TY - JOUR
T1 - Perivascular spaces as a marker of disease severity and neurodegeneration in patients with behavioral variant frontotemporal dementia
AU - Moses, Jasmine
AU - Sinclair, Benjamin
AU - Schwartz, Daniel L.
AU - Silbert, Lisa C.
AU - O’Brien, Terence J.
AU - Law, Meng
AU - Vivash, Lucy
N1 - Publisher Copyright:
Copyright © 2022 Moses, Sinclair, Schwartz, Silbert, O’Brien, Law and Vivash.
PY - 2022/10/20
Y1 - 2022/10/20
N2 - Background: Behavioural 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 methods: Serial 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”). Results: Overall, 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). Conclusion: Analysis 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.
AB - Background: Behavioural 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 methods: Serial 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”). Results: Overall, 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). Conclusion: Analysis 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.
KW - Behavioural Variant Frontotemporal Dementia
KW - anti-tau therapy
KW - clinical trial
KW - frontotemporal lobar degeneration
KW - perivascular spaces
KW - sodium selenate
KW - tau
UR - http://www.scopus.com/inward/record.url?scp=85141132183&partnerID=8YFLogxK
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U2 - 10.3389/fnins.2022.1003522
DO - 10.3389/fnins.2022.1003522
M3 - Article
AN - SCOPUS:85141132183
SN - 1662-4548
VL - 16
JO - Frontiers in Neuroscience
JF - Frontiers in Neuroscience
M1 - 1003522
ER -