Biology subjects

Weiss, A. R.

Publications and source records attributed to Weiss, A. R..

10 recordsLinked to original sources

bioRxiv2026

Hybrid transcriptome assembly and annotation of Japanese macaque prefrontal cortex

Japanese macaque (Macaca fuscata) is used in biomedical and neurobiology research, yet transcriptomic resources for the brain are limited. We present a hybrid RNA sequencing dataset and a prefrontal cortex transcriptome assembly from two healthy 6-year-old animals. Short-read Illumina ({approx}70 million paired-end reads per sample) and long-read Oxford Nanopore direct RNA sequencing ({approx}2.5 million reads per sample) were combined. Reads were quality controlled, aligned to the macFus_1.0 reference genome, and assembled with StringTie2. Transcripts were annotated using Trinotate and eggNOG-mapper, and open reading frames were predicted with TransDecoder. The released data package includes raw reads (NCBI SRA BioProject PRJNA1295993), transcript sequences and structural annotation files, predicted coding sequences and proteins, functional annotation tables, and transcript abundance estimates (TPM). Technical validation includes read-level QC and protein-level comparisons to expressed gene sets from human, rhesus macaque and chimpanzee prefrontal cortex. These resources enable reuse for transcript-level expression studies, isoform characterization and comparative primate neurogenomics.

neuroscience↗

bioRxiv2026

Aging macaques bridge the translational gap in perivascular space biology

The prevalence of MR-visible perivascular spaces (PVS) is age-dependent in rhesus macaques. Automated quantification in 94 male and female animals ranging 5-28 years of age demonstrated a robust association between age and PVS burden, with an anatomical distribution paralleling that of humans. Preliminary ex vivo validation confirmed that the MRI-detected tubular structures correspond to perivascular spaces. These findings establish the rhesus macaque as a tractable model for understanding the role of perivascular dysfunction in age-related brain vulnerability.

neuroscience↗

bioRxiv2025

Prodromal pathogenesis of CLN7 Batten Disease revealed by multimodal biomarkers in macaques

Neuronal ceroid lipofuscinosis type 7 (CLN7) is a devastating paediatric neurodegenerative disorder with no cure and limited natural history data to guide therapeutic development. Here, we present the first multimodal characterization of prodromal and early-stage CLN7 disease in Japanese macaques carrying a spontaneous CLN7-/- mutation. Using structural T2-weighted MRI for volumetry, [18F]FDG PET for glucose metabolism, and [11C]PBR28 PET for neuroinflammation, we observed region-dependent patterns in volumetric, molecular, and metabolic alterations. MRI confirmed the presence of disease-associated atrophy in many cortical and subcortical brain regions, consistent with human pathology, [18F]FDG PET revealed early cortical and subcortical widespread hypometabolism, and [11C]PBR28 PET imaging detected progressive neuroinflammation in the same brain areas. CSF analyses further showed age-dependent increases in neurofilament light (NfL), providing convergent evidence for neurodegeneration. Together, these results define a prodromal trajectory in CLN7 disease, establish sensitive imaging and fluid biomarkers, and validate the macaque model as a powerful platform for testing interventions.

neuroscience↗

bioRxiv2025

Longitudinal Investigation of Structural and Resting-State Effective Connectivity Alterations in a Non-Human Primate Model of Huntington's Disease

Huntingtons disease (HD) is a genetic neurodegenerative disorder caused by expanded CAG repeats in the huntingtin gene which produce a mutant huntingtin (mHTT) protein that contributes to progressive striatal, cortical, and white-matter atrophy, resulting in motor dysfunction and cognitive decline. Recently, a non-human primate (NHP) model of HD was developed via stereotaxic delivery of an adeno-associated viral vector expressing 85 CAG repeats (85Q) into the striatum. This model recapitulates several neuropathological changes and symptoms observed in people with HD (PwHD) including chorea and mild cognitive impairment. A previous longitudinal, multimodal MRI investigation in this model revealed volumetric and resting-state functional connectivity (rs-FC) changes compared to controls, in key regions involved in HD, over the course of 30 months. We aimed to study longitudinal changes in structural connectivity (SC), obtained from diffusion MRI scans from the same animals, comparing the 85Q animals to the control (Buffer) group. Additionally, going beyond the correlative rs-FC analyses, we investigated changes in causal, inter-regional functional interactions by estimating effective connectivity (EC) from rs functional MRI scans, constrained to strong structural connections. We found that the SC between basal ganglia regions and the cortex was reduced in the 85Q primates compared to the Buffer group at 14-months post virus injection, aligning with the pathological process observed in PwHD at later stages of the disease. EC from the caudate and putamen to the motor cortex was significantly reduced in the 85Q animals as early as 3-months post-injection providing novel insights into early alterations in causal functional interactions.

neuroscience↗

bioRxiv2024

Brain Charts for the Rhesus Macaque Lifespan

Recent efforts to chart human brain growth across the lifespan using large-scale MRI data have provided reference standards for human brain development. However, similar models for nonhuman primate (NHP) growth are lacking. The rhesus macaque, a widely used NHP in translational neuroscience due to its similarities in brain anatomy, phylogenetics, cognitive, and social behaviors to humans, serves as an ideal NHP model. This study aimed to create normative growth charts for brain structure across the macaque lifespan, enhancing our understanding of neurodevelopment and aging, and facilitating cross-species translational research. Leveraging data from the PRIMatE Data Exchange (PRIME-DE) and other sources, we aggregated 1,522 MRI scans from 1,024 rhesus macaques. We mapped non-linear developmental trajectories for global and regional brain structural changes in volume, cortical thickness, and surface area over the lifespan. Our findings provided normative charts with centile scores for macaque brain structures and revealed key developmental milestones from prenatal stages to aging, highlighting both species-specific and comparable brain maturation patterns between macaques and humans. The charts offer a valuable resource for future NHP studies, particularly those with small sample sizes. Furthermore, the interactive open resource (https://interspeciesmap.childmind.org) supports cross-species comparisons to advance translational neuroscience research.

neuroscience↗

bioRxiv2023

Layer 5a Corticostriatal Projection Neurons are Selectively Vulnerable in Huntington's Disease

The properties of the cell types that are selectively vulnerable in Huntingtons disease (HD) cortex, the nature of somatic CAG expansions of mHTT in these cells, and their importance in CNS circuitry have not been delineated. Here we employed serial fluorescence activated nuclear sorting (sFANS), deep molecular profiling, and single nucleus RNA sequencing (snRNAseq) to demonstrate that layer 5a pyramidal neurons are vulnerable in primary motor cortex and other cortical areas of HD donors. Extensive mHTT-CAG expansions occur in vulnerable layer 5a pyramidal cells, and in Betz cells, layer 6a, layer 6b neurons that are resilient in HD. Retrograde tracing experiments in macaque brains identify the vulnerable layer 5a neurons as corticostriatal pyramidal cells. We propose that enhanced somatic mHTT-CAG expansion and altered synaptic function act together to cause corticostriatal disconnection and selective neuronal vulnerability in the HD cerebral cortex.

neuroscience↗

bioRxiv2022

A novel rhesus macaque model of Huntington's disease recapitulates key neuropathological changes along with progressive motor and cognitive decline

We created a new nonhuman primate model of the genetic neurodegenerative disorder, Huntingtons disease (HD), by injecting a mixture of recombinant adeno-associated viral vectors, serotypes AAV2 and AAV2.retro, each expressing a fragment of human mutant HTT (mHTT) into the caudate and putamen of adult rhesus macaques. This novel modeling strategy results in robust expression of mutant huntingtin protein (mHTT) in the injected brain regions, as well as dozens of other cortical and subcortical brain regions that are also affected in human HD patients. We queried the disruption of cortico-basal ganglia circuitry for 20-months post-surgery using a variety of behavioral and imaging readouts. Compared to controls, mHTT-treated macaques developed progressive working memory decline and motor impairment. Multimodal imaging revealed circuit-wide white and gray matter degenerative processes in several key brain regions affected in HD. This novel model will aid in the development of disease biomarkers and therapeutic strategies for this devastating disorder.

neuroscience↗

bioRxiv2020

The macaque brain ONPRC18 template with combined gray and white matter labelmap for multimodal neuroimaging studies of nonhuman primates

Macaques are the most common nonhuman primate (NHP) species used in neuroscience research. With the advancement of many neuroimaging techniques, new studies are beginning to apply multiple types of in vivo magnetic resonance imaging (MRI), such as structural imaging (sMRI) with T1 and T2 weighted contrasts alongside diffusion weighed (DW) imaging. In studies involving rhesus macaques, this approach can be used to better understand micro-structural changes that occur during development, in various disease states or with normative aging. However, many of the available rhesus brain atlases have been designed for only one imaging modality, making it difficult to consistently define the same brain regions across multiple imaging modalities in the same subject. To address this, we created a brain atlas from 18 adult rhesus macaques that includes co-registered templates constructed from images frequently used to characterize macroscopic brain structure (T2/SPACE and T1/MP-RAGE), and a diffusion tensor imaging (DTI) template. The DTI template was up-sampled from 1 mm isotropic resolution to resolution match to the T1 and T2-weighted images (0.5 mm isotropic), and the parameter map was derived for fractional anisotropy (FA). The labelmap volumes delineate 57 gray matter regions of interest (ROIs; 36 cortical regions and 21 subcortical structures), as well as 74 white matter tracts. Importantly, the labelmap overlays both the structural and diffusion templates, enabling the same regions to be consistently identified across imaging modalities. A specialized condensed version of the labelmap ROIs are also included to further extend the usefulness of this tool for imaging data with lower spatial resolution, such as functional MRI (fMRI) or positron emission tomography (PET). O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY Graphical Abstract C_FIG_DISPLAY

neuroscience↗

bioRxiv2020

Sexually dimorphic responses to MPTP found in microglia, inflammation and gut microbiota in a progressive monkey model of Parkinson's disease

Inflammation has been linked to the development of nonmotor symptoms in Parkinsons disease (PD), which greatly impact patients quality of life and can often precede motor symptoms. Suitable animal models are critical for our understanding of the mechanisms underlying disease and the associated prodromal disturbances. The neurotoxin 1- methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkey model is commonly seen as a "gold standard" model that closely mimics the clinical motor symptoms and the nigrostriatal dopaminergic loss of PD, however MPTP toxicity extends to other nondopaminergic regions. Yet, there are limited reports monitoring the MPTP-induced progressive central and peripheral inflammation as well as other nonmotor symptoms such as gastrointestinal function and microbiota. The main objective of this study is to gain a broader understanding of central and peripheral inflammatory dysfunction triggered by exposure to a neurotoxicant known to degenerate nigral dopaminergic neurons in order to understand the potential role of inflammation in prodromal/pre-motor features of PD-like degeneration in a progressive non-human primate model of the disease. We measured inflammatory proteins in plasma and CSF and performed [18F]FEPPA PET scans to evaluate translocator proteins (TSPO) or microglial activation in a small cohort of rhesus monkeys (n=5) given weekly low doses of MPTP (0.2-0.8 mg/kg, im). Additionally, monkeys were evaluated for working memory and executive function using various behavior tasks and for gastrointestinal hyperpermeability and microbiota composition. Monkeys were also treated with novel TNF inhibitor XPro1595 (10mg/kg, n=3) or vehicle (n=2) every three days starting 11 weeks after the initiation of MPTP to determine whether nonmotor symptoms are tied to TNF signaling and whether XPro1595 would alter inflammation and microglial behavior in a progressive model of PD. Our analyses revealed sex-dependent sensitivity to MPTP that resulted in early microglial activation by PET, acute plasma IL-6 and CSF TNF, and earlier parkinsonism as measured by motor deficits in males compared to female monkeys. Sex differences were also identified in microbiota and their metabolites and targeted short chain fatty acids at both basal levels and in response to MPTP. Both sexes displayed cognitive impairment prior to a significant motor phenotype. Importantly, XPro1595 shifted peripheral and central inflammation, and significantly reduced CD68-immunoreactivity in the colon. As such, our findings revealed a sexually dimorphic inflammatory response to chronic MPTP treatment and suggest that males may have higher vulnerability than females to inflammation-induced degeneration. If these findings reflect potential differences in humans, these sex differences have significant implications for therapeutic development of inflammatory targets in the clinic.

neuroscience↗

bioRxiv2020

Intra-striatal AAV2.retro administration leads to extensive retrograde transport in the rhesus macaque brain: implications for disease modeling and therapeutic development

Recently, AAV2.retro, a new capsid variant capable of efficient retrograde transport in brain, was generated in mice using a directed evolution approach. However, it remains unclear to what degree transport will be recapitulated in the substantially larger and more complex nonhuman primate (NHP) brain. Here, we compared the biodistribution of AAV2.retro with its parent serotype, AAV2, in adult macaques following delivery into the caudate and putamen, brain regions which comprise the striatum. While AAV2 transduction was primarily limited to the injected brain regions, AAV2.retro transduced cells in the striatum and in dozens of cortical and subcortical regions with known striatal afferents. We then evaluated the capability of AAV2.retro to deliver disease-related gene cargo to biologically-relevant NHP brain circuits by packaging a fragment of human mutant HTT, the causative gene mutation in Huntingtons disease. Following intra-striatal delivery, pathological mHTT-positive protein aggregates were distributed widely among cognitive, motor, and limbic cortico-basal ganglia circuits. Together, these studies demonstrate strong retrograde transport of AAV2.retro in NHP brain, highlight its utility in developing novel NHP models of brain disease and suggest its potential for querying circuit function and delivering therapeutic genes in the brain, particularly where treating dysfunctional circuits, versus single brain regions, is warranted.

neuroscience↗