| 1. |
- Bocci, Matteo, et al.
(författare)
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Infection of Brain Pericytes Underlying Neuropathology of COVID-19 Patients.
- 2021
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Ingår i: International journal of molecular sciences. - : MDPI AG. - 1422-0067 .- 1661-6596. ; 22:21
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Tidskriftsartikel (refereegranskat)abstract
- A wide range of neurological manifestations have been associated with the development of COVID-19 following SARS-CoV-2 infection. However, the etiology of the neurological symptomatology is still largely unexplored. Here, we used state-of-the-art multiplexed immunostaining of human brains (n = 6 COVID-19, median age = 69.5 years; n = 7 control, median age = 68 years) and demonstrated that expression of the SARS-CoV-2 receptor ACE2 is restricted to a subset of neurovascular pericytes. Strikingly, neurological symptoms were exclusive to, and ubiquitous in, patients that exhibited moderate to high ACE2 expression in perivascular cells. Viral dsRNA was identified in the vascular wall and paralleled by perivascular inflammation, as signified by T cell and macrophage infiltration. Furthermore, fibrinogen leakage indicated compromised integrity of the blood-brain barrier. Notably, cerebrospinal fluid from additional 16 individuals (n = 8 COVID-19, median age = 67 years; n = 8 control, median age = 69.5 years) exhibited significantly lower levels of the pericyte marker PDGFRβ in SARS-CoV-2-infected cases, indicative of disrupted pericyte homeostasis. We conclude that pericyte infection by SARS-CoV-2 underlies virus entry into the privileged central nervous system space, as well as neurological symptomatology due to perivascular inflammation and a locally compromised blood-brain barrier.
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| 2. |
- Rosenstein, Igal, 1984, et al.
(författare)
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Four Swedish cases of CSF1R-related leukoencephalopathy: Visualization of clinical phenotypes
- 2022
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Ingår i: Acta Neurologica Scandinavica. - : Hindawi Limited. - 0001-6314 .- 1600-0404. ; 145:5, s. 599-609
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Tidskriftsartikel (refereegranskat)abstract
- Colony stimulating factor 1 receptor (CSF1R)-related leukoencephalopathy is a rare, genetic disease caused by heterozygous mutations in the CSF1R gene with rapidly progressive neurodegeneration, behavioral, cognitive, motor disturbances. Objective: To describe four cases of CSF1R-related leukoencephalopathy from three families with two different pathogenic mutations in the tyrosine kinase domain of CSF1R and to develop an integrated presentation of inter-individual diversity of clinical presentations. Methods: This is an observational study of a case series. Patients diagnosed with CSF1R encephalopathy were evaluated with standardized functional estimation scores and subject to analysis of cerebrospinal fluid biomarkers. Brain computed tomography (CT) and magnetic resonance imaging (MRI) were evaluated. We performed a functional phosphorylation assay to confirm the dysfunction of mutated CSF1R protein. Results: Two heterozygous missense mutations in the CSF1R gene were identified, c.2344C>T; p.Arg777Trp and c.2329C>T; p.Arg782Cys. A phosphorylation assay in vitro showed markedly reduced autophosphorylation in cells expressing mutations. According to ACMG criteria, both mutations were pathogenic. A radiological investigation revealed typical white matter lesions in all cases. There was inter-individual diversity in the loss of cognitive, motor-neuronal, and extrapyramidal functions. Conclusions: Including the present cases, currently three CSF1R mutations are known in Sweden. We present a visualization tool to describe the clinical diversity, with potential use for longitudinal follow-up for this and other leukoencephalopathies.
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| 3. |
- Spotorno, Nicola, et al.
(författare)
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Plasma neurofilament light protein correlates with diffusion tensor imaging metrics in frontotemporal dementia
- 2020
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Ingår i: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 15:10
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Tidskriftsartikel (refereegranskat)abstract
- Neurofilaments are structural components of neurons and are particularly abundant in highly myelinated axons. The levels of neurofilament light chain (NfL) in both cerebrospinal fluid (CSF) and plasma have been related to degeneration in several neurodegenerative conditions including frontotemporal dementia (FTD) and NfL is currently considered as the most promising diagnostic and prognostic fluid biomarker in FTD. Although the location and function of filaments in the healthy nervous system suggests a link between increased NfL and white matter degeneration, such a claim has not been fully elucidated in vivo, especially in the context of FTD. The present study provides evidence of an association between the plasma levels of NfL and white matter involvement in behavioral variant FTD (bvFTD) by relating plasma concentration of NfL to diffusion tensor imaging (DTI) metrics in a group of 20 bvFTD patients. The results of both voxel-wise and tract specific analysis showed that increased plasma NfL concentration is associated with a reduction in fractional anisotropy (FA) in a widespread set of white matter tracts including the superior longitudinal fasciculus, the fronto-occipital fasciculus the anterior thalamic radiation and the dorsal cingulum bundle. Plasma NfL concentration also correlated with cortical thinning in a portion of the right medial prefrontal cortex and of the right lateral orbitofrontal cortex. These results support the hypothesis that blood NfL levels reflect the global level of neurodegeneration in bvFTD and help to advance our understanding of the association between this blood biomarker for FTD and the disease process.
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| 4. |
- Zampeli, Ariadne, et al.
(författare)
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Structural association between heterotopia and cortical lesions visualised with 7 T MRI in patients with focal epilepsy
- 2022
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Ingår i: Seizure-European Journal of Epilepsy. - : Elsevier BV. - 1059-1311 .- 1532-2688. ; 101, s. 177-183
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: To analyze structural characteristics of malformations of cortical development (MCD) at 7T and 3T MRI. Methods: Twenty-five patients were examined with a 7T MRI-scanner in addition to 3T examinations performed for epilepsy evaluation. 7T sequences included a 3D-T1-weighted (T1w) MPRAGE, 3D-T2w FLAIR, and heavily T2w axial and coronal high-resolution (0.5 x 0.5 x 0.75-1.0 mm3) 2D-TSE sequences. Images were reviewed for 7T MRI imaging characteristics of MCD, visibility and frequency of identified lesions on 7T and on 3T (original reports and second reading). Results: In 25 patients 112 lesions were identified (57 gray matter (GM) heterotopia, 37 focal cortical dysplasia (FCD), and 18 other MCD). Imaging characteristics of the 37 FCD were cortical thickening (n = 11); GM-WM border blurring (n = 30); GM signal intensity changes (n = 18); juxtacortical WM signal intensity changes (n = 18); and transmantle WM signal intensity changes (n = 11). None of the 7T MRI sequences was sufficient to detect all types of lesions. Heterotopia were in general isointense to normal GM. Structural associations between 36 heterotopia and overlaying cortex were observed, composed either of a direct connection, vessel-like struc-tures, or GM-like bridges. FCD were mentioned in 30% (11 of 37) of the original reports at 3T, and in 57% (21 of 37) after second reading. FCD connections to subcortical heterotopia were clinically not reported at all. Conclusion: 7T MRI revealed subtle connections between heterotopia and previous unidentified pathology in overlaying cortex. These findings may be significant for the understanding of the anatomical seizure origin and propagation pathways.
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