Welcome to the AD/PD™ 2022 Interactive Program
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LEVERAGING GENETIC CONTEXT TO MODEL VASCULAR CONTRIBUTIONS TO COGNITIVE DECLINE AND DEMENTIA
Abstract
Aims
Vascular contributions to cognitive decline and dementia (VCID) are now widely appreciated but the underlying genetic causes remain elusive. Current studies relevant to VCID use mouse models focused on environmental risk factors such as diet-induced obesity. We have employed mouse genetic diversity to understand the mechanisms underlying VCID.
Methods
We performed a strain survey using amyloid drivers APPswe and PSEN1de9 (APP/PS1). APP/PS1 transgenes were backcrossed from C57BL/6J to nine strains including wild-derived WSB/EiJ, PWK/PhJ and CAST/EiJ. All strains were assessed for cerebral amyloid angiopathy (CAA). CAA is found in 85-95% of AD cases, and is one of the strongest vascular contributors to age-related cognitive decline.
Results
WSB showed the greatest propensity of CAA. Male and female WSB.APP/PS1 and WSB mice were aged from 4 to 18 months. Vascular amyloid was observed at 8 months in cortical and leptomeningeal vessels. These deposits colocalized with astrocyte processes, but were devoid of microglia and collagen. Brain transcriptional profiling identified genes relating to vascular health including basement membrane, endothelial function and blood vessel formation. Microbleeds were present in aged WSB mice – even in the absence of amyloid. Deficits in mitochondria function may underlie vascular dysfunction as high-resolution respirometry indicated a significant depression of respiration in the hippocampus from 4 months, prior to observed CAA. Efforts are underway to include clinically relevant genetic risk factors such as humanized amyloid, tau and apolipoprotein E.
Conclusions
These data suggest that the WSB genetic context provides a new platform to dissect vascular contributions to dementia and development of preclinical models.
CONTRIBUTION OF CARDIOVASCULAR RISK FACTORS AND CARBONIC ANHYDRASES TO ENDOTHELIAL AND NEUROVASCULAR DYSFUNCTION IN AD MODELS
Abstract
Aims
Endothelial cells are crucial to maintain neurovascular unit (NVU) function. Indeed, vascular dysfunction is one of the earliest events in Alzheimer’s disease (AD) pathogenesis. Vascular risk factors are known to contribute to AD risk and to accelerate cerebrovascular pathology, but the specific molecular mechanisms are not yet clear. In our studies, we aim to clarify the mechanisms driving cerebrovascular cell dysfunction and death in AD and amyloidosis, the contribution of comorbid vascular risk factors, and to highlight new possible therapeutic targets.
Methods
Using human cerebral microvascular endothelial cells and glial cells in culture, as well as mouse models of amyloidosis, we analyzed death-receptor mediated cell death mechanisms, mitochondrial and BBB dysfunction, as well as NVU dysfunction in vitro and in vivo.
Results
Amyloid beta (Aβ) challenge and CV risk factors, such as hyperhomocysteinemia and hypoperfusion, induced death receptors activation with mitochondrial metabolic and respiratory deficits. Aβ and CV risk factors had additive effects on BBB permeability and endothelial dysfunction markers. Carbonic anhydrase (CA) inhibitors prevented the toxic effects of Aβ in both cell and animal models. We found that these effects are mediated by the inhibition of specific CA isoforms.
Conclusions
Our studies are clarifying novel mechanisms by which Aβ and CV risk factors contribute to vascular dysfunction and endothelial cell stress. In addition, we are understanding for the first time the importance of CA specific isoforms in AD and related disorders.
AMYLOID BURDEN AND VASCULAR RISK FACTORS CORRELATE WITH REGIONAL CEREBRAL BLOOD FLOW IN COGNITIVELY UNIMPAIRED POPULATION
Abstract
Aims
To assess the regional relationship between Cerebral Blood Flow (CBF), amyloid burden and vascular risk factors (VRF) in a cognitively unimpaired population.
Methods
We included 196 (average age of 70±7.3 years; 57% female) cognitively unimpaired participants from the EMIF-AD PreclinAD Twin60++ cohort. Four years after baseline, 135 subjects were scanned again. Using PET imaging, cortical amyloid burden was quantified with the Centiloid method globally and for 4 early amyloid accumulation regions extracted from the LEAP atlas (Figure1): Early Frontal (orbital frontal + basal frontal), Precuneus, Superior Frontal Gyrus and Lingual Gyrus. Arterial Spin Labeling (ASL) imaging was used to quantify CBF with ExploreASL both with the LEAP atlas and the Vascular Territories (VT) atlas (Figures 1&2). Associations between CBF, amyloid and VRF (Framingham) were assessed using generalized estimating equations (GEEs). Models were adjusted for age, sex, and twin dependency. Both global and regional values were investigated.
Results
We found significant associations between regional Centiloid and CBF in corresponding regions from the LEAP atlas (Table1). A significant interaction between global Centiloid and Framingham scores on VT CBF values was found, both globally and regionally (Table2). Longitudinally, only Precuneus centiloid at baseline significantly predicted total CBF changes over time (Figure3).
Conclusions
In this study, we investigated the association between amyloid and CBF for neurodegenerative (amyloid) ROIs and for vascular (ASL) territories. We found regional amyloid burden in AD signature regions to be associated with altered CBF in cognitively intact individuals. Future work will include the investigation of their joint impact on cognitive performance.
AMBIENT AIR POLLUTION, COVERT CEREBROVASCULAR DISEASE AND COGNITION: RESULTS FROM THE ISSYS STUDY
Abstract
Aims
Several studies have reported associations between air pollution (AP) and stroke and dementia, but data regarding covert cerebrovascular disease (cCVD), which is comprehended in the same pathological spectrum, and cognitive function over time, in which AP might influence via different pathways, is sparser. Thus, we hypothesized they might be both associated as well with air pollution.
Methods
Prospective population-based study on 976 stroke-free and non-demented individuals living on Barcelona between 2010 and 2016. Residential levels of NO2, NOx, PM10, PM2.5, PMcoarse and PMabs were estimated for the geocoded postal address of each participant using a land-use-regression (LUR) model. Cognitive status and function and cCVD (brain infarcts, subcortical white matter hyperintensities) were assessed at baseline (n=976) and after 4 years of follow-up (n=350). Linear and logistic regression models were used to obtain adjusted estimates for associations between environmental exposures and cCVD and cognition at baseline. Mixed-effects regression models were used to estimate associations longitudinally over follow-up time.
Results
Median NO2 and particulate matter (PM10 and PM2.5) levels were higher than WHO proposed cut-offs. Regarding cardiovascular risk factors, only atrial fibrillation was associated with PM levels. Both the burden and progression of cCVD were predicted by air pollutants levels. Global cognitive function at baseline was mildly and inversely correlated with PM10 and PMcoarse, although no consistent associations were found with cognitive changes over the follow-up.
Conclusions
AP predicts the presence and accumulation of covert cerebrovascular lesions over time. It remains to be determined their impact in cognitive impairment.
TOWARDS AN UNDERSTANDING OF THE EARLY “BIOCHEMICAL” PHASE OF CAA
Abstract
Aims
The atypical accumulation of amyloid deposits in the walls of small cerebral blood vessels can lead to CAA, a cerebrovascular disorder that contributes to vascular dysfunction and intracerebral hemorrhage. Although shorter Aβ peptides have an increased tendency to accumulate in the cerebrovasculature (i.e. Aβ40 > Aβ42 > Aβ43, the mystery remains as to why Aβ40 (i.e. soluble and less neurotoxic than Aβ42) contributes to the increased amyloid load and pathological deposits in CAA. Although CAA occurs in most AD patients (over 70%) consequences of CAA itself include intracerebral microhaemorrhages and cognitive impairment.
Methods
Mass Spectrometry (MALDI, LC-MS), enzymatic, aggregation and toxicity assays; MSD multiplexing and SPR, MAS Solid-State NMR
Results
We have investigated the mechanisms that likely regulate amyloid aggregation during the early “biochemical” phase of CAA and/ or AD by focussing upon the minority of overlooked Aβ species (longer and truncated forms) that can self-aggregate and either trigger or inhibit the aggregation and toxicity of species frequently found in CAA- (Aβ40) and AD-specific (Aβ42) amyloid deposits. We found that small peptide modifications have profound effects upon the structural and functional dynamics of Aβ40 aggregtaion. We identified candidate molecules that likely can prompt or inhibit the mysterious conversion of soluble Aβ40 into pathological amyloid deposits in the cerebrovasculature of sporadic CAA patients.
Conclusions
Since most AD patients also suffer from CAA, there is an urgent need to better understand the amyloid nucleation process but also to generate selective Aβ40 aggregation inhibitors.
TRANSTHYRETIN INFLUENCES THE CEREBROVASCULAR SYSTEM IN ALZHEIMER’S DISEASE – DECIPHERING THE UNDERLYING PATHWAYS
Abstract
Aims
Cerebrovascular dysfunction is common in Alzheimer's disease (AD), often preceding many of the AD typical hallmarks. Transthyretin (TTR) is a recognized neuroprotective protein in AD, although diminished in the pathology. Here, we aimed to investigate the role of TTR in these vascular alterations and the effect of TTR tetrameric stabilization to improve its function and revert cerebrovascular dysfunction.
Methods
The thickness of the basement membrane (BM) and vessel density were assessed using immunohistochemistry for collagen IV, in AD and non-transgenic (NT) mice with one (TTR+/-) or two (TTR+/+) TTR gene copies. Using a human cerebral vascular endothelial cell line, the effect of TTR on the expression of angiogenic key molecules was evaluated by immunocytochemistry and flow cytometry.
Results
7-month-old AD/TTR+/− mice showed a ticker BM compared to AD/TTR+/+, both in the cortex and hippocampus. Vessel density was reduced in AD/TTR+/- only in the hippocampus, suggesting BM thickening precedes the decrease in vessel length. 3-month-old NT/TTR+/- mice also showed increased BM thickness as compared to NT/TTR+/+, indicating TTR affects directly the structure of cerebral vasculature. No alterations were detected in vessel length in 3-month-old NT mice, again suggesting that BM thickening precedes vessel length decrease. Mice treated with a TTR tetrameric stabilizer, Iodiflunisal, presented decreased BM thickness and increased vessel length, compared to controls. In vitro, TTR stimulated the expression of angiogenic markers VEGF, Ang-2, IL-6, and IL-8.
Conclusions
Our findings show TTR has a direct impact on the vascular changes that occur in AD and might be used to revert vascular dysfunction.
RELATIONSHIP BETWEEN AMYLOID-PET BINDING, WHITE MATTER MICROSTRUCTURE AND COGNITION IN A MIXED COHORT OF SMALL VESSEL DISEASE AND ALZHEIMER’S PATHOLOGY
Abstract
Aims
To investigate the neurobiological underpinnings of amyloid-PET binding in the white matter (WM) using free-water diffusion MRI in a multi-centre mixed cohort of small vessel disease (SVD) and Alzheimer’s disease (AD) pathology.
Methods
We included sixty participants with moderate-to-severe white matter hyperintensity burden (WMH; median(IQR): 30.51(22.14)cm3) from dementia/stroke-prevention clinics (48% amyloid-positive). Additionally, we included sixty cognitively normal/early-MCI with mild-to-moderate WMH (median(IQR): 5.82(9.29)cm3) from ADNI (22% amyloid-positive). We applied a bi-tensor diffusion MRI model that differentiates between extracellular (free-water fraction) and tract-specific WM compartments (free-water adjusted fractional anisotropy or FAadjusted) (Fig.1). We tested associations of these diffusion metrics with amyloid-SUVR in both WMH and normal-appearing WM, and with cognition (MMSE, semantic, and executive function). To further investigate how the diffusion metrics and the demographical variables including age, sex, education, WMH volume, and cortical amyloid-SUVR covary with WM amyloid-SUVR, we performed partial-least-square analysis using ten-fold cross-validation with five repeats.
Results
In WMH, amyloid-SUVR was significantly lower compared to normal-appearing WM and associated strongly with higher free-water (β=-0.36±0.13, P=0.005; 95%CIbootstrap[-0.50,-0.23]). Partial-least-square analysis in the moderate-to-severe burden group showed that free-water was most strongly associated with amyloid-SUVR in WMH (Fig.2-left; component-1 explaining 24% variance), while FAadjusted was strongly associated with amyloid-SUVR in normal-appearing WM (Fig.2-right; component-1 explaining 31% variance). Free-water within both WMH and normal-appearing WM significantly predicted cognitive impairment.
Conclusions
In mixed AD and SVD, representative of the more common AD population, amyloid-PET changes in WM lesions may largely reflect extracellular free-water. In contrast, normal-appearing WM changes may reflect tract-specific injury (possibly demyelination).
TAU DISRUPTS THE COVARIANCE BETWEEN CORTICAL THICKNESS AND WHITE MATTER ARCHITECTURE IN AD.
Abstract
Aims
The current literature investigating the effects of AD pathological hallmarks on the covariance between the gray matter and white matter architecture is limited. Here, we aimed to elucidate tau may impose a significant disturbance in the covariance between the cortical thickness and global graph theory metrics and lead to cognitive decline in AD.
Methods
A total of 214 participants (103 A-T-, 32 A+T-, 79 A+T+) from the TRIAD cohort underwent T1 for cortical thickness, multiband DWI for global graph theory metrics, [18F]AZD4694 and [18F]MK6240 PET, and MMSE. A multivariate PLS analysis model was conducted to evaluate the covariance between regional cortical thickness and global graph theory metrics. Then, the difference in the LV scores between the AD continuum groups, and their effects on cognition were investigated based on a multiple regression with age, sex, education, and APOEε4 as covariates.
Results
Our study revealed two significant LVs that explained 67% and 16%, respectively. While both LV scores showed significant effects on MMSE, only the first LV score showed a significant reduction in A+T+ compared to A-T- and A+T- only. Upon further examination of the first LV, the cortical thickness in the AD vulnerable regions such as precuneus showed the largest positive effects on transitivity, small worldness, clustering, strength, and modularity but negative effects on global efficiency.
Conclusions
: This study highlights a significant covariance between the cortical thickness and global graph theory metrics. Notably, reduced LV scores in A+T+ suggest tau may disrupt the relationship between gray and white matter in AD.
