The role of n-3 PUFA in the prevention and treatment de la vascular dementia
Vascular dementia is an entity commonly observed in clinical situations, in particular after stroke. It often appears in elderly patients and represents a major cause of functional loss and institutionalisation. It is an entity with heterogeneous clinical expressions due to a multifactor pathogenic-structural substrate which include cognitive-behavioural impairment, which can be caused by various ischaemic and/or haemorrhagic lesions. The typical example is dementia produced by a series of infarctions due to the occlusion of large calibre vessels (classic multi-infarct dementia) or small vessel disease with multiple lacunar infarcts (lacunar state) and chronic ischaemic white matter.
Thus, dementia can be the result of a single infarction (or haemorrhage) that damages a cortical or subcortical area of the brain that is strategically important for cognitive functions (e.g. the angular gyrus of the dominant hemisphere, the anterior thalamus). Cerebral microinfarcts, which are highly prevalent among the elderly, have secondary effects on the development of geriatric neurological disorders, including vascular dementia and Alzheimer’s disease. A cerebral microinfarct is defined as a microscopic vascular occlusion (<1 mm in size). In post-mortem studies and using neuroimaging techniques, cerebral microinfarcts are frequently detected in the brains of patients with mild cognitive impairment, vascular dementia, Alzheimer’s disease and depression. Although the pathogenesis of cerebral microinfarcts has not been clearly established, neuroinflammation, oxidative stress and apoptosis have been proposed as the main precipitating factors; but little is known about the physiopathological mechanisms underlying the course of microinfarcts and their causal effects in neuropsychiatric manifestations.
In recent decades, numerous epidemiological and clinical studies have shown that increased ingestion of omega-3 polyunsaturated fatty acids (n-3 PUFAs), particularly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), is related to lower risk of cognitive disorders or has a therapeutic effect on them. Furthermore, the increase in n-3 PUFA consumption has significantly improved histological, neurological and behavioural results in focal cerebral ischaemia stroke models, by modulating the inflammatory, antioxidative, neurotrophic and anti-apoptotic responses.
An experimental study was carried out (with the collaboration of various Chinese institutions) to ascertain whether n-3 PUFA can attenuate microinfarcts and improve the associated cognitive damage. It used a ‘single cortical microinfarct model’ and a ‘multiple diffuse microinfarct model’ in Fat-1 transgenic mice (with a Fat1 gene that converts n-6 PUFA into n-3 PUFA, leading to an abundance of n-3 PUFA and a high n-3 PUFA/n-6 PUFA ratio in tissues). In the former model, a penetrating arteriole was occluded by laser ablation and in the latter cholesterol crystals were injected into the internal carotid artery.
In the ‘single cortical microinfarct model’, the intervention produced a cortical microinfarct, which presented with neuronal loss and activated glial cell occupation of the ischaemic nucleus. Both endogenous n-3 PUFAs and exogenous n-3 PUFAs administered in diet significantly inhibited activation of receptor-interacting serin/threonine protein kinase-1 and the apoptosis-related proteins produced by this pathway, mitigated cellular apoptosis and, anatomically, reduced the size of the microinfarct.
In the ‘diffuse multiple microinfarct model’, the n-3 PUFAs significantly reduced cellular apoptosis and the volume of the damaged area, and improved functional deficiencies (they reduced spontaneous anxiety, increased curiosity in new objects and improved ‘hippocampus-based’ learning and short-term memory).
These results show that increasing n-3 PUFA levels in the brain is effective in reducing the consequences of microinfarcts and improving functional deficiencies, thus supporting the use of n-3 PUFA in the prevention and treatment of geriatric neurological disorders, including vascular dementia.
Luo C, Ren H, Yao X, Shi Z, Liang F, Kang JX, et al. Enriched Brain Omega-3 Polyunsaturated Fatty Acids Confer Neuroprotection against Microinfarction. EBioMedicine. 2018 Jun 4. [Epub ahead of print] https://www.ebiomedicine.com/article/S2352-3964(18)30193-2/fulltext
Rodríguez García PL, Rodríguez García D. Diagnóstico del deterioro cognitivo vascular y sus principales categorías. Neurología. 2015;30(4):223-39. http://www.elsevier.es/es-revista-neurologia-295-articulo-diagnostico-del-deterioro-cognitivo-vascular-S0213485312000151