Trans ε-Viniferin Decreases Amyloid Deposits With Greater Efficiency Than Resveratrol in an Alzheimer’s Mouse Model

In a previous study, we showed that viniferin decreased amyloid deposits and reduced neuroinflammation in APPswePS1dE9 transgenic mice between 3 and 6 months of age. In the present study, wild type and APPswePS1dE9 transgenic mice were treated from 7 to 11 or from 3 to 12 months by a weekly intraperitoneal injection of either 20 mg/kg viniferin or resveratrol or their vehicle, the polyethylene glycol 200 (PEG 200). The cognitive status of the mice was evaluated by the Morris water maze test. Then, amyloid burden and neuroinflammation were quantified by western-blot, Enzyme-Linked ImmunoSorbent Assay (ELISA), immunofluorescence, and in vivo micro-Positon Emission Tomography (PET) imaging. Viniferin decreased hippocampal amyloid load and deposits with greater efficiency than resveratrol, and both treatments partially prevented the cognitive decline. Furthermore, a significant decrease in brain uptake of the TSPO PET tracer [18F]DPA-714 was observed with viniferin compared to resveratrol. Expression of GFAP, IBA1, and IL-1β were decreased by viniferin but PEG 200, which was very recently shown to be a neuroinflammatory inducer, masked the neuroprotective power of viniferin.

Neddylation-dependent protein degradation is a nexus between synaptic insulin resistance, neuroinflammation and Alzheimer’s disease

Background The metabolic syndrome is a consequence of modern lifestyle that causes synaptic insulin resistance and cognitive deficits and that in interaction with a high amyloid load is an important risk factor for Alzheimer's disease. It has been proposed that neuroinflammation might be an intervening variable, but the underlying mechanisms are currently unknown. Methods We utilized primary neurons to induce synaptic insulin resistance as well as a mouse model of high-risk aging that includes a high amyloid load, neuroinflammation, and diet-induced obesity to test hypotheses on underlying mechanisms. Results We found that neddylation and subsequent activation of cullin-RING ligase complexes induced synaptic insulin resistance through ubiquitylation and degradation of the insulin-receptor substrate IRS1 that organizes synaptic insulin signaling. Accordingly, inhibition of neddylation preserved synaptic insulin signaling and rescued memory deficits in mice with a high amyloid load, which were fed with a 'western diet'. Conclusions Collectively, the data suggest that neddylation and degradation of the insulin-receptor substrate is a nodal point that links high amyloid load, neuroinflammation, and synaptic insulin resistance to cognitive decline and impaired synaptic plasticity in high-risk aging.

Classification of 18F-Flutemetamol Scans in Cognitively Normal Older Adults Using Machine Learning Trained with Neuropathology as Groundtruth

PURPOSE: End-of-life studies have validated the binary visual reads of 18F-labeled amyloid PET tracers as an accurate tool for the presence or absence of increased neuritic amyloid plaque density. In this study, the performance of a support vector machine (SVM) based classifier will be tested against pathological groundtruths and its performance determined in cognitively healthy older adults.METHODS: We applied SVM with a linear kernel to an 18F-Flutemetamol end-of-life dataset to determine the regions with the highest feature weights in a data-driven manner and to compare between two different pathological groundtruths: based on neuritic amyloid plaque density or on amyloid phases, respectively. We also trained and tested classifiers based on the 10% voxels with the highest feature weights for each of the two neuropathological groundtruths. Next, we tested the classifiers’ diagnostic performance in the asymptomatic Alzheimer’s disease (AD) phase, a phase of interest for future drug development, in an independent dataset of cognitively intact older adults, the Flemish Prevent AD Cohort-KU Leuven (F-PACK). A regression analysis was conducted between the Centiloid (CL) value in a composite volume of interest (VOI), as index for amyloid load, and the distance to the hyperplane for each of the two classifiers, based on the two pathological groundtruths. A Receiver-Operating-Characteristic analysis was also performed to determine the CL threshold that optimally discriminates between neuritic amyloid plaque positivity versus negativity, or amyloid phase positivity versus negativity, within F-PACK.RESULTS: The classifiers yielded adequate sensitivity and specificity within the end-of-life dataset (neuritic amyloid plaque density classifier: specificity of 90.2% and sensitivity of 83.7%; amyloid phase classifier: specificity of 98.4% and sensitivity of 84.0%). The regions with the highest feature weights corresponded to precuneus, caudate, anteromedial prefrontal, and also posterior inferior temporal and inferior parietal cortex. In the cognitively normal cohort, the correlation coefficient between CL and distance to the hyperplane was -0.66 for the classifier trained with neuritic amyloid plaque density, and -0.88 for the classifier trained with amyloid phases. This difference was significant. The optimal CL cut-off for discriminating positive versus negative scans was CL = 48-51 for the different classifiers (area under the curve (AUC) = 99.9%), except for the classifier trained with amyloid phases and based on the 10% voxels with highest feature weights. There the cut-off was CL = 26 (AUC = 99.5%).DISCUSSION: A neuropathologically validated classifier applied in cognitively normal older adults reveals that amyloid PET values (Centiloids) correlate best with amyloid phases. A CL cut-off of 26 reliably discriminated between amyloid phase 0-2 and 3-5 while only a CL around 50 discriminated between no or sparse and moderate to severe neuritic amyloid plaque density.

Difference in Amyloid Load Between Single Memory Domain and Multidomain Subjective Cognitive Decline: A Study from the SILCODE

Background: Subjective cognitive decline (SCD), an at-risk condition of Alzheimer’s disease (AD), can involve various cognitive domains, such as memory, language, planning, and attention. Objective: We aims to explore the differences in amyloid load between the single memory domain SCD (sd-SCD) and the multidomain SCD (md-SCD) and assess the relationship of amyloid pathology with quantitative SCD scores and objective cognition. Methods: A total of 63 SCD participants from the SILCODE study underwent the clinical evaluation, neuropsychological assessment, and 18F-florbetapir PET scan. Global amyloid standard uptake value ratio (SUVr) was calculated. Additionally, regional amyloid SUVr was quantified in 12 brain regions of interests. A nonparametric rank ANCOVA was used to compare the global and regional amyloid SUVr between the md-SCD (n = 34) and sd-SCD (n = 29) groups. A multiple linear regression analysis was conducted to test the relationship of amyloid SUVr with quantitative SCD scores and objective cognition. Results: Compared with individuals with sd-SCD, individuals with md-SCD had increased global amyloid SUVr (F = 5.033, p = 0.029) and regional amyloid SUVr in the left middle temporal gyrus (F = 12.309, p = 0.001; Bonferroni corrected), after controlling for the effects of age, sex, and education. When pooling all SCD participants together, the increased global amyloid SUVr was related with higher SCD-plus sum scores and lower Auditory Verbal Learning Test-delayed recall scores. Conclusion: According to our findings, individuals with md-SCD showed higher amyloid accumulation than individuals with sd-SCD, suggesting that md-SCD may experience a more advanced stage of SCD. Additionally, increased global amyloid load was predictive of a poorer episodic memory function in SCD individuals.

Personality Impact on Alzheimer’s Disease-Signature and Vascular Imaging Markers: A PET-MRI Study

Background: Several studies postulated that personality is an independent determinant of cognitive trajectories in old age. Objective: This study explores the impact of personality on widely used Alzheimer’s disease (AD) and vascular imaging markers. Methods: We examined the association between personality and three classical AD imaging markers (centiloid-based-amyloid load, MRI volumetry in hippocampus, and media temporal lobe atrophy), and two vascular MRI parameters (Fazekas score and number of cortical microbleeds) assessed at baseline and upon a 54-month-follow-up. Personality was assessed with the Neuroticism Extraversion Openness Personality Inventory-Revised. Regression models were used to identify predictors of imaging markers including sex, personality factors, presence of APOE ɛ4 allele and cognitive evolution over time. Results: Cortical GM volumes were negatively associated with higher levels of Conscientiousness both at baseline and follow-up. In contrast, higher scores of Openness were related to better preservation of left hippocampal volumes in these two time points and negatively associated with medial temporal atrophy at baseline. Amyloid load was not affected by personality factors. Cases with higher Extraversion scores displayed higher numbers of cortical microbleeds at baseline. Conclusion: Personality impact on brain morphometry is detected only in some among the routinely used imaging markers. The most robust associations concern the positive role of high levels of Conscientiousness and Openness on AD-signature MRI markers. Higher extraversion levels are associated with increased vulnerability to cortical microbleeds pointing to the fact that the socially favorable traits may have a detrimental effect on brain integrity in old age.

Angiotensin Receptor Blockers Upregulate Angiotensin Type 4 Receptor in Brains of Cognitively Intact Individuals

The primary dementia-protective benefits of Angiotensin receptor type 1 (AT1R) blockers (ARBs) are believed to arise from systemic effects on blood pressure. However, there is a brain-specific renin-angiotensin system (b-RAS) that acts mainly through three receptor subtypes: AT1R, AT2R, and AT4R. AT1R promotes inflammation and oxidative stress (OS). AT2R increases nitric oxide. AT4R is essential for dopamine release and mediates memory consolidation. Here, we aimed to investigate the effects of ARBs on b-RAS, OS, inflammation, PHF-tau, and beta-amyloid load. Postmortem frontal-cortex brains of age- and sex-matched cognitively intact (CI) individuals using (n=30) and not using ARBs (n=30) and Alzheimer's disease (AD) patients using (n=30) and not using ARBs (n=30) were studied. Protein levels of receptors were measured by Western blot. Protein carbonyl (PC) and cytokine levels were measured by ELISA. Tangle and amyloid-β scores were used as outcomes. In CI individuals, our data shows that ARB treatment was associated with higher protein levels of AT4R (median(range) 0.69(1.92) vs 0.17(1.18) CI+ARBs vs CI, p=0.02), lower level of OS marker PC (10.60(8.32) vs 11.26(7.44), CI+ARBs vs CI, p=0.03) and lower hippocampal and overall amyloid scores (0(5.45) vs 1.15(4.21) p=0.03, 0.79(12.75) vs 3.41(13.36) p=0.04, CI+ARBs vs CI, respectively). In AD group, ARB treatment was associated with lower AT1R protein levels (0.47(1.15) vs 0.59(1.99), AD+ARBs vs AD, p=0.02). No significant changes were observed in OS, inflammation, or PHF-tau and amyloid load in AD brains treated with ARBs. Our results highlight the impact of ARBs on the brains of cognitively intact and AD older individuals.