Annemieke ter Telgte

Incidental hyperintense lesions on diffusion-weighted imaging (DWI) are suggested as emerging marker of cerebral small vessel disease (SVD). To further determine their role in SVD, we aimed to describe their prevalence on high-resolution DWI in 2 distinct SVD types. Second, in each SVD type, we aimed to assess incidental DWI-positive lesion distribution and associations with clinical variables. Data from 2 hospital-based prospective cohorts in the Netherlands and Germany were used, which included patients meeting the modified Boston criteria for probable cerebral amyloid angiopathy (CAA, BIONIC study) and patients with a confirmed diagnosis of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL, VASCAMY study). In case of a stroke history, patients ≤3 months poststroke were excluded. 3T high-resolution baseline MRIs of patients with probable CAA and baseline, 18-month, and 36-month MRIs of patients with CADASIL were included. All MRI markers were rated following STRIVE-2. Within patient groups, we explored in univariable analyses the association between cardiovascular risk factors and MRI markers and incidental DWI-positive lesions and in multiple regression the association between fluid biomarkers and incidental DWI-positive lesions. Baseline data were available for 43 CAA patients (mean baseline age 71 ± 6 years, 44% female) and 75 CADASIL patients (mean baseline age 53 ± 9.9 years, 62% female). Cross-sectionally, incidental DWI-positive lesions were detected in 24/43 (56% [95% CI 41%-70%]) CAA patients and 16/75 (21% [95% CI 14%-32%]) CADASIL patients. In CAA, 65% of lesions were located in the cortex, whereas in CADASIL, 95% of lesions were located in the subcortical white or gray matter. In CAA patients, DWI-positive lesions were significantly associated with increased neurofilament light chain (NfL) in serum and CSF, but not with other CSF, MRI, or cardiovascular risk factors. In CADASIL patients, DWI-positive lesions were significantly associated with increased serum NfL, increased white matter hyperintensity volume and lacune presence. In CAA and CADASIL, the prevalence of incidental DWI-positive lesions is high, and lesions have disease-specific distribution, and associations with serum, CSF, and MRI biomarkers, suggesting that incidental DWI-positive lesions are a feature of SVD. Future studies should investigate their prognostic value.

BACKGROUND: Hypertension is a major risk factor for cerebral small vessel disease (SVD), but the underlying mechanisms remain incompletely understood. Blood-brain barrier (BBB) leakage is hypothesized to be involved in SVD pathogenesis, but this was mainly demonstrated in older patients with established SVD on magnetic resonance imaging. We investigated BBB leakage in young patients with hypertension, at risk for SVD, compared with controls. METHODS: BBB leakage of gadolinium contrast agent was measured with 3T magnetic resonance imaging in 59 patients with hypertension (mean age, 35.8 ± 9.7 years; 54% female; mean blood pressure, 146/92 mm Hg) and 21 healthy controls (mean age, 29.9 ± 4.8 years; 52% female; mean blood pressure, 120/75 mm Hg). Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was used to measure BBB leakage (leakage rate, Ki [min ⁻¹ ] and blood plasma volume fraction [ Vp ]). Linear regression adjusted for age and sex was used to compare BBB leakage between patients and controls. We additionally adjusted for the amended SVD score and white matter hyperintensity volume. We also compared patients with primary aldosteronism to those with hypertension due to other causes. RESULTS: Patients with hypertension had 17% higher BBB leakage ( Ki ) in the white matter ( P =0.049) and 15% in the gray matter ( P =0.070) compared with controls, independent of SVD burden. No differences were found in Vp or between patients with primary aldosteronism and other causes. CONCLUSIONS: Young patients with hypertension show BBB disruption independent of MRI–detectable SVD. This suggests a possible role of BBB dysfunction in SVD pathogenesis. Restoration of BBB integrity may be a relevant target for interventions in SVD, but longitudinal and intervention studies are needed to confirm causality. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT06175663.

Objective: Cerebral Small vessel disease (SVD) is a disorder of the cerebral microvessels and is the commonest vascular cause of stroke and dementia. Hypertension is the most established risk factor for SVD, but the pathophysiological mechanisms following hypertension that cause SVD remain poorly understood. We aim to examine the effects of changes in blood pressure on cerebral microvasculature in young- and middle-aged adults with hypertension to detect the earliest microvascular changes associated with SVD. Design and method: The Hyperintense study is an ongoing observational cohort study aiming to include 50 hypertensive adults (18–55 years). These patients temporarily discontinue antihypertensive medication for diagnostic purposes, often leading to a temporary increase in blood pressure. Data are collected before medication withdrawal (T = 0), once antihypertensives are withdrawn (T = 1), when patients have restarted medication and reached target blood pressure (T = 2) and 1 year later (T = 3). At each time-point, high-resolution 3T MRI scans are performed with conventional structural sequences and advanced techniques to assess various aspects of microvascular integrity, including integrity of the blood-brain barrier, microperfusion and microstructural integrity. Clinical data includes motor and cognitive examinations and blood sampling. Results: Between July-December 2021, 7 patients (86% male, mean age 47.4 ± 4.4 years) were enrolled. Baseline characteristics and SVD burden are shown in Table. In 3/4 participants who completed T = 1, systolic blood pressure increased after medication withdrawal (median increase systolic blood pressure: 13.7 [3.3 – 15.3] mmHg), demonstrating proof of principle of our approach. Conclusions: First data show increased blood pressure after medication withdrawal in most participants and demonstrate feasibility of our design. Analysis of the effect of blood pressure increase and decrease on MRI outcomes will improve understanding of the pathological mechanisms following hypertension that may lead to MRI markers of SVD. This knowledge can help identify new targets for treatment of SVD, aimed at preventing or limiting disease progression.

While structural network analysis consolidated the hypothesis of cerebral small vessel disease (SVD) being a disconnection syndrome, little is known about functional changes on the level of brain networks. In patients with genetically defined SVD (CADASIL, n = 41) and sporadic SVD (n = 46), we independently tested the hypothesis that functional networks change with SVD burden and mediate the effect of disease burden on cognitive performance, in particular slowing of processing speed. We further determined test–retest reliability of functional network measures in sporadic SVD patients participating in a high‐frequency (monthly) serial imaging study (RUN DMC—InTENse, median: 8 MRIs per participant). Functional networks for the whole brain and major subsystems (i.e., default mode network, DMN; fronto‐parietal task control network, FPCN; visual network, VN; hand somatosensory‐motor network, HSMN) were constructed based on resting‐state multi‐band functional MRI. In CADASIL, global efficiency (a graph metric capturing network integration) of the DMN was lower in patients with high disease burden (standardized beta = −.44; p [corrected] = .035) and mediated the negative effect of disease burden on processing speed (indirect path: std. beta = −.20, p = .047; direct path: std. beta = −.19, p = .25; total effect: std. beta = −.39, p = .02). The corresponding analyses in sporadic SVD showed no effect. Intraclass correlations in the high‐frequency serial MRI dataset of the sporadic SVD patients revealed poor test–retest reliability and analysis of individual variability suggested an influence of age, but not disease burden, on global efficiency. In conclusion, our results suggest that changes in functional connectivity networks mediate the effect of SVD‐related brain damage on cognitive deficits. However, limited reliability of functional network measures, possibly due to age‐related comorbidities, impedes the analysis in elderly SVD patients.

Objective To investigate the prevalence of asymptomatic diffusion-weighted imaging–positive (DWI+) lesions in individuals with cerebral small vessel disease (SVD) and identify their role in the origin of SVD markers on MRI. Methods We included 503 individuals with SVD from the Radboud University Nijmegen Diffusion Tensor and Magnetic Resonance Imaging Cohort (RUN DMC) study (mean age 65.6 years [SD 8.8], 56.5% male) with 1.5T MRI in 2006 and, if available, follow-up MRI in 2011 and 2015. We screened DWI scans (n = 1,152) for DWI+ lesions, assessed lesion evolution on follow-up fluid-attenuated inversion recovery, T1 and T2* images, and examined the association between DWI+ lesions and annual SVD progression (white matter hyperintensities [WMH], lacunes, microbleeds). Results We found 50 DWI+ lesions in 39 individuals on 1,152 DWI (3.4%). Individuals with DWI+ lesions were older (p = 0.025), more frequently had a history of hypertension (p = 0.021), and had a larger burden of preexisting SVD MRI markers (WMH, lacunes, microbleeds: all p < 0.001) compared to individuals without DWI+ lesions. Of the 23 DWI+ lesions with available follow-up MRI, 14 (61%) evolved into a WMH, 8 (35%) resulted in a cavity, and 1 (4%) was no longer visible. Presence of DWI+ lesions was significantly associated with annual WMH volume increase and yearly incidence of lacunes and microbleeds (all p < 0.001). Conclusion Over 3% of individuals with SVD have DWI+ lesions. Although DWI+ lesions play a role in the progression of SVD, they may not fully explain progression of SVD markers on MRI, suggesting that other factors than acute ischemia are at play.

Objective: To determine the contribution of acute infarcts, evidenced by diffusion‐weighted imaging positive (DWI+) lesions, to progression of white matter hyperintensities (WMH) and other cerebral small vessel disease (SVD) markers.Methods: We performed monthly 3T magnetic resonance imaging (MRI) for 10 consecutive months in 54 elderly individuals with SVD. MRI included high‐resolution multishell DWI, and 3‐dimensional fluid‐attenuated inversion recovery, T1, and susceptibility‐weighted imaging. We determined DWI+ lesion evolution, WMH progression rate (ml/mo), and number of incident lacunes and microbleeds, and calculated for each marker the proportion of progression explained by DWI+ lesions.Results: We identified 39 DWI+ lesions on 21 of 472 DWI scans in 9 of 54 subjects. Of the 36 DWI+ lesions with follow‐up MRI, 2 evolved into WMH, 4 evolved into a lacune (3 with cavity p = 0.195). Of the 2 DWI+ lesions evolving into WMH on follow‐up, one explained 23% of the total WMH volume increase in one subject, whereas the WMH regressed in the other subject. DWI+ lesions preceded 4 of 5 incident lacunes and 3 of 10 incident microbleeds.Interpretation: DWI+ lesions explain only a small proportion of the total WMH progression. Hence, WMH progression seems to be mostly driven by factors other than acute infarcts. DWI+ lesions explain the majority of incident lacunes and small cavities, and almost one‐third of incident microbleeds, confirming that WMH, lacunes, and microbleeds, although heterogeneous on MRI, can have a common initial appearance on MRI. ANN NEUROL 2019;86:582–592

Objective: Cerebral amyloid angiopathy (CAA) is characterized by the accumulation of amyloid β (Aβ) in the walls of cortical vessels and the accrual of microbleeds and microinfarcts over time. The relationship between CAA severity and microbleeds and microinfarcts as well as the sequence of events that lead to lesion formation remain poorly understood.Methods: We scanned intact formalin‐fixed hemispheres of 12 CAA cases with magnetic resonance imaging (MRI), followed by histopathological examination in predefined areas and serial sectioning in targeted areas with multiple lesions.Results: In total, 1,168 cortical microbleeds and 472 cortical microinfarcts were observed on ex vivo MRI. Increasing CAA severity at the whole‐brain or regional level was not associated with the number of microbleeds or microinfarcts. However, locally, the density of Aβ‐positive cortical vessels was lower surrounding a microbleed compared to a simulated control lesion, and higher surrounding microinfarcts. Serial sectioning revealed that for (n = 28) microbleeds, both Aβ (4%) and smooth muscle cells (4%) were almost never present in the vessel wall at the site of bleeding, but Aβ was frequently observed upstream or downstream (71%), as was extensive fibrin(ogen) buildup (87%). In contrast, for (n = 22) microinfarcts, vascular Aβ was almost always observed at the core of the lesion (91%, p < 0.001) as well as upstream or downstream (82%), but few vessels associated with microinfarcts had intact smooth muscle cells (9%).Interpretation: These observations provide a model for how a single neuropathologic process such as CAA may result in hemorrhagic or ischemic brain lesions potentially through 2 different mechanistic pathways. ANN NEUROL 2019;86:279–292

Background: Neuroimaging in older adults commonly reveals signs of cerebral small vessel disease (SVD). SVD is believed to be caused by chronic hypoperfusion based on animal models and longitudinal studies with inter-scan intervals of years. Recent imaging evidence, however, suggests a role for acute ischaemia, as indicated by incidental diffusion-weighted imaging lesions (DWI+ lesions), in the origin of SVD. Furthermore, it becomes increasingly recognised that focal SVD lesions likely affect the structure and function of brain areas remote from the original SVD lesion. However, the temporal dynamics of these events are largely unknown. Aims: (1) To investigate the monthly incidence of DWI+ lesions in subjects with SVD; (2) to assess to which extent these lesions explain progression of SVD imaging markers; (3) to investigate their effects on cortical thickness, structural and functional connectivity and cognitive and motor performance; and (4) to investigate the potential role of the innate immune system in the pathophysiology of SVD. Design/methods: The RUN DMC – InTENse study is a longitudinal observational study among 54 non-demented RUN DMC survivors with mild to severe SVD and no other presumed cause of ischaemia. We performed MRI assessments monthly during 10 consecutive months (totalling up to 10 scans per subject), complemented with clinical, motor and cognitive examinations. Discussion: Our study will provide a better understanding of the role of DWI+ lesions in the pathophysiology of SVD and will further unravel the structural and functional consequences and clinical importance of these lesions, with an unprecedented temporal resolution. Understanding the role of acute, potentially ischaemic, processes in SVD may provide new strategies for therapies.