V. C. Hachinski, P. Potter, and H. Merskey, Leuko-araiosis: an ancient term for a new problem, Can J Neurol Sci, vol.13, pp.533-537, 1986.

J. M. Wardlaw, E. E. Smith, G. J. Biessels, C. Cordonnier, F. Fazekas et al., Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration, Lancet Neurol, vol.12, pp.822-860, 2013.

L. Pantoni and J. H. Garcia, Pathogenesis of leukoaraiosis: a review, Stroke, vol.28, pp.652-661, 1997.

F. Moroni, E. Ammirati, M. A. Rocca, M. Filippi, M. Magnoni et al., Cardiovascular disease and brain health: focus on white matter hyper-intensities, Int J Cardiol Heart Vasc, vol.19, pp.63-72, 2018.

A. Viswanathan and S. M. Greenberg, Cerebral amyloid angiopathy in the elderly, Ann Neurol, vol.70, pp.871-80, 2011.

J. M. Wardlaw, C. Smith, and M. Dichgans, Mechanisms of sporadic cerebral small vessel disease: insights from neuroimaging, Lancet Neurol, vol.12, pp.483-97, 2013.

A. Low, E. Mak, J. B. Rowe, H. S. Markus, O. 'brien et al., Inflammation and cerebral small vessel disease: a systematic review, Ageing Res Rev, vol.53, p.100916, 2019.

K. E. Mcaleese, L. Walker, S. Graham, E. Moya, M. Johnson et al., Parietal white matter lesions in Alzheimer's disease are associated with cortical neurodegenerative pathology, but not with small vessel disease, Acta Neuropathol, vol.134, pp.459-73, 2017.

N. D. Prins and P. Scheltens, White matter hyper-intensities, cognitive impairment and dementia: an update, Nat Rev Neurol, vol.11, pp.157-65, 2015.

F. Fazekas, J. B. Chawluk, A. Alavi, H. I. Hurtig, and R. A. Zimmerman, MR signal abnormalities at 1.5T in Alzheimer's dementia and normal aging, AJR Am J Roentgenol, vol.149, pp.351-357, 1987.

M. E. Caligiuri, P. Perrotta, A. Augimeri, F. Rocca, A. Quattrone et al., Automatic detection of white matter hyper-intensities in healthy aging and pathology using magnetic resonance imaging: a review, Neuroinformatics, vol.13, pp.261-76, 2015.

F. De-leeuw, J. C. De-groot, E. Achten, M. Oudkerk, L. Ramos et al., Prevalence of cerebral white matter lesions in elderly people: a population based magnetic resonance imaging study. The Rotterdam Scan study, J Neurol Neurosurg Psychiatry, vol.70, pp.9-14, 2001.

R. O. Hopkins, C. J. Beck, D. L. Burnett, L. K. Weaver, J. Victoroff et al., Prevalence of white matter hyper-intensities in a young healthy population, J Neuroimaging, vol.16, pp.243-51, 2006.

M. Habes, A. Sotiras, G. Erus, J. B. Toledo, D. Janowitz et al., White matter lesions: spatial heterogeneity, links to risk factors, cognition, genetics, and atrophy, Neurology, vol.91, pp.964-75, 2018.

B. Verhaaren, S. Debette, J. C. Bis, J. A. Smith, M. K. Ikram et al., Multi-ethnic genome-wide association study of cerebral white matter hyperintensities on MRI, Circ Cardiovasc Genet, vol.8, pp.398-409, 2015.

C. Dufouil, A. De-kersaint-gilly, V. Besancon, C. Levy, E. Auffray et al., Longitudinal study of blood pressure and white matter hyper-intensities: the EVA MRI cohort, Neurology, vol.56, pp.921-927, 2001.

S. R. Cox, D. M. Lyall, S. J. Ritchie, M. E. Bastin, M. A. Harris et al., Associations between vascular risk factors and brain MRI indices in UK Biobank, Eur Heart J, vol.40, pp.2290-300, 2019.

S. Debette and H. S. Markus, The clinical importance of white matter hyper-intensities on brain magnetic resonance imaging: systematic review and meta-analysis, BMJ, vol.341, p.3666, 2010.

, Diagnostic and statistical manual of mental disorders: DSM-5, 2013.

A. Kapasi, C. Decarli, and J. A. Schneider, Impact of multiple pathologies on the threshold for clinically overt dementia, Acta Neuropathol, vol.134, pp.171-86, 2017.

S. Bombois, S. Debette, A. Bruandet, X. Delbeuck, C. Delmaire et al., Vascular subcortical hyper-intensities predict conversion to vascular and mixed dementia in MCI patients, Stroke, vol.39, pp.2046-51, 2008.

M. R. Benedictus, A. C. Van-harten, A. E. Leeuwis, T. Koene, P. Scheltens et al., White matter hyper-intensities relate to clinical progression in subjective cognitive decline, Stroke, vol.46, pp.2661-2665, 2015.

N. Bolandzadeh, J. C. Davis, R. Tam, T. C. Handy, and T. Liu-ambrose, The association between cognitive function and white matter lesion location in older adults: a systematic review, BMC Neurol, vol.12, p.126, 2012.

R. P. Kloppenborg, P. J. Nederkoorn, M. I. Geerlings, and E. Van-den-berg, Presence and progression of white matter hyper-intensities and cognition: a meta-analysis, Neurology, vol.82, pp.2127-2165, 2014.

Y. A. Berlow, W. M. Wells, J. Ellison, Y. H. Sung, P. F. Renshaw et al., Neuropsychiatric correlates of white matter hyper-intensities in Alzheimer's disease, Int J Geriatr Psychiatry, vol.25, pp.780-788, 2010.

L. L. Herrmann, L. Masurier, M. Ebmeier, and K. P. , White matter hyper-intensities in late life depression: a systematic review, J Neurol Neurosurg Psychiatry, vol.79, pp.619-643, 2007.

D. Inzitari, G. Pracucci, A. Poggesi, G. Carlucci, F. Barkhof et al., Changes in white matter as determinant of global functional decline in older independent outpatients: three-year follow-up of LADIS (leukoaraiosis and disability) study cohort, BMJ, vol.339, p.2477, 2009.

M. I. Bergkamp, J. Wissink, E. Van-leijsen, M. Ghafoorian, D. G. Norris et al., Risk of nursing home admission in cerebral small vessel disease, Stroke, vol.49, pp.2659-65, 2018.

M. Maltais, P. De-souto-barreto, S. Y. Moon, Y. Rolland, and B. Vellas, Prospective association of white matter hyperintensity volume and frailty in older adults, Exp Gerontol, vol.118, pp.51-55, 2019.

M. E. Taylor, S. R. Lord, K. Delbaere, W. Wen, J. Jiang et al., White matter hyper-intensities are associated with falls in older people with dementia, Brain Imaging Behav, vol.13, pp.1265-72, 2018.

D. A. Fleischman, J. Yang, K. Arfanakis, Z. Arvanitakis, S. E. Leurgans et al., Physical activity, motor function, and white matter hyperintensity burden in healthy older adults, Neurology, vol.84, pp.1294-300, 2015.

T. Ghanavati, M. S. Smitt, S. R. Lord, P. Sachdev, W. Wen et al., Deep white matter hyper-intensities, microstructural integrity and dual task walking in older people, Brain Imaging Behav, vol.12, pp.1488-96, 2018.

, G Model REVMED-5852; No. of Pages 10

J. Zheng, S. R. Lord, J. Close, P. S. Sachdev, W. Wen et al., Brain white matter hyper-intensities, executive dysfunction, instability, and falls in older people: a prospective cohort study, J Gerontol A Biol Sci Med Sci, vol.67, pp.1085-91, 2012.

A. Poggesi, G. Pracucci, H. Chabriat, T. Erkinjuntti, F. Fazekas et al., Urinary complaints in non-disabled elderly people with age-related white matter changes: the leukoaraiosis and disability (LADIS) study, J Am Geriatr Soc, vol.56, pp.1638-1681, 2008.

M. M. Esiri, Z. Nagy, M. Z. Smith, L. Barnetson, and A. D. Smith, Cerebrovascular disease and threshold for dementia in the early stages of Alzheimer's disease, Lancet, vol.354, pp.919-939, 1999.

B. V. Zlokovic, Neurovascular pathways to neurodegeneration in Alzheimer's disease and other disorders, Nat Rev Neurosci, vol.12, pp.723-761, 2011.

T. Grimmer, M. Faust, F. Auer, P. Alexopoulos, H. Förstl et al., White matter hyper-intensities predict amyloid increase in Alzheimer's disease, Neurobiol Aging, vol.33, pp.2766-73, 2012.

S. Lee, F. Viqar, M. E. Zimmerman, A. Narkhede, G. Tosto et al., White matter hyper-intensities are a core feature of Alzheimer's disease: evidence from the dominantly inherited Alzheimer network: white matter hyper-intensities in familial AD, Ann Neurol, vol.79, pp.929-968, 2016.

F. Forette, M. Seux, J. A. Staessen, L. Thijs, W. H. Birkenhäger et al., Prevention of dementia in randomised double-blind placebo-controlled Systolic Hypertension in Europe (Syst-Eur) trial, Lancet, vol.352, pp.1347-51, 1998.

R. Peters, N. Beckett, F. Forette, J. Tuomilehto, R. Clarke et al., Incident dementia and blood pressure lowering in the Hypertension in the Very Elderly Trial Cognitive function assessment (HYVET-COG): a double-blind, placebo controlled trial, Lancet Neurol, vol.7, pp.683-692, 2008.

L. A. Pearce, L. A. Mcclure, D. C. Anderson, C. Jacova, M. Sharma et al., Effects of long-term blood pressure lowering and dual antiplatelet treatment on cognitive function in patients with recent lacunar stroke: a secondary analysis from the SPS3 randomised trial, Lancet Neurol, vol.13, pp.1177-85, 2014.

J. D. Williamson, N. M. Pajewski, A. P. Auchus, R. N. Bryan, G. Chelune et al., Effect of intensive vs. standard blood pressure control on probable dementia: a randomised clinical trial, JAMA, vol.12, pp.553-61, 2019.

J. D. Williamson, L. J. Launer, R. N. Bryan, L. H. Coker, R. M. Lazar et al., Cognitive function and brain structure in persons with type 2 diabetes mellitus after intensive lowering of blood pressure and lipid levels: a randomised clinical trial, JAMA Intern Med, vol.174, pp.324-357, 2014.

T. Van-middelaar, T. E. Argillander, F. Schreuder, J. Deinum, E. Richard et al., Effect of antihypertensive medication on cerebral small vessel disease: a systematic review and meta-analysis, Stroke, vol.49, pp.1531-1534, 2018.

O. R. Sps3-investigatorsbenavente, R. G. Hart, L. A. Mcclure, J. M. Szychowski, and C. S. Coffey, Effects of clopidogrel added to aspirin in patients with recent lacunar stroke, N Engl J Med, vol.367, pp.817-842, 2012.

C. S. Kwok, A. Shoamanesh, H. C. Copley, P. K. Myint, Y. K. Loke et al., Efficacy of antiplatelet therapy in secondary prevention following lacunar stroke: pooled analysis of randomised trials, Stroke, vol.46, pp.1014-1037, 2015.

S. A. Ward, P. Raniga, N. J. Ferris, R. L. Woods, E. Storey et al., ASPREE-NEURO study protocol: a randomised controlled trial to determine the effect of low-dose aspirin on cerebral microbleeds, white matter hyper-intensities, cognition, and stroke in the healthy elderly, Int J Stroke, vol.12, pp.108-121, 2017.

V. H. Ten-dam, D. Van-den-heuvel, M. A. Van-buchem, R. Westendorp, E. Bollen et al., Effect of pravastatin on cerebral infarcts and white matter lesions, Neurology, vol.64, pp.1807-1816, 2005.

H. Zhang, Y. Cui, Y. Zhao, Y. Dong, D. Duan et al., Effects of sartans and lowdose statins on cerebral white matter hyper-intensities and cognitive function in older patients with hypertension: a randomised, double-blind and placebocontrolled clinical trial, Hypertens Res, vol.42, pp.717-746, 2019.

T. Ji, Y. Zhao, J. Wang, Y. Cui, D. Duan et al., Effect of low-dose statins and apolipoprotein E genotype on cerebral small vessel disease in older hypertensive patients: a subgroup analysis of a randomised clinical trial, J Am Med Dir Assoc, vol.19, pp.995-1002, 2018.

C. E. Sexton, J. F. Betts, N. Demnitz, H. Dawes, K. P. Ebmeier et al., A systematic review of MRI studies examining the relationship between physical fitness and activity and the white matter of the ageing brain, Neuroimage, vol.131, pp.81-90, 2016.

V. K. Venkatraman, A. Sanderson, K. L. Cox, K. A. Ellis, C. Steward et al., Effect of a 24-month physical activity program on brain changes in older adults at risk of Alzheimer's disease: the AIBL Active trial, Neurobiol Aging, issue.19, pp.30155-30156, 2019.

H. Gardener, N. Scarmeas, Y. Gu, B. Boden-albala, M. Elkind et al., Mediterranean diet and white matter hyperintensity volume in the Northern Manhattan Study, Arch Neurol, vol.69, pp.251-257, 2012.

J. K. Virtanen, D. S. Siscovick, W. T. Longstreth, L. H. Kuller, and D. Mozaffarian, Fish consumption and risk of subclinical brain abnormalities on MRI in older adults, Neurology, vol.71, pp.439-485, 2008.

G. Bowman, L. Silbert, H. Dodge, D. Lahna, K. Hagen et al., Randomised trial of marine n-3 polyunsaturated fatty acids for the prevention of cerebral small vessel disease and inflammation in aging (PUFA trial): rationale, design and baseline results, Nutrients, vol.11, p.735, 2019.

M. Cavalieri, R. Schmidt, C. Chen, V. Mok, G. De-freitas et al., B vitamins and magnetic resonance imaging-detected ischemic brain lesions in patients with recent transient ischemic attack or stroke, Stroke, vol.43, pp.3266-70, 2012.

H. Edrissi, S. C. Schock, R. Cadonic, A. M. Hakim, and C. S. Thompson, Cilostazol reduces blood brain barrier dysfunction, white matter lesion formation and motor deficits following chronic cerebral hypoperfusion, Brain Res, vol.1646, pp.494-503, 2016.

E. Richard, A. A. Gouw, P. Scheltens, and W. A. Van-gool, Vascular care in patients with Alzheimer disease with cerebrovascular lesions slows progression of white matter lesions on MRI: the Evaluation of Vascular care in Alzheimer's disease (EVA) study, Stroke, vol.41, pp.554-560, 2010.

M. A. Espeland, K. Erickson, R. H. Neiberg, J. M. Jakicic, T. A. Wadden et al., Brain and white matter hyperintensity volumes after 10 years of random assignment to lifestyle intervention, Diabetes Care, vol.39, pp.764-71, 2016.

R. Stephen, Y. Liu, T. Ngandu, R. Antikainen, J. Hulkkonen et al., Brain volumes and cortical thickness on MRI in the Finnish Geriatric Intervention study to prevent cognitive impairment and disability (FINGER), Alzheimers Res Ther, vol.11, p.53, 2019.

J. W. Van-dalen, M. Van-charante, E. P. Caan, M. Scheltens, P. Majoie et al., Effect of long-term vascular care on progression of cerebrovascular lesions: magnetic resonance imaging substudy of the PreDIVA Trial (Prevention of Dementia by Intensive Vascular Care), Stroke, vol.48, pp.1842-1850, 2017.

H. Kavirajan and L. S. Schneider, Efficacy and adverse effects of cholinesterase inhibitors and memantine in vascular dementia: a meta-analysis of randomised controlled trials, Lancet Neurol, vol.6, pp.782-92, 2007.

G. Poisnel, E. Arenaza-urquijo, C. F. Klimecki, O. M. Marchant, N. L. Wirth et al., The Age-Well randomised controlled trial of the Medit-Ageing European project: effect of meditation or foreign language training on brain and mental health in older adults, Alzheimers Dement, vol.4, pp.714-737, 2018.

P. Schmidt, C. Gaser, M. Arsic, D. Buck, A. Förschler et al., An automated tool for detection of FLAIR-hyperintense white-matter lesions in multiple sclerosis, Neuroimage, vol.59, pp.3774-83, 2012.