The pallido-nigro-luysian axis and nigrostriatal system serve as sensitive targets for detecting tau deposition and monoaminergic disruption in PSP and local striatal tau pathology and tau burden were associated with monoaminergic disruption in PSP.
Abstract
Purpose: Progressive supranuclear palsy (PSP) is a tauopathy marked by widespread tau aggregation and prominent monoaminergic dysfunction, yet the relationship between regional tau burden and monoaminergic impairment remains unclear. In this study, we determine whether regional tau burden is associated with nigrostriatal monoaminergic dysfunction in PSP using PET imaging. Patients and Methods: A subset of 20 patients with PSP and monoaminergic impairment, identified by 18F-FP-DTBZ PET, was recruited and subsequently underwent 18F-APN-1607 PET to assess tau deposition. All images were spatially normalized and analyzed based on predefined volumes of interest. Erosion-based cerebral white matter was used as the reference region to calculate standardized uptake value ratios (SUVRs) for 18F-APN-1607 PET. Results: The SUVRs of 18F-APN-1607 PET differed significantly between patients with PSP and healthy controls in the globus pallidus, substantia nigra, subthalamus nucleus, and red nucleus, while a significant difference in 18F-FP-DTBZ SUVRs was observed in all the striatal regions and substantia nigra. Regression analysis discovered negative associations between tau load and monoaminergic disruption in the putamen and caudate, whereas tau accumulation in the substantia nigra was not significantly associated with nigrostriatal impairment. Conclusions: The pallido-nigro-luysian axis and nigrostriatal system serve as sensitive targets for detecting tau deposition and monoaminergic disruption in PSP. Local striatal tau pathology and tau burden were associated with monoaminergic disruption in PSP.
PURPOSE
Progressive supranuclear palsy (PSP) and Alzheimer's disease (AD) exhibit different tau distributions. We compared tract-specific associations between florzolotau(18F) retention, white matter (WM) microstructure, and clinical impairment.
METHODS
Forty-nine patients with PSP, 40 with AD, and 30 cognitively unimpaired controls underwent florzolotau(18F) PET. Tractography evaluated projection and association fibers, including the dentatorubrothalamic tract (DRTT) and superior longitudinal fasciculus (SLF). Regional SUVRs were calculated using WM-PERSI normalization. Associations among uptake, diffusion measures, brain volume, and clinical outcomes were evaluated using covariate-adjusted correlations with Bonferroni correction, partial canonical correlation, and exploratory path analyses.
RESULTS
PSP was characterized by predominantly subcortical and brainstem florzolotau(18F) retention and more extensive WM abnormalities, including DRTT involvement. AD showed predominantly cortical retention and microstructural abnormalities of SLF branches. In PSP, regional subcortical uptake was associated with DRTT microstructure, while DRTT mean diffusivity and frontal volume contributed most strongly to the canonical variate associated with motor impairment (canonical correlation = 0.82, p = 0.001). In AD, cortical uptake was associated with SLF microstructure, while cortical volume and SLF mean diffusivity contributed to the canonical variate associated with executive function (canonical correlation = 0.83, p = 0.001). Exploratory path models were consistent with indirect associations involving white matter microstructure and cortical volume.
CONCLUSION
PSP and AD showed distinct patterns of tract vulnerability associated with regional florzolotau(18F) retention and clinical impairment. These cross-sectional findings support further longitudinal investigation of disease-specific network degeneration.
Chi-Wei Huang, Hsin-I Chang, T. Chang et al.· European Journal of Nuclear...· 0 citations
Background Progressive supranuclear palsy (PSP) is a primary tauopathy defined by the accumulation of 4R tau isoforms in neurons, oligodendrocytes and astrocytes. Despite evidence of genetic susceptibility operating through glial cell types, it remains poorly understood how cell type-specific epigenetic-transcriptional programs evolve with progression of tau pathology. Methods We conducted single-nucleus chromatin accessibility (snATACseq) and RNA sequencing (snRNAseq) on postmortem frontal cortex samples from PSP patients (n = 8) and matched controls (n = 8), yielding over 144,000 nuclei passing quality control. Tau pathology burden, including neurofibrillary tangles, coiled bodies, and tufted astrocytes, was quantified on AT8-immunostained sections from the same individuals. We integrated differential gene expression analysis, transcription factor motif enrichment, weighted gene co-expression network analysis, and pseudotime modeling anchored to cell type-specific tau pathology burden to delineate molecular pseudo-progression trajectories. Results In eight cell types, 20 subclasses, and 70 subclusters, PSP brains displayed a selective depletion of certain excitatory deep-layer neurons and oligodendrocyte subclusters, with relative preservation of inhibitory neurons and vascular cells. Genetic risk enrichment was localized to astrocytes and oligodendrocytes, whereas excitatory neurons exhibited the greatest transcriptional dysregulation. Oligodendrocyte pseudo-progression indicated a transition from homeostatic myelination programs (MBP, MOBP) through glucocorticoid-responsive stress (FKBP5, ZBTB16), to compensatory myelination (PLP1, CNP) and proteostasis stress (UCHL1, CYRAB, CLU). Neuronal pseudo- progression revealed early dysregulation of synaptic (RORB2, NRG3, NPTX1), microtubule dynamics (KIF2C, RAB27B, TUBA/B), and survival (MEG3, FTX) pathways, alongside a transient increase in neuron-glia interactions (GRIP, CNTNAP4, ERBB4), converging late on ribosomal translation and vesicular trafficking modules across all neuronal subtypes. Cross-modal integration with independent cerebrospinal fluid proteomics identified a concordant subset of glial reactivity, axonal injury, and synaptic markers jointly dysregulated in inhibitory neurons, oligodendrocytes, and excitatory deep-layer neurons. Conclusion PSP pathogenesis reflects a combination of glial genetic susceptibility and staged, cell type-specific transcriptional dysfunction. Oligodendrocytes transition from myelination-competent states to FKBP5-mediated stress states, while neurons show variably timed loss of synaptic excitability and survival programs, preceded by neuron-glia interactions and followed by convergent ribosomal-proteostatic failure. These cytopathology-anchored trajectories outline a potential pathophysiological sequence and may inform candidate selection for stage-specific therapeutic interventions in PSP.
N. Briel, Viktoria C. Ruf, Paul L. C. Feyen et al.· bioRxiv· 0 citations
Background: Corticobasal syndrome (CBS) is a neurodegenerative syndrome that often results from a 4-repeat tauopathy. Abnormalities on tau PET, structural MRI, and diffusion MRI (dMRI) have been observed in CBS, although no prior work has systematically compared the relative sensitivity of these modalities. In addition, the relationships between tau uptake, volume loss, and white matter degeneration remain incompletely understood. Objective: To compare the sensitivity of tau PET, structural volume, and dMRI metrics to differentiate CBS from controls, and to characterize relationships between regional tau uptake, volume loss, and white matter tract abnormalities. Methods: Thirty-two participants meeting criteria for possible or probable CBS and 35 healthy controls underwent standardized 3T dMRI, 18F-flortaucipir tau PET, and detailed neurologic assessment. Diffusion data were processed using complementary diffusion tensor, free-water, and Neurite Orientation Dispersion and Density Imaging (NODDI) pipelines, with tract-level metrics extracted using the Johns Hopkins University-Eve (JHU EVE) White Matter atlas. Regional gray matter volumes and flortaucipir standardized uptake value ratios (SUVRs) were calculated. Global tau PET uptake, represented by the first principal component (PC1), was removed in a secondary tau analysis. Modality-level discrimination was assessed using area under the curve (AUC) analyses. Cross-modality relationships were evaluated using regional correlations and covariate-adjusted models comparing volume- and tau-related predictors of white matter abnormalities. Results: Relative to controls, CBS showed widespread higher mean diffusivity (MD) and lower intracellular volume fraction (ICVF), especially in sensorimotor and projection white matter pathways. Structural volume reductions were most prominent in precentral cortex and subcortical regions including putamen, thalamus, and pallidum, whereas tau PET abnormalities were weaker and less spatially extensive. MD showed the strongest overall discrimination between CBS and controls, followed by ICVF, structural volume, PC1-removed tau PET, and original tau PET. In targeted sensorimotor analyses, higher DTI-MD was most strongly associated with lower gray matter volume. PC1-removed sensorimotor tau uptake was also associated with higher sensorimotor DTI-MD, whereas original tau uptake and broader cortical or subcortical tau measures were not significant predictors. Conclusions: White matter microstructural disruption is a dominant imaging signature of CBS and is more closely linked to gray matter volume loss than to measurable uptake on tau PET. dMRI, particularly MD and ICVF, may provide greatest sensitivity for detecting disease-related changes in CBS.
Yuqi Tian, Ryota Satoh, Val J. Lowe et al.· medRxiv· 0 citations
Background: Progressive supranuclear palsy (PSP) is a primary 4-repeat tauopathy in which neurodegeneration may be accompanied by neuroinflammatory and peripheral immune alterations. Whether peripheral inflammatory activity reflects structural degeneration within vulnerable brain networks remains unclear. Methods: This retrospective case–control study included 12 patients with PSP and 12 patients with Parkinson’s disease (PD). Automated volumetric analysis of 3-Tesla MRI was performed using volBrain 2.0. Blood-derived inflammatory indices included neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), systemic inflammation response index (SIRI), and red blood cell distribution with coefficient of variation (RDW-CV). Results: Patients with PSP showed significantly lower normalized superior frontal gyrus and pallidal volumes than patients with PD. Within the PSP group, higher values of selected blood-derived inflammatory indices were associated with lower frontal network volumes. After adjustment for age, MLR was inversely associated with the composite Frontal Network Score (partial r = −0.7333, p = 0.0067, FDR q = 0.020). The strongest regional association was observed between SIRI and medial frontal cortex volume (rho = −0.748, p = 0.0051); however, regional associations did not remain significant after FDR correction. Conclusions: Peripheral inflammatory markers were associated with MRI-derived measures of frontal network degeneration in PSP. The association between MLR and the composite Frontal Network Score supports a link between systemic immune alterations and network-level neurodegeneration in PSP.
B. Migda, M. Kutyłowski, Natalia Madetko-Alster et al.· Neurology International· 0 citations
BACKGROUND
The relative value of nigrostriatal volumetry, quantitative T1 relaxation, and multicompartment diffusion MRI in neurodegenerative Parkinson syndromes is unclear.
OBJECTIVES
To compare quantitative T1 relaxation and diffusion microstructure imaging-derived free fluid fraction (V-CSF) in the putamen and substantia nigra, together with putaminal volume, across Parkinson's disease, multiple system atrophy, progressive supranuclear palsy, and healthy controls.
METHODS
We retrospectively studied 178 participants, including 59 individuals with Parkinson's disease, 30 with MSA, 60 with PSP, and 29 healthy controls assessed between 2018 and 2023. Linear models adjusted for age and sex tested group differences and associations with Hoehn and Yahr stage.
RESULTS
Putaminal volume and V-CSF differed across groups (both p < 0.001), whereas putaminal quantitative T1 did not (p = 0.10). Nigral V-CSF showed broader separation than nigral quantitative T1. In multiple system atrophy, lower putaminal quantitative T1 was associated with higher Hoehn and Yahr stage (p = 0.028).
CONCLUSIONS
Diffusion-derived free fluid and volumetry captured neurodegeneration more consistently than quantitative T1.
N. Schröter, Lucas A. Both, Wolfgang H. Jost et al.· Parkinsonism & Related Disor...· 0 citations
We use cookies to run the site and, with your consent, for analytics and to show ads.
See our Cookie Policy.
