Abstract
Cerebral amyloid angiopathy (CAA) is caused by the deposition of the amyloid β-protein (Aβ) in the wall of cerebral and leptomeningeal blood vessels and is related to Alzheimer’s disease (AD). Capillary Aβ deposition is observed in a subset of CAA cases and represents a distinct type of CAA named capillary CAA or CAA type 1. This type of CAA is strongly associated with the presence of the apolipoprotein E ε4 allele. CAA type 1-associated AD cases often exhibit a more severe Aβ plaque pathology but less widespread neurofibrillary tangle (NFT) pathology. The objective of this study was to analyze whether capillary CAA and its effects on cerebral blood flow have an impact on dementia. To address this objective, we performed neuropathological evaluation of 284 autopsy cases of demented and non-demented individuals. We assessed the presence of CAA and its subtypes as well as for that of hemorrhages and infarcts. Capillary CAA and CAA severity were associated with allocortical microinfarcts, comprising the CA1 region of the hippocampus. Allocortical microinfarcts, capillary CAA and CAA severity were, thereby, associated with cognitive decline. In conclusion, allocortical microinfarcts, CAA severity, and the capillary type of CAA were associated with one another and with the development of cognitive decline. Thus, AD cases with CAA type 1 (capillary CAA) appear to develop dementia symptoms not only due to AD-related Aβ plaque and NFT pathology but also due to hippocampal microinfarcts that are associated with CAA type 1 and CAA severity, and that damage a brain region important for memory function.
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References
Agresti A (2002) Categorical data analysis. Wiley, Hoboken
Amador-Ortiz C, Lin WL, Ahmed Z, Personett D, Davies P, Duara R, Graff-Radford NR, Hutton ML, Dickson DW (2007) TDP-43 immunoreactivity in hippocampal sclerosis and Alzheimer’s disease. Ann Neurol 61:435–445
Arvanitakis Z, Capuano AW, Leurgans SE, Buchman AS, Bennett DA, Schneider JA (2017) The relationship of cerebral vessel pathology to brain microinfarcts. Brain Pathol 27:77–85
Arvanitakis Z, Leurgans SE, Barnes LL, Bennett DA, Schneider JA (2011) Microinfarct pathology, dementia, and cognitive systems. Stroke 42:722–727
Attems J, Yamaguchi H, Saido TC, Thal DR (2010) Capillary CAA and perivascular Aβ-deposition: two distinct features of Alzheimer’s disease pathology. J Neurol Sci 299:155–162
Braak H, Alafuzoff I, Arzberger T, Kretzschmar H, Del Tredici K (2006) Staging of Alzheimer disease-associated neurofibrillary pathology using paraffin sections and immunocytochemistry. Acta Neuropathol 112:389–404
Braak H, Braak E (1991) Neuropathological staging of Alzheimer-related changes. Acta Neuropathol 82:239–259
Brenowitz WD, Hubbard RA, Keene CD, Hawes SE, Longstreth WT Jr, Woltjer RL, Kukull WA (2017) Mixed neuropathologies and associations with domain-specific cognitive decline. Neurology 89:1773–1781
Calhoun ME, Burgermeister P, Phinney AL, Stalder M, Tolnay M, Wiederhold KH, Abramowski D, Sturchler-Pierrat C, Sommer B, Staufenbiel M, Jucker M (1999) Neuronal overexpression of mutant amyloid precursor protein results in prominent deposition of cerebrovascular amyloid. Proc Natl Acad Sci USA 96:14088–14093
Carare RO, Hawkes CA, Jeffrey M, Kalaria RN, Weller RO (2013) Review: cerebral amyloid angiopathy, prion angiopathy, CADASIL and the spectrum of protein elimination failure angiopathies (PEFA) in neurodegenerative disease with a focus on therapy. Neuropathol Appl Neurobiol 39:593–611
Charidimou A, Boulouis G, Gurol ME, Ayata C, Bacskai BJ, Frosch MP, Viswanathan A, Greenberg SM (2017) Emerging concepts in sporadic cerebral amyloid angiopathy. Brain 140:1829–1850
Dickson DW (1997) The pathogenesis of senile plaques. J Neuropathol Exp Neurol 56:321–339
Erkinjuntti T, Haltia M, Palo J, Sulkava R, Paetau A (1988) Accuracy of the clinical diagnosis of vascular dementia: a prospective clinical and post-mortem neuropathological study. J Neurol Neurosurg Psychiatry 51:1037–1044
Esiri MM, Nagy Z, Smith MZ, Barnetson L, Smith AD (1999) Cerebrovascular disease and threshold for dementia in the early stages of Alzheimer’s disease. Lancet 354:919–920
Glenner GG, Wong CW (1984) Alzheimer’s disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem Biophys Res Commun 120:885–890
Gold G, Giannakopoulos P, Herrmann FR, Bouras C, Kovari E (2007) Identification of Alzheimer and vascular lesion thresholds for mixed dementia. Brain 130:2830–2836
Greenberg SM, Vernooij MW, Cordonnier C, Viswanathan A, Al-Shahi Salman R, Warach S, Launer LJ, Van Buchem MA, Breteler MM (2009) Cerebral microbleeds: a guide to detection and interpretation. Lancet Neurol 8:165–174
Grinberg LT, Thal DR (2010) Vascular pathology in the aged human brain. Acta Neuropathol 119:277–290
Hartley T, Lever C, Burgess N, O’Keefe J (2014) Space in the brain: how the hippocampal formation supports spatial cognition. Philos Trans R Soc Lond B 369:20120510
Hawkes CA, Michalski D, Anders R, Nissel S, Grosche J, Bechmann I, Carare RO, Hartig W (2013) Stroke-induced opposite and age-dependent changes of vessel-associated markers in co-morbid transgenic mice with Alzheimer-like alterations. Exp Neurol 250:270–281
Hughes CP, Berg L, Danziger WL, Coben LA, Martin RL (1982) A new clinical scale for the staging of dementia. Br J Psychiatry 140:566–572
Hyman BT, Phelps CH, Beach TG, Bigio EH, Cairns NJ, Carrillo MC, Dickson DW, Duyckaerts C, Frosch MP, Masliah E, Mirra SS, Nelson PT, Schneider JA, Thal DR, Thies B, Trojanowski JQ, Vinters HV, Montine TJ (2012) National Institute on Aging–Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease. Alzheimers Dement 8:1–13
Ince PG, Minett T, Forster G, Brayne C, Wharton SB, Medical Research Council Cognitive F, Ageing Neuropathology S (2017) Microinfarcts in an older population-representative brain donor cohort (MRC CFAS): Prevalence, relation to dementia and mobility, and implications for the evaluation of cerebral Small Vessel Disease. Neuropathol Appl Neurobiol 43:409–418
Joachim CL, Morris JH, Selkoe DJ (1988) Clinically diagnosed Alzheimer’s disease: autopsy results in 150 cases. Ann Neurol 24:50–56
Kovari E, Herrmann FR, Gold G, Hof PR, Charidimou A (2017) Association of cortical microinfarcts and cerebral small vessel pathology in the ageing brain. Neuropathol Appl Neurobiol 43:505–513
Larionov S, Dedeck O, Birkenmeier G, Orantes M, Ghebremedhin E, Thal DR (2006) The intronic deletion polymorphism of the a2-macroglobulin gene modulates the severity and extent of atherosclerosis in the circle of Willis. Neuropathol Appl Neurobiol 32:451–454
Lauer A, van Veluw SJ, William CM, Charidimou A, Roongpiboonsopit D, Vashkevich A, Ayres A, Martinez-Ramirez S, Gurol EM, Biessels GJ, Frosch M, Greenberg SM, Viswanathan A (2016) Microbleeds on MRI are associated with microinfarcts on autopsy in cerebral amyloid angiopathy. Neurology 87:1488–1492
Launer LJ, Hughes TM, White LR (2011) Microinfarcts, brain atrophy, and cognitive function: the Honolulu Asia Aging Study Autopsy Study. Ann Neurol 70:774–780
Lee JH, Olichney JM, Hansen LA, Hofstetter CR, Thal LJ (2000) Small concomitant vascular lesions do not influence rates of cognitive decline in patients with Alzheimer disease. Arch Neurol 57:1474–1479
Makela M, Paetau A, Polvikoski T, Myllykangas L, Tanskanen M (2016) Capillary amyloid-beta protein deposition in a population-based study (Vantaa 85 +). J Alzheimers Dis 49:149–157
Mandybur TI (1986) Cerebral amyloid angiopathy: the vascular pathology and complications. J Neuropathol Exp Neurol 45:79–90
Mirra SS, Heyman A, McKeel D, Sumi SM, Crain BJ, Brownlee LM, Vogel FS, Hughes JP, van Belle G, Berg L (1991) The Consortium to establish a registry for Alzheimer’s disease (CERAD). Part II. Standardization of the neuropathologic assessment of Alzheimer’s disease. Neurology 41:479–486
Morel F (1950) Petite contribution a l’etude d’une angiopathie apparemment dyshorique et topistique. Monatsschr Psychiatr Neurol 120:352–357
Morris AW, Sharp MM, Albargothy NJ, Fernandes R, Hawkes CA, Verma A, Weller RO, Carare RO (2016) Vascular basement membranes as pathways for the passage of fluid into and out of the brain. Acta Neuropathol 131:725–736
Morris JC (1993) The Clinical Dementia Rating (CDR): current version and scoring rules. Neurology 43:2412–2414
Morris JC, Heyman A, Mohs RC, Hughes JP, van Belle G, Fillenbaum G, Mellits ED, Clark C (1989) The Consortium to Establish a Registry for Alzheimer’s Disease (CERAD). Part I. Clinical and neuropsychological assessment of Alzheimer’s disease. Neurology 39:1159–1165
Moser EI, Moser MB, McNaughton BL (2017) Spatial representation in the hippocampal formation: a history. Nat Neurosci 20:1448–1464
Niwa K, Carlson GA, Iadecola C (2000) Exogenous A beta1-40 reproduces cerebrovascular alterations resulting from amyloid precursor protein overexpression in mice. J Cereb Blood Flow Metab 20:1659–1668
Niwa K, Younkin L, Ebeling C, Turner SK, Westaway D, Younkin S, Ashe KH, Carlson GA, Iadecola C (2000) Abeta 1-40-related reduction in functional hyperemia in mouse neocortex during somatosensory activation. Proc Natl Acad Sci USA 97:9735–9740
Okamoto Y, Yamamoto T, Kalaria RN, Senzaki H, Maki T, Hase Y, Kitamura A, Washida K, Yamada M, Ito H, Tomimoto H, Takahashi R, Ihara M (2012) Cerebral hypoperfusion accelerates cerebral amyloid angiopathy and promotes cortical microinfarcts. Acta Neuropathol 123:381–394
Park L, Koizumi K, El Jamal S, Zhou P, Previti ML, Van Nostrand WE, Carlson G, Iadecola C (2014) Age-dependent neurovascular dysfunction and damage in a mouse model of cerebral amyloid angiopathy. Stroke 45:1815–1821
Shin HK, Jones PB, Garcia-Alloza M, Borrelli L, Greenberg SM, Bacskai BJ, Frosch MP, Hyman BT, Moskowitz MA, Ayata C (2007) Age-dependent cerebrovascular dysfunction in a transgenic mouse model of cerebral amyloid angiopathy. Brain 130:2310–2319
Skrobot OA, Attems J, Esiri M, Hortobagyi T, Ironside JW, Kalaria RN, King A, Lammie GA, Mann D, Neal J, Ben-Shlomo Y, Kehoe PG, Love S (2016) Vascular cognitive impairment neuropathology guidelines (VCING): the contribution of cerebrovascular pathology to cognitive impairment. Brain 139:2957–2969
Small SA, Schobel SA, Buxton RB, Witter MP, Barnes CA (2011) A pathophysiological framework of hippocampal dysfunction in ageing and disease. Nat Rev Neurosci 12:585–601
Smith ML, Auer RN, Siesjo BK (1984) The density and distribution of ischemic brain injury in the rat following 2–10 min of forebrain ischemia. Acta Neuropathol 64:319–332
Thal DR, Capetillo-Zarate E, Larionov S, Staufenbiel M, Zurbruegg S, Beckmann N (2009) Capillary cerebral amyloid angiopathy is associated with vessel occlusion and cerebral blood flow disturbances. Neurobiol Aging 30:1936–1948
Thal DR, Ghebremedhin E, Orantes M, Wiestler OD (2003) Vascular pathology in Alzheimer’s disease: correlation of cerebral amyloid angiopathy and arteriosclerosis/lipohyalinosis with cognitive decline. J Neuropathol Exp Neurol 62:1287–1301
Thal DR, Ghebremedhin E, Rüb U, Yamaguchi H, Del Tredici K, Braak H (2002) Two types of sporadic cerebral amyloid angiopathy. J Neuropathol Exp Neurol 61:282–293
Thal DR, Griffin WST, De Vos RAI, Ghebremedhin E (2008) Cerebral amyloid angiopathy and its relationship to Alzheimer’s disease. Acta Neuropathol 115:599–609
Thal DR, Papassotiropoulos A, Saido TC, Griffin WS, Mrak RE, Kölsch H, Del Tredici K, Attems J, Ghebremedhin E (2010) Capillary cerebral amyloid angiopathy identifies a distinct APOE epsilon4-associated subtype of sporadic Alzheimer’s disease. Acta Neuropathol 120:169–183
Thal DR, Rüb U, Orantes M, Braak H (2002) Phases of Abeta-deposition in the human brain and its relevance for the development of AD. Neurology 58:1791–1800
Thal DR, Rüb U, Schultz C, Sassin I, Ghebremedhin E, Del Tredici K, Braak E, Braak H (2000) Sequence of Abeta-protein deposition in the human medial temporal lobe. J Neuropathol Exp Neurol 59:733–748
Vinters HV (1992) Cerebral amyloid angiopathy. In: Barnett HJM, Mohr JP, Stein BM, Yatsu FM (eds) Stroke Pathophysiology, diagnosis and management. Churchill Livingstone, New York, pp 821–858
Vinters HV, Ellis WG, Zarow C, Zaias BW, Jagust WJ, Mack WJ, Chui HC (2000) Neuropathologic substrates of ischemic vascular dementia. J Neuropathol Exp Neurol 59:931–945
Vonsattel JP, Myers RH, Hedley-Whyte ET, Ropper AH, Bird ED, Richardson EP Jr (1991) Cerebral amyloid angiopathy without and with cerebral hemorrhages: a comparative histological study. Ann Neurol 30:637–649
Weller RO, Massey A, Newman TA, Hutchings M, Kuo YM, Roher AE (1998) Cerebral amyloid angiopathy: amyloid beta accumulates in putative interstitial fluid drainage pathways in Alzheimer’s disease. Am J Pathol 153:725–733
White L, Petrovitch H, Hardman J, Nelson J, Davis DG, Ross GW, Masaki K, Launer L, Markesbery WR (2002) Cerebrovascular pathology and dementia in autopsied Honolulu-Asia Aging Study participants. Ann NY Acad Sci 977:9–23
Wyler AR, Dohan FC, Schweitzer JB, Berry AD III (1992) A grading system for mesial temporal pathology (hippocampal sclerosis) from anterior temporal lobectomy. J Epilepsy 5:220–225
Acknowledgements
This study was funded by grants from Alzheimer Forschung Initiative (AFI) Grant no.: #13803 (DRT); Fonds Wetenschappelijk Onderzoek Vlaanderen (FWO- G0F8516 N Odysseus) (DRT), Vlaamse Impulsfinanciering voor Netwerken voor Dementie-onderzoek (IWT 135043) (DRT), the German Federal Ministry of Education and Research (FTLDc O1GI1007A) (MO), the EU (FAIRPARKII 633190) (MO), the foundation of the state Baden-Württemberg (D.3830) (MO), Thierry Latran Foundation (MO), ALS Association (MO), and BIU(MO). The authors gratefully thank Ms. Alicja Ronisz, Marta Koper, Irina Kosterin, Christine Schneider, Kathrin Pruy, Daniela Demharter, and Alice Yeates for technical help. We acknowledge the help of Ms. Jill Holbrook and Sandra Tomé for reading the manuscript.
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DRT received consultant honorary from GE-Healthcare and Covance Laboratories and collaborated with Novartis Pharma AG, and Janssen Pharmaceutical Companies. CAFVA received research support from Roche Diagnostics, Biologische Heilmittel Heel, and ViaMed, honoraria from serving on the scientific advisory board of Nutricia, and received speaker honoraria from Nutricia, Lilly Germany, Desitin Arzneimittel, Biogen and Dr. Willmar Schwabe GmbH&Co.KG.
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Hecht, M., Krämer, L.M., von Arnim, C.A.F. et al. Capillary cerebral amyloid angiopathy in Alzheimer’s disease: association with allocortical/hippocampal microinfarcts and cognitive decline. Acta Neuropathol 135, 681–694 (2018). https://doi.org/10.1007/s00401-018-1834-y
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DOI: https://doi.org/10.1007/s00401-018-1834-y