Damage to the walls of the smallest blood vessels of the brain correlates with future cognitive deterioration, report scientists in the June 6 JAMA Neurology online. Among thousands of volunteers who all started out cognitively normal, those who had cerebral microbleeds declined sooner on cognitive tests and were likelier to later receive a dementia diagnosis than people who didn’t have those lesions, according to researchers led by Meike Vernooij, Erasmus MC University Medical Center Rotterdam, The Netherlands. The results imply that people with microbleeds, an imaging marker of small vessel disease, are at higher risk for dementia, and strengthen the notion that cerebrovascular problems contribute to the pathogenesis of Alzheimer’s, said first author Saloua Akoudad.

“The large number of patients and long duration of follow-up make this a well-powered study,” said Wiesje van der Flier, VU University Medical Center, Amsterdam. 

Spotty Image.

Cerebral microbleeds (black circles) dot the lobar regions of a person without dementia. [Courtesy of Saloua Akoudad]

Cerebral microbleeds, visible in magnetic resonance imaging, mark the spots where tiny brain hemorrhages occurred. Clusters of hemosiderin-laden macrophages stick around after sopping up the blood and patch up ruptured vessel walls, appearing as small black dots (see image at left). Microbleeds occur in 11 to nearly 40 percent of older adults and signify that the walls of small blood vessels have weakened (Vernooij et al., 2008; Sveinbjornsdottir et al., 2008). It is generally thought that microbleeds in the frontal, temporal, parietal, and occipital lobes result from amyloid depositing in blood vessels there; bleeds in the deep white matter seem to stem from hypertension, diabetes, or smoking (for a review, see Martinez-Ramirez et al., 2014). 

Previous studies suggest that microbleeds are associated with cognitive impairment, measured in lower MMSE scores and declining performance in particular cognitive domains (Meier et al., 2014Poels et al., 2012; Qiu et al., 2010). However, in people who already have dementia, these lesions have no effect on how fast a patient’s cognition declines further (van der Vlies et al., 2012). Scientists have yet to examine whether cognitively healthy people who have microbleeds are at greater risk of dementia down the road, and whether that depends on how many of these lesions are there and where in the brain they appear.

To find out, Akoudad and colleagues did a prospective analysis within the Rotterdam Study, a large ongoing project in the Netherlands that examines risk factors for cardiovascular, endocrine, ophthalmological, and neurologic diseases. The researchers included data from 4,841 cognitively healthy middle-aged and elderly people, average age 64, who had an MRI scan at baseline. Every person was followed via cognitive assessments and/or medical records. A subset of 3,257 people took a neuropsychological test battery at baseline and about six years later. It assessed changes in information processing, motor speed, executive function, and memory.

For participants who took baseline and follow-up cognitive tests, having more than four microbleeds associated with decline. That suggests the number of microbleeds, which presumably correlates with the severity of small vessel disease, is important for cognitive decline, Akoudad told Alzforum. If these lesions were in lobar regions, the decline was in information processing, memory, and executive function. Deep microbleeds predicted slowing motor speed.

During the follow-up period, 72 people were diagnosed with dementia, 53 of whom had AD. Having microbleeds in any part of the brain doubled a person’s risk of dementia, though the association weakened, then lost significance, after adjusting for ApoE4 and cardiovascular risk factors. Nevertheless, the overall data suggest that for dementia, the location of microbleeds makes no difference, said Akoudad. This, in turn, implies that any cause of small vessel disease—be it cerebral amyloid angiopathy, hypertension, or diabetes—raises the dementia risk.

The finding of higher dementia risk regardless of where the microbleeds were intrigued van der Flier. Last year, she reported that among AD patients, lesions in lobar vs. non-lobar regions associated with different outcomes, i.e., increased risk for stroke or cardiovascular events, respectively (Mar 2015 news). Van der Flier noted that the risk elevation for dementia is small in this relatively healthy population, and not significant when adjusted for related risk factors.

The result needs to be replicated before it can be considered robust, conceded Akoudad, who would also like to repeat the baseline MRI scan to see how small vessel disease progressed relative to dementia.

“The association between microbleeds and Alzheimer's disease is unexpected,” wrote Joe Verghese, Albert Einstein College of Medicine, Bronx, New York, to Alzforum. “These findings lend support to vascular causes of Alzheimer's disease.” In a cross-sectional study based in India, Verghese saw no association between microbleeds and a pre-dementia state, though he did find a correlation with lacunar infarctions, another type of cerebral small vessel disease (Wang et al., 2016). Most of these studies have been conducted in Western populations, he said, and there may be regional or ethnic differences in the types of cerebral small vessel diseases and their association with cognition.

In an accompanying editorial, Philip Gorelick and Muhammad Farooq of Michigan State University, Grand Rapids, called the study well-executed. They noted that the new data raises questions about the safety of using drugs that reduce blood clots and can increase bleeding to prevent stroke in people who have cerebral microbleeds. The current study does not examine whether such treatment affects the rate of dementia.—Gwyneth Dickey Zakaib 

Comments

  1. Whether cerebral microbleeds (CMBs) are associated with cognitive decline or not has long been debated. Akoudad et al. study the effects of number and location of CMBs on cognition in the population-based Rotterdam study. They suggest CMBs may be the missing link that bridges the vascular and amyloid hypotheses in Alzheimer’s disease.

    A thorough longitudinal neuropsychological test battery was used in the assessment of cognition, and a total of 4,841 patients were included in the analysis. Akoudad et al. found that a high CMB count (>4) is associated with cognitive decline, and that the presence of CMBs is associated with an increased risk of dementia. 

    Prior thorough studies on CMBs and cognition in general populations are scarce. Yet data so far suggest that CMBs indeed may be associated with cognitive decline. In memory clinic populations, CMBs have been shown to be associated with Aβ42 (Shams et al., 2016; Shams et al., 2016; Goos et al., 2012; Goos et al., 2009; Park et al., 2013), with more CMBs being associated with increased amyloid deposition in the brain. Further, CMBs have been shown to be associated with high age, high mortality, and a suggested decreased cognitive performance, although studies on the last point are discrepant (Goos et al., 2009; Shams et al., 2015; Pettersen et al., 2008; Chiang et al., 2015; Benedictus et al., 2015; Ye et al., 2015; van der Vlies et al., 2012; Wu et al., 2014). Cortical CMBs have also been shown to be associated with lower cerebral blood flow in cognitively normal individuals (Gregg et al., 2015). Finally, patients with subjective cognitive decline with white matter hyperintensities, another marker of small vessel disease, have been shown to be at increased risk of cognitive decline and clinical disease progression (Benedictus et al., 2015). 

    Associations with cognitive decline have likewise been seen in elderly populations. In the Rotterdam Scan Study, a prior report highlights the association between multiple CMBs and worse cognitive function (Poels et al., 2012). Multiple CMBs have been associated with a high global neuropsychiatric burden (Xu et al., 2016). In older participants, the total score of imaging small vessel disease markers has shown associations with lower general cognitive ability (Staals et al., 2015). Infratentorial CMBs have further shown an association with a loss in cognitive function (van Es et al., 2011). In the AGES-Reykjavik study it has been shown that multiple CMBs are associated with vascular cognitive impairment (Qiu et al., 2012). Lobar CMBs, and CMBs in general, have further been associated with executive function decline (Meier et al., 2014; Yamashiro et al., 2014). 

    In conclusion, many studies point to the fact that CMBs are associated with cognitive decline. This current study is among the most thorough in examining CMB burden and associations with cognition, corroborating previous data.

    References:

    . Cerebrospinal fluid profiles with increasing number of cerebral microbleeds in a continuum of cognitive impairment. J Cereb Blood Flow Metab. 2016 Mar;36(3):621-8. Epub 2015 Sep 30 PubMed.

    . Cerebral microbleeds topography and cerebrospinal fluid biomarkers in cognitive impairment. J Cereb Blood Flow Metab. 2016 May 13; PubMed.

    . Microbleeds relate to altered amyloid-β metabolism in Alzheimer's disease. Neurobiol Aging. 2012 May;33(5):1011.e1-9. Epub 2011 Nov 26 PubMed.

    . Patients with Alzheimer disease with multiple microbleeds: relation with cerebrospinal fluid biomarkers and cognition. Stroke. 2009 Nov;40(11):3455-60. PubMed.

    . Pathogenesis of cerebral microbleeds: In vivo imaging of amyloid and subcortical ischemic small vessel disease in 226 individuals with cognitive impairment. Ann Neurol. 2013 Jan 29; PubMed.

    . Cerebral microbleeds: different prevalence, topography, and risk factors depending on dementia diagnosis—the Karolinska Imaging Dementia Study. AJNR Am J Neuroradiol. 2015 Apr;36(4):661-6. Epub 2014 Dec 18 PubMed.

    . Microbleed topography, leukoaraiosis, and cognition in probable Alzheimer disease from the Sunnybrook dementia study. Arch Neurol. 2008 Jun;65(6):790-5. PubMed.

    . Cerebral Microbleeds, CSF p-Tau, and Cognitive Decline: Significance of Anatomic Distribution. AJNR Am J Neuroradiol. 2015 Sep;36(9):1635-41. Epub 2015 Jul 30 PubMed.

    . Microbleeds, Mortality, and Stroke in Alzheimer Disease: The MISTRAL Study. JAMA Neurol. 2015 May;72(5):539-45. PubMed.

    . Effects of amyloid and vascular markers on cognitive decline in subcortical vascular dementia. Neurology. 2015 Nov 10;85(19):1687-93. Epub 2015 Oct 14 PubMed.

    . Microbleeds do not affect rate of cognitive decline in Alzheimer disease. Neurology. 2012 Aug 21;79(8):763-9. Epub 2012 Aug 8 PubMed.

    . A meta-analysis of association between cerebral microbleeds and cognitive impairment. Med Sci Monit. 2014 Nov 7;20:2189-98. PubMed.

    . Incidental Cerebral Microbleeds and Cerebral Blood Flow in Elderly Individuals. JAMA Neurol. 2015 Sep;72(9):1021-8. PubMed.

    . White Matter Hyperintensities Relate to Clinical Progression in Subjective Cognitive Decline. Stroke. 2015 Sep;46(9):2661-4. Epub 2015 Jul 14 PubMed.

    . Cerebral microbleeds are associated with worse cognitive function: the Rotterdam Scan Study. Neurology. 2012 Jan 31;78(5):326-33. Epub 2012 Jan 18 PubMed.

    . Cerebral microbleeds and neuropsychiatric symptoms in an elderly Asian cohort. J Neurol Neurosurg Psychiatry. 2016 Jun 3; PubMed.

    . Total MRI load of cerebral small vessel disease and cognitive ability in older people. Neurobiol Aging. 2015 Oct;36(10):2806-11. Epub 2015 Jun 26 PubMed.

    . Cerebral microbleeds and cognitive functioning in the PROSPER study. Neurology. 2011 Oct 11;77(15):1446-52. Epub 2011 Sep 28 PubMed.

    . Cerebral microbleeds and age-related macular degeneration: the AGES-Reykjavik Study. Neurobiol Aging. 2012 Dec;33(12):2935-7. Epub 2012 Mar 3 PubMed.

    . Lobar microbleeds are associated with a decline in executive functioning in older adults. Cerebrovasc Dis. 2014;38(5):377-83. Epub 2014 Nov 25 PubMed.

    . Associations of durations of antiplatelet use and vascular risk factors with the presence of cerebral microbleeds. J Stroke Cerebrovasc Dis. 2014 Mar;23(3):433-40. Epub 2013 Apr 28 PubMed.

  2. The association between cortical microbleeds (CMB) and Alzheimer's disease is unexpected, though these findings lend support to vascular causes of Alzheimer's disease. The significance of small vessel disease findings such as CMBs on imaging studies in patients with memory complaints has been uncertain. These results suggest that clinicians need to pay attention to these types of lesions on imaging studies, as they may have treatable causes.

    In a cross-sectional study based in India, we did not find an association between CMB and Motoric Cognitive Risk syndrome, a pre-dementia state (Wang et al., 2015). We did, however, see an association between lacunar infarctions (another type of cerebral small vessel disease) in the frontal lobe and MCR syndrome. Most small vessel disease and cognition studies have been conducted in Western populations, and there may be regional or ethnic differences in the association between the types of cerebral small vessel diseases and cognition.

    References:

    . Cerebral Small Vessel Disease and Motoric Cognitive Risk Syndrome: Results from the Kerala-Einstein Study. J Alzheimers Dis. 2015;50(3):699-707. PubMed.

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References

News Citations

  1. Small Brain Bleeds Lead To Bigger Problems in Alzheimer’s

Paper Citations

  1. . Prevalence and risk factors of cerebral microbleeds: the Rotterdam Scan Study. Neurology. 2008 Apr 1;70(14):1208-14. PubMed.
  2. . Cerebral microbleeds in the population based AGES-Reykjavik study: prevalence and location. J Neurol Neurosurg Psychiatry. 2008 Sep;79(9):1002-6. Epub 2008 Feb 12 PubMed.
  3. . Cerebral microbleeds: overview and implications in cognitive impairment. Alzheimers Res Ther. 2014;6(3):33. Epub 2014 Jun 11 PubMed.
  4. . Lobar microbleeds are associated with a decline in executive functioning in older adults. Cerebrovasc Dis. 2014;38(5):377-83. Epub 2014 Nov 25 PubMed.
  5. . Cerebral microbleeds are associated with worse cognitive function: the Rotterdam Scan Study. Neurology. 2012 Jan 31;78(5):326-33. Epub 2012 Jan 18 PubMed.
  6. . Cerebral microbleeds, retinopathy, and dementia: the AGES-Reykjavik Study. Neurology. 2010 Dec 14;75(24):2221-8. PubMed.
  7. . Microbleeds do not affect rate of cognitive decline in Alzheimer disease. Neurology. 2012 Aug 21;79(8):763-9. Epub 2012 Aug 8 PubMed.
  8. . Cerebral Small Vessel Disease and Motoric Cognitive Risk Syndrome: Results from the Kerala-Einstein Study. J Alzheimers Dis. 2015;50(3):699-707. PubMed.

Further Reading

Papers

  1. . Cerebral microbleeds: a guide to detection and interpretation. Lancet Neurol. 2009 Feb;8(2):165-74. PubMed.
  2. . Vascular contributions to cognitive impairment, clinical Alzheimer's disease, and dementia in older persons. Biochim Biophys Acta. 2016 May;1862(5):878-86. Epub 2016 Jan 5 PubMed.

Primary Papers

  1. . Association of Cerebral Microbleeds With Cognitive Decline and Dementia. JAMA Neurol. 2016 Aug 1;73(8):934-43. PubMed.