Perivascular spaces as a marker of disease severity and neurodegeneration in patients with behavioral variant frontotemporal dementia
BackgroundBehavioural Variant Frontotemporal Dementia (bvFTD) is a rapidly progressing neurodegenerative proteinopathy. Perivascular spaces (PVS) form a part of the brain’s glymphatic clearance system. When enlarged due to poor glymphatic clearance of toxic proteins, PVS become larger and more consp...
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Frontiers Media S.A.
2022-10-01
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| Series: | Frontiers in Neuroscience |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fnins.2022.1003522/full |
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| author | Jasmine Moses Benjamin Sinclair Benjamin Sinclair Benjamin Sinclair Daniel L. Schwartz Daniel L. Schwartz Lisa C. Silbert Lisa C. Silbert Terence J. O’Brien Terence J. O’Brien Terence J. O’Brien Terence J. O’Brien Meng Law Meng Law Meng Law Lucy Vivash Lucy Vivash Lucy Vivash Lucy Vivash |
| author_facet | Jasmine Moses Benjamin Sinclair Benjamin Sinclair Benjamin Sinclair Daniel L. Schwartz Daniel L. Schwartz Lisa C. Silbert Lisa C. Silbert Terence J. O’Brien Terence J. O’Brien Terence J. O’Brien Terence J. O’Brien Meng Law Meng Law Meng Law Lucy Vivash Lucy Vivash Lucy Vivash Lucy Vivash |
| author_sort | Jasmine Moses |
| collection | DOAJ |
| description | BackgroundBehavioural Variant Frontotemporal Dementia (bvFTD) is a rapidly progressing neurodegenerative proteinopathy. Perivascular spaces (PVS) form a part of the brain’s glymphatic clearance system. When enlarged due to poor glymphatic clearance of toxic proteins, PVS become larger and more conspicuous on MRI. Therefore, enlarged PVS may be a useful biomarker of disease severity and progression in neurodegenerative proteinopathies such as bvFTD. This study aimed to determine the utility of PVS as a biomarker of disease progression in patients with bvFTD.Materials and methodsSerial baseline and week 52 MRIs acquired from ten patients with bvFTD prospectively recruited and followed in a Phase 1b open label trial of sodium selenate for bvFTD were used in this study. An automated algorithm quantified PVS on MRI, which was visually inspected and validated by a member of the study team. The number and volume of PVS were extracted and mixed models used to assess the relationship between PVS burden and other measures of disease (cognition, carer burden scale, protein biomarkers). Additional exploratory analysis investigated PVS burden in patients who appeared to not progress over the 12 months of selenate treatment (i.e., “non-progressors”).ResultsOverall, PVS cluster number (ß = −3.27, CI [−7.80 – 1.27], p = 0.267) and PVS volume (ß = −36.8, CI [−84.9 – 11.3], p = 0.171) did not change over the paired MRI scans 12 months apart. There was association between cognition total composite scores and the PVS burden (PVS cluster ß = −0.802e–3, CI [9.45e–3 – −6.60e–3, p ≤ 0.001; PVS volume ß = −1.30e–3, CI [−1.55e–3 – −1.05e–3], p ≤ 0.001), as well as between the change in the cognition total composite score and the change in PVS volume (ß = 4.36e–3, CI [1.33e–3 – 7.40e–3], p = 0.046) over the trial period. There was a significant association between CSF t-tau and the number of PVS clusters (ß = 2.845, CI [0.630 – 5.06], p = 0.036). Additionally, there was a significant relationship between the change in CSF t-tau and the change in the number of PVS (ß = 1.54, CI [0.918 – 2.16], p < 0.001) and PVS volume (ß = 13.8, CI [6.37 – 21.1], p = 0.003) over the trial period. An association was found between the change in NfL and the change in PVS volume (ß = 1.40, CI [0.272 – 2.52], p = 0.045) over time. Within the “non-progressor” group (n = 7), there was a significant relationship between the change in the CSF total-tau (t-tau) levels and the change in the PVS burden (PVS cluster (ß = 1.46, CI [0.577 – 2.34], p = 0.014; PVS volume ß = 14.6, CI [3.86 – 25.4], p = 0.032) over the trial period. Additionally, there was evidence of a significant relationship between the change in NfL levels and the change in the PVS burden over time (PVS cluster ß = 0.296, CI [0.229 – 0.361], p ≤ 0.001; PVS volume ß = 3.67, CI [2.42 – 4.92], p = 0.002).ConclusionAnalysis of serial MRI scans 12 months apart in patients with bvFTD demonstrated a relationship between PVS burden and disease severity as measured by the total cognitive composite score and CSF t-tau. Further studies are needed to confirm PVS as a robust marker of neurodegeneration in proteinopathies. |
| first_indexed | 2024-04-13T17:51:51Z |
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| institution | Directory Open Access Journal |
| issn | 1662-453X |
| language | English |
| last_indexed | 2024-04-13T17:51:51Z |
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| spelling | doaj.art-d08c4c3c13c947f3baa1692a981bf17a2022-12-22T02:36:40ZengFrontiers Media S.A.Frontiers in Neuroscience1662-453X2022-10-011610.3389/fnins.2022.10035221003522Perivascular spaces as a marker of disease severity and neurodegeneration in patients with behavioral variant frontotemporal dementiaJasmine Moses0Benjamin Sinclair1Benjamin Sinclair2Benjamin Sinclair3Daniel L. Schwartz4Daniel L. Schwartz5Lisa C. Silbert6Lisa C. Silbert7Terence J. O’Brien8Terence J. O’Brien9Terence J. O’Brien10Terence J. O’Brien11Meng Law12Meng Law13Meng Law14Lucy Vivash15Lucy Vivash16Lucy Vivash17Lucy Vivash18Department of Neuroscience, Central Clinical School, Monash University, Melbourne, VIC, AustraliaDepartment of Neuroscience, Central Clinical School, Monash University, Melbourne, VIC, AustraliaDepartment of Neurology, Alfred Hospital, Melbourne, VIC, AustraliaDepartment of Medicine, Royal Melbourne Hospital, University of Melbourne, Melbourne, VIC, AustraliaNIA-Layton Oregon Aging and Alzheimer’s Disease Research Center, Oregon Health & Science University, Portland, OR, United StatesAdvanced Imaging Research Center, Oregon Health and Science University, Portland, OR, United StatesNIA-Layton Oregon Aging and Alzheimer’s Disease Research Center, Oregon Health & Science University, Portland, OR, United StatesDepartment of Neurology, Portland Veterans Affairs Health Care System, Portland, OR, United StatesDepartment of Neuroscience, Central Clinical School, Monash University, Melbourne, VIC, AustraliaDepartment of Neurology, Alfred Hospital, Melbourne, VIC, AustraliaDepartment of Medicine, Royal Melbourne Hospital, University of Melbourne, Melbourne, VIC, AustraliaDepartment of Neurology, Royal Melbourne Hospital, University of Melbourne, Melbourne, VIC, AustraliaDepartment of Neuroscience, Central Clinical School, Monash University, Melbourne, VIC, AustraliaDepartment of Radiology, Alfred Health, Melbourne, VIC, AustraliaDepartment of Electrical and Computer Systems Engineering, Monash University, Melbourne, VIC, AustraliaDepartment of Neuroscience, Central Clinical School, Monash University, Melbourne, VIC, AustraliaDepartment of Neurology, Alfred Hospital, Melbourne, VIC, AustraliaDepartment of Medicine, Royal Melbourne Hospital, University of Melbourne, Melbourne, VIC, AustraliaDepartment of Neurology, Royal Melbourne Hospital, University of Melbourne, Melbourne, VIC, AustraliaBackgroundBehavioural Variant Frontotemporal Dementia (bvFTD) is a rapidly progressing neurodegenerative proteinopathy. Perivascular spaces (PVS) form a part of the brain’s glymphatic clearance system. When enlarged due to poor glymphatic clearance of toxic proteins, PVS become larger and more conspicuous on MRI. Therefore, enlarged PVS may be a useful biomarker of disease severity and progression in neurodegenerative proteinopathies such as bvFTD. This study aimed to determine the utility of PVS as a biomarker of disease progression in patients with bvFTD.Materials and methodsSerial baseline and week 52 MRIs acquired from ten patients with bvFTD prospectively recruited and followed in a Phase 1b open label trial of sodium selenate for bvFTD were used in this study. An automated algorithm quantified PVS on MRI, which was visually inspected and validated by a member of the study team. The number and volume of PVS were extracted and mixed models used to assess the relationship between PVS burden and other measures of disease (cognition, carer burden scale, protein biomarkers). Additional exploratory analysis investigated PVS burden in patients who appeared to not progress over the 12 months of selenate treatment (i.e., “non-progressors”).ResultsOverall, PVS cluster number (ß = −3.27, CI [−7.80 – 1.27], p = 0.267) and PVS volume (ß = −36.8, CI [−84.9 – 11.3], p = 0.171) did not change over the paired MRI scans 12 months apart. There was association between cognition total composite scores and the PVS burden (PVS cluster ß = −0.802e–3, CI [9.45e–3 – −6.60e–3, p ≤ 0.001; PVS volume ß = −1.30e–3, CI [−1.55e–3 – −1.05e–3], p ≤ 0.001), as well as between the change in the cognition total composite score and the change in PVS volume (ß = 4.36e–3, CI [1.33e–3 – 7.40e–3], p = 0.046) over the trial period. There was a significant association between CSF t-tau and the number of PVS clusters (ß = 2.845, CI [0.630 – 5.06], p = 0.036). Additionally, there was a significant relationship between the change in CSF t-tau and the change in the number of PVS (ß = 1.54, CI [0.918 – 2.16], p < 0.001) and PVS volume (ß = 13.8, CI [6.37 – 21.1], p = 0.003) over the trial period. An association was found between the change in NfL and the change in PVS volume (ß = 1.40, CI [0.272 – 2.52], p = 0.045) over time. Within the “non-progressor” group (n = 7), there was a significant relationship between the change in the CSF total-tau (t-tau) levels and the change in the PVS burden (PVS cluster (ß = 1.46, CI [0.577 – 2.34], p = 0.014; PVS volume ß = 14.6, CI [3.86 – 25.4], p = 0.032) over the trial period. Additionally, there was evidence of a significant relationship between the change in NfL levels and the change in the PVS burden over time (PVS cluster ß = 0.296, CI [0.229 – 0.361], p ≤ 0.001; PVS volume ß = 3.67, CI [2.42 – 4.92], p = 0.002).ConclusionAnalysis of serial MRI scans 12 months apart in patients with bvFTD demonstrated a relationship between PVS burden and disease severity as measured by the total cognitive composite score and CSF t-tau. Further studies are needed to confirm PVS as a robust marker of neurodegeneration in proteinopathies.https://www.frontiersin.org/articles/10.3389/fnins.2022.1003522/fullBehavioural Variant Frontotemporal Dementiafrontotemporal lobar degenerationperivascular spacestauclinical trialanti-tau therapy |
| spellingShingle | Jasmine Moses Benjamin Sinclair Benjamin Sinclair Benjamin Sinclair Daniel L. Schwartz Daniel L. Schwartz Lisa C. Silbert Lisa C. Silbert Terence J. O’Brien Terence J. O’Brien Terence J. O’Brien Terence J. O’Brien Meng Law Meng Law Meng Law Lucy Vivash Lucy Vivash Lucy Vivash Lucy Vivash Perivascular spaces as a marker of disease severity and neurodegeneration in patients with behavioral variant frontotemporal dementia Frontiers in Neuroscience Behavioural Variant Frontotemporal Dementia frontotemporal lobar degeneration perivascular spaces tau clinical trial anti-tau therapy |
| title | Perivascular spaces as a marker of disease severity and neurodegeneration in patients with behavioral variant frontotemporal dementia |
| title_full | Perivascular spaces as a marker of disease severity and neurodegeneration in patients with behavioral variant frontotemporal dementia |
| title_fullStr | Perivascular spaces as a marker of disease severity and neurodegeneration in patients with behavioral variant frontotemporal dementia |
| title_full_unstemmed | Perivascular spaces as a marker of disease severity and neurodegeneration in patients with behavioral variant frontotemporal dementia |
| title_short | Perivascular spaces as a marker of disease severity and neurodegeneration in patients with behavioral variant frontotemporal dementia |
| title_sort | perivascular spaces as a marker of disease severity and neurodegeneration in patients with behavioral variant frontotemporal dementia |
| topic | Behavioural Variant Frontotemporal Dementia frontotemporal lobar degeneration perivascular spaces tau clinical trial anti-tau therapy |
| url | https://www.frontiersin.org/articles/10.3389/fnins.2022.1003522/full |
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