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Current Alzheimer Research


ISSN (Print): 1567-2050
ISSN (Online): 1875-5828

Research Article

Cerebral Microbleeds and White Matter Hyperintensities are Associated with Cognitive Decline in an Asian Memory Clinic Study

Author(s): Bibek Gyanwali, Benedict Lui, Chuen S. Tan, Eddie J.Y. Chong, Henri Vrooman, Christopher Chen and Saima Hilal*

Volume 18 , Issue 5 , 2021

Published on: 20 August, 2021

Page: [399 - 413] Pages: 15

DOI: 10.2174/1567205018666210820125543

Price: $65


Background: Cerebral Small Vessel Disease (SVD); lacunes, Cerebral Microbleeds (CMBs), and White Matter Hyperintensities (WMH) have a vital role in cognitive impairment and dementia. SVD in lobar location is related to cerebral amyloid angiopathy, whereas SVD in a deep location with hypertensive arteriopathy. It remains unclear how different locations of SVD affect long-term cognitive decline. The present study aimed to analyse the association between different locations and severity of SVD with global and domain-specific cognitive decline over the follow-up interval of 3 years.

Methods: We studied 428 participants who had performed MRI scans at baseline and at least 3 neuropsychological assessments. Locations of lacunes and CMBs were categorized into strictly lobar, strictly deep and mixed-location, WMH volume into anterior and posterior. The National Institute of Neurological Disorders and Stroke-Canadian Stroke Network Harmonization Neuropsychological Battery was used to assess cognitive function. To analyse the association between baseline location and severity of SVD with cognitive decline, linear regression models with generalized estimated equations were constructed to calculate the mean difference, 95% confidence interval and two-way interaction factor between time and SVD.

Results: Increased numbers of baseline CMBs were associated with a decline in global cognition as well as a decline in executive function and memory domains. Location-specific analysis showed similar results with strictly lobar CMBs. There was no association with strictly deep and mixed-location CMBs with cognitive decline. Baseline WMH volume was associated with a decline in global cognition, executive function and memory. Similar results were obtained with anterior and posterior WMH volumes. Lacunes and their locations were not associated with cognitive decline.

Conclusion: Strictly lobar CMBs, as well as WMH volume in anterior and posterior regions, were associated with cognitive decline. Future research focuses are warranted to evaluate interventions that may prevent cognitive decline related to SVD.

Keywords: Cerebral small vessel disease, cognitive decline, memory clinic, mixed-location, strictly lobar, strictly deep.

Pantoni L, Poggesi A, Inzitari D. Cognitive decline and dementia related to cerebrovascular diseases: some evidence and concepts. Cerebrovasc Dis 2009; 27(1): 191-6.
[] [PMID: 19342851]
Charidimou A, Pantoni L, Love S. The concept of sporadic cerebral small vessel disease: A road map on key definitions and current concepts. Int J Stroke 2016; 11(1): 6-18.
[] [PMID: 26763016]
Charidimou A, Boulouis G, Pasi M, et al. MRI-visible perivascular spaces in cerebral amyloid angiopathy and hypertensive arteriopathy. Neurology 2017; 88: 1157-64.
[] [PMID: 28228568]
Pasi M, Boulouis G, Fotiadis P, et al. Distribution of lacunes in cerebral amyloid angiopathy and hypertensive small vessel disease. Neurology 2017; 88(23): 2162-8.
[] [PMID: 28476760]
Charidimou A, Boulouis G, Haley K, et al. White matter hyperintensity patterns in cerebral amyloid angiopathy and hypertensive arteriopathy. Neurology 2016; 86(6): 505-11.
[] [PMID: 26747886]
Pantoni L. Cerebral small vessel disease: From pathogenesis and clinical characteristics to therapeutic challenges. Lancet Neurol 2010; 9: 689-701.
[] [PMID: 20610345]
de Laat KF, Tuladhar AM, van Norden AG, Norris DG, Zwiers MP, de Leeuw FE. Loss of white matter integrity is associated with gait disorders in cerebral small vessel disease. Brain 2011; 134: 73-83.
[] [PMID: 21156660]
Mataró M, Soriano-Raya JJ, López-Olóriz J, Miralbell J, Dacosta-Aguayo R. Cerebrovascular markers in lowered cognitive function. J Alzheimers Dis 2014; 42(Suppl. 4): S383-91.
[] [PMID: 25190627]
Li ZC, Wang Y, Zhao X, et al. Risk factors of cerebral microbleeds in strictly deep or lobar brain regions differed. J Stroke Cerebrovasc Dis 2015; 24: 24-30.
Charidimou A, Werring DJ. Cerebral microbleeds and cognition in cerebrovascular disease: An update. J Neurol Sci 2012; 322(1-2): 50-5.
[] [PMID: 22717258]
Pasi M, Charidimou A, Boulouis G, et al. Mixed-location cerebral hemorrhage/microbleeds: Underlying microangiopathy and recurrence risk. Neurology 2018; 90(2): e119-26.
[] [PMID: 29247070]
Debette S, Markus HS. The clinical importance of white matter hyperintensities on brain magnetic resonance imaging: systematic review and meta-analysis. BMJ 2010; 341: c3666.
[] [PMID: 20660506]
Smith EE, Egorova S, Blacker D, et al. Magnetic resonance imaging white matter hyperintensities and brain volume in the prediction of mild cognitive impairment and dementia. Arch Neurol 2008; 65(1): 94-100.
[] [PMID: 18195145]
Dufouil C, Godin O, Chalmers J, et al. Severe cerebral white matter hyperintensities predict severe cognitive decline in patients with cerebrovascular disease history. Stroke 2009; 40(6): 2219-21.
[] [PMID: 19390070]
Prins ND, van Dijk EJ, den Heijer T, et al. Cerebral small-vessel disease and decline in information processing speed, executive function and memory. Brain 2005; 128: 2034-41.
[] [PMID: 15947059]
Debette S, Bombois S, Bruandet A, et al. Subcortical hyperintensities are associated with cognitive decline in patients with mild cognitive impairment. Stroke 2007; 38: 2924-30.
[] [PMID: 17885256]
Jokinen H, Kalska H, Ylikoski R, et al. Longitudinal cognitive decline in subcortical ischemic vascular disease--the LADIS Study. Cerebrovasc Dis 2009; 27(4): 384-91.
[] [PMID: 19276621]
Meier IB, Gu Y, Guzaman VA, et al. Lobar microbleeds are associated with a decline in executive functioning in older adults. Cerebrovasc Dis 2014; 38(5): 377-83.
[] [PMID: 25427958]
Akoudad S, Wolters FJ, Viswanathan A, et al. Association of cerebral microbleeds with cognitive decline and dementia. JAMA Neurol 2016; 73(8): 934-43.
[] [PMID: 27271785]
Xu X, Chan QL, Hilal S, et al. The diagnostic utility of the NINDS-CSN neuropsychological battery in memory clinics. Dement Geriatr Cogn Disord Extra 2016; 6(2): 276-82.
[] [PMID: 27504116]
McKhann GM, Knopman DS, Chertkow H, et al. The diagnosis of dementia due to Alzheimer’s disease: Recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 2011; 7(3): 263-9.
[] [PMID: 21514250]
Román GC, Tatemichi TK, Erkinjuntti T, et al. Vascular dementia: diagnostic criteria for research studies. Report of the NINDS-AIREN International Workshop. Neurology 1993; 43(2): 250-60.
[] [PMID: 8094895]
Chen C, Homma A, Mok VC, et al. Alzheimer’s disease with cerebrovascular disease: current status in the Asia-Pacific region. J Intern Med 2016; 280(4): 359-74.
[] [PMID: 26992016]
Wardlaw JM, Smith EE, Biessels GJ, et al. Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration. Lancet Neurol 2013; 12(8): 822-38.
[] [PMID: 23867200]
Gregoire SM, Chaudhary UJ, Brown MM, et al. The Microbleed Anatomical Rating Scale (MARS): reliability of a tool to map brain microbleeds. Neurology 2009; 73(21): 1759-66.
[] [PMID: 19933977]
Wilson D, Ambler G, Lee KJ, et al. Cerebral microbleeds and stroke risk after ischaemic stroke or transient ischaemic attack: a pooled analysis of individual patient data from cohort studies. Lancet Neurol 2019; 18(7): 653-65.
[] [PMID: 31130428]
Gyanwali B, Shaik MA, Tan CS, et al. Mixed-location cerebral microbleeds as a biomarker of neurodegeneration in a memory clinic population. Aging (Albany NY) 2019; 11(22): 10581-96.
[] [PMID: 31767809]
Gyanwali B, Vrooman H, Venketasubramanian N, et al. Cerebral small vessel disease and enlarged perivascular spaces-data from memory clinic and population-based settings. Front Neurol 2019; 10: 669.
[] [PMID: 31293506]
Vrooman HA, Cocosco CA, van der Lijn F, et al. Multi-spectral brain tissue segmentation using automatically trained k-Nearest-Neighbor classification. Neuroimage 2007; 37(1): 71-81.
[] [PMID: 17572111]
de Boer R, Vrooman HA, van der Lijn F, et al. White matter lesion extension to automatic brain tissue segmentation on MRI. Neuroimage 2009; 45(4): 1151-61.
[] [PMID: 19344687]
Polvikoski TM, van Straaten ECW, Barkhof F, et al. Frontal lobe white matter hyperintensities and neurofibrillary pathology in the oldest old. Neurology 2010; 75(23): 2071-8.
[] [PMID: 21048201]
Zhu YC, Chabriat H, Godin O, et al. Distribution of white matter hyperintensity in cerebral hemorrhage and healthy aging. J Neurol 2012; 259(3): 530-6.
[] [PMID: 21877206]
Marquine MJ, Attix DK, Goldstein LB, et al. Differential patterns of cognitive decline in anterior and posterior white matter hyperintensity progression. Stroke 2010; 41(9): 1946-50.
[] [PMID: 20651266]
Hilal S, Saini M, Tan CS, et al. Intracranial stenosis, cerebrovascular diseases, and cognitive impairment in chinese. Alzheimer Dis Assoc Disord 2015; 29(1): 12-7.
[] [PMID: pub-id-type="pmid">24731981]
Gouw AA, van der Flier WM, Fazekas F, et al. Progression of white matter hyperintensities and incidence of new lacunes over a 3-year period: the Leukoaraiosis and Disability study. Stroke 2008; 39(5): 1414-20.
[] [PMID: 18323505]
Gyanwali B, Shaik MA, Tan BY, Venketasubramanian N, Chen C, Hilal S. Risk factors for and clinical relevance of incident and progression of cerebral small vessel disease markers in an Asian memory clinic population. J Alzheimers Dis 2019; 67(4): 1209-19.
[] [PMID: 30714960]
Schmidt R, Seiler S, Loitfelder M. Longitudinal change of small-vessel disease-related brain abnormalities. J Cereb Blood Flow Metab 2016; 36(1): 26-39.
[] [PMID: 25899293]
Chung CP, Chou KH, Chen WT, et al. Strictly lobar cerebral microbleeds are associated with cognitive impairment. Stroke 2016; 47(10): 2497-502.
[] [PMID: 27625380]
van Dijk EJ, Prins ND, Vrooman HA, Hofman A, Koudstaal PJ, Breteler MM. Progression of cerebral small vessel disease in relation to risk factors and cognitive consequences: Rotterdam Scan study. Stroke 2008; 39(10): 2712-9.
[] [PMID: 18635849]
Jokinen H, Gouw AA, Madureira S, et al. Incident lacunes influence cognitive decline: the LADIS study. Neurology 2011; 76(22): 1872-8.
[] [PMID: 21543730]
Liem MK, Lesnik Oberstein SA, Haan J, et al. MRI correlates of cognitive decline in CADASIL: A 7-year follow-up study. Neurology 2009; 72(2): 143-8.
[] [PMID: 19139365]
Nyenhuis DL, Gorelick PB, Geenen EJ, et al. The pattern of neuropsychological deficits in Vascular Cognitive Impairment-No Dementia (Vascular CIND). Clin Neuropsychol 2004; 18(1): 41-9.
[] [PMID: 15595357]
Martinez-Ramirez S, Greenberg SM, Viswanathan A. Cerebral microbleeds: overview and implications in cognitive impairment. Alzheimers Res Ther 2014; 6(3): 33-.
[] [PMID: 24987468]
Cianchetti FA, Kim DH, Dimiduk S, Nishimura N, Schaffer CB. Stimulus-evoked calcium transients in somatosensory cortex are temporarily inhibited by a nearby microhemorrhage. PLoS One 2013; 8(5)e65663
[] [PMID: 23724147]
Heringa SM, Reijmer YD, Leemans A, Koek HL, Kappelle LJ, Biessels GJ. Multiple microbleeds are related to cerebral network disruptions in patients with early Alzheimer’s disease. J Alzheimers Dis 2014; 38(1): 211-21.
[] [PMID: 23948936]
Akoudad S, de Groot M, Koudstaal PJ, et al. Cerebral microbleeds are related to loss of white matter structural integrity. Neurology 2013; 81(22): 1930-7.
[] [PMID: 24174590]
Bonelli RM, Cummings JL. Frontal-subcortical circuitry and behavior. Dialogues Clin Neurosci 2007; 9(2): 141-51.
[] [PMID: 17726913]
Gregoire SM, Smith K, Jäger HR, et al. Cerebral microbleeds and long-term cognitive outcome: longitudinal cohort study of stroke clinic patients. Cerebrovasc Dis 2012; 33(5): 430-5.
[] [PMID: 22456577]
Ding J, Sigurðsson S, Jónsson PV, et al. Space and location of cerebral microbleeds, cognitive decline, and dementia in the community. Neurology 2017; 88(22): 2089-97.
[] [PMID: 28468844]
Smith EE. Cerebral amyloid angiopathy as a cause of neurodegeneration. J Neurochem 2018; 144(5): 651-8.
[] [PMID: 28833176]
Chen YK, Qu JF, Xiao WM, et al. Intracranial atherosclerosis and poststroke depression in chinese patients with ischemic stroke. J Stroke Cerebrovasc Dis 2016; 25(4): 998-1004.
[] [PMID: 26851972]
Puzo C, Labriola C, Sugarman MA, et al. Independent effects of white matter hyperintensities on cognitive, neuropsychiatric, and functional decline: A longitudinal investigation using the National Alzheimer’s Coordinating Center Uniform Data Set. Alzheimers Res Ther 2019; 11(1): 64.
[] [PMID: 31351489]
Akoudad S, Ikram MA, Koudstaal PJ, et al. Cerebral microbleeds are associated with the progression of ischemic vascular lesions. Cerebrovasc Dis 2014; 37(5): 382-8.
[] [PMID: 24970709]
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; 79(8): 763-9.
[] [PMID: 22875093]
Benjamin P, Trippier S, Lawrence AJ, et al. Lacunar infarcts, but not perivascular spaces, are predictors of cognitive decline in cerebral small-vessel disease. Stroke 2018; 49(3): 586-93.
[] [PMID: 29438074]
van Dijk EJ, Prins ND, Vermeer SE, et al. C-reactive protein and cerebral small-vessel disease: The Rotterdam Scan Study. Circulation 2005; 112(6): 900-5.
[] [PMID: 16061741]
Shoamanesh A, Preis SR, Beiser AS, et al. Inflammatory biomarkers, cerebral microbleeds, and small vessel disease: Framingham Heart Study. Neurology 2015; 84(8): 825-32.
[] [PMID: 25632086]
Mortamais M, Artero S, Ritchie K. Cerebral white matter hyperintensities in the prediction of cognitive decline and incident dementia. Int Rev Psychiatry 2013; 25(6): 686-98.
[] [PMID: 24423222]
Rosano C, Kuller LH, Chung H, Arnold AM, Longstreth WT Jr, Newman AB. Subclinical brain magnetic resonance imaging abnormalities predict physical functional decline in high-functioning older adults. J Am Geriatr Soc 2005; 53(4): 649-54.
[] [PMID: 15817012]
Román GC, Kalaria RN. Vascular determinants of cholinergic deficits in Alzheimer disease and vascular dementia. Neurobiol Aging 2006; 27(12): 1769-85.
[] [PMID: 16300856]
Lin J, Wang D, Lan L, Fan Y. Multiple Factors Involved in the Pathogenesis of White Matter Lesions. BioMed Res Int 2017; 2017: 9372050-0.
[] [PMID: 28316994]
Williamson JB, Nyenhuis DL, Pedelty L, et al. Baseline differences between vascular cognitive impairment no dementia reverters and non-reverters. J Neurol Neurosurg Psychiatry 2008; 79(11): 1208-14.
[] [PMID: 18477711]

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