Advertisement

Cerebral small vessel disease: neuroimaging markers and clinical implication

  • Xiaodong Chen
  • Jihui Wang
  • Yilong Shan
  • Wei Cai
  • Sanxin Liu
  • Mengyan Hu
  • Siyuan Liao
  • Xuehong Huang
  • Bingjun Zhang
  • Yuge Wang
  • Zhengqi Lu
Review
  • 135 Downloads

Abstract

Cerebral small vessel disease (CSVD) is a broad category of cerebrovascular diseases which primarily affect the perforating arterioles, capillaries and venules with multiple distinct etiologies. In spite of distinctive pathogenesis, CSVD shares similar neuroimaging markers, including recent small subcortical infarct, lacune of presumed vascular origin, white matter hyperintensity of presumed vascular origin, perivascular space and cerebral microbleeds. The radiological features of neuroimaging markers are indicative for etiological analysis. Furthermore, in sporadic arteriosclerotic pathogenesis associated CSVD, the total CSVD burden is a significant predictor for stroke events, global cognitive impairment, psychiatric disorders and later life quality. This review aims to summarize the radiological characteristics as well as the clinical implication of CSVD markers and neuroimaging interpretation for CSVD symptomatology.

Keywords

Cerebral small vessel disease Arteriolosclerosis Neuroimaging markers Cognition 

Notes

Compliance with ethical standards

Conflicts of interest

We declare that we have no conflicts of interest to this work.

Ethical standards

The manuscript does not contain any clinical studies or animal experiments.

References

  1. 1.
    Pantoni L (2010) Cerebral small vessel disease: from pathogenesis and clinical characteristics to therapeutic challenges. Lancet Neurol 9:689–701PubMedCrossRefGoogle Scholar
  2. 2.
    Wardlaw JM, Smith EE, Biessels GJ, Cordonnier C, Fazekas F, Frayne R, Lindley RI, O’Brien JT, Barkhof F, Benavente OR, Black SE, Brayne C, Breteler M, Chabriat H, Decarli C, de Leeuw FE, Doubal F, Duering M, Fox NC, Greenberg S, Hachinski V, Kilimann I, Mok V, Oostenbrugge R, Pantoni L, Speck O, Stephan BC, Teipel S, Viswanathan A, Werring D, Chen C, Smith C, van Buchem M, Norrving B, Gorelick PB, Dichgans M (2013) Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration. Lancet Neurol 12:822–838PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Staals J, Makin SD, Doubal FN, Dennis MS, Wardlaw JM (2014) Stroke subtype, vascular risk factors, and total MRI brain small-vessel disease burden. Neurology 83:1228–1234PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Li Y, Li M, Zuo L, Shi Q, Qin W, Yang L, Jiang T, Hu W (2018) Compromised blood–brain barrier integrity is associated with total magnetic resonance imaging burden of cerebral small vessel disease. Front Neurol 9:221PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Pavlovic AM, Pekmezovic T, Zidverc Trajkovic J, Svabic Medjedovic T, Veselinovic N, Radojicic A, Mijajlovic M, Tomic G, Jovanovic Z, Norton M, Sternic N (2016) Baseline characteristic of patients presenting with lacunar stroke and cerebral small vessel disease may predict future development of depression. Int J Geriatr Psychiatry 31:58–65PubMedCrossRefGoogle Scholar
  6. 6.
    Zhang X, Tang Y, Xie Y, Ding C, Xiao J, Jiang X, Shan H, Lin Y, Li C, Hu D, Li T, Sheng L (2017) Total magnetic resonance imaging burden of cerebral small-vessel disease is associated with post-stroke depression in patients with acute lacunar stroke. Eur J Neurol 24:374–380PubMedCrossRefGoogle Scholar
  7. 7.
    Liang Y, Chen YK, Deng M, Mok VCT, Wang DF, Ungvari GS, Chu CW, Kamiya A, Tang WK (2017) Association of cerebral small vessel disease burden and health-related quality of life after acute ischemic stroke. Front Aging Neurosci 9:372PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Sacco S, Marini C, Totaro R, Russo T, Cerone D, Carolei A (2006) A population-based study of the incidence and prognosis of lacunar stroke. Neurology 66:1335–1338PubMedCrossRefGoogle Scholar
  9. 9.
    Moran C, Phan TG, Srikanth VK (2012) Cerebral small vessel disease: a review of clinical, radiological, and histopathological phenotypes. Int J Stroke 7:36–46PubMedCrossRefGoogle Scholar
  10. 10.
    Arboix A, Estevez S, Rouco R, Oliveres M, Garcia-Eroles L, Massons J (2015) Clinical characteristics of acute lacunar stroke in young adults. Exp Rev Neurother 15:825–831CrossRefGoogle Scholar
  11. 11.
    Rutten-Jacobs LCA, Markus HS (2017) Vascular risk factor profiles differ between magnetic resonance imaging-defined subtypes of younger-onset lacunar stroke. Stroke 48:2405–2411PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Zhu S, McClure LA, Lau H, Romero JR, White CL, Babikian V, Nguyen T, Benavente OR, Kase CS, Pikula A (2015) Recurrent vascular events in lacunar stroke patients with metabolic syndrome and/or diabetes. Neurology 85:935–941PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Klarenbeek P, van Oostenbrugge RJ, Rouhl RP, Knottnerus IL, Staals J (2013) Ambulatory blood pressure in patients with lacunar stroke: association with total MRI burden of cerebral small vessel disease. Stroke 44:2995–2999PubMedCrossRefGoogle Scholar
  14. 14.
    Benavente OR, Coffey CS, Conwit R, Hart RG, McClure LA, Pearce LA, Pergola PE, Szychowski JM (2013) Blood-pressure targets in patients with recent lacunar stroke: the SPS3 randomised trial. Lancet 382:507–515PubMedCrossRefGoogle Scholar
  15. 15.
    Arboix A, Font A, Garro C, Garcia-Eroles L, Comes E, Massons J (2007) Recurrent lacunar infarction following a previous lacunar stroke: a clinical study of 122 patients. J Neurol Neurosurg Psychiatry 78:1392–1394PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Traylor M, Bevan S, Baron JC, Hassan A, Lewis CM, Markus HS (2015) Genetic architecture of lacunar stroke. Stroke 46:2407–2412PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Neurology Working Group of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium tSGNS, and the International Stroke Genetics Consortium (ISGC) (2016) Identification of additional risk loci for stroke and small vessel disease: a meta-analysis of genome-wide association studies. Lancet Neurol 15:695–707CrossRefGoogle Scholar
  18. 18.
    Traylor M, Rutten-Jacobs LC, Thijs V, Holliday EG, Levi C, Bevan S, Malik R, Boncoraglio G, Sudlow C, Rothwell PM, Dichgans M, Markus HS (2016) Genetic associations with white matter hyperintensities confer risk of lacunar stroke. Stroke 47:1174–1179PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Fisher CM (1991) Lacunar infarct: a review. Cerebrovasc Dis 1:311–320CrossRefGoogle Scholar
  20. 20.
    Arboix A, Lopez-Grau M, Casasnovas C, Garcia-Eroles L, Massons J, Balcells M (2006) Clinical study of 39 patients with atypical lacunar syndrome. J Neurol Neurosurg Psychiatry 77:381–384PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Grau-Olivares M, Arboix A, Bartres-Faz D, Junque C (2007) Neuropsychological abnormalities associated with lacunar infarction. J Neurol Sci 257:160–165PubMedCrossRefGoogle Scholar
  22. 22.
    Blanco-Rojas L, Arboix A, Canovas D, Grau-Olivares M, Oliva Morera JC, Parra O (2013) Cognitive profile in patients with a first-ever lacunar infarct with and without silent lacunes: a comparative study. BMC neurology 13:203PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Bonnin-Vilaplana M, Arboix A, Parra O, Garcia-Eroles L, Montserrat JM, Massons J (2009) Sleep-related breathing disorders in acute lacunar stroke. J Neurol 256:2036–2042PubMedCrossRefGoogle Scholar
  24. 24.
    Arboix A, Marti-Vilalta JL (2004) New concepts in lacunar stroke etiology: the constellation of small-vessel arterial disease. Cerebrovasc Dis 17(Suppl 1):58–62PubMedCrossRefGoogle Scholar
  25. 25.
    Arboix A, Blanco-Rojas L, Marti-Vilalta JL (2014) Advancements in understanding the mechanisms of symptomatic lacunar ischemic stroke: translation of knowledge to prevention strategies. Expert Rev Neurother 14:261–276PubMedCrossRefGoogle Scholar
  26. 26.
    Benavente OR, Pearce LA, Bazan C, Roldan AM, Catanese L, Bhat Livezey VM, Vidal-Pergola G, McClure LA, Hart RG (2014) Clinical-MRI correlations in a multiethnic cohort with recent lacunar stroke: the SPS3 trial. Int J Stroke 9:1057–1064PubMedCrossRefGoogle Scholar
  27. 27.
    Valdes Hernandez MD, Qiu X, Wang X, Wiseman S, Sakka E, Maconick LC, Doubal F, Sudlow CL, Wardlaw JM (2017) Interhemispheric characterization of small vessel disease imaging markers after subcortical infarct. Brain Behav 7:e00595PubMedCrossRefGoogle Scholar
  28. 28.
    Valdes Hernandez Mdel C, Maconick LC, Munoz Maniega S, Wang X, Wiseman S, Armitage PA, Doubal FN, Makin S, Sudlow CL, Dennis MS, Deary IJ, Bastin M, Wardlaw JM (2015) A comparison of location of acute symptomatic vs. ‘silent’ small vessel lesions. Int J Stroke 10:1044–1050PubMedCrossRefGoogle Scholar
  29. 29.
    Duan Z, Fu C, Chen B, Xu G, Tao L, Tang T, Hou H, Fu X, Yang M, Liu Z, Zhang X (2015) Lesion patterns of single small subcortical infarct and its association with early neurological deterioration. Neurol Sci 36:1851–1857PubMedCrossRefGoogle Scholar
  30. 30.
    Duan Z, Sun W, Liu W, Xiao L, Huang Z, Cao L, Li H, Xiong Y, Liu D, Xu G, Liu X (2015) Acute diffusion-weighted imaging lesion patterns predict progressive small subcortical infarct in the perforator territory of the middle cerebral artery. Int J Stroke 10:207–212PubMedCrossRefPubMedCentralGoogle Scholar
  31. 31.
    Arboix A, Garcia-Plata C, Garcia-Eroles L, Massons J, Comes E, Oliveres M, Targa C (2005) Clinical study of 99 patients with pure sensory stroke. J Neurol 252:156–162PubMedCrossRefPubMedCentralGoogle Scholar
  32. 32.
    Arboix A, Padilla I, Massons J, Garcia-Eroles L, Comes E, Targa C (2001) Clinical study of 222 patients with pure motor stroke. J Neurol Neurosurg Psychiatry 71:239–242PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Duering M, Csanadi E, Gesierich B, Jouvent E, Herve D, Seiler S, Belaroussi B, Ropele S, Schmidt R, Chabriat H, Dichgans M (2013) Incident lacunes preferentially localize to the edge of white matter hyperintensities: insights into the pathophysiology of cerebral small vessel disease. Brain 136:2717–2726PubMedCrossRefPubMedCentralGoogle Scholar
  34. 34.
    Gesierich B, Duchesnay E, Jouvent E, Chabriat H, Schmidt R, Mangin JF, Duering M, Dichgans M (2016) Features and determinants of lacune shape: relationship with fiber tracts and perforating arteries. Stroke 47:1258–1264PubMedCrossRefGoogle Scholar
  35. 35.
    Tsai HH, Pasi M, Tsai LK, Chen YF, Lee BC, Tang SC, Fotiadis P, Huang CY, Yen RF, Gurol ME, Jeng JS (2018) Distribution of lacunar infarcts in asians with intracerebral hemorrhage: a magnetic resonance imaging and amyloid positron emission tomography study. Stroke 49:1515–1517PubMedCrossRefGoogle Scholar
  36. 36.
    Hong YJ, Kim CM, Kim JE, Roh JH, Kim JS, Seo SW, Na DL, Lee JH (2017) Regional amyloid burden and lacune in pure subcortical vascular cognitive impairment. Neurobiol Aging 55:20–26PubMedCrossRefGoogle Scholar
  37. 37.
    Benjamin P, Trippier S, Lawrence AJ, Lambert C, Zeestraten E, Williams OA, Patel B, Morris RG, Barrick TR, MacKinnon AD, Markus HS (2018) Lacunar infarcts, but not perivascular spaces, are predictors of cognitive decline in cerebral small-vessel disease. Stroke 49:586–593PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Chen Y, Wang A, Tang J, Wei D, Li P, Chen K, Wang Y, Zhang Z (2015) Association of white matter integrity and cognitive functions in patients with subcortical silent lacunar infarcts. Stroke 46:1123–1126PubMedCrossRefGoogle Scholar
  39. 39.
    Reijmer YD, Freeze WM, Leemans A, Biessels GJ (2013) The effect of lacunar infarcts on white matter tract integrity. Stroke 44:2019–2021PubMedCrossRefGoogle Scholar
  40. 40.
    Thong JY, Hilal S, Wang Y, Soon HW, Dong Y, Collinson SL, Anh TT, Ikram MK, Wong TY, Venketasubramanian N, Chen C, Qiu A (2013) Association of silent lacunar infarct with brain atrophy and cognitive impairment. J Neurol Neurosurg Psychiatry 84:1219–1225PubMedCrossRefPubMedCentralGoogle Scholar
  41. 41.
    Makin SD, Turpin S, Dennis MS, Wardlaw JM (2013) Cognitive impairment after lacunar stroke: systematic review and meta-analysis of incidence, prevalence and comparison with other stroke subtypes. J Neurol Neurosurg Psychiatry 84:893–900PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    van Leijsen EMC, Bergkamp MI, van Uden IWM, Ghafoorian M, van der Holst HM, Norris DG, Platel B, Tuladhar AM, de Leeuw FE (2018) Progression of white matter hyperintensities preceded by heterogeneous decline of microstructural integrity. Stroke 49:1386–1393PubMedCrossRefPubMedCentralGoogle Scholar
  43. 43.
    Fazekas F, Chawluk JB, Alavi A, Hurtig HI, Zimmerman RA (1987) MR signal abnormalities at 1.5 T in Alzheimer’s dementia and normal aging. Am J Roentgenol 149:351–356CrossRefGoogle Scholar
  44. 44.
    Lampe L, Kharabian-Masouleh S, Kynast J, Arelin K, Steele CJ, Loffler M, Witte AV, Schroeter ML, Villringer A, Bazin PL (2017) Lesion location matters: the relationships between white matter hyperintensities on cognition in the healthy elderly. J Cereb Blood Flow Metab.  https://doi.org/10.1177/0271678X17740501 (Epub ahead of print) CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Shim YS, Yang DW, Roe CM, Coats MA, Benzinger TL, Xiong C, Galvin JE, Cairns NJ, Morris JC (2015) Pathological correlates of white matter hyperintensities on magnetic resonance imaging. Dement Geriatr Cogn Disord 39:92–104PubMedCrossRefPubMedCentralGoogle Scholar
  46. 46.
    Zhang CE, Wong SM, Uiterwijk R, Backes WH, Jansen JFA, Jeukens C, van Oostenbrugge RJ, Staals J (2018) Blood–brain barrier leakage in relation to white matter hyperintensity volume and cognition in small vessel disease and normal aging. Brain Imaging Behav.  https://doi.org/10.1007/s11682-018-9855-7 (Epub ahead of print) CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Osborn KE, Liu D, Samuels LR, Moore EE, Cambronero FE, Acosta LMY, Bell SP, Babicz MA, Gordon EA, Pechman KR, Davis LT, Gifford KA, Hohman TJ, Blennow K, Zetterberg H, Jefferson AL (2018) Cerebrospinal fluid beta-amyloid42 and neurofilament light relate to white matter hyperintensities. Neurobiol Aging 68:18–25PubMedCrossRefPubMedCentralGoogle Scholar
  48. 48.
    Scott JA, Braskie MN, Tosun D, Maillard P, Thompson PM, Weiner M, DeCarli C, Carmichael OT (2016) Cerebral amyloid is associated with greater white-matter hyperintensity accrual in cognitively normal older adults. Neurobiol Aging 48:48–52PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Valdes Hernandez M, Allerhand M, Glatz A, Clayson L, Munoz Maniega S, Gow A, Royle N, Bastin M, Starr J, Deary I, Wardlaw J (2016) Do white matter hyperintensities mediate the association between brain iron deposition and cognitive abilities in older people? Eur J Neurol 23:1202–1209PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Nam KW, Kwon HM, Jeong HY, Park JH, Kim SH, Jeong SM, Yoo TG, Kim S (2017) Cerebral white matter hyperintensity is associated with intracranial atherosclerosis in a healthy population. Atherosclerosis 265:179–183PubMedCrossRefPubMedCentralGoogle Scholar
  51. 51.
    Squair JW, Field TS, Phillips AA (2018) Journal club: relationship between carotid arterial properties and cerebral white matter hyperintensities. Neurology 90:338–340PubMedCrossRefPubMedCentralGoogle Scholar
  52. 52.
    Della-Morte D, Dong C, Markert MS, Elkind MSV, Sacco RL, Wright CB, Rundek T (2018) Carotid intima-media thickness is associated with white matter hyperintensities: the Northern Manhattan study. Stroke 49:304–311PubMedCrossRefPubMedCentralGoogle Scholar
  53. 53.
    Park JH, Kwon HM, Lee J, Kim DS, Ovbiagele B (2015) Association of intracranial atherosclerotic stenosis with severity of white matter hyperintensities. Eur J Neurol 22:44–52, e42–43PubMedCrossRefPubMedCentralGoogle Scholar
  54. 54.
    Rostanski SK, Zimmerman ME, Schupf N, Manly JJ, Westwood AJ, Brickman AM, Gu Y (2016) Sleep disordered breathing and white matter hyperintensities in community-dwelling elders. Sleep 39:785–791PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Cloonan L, Fitzpatrick KM, Kanakis AS, Furie KL, Rosand J, Rost NS (2015) Metabolic determinants of white matter hyperintensity burden in patients with ischemic stroke. Atherosclerosis 240:149–153PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Silbert LC, Lahna D, Promjunyakul NO, Boespflug E, Ohya Y, Higashiuesato Y, Nishihira J, Katsumata Y, Tokashiki T, Dodge HH (2018) Risk factors associated with cortical thickness and white matter hyperintensities in dementia free Okinawan elderly. J Alzheimers Dis 63:365–372PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Molad J, Kliper E, Korczyn AD, Ben Assayag E, Ben Bashat D, Shenhar-Tsarfaty S, Aizenstein O, Shopin L, Bornstein NM, Auriel E (2017) Only white matter hyperintensities predicts post-stroke cognitive performances among cerebral small vessel disease markers: results from the TABASCO study. J Alzheimers Dis 56:1293–1299PubMedCrossRefPubMedCentralGoogle Scholar
  58. 58.
    Honningsvag LM, Haberg AK, Hagen K, Kvistad KA, Stovner LJ, Linde M (2018) White matter hyperintensities and headache: a population-based imaging study (HUNT MRI). Cephalalgia.  https://doi.org/10.1177/0333102418764891 (Epub ahead of print) CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Moon SY, de Souto Barreto P, Rolland Y, Chupin M, Bouyahia A, Fillon L, Mangin JF, Andrieu S, Cesari M, Vellas B (2018) Prospective associations between white matter hyperintensities and lower extremity function. Neurology 90:e1291–e1297PubMedCrossRefPubMedCentralGoogle Scholar
  60. 60.
    Habes M, Erus G, Toledo JB, Bryan N, Janowitz D, Doshi J, Volzke H, Schminke U, Hoffmann W, Grabe HJ, Wolk DA, Davatzikos C (2018) Regional tract-specific white matter hyperintensities are associated with patterns to aging-related brain atrophy via vascular risk factors, but also independently. Alzheimer’s Dement (Amsterdam, Neth) 10:278–284Google Scholar
  61. 61.
    Tuladhar AM, Reid AT, Shumskaya E, de Laat KF, van Norden AG, van Dijk EJ, Norris DG, de Leeuw FE (2015) Relationship between white matter hyperintensities, cortical thickness, and cognition. Stroke 46:425–432PubMedCrossRefPubMedCentralGoogle Scholar
  62. 62.
    Kynast J, Lampe L, Luck T, Frisch S, Arelin K, Hoffmann KT, Loeffler M, Riedel-Heller SG, Villringer A, Schroeter ML (2018) White matter hyperintensities associated with small vessel disease impair social cognition beside attention and memory. J Cereb Blood Flow Metab 38:996–1009PubMedCrossRefPubMedCentralGoogle Scholar
  63. 63.
    van den Berg E, Geerlings MI, Biessels GJ, Nederkoorn PJ, Kloppenborg RP (2018) White matter hyperintensities and cognition in mild cognitive impairment and Alzheimer’s disease: a domain-specific meta-analysis. J Alzheimers Dis 63:515–527PubMedCrossRefPubMedCentralGoogle Scholar
  64. 64.
    Iliff JJ, Lee H, Yu M, Feng T, Logan J, Nedergaard M, Benveniste H (2013) Brain-wide pathway for waste clearance captured by contrast-enhanced MRI. J Clin Investig 123:1299–1309PubMedCrossRefPubMedCentralGoogle Scholar
  65. 65.
    Iliff JJ, Wang M, Liao Y, Plogg BA, Peng W, Gundersen GA, Benveniste H, Vates GE, Deane R, Goldman SA, Nagelhus EA, Nedergaard M (2012) A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid beta. Sci Transl Med 4:147ra111PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Weed LH (1914) Studies on cerebro-spinal fluid. No. III: The pathways of escape from the subarachnoid spaces with particular reference to the arachnoid villi. J Med Res 31:51–91PubMedPubMedCentralGoogle Scholar
  67. 67.
    Aspelund A, Antila S, Proulx ST, Karlsen TV, Karaman S, Detmar M, Wiig H, Alitalo K (2015) A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules. J Exp Med 212:991–999PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Louveau A, Smirnov I, Keyes TJ, Eccles JD, Rouhani SJ, Peske JD, Derecki NC, Castle D, Mandell JW, Lee KS, Harris TH, Kipnis J (2015) Structural and functional features of central nervous system lymphatic vessels. Nature 523:337–341PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Hurford R, Charidimou A, Fox Z, Cipolotti L, Jager R, Werring DJ (2014) MRI-visible perivascular spaces: relationship to cognition and small vessel disease MRI markers in ischaemic stroke and TIA. J Neurol Neurosurg Psychiatry 85:522–525PubMedCrossRefPubMedCentralGoogle Scholar
  70. 70.
    Shams S, Martola J, Charidimou A, Larvie M, Granberg T, Shams M, Kristoffersen-Wiberg M, Wahlund LO (2017) Topography and determinants of magnetic resonance imaging (MRI)-visible perivascular spaces in a large memory clinic cohort. J Am Heart Assoc 6:e006279PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Zhu YC, Tzourio C, Soumare A, Mazoyer B, Dufouil C, Chabriat H (2010) Severity of dilated Virchow–Robin spaces is associated with age, blood pressure, and MRI markers of small vessel disease: a population-based study. Stroke 41:2483–2490PubMedCrossRefGoogle Scholar
  72. 72.
    Xiao L, Lan W, Sun W, Dai Q, Xiong Y, Li L, Zhou Y, Zheng P, Fan W, Ma N, Guo Z, Chen X, Xie X, Xu L, Zhu W, Xu G, Liu X (2015) Chronic kidney disease in patients with lacunar stroke: association with enlarged perivascular spaces and total magnetic resonance imaging burden of cerebral small vessel disease. Stroke 46:2081–2086PubMedCrossRefGoogle Scholar
  73. 73.
    Yang S, Zhang X, Yuan J, Yin J, Hu W (2017) Serum uric acid is independently associated with enlarged perivascular spaces. Sci Rep 7:16435PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    Duperron MG, Tzourio C, Sargurupremraj M, Mazoyer B, Soumare A, Schilling S, Amouyel P, Chauhan G, Zhu YC, Debette S (2018) Burden of dilated perivascular spaces, an emerging marker of cerebral small vessel disease, is highly heritable. Stroke 49:282–287PubMedCrossRefGoogle Scholar
  75. 75.
    Charidimou A, Meegahage R, Fox Z, Peeters A, Vandermeeren Y, Laloux P, Baron JC, Jager HR, Werring DJ (2013) Enlarged perivascular spaces as a marker of underlying arteriopathy in intracerebral haemorrhage: a multicentre MRI cohort study. J Neurol Neurosurg Psychiatry 84:624–629PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Riba-Llena I, Jimenez-Balado J, Castane X, Girona A, Lopez-Rueda A, Mundet X, Jarca CI, Alvarez-Sabin J, Montaner J, Delgado P (2018) Arterial stiffness is associated with basal ganglia enlarged perivascular spaces and cerebral small vessel disease load. Stroke 49:1279–1281PubMedCrossRefGoogle Scholar
  77. 77.
    Del Brutto OH, Mera RM (2017) Enlarged perivascular spaces in the basal ganglia are independently associated with intracranial atherosclerosis in the elderly. Atherosclerosis 267:34–38PubMedCrossRefGoogle Scholar
  78. 78.
    van Veluw SJ, Biessels GJ, Bouvy WH, Spliet WG, Zwanenburg JJ, Luijten PR, Macklin EA, Rozemuller AJ, Gurol ME, Greenberg SM, Viswanathan A, Martinez-Ramirez S (2016) Cerebral amyloid angiopathy severity is linked to dilation of juxtacortical perivascular spaces. J Cereb Blood Flow Metab 36:576–580PubMedCrossRefGoogle Scholar
  79. 79.
    Charidimou A, Hong YT, Jager HR, Fox Z, Aigbirhio FI, Fryer TD, Menon DK, Warburton EA, Werring DJ, Baron JC (2015) White matter perivascular spaces on magnetic resonance imaging: marker of cerebrovascular amyloid burden? Stroke 46:1707–1709PubMedCrossRefGoogle Scholar
  80. 80.
    Hansen TP, Cain J, Thomas O, Jackson A (2015) Dilated perivascular spaces in the Basal Ganglia are a biomarker of small-vessel disease in a very elderly population with dementia. Am J Neuroradiol 36:893–898PubMedCrossRefGoogle Scholar
  81. 81.
    Yao M, Zhu YC, Soumare A, Dufouil C, Mazoyer B, Tzourio C, Chabriat H (2014) Hippocampal perivascular spaces are related to aging and blood pressure but not to cognition. Neurobiol Aging 35:2118–2125PubMedCrossRefGoogle Scholar
  82. 82.
    Jimenez-Balado J, Riba-Llena I, Garde E, Valor M, Gutierrez B, Pujadas F, Delgado P (2018) Prevalence of hippocampal enlarged perivascular spaces in a sample of patients with hypertension and their relation with vascular risk factors and cognitive function. J Neurol Neurosurg Psychiatry 89:651–656PubMedCrossRefGoogle Scholar
  83. 83.
    Zhu YC, Dufouil C, Mazoyer B, Soumare A, Ricolfi F, Tzourio C, Chabriat H (2011) Frequency and location of dilated Virchow–Robin spaces in elderly people: a population-based 3D MR imaging study. Am J Neuroradiol 32:709–713PubMedCrossRefGoogle Scholar
  84. 84.
    Bouvy WH, Zwanenburg JJ, Reinink R, Wisse LE, Luijten PR, Kappelle LJ, Geerlings MI, Biessels GJ (2016) Perivascular spaces on 7 T brain MRI are related to markers of small vessel disease but not to age or cardiovascular risk factors. J Cereb Blood Flow Metab 36:1708–1717PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Liang Y, Chan YL, Deng M, Chen YK, Mok V, Wang F, Ungvari GS, Chu CW, Tang WK (2018) Enlarged perivascular spaces in the centrum semiovale are associated with poststroke depression: a 3-month prospective study. J Affect Disord 228:166–172PubMedCrossRefGoogle Scholar
  86. 86.
    Arba F, Quinn TJ, Hankey GJ, Lees KR, Wardlaw JM, Ali M, Inzitari D (2018) Enlarged perivascular spaces and cognitive impairment after stroke and transient ischemic attack. Int J Stroke 13:47–56PubMedCrossRefGoogle Scholar
  87. 87.
    Ding J, Sigurethsson S, Jonsson PV, Eiriksdottir G, Charidimou A, Lopez OL, van Buchem MA, Guethnason V, Launer LJ (2017) Large perivascular spaces visible on magnetic resonance imaging, cerebral small vessel disease progression, and risk of dementia: the age, gene/environment susceptibility-Reykjavik study. JAMA Neurol 74:1105–1112PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Ishikawa M, Yamada S, Yamamoto K (2018) Dilated perivascular spaces in the centrum semiovale begin to develop in middle age. J Alzheimers Dis 61:1619–1626PubMedCrossRefGoogle Scholar
  89. 89.
    Charidimou A, Jaunmuktane Z, Baron JC, Burnell M, Varlet P, Peeters A, Xuereb J, Jager R, Brandner S, Werring DJ (2014) White matter perivascular spaces: an MRI marker in pathology-proven cerebral amyloid angiopathy? Neurology 82:57–62PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Banerjee G, Kim HJ, Fox Z, Jager HR, Wilson D, Charidimou A, Na HK, Na DL, Seo SW, Werring DJ (2017) MRI-visible perivascular space location is associated with Alzheimer’s disease independently of amyloid burden. Brain 140:1107–1116PubMedCrossRefGoogle Scholar
  91. 91.
    Laveskog A, Wang R, Bronge L, Wahlund LO, Qiu C (2018) Perivascular spaces in old age: assessment, distribution, and correlation with white matter hyperintensities. Am J Neuroradiol 39:70–76PubMedCrossRefGoogle Scholar
  92. 92.
    Lee WJ, Jung KH, Ryu YJ, Kim JM, Lee ST, Chu K, Kim M, Lee SK, Roh JK (2018) Association of cardiac hemodynamic factors with severity of white matter hyperintensities in chronic valvular heart disease. JAMA Neurol 75:80–87PubMedCrossRefGoogle Scholar
  93. 93.
    Shams S, Granberg T, Martola J, Charidimou A, Li X, Shams M, Fereshtehnejad SM, Cavallin L, Aspelin P, Wiberg-Kristoffersen M, Wahlund LO (2017) Cerebral microbleeds topography and cerebrospinal fluid biomarkers in cognitive impairment. J Cereb Blood Flow Metab 37:1006–1013PubMedCrossRefGoogle Scholar
  94. 94.
    Akoudad S, Portegies ML, Koudstaal PJ, Hofman A, van der Lugt A, Ikram MA, Vernooij MW (2015) Cerebral microbleeds are associated with an increased risk of stroke: the Rotterdam study. Circulation 132:509–516PubMedCrossRefGoogle Scholar
  95. 95.
    Laible M, Horstmann S, Mohlenbruch M, Wegele C, Rizos T, Schuler S, Zorn M, Veltkamp R (2015) Renal dysfunction is associated with deep cerebral microbleeds but not white matter hyperintensities in patients with acute intracerebral hemorrhage. J Neurol 262:2312–2322PubMedCrossRefGoogle Scholar
  96. 96.
    Romero JR, Preis SR, Beiser A, DeCarli C, Viswanathan A, Martinez-Ramirez S, Kase CS, Wolf PA, Seshadri S (2014) Risk factors, stroke prevention treatments, and prevalence of cerebral microbleeds in the Framingham Heart Study. Stroke 45:1492–1494PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Yang Q, Yang Y, Li C, Li J, Liu X, Wang A, Zhao J, Wang M, Zeng X, Fan D (2015) Quantitative assessment and correlation analysis of cerebral microbleed distribution and leukoaraiosis in stroke outpatients. Neurol Res 37:403–409CrossRefGoogle Scholar
  98. 98.
    Chung CP, Chou KH, Chen WT, Liu LK, Lee WJ, Huang AC, Chen LK, Lin CP, Wang PN (2017) Location of cerebral microbleeds and their association with carotid intima-media thickness: a community-based study. Sci Rep 7:12058PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Ding L, Hong Y, Peng B (2017) Association between large artery atherosclerosis and cerebral microbleeds: a systematic review and meta-analysis. Stroke Vasc Neurol 2:7–14PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Romero JR, Preis SR, Beiser A, DeCarli C, D’Agostino RB, Wolf PA, Vasan RS, Polak JF, Seshadri S (2016) Carotid atherosclerosis and cerebral microbleeds: the Framingham Heart Study. J Am Heart Assoc 5:e002377PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Ding J, Mitchell GF, Bots ML, Sigurdsson S, Harris TB, Garcia M, Eiriksdottir G, van Buchem MA, Gudnason V, Launer LJ (2015) Carotid arterial stiffness and risk of incident cerebral microbleeds in older people: the Age, Gene/Environment Susceptibility (AGES)-Reykjavik study. Arterioscler Thromb Vasc Biol 35:1889–1895PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Banerjee G, Wahab KW, Gregoire SM, Jichi F, Charidimou A, Jager HR, Rantell K, Werring DJ (2016) Impaired renal function is related to deep and mixed, but not strictly lobar cerebral microbleeds in patients with ischaemic stroke and TIA. J Neurol 263:760–764PubMedCrossRefGoogle Scholar
  103. 103.
    Overbeek EC, Staals J, van Oostenbrugge RJ (2016) Decreased kidney function relates to progression of cerebral microbleeds in lacunar stroke patients. Int J Stroke 11:695–700PubMedCrossRefGoogle Scholar
  104. 104.
    Zhang JB, Liu LF, Li ZG, Sun HR, Ju XH (2015) Associations between biomarkers of renal function with cerebral microbleeds in hypertensive patients. Am J Hypertens 28:739–745PubMedCrossRefGoogle Scholar
  105. 105.
    Ding J, Sigurdsson S, Garcia M, Phillips CL, Eiriksdottir G, Gudnason V, van Buchem MA, Launer LJ (2015) Risk factors associated with incident cerebral microbleeds according to location in older people: the age, gene/environment susceptibility (AGES)-Reykjavik study. JAMA Neurol 72:682–688PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Chung PW, Park KY, Kim JM, Shin DW, Ha SY (2014) Carotid artery calcification is associated with deep cerebral microbleeds. Eur Neurol 72:60–63PubMedCrossRefGoogle Scholar
  107. 107.
    Yates PA, Desmond PM, Phal PM, Steward C, Szoeke C, Salvado O, Ellis KA, Martins RN, Masters CL, Ames D, Villemagne VL, Rowe CC (2014) Incidence of cerebral microbleeds in preclinical Alzheimer disease. Neurology 82:1266–1273PubMedPubMedCentralCrossRefGoogle Scholar
  108. 108.
    Gregg NM, Kim AE, Gurol ME, Lopez OL, Aizenstein HJ, Price JC, Mathis CA, James JA, Snitz BE, Cohen AD, Kamboh MI, Minhas D, Weissfeld LA, Tamburo EL, Klunk WE (2015) Incidental cerebral microbleeds and cerebral blood flow in elderly individuals. JAMA Neurol 72:1021–1028PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Graff-Radford J, Simino J, Kantarci K, Mosley TH Jr, Griswold ME, Windham BG, Sharrett AR, Albert MS, Gottesman RF, Jack CR Jr, Vemuri P, Knopman DS (2017) Neuroimaging correlates of cerebral microbleeds: The ARIC study (Atherosclerosis Risk in Communities). Stroke 48:2964–2972PubMedCrossRefGoogle Scholar
  110. 110.
    Akoudad S, Wolters FJ, Viswanathan A, de Bruijn RF, van der Lugt A, Hofman A, Koudstaal PJ, Ikram MA, Vernooij MW (2016) Association of cerebral microbleeds with cognitive decline and dementia. JAMA Neurol 73:934–943PubMedPubMedCentralCrossRefGoogle Scholar
  111. 111.
    Chung CP, Chou KH, Chen WT, Liu LK, Lee WJ, Chen LK, Lin CP, Wang PN (2016) Strictly lobar cerebral microbleeds are associated with cognitive impairment. Stroke 47:2497–2502PubMedCrossRefGoogle Scholar
  112. 112.
    Marti-Fabregas J, Delgado-Mederos R, Granell E, Morenas Rodriguez E, Marin Lahoz J, Dinia L, Carrera D, Perez de la Ossa N, Sanahuja J, Sobrino T, De Arce AM, Alonso de Lecinana M (2013) Microbleed burden and hematoma expansion in acute intracerebral hemorrhage. Eur Neurol 70:175–178PubMedCrossRefGoogle Scholar
  113. 113.
    Tsivgoulis G, Zand R, Katsanos AH, Turc G, Nolte CH, Jung S, Cordonnier C, Fiebach JB, Scheitz JF, Klinger-Gratz PP, Oppenheim C, Goyal N, Safouris A, Mattle HP, Alexandrov AW, Schellinger PD, Alexandrov AV (2016) Risk of symptomatic intracerebral hemorrhage after intravenous thrombolysis in patients with acute ischemic stroke and high cerebral microbleed burden: a meta-analysis. JAMA Neurol 73:675–683PubMedCrossRefGoogle Scholar
  114. 114.
    Charidimou A, Imaizumi T, Moulin S, Biffi A, Samarasekera N, Yakushiji Y, Peeters A, Vandermeeren Y, Laloux P, Baron JC, Hernandez-Guillamon M, Montaner J, Casolla B, Gregoire SM, Kang DW, Kim JS, Naka H, Smith EE, Viswanathan A, Jager HR, Al-Shahi Salman R, Greenberg SM, Cordonnier C, Werring DJ (2017) Brain hemorrhage recurrence, small vessel disease type, and cerebral microbleeds: a meta-analysis. Neurology 89:820–829PubMedPubMedCentralCrossRefGoogle Scholar
  115. 115.
    Lau KK, Lovelock CE, Li L, Simoni M, Gutnikov S, Kuker W, Mak HKF, Rothwell PM (2018) Antiplatelet treatment after transient ischemic attack and ischemic stroke in patients with cerebral microbleeds in 2 large cohorts and an updated systematic review. Stroke 6:1434–1442CrossRefGoogle Scholar
  116. 116.
    Wilson D, Charidimou A, Ambler G, Fox ZV, Gregoire S, Rayson P, Imaizumi T, Fluri F, Naka H, Horstmann S, Veltkamp R, Rothwell PM, Kwa VI, Thijs V, Lee YS, Kim YD, Huang Y, Wong KS, Jager HR, Werring DJ (2016) Recurrent stroke risk and cerebral microbleed burden in ischemic stroke and TIA: a meta-analysis. Neurology 87:1501–1510PubMedPubMedCentralCrossRefGoogle Scholar
  117. 117.
    Lau KK, Wong YK, Teo KC, Chang RSK, Tse MY, Hoi CP, Chan CY, Chan OL, Cheung RHK, Wong EKM, Kwan JSK, Hui ES, Mak HKF (2017) Long-term prognostic implications of cerebral microbleeds in chinese patients with ischemic stroke. J Am Heart Assoc 6:e007360.  https://doi.org/10.1161/JAHA.117.007360 CrossRefPubMedPubMedCentralGoogle Scholar
  118. 118.
    Charidimou A, Boulouis G, Shams S, Calvet D, Shoamanesh A (2017) Intracerebral haemorrhage risk in microbleed-positive ischaemic stroke patients with atrial fibrillation: preliminary meta-analysis of cohorts and anticoagulation decision schema. J Neurol Sci 378:102–109PubMedCrossRefGoogle Scholar
  119. 119.
    Wilson D, Ambler G, Shakeshaft C, Brown MM, Charidimou A, Al-Shahi Salman R, Lip GYH, Cohen H, Banerjee G, Houlden H, White MJ, Yousry TA, Harkness K, Flossmann E, Smyth N, Shaw LJ, Warburton E, Muir KW, Jager HR, Werring DJ (2018) Cerebral microbleeds and intracranial haemorrhage risk in patients anticoagulated for atrial fibrillation after acute ischaemic stroke or transient ischaemic attack (CROMIS-2): a multicentre observational cohort study. Lancet Neurol 17:539–547PubMedPubMedCentralCrossRefGoogle Scholar
  120. 120.
    Romero JR, Preis SR, Beiser A, Himali JJ, Shoamanesh A, Wolf PA, Kase CS, Vasan RS, DeCarli C, Seshadri S (2017) Cerebral microbleeds as predictors of mortality: the Framingham Heart Study. Stroke 48:781–783PubMedPubMedCentralCrossRefGoogle Scholar
  121. 121.
    Romero JR, Beiser A, Himali JJ, Shoamanesh A, DeCarli C, Seshadri S (2017) Cerebral microbleeds and risk of incident dementia: the Framingham Heart Study. Neurobiol Aging 54:94–99PubMedPubMedCentralCrossRefGoogle Scholar
  122. 122.
    Xu X, Chan QL, Hilal S, Goh WK, Ikram MK, Wong TY, Cheng CY, Chen CL, Venketasubramanian N (2017) Cerebral microbleeds and neuropsychiatric symptoms in an elderly Asian cohort. J Neurol Neurosurg Psychiatry 88:7–11PubMedCrossRefGoogle Scholar
  123. 123.
    van Norden AG, van Uden IW, de Laat KF, Gons RA, Kessels RP, van Dijk EJ, de Leeuw FE (2013) Cerebral microbleeds are related to subjective cognitive failures: the RUN DMC study. Neurobiol Aging 34:2225–2230PubMedCrossRefGoogle Scholar
  124. 124.
    Banerjee G, Jang H, Kim HJ, Kim ST, Kim JS, Lee JH, Im K, Kwon H, Lee JM, Na DL, Seo SW, Werring DJ (2018) Total MRI small vessel disease burden correlates with cognitive performance, cortical atrophy, and network measures in a memory clinic population. J Alzheimers Dis 63:1485–1497PubMedCrossRefGoogle Scholar
  125. 125.
    Cummings JL (1993) Frontal-subcortical circuits and human behavior. Arch Neurol 50:873–880PubMedCrossRefGoogle Scholar
  126. 126.
    De Groot JC, De Leeuw FE, Oudkerk M, Van Gijn J, Hofman A, Jolles J, Breteler MM (2002) Periventricular cerebral white matter lesions predict rate of cognitive decline. Ann Neurol 52:335–341PubMedCrossRefGoogle Scholar
  127. 127.
    Filley CM (1998) The behavioral neurology of cerebral white matter. Neurology 50:1535–1540PubMedCrossRefGoogle Scholar
  128. 128.
    van den Heuvel MP, Sporns O (2011) Rich-club organization of the human connectome. J Neurosci 31:15775–15786PubMedCrossRefGoogle Scholar
  129. 129.
    Tuladhar AM, Lawrence A, Norris DG, Barrick TR, Markus HS, de Leeuw FE (2017) Disruption of rich club organisation in cerebral small vessel disease. Hum Brain Mapp 38:1751–1766PubMedCrossRefGoogle Scholar
  130. 130.
    Lawrence AJ, Zeestraten EA, Benjamin P, Lambert CP, Morris RG, Barrick TR, Markus HS (2018) Longitudinal decline in structural networks predicts dementia in cerebral small vessel disease. Neurology 90:e1898–e1910PubMedPubMedCentralCrossRefGoogle Scholar
  131. 131.
    Loos CMJ, Makin SDJ, Staals J, Dennis MS, van Oostenbrugge RJ, Wardlaw JM (2018) Long-term morphological changes of symptomatic lacunar infarcts and surrounding white matter on structural magnetic resonance imaging. Stroke 49:1183–1188PubMedPubMedCentralCrossRefGoogle Scholar
  132. 132.
    Hatate J, Miwa K, Matsumoto M, Sasaki T, Yagita Y, Sakaguchi M, Kitagawa K, Mochizuki H (2016) Association between cerebral small vessel diseases and mild parkinsonian signs in the elderly with vascular risk factors. Parkinson Relat Disord 26:29–34CrossRefGoogle Scholar
  133. 133.
    van der Holst HM, van Uden IW, Tuladhar AM, de Laat KF, van Norden AG, Norris DG, van Dijk EJ, Esselink RA, Platel B, de Leeuw FE (2015) Cerebral small vessel disease and incident parkinsonism: the RUN DMC study. Neurology 85:1569–1577PubMedPubMedCentralCrossRefGoogle Scholar
  134. 134.
    de Laat KF, Tuladhar AM, van Norden AG, Norris DG, Zwiers MP, de Leeuw FE (2011) Loss of white matter integrity is associated with gait disorders in cerebral small vessel disease. Brain 134:73–83PubMedCrossRefPubMedCentralGoogle Scholar
  135. 135.
    van der Holst HM, Tuladhar AM, Zerbi V, van Uden IWM, de Laat KF, van Leijsen EMC, Ghafoorian M, Platel B, Bergkamp MI, van Norden AGW, Norris DG, van Dijk EJ, Kiliaan AJ, de Leeuw FE (2018) White matter changes and gait decline in cerebral small vessel disease. Neuroimage Clin 17:731–738PubMedCrossRefPubMedCentralGoogle Scholar
  136. 136.
    Kim YJ, Kwon HK, Lee JM, Cho H, Kim HJ, Park HK, Jung NY, San Lee J, Lee J, Jang YK, Kim ST, Lee KH, Choe YS, Kim YJ, Na DL, Seo SW (2016) Gray and white matter changes linking cerebral small vessel disease to gait disturbances. Neurology 86:1199–1207PubMedCrossRefPubMedCentralGoogle Scholar
  137. 137.
    Zijlmans JC, Daniel SE, Hughes AJ, Revesz T, Lees AJ (2004) Clinicopathological investigation of vascular parkinsonism, including clinical criteria for diagnosis. Mov Disord 19:630–640PubMedCrossRefPubMedCentralGoogle Scholar
  138. 138.
    Rensma SP, van Sloten TT, Launer LJ, Stehouwer CDA (2018) Cerebral small vessel disease and risk of incident stroke, dementia and depression, and all-cause mortality: a systematic review and meta-analysis. Neurosci Biobehav Rev 90:164–173PubMedCrossRefPubMedCentralGoogle Scholar
  139. 139.
    Brookes RL, Herbert V, Lawrence AJ, Morris RG, Markus HS (2014) Depression in small-vessel disease relates to white matter ultrastructural damage, not disability. Neurology 83:1417–1423PubMedPubMedCentralCrossRefGoogle Scholar
  140. 140.
    Taylor WD, Aizenstein HJ, Alexopoulos GS (2013) The vascular depression hypothesis: mechanisms linking vascular disease with depression. Mol Psychiatry 18:963–974PubMedPubMedCentralCrossRefGoogle Scholar
  141. 141.
    Hollocks MJ, Lawrence AJ, Brookes RL, Barrick TR, Morris RG, Husain M, Markus HS (2015) Differential relationships between apathy and depression with white matter microstructural changes and functional outcomes. Brain 138:3803–3815PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of NeurologyThe Third Affiliated Hospital of Sun Yat-sen UniversityGuangzhouChina
  2. 2.Department of PsychiatryThe Third Affiliated Hospital of Sun Yat-sen UniversityGuangzhouChina

Personalised recommendations