Cerebrovascular Alterations in Alzheimer Disease
2018; Lippincott Williams & Wilkins; Volume: 123; Issue: 4 Linguagem: Inglês
10.1161/circresaha.118.313400
ISSN1524-4571
AutoresCostantino Iadecola, Rebecca F. Gottesman,
Tópico(s)Alzheimer's disease research and treatments
ResumoHomeCirculation ResearchVol. 123, No. 4Cerebrovascular Alterations in Alzheimer Disease Free AccessArticle CommentaryPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessArticle CommentaryPDF/EPUBCerebrovascular Alterations in Alzheimer DiseaseIncidental or Pathogenic? Costantino Iadecola and Rebecca F. Gottesman Costantino IadecolaCostantino Iadecola Correspondence to Costantino Iadecola, MD, Weill Cornell Medicine, Feil Family Brain and Mind Research Institute, 407 E 61st St, RR-303, New York, NY 10065. Email E-mail Address: [email protected] From the Weill Cornell Medicine, Feil Family Brain and Mind Research Institute, New York (C.I.) Search for more papers by this author and Rebecca F. GottesmanRebecca F. Gottesman Department of Neurology and Epidemiology, Johns Hopkins University, Baltimore, MD (R.F.G.). Search for more papers by this author Originally published2 Aug 2018https://doi.org/10.1161/CIRCRESAHA.118.313400Circulation Research. 2018;123:406–408Alzheimer disease (AD)—the leading cause of cognitive impairment in the elderly—has traditionally been considered a disease of neurons. Structural and functional alterations of cerebral blood vessels also occur, but direct evidence of a causal involvement in the pathobiology of the disease has been lacking. This viewpoint will review new data that may help shed light into the intriguing association between vascular and neurodegenerative pathology.AD—the most common cause of age-related cognitive impairment—has emerged as a leading health challenge of our times. Afflicting ≈6 million people in the United States, at a staggering cost of $259 billion, AD has risen to be the sixth most common cause of death (http://www.who.int/en/news-room/fact-sheets/detail/dementia). Although there is evidence of a decrease in incidence,1 because of demographic shifts and lack of disease-modifying treatments, the number of affected individuals is anticipated to approach 150 million worldwide by 2050 (http://www.who.int/en/news-room/fact-sheets/detail/dementia).AD has traditionally been considered a neurodegenerative disease affecting neurons, but alterations of the cerebral macrovasculature and microvasculature are also present. Considering the brain’s critical dependence on a finely regulated blood supply and blood-brain barrier exchange,2 these vascular alterations could play a role in the neuronal dysfunction and damage underlying the dementia. However, it remains unclear whether the vascular changes interact with the neurodegenerative process or act independently through hypoxic-ischemic damage. In this viewpoint, we will briefly review recent epidemiological, imaging, and basic science developments to provide an updated assessment of the vascular contributions to AD and flesh out questions still outstanding.The classic neuropathological hallmarks of AD are amyloid plaques and neurofibrillary tangles. Amyloid plaques consist mainly of extracellular aggregates of Aβ (amyloid-β)—a 40 to 42 amino acid peptide cleaved from APP (amyloid precursor protein).3 Neurofibrillary tangles are intraneuronal aggregates of the microtubule-associated protein tau, which undergo excessive phosphorylation and aggregation.3 Lower order aggregates (oligomers) of Aβ and tau, rather than plaques and tangles per se, are thought to mediate cognitive impairment in AD by disrupting synaptic function in critical brain regions.3 In familial AD, in which there are mutations of the APP gene, amyloid accumulation results from increased Aβ production,3 but in the more common sporadic forms, there is a failure of Aβ clearance.3 On these bases, AD has traditionally been considered strictly a neurodegenerative disease.Contrary to this view, only 24% of patients with dementia have pure AD pathology (plaques and tangles), whereas >50% have vascular lesions (microinfarcts and macroinfarcts, microhemorrhages, lacunar strokes, and white matter lesions), either alone or in association with AD pathology.4 Furthermore, large and small cerebral arteries of patients with AD have more atherosclerosis.5 Therefore, mixed dementia encompassing both AD and vascular pathology is the most common cause of age-related dementia, especially in older individuals.Epidemiological and imaging studies also point to vascular dysfunction and damage in AD. Thus, vascular risk factors, such as midlife hypertension, obesity, diabetes mellitus, are each associated not only with an elevated risk of dementia6 but also with a 2- to 3-fold increased risk of elevated cerebral amyloid later in life (evaluated by positron emission tomography).7 Furthermore, presymptomatic individuals at risk for AD exhibit cerebrovascular dysfunction, reduced cerebral blood flow,8 and altered blood-brain barrier permeability.2 These observations have raised the possibility that cerebrovascular dysfunction is a presymptomatic correlate of AD pathology.8Experimental data also suggest a vascular contribution to AD pathology. Transgenic mice with amyloid accumulation have a profound disruption of neurovascular regulation before the expression of cognitive deficits and amyloid plaques.2 Thus, the increase in cerebral blood flow produced by neural activity and endothelial vasomotor function is markedly impaired, while cerebrovascular autoregulation is suspended rendering cerebral perfusion totally dependent on arterial blood pressure.2 The neurovascular dysfunction is mediated by Aβ-induced activation of scavenger receptors on perivascular macrophages leading to radical formation through a Nox2-containing NADPH (nicotinamide adenine dinucleotide phosphate) oxidase.2 The resulting poly-ADP-ribose polymerase activation leads to endothelial Ca2+ overload and dysfunction via the transient potential receptor melastatin 2.2Collectively, this body of work has revealed a close association between vascular and AD pathology. But, the pathogenic significance of the association remains to be established, and many questions remain. For example,Do Vascular and AD Pathologies Interact, Promoting Each Other?Experimental studies suggest that Aβ can reduce cerebral blood flow, induce neurovascular dysfunction, and increase the susceptibility of the brain to ischemia.2 Indeed, patients with a clinical diagnosis of AD have an increased stroke risk,9 suggesting that AD pathology could promote vascular pathology (Figure). Conversely, there might be a mechanistic link between vascular factors and AD pathology. For example, although experimental hypertension increases Aβ production, the vascular damage produced by hypertension reduces the clearance of Aβ and possibly tau, promoting amyloid accumulation and neurofibrillary tangles2 (Figure). In support of this hypothesis, imaging and autopsy studies have shown evidence of increased amyloid or tau accumulation in participants with vascular risk factors.7 Therefore, AD and vascular pathologies could interact enhancing each other, but more definitive evidence for a causal link between the 2 is lacking. For example, there is no evidence that hypoxia-ischemia increases amyloid tracers in patients,10 and longitudinal studies indicate that vascular pathology develops independently of AD pathology.11 However, studies using positron emission tomography imaging with amyloid or tau tracers, which reflect aggregates, cannot exclude the possibility that monomeric or oligomeric Aβ or tau is increased by ischemia during critical periods of the disease process. Therefore, although biologically plausible, establishing a causal relationship between vascular factors and AD pathology in humans has been challenging. More sensitive biomarkers of soluble Aβ and tau, either via positron emission tomography or using cerebrospinal fluid, would help provide further insight into this issue.Download figureDownload PowerPointFigure. Alzheimer disease (AD) pathology leads to dysfunction and damage to cerebral blood vessels by inducing vascular dysregulation, blood-brain barrier (BBB) disruption, and promoting atherosclerosis. In turn, poor vascular health promotes amyloid accumulation by increasing Aβ production and reducing its vascular clearance. The harmful effects of vascular and AD pathology converge on the brain to induce neuronal dysfunction and cognitive impairment.What Is the Relative Impact of Vascular and AD Pathology on Cognition?AD and vascular pathology could each contribute to the cognitive demise in an additive fashion or act synergistically to enhance their respective impacts. Some studies have suggested that vascular pathology may amplify the deleterious effect of AD pathology, consistent with the interaction between vascular and AD pathology mentioned above (Figure). For example, given the same degree of AD pathology, vascular lesions with minimal or no impact on cognition may result in more severe dementia.4 However, the 2 processes could be simply additive: the cognitive impact of vascular lesions summing up with that of AD pathology. Such a scenario has been suggested by studies demonstrating that the vascular pathology aggravates the expression of the cognitive impairment independently of AD pathology.12 However, investigating these relationships in vivo is challenging because the relative contribution of the 2 pathologies is likely to vary from patient to patient depending on the type and location of vascular pathology, genetic background, degree of AD pathology, and cognitive reserve. Vascular pathology can be diffuse, for example, microinfarcts and microhemorrhages, or targeted to brain regions subserving specific cognitive domains.13 It is conceivable that the reduction in connectivity caused by white matter pathology could enhance the impact of AD pathology by impairing the recruitment of alternative cognitive networks or developing cognitive strategies to overcome the deficits. Cognitive reserve, determining the ability of the brain to cope with pathology, and ApoE (apolipoprotein E) genotype may also influence the threshold for expression of the cognitive deficits. Therefore, the nature and topology of the vascular pathology may determine cognitive impact of AD pathology, depending on cognitive reserve.Does Promoting Vascular Health Help Stave Off AD?One major motivation for a research focus on the vascular contribution to AD is the therapeutic potential. Although AD pathology is currently untreatable, vascular risk factors are treatable or even preventable. Despite compelling evidence of an association and a biologically plausible mechanism behind this association, therapeutic translation of these concepts is limited by the lack of clinical trial data demonstrating a benefit from treatment of vascular risk factors on cognitive outcomes. Only 1 major trial to date, Syst-Eur,14 demonstrated a reduction in dementia rates for individuals treated for hypertension, but actual event rates were low, and these results have not been replicated in other trials. This discrepancy between observational longitudinal data and clinical trial results may be because of the need for a longer interval between vascular risk exposure and cognitive outcomes; risk factors are most strongly associated with late-life dementia when considered in midlife, and most trials do not extend from midlife through later life. SPRINT-MIND (The SPRINT Memory and Cognition in Decreased Hypertension) is an ongoing trial, accompanying the SPRINT trial,15 which will include cognitive outcomes and further address this important question. Ongoing trials considering multimodal therapies that address vascular risk factors and include lifestyle modifications might also help provide insight into ideal management of vascular risk and its potential impact on AD.ConclusionsVascular and neurodegenerative changes are distinct yet inextricably intertwined substrates of age-related cognitive impairment. But in what measure each pathology contributes to the clinical expression of the dementia has been difficult to assess in humans. Although imaging studies have confirmed their association and potential interaction in vivo, more sophisticated biomarkers of vascular and neurodegenerative pathology, as well as longer lasting longitudinal studies, are needed to more precisely define their respective impact on cognitive function. Considering that therapeutic approaches targeting neurodegeneration have not been successful to date, there is a strong rationale for adopting aggressive strategies to counteract vascular risk factors in midlife, to protect the brain for the cumulative effect of vascular damage on cognitive health later in life.Sources of FundingSupported by National Institutes of Health grants R37-NS089323 (Dr Iadecola), R01-NS100447 (Dr Iadecola), R01-NS09544 (Dr Iadecola), R01-NS/HL037853 (Dr Iadecola), K24-AG052573 (R.F. Gottesman), RF1-AG050745 (R.F. Gottesman), and R01-AG040282 (R.F. Gottesman).DisclosuresDr Iadecola serves on the Scientific Advisory Board of Broadview Ventures. R.F. Gottesman is Associate Editor for the journal Neurology.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Correspondence to Costantino Iadecola, MD, Weill Cornell Medicine, Feil Family Brain and Mind Research Institute, 407 E 61st St, RR-303, New York, NY 10065. Email [email protected]cornell.eduReferences1. Satizabal CL, Beiser AS, Chouraki V, Chêne G, Dufouil C, Seshadri S. Incidence of dementia over three decades in the Framingham Heart Study.N Engl J Med. 2016; 374:523–532. doi: 10.1056/NEJMoa1504327.CrossrefMedlineGoogle Scholar2. Iadecola C. The neurovascular unit coming of age: a journey through neurovascular coupling in health and disease.Neuron. 2017; 96:17–42. doi: 10.1016/j.neuron.2017.07.030.CrossrefMedlineGoogle Scholar3. De Strooper B, Karran E. The cellular phase of Alzheimer’s disease.Cell. 2016; 164:603–615. doi: 10.1016/j.cell.2015.12.056.CrossrefMedlineGoogle Scholar4. Azarpazhooh MR, Avan A, Cipriano LE, Munoz DG, Sposato LA, Hachinski V. Concomitant vascular and neurodegenerative pathologies double the risk of dementia.Alzheimers Dement. 2018; 14:148–156. doi: 10.1016/j.jalz.2017.07.755.CrossrefMedlineGoogle Scholar5. Dearborn JL, Zhang Y, Qiao Y, Suri MFK, Liu L, Gottesman RF, Rawlings AM, Mosley TH, Alonso A, Knopman DS, Guallar E, Wasserman BA. Intracranial atherosclerosis and dementia: the Atherosclerosis Risk in Communities (ARIC) Study.Neurology. 2017; 88:1556–1563. doi: 10.1212/WNL.0000000000003837.CrossrefMedlineGoogle Scholar6. Gottesman RF, Albert MS, Alonso A, Coker LH, Coresh J, Davis SM, Deal JA, McKhann GM, Mosley TH, Sharrett AR, Schneider ALC, Windham BG, Wruck LM, Knopman DS. Associations between midlife vascular risk factors and 25-year incident dementia in the Atherosclerosis Risk in Communities (ARIC) cohort.JAMA Neurol. 2017; 74:1246–1254.CrossrefMedlineGoogle Scholar7. Gottesman RF, Schneider AL, Zhou Y, Coresh J, Green E, Gupta N, Knopman DS, Mintz A, Rahmim A, Sharrett AR, Wagenknecht LE, Wong DF, Mosley TH. Association between midlife vascular risk factors and estimated brain amyloid deposition.JAMA. 2017; 317:1443–1450. doi: 10.1001/jama.2017.3090.CrossrefMedlineGoogle Scholar8. Iturria-Medina Y, Sotero RC, Toussaint PJ, Mateos-Pérez JM, Evans AC; Alzheimer’s Disease Neuroimaging Initiative. Early role of vascular dysregulation on late-onset Alzheimer’s disease based on multifactorial data-driven analysis.Nat Commun. 2016; 7:11934. doi: 10.1038/ncomms11934.CrossrefMedlineGoogle Scholar9. Chi NF, Chien LN, Ku HL, Hu CJ, Chiou HY. Alzheimer disease and risk of stroke: a population-based cohort study.Neurology. 2013; 80:705–711. doi: 10.1212/WNL.0b013e31828250af.CrossrefMedlineGoogle Scholar10. Sahathevan R, Linden T, Villemagne VL, Churilov L, Ly JV, Rowe C, Donnan G, Brodtmann A. Positron emission tomographic imaging in stroke: cross-sectional and follow-up assessment of amyloid in ischemic stroke.Stroke. 2016; 47:113–119. doi: 10.1161/STROKEAHA.115.010528.LinkGoogle Scholar11. Dodge HH, Zhu J, Woltjer Ret al; SMARTDataConsortium. Risk of incident clinical diagnosis of Alzheimer’s disease-type dementia attributable to pathology-confirmed vascular disease.Alzheimers Dement. 2017; 13:613–623. doi: 10.1016/j.jalz.2016.11.003.CrossrefMedlineGoogle Scholar12. Ezzati A, Wang C, Lipton RB, Altschul D, Katz MJ, Dickson DW, Derby CA. Association between vascular pathology and rate of cognitive decline independent of Alzheimer’s disease pathology.J Am Geriatr Soc. 2017; 1:61–66.Google Scholar13. Biesbroek JM, Weaver NA, Biessels GJ. Lesion location and cognitive impact of cerebral small vessel disease.Clin Sci (Lond). 2017; 131:715–728. doi: 10.1042/CS20160452.CrossrefMedlineGoogle Scholar14. Forette F, Seux ML, Staessen JAet al. Prevention of dementia in randomised double-blind placebo-controlled Systolic Hypertension in Europe (Syst-Eur) trial.Lancet. 1998; 352:1347–1351.CrossrefMedlineGoogle Scholar15. Wright JT, Williamson JD, Whelton PKet al; SPRINT Research Group. A randomized trial of intensive versus standard blood-pressure control.N Engl J Med. 2015; 373:2103–2116. doi: 10.1056/NEJMoa1511939.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Wareham L, Liddelow S, Temple S, Benowitz L, Di Polo A, Wellington C, Goldberg J, He Z, Duan X, Bu G, Davis A, Shekhar K, Torre A, Chan D, Canto-Soler M, Flanagan J, Subramanian P, Rossi S, Brunner T, Bovenkamp D and Calkins D (2022) Solving neurodegeneration: common mechanisms and strategies for new treatments, Molecular Neurodegeneration, 10.1186/s13024-022-00524-0, 17:1, Online publication date: 1-Dec-2022. Liu L, Volpe S, Ross J, Grimm J, Van Bockstaele E and Eisen H (2021) Dietary sugar intake and risk of Alzheimer's disease in older women, Nutritional Neuroscience, 10.1080/1028415X.2021.1959099, 25:11, (2302-2313), Online publication date: 2-Nov-2022. Lansdell T, Chambers L and Dorrance A (2022) Endothelial Cells and the Cerebral Circulation Comprehensive Physiology, 10.1002/cphy.c210015, (3449-3508) Taylor J, Pritchard H, Walsh K, Strangward P, White C, Hill-Eubanks D, Alakrawi M, Hennig G, Allan S, Nelson M and Greenstein A (2022) Functionally linked potassium channel activity in cerebral endothelial and smooth muscle cells is compromised in Alzheimer’s disease, Proceedings of the National Academy of Sciences, 10.1073/pnas.2204581119, 119:26, Online publication date: 28-Jun-2022. Tarafdar A, Wolska N, Krisp C, Schlüter H and Pula G (2022) The amyloid peptide β disrupts intercellular junctions and increases endothelial permeability in a NADPH oxidase 1-dependent manner, Redox Biology, 10.1016/j.redox.2022.102287, 52, (102287), Online publication date: 1-Jun-2022. Gupta A, Uthayaseelan K, Uthayaseelan K, Kadari M, Subhan M, Saji Parel N, Krishna P and Sange I Alzheimer's Disease and Stroke: A Tangled Neurological Conundrum, Cureus, 10.7759/cureus.25005 Sundarakumar J, Stezin A, Menesgere A and Ravindranath V (2022) Rural-urban and gender differences in metabolic syndrome in the aging population from southern India: Two parallel, prospective cohort studies, eClinicalMedicine, 10.1016/j.eclinm.2022.101395, 47, (101395), Online publication date: 1-May-2022. Barbeau‐Meunier C, Bernier M, Côté S, Gilbert G, Bocti C and Whittingstall K (2021) Sexual dimorphism in the cerebrovascular network: Brain MRI shows lower arterial density in women, Journal of Neuroimaging, 10.1111/jon.12951, 32:2, (337-344), Online publication date: 1-Mar-2022. Ho T, Ahmadi S and Kerman K (2022) Do glutathione and copper interact to modify Alzheimer's disease pathogenesis?, Free Radical Biology and Medicine, 10.1016/j.freeradbiomed.2022.01.025, 181, (180-196), Online publication date: 1-Mar-2022. Hsiu H, Lin S, Weng W, Hung C, Chang C, Lee C and Chen C (2022) Discrimination of the Cognitive Function of Community Subjects Using the Arterial Pulse Spectrum and Machine-Learning Analysis, Sensors, 10.3390/s22030806, 22:3, (806) Huuskonen M, Wang Y, Nikolakopoulou A, Montagne A, Dai Z, Lazic D, Sagare A, Zhao Z, Fernandez J, Griffin J and Zlokovic B (2021) Protection of ischemic white matter and oligodendrocytes in mice by 3K3A-activated protein C, Journal of Experimental Medicine, 10.1084/jem.20211372, 219:1, Online publication date: 3-Jan-2022. Lee K and Kang K (2022) Association between Cerebral Small Vessel and Alzheimer’s Disease, Journal of the Korean Society of Radiology, 10.3348/jksr.2022.0041, 83:3, (486), . Apátiga-Pérez R, Soto-Rojas L, Campa-Córdoba B, Luna-Viramontes N, Cuevas E, Villanueva-Fierro I, Ontiveros-Torres M, Bravo-Muñoz M, Flores-Rodríguez P, Garcés-Ramirez L, de la Cruz F, Montiel-Sosa J, Pacheco-Herrero M and Luna-Muñoz J (2021) Neurovascular dysfunction and vascular amyloid accumulation as early events in Alzheimer's disease, Metabolic Brain Disease, 10.1007/s11011-021-00814-4, 37:1, (39-50), Online publication date: 1-Jan-2022. Rhea E, Hansen K, Pemberton S, Torres E, Holden S, Raber J and Banks W (2021) Effects of apolipoprotein E isoform, sex, and diet on insulin BBB pharmacokinetics in mice, Scientific Reports, 10.1038/s41598-021-98061-1, 11:1, Online publication date: 1-Dec-2021. Lin S, Hsiu H, Chen H and Yang C (2021) Classification of patients with Alzheimer’s disease using the arterial pulse spectrum and a multilayer-perceptron analysis, Scientific Reports, 10.1038/s41598-021-87903-7, 11:1, Online publication date: 1-Dec-2021. Tahmi M, Palta P and Luchsinger J (2021) Metabolic Syndrome and Cognitive Function, Current Cardiology Reports, 10.1007/s11886-021-01615-y, 23:12, Online publication date: 1-Dec-2021. Jiang J, Liu H, Wang Z, Tian H, Wang S, Yang J, Ren J and Xu M (2021) Electroacupuncture could balance the gut microbiota and improve the learning and memory abilities of Alzheimer’s disease animal model, PLOS ONE, 10.1371/journal.pone.0259530, 16:11, (e0259530) Zhang Z, Na H, Gan Q, Tao Q, Alekseyev Y, Hu J, Yan Z, Yang J, Tian H, Zhu S, Li Q, Rajab I, Blusztajn J, Wolozin B, Emili A, Zhang X, Stein T, Potempa L and Qiu W (2021) Monomeric C‐reactive protein via endothelial CD31 for neurovascular inflammation in an ApoE genotype‐dependent pattern: A risk factor for Alzheimer’s disease?, Aging Cell, 10.1111/acel.13501, 20:11, Online publication date: 1-Nov-2021. Kehoe P, Turner N, Howden B, Jarutyte L, Clegg S, Malone I, Barnes J, Nielsen C, Sudre C, Wilson A, Thai N, Blair P, Coulthard E, Lane J, Passmore P, Taylor J, Mutsaerts H, Thomas D, Fox N, Wilkinson I, Ben-Shlomo Y, Harkness K, Kuruvilla T, McShane R, Connelly P, Duncan G, Calvert L, Lawrie A, Sheridan M, Jackson E, Udeze B, Pearson S, Langheinrich T, Wagle S, Butchart J, Macharouthu A, Donaldson A, Neil W, Pattan V, Findlay D, Thomas A, Barber R, Byrne A, Dalvi M, Negi R and McGuinness B (2021) Safety and efficacy of losartan for the reduction of brain atrophy in clinically diagnosed Alzheimer's disease (the RADAR trial): a double-blind, randomised, placebo-controlled, phase 2 trial, The Lancet Neurology, 10.1016/S1474-4422(21)00263-5, 20:11, (895-906), Online publication date: 1-Nov-2021. Claassen J, Thijssen D, Panerai R and Faraci F (2021) Regulation of cerebral blood flow in humans: physiology and clinical implications of autoregulation, Physiological Reviews, 10.1152/physrev.00022.2020, 101:4, (1487-1559), Online publication date: 1-Oct-2021. Ungvari Z, Toth P, Tarantini S, Prodan C, Sorond F, Merkely B and Csiszar A (2021) Hypertension-induced cognitive impairment: from pathophysiology to public health, Nature Reviews Nephrology, 10.1038/s41581-021-00430-6, 17:10, (639-654), Online publication date: 1-Oct-2021. Zhao X, Li C, Ding G, Heng Y, Li A, Wang W, Hou H, Wen J and Zhang Y The Burden of Alzheimer’s Disease Mortality in the United States, 1999-2018, Journal of Alzheimer's Disease, 10.3233/JAD-210225, 82:2, (803-813) Liu D, Ahmet I, Griess B, Tweedie D, Greig N and Mattson M (2020) Age-related impairment of cerebral blood flow response to K ATP channel opener in Alzheimer’s disease mice with presenilin-1 mutation , Journal of Cerebral Blood Flow & Metabolism, 10.1177/0271678X20964233, 41:7, (1579-1591), Online publication date: 1-Jul-2021. Lachén-Montes M, Íñigo-Marco I, Cartas-Cejudo P, Fernández-Irigoyen J and Santamaría E (2021) Olfactory Bulb Proteomics Reveals Widespread Proteostatic Disturbances in Mixed Dementia and Guides for Potential Serum Biomarkers to Discriminate Alzheimer Disease and Mixed Dementia Phenotypes, Journal of Personalized Medicine, 10.3390/jpm11060503, 11:6, (503) Zhou Y, Zhong F, Yan P, Lee J and Hu S (2021) Simultaneous imaging of amyloid deposition and cerebrovascular function using dual-contrast photoacoustic microscopy, Optics Letters, 10.1364/OL.419817, 46:11, (2561), Online publication date: 1-Jun-2021. Pålhaugen L, Sudre C, Tecelao S, Nakling A, Almdahl I, Kalheim L, Cardoso M, Johnsen S, Rongve A, Aarsland D, Bjørnerud A, Selnes P and Fladby T (2020) Brain amyloid and vascular risk are related to distinct white matter hyperintensity patterns, Journal of Cerebral Blood Flow & Metabolism, 10.1177/0271678X20957604, 41:5, (1162-1174), Online publication date: 1-May-2021. Roy T and Secomb T (2020) Effects of impaired microvascular flow regulation on metabolism‐perfusion matching and organ function, Microcirculation, 10.1111/micc.12673, 28:3, Online publication date: 1-Apr-2021. Sabbatinelli J, Ramini D, Giuliani A, Recchioni R, Spazzafumo L and Olivieri F (2021) Connecting vascular aging and frailty in Alzheimer’s disease, Mechanisms of Ageing and Development, 10.1016/j.mad.2021.111444, 195, (111444), Online publication date: 1-Apr-2021. Wang N, Li J, Liu W, Huang Q, Li W, Tan Y, Liu F, Song Z, Wang M, Xie N, Mao R, Gan P, Ding Y, Zhang Z, Shan B, Chen L, Zhou Q and Xu L (2021) Ferulic Acid Ameliorates Alzheimer’s Disease-like Pathology and Repairs Cognitive Decline by Preventing Capillary Hypofunction in APP/PS1 Mice, Neurotherapeutics, 10.1007/s13311-021-01024-7, 18:2, (1064-1080), Online publication date: 1-Apr-2021. Jackson W (2021) Capillary Inward-Rectifying K+ Crippled in a Mouse Model of Alzheimer’s Disease: Phosphatidylinositol 4,5-Bisphosphate to the Rescue!, Function, 10.1093/function/zqab017, 2:3, Online publication date: 22-Mar-2021. Lennon M, Koncz R and Sachdev P (2020) Hypertension and Alzheimer's disease: is the picture any clearer?, Current Opinion in Psychiatry, 10.1097/YCO.0000000000000684, 34:2, (142-148), Online publication date: 1-Mar-2021. Mughal A, Harraz O, Gonzales A, Hill-Eubanks D and Nelson M (2021) PIP2 Improves Cerebral Blood Flow in a Mouse Model of Alzheimer’s Disease, Function, 10.1093/function/zqab010, 2:2, Online publication date: 10-Feb-2021. Balasubramanian P, Kiss T, Tarantini S, Nyúl-Tóth Á, Ahire C, Yabluchanskiy A, Csipo T, Lipecz A, Tabak A, Institoris A, Csiszar A and Ungvari Z (2021) Obesity-induced cognitive impairment in older adults: a microvascular perspective, American Journal of Physiology-Heart and Circulatory Physiology, 10.1152/ajpheart.00736.2020, 320:2, (H740-H761), Online publication date: 1-Feb-2021. Boltze J, Aronowski J, Badaut J, Buckwalter M, Caleo M, Chopp M, Dave K, Didwischus N, Dijkhuizen R, Doeppner T, Dreier J, Fouad K, Gelderblom M, Gertz K, Golubczyk D, Gregson B, Hamel E, Hanley D, Härtig W, Hummel F, Ikhsan M, Janowski M, Jolkkonen J, Karuppagounder S, Keep R, Koerte I, Kokaia Z, Li P, Liu F, Lizasoain I, Ludewig P, Metz G, Montagne A, Obenaus A, Palumbo A, Pearl M, Perez-Pinzon M, Planas A, Plesnila N, Raval A, Rueger M, Sansing L, Sohrabji F, Stagg C, Stetler R, Stowe A, Sun D, Taguchi A, Tanter M, Vay S, Vemuganti R, Vivien D, Walczak P, Wang J, Xiong Y and Zille M (2021) New Mechanistic Insights, Novel Treatment Paradigms, and Clinical Progress in Cerebrovascular Diseases, Frontiers in Aging Neuroscience, 10.3389/fnagi.2021.623751, 13 Verdelho A and Pereira M (2021) Management of Vascular Risk Factors in Dementia Management of Patients with Dementia, 10.1007/978-3-030-77904-7_8, (155-178), . Nyúl-Tóth Á, Tarantini S, Kiss T, Toth P, Galvan V, Tarantini A, Yabluchanskiy A, Csiszar A and Ungvari Z (2020) Increases in hypertension-induced cerebral microhemorrhages exacerbate gait dysfunction in a mouse model of Alzheimer’s disease, GeroScience, 10.1007/s11357-020-00256-3, 42:6, (1685-1698), Online publication date: 1-Dec-2020. Czakó C, Kovács T, Ungvari Z, Csiszar A, Yabluchanskiy A, Conley S, Csipo T, Lipecz A, Horváth H, Sándor G, István L, Logan T, Nagy Z and Kovács I (2020) Retinal biomarkers for Alzheimer’s disease and vascular cognitive impairment and dementia (VCID): implication for early diagnosis and prognosis, GeroScience, 10.1007/s11357-020-00252-7, 42:6, (1499-1525), Online publication date: 1-Dec-2020. Kapadia A, Mirrahimi A and Dmytriw A (2020) Intersection between sleep and neurovascular coupling as the driving pathophysiology of Alzheimer’s disease, Medical Hypotheses, 10.1016/j.mehy.2020.110283, 144, (110283), Online publication date: 1-Nov-2020. Aires A, Andrade A, Azevedo E, Gomes F, Araújo J and Castro P (2020) Neurovascular Coupling Impairment in Heart Failure with Reduction Ejection Fraction, Brain Sciences, 10.3390/brainsci10100714, 10:10, (714) Zhang Y and Yang X (2020) The Roles of TGF-β Signaling in Cerebrovascular Diseases, Frontiers in Cell and Developmental Biology, 10.3389/fcell.2020.567682, 8 Park L, Hochrainer K, Hattori Y, Ahn S, Anfray A, Wang G, Uekawa K, Seo J, Palfini V, Blanco I, Acosta D, Eliezer D, Zhou P, Anrather J and Iadecola C (2020) Tau induces PSD95–neuronal NOS uncoupling and neurovascular dysfunction independent of neurodegeneration, Nature Neuroscience, 10.1038/s41593-020-0686-7, 23:9, (1079-1089), Online publication date: 1-Sep-2020. Rosas-Hernandez H, Cuevas E, Raymick J, Robinson B and Sarkar S (2020) Impaired Amyloid Beta Clearance and Brain Microvascular Dysfunction are Present in the Tg-SwDI Mouse Model of Alzheimer’s Disease, Neuroscience, 10.1016/j.neuroscience.2020.05.024, 440, (48-55), Online publication date: 1-Aug-2020. Iadecola C (2020) Revisiting atherosclerosis and dementia, Nature Neuroscience, 10.1038/s41593-020-0626-6, 23:6, (691-692), Online publication date: 1-Jun-2020. de Montgolfier O, Thorin-Trescases N and Thorin E (2020) Pathological Continuum From the Rise in Pulse Pressure to Impaired Neurovascular Coupling and Cognitive Decline, American Journal of Hypertension, 10.1093/ajh/hpaa001, 33:5, (375-390), Online publication date: 29-Apr-2020. Burnier M, Polychronopoulou E and Wuerzner G (2020) Hypertension and Drug Adherence in the Elderly, Frontiers in Cardiovascular Medicine, 10.3389/fcvm.2020.00049, 7 Fierini F (2020) Mixed dementia: Neglected clinical entity or nosographic artifice?, Journal of the Neurological Sciences, 10.1016/j.jns.2019.116662, 410, (116662), Online publication date: 1-Mar-2020. Hao Q, Feldmann E, Balucani C, Zubizarreta N, Zhong X and Levine S (2019) A New Transcranial Doppler Scoring System for Evaluating Middle Cerebral Artery Stenosis, Journal of Neuroimaging, 10.1111/jon.12678, 30:1, (97-103), Online publication date: 1-Jan-2020. Greenberg S, Bacskai B, Hernandez-Guillamon M, Pruzin J, Sperling R and van Veluw S (2019) Cerebral amyloid angiopathy and Alzheimer disease — one peptide, two pathways, Nature Reviews Neurology, 10.1038/s41582-019-0281-2, 16:1, (30-42), Online publication date: 1-Jan-2020. Román G, Jackson R, Reis J, Román A, Toledo J and Toledo E (2019) Extra-virgin olive oil for potential prevention of Alzheimer disease, Revue Neurologique, 10.1016/j.neurol.2019.07.017, 175:10, (705-723), Online publication date: 1-Dec-2019. Zhou G, Zhao X, Lou Z, Zhou S, Shan P, Zheng N, Yu X and Ma L Impaired Cerebral Autoregulation in Alzheimer’s Disease: A Transcranial Doppler Study, Journal of Alzheimer's Disease, 10.3233/JAD-190296, 72:2, (623-631) Cortes-Canteli M, Kruyer A, Fernandez-Nueda I, Marcos-Diaz A, Ceron C, Richards A, Jno-Charles O, Rodriguez I, Callejas S, Norris E, Sanchez-Gonzalez J, Ruiz-Cabello J, Ibanez B, Strickland S and Fuster V (2019) Long-Term Dabigatran Treatment Delays Alzheimer’s Disease Pathogenesis in the TgCRND8 Mouse Model, Journal of the American College of Cardiology, 10.1016/j.jacc.2019.07.081, 74:15, (1910-1923), Online publication date: 1-Oct-2019. Csipo T, Lipecz A, Fulop G, Hand R, Ngo B, Dzialendzik M, Tarantini S, Balasubramanian P, Kiss T, Yabluchanska V, Silva-Palacios F, Courtney D, Dasari T, Sorond F, Sonntag W, Csiszar A, Ungvari Z and Yabluchanskiy A (2019) Age-related decline in peripheral vascular health predicts cognitive impairment, GeroScience, 10.1007/s11357-019-00063-5, 41:2, (125-136), Online publication date: 1-Apr-2019. Iadecola C and Gottesman R (2019) Neurovascular and Cognitive Dysfunction in Hypertension, Circulation Research, 124:7, (1025-1044), Online publication date: 29-Mar-2019. Narula J, Ibáñez B and Fuster V (2019) From Heart to Head, Thrombi to Emboli, and Inferences to Extrapolation, Journal of the American College of Cardiology, 10.1016/j.jacc.2019.01.025, 73:9, (1000-1003), Online publication date: 1-Mar-2019. Santisteban M and Iadecola C (2018) Hypertension, dietary salt and cognitive impairment, Journal of Cerebral Blood Flow & Metabolism, 10.1177/0271678X18803374, 38:12, (2112-2128), Online publication date: 1-Dec-2018. August 3, 2018Vol 123, Issue 4 Advertisement Article InformationMetrics © 2018 American Heart Association, Inc.https://doi.org/10.1161/CIRCRESAHA.118.313400PMID: 30355253 Originally publishedAugust 2, 2018 Keywordsneuronsrisk factorsblood-brain barrierdementiaAlzheimer diseasePDF download Advertisement
Referência(s)