Joost J. A. de Jong

In neurovascular and neurodegenerative diseases, blood–brain barrier (BBB) disruption can be subtle and diffuse, and MRI-derived measures are confounded by microvascular architecture. Therefore, we aimed to disentangle the MRI-derived blood–brain barrier leakage rate ( K _i ) into intrinsic vascular permeability ( P ) and surface area ( S ). In this cross-sectional study, 45 patients with cSVD and 26 elderly controls underwent dynamic contrast-enhanced (DCE) MRI to determine K _i and vessel architecture imaging (VAI) to estimate S . These measures were used to calculate P . Compared to normal-appearing white matter (NAWM), K _i was higher in WMH (β = 0.297, p < 0.001) and deep gray matter (DGM; β = 0.210, p = 0.007). P was higher in WMH (β = 0.410, p < 0.001) and similar between NAWM and DGM. S was smaller in WMH (β = −0.467, p < 0.001) and larger in DGM (β = 0.540, p < 0.001). K _i (β = 0.289, p = 0.007) and P (β = 0.249, p = 0.021) were only higher in patients than controls in concentric shells surrounding WMH. S was smaller in WMH of patients than controls (β = −0.085, p = 0.049). With age, K _i (β = 0.260, p = 0.008) and P increased (β = 0.273, p < 0.001), while S decreased (β = −0.079, p = 0.025). Disentangling P and S from the BBB leakage rate provides two biologically more specific and interpretable measures, which have counteracting effects on the BBB leakage in aging and disease.

Background: Huntington's Disease (HD) is a hereditary neurodegenerative disorder caused by a cytosine-adenine-guanine (CAG) repeat expansion (CAG > 35) in the Huntingtin ( HTT ) gene. Intermediate alleles (IAs, CAG = 27–35) are generally not associated with HD. However, IA carriers with symptoms have been reported in literature. Objective: To review the existing literature on IAs, in order to provide an overview of the clinical phenotype of IA carriers. Methods: Peer-reviewed articles published between 1993 and July 2024 from three databases (Embase, PubMed, and Web of Science) were included. Results: In case reports, a high percentage (90%) of IA carriers was reported to have symptoms (HD-related and -unrelated), or abnormalities in neuroimaging. Cohort studies also reported evidence of symptoms in IA carriers, although most cohorts did not obtain significant differences compared to controls. Conclusion: Based on this review, we argue that there is not enough evidence to draw a clear conclusion on the clinical phenotype of individuals carrying an intermediate allele of the HTT gene. Literature reports symptomatic IA carriers, but reported symptoms are non-specific and common in the general population. Additionally, the quality of the data is suboptimal, due to lack of detailed symptom descriptions, the absence of differential diagnoses, a selection bias, and a considerable publication bias towards IA carriers with symptoms. More research is needed to provide a better insight into the clinical phenotype of IA carriers.

Obsessive–compulsive disorder (OCD) manifests with diverse symptom constellations that likely arise from dysfunction in partially distinct neural circuits. Deep brain stimulation (DBS), paired with high-resolution connectomics, offers a unique window into these pathways in humans. Here, we analyzed clinical outcomes and stimulation sites from 77 treatment-refractory patients with OCD and 39 with Tourette’s syndrome (TS) exhibiting comorbid obsessive–compulsive behaviors (244 electrodes across 15 cohorts and eight targets). Engagement of the previously defined OCD response tract predicted global obsessive-compulsive symptom improvement across heterogeneous targets and diagnoses, spanning both OCD and TS. Beyond broad symptoms, obsessions, compulsions, anxiety, and depression mapped onto distinct yet overlapping subcircuits fragmenting the anterior limb of the internal capsule along a dorsoventral axis. This fine-scale architecture of OCD circuit dysfunction was reproducible across cross-validation schemes and patient subsets. Exploratory analyses identified additional subcircuits for cognitive control and flexibility. Global functional recovery was better explained by combined engagement of multiple symptom-specific rather than a single tract. Collectively, these findings illustrate how invasive neuromodulation can delineate a multi-symptom circuit taxonomy of compulsivity that may guide personalized neuromodulation.

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.

BACKGROUND: Blood-brain barrier (BBB) integrity is presumed to be impaired in hypertension, resulting from cerebral endothelial dysfunction. Hypertension precedes various cerebrovascular diseases, such as cerebral small vessel disease, and is a risk factor for developing neurodegenerative diseases for which BBB disruption is a preceding pathophysiological process. In this cross-sectional study, we investigated the relation between hypertension, current blood pressure, and BBB leakage in human subjects. METHODS: BBB leakage was determined in 22 patients with hypertension and 19 age- and sex-matched normotensive controls (median age [range], 65 [45–80] years; 19 men) using a sparsely time-sampled contrast-enhanced 7T magnetic resonance imaging protocol. Structural cerebral small vessel disease markers were visually rated. Multivariable regression analyses, adjusted for age, sex, cardiovascular risk factors, and cerebral small vessel disease markers, were performed to determine the relation between hypertension status, systolic and diastolic blood pressure, mean arterial pressure, drug treatment, and BBB leakage. RESULTS: Both hypertensive and normotensive participants showed mild scores of cerebral small vessel disease. BBB leakage did not differ between hypertensive and normotensive participants; however, it was significantly higher for systolic blood pressure, diastolic blood pressure, and mean arterial pressure in the cortex, and diastolic blood pressure and mean arterial pressure in the gray matter. Effectively treated patients showed less BBB leakage than those with current hypertension. CONCLUSIONS: BBB integrity in the total and cortical gray matter decreases with increasing blood pressure but is not related to hypertension status. These findings show that BBB disruption already occurs with increasing blood pressure, before the presence of overt cerebral tissue damage. Additionally, our results suggest that effective antihypertensive medication has a protective effect on the BBB. REGISTRATION: URL: https://trialsearch.who.int/ ; Unique identifier: NL7537.

Background: Microvascular dysfunction is involved in the development of various cerebral disorders. It may contribute to these disorders by disrupting white matter tracts and altering brain connectivity, but evidence is scarce. We investigated the association between multiple biomarkers of microvascular function and whole‐brain white matter connectivity. Methods and Results: Cross‐sectional data from The Maastricht Study, a Dutch population‐based cohort (n=4326; age, 59.4±8.6 years; 49.7% women). Measures of microvascular function included urinary albumin excretion, central retinal arteriolar and venular calibers, composite scores of flicker light–induced retinal arteriolar and venular dilation, and plasma biomarkers of endothelial dysfunction (intercellular adhesion molecule‐1, vascular cell adhesion molecule‐1, E‐selectin, and von Willebrand factor). White matter connectivity was calculated from 3T diffusion magnetic resonance imaging to quantify the number (average node degree) and organization (characteristic path length, global efficiency, clustering coefficient, and local efficiency) of white matter connections. A higher plasma biomarkers of endothelial dysfunction composite score was associated with a longer characteristic path length (β per SD, 0.066 [95% CI, 0.017–0.114]) after adjustment for sociodemographic, lifestyle, and cardiovascular factors but not with any of the other white matter connectivity measures. After multiple comparison correction, this association was nonsignificant. None of the other microvascular function measures were associated with any of the connectivity measures. Conclusions: These findings suggest that microvascular dysfunction as measured by indirect markers is not associated with whole‐brain white matter connectivity.

Background Blood-brain barrier (BBB) integrity is presumed to be impaired in hypertension, resulting from cerebral endothelial dysfunction. Hypertension antedates various cerebrovascular diseases, such as cerebral small vessel disease (cSVD), and is a risk factor for developing neurodegenerative diseases for which BBB disruption is a preceding pathophysiological process. In this study, we investigated the relation between hypertension, current blood pressure and BBB leakage in human subjects. Methods BBB leakage was determined in twenty-two patients with hypertension and nineteen normotensive controls, age- and sex-matched (median age[range]:65[45-80] years,19 males), using a sparsely time-sampled contrast-enhanced 7 Tesla MRI protocol. Structural cSVD markers were visually rated. Multivariable regression analyses, adjusted for age, sex, cardiovascular risk factors and cSVD markers, were performed to determine the relation between hypertension status, systolic and diastolic blood pressure (SBP and DBP), mean arterial pressure (MAP), drug treatment, and BBB leakage. Results Both hypertensive and normotensive participants showed mild scores of cSVD. BBB leakage did not differ between hypertensive and normotensive participants, however was significantly higher for SBP, DBP and MAP in the cortex, and DBP and MAP in the grey matter. Effectively treated patients showed less BBB leakage than those with current hypertension. Conclusion BBB integrity in the total and cortical grey matter decreases with increasing blood pressure, but is not related to hypertension status. These findings show that BBB disruption already occurs with increasing blood pressure, before the presence of overt cerebral tissue damage. Additionally, our results suggest that effective antihypertensive medication has a protective effect on the BBB. Registered at: https://trialsearch.who.int/; Unique identifier: NL7537

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.

White matter hyperintensity volume, local efficiency, and information processing speed scores are interrelated, and local network alterations as response to white matter abnormality explain detrime... Background Lesions of cerebral small vessel disease, such as white matter hyperintensities (WMHs) in individuals with cardiometabolic risk factors, interfere with the trajectories of the white matt...

Purpose: Blood–brain barrier (BBB) disruption is commonly measured with DCE‐MRI using continuous dynamic scanning. For precise measurement of subtle BBB leakage, a long acquisition time (>20 minutes) is required. As extravasation of the contrast agent is slow, discrete sampling at strategic time points might be beneficial, and gains scan time for additional sequences. Here, we aimed to explore the feasibility of a sparsely sampled MRI protocol at 7 T.Methods: The scan protocol consisted of a precontrast quantitative T₁ measurement, using an MP2RAGE sequence, and after contrast agent injection, a fast‐sampling dynamic gradient‐echo perfusion scan and two postcontrast quantitative T₁ measurements were applied. Simulations were conducted to determine the optimal postcontrast sampling time points for measuring subtle BBB leakage. The graphical Patlak approach was used to quantify the leakage rate (K_i) and blood plasma volume (v_p) of normal‐appearing white and gray matter.Results: The simulations showed that two postcontrast T₁ maps are sufficient to detect subtle leakage, and most sensitive when the last T₁ map is acquired late, approximately 30 minutes, after contrast agent administration. The in vivo measurements found K_i and v_p values in agreement with other studies, and significantly higher values in gray matter compared with white matter (both p = .04).Conclusion: The sparsely sampled protocol was demonstrated to be sensitive to quantify subtle BBB leakage, despite using only three T₁ maps. Due to the time‐efficiency of this method, it will become more feasible to incorporate BBB leakage measurements in clinical research MRI protocols.