Vladimir Grouza

Tropomyosin receptor kinases family members TrkA, TrkB, and TrkC mediate critical processes, such as neuronal growth, survival, and synaptic plasticity, and have been implicated in neuropsychiatric disorders. In this work, we characterized the pharmacokinetics of the novel positron emission tomography (PET) radioligand [ ¹⁸ F]TRACK for in vivo quantification of TrkB/C in the human brain. Seven healthy volunteers (three men; 20–61 years) underwent a 90 min PET scan following an intravenous bolus injection of [ ¹⁸ F]TRACK. Arterial blood sampling was performed throughout image acquisition. [ ¹⁸ F]TRACK was slowly metabolized, accounting for 60% of the plasma activity at 90 min, with two more polar radiometabolites observed. Regional time-activity curves (TACs) showed moderate uptake (SUV: 1–2) and good reversibility in gray matter regions. Across regions, the two-tissue compartment model (2TCM) yielded superior fits than the 1TCM for 98% of extra-striatal gray-matter TACs, whereas it improved fits for only 52% of striatal TACs. Total distribution volume ( V _T ) ranged from 2.49 ± 0.30 ml/cm ³ (thalamus) to 1.94 ± 0.21 ml/cm ³ (hippocampus) showing good identifiability (%SE: 1%–5%) and low inter-subject variability (%CoV 18 F]TRACK in tissue and plasma was reached at approximately 70 min. Shortening the scan duration to 60 min preserved V _T accuracy and precision.

Purpose: To evaluate the correspondence between myelin water fraction (MWF) estimates derived from multi‐echo spin echo (MESE) and multi‐echo gradient echo (MGRE) imaging in fixed mouse brain tissue, using a panel of myelin basic protein ( Mbp ) enhancer‐edited mouse lines exhibiting graded hypomyelination. Methods: Fifteen mouse brains from five genetically modified mouse lines were imaged using ex vivo 7 T MRI with high‐resolution 3D MESE and MGRE protocols. MWF maps were computed from the MESE approach using regularized non‐negative least squares (NNLS) decomposition, and from the MGRE approach using robust principal component analysis (rPCA). MWF values were then parcellated across major white matter tracts using an atlas‐based pipeline and validated against biological markers, including Mbp gene expression and FluoroMyelin fluorescence intensity. Results: Both MESE‐ and MGRE‐derived MWF maps exhibited high sensitivity to myelin content and resolved mouse line‐dependent differences across white matter tracts. Region‐specific MWF estimates were highly correlated across contrasts ( r = 0.96), with MGRE yielding consistently higher MWF values, particularly in smaller tracts. MESE derived MWF values showed subtle underestimation of myelin content in hypomyelinated white matter regions. Both MWF measures showed strong correlations with Mbp messenger ribonucleic acid (mRNA) ( r = 0.72–0.97) and FluoroMyelin staining ( r = 0.50–0.92), with stronger histological correlations for MGRE‐derived values. Conclusion: Both MESE and MGRE sequences provide biologically meaningful estimates of myelin content in fixed tissue but exhibit contrast‐specific sensitivities and biases. MGRE combined with rPCA offers time efficient imaging and robustness in fine white matter structures, supporting its utility for high‐resolution preclinical myelin mapping.

Background: MS imaging studies have demonstrated an ependymal “surface-in” distribution of white matter damage. The origin of this effect and how it impacts myelinated axons in people with MS (PwMS) is poorly understood. Objectives: To investigate (1) whether there is clear evidence of tract-wise, periventricular damage, based on fractional anisotropy, mean diffusivity, axonal water fraction (AWF) and myelin volume fraction (MVF), in PwMS, (2) if such tissue damage is associated with T ₁ -“black-hole” (T ₁ -BH) and/or non-BH lesions, and (3) if periventricular quantitative MRI abnormalities are correlated with lateral ventricle (LV) and choroid plexus (CP) enlargement. Methods: We applied structural, MT-weighted, and multi-shell diffusion MRI in healthy controls and PwMS to quantify periventricular gradient damage to axons and myelin. We also evaluated the correlation between such gradient damage and both non-BH and T ₁ -BH lesion loads, and brain volume changes. Results: Clear periventricular gradients exist in both AWF and MVF measures in the Association and Projection Tracts. They are strongly correlated with T ₁ -BH lesion load, and with LV and CP enlargement in PwMS with EDSS > 2. Conclusions: Tract-specific, periventricular gradients in PwMS exist prominently in AWF and MVF, are strongly associated with T ₁ -BH lesion loads, and correlate with LV and CP enlargement.

A growing body of research suggests a link between immune system activation and the development of Parkinson’s disease (PD). Previous work showed that repeated gastrointestinal infection with Citrobacter rodentium can induce PD-like motor dysfunction in Pink1 knockout (KO) mice, along with immune cell infiltration into the brain. To better understand mechanisms underlying immune-mediated brain attack in this model, we tested whether mild infections are sufficient to increase blood-brain barrier (BBB) permeability and trigger brain inflammation. Pink1 wild-type (WT) and KO mice were infected with C. rodentium , and gadolinium-enhanced magnetic resonance imaging (MRI) was performed at days 13 and 26 post-infection to assess BBB integrity. Quantitative MRI analysis revealed increased BBB permeability at day 26 in both WT and KO mice, particularly in the striatum, dentate gyrus, somatosensory cortex, and thalamus. Notably, this permeability was not associated with changes in tight junction protein expression or dopamine system markers in the striatum at either time point. However, persistent microglial activation was observed at day 26 post-infection, along with elevated levels of inflammatory mediators such as eotaxin, IFN-γ, CXCL9, IL-17, and MIP-2 in the striatum. Additionally, serum levels of IL-17 and CXCL1 were increased in infected Pink1 KO mice. Flow cytometry revealed neutrophil infiltration in the brain at day 26 post-infection. Finally, a bulk RNA-seq transcriptome analysis revealed that gene sets related to synaptic function were particularly influenced by the infection and that inflammation-related genes were upregulated by the infection in the Pink1 KO mice. These findings support the hypothesis that even mild gastrointestinal infections can increase BBB permeability, disrupt brain homeostasis, and promote chronic neuroinflammation. In genetically susceptible individuals, such as those with Pink1 deficiency, this may represent a first hit that contributes to subsequent induction of PD pathology with aging. Author summary: We hypothesize that immune system activation is linked to the development of Parkinson’s disease (PD). Previous work revealed that repeated gastrointestinal infections with Citrobacter rodentium causes PD-like symptoms and immune cell invasion in the brain of Pink1 knockout (KO) mice. In the current study, we tested whether a single mild gut infection alters blood-brain barrier (BBB) permeability and causes brain inflammation. We infected Pink1 WT and KO mice with Citrobacter rodentium and used gadolinium-enhanced MRI to detect BBB permeability changes at 13- and 26-days post-infection. Results showed increased BBB permeability in specific brain regions at 26 days. While tight-junction and dopamine (DA)-related proteins remained unchanged, we observed altered expression of synaptic genes, chronic microglial activation, elevated inflammatory markers, and neutrophil infiltration in the brain. Our findings suggest that even mild gastrointestinal infections can increase BBB permeability, potentially enabling immune cell infiltration into the brain and exacerbating pathways implicated in the development of PD, particularly among individuals with genetic risk factors.

Myelin Basic Protein (MBP) is essential for both elaboration and maintenance of CNS myelin, and its reduced accumulation results in hypomyelination. How different Mbp mRNA levels affect myelin dimensions across the lifespan and how resident glial cells may respond to such changes are unknown. Here, to investigate these questions, we used enhancer‐edited mouse lines that accumulate Mbp mRNA levels ranging from 8% to 160% of wild type. In young mice, reduced Mbp mRNA levels resulted in corresponding decreases in Mbp protein accumulation and myelin sheath thickness, confirming the previously demonstrated rate‐limiting role of Mbp transcription in the control of initial myelin synthesis. However, despite maintaining lower line specific Mbp mRNA levels into old age, both MBP protein levels and myelin thickness improved or fully normalized at rates defined by the relative Mbp mRNA level. Sheath length, in contrast, was affected only when mRNA levels were very low, demonstrating that sheath thickness and length are not equally coupled to Mbp mRNA level. Striking abnormalities in sheath structure also emerged with reduced mRNA levels. Unexpectedly, an increase in the density of all glial cell types arose in response to reduced Mbp mRNA levels. This investigation extends understanding of the role MBP plays in myelin sheath elaboration, architecture, and plasticity across the mouse lifespan and illuminates a novel axis of glial cell crosstalk.