Cerebral microbleeds are predictive of mortality in the elderly.
ABSTRACT To investigate the prognostic value of cerebral microbleeds (CMB) regarding overall, cardiovascular-related, and stroke-related mortality and to investigate possible differences based on a cerebral amyloid angiopathy-type and nonlobar distribution of microbleeds.
We included 435 subjects who were participants from the nested MRI substudy of the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER). Cox proportional hazard models were applied to estimate the risk of overall, cardiovascular-related, and stroke-related death associated with microbleeds in general and microbleeds with a lobar distribution suggestive of the presence of cerebral amyloid angiopathy. The corresponding Kaplan-Meier survival curves were calculated.
Subjects with >1 CMB had a 6-fold risk of stroke-related death compared to subjects without CMB (hazard ratio, 5.97; 95% CI, 1.60-22.26; P=0.01). The diagnosis of nonlobar microbleeds was associated with >2-fold risk of cardiovascular death compared to subjects without microbleeds (hazard ratio, 2.67; 95% CI, 1.23-5.81; P=0.01). Subjects with probable cerebral amyloid angiopathy-type microbleeds had >7-fold risk of stroke-related death compared to subjects without CMB (hazard ratio, 7.20; 95% CI, 1.44-36.10; P=0.02).
This is the first study investigating the association between microbleeds and risk of overall, cardiovascular-related, and stroke-related mortality in an elderly population. Our findings indicate that the diagnosis of microbleeds is potentially of clinical relevance. Larger studies are needed to expand our observations and to address potential clinical implications and cost-benefits of such a policy.
- SourceAvailable from: Brian Lieberman[Show abstract] [Hide abstract]
ABSTRACT: β-Amyloid plaques (Aβ plaques) in the brain are associated with cerebral amyloid angiopathy (CAA). Imaging agents that could target the Aβ plaques in the living human brain would be potentially valuable as biomarkers in patients with CAA. A new series of (18)F styrylpyridine derivatives with high molecular weights for selectively targeting Aβ plaques in the blood vessels of the brain but excluded from the brain parenchyma is reported. The styrylpyridine derivatives, 8a-c, display high binding affinities and specificity to Aβ plaques (K(i) = 2.87, 3.24, and 7.71 nM, respectively). In vitro autoradiography of [(18)F]8a shows labeling of β-amyloid plaques associated with blood vessel walls in human brain sections of subjects with CAA and also in the tissue of AD brain sections. The results suggest that [(18)F]8a may be a useful PET imaging agent for selectively detecting Aβ plaques associated with cerebral vessels in the living human brain.Journal of Medicinal Chemistry 12/2011; 54(23):8085-98. · 5.61 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Cerebral microbleeds (MBs) are small chronic brain hemorrhages which are likely caused by structural abnormalities of the small vessels of the brain. Owing to the paramagnetic properties of blood degradation products, MBs can be detected in vivo by using specific magnetic resonance imaging (MRI) sequences. Over the last decades, the implementation of these MRI sequences in both epidemiological and clinical studies has revealed MBs as a common finding in many different populations, including healthy individuals. Also, the topographic distribution of these MBs has been shown to be potentially associated with specific underlying vasculopathies. However, the clinical and prognostic significance of these small hemorrhages is still a matter of debate as well as a focus of extensive research. In this article, we aim to review the current knowledge on the pathophysiology and clinical implications of MBs, with special emphasis on the links between lobar MBs, cerebral amyloid angiopathy, and Alzheimer’s disease.Alzheimer's Research and Therapy 06/2014; 6(33). · 4.39 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Cerebral microbleeds (CMB) are small haemosiderin deposits, detected with varying sensitivity by specific MRI sequences. CMB prevalence increases most clearly and reliably with age, but CMB are also associated with various acquired and heritable cerebral vasculopathies (most commonly arteriolosclerosis and amyloid angiopathy). CMB often coincide with the other radiological features of small vessel disease, cortical microinfarction, lacunar infarction and periventricular white matter hyperintensity. CMB distribution may suggest an underlying cause; in particular, lobar-restricted or corticosubcortical CMB suggest amyloid angiopathy. In both ischaemic stroke and intracerebral haemorrhage, CMB appear to be a marker of underlying vasculopathy severity, and therefore a predictor of recurrence. Although CMB are also associated with several broad clinical neurological impairments (cognitive impairment, depression and gait instability), it is debatable whether CMB themselves are causative. The clinical implications of CMB detection remain unclear. Thrombolysis for ischaemic stroke is not contraindicated. It is uncertain whether more conservative antithrombotic strategies are warranted if CMB are detected in patients with symptomatic vascular disease or atrial fibrillation. Studies (observational and randomized) of various treatment strategies in patients with CMB and these concomitant conditions are required to resolve these treatment dilemmas.Journal of Clinical Neuroscience 05/2013; · 1.25 Impact Factor
Cerebral microbleeds are predictive of mortality in the elderly
I. Schneider1, S. Trompet1, A. J. de Craen1, A. C. van Es1, M. A. van Buchem1, and J. van der Grond1
1Leiden University Medical Center, Leiden, Netherlands
Cerebral microbleeds represent focal hemosiderin deposits (1) which result from minimal blood leakage from damaged small vessels and can be
detected on T2*-weighted MRI, which is highly sensitive for iron-containing compounds (2). In terms of etiology, cerebral microbleeds can be
divided into microbleeds probably associated with cerebral amyloid angiopathy (CAA) which are located in the cerebral lobes (3) and microbleeds
associated with hypertension and atherosclerosis which are located in the thalamus, basal ganglia, brain stem and cerebellum (4). Microbleeds are not
only common in patients with ischemic stroke (5), intracerebral hemorrhage (ICH) (6) and Alzheimer disease (7) but also in healthy aging (8).
Recently Hennemann et al. have shown that microbleeds are the strongest predictor of all-cause mortality within a group of MRI biomarkers of
vascular damage and atrophy in a memory clinic population (9). To our knowledge it is not known whether microbleeds or distributive patterns of
microbleeds are also predictive of mortality in the general population. Therefore, we investigated the prognostic value of microbleeds in terms of all-
cause mortality and cardiovascular mortality in a population suffering from vascular disease or at high risk for developing this condition.
Patients were included from the nested MRI substudy of the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) who were recruited
from the general population. Inclusion and exclusion criteria have been described in detail elsewhere (10). A susceptibility-weighted scan for
microbleed score was available for 435 women and men aged between 70 and 82 years. All imaging was performed on an MR system operating at a
field strength of 1.5 T (Philips Medical Systems, Best, The Netherlands). Dual fast spin echo [repetition time (TR) = 3,000 ms; echo time (TE) =
27/120 ms; slice thickness = 3 mm; 48 slices; no interslice gap; field of view (FOV) = 220 x 220 mm; matrix = 256 x 204], FLAIR (TR = 8,000 ms;
TE = 100 ms; slice thickness = 3 mm; 48 slices; no interslice gap; FOV = 220 x 176 mm; matrix = 256 x 153) and susceptibility-weighted images
(multislice gradient echo sequence; TR = 2593 ms; TE = 48 ms; slice thickness = 6 mm; 22 slices; interslice gap = 0.6 mm; whole brain coverage;
FOV = 220 x 198 mm; matrix = 256 x 176) were obtained from all subjects.. All MRI scans were read in consensus by 2 experienced raters, who
were blinded to the clinical history. Microbleeds were defined as focal areas of signal loss on T2-weighted images that increased in size on the T2-
weighted gradient echo planar images (‘blooming effect’) (Figure 1) (11). In this way, microbleeds were differentiated from areas of signal loss based
on vascular flow void. Areas of symmetric hypointensity in the basal ganglia likely to represent calcification or nonhemorrhagic iron deposits were
disregarded. The location, number, and size of microbleeds were recorded (12). In a first analysis, we dichotomized subjects into a group having at
most 1 microbleed and into a group having two or more microbleeds. Subsequently, we applied the so-called Boston criteria for cerebral amyloid
angiopathy (CAA) in all subjects. The Boston criteria are designed to estimate the likelihood of the presence of CAA during life by means of location
and number of intracerbral hemorrhages (13, 14). Mean follow-up time of all-cause mortality was 6.4 (± 1.8) years. Mean follow-up time of
cardiovascular mortality was
5.7 (± 1.5) years.
Figure 2 shows Kaplan Meier
survival curves for
microbleeds for all-cause
mortality. Cox proportional
hazard models show that
subjects with two or more
microbleeds had a statistical
significant increased risk of
death compared to persons
with no or 1 microbleed (HR
1.75, 95% CI 1.07-2.87, p = 0.027). In terms of cardiovascular mortality Kaplan Meier survival curves show the same trend although reaching no
statistical significance (HR 2.12, 95% CI 0.95-4.72, p = 0.07). Figure 3 shows Kaplan Meier survival curves for microbleeds for cardiovascular
mortality during follow-up period II with microbleeds scored according to the Boston criteria. Cox proportional hazard models show that non-CAA
had a strong predictive effect. Persons diagnosed with non-CAA had a more than 4 fold risk of death compared to persons with at most 1 microbleed
(HR 4.21, 95% CI 1.85-9.58, p = 0.001). In terms of all-cause mortality Cox proportional hazard models show that probable CAA and non-CAA had
a predictive effect although reaching no statistical significance (HR 1.65, 95% CI 0.89-3.08, p = 0.11 and HR 1.73, 95% CI 0.92-3.23, p = 0.09
In this population-based study we found that the presence of two or more microbleeds implicates an increased risk of overall death. Furthermore, only
“non-CAA” type microbleeds were associated with increased risk of cardiovascular death, which is in line with the assumption that these microbleeds
are associated with hypertension and atherosclerosis. Therefore, CAA type small vessel disease cannot be considered as risk factor for
1) Offenbacher H. et al. AJNR Am J Neuroradiol 1996;17(3):573-8. 2) Roob G. et al. Neurology 1999;52(5):991-4. 3) Sveinbjornsdottir S. et al. J
Neurol Neurosurg Psychiatry 2008;79(9):1002-6. 4) Tanaka A. et al. Stroke 1999;30(8):1637-42. 5) Werring D.J. et al. Neurology 2005;65(12):1914-
8. 6) Fazekas F. et al. AJNR Am J Neuroradiol 1999;20(4):637-42. 7) Pettersen J.A. et al. Arch Neurol 2008;65(6):790-5. 8) Tsushima Y. et al.
Neuroradiology 2002;44(1):31-6. 9) Henneman W.J. et al. Stroke 2009;40(2):492-8. 10) Shepherd J. et al. Am J Cardiol 1999;84(10):1192-7. 11)
Greenberg S.M. et al. Lancet Neurol 2009;8(2):165-74. 12) van Es A.C. et al. Cerebrovasc Dis 2008;26(4):397-403. 13) Greenberg S.M. et al.
Neurology 1998;51(3):690-4. 14) van Rooden S. et al. Stroke 2009;40(9):3022-7.