Β-amyloid Load Research Articles

Oleocanthal-rich extra-virgin olive oil enhances donepezil effect by reducing amyloid-β load and related toxicity in a mouse model of Alzheimer’s disease

Previous evidence suggested that extra-virgin olive oil (EVOO) is linked to attenuating amyloid-β (Aβ) pathology and improving cognitive function in Alzheimer’s disease (AD) mouse models. In addition, we recently reported the beneficial effect of oleocanthal, a phenolic compound in EVOO, against AD pathology. Currently, medications available to target AD pathology are limited. Donepezil is an acetylcholine esterase inhibitor approved for use for all AD stages. Donepezil has been reported to have limited Aβ-targeting mechanisms beside its acetylcholine esterase inhibition. The aim of this study was to investigate the consumption of EVOO rich with oleocanthal (hereafter EVOO) as a medical food on enhancing the effect of donepezil on attenuating Aβ load and related toxicity in 5xFAD mouse model of AD. Our results showed that EVOO consumption in combination with donepezil significantly reduced Aβ load and related pathological changes. Reduced Aβ load could be explained, at least in part, by enhancing Aβ clearance pathways including blood–brain barrier (BBB) clearance and enzymatic degradation, and shifting amyloid precursor protein processing toward the nonamyloidogenic pathway. Furthermore, EVOO combination with donepezil up-regulated synaptic proteins, enhanced BBB tightness and reduced neuroinflammation associated with Aβ pathology. In conclusion, EVOO consumption as a medical food combined with donepezil offers an effective therapeutic approach by enhancing the noncholinergic mechanisms of donepezil and by providing additional mechanisms to attenuate Aβ-related pathology in AD patients.

Low cortical iron and high entorhinal cortex volume promote cognitive functioning in the oldest-old

The aging brain is characterized by an increased presence of neurodegenerative and vascular pathologies. However, there is substantial variation regarding the relationship between an individual's pathological burden and resulting cognitive impairment. To identify correlates of preserved cognitive functioning at highest age, the relationship between β-amyloid plaque load, presence of small vessel cerebrovascular disease (SVCD), iron-burden, and brain atrophy was investigated. Eighty cognitively unimpaired participants (44 oldest-old, aged 85–96 years; 36 younger-old, aged 55–80 years) were scanned by integrated positron emission tomography–magnetic resonance imaging for assessing beta regional amyloid plaque load (18F-flutemetamol), white matter hyperintensities as an indicator of SVCD (fluid-attenuated inversion recovery–magnetic resonance imaging), and iron load (quantitative susceptibility mapping). For the oldest-old group, lower cortical volume, increased β-amyloid plaque load, prevalence of SVCD, and lower cognitive performance in the normal range were found. However, compared to normal-old, cortical iron burden was lower in the oldest-old. Moreover, only in the oldest-old, entorhinal cortex volume positively correlated with β-amyloid plaque load. Our data thus indicate that the co-occurrence of aging-associated neuropathologies with reduced quantitative susceptibility mapping measures of cortical iron load constitutes a lower vulnerability to cognitive loss.

Validation of Noninvasive Tracer Kinetic Analysis of 18F-Florbetaben PET Using a Dual-Time-Window Acquisition Protocol.

Accurate amyloid PET quantification is necessary for monitoring amyloid-β accumulation and response to therapy. Currently, most of the studies are analyzed using the static SUV ratio (SUVR) approach because of its simplicity. However, this approach may be influenced by changes in cerebral blood flow (CBF) or radiotracer clearance. Full tracer kinetic models require arterial blood sampling and dynamic image acquisition. The objectives of this work were, first, to validate a noninvasive kinetic modeling approach for 18F-florbetaben PET using an acquisition protocol with the best compromise between quantification accuracy and simplicity and, second, to assess the impact of CBF changes and radiotracer clearance on SUVRs and noninvasive kinetic modeling data in 18F-florbetaben PET. Methods: Using data from 20 subjects (10 patients with probable Alzheimer dementia and 10 healthy volunteers), the nondisplaceable binding potential (BPND) obtained from the full kinetic analysis was compared with the SUVR and with noninvasive tracer kinetic methods (simplified reference tissue model and multilinear reference tissue model 2). Various approaches using shortened or interrupted acquisitions were compared with the results of the full acquisition (0-140 min). Simulations were performed to assess the effect of CBF and radiotracer clearance changes on SUVRs and noninvasive kinetic modeling outputs. Results: An acquisition protocol using time windows of 0-30 and 120-140 min with appropriate interpolation of the missing time points provided the best compromise between patient comfort and quantification accuracy. Excellent agreement was found between BPND obtained using the full protocol and BPND obtained using the dual-window protocol (for multilinear reference tissue model 2, BPND [dual-window] = 0.01 + 1.00·BPND [full], R2 = 0.97; for simplified reference tissue model, BPND [dual-window] = 0.05 + 0.92·BPND [full], R2 = 0.93). Simulations showed a limited impact of CBF and radiotracer clearance changes on multilinear reference tissue model parameters and SUVR. Conclusion: This study demonstrated accurate noninvasive kinetic modeling of 18F-florbetaben PET data using a dual-window acquisition, thus providing a good compromise between quantification accuracy, scan duration, and patient burden. The influence of CBF and radiotracer clearance changes on amyloid-β load estimates was small. For most clinical research applications, the SUVR approach is appropriate. However, for longitudinal studies in which maximum quantification accuracy is desired, this noninvasive dual-window acquisition with kinetic analysis is recommended.

Association of Cortical β-Amyloid with Erythrocyte Membrane Monounsaturated and Saturated Fatty Acids in Older Adults at Risk of Dementia.

We examined the relationships between erythrocyte membrane monounsaturated fatty acids (MUFAs) and saturated fatty acids (SFAs) and cortical β-amyloid (Aβ) load in older adults reporting subjective memory complaints. This is a cross-sectional study using data from the Multidomain Alzheimer Preventive Trial (MAPT); a randomised controlled trial. French community dwellers aged 70 or over reporting subjective memory complaints, but free from a diagnosis of clinical dementia. Participants of this study were 61 individuals from the placebo arm of the MAPT trial with data on erythrocyte membrane fatty acid levels and cortical Aβ load. Cortical-to-cerebellar standard uptake value ratios were assessed using [18F] florbetapir positron emission tomography (PET). Fatty acids were measured in erythrocyte cell membranes using gas chromatography. Associations between erythrocyte membrane MUFAs and SFAs and cortical Aβ load were explored using adjusted multiple linear regression models and were considered significant at p ≤ 0.005 (10 comparisons) after correction for multiple testing. We found no significant associations between fatty acids and cortical Aβ load using multiple linear regression adjusted for age, sex, education, cognition, PET-scan to clinical assessment interval, PET-scan to blood collection interval and apolipoprotein E (ApoE) status. The association closest to significance was that between erythrocyte membrane stearic acid and Aβ (B-coefficient 0.03, 95 % CI: 0.00,0.05, p = 0.05). This association, although statistically non-significant, appeared to be stronger amongst ApoE ε4 carriers (B-coefficient 0.04, 95 % CI: -0.01,0.09, p = 0.08) compared to ApoE ε4 non-carriers (B-coefficient 0.02, 95 % CI: -0.01,0.05, p = 0.18) in age and sex stratified analysis. Future research in the form of large longitudinal observational study is needed to validate our findings, particularly regarding the potential association of stearic acid with cortical Aβ.

SEN1500, a novel oral amyloid-β aggregation inhibitor, attenuates brain pathology in a mouse model of Alzheimer's disease.

Amyloid-β (Aβ) aggregation is thought to be a major pathogenic event underlying the neuropathology of Alzheimer's disease (AD). The development of new drugs inhibiting the Aβ aggregation process is, therefore, important. SEN1500, an orally bioavailable and CNS-penetrant Aβ aggregation inhibitor, has previously been shown to reduce spatial learning and memory deficits in an APP transgenic mouse model. To verify that the pharmacological properties of SEN1500 are not unique to this model, we investigated brain Aβ pathology, neuroinflammation, as well as memory in a different mouse model of AD expressing the human amyloid precursor protein with Swedish and London mutations (APPSL). APPSL transgenic mice and non-transgenic littermates were treated with SEN1500 via food pellets from three months of age for four months. At the end of the treatment, animals were tested for memory deficits using the contextual fear conditioning test and brain tissue was analyzed for soluble and insoluble amyloid-β1-38, -40, -42, β-amyloid plaques, β-sheet plaque cores, as well as for astrocytosis and activated microglia. SEN1500 treatment lowered insoluble Aβ levels and β-amyloid plaque load in the brain compared with control-treated APPSL mice. Activated microglia were significantly reduced in the cortex but not the hippocampus of SEN1500-treated APPSL mice. Memory deficits of APPSL mice could not be rescued by SEN1500. SEN1500 is not only able to reduce Aβ pathology and activated microglia but also to improve learning and memory as previously shown, making SEN1500 a potential candidate for human AD treatment. This Aβ aggregation inhibitor could be a promising therapeutic agent for the disease-modifying treatment of AD.

Cerebral quantitative susceptibility mapping predicts amyloid-β-related cognitive decline.

See Derry and Kent (doi:10.1093/awx167) for a scientific commentary on this article.The large variance in cognitive deterioration in subjects who test positive for amyloid-β by positron emission tomography indicates that convergent pathologies, such as iron accumulation, might combine with amyloid-β to accelerate Alzheimer's disease progression. Here, we applied quantitative susceptibility mapping, a relatively new magnetic resonance imaging method sensitive to tissue iron, to assess the relationship between iron, amyloid-β load, and cognitive decline in 117 subjects who underwent baseline magnetic resonance imaging and amyloid-β positron emission tomography from the Australian Imaging, Biomarkers and Lifestyle study (AIBL). Cognitive function data were collected every 18 months for up to 6 years from 100 volunteers who were either cognitively normal (n = 64) or diagnosed with mild cognitive impairment (n = 17) or Alzheimer's disease (n = 19). Among participants with amyloid pathology (n = 45), higher hippocampal quantitative susceptibility mapping levels predicted accelerated deterioration in composite cognition tests for episodic memory [β(standard error) = -0.169 (0.034), P = 9.2 × 10-7], executive function [β(standard error) = -0.139 (0.048), P = 0.004), and attention [β(standard error) = -0.074 (0.029), P = 0.012]. Deteriorating performance in a composite of language tests was predicted by higher quantitative susceptibility mapping levels in temporal lobe [β(standard error) = -0.104 (0.05), P = 0.036] and frontal lobe [β(standard error) = -0.154 (0.055), P = 0.006]. These findings indicate that brain iron might combine with amyloid-β to accelerate clinical progression and that quantitative susceptibility mapping could be used in combination with amyloid-β positron emission tomography to stratify individuals at risk of decline.

UNC5C variants are associated with cerebral amyloid angiopathy.

Objective:To determine whether common genetic variants in UNC5C, a recently identified late-onset Alzheimer disease (LOAD) dementia susceptibility gene, are associated with AD susceptibility or AD-related clinical/pathologic phenotypes.Methods:We used data from deceased individuals of European descent who participated in the Religious Orders Study or the Rush Memory and Aging Project (n = 1,288). We examined whether there were associations between single nucleotide polymorphisms (SNPs) within ±100 kb of the UNC5C gene and a diagnosis of AD dementia, global cognitive decline, a pathologic diagnosis of AD, β-amyloid load, neuritic plaque count, diffuse plaque count, paired helical filament tau density, neurofibrillary tangle count, and cerebral amyloid angiopathy (CAA) score. We also evaluated the relation of the CAA-associated variant and dorsolateral prefrontal cortex (DLPFC) UNC5C RNA expression. Secondary analyses were performed to examine the interaction of the CAA-associated SNP and known genetic risk factors of CAA as well as the association of the SNP with other cerebrovascular pathologies.Results:A set of UNC5C SNPs tagged by rs28660566T was associated with a higher CAA score (p = 2.3 × 10−6): each additional rs28660566T allele was associated with a 0.60 point higher CAA score, which is equivalent to approximately 75% of the higher CAA score associated with each allele of APOE ε4. rs28660566T was weakly associated with lower UNC5C expression in the human DLPFC (p = 0.036). Moreover, rs28660566T had a synergistic interaction with APOE ε4 on their association with higher CAA severity (p = 0.027) and was associated with more severe arteriolosclerosis (p = 0.0065).Conclusions:Targeted analysis of the UNC5C region uncovered a set of SNPs associated with CAA.

Elevated plasma ferritin in elderly individuals with high neocortical amyloid-β load.

Ferritin, an iron storage and regulation protein, has been associated with Alzheimer's disease (AD); however, it has not been investigated in preclinical AD, detected by neocortical amyloid-β load (NAL), before cognitive impairment. Cross-sectional analyses were carried out for plasma and serum ferritin in participants in the Kerr Anglican Retirement Village Initiative in Aging Health cohort. Subjects were aged 65-90 years and were categorized into high and low NAL groups via positron emission tomography using a standard uptake value ratio cutoff=1.35. Ferritin was significantly elevated in participants with high NAL compared with those with low NAL, adjusted for covariates age, sex, apolipoprotein E ɛ4 carriage and levels of C-reactive protein (an inflammation marker). Ferritin was also observed to correlate positively with NAL. A receiver operating characteristic curve based on a logistic regression of the same covariates, the base model, distinguished high from low NAL (area under the curve (AUC)=0.766), but was outperformed when plasma ferritin was added to the base model (AUC=0.810), such that at 75% sensitivity, the specificity increased from 62 to 71% on adding ferritin to the base model, indicating that ferritin is a statistically significant additional predictor of NAL over and above the base model. However, ferritin's contribution alone is relatively minor compared with the base model. The current findings suggest that impaired iron mobilization is an early event in AD pathogenesis. Observations from the present study highlight ferritin's potential to contribute to a blood biomarker panel for preclinical AD.

BRAIN VOLUME, CEREBRAL β-AMYLOID DEPOSITION, AND AGEING: A STUDY OF OVER 200 INDIVIDUALS BORN IN THE SAME WEEK IN 1946

Ageing is associated with cerebral atrophy and accumulation of cerebral β-amyloid. We examined the relationships between β-amyloid load and brain volume in a large cohort of individuals born in the same week in 1946. We analysed cross-sectional data from Insight 46; a sub-study of the MRC National Survey of Health and Development(NSHD) which includes individuals born in mainland Britain in one week in 1946. Participants had 18F-Florbetapir PET and volumetric T1-weighted MRI on the same 3T-PET/MR unit. β-amyloid load was quantified as a cortical standard uptake value ratios (SUVR) using a cerebellar reference region. The relationship between automated measurements of whole brain, ventricle, hippocampal and lobar volumes, age at time of scan and β-amyloid load was examined using regression models and voxel based morphometry, incorporating total intracranial volume and gender as co-variates. Data from 210 individuals without dementia or significant neurological/psychiatric illness were included. Mean age at scanning was 70.1±0.39 years (range 69.3–70.8). 38 individuals were β-amyloid positive: defined as SUVr=>1.078. Comparison of positive and negative groups revealed no difference in volumetric measurements. However, within β-amyloid-positive individuals, SUVR was negatively associated with total brain volume(p=0.034). There was also evidence of an interaction between β-amyloid status(positive/negative) and SUVR in terms of their effects on total brain volume(p=0.006) across the whole sample. Age at scanning was associated with increased ventricular volume (p=0.014) and with lower total brain(p<0.001), hippocampal(p=0.003), frontal lobe(p=0.023) and temporal lobe(p=0.042) volumes. Whole-brain voxel based morphometry analysis(FWE corrected, p<0.05) revealed age to be associated with volume loss in fronto-temporal regions, thalamus, and cingulate gyri. These preliminary data suggest that there is no significant difference in brain volume between β-amyloid positive and negative individuals aged ∼70 years, but there is some evidence for volume loss once a β-amyloid threshold level is reached. Unexpectedly, there was also a relationship between age and total brain volume independent of β-amyloid load over a very narrow age range. Whether this reflects recruitment bias, non-AD pathologies or ageing effects is unclear. These findings will be examined in a larger sample size utilizing life course and genetic data in the future.

METHODOLOGICAL AND LOGISTIC STRATEGIES FOR A LARGE MULTI-CENTER β-AMYLOID PET EUROPEAN PROJECT: AMYLOID IMAGING TO PREVENT ALZHEIMER’S DISEASE (AMYPAD)

‘Amyloid imaging to prevent Alzheimer's disease’ (AMYPAD; www.amypad.org) is a 5-year programme within the Innovative Medicines Initiative (IMI), a joint undertaking between the European Union and the European Federation of Pharmaceutical Industries and Associations (EFPIA). AMYPAD will study the impact of β-amyloid PET imaging on the diagnosis and management of AD, the natural history of amyloid accumulation in the pre-symptomatic stage of AD and the selection of individuals for secondary prevention trials. To this end, a network of ∼20 European PET centres aims to conduct a total of 6000 scans. AMYPAD's work package 2 (WP2) will support these goals by developing an efficient tracer supply strategy, setting-up a clinical imaging network, developing image acquisition, quality control and quantification protocols, and deploying a centralized platform for image transfer, analysis and sharing. Since both NeuraCeq (Piramal Imaging) and Vizamyl (GE Healthcare) will be used in AMYPAD, standardization of β-amyloid load measurements across tracers will be crucial to ensure full comparability of the quantitative outcomes of the project. On top of this, specific sub-studies in WP2 will focus on: 1) accurate determination of amyloid change rates though dynamic PET scanning, 2) further development of the role of PET/MR for β-amyloid imaging, 3) refinement of amyloid quantification methods, and 4) identification of lifestyle and environmental factors affecting amyloid accumulation. Quantitative outcomes in AMYPAD will be expressed in the Centiloid scale (Klunk et al. Alzheimers Dement. 2015) in order to ensure the full comparability across tracers and to enable generalization the project's results. At present, WP2 has designed the tracer distribution strategy, set-up the clinical imaging network, and deployed the platform for image transfer and quantification. AMYPAD will improve our understanding of the utility of β-amyloid PET imaging in both clinical and research contexts and will generate a large amount of image data of high value for research purposes. Through WP2, AMYPAD will apply methodologies for quantitative β-amyloid imaging and will leverage with EPAD (European Prevention of Alzheimer's Dementia) to reconcile the datasets gathered in the context of these two IMI projects and share them with the general scientific community.

Decreased Glutamate Levels in Patients with Amnestic Mild Cognitive Impairment: An sLASER Proton MR Spectroscopy and PiB-PET Study.

Glutamate levels may be informative about the declining neuronal health in the central nervous system. We used an advanced proton MR spectroscopy (1 H-MRS) protocol composed of semi-localization by adiabatic selective refocusing (sLASER) localization and FAST(EST)MAP shimming for detection of alterations in brain glutamate concentrations in patients with amnestic mild cognitive impairment. Participants with amnestic mild cognitive impairment (n = 14; median age = 80) and age- and sex-matched clinically normal controls (n = 32; median age = 79) from the population-based Mayo Clinic Study of Aging were recruited prospectively to the 3T single-voxel 1 H-MRS study that examined metabolite changes in the posterior cingulate gyri. To be included, controls had to have low β-amyloid load on [11 C] Pittsburgh Compound B (PiB)-PET (standard uptake value ratio; SUVr < 1.42) and patients with amnestic mild cognitive impairment had to have high β-amyloid load (SUVr ≥ 1.42). Glutamate concentration and the glutamate/myo-inositol ratio were lower in patients with amnestic mild cognitive impairment than clinically normal controls (P < .05). Higher global cortical PiB-PET SUVr correlated with lower glutamate/myo-inositol (r = -.3, P = .04). The advanced sLASER with FAST(EST)MAP shimming is a promising protocol for identifying glutamate alterations. Advanced 1 H-MRS protocols may add to the understanding of early Alzheimer's disease pathophysiology through detection of glutamate concentration in posterior cingulate gyri of individuals with amnestic mild cognitive impairment.

Increased Carbohydrate Intake is Associated with Poorer Performance in Verbal Memory and Attention in an APOE Genotype-Dependent Manner.

Evidence suggests that a diet low in carbohydrates can impact on cognitive performance among those with Alzheimer's disease (AD). However, there is a lack of data assessing this relationship among cognitively normal (CN) older adults at increased future risk of developing AD due to carriage of the apolipoprotein E (APOE) ɛ4 allele. We assessed the cross-sectional association between carbohydrate intake, cognitive performance, and cerebral amyloid-β (Aβ) load in CN older adults, genotyped for APOEɛ4 allele carrier status. Greater carbohydrate intake was associated with poorer performance in verbal memory in APOEɛ4 allele non-carriers, and poorer performance in attention in APOEɛ4 allele carriers. There were no associations between carbohydrate intake and cerebral Aβ load. These results provide support to the idea that decreasing carbohydrate intake may offer neurocognitive benefits, with specific cognitive domains affected in an APOE genotype-dependent manner. These findings warrant further investigation utilizing a longitudinal study design.

Entorhinal Cortex: Antemortem Cortical Thickness and Postmortem Neurofibrillary Tangles and Amyloid Pathology.

The entorhinal cortex, a critical gateway between the neocortex and hippocampus, is one of the earliest regions affected by Alzheimer disease-associated neurofibrillary tangle pathology. Although our prior work has automatically delineated an MR imaging-based measure of the entorhinal cortex, whether antemortem entorhinal cortex thickness is associated with postmortem tangle burden within the entorhinal cortex is still unknown. Our objective was to evaluate the relationship between antemortem MRI measures of entorhinal cortex thickness and postmortem neuropathological measures. We evaluated 50 participants from the Rush Memory and Aging Project with antemortem structural T1-weighted MR imaging and postmortem neuropathologic assessments. Here, we focused on thickness within the entorhinal cortex as anatomically defined by our previously developed MR imaging parcellation system (Desikan-Killiany Atlas in FreeSurfer). Using linear regression, we evaluated the association between entorhinal cortex thickness and tangles and amyloid-β load within the entorhinal cortex and medial temporal and neocortical regions. We found a significant relationship between antemortem entorhinal cortex thickness and entorhinal cortex (P = .006) and medial temporal lobe tangles (P = .002); we found no relationship between entorhinal cortex thickness and entorhinal cortex (P = .09) and medial temporal lobe amyloid-β (P = .09). We also found a significant association between entorhinal cortex thickness and cortical tangles (P = .003) and amyloid-β (P = .01). We found no relationship between parahippocampal gyrus thickness and entorhinal cortex (P = .31) and medial temporal lobe tangles (P = .051). Our findings indicate that entorhinal cortex-associated in vivo cortical thinning may represent a marker of postmortem medial temporal and neocortical Alzheimer disease pathology.

Self-reported confusion is related to global and regional β-amyloid: data from the Women's healthy ageing project.

Disease-modifying treatments for Alzheimer's disease (AD) may require implementation during early stages of β-amyloid accumulation, well before patients have objective cognitive decline. In this study we aimed to assess the clinical value of subjective cognitive impairment (SCI) by examining the cross-sectional relationship between β-amyloid load and SCI. Cerebral β-amyloid and SCI was assessed in a cohort of 112 cognitively normal subjects. Subjective cognition was evaluated using specific questions on memory and cognition and the MAC-Q. Participants had cerebral β-amyloid load measured with 18F-Florbetaben Positron Emission Tomography (PET). No associations were found between measures of subjective memory impairment and cerebral β-amyloid. However, by self-reported confusion was predictive of a higher global β-amyloid burden (p=0.002), after controlling for confounders. Regional analysis revealed significant associations of confusion with β-amyloid in the prefrontal region (p=0.004), posterior cingulate and precuneus cortices (p=0.004) and the lateral temporal lobes (p=0.001) after controlling for confounders. An in vivo biomarker for AD pathology was associated with SCI by self-reported confusion on cross-sectional analysis. Whilst there has been a large body of research on SMC, our results indicate more research is needed to explore symptoms of confusion.

Amyloid β‐induced astrogliosis is mediated by β1‐integrin via NADPH oxidase 2 in Alzheimer's disease

SummaryAstrogliosis is a hallmark of Alzheimer′s disease (AD) and may constitute a primary pathogenic component of that disorder. Elucidation of signaling cascades inducing astrogliosis should help characterizing the function of astrocytes and identifying novel molecular targets to modulate AD progression. Here, we describe a novel mechanism by which soluble amyloid‐β modulates β1‐integrin activity and triggers NADPH oxidase (NOX)‐dependent astrogliosis in vitro and in vivo. Amyloid‐β oligomers activate a PI3K/classical PKC/Rac1/NOX pathway which is initiated by β1‐integrin in cultured astrocytes. This mechanism promotes β1‐integrin maturation, upregulation of NOX2 and of the glial fibrillary acidic protein (GFAP) in astrocytes in vitro and in hippocampal astrocytes in vivo. Notably, immunochemical analysis of the hippocampi of a triple‐transgenic AD mouse model shows increased levels of GFAP, NOX2, and β1‐integrin in reactive astrocytes which correlates with the amyloid β‐oligomer load. Finally, analysis of these proteins in postmortem frontal cortex from different stages of AD (II to V/VI) and matched controls confirmed elevated expression of NOX2 and β1‐integrin in that cortical region and specifically in reactive astrocytes, which was most prominent at advanced AD stages. Importantly, protein levels of NOX2 and β1‐integrin were significantly associated with increased amyloid‐β load in human samples. These data strongly suggest that astrogliosis in AD is caused by direct interaction of amyloid β oligomers with β1‐integrin which in turn leads to enhancing β1‐integrin and NOX2 activity via NOX‐dependent mechanisms. These observations may be relevant to AD pathophysiology.

Rescue of Early bace-1 and Global DNA Demethylation by S-Adenosylmethionine Reduces Amyloid Pathology and Improves Cognition in an Alzheimer's Model.

General DNA hypomethylation is associated with Alzheimer’s disease (AD), but it is unclear when DNA hypomethylation starts or plays a role in AD pathology or whether DNA re-methylation would rescue early amyloid-related cognitive impairments. In an APP transgenic mouse model of AD-like amyloid pathology we found that early intraneuronal amyloid beta build-up is sufficient to unleash a global and beta-site amyloid precursor protein cleaving enzyme 1 (bace-1) DNA demethylation in AD-vulnerable brain regions. S-adenosylmethionine administration at these early stages abolished this hypomethylation, diminished the amyloid pathology and restored cognitive capabilities. To assess a possible human significance of findings, we examined the methylation at 12 CpGs sites in the bace-1 promoter, using genome-wide DNA methylation data from 740 postmortem human brains. Thus, we found significant associations of bace-1 promoter methylation with β-amyloid load among persons with AD dementia, and PHFtau tangle density. Our results support a plausible causal role for the earliest amyloid beta accumulation to provoke DNA hypomethylation, influencing AD pathological outcomes.

Optimizing PiB-PET SUVR change-over-time measurement by a large-scale analysis of longitudinal reliability, plausibility, separability, and correlation with MMSE

Quantitative measurements of change in β-amyloid load from Positron Emission Tomography (PET) images play a critical role in clinical trials and longitudinal observational studies of Alzheimer's disease. These measurements are strongly affected by methodological differences between implementations, including choice of reference region and use of partial volume correction, but there is a lack of consensus for an optimal method. Previous works have examined some relevant variables under varying criteria, but interactions between them prevent choosing a method via combined meta-analysis. In this work, we present a thorough comparison of methods to measure change in β-amyloid over time using Pittsburgh Compound B (PiB) PET imaging. MethodsWe compare 1,024 different automated software pipeline implementations with varying methodological choices according to four quality metrics calculated over three-timepoint longitudinal trajectories of 129 subjects: reliability (straightness/variance); plausibility (lack of negative slopes); ability to predict accumulator/non-accumulator status from baseline value; and correlation between change in β-amyloid and change in Mini Mental State Exam (MMSE) scores. Results and conclusionFrom this analysis, we show that an optimal longitudinal measure of β-amyloid from PiB should use a reference region that includes a combination of voxels in the supratentorial white matter and those in the whole cerebellum, measured using two-class partial volume correction in the voxel space of each subject's corresponding anatomical MR image.

Long-Term Treatment with Liraglutide, a Glucagon-Like Peptide-1 (GLP-1) Receptor Agonist, Has No Effect on β-Amyloid Plaque Load in Two Transgenic APP/PS1 Mouse Models of Alzheimer's Disease.

One of the major histopathological hallmarks of Alzheimer’s disease (AD) is cerebral deposits of extracellular β-amyloid peptides. Preclinical studies have pointed to glucagon-like peptide 1 (GLP-1) receptors as a potential novel target in the treatment of AD. GLP-1 receptor agonists, including exendin-4 and liraglutide, have been shown to promote plaque-lowering and mnemonic effects of in a number of experimental models of AD. Transgenic mouse models carrying genetic mutations of amyloid protein precursor (APP) and presenilin-1 (PS1) are commonly used to assess the pharmacodynamics of potential amyloidosis-lowering and pro-cognitive compounds. In this study, effects of long-term liraglutide treatment were therefore determined in two double APP/PS1 transgenic mouse models of Alzheimer’s disease carrying different clinical APP/PS1 mutations, i.e. the ‘London’ (hAPPLon/PS1A246E) and ‘Swedish’ mutation variant (hAPPSwe/PS1ΔE9) of APP, with co-expression of distinct PS1 variants. Liraglutide was administered in 5 month-old hAPPLon/PS1A246E mice for 3 months (100 or 500 ng/kg/day, s.c.), or 7 month-old hAPPSwe/PS1ΔE9 mice for 5 months (500 ng/kg/day, s.c.). In both models, regional plaque load was quantified throughout the brain using stereological methods. Vehicle-dosed hAPPSwe/PS1ΔE9 mice exhibited considerably higher cerebral plaque load than hAPPLon/PS1A246E control mice. Compared to vehicle-dosed transgenic controls, liraglutide treatment had no effect on the plaque levels in hAPPLon/PS1A246E and hAPPSwe/PS1ΔE9 mice. In conclusion, long-term liraglutide treatment exhibited no effect on cerebral plaque load in two transgenic mouse models of low- and high-grade amyloidosis, which suggests differential sensitivity to long-term liraglutide treatment in various transgenic mouse models mimicking distinct pathological hallmarks of AD.

Hippocampal Amyloid Burden with Downstream Fusiform Gyrus Atrophy Correlate with Face Matching Task Scores in Early Stage Alzheimer's Disease.

Purpose: Neuronal activity during face matching shows co-activation of the fusiform gyrus (FG) and areas along the ventral visual network. To elucidate the mechanisms related to the facial discrimination deficits in Alzheimer’s disease (AD), the study evaluates the relationships between β-amyloid (Aβ) load and gray matter (GM) atrophy within the ventral visual network.Methods: Comprehensive cognitive assessments and GM volumetry using 3-dimentional T1-weighted images and AV-45 positron emission tomography (PET) were studied in 44 patients with AD. We used AV-45 PET to measure regional Aβ to analyze the correlations between the regional neocortical AV-45 retention and atrophy in patients with AD.Results: FG volume was positively correlated with the para-hippocampus (β = 0.565, P < 0.001), posterior cingulate cortex (PCC; β = 0.402, P < 0.001), and hippocampus volumes (β = 0.209, P = 0.044). After carefully confounded all possible factors simultaneously, the hippocampus standardized uptake value (SUV) ratio was independently associated with FG volume (β = −0.151, P = 0.017). Furthermore, volumes of the hippocampus (r = 0.473, P = 0.003), para-hippocampus (r = 0.515, P = 0.001), and FG (r = 0.383, P = 0.018) were associated with Benton’s facial recognition test (BFRT).Conclusions: In conclusion, our study indicated that amyloid burden within the hippocampus might contribute to FG cortical hub GM atrophy. While the face matching task scores were related to the FG, hippocampus, and para-hippocampus volumes, concordant changes of the aforementioned three structures suggested the importance of the three ventral visual network hubs in AD.

Cerebrospinal fluid analysis detects cerebral amyloid-β accumulation earlier than positron emission tomography.

Cerebral accumulation of amyloid-β is thought to be the starting mechanism in Alzheimer's disease. Amyloid-β can be detected by analysis of cerebrospinal fluid amyloid-β42 or amyloid positron emission tomography, but it is unknown if any of the methods can identify an abnormal amyloid accumulation prior to the other. Our aim was to determine whether cerebrospinal fluid amyloid-β42 change before amyloid PET during preclinical stages of Alzheimer's disease. We included 437 non-demented subjects from the prospective, longitudinal Alzheimer's Disease Neuroimaging Initiative (ADNI) study. All underwent (18)F-florbetapir positron emission tomography and cerebrospinal fluid amyloid-β42 analysis at baseline and at least one additional positron emission tomography after a mean follow-up of 2.1 years (range 1.1-4.4 years). Group classifications were based on normal and abnormal cerebrospinal fluid and positron emission tomography results at baseline. We found that cases with isolated abnormal cerebrospinal fluid amyloid-β and normal positron emission tomography at baseline accumulated amyloid with a mean rate of 1.2%/year, which was similar to the rate in cases with both abnormal cerebrospinal fluid and positron emission tomography (1.2%/year, P = 0.86). The mean accumulation rate of those with isolated abnormal cerebrospinal fluid was more than three times that of those with both normal cerebrospinal fluid and positron emission tomography (0.35%/year, P = 0.018). The group differences were similar when analysing yearly change in standardized uptake value ratio of florbetapir instead of percentage change. Those with both abnormal cerebrospinal fluid and positron emission tomography deteriorated more in memory and hippocampal volume compared with the other groups (P < 0.001), indicating that they were closer to Alzheimer's disease dementia. The results were replicated after adjustments of different factors and when using different cut-offs for amyloid-β abnormality including a positron emission tomography classification based on the florbetapir uptake in regions where the initial amyloid-β accumulation occurs in Alzheimer's disease. This is the first study to show that individuals who have abnormal cerebrospinal amyloid-β42 but normal amyloid-β positron emission tomography have an increased cortical amyloid-β accumulation rate similar to those with both abnormal cerebrospinal fluid and positron emission tomography and higher rate than subjects where both modalities are normal. The results indicate that cerebrospinal fluid amyloid-β42 becomes abnormal in the earliest stages of Alzheimer's disease, before amyloid positron emission tomography and before neurodegeneration starts.