23 research outputs found
Cerebral amyloid angiopathy: detection, diagnosis, and hemorrhage prediction
The overall aim of the studies described in this thesis was to improve cerebral amyloid angiopathy (CAA) detection and diagnosis, and to make predictions about intracerebral hemorrhage.The first part of this thesis investigates methods to detect CAA pathology more directly in both an early and later phase by 1) measuring levels of Amyloid-ß in the cerebrospinal fluid, 2) measuring the thickness of the retinal nerve fiber layer with spectral domain optical coherence tomography, 3) looking for new markers in 7-Tesla MRI, and 4) testing the Edinburgh CT criteria for CAA-related lobar intracerebral hemorrhage in D-CAA mutation carriers. In the second part of this thesis, trigger factors for spontaneous intracerebral hemorrhage are studied with a case-crossover design, prognosis of patients with isolated microbleeds is compared with patients presenting with lobar ICH, the association between small vessel disease markers and the extent of bleeding in the acute phase is studied, and the disease course of D-CAA mutation carriers and patients with sporadic CAA after a lobar intracerebral hemorrhage is described. The research projects described in this thesis were supported by the Dutch Heart Foundation (grant no. 2016T086; 2012T077), the Netherlands Organisation for Scientific Research (NWO) as part of the joint strategic research programme: ‘Earlier recognition of cardiovascular diseases’, the Netherlands Organisation for Health Research and Development (ZonMW; no. 733.050.202, 015.008.048), the National Institute of Health (NIH, R01-NS070834, R01-AG026484, R01-NS073344), the National Institute of Neurologic Disorders and Stroke (K23-NS083711, T32-NS048005, R01-NS070834), the National Institute on Aging (R01-AG26484), and the Dutch Alzheimer Foundation
Migraine with aura as early disease marker in Hereditary Dutch-type Cerebral Amyloid Angiopathy
Background and purpose: To determine whether migraine, which has often been described as an inaugural manifestation in monogenic cerebrovascular syndromes, is associated with cerebral amyloid pathology we assessed migraine and its correlation with MRI markers in Hereditary Dutch-type Cerebral Amyloid Angiopathy (D-CAA or HCHWA-D).Methods: All D-CAA mutation carriers who visited our clinic between 2012-2018 were included. Migraine was diagnosed by an interview and classified according to the International Classification of Headache Disorders. MRIs were scored for intracerebral hemorrhage (ICH) location(s) and presence of cortical superficial siderosis (cSS). Kaplan Meier survival analysis was used for age of ICH onset in carriers with and without migraine. Correlation with ICH location(s) and cSS were calculated with Poisson regression analysis adjusted for confounders.Results: We included 86 D-CAA mutation carriers (57% women, mean age 57 years), 48 (56%) suffered from migraine, all with aura. Prevalence was higher than expected compared with the general population (women pConclusions: Migraine with aura is an important, often inaugural symptom in D-CAA. Aura attacks lasting ≥60 minutes may signal acute ICH in D-CAA. Migraine with aura may be regarded as an early marker of disease in hereditary CAA preceding the occurrence of symptomatic ICH by several years.Paroxysmal Cerebral Disorder
Optical coherence tomography detects retinal changes in hereditary cerebral amyloid angiopathy
Background and purpose Investigating mutation carriers with Dutch-type hereditary (D-) cerebral amyloid angiopathy (CAA), offers the possibility to identify markers in pre- and symptomatic stages of CAA. Optical coherence tomography (OCT) has shown potential to detect retinal changes in several neurodegenerative diseases. The aim of the present exploratory study was to investigate thinning of retinal layers as a possible (early) biomarker in D-CAA mutation carriers. Methods Twenty-one D-CAA mutation carriers (n = 8 presymptomatic,n = 13 symptomatic, median age 50 years) and nine controls (median age 53 years) were scanned using spectral-domain OCT. Symptomatic mutation carriers were defined as having a history of >= 1 symptomatic intracerebral hemorrhage. D-CAA mutation carriers and controls were recruited from our D-CAA cohort and a healthy control cohort. Total peripapillary retinal nerve fiber layer (pRNFL) thickness, six regions of pRNFL, total macular volume (TMV), and individual macular region thickness were measured and analysed, adjusted for age. Results The overall median (interquartile range) thickness of pRNFL was lower in symptomatic, but not presymptomatic D-CAA mutation carriers compared with controls [91 (86-95) mu m vs. 99 (87-108) mu m;P = 0.006]. Both presymptomatic [111 (93-122) mu m vs. 131 (123-143) mu m;P < 0.001] and symptomatic carriers [119 (95-128) mu m vs. 131 (123-143) mu m;P = 0.034] had a thinner temporal-superior quadrant of the pRNFL versus controls. TMV or individual macular layer thickness did not differ between carriers and controls. Conclusions Thinning of the retinal nerve fiber layer may be a candidate marker of disease in hereditary CAA. Further studies are needed to determine whether retinal thinning is present in sporadic CAA and estimate its value as a marker for disease progression.Ophthalmic researc
Spatial and temporal intracerebral hemorrhage patterns in Dutch-type hereditary cerebral amyloid angiopathy
Aim To investigate whether there is a topographical and temporal pattern of index and recurrent intracerebral hemorrhages (ICH) in Dutch-type hereditary Cerebral Amyloid Angiopathy (D-CAA) to increase our understanding on CAA-related ICH development. Methods We included patients with DNA confirmed D-CAA or a history with >= 1 lobar ICH and >= 1 first-degree relative with D-CAA. Topographical pattern was studied by location (proportion frontal/parietal/temporal/occipital; infra/supratentorial and occurrence ratios relative to lobe volume) and volume of index and recurrent ICHs were determined on CT. Temporal pattern was examined by time between recurrent ICHs was retrieved from medical records. Results We included 72 patients with D-CAA (mean age at index ICH 55 years) with in total 214 ICH. The median follow-up time was 7 years (range 0.8 to 28 years). All ICH were lobar and supratentorial. The index ICH was most frequently located in the occipital lobe (34% vs. 22% in the other three lobes; with index ICH occurrence ratios relative to lobe volume of 1.9 for occipital, 1.0 for temporal, 1.2 for parietal, and 0.5 for frontal, p = 0.001). In 16/47 (34%) patients with multiple ICH, the second ICH was located in the same lobe as the index ICH. The median time-interval between subsequent ICH was #1-2 ICH 27 months, #2-3 ICH 14 months, and #3-4 ICH 7 months (p = 0.6) There was no difference in volume between index and recurrent ICHs. Conclusions We found that index and recurrent ICHs in D-CAA have a preference for the occipital lobe and are least frequent in the frontal lobe, which adds to the existing knowledge of histopathological studies on amyloid load in CAA. Surprisingly, there was no acceleration in time nor gradual increase of hematoma volume between subsequent ICHs.Neuro Imaging Researc
Cerebellar hemorrhages in patients with Dutch-type hereditary cerebral amyloid angiopathy
Background Recent studies suggest that superficially located cerebellar intracerebral hemorrhage (ICH) and microbleeds might point towards sporadic cerebral amyloid angiopathy (CAA). Aims We investigated the proportion of cerebellar ICH and asymptomatic macro- and microbleeds in Dutch-type hereditary CAA (D-CAA), a severe and essentially pure form of CAA. Methods Symptomatic patients with D-CAA (defined as >= 1 symptomatic ICH) and presymptomatic D-CAA mutation-carriers were included. We assessed magnetic resonance imaging scans for symptomatic (cerebellar) ICH and asymptomatic cerebellar macro- and microbleeds according to the STRIVE-criteria. Location was assessed as superficial-cerebellar (cortex, vermis or juxta-cortical) or deep-cerebellar (white matter, pedunculi cerebelli and gray nuclei). Results We included 63 participants (mean age 58 years, 60% women, 42 symptomatic). In total, the 42 symptomatic patients with D-CAA had 107 symptomatic ICH (range 1-7). None of these ICH were located in the cerebellum. Six of 42 (14%, 95%CI 4-25%) symptomatic patients and none of the 21 (0%, 95%CI 0-0%) presymptomatic carriers had >= 1 asymptomatic cerebellar macrobleed(s). All macrobleeds were superficially located. Cerebellar microbleeds were found in 40 of 63 (64%, 95%CI 52-76) participants (median 1.0, range 0-159), 81% in symptomatic patients and 29% in presymptomatic carriers. All microbleeds were strictly or predominantly superficially (ratio superficial versus deep 15:1) located. Conclusions Superficially located asymptomatic cerebellar macrobleeds and microbleeds are common in D-CAA. Cerebellar microbleeds are already present in the presymptomatic stage. Despite the high frequency of cerebellar micro and macrobleeds, CAA pathology did not result in symptomatic cerebellar ICH in patients with D-CAA.Paroxysmal Cerebral Disorder
Minocycline for sporadic and hereditary cerebral amyloid angiopathy (BATMAN): study protocol for a placebo-controlled randomized double-blind trial
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 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.Radiolog
Occipital cortical calcifications in cerebral amyloid angiopathy
Background and Purpose:Cortical calcifications have been reported in patients with cerebral amyloid angiopathy (CAA), although their prevalence and pathophysiology are unknown. We investigated the frequency of calcifications on computed tomography, their association with intracerebral hemorrhage (ICH) and their coexistence with a striped pattern of the occipital cortex reflecting microcalcifications on ultra-high-field 7T-magnetic resonance imaging in Dutch-type hereditary CAA (D-CAA) and sporadic CAA.Methods:We included D-CAA mutation carriers with a proven APP (amyloid precursor protein) mutation or >= 1 lobar ICH and >= 1 first-degree relative with D-CAA and sporadic CAA patients with probable CAA according to the modified Boston criteria. D-CAA carriers were regarded symptomatic when they had a history of symptomatic ICH. We assessed the presence, location, and progression of calcifications and their association with ICH and the striped occipital cortex.Results:We found cortical calcifications in 15/81 (19% [95% CI, 11-29]) D-CAA mutation carriers (15/69 symptomatic and 0/12 presymptomatic) and in 1/59 (2% [95% CI, 0-9]) sporadic CAA patients. Calcifications were all bilateral located in the occipital lobes. In 3/15 (20%) of the symptomatic D-CAA patients the calcifications progressed over a period up to 10 years. There was evidence of an association between cortical calcifications and new ICH development (hazard ratio, 7.1 [95% CI, 0.9-54.9], log-rank P=0.03). In 7/25 D-CAA symptomatic carriers in whom a 7T-magnetic resonance imaging was performed, a striped pattern of the occipital cortex was present; in 3/3 (100%) of those with calcifications on computed tomography and 4/22 (18%) of those without calcifications.Conclusions:Occipital cortical calcifications are frequent in D-CAA but seem to be rare in sporadic CAA. Their absence in presymptomatic carriers and their association with ICH might suggest that they are a marker for advanced CAA. Cortical calcifications on computed tomography seem to be associated with the striped occipital cortex on 7T-magnetic resonance imaging which may possibly represent an early stage of calcification.Development and application of statistical models for medical scientific researc
MRI Susceptibility Changes Suggestive of Iron Deposition in the Thalamus after Ischemic Stroke
Neuro Imaging Researc
Sensitivity of the Edinburgh Criteria for Lobar Intracerebral Hemorrhage in Hereditary Cerebral Amyloid Angiopathy
Background and Purpose:The Edinburgh computed tomography and genetic criteria enable diagnosis of cerebral amyloid angiopathy (CAA) associated lobar intracerebral hemorrhage (ICH) but have not been validated in living patients. We assessed the sensitivity of the Edinburgh criteria in patients with acute lobar ICH due to Dutch-type hereditary CAA; a genetic and pure form of CAA.Methods:We retrospectively analyzed computed tomography-scans from a cohort of consecutive Dutch-type hereditary CAA patients who presented with >= 1 episode(s) of acute lobar ICH at the Leiden University Medical Center. Presence of subarachnoid hemorrhage (SAH) and finger-like projections (FLP) were determined. Association of SAH and FLP with ICH volume was analyzed using multivariate linear regression.Results:We included 55 Dutch-type hereditary CAA patients (mean age 56 years, 55% men) with a total of 107 episodes of acute lobar ICH. SAH was present in 82/107 (76%) and FLP in 62/107 (58%), resulting in a sensitivity of 76% for SAH and 58% for FLP. In 56 (52%), both markers were present. Nineteen (18%) lobar ICH showed no SAH extension or FLP. ICH volume was significantly associated with presence of SAH (median volume 4 versus 28 mL; P=0.001) and presence of FLP (median volume 7 versus 39 mL; P= 40 mL, the sensitivity of the presence of both SAH and FLP was >81% (95% CI, 70%-92%), whereas in ICH volumes Conclusions:The computed tomography-based Edinburgh criteria seem to be a sensitive diagnostic test for CAA-associated lobar ICH, although they should be used with caution in small-sized lobar ICH.Development and application of statistical models for medical scientific researc
Recurrent hemorrhage risk and long-term mortality after a first intracerebral hemorrhage in hereditary and sporadic cerebral amyloid angiopathy
Neuro Imaging Researc