Ruiqing Ni

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Ni

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Ruiqing

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0000-0002-0793-2113

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Publications 1 - 10 of 78

Probing Chemical Complexity of Amyloid Plaques in Alzheimer’s Disease Mice using Hyperspectral Raman Imaging
Mrđenović, Dušan; Combes, Benjamin F.; Ni, Ruiqing; et al. (2024)
ACS Chemical Neuroscience
One of the distinctive pathological features of Alzheimer’s disease (AD) is the deposition of amyloid plaques within the brain of affected individuals. These plaques have traditionally been investigated using labeling techniques such as immunohistochemical imaging. However, the use of labeling can disrupt the structural integrity of the molecules being analyzed. Hence, it is imperative to employ label-free imaging methods for noninvasive examination of amyloid deposits in their native form, thereby providing more relevant information pertaining to AD. This study presents compelling evidence that label-free and nondestructive confocal Raman imaging is a highly effective approach for the identification and chemical characterization of amyloid plaques within cortical regions of an arcAβ mouse model of AD. Furthermore, this investigation elucidates how the spatial correlation of Raman signals can be exploited to identify robust Raman marker bands and discern proteins and lipids from amyloid plaques. Finally, this study uncovers the existence of distinct types of amyloid plaques in the arcAβ mouse brain, exhibiting significant disparities in terms of not only shape and size but also molecular composition.
Multimodal imaging of murine cerebrovascular dynamics induced by transcranial pulse stimulation
Karakatsani, Maria Eleni; Nozdriukhin, Daniil; Tiemann, Savannah; et al. (2025)
Alzheimer's & Dementia: The Journal of the Alzheimer's Association
INTRODUCTION: Transcranial pulse stimulation (TPS) is increasingly being investigated as a promising potential treatment for Alzheimer's disease (AD). Although the safety and preliminary clinical efficacy of TPS short pulses have been supported by neuropsychological scores in treated AD patients, its fundamental mechanisms are uncharted. METHODS: Herein, we used a multi-modal preclinical imaging platform combining real-time volumetric optoacoustic tomography, contrast-enhanced magnetic resonance imaging, and ex vivo immunofluorescence to comprehensively analyze structural and hemodynamic effects induced by TPS. Cohorts of healthy and AD transgenic mice were imaged during and after TPS exposure at various per-pulse energy levels. RESULTS: TPS enhanced the microvascular network, whereas the blood-brain barrier remained intact following the procedure. Notably, higher pulse energies were necessary to induce hemodynamic changes in AD mice, arguably due to their impacted vessels. DISCUSSION: These findings shed light on cerebrovascular dynamics induced by TPS treatment, and hence are expected to assist improving safety and therapeutic outcomes. Highlights center dot Transcranial pulse stimulation (TPS) facilitates transcranial wave propagation using short pulses to avoid tissue heating. center dot Preclinical multi-modal imaging combines real-time volumetric optoacoustic (OA) tomography, contrast-enhanced magnetic resonance imaging (CE-MRI), and ex vivo immunofluorescence to comprehensively analyze structural and hemodynamic effects induced by TPS. center dot Blood volume enhancement in microvascular networks was reproducibly observed with real-time OA imaging during TPS stimulation. center dot CE-MRI and gross pathology further confirmed that the brain architecture was maintained intact without blood-brain barrier (BBB) opening after TPS exposure, thus validating the safety of the procedure. center dot Higher pulse energies were necessary to induce hemodynamic changes in AD compared to wild-type animals, arguably due to their pathological vessels.
Transcranial pulse stimulation modulates neuronal activity and functional network dynamics
Karakatsani, Maria Eleni; Gezginer , Irmak; Nozdriukhin, Daniil; et al. (2025)
Brain Stimulation
Background Transcranial pulse stimulation (TPS) has recently been proposed as a promising non-invasive technique for treating neurological disorders. While neuropsychological improvements in treated Alzheimer's disease (AD) patients support its safety and preliminary clinical effectiveness, the fundamental mechanisms of TPS action on the brain remain unclear. Objective In this study, we explore the effects of TPS on neuronal activity and brain circuitry in healthy and AD mouse models. Methods We utilized fluorescence calcium imaging combined with resting-state functional magnetic resonance imaging and c-Fos immunohistochemistry for validation. We imaged TPS-treated mouse brains expressing genetically encoded calcium indicator and compared the imaging data from AD mouse strains to wild-type controls, followed by immunohistochemical analysis of neuronal activation to support the in vivo imaging findings. Results TPS induced robust calcium influxes in GCaMP + mice, increased c-Fos expression in the dentate gyrus, and rapidly but transiently reorganized functional connectivity across brain networks, particularly within the hypothalamus, hippocampus, and other limbic regions. At higher stimulation intensities, TPS is shown to trigger spreading depolarization waves. Conclusion These findings support the hypothesis that TPS-induced mechanical effects can effectively modulate brain activity while averting tissue heating and cavitation, thus shedding light on observed beneficial effects in patients and paving the way for further optimization of TPS as a therapeutic strategy for neurodegenerative diseases.
Discerning Amyloid-β and Tau Pathologies with Learning-Based Quantum Sensing
Sundar, Shruti; Jabir , Marakkarakath Vadakkepurayil; Glandorf, Lukas Benjamin; et al. (2025)
ACS Photonics
Photon entanglement, a key feature of quantum correlations, provides a level of coherence absent in classical correlations, potentially offering new information when interacting with biological matter. One promising application is using entanglement decoherence to distinguish between healthy and diseased samples. However, achieving this requires efficient entangled photon sources capable of surviving through biological samples for reliable detection. In this work, we show the applicability of a polarization-entangled photon source as a label-free diagnostic tool for distinguishing between transgenic mouse models of amyloidosis and tauopathy and their respective control strains. We investigated cortical and hippocampal regions of these models, and our findings revealed greater preservation of entanglement in the transgenic samples compared to controls. To further enhance classification accuracy, we employed a supervised machine learning approach, achieving reliable distinctions between disease and control groups in unseen test samples. The quantum-based results were further validated through confocal imaging of the transgenic and control samples. These findings suggest that quantum sensing could serve as a label-free approach for distinguishing biological samples, with potential applications in the study of neurodegenerative disorders.
Non-invasive large-scale imaging of concurrent neuronal, astrocytic, and hemodynamic activity with hybrid multiplexed fluorescence and magnetic resonance imaging (HyFMRI)
Chen , Zhenyue; Chen , Yi; Gezginer , Irmak; et al. (2025)
Light: Science & Applications
A critical gap currently exists in systematic understanding and experimental validation of the role of astrocytes in neurovascular coupling and their functional links with other brain cells. Despite a broad selection of functional neuroimaging tools for multi-scale brain interrogations, no methodology currently exists that can discern responses from neural and glial cells while simultaneously mapping the associated hemodynamic activity on a large scale. We present a hybrid multiplexed fluorescence and magnetic resonance imaging (HyFMRI) platform for measuring neuronal and astrocytic activity registered to concurrently recorded brain-wide hemodynamic responses. It features a fiberscope-based imaging system for multichannel fluorescence and optical intrinsic signal recordings and a custom surface radiofrequency coil, which are incorporated into the bore of a preclinical magnetic resonance imaging (MRI) scanner. We used HyFMRI to study peripheral-stimulus-evoked brain responses in mice differentially labeled with RCaMP and GCaMP genetically-encoded calcium indicators. Stimulation-evoked neuronal responses displayed the fastest kinetics and highest activation amplitude followed by astrocytic signals and the hemodynamic responses simultaneously recorded with functional MRI. In addition, the activation traces from neurons and astrocytes exhibited high linear correlation, thus providing direct evidence of astrocytic mediation in neurovascular coupling. This newly developed capacity to capture cell-type-specific calcium signaling alongside whole-brain hemodynamics enables the simultaneous investigation of neuro-glial-vascular interactions in health and disease. HyFMRI thus expands the current neuroimaging toolbox for a wide range of studies into synaptic plasticity, neural circuitry, brain function and disorders.
Reduced synaptic vesicle protein 2A in extracellular vesicles and brains of Alzheimer’s disease: associations with Aβ, tau, synaptic proteins and APOE ε4
Nussbaumer , Jana; Barve , Aatmika; Zufferey , Valentin; et al. (2025)
Translational Neurodegeneration
Background: Alzheimer’s disease (AD) is characterized by accumulation of amyloid-β (Aβ) plaques, tau neurofibrillary Tangles and synaptic dysfunction. The aim of this study was to map the distributions of synaptic vesicle protein 2A (SV2A) and other synaptic proteins in the brain and the brain-derived extracellular vesicles (BDEVs) of AD patients, analyze their associations with Aβ, tau, and the apolipoprotein E (APOE) ε4 allele, and investigate the biological role of SV2A. Methods: Mass spectrometry-based proteomics of BDEVs and immunohistochemistry staining were conducted on postmortem brain samples from 57 AD patients and 48 nondemented controls. The levels of SV2A, synaptophysin (SYP), and other synaptic proteins in the brain tissues and the BDEVs, and their associations with Aβ, tau (phospho-tau and Braak stages), other proteins and the APOE ε4 allele, were analyzed. Results: SV2A levels were significantly lower in AD patients than in nondemented controls, particularly in the hippocampus and entorhinal cortex. APOE ε4 carriers presented further reductions in SV2A levels compared with noncarriers. The SV2A levels in BDEVs and brain tissues were positively correlated with SYP levels and negatively correlated with Aβ and phospho-tau levels. Reductions in SV2A were associated with decreased levels of other synaptic proteins, such as synaptotagmins, GAP43, and SNAP25. SV2A emerged as a central hub with interactions with proteins from subnetworks related to synaptic vesicle formation and fusion. Conclusion: SV2A levels in brain tissues and BDEVs are reduced in AD patients, particularly in those carrying the APOE ε4 allele, and are correlated with Aβ and tau pathologies. SV2A may serve as a valuable biomarker for monitoring synaptic dysfunction and progression in AD.
In vivo Imaging of Cannabinoid Type 2 Receptors: Functional and Structural Alterations in Mouse Model of Cerebral Ischemia by PET and MRI
Ni, Ruiqing; Müller Herde, Adrienne; Haider, Ahmed; et al. (2022)
Molecular Imaging and Biology
Purpose Stroke is one of the most prevalent vascular diseases. Non-invasive molecular imaging methods have the potential to provide critical insights into the temporal dynamics and follow alterations of receptor expression and metabolism in ischemic stroke. The aim of this study was to assess the cannabinoid type 2 receptor (CB2R) levels in transient middle cerebral artery occlusion (tMCAO) mouse models at subacute stage using positron emission tomography (PET) with our novel tracer [18F]RoSMA-18-d6 and structural imaging by magnetic resonance imaging (MRI). Procedures Our recently developed CB2R PET tracer [18F]RoSMA-18-d6 was used for imaging neuroinflammation at 24 h after reperfusion in tMCAO mice. The RNA expression levels of CB2R and other inflammatory markers were analyzed by quantitative real-time polymerase chain reaction using brain tissues from tMCAO (1 h occlusion) and sham-operated mice. [18F]fluorodeoxyglucose (FDG) was included for evaluation of the cerebral metabolic rate of glucose (CMRglc). In addition, diffusion-weighted imaging and T2-weighted imaging were performed for anatomical reference and delineating the lesion in tMCAO mice. Results mRNA expressions of inflammatory markers TNF-α, Iba1, MMP9 and GFAP, CNR2 were increased to 1.3–2.5 fold at 24 h after reperfusion in the ipsilateral compared to contralateral hemisphere of tMCAO mice, while mRNA expression of the neuronal marker MAP-2 was markedly reduced to ca. 50 %. Reduced [18F]FDG uptake was observed in the ischemic striatum of tMCAO mouse brain at 24 h after reperfusion. Although higher activity of [18F]RoSMA-18-d6 in ex vivo biodistribution studies and higher standard uptake value ratio (SUVR) were detected in the ischemic ipsilateral compared to contralateral striatum in tMCAO mice, the in vivo specificity of [18F]RoSMA-18-d6 was confirmed only in the CB2R-rich spleen. Conclusions This study revealed an increased [18F]RoSMA-18-d6 measure of CB2R and a reduced [18F]FDG measure of CMRglc in the ischemic striatum of tMCAO mice at subacute stage. [18F]RoSMA-18-d6 might be a promising PET tracer for detecting CB2R alterations in animal models of neuroinflammation without neuronal loss.
Amyloid and Tau Positron Emission Tomography Imaging in Alzheimer’s Disease and Other Tauopathies
Maschio, Cinzia; Ni, Ruiqing (2022)
Frontiers in Aging Neuroscience
The detection and staging of Alzheimer’s disease (AD) using non-invasive imaging biomarkers is of substantial clinical importance. Positron emission tomography (PET) provides readouts to uncover molecular alterations in the brains of AD patients with high sensitivity and specificity. A variety of amyloid-β (Aβ) and tau PET tracers are already available for the clinical diagnosis of AD, but there is still a lack of imaging biomarkers with high affinity and selectivity for tau inclusions in primary tauopathies, such as progressive supranuclear palsy (PSP), corticobasal degeneration (CBD) and Pick’s disease (PiD). This review aims to provide an overview of the existing Aβ and tau PET imaging biomarkers and their binding properties from in silico, in vitro, and in vivo assessment. Imaging biomarkers for pathologic proteins are vital for clinical diagnosis, disease staging and monitoring of the potential therapeutic approaches of AD. Off-target binding of radiolabeled tracers to white matter or other neural structures is one confounding factor when interpreting images. To improve binding properties such as binding affinity and to eliminate off-target binding, second generation of tau PET tracers have been developed. To conclude, we further provide an outlook for imaging tauopathies and other pathological features of AD and primary tauopathies.
Efficient characterization of multiple binding sites of small molecule imaging ligands on amyloid-beta, tau and alpha-synuclein
Sobek, Jens; Li, Junhao; Combes, Benjamin F.; et al. (2024)
European Journal of Nuclear Medicine and Molecular Imaging
PurposeThere is an unmet need for compounds to detect fibrillar forms of alpha-synuclein (alpha Syn) and 4-repeat tau, which are critical in many neurodegenerative diseases. Here, we aim to develop an efficient surface plasmon resonance (SPR)-based assay to facilitate the characterization of small molecules that can bind these fibrils.MethodsSPR measurements were conducted to characterize the binding properties of fluorescent ligands/compounds toward recombinant amyloid-beta (A beta)42, K18-tau, full-length 2N4R-tau and alpha Syn fibrils. In silico modeling was performed to examine the binding pockets of ligands on alpha Syn fibrils. Immunofluorescence staining of postmortem brain tissue slices from Parkinson's disease patients and mouse models was performed with fluorescence ligands and specific antibodies.ResultsWe optimized the protocol for the immobilization of A beta 42, K18-tau, full-length 2N4R-tau and alpha Syn fibrils in a controlled aggregation state on SPR-sensor chips and for assessing their binding to ligands. The SPR results from the analysis of binding kinetics suggested the presence of at least two binding sites for all fibrils, including luminescent conjugated oligothiophenes, benzothiazole derivatives, nonfluorescent methylene blue and lansoprazole. In silico modeling studies for alpha Syn (6H6B) revealed four binding sites with a preference for one site on the surface. Immunofluorescence staining validated the detection of pS129-alpha Syn positivity in the brains of Parkinson's disease patients and alpha Syn preformed-fibril injected mice, 6E10-positive A beta in arcA beta mice, and AT-8/AT-100-positivity in pR5 mice.ConclusionSPR measurements of small molecules binding to A beta 42, K18/full-length 2N4R-tau and alpha Syn fibrils suggested the existence of multiple binding sites. This approach may provide efficient characterization of compounds for neurodegenerative disease-relevant proteinopathies.
Arterial spin labeling demonstrates preserved regional cerebral blood flow in the P301L mouse model of tauopathy
Kindler, Diana; Maschio, Cinzia; Ni, Ruiqing; et al. (2022)
Journal of Cerebral Blood Flow & Metabolism
There is growing evidence for the vascular contribution to cognitive impairment and dementia in Alzheimer’s disease (AD) and other neurodegenerative diseases. While perfusion deficits have been observed in patients with Alzheimer’s disease and tauopaties, little is known about the role of tau in vascular dysfunction. In the present study, regional cerebral blood (rCBF) was characterized in P301L mice with arterial spin labeling. No differences in rCBF in P301L mice compared to their age-matched non-transgenic littermates at mid (10-12 months of age) and advanced (19-21 months of age) disease stages. This was concomitant with preservation of cortical brain structure as assessed with structural T2-weighted magnetic resonance imaging. These results show that hypoperfusion and neurodegeneration are not a phenotype of P301L mice. More studies are thus needed to understand the relationship of tau, neurodegeneration and vascular dysfunction and its modulators in AD and primary tauopathies.

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