Dataset Information

Microstructural white matter integrity in relation to vascular reactivity in Dutch-type hereditary cerebral amyloid angiopathy.

ABSTRACT: Cerebral Amyloid Angiopathy (CAA) is characterized by cerebrovascular amyloid-β accumulation leading to hallmark cortical MRI markers, such as vascular reactivity, but white matter is also affected. By studying the relationship in different disease stages of Dutch-type CAA (D-CAA), we tested the relation between vascular reactivity and microstructural white matter integrity loss. In a cross-sectional study in D-CAA, 3 T MRI was performed with Blood-Oxygen-Level-Dependent (BOLD) fMRI upon visual activation to assess vascular reactivity and diffusion tensor imaging to assess microstructural white matter integrity through Peak Width of Skeletonized Mean Diffusivity (PSMD). We assessed the relationship between BOLD parameters - amplitude, time-to-peak (TTP), and time-to-baseline (TTB) - and PSMD, with linear and quadratic regression modeling. In total, 25 participants were included (15/10 pre-symptomatic/symptomatic; mean age 36/59 y). A lowered BOLD amplitude (unstandardized β = 0.64, 95%CI [0.10, 1.18], p = 0.02, Adjusted R² = 0.48), was quadratically associated with increased PSMD levels. A delayed BOLD response, with prolonged TTP (β = 8.34 × 10^-6, 95%CI [1.84 × 10^-6, 1.48 × 10^-5], p = 0.02, Adj. R² = 0.25) and TTB (β = 6.57 × 10^-6, 95%CI [1.92 × 10^-6, 1.12 × 10^-5], p = 0.008, Adj. R² = 0.29), was linearly associated with increased PSMD. In D-CAA subjects, predominantly in the symptomatic stage, impaired cerebrovascular reactivity is related to microstructural white matter integrity loss. Future longitudinal studies are needed to investigate whether this relation is causal.

SUBMITTER: Schipper MR

PROVIDER: S-EPMC10925868 | biostudies-literature | 2023 Dec

REPOSITORIES: biostudies-literature

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Microstructural white matter integrity in relation to vascular reactivity in Dutch-type hereditary cerebral amyloid angiopathy.

Schipper Manon R MR Vlegels Naomi N van Harten Thijs W TW Rasing Ingeborg I Koemans Emma A EA Voigt Sabine S Luca Alberto de A Kaushik Kanishk K van Etten Ellis S ES van Zwet Erik W EW Terwindt Gisela M GM Biessels Geert Jan GJ van Osch Matthias Jp MJ van Walderveen Marianne Aa MA Wermer Marieke Jh MJ

Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 20230914 12

Cerebral Amyloid Angiopathy (CAA) is characterized by cerebrovascular amyloid-β accumulation leading to hallmark cortical MRI markers, such as vascular reactivity, but white matter is also affected. By studying the relationship in different disease stages of Dutch-type CAA (D-CAA), we tested the relation between vascular reactivity and microstructural white matter integrity loss. In a cross-sectional study in D-CAA, 3 T MRI was performed with Blood-Oxygen-Level-Dependent (BOLD) fMRI upon visual ...[more]

PMID: 37708241

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Project description:BackgroundThe temporal ordering of biomarkers for cerebral amyloid angiopathy (CAA) is important for their use in trials and for the understanding of the pathological cascade of CAA. We investigated the presence and abnormality of the most common biomarkers in the largest (pre)symptomatic Dutch-type hereditary CAA (D-CAA) cohort to date.MethodsWe included cross-sectional data from participants with (pre)symptomatic D-CAA and controls without CAA. We investigated CAA-related cerebral small vessel disease markers on 3T-MRI, cerebrovascular reactivity with functional 7T-MRI (fMRI) and amyloid-β40 and amyloid-β42 levels in cerebrospinal fluid. We calculated frequencies and plotted biomarker abnormality according to age to form scatterplots.ResultsWe included 68 participants with D-CAA (59% presymptomatic, mean age, 50 [range, 26-75] years; 53% women), 53 controls (mean age, 51 years; 42% women) for cerebrospinal fluid analysis and 36 controls (mean age, 53 years; 100% women) for fMRI analysis. Decreased cerebrospinal fluid amyloid-β40 and amyloid-β42 levels were the earliest biomarkers present: all D-CAA participants had lower levels of amyloid-β40 and amyloid-β42 compared with controls (youngest participant 30 years). Markers of nonhemorrhagic injury (>20 enlarged perivascular spaces in the centrum semiovale and white matter hyperintensities Fazekas score, ≥2, present in 83% [n=54]) and markers of impaired cerebrovascular reactivity (abnormal BOLD amplitude, time to peak and time to baseline, present in 56% [n=38]) were present from the age of 30 years. Finally, markers of hemorrhagic injury were present in 64% (n=41) and only appeared after the age of 41 years (first microbleeds and macrobleeds followed by cortical superficial siderosis).ConclusionsOur results suggest that amyloid biomarkers in cerebrospinal fluid are the first to become abnormal in CAA, followed by MRI biomarkers for cerebrovascular reactivity and nonhemorrhagic injury and lastly hemorrhagic injury. This temporal ordering probably reflects the pathological stages of CAA and should be taken into account when future therapeutic trials targeting specific stages are designed.

Project description:Background and Purpose- Magnetic resonance imaging visible perivascular spaces in the centrum semiovale (CSO-PVS) have been associated with cerebral amyloid angiopathy (CAA).We aimed to further confirm this link by evaluating CSO-PVS volume in pathologically-demonstrated sporadic and genetically-demonstrated hereditary forms of the disease. Methods- We studied a retrospective hospital-based cohort consisting of 63 individuals aged >55 having brain magnetic resonance imaging and pathological assessment of CAA (mean age, 73.6±8.5; 46% female), and a separate cohort consisting of 26 carriers, and 28 noncarriers of the hereditary cerebral hemorrhage with amyloidosis-Dutch type (mean age, 46.7±12.8; 61.1% female). CSO-PVS volume was quantified on a single magnetic resonance imaging slice using a computer-assisted segmentation method and expressed as the relative volume of the intracranial volume in that particular slice (CSO-PVS relative volume). We compared CSO-PVS relative volume (1) between subjects with and without the disease in both cohorts; (2) between non-CAA, CAA without hemorrhage, and CAA with hemorrhage cases in the sporadic CAA cohort. All variables reaching P<0.1 in bivariate analyses were entered in logistic regression models. Results- In both sporadic and Dutch cohorts, cases with CAA had significantly higher CSO-PVS relative volume than cases without (median [IQR]: 3.7% [2.5-5.3] versus 1.8% [1.2-2.4], P<0.0001; 3.8% [0.6-6.2] versus 0.7% [0.4-1.6], P=0.007; respectively). In linear regression models, sporadic CAA was associated with higher CSO-PVS relative volume ( P=0.008). In the sporadic CAA cohort, compared with non-CAA cases, CSO-PVS relative volume was higher in both CAA with hemorrhage and without hemorrhage (4.4% [2.6-6.1] and 3% [2.4-3.6] versus 1.8% [1.2-2.4], P<0.001 and P=0.005, respectively). Higher CSO-PVS relative volume was associated with CAA in regression models, both when hemorrhage was present (odds ratio, 2.63; [95% confidence interval, 1.33-5.18]; P=0.005) and absent (odds ratio, 4.55; [95% confidence interval, 0.98-21.04]; P=0.05). Conclusions- Increased CSO-PVS volume is a consistent magnetic resonance imaging marker of cerebrovascular amyloid deposition and a promising diagnostic tool for sporadic CAA without hemorrhagic manifestations.

Dataset Information

Microstructural white matter integrity in relation to vascular reactivity in Dutch-type hereditary cerebral amyloid angiopathy.

Publications

Microstructural white matter integrity in relation to vascular reactivity in Dutch-type hereditary cerebral amyloid angiopathy.

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