bioRxiv Science⌕ Search

Biology subjects

Mapstone, M.

Publications and source records attributed to Mapstone, M..

4 recordsLinked to original sources
bioRxiv2024

Parallel neuroinflammatory pathways to cerebrovascular injury and amyloid-beta in Alzheimer's disease

ImportanceWhile the hallmark pathologies of amyloid-beta (A{beta}) and tau in Alzheimers disease (AD) are well documented and even part of the definition, upstream neuroinflammation is thought to play an important role but remains poorly understood. ObjectivesWe tested whether two distinct neuroinflammatory markers are associated with cerebrovascular injury and A{beta}, and whether these markers are associated with plasma phosphorylated tau (pTau) concentration, medial temporal lobe (MTL) cortical and hippocampal atrophy, and memory deficits. We examined neuroinflammatory markers plasma YKL-40 and GFAP, due to previous conflicting evidence relating YKL-40 and GFAP to AD pathogenic markers. DesignCross-sectional data from a community observational study (Biomarker Exploration in Aging, Cognition, and Neurodegeneration - BEACoN) were included. SettingAll participants were enrolled in a single site, at University of California, Irvine. Participants126 participants were included if they had at least one of the following measures available: neuropsychological data, MRI, A{beta}-PET, or plasma. ExposuresPlasma YKL-40 and plasma glial fibrillary acidic protein (GFAP) levels. Main outcomes and measuresWhite matter hyperintensity (WMH) volume, 18F-florbetapir (FBP) PET mean SUVR, plasma phosphorylated tau (pTau-217) concentration, MTL cortical thickness, hippocampal volume, and memory function assessed by Rey Auditory Verbal Learning Test. Using path analysis, we tested whether higher plasma YKL-40 and GFAP are associated with WMH and A{beta}, and whether these converge to downstream markers of tauopathy, MTL neurodegeneration, and memory deficits. ResultsIn older adults without dementia (N=126, age=70.60+6.29, 62% women), we found that higher plasma YKL-40 concentration was associated with greater WMH volume, while higher plasma GFAP concentration was related to increased FBP SUVR. Further, higher plasma GFAP, WMH and FBP SUVR were independently associated with increased pTau-217. In turn, plasma pTau-217 was associated with reduced MTL cortical thickness and hippocampal volume. Subsequently, only reduced hippocampal volume was related to lower memory function. Conclusions and RelevanceNeuroinflammatory markers contribute to parallel pathways of cerebrovascular injury and A{beta}, which converge to tau-associated neurodegeneration and memory deficits in older adults. These observations underscore the need for a more comprehensive approach to developing an AD framework and treatment strategies. KEY POINTSO_ST_ABSQuestionC_ST_ABSHow does neuroinflammation impact downstream features of cerebrovascular injury and amyloid-beta (A{beta}) in Alzheimers disease? FindingsIn this study of 126 older adults without dementia, we found evidence for two distinct neuroinflammatory pathways that lead to neurodegeneration and memory deficits. One path involves plasma YKL-40 and its impact on cerebrovascular injury, as measured by white matter hyperintensities (WMH) on MRI scans. The other involves plasma glial fibrillary acidic protein (GFAP) and its impact on A{beta} deposition measured via 18F-florbetapir (FBP) PET. Both pathways converged on tauopathy, measured by plasma pTau-217, which was associated with lower medial temporal lobe (MTL) cortical thickness and hippocampal volume, and consequently, memory deficits. MeaningInflammation acts on Alzheimers disease mechanisms via multiple distinct and parallel pathways which converge downstream onto neurodegeneration. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=110 SRC="FIGDIR/small/616579v1_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@2d3c39org.highwire.dtl.DTLVardef@1ccc453org.highwire.dtl.DTLVardef@6d40bdorg.highwire.dtl.DTLVardef@b543cb_HPS_FORMAT_FIGEXP M_FIG C_FIG Credit: BioRender was used to help create this graphical abstract.

neuroscience↗
bioRxiv2024

Multi-omic ADNI CSF and plasma data integration identifies distinct metabolic transitions in disease progression in Alzheimer's Disease

Age and APOE genotype are the strongest known risk factors for late-onset Alzheimers disease (AD), but the mechanisms linking them to neuronal loss remain incompletely defined. Using multiomic data from the Alzheimers Disease Neuroimaging Initiative (ADNI), we propose a unified hypothesis in which two interdependent failure modes--saturation of microglial lipid flux capacity and disruption of the astrocyte-neuron lactate shuttle (ANLS) due to excess astrocytic membrane cholesterol--drive disease progression upstream of amyloid and tau pathology. Stratifying participants by cognitive score quartiles, we find consistent associations linking impaired lipid clearance, metabolic stress, and genetic variants regulating cholesterol handling. These processes appear to reinforce each other, resulting in accelerating neurodegeneration. Our hypothesis reframes AD as a systems-level collapse in metabolic coordination, rather than a purely linear pathological cascade. These insights emerged during the development of digital twin models for personalized interventions, highlighting the power of systems approaches to reveal hidden drivers of neurodegeneration.

neuroscience↗
bioRxiv2022

Longitudinal analysis of the gut microbiome in the 5xfAD mouse model of Alzheimer's disease

INTRODUCTIONMicrobial exposures impact Alzheimers disease (AD), and a baseline understanding of AD model microbiomes is vital for improving model efficacy. We describe the evaluation of the microbiome and metabolome in longitudinal samples from the 5xfAD transgenic mouse model. METHODSCecal and fecal samples from 5xfAD and wild-type B6J (WT) animals from 4- 18 months of age were subjected to DNA extraction and shotgun Illumina sequencing. Metabolomics was performed on plasma and feces from a subset of animals. RESULTSSignificant sex, age, and cage-specific differences were observed in the microbiome. Eight bacteria species were elevated in older 5xfAD mice and nine were depleted, including Turicibacter spp. Contradicting published findings covering persons with AD, plasma measurements revealed elevated serotonin in 18 month 5xfAD animals. DISCUSSIONTaken together, these findings strengthen the link between Turicibacter abundance and AD and provide a basis for further microbiome studies of murine models for AD.

microbiology↗
bioRxiv2018

Differentiation of Alzheimer’s disease based on local and global parameters in personalized Virtual Brain models

Alzheimers disease (AD) is marked by cognitive dysfunction emerging from neuropathological processes impacting brain function. AD affects brain dynamics at the local level, such as changes in the balance of inhibitory and excitatory neuronal populations, as well as long-range changes to the global network. Individual differences in these changes as they relate to behaviour are poorly understood. Here, we use a multi-scale neurophysiological model, \"The Virtual Brain (TVB)\", based on empirical multi-modal neuroimaging data, to study how local and global dynamics correlate with individual differences in cognition. In particular, we modeled individual resting-state functional activity of 124 individuals across the behavioral spectrum from healthy aging, to amnesic Mild Cognitive Impairment (MCI), to AD. The model parameters required to accurately simulate empirical functional brain imaging data correlated significantly with cognition, and exceeded the predictive capacity of empirical connectomes.

neuroscience↗