Biology subjects

Brickman, A. M.

Publications and source records attributed to Brickman, A. 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↗

bioRxiv2022

Posterior white matter hyperintensities are associated with reduced medial temporal lobe subregional integrity and long-term memory in older adults

White matter hyperintensities are a marker of small vessel cerebrovascular disease that are strongly related to cognition in older adults. Similarly, medial temporal lobe atrophy is well-documented in aging and Alzheimers disease and is associated with memory decline. Here, we assessed the relationship between lobar white matter hyperintensities, medial temporal lobe subregional volumes, and hippocampal memory in older adults. We collected MRI scans in a sample of 139 older adults without dementia (88 females, mean age (SD) = 76.95 (10.61)). Participants were administered the Rey Auditory Verbal Learning Test (RAVLT). Regression analyses tested for associations among medial temporal lobe subregional volumes, regional white matter hyperintensities and memory, while adjusting for age, sex, and education and correcting for multiple comparisons. Increased occipital white matter hyperintensities were related to worse RAVLT delayed recall performance, and to reduced CA1, dentate gyrus, perirhinal cortex (Brodmann area 36), and parahippocampal cortex volumes. These medial temporal lobe subregional volumes were related to delayed recall performance. The association of occipital white matter hyperintensities with delayed recall performance was fully mediated statistically only by perirhinal cortex volume. These results suggest that white matter hyperintensities may be associated with memory decline through their impact on medial temporal lobe atrophy. These findings provide new insights into the role of vascular pathologies in memory loss in older adults and suggest that future studies should further examine the neural mechanisms of these relationships in longitudinal samples.

neuroscience↗

bioRxiv2020

Brain Amyloid and the Transition to Dementia in Down Syndrome

INTRODUCTIONDown syndrome (DS) is associated with elevated risk for Alzheimers disease (AD) due to beta amyloid (A{beta}) lifelong accumulation. We hypothesized that the spatial distribution of brain A{beta} predicts future dementia conversion in individuals with DS. METHODSWe acquired 18F-Florbetapir PET scans from 19 nondemented individuals with DS at baseline and monitored them for four years, with five individuals transitioning to dementia. Machine learning classification determined features on 18F-Florbetapir standardized uptake value ratio (SUVR) maps that predicted transition. RESULTSIn addition to "AD signature" regions including the inferior parietal cortex, temporal lobes, and the cingulum, we found that A{beta} cortical binding in the prefrontal and superior frontal cortices distinguished subjects who transitioned to dementia. Classification did well in predicting transitioners. DISCUSSIONOur study suggests that specific regional profiles of brain amyloid in older adults with DS may predict cognitive decline and are informative in evaluating the risk for dementia. HighlightsO_LIRegional [18F]-Florbetapir PET predicts future transition to dementia in Downs Syndrome. C_LIO_LIIncreased amyloid in prefrontal, inferior parietal, superior frontal, rostral middle frontal, and posterior cingulate cortices detect transitioiners, with prefrontal and superior frontal being best overall. C_LIO_LIAmyloid PET-based classification able to discriminate between transitioners and non-transitioners. C_LI

neuroscience↗

bioRxiv2018

Whole Exome Sequencing in 20,197 Persons for Rare Variants in Alzheimer Disease

ObjectiveThe genetic bases of Alzheimers disease remain uncertain. An international effort to fully articulate genetic risks and protective factors is underway with the hope of identifying potential therapeutic targets and preventive strategies. The goal here was to identify and characterize the frequency and impact of rare and ultra-rare variants in Alzheimers disease using whole exome sequencing in 20,197 individuals.\n\nMethodsWe used a gene-based collapsing analysis of loss-of-function ultra-rare variants in a case-control study design with data from the Washington Heights-Inwood Columbia Aging Project, the Alzheimers Disease Sequencing Project and unrelated individuals from the Institute of Genomic Medicine at Columbia University.\n\nResultsWe identified 19 cases carrying extremely rare SORL1 loss-of-function variants among a collection of 6,965 cases and a single loss-of-function variant among 13,252 controls (p = 2.17 x 10-8; OR 36.2 [95%CI 5.8 - 1493.0]). Age-at-onset was seven years earlier for patients with SORL1 qualifying variant compared with non-carriers. No other gene attained a study-wide level of statistical significance, but multiple top-ranked genes, including GRID2IP, WDR76 and GRN, were among candidates for follow-up studies.\n\nInterpretationThis study implicates ultra-rare, loss-of-function variants in SORL1 as a significant genetic risk factor for Alzheimers disease and provides a comprehensive dataset comparing the burden of rare variation in nearly all human genes in Alzheimers disease cases and controls. This is the first investigation to establish a genome-wide statistically significant association between multiple extremely rare loss-of-function variants in SORL1 and Alzheimers disease in a large whole-exome study of unrelated cases and controls.

genetics↗