Relationship between cortical microinfarcts and cognitive impairment in Alzheimer's disease

Damasceno, Benito P.

doi:10.1590/S1980-57642012DN06030004

ABSTRACT

Cerebrovascular disease and AD pathology co-exist in most dementia cases, and microinfarcts (MIs), particularly if cortical and multiple, play an additive and independent role in AD cognitive impairment. The main cause of cortical MIs is chronic cerebral hypoperfusion but occlusive vascular diseases, embolism and blood-brain barrier disruptions, isolated or combined, may also play a role. The precise mechanisms by which MIs cause cognitive impairment are not well known, but one plausible explanation is that they are widespread and accompanied by diffuse hypoperfusion, hypoxia, oxidative stress and inflammation, particularly in the watershed areas of the tertiary association cortex, and hence could damage cognition networks and explain many of AD's cognitive and behavioral disturbances. Therefore, it is crucial to control vascular risk factors and avoid uncontrolled use of the antihypertensives, neuroleptics and other sedative drugs frequently prescribed to AD patients.

Key words:
Alzheimer's disease; vascular cognitive impairment; dementia; microinfarcts; cerebral amyloid angiopathy; neurofunctional networks

RESUMO

Doença cerebrovascular e patologia da doença de Alzheimer (DA) coexistem na maioria dos casos de demência, nos quais os microinfartos desempenham papel relevante, aditivo e independente. A principal causa de microinfartos corticais é a hipoperfusão cerebral crônica, porém doenças vasculares oclusivas, embolismo, lesões da barreira hematoencefálica, isolados ou combinados, podem também influir. O mecanismo preciso pelo qual microinfartos comprometem a cognição não são bem conhecidos, entretanto uma explicação plausível seria que eles são extensamente distribuídos e acompanhados de hipoperfusão difusa, hipóxia, estresse oxidativo e inflamação, principalmente nas zonas de fronteiras arteriais do córtex associativo terciário, e deste modo, eles poderiam lesar as redes neurais da cognição e explicar muitos dos transtornos cognitivos e comportamentais da DA. Por isso, é crucial prevenir os fatores de risco vascular e evitar o uso exagerado de anti-hipertensivos, neurolépticos e drogas sedativas frequentemente prescritas para pacientes com DA.

Palavras-chave:
doença de Alzheimer; comprometimento cognitivo vascular; demência; microinfartos; angiopatia amilóide cerebral; redes neurofuncionais

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REFERENCES

Di Legge S, Hachinski V. Vascular cognitive impairment (VCI): progress towards knowledge and treatment. Dement Neuropsychol 2010;4:4-13.
Cechetto DF, Hachinski V, Whitehead SN. Vascular risk factors and Alzheimer's disease. Exp Rev Neurotherapeut 2008;8:743-750.
Viswanathan A, Rocca WA, Tzourio C. Vascular risk factors and dementia: How to move forward. Neurology 2009;72:368-374.
Merino JG, Hachinski V. Vascular cognitive impairment: Evolution of the concept. JINS 2009;15:924-926.
Greenberg SM, Gurol ME, Rosand J, Smith EE. Amyloid angiopathy-related vascular cognitive impairment. Stroke 2004;35:2616-2619.
Zhou A, Jia J. Different cognitive profiles between mild cognitive impairment due to cerebral small vessel disease and mild cognitive impairment of Alzheimer's disease origin. JINS 2009;15:898-905.
Delano-Wood L, Bondi MW, Sacco J, et al. Heterogeneity in mild cognitive impairment: Differences in neuropsychological profile and associated white matter lesion pathology. JINS 2009;15:906-914.
Sachdev PS, Chen X, Brodaty H, Thompson C, Altendorf A, Wen W. The determinants and longitudinal course of post-stroke mild cognitive impairment. JINS 2009;15:915-923.
Hachinski V, Iadecola C, Petersen RC, et al. National Institute of Neurological Disorders and Stroke - Canadian Stroke Network Vascular Cognitive Impairment Harmonization Standards. Stroke 2006;37:2220-2241.
Kalaria RN, Erkinjuntti T. Small vessel disease and subcortical vascular dementia. J Clin Neurol 2006;2:1-11.
Jiwa NS, Garrard P, Hainsworth AH. Experimental models of vascular dementia and vascular cognitive impairment: a systematic review. J Neurochem 2010;115:814-828.
Engelhardt E, Tocquer C, André C, et al. Vascular dementia: diagnostic criteria and supplementary exams. Recommendations of the Scientific Department of Cognitive Neurology and Aging of the Brazilian Academy of Neurology. Part I. Dement Neuropsychol 2011;5:251-263.
Kövari E, Gold G, Herrmann FR, et al. Cortical microinfarcts and demyelination affect cognition in cases at high risk for dementia. Neurology 2007;68:927-931.
Suter OC, Sunthorn T, Kraftsik R, et al. Cerebral hypoperfusion generates cortical watershed microinfarcts in Alzheimer disease. Stroke 2002;33:1986-1992.
Brundel M, de Bresser J, van Dillen JJ, Kappelle LJ, Biessels GJ. Cerebral microinfarcts: a systematic review of neuropathological studies. J Cereb Blood Flow Metab 2012;32:425-436.
Kövari E, Gold G, Herrmann FR, et al. Cortical microinfarcts and demyelination affect cognition in cases at high risk for dementia. Neurology 2007;68:927-931.
Arvanitakis Z, Leurgans SE, Barnes LL, Bennet DA, Schneider JA. Microinfarct pathology, dementia, and cognitive systems. Stroke 2011;42: 722-727.
Smith EE, Schneider JA, Wardlaw JM, Greenberg SM. Cerebral microinfarcts: the invisible lesions. Lancet Neurol 2012;11:272-282.
Jouvent E, Poupon C, Gray F, et al. Intracortical infarcts in small vessel disease: a combined 7-T postmortem MRI and neuropathological case study in cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Stroke 2011;42:e27-30.
Okamoto Y, Ihara M, Fujita Y, Ito H, Takahashi R, Tomimoto H. Cortical microinfarcts in Alzheimer's disease and subcortical vascular dementia. Neuroreport 2009;20(11):990-996.
Smith EE, Greenberg SM. b-amyloid, blood vessels, and brain function. Stroke 2009;40:2601-2606.
Okamoto Y, Yamamoto T, Kalaria RN, et al. Cerebral hypoperfusion accelerates cerebral amyloid angiopathy and promotes cortical microinfarcts. Acta Neuropathol 2012;123:381.
Van Norden AG, van den Berg HA, de Laat KF, Gons RA, van Dijk EJ, de Leeuw FE. Frontal and temporal microbleeds are related to cognitive function: the Radboud University Nijmegen Diffusion Tensor and Magnetic Resonance Cohort (RUN DMC) Study. Stroke 2011;42(12):3382-3386.
Poels MM, Ikram MA, van der Lugt A, et al. Cerebral microbleeds are associated with worse cognitive function: the Rotterdam Scan Study. Neurology 2012;78:326-333.
Miklossy J. Cerebral hypoperfusion induces cortical watershed microinfarcts which may further aggravate cognitive decline in Alzheimer's disease. Neurol Res 2003;25:605-610.
Troncoso JC, Zonderman AB, Resnick SM, Crain B, Pletnikova O, O'Brien RJ. Effect of infarcts on dementia in the Baltimore Longitudinal Study of Aging. Ann Neurol 2008;64:168-176.
Snowdon DA, Greiner LH, Mortimer JA, Riley KP, Greiner PA, Markesbery WR. Brain infarction and the clinical expression of Alzheimer's disease. The Nun Study. JAMA 1997;277:813-817.
Kövari E, Gold G, Herrmann FR, et al. Cortical microinfarcts and demyelination significantly affect cognition in brain aging. Stroke 2004;35:410-414.
Launer LJ, Hughes TM, White LR. Microinfarcts, brain atrophy, and cognitive function: the Honolulu Asia Aging Study Autopsy Study. Ann Neurol 2011;70:774-780.
Geurts JJ, Barkhof F. Grey matter pathology in multiple sclerosis. Lancet Neurol 2008;7:841-851.
Amato MP, Ponziani G, Siracusa G, Sorbi S. Cognitive dysfunction in early-onset multiple sclerosis: a reappraisal after 10 years. Arch Neurol 2001;58:1602-1606.
Luria AR. The working brain. New York: Basic Books, 1973.
Mesulam M-M. From sensation to cognition. Brain 1998;121:1013-1052.
Mesulam M-M. Representation, inference, and transcendent encoding in neurocognitive networks of the human brain. Ann Neurol 2008;64: 367-378.
Damasceno BP. Research on cognition disorder: methodological issues. In: J. P. Tsai (editor), Leading-Edge Cognitive Disorders Research. New York: Nova Science Publishers, Inc., 2008:131-154.
Damasio AR. Time-locked multiregional retroactivation: a systems-level proposal for the neural substrates of recall and recognition. Cognition 1989;33:25-62.
Buckner RL, Sepulcre J, Talukdar T, et al. Cortical hubs revealed by intrinsic functional connectivity: mapping, assessment of stability, and relation to Alzheimer's disease. J Neurosci 2009;29:1860-1873.
Seeley WW, Crawford RK, Zhou J, et al. Neurodegenerative diseases target large-scale human brain networks. Neuron 2009;62:42-52.
Greicius MD, Srivastava G, Reiss AL, Menon V. Default-mode network activity distinguishes Alzheimer's disease from healthy aging: Evidence from functional MRI. PNAS 2004; 101:4637-4642.
Zhang HY, Wang SJ, Liu B, et al. Resting brain connectivity: changes during the progress of Alzheimer's disease. Radiology 2010; 256:598-606.
Hillis AE. Aphasia: progress in the last quarter of a century. Neurology 2007;69;200-213.
Hart J, Kraut MA. Neural basis of semantic memory. Cambridge: Cambridge University Press, 2007.
White L, Petrovitch H, Hardman J, et al. Cerebrovascular pathology and dementia in autopsied Honolulu-Asia Aging Study participants. Ann N Y Acad Sci 2002;977:9-23.
Kapogiannis D, Mattson MP. Disrupted energy metabolism and neuronal circuit dysfunction in cognitive impairment and Alzheimer's disease. Lancet Neurol 2011;10:187-198.
Mesulam M-M. Principles of Behavioral and Cognitive Neurology (2nd Ed). Oxford: Oxford University Press, 2000.
Price BH, Gurvit H, Weintraub S, Geula C, Leimkuhler E, Mesulam M. Neuropsychological patterns and language déficits in 20 consecutive cases of autopsy-confirmed Alzheimer's disease. Arch Neurol 1993;50:9319937.
Hier DB, Hagenlocker K, Shindler AG. Language disintegration in dementia: effects of etiology and severity. Brain Lang 1985;25:117-133.
Cummings JL, Benson F, Hill MA, Read S. Aphasia in dementia of the Alzheimer type. Neurology 1985;35:394-397.
Benke T, Andree B, Hittmair M, Gerstenbrand F. Speech changes in dementia. Fortschr Neurol Psychiatr 1990;58:215-223.
Budson AE, Price BH. Memory dysfunction. N Engl J Med 2005;352: 692-699.
Damasio H, Tranel D, Grabowski T, Adolphs R, Damasio A. Neural systems behind word and concept retrieval. Cognition 2004;92:179-229.
Balthazar MLF, Cendes F, Damasceno BP. Semantic error patterns on the Boston Naming Test in normal aging, amnestic mild cognitive impairment, and mild Alzheimer's disease: is there semantic disruption? Neuropsychology 2008;22:703-709.

Publication Dates

Publication in this collection
Jul-Sep 2012

History

Received
10 Mar 2012
Accepted
15 May 2012

This is an open-access article distributed under the terms of the Creative Commons Attribution License

[1] Di Legge S, Hachinski V. Vascular cognitive impairment (VCI): progress towards knowledge and treatment. Dement Neuropsychol 2010;4:4-13.

[2] Cechetto DF, Hachinski V, Whitehead SN. Vascular risk factors and Alzheimer's disease. Exp Rev Neurotherapeut 2008;8:743-750.

[3] Viswanathan A, Rocca WA, Tzourio C. Vascular risk factors and dementia: How to move forward. Neurology 2009;72:368-374.

[4] Merino JG, Hachinski V. Vascular cognitive impairment: Evolution of the concept. JINS 2009;15:924-926.

[5] Greenberg SM, Gurol ME, Rosand J, Smith EE. Amyloid angiopathy-related vascular cognitive impairment. Stroke 2004;35:2616-2619.

[6] Zhou A, Jia J. Different cognitive profiles between mild cognitive impairment due to cerebral small vessel disease and mild cognitive impairment of Alzheimer's disease origin. JINS 2009;15:898-905.

[7] Delano-Wood L, Bondi MW, Sacco J, et al. Heterogeneity in mild cognitive impairment: Differences in neuropsychological profile and associated white matter lesion pathology. JINS 2009;15:906-914.

[8] Sachdev PS, Chen X, Brodaty H, Thompson C, Altendorf A, Wen W. The determinants and longitudinal course of post-stroke mild cognitive impairment. JINS 2009;15:915-923.

[9] Hachinski V, Iadecola C, Petersen RC, et al. National Institute of Neurological Disorders and Stroke - Canadian Stroke Network Vascular Cognitive Impairment Harmonization Standards. Stroke 2006;37:2220-2241.

[10] Kalaria RN, Erkinjuntti T. Small vessel disease and subcortical vascular dementia. J Clin Neurol 2006;2:1-11.

[11] Jiwa NS, Garrard P, Hainsworth AH. Experimental models of vascular dementia and vascular cognitive impairment: a systematic review. J Neurochem 2010;115:814-828.

[12] Engelhardt E, Tocquer C, André C, et al. Vascular dementia: diagnostic criteria and supplementary exams. Recommendations of the Scientific Department of Cognitive Neurology and Aging of the Brazilian Academy of Neurology. Part I. Dement Neuropsychol 2011;5:251-263.

[13] Kövari E, Gold G, Herrmann FR, et al. Cortical microinfarcts and demyelination affect cognition in cases at high risk for dementia. Neurology 2007;68:927-931.

[14] Suter OC, Sunthorn T, Kraftsik R, et al. Cerebral hypoperfusion generates cortical watershed microinfarcts in Alzheimer disease. Stroke 2002;33:1986-1992.

[15] Brundel M, de Bresser J, van Dillen JJ, Kappelle LJ, Biessels GJ. Cerebral microinfarcts: a systematic review of neuropathological studies. J Cereb Blood Flow Metab 2012;32:425-436.

[16] Kövari E, Gold G, Herrmann FR, et al. Cortical microinfarcts and demyelination affect cognition in cases at high risk for dementia. Neurology 2007;68:927-931.

[17] Arvanitakis Z, Leurgans SE, Barnes LL, Bennet DA, Schneider JA. Microinfarct pathology, dementia, and cognitive systems. Stroke 2011;42: 722-727.

[18] Smith EE, Schneider JA, Wardlaw JM, Greenberg SM. Cerebral microinfarcts: the invisible lesions. Lancet Neurol 2012;11:272-282.

[19] Jouvent E, Poupon C, Gray F, et al. Intracortical infarcts in small vessel disease: a combined 7-T postmortem MRI and neuropathological case study in cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Stroke 2011;42:e27-30.

[20] Okamoto Y, Ihara M, Fujita Y, Ito H, Takahashi R, Tomimoto H. Cortical microinfarcts in Alzheimer's disease and subcortical vascular dementia. Neuroreport 2009;20(11):990-996.

[21] Smith EE, Greenberg SM. b-amyloid, blood vessels, and brain function. Stroke 2009;40:2601-2606.

[22] Okamoto Y, Yamamoto T, Kalaria RN, et al. Cerebral hypoperfusion accelerates cerebral amyloid angiopathy and promotes cortical microinfarcts. Acta Neuropathol 2012;123:381.

[23] Van Norden AG, van den Berg HA, de Laat KF, Gons RA, van Dijk EJ, de Leeuw FE. Frontal and temporal microbleeds are related to cognitive function: the Radboud University Nijmegen Diffusion Tensor and Magnetic Resonance Cohort (RUN DMC) Study. Stroke 2011;42(12):3382-3386.

[24] Poels MM, Ikram MA, van der Lugt A, et al. Cerebral microbleeds are associated with worse cognitive function: the Rotterdam Scan Study. Neurology 2012;78:326-333.

[25] Miklossy J. Cerebral hypoperfusion induces cortical watershed microinfarcts which may further aggravate cognitive decline in Alzheimer's disease. Neurol Res 2003;25:605-610.

[26] Troncoso JC, Zonderman AB, Resnick SM, Crain B, Pletnikova O, O'Brien RJ. Effect of infarcts on dementia in the Baltimore Longitudinal Study of Aging. Ann Neurol 2008;64:168-176.

[27] Snowdon DA, Greiner LH, Mortimer JA, Riley KP, Greiner PA, Markesbery WR. Brain infarction and the clinical expression of Alzheimer's disease. The Nun Study. JAMA 1997;277:813-817.

[28] Kövari E, Gold G, Herrmann FR, et al. Cortical microinfarcts and demyelination significantly affect cognition in brain aging. Stroke 2004;35:410-414.

[29] Launer LJ, Hughes TM, White LR. Microinfarcts, brain atrophy, and cognitive function: the Honolulu Asia Aging Study Autopsy Study. Ann Neurol 2011;70:774-780.

[30] Geurts JJ, Barkhof F. Grey matter pathology in multiple sclerosis. Lancet Neurol 2008;7:841-851.

[31] Amato MP, Ponziani G, Siracusa G, Sorbi S. Cognitive dysfunction in early-onset multiple sclerosis: a reappraisal after 10 years. Arch Neurol 2001;58:1602-1606.

[32] Luria AR. The working brain. New York: Basic Books, 1973.

[33] Mesulam M-M. From sensation to cognition. Brain 1998;121:1013-1052.

[34] Mesulam M-M. Representation, inference, and transcendent encoding in neurocognitive networks of the human brain. Ann Neurol 2008;64: 367-378.

[35] Damasceno BP. Research on cognition disorder: methodological issues. In: J. P. Tsai (editor), Leading-Edge Cognitive Disorders Research. New York: Nova Science Publishers, Inc., 2008:131-154.

[36] Damasio AR. Time-locked multiregional retroactivation: a systems-level proposal for the neural substrates of recall and recognition. Cognition 1989;33:25-62.

[37] Buckner RL, Sepulcre J, Talukdar T, et al. Cortical hubs revealed by intrinsic functional connectivity: mapping, assessment of stability, and relation to Alzheimer's disease. J Neurosci 2009;29:1860-1873.

[38] Seeley WW, Crawford RK, Zhou J, et al. Neurodegenerative diseases target large-scale human brain networks. Neuron 2009;62:42-52.

[39] Greicius MD, Srivastava G, Reiss AL, Menon V. Default-mode network activity distinguishes Alzheimer's disease from healthy aging: Evidence from functional MRI. PNAS 2004; 101:4637-4642.

[40] Zhang HY, Wang SJ, Liu B, et al. Resting brain connectivity: changes during the progress of Alzheimer's disease. Radiology 2010; 256:598-606.

[41] Hillis AE. Aphasia: progress in the last quarter of a century. Neurology 2007;69;200-213.

[42] Hart J, Kraut MA. Neural basis of semantic memory. Cambridge: Cambridge University Press, 2007.

[43] White L, Petrovitch H, Hardman J, et al. Cerebrovascular pathology and dementia in autopsied Honolulu-Asia Aging Study participants. Ann N Y Acad Sci 2002;977:9-23.

[44] Kapogiannis D, Mattson MP. Disrupted energy metabolism and neuronal circuit dysfunction in cognitive impairment and Alzheimer's disease. Lancet Neurol 2011;10:187-198.

[45] Mesulam M-M. Principles of Behavioral and Cognitive Neurology (2nd Ed). Oxford: Oxford University Press, 2000.

[46] Price BH, Gurvit H, Weintraub S, Geula C, Leimkuhler E, Mesulam M. Neuropsychological patterns and language déficits in 20 consecutive cases of autopsy-confirmed Alzheimer's disease. Arch Neurol 1993;50:9319937.

[47] Hier DB, Hagenlocker K, Shindler AG. Language disintegration in dementia: effects of etiology and severity. Brain Lang 1985;25:117-133.

[48] Cummings JL, Benson F, Hill MA, Read S. Aphasia in dementia of the Alzheimer type. Neurology 1985;35:394-397.

[49] Benke T, Andree B, Hittmair M, Gerstenbrand F. Speech changes in dementia. Fortschr Neurol Psychiatr 1990;58:215-223.

[50] Budson AE, Price BH. Memory dysfunction. N Engl J Med 2005;352: 692-699.

[51] Damasio H, Tranel D, Grabowski T, Adolphs R, Damasio A. Neural systems behind word and concept retrieval. Cognition 2004;92:179-229.

[52] Balthazar MLF, Cendes F, Damasceno BP. Semantic error patterns on the Boston Naming Test in normal aging, amnestic mild cognitive impairment, and mild Alzheimer's disease: is there semantic disruption? Neuropsychology 2008;22:703-709.

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