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Clinical aspects of microbleeds in Alzheimer's disease

  • Wiesje M. van der Flier
    Correspondence
    Alzheimer Center PK-1 Z 44, VU University Medical Center, de Boelelaan 1118, 1081 HZ Amsterdam, The Netherlands. Tel.: +31 20 4440816; fax: +31 20 4440715.
    Affiliations
    Alzheimer Center, Department of Neurology, VU University Medical Center, Amsterdam, The Netherlands
    Department of Epidemiology & Biostatistics, VU University Medical Center, Amsterdam, The Netherlands
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Open AccessPublished:July 26, 2012DOI:https://doi.org/10.1016/j.jns.2012.07.009

      Abstract

      Microbleeds are small lesions, appearing as black dots on T2*-weighted magnetic resonance imaging. They occur frequently in Alzheimer's disease (AD), but the clinical relevance of these radiological observations remains unclear. In this paper an overview is given on currently available evidence on the clinical relevance of microbleeds in AD. The evidence linking microbleeds to severity of cognitive impairment in AD is not unambiguous. From the existing literature, it seems reasonable to conclude that multiple microbleeds negatively impact cognitive performance, but there is less consensus on the importance of location of microbleeds in this respect. Regarding progression of disease, there is hardly any evidence that microbleeds affect disease course in terms of progression to AD in patients with MCI or with respect to rate of cognitive decline in AD patients. This may imply that microbleeds simply do not affect disease course, but an alternative explanation for the negative findings would be that these studies are hampered by selective drop-out, as individuals with many microbleeds have an increased risk of (stroke-related) mortality.

      Keywords

      1. Introduction

      Microbleeds are small lesions, appearing as black dots on T2*-weighted magnetic resonance imaging. Microbleeds, which have long been considered to be innocent observations on MRI, have now been shown to occur more frequently in patients with Alzheimer's disease (AD) than in the general population, with an estimated prevalence of 23% [
      • Cordonnier C.
      • van der Flier W.M.
      • Sluimer J.D.
      • Leys D.
      • Barkhof F.
      • Scheltens P.
      Prevalence and severity of microbleeds in a memory clinic setting.
      ,
      • Nakata-Kudo Y.
      • Mizuno T.
      • Yamada K.
      • Shiga K.
      • Yoshikawa K.
      • Mori S.
      • et al.
      Microbleeds in Alzheimer disease are more related to cerebral amyloid angiopathy than cerebrovascular disease.
      ,
      • Hanyu H.
      • Tanaka Y.
      • Shimizu S.
      • Takasaki M.
      • Abe K.
      Cerebral microbleeds in Alzheimer's disease.
      ,
      • Pettersen J.A.
      • Sathiyamoorthy G.
      • Gao F.Q.
      • Szilagyi G.
      • Nadkarni N.K.
      • St George-Hyslop P.
      • et al.
      Microbleed topography, leukoaraiosis, and cognition in probable Alzheimer disease from the Sunnybrook dementia study.
      ,
      • Cordonnier C.
      • van der Flier W.M.
      Brain microbleeds and Alzheimer's disease: innocent observation or key player?.
      ]. An example of microbleeds in a patient with AD is shown in Fig. 1. Together with white matter hyperintensities and lacunes, microbleeds can be considered a third expression of small vessel disease on MRI. Many questions still surround the observation of microbleeds: for example, it is unclear what their underlying pathological substrate is. Furthermore, the clinical implications of microbleeds are insufficiently known.
      Figure thumbnail gr1
      Fig. 1A 56-year old female patient with Alzheimer's disease. On the Mini-Mental State Examination, she has a score of 16. On MRI, axial susceptibility-weighted imaging (left panel) shows multiple lobar microbleeds. On the coronal T1-weighted image (right panel), atrophy of the medial temporal lobe can be appreciated.
      Based on mainly epidemiological evidence, the hypothesis has been coined that the etiology of microbleeds differs according to their location. Microbleeds with a deep location supposedly result from underlying hypertensive vasculopathy, while microbleeds in a lobar location are thought to reflect underlying cerebral amyloid angiopathy (CAA). This makes microbleeds especially relevant in the context of AD, in which diseases both amyloid pathology (including amyloid deposition in parenchyma [plaques] and in vessels [CAA]) and ischemic vascular pathology play a role. It is not known how these two types of pathology interact, but the fact that microbleeds appear to be related to both types of pathology makes them highly relevant [
      • Cordonnier C.
      • van der Flier W.M.
      Brain microbleeds and Alzheimer's disease: innocent observation or key player?.
      ].

      2. Microbleeds reflect amyloid burden

      In a proof of principle study, we retrospectively selected AD patients with many microbleeds (arbitrarily defined as >8, corresponding to the top 5%) and matched these for age and gender on a one-to-two basis with AD patients without any microbleeds [
      • Goos J.D.
      • Kester M.I.
      • Barkhof F.
      • Klein M.
      • Blankenstein M.A.
      • Scheltens P.
      • et al.
      Patients with Alzheimer disease with multiple microbleeds: relation with cerebrospinal fluid biomarkers and cognition.
      ]. There were no differences between groups in the degree of (medial temporal) atrophy. Patients with many microbleeds however, had more severe white matter hyperintensities, confirming the association with small vessel disease. Moreover, they had lower (i.e. more abnormal) levels of amyloid-beta 1–42 in their cerebrospinal fluid (CSF), providing evidence for a link with amyloid burden. We recently confirmed the latter finding in a completely independent sample of patients with ≥1 microbleed which we compared with an age and gender matched group of patients without any microbleeds [
      • Goos J.D.
      • Teunissen C.E.
      • Veerhuis R.
      • Verwey N.A.
      • Barkhof F.
      • Blankenstein M.A.
      • et al.
      Microbleeds relate to altered amyloid-beta metabolism in Alzheimer's disease.
      ]. Patients with microbleeds had lower (i.e. more abnormal) levels of CSF amyloid-beta 1–42, but contrary to our expectation, there was no relation with CSF amyloid-beta 1–40. This may have several potential explanations. First, microbleeds in AD may represent an earlier stage or milder form of CAA compared to sporadic CAA patients presenting with full blown hemorrhages. Alternatively, AD patients may have a different subtype of CAA, arising from a different pathomechanism. The finding of lowered amyloid-beta 1–42 was largely attributable to patients with lobar microbleeds, providing circumstantial evidence that lobar microbleeds in AD are related to CAA. Additional evidence for a spatial relationship between microbleeds and amyloid-beta comes from an elegant study using Positron Emission Tomography (PET) with Pittsburgh-compound-B (PIB), which showed a local increase in PIB retention at the site of microbleeds [
      • Dierksen G.A.
      • Skehan M.E.
      • Khan M.A.
      • Jeng J.
      • Nandigam R.N.
      • Becker J.A.
      • et al.
      Spatial relation between microbleeds and amyloid deposits in amyloid angiopathy.
      ]. Regions of interest in concentric circles around the microbleed showed a gradual decline in PIB retention with increasing distance from the microbleed location.

      3. ARIA

      The studies above underline the relevance of microbleeds in the context of AD. Interest in microbleeds has further boosted because of the observation of microbleeds and vasogenic edema as side effects of immunization therapy [
      • Black R.S.
      • Sperling R.A.
      • Safirstein B.
      • Motter R.N.
      • Pallay A.
      • Nichols A.
      • et al.
      A single ascending dose study of bapineuzumab in patients with Alzheimer disease.
      ,
      • Salloway S.
      • Sperling R.
      • Gilman S.
      • Fox N.C.
      • Blennow K.
      • Raskind M.
      • et al.
      A phase 2 multiple ascending dose trial of bapineuzumab in mild to moderate Alzheimer disease.
      ]. This has led to the recent introduction of the term Amyloid Related Imaging Abnormalities (ARIA) [
      • Sperling R.A.
      • Jack Jr., C.R.
      • Black S.E.
      • Frosch M.P.
      • Greenberg S.M.
      • Hyman B.T.
      • et al.
      Amyloid-related imaging abnormalities in amyloid-modifying therapeutic trials: recommendations from the Alzheimer's Association Research Roundtable Workgroup.
      ]. ARIA encompass both vasogenic edema related observations (ARIA-E) supposedly reflecting an increase in extracellular fluid, and hemosiderin-related observations (ARIA-H). The latter include both microbleeds and superficial siderosis. The article attempts to provide recommendations for the detection and monitoring of ARIA in AD clinical trials, but at the same time acknowledges that many aspects regarding the etiology of these radiological observations, and especially regarding their clinical relevance remain unclear. In the remainder of this paper, I will give an overview of currently available evidence on the clinical relevance of microbleeds in AD. First, I will focus on cross-sectional studies studying the relationship between microbleeds and severity of cognitive impairment. Subsequently, I will discuss the relationship between microbleeds and rate of decline.

      4. Cognitive impairment

      Most studies in AD have shown hardly any relationship between the presence of microbleeds and cognition [
      • Cordonnier C.
      • van der Flier W.M.
      • Sluimer J.D.
      • Leys D.
      • Barkhof F.
      • Scheltens P.
      Prevalence and severity of microbleeds in a memory clinic setting.
      ,
      • Nakata-Kudo Y.
      • Mizuno T.
      • Yamada K.
      • Shiga K.
      • Yoshikawa K.
      • Mori S.
      • et al.
      Microbleeds in Alzheimer disease are more related to cerebral amyloid angiopathy than cerebrovascular disease.
      ,
      • Pettersen J.A.
      • Sathiyamoorthy G.
      • Gao F.Q.
      • Szilagyi G.
      • Nadkarni N.K.
      • St George-Hyslop P.
      • et al.
      Microbleed topography, leukoaraiosis, and cognition in probable Alzheimer disease from the Sunnybrook dementia study.
      ,
      • Werring D.J.
      • Gregoire S.M.
      • Cipolotti L.
      Cerebral microbleeds and vascular cognitive impairment.
      ]. The relatively small sample sizes and the low number of microbleeds (most patients with microbleeds have only one microbleed) may account for these negative findings. Alternatively, the disease process may have advanced too far, masking the subtle effect of microbleeds on cognition. To account for the problem of low number of microbleeds, we took a proof of principle approach, comparing AD patients with many microbleeds to age and gender matched AD patients without any microbleeds [
      • Goos J.D.
      • Kester M.I.
      • Barkhof F.
      • Klein M.
      • Blankenstein M.A.
      • Scheltens P.
      • et al.
      Patients with Alzheimer disease with multiple microbleeds: relation with cerebrospinal fluid biomarkers and cognition.
      ]. We found that patients with many microbleeds performed five points worse on their Mini-Mental State Examination at first examination. This effect remained significant after adjustment for age, gender, medial temporal lobe atrophy and white matter hyperintensities, and shows that number of microbleeds may be a highly relevant factor to take into account.
      Epidemiological studies of large cohorts of non-demented individuals may reveal the subtle impact of microbleeds on cognition that may become obscured later in the disease process. In the Rotterdam study, a respectable number of 3979 elderly from the general population (60±9 years; 54% female, MMSE 28±2, ≥1 microbleed: 15%) were included [
      • Poels M.M.
      • Ikram M.A.
      • van der Lugt A.
      • Hofman A.
      • Niessen W.J.
      • Krestin G.P.
      • et al.
      Cerebral microbleeds are associated with worse cognitive function: the Rotterdam scan study.
      ]. The researchers found an association between a higher number of microbleeds and lower MMSE-score and worse performance on tests for information processing speed and motor speed. These associations were mostly attributable to individuals with many microbleeds (≥5), preferably with a lobar location. In a non-demented cohort of 500 patients with small vessel disease (RUN DMC cohort; 66±9 years; 43% female, MMSE 28±2, ≥1 microbleed: 10%) associations between both presence and number of microbleeds and measures of global cognition, memory, speed and attention were found [
      • van Norden A.G.
      • van den Berg H.A.
      • de Laat K.F.
      • Gons R.A.
      • van Dijk E.J.
      • de Leeuw F.E.
      Frontal and temporal microbleeds are related to cognitive function: the Radboud University Nijmegen diffusion tensor and magnetic resonance cohort (RUN DMC) study.
      ]. The relationship between microbleeds and cognitive performance was mainly driven by frontal and temporal (lobar) microbleeds. Additionally, deep microbleeds were related to worse global cognitive function, psychomotor speed and attention. Finally, the PROSPER study investigated 439 nondemented individuals with vascular risk factors (78±3 years; 40% female, MMSE 28, ≥1 microbleed: 24%) and found no effect of microbleeds on cognitive performance [
      • van Es A.C.
      • van der Grond J.
      • de Craen A.J.
      • Westendorp R.G.
      • Bollen E.L.
      • Blauw G.J.
      • et al.
      Cerebral microbleeds and cognitive functioning in the PROSPER study.
      ]. In a direct comparison between patients with infratentorial microbleeds and patients without infratentorial microbleeds (including patients with microbleeds in another location) however, they found that the former group performed worse on memory tests.

      5. Rate of decline

      Subsequently, one may question whether the presence of microbleeds negatively impacts the course of the disease. Progression of disease can be defined in a number of ways. A first and important question is whether the presence of microbleeds predicts progression to AD among patients with mild cognitive impairment (MCI). We followed 152 patients with MCI presenting at our memory clinic for an average of 2±1 years [
      • Staekenborg S.S.
      • Koedam E.L.
      • Henneman W.J.
      • Stokman P.
      • Barkhof F.
      • Scheltens P.
      • et al.
      Progression of mild cognitive impairment to dementia: contribution of cerebrovascular disease compared with medial temporal lobe atrophy.
      ]. At follow-up, 80 patients (53%) had remained stable, 56 (37%) had developed AD, and 16 (10%) had developed another type of dementia (e.g. vascular dementia, frontotemporal dementia, dementia with Lewy bodies). On baseline MRI, atrophies of the medial temporal lobe and white matter hyperintensities were graded using a simple visual rating scale and microbleeds were counted. We found that atrophy of the medial temporal lobe predicted progression to AD, while white matter hyperintensities and presence of microbleeds predicted progression to another type of dementia, but not to AD.
      A second way to look at progression of disease, is by looking at rate of cognitive decline. We followed 221 patients with AD (68±9 years; 49% female, baseline MMSE 22±4, ≥1 microbleed: 18%) for an average duration of follow-up of 3±1 years [
      • van der Vlies A.E.
      • Goos J.D.
      • Barkhof F.
      • Scheltens P.
      • van der Flier W.M.
      Microbleeds do not affect rate of cognitive decline in Alzheimer's disease.
      ]. Cognitive performance was repeatedly measured using MMSE. Linear mixed models showed that on average, patients lost 2 MMSE points per year. There was no relation between presence or number of microbleeds and baseline MMSE or change in MMSE over time. Results did not change when we took location of microbleeds into account. It is still possible that subtle effects of microbleeds on rate of decline in specific cognitive domains would have been found when other neuropsychological tests had been used. Nonetheless, the abovementioned study shows that presence and number of microbleeds are not a major determinant of disease course.
      A third way to look at disease progression is by taking mortality as outcome measure. We followed 1138 patients from our memory clinic (including 357 patients with AD) for an average period of 3±2 years [
      • Henneman W.J.
      • Sluimer J.D.
      • Cordonnier C.
      • Baak M.M.
      • Scheltens P.
      • Barkhof F.
      • et al.
      MRI biomarkers of vascular damage and atrophy predicting mortality in a memory clinic population.
      ]. Information on mortality was obtained from the general practicioner and/or the patient file. Baseline MRI was assessed using simple visual rating scales for atrophy of the medial temporal lobe, global cortical atrophy, white matter hyperintensities and microbleeds (categorized as 0/1–2/≥3). We found that the presence of multiple microbleeds was the strongest predictor of mortality with an almost two and a half times increased risk of mortality, after adjustment for other MRI-measures and vascular risk factors. In this study, information on cause of death was not available. An attempt to take into account the cause of death was made in a study based on the PROPSER cohort [
      • Altmann-Schneider I.
      • Trompet S.
      • de Craen A.J.
      • van Es A.C.
      • Jukema J.W.
      • Stott D.J.
      • et al.
      Cerebral microbleeds are predictive of mortality in the elderly.
      ]. The cohort of 435 nondemented individuals with vascular risk factors was followed for 7±2 years. Information on cause of death was obtained from the Central Bureau of Statistics of the Netherlands. In this study, multiple (>1) microbleeds modestly though non-significantly, predicted overall mortality, but they strongly predicted stroke-related mortality (hazard ratio 6). Furthermore, this increased risk of stroke-related mortality was largely attributable to microbleeds with a strictly lobar distribution.

      6. Conclusion and discussion

      Microbleeds are a radiological construct, reflecting deposits of hemosiderin. They can presumably result from two neuropathological routes; [
      • Cordonnier C.
      • van der Flier W.M.
      • Sluimer J.D.
      • Leys D.
      • Barkhof F.
      • Scheltens P.
      Prevalence and severity of microbleeds in a memory clinic setting.
      ] hypertensive vasculopathy and [
      • Nakata-Kudo Y.
      • Mizuno T.
      • Yamada K.
      • Shiga K.
      • Yoshikawa K.
      • Mori S.
      • et al.
      Microbleeds in Alzheimer disease are more related to cerebral amyloid angiopathy than cerebrovascular disease.
      ] cerebral amyloid angiopathy. Microbleeds are of particular interest in the context of AD for a number of reasons. First, their prevalence is higher in patients with AD than in the general population. Second, resulting from two neuropathological routes, they may form a bridge between amyloid initiated brain changes and ischemic cerebrovascular pathology. Associations with expressions of small vessel disease on the one hand and with amyloid-beta on the other hand provide evidence for this double association. Finally, interest in microbleeds has boosted due to their occurrence as side effect of anti-amyloid immunization therapy [
      • Sperling R.A.
      • Jack Jr., C.R.
      • Black S.E.
      • Frosch M.P.
      • Greenberg S.M.
      • Hyman B.T.
      • et al.
      Amyloid-related imaging abnormalities in amyloid-modifying therapeutic trials: recommendations from the Alzheimer's Association Research Roundtable Workgroup.
      ]. At the same time, relatively little is known about their clinical relevance.
      The evidence linking microbleeds to severity of cognitive impairment is not unambiguous. From the existing literature, we can conclude that multiple microbleeds negatively impact cognitive performance. There is no consensus on the importance of location of microbleeds in this respect, however. The conflicting findings may be partly explained by the specific characteristics of the cohorts under study. In the context of (preclinical) AD, lobar microbleeds may impact cognitive performance most, while in the context of cerebrovascular disease, microbleeds with a deep or infratentorial location may have a stronger impact on cognitive performance.
      Regarding progression of disease, it seems that microbleeds do not affect the course of AD in terms of progression to AD in patients with MCI or with respect to rate of cognitive decline. A potential explanation for this finding is that microbleeds have only a subtle effect on cognition and disease course, which is diluted once the disease has progressed too far. An alternative explanation would be that selective drop-out accounts for the negative findings in longitudinal studies. This would be the case when patients with multiple microbleeds are at risk of such fast disease progression that they are less likely to return to the memory clinic for follow-up evaluation. Circumstantial evidence for this line of reasoning stems from studies showing that individuals with many microbleeds have an increased risk of (stroke-related) mortality [
      • Henneman W.J.
      • Sluimer J.D.
      • Cordonnier C.
      • Baak M.M.
      • Scheltens P.
      • Barkhof F.
      • et al.
      MRI biomarkers of vascular damage and atrophy predicting mortality in a memory clinic population.
      ,
      • Altmann-Schneider I.
      • Trompet S.
      • de Craen A.J.
      • van Es A.C.
      • Jukema J.W.
      • Stott D.J.
      • et al.
      Cerebral microbleeds are predictive of mortality in the elderly.
      ]. In the context of clinical trials, this means that one or a few microbleeds seem to be unharmful, but patients with many microbleeds should not be exposed to unnecessary risks [
      • Sperling R.A.
      • Jack Jr., C.R.
      • Black S.E.
      • Frosch M.P.
      • Greenberg S.M.
      • Hyman B.T.
      • et al.
      Amyloid-related imaging abnormalities in amyloid-modifying therapeutic trials: recommendations from the Alzheimer's Association Research Roundtable Workgroup.
      ]. At this point, there is insufficient evidence to make recommendations about the specific number of microbleeds that might be harmful. Moreover, it is not known yet if microbleeds developing as a result of immunization trials (i.e. ARIA-H) have the same neuropathological substrate and risk profile as spontaneously developing microbleeds. This implies that we do not know yet if results of studies on risks associated with microbleeds can be generalized to ARIA-H. Furthermore, data regarding the question whether baseline microbleeds actually increase the risk of incident hemorrhage and vasogenic edema (ARIA-E) are dearly needed.

      Conflict of interest

      None.

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