Biology subjects

Hopkins, W. D.

Publications and source records attributed to Hopkins, W. D..

At least 19 recordsLinked to original sources

bioRxiv2026

Integration of Neuroimaging and Histopathology in a Squirrel Monkey Model of Spontaneous Cerebral Amyloid Angiopathy and Amyloid-Related Imaging Abnormalities

Cerebral amyloid angiopathy (CAA) is a prevalent cerebrovascular pathology in AD and contributes to amyloid-related imaging abnormalities (ARIA), a major complication of current anti-amyloid immunotherapy. Despite its growing clinical importance, critical gaps remain in the development of reliable biomarkers for antemortem diagnosis of CAA. Squirrel monkeys (SQMs) are a valuable non-human primate model with translational relevance due to their universal propensity to develop abundant CAA and spontaneous ARIA in geriatric animals. The present study employed R2*, the apparent transverse relaxation rate, which is sensitive to susceptibility-related tissue properties, including iron content and blood oxygenation levels, to monitor age-related brain pathology in SQMs with varying CAA severity. Young, early geriatric, and late geriatric SQMs underwent 7T MRI using a dual-purpose T2*-w 3D multi-gradient-echo sequence for high-resolution anatomy and quantitative R2* mapping, alongside T2-w/FLAIR imaging. Whole-brain and gray matter R2* increased with age. In contrast, white matter R2* showed an initial increase followed by a late-life reversal, likely reflecting age-related changes in myelin integrity, tissue microstructure, and tissue water content. MRI-histopathology correlation linked T2*-w MRI hypointensities to CAA-positive iron-laden vessels associated with perivascular inflammation and, in some cases, hemosiderin deposits. Here we confirmed the occurrence of ARIA-H and ARIA-E events in geriatric animals. SQMs provided a valuable opportunity to examine the underlying pathology of spontaneous ARIA-E, revealing distinctive tissue signatures associated with its manifestation. ARIA-E hyperintensities were characterized by reactive gliosis and BBB disruption, whereas more advanced lesions exhibited perivascular lymphocytic infiltration and evidence of myelin and axonal injury. The current study presents compelling evidence linking R2* alterations with CAA severity and ARIA-related tissue injury, providing a foundation for further advancing early detection of CAA, ARIA risk assessment, and treatment strategies.

neuroscience↗

bioRxiv2026

Clinically Relevant Biomarkers of Alzheimers Disease Are Associated with Age and Cortical Atrophy in Chimpanzees (Pan troglodytes)

Chimpanzees share a number of age-related brain changes with humans, such as reductions in neurons and increases in neuropathology. To date, there are no published studies of peripheral biomarkers related to Alzheimers pathology and their associations with age and cortical atrophy in chimpanzees. Here we examined cross-sectional differences and longitudinal changes in biomarkers of pathological protein aggregation, neuroinflammation, and microglial function measured in serum. We examined the relationships between biomarkers and clinically relevant biomarker ratios with both age and cortical atrophy. We found linear and quadratic relationships between age and several biomarkers and ratios. Most biomarkers increased with age. While controlling for sex, we found significant negative associations between age and sulci surface area, mean depth, and gray matter thickness and a positive association with fold opening. A{beta}42 and A{beta}40 showed higher biomarker values associated with lower surface area, mean depth, and gray matter thickness and higher fold opening values. The clinically relevant biomarker ratios were also associated with cortical atrophy - A{beta}42/A{beta}40 was negatively associated with gray matter thickness, and pTau217/A{beta}42 (both total and brain-derived) was positively associated with surface area and gray matter thickness and negatively associated with fold opening. Consistent with our hypotheses and previous findings in humans, many peripheral biomarkers associated with neurodegeneration and Alzheimers disease increase as chimpanzees age. We believe this is the first evidence demonstrating an association between these clinically relevant biomarkers of Alzheimers disease and phenotypes of brain aging in nonhuman primates, underscoring their importance as models of aging and neurodegenerative disease.

neuroscience↗

bioRxiv2026

A Comparative Study of Plasma Biomarkers of Neurodegeneration in Rhesus Monkeys (Macaca mulatta) and Baboons (Papio anubis)

Many nonhuman primate species recapitulate the neuropathological features of sporadic Alzheimers disease (AD) to varying degrees. As with humans, the assessment of AD-related pathology in nonhuman primates has historically relied on the use of postmortem brain tissues. In vivo alternatives, such as PET imaging tracers and fluid biomarkers, have been developed for use in humans but require further validation in nonhuman primates before replacing postmortem analyses. Here we employed the Nucleic Acid-Linked Immuno-Sandwich Assay (NULISATM) CNS Disease panel to compare age-related changes in plasma biomarkers in two nonhuman primate species (rhesus monkeys and baboons). In addition, we examined whether amyloid and tau biomarkers were associated with brain atrophy, as measured by gray matter volume. We found significant associations between age and multiple biomarkers of neurodegeneration for both species, as well as significant differences in the patterns of these associations between the two species. For the phosphorylated tau measures, though rhesus monkeys had higher values, baboons showed significant and stronger associations with age. By contrast, rhesus monkeys exhibited an earlier age-related decline in A{beta}42/A{beta}40 ratio than baboons. Finally, in both species, lower A{beta}42/A{beta}40 ratios were associated with lower gray matter volumes. This is the first systematic comparative study of age-related changes in neurodegeneration biomarkers in two closely related nonhuman primates using comparable age ranges and sample sizes, and the same multiplex assay. Future studies should examine longitudinal changes in these biomarkers as well as validate the plasma findings using cerebral spinal fluid.

neuroscience↗

bioRxiv2025

Mapping the Structural Brain Network of Psychopathy: Convergent Evidence from Humans and Chimpanzees

Psychopathy, a condition characterized by profound emotional and interpersonal deficits, has long been hypothesized to stem, in part, from structural brain abnormalities. Yet neuroimaging findings remain inconsistent. To address these discrepancies, we applied a novel structural network mapping approach combined with cross-species analyses. Traditional meta-analysis revealed weak spatial convergence across 20 samples. Nevertheless, we found that heterogeneous peak locations coalesced into a distributed set of regions encompassing the insular, and prefrontal cortices. This network overlapped strikingly (r = .93) with a lesion-derived network causally linked to antisocial behaviour, and variation within it predicted volumetric risk scores in both humans (n = 107, R{superscript 2} = .16) and chimpanzees (n = 148, R{superscript 2} = .21). These findings suggest that psychopathy reflects abnormalities across a collection of distributed regions rather than isolated areas, providing a unifying explanation for decades of inconsistent results and advancing our understanding of its clinical, biological, and evolutionary bases.

neuroscience↗

bioRxiv2025

A morphological comparison of the caudal rami of the superior temporal sulcus in humans, chimpanzees, and other great apes

For centuries, anatomists have charted the folding patterns of the sulci of the cerebral cortex in primates. Improvements in neuroimaging technologies over the past decades have led to advancements in understanding of the sulcal organization of the human cerebral cortex, yet comparisons to chimpanzees, one of humans closest extant phylogenetic relatives, remain to be performed in many regions, such as superior temporal cortex. For example, while several posterior branches, or rami, of the superior temporal sulcus (STS) have been identified in great apes since the late 1800s, no study has yet to comprehensively identify and quantitatively compare these rami across species. To fill this gap in knowledge, in the present study, we defined the three caudal branches of the STS (cSTS) in 72 human and 29 chimpanzee brains (202 total hemispheres) and then extracted and compared the morphological (depth and surface area) properties of these sulci. We report three main findings. First, modern methods replicate classic findings that three rami of the posterior STS are unique to the hominid lineage (i.e., humans and great apes). Second, normalizing for brain size, the cSTS rami were relatively deeper in chimpanzees compared to humans. Third, the cSTS branches were relatively larger in surface area in humans compared to chimpanzees. Finally, we share probabilistic predictions of the cSTS to guide the identification of these sulci in future studies. Altogether, these findings bridge the gap between historic qualitative observations and modern quantitative measurements in a part of the brain that has expanded substantially throughout evolution and that is involved in human-specific aspects of cognition.

neuroscience↗

bioRxiv2025

Evolution of the cellular landscape in mammalian striatum

The dorsal striatum is important for highly specialized functions including movement, learning, and habit formation. However, it is not known if species-specialized behaviors are associated with cellular specializations in the striatum. Here, we compared single-nucleus RNA sequencing (snRNA-seq) data from human, chimpanzee, rhesus macaque, common marmoset, and pale spear-nosed bat caudate (CN) and putamen (Pu) separately as well as mouse caudoputamen (C-Pu), which represents divergence among species spanning approximately 94 million years of evolution. We observed a lower neuron-to-glia ratio in primate striata compared to non-primates, reflecting the allometric scaling of neuron density and relative glia density invariance in larger brains. Among neurons, eccentric spiny projection neurons (eSPNs) - an SPN of unknown function - showed significantly lower proportions in non-primate striata for both CN and Pu. Focusing on the heterogeneity within interneurons, we identified two bat striatal interneuron cell types that are nearly absent in other species: which express LMO3, and co-express FOXP2 and TSHZ2. Other striatal interneurons also showed significantly differential abundance between primates and non-primates. In summary, we provide a comprehensive snRNA- seq dataset of dorsal striatum, identify novel interneuron innovations in bat, and uncover fundamental cellular composition differences between primate and non-primate striata.

genomics↗

bioRxiv2025

Transcriptomic changes across subregions of the primate cerebellum support the evolution of uniquely human behaviors

BackgroundCompared to other primates, humans display unique behaviors including language and complex tool use. These abilities are made possible in part by the cerebellum. This region of the hindbrain, comprising the flocculus, vermis, and lateral hemispheres, has expanded throughout primate evolution, particularly in great apes. Given the cerebellums architecture--differing in connectivity, neuron content, and functions across subregions--examining subregional differences is crucial to understanding its evolutionary trajectory. ResultsWe performed bulk RNA-seq across samples from six primate species, representing 40-50 million years of evolutionary history, across four subregions of the cerebellum (vermis, flocculus, right lateral hemisphere, left lateral hemisphere). We analyzed changes in gene expression with respect to evolutionary relationships via the Ornstein-Uhlenbeck model and found that, on average, 8.5% of orthologous genes are differentially expressed in humans relative to other non-human primates. Subregion-specific gene expression patterns reveal that the primate lateral hemispheres exhibit significant differences in synaptic activity and glucose metabolism, which in turn are highly implicated in neural processing. ConclusionsThis study provides a novel perspective on gene expression divergences across cerebellar subregions in multiple primate species, offering valuable insights into the evolution of this brain structure. Our findings reveal distinct subregional transcriptomic patterns, with the lateral hemispheres emerging as key sites of divergence across the six primate species. The enrichment of genes related to synaptic activity, glucose metabolism, locomotion, and vocalization highlights the cerebellums crucial role in supporting the neural complexity underlying uniquely human and other species-specific primate behaviors.

genomics↗

bioRxiv2024

Left-Right Brain-Wide Asymmetry of Neuroanatomy in the Mouse Brain

Left-right asymmetry of the human brain is widespread through its anatomy and function. However, limited microscopic understanding of it exists, particularly for anatomical asymmetry where there are few well-established animal models. In humans, most brain regions show subtle, population-average regional asymmetries in thickness or surface area, alongside a macro-scale twisting called the cerebral petalia in which the right hemisphere protrudes anteriorly past the left. Here, we ask whether neuroanatomical asymmetries can be observed in mice, leveraging 6 mouse neuroimaging cohorts from 5 different research groups ([~]3,500 animals). We found an anterior-posterior pattern of volume asymmetry with anterior regions larger on the right and posterior regions larger on the left. This pattern appears driven by similar trends in surface area and positional asymmetries, with the results together indicating a small brain-wide twisting pattern, similar to the human cerebral petalia. Furthermore, the results show no apparent relationship to known functional asymmetries in mice, emphasizing the complexity of the structure-function relationship in brain asymmetry. By establishing a signature of anatomical brain asymmetry in mice, we aim to provide a foundation for future studies to probe the mechanistic underpinnings of brain asymmetry seen in humans - a feature of the brain with extremely limited understanding. Significance StatementThe human brain shows significant left-right anatomical asymmetry. Understanding its microscopic basis has implications for studies of autism and schizophrenia, evolution, embryonic brain development, and the relationship between structure and function in the brain. One of the biggest challenges to understanding this aspect of the brain is that animal models are limited. Here we show a brain-wide twisting pattern of asymmetry in the mouse brain using over 3,500 animals from six independent cohorts. These findings provide a basis for using mice to interrogate the microscopic underpinnings of anatomical asymmetry in humans and a roadmap for exploring anatomical asymmetry in additional species.

neuroscience↗

bioRxiv2023

In vivo mapping of the deep and superficial whitematter connectivity in the chimpanzee brain

Mapping the chimpanzee brain connectome, and comparing it to humans, is key to our understanding of similarities and differences in primate evolution that occurred after the split from their common ancestor around 6 million years ago. In contrast with macaque species brain studies, less studies have specifically addressed the structural connectivity of the chim-panzee brain and its comparison with the human brain. Most comparative studies in the liter-ature focus on the anatomy of the cortex and deep nuclei to evaluate how their morphometry and asymmetry differs from that of the human brain, and some studies have emerged concern-ing the study of brain connectivity between primates. In this work, we established a new white matter atlas of the deep and superficial white matter structural connectivity in chimpanzees. In vivo anatomical and diffusion weighted magnetic resonance imaging (MRI) data were collected on a 3 Tesla magnetic resonance imaging (MRI) system in 39 chimpanzees. These datasets were subsequently processed using a dedicated fiber clustering pipeline adapted to the chimpanzee brain enabling us to create two novel deep and superficial white matter connectivity atlases representative of the chimpanzee brain. These atlases provide the scientific community with an important and novel set of reference data for understanding the commonalities and differ-ences of the structural connectivity between the human and chimpanzee brains, which will contribute to a better understanding of the hominin brain evolution.

neuroscience↗

bioRxiv2023

Uncovering the Morphological Evolution of Language-Relevant Brain Areas

Human language is supported by a cortical network involving Brocas area which comprises Brodmann Areas 44 and 45 (BA44, BA45). While cytoarchitectonic homolog areas have been identified in nonhuman primates, it remains unknown how these regions evolved to support human language. Here, we use histological data and advanced cortical registration methods to precisely compare the morphology of BA44 and 45 between humans and chimpanzees. We found a general expansion of Brocas areas in humans, with the left BA44 enlarging the most, growing anteriorly into a region known to process syntax. Together with recent functional studies, our findings show that BA44 evolved from a purely action-related region to a more expanded region in humans, with a posterior portion supporting action and an anterior portion supporting syntactic processes. Furthermore, our findings provide a solution for the longstanding debate concerning the structural and functional evolution of Brocas area and its role in action and language.

neuroscience↗

bioRxiv2022

The Uniqueness of Human Vulnerability to Brain Aging in Great Ape Evolution

Aging is associated with robust decline of the brains gray matter. This spatially specific, morphological change in humans has recently been found in chimpanzees. Direct comparison of age-related brain deterioration between these great ape species can provide a unique evolutionary perspective on human brain aging. Here, we present a data-driven, cross-species comparative framework to explore the relationship between gray matter atrophy with age and cross-species cerebral expansion in chimpanzees and humans. In humans, we found a positive relationship between cerebral aging and cortical expansion, whereas, in chimpanzees no such relationship was found. The greater aging and expansion effects in higher-order cognitive regions like the orbito-frontal cortex were observed to be unique to humans. This resembles the last in, first out hypothesis for neurodevelopment and may represent a biological cost for recent evolutionary developments of human faculties.

neuroscience↗

bioRxiv2022

Comparative transcriptomics reveals human-specific cortical features

Humans have unique cognitive abilities among primates, including language, but their molecular, cellular, and circuit substrates are poorly understood. We used comparative single nucleus transcriptomics in adult humans, chimpanzees, gorillas, rhesus macaques, and common marmosets from the middle temporal gyrus (MTG) to understand human-specific features of cellular and molecular organization. Human, chimpanzee, and gorilla MTG showed highly similar cell type composition and laminar organization, and a large shift in proportions of deep layer intratelencephalic-projecting neurons compared to macaque and marmoset. Species differences in gene expression generally mirrored evolutionary distance and were seen in all cell types, although chimpanzees were more similar to gorillas than humans, consistent with faster divergence along the human lineage. Microglia, astrocytes, and oligodendrocytes showed accelerated gene expression changes compared to neurons or oligodendrocyte precursor cells, indicating either relaxed evolutionary constraints or positive selection in these cell types. Only a few hundred genes showed human-specific patterning in all or specific cell types, and were significantly enriched near human accelerated regions (HARs) and conserved deletions (hCONDELS) and in cell adhesion and intercellular signaling pathways. These results suggest that relatively few cellular and molecular changes uniquely define adult human cortical structure, particularly by affecting circuit connectivity and glial cell function.

neuroscience↗

bioRxiv2022

Variation in subcortical anatomy: relating interspecies differences, heritability, and brain-behavior relationships

There has been an immense research focus on the topic of cortical reorganization in human evolution, but much less is known regarding the reorganization of subcortical circuits which are intimate working partners of the cortex. Here, by combining advanced image analysis techniques with comparative neuroimaging data, we systematically map organizational differences in striatal, pallidal and thalamic anatomy between humans and chimpanzees. We relate interspecies differences, a proxy for evolutionary changes, to genetics and behavioral correlates. We show that highly heritable morphological measures are significantly expanded across species, in contrast to previous findings in the cortex. The identified morphological-cognitive latent variables were associated with striatal expansion, and affective latent variables were associated with more evolutionarily-conserved areas in the thalamus and globus pallidus. These findings provide new insight into the architecture of these subcortical hubs and can provide greater information on the role of these structures in health and illness.

neuroscience↗

bioRxiv2021

Age- and sex-related differences in baboon (Papio anubis) gray matter covariation

Age-related changes in cognition, brain morphology, and behavior are exhibited in several primate species. Baboons, like humans, naturally develop Alzheimers disease-like pathology and cognitive declines with age and are an underutilized model for studies of aging. To determine age-related differences in gray matter covariation of 89 olive baboons (Papio anubis), we used source-based morphometry (SBM) to analyze data from magnetic resonance images. We hypothesized that we would find significant age effects in one or more SBM components, particularly those which include regions influenced by age in humans and other nonhuman primates (NHPs). A multivariate analysis of variance revealed that individual weighted gray matter covariation scores differed across the age classes. Elderly baboons contributed significantly less to gray matter covariation components including the brainstem, superior parietal cortex, thalamus, and pallidum compared to juveniles, and middle and superior frontal cortex compared to juveniles and young adults (p<0.05). Future studies should examine the relationship between the changes in gray matter covariation reported here and age-related cognitive decline.

neuroscience↗

bioRxiv2021

Tempo and mode of gene expression evolution in the brain across Primates

Primate evolution has led to a remarkable diversity of behavioral specializations and pronounced brain size variation among species 1,2. Gene expression provides a promising opportunity for studying the molecular basis of brain evolution, but it has been explored in very few primate species to date e.g. 3,4. To understand the landscape of gene expression evolution across the primate lineage, we generated and analyzed RNA-Seq data from four brain regions in an unprecedented eighteen species. Here we show a remarkable level of variation in gene expression among hominid species, including humans and chimpanzees, despite their relatively recent divergence time from other primates. We found that individual genes display a wide range of expression dynamics across evolutionary time reflective of the diverse selection pressures acting on genes within primate brain tissue. Using our sample that represents an unprecedented 190-fold difference in primate brain size, we identified genes with variation in expression most correlated with brain size and found several with signals of positive selection in their regulatory regions. Our study extensively broadens the context of what is known about the molecular evolution of the brain across primates and identifies novel candidate genes for study of genetic regulation of brain development and evolution.

evolutionary biology↗

bioRxiv2021

Divergent Connectional Asymmetries of the Inferior Parietal Lobule Shape Hemispheric Specialization in Humans, Chimpanzees, and Macaque Monkeys

The inferior parietal lobule (IPL) is one of the most expanded cortical regions in humans relative to other primates. It is also among the most structurally and functionally asymmetric regions in the human cerebral cortex. Whether the structural and connectional asymmetries of IPL subdivisions differ across primate species and how this relates to functional asymmetries remain unclear. We identified IPL subregions that exhibited positive allometric in both hemispheres, scaling across rhesus macaque monkeys, chimpanzees, and humans. The patterns of IPL subregions asymmetry were similar in chimpanzees and humans, but no IPL asymmetries were evident in macaques. Among the comparative sample of primates, humans showed the most widespread asymmetric connections in the frontal, parietal, and temporal cortices, constituting leftward asymmetric networks that may provide an anatomical basis for language and tool use. Unique human asymmetric connectivity between the IPL and primary motor cortex might be related to handedness. These findings suggest that structural and connectional asymmetries may underlie hemispheric specialization of the human brain.

neuroscience↗

bioRxiv2020

Comparative morphology of the corpus callosum across the adult lifespan in chimpanzees (Pan troglodytes) and humans

The human corpus callosum exhibits substantial atrophy in old age, which is stronger than what would be predicted from parallel changes in overall brain anatomy. To date, however, it has not been conclusively established whether this accentuated decline represents a common feature of brain aging across species, or whether it is a specific characteristic of the aging human brain. In the present cross-sectional study, we address this question by comparing age-related difference in corpus callosum morphology of chimpanzees and humans. For this purpose, we measured total midsagittal area and regional thickness of the corpus callosum from T1-weighted MRI data from 213 chimpanzees, aged between 9 and 54 years. The results were compared with data drawn from a large-scale human samples which was age-range matched using two strategies: (a) matching by chronological age (human sample size: n = 562), or (b) matching by accounting for differences in longevity and various maturational events between the species (i.e., adjusted human age range: 13.6 to 80.9 years; n = 664). Using generalized additive modelling to fit and compare aging trajectories, we found significant differences between the two species. The chimpanzee aging trajectory compared to the human trajectory was characterized by a slower increase from adolescence to middle adulthood, and by a lack of substantial decline from middle to old adulthood, which, however, was present in humans. Thus, the accentuated decline of the corpus callosum found in aging humans, is not an universal characteristic of the aging brain, and appears to be human-specific.

neuroscience↗

bioRxiv2020

Age-Related Changes in Chimpanzee (Pan troglodytes) Cognition: Cross-Sectional and Longitudinal Analyses

Chimpanzees are the species most closely related to humans yet age-related changes in brain and cognition remain poorly understood. The lack of studies on age-related changes in cognition in chimpanzees is particularly unfortunate in light of the recent evidence demonstrating that this species naturally develops Alzheimers disease (AD) neuropathology. Here, we tested 213 young, middle-aged, and elderly chimpanzees on the Primate Cognitive Test Battery (PCTB), a set of 13 tasks that assess physical and social cognition in nonhuman primates. A subset of these chimpanzees (n=146) were tested a second time on a portion of the PCTB tasks as a means of evaluating longitudinal changes in cognition. Cross-sectional analyses revealed a significant quadratic association between age and cognition with younger and older chimpanzees performing more poorly than middle-aged individuals. Longitudinal analyses showed that, while young chimpanzees performance improved from test 1 to test 2, middle-aged and elderly chimpanzees performance showed significant decline over time. The collective data show that chimpanzees, like other nonhuman primates, show age-related decline in cognition. Further investigations into whether the observed cognitive decline is associated with AD pathologies in chimpanzees would be invaluable in understanding the comparative biology of aging and neuropathology in primates.

animal behavior and cognition↗