The vascular hypothesis of Alzheimer’s disease (VHAD) was proposed 24 years ago from observations made in our laboratory using aging rats subjected to chronic brain hypoperfusion. In recent years, VHAD has become a mother-lode to numerous neuroimaging studies targeting cerebral hemodynamic changes, particularly brain hypoperfusion in elderly patients at risk of developing Alzheimer’s disease (AD). There is a growing consensus among neuroradiologists that brain hypoperfusion is likely involved in the pathogenesis of AD and that disturbed cerebral blood flow (CBF) can serve as a key biomarker for predicting conversion of mild cognitive impairment to AD. The use of cerebral hypoperfusion as a preclinical predictor of AD is becoming decisive in stratifying low and high risk patients that may develop cognitive decline and for assessing the effectiveness of therapeutic interventions. There is currently an international research drive from neuroimaging groups to seek new perspectives that can broaden our understanding of AD and improve lifestyle. Diverse neuroimaging methods are currently being used to monitor normal and dyscognitive brain activity. Some techniques are very powerful and can detect, diagnose, quantify, prognose, and predict cognitive decline before AD onset, even from a healthy cognitive state. Multimodal imaging offers new insights in the treatment and prevention of cognitive decline during advanced aging and better understanding of the functional and structural organization of the human brain. This review discusses the impact the VHAD and CBF are having on the neuroimaging technology that can usher practical strategies to help prevent AD.
de la TorreJC, MussivandT (1993) Can disturbed brain microcirculation cause Alzheimer’s disease?Neurol Res15, 146–153.
2.
de la TorreJC, FortinT (1994) A chronic physiological rat model of dementia. Behav Brain Res63, 35–40.
3.
de la TorreJC (1994) Impaired brain microcirculation may trigger Alzheimer’s disease. Neurosci Biobehav Rev18, 397–401.
4.
de la TorreJC (1997) Hemodynamic consequences of deformed microvessels in the brain in Alzheimer’s disease. Ann N Y Acad Sci826, 75–91.
5.
de la TorreJC (1997) Cerebromicrovascular pathology in Alzheimer’s disease and normal aging. Gerontology43, 26–43.
6.
SkoogI, LernfeltB, LandahlS (1996) A 15-year longitudinal study of blood pressure and dementia. Lancet347, 1141–1145.
7.
HofmanA, OttA, BretelerMM, BotsML, SlooterAJ, van HarskampF, van DuijnCN, Van BroeckhovenC, GrobbeeDE (1997) Atherosclerosis, apolipoprotein E, and prevalence of dementia and Alzheimer’s disease in the Rotterdam Study. Lancet349, 151–154.
8.
de la TorreJC (1999) Critical threshold cerebral hypoperfusion causes Alzheimer’s disease. Acta Neuropathol98, 1–8.
9.
de la TorreJC (2000) Critically attained threshold of cerebral hypoperfusion: The CATCH hypothesis of Alzheimer’s pathogenesis. Neurobiol Aging21, 331–342.
10.
de la TorreJC, StefanoGB (2000) Evidence that Alzheimer’s disease is a microvascular disorder: Role of constitutive nitric oxide. Brain Res Rev34, 119–136.
11.
de la TorreJC (2012) Cerebral hemodynamics and vascular risk factors: Setting the stage for Alzheimer’s disease. J Alzheimers Dis32, 553–567.
12.
KumeK, HanyuH, SatoT, HiraoK, ShimizuS, KanetakaH, SakuraiH, IwamotoT (2011) Vascular risk factors are associated with faster decline of Alzheimer disease: A longitudinal SPECT study. J Neurol258, 1295–1303.
13.
LeendersKL, PeraniD, LammertsmaAA, HeatherJD, BuckinghamP, HealyMJ, GibbsJM, WiseRJ, HatazawaJ, HeroldS (1990) Cerebral blood flow, blood volume and oxygen utilization. Normal values and effect of age. Brain113(Pt 1), 27–47.
14.
ChenJJ, RosasHD, SalatDH (2011) Age-associated reductions in cerebral blood flow are independent from regional atrophy. Neuroimage55, 468–478.
15.
de la TorreJC (2016) Alzheimer’s Turning Point: A Vascular Approach to Clinical Prevention. Springer, Geneva, Switzerland, pp. 185–197.
16.
KhanS, DaviesIB (2008) Hypoxia and Alzheimer disease. CMAJ178, 1687.
17.
SalminenA, KauppinenA, KaarnirantaK (2017) Hypoxia/ischemia activate processing of amyloid precursor protein: Imact of vascular dysfunction in the pathogenesis of Alzheimer’s disease. J Neurochem140, 536–549.
18.
IyerNV, KotchLE, AganiF, LeungSW, LaughnerE, WengerRH, GassmannM, GearhartJD, LawlerAM, YuAY, SemenzaGL (1998) Cellular and developmental control of O2 homeostasis by hypoxia-inducible factor 1 alpha. Genes Dev12, 149–162.
19.
OgunsholaOO, AntoniouX (2009) Contribution of hypoxia to Alzheimer’s disease: Is HIF-1alpha a mediator of neurodegeneration?Cell Mol Life Sci66, 3555–3563.
XiangJ (2017) Carotid atherosclerosis promotes the progression of Alzheimer’s disease: A three-year prospective study. Exp Ther Med14, 1321–1326.
22.
PolidoriMC, PientkaL, MecocciP (2012) A review of the major vascular risk factors related to Alzheimer’s disease. J Alzheimers Dis32, 521–530.
23.
MoongaI, NiccoliniF, WilsonH, PaganoG, PolitisM, Alzheimer’s Disease Neuroimaging Initiative (2017) Hypertension is associated with worse cognitive function and hippocampal hypometabolism in Alzheimer’s disease. Eur J Neurol9, 1173–1182.
24.
ShatensteinB, Barberger-GateauP, MecocciP (2015) Prevention of age-related cognitive decline: Which strategies, when, and for whom?J Alzheimers Dis48, 35–53.
25.
WestNA, HaanMN (2009) Body adiposity in late life and risk of dementia or cognitive impairment in a longitudinal community-based study. J Gerontol A Biol Sci Med Sci64, 103–109.
26.
DicksteinDL, WalshJ, BrautigamH, StocktonSDJr, GandyS, HofPR (2010) Role of vascular risk factors and vascular dysfunction in Alzheimer’s disease. Mt Sinai J Med77, 82–102.
27.
MurrayIV, ProzaJF, SohrabjiF, LawlerJM (2011) Vascular and metabolic dysfunction in Alzheimer’s disease: A review. Exp Biol Med (Maywood)236, 772–782.
28.
LuchsingerJA, ReitzC, HonigLS (2005) Aggregation of vascular risk factors and risk of incident Alzheimer disease. Neurology65, 545–551.
JeffersonAL, PoppasA, PaulRH, CohenRA (2007) Systemic hypoperfusion is associated with executive dysfunction in geriatric cardiac patients. Neurobiol Aging28, 477–483.
33.
YaffeK, VittinghoffE, PletcherMJ, HoangTD, LaunerLJ, WhitmerR, CokerLH, SidneyS (2014) Early adult to midlife cardiovascular risk factors and cognitive function, Circulation129, 1560–1567.
34.
JeffersonAL, BeiserAS, HimaliJJ, SeshadriS, O’DonnellCJ, ManningWJ, WolfPA, AuR, BenjaminEJ (2015) Low cardiac index is associated with incident dementia and Alzheimer disease: The Framingham Heart Study. Circulation131, 1333–1339.
35.
BursiF, RoccaWA, KillianJM, WestonSA, KnopmanDS, JacobsenSJ (2006) Heart disease and dementia: A population-based study. Am J Epidemiol163, 135–141.
36.
SchievinkSHJ, van BoxtelMPJ, DeckersK, van OostenbruggeRJ, VerheyFRJ, KöhlerS (2017) Cognitive changes in prevalent and incident cardiovascular disease: A 12-year follow-up in the Maastricht Aging Study (MAAS). Eur Heart J. doi: 10.1093/eurheartj/ehx365.
37.
OhJE, ShinJW, SohnEH, JungJO, JeongSH, SongHJ, KimJM, LeeAY (2012) Effect of cardiac function on cognition and brain structural changes in dementia. J Clin Neurol8, 123–129.
38.
GottesmanRF, AlbertMS, AlonsoA, CokerLH, CoreshJ, DavisSM, DealJA, McKhannGM, MosleyTH, SharrettAR, SchneiderALC, WindhamBG, WruckLM, KnopmanDS (2017) Associations Between Midlife Vascular Risk Factors and 25-Year Incident Dementia in the Atherosclerosis Risk in Communities (ARIC) Cohort. JAMA Neurol74, 1246–1254.
KövariE, HerrmannFR, HofPR, BourasC (2013) The relationship between cerebral amyloid angiopathy and cortical microinfarcts in brain ageing and Alzheimer’s disease. Neuropathol Appl Neurobiol39, 498–509.
43.
de la TorreJC (2009) Carotid artery ultrasound and echocardiography testing to lower the prevalence of Alzheimer’s disease. J Stroke Cerebrovasc Dis18, 319–328.
44.
de la TorreJC (1993) La defaillance de la microhémodynamique cérébrale peut-elle provoker la maladie d’Alzheimer?. Alzheimer Actualités75, 6–7.
45.
de la TorreJC (2008) Pathophysiology of neuronal energy crisis in Alzheimer’s disease. Neurodegener Dis5, 126–132.
46.
KeppKP (2017) Ten challenges of the amyloid hypothesis of Alzheimer’s disease. J Alzheimers Dis55, 447–457.
de la TorreJC, FortinT, ParkGA, ButlerKS, KozlowskiP, PappasBA, de SocarrazH, SaundersJK (1992) Chronic cerebrovascular insufficiency induces dementia-like deficits in aged rats. Brain Res582, 186–195.
49.
de la TorreJC, FortinT, ParkGA, SaundersJK, KozlowskiP, ButlerK, de SocarrazH, PappasB (1992) Aged but not young rats develop metabolic, memory deficits after chronic brain ischaemia. Neurol Res14(2 Suppl), 177–180.
50.
NiJW, MatsumotoK, LiHB, MurakamiY, WatanabeH (1995) Neuronal damage and decrease of central acetylcholine level following permanent occlusion of bilateral common carotid arteries in rat. Brain Res673, 290–296.
51.
De JongGI, FarkasE, PlassJ, KeijserJN, de la TorreJC, LuitenPGM (1999) Cerebral hypoperfusion yields capillary damage in hippocampus CA1 that correlates to spatial memory impairment. Neuroscience91, 203–210.
52.
SopalaM, DanyszW (2001) Chronic cerebral hypoperfusion in the rat enhances age-related deficits in spatial memory. J Neural Transm108, 1445–1456.
53.
LiuHX, ZhangJJ, ZhengP, ZhangY (2005) Altered expression of MAP-2, GAP-43, and synaptophysin in the hippocampus of rats with chronic cerebral hypoperfusion correlates with cognitive impairment. Brain Res Mol Brain Res139, 169–177.
54.
PappasBA, de la TorreJC, DavidsonCM, KeyesMT, FortinT (1996) Chronic reduction of cerebral blood flow in the adult rat: Late-emerging CA1 cell loss and memory dysfunction. Brain Res708, 50–58.
55.
HendersonB, de la TorreJC (1999) Reversal of chronic ischemia in the adult rat: Common carotid anastomosis and improvement in memory dysfunction. Soc Neurosci25, 55.
BangenKJ, RestomK, LiuTT, WierengaCE, JakAJ, SalmonDP, BondiMW (2012) Assessment of Alzheimer’s disease risk with functional magnetic resonance imaging: An arterial spin labeling study. J Alzheimers Dis31(Suppl 3), S59–74.
58.
BretelerMM (2000) Vascular risk factors for Alzheimer’s disease: An epidemiologic perspective. Neurobiol Aging21, 153–160.
59.
GrovesWC, BrandtJ, SteinbergM, WarrenA, RosenblattA, BakerA, LyketsosCG (2000) Vascular dementia and Alzheimer’s disease: Is there a difference? A comparison of symptoms by disease duration. J Neuropsychiatry Clin Neurosci12, 305–315
.
60.
ViswanathanA, MacklinEA, BetenskyR, HymanB, SmithEE, BlackerD, WangF, GuoX, ShenX, KreamRM, MantioneKJ, StefanoGB (2014) Vascular dysfunction associated with type 2 diabetes and Alzheimer’s disease: A potential etiological linkage. Med Sci Monit Basic Res20, 118–129.
61.
AttemsJ, JellingerKA (2014) The overlap between vascular disease and Alzheimer’s disease–lessons from pathology. BMC Med12, 206.
62.
JangH, KwonH, YangJJ, HongJ, KimY, KimKW, LeeJS, JangYK, KimST, LeeKH, LeeJH, NaDL, SeoSW, KimHJ, LeeJM (2017) Correlations between gray matter and white matter degeneration in pure Alzheimer’s disease, pure subcortical vascular dementia, and mixed dementia. Sci Rep7, 9541.
HardyJ, SelkoeDJ (2002) The amyloid hypothesis of Alzheimer’s disease: Progress and problems on the road to therapeutics. Science297, 353–356.
65.
Erten-LyonsD, WoltjerRL, DodgeH, NixonR, VorobikR, CalvertJF, LeahyM, MontineT, KayeJ (2009) Factors associated with resistance to dementia despite high Alzheimer disease pathology. Neurology72, 354–360.
66.
SloaneJA, PietropaoloMF, RoseneDL, MossMB, PetersA, KemperT, AbrahamCR (1997) Lack of correlation between plaque burden and cognition in the aged monkey. Acta Neuropathol94, 471–478.
67.
KurkinenM (2017) The amyloid hypothesis is too good to be true. Alzheimers Dement Cogn Neurol1doi: 10.15761/ADCN.1000106.
BenilovaI, KarranE, De StrooperB (2012) The toxic Aβ oligomer and Alzheimer’s disease: An emperor in need of clothes. Nat Neurosci15, 349–357.
70.
Pujol-PinaR, Vilaprinyó-PascualS, MazzucatoR, ArcellaA, VilasecaM, OrozcoM, CarullaN (2015) SDS-PAGE analysis of Aβ oligomers is disserving research into Alzheimer's disease: Appealing for ESI-IM-MS. Sci Rep5, 14809.
71.
WattAD, PerezKA, RembachA, SherratNA, HungLW, JohanssenT, McLeanCA, KokWM, HuttonCA, Fodero-TavolettiM, MastersCL, VillemagneVL, BarnhamKJ (2013) Oligomers, fact or artefact? SDS-PAGE induces dimerization of beta-amyloid in human brain samples. Acta Neuropathol125, 549–564.
72.
de la TorreJC (2002) Alzheimer’s disease: How does it start?J Alzheimers Dis4, 497–512.
73.
de la TorreJC (2011) Three postulates to help identify the cause of Alzheimer’s disease. J Alzheimers Dis24, 657–668.
74.
de la TorreJC (2002) Alzheimer disease as a vascular disorder: Nosological evidence. Stroke33, 1152–1162.
75.
LeeHG, CasadesusG, ZhuX, TakedaA, PerryG, SmithMA (2004) Challenging the amyloid cascade hypothesis: Senile plaques and amyloid-beta as protective adaptations to Alzheimer disease. Ann N Y Acad Sci1019, 1–4.
76.
RobakisNK (2010) Are Abeta and its derivatives causative agents or innocent bystanders in AD?Neurodegener Dis7, 32–37.
77.
HerrupK (2015) The case for rejecting the amyloid cascade hypothesis. Nat Neurosci18, 794–799.
78.
MorrisGP, ClarkIA, VisselB (2014) Inconsistencies and controversies surrounding the amyloid hypothesis of Alzheimer’s disease. Acta Neuropathol Commun2, 135.
79.
DrachmanDA (2014) The amyloid hypothesis, time to move on: Amyloid is the downstream result, not cause, of Alzheimer’s disease. Alzheimers Dement10, 372–380.
80.
HonigLS, VellasB, WoodwardM, BoadaM, BullockR (2018) Trial of solanezumab for mild dementia due to Alzheimer’s disease. N Engl J Med378, 321–330.
81.
DoodyRS, ThomasRG, FarlowM (2014) Phase 3 trials of solanezumab for mild-to-moderate Alzheimer’s disease. N Engl J Med370, 311–321.
82.
SallowayS, SperlingR, FoxNC, BlennowK, KlunkW, RaskindM, SabbaghM, HonigLS, PorsteinssonAP, FerrisS, ReichertM, KetterN, NejadnikB, GuenzlerV, MiloslavskyM, WangD, LuY, LullJ, TudorIC, LiuE, GrundmanM, YuenE, BlackR, BrashearHR, Bapineuzumab 301 and 302 Clinical Trial Investigators (2014) Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer’s disease. N Engl J Med370, 322–333.
HolmesC, BocheD, WilkinsonD, YadegarfarG, HopkinsV, BayerA, JonesRW, BullockR, LoveS, NealJW, ZotovaE, NicollJA (2008) Long-term effects of Abeta42 immunisation in Alzheimer’s disease: Follow-up of a randomised, placebo-controlled phase I trial. Lancet372, 216–223.
85.
OstrowitzkiS, LasserRA, DorflingerE, ScheltensP, BarkhofF, NikolchevaT, AshfordE, RetoutS, HofmannC, DelmarP, KleinG, AndjelkovicM, DuboisB, BoadaM, BlennowK, SantarelliL, FontouraP (2017) SCarlet RoAD Investigators. A phase III randomized trial of gantenerumab in prodromal Alzheimer’s disease. Alzheimers Res Ther9, 95.
86.
CastelloMA, JeppsonJD, SorianoS (2014) Moving beyond anti-amyloid therapy for the prevention and treatment of Alzheimer’s disease. BMC Neurol4, 169.
87.
MarchesiVT (2011) Alzheimer’s dementia begins as a disease of small blood vessels, damaged by oxidative-induced inflammation and dysregulated amyloid metabolism: Implications for early detection and therapy. FASEB J25, 5–13.
88.
BishopGM, RobinsonSR (2002) The amyloid hypothesis: Let sleeping dogmas lie?Neurobiol Aging23, 1101–1105.
89.
AbbottA, DolginE (2016) Failed Alzheimer’s trial does not kill leading theory of disease. Nature540, 15–16.
90.
SelkoeDJ, HardyJ (2016) The amyloid hypothesis of Alzheimer’s disease at 25 years. EMBO Mol Med8, 595–608.
91.
FerrerI, Boada RoviraM, Sánchez GuerraML, ReyMJ, Costa-JussáF (2004) Neuropathology and pathogenesis of encephalitis following amyloid-beta immunization in Alzheimer’s disease. Brain Pathol4, 11–20.
92.
OrgogozoJM, GilmanS, DartiguesJF, LaurentB, PuelM, KirbyLC, JouannyP, DuboisB, EisnerL, FlitmanS, MichelBF, BoadaM, FrankA, HockC (2003) Subacute meningoencephalitis in a subset of patients with AD after Abeta42 immunization. Neurology61, 46–54.
93.
de la TorreJC (2014) Phase 3 trials of solanezumab and bapineuzumab for Alzheimer’s disease. N Engl J Med370, 1459–1460.
94.
FirensteinS (2012), Ignorance: How it Drives Science. Oxford University Press, Oxford, UK.
95.
XekardakiA, RodriguezC, MontandonML, TomaS, TombeurE, HerrmannFR, ZekryD, LovbladKO, BarkhofBF, GiannakopoulosP, HallerS (2014) Arterial spin labeling may contribute to the prediction of cognitive deterioration in healthy elderly individuals. Radiology274, 490–499.
96.
GlodzikL, RusinekH, BrysM, TsuiWH, SwitalskiR, MosconiL, MisturR, PirragliaE, de SantiS, LiY, GoldowskyA, de LeonMJ (2011) Framingham cardiovascular risk profile correlates with impaired hippocampal and cortical vasoreactivity to hypercapnia. J Cereb Blood Flow Metab31, 671–679.
97.
ChetelatG, DesgrangesB, de la SayetteV (2003) Mild cognitive impairment: Can FDG-PETpredict who is to rapidly convert to Alzheimer’s disease?Neurology60, 1374–1377.
98.
MosconiL (2013) Glucose metabolism in normal aging and Alzheimer’s disease: Methodological and physiological considerations for PET studies. Clin Transl Imaging1. doi: 10.1007/s40336-013-0026-y.
99.
AlsopDC, DetreJA, GrossmanM (2000) Assessment of cerebral blood flow in Alzheimer’s disease by spin-labeled magnetic resonance imaging. Ann Neurol47, 93–100.
100.
DrzezgaA, GrimmerT, RiemenschneiderM, LautenschlagerN, SiebnerH, AlexopoulusP, MinoshimaS, SchwaigerM, KurzA (2005) Prediction of individual clinical outcome in MCI by means of genetic assessment and (18)F-FDG PET. J Nucl Med46, 1625–1632.
101.
EwersM, SperlingRA, KlunkWE, WeinerMW, HampelH (2011) Neuroimaging markers for the prediction and early diagnosis of Alzheimer’s disease dementia. Trends Neurosci34, 430–442.
102.
JohnsonNA, JahngGH, WeinerMW, MillerBL, JagustWJ, Gorno-TempiniML, SchuffN (2005) Pattern of cerebral hypoperfusion in Alzheimer disease and mild cognitive impairment measured with arterial spin-labeling MR imaging: Initial experience. Radiology234, 851–859.
103.
Iturria-MedinaY, SoteroRC, ToussaintPJ, Mateos-PérezJM, EvansAC, Alzheimer’s Disease Neuroimaging Initiative (2016) Early role of vascular dysregulation on late-onset Alzheimer’s disease based on multifactorial data-driven analysis. Nat Commun7, 11934.
104.
Iturria-MedinaY, CarbonellFM, SoteroRC, Chouinard-DecorteF, EvansAC, Alzheimer’s Disease Neuroimaging Initiative (2017) Multifactorial causal model of brain (dis)organization and therapeutic intervention: Application to Alzheimer’s disease. Neuroimage152, 60–77.
ChaoLL, BuckleyST, KornakJ, SchuffN, MadisonC, YaffeK, MillerBL, KramerJH, WeinerMW (2010) ASL perfusion MRI predicts cognitive decline and conversion from MCI to dementia. Alzheimer Dis Assoc Disord24, 19–27.
109.
WierengaCE, HaysCC, ZlatarZZ (2014) Cerebral blood flow measured by arterial spin labeling MRI as a preclinical marker of Alzheimer’s disease. J Alzheimers Dis42(Suppl 4), S411–419.
110.
HiraoK, OhnishiT, HirataY, YamashitaF, MoriT, MoriguchiY, MatsudaH, NemotoK, ImabayashiE, YamadaM, IwamotoT, ArimaK, AsadaT (2005) The prediction of rapid conversion to Alzheimer’s disease in mild cognitive impairment using regional cerebral blood flow SPECT. Neuroimage28, 1014–1021.
111.
MosconiL, PeraniD, SorbiS, HerholzK, NacmiasB, HolthoffV, SalmonE, BaronJC, De CristofaroMT, PadovaniA, BorroniB, FranceschiM, BraccoL, PupiA (2004) MCI conversion to dementia and the APOE genotype: A prediction study with FDG-PET. Neurology63, 2332–2340.
112.
ChenY, WolkDA, ReddinJS, KorczykowskiM, MartinezPM, MusiekES, NewbergAB, JulinP, ArnoldSE, GreenbergJH, DetreJA (2011) Voxel-level comparison of arterial spin-labeled perfusion MRI and FDG-PET in Alzheimer disease. Neurology77, 1977–1985
.
113.
BangenKJ, PreisSR, Delano-WoodL, WolfPA, LibonDJ, BondiMW, AuR, DeCarliC, BrickmanAM (2018) Baseline white matter hyperintensities and hippocampal volume are associated with conversion from normal cognition to mild cognitive impairment in the Framingham Offspring Study. Alzheimer Dis Assoc Disord32, 50–56.
NiwaF, KondoM, SakuradaK, NakagawaM, ImanishiJ, MizunoT (2016) Regional cerebral blood flow in [123] I-IMP single-photon emission computed tomography and the Wechsler Memory Scale-revised in nondemented elderly subjects with subjective cognitive impairment. Intern Med55, 3571–3578.
116.
AlegretM, Cuberas-BorrósG, EspinosaA, ValeroS, HernándezI, RuízA, BeckerJT, Rosende-RocaM, MauleónA, SotolongoO, Castell-ConesaJ, RocaI, TárragaL, BoadaM (2014) Cognitive, genetic, and brain perfusion factors associated with four year incidence of Alzheimer’s disease from mild cognitive impairment. J Alzheimers Dis41, 739–748.
117.
SchuffN, MatsumotoS, KmiecikJ, StudholmeC, DuA, EzekielF, MillerBL, KramerJH, JagustWJ, WeinerMW (2009) Cerebral blood flow in ischemic vascular dementia and Alzheimer’s disease, measured by arterial spin-labeling magnetic resonance imaging. Alzheimers Dement5, 454–462.
118.
DaiW, LopezOL, CarmichaelOT, BeckerJT, KullerLH, GachHM (2009) Mild cognitive impairment and Alzheimer disease: Patterns of altered cerebral blood flow at MR imaging. Radiology250, 856–866.
119.
XuG, AntuonoPG, JonesJ, XuY, WuG, WardD, LiS-J (2007) Perfusion fMRI detects deficits in regional CBF during memory-encoding tasks in MCI subjects. Neurology69, 1650–1656.
120.
ParkKW, YoonHJ, KangD-Y, KimBC, KimS, KimJW (2012) Regional cerebral blood flow differences in patients with mild cognitive impairment between those who did and did not develop Alzheimer’s disease. Psychiatry Res203, 201–206.
121.
AlexopoulosP, SorgC, FörschlerA, GrimmerT, SkokouM, WohlschlägerA, PerneczkyR, ZimmerC, KurzA, PreibischC (2012) Perfusion abnormalities in mild cognitive impairment and mild dementia in Alzheimer’s disease measured by pulsed arterial spin labeling MRI. Eur Arch Psychiatry Clin Neurosci262, 69–77.
122.
ZeestratenEA, LawrenceAJ, LambertC, BenjaminP, BrookesRL, MackinnonAD, MorrisRG, BarrickTR, MarkusHS (2017) Change in multimodal MRI markers predicts dementia risk in cerebral small vessel disease. Neurology89, 1869–1876.
123.
ShimG, ChoiKY, KimD, SuhSI, LeeS, JeongHG, JeongB (2017) Predicting neurocognitive function with hippocampal volumes and DTI metrics in patients with Alzheimer’s dementia and mild cognitive impairment. Brain Behav7, e00766.
124.
JueptnerM, WeillerC (1995) Review: Does measurement of regional cerebral blood flow reflect synaptic activity? Implications for PET and fMRI. Neuroimage2, 148–156.
125.
InuiY, ItoK, KatoT, SEAD-J Study Group (2017) Longer-term investigation of the value of 18F-FDG-PET and magnetic resonance imaging for predicting the conversion of mild cognitive impairment to Alzheimer’s disease: A multicenter study. J Alzheimers Dis60, 877–887.
126.
LandauSM, HarveyD, MadisonCM, ReimanEM, FosterNL, AisenPS, PetersenRC, ShawLM, TrojanowskiJQ, JackCRJr, WeinerMW, JagustWJ, Alzheimer’s Disease Neuroimaging Initiative (2010) Comparing predictors of conversion and decline in mild cognitive impairment. Neurology75, 230–238.
127.
ShafferJL, PetrellaJR, SheldonFC, ChoudhuryKR, CalhounVD, ColemanRE, DoraiswamyPM, Alzheimer’s Disease Neuroimaging Initiative (2013) Predicting cognitive decline in subjects at risk for Alzheimer disease by using combined cerebrospinal fluid, MR imaging, and PET biomarkers. Radiology266, 583–591.
128.
AnchisiD, BorroniB, FranceschiM, KerroucheN, KalbeE, Beuthien-BeumannB, CappaS, LenzO, LudeckeS, MarconeA, MielkeR, OrtelliP, PadovaniA, PelatiO, PupiA, ScarpiniE, WeisenbachS, HerholzK, SalmonE, HolthoffV, SorbiS (2005) Heterogeneity of brain glucose metabolism in mild cognitive impairment and clinical progression to Alzheimer disease. Arch Neurol62, 1728–1733.
129.
GomarJJ, Conejero-GoldbergC, DaviesP, GoldbergTE (2014) Alzheimer’s disease Neuroimaging Initiative. Extension and refinement of the predictive value of different classes of markers in ADNI: Four-year follow-up data. Alzheimers Dement10, 704–712.
130.
AaslidR, MarkwalderTM, NornesH (1982) Noninvasive transcranial Doppler ultrasound recording of flow velocity in basal cerebral arteries. J Neurosurg57, 769–774.
131.
TopcuogluMA (2012) Transcranial Doppler ultrasound in neurovascular diseases: Diagnostic and therapeutic aspects. J Neurochem123(Suppl 2), 39–51.
132.
BeishonL, HauntonVJ, PaneraiRB, RobinsonTG (2017) Cerebral hemodynamics in mild cognitive impairment: A systematic review. J Alzheimers Dis59, 369–385.
133.
RuitenbergA, den HeijerT, BakkerSL, van SwietenJC, KoudstaalPJ, HofmanA, BretelerMM (2005) Cerebral hypoperfusion and clinical onset of dementia: The Rotterdam Study. Ann Neurol57, 789–794.
134.
RoherAE, GaramiZ, TyasSL, MaaroufCL, KokjohnTA, BelohlavekM, VeddersLJ, ConnorD, SabbaghMN, BeachTG, EmmerlingMR (2011) Transcranial doppler ultrasound blood flow velocity and pulsatility index as systemic indicators for Alzheimer’s disease. Alzheimers Dement7, 445–455.
135.
ChungCP, LeeHY, LinPC, WangPN (2017) Cerebral artery pulsatility is associated with cognitive impairment and predicts dementia in Individuals with subjective memory decline or mild cognitive impairment. J Alzheimers Dis60, 625–632.
136.
HanssonO, PalmqvistS, LjungH, CronbergT, van WestenD, SmithR (2018) Cerebral hypoperfusion is not associated with an increase in amyloid β pathology in middle-aged or elderly people. Alzheimers Dement14, 54–61.
137.
LoveS, MinersJS (2016) Cerebrovascular disease in ageing and Alzheimer’s disease. Acta Neuropathol131, 645–658.
138.
SojkovaJ, ZhouY, AnY, KrautMA, FerrucciL, WongDF, ResnickSM (2011) Longitudinal patterns of β-amyloid deposition in nondemented older adults. Arch Neurol68, 644–649.
139.
HeddenT, OhH, YoungerAP, PatelTA (2013) Meta-analysis of amyloid-cognition relations in cognitively normal older adults. Neurology80, 1341–1348.
