Yue Liu1, Nady Braidy2, Anne Poljak3, Daniel K Y Chan4, Perminder Sachdev5. 1. Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney, Australia. 2. Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney, Australia. Electronic address: n.braidy@unsw.edu.au. 3. Mark Wainwright Analytical Centre, University of New South Wales, Sydney, Australia; School of Medical Sciences, University of New South Wales, Sydney, Australia. 4. Department of Aged Care and Rehabilitation, Bankstown Hospital, Bankstown, NSW, Australia. 5. Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney, Australia; Neuropsychiatric Institute, Euroa Centre, Prince of Wales Hospital, Sydney, Australia.
Abstract
BACKGROUND: Cerebral small vessel disease (CSVD) comprises a variety of disorders affecting small arteries and microvessels of the brain, manifesting as white matter hyperintensities (WMHs), cerebral microbleeds (CMBs), and deep brain infarcts. In addition to its contribution to vascular dementia (VaD), it has also been suggested to contribute to the pathogenesis of Alzheimer's disease (AD). METHOD: A systematic review of the literature available on Medline, Embase and Pubmed was undertaken, whereby CSVD was divided into WMHs, CMBs and deep brain infarcts. Biomarkers of AD pathology in the cerebrospinal fluid or plasma, or positron emission tomographic imaging for amyloid and/or tau deposition were used for AD pathology. RESULTS: A total of 4117 articles were identified and 41 articles met criteria for inclusion. These consisted of 17 articles on vascular risk factors for clinical AD, 21 articles on Aβ pathology and 15 articles on tau pathology, permitting ten meta-analyses. CMBs or lobar CMBs were associated with pooled relative risk (RR) of AD at 1.546, (95%CI 0.842-2.838, z = 1.41 p = 0.160) and 1.526(95%CI 0.760-3.063, z = 1.19, p = 0.235) respectively, both non-significant. Microinfarcts were associated with significantly increased AD risk, with pooled odds ratio OR at 1.203(95%CI 1.014-1.428, 2.12 p = 0.034). Aβ pathology was significantly associated with WMHs in AD patients but not in normal age-matched controls. The pooled β (linear regression) for total WMHs with CSF Aβ42 in AD patients was -0.19(95%CI -0.26-0.11, z = 4.83 p = 0.000) and the pooled r (correlation coefficient) for WMHs and PiB in the normal population was -0.10 (95%CI -0.11-0.30, 0.93 p = 0.351). CMBs were significantly associated with Aβ pathology in AD patients. The pooled standardized mean difference (SMD) was -0.453, 95%CI -0.697- -0.208, z = 3.63 p = 0.000. There was no significant relationship between the incidence of lacunes and levels of CSFAβ, with a pooled β of 0.057 (95%CI -0.050-0.163, z = 1.05 p = 0.295). No significant relationship was found between CMBs and the levels of CSFt-tau/CSFp-tau in AD patients (-0.014, 95%CI -0.556-0.529, z = 0.05 p = 0.960; -0.058, 95%CI -0.630-0.515, z = 0.20 p = 0.844) and cortical CMBs and CSF p-tau in the normal population (0.000, 95%CI -0.706-0.706, z = 0.00 p = 0.999). CONCLUSIONS: Some CSVD markers were significantly associated with clinical AD pathology and may be associated with Aβ/tau pathology. WMHs and microinfarcts were associated with increased risk of AD. It remains unclear whether they precede or follow AD pathology.
BACKGROUND:Cerebral small vessel disease (CSVD) comprises a variety of disorders affecting small arteries and microvessels of the brain, manifesting as white matter hyperintensities (WMHs), cerebral microbleeds (CMBs), and deep brain infarcts. In addition to its contribution to vascular dementia (VaD), it has also been suggested to contribute to the pathogenesis of Alzheimer's disease (AD). METHOD: A systematic review of the literature available on Medline, Embase and Pubmed was undertaken, whereby CSVD was divided into WMHs, CMBs and deep brain infarcts. Biomarkers of AD pathology in the cerebrospinal fluid or plasma, or positron emission tomographic imaging for amyloid and/or tau deposition were used for AD pathology. RESULTS: A total of 4117 articles were identified and 41 articles met criteria for inclusion. These consisted of 17 articles on vascular risk factors for clinical AD, 21 articles on Aβ pathology and 15 articles on tau pathology, permitting ten meta-analyses. CMBs or lobar CMBs were associated with pooled relative risk (RR) of AD at 1.546, (95%CI 0.842-2.838, z = 1.41 p = 0.160) and 1.526(95%CI 0.760-3.063, z = 1.19, p = 0.235) respectively, both non-significant. Microinfarcts were associated with significantly increased AD risk, with pooled odds ratio OR at 1.203(95%CI 1.014-1.428, 2.12 p = 0.034). Aβ pathology was significantly associated with WMHs in ADpatients but not in normal age-matched controls. The pooled β (linear regression) for total WMHs with CSF Aβ42 in ADpatients was -0.19(95%CI -0.26-0.11, z = 4.83 p = 0.000) and the pooled r (correlation coefficient) for WMHs and PiB in the normal population was -0.10 (95%CI -0.11-0.30, 0.93 p = 0.351). CMBs were significantly associated with Aβ pathology in ADpatients. The pooled standardized mean difference (SMD) was -0.453, 95%CI -0.697- -0.208, z = 3.63 p = 0.000. There was no significant relationship between the incidence of lacunes and levels of CSFAβ, with a pooled β of 0.057 (95%CI -0.050-0.163, z = 1.05 p = 0.295). No significant relationship was found between CMBs and the levels of CSFt-tau/CSFp-tau in ADpatients (-0.014, 95%CI -0.556-0.529, z = 0.05 p = 0.960; -0.058, 95%CI -0.630-0.515, z = 0.20 p = 0.844) and cortical CMBs and CSF p-tau in the normal population (0.000, 95%CI -0.706-0.706, z = 0.00 p = 0.999). CONCLUSIONS: Some CSVD markers were significantly associated with clinical AD pathology and may be associated with Aβ/tau pathology. WMHs and microinfarcts were associated with increased risk of AD. It remains unclear whether they precede or follow AD pathology.
Authors: Leonardo A Rivera-Rivera; Karly A Cody; Laura Eisenmenger; Paul Cary; Howard A Rowley; Cynthia M Carlsson; Sterling C Johnson; Kevin M Johnson Journal: J Cereb Blood Flow Metab Date: 2020-03-13 Impact factor: 6.200
Authors: Muzaimi Mustapha; Che Mohd Nasril Che Mohd Nassir; Niferiti Aminuddin; Amanina Ahmad Safri; Mazira Mohamad Ghazali Journal: Front Physiol Date: 2019-10-24 Impact factor: 4.566