Small vessel (SV) and large vessel (LV) brain infarcts are distinct pathologies. Using a homebound elderly sample, the numbers of either infarct subtypes were similar between those apolipoprotein E4 allele (ApoE4) carriers (n = 80) and noncarriers (n = 243). We found that the higher the number of SV infarcts, but not LV infarcts, a participant had, the higher the activity of substrate V degradation in serum especially among ApoE4 carriers (β = +0.154, SE = 0.031, P < .0001) after adjusting for the confounders. Since substrate V degradation could be mediated by insulin-degrading enzyme (IDE) or/and angiotensin-converting enzyme (ACE), but no relationship was found between SV infarcts and specific ACE activities, blood IDE may be a useful biomarker to distinguish the brain infarct subtypes. Insulin-degrading enzyme in blood may also imply an important biomarker and a pathological event in Alzheimer disease through SV infarcts in the presence of ApoE4.
RoviraAGriveERoviraAAlvarez-SabinJ. Distribution territories and causative mechanisms of ischemic stroke. Eur Radiol. 2005;15(3):416–426.
2.
de JongGKesselsFLodderJ. Two types of lacunar infarcts: further arguments from a study on prognosis. Stroke. 2002;33(8):2072–2076.
3.
GreenbergSMRebeckGWVonsattelJPGomez-IslaTHymanBT. Apolipoprotein E epsilon 4 and cerebral hemorrhage associated with amyloid angiopathy. Ann Neurol. 1995;38(2):254–259.
4.
UtterSTamboliIYWalterJ. Cerebral small vessel disease-induced apolipoprotein E leakage is associated with Alzheimer disease and the accumulation of amyloid beta-protein in perivascular astrocytes. J Neuropathol Exp Neurol. 2008;67(9):842–856.
5.
JellingerKA. Prevalence and impact of cerebrovascular lesions in Alzheimer and lewy body diseases. Neurodegener Dis. 2010;7(1-3):112–115.
6.
ThalDRGriffinWSde VosRAGhebremedhinE. Cerebral amyloid angiopathy and its relationship to Alzheimer's disease. Acta Neuropathol. 2008;115(6):599–609.
7.
FryerJDSimmonsKParsadanianM. Human apolipoprotein E4 alters the amyloid-beta 40:42 ratio and promotes the formation of cerebral amyloid angiopathy in an amyloid precursor protein transgenic model. J Neurosci. 2005;25(11):2803–2810.
8.
GreenbergSMVonsattelJP. Diagnosis of cerebral amyloid angiopathy. Sensitivity and specificity of cortical biopsy. Stroke. 1997;28(7):1418–1422.
9.
VasilevkoVPassosGFQuiringD. Aging and cerebrovascular dysfunction: contribution of hypertension, cerebral amyloid angiopathy, and immunotherapy. Ann N Y Acad Sci. 2010;1207:58–70.
10.
SelkoeDJ. Biochemistry and molecular biology of amyloid beta-protein and the mechanism of Alzheimer's disease. Handb Clin Neurol. 2008;89:245–260.
11.
ThalDRGriffinWSBraakH. Parenchymal and vascular Abeta-deposition and its effects on the degeneration of neurons and cognition in Alzheimer's disease. J Cell Mol Med. 2008;12(5B):1848–1862.
12.
LiuZZhuHFangGG. Characterization of insulin degrading enzyme and other amyloid-beta degrading proteases in human serum: a role in Alzheimer's disease?J Alzheimers Dis. 2012;29(2):329–340.
13.
ScottTMPeterITuckerKL. The Nutrition, Aging, and Memory in Elders (NAME) study: design and methods for a study of micronutrients and cognitive function in a homebound elderly population. Int J Geriatr Psychiatry. 2006;21(6):519–528.
14.
QiuWQSunXSelkoeDJ. Depression is associated with low plasma Abeta42 independently of cardiovascular disease in the homebound elderly. Int J Geriatr Psychiatry. 2007;22(6):536–542.
15.
ScottTMTuckerKLBhadeliaA. Homocysteine and B vitamins relate to brain volume and white-matter changes in geriatric patients with psychiatric disorders. Am J Geriatr Psychiatry. 2004;12(6):631–638.
16.
BryanRNWellsSWMillerTJ. Infarctlike lesions in the brain: prevalence and anatomic characteristics at MR imaging of the elderly--data from the Cardiovascular Health Study. Radiology. 1997;202(1):47–54.
17.
LanXXuJKiyotaTPengHZhengJCIkezuT. HIV-1 reduces A{beta}-degrading enzymatic activities in primary human mononuclear phagocytes. J Immunol. 2011;186(12):6925–6932.
18.
LahozCOsgoodDWilsonPWSchaeferEJOrdovasJM. Frequency of phenotype-genotype discrepancies at the apolipoprotein E locus in a large population study. Clin Chem. 1996;42(11):1817–1823.
19.
SunXSatoSMurayamaO. Lithium inhibits amyloid secretion in COS7 cells transfected with amyloid precursor protein C100. Neurosci Lett. 2002;321(1-2):61–64.
20.
FukumotoHTennisMLocascioJJHymanBTGrowdonJHIrizarryMC. Age but not diagnosis is the main predictor of plasma amyloid beta-protein levels. Arch Neurol. 2003;60(7):958–964.
21.
McKhannGDrachmanDFolsteinMKatzmanRPriceDStadlanEM. Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology. 1984;34(7):939–944.
22.
KurochkinIVGotoS. Alzheimer's beta-amyloid peptide specifically interacts with and is degraded by insulin degrading enzyme. FEBS Lett. 1994;345(1):33–37.
23.
QiuWQWalshDMYeZ. Insulin-degrading enzyme regulates extracellular levels of amyloid beta-protein by degradation. J Biol Chem. 1998;273(49):32730–32738.
24.
AlonzoNCHymanBTRebeckGWGreenbergSM. Progression of cerebral amyloid angiopathy: accumulation of amyloid-beta40 in affected vessels. J Neuropathol Exp Neurol. 1998;57(4):353–359.
25.
ReveszTHoltonJLLashleyT. Sporadic and familial cerebral amyloid angiopathies. Brain Pathol. 2002;12(3):343–357.
26.
NakamuraSTamaokaASawamuraN. Carboxyl end-specific monoclonal antibodies to amyloid beta protein (A beta) subtypes (A beta 40 and A beta 42(43)) differentiate A beta in senile plaques and amyloid angiopathy in brains of aged cynomolgus monkeys. Neurosci Lett. 1995;201(2):151–154.
27.
UrmoneitBPrikulisIWihlG. Cerebrovascular smooth muscle cells internalize Alzheimer amyloid beta protein via a lipoprotein pathway: implications for cerebral amyloid angiopathy. Lab Invest. 1997;77(2):157–166.
28.
HerzigMCWinklerDTBurgermeisterP. Abeta is targeted to the vasculature in a mouse model of hereditary cerebral hemorrhage with amyloidosis. Nat Neurosci. 2004;7(9):954–960.
29.
MorelliLLloveraRGonzalezSA. Differential degradation of amyloid beta genetic variants associated with hereditary dementia or stroke by insulin-degrading enzyme. J Biol Chem. 2003;278(26):23221–23226.
30.
MorelliLLloveraREMathovI. Insulin-degrading enzyme in brain microvessels: proteolysis of amyloid {beta} vasculotropic variants and reduced activity in cerebral amyloid angiopathy. J Biol Chem. 2004;279(53):56004–56013.
31.
NicollJAYamadaMFrackowiakJMazur-KoleckaBWellerRO. Cerebral amyloid angiopathy plays a direct role in the pathogenesis of Alzheimer's disease. Pro-CAA position statement. Neurobiol Aging. 2004;25(5):589–597.
32.
HuJIgarashiAKamataMNakagawaH. Angiotensin-converting enzyme degrades Alzheimer amyloid beta-peptide (A beta ); retards A beta aggregation, deposition, fibril formation; and inhibits cytotoxicity. J Biol Chem. 2001;276(51):47863–47868.
33.
HemmingMLSelkoeDJ. Amyloid beta-protein is degraded by cellular angiotensin-converting enzyme (ACE) and elevated by an ACE inhibitor. J Biol Chem. 2005;280(45):37644–37650.
34.
BrennerDLabreucheJPicoF. The renin-angiotensin-aldosterone system in cerebral small vessel disease. J Neurol. 2008;255(7):993–1000.
35.
StrittmatterWJSaundersAMSchmechelD. Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc Natl Acad Sci U S A. 1993;90(5):1977–1981.
ZhangFEckmanCYounkinSHsiaoKKIadecolaC. Increased susceptibility to ischemic brain damage in transgenic mice overexpressing the amyloid precursor protein. J Neurosci. 1997;17(20):7655–7661.
38.
KoistinahoMKettunenMIHoltzmanDMKauppinenRAHigginsLSKoistinahoJ. Expression of human apolipoprotein E downregulates amyloid precursor protein-induced ischemic susceptibility. Stroke. 2002;33(7):1905–1910.
39.
JellingerKA. The pathology of ischemic-vascular dementia: an update. J Neurol Sci. 2002;203-204:153–157.
