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

Views & Reviews Dement Neuropsychol 2012 September;6(3):131-136 Relationship between cortical microinfarcts and cognitive impairment in Alzheimer’s disease Benito P. Damasceno 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. RELAÇÃO ENTRE MICROINFARTOS CORTICAIS E COMPROMETIMENTO COGNITIVO EM DOENÇA DE ALZHEIMER 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 INTRODUCTION C erebrovascular disease (CVD) is the second most common cause of cognitive impairment and dementia in the elderly, after Alzheimer’s disease. CVD can cause a broad spectrum of cognitive, mental-behavioral and functional impairment ranging from very mild forms to severe dementia, thus constituting a “vascular cognitive impairment (VCI) - vascular dementia (VaD)” spectrum. According to Di Legge & Hachinski,1 the concept of VCI refers to any cognitive impairment caused or associated with vascular risk factors, and also includes the link between CVD and Alzheimer’s disease (AD). VCI and AD have a mixed etiology and share common risk factors for cognitive impairment, such as hypertension, diabetes mellitus, atherosclerotic disease, inflammation, and atrial fibrillation,2-4 hence the possibility to prevent both diseases. As highlighted by Di Legge & Hachinski,1 cognitive impairment related to Professor of the Department of Neurology, Medical School, State University of Campinas (UNICAMP), Campinas SP, Brazil. Benito Pereira Damasceno. Rua Maria Monteiro, 1710 / Apto. 24 – 13025-152 Campinas SP – Brazil. E-mail: Disclosure: The authors report no conflicts of interest. Received March 10, 2012. Accepted in final form May 15, 2012. Damasceno BP    Cortical microinfarcts and cognitive impairment 131 ■ Dement Neuropsychol 2012 September;6(3):131-136 CVD and AD share common elements: [1] stroke may precede, trigger, co-exist, or exacerbate AD-type cognitive impairment; and [2] AD-associated cerebral amyloid angiopathy (CAA) impairs blood vessel function and can cause brain ischemia and cognitive impairment independent of stroke (see also Greenberg et al.).5 As yet there is no universally accepted diagnostic criteria for VCI, especially because the studies available have used different neuropsychological test batteries, neuroimaging criteria, and definitions of cognitive impairment.4,6-8 In order to tackle these methodological heterogeneities and pave the way for a consensus diagnosis, the National Institute of Neurological Disorders and Stroke (NINDS) and the Canadian Stroke Network (CSN) have recommended harmonization criteria concerning VCI clinical features, neuropsychology, neuroimaging, neuropathology, experimental models, genetics, biomarkers, and clinical trials.9 The most common cause of VCI is ischemia or infarct in the territories of small caliber arteries and arterioles (cerebral arteriolosclerosis or small-vessel disease), with isolated lacunar infarcts and diffuse, ischemic white matter lesions (leukoaraiosis) in periventricular and deep subcortical white matter.10,11 Other common neuropathological causes are: [1] large vessel disease with single, strategic (e.g., thalamic) or multiple, corticosubcortical infarcts (multi-infarct dementia); [2] severe hypoperfusion state, with maximal damage in hippocampal CA1 neurons, cortical watershed areas and deep white matter; [3] hereditary vasculopathy (e.g., cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, CADASIL); and [4] CAA with haemorrhage or microbleeds.11,12 Cortical microinfarcts also contribute to the cognitive decline in individuals at high risk for Alzheimer’s dementia.13 In experimental models of VCI in rodents and primates, neuropathological changes comprise microinfarcts, diffuse white matter lesions, hippocampal neuronal loss, focal ischemic lesions and micro-haemorrhages, with subsequent deficits mostly in working and reference memory, as shown in a systematic review of 107 studies by Jiwa et al.11 These models consist of brief global ischemic insults or chronic global hypoperfusion; embolic lesions; chronic hypertension; strategic or multiple ischemic lesions, and generalised vasculopathies (e.g., in transgenic mice models of CAA and CADASIL). Thus, as yet we have an incomplete understanding of the relationships between the pathophysiology and neuropsychological features of VCI and between vascular disease and Alzheimer’s neurodegenerative brain changes. In this regard, the aim of this article was to re- 132 Cortical microinfarcts and cognitive impairment     Damasceno BP view the literature focusing on the relationship between microinfarcts (MIs) and Alzheimer’s dementia, given the additive and independent role they play in AD cognitive impairment, even in the 15% of cases wi (...truncated)