BackgroundCerebral amyloid angiopathy (CAA) is a disease caused by the accumulation of the amyloid-beta protein and is a major cause of intracerebral hemorrhage (ICH) and vascular dementia in the... Show moreBackgroundCerebral amyloid angiopathy (CAA) is a disease caused by the accumulation of the amyloid-beta protein and is a major cause of intracerebral hemorrhage (ICH) and vascular dementia in the elderly. The presence of the amyloid-beta protein in the vessel wall may induce a chronic state of cerebral inflammation by activating astrocytes, microglia, and pro-inflammatory substances. Minocycline, an antibiotic of the tetracycline family, is known to modulate inflammation, gelatinase activity, and angiogenesis. These processes are suggested to be key mechanisms in CAA pathology. Our aim is to show the target engagement of minocycline and investigate in a double-blind placebo-controlled randomized clinical trial whether treatment with minocycline for 3 months can decrease markers of neuroinflammation and of the gelatinase pathway in cerebrospinal fluid (CSF) in CAA patients.MethodsThe BATMAN study population consists of 60 persons: 30 persons with hereditary Dutch type CAA (D-CAA) and 30 persons with sporadic CAA. They will be randomized for either placebo or minocycline (15 sporadic CAA/15 D-CAA minocycline, 15 sporadic CAA/15 D-CAA placebo). At t = 0 and t = 3 months, we will collect CSF and blood samples, perform a 7-T MRI, and collect demographic characteristics.DiscussionThe results of this proof-of-principle study will be used to assess the potential of target engagement of minocycline for CAA. Therefore, our primary outcome measures are markers of neuroinflammation (IL-6, MCP-1, and IBA-1) and of the gelatinase pathway (MMP2/9 and VEGF) in CSF. Secondly, we will look at the progression of hemorrhagic markers on 7-T MRI before and after treatment and investigate serum biomarkers. Show less
Cerebral amyloid angiopathy (CAA) is a cerebrovascular disease affecting the small arteries in the brain with hallmark depositions of amyloid-β in the vessel wall, leading to cognitive decline and... Show moreCerebral amyloid angiopathy (CAA) is a cerebrovascular disease affecting the small arteries in the brain with hallmark depositions of amyloid-β in the vessel wall, leading to cognitive decline and intracerebral hemorrhage (ICH). An emerging MRI marker for CAA is cortical superficial siderosis (cSS) as it is strongly related to the risk of (recurrent) ICH. Current assessment of cSS is mainly done on T2*- weighted MRI using a qualitative score consisting of 5 categories of severity which is hampered by ceiling effects. Therefore, the need for a more quantitative measurement is warranted to better map disease progression for prognosis and future therapeutic trials. We propose a semi-automated method to quantify cSS burden on MRI and investigated it in 20 patients with CAA and cSS. The method showed excellent inter-observer (Pearson’s 0.991, P < 0.001) and intra-observer reproducibility (ICC 0.995, P < 0.001). Furthermore, in the highest category of the multifocality scale a large spread in the quantitative score is observed, demonstrating the ceiling effect in the traditional score. We observed a quantitative increase in cSS volume in two of the 5 patients who had a 1 year follow up, while the traditional qualitative method failed to identify an increase because these patients were already in the highest category. The proposed method could therefore potentially be a better way of tracking progression.In conclusion, semi-automated segmenting and quantifying cSS is feasible and repeatable and may be used for further studies in CAA cohorts. Show less
Background: Perihematomal edema (PHE) after spontaneous intracerebral hemorrhage (sICH) is associated with clinical deterioration, but the etiology of PHE development is only partly understood.Aims:.. Show moreBackground: Perihematomal edema (PHE) after spontaneous intracerebral hemorrhage (sICH) is associated with clinical deterioration, but the etiology of PHE development is only partly understood.Aims: We aimed to investigate the association between systemic blood pressure (BP) variability (BPV) and formation of PHE.Methods: From a multicenter prospective observational study, we selected patients with sICH who underwent 3T brain MRI within 21 days after sICH, and had at least 5 BP measurements available in the first week after sICH. Primary outcome was the association between coefficient of variation (CV) of systolic BP (SBP) and edema extension distance (EED) using multivariable linear regression, adjusting for age, sex, ICH volume and timing of the MRI. In addition, we investigated the associations of mean SBP, mean arterial pressure (MAP), their CVs with EED and absolute and relative PHE volume.Results: We included 92 patients (mean age 64 years; 74% men; median ICH volume 16.8 mL (IQR 6.6–36.0), median PHE volume 22.5 mL (IQR 10.2–41.4). Median time between symptom onset and MRI was 6 days (IQR 4–11), median number of BP measurements was 25 (IQR 18–30). Log-transformed CV of SBP was not associated with EED (B = 0.050, 95%-CI −0.186 to 0.286, p = 0.673). Furthermore, we found no association between mean SBP, mean and CV of MAP and EED, nor between mean SBP, mean MAP or their CVs and absolute or relative PHE.Discussion: Our results do not support a contributing role for BPV on PHE, suggesting mechanisms other than hydrostatic pressure such as inflammatory processes, may play a more important role. Show less
Kort, A.M. de; Kuiperij, H.B.; Marques, T.M.; Jäkel, L.; Berg, E. van den; Kersten, I.; ... ; Verbeek, M.M. 2023
ObjectiveVascular amyloid β (Aβ) accumulation is the hallmark of cerebral amyloid angiopathy (CAA). The composition of cerebrospinal fluid (CSF) of CAA patients may serve as a diagnostic biomarker... Show moreObjectiveVascular amyloid β (Aβ) accumulation is the hallmark of cerebral amyloid angiopathy (CAA). The composition of cerebrospinal fluid (CSF) of CAA patients may serve as a diagnostic biomarker of CAA. We studied the diagnostic potential of the peptides Aβ38, Aβ40, Aβ42, and Aβ43 in patients with sporadic CAA (sCAA), hereditary Dutch-type CAA (D-CAA), and Alzheimer disease (AD).MethodsAβ peptides were quantified by immunoassays in a discovery group (26 patients with sCAA and 40 controls), a validation group (40 patients with sCAA, 40 patients with AD, and 37 controls), and a group of 22 patients with D-CAA and 54 controls. To determine the diagnostic accuracy, the area under the curve (AUC) was calculated using a receiver operating characteristic curve with 95% confidence interval (CI).ResultsWe found decreased levels of all Aβ peptides in sCAA patients and D-CAA patients compared to controls. The difference was most prominent for Aβ42 (AUC of sCAA vs controls for discovery: 0.90, 95% CI = 0.82–0.99; for validation: 0.94, 95% CI = 0.89–0.99) and Aβ43 (AUC of sCAA vs controls for discovery: 0.95, 95% CI = 0.88–1.00; for validation: 0.91, 95% CI = 0.83–1.0). All Aβ peptides except Aβ43 were also decreased in sCAA compared to AD (CSF Aβ38: AUC = 0.82, 95% CI = 0.71–0.93; CSF Aβ40: AUC = 0.88, 95% CI = 0.80–0.96; CSF Aβ42: AUC = 0.79, 95% CI = 0.66–0.92). Show less
BackgroundWe observed subarachnoid cerebrospinal fluid (CSF) hyperintensities at non-contrast 7-tesla (T) fluid-attenuated inversion recovery (FLAIR) MRI, frequently topographically associated with... Show moreBackgroundWe observed subarachnoid cerebrospinal fluid (CSF) hyperintensities at non-contrast 7-tesla (T) fluid-attenuated inversion recovery (FLAIR) MRI, frequently topographically associated with cortical superficial siderosis (cSS), in participants with cerebral amyloid angiopathy (CAA). To systemically evaluate these CSF hyperintensities we investigated their frequency and anatomical and temporal relationship with cSS on 7T and 3T MRI in hereditary Dutch-type CAA (D-CAA), sporadic CAA (sCAA), and non-CAA controls.MethodsCAA participants were included from two prospective natural history studies and non-CAA controls from a 7T study in healthy females and females with ischemic stroke. CSF hyperintensities were scored by two independent observers.ResultsWe included 38 sCAA participants (mean age 72y), 50 D-CAA participants (mean age 50y) and 44 non-CAA controls (mean age 53y, 15 with stroke). In total 27/38 (71 %, 95 %CI 56–84) sCAA and 23/50 (46 %, 95 %CI 33–60) D-CAA participants had subarachnoid CSF hyperintensities at baseline 7T. Most (96 %) of those had cSS, in 54 % there was complete topographical overlap with cSS. The remaining 46 % had ≥1 sulcus with CSF hyperintensities without co-localizing cSS. None of the healthy controls and 2/15 (13 %, 95 %CI 2–41, 100 % cSS overlap) of the stroke controls had CSF hyperintensities. In 85 % of the CAA participants CSF hyperintensities could retrospectively be identified at 3T. Of the 35 CAA participants with follow-up 7T after two years, 17/35 (49 %) showed increase and 6/35 (17 %) decrease of regional CSF hyperintensities. In 2/11 (18 %) of participants with follow-up who had baseline CSF hyperintensities without overlapping cSS, new cSS developed at those locations.ConclusionsSubarachnoid CSF hyperintensities at 7T FLAIR MRI occur frequently in CAA and are associated with cSS, although without complete overlap. We hypothesize that the phenomenon could be a sign of subtle plasma protein or blood product leakage into the CSF, resulting in CSF T1-shortening. Show less
Gooskens, C.; Heuven, V.J.J.P. van; Golubović, J.; Schüppert, A.; Swarte, F.; Voigt, S. 2017
By means of a large-scale web-based investigation, we established the degree of mutual intelligibility of 16 closely related spoken languages within the Germanic, Slavic and Romance language... Show moreBy means of a large-scale web-based investigation, we established the degree of mutual intelligibility of 16 closely related spoken languages within the Germanic, Slavic and Romance language families in Europe. We first present the results of a selection of 1833 listeners representing the mutual intelligibility between young, educated Europeans from the same 16 countries where the test languages are spoken. Next, we present the data from a sub-group of listeners who had not learned the test language and had had minimal exposure to it. This allows us to investigate how well the listeners understand the test language on the basis of structural similarities between their own language and the test languages. Finally, we compare the results of the two data sets to the traditional genealogic characterisation of the three language groups. We expect the intelligibility results from the second group of listeners who had had minimal exposure to the test language to be a better reflection of the genealogical characterisation than the results from the larger group who had sometimes been exposed to the test language or had learned it at school. Show less
Gooskens, C.; Heuven, V.J.J.P. van; Golubović, J.; Schüppert, A.; Swarte, F.; Voigt, S. 2017
By means of a large-scale web-based investigation, we established the degree of mutual intelligibility of 16 closely related spoken languages within the Germanic, Slavic and Romance language... Show moreBy means of a large-scale web-based investigation, we established the degree of mutual intelligibility of 16 closely related spoken languages within the Germanic, Slavic and Romance language families in Europe. We first present the results of a selection of 1833 listeners representing the mutual intelligibility between young, educated Europeans from the same 16 countries where the test languages are spoken. Next, we present the data from a sub-group of listeners who had not learned the test language and had had minimal exposure to it. This allows us to investigate how well the listeners understand the test language on the basis of structural similarities between their own language and the test languages. Finally, we compare the results of the two data sets to the traditional genealogic characterisation of the three language groups. We expect the intelligibility results from the second group of listeners who had had minimal exposure to the test language to be a better reflection of the genealogical characterisation than the results from the larger group who had sometimes been exposed to the test language or had learned it at school. Show less
Gooskens, C.; Heuven, V.J.J.P. van; Golubović, J.; Schüppert, A.; Swarte, F.; Voigt, S. 2017
By means of a large-scale web-based investigation, we established the degree of mutual intelligibility of 16 closely related spoken languages within the Germanic, Slavic and Romance language... Show moreBy means of a large-scale web-based investigation, we established the degree of mutual intelligibility of 16 closely related spoken languages within the Germanic, Slavic and Romance language families in Europe. We first present the results of a selection of 1833 listeners representing the mutual intelligibility between young, educated Europeans from the same 16 countries where the test languages are spoken. Next, we present the data from a sub-group of listeners who had not learned the test language and had had minimal exposure to it. This allows us to investigate how well the listeners understand the test language on the basis of structural similarities between their own language and the test languages. Finally, we compare the results of the two data sets to the traditional genealogic characterisation of the three language groups. We expect the intelligibility results from the second group of listeners who had had minimal exposure to the test language to be a better reflection of the genealogical characterisation than the results from the larger group who had sometimes been exposed to the test language or had learned it at school. Show less
Gooskens, C.; Heuven, V.J.J.P. van; Golubović, J.; Schüppert, A.; Swarte, F.; Voigt, S. 2017
By means of a large-scale web-based investigation, we established the degree of mutual intelligibility of 16 closely related spoken languages within the Germanic, Slavic and Romance language... Show moreBy means of a large-scale web-based investigation, we established the degree of mutual intelligibility of 16 closely related spoken languages within the Germanic, Slavic and Romance language families in Europe. We first present the results of a selection of 1833 listeners representing the mutual intelligibility between young, educated Europeans from the same 16 countries where the test languages are spoken. Next, we present the data from a sub-group of listeners who had not learned the test language and had had minimal exposure to it. This allows us to investigate how well the listeners understand the test language on the basis of structural similarities between their own language and the test languages. Finally, we compare the results of the two data sets to the traditional genealogic characterisation of the three language groups. We expect the intelligibility results from the second group of listeners who had had minimal exposure to the test language to be a better reflection of the genealogical characterisation than the results from the larger group who had sometimes been exposed to the test language or had learned it at school. Show less
Gooskens, C.; Heuven, V.J.J.P. van; Golubović, J.; Schüppert, A.; Swarte, F.; Voigt, S. 2017
By means of a large-scale web-based investigation, we established the degree of mutual intelligibility of 16 closely related spoken languages within the Germanic, Slavic and Romance language... Show moreBy means of a large-scale web-based investigation, we established the degree of mutual intelligibility of 16 closely related spoken languages within the Germanic, Slavic and Romance language families in Europe. We first present the results of a selection of 1833 listeners representing the mutual intelligibility between young, educated Europeans from the same 16 countries where the test languages are spoken. Next, we present the data from a sub-group of listeners who had not learned the test language and had had minimal exposure to it. This allows us to investigate how well the listeners understand the test language on the basis of structural similarities between their own language and the test languages. Finally, we compare the results of the two data sets to the traditional genealogic characterisation of the three language groups. We expect the intelligibility results from the second group of listeners who had had minimal exposure to the test language to be a better reflection of the genealogical characterisation than the results from the larger group who had sometimes been exposed to the test language or had learned it at school. Show less
Gooskens, C.; Heuven, V.J.J.P. van; Golubović, J.; Schüppert, A.; Swarte, F.; Voigt, S. 2017
By means of a large-scale web-based investigation, we established the degree of mutual intelligibility of 16 closely related spoken languages within the Germanic, Slavic and Romance language... Show moreBy means of a large-scale web-based investigation, we established the degree of mutual intelligibility of 16 closely related spoken languages within the Germanic, Slavic and Romance language families in Europe. We first present the results of a selection of 1833 listeners representing the mutual intelligibility between young, educated Europeans from the same 16 countries where the test languages are spoken. Next, we present the data from a sub-group of listeners who had not learned the test language and had had minimal exposure to it. This allows us to investigate how well the listeners understand the test language on the basis of structural similarities between their own language and the test languages. Finally, we compare the results of the two data sets to the traditional genealogic characterisation of the three language groups. We expect the intelligibility results from the second group of listeners who had had minimal exposure to the test language to be a better reflection of the genealogical characterisation than the results from the larger group who had sometimes been exposed to the test language or had learned it at school. Show less
Gooskens, C.; Heuven, V.J.J.P. van; Golubović, J.; Schüppert, A.; Swarte, F.; Voigt, S. 2017
By means of a large-scale web-based investigation, we established the degree of mutual intelligibility of 16 closely related spoken languages within the Germanic, Slavic and Romance language... Show moreBy means of a large-scale web-based investigation, we established the degree of mutual intelligibility of 16 closely related spoken languages within the Germanic, Slavic and Romance language families in Europe. We first present the results of a selection of 1833 listeners representing the mutual intelligibility between young, educated Europeans from the same 16 countries where the test languages are spoken. Next, we present the data from a sub-group of listeners who had not learned the test language and had had minimal exposure to it. This allows us to investigate how well the listeners understand the test language on the basis of structural similarities between their own language and the test languages. Finally, we compare the results of the two data sets to the traditional genealogic characterisation of the three language groups. We expect the intelligibility results from the second group of listeners who had had minimal exposure to the test language to be a better reflection of the genealogical characterisation than the results from the larger group who had sometimes been exposed to the test language or had learned it at school. Show less
