INTRODUCTIONWe aimed to investigate the association between white matter hyperintensity (WMH) shape and volume and the long-term dementia risk in community-dwelling older adults. METHODSThree... Show moreINTRODUCTIONWe aimed to investigate the association between white matter hyperintensity (WMH) shape and volume and the long-term dementia risk in community-dwelling older adults. METHODSThree thousand seventy-seven participants (mean age: 75.6 +/- 5.2 years) of the Age Gene/Environment Susceptibility (AGES)-Reykjavik study underwent baseline 1.5T brain magnetic resonance imaging and were followed up for dementia (mean follow-up: 9.9 +/- 2.6 years). RESULTSMore irregular shape of periventricular/confluent WMH (lower solidity (hazard ratio (95% confidence interval) 1.34 (1.17 to 1.52), p < .001) and convexity 1.38 (1.28 to 1.49), p < .001); higher concavity index 1.43 (1.32 to 1.54), p < .001) and fractal dimension 1.45 (1.32 to 1.58), p < .001)), higher total WMH volume (1.68 (1.54 to 1.87), p < .001), higher periventricular/confluent WMH volume (1.71 (1.55 to 1.89), p < .001), and higher deep WMH volume (1.17 (1.08 to 1.27), p < .001) were associated with an increased long-term dementia risk. DISCUSSIONWMH shape markers may in the future be useful in determining patient prognosis and may aid in patient selection for future preventive treatments in community-dwelling older adults. Show less
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
Pont, L.M.H. de; Steekelenburg, J.M. van; Verbist, B.M.; Buchem, M.A. van; Blom, H.M.; Hammer, S. 2020
Purpose of ReviewMeniere's disease (MD) is a burdensome and not well understood inner ear disorder that has received increasing attention of scientists over the past decade. Until 2007, a certain... Show morePurpose of ReviewMeniere's disease (MD) is a burdensome and not well understood inner ear disorder that has received increasing attention of scientists over the past decade. Until 2007, a certain diagnosis of endolymphatic hydrops (EH) required post-mortem histology. Today, dedicated high-resolution magnetic resonance imaging (MRI) protocols enable detection of disease-related changes in the membranous labyrinth in vivo. In this review, we summarize the current status of MR imaging for MD.Recent FindingsThe mainstays of hydrops imaging are inversion recovery sequences using delayed acquisition after intravenous or intratympanic contrast administration. Based on these techniques, several methods have been developed to detect and classify EH. In addition, novel imaging features of MD, such as blood-labyrinth barrier impairment, have recently been observed.SummaryDelayed contrast enhanced MRI has emerged as a reliable technique to demonstrate EH in vivo, with promising application in the diagnosis and follow-up of MD patients. Therefore, familiarity with current techniques and diagnostic imaging criteria is increasingly important. Show less
Vos, F. de; Schouten, T.M.; Koini, M.; Bouts, M.J.R.J.; Feis, R.A.; Lechner, A.; ... ; Rombouts, S.A.R.B. 2020
Anatomical magnetic resonance imaging (MRI), diffusion MRI and resting state functional MRI (rs-fMRI) have been used for Alzheimer's disease (AD) classification. These scans are typically used to... Show moreAnatomical magnetic resonance imaging (MRI), diffusion MRI and resting state functional MRI (rs-fMRI) have been used for Alzheimer's disease (AD) classification. These scans are typically used to build models for discriminating AD patients from control subjects, but it is not clear if these models can also discriminate AD in diverse clinical populations as found in memory clinics.To study this, we trained MRI-based AD classification models on a single centre data set consisting of AD patients (N = 76) and controls (N = 173), and used these models to assign AD scores to subjective memory complainers (N = 67), mild cognitive impairment (MCI) patients (N = 61), and AD patients (N = 61) from a multi-centre memory clinic data set. The anatomical MRI scans were used to calculate grey matter density, subcortical volumes and cortical thickness, the diffusion MRI scans were used to calculate fractional anisotropy, mean, axial and radial diffusivity, and the rs-fMRI scans were used to calculate functional connectivity between resting state networks and amplitude of low frequency fluctuations. Within the multi-centre memory clinic data set we removed scan site differences prior to applying the models.For all models, on average, the AD patients were assigned the highest AD scores, followed by MCI patients, and later followed by SMC subjects. The anatomical MRI models performed best, and the best performing anatomical MRI measure was grey matter density, separating SMC subjects from MCI patients with an AUC of 0.69, MCI patients from AD patients with an AUC of 0.70, and SMC patients from AD patients with an AUC of 0.86. The diffusion MRI models did not generalise well to the memory clinic data, possibly because of large scan site differences. The functional connectivity model separated SMC subjects and MCI patients relatively good (AUC = 0.66). The multimodal MRI model did not improve upon the anatomical MRI model.In conclusion, we showed that the grey matter density model generalises best to memory clinic subjects. When also considering the fact that grey matter density generally performs well in AD classification studies, this feature is probably the best MRI-based feature for AD diagnosis in clinical practice. Show less
BackgroundFrontotemporal dementia (FTD) and Alzheimer's disease (AD) are associated with divergent differences in grey matter volume, white matter diffusion, and functional connectivity. However,... Show moreBackgroundFrontotemporal dementia (FTD) and Alzheimer's disease (AD) are associated with divergent differences in grey matter volume, white matter diffusion, and functional connectivity. However, it is unknown at what disease stage these differences emerge. Here, we investigate whether divergent differences in grey matter volume, white matter diffusion, and functional connectivity are already apparent between cognitively healthy carriers of pathogenic FTD mutations, and cognitively healthy carriers at increased AD risk.MethodsWe acquired multimodal magnetic resonance imaging (MRI) brain scans in cognitively healthy subjects with (n=39) and without (n=36) microtubule-associated protein Tau (MAPT) or progranulin (GRN) mutations, and with (n=37) and without (n=38) apolipoprotein E epsilon 4 (APOE4) allele. We evaluated grey matter volume using voxel-based morphometry, white matter diffusion using tract-based spatial statistics (TBSS), and region-to-network functional connectivity using dual regression in the default mode network and salience network. We tested for differences between the respective carriers and controls, as well as for divergence of those differences. For the divergence contrast, we additionally performed region-of-interest TBSS analyses in known areas of white matter diffusion differences between FTD and AD (i.e., uncinate fasciculus, forceps minor, and anterior thalamic radiation).ResultsMAPT/GRN carriers did not differ from controls in any modality. APOE4 carriers had lower fractional anisotropy than controls in the callosal splenium and right inferior fronto-occipital fasciculus, but did not show grey matter volume or functional connectivity differences. We found no divergent differences between both carrier-control contrasts in any modality, even in region-of-interest analyses.ConclusionsConcluding, we could not find differences suggestive of divergent pathways of underlying FTD and AD pathology in asymptomatic risk mutation carriers. Future studies should focus on asymptomatic mutation carriers that are closer to symptom onset to capture the first specific signs that may differentiate between FTD and AD. Show less
Rostamian, S.; Haan, S. de; Grond, J. van der; Buchem, M.A. van; Ford, I.; Jukema, J.W.; Sabayan, B. 2019
BackgroundImpairment in domain-specific cognitive function is associated with the increased risk of mortality. We prospectively evaluated the association of executive function and memory with the... Show moreBackgroundImpairment in domain-specific cognitive function is associated with the increased risk of mortality. We prospectively evaluated the association of executive function and memory with the risk of long-term mortality in dementia-free older subjects. Moreover, we investigated the role of structural brain abnormalities in this association.MethodsWe included 547 dementia-free participants (mean age 78 years, 56.5% male) from the nested magnetic resonance imaging sub-study of the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER). Cox proportional hazard models were used to model 10-year risk of all-cause, cardiovascular, and noncardiovascular mortality in relation to performance in executive function and memory. Moreover, we evaluated the role of total brain parenchymal volume, cerebral blood flow, white matter hyperintensity, and the presence of microbleeds and infarcts in the link between cognitive function and mortality.ResultsIn the multivariable model, lower performance in executive function was associated with greater risk of all-cause (hazard ratio [HR] 1.49; 95% confidence interval [CI], 1.31-1.70), cardiovascular (HR 1.69; 95% CI, 1.36-2.11), and noncardiovascular (HR 1.36; 95% CI, 1.15-1.62) mortality. Similarly, poorer performance in memory tests associated with higher risk of all-cause (HR 1.47; 95% CI, 1.29-1.68), cardiovascular (HR 1.45; 95% CI, 1.15-1.83), and noncardiovascular (HR 1.49; 95% CI, 1.27-1.76) mortality. The associations were similar in subjects with various levels of brain structural abnormalities and cerebral blood flow (all P for interaction ≫ .05).ConclusionsPoorer performance in both executive function and memory tests associates with all-cause, cardiovascular, and noncardiovascular mortality in elderly individuals. This association is independent of cardiovascular risk factors and diseases, brain structural abnormalities, and cerebral blood flow. Show less
OBJECTIVES The purpose of this study was to randomly compare the incidence of asymptomatic cerebral embolism (ACE) between the second-generation pulmonary vein ablation catheter (PVAC Gold) and the... Show moreOBJECTIVES The purpose of this study was to randomly compare the incidence of asymptomatic cerebral embolism (ACE) between the second-generation pulmonary vein ablation catheter (PVAC Gold) and the irrigated Thermocool catheter.BACKGROUND Pulmonary vein isolation (PVI) with the PVAC is associated with ACE. The PVAC Gold was designed to avoid this complication.METHODS Patients with paroxysmal atrial fibrillation were randomized 1:1 to PVI with the PVAC Gold or Thermocool catheter. Cerebral magnetic resonance imaging was performed in the days before and after ablation and repeated after 3 months in case of a new lesion. Monitoring for microembolic signals (MES) was performed by using transcranial Doppler ultrasonography. Parameters of coagulation were determined before, during, and after ablation. Neuropsychological tests and questionnaires were applied 10 days before and 3 months after ablation.RESULTS Seventy patients were included in the study (mean age 61 +/- 9 years; 43 male subjects; CHA(2)DS(2)-VASc [congestive heart failure, hypertension, age >= 75 years, diabetes mellitus, stroke/transient ischemic attack, vascular disease, age 65 to 74 years, sex category] score 1.6 +/- 1.2; international normalized ratio 2.7 +/- 0.5; activated clotting time 374 +/- 24 s; p > 0.05 for all parameters). Procedural duration was shorter in the PVAC Gold group (140 +/- 34 vs. 207 +/- 44 min; p < 0.001). Eight (23%; 7 infarcts) patients in the PVAC Gold group exhibited a new ACE, compared with 2 (6%; no infarcts) patients in the Thermocool group (p = 0.042). Median number of MES was higher in the PVAC Gold group (1,111 [interquartile range, 715-2,234] vs. 787 [interquartile range, 532-1,053]; p < 0.001). There were no differences between groups regarding coagulation and neuropsychological outcomes.CONCLUSIONS PVI with the new PVAC Gold was associated with a higher incidence of ACE/cerebral infarcts and number of MES. Both catheters induced a comparable procoagulant state. Because there were no measurable differences in neuropsychological status, the clinical significance of ACE remains unclear. (Cerebral Embolism [CE] in Catheter Ablation of Atrial Fibrillation [AF] [CE-AF]; NCT01361295) (C) 2019 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation. Show less
Hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D) is an early onset hereditary form of cerebral amyloid angiopathy (CAA) caused by a point mutation resulting in an amino acid... Show moreHereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D) is an early onset hereditary form of cerebral amyloid angiopathy (CAA) caused by a point mutation resulting in an amino acid change (NP_000475.1:p.Glu693Gln) in the amyloid precursor protein (APP). Post-mortem frontal and occipital cortical brain tissue from nine patients and nine age-related controls was used for RNA sequencing to identify biological pathways affected in HCHWA-D. Although previous studies indicated that pathology is more severe in the occipital lobe in HCHWA-D compared to the frontal lobe, the current study showed similar changes in gene expression in frontal and occipital cortex and the two brain regions were pooled for further analysis. Significantly altered pathways were analyzed using gene set enrichment analysis (GSEA) on 2036 significantly differentially expressed genes. Main pathways over-represented by down-regulated genes were related to cellular aerobic respiration (including ATP synthesis and carbon metabolism) indicating a mitochondrial dysfunction. Principal up-regulated pathways were extracellular matrix (ECM)-receptor interaction and ECM proteoglycans in relation with an increase in the transforming growth factor beta (TGF beta) signaling pathway. Comparison with the publicly available dataset from pre-symptomatic APP-E693Q transgenic mice identified overlap for the ECM-receptor interaction pathway, indicating that ECM modification is an early disease specific pathomechanism. Show less
Nabuurs, R.J.A.; Kapoerchan, V.V.; Metaxas, A.; Hafith, S.; Backer, M. de; Welling, M.M.; ... ; Weerd, L. van der 2016
In the context of chronic childhood emotional maltreatment (CEM; emotional abuse and/or neglect), adequately responding to facial expressions is an important skill. Over time, however, this... Show moreIn the context of chronic childhood emotional maltreatment (CEM; emotional abuse and/or neglect), adequately responding to facial expressions is an important skill. Over time, however, this adaptive response may lead to a persistent vigilance for emotional facial expressions. The amygdala and the medial prefrontal cortex (mPFC) are key regions in face processing. However, the neurobiological correlates of face processing in adults reporting CEM are yet unknown. We examined amydala and mPFC reactivity to emotional faces (Angry, Fearful, Sad, Happy, Neutral) vs scrambled faces in healthy controls and unmedicated patients with depression and/or anxiety disorders reporting CEM before the age of 16 years (n = 60), and controls and patients who report no childhood abuse (n = 75). We found that CEM was associated with enhanced bilateral amygdala reactivity to emotional faces in general, and independent of psychiatric status. Furthermore, we found no support for differential mPFC functioning, suggesting that amygdala hyper-responsivity to emotional facial perception in adults reporting CEM may be independent from top-down influences of the mPFC. These findings may be key in understanding the increased emotional sensitivity and interpersonal difficulties, that have been reported in individuals with a history of CEM. Show less
Duijn, S. van; Nabuurs, R.J.A.; Duinen, S.G. van; Natte, R.; Buchem, M.A. van; Alia, A. 2013
