Biology subjects

McMillan, L.

Publications and source records attributed to McMillan, L..

9 recordsLinked to original sources

bioRxiv2025

Divergence of Functional Brain Network Configurations in Same and Other Race Face Recognition

The "Other-Race Effect" (ORE) refers to the enhanced memory individuals have for faces within their own racial group compared to other races. This effect is attributed to limited exposure to different races and social-motivational factors affecting face processing. While past research has explored this effect through neuroimaging methods, the precise neural mechanisms that underlie the ORE remain a subject of ongoing investigation. Previous studies have largely adopted a modular perspective, concentrating on the differential activation of face-processing regions when comparing same-race and other-race facial recognition behaviors. However, given the multifaceted nature of the ORE, an exclusive focus on specialized regions may miss the pivotal role played by non-face-preferential brain areas in modulating this phenomenon. In the present study, we take a broader data-driven perspective using graph-theoretical techniques to investigate whole-brain network disparities in same- and other-race facial recognition. Our findings reveal a substantial impact of race on functional connectivity during face memorization. While other-race face recognition benefitted from higher local efficiency during encoding, reduced local efficiency was advantageous for memorization of same-race faces. Notably, successful other-race recognition was disproportionately supported by locally efficient processing in regions among the ventral and dorsal attention networks.

neuroscience↗

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

Amyloid-β deposition in basal frontotemporal cortex is associated with selective disruption of temporal mnemonic discrimination

Cerebral amyloid-beta (A{beta}) accumulation, a hallmark pathology of Alzheimers disease (AD), precedes clinical impairment by two to three decades. However, it is unclear whether A{beta} contributes to subtle memory deficits observed during the preclinical stage. The heterogenous emergence of A{beta} deposition may selectively impact certain memory domains, which rely on distinct underlying neural circuits. In this context, we tested whether specific domains of mnemonic discrimination, a neural computation essential for episodic memory, exhibit specific deficits related to early A{beta} deposition. We tested 108 cognitively unimpaired human older adults (66% female) who underwent 18F-florbetapir positron emission tomography (A{beta}-PET), and a control group of 35 young adults, on a suite of mnemonic discrimination tasks taxing object, spatial, and temporal domains. We hypothesized that A{beta} pathology would be selectively associated with temporal discrimination performance due to A{beta}s propensity to accumulate in the basal frontotemporal cortex, which supports temporal processing. Consistent with this hypothesis, we found a dissociation in which generalized age-related deficits were found for object and spatial mnemonic discrimination, while A{beta}-PET levels were selectively associated with deficits in temporal mnemonic discrimination. Further, we found that higher A{beta}-PET levels in medial orbitofrontal and inferior temporal cortex, regions supporting temporal processing, were associated with greater temporal mnemonic discrimination deficits, pointing to the selective vulnerability of circuits related to temporal processing early in AD progression. These results suggest that A{beta} accumulation within basal frontotemporal regions may disrupt temporal mnemonic discrimination in preclinical AD, and may serve as a sensitive behavioral biomarker of emerging AD progression.

neuroscience↗

bioRxiv2023

NODDI-derived measures of microstructural integrity in medial temporal lobe white matter pathways are associated with Alzheimer's disease pathology and cognitive outcomes

INTRODUCTIONDiffusion tensor imaging has been used to assess white matter (WM) changes in the early stages of Alzheimers disease (AD). However, the tensor model is necessarily limited by its assumptions. Neurite Orientation Dispersion and Density Imaging (NODDI) can offer insights into microstructural features of WM change. We assessed whether NODDI more sensitively detects AD-related changes in medial temporal lobe WM than traditional tensor metrics. METHODSStandard diffusion and NODDI metrics were calculated for medial temporal WM tracts from 199 older adults drawn from ADNI3 who also received PET to measure pathology and neuropsychological testing. RESULTSNODDI measures in medial temporal tracts were more strongly correlated to cognitive performance and pathology than standard measures. The combination of NODDI and standard metrics exhibited the strongest prediction of cognitive performance in random forest analyses. CONCLUSIONSNODDI metrics offer additional insights into contributions of WM degeneration to cognitive outcomes in the aging brain.

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↗

bioRxiv2022

Entorhinal-hippocampal circuit integrity is related to mnemonic discrimination and amyloid-β pathology in older adults

Mnemonic discrimination, a cognitive process that relies on hippocampal pattern separation, is one of the first memory domains to decline in aging and preclinical Alzheimers disease. We tested if functional connectivity (FC) within the entorhinal-hippocampal circuit, measured with high-resolution resting state fMRI, is associated with mnemonic discrimination and A{beta} pathology, measured with PET, in nondemented older adults. Low object mnemonic discrimination performance was specifically associated with increased FC between anterolateral entorhinal cortex (alEC) and dentate gyrus (DG)/CA3, supporting the importance of this connection to object memory. This hyperconnectivity between alEC-DG/CA3 was related to A{beta} pathology and decreased entorhinal cortex volume. In contrast, spatial mnemonic discrimination was not associated with altered FC. A{beta} was further associated with decreased FC and volume within hippocampal subfields. Our findings suggest that A{beta} may indirectly lead to memory impairment through entorhinal-hippocampal circuit dysfunction and neurodegeneration, and provide a mechanism for vulnerability of object mnemonic discrimination.

neuroscience↗

bioRxiv2019

The Collaborative Cross Graphical Genome

The mouse reference is one of the most widely used and accurately assembled mammalian genomes, and is the foundation for a wide range of bioinformatics and genetics tools. However, it represents the genomic organization of a single inbred mouse strain. Recently, inexpensive and fast genome sequencing has enabled the assembly of other common mouse strains at a quality approaching that of the reference. However, using these alternative assemblies in standard genomics analysis pipelines presents significant challenges. It has been suggested that a pangenome reference assembly, which incorporates multiple genomes into a single representation, are the path forward, but there are few standards for, or instances of practical pangenome representations suitable for large eukaryotic genomes. We present a pragmatic graph-based pangenome representation as a genomic resource for the widely-used recombinant-inbred mouse genetic reference population known as the Collaborative Cross (CC) and its eight founder genomes. Our pangenome representation leverages existing standards for genomic sequence representations with backward-compatible extensions to describe graph topology and genome-specific annotations along paths. It packs 83 mouse genomes (8 founders + 75 CC strains) into a single graph representation that captures important notions relating genomes such as identity-by-descent and highly variable genomic regions. The introduction of special anchor nodes with sequence content provides a valid coordinate framework that divides large eukaryotic genomes into homologous segments and addresses most of the graph-based position reference issues. Parallel edges between anchors place variants within a context that facilitates orthogonal genome comparison and visualization. Furthermore, our graph structure allows annotations to be placed in multiple genomic contexts and simplifies their maintenance as the assembly improves. The CC reference pangenome provides an open framework for new tool chain development and analysis.

bioinformatics↗

bioRxiv2019

Integrity of the Uncinate Fasciculus Predicts Emotional Pattern Separation-Related fMRI Signals in the Hippocampal Dentate and CA3

Alterations in white matter integrity have been demonstrated in a number of psychiatric disorders that involve disruptions in emotional processing. One such pathway - the uncinate fasciculus (UF) - connects the orbitofrontal cortex (OFC) to the medial temporal lobes (MTL) and has been associated with early life adversity, maltreatment, anxiety, and depression. While it is purported to play a role in episodic memory and discrimination, its exact function remains poorly understood. We have previously described the role of the amygdala and dentate (DG)/CA3 fields of the hippocampus in the mnemonic discrimination of emotional experiences (i.e. emotional pattern separation). However, how this computation may be modulated by connectivity between the medial temporal lobes and the orbitofrontal cortex remains unknown. Here we ask the question of whether the uncinate fasciculus plays a role in influencing MTL subregional activity during emotional pattern separation. By combining diffusion imaging with high-resolution functional MRI, we found that reduced integrity of the UF is related to higher activation in the DG/CA3 subregions of the hippocampus during an emotional pattern separation task. We additionally report that higher levels of DG/CA3 activity are associated with poorer memory performance, suggesting that hyperexcitability in this network (which may be driven by CA3 recurrent collaterals) is associated with memory errors and that the UF may allow the OFC to exert inhibitory control on this network and improve discrimination of emotional experiences. This work provides novel mechanistic insight into the role of prefrontal interactions with the MTL, particularly in the context of emotional memory.

neuroscience↗

bioRxiv2018

A diallel of the mouse Collaborative Cross founders reveals strong strain-specific maternal effects on litter size

Reproductive success in the eight founder strains of the Collaborative Cross (CC) was measured using a diallel-mating scheme. Over a 48-month period we generated 4,448 litters, and 24,782 weaned pups were used across 16 different published experiments. We identified factors that affect the average litter size in a cross by estimating the overall contribution of parent-of-origin, heterosis, inbred, and epistatic effects using a Bayesian zero-truncated overdispersed Poisson mixed model. The phenotypic variance of litter size has a substantial contribution (79%) from unexplained and environmental sources, but no detectable effect of seasonality. Most of the explained variance was due to additive effects (9.2%) and parental sex (maternal vs paternal strain; 5.8%), with epistasis accounting for 3.4%. Within the parental effects, the effect of the dams strain explained more than the sires strain (13.2% vs. 1.8%), and the dams strain effects account for 74.2% of total variation explained. Dams from strains C57BL/6J and NOD/ShiLtJ increased the expected litter size by a mean of 1.66 and 1.79 pups, whereas dams from strains WSB/EiJ, PWK/PhJ, and CAST/EiJ reduced expected litter size by a mean of 1.51, 0.81, and 0.90 pups. Finally, there was no strong evidence for strain-specific effects on sex ratio distortion. Overall, these results demonstrate that strains vary substantially in their reproductive ability depending on their genetic background and that litter size is largely determined by dam.strain rather than sire.strain effects, as expected. This analysis adds to our understanding of factors that influence litter size in mammals, and also helps to explain breeding successes and failures in the extinct lines and surviving CC strains.

genetics↗