Blood-Brain Barrier Leakage in Patients with Early Alzheimer Disease.

Purpose To investigate whether the blood-brain barrier (BBB) leaks blood-circulating substances in patients with early forms of Alzheimer disease (AD), and if so, to examine the extent and pattern of leakage. Materials and Methods This study was approved by the local medical ethical committees of the Maastricht University Medical Center and Leiden University Medical Center, and written informed consent was obtained from all subjects. For this pilot study, 16 patients with early AD and 17 healthy age-matched control subjects underwent dynamic contrast material-enhanced magnetic resonance (MR) imaging sequence with dual time resolution for 25 minutes. The Patlak graphical approach was used to quantify the BBB leakage rate and local blood plasma volume. Subsequent histogram analysis was used to determine the volume fraction of the leaking brain tissue. Differences were assessed with linear regression analysis, adjusted for confounding variables. Results The BBB leakage rate was significantly higher in patients compared with that in control subjects in the total gray matter (P < .05) and cortex (P = .03). Patients had a significantly higher volume fraction of the leaking brain tissue in the gray matter (P = .004), normal-appearing white matter (P < .04), deep gray matter (P = .01), and cortex (P = .004). When all subjects were considered, scores on the Mini-Mental State Examination decreased significantly with increasing leakage in the deep gray matter (P = .007) and cortex (P < .05). Conclusion The results of this study showed global BBB leakage in patients with early AD that is associated with cognitive decline. A compromised BBB may be part of a cascade of pathologic events that eventually lead to cognitive decline and dementia. ©RSNA, 2016 Online supplemental material is available for this article.

The optimal strategy for proximal mesh fixation during laparoscopic ventral rectopexy for rectal prolapse: an ex vivo study.

BACKGROUND: Laparoscopic ventral rectopexy (LVR) is an established technique for the treatment of rectal prolapse. Several techniques and devices can be used for proximal mesh fixation on the sacral promontory during this procedure. The aim of this study was to compare the fixation strength of a recently introduced screw for mesh fixation on the promontory during LVR with two other frequently used techniques. METHODS: An ex vivo experimental model using a porcine spinal column was designed to measure the strength of proximal mesh fixation. In a laparoscopic box trainer, a polypropylene mesh was anchored on the spinal column using three different fixation methods, i.e., the Protack 5-mm tacker device, Ethibond Excel 2-0 stitches, and the Karl Storz screw. Subsequently, increasing traction was applied to the mesh. This traction was applied at a standardized angle as determined by measuring the mean angle between the site of distal mesh fixation on the rectum and a line straight through the sacral promontory on 12 random dynamic MR scans of the pelvic floor after the LVR procedure. The applied force was measured at the moment that the fixation broke, using a calibrated electronic Newton meter. All fixation methods were tested ten times. RESULTS: The mean angle, as measured on the MR scans, was 100°. The mean disruption force, which led to a break of the proximal mesh fixation, was 58 N for the three Protack tacks, 55 N for the two stitches, and 70 N for the new screw. The use of a screw therefore led to a significantly stronger fixation compared to the use of stitches (p ≤ 0.05). No significant difference was determined between the tacks and the screw fixation and between the tacks and the stitches fixation. CONCLUSION: The new screw for proximal mesh fixation during LVR procedures offers similar fixation strength when compared to tacks. The use of one screw for proximal mesh fixation is therefore a reasonable alternative to the use of several tacks or sutures.

Blood-brain barrier leakage is more widespread in patients with cerebral small vessel disease.

OBJECTIVE: As blood-brain barrier (BBB) dysfunction may occur in normal aging but may also play a pivotal role in the pathophysiology of cerebral small vessel disease (cSVD), we used dynamic contrast-enhanced (DCE)-MRI to quantify the rate and the spatial extent of BBB leakage in patients with cSVD and age- and sex-matched controls to discern cSVD-related BBB leakage from aging-related leakage. METHODS: We performed structural brain MRI and DCE-MRI in 80 patients with clinically overt cSVD and 40 age- and sex-matched controls. Using the Patlak pharmacokinetic model, we calculated the leakage rate. The mean leakage rate and relative leakage volume were calculated using noise-corrected histogram analysis. Leakage rate and leakage volume were compared between patients with cSVD and controls for the normal-appearing white matter (NAWM), white matter hyperintensities (WMH), cortical gray matter (CGM), and deep gray matter. RESULTS: Multivariable linear regression analyses adjusting for age, sex, and cardiovascular risk factors showed that the leakage volume of the NAWM, WMH, and CGM was significantly larger in patients with cSVD compared with controls. No significant difference was found for leakage rate in any of the tissue regions. CONCLUSION: We demonstrated a larger tissue volume with subtle BBB leakage in patients with cSVD than in controls. This was shown in the NAWM, WMH, and CGM, supporting the generalized nature of cSVD.

Subtle blood-brain barrier leakage rate and spatial extent: Considerations for dynamic contrast-enhanced MRI.

PURPOSE: Dynamic contrast-enhanced (DCE) MRI can be used to measure blood-brain barrier (BBB) leakage. In neurodegenerative disorders such as small vessel disease and dementia, the leakage can be very subtle and the corresponding signal can be rather noisy. For these reasons, an optimized DCE-MRI measurement and study design is required. To this end, a new measure indicative of the spatial extent of leakage is introduced and the effects of scan time and sample size are explored. METHODS: Dual-time resolution DCE-MRI was performed in 16 patients with early Alzheimer's disease (AD) and 17 healthy controls. The leakage rate (Ki ) and volume fraction of detectable leaking tissue (vL ) to quantify the spatial extent of BBB leakage were calculated in cortical gray matter and white matter using noise-corrected histogram analysis of leakage maps. Computer simulations utilizing realistic Ki histograms, mimicking the strong effect of noise and variation in Ki values, were performed to understand the influence of scan time on the estimated leakage. RESULTS: The mean Ki was very low (order of 10-4 min-1 ) and highly influenced by noise, causing the Ki to be increasingly overestimated at shorter scan times. In the white matter, the Ki was not different between patients with early AD and controls, but was higher in the cortex for patients, reaching significance after 14.5 min of scan time. To detect group differences, vL proved more suitable, showing significantly higher values for patients compared with controls in the cortex after 8 minutes of scan time, and in white matter after 15.5 min. CONCLUSIONS: Several ways to improve the sensitivity of a DCE-MRI experiment to subtle BBB leakage were presented. We have provided vL as an attractive and potentially more time-efficient alternative to detect group differences in subtle and widespread blood-brain barrier leakage compared with leakage rate Ki . Recommendations on group size and scan time are made based on statistical power calculations to aid future research.

Neurovascular unit impairment in early Alzheimer's disease measured with magnetic resonance imaging.

The neurovascular unit, which protects neuronal cells and supplies them with essential molecules, plays an important role in the pathophysiology of Alzheimer's Disease (AD). The aim of this study was to noninvasively investigate 2 linked functional elements of the neurovascular unit, blood-brain barrier (BBB) permeability and cerebral blood flow (CBF), in patients with early AD and healthy controls. Therefore, both dynamic contrast-enhanced magnetic resonance imaging and arterial spin labeling magnetic resonance imaging were applied to measure BBB permeability and CBF, respectively. The patients with early AD showed significantly lower CBF and local blood volume in the gray matter, compared with controls. In the patients, we also found that a reduction in CBF is correlated with an increase in leakage rate. This finding supports the hypothesis that neurovascular damage, and in particular impairment of the neurovascular unit constitutes the pathophysiological link between CBF reduction and BBB impairment in AD.

Cerebral blood flow, blood supply, and cognition in Type 2 Diabetes Mellitus.

We investigated whether type 2 diabetes (T2DM) and the presence of cognitive impairment are associated with altered cerebral blood flow (CBF). Forty-one participants with and thirty-nine without T2DM underwent 3-Tesla MRI, including a quantitative technique measuring (macrovascular) blood flow in the internal carotid artery and an arterial spin labeling technique measuring (microvascular) perfusion in the grey matter (GM). Three analysis methods were used to quantify the CBF: a region of interest analysis, a voxel-based statistical parametric mapping technique, and a 'distributed deviating voxels' method. Participants with T2DM exhibited significantly more tissue with low CBF values in the cerebral cortex and the subcortical GM (3.8-fold increase). The latter was the only region where the hypoperfusion remained after correcting for atrophy, indicating that the effect of T2DM on CBF, independent of atrophy, is small. Subcortical CBF was associated with depression. No associations were observed for CBF in other regions with diabetes status, for carotid blood flow with diabetes status, or for CBF or flow in relation with cognitive function. To conclude, a novel method that tallies total 'distributed deviating voxels' demonstrates T2DM-associated hypoperfusion in the subcortical GM, not associated with cognitive performance. Whether a vascular mechanism underlies cognitive decrements remains inconclusive.

Blood-brain barrier impairment in dementia: current and future in vivo assessments.

Increasing evidence indicates that blood-brain barrier (BBB) impairment may play a role in the pathophysiology of cognitive decline and dementia. In vivo imaging studies are needed to quantify and localize the BBB defects during life, contemplating the circulatory properties. We reviewed the literature for imaging studies investigating BBB impairment in patients suffering from dementia. After selection, 11 imaging studies were included, of which 6 used contrast-enhanced magnetic resonance imaging (MRI), 2 used contrast-enhanced computed tomography (CT), and 3 positron emission tomography (PET). Primarily the MRI studies hint at a subtle increasing permeability of the BBB, particularly in patients already exhibiting cerebrovascular pathology. More elaborate studies are required to provide convincing evidence on BBB impairment in patients with various stages of dementia with and without obvious cerebrovascular pathology. In the future, dynamic contrast enhanced MRI techniques and transport specific imaging using PET may further detail the research on the molecular nature of BBB defects.

Amyloid-ß interacts with blood-brain barrier function in dementia: a systematic review.

To date, the exact pathogenesis of dementia is still unknown. The most frequently hypothesized initiating factor is an accumulation of the protein amyloid-ß in the brain, which has been associated with dementia of the Alzheimer type. Another potentially important initiating factor is a disrupted blood-brain barrier. This can initiate cerebral microangiopathy, which has frequently been associated with vascular dementia. Although amyloid-ß and blood-brain barrier dysfunction have both been associated with one particular type of dementia (Alzheimer's disease and vascular dementia, respectively), they co-exist in most demented patients. In fact, increasing evidence indicates that amyloid-ß and blood-brain barrier disruption may interact and facilitate each other in their effect on neurodegeneration. The present systematic analysis describes the available evidence for a significant interplay between amyloid-ß and blood-brain barrier function in dementia.