About
Wenzhen Duan is a Professor of Psychiatry and Behavioral Sciences at Johns Hopkins University, affiliated with the Solomon H. Snyder Department of Neuroscience. Her research focuses on neurobiology of disease, particularly in the context of neurodegenerative disorders such as Huntington's disease (HD) and Alzheimer's disease (AD). She leads the Translational Neurobiology Laboratory, which aims to bridge basic science and clinical applications by developing therapeutics and biomarkers for these conditions. Her work involves advanced neuroimaging techniques, including in vivo MRI with deformation-based morphometry, to study structural brain changes associated with neurodegeneration. Her research program emphasizes the importance of brain barriers and brain-immune interactions in maintaining brain health and their roles in neurological diseases. She investigates mechanisms regulating brain barrier integrity, the crosstalk between the neurovascular unit and immune cells, and how these interactions influence neurodegenerative processes. Her team employs molecular biology, genetics, neuroimaging, and computational analysis, collaborating with experts in clinical translation, biomedical engineering, radiology, and gene therapy to develop innovative therapeutic strategies and identify reliable biomarkers. Her work aims to translate laboratory discoveries into clinical care, ultimately benefiting patients and their families.
Research topics
- Medicine
- Pathology
- Nuclear magnetic resonance
- Genetics
- Biology
- Molecular biology
- Chemistry
- Biochemistry
- Internal medicine
- Psychology
- Endocrinology
- Radiology
- Neuroscience
Selected publications
bioRxiv (Cold Spring Harbor Laboratory) · 2025-04-26 · 1 citations
preprintOpen accessSenior authorCorrespondingSummary Altered cerebral metabolism and blood-brain barrier (BBB) dysfunction are emerging as critical contributors to the preclinical phase of Alzheimer’s disease (AD), underscoring their role in early pathogenesis. To identify sensitive biomarkers before irreversible neuronal loss and cognitive decline, we examined 5XFAD mice at 3 months of age by applying multiple advanced MRI techniques. Arterial spin tagging based MRI revealed increased BBB permeability and water extraction fraction, indicating compromised BBB integrity at the early stage of pathogenesis in 5×FAD mice. Despite preserved cerebral blood flow, a decreased unit mass cerebral metabolic rate of oxygen (CMRO2) was evident in the same cohorts of 5XFAD mice. Interestingly, a region-specific decrease of tissue pH values was detected in the hippocampus of these 5XFAD mice by creatine chemical exchange saturation transfer MRI. Elevated neuronal H4K12 lactylation in the hippocampus supports the reduced pH values. To further dissect the cellular and molecular mechanisms underlying these MRI-detectable changes in 5XFAD mice, we conducted single-nucleus RNA sequencing (snRNA-Seq) with optimized blood vessel enrichment protocols. Our results revealed cell type-specific transcriptomic changes in the hippocampus of 3-month-old 5XFAD mice, including downregulation of synaptogenesis and synaptic transmission genes in the CA1 and dentate gyrus excitatory neurons, impaired endothelial gene expression linked to brain barrier function and angiogenesis, altered innate immune response genes in astrocytes, as well as upregulation of cholesterol biosynthesis and metabolism genes in the CA1 excitatory neurons. These findings underlie the intricate interplay between BBB disruption and metabolic dysregulation before the onset of cognitive decline in AD. Our study demonstrates that BBB dysfunction and cerebral metabolic alterations preceded brain hypoperfusion and cognitive decline, emphasizing potential molecular pathways for early intervention. These findings, once validated in human studies, could significantly enhance early diagnosis and inform novel therapeutic strategies targeting early AD pathogenesis.
bioRxiv (Cold Spring Harbor Laboratory) · 2025-03-16
preprintOpen accessSenior authorCorrespondingAbstract Huntington’s disease (HD) is a progressive neurodegenerative disorder caused by a CAG-repeat expansion in exon-1 of the huntingtin gene. Currently, no disease-modifying therapies are available, with a significant challenge in evaluating therapeutic efficacy before clinical symptoms emerge. This highlights the need for early biomarkers and intervention strategies. Therefore, it is essential to develop and characterize accurate mouse models and identify early biomarkers for preclinical therapeutic development. In this study, we characterized the pathological progression of the heterozygous zQ175 neo-deleted knock in (zQ175DN) mouse model across four age groups: 3, 6, 10, and 16 months to identify human translatable outcome measures. T2-relaxation-under-spin-tagging (TRUST) MRI was used to assess global CMRO 2 , while T2-weighted MRI was used to analyze brain volumes. Significant brain volume loss was detected as early as 6 months of age, worsening progressively with age in the zQ175 DN mice, resembling HD brain volumetric changes. A decline in CMRO 2 was observed in 6-month-old zQ175 DN mice, with significant and progressive reductions in 10- and 16-months old HD mice. Additionally, PHP1-positive mutant huntingtin (mHTT) aggregates were present in the striatum of zQ175 DN mice at all four age groups, with intranuclear localization prior to 6 months, transitioning to both intranuclear and neuropil aggregates in older zQ175 DN mice, suggesting that the localization of mHTT aggregates may reflect the severity of HD pathogenesis. Interestingly, plasma neurofilament light chain (NfL) protein concentrations were significantly elevated at 6 months of age and older zQ175DN mice. These findings provide valuable insights for selecting outcome measures in preclinical evaluations of HD therapies using the zQ175 DN mouse model.
Ocular perforating injury by an acupuncture needle: two cases reports
International Journal of Ophthalmology · 2025-11-17
articleOpen accessSenior authorExperimental Neurology · 2025-09-12 · 1 citations
articleOpen accessSenior authorCorrespondingHuntington's disease (HD) is a progressive neurodegenerative disorder caused by a CAG-repeat expansion in exon-1 of the huntingtin gene. Currently, no disease-modifying therapies are available, with a significant challenge in evaluating therapeutic efficacy before clinical symptoms emerge. This highlights the need for early biomarkers and intervention strategies. Therefore, it is essential to develop and characterize accurate mouse models and identify early biomarkers for preclinical therapeutic development. In this study, we characterized the pathological progression of the heterozygous zQ175 neodeleted knock in (zQ175DN) mouse model across four age groups: 3, 6, 10, and 16 months to identify human translatable outcome measures. T2-relaxation-under-spin-tagging (TRUST) MRI was used to assess global CMRO 2 , while T2-weighted MRI was used to analyze regional brain volumes. Significant striatal volume loss was detected as early as 6 months of age, worsening progressively with age in the zQ175 DN mice, resembling HD progressive striatal atrophy. A decline in CMRO 2 was observed in 6-month-old zQ175 DN mice, with significant and progressive reductions in 10- and 16- months old HD mice. Additionally, PHP1-positive mutant huntingtin (mHTT) aggregates were detectable in the striatum and cortex of zQ175 DN mice at all four ages, with intranuclear localization prior to 6 months, transitioning to co-exist of intranuclear and increased extracellular aggregates in older zQ175 DN mice, suggesting that the localization of mHTT aggregates may reflect the severity of HD pathogenesis. Interestingly, plasma neurofilament light chain (NfL) protein levels were significantly elevated at 6 months of age and older zQ175DN mice. These findings provide valuable insights for selecting outcome measures in preclinical evaluations of HD therapies using the zQ175 DN mouse model. • zQ175DN mice show early striatal atrophy and progressive HD pathology. • CMRO2 reduction and rising plasma NfL track disease progression. • MRI measures and NfL levels could serve as translational biomarkers for HD therapies.
Proceedings on CD-ROM - International Society for Magnetic Resonance in Medicine. Scientific Meeting and Exhibition/Proceedings of the International Society for Magnetic Resonance in Medicine, Scientific Meeting and Exhibition · 2025-09-16
articleMotivation: Mixed etiology involving AD and vascular issues is a common finding in clinics. However, the underlying mechanism of vascular dysfunction in AD remained to be fully understood. Goal(s): We aim to examine cerebrovascular reactivity (CVR) in an AD model and explore biological underpinnings with histology. Approach: CVR was assessed by a hypercapnia challenge with phase-contrast (PC) and arterial-spin-labeling (ASL) MRI in 9-month-old 5xFAD mice. Immunofluorescent staining was performed to examine amyloid-plaque deposits and vascular-smooth-muscle-cell (VSMC) densities. Results: 5xFAD mice exhibit impaired CVR in the hippocampus, which is associated with microhemorrhage and VSMC loss. Parenchymal amyloid plaque deposits alone are insufficient to jeopardize CVR. Impact: Impaired cerebral vascular reactivity (CVR) is associated with the loss of vascular smooth muscle cells in the hippocampus of 5xFAD model at 9 months of age.
Vascular Microbleeds Without Brain Atrophy: A Microvascular Signature of Mid-Stage 5xFAD Pathology
bioRxiv (Cold Spring Harbor Laboratory) · 2025-12-11 · 1 citations
articleOpen accessAbstract Cerebral microbleeds are increasingly recognized as a downstream manifestation of vascular injury in Alzheimer’s disease (AD), arising secondary to cerebral amyloid angiopathy (CAA). Here, we examined the pathological specificity of microbleeds by comparing an amyloidosis mouse model (5xFAD) with a small-vessel disease (SVD) model characterized by vascular smooth-muscle cell loss. In vivo multimodal MRI, including gradient-echo, spin-echo, and diffusion-weighted imaging, was complemented by ex vivo high-resolution anatomical scans for validation. Both in vivo and ex vivo gradient-echo MRI consistently revealed hippocampal microbleeds in the 5xFAD model without macroscopic atrophy or ventricular enlargement, whereas no microbleeds or blood-brain barrier disruption were detected in the SVD model. Diffusion-weighted MRI further showed region-specific alterations in apparent diffusion coefficient within the midbrain of 5xFAD mice, but not in other regions or in the SVD cohort. These findings indicate that microbleeds are a pathology-specific marker of amyloid-related vascular injury. The imaging evidence underscores the potential of microbleeds as a disease-specific biomarker for detecting amyloid-driven vascular fragility and refining diagnostic and therapeutic strategies for AD.
The glymphatic system in Huntington's disease
Journal of Huntington s Disease · 2025-03-28 · 3 citations
reviewOpen access1st authorCorrespondingThe glymphatic system, a macroscopic waste clearance network in the brain, plays a vital role in maintaining neuronal health and brain homeostasis. Functionally analogous to the lymphatic system in other organs, the term "glymphatic" combines "glial" and "lymphatic." This system facilitates the exchange of cerebrospinal fluid (CSF) and interstitial fluid (ISF) in the parenchyma, aiding in the removal of soluble proteins and metabolites while distributing essential nutrients and signaling molecules. Its functionality is closely tied to aquaporin 4 (AQP4) water channels, located primarily on astrocytic endfeet, which mediate water movement between the CSF and ISF. Proper glymphatic function relies on the cellular distribution of AQP4 channels and its astroglial endfeet polarization. Emerging evidence links glymphatic dysfunction to several neurodegenerative disorders, including Huntington's disease (HD). Understanding the role of the glymphatic system in HD pathogenesis could provide novel insights into disease pathogenesis and new therapeutic approaches. This review examines the connection between glymphatic dysfunction and HD, highlighting future research directions and therapeutic advancement for HD. It explores pharmacological interventions and lifestyle modifications aimed at optimizing glymphatic function to improve HD management.
Imaging Neuroscience · 2025-01-01 · 1 citations
articleOpen accessTauopathies, including Alzheimer's disease (AD), are neurodegenerative disorders characterized by hyperphosphorylated tau protein aggregates in the brain. In addition to protein aggregates, microglia-mediated inflammation and iron dyshomeostasis are other pathological features observed in AD and other tauopathies. It is known that these alterations at the subcellular level occur much before the onset of macroscopic tissue atrophy or cognitive deficits. The ability to detect these microstructural changes with MRI, therefore, has substantive importance for improved characterization of disease pathogenesis. In this study, we demonstrate that quantitative susceptibility mapping (QSM) with paramagnetic and diamagnetic susceptibility source separation has the potential to distinguish neuropathological alterations in a transgenic mouse model of tauopathy. 3D multi-echo gradient echo data were acquired from fixed brains of PS19 (Tau) transgenic mice and age-matched wild-type (WT) mice (n = 5 each) at 11.7 T. The multi-echo data were fit to a 3-pool complex signal model to derive maps of paramagnetic component susceptibility (PCS) and diamagnetic component susceptibility (DCS). Group-averaged signal fraction and composite susceptibility maps showed significant region-specific differences between the WT and Tau mouse brains. Significant bilateral increases in PCS and |DCS| were observed in specific hippocampal and cortical sub-regions of the Tau mice relative to WT controls. Comparison with immunohistological staining for microglia (Iba1) and phosphorylated-tau (AT8) further indicated that the PCS and DCS differences corresponded to regional microgliosis and tau deposition in the PS19 mouse brains, respectively. The results demonstrate that quantitative susceptibility source separation may provide sensitive imaging markers to detect distinct pathological alterations in tauopathies.
Nature Medicine · 2025-11-26
articleOpen accessSenior authorSSRN Electronic Journal · 2025-01-01
preprintOpen accessSenior author
Recent grants
NIH · $2.0M · 2019
Imaging brain glucose uptake by onVDMP MRI in Huntington's Disease
NIH · $465k · 2020–2023
NIH · $395k · 2010
NIH · $394k · 2010
NIH · $451k · 2014
Frequent coauthors
- 124 shared
Christopher A. Ross
- 76 shared
Mark P. Mattson
Johns Hopkins University
- 67 shared
Peng Qi
Zhejiang Sci-Tech University
- 67 shared
Mali Jiang
Johns Hopkins University
- 58 shared
Susumu Mori
Johns Hopkins University
- 56 shared
Zhipeng Hou
- 51 shared
Hongshuai Liu
Shandong University of Traditional Chinese Medicine
- 44 shared
Jiadi Xu
Johns Hopkins Medicine
Education
- 1998
PhD, Neuropharmacology
Chinese Academy of Medical Sciences & Peking Union Medical College
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