Abstract Background Alzheimer’s disease (AD) is a multifactorial disease, characterized not only by pathological protein aggregation (Ab and tau), but also by early vascular dysfunctions and functional connectivity alterations (Iturria‐Medina 2016; van der Kant 2019). The study objective was to investigate the association between different markers of vascular health as well as brain β‐amyloid burden and brain network functional connectivity across the AD spectrum. Method The sample included 131 participants with normal cognition, subjective cognitive decline, mild cognitive impairment and clinical AD from the IMAP cohort (Caen, France). Vascular risk factors comprised mean arterial pressure, body‐mass‐index (BMI), glycemia and HbA1c levels. White matter hyperintensities (WMH) were segmented from FLAIR‐MRI using the “lesion‐segmentation‐tool” (Schmidt, 2017). Brain β‐amyloid burden was measured by the mean of AV45‐SUVR in an AD‐related neocortex mask (LaJoie 2012). Resting‐state functional connectivity (RSFC) was determined within seven predefined functional networks (Schaefer 2018, Verfaillie 2018). Partial correlation analyses were run to assess associations of vascular risk factors, total WMH load and β‐amyloid burden with RSFC. Additionally, we tested for interaction effects with β‐amyloid status in linear regression analyses. All models were age‐ and sex‐adjusted. Result Participant characteristics are presented in Figure 1. Across all participants, higher BMI and higher glycemia were associated with lower RSFC within the default‐mode, salience/ventral‐attention, fronto‐parietal and dorsal‐attention networks (Figure 2 and 3). Results remained significant after correction for diagnostic group status. No associations were found between RSFC and total WMH load or β‐amyloid burden (p≥0.05). There were no significant moderation effects by β‐amyloid positivity (p≥0.05). Conclusion These findings demonstrate that metabolic‐related vascular risk factors, but not cerebrovascular or β‐amyloid pathologies, are associated with functional connectivity specifically within cognition‐related functional networks. Our study further highlights that connectivity alterations associated with metabolic risk, previously shown in diabetes patients (Musen 2012; Chen 2015), are also present in a non‐diabetic aging and AD cohort. Given that functional connectivity supports reserve capacity, connectivity failure within higher‐order networks may limit resilience against aging and pathological processes.
Vascular risk factors are associated with increased risk of Alzheimer disease (AD), but it is unclear whether there is a direct association of these risk factors with AD pathogenesis.
Objectives
To assess the associations of vascular risk factors with AD pathogenesis in asymptomatic individuals, and to test whether this association is moderated among individuals who use vascular medications.
Design, Setting, and Participants
This cross-sectional study used data from the Presymptomatic Evaluation of Experimental or Novel Treatments for Alzheimer Disease (PREVENT-AD) cohort of cognitively unimpaired individuals aged 55 to 82 years with a parental or multiple-sibling history of sporadic AD, who were recruited via advertisement from the greater Montreal, Quebec, Canada, metropolitan area. Participants were enrolled between September 9, 2011, to May, 3, 2017, and stratified by use vs no use of vascular medications. Data were analyzed July 1, 2018, to April 5, 2019.
Main Outcomes and Measures
Principal analyses investigated associations of total, high-density lipoprotein, and low-density lipoprotein cholesterol levels, systolic and diastolic blood pressure, pulse pressure, and a combined vascular risk score (measured using the Framingham Coronary Risk Profile) with global β-amyloid peptide (Aβ) and entorhinal tau burden as measured by positron emission tomography (PET). Potential moderating associations of use of vascular medications with these associations were examined. Secondary similar analyses considered cerebrospinal fluid (CSF) Aβ1-42 and phosphorylated tau levels.
Results
Among 215 participants (mean [SD] age, 62.3 [5.0] years; 161 [74.8%] women), 120 participants underwent PET, including 75 participants (62.5%) who were not using vascular medications, and 162 participants underwent CSF assessment, including 113 participants (69.8%) who were not using vascular medications. There was an overlap of 67 participants who underwent PET and CSF assessment. Interaction analyses showed that among participants not using vascular medications, higher Aβ deposition as measured by PET was associated with higher total cholesterol level (β = −0.002 [SE, 0.001];P = .02), low-density lipoprotein cholesterol level (β = −0.002 [SE, 0.001];P = .006), systolic blood pressure (β = −0.006 [SE, 0.002];P = .02), pulse pressure (β = −0.007 [SE, 0.002];P = .004), and Framingham Coronary Risk Profile score (β = −0.038 [SE, 0.011];P = .001), but such associations were absent in participants who used vascular medications. Interactions were also found between vascular medication use and high-density lipoprotein cholesterol (β = −3.302 [SE, 1.540];P = .03), low-density lipoprotein cholesterol (β = 1.546 [SE, 0.754];P = .04), and Framingham Coronary Risk Profile score (β = 23.102 [SE, 10.993];P = .04) on Aβ1-42 burden as measured in CSF. Higher Framingham Coronary Risk Profile scores were associated with reduced tau burden among participants using vascular medications but not among participants not using vascular medications (interaction, β = −0.010 [SE, 0.005];P = .046).
Conclusions and Relevance
These findings corroborate previously reported associations of vascular risk factors with Aβ burden but not tau burden. However, these associations were found only among individuals who were not using vascular medications. These results suggest that medication use or other control of vascular risk factors should be considered in Alzheimer disease prevention trials.
Abstract: 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. Keywords: older people, MCI, pilot study, intervention study, cognitively stimulating leisure activities, training program, daily activity protocols
Resting-state functional connectivity is suggested to be cross-sectionally associated with both vascular burden and Alzheimer's disease (AD) pathology. However, evidence is lacking regarding longitudinal changes in functional connectivity. This study includes 247 cognitively unimpaired individuals with a family history of sporadic AD (185 women/ 62 men; mean [SD] age of 63 [5.3] years). Plasma total-, HDL-, and LDL-cholesterol and systolic and diastolic blood pressure were measured at baseline. Global (whole-brain) brain functional connectivity and connectivity from canonical functional networks were computed from resting-state functional MRI obtained at baseline and ~3.5 years of annual follow-ups, using a predefined functional parcellation. A subsample underwent Aβ- and tau-PET (n=91). Linear mixed-effects models demonstrated that global functional connectivity increased over time across the entire sample. In contrast, higher total-cholesterol and LDL-cholesterol levels were associated with greater reduction of functional connectivity in the default-mode network over time. In addition, higher diastolic blood pressure was associated with global functional connectivity reduction. The associations were similar when the analyses were repeated using two other functional brain parcellations. Aβ and tau deposition in the brain were not associated with changes in functional connectivity over time in the subsample. These findings provide evidence that vascular burden is associated with a decrease in functional connectivity over time in older adults with elevated risk for AD. Future studies are needed to determine if the impact of vascular risk factors on functional brain changes precede the impact of AD pathology on functional brain changes.
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, placebo-controlled 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 (0.9 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.
1 A bstract Regular musical activity as a highly-stimulating lifestyle activity is proposed to be protective against age-related cognitive decline and Alzheimer’s disease (AD). This study investigated associations between lifelong regular musical instrument playing, late-life cognitive abilities and brain morphology in older adults. We show that musical activity over the life course is associated with better global cognition, working memory, executive functions, language, and visuospatial abilities accounting for reserve proxies. Playing music is not significantly associated with gray matter volume in regions most affected by aging and AD. Selectively in the musically active participants, multi-domain cognitive abilities were enhanced with preserved gray matter volume in frontal and temporal regions. Our correlational findings suggest that playing a musical instrument may improve the recruitment of existing brain resources to facilitate late-life cognitive capacities. We propose that engaging in regular musical activity could serve as a low-threshold multimodal enrichment strategy that may promote cognitive resilience in advanced age.
Regional variation in the degree of functional (i.e., hypoperfusion and hypometabolism) and structural brain injury is seen in Alzheimer's disease (AD) patients, often accompanied by cerebrovascular burden. These AD pathological hallmarks need further characterization at prodromal disease stages (Mattsson et al., 2014) to develop sensitive biomarkers for early AD detection (Wierenga et al., 2014). We evaluated cerebral hypoperfusion, gray-matter atrophy, and white-matter lesions (WMLs) in incipient AD using magnetic resonance imaging (MRI). Cognitively-normal older adults (n=107, 63±7 years) and mild cognitive impairment (MCI) patients (n=52, 67±8 years) were examined. Cerebral perfusion (blood volume and blood flow, measured using dynamic-susceptibility contrast imaging), gray-matter atrophy (measured by volume and, if available, cortical thickness using structural MRI) were extracted within AD-sensitive regions of interest. Regional biomarker variation was compared between diagnostic groups (adjusting for age and sex) and relationships with WML volumes were assessed. In MCI patients, region-specific cerebral hypoperfusion (mainly blood flow reduction, Figure 1) was detected in temporo-parietal regions and the basal ganglia compared to cognitively-normal older adults; region-specific atrophy occurred in the hippocampus (Figure 1). Both, hypoperfusion and atrophy (i.e., cortical thinning) were present in entorhinal cortex and isthmus cingulate. WMLs were correlated with hypoperfusion in temporo-partial regions and the basal ganglia and with atrophy in hippocampal and entorhinal regions across diagnostic groups. Results of multiple regression models with cerebral blood volume, cerebral blood flow (both normalized to gray- matter cerebellum), gray-matter volume (normalized for intracranial volume), or cortical thickness as dependent variable; diagnostic group (cognitively-normal older adults, MCI patients) as independent variable, adjusted for age and sex. Standardized regression coefficients for effects of diagnostic group are provided with significance indicated (*p<0.05, uncorrected). Negative values reflect hypoperfusion or gray-matter atrophy in MCI patients. Our data indicate extensive cerebral blood flow alterations within AD-sensitive regions in incipient AD. We also document divergent patterns in the degree of regional hypoperfusion and atrophy, pointing toward applicability as sensitive and independent MRI-based biomarkers in early AD detection. Hypoperfusion and atrophy were both affected by white-matter pathology, suggesting additive effects of regional pathological mechanisms and cerebrovascular burden at prodromal stages of AD.
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 75 years) 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*| = 980 Pa) 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.
Abstract Background Subjective Cognitive Decline (SCD) may represent the earliest clinical manifestation of Alzheimer’s disease (AD) (Jessen et al. 2014). In individuals with SCD and mild cognitive impairment (MCI), changes in white matter (WM) microstructure have been shown using diffusion weighted (DW) imaging (Brueggen et al. 2019). However, it is unknown to which extent these alterations are associated with cognitive and psychological deficits. Thus, this study aims to investigate the relationship between WM tract metrics and cognitive performance as well as psychological traits in pre‐dementia stages of AD. Method In total, 88 patients with MCI, 90 individuals with SCD, and 47 healthy controls (mean age 69±7 years) underwent neuropsychological testing and DW magnetic resonance imaging. Selected questionnaires on stress coping, worry, and rumination were included to evaluate the psychological profile of SCD. Fractional Anisotropy (FA) and Mean Diffusivity (MD) from the DW images were obtained for selected WM tracts of interest using the TRACULA pipeline (Yendiki et al. 2011). Composite scores for memory and executive function were calculated. General linear models adjusted for age, sex, education, cardiovascular risk, and group membership were conducted. Due to the exploratory nature of this study, we did not correct for multiple testing. Result Across the entire study sample, higher memory performance was associated with DW parameters of the angular bundle of the cingulum (higher FA, p=0.004; lower MD, p=0.019). Higher FA of the anterior thalamic radiation (ATR) was related to a lower memory score (p=0.049). Higher executive function was related to DW metrics of the uncinate fasciculus (UNC) (higher FA, p=0.038; lower MD, p=0.034) and of the ATR (lower MD, p<0.001). Within SCD subjects, MD of the UNC was positively associated with positive stress coping strategies (p=0.005). Conclusion Our findings suggest that higher memory performance and executive functions are associated with favourable tract‐specific DW parameters in pre‐dementia stages of AD. The relationship of higher positive stress coping with WM microstructural alterations in SCD (i.e., increased MD of the UNC) might be explained by psychological compensatory mechanisms in the presence of early WM pathology. Further investigation is needed to elucidate possible clinical implications of these findings.
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