1:1 allocation ratio. The primary outcome is the change in memory performance between baseline and post-intervention visits (12 months after baseline). Secondary outcomes include the change in memory performance from baseline to follow-up assessment (18months after baseline), as well as changes in neurocognitive, behavioral, and physiological parameters (including blood and neuroimaging biomarkers), assessed at baseline and post-intervention. Discussion: The SmartAge trial aims to provide evidence of the impact of spermidine supplementation on memory performance in older individuals with SCD. In addition, we will identify possible neurophysiological mechanisms of action underlying the anticipated cognitive benefits. Overall, this trial will contribute to the establishment of nutrition intervention in the prevention of Alzheimer’s disease

Effects of Spermidine Supplementation on Cognition and Biomarkers in Older Adults With Subjective Cognitive Decline : Decline A Randomized Clinical Trial

IMPORTANCE Developing interventions against age-related memory decline and for older adults experiencing neurodegenerative disease is one of the greatest challenges of our generation. Spermidine supplementation has shown beneficial effects on brain and cognitive health in animal models, and there has been preliminary evidence of memory improvement in individuals with subjective cognitive decline. OBJECTIVE To determine the effect of longer-term spermidine supplementation on memory performance and biomarkers in this at-risk group. DESIGN, SETTING, AND PARTICIPANTS This 12-month randomized, double-masked, placebocontrolled phase 2b trial (the SmartAge trial) was conducted between January 2017 and May 2020. The study was a monocenter trial carried out at an academic clinical research center in Germany. Eligible individuals were aged 60 to 90 years with subjective cognitive decline who were recruited from health care facilities as well as through advertisements in the general population. Data analysis was conducted between January and March 2021. INTERVENTIONS One hundred participants were randomly assigned (1:1 ratio) to 12 months of dietary supplementation with either a spermidine-rich dietary supplement extracted from wheat germ (O.9 mg spermidine/d) or placebo (microcrystalline cellulose). Eighty-nine participants (89%) successfully completed the trial intervention. MAIN OUTCOMES AND MEASURES Primary outcome was change in memory performance from baseline to 12-month postintervention assessment (intention-to-treat analysis), operationalized by mnemonic discrimination performance assessed by the Mnemonic Similarity Task. Secondary outcomes included additional neuropsychological, behavioral, and physiological parameters. Safety was assessed in all participants and exploratory per-protocol, as well as subgroup, analyses were performed. RESULTS A total of 100 participants (51 in the spermidine group and 49 in the placebo group) were included in the analysis (mean [SD] age, 69 [5] years; 49 female participants [49%]). Over 12 months, no significant changes were observed in mnemonic discrimination performance (between-group difference, -0.03; 95% CI, -0.11 to 0.05; P = .47) and secondary outcomes. Exploratory analyses indicated possible beneficial effects of the intervention on inflammation and verbal memory. Adverse events were balanced between groups. CONCLUSIONS AND RELEVANCE In this randomized clinical trial, longer-term spermidine supplementation in participants with subjective cognitive decline did not modify memory and biomarkers compared with placebo. Exploratory analyses indicated possible beneficial effects on verbal memory and inflammation that need to be validated in future studies at higher dosage.Peer reviewe

Impact of lifestyle and genetics factors on brain structure and function of healthy older adults and patients with mild cognitive impairment

In unserer zunehmend älter werdenden Gesellschaft nimmt die Zahl an Demenzerkrankungen rasant zu. Daher ist es von großer Bedeutung genetische und lebensstilbezogene Risikofaktoren zu identifizieren und frühzeitige Präventions- und Interventionsstrategien zu entwickeln. Die vorliegende Dissertationsschrift fasst zwei Querschnittsstudien und eine Interventionsstudie zusammen, in denen der Einfluss eines genetischen sowie eines ernährungsassoziierten Risikofaktors und der Einfluss einer multifaktoriellen Intervention auf die Gehirnstruktur und –funktion von gesunden Älteren oder Patienten mit leichten Gedächtniseinschränkungen (MCI) untersucht wurde. In der ersten Studie wurde der Einfluss des KIBRA-Genotyps auf die Lern- und Gedächtnisleistung sowie Struktur und funktionelle Konnektivität des Hippocampus von gesunden Älteren untersucht. Hierfür wurden 140 Studienteilnehmer genotypisiert, auf ihre Gedächtnisleistung getestet und erhielten eine 3-Tesla Magnetresonanztomographie (MRT). KIBRA-T-Allel-Träger zeigten gegenüber Nicht-T-Allel-Trägern eine tendenziell bessere Gedächtnisleistung und sowohl ein signifikant größeres Volumen der hippocampalen Subfelder cornu ammonis (CA)2/3 bzw. CA4/ Gyrus dentatus (DG) als auch eine bessere Mikrostruktur letzterer. Weiterhin zeigten T-Allel- Träger eine geringere funktionelle Konnektivität zwischen linkem Hippocampus und Hirnarealen außerhalb des synchronisierten Hippocampusnetzwerkes. Die Ergebnisse bekräftigen den genetischen Einfluss von KIBRA auf Hirnstruktur und -funktion, was in zukünftigen Studien berücksichtigt werden sollte. Die zweite Studie wurde zur Analyse des Zusammenhangs zwischen Vitamin-B12-Konzentration (VitB12) im normalen Bereich, Gedächtnisfunktion und Hippocampusstruktur bei MCI-Patienten durchgeführt. Hierfür wurden 100 Patienten neuropsychologisch getestet, erhielten eine zerebrale 3-Tesla MRT (n=86) und bekamen Nüchternblutproben entnommen. Im Vergleich zu MCI-Patienten mit VitB12 im oberen Normbereich wiesen Patienten mit VitB12 im unteren Normbereich eine schlechtere Lern- und Gedächtnisleistung auf. Weiterhin war ein niedrigerer VitB12-Spiegel mit einer schlechteren Mikrostruktur der CA4/DG-Subfelder assoziiert, wodurch der Einfluss von VitB12 auf die Gedächtnisleistung teilweise erklärt werden kann. Zukünftige Diagnostik- und Behandlungsstrategien sollten VitB12-Werte im aktuell unteren Normbereich bereits als pathologisch betrachten. Ziel der dritten Studie war es zu untersuchen, ob eine kombinierte Intervention mit Omega-3-Fettsäuren, körperlichem Training und kognitiver Stimulation (Zielintervention; n=13) effektiver gegenüber einer Einzelintervention mit Omega-3-Fettsäuren und Gymnastikübungen (Kontrollintervention; n=9) ist. Vor und nach sechsmonatiger Intervention erhielten 22 MCI-Patienten eine neuropsychologische Testuntersuchung, ein 3-Tesla MRT (n=20), eine Nüchternblutabnahme und eine Bestimmung vaskulärer Parameter. Es war eine Volumenreduktion der grauen Substanz im frontalen, parietalen und cingulären Cortex nach der Kontrollintervention zu verzeichnen, wohingegen nach der Zielintervention keine Veränderung bzw. sogar eine Volumenzunahme festgestellt wurde - teilweise assoziiert mit einer Verringerung der Homocysteinkonzentration. Hinsichtlich der kognitiven Leistung sowie der vaskulären und entzündungsanzeigenden Marker wurden über die Zeit keine Gruppenunterschiede gefunden. Der hier gezeigte positive Effekt einer kombinierten Intervention stellt eine vielversprechende Grundlage für größere Interventionsstudien dar.The number of patients with dementia is steadily increasing due to the aging society. Therefore, it is from great health and socioeconomic interest to identify genetic and lifestyle risk factors and to develop early preventive and interventional strategies. The present thesis comprising two cross- sectional studies and one longitudinal study addresses the impact of a genetic and a dietary risk factor and a multicomponent intervention on brain structure and function in healthy older adults or patients with mild cognitive impairment (MCI). The first study tested the impact of KIBRA genotype on learning and memory function, hippocampal structure and functional connectivity in healthy older adults. 140 subjects were KIBRA genotyped, tested for memory performance and MRI-scanned at 3-Tesla. KIBRA T-allele carriers showed a trend for better memory performance, significantly higher volumes and partly better microstructure in the hippocampus cornu ammonis (CA)2/3 and CA4/dentate gyrus (DG) subfields, compared to non-T-allele carriers. Moreover, T-allele carriers exhibited lower functional connectivity of the left hippocampus with areas outside the synchronized hippocampus network. The results support a genetic impact of KIBRA on brain structure and function that should be considered in ongoing trials. The second study determined whether vitamin B12 concentrations (VitB12) within the normal range are linked to memory function and related neuronal structures in MCI patients. 100 patients underwent fasting blood sampling, neuropsychological testing and 3-Tesla MRI (n=86). Compared to MCI patients with high-normal VitB12, patients with low-normal VitB12 showed a significant poorer learning and recognition performance and a worse microstructure of the CA4/DG region, partially mediating the effect of VitB12 on memory performance. Future diagnostic and treatment strategies that aim to raise VitB12 to high-normal concentrations should be considered. The third study aimed to elucidate potential superior effects of a six months combined intervention with omega-3 fatty acids, physical exercise and cognitive stimulation (target intervention; n=13) compared to a single intervention with omega-3 fatty acids and control exercise (control intervention; n=9). Before and after interventions, all 22 MCI patients underwent a neuropsychological testing, MRI at 3-Tesla (n=20), assessment of vascular markers and fasting blood samples. Gray matter volume of the frontal, parietal and cingulate cortex decreased after control intervention, while it was preserved or even increased after target intervention, partially associated with a decrease in homocysteine. Group differences in cognitive performance, vascular and inflammatory parameters were not observed. The beneficial effects after combined intervention provide a promising basis for larger interventional trial

Functional connectivity in cognitive control networks mitigates the impact of white matter lesions in the elderly

Abstract Background Cerebrovascular pathology, quantified by white matter lesions (WML), is known to affect cognition in aging, and is associated with an increased risk of dementia. The present study aimed to investigate whether higher functional connectivity in cognitive control networks mitigates the detrimental effect of WML on cognition. Methods Nondemented older participants (≥ 50 years; n = 230) underwent cognitive evaluation, fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI), and resting state functional magnetic resonance imaging (fMRI). Total WML volumes were quantified algorithmically. Functional connectivity was assessed in preselected higher-order resting state networks, namely the fronto-parietal, the salience, and the default mode network, using global and local measures. Latent moderated structural equations modeling examined direct and interactive relationships between WML volumes, functional connectivity, and cognition. Results Larger WML volumes were associated with worse cognition, having a greater impact on executive functions (β = −0.37, p < 0.01) than on memory (β = −0.22, p < 0.01). Higher global functional connectivity in the fronto-parietal network and higher local connectivity between the salience network and medial frontal cortex significantly mitigated the impact of WML on executive functions, (unstandardized coefficients: b = 2.39, p = 0.01; b = 3.92, p = 0.01) but not on memory (b = -5.01, p = 0.51, b = 2.01, p = 0.07, respectively). No such effects were detected for the default mode network. Conclusion Higher functional connectivity in fronto-parietal and salience networks may protect against detrimental effects of WML on executive functions, the cognitive domain that was predominantly affected by cerebrovascular pathology. These results highlight the crucial role of cognitive control networks as a neural substrate of cognitive reserve in older individuals

Combining viscoelasticity, diffusivity and volume of the hippocampus for the diagnosis of Alzheimer's disease based on magnetic resonance imaging

Dementia due to Alzheimer's Disease (AD) is a neurodegenerative disease for which treatment strategies at an early stage are of great clinical importance. So far, there is still a lack of non-invasive diagnostic tools to sensitively detect AD in early stages and to predict individual disease progression. Magnetic resonance elastography (MRE) of the brain may be a promising novel tool. In this proof-of-concept study, we investigated whether multifrequency-MRE (MMRE) can detect differences in hippocampal stiffness between patients with clinical diagnosis of dementia due to AD and healthy controls (HC). Further, we analyzed if the combination of three MRI-derived parameters, i.e., hippocampal stiffness, hippocampal volume and mean diffusivity (MD), improves diagnostic accuracy.Diagnostic criteria for probable dementia due to AD were in line with the NINCDS-ADRDA criteria and were verified through history-taking (patient and informant), neuropsychological testing, routine blood results and routine MRI to exclude other medical causes of a cognitive decline.21 AD patients and 21 HC (median age 75years) underwent MMRE and structural MRI, from which hippocampal volume and MD were calculated. From the MMRE-images maps of the magnitude |G*| and phase angle φ of the complex shear modulus were reconstructed using multifrequency inversion. Median values of |G*| and φ were extracted within three regions of interest (hippocampus, thalamus and whole brain white matter). To test the predictive value of the main outcome parameters, we performed receiver operating characteristic (ROC) curve analyses.Hippocampal stiffness (|G*|) and viscosity (φ) were significantly lower in the patient group (both p<0.001). ROC curve analyses showed an area under the curve (AUC) for |G*| of 0.81 [95%CI 0.68–0.94]; with sensitivity 86%, specificity 67% for cutoff at |G*|=980Pa) and for φ an AUC of 0.79 [95%CI 0.66–0.93]. In comparison, the AUC of MD and hippocampal volume were 0.83 [95%CI 0.71–0.95] and 0.86 [95%CI 0.74–0.97], respectively. A combined ROC curve of |G*|, MD and hippocampal volume yielded a significantly improved AUC of 0.90 [95%CI 0.81–0.99].In conclusion, we demonstrated reduced hippocampal stiffness and reduced hippocampal viscosity, as determined by MMRE, in patients with clinical diagnosis of dementia of the AD type. Diagnostic sensitivity was further improved by the combination with two other MRI-based hippocampal parameters. These findings motivate further investigation whether MMRE can detect decreased brain stiffness already in pre-dementia stages, and whether these changes predict cognitive decline. Keywords: Alzheimer's disease, MR elastography, Viscoelasticity, Diffusivity, Hippocampus, Hippocampal volume, RO