Akoudad S, Wolters FJ, Viswanathan A, de Bruijn RF, van der Lugt A, Hofman A, Koudstaal PJ, Ikram MA, Vernooij MW.
Association of Cerebral Microbleeds With Cognitive Decline and Dementia.
JAMA Neurol. 2016 Aug 1;73(8):934-43.
PubMed.
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:
Shams S, Granberg T, Martola J, Li X, Shams M, Fereshtehnejad SM, Cavallin L, Aspelin P, Kristoffersen-Wiberg M, Wahlund LO.
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.
Shams S, Granberg T, Martola J, Charidimou A, Li X, Shams M, Fereshtehnejad SM, Cavallin L, Aspelin P, Wiberg-Kristoffersen M, Wahlund LO.
Cerebral microbleeds topography and cerebrospinal fluid biomarkers in cognitive impairment.
J Cereb Blood Flow Metab. 2016 May 13;
PubMed.
Goos JD, Teunissen CE, Veerhuis R, Verwey NA, Barkhof F, Blankenstein MA, Scheltens P, van der Flier WM.
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.
Goos JD, Kester MI, Barkhof F, Klein M, Blankenstein MA, Scheltens P, van der Flier WM.
Patients with Alzheimer disease with multiple microbleeds: relation with cerebrospinal fluid biomarkers and cognition.
Stroke. 2009 Nov;40(11):3455-60.
PubMed.
Park JH, Seo SW, Kim C, Kim GH, Noh HJ, Kim ST, Kwak KC, Yoon U, Lee JM, Lee JW, Shin JS, Kim CH, Noh Y, Cho H, Kim HJ, Yoon CW, Oh SJ, Kim JS, Choe YS, Lee KH, Lee JH, Ewers M, Weiner MW, Werring DJ, Na DL.
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.
Shams S, Martola J, Granberg T, Li X, Shams M, Fereshtehnejad SM, Cavallin L, Aspelin P, Kristoffersen-Wiberg M, Wahlund LO.
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.
Pettersen JA, Sathiyamoorthy G, Gao FQ, Szilagyi G, Nadkarni NK, St George-Hyslop P, Rogaeva E, Black SE.
Microbleed topography, leukoaraiosis, and cognition in probable Alzheimer disease from the Sunnybrook dementia study.
Arch Neurol. 2008 Jun;65(6):790-5.
PubMed.
Chiang GC, Cruz Hernandez JC, Kantarci K, Jack CR Jr, Weiner MW, Alzheimer's Disease Neuroimaging Initiative.
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.
Benedictus MR, Prins ND, Goos JD, Scheltens P, Barkhof F, van der Flier WM.
Microbleeds, Mortality, and Stroke in Alzheimer Disease: The MISTRAL Study.
JAMA Neurol. 2015 May;72(5):539-45.
PubMed.
Ye BS, Seo SW, Kim JH, Kim GH, Cho H, Noh Y, Kim HJ, Yoon CW, Woo SY, Kim SH, Park HK, Kim ST, Choe YS, Lee KH, Kim JS, Oh SJ, Kim C, Weiner M, Lee JH, Na DL.
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.
van der Vlies AE, Goos JD, Barkhof F, Scheltens P, van der Flier WM.
Microbleeds do not affect rate of cognitive decline in Alzheimer disease.
Neurology. 2012 Aug 21;79(8):763-9. Epub 2012 Aug 8
PubMed.
Wu R, Feng C, Zhao Y, Jin AP, Fang M, Liu X.
A meta-analysis of association between cerebral microbleeds and cognitive impairment.
Med Sci Monit. 2014 Nov 7;20:2189-98.
PubMed.
Gregg NM, Kim AE, Gurol ME, Lopez OL, Aizenstein HJ, Price JC, Mathis CA, James JA, Snitz BE, Cohen AD, Kamboh MI, Minhas D, Weissfeld LA, Tamburo EL, Klunk WE.
Incidental Cerebral Microbleeds and Cerebral Blood Flow in Elderly Individuals.
JAMA Neurol. 2015 Sep;72(9):1021-8.
PubMed.
Benedictus MR, van Harten AC, Leeuwis AE, Koene T, Scheltens P, Barkhof F, Prins ND, van der Flier WM.
White Matter Hyperintensities Relate to Clinical Progression in Subjective Cognitive Decline.
Stroke. 2015 Sep;46(9):2661-4. Epub 2015 Jul 14
PubMed.
Poels MM, Ikram MA, van der Lugt A, Hofman A, Niessen WJ, Krestin GP, Breteler MM, Vernooij MW.
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.
Xu X, Chan QL, Hilal S, Goh WK, Ikram MK, Wong TY, Cheng CY, Chen CL, Venketasubramanian N.
Cerebral microbleeds and neuropsychiatric symptoms in an elderly Asian cohort.
J Neurol Neurosurg Psychiatry. 2016 Jun 3;
PubMed.
Staals J, Booth T, Morris Z, Bastin ME, Gow AJ, Corley J, Redmond P, Starr JM, Deary IJ, Wardlaw JM.
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.
van Es AC, van der Grond J, de Craen AJ, Westendorp RG, Bollen EL, Blauw GJ, Greenberg SM, van Buchem MA, PROSPER Study Group.
Cerebral microbleeds and cognitive functioning in the PROSPER study.
Neurology. 2011 Oct 11;77(15):1446-52. Epub 2011 Sep 28
PubMed.
Qiu C, Cotch MF, Sigurdsson S, Eiriksdottir G, Jonasson F, Klein R, Klein BE, Harris TB, van Buchem MA, Gudnason V, Launer LJ.
Cerebral microbleeds and age-related macular degeneration: the AGES-Reykjavik Study.
Neurobiol Aging. 2012 Dec;33(12):2935-7. Epub 2012 Mar 3
PubMed.
Meier IB, Gu Y, Guzaman VA, Wiegman AF, Schupf N, Manly JJ, Luchsinger JA, Viswanathan A, Martinez-Ramirez S, Greenberg SM, Mayeux R, Brickman AM.
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.
Yamashiro K, Tanaka R, Okuma Y, Ueno Y, Tanaka Y, Hattori N, Urabe T.
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.
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:
Wang N, Allali G, Kesavadas C, Noone ML, Pradeep VG, Blumen HM, Verghese J.
Cerebral Small Vessel Disease and Motoric Cognitive Risk Syndrome: Results from the Kerala-Einstein Study.
J Alzheimers Dis. 2015;50(3):699-707.
PubMed.
Comments
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:
Shams S, Granberg T, Martola J, Li X, Shams M, Fereshtehnejad SM, Cavallin L, Aspelin P, Kristoffersen-Wiberg M, Wahlund LO. 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.
Shams S, Granberg T, Martola J, Charidimou A, Li X, Shams M, Fereshtehnejad SM, Cavallin L, Aspelin P, Wiberg-Kristoffersen M, Wahlund LO. Cerebral microbleeds topography and cerebrospinal fluid biomarkers in cognitive impairment. J Cereb Blood Flow Metab. 2016 May 13; PubMed.
Goos JD, Teunissen CE, Veerhuis R, Verwey NA, Barkhof F, Blankenstein MA, Scheltens P, van der Flier WM. 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.
Goos JD, Kester MI, Barkhof F, Klein M, Blankenstein MA, Scheltens P, van der Flier WM. Patients with Alzheimer disease with multiple microbleeds: relation with cerebrospinal fluid biomarkers and cognition. Stroke. 2009 Nov;40(11):3455-60. PubMed.
Park JH, Seo SW, Kim C, Kim GH, Noh HJ, Kim ST, Kwak KC, Yoon U, Lee JM, Lee JW, Shin JS, Kim CH, Noh Y, Cho H, Kim HJ, Yoon CW, Oh SJ, Kim JS, Choe YS, Lee KH, Lee JH, Ewers M, Weiner MW, Werring DJ, Na DL. 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.
Shams S, Martola J, Granberg T, Li X, Shams M, Fereshtehnejad SM, Cavallin L, Aspelin P, Kristoffersen-Wiberg M, Wahlund LO. 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.
Pettersen JA, Sathiyamoorthy G, Gao FQ, Szilagyi G, Nadkarni NK, St George-Hyslop P, Rogaeva E, Black SE. Microbleed topography, leukoaraiosis, and cognition in probable Alzheimer disease from the Sunnybrook dementia study. Arch Neurol. 2008 Jun;65(6):790-5. PubMed.
Chiang GC, Cruz Hernandez JC, Kantarci K, Jack CR Jr, Weiner MW, Alzheimer's Disease Neuroimaging Initiative. 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.
Benedictus MR, Prins ND, Goos JD, Scheltens P, Barkhof F, van der Flier WM. Microbleeds, Mortality, and Stroke in Alzheimer Disease: The MISTRAL Study. JAMA Neurol. 2015 May;72(5):539-45. PubMed.
Ye BS, Seo SW, Kim JH, Kim GH, Cho H, Noh Y, Kim HJ, Yoon CW, Woo SY, Kim SH, Park HK, Kim ST, Choe YS, Lee KH, Kim JS, Oh SJ, Kim C, Weiner M, Lee JH, Na DL. 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.
van der Vlies AE, Goos JD, Barkhof F, Scheltens P, van der Flier WM. Microbleeds do not affect rate of cognitive decline in Alzheimer disease. Neurology. 2012 Aug 21;79(8):763-9. Epub 2012 Aug 8 PubMed.
Wu R, Feng C, Zhao Y, Jin AP, Fang M, Liu X. A meta-analysis of association between cerebral microbleeds and cognitive impairment. Med Sci Monit. 2014 Nov 7;20:2189-98. PubMed.
Gregg NM, Kim AE, Gurol ME, Lopez OL, Aizenstein HJ, Price JC, Mathis CA, James JA, Snitz BE, Cohen AD, Kamboh MI, Minhas D, Weissfeld LA, Tamburo EL, Klunk WE. Incidental Cerebral Microbleeds and Cerebral Blood Flow in Elderly Individuals. JAMA Neurol. 2015 Sep;72(9):1021-8. PubMed.
Benedictus MR, van Harten AC, Leeuwis AE, Koene T, Scheltens P, Barkhof F, Prins ND, van der Flier WM. White Matter Hyperintensities Relate to Clinical Progression in Subjective Cognitive Decline. Stroke. 2015 Sep;46(9):2661-4. Epub 2015 Jul 14 PubMed.
Poels MM, Ikram MA, van der Lugt A, Hofman A, Niessen WJ, Krestin GP, Breteler MM, Vernooij MW. 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.
Xu X, Chan QL, Hilal S, Goh WK, Ikram MK, Wong TY, Cheng CY, Chen CL, Venketasubramanian N. Cerebral microbleeds and neuropsychiatric symptoms in an elderly Asian cohort. J Neurol Neurosurg Psychiatry. 2016 Jun 3; PubMed.
Staals J, Booth T, Morris Z, Bastin ME, Gow AJ, Corley J, Redmond P, Starr JM, Deary IJ, Wardlaw JM. 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.
van Es AC, van der Grond J, de Craen AJ, Westendorp RG, Bollen EL, Blauw GJ, Greenberg SM, van Buchem MA, PROSPER Study Group. Cerebral microbleeds and cognitive functioning in the PROSPER study. Neurology. 2011 Oct 11;77(15):1446-52. Epub 2011 Sep 28 PubMed.
Qiu C, Cotch MF, Sigurdsson S, Eiriksdottir G, Jonasson F, Klein R, Klein BE, Harris TB, van Buchem MA, Gudnason V, Launer LJ. Cerebral microbleeds and age-related macular degeneration: the AGES-Reykjavik Study. Neurobiol Aging. 2012 Dec;33(12):2935-7. Epub 2012 Mar 3 PubMed.
Meier IB, Gu Y, Guzaman VA, Wiegman AF, Schupf N, Manly JJ, Luchsinger JA, Viswanathan A, Martinez-Ramirez S, Greenberg SM, Mayeux R, Brickman AM. 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.
Yamashiro K, Tanaka R, Okuma Y, Ueno Y, Tanaka Y, Hattori N, Urabe T. 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.
View all comments by Sara ShamsAlbert Einstein College of Medicine
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:
Wang N, Allali G, Kesavadas C, Noone ML, Pradeep VG, Blumen HM, Verghese J. Cerebral Small Vessel Disease and Motoric Cognitive Risk Syndrome: Results from the Kerala-Einstein Study. J Alzheimers Dis. 2015;50(3):699-707. PubMed.
View all comments by Joe VergheseMake a Comment
To make a comment you must login or register.