Top

Published in:

01-01-2021 | Cerebral Small Vessel Disease | Review

Brain arteriolosclerosis

Authors: Brittney L. Blevins, Harry V. Vinters, Seth Love, Donna M. Wilcock, Lea T. Grinberg, Julie A. Schneider, Rajesh N. Kalaria, Yuriko Katsumata, Brian T. Gold, Danny J. J. Wang, Samantha J. Ma, Lincoln M. P. Shade, David W. Fardo, Anika M. S. Hartz, Gregory A. Jicha, Karin B. Nelson, Shino D. Magaki, Frederick A. Schmitt, Merilee A. Teylan, Eseosa T. Ighodaro, Panhavuth Phe, Erin L. Abner, Matthew D. Cykowski, Linda J. Van Eldik, Peter T. Nelson

Published in: Acta Neuropathologica | Issue 1/2021

Abstract

Brain arteriolosclerosis (B-ASC), characterized by pathologic arteriolar wall thickening, is a common finding at autopsy in aged persons and is associated with cognitive impairment. Hypertension and diabetes are widely recognized as risk factors for B-ASC. Recent research indicates other and more complex risk factors and pathogenetic mechanisms. Here, we describe aspects of the unique architecture of brain arterioles, histomorphologic features of B-ASC, relevant neuroimaging findings, epidemiology and association with aging, established genetic risk factors, and the co-occurrence of B-ASC with other neuropathologic conditions such as Alzheimer’s disease and limbic-predominant age-related TDP-43 encephalopathy (LATE). There may also be complex physiologic interactions between metabolic syndrome (e.g., hypertension and inflammation) and brain arteriolar pathology. Although there is no universally applied diagnostic methodology, several classification schemes and neuroimaging techniques are used to diagnose and categorize cerebral small vessel disease pathologies that include B-ASC, microinfarcts, microbleeds, lacunar infarcts, and cerebral amyloid angiopathy (CAA). In clinical-pathologic studies that factored in comorbid diseases, B-ASC was independently associated with impairments of global cognition, episodic memory, working memory, and perceptual speed, and has been linked to autonomic dysfunction and motor symptoms including parkinsonism. We conclude by discussing critical knowledge gaps related to B-ASC and suggest that there are probably subcategories of B-ASC that differ in pathogenesis. Observed in over 80% of autopsied individuals beyond 80 years of age, B-ASC is a complex and under-studied contributor to neurologic disability.

Available only for authorised users

Abbott NJ, Pizzo ME, Preston JE, Janigro D, Thorne RG (2018) The role of brain barriers in fluid movement in the CNS: is there a ‘glymphatic’ system? Acta Neuropathol 135:387–407. https://doi.org/10.1007/s00401-018-1812-4CrossRefPubMed

Abbott NJ, Revest PA, Romero IA (1992) Astrocyte-endothelial interaction: physiology and pathology. Neuropathol Appl Neurobiol 18:424–433. https://doi.org/10.1111/j.1365-2990.1992.tb00808.xCrossRefPubMed

Abner EL, Nelson PT, Kryscio RJ et al (2016) Diabetes is associated with cerebrovascular but not Alzheimer neuropathology. Alzheimers Dement. https://doi.org/10.1016/j.jalz.2015.12.006 ((ePub Jan 23, Available on PubMed))CrossRefPubMedPubMedCentral

Abrahamson EE, Ikonomovic MD (2020) Brain injury-induced dysfunction of the blood brain barrier as a risk for dementia. Exp Neurol 328:113257. https://doi.org/10.1016/j.expneurol.2020.113257CrossRefPubMed

Adib-Samii P, Devan W, Traylor M et al (2015) Genetic architecture of white matter hyperintensities differs in hypertensive and nonhypertensive ischemic stroke. Stroke 46:348–353. https://doi.org/10.1161/STROKEAHA.114.006849CrossRefPubMedPubMedCentral

Adib-Samii P, Rost N, Traylor M et al (2013) 17q25 Locus is associated with white matter hyperintensity volume in ischemic stroke, but not with lacunar stroke status. Stroke 44:1609–1615. https://doi.org/10.1161/STROKEAHA.113.679936CrossRefPubMedPubMedCentral

Al-Janabi OM, Brown CA, Bahrani AA et al (2018) Distinct white matter changes associated with cerebrospinal fluid Amyloid-beta1-42 and hypertension. J Alzheimers Dis 66:1095–1104. https://doi.org/10.3233/JAD-180663CrossRefPubMedPubMedCentral

Alafuzoff I, Gelpi E, Al-Sarraj S et al (2012) The need to unify neuropathological assessments of vascular alterations in the ageing brain: multicentre survey by the BrainNet Europe consortium. Exp Gerontol 47:825–833. https://doi.org/10.1016/j.exger.2012.06.001CrossRefPubMed

Alber J, Alladi S, Bae HJ et al (2019) White matter hyperintensities in vascular contributions to cognitive impairment and dementia (VCID): knowledge gaps and opportunities. Alzheimers Dement (N Y) 5:107–117. https://doi.org/10.1016/j.trci.2019.02.001CrossRef

10.

Aliev G, Priyadarshini M, Reddy VP et al (2014) Oxidative stress mediated mitochondrial and vascular lesions as markers in the pathogenesis of Alzheimer disease. Curr Med Chem 21:2208–2217. https://doi.org/10.2174/0929867321666131227161303CrossRefPubMed

11.

Aliev G, Smith MA, Seyidov D et al (2002) The role of oxidative stress in the pathophysiology of cerebrovascular lesions in Alzheimer’s disease. Brain Pathol 12:21–35. https://doi.org/10.1111/j.1750-3639.2002.tb00419.xCrossRefPubMed

12.

Altamura C, Scrascia F, Quattrocchi CC et al (2016) Regional MRI diffusion, white-matter hyperintensities, and cognitive function in Alzheimer’s disease and vascular dementia. J Clin Neurol 12:201–208. https://doi.org/10.3988/jcn.2016.12.2.201CrossRefPubMedPubMedCentral

13.

Amador-Ortiz C, Lin WL, Ahmed Z et al (2007) TDP-43 immunoreactivity in hippocampal sclerosis and Alzheimer’s disease. Ann Neurol 61:435–445. https://doi.org/10.1002/ana.21154CrossRefPubMedPubMedCentral

14.

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 14:261–276. https://doi.org/10.1586/14737175.2014.884926CrossRefPubMed

15.

Arima K, Yanagawa S, Ito N, Ikeda S (2003) Cerebral arterial pathology of CADASIL and CARASIL (Maeda syndrome). Neuropathology 23:327–334. https://doi.org/10.1046/j.1440-1789.2003.00519.xCrossRefPubMed

16.

Armstrong NJ, Mather KA, Sargurupremraj M et al (2020) Common genetic variation indicates separate causes for periventricular and deep white matter hyperintensities. Stroke. https://doi.org/10.1161/STROKEAHA.119.027544CrossRefPubMedPubMedCentral

17.

Arnold AC, Gallagher PE, Diz DI (2013) Brain renin-angiotensin system in the nexus of hypertension and aging. Hypertens Res 36:5–13. https://doi.org/10.1038/hr.2012.161CrossRefPubMed

18.

Arvanitakis Z, Capuano AW, Lamar M et al (2018) Late-life blood pressure association with cerebrovascular and Alzheimer disease pathology. Neurology 91:e517–e525. https://doi.org/10.1212/WNL.0000000000005951CrossRefPubMedPubMedCentral

19.

Arvanitakis Z, Capuano AW, Leurgans SE, Bennett DA, Schneider JA (2016) Relation of cerebral vessel disease to Alzheimer’s disease dementia and cognitive function in elderly people: a cross-sectional study. Lancet Neurol 15:934–943. https://doi.org/10.1016/S1474-4422(16)30029-1CrossRefPubMedPubMedCentral

20.

Attwell D, Mishra A, Hall CN, O’Farrell FM, Dalkara T (2016) What is a pericyte? J Cereb Blood Flow Metab 36:451–455. https://doi.org/10.1177/0271678X15610340CrossRefPubMed

21.

Baik I, Seo HS, Yoon D, Kim SH, Shin C (2015) Associations of sleep apnea, NRG1 polymorphisms, alcohol consumption, and cerebral white matter hyperintensities: analysis with genome-wide association data. Sleep 38:1137–1143. https://doi.org/10.5665/sleep.4830CrossRefPubMedPubMedCentral

22.

Barnes LL, Leurgans S, Aggarwal NT et al (2015) Mixed pathology is more likely in black than white decedents with Alzheimer dementia. Neurology 85:528–534. https://doi.org/10.1212/WNL.0000000000001834CrossRefPubMedPubMedCentral

23.

Beckner ME (2020) A roadmap for potassium buffering/dispersion via the glial network of the CNS. Neurochem Int 136:104727. https://doi.org/10.1016/j.neuint.2020.104727CrossRefPubMed

24.

Bellot-Saez A, Kekesi O, Morley JW, Buskila Y (2017) Astrocytic modulation of neuronal excitability through K(+) spatial buffering. Neurosci Biobehav Rev 77:87–97. https://doi.org/10.1016/j.neubiorev.2017.03.002CrossRefPubMed

25.

Bergers G, Song S (2005) The role of pericytes in blood-vessel formation and maintenance. Neuro Oncol 7:452–464. https://doi.org/10.1215/S1152851705000232CrossRefPubMedPubMedCentral

26.

Besser LM, Kukull WA, Teylan MA et al (2018) The revised national Alzheimer’s coordinating center’s neuropathology form-available data and new analyses. J Neuropathol Exp Neurol 77:717–726. https://doi.org/10.1093/jnen/nly049CrossRefPubMedPubMedCentral

27.

Bevan JA, Dodge J, Walters CL, Wellman T, Bevan RD (1999) As human pial arteries (internal diameter 200–1000 microm) get smaller, their wall thickness and capacity to develop tension relative to their diameter increase. Life Sci 65:1153–1161. https://doi.org/10.1016/s0024-3205(99)00349-5CrossRefPubMed

28.

Borshchev YY, Uspensky YP, Galagudza MM (2019) Pathogenetic pathways of cognitive dysfunction and dementia in metabolic syndrome. Life Sci 237:116932. https://doi.org/10.1016/j.lfs.2019.116932CrossRefPubMed

29.

Bourassa P, Tremblay C, Schneider JA, Bennett DA, Calon F (2020) Brain mural cell loss in the parietal cortex in Alzheimer’s disease correlates with cognitive decline and TDP-43 pathology. Neuropathol Appl Neurobiol 46(5):458–477. https://doi.org/10.1111/nan.12599CrossRefPubMedPubMedCentral

30.

Boyle PA, Yu L, Leurgans SE et al (2019) Attributable risk of Alzheimer’s dementia attributed to age-related neuropathologies. Ann Neurol 85:114–124. https://doi.org/10.1002/ana.25380CrossRefPubMed

31.

Brenowitz WD, Nelson PT, Besser LM, Heller KB, Kukull WA (2015) Cerebral amyloid angiopathy and its co-occurrence with Alzheimer’s disease and other cerebrovascular neuropathologic changes. Neurobiol Aging 36(10):2702–2708. https://doi.org/10.1016/j.neurobiolaging.2015.06.028CrossRefPubMedPubMedCentral

32.

Bridges LR, Andoh J, Lawrence AJ et al (2014) Blood-brain barrier dysfunction and cerebral small vessel disease (arteriolosclerosis) in brains of older people. J Neuropathol Exp Neurol 73:1026–1033. https://doi.org/10.1097/NEN.0000000000000124CrossRefPubMed

33.

Buchman AS, Leurgans SE, Nag S, Bennett DA, Schneider JA (2011) Cerebrovascular disease pathology and parkinsonian signs in old age. Stroke 42:3183–3189. https://doi.org/10.1161/STROKEAHA.111.623462CrossRefPubMedPubMedCentral

34.

Buchman AS, Leurgans SE, Nag S et al (2017) Spinal arteriolosclerosis is common in older adults and associated with parkinsonism. Stroke 48:2792–2798. https://doi.org/10.1161/STROKEAHA.117.017643CrossRefPubMedPubMedCentral

35.

Buchman AS, Wilson RS, Shulman JM et al (2016) Parkinsonism in older adults and its association with adverse health outcomes and neuropathology. J Gerontol A Biol Sci Med Sci 71:549–556. https://doi.org/10.1093/gerona/glv153CrossRefPubMed

36.

Camici GG, Savarese G, Akhmedov A, Luscher TF (2015) Molecular mechanism of endothelial and vascular aging: implications for cardiovascular disease. Eur Heart J 36:3392–3403. https://doi.org/10.1093/eurheartj/ehv587CrossRefPubMed

37.

Cechetto DF, Hachinski V, Whitehead SN (2008) Vascular risk factors and Alzheimer’s disease. Expert Rev Neurother 8:743–750. https://doi.org/10.1586/14737175.8.5.743CrossRefPubMed

38.

Cervos-Navarro J, Gertz HJ, Frydl V (1987) Cerebral blood vessel changes in old people. Mech Ageing Dev 39:223–231. https://doi.org/10.1016/0047-6374(87)90062-5CrossRefPubMed

39.

Chou SH, Shulman JM, Keenan BT et al (2013) Genetic susceptibility for ischemic infarction and arteriolosclerosis based on neuropathologic evaluations. Cerebrovasc Dis 36:181–188. https://doi.org/10.1159/000352054CrossRefPubMed

40.

Chung J, Marini S, Pera J et al (2019) Genome-wide association study of cerebral small vessel disease reveals established and novel loci. Brain 142:3176–3189. https://doi.org/10.1093/brain/awz233CrossRefPubMedPubMedCentral

41.

Craft S (2006) Insulin resistance syndrome and Alzheimer disease: pathophysiologic mechanisms and therapeutic implications. Alzheimer Dis Assoc Disord 20:298–301. https://doi.org/10.1097/01.wad.0000213866.86934.7eCrossRefPubMed

42.

Craggs LJ, Yamamoto Y, Deramecourt V, Kalaria RN (2014) Microvascular pathology and morphometrics of sporadic and hereditary small vessel diseases of the brain. Brain Pathol 24:495–509. https://doi.org/10.1111/bpa.12177CrossRefPubMedPubMedCentral

43.

Daneman R, Prat A (2015) The blood-brain barrier. Cold Spring Harb Perspect Biol 7:a020412. https://doi.org/10.1101/cshperspect.a020412CrossRefPubMedPubMedCentral

44.

Deramecourt V, Slade JY, Oakley AE et al (2012) Staging and natural history of cerebrovascular pathology in dementia. Neurology 78:1043–1050. https://doi.org/10.1212/WNL.0b013e31824e8e7fCrossRefPubMedPubMedCentral

45.

Dirnagl U (2012) Pathobiology of injury after stroke: the neurovascular unit and beyond. Ann N Y Acad Sci 1268:21–25. https://doi.org/10.1111/j.1749-6632.2012.06691.xCrossRefPubMed

46.

Esiri MM, Wilcock GK, Morris JH (1997) Neuropathological assessment of the lesions of significance in vascular dementia. J Neurol Neurosurg Psychiatry 63:749–753CrossRefPubMedPubMedCentral

47.

Feinkohl I, Janke J, Hadzidiakos D et al (2019) Associations of the metabolic syndrome and its components with cognitive impairment in older adults. BMC Geriatr 19:77. https://doi.org/10.1186/s12877-019-1073-7CrossRefPubMedPubMedCentral

48.

Ferrer I (2010) Cognitive impairment of vascular origin: neuropathology of cognitive impairment of vascular origin. J Neurol Sci 299:139–149. https://doi.org/10.1016/j.jns.2010.08.039CrossRefPubMed

49.

Ferrer I, Bella R, Serrano MT, Marti E, Guionnet N (1990) Arteriolosclerotic leucoencephalopathy in the elderly and its relation to white matter lesions in Binswanger’s disease, multi-infarct encephalopathy and Alzheimer’s disease. J Neurol Sci 98:37–50. https://doi.org/10.1016/0022-510x(90)90180-uCrossRefPubMed

50.

Fishbein GA, Fishbein MC (2009) Arteriosclerosis: rethinking the current classification. Arch Pathol Lab Med 133:1309–1316. https://doi.org/10.1043/1543-2165-133.8.1309CrossRefPubMed

51.

Fishbein MC, Fishbein GA (2015) Arteriosclerosis: facts and fancy. Cardiovasc Pathol 24:335–342. https://doi.org/10.1016/j.carpath.2015.07.007CrossRefPubMed

52.

Flanagan M, Larson EB, Latimer CS et al (2016) Clinical-pathologic correlations in vascular cognitive impairment and dementia. Biochim Biophys Acta 1862:945–951. https://doi.org/10.1016/j.bbadis.2015.08.019CrossRefPubMed

53.

Fornage M, Debette S, Bis JC et al (2011) Genome-wide association studies of cerebral white matter lesion burden: the CHARGE consortium. Ann Neurol 69:928–939. https://doi.org/10.1002/ana.22403CrossRefPubMedPubMedCentral

54.

Francis F, Ballerini L, Wardlaw JM (2019) Perivascular spaces and their associations with risk factors, clinical disorders and neuroimaging features: a systematic review and meta-analysis. Int J Stroke 14:359–371. https://doi.org/10.1177/1747493019830321CrossRefPubMed

55.

French CR, Seshadri S, Destefano AL et al (2014) Mutation of FOXC1 and PITX2 induces cerebral small-vessel disease. J Clin Invest 124:4877–4881. https://doi.org/10.1172/JCI75109CrossRefPubMedPubMedCentral

56.

Frey BM, Petersen M, Mayer C et al (2019) Characterization of white matter hyperintensities in large-scale MRI-studies. Front Neurol 10:238. https://doi.org/10.3389/fneur.2019.00238CrossRefPubMedPubMedCentral

57.

Frosen J, Joutel A (2018) Smooth muscle cells of intracranial vessels: from development to disease. Cardiovasc Res 114:501–512. https://doi.org/10.1093/cvr/cvy002CrossRefPubMed

58.

Furie KL, Smith EE (2007) Metabolic syndrome: a target for preventing leukoaraiosis and age-related dementia? Neurology 69:951–952. https://doi.org/10.1212/01.wnl.0000271094.43789.0eCrossRefPubMed

59.

Gallart-Palau X, Tan LM, Serra A et al (2019) Degenerative protein modifications in the aging vasculature and central nervous system: a problem shared is not always halved. Ageing Res Rev 53:100909. https://doi.org/10.1016/j.arr.2019.100909CrossRefPubMed

60.

Gangwar RS, Bevan GH, Palanivel R, Das L, Rajagopalan S (2020) Oxidative stress pathways of air pollution mediated toxicity: recent insights. Redox Biol. https://doi.org/10.1016/j.redox.2020.101545CrossRefPubMedPubMedCentral

61.

Garland P, Morton MJ, Haskins W et al (2020) Haemoglobin causes neuronal damage in vivo which is preventable by haptoglobin. Brain Commun 2:fcz053. https://doi.org/10.1093/braincomms/fcz053CrossRefPubMedPubMedCentral

62.

Goetz CG, Tilley BC, Shaftman SR et al (2008) Movement disorder society-sponsored revision of the unified Parkinson’s Disease Rating Scale (MDS-UPDRS): scale presentation and clinimetric testing results. Mov Disord 23:2129–2170. https://doi.org/10.1002/mds.22340CrossRefPubMed

63.

Grinberg LT, Amaro E Jr, Teipel S et al (2008) Assessment of factors that confound MRI and neuropathological correlation of human postmortem brain tissue. Cell Tissue Bank 9:195–203. https://doi.org/10.1007/s10561-008-9080-5CrossRefPubMed

64.

Grinberg LT, Heinsen H (2010) Toward a pathological definition of vascular dementia. J Neurol Sci 299:136–138. https://doi.org/10.1016/j.jns.2010.08.055CrossRefPubMedPubMedCentral

65.

Grinberg LT, Thal DR (2010) Vascular pathology in the aged human brain. Acta Neuropathol 119:277–290. https://doi.org/10.1007/s00401-010-0652-7CrossRefPubMedPubMedCentral

66.

Group SMIftSR, Nasrallah IM, Pajewski NM et al (2019) Association of intensive vs standard blood pressure control with cerebral white matter lesions. JAMA 322:524–534. https://doi.org/10.1001/jama.2019.10551CrossRef

67.

Group SMIftSR, Williamson JD, Pajewski NM et al (2019) Effect of intensive vs standard blood pressure control on probable dementia: a randomized clinical trial. JAMA 321:553–561. https://doi.org/10.1001/jama.2018.21442CrossRef

68.

Grubb S, Cai C, Hald BO et al (2020) Precapillary sphincters maintain perfusion in the cerebral cortex. Nat Commun 11:395. https://doi.org/10.1038/s41467-020-14330-zCrossRefPubMedPubMedCentral

69.

Gull WW, Sutton HG (1872) On the pathology of the morbid state commonly called chronic Bright’s Disease with contracted kidney, (“Arterio-capillary fibrosis”). Med Chir Trans 55(273–330):271. https://doi.org/10.1177/095952877205500116CrossRef

70.

Gurol ME, Biessels GJ, Polimeni JR (2020) Advanced neuroimaging to unravel mechanisms of cerebral small vessel diseases. Stroke 51:29–37. https://doi.org/10.1161/STROKEAHA.119.024149CrossRefPubMed

71.

Hainsworth AH, Allan SM, Boltze J et al (2017) Translational models for vascular cognitive impairment: a review including larger species. BMC Med 15:16. https://doi.org/10.1186/s12916-017-0793-9CrossRefPubMedPubMedCentral

72.

Hainsworth AH, Oommen AT, Bridges LR (2015) Endothelial cells and human cerebral small vessel disease. Brain Pathol 25:44–50. https://doi.org/10.1111/bpa.12224CrossRefPubMed

73.

Harris R, Miners JS, Allen S, Love S (2018) VEGFR1 and VEGFR2 in Alzheimer’s Disease. J Alzheimers Dis 61:741–752. https://doi.org/10.3233/JAD-170745CrossRefPubMed

74.

Haruwaka K, Ikegami A, Tachibana Y et al (2019) Dual microglia effects on blood brain barrier permeability induced by systemic inflammation. Nat Commun 10:5816. https://doi.org/10.1038/s41467-019-13812-zCrossRefPubMedPubMedCentral

75.

Hase Y, Polvikoski TM, Firbank MJ et al (2020) Small vessel disease pathological changes in neurodegenerative and vascular dementias concomitant with autonomic dysfunction. Brain Pathol 30:191–202. https://doi.org/10.1111/bpa.12769CrossRefPubMed

76.

Hatate J, Miwa K, Matsumoto M et al (2016) Association between cerebral small vessel diseases and mild parkinsonian signs in the elderly with vascular risk factors. Parkinsonism Relat Disord 26:29–34. https://doi.org/10.1016/j.parkreldis.2016.02.011CrossRefPubMed

77.

Hayashi M, Miwa-Saito N, Tanuma N, Kubota M (2012) Brain vascular changes in Cockayne syndrome. Neuropathology 32:113–117. https://doi.org/10.1111/j.1440-1789.2011.01241.xCrossRefPubMed

78.

Herrmann SM, Textor SC (2019) Renovascular hypertension. Endocrinol Metab Clin North Am 48:765–778. https://doi.org/10.1016/j.ecl.2019.08.007CrossRefPubMedPubMedCentral

79.

Hill RA, Tong L, Yuan P et al (2015) Regional blood flow in the normal and ischemic brain Is controlled by arteriolar smooth muscle cell contractility and not by capillary pericytes. Neuron 87:95–110. https://doi.org/10.1016/j.neuron.2015.06.001CrossRefPubMedPubMedCentral

80.

Huang YH, Zhang WW, Lin L et al (2010) Could changes in arterioles impede the perivascular drainage of interstitial fluid from the cerebral white matter in leukoaraiosis? Neuropathol Appl Neurobiol 36:237–247. https://doi.org/10.1111/j.1365-2990.2009.01049.xCrossRefPubMed

81.

Huther G, Dorfl J, Van der Loos H, Jeanmonod D (1998) Microanatomic and vascular aspects of the temporomesial region. Neurosurgery 43:1118–1136CrossRefPubMed

82.

Iadecola C (2017) The neurovascular unit coming of age: a journey through neurovascular coupling in health and disease. Neuron 96:17–42. https://doi.org/10.1016/j.neuron.2017.07.030CrossRefPubMedPubMedCentral

83.

Ighodaro ET, Abner EL, Fardo DW et al (2017) Risk factors and global cognitive status related to brain arteriolosclerosis in elderly individuals. J Cereb Blood Flow Metab 37:201–216. https://doi.org/10.1177/0271678X15621574CrossRefPubMed

84.

Ighodaro ET, Nelson PT, Kukull WA et al (2017) Challenges and considerations related to studying dementia in Blacks/African Americans. J Alzheimers Dis 60:1–10. https://doi.org/10.3233/JAD-170242CrossRefPubMedPubMedCentral

85.

Imfeld P, Bodmer M, Schuerch M, Jick SS, Meier CR (2013) Seizures in patients with Alzheimer’s disease or vascular dementia: a population-based nested case-control analysis. Epilepsia 54:700–707. https://doi.org/10.1111/epi.12045CrossRefPubMed

86.

Iulita MF, Noriega de la Colina A, Girouard H (2018) Arterial stiffness, cognitive impairment and dementia: confounding factor or real risk? J Neurochem 144:527–548. https://doi.org/10.1111/jnc.14235CrossRefPubMed

87.

Janaway BM, Simpson JE, Hoggard N et al (2014) Brain haemosiderin in older people: pathological evidence for an ischaemic origin of magnetic resonance imaging (MRI) microbleeds. Neuropathol Appl Neurobiol 40:258–269. https://doi.org/10.1111/nan.12062CrossRefPubMedPubMedCentral

88.

Jellinger KA, Attems J (2010) Prevalence of dementia disorders in the oldest-old: an autopsy study. Acta Neuropathol 119:421–433. https://doi.org/10.1007/s00401-010-0654-5CrossRefPubMed

89.

Josephs KA, Murray ME, Whitwell JL et al (2014) Staging TDP-43 pathology in Alzheimer’s disease. Acta Neuropathol 127:441–450. https://doi.org/10.1007/s00401-013-1211-9CrossRefPubMed

90.

Joutel A, Corpechot C, Ducros A et al (1996) Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia. Nature 383:707–710. https://doi.org/10.1038/383707a0CrossRefPubMed

91.

Joutel A, Haddad I, Ratelade J, Nelson MT (2016) Perturbations of the cerebrovascular matrisome: a convergent mechanism in small vessel disease of the brain? J Cereb Blood Flow Metab 36:143–157. https://doi.org/10.1038/jcbfm.2015.62CrossRefPubMedPubMedCentral

92.

Kalaria RN (2016) Neuropathological diagnosis of vascular cognitive impairment and vascular dementia with implications for Alzheimer’s disease. Acta Neuropathol 131:659–685. https://doi.org/10.1007/s00401-016-1571-zCrossRefPubMedPubMedCentral

93.

Kalaria RN, Ferrer I, Love S (2015) Vascular disease, hypoxia, and related conditions. In: S. Love, A. Perry, J.W. Ironside, H. Budka (Eds.), Greenfield’s Neuropathology, CRC Press

94.

Kalaria RN, Hase Y (2019) Neurovascular ageing and age-related diseases. Subcell Biochem 91:477–499. https://doi.org/10.1007/978-981-13-3681-2_17CrossRefPubMed

95.

Kalaria RN, Kenny RA, Ballard CG et al (2004) Towards defining the neuropathological substrates of vascular dementia. J Neurol Sci 226:75–80. https://doi.org/10.1016/j.jns.2004.09.019CrossRefPubMed

96.

Kalmijn S, Foley D, White L et al (2000) Metabolic cardiovascular syndrome and risk of dementia in Japanese-American elderly men. The Honolulu-Asia aging study. Arterioscler Thromb Vasc Biol 20:2255–2260CrossRefPubMed

97.

Kamp JA, Moursel LG, Haan J et al (2014) Amyloid beta in hereditary cerebral hemorrhage with amyloidosis-Dutch type. Rev Neurosci 25:641–651. https://doi.org/10.1515/revneuro-2014-0008CrossRefPubMed

98.

Kang CK, Park CA, Lee H et al (2009) Hypertension correlates with lenticulostriate arteries visualized by 7T magnetic resonance angiography. Hypertension 54:1050–1056. https://doi.org/10.1161/HYPERTENSIONAHA.109.140350CrossRefPubMed

99.

Kapasi A, DeCarli C, Schneider JA (2017) Impact of multiple pathologies on the threshold for clinically overt dementia. Acta Neuropathol 134:171–186. https://doi.org/10.1007/s00401-017-1717-7CrossRefPubMedPubMedCentral

100.

Katsumata Y, Fardo DW, Kukull WA, Nelson PT (2018) Dichotomous scoring of TDP-43 proteinopathy from specific brain regions in 27 academic research centers: associations with Alzheimer’s disease and cerebrovascular disease pathologies. Acta Neuropathol Commun 6:142. https://doi.org/10.1186/s40478-018-0641-yCrossRefPubMedPubMedCentral

101.

Kim JB, Prunicki M, Haddad F et al (2020) Cumulative lifetime burden of cardiovascular disease from early exposure to air pollution. J Am Heart Assoc 9:e014944. https://doi.org/10.1161/JAHA.119.014944CrossRefPubMedPubMedCentral

102.

Kim KJ, Ramiro Diaz J, Iddings JA, Filosa JA (2016) Vasculo-neuronal coupling: retrograde vascular communication to brain neurons. J Neurosci 36:12624–12639. https://doi.org/10.1523/JNEUROSCI.1300-16.2016CrossRefPubMedPubMedCentral

103.

Kim SH, Shin DW, Yun JM et al (2017) Kidney dysfunction and cerebral microbleeds in neurologically healthy adults. PLoS ONE 12:e0172210. https://doi.org/10.1371/journal.pone.0172210CrossRefPubMedPubMedCentral

104.

Kisler K, Nelson AR, Montagne A, Zlokovic BV (2017) Cerebral blood flow regulation and neurovascular dysfunction in Alzheimer disease. Nat Rev Neurosci 18:419–434. https://doi.org/10.1038/nrn.2017.48CrossRefPubMedPubMedCentral

105.

Koehler RC, Roman RJ, Harder DR (2009) Astrocytes and the regulation of cerebral blood flow. Trends Neurosci 32:160–169. https://doi.org/10.1016/j.tins.2008.11.005CrossRefPubMed

106.

Koizumi T, Kerkhofs D, Mizuno T, Steinbusch HWM, Foulquier S (2019) Vessel-associated immune cells in cerebrovascular diseases: from perivascular macrophages to vessel-associated microglia. Front Neurosci 13:1291. https://doi.org/10.3389/fnins.2019.01291CrossRefPubMedPubMedCentral

107.

Kolar GR, Kothari PH, Khanlou N et al (2014) Neuropathology and genetics of cerebroretinal vasculopathies. Brain Pathol 24:510–518. https://doi.org/10.1111/bpa.12178CrossRefPubMedPubMedCentral

108.

Lam DW, LeRoith D (2000) Metabolic Syndrome. In: K.R. Feingold, B. Anawalt, A. Boyce, G. Chrousos, K. Dungan, A. Grossman, J.M. Hershman, G. Kaltsas, C. Koch, P. Kopp, M. Korbonits, R. McLachlan, J.E. Morley, M. New, L. Perreault, J. Purnell, R. Rebar, F. Singer, D.L. Trence, A. Vinik, D.P. Wilson (Eds.), Endotext, South Dartmouth

109.

Lammie GA (2002) Hypertensive cerebral small vessel disease and stroke. Brain Pathol 12:358–370. https://doi.org/10.1111/j.1750-3639.2002.tb00450.xCrossRefPubMed

110.

Lammie GA, Brannan F, Slattery J, Warlow C (1997) Nonhypertensive cerebral small-vessel disease. An autopsy study. Stroke 28:2222–2229. https://doi.org/10.1161/01.str.28.11.2222CrossRefPubMed

111.

Lee RM (1995) Morphology of cerebral arteries. Pharmacol Ther 66:149–173. https://doi.org/10.1016/0163-7258(94)00071-aCrossRefPubMed

112.

Lee SJ, Blanchett-Anderson S, Keep SG, Gasche MB, Wang MM (2020) Tripartite factors leading to molecular divergence between human and murine smooth muscle. PLoS ONE 15:e0227672. https://doi.org/10.1371/journal.pone.0227672CrossRefPubMedPubMedCentral

113.

Lim AS, Yu L, Schneider JA, Bennett DA, Buchman AS (2016) Sleep fragmentation, cerebral arteriolosclerosis, and brain infarct pathology in community-dwelling older people. Stroke 47:516–518. https://doi.org/10.1161/STROKEAHA.115.011608CrossRefPubMedPubMedCentral

114.

Lin Q, Huang WQ, Tzeng CM (2015) Genetic associations of leukoaraiosis indicate pathophysiological mechanisms in white matter lesions etiology. Rev Neurosci 26:343–358. https://doi.org/10.1515/revneuro-2014-0082CrossRefPubMed

115.

Lin WL, Castanedes-Casey M, Dickson DW (2009) Transactivation response DNA-binding protein 43 microvasculopathy in frontotemporal degeneration and familial Lewy body disease. J Neuropathol Exp Neurol 68:1167–1176. https://doi.org/10.1097/NEN.0b013e3181baacecCrossRefPubMed

116.

Lobstein JF (1833) Traite d'anatomie pathologique. Levrault

117.

Long DL, Howard G, Long DM et al (2019) An investigation of selection bias in estimating racial disparity in stroke risk factors. Am J Epidemiol 188:587–597. https://doi.org/10.1093/aje/kwy253CrossRefPubMed

118.

Love S, Miners JS (2016) Cerebrovascular disease in ageing and Alzheimer’s disease. Acta Neuropathol 131:645–658. https://doi.org/10.1007/s00401-015-1522-0CrossRefPubMed

119.

Love S, Miners JS (2017) Small vessel disease, neurovascular regulation and cognitive impairment: post-mortem studies reveal a complex relationship, still poorly understood. Clin Sci (Lond) 131:1579–1589. https://doi.org/10.1042/CS20170148CrossRef

120.

Lozic M, Sarenac O, Murphy D, Japundzic-Zigon N (2018) Vasopressin, central autonomic control and blood pressure regulation. Curr Hypertens Rep 20:11. https://doi.org/10.1007/s11906-018-0811-0CrossRefPubMed

121.

Ma SJ, Sarabi MS, Yan L et al (2019) Characterization of lenticulostriate arteries with high resolution black-blood T1-weighted turbo spin echo with variable flip angles at 3 and 7Tesla. Neuroimage 199:184–193. https://doi.org/10.1016/j.neuroimage.2019.05.065CrossRefPubMed

122.

Magaki S, Yong WH, Khanlou N, Tung S, Vinters HV (2014) Comorbidity in dementia: update of an ongoing autopsy study. J Am Geriatr Soc 62:1722–1728. https://doi.org/10.1111/jgs.12977CrossRefPubMedPubMedCentral

123.

Malik R, Chauhan G, Traylor M et al (2018) Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes. Nat Genet 50:524–537. https://doi.org/10.1038/s41588-018-0058-3CrossRefPubMedPubMedCentral

124.

Marini S, Anderson CD, Rosand J (2020) Genetics of cerebral small vessel disease. Stroke 51:12–20. https://doi.org/10.1161/STROKEAHA.119.024151CrossRefPubMed

125.

Marini S, Georgakis MK, Chung J et al (2020) Genetic overlap and causal inferences between kidney function and cerebrovascular disease. Neurology. https://doi.org/10.1212/WNL.0000000000009642CrossRefPubMedPubMedCentral

126.

Martinez-Lemus LA (2012) The dynamic structure of arterioles. Basic Clin Pharmacol Toxicol 110:5–11. https://doi.org/10.1111/j.1742-7843.2011.00813.xCrossRefPubMed

127.

McAleese KE, Alafuzoff I, Charidimou A et al (2016) Post-mortem assessment in vascular dementia: advances and aspirations. BMC Med 14:129. https://doi.org/10.1186/s12916-016-0676-5CrossRefPubMedPubMedCentral

128.

McAleese KE, Graham S, Dey M et al (2019) Extravascular fibrinogen in the white matter of Alzheimer’s disease and normal aged brains: implications for fibrinogen as a biomarker for Alzheimer’s disease. Brain Pathol 29:414–424. https://doi.org/10.1111/bpa.12685CrossRefPubMedPubMedCentral

129.

McAuley G, Schrag M, Barnes S et al (2011) Iron quantification of microbleeds in postmortem brain. Magn Reson Med 65:1592–1601. https://doi.org/10.1002/mrm.22745CrossRefPubMed

130.

McNeal DW, Brandner DD, Gong X et al (2016) Unbiased stereological analysis of reactive astrogliosis to estimate age-associated cerebral white matter injury. J Neuropathol Exp Neurol 75:539–554. https://doi.org/10.1093/jnen/nlw032CrossRefPubMedPubMedCentral

131.

Meng N, Mu X, Lv X et al (2019) Autophagy represses fascaplysin-induced apoptosis and angiogenesis inhibition via ROS and p8 in vascular endothelia cells. Biomed Pharmacother 114:108866. https://doi.org/10.1016/j.biopha.2019.108866CrossRefPubMed

132.

Mestre H, Mori Y, Nedergaard M (2020) The brain’s glymphatic system: current controversies. Trends Neurosci 43(7):458–466. https://doi.org/10.1016/j.tins.2020.04.003CrossRefPubMedPubMedCentral

133.

Meuwissen ME, Halley DJ, Smit LS et al (2015) The expanding phenotype of COL4A1 and COL4A2 mutations: clinical data on 13 newly identified families and a review of the literature. Genet Med 17:843–853. https://doi.org/10.1038/gim.2014.210CrossRefPubMed

134.

Miao Q, Paloneva T, Tuominen S et al (2004) Fibrosis and stenosis of the long penetrating cerebral arteries: the cause of the white matter pathology in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Brain Pathol 14:358–364. https://doi.org/10.1111/j.1750-3639.2004.tb00078.xCrossRefPubMed

135.

Mills KT, Stefanescu A, He J (2020) The global epidemiology of hypertension. Nat Rev Nephrol 16:223–237. https://doi.org/10.1038/s41581-019-0244-2CrossRefPubMedPubMedCentral

136.

Miners JS, Palmer JC, Love S (2016) Pathophysiology of hypoperfusion of the precuneus in early Alzheimer’s disease. Brain Pathol 26:533–541. https://doi.org/10.1111/bpa.12331CrossRefPubMed

137.

Mishra A, Chauhan G, Violleau MH et al (2019) Association of variants in HTRA1 and NOTCH3 with MRI-defined extremes of cerebral small vessel disease in older subjects. Brain 142:1009–1023. https://doi.org/10.1093/brain/awz024CrossRefPubMedPubMedCentral

138.

Mishra A, Reynolds JP, Chen Y et al (2016) Astrocytes mediate neurovascular signaling to capillary pericytes but not to arterioles. Nat Neurosci 19:1619–1627. https://doi.org/10.1038/nn.4428CrossRefPubMedPubMedCentral

139.

Mistriotis P, Andreadis ST (2017) Vascular aging: molecular mechanisms and potential treatments for vascular rejuvenation. Ageing Res Rev 37:94–116. https://doi.org/10.1016/j.arr.2017.05.006CrossRefPubMed

140.

Mock C, Teylan M, Beecham G et al (2020) The utility of the National Alzheimer’s Coordinating Center’s Database for the rapid assessment of evolving neuropathologic conditions. Alzheimer Dis Assoc Disord 34:105–111. https://doi.org/10.1097/WAD.0000000000000380CrossRefPubMedPubMedCentral

141.

Montagne A, Nation DA, Sagare AP et al (2020) APOE4 leads to blood-brain barrier dysfunction predicting cognitive decline. Nature 581:71–76. https://doi.org/10.1038/s41586-020-2247-3CrossRefPubMedPubMedCentral

142.

Montine TJ, Phelps CH, Beach TG et al (2012) National Institute on Aging-Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease: a practical approach. Acta Neuropathol 123:1–11. https://doi.org/10.1007/s00401-011-0910-3CrossRefPubMed

143.

Moretti R, Caruso P (2020) Small vessel disease-related dementia: an invalid neurovascular coupling? Int J Mol Sci. https://doi.org/10.3390/ijms21031095CrossRefPubMedPubMedCentral

144.

Moritz AR, Oldt MR (1937) Arteriolar sclerosis in hypertensive and non-hypertensive individuals. Am J Pathol 13(679–728):677

145.

Nag S, Kilty DW (1997) Cerebrovascular changes in chronic hypertension. Protective effects of enalapril in rats. Stroke 28:1028–1034. https://doi.org/10.1161/01.str.28.5.1028CrossRefPubMed

146.

Nag S, Yu L, Boyle PA et al (2018) TDP-43 pathology in anterior temporal pole cortex in aging and Alzheimer’s disease. Acta Neuropathol Commun 6:33. https://doi.org/10.1186/s40478-018-0531-3CrossRefPubMedPubMedCentral

147.

Nakano T, Munakata A, Shimaura N, Asano K, Ohkuma H (2012) Augmentation index is related to white matter lesions. Hypertens Res 35:729–732. https://doi.org/10.1038/hr.2012.24CrossRefPubMed

148.

Nelson PT, Abner EL, Patel E et al (2018) The amygdala as a locus of pathologic misfolding in neurodegenerative diseases. J Neuropathol Exp Neurol 77:2–20. https://doi.org/10.1093/jnen/nlx099CrossRefPubMed

149.

Nelson PT, Dickson DW, Trojanowski JQ et al (2019) Limbic-predominant age-related TDP-43 encephalopathy (LATE): consensus working group report. Brain. https://doi.org/10.1093/brain/awz099CrossRefPubMedPubMedCentral

150.

Nelson PT, Head E, Schmitt FA et al (2011) Alzheimer’s disease is not “brain aging”: neuropathological, genetic, and epidemiological human studies. Acta Neuropathol 121:571–587. https://doi.org/10.1007/s00401-011-0826-yCrossRefPubMedPubMedCentral

151.

Nelson PT, Jicha GA, Wang WX et al (2015) ABCC9/SUR2 in the brain: Implications for hippocampal sclerosis of aging and a potential therapeutic target. Ageing Res Rev 24:111–125. https://doi.org/10.1016/j.arr.2015.07.007CrossRefPubMedPubMedCentral

152.

Nelson PT, Smith CD, Abner EA et al (2009) Human cerebral neuropathology of Type 2 diabetes mellitus. Biochim Biophys Acta 1792:454–469. https://doi.org/10.1016/j.bbadis.2008.08.005CrossRefPubMed

153.

Neltner JH, Abner EL, Baker S et al (2014) Arteriolosclerosis that affects multiple brain regions is linked to hippocampal sclerosis of ageing. Brain 137:255–267. https://doi.org/10.1093/brain/awt318CrossRefPubMed

154.

Neltner JH, Abner EL, Jicha GA et al (2016) Brain pathologies in extreme old age. Neurobiol Aging 37:1–11. https://doi.org/10.1016/j.neurobiolaging.2015.10.009CrossRefPubMed

155.

Niiya Y, Abumiya T, Shichinohe H et al (2006) Susceptibility of brain microvascular endothelial cells to advanced glycation end products-induced tissue factor upregulation is associated with intracellular reactive oxygen species. Brain Res 1108:179–187. https://doi.org/10.1016/j.brainres.2006.06.038CrossRefPubMed

156.

Norris CM, Kadish I, Blalock EM et al (2005) Calcineurin triggers reactive/inflammatory processes in astrocytes and is upregulated in aging and Alzheimer’s models. J Neurosci 25:4649–4658. https://doi.org/10.1523/JNEUROSCI.0365-05.2005CrossRefPubMedPubMedCentral

157.

Okeda R (2003) Pathological changes in the cerebral medullary arteries of five autopsy cases of malignant nephrosclerosis: observation by morphometry and reconstruction of serial sections. Neuropathology 23:153–160. https://doi.org/10.1046/j.1440-1789.2003.00492.xCrossRefPubMed

158.

Okeda R, Murayama S, Sawabe M, Kuroiwa T (2004) Pathology of the cerebral artery in binswanger’s disease in the aged: observation by serial sections and morphometry of the cerebral arteries. Neuropathology 24:21–29. https://doi.org/10.1111/j.1440-1789.2003.00534.xCrossRefPubMed

159.

Ovbiagele B, Saver JL (2006) Cerebral white matter hyperintensities on MRI: current concepts and therapeutic implications. Cerebrovasc Dis 22:83–90. https://doi.org/10.1159/000093235CrossRefPubMed

160.

Oveisgharan S, Arvanitakis Z, Yu L et al (2018) Sex differences in Alzheimer’s disease and common neuropathologies of aging. Acta Neuropathol 136:887–900. https://doi.org/10.1007/s00401-018-1920-1CrossRefPubMedPubMedCentral

161.

Ozen I, Deierborg T, Miharada K et al (2014) Brain pericytes acquire a microglial phenotype after stroke. Acta Neuropathol 128:381–396. https://doi.org/10.1007/s00401-014-1295-xCrossRefPubMedPubMedCentral

162.

Pasi M, Rocha E, Samore W et al (2020) Premature vascular disease in young adult stroke: a pathology-based case series. J Neurol 267:1063–1069. https://doi.org/10.1007/s00415-019-09623-3CrossRefPubMed

163.

Paternoster L, Chen W, Sudlow CL (2009) Genetic determinants of white matter hyperintensities on brain scans: a systematic assessment of 19 candidate gene polymorphisms in 46 studies in 19,000 subjects. Stroke 40:2020–2026. https://doi.org/10.1161/STROKEAHA.108.542050CrossRefPubMed

164.

Petito CK, Levy DE (1980) The importance of cerebral arterioles in alterations of the blood-brain barrier. Lab Invest 43:262–268PubMed

165.

Popa-Wagner A, Buga AM, Popescu B, Muresanu D (2015) Vascular cognitive impairment, dementia, aging and energy demand. A vicious cycle. J Neural Transm (Vienna) 122(Suppl 1):S47-54. https://doi.org/10.1007/s00702-013-1129-3CrossRef

166.

Popescu BO, Toescu EC, Popescu LM et al (2009) Blood-brain barrier alterations in ageing and dementia. J Neurol Sci 283:99–106. https://doi.org/10.1016/j.jns.2009.02.321CrossRefPubMed

167.

Price BR, Norris CM, Sompol P, Wilcock DM (2018) An emerging role of astrocytes in vascular contributions to cognitive impairment and dementia. J Neurochem 144:644–650. https://doi.org/10.1111/jnc.14273CrossRefPubMedPubMedCentral

168.

Rannikmae K, Sivakumaran V, Millar H et al (2017) COL4A2 is associated with lacunar ischemic stroke and deep ICH: meta-analyses among 21,500 cases and 40,600 controls. Neurology 89:1829–1839. https://doi.org/10.1212/WNL.0000000000004560CrossRefPubMedPubMedCentral

169.

Reitz C, Patel B, Tang MX et al (2007) Relation between vascular risk factors and neuropsychological test performance among elderly persons with Alzheimer’s disease. J Neurol Sci 257:194–201. https://doi.org/10.1016/j.jns.2007.01.030CrossRefPubMedPubMedCentral

170.

Richards A, van den Maagdenberg AM, Jen JC et al (2007) C-terminal truncations in human 3′-5′ DNA exonuclease TREX1 cause autosomal dominant retinal vasculopathy with cerebral leukodystrophy. Nat Genet 39:1068–1070. https://doi.org/10.1038/ng2082CrossRefPubMed

171.

Richardson K, Stephan BC, Ince PG et al (2012) The neuropathology of vascular disease in the Medical Research Council Cognitive Function and Ageing Study (MRC CFAS). Curr Alzheimer Res 9:687–696CrossRefPubMed

172.

Rosenberg GA (2017) Extracellular matrix inflammation in vascular cognitive impairment and dementia. Clin Sci (Lond) 131:425–437. https://doi.org/10.1042/CS20160604CrossRef

173.

Rosman NP, Anselm I, Bhadelia RA (2001) Progressive intracranial vascular disease with strokes and seizures in a boy with progeria. J Child Neurol 16:212–215. https://doi.org/10.1177/088307380101600309CrossRefPubMed

174.

Rouhl RP, Damoiseaux JG, Lodder J et al (2012) Vascular inflammation in cerebral small vessel disease. Neurobiol Aging 33:1800–1806. https://doi.org/10.1016/j.neurobiolaging.2011.04.008CrossRefPubMed

175.

Saito R, Nozaki H, Kato T et al (2019) Retinal vasculopathy with cerebral leukodystrophy: clinicopathologic features of an autopsied patient with a heterozygous TREX 1 mutation. J Neuropathol Exp Neurol 78:181–186. https://doi.org/10.1093/jnen/nly115CrossRefPubMed

176.

Saklayen MG (2018) The global epidemic of the metabolic syndrome. Curr Hypertens Rep 20:12. https://doi.org/10.1007/s11906-018-0812-zCrossRefPubMedPubMedCentral

177.

Sartorius T, Peter A, Heni M et al (2015) The brain response to peripheral insulin declines with age: a contribution of the blood-brain barrier? PLoS ONE 10:e0126804. https://doi.org/10.1371/journal.pone.0126804CrossRefPubMedPubMedCentral

178.

Schlesinger D, Grinberg LT, Alba JG et al (2013) African ancestry protects against Alzheimer’s disease-related neuropathology. Mol Psychiatry 18:79–85. https://doi.org/10.1038/mp.2011.136CrossRefPubMed

179.

Shindo A, Ishikawa H, Ii Y, Niwa A, Tomimoto H (2020) Clinical features and experimental models of cerebral small vessel disease. Front Aging Neurosci 12:109. https://doi.org/10.3389/fnagi.2020.00109CrossRefPubMedPubMedCentral

180.

Silverman A, Petersen NH (2020) Physiology, cerebral autoregulation. StatPearls, Treasure Island

181.

Simard M, Arcuino G, Takano T, Liu QS, Nedergaard M (2003) Signaling at the gliovascular interface. J Neurosci 23:9254–9262CrossRefPubMedPubMedCentral

182.

Skrobot OA, Attems J, Esiri M et al (2016) Vascular cognitive impairment neuropathology guidelines (VCING): the contribution of cerebrovascular pathology to cognitive impairment. Brain 139:2957–2969. https://doi.org/10.1093/brain/aww214CrossRefPubMed

183.

Smallwood A, Oulhaj A, Joachim C et al (2012) Cerebral subcortical small vessel disease and its relation to cognition in elderly subjects: a pathological study in the Oxford Project to Investigate Memory and Ageing (OPTIMA) cohort. Neuropathol Appl Neurobiol 38:337–343. https://doi.org/10.1111/j.1365-2990.2011.01221.xCrossRefPubMed

184.

Smith AS, Wiznitzer M, Karaman BA, Horwitz SJ, Lanzieri CF (1993) MRA detection of vascular occlusion in a child with progeria. AJNR Am J Neuroradiol 14:441–443PubMedPubMedCentral

185.

Smith EE, O’Donnell M, Dagenais G et al (2015) Early cerebral small vessel disease and brain volume, cognition, and gait. Ann Neurol 77:251–261. https://doi.org/10.1002/ana.24320CrossRefPubMedPubMedCentral

186.

Snyder HM, Corriveau RA, Craft S et al (2015) Vascular contributions to cognitive impairment and dementia including Alzheimer’s disease. Alzheimers Dement 11:710–717. https://doi.org/10.1016/j.jalz.2014.10.008CrossRefPubMed

187.

Sonnen JA, Larson EB, Haneuse S et al (2009) Neuropathology in the adult changes in thought study: a review. J Alzheimers Dis 18:703–711. https://doi.org/10.3233/JAD-2009-1180CrossRefPubMedPubMedCentral

188.

Spence JD (2019) Blood pressure gradients in the brain: Their importance to understanding pathogenesis of cerebral small vessel disease. Brain Sci. https://doi.org/10.3390/brainsci9020021CrossRefPubMedPubMedCentral

189.

Staiculescu MC, Foote C, Meininger GA, Martinez-Lemus LA (2014) The role of reactive oxygen species in microvascular remodeling. Int J Mol Sci 15:23792–23835. https://doi.org/10.3390/ijms151223792CrossRefPubMedPubMedCentral

190.

Sudduth TL, Powell DK, Smith CD, Greenstein A, Wilcock DM (2013) Induction of hyperhomocysteinemia models vascular dementia by induction of cerebral microhemorrhages and neuroinflammation. J Cereb Blood Flow Metab 33:708–715. https://doi.org/10.1038/jcbfm.2013.1CrossRefPubMedPubMedCentral

191.

Sudduth TL, Weekman EM, Price BR et al (2017) Time-course of glial changes in the hyperhomocysteinemia model of vascular cognitive impairment and dementia (VCID). Neuroscience 341:42–51. https://doi.org/10.1016/j.neuroscience.2016.11.024CrossRefPubMed

192.

Suemoto CK, Ferretti-Rebustini RE, Rodriguez RD et al (2017) Neuropathological diagnoses and clinical correlates in older adults in Brazil: a cross-sectional study. PLoS Med 14:e1002267. https://doi.org/10.1371/journal.pmed.1002267CrossRefPubMedPubMedCentral

193.

Suemoto CK, Leite REP, Ferretti-Rebustini REL et al (2019) Neuropathological lesions in the very old: results from a large Brazilian autopsy study. Brain Pathol 29:771–781. https://doi.org/10.1111/bpa.12719CrossRefPubMedPubMedCentral

194.

Sweeney MD, Ayyadurai S, Zlokovic BV (2016) Pericytes of the neurovascular unit: key functions and signaling pathways. Nat Neurosci 19:771–783. https://doi.org/10.1038/nn.4288CrossRefPubMedPubMedCentral

195.

Tamura Y, Araki A (2015) Diabetes mellitus and white matter hyperintensity. Geriatr Gerontol Int 15(Suppl 1):34–42. https://doi.org/10.1111/ggi.12666CrossRefPubMed

196.

Tanoi Y, Okeda R, Budka H (2000) Binswanger’s encephalopathy: serial sections and morphometry of the cerebral arteries. Acta Neuropathol 100:347–355. https://doi.org/10.1007/s004010000203CrossRefPubMed

197.

Tesauro M, Mauriello A, Rovella V et al (2017) Arterial ageing: from endothelial dysfunction to vascular calcification. J Intern Med 281:471–482. https://doi.org/10.1111/joim.12605CrossRefPubMed

198.

Thal DR, Ghebremedhin E, Orantes M, Wiestler OD (2003) Vascular pathology in Alzheimer disease: correlation of cerebral amyloid angiopathy and arteriosclerosis/lipohyalinosis with cognitive decline. J Neuropathol Exp Neurol 62:1287–1301CrossRefPubMed

199.

Thal DR, Grinberg LT, Attems J (2012) Vascular dementia: different forms of vessel disorders contribute to the development of dementia in the elderly brain. Exp Gerontol 47:816–824. https://doi.org/10.1016/j.exger.2012.05.023CrossRefPubMedPubMedCentral

200.

Tomimoto H, Akiguchi I, Wakita H et al (1999) Coagulation activation in patients with Binswanger disease. Arch Neurol 56:1104–1108. https://doi.org/10.1001/archneur.56.9.1104CrossRefPubMed

201.

Traylor M, Malik R, Nalls MA et al (2017) Genetic variation at 16q24.2 is associated with small vessel stroke. Ann Neurol 81:383–394. https://doi.org/10.1002/ana.24840CrossRefPubMedPubMedCentral

202.

Traylor M, Tozer DJ, Croall ID et al (2019) Genetic variation in PLEKHG1 is associated with white matter hyperintensities (n = 11,226). Neurology 92:e749–e757. https://doi.org/10.1212/WNL.0000000000006952CrossRefPubMedPubMedCentral

203.

Traylor M, Zhang CR, Adib-Samii P et al (2016) Genome-wide meta-analysis of cerebral white matter hyperintensities in patients with stroke. Neurology 86:146–153. https://doi.org/10.1212/WNL.0000000000002263CrossRefPubMedPubMedCentral

204.

Uemura MT, Ihara M, Maki T et al (2018) Pericyte-derived bone morphogenetic protein 4 underlies white matter damage after chronic hypoperfusion. Brain Pathol 28:521–535. https://doi.org/10.1111/bpa.12523CrossRefPubMed

205.

Uemura MT, Maki T, Ihara M, Lee VMY, Trojanowski JQ (2020) Brain microvascular pericytes in vascular cognitive impairment and dementia. Front Aging Neurosci 12:80. https://doi.org/10.3389/fnagi.2020.00080CrossRefPubMedPubMedCentral

206.

Ungvari Z, Tarantini S, Donato AJ, Galvan V, Csiszar A (2018) Mechanisms of vascular aging. Circ Res 123:849–867. https://doi.org/10.1161/CIRCRESAHA.118.311378CrossRefPubMedPubMedCentral

207.

Utz SG, See P, Mildenberger W et al (2020) Early fate defines microglia and non-parenchymal brain macrophage development. Cell 181(557–573):e518. https://doi.org/10.1016/j.cell.2020.03.021CrossRef

208.

van Osch MJ, Teeuwisse WM, Chen Z et al (2018) Advances in arterial spin labelling MRI methods for measuring perfusion and collateral flow. J Cereb Blood Flow Metab 38:1461–1480. https://doi.org/10.1177/0271678X17713434CrossRefPubMed

209.

van Swieten JC, van den Hout JH, van Ketel BA et al (1991) Periventricular lesions in the white matter on magnetic resonance imaging in the elderly. A morphometric correlation with arteriolosclerosis and dilated perivascular spaces. Brain 114(Pt 2):761–774. https://doi.org/10.1093/brain/114.2.761CrossRefPubMed

210.

Vanlandewijck M, He L, Mae MA et al (2018) A molecular atlas of cell types and zonation in the brain vasculature. Nature 554:475–480. https://doi.org/10.1038/nature25739CrossRefPubMed

211.

Vinters HV, Ellis WG, Zarow C et al (2000) Neuropathologic substrates of ischemic vascular dementia. J Neuropathol Exp Neurol 59:931–945CrossRefPubMed

212.

Vinters HV, Zarow C, Borys E et al (2018) Review: vascular dementia: clinicopathologic and genetic considerations. Neuropathol Appl Neurobiol 44:247–266. https://doi.org/10.1111/nan.12472CrossRefPubMed

213.

Wallin A, Roman GC, Esiri M et al (2018) Update on vascular cognitive impairment Associated with subcortical small-vessel disease. J Alzheimers Dis 62:1417–1441. https://doi.org/10.3233/JAD-170803CrossRefPubMedPubMedCentral

214.

Wardlaw JM, Benveniste H, Nedergaard M et al (2020) Perivascular spaces in the brain: anatomy, physiology and pathology. Nat Rev Neurol 16:137–153. https://doi.org/10.1038/s41582-020-0312-zCrossRefPubMed

215.

Wardlaw JM, Smith EE, Biessels GJ et al (2013) Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration. Lancet Neurol 12:822–838. https://doi.org/10.1016/S1474-4422(13)70124-8CrossRefPubMedPubMedCentral

216.

Wardlaw JM, Valdes Hernandez MC, Munoz-Maniega S (2015) What are white matter hyperintensities made of? Relevance to vascular cognitive impairment. J Am Heart Assoc 4:001140. https://doi.org/10.1161/JAHA.114.001140CrossRefPubMed

217.

Warnert EA, Rodrigues JC, Burchell AE et al (2016) Is high blood pressure self-protection for the brain? Circ Res 119:e140–e151. https://doi.org/10.1161/CIRCRESAHA.116.309493CrossRefPubMed

218.

Woo D, Falcone GJ, Devan WJ et al (2014) Meta-analysis of genome-wide association studies identifies 1q22 as a susceptibility locus for intracerebral hemorrhage. Am J Hum Genet 94:511–521. https://doi.org/10.1016/j.ajhg.2014.02.012CrossRefPubMedPubMedCentral

219.

Yamazaki T, Mukouyama YS (2018) Tissue specific origin, development, and pathological perspectives of pericytes. Front Cardiovasc Med 5:78. https://doi.org/10.3389/fcvm.2018.00078CrossRefPubMedPubMedCentral

220.

Yang F, Qian D, Hu D et al (2016) Prevalence, awareness, treatment, and control of hypertension in the older population: results from the multiple national studies on ageing. J Am Soc Hypertens 10:140–148. https://doi.org/10.1016/j.jash.2015.11.016CrossRefPubMed

221.

Yates PA, Villemagne VL, Ellis KA et al (2014) Cerebral microbleeds: a review of clinical, genetic, and neuroimaging associations. Front Neurol 4:205. https://doi.org/10.3389/fneur.2013.00205CrossRefPubMedPubMedCentral

222.

Yip AG, McKee AC, Green RC et al (2005) APOE, vascular pathology, and the AD brain. Neurology 65:259–265. https://doi.org/10.1212/01.wnl.0000168863.49053.4dCrossRefPubMed

223.

Zeng Y, Zhang L, Hu Z (2016) Cerebral insulin, insulin signaling pathway, and brain angiogenesis. Neurol Sci 37:9–16. https://doi.org/10.1007/s10072-015-2386-8CrossRefPubMed

Title: Brain arteriolosclerosis
Authors: Brittney L. Blevins
Harry V. Vinters
Seth Love
Donna M. Wilcock
Lea T. Grinberg
Julie A. Schneider
Rajesh N. Kalaria
Yuriko Katsumata
Brian T. Gold
Danny J. J. Wang
Samantha J. Ma
Lincoln M. P. Shade
David W. Fardo
Anika M. S. Hartz
Gregory A. Jicha
Karin B. Nelson
Shino D. Magaki
Frederick A. Schmitt
Merilee A. Teylan
Eseosa T. Ighodaro
Panhavuth Phe
Erin L. Abner
Matthew D. Cykowski
Linda J. Van Eldik
Peter T. Nelson
Publication date: 01-01-2021
Publisher: Springer Berlin Heidelberg
Keywords: Cerebral Small Vessel Disease
Arterial Occlusive Disease
Published in: Acta Neuropathologica / Issue 1/2021
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI: https://doi.org/10.1007/s00401-020-02235-6

At a glance: The STEP trials

Springer Medicine

Brain arteriolosclerosis

Abstract

At a glance: The STEP trials

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 1/2021

MOG-expressing teratoma followed by MOG-IgG-positive optic neuritis

Malignant transformation of a polymorphous low grade neuroepithelial tumor of the young (PLNTY)

Direct neural transmission of vCJD/BSE in macaque after finger incision

Archeological neuroimmunology: resurrection of a pathogenic immune response from a historical case sheds light on human autoimmune encephalomyelitis and multiple sclerosis

Accumulation of amyloid precursor protein C-terminal fragments triggers mitochondrial structure, function, and mitophagy defects in Alzheimer’s disease models and human brains

Neuropathological evaluation of a vertebrate brain aged ~ 245 years