Abstract
To a great extent, cognitive health depends on cerebrovascular health and a deeper understanding of the subtle interactions between cerebrovascular function and cognition is needed to protect humans from one of the most devastating affliction, dementia. However, the underlying biological mechanisms are still not completely clear. Many studies demonstrated that the neurovascular unit is compromised in cerebrovascular diseases and also in other types of dementia. The hemodynamic neurovascular coupling ensures a strong increase of the cerebral blood flow (CBF) and an acute increase in neuronal glucose uptake upon increased neural activity. Dysfunction of cerebral autoregulation with increasing age along with age-related structural and functional alterations in cerebral blood vessels including accumulation of amyloid-beta (Aβ) in the media of cortical arterioles, neurovascular uncoupling due to astrocyte endfeet retraction, impairs the CBF and increases the neuronal degeneration and susceptibility to hypoxia and ischemia. A decreased cerebral glucose metabolism is an early event in Alzheimer’s disease (AD) pathology and may precede the neuropathological Aβ deposition associated with AD. Aβ accumulation in turn leads to further decreases in the CBF closing the vicious cycle. Alzheimer, aging and diabetes are also influenced by insulin/insulin-like growth factor-1 signaling, and accumulated evidence indicates sporadic AD is associated with disturbed brain insulin metabolism. Understanding how vascular and metabolic factors interfere with progressive loss of functional neuronal networks becomes essential to develop efficient drugs to prevent cognitive decline in elderly.
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References
Aichner F, Bauer G (2005) Cerebral anoxia. In: Niedermeyer E, Lopez da Silva F (eds) Electroencephalography: basic principles, clinical applications and related fields, Williams & Wilkins, Baltimore, pp 455–470
Baquer NZ, Taha A, Kumar P et al (2009) A metabolic and functional overview of brain aging linked to neurological disorders. Biogerontology 10:377–413
Barone FC, Rosenbaum DM, Zhou J et al (2009) Vascular cognitive impairment: dementia biology and translational animal models. Curr Opin Investig Drugs 10:624–637
Biagi L, Abbruzzese A, Bianchi MC et al (2007) Age dependence of cerebral perfusion assessed by magnetic resonance continuous arterial spin labeling. Magn Reson Imaging 25:696–702
Biessels GJ, Staekenborg S, Brunner E, Brayne C, Scheltens P (2006) Risk of dementia in diabetes mellitus: a systematic review. Lancet Neurol 5:64–74
Breteler MM (2000) Vascular risk factors for Alzheimer’s disease: an epidemiologic perspective. Neurobiol Aging 21:153–160
Chen Z, Zhong C (2013) Decoding Alzheimer’s disease from perturbed cerebral glucose metabolism: implications for diagnostic and therapeutic strategies. Prog Neurobiol 108:21–43
Chen W, Novotny EJ, Zhu X, Rothman DL, Shulman RG (1993) Localized 1H NMR measurement of glucose consumption in the human brain during visual stimulation. Proc Natl Acad Sci USA 90:9896–9900
Chua LM, Lim ML, Chong PR, Hu ZP, Cheung NS, Wong BS (2012) Impaired neuronal insulin signaling precedes Aβ42 accumulation in female AβPPsw/PS1ΔE9 mice. J Alzheimers Dis 29:783–791
Correia SC, Santos RX, Perry G, Zhu X, Moreira PI, Smith MA (2011) Insulin-resistant brain state: the culprit in sporadic Alzheimer’s disease? Ageing Res Rev 10:264–273
de la Torre JC, Mussivand T (1993) Can disturbed brain microcirculation cause Alzheimer’s disease? Neurol Res 15:146–153
den Dunnen WF, Brouwer WH, Bijlard E et al (2008) No disease in the brain of a 115-year-old woman. Neurobiol Aging 29:1127–1132
Desmond DW, Moroney JT, Sano M et al (2002) Incidence of dementia after ischemic stroke: results of a longitudinal study. Stroke 33:2254–2260
Dugan LL, Kim-Han JS (2006) Hypoxic-ischemic brain injury and oxidative stress. In: Siegel GJ, Albers RW, Brady ST, Price DL (eds) Basic neurochemistry: molecular, cellular and medical aspects. Elsevier, AP, pp 559–573
Emmanuel Y, Cochlin LE, Tyler DJ, de Jager CA, David Smith A, Clarke K (2013) Human hippocampal energy metabolism is impaired during cognitive activity in a lipid infusion model of insulin resistance. Brain Behav 3:134–144
Enciu AM, Constantinescu SN, Popescu LM, Mureşanu DF, Popescu BO (2011) Neurobiology of vascular dementia. J Aging Res 2011:401604
Fotuhi M, Hachinski V, Whitehouse PJ (2009) Changing perspectives regarding late-life dementia. Nat Rev Neurol 5:649–658
Games D, Buttini M, Kobayashi D, Schenk D, Seubert P (2006) Mice as models: transgenic approaches and Alzheimer’s disease. J Alzheimers Dis 9:133–149
Giménez-Llort L, Blázquez G, Cañete T, Johansson B et al (2007) Modeling behavioral and neuronal symptoms of Alzheimer’s disease in mice: a role for intraneuronal amyloid. Neurosci Biobehav Rev 31:125–147
Gorelick PB, Scuteri A, Black SE, Decarli C, Greenberg SM, Iadecola C, et al (2011) Vascular contributions to cognitive impairment and dementia: a statement for healthcare professionals from the american heart association/American stroke association. Stroke 42:2672–713
Grau-Olivares M, Arboix A (2009) Mild cognitive impairment in stroke patients with ischemic cerebral small-vessel disease: a forerunner of vascular dementia? Expert Rev Neurother 9:1201–1217
Hachinski VC, Lassen NA, Marshall J (1974) Multi-infarct dementia: a cause of mental deterioration in the elderly. Lancet 2:207–210
Hachinski V, Iadecola C, Petersen RC et al (2006) National institute of neurological disorders and stroke-Canadian stroke network vascular cognitive impairment harmonization standards. Stroke 37:2220–2241
Henneberg N, Hoyer S (1995) Desensitization of the neuronal insulin receptor: a new approach in the etiopathogenesis of late-onset sporadic dementia of the Alzheimer type (SDAT)? Arch Gerontol Geriatr 21:63–74
Hermann DM, Chopp M (2012) Promoting brain remodelling and plasticity for stroke recovery: therapeutic promise and potential pitfalls of clinical translation. Lancet Neurol 11:369–380
Hoyer S (1991) Abnormalities of glucose metabolism in Alzheimer’s disease. Ann NY Acad Sci 640:53–58
Hoyer S (2002) The brain insulin signal transduction system and sporadic (type II) Alzheimer disease: an update. J Neural Transm 109:341–360
Hoyer S, Lannert H, Latteier E, Meisel T (2004) Relationship between cerebral energy metabolism in parietotemporal cortex and hippocampus and mental activity during aging in rats. J Neural Transm 111:575–589
Iadecola C (2004) Neurovascular regulation in the normal brain and in Alzheimer’s disease. Nat Rev Neurosci 5:347–360
Iadecola C (2010) The overlap between neurodegenerative and vascular factors in the pathogenesis of dementia. Acta Neuropathol 120:287–296
Iadecola C, Gorelick PB (2003) Converging pathogenic mechanisms in vascular and neurodegenerative dementia. Stroke 34:335–337
Iadecola C, Nedergaard M (2007) Glial regulation of the cerebral microvasculature. Nat Neurosci 10:1369–1376
Itoh Y, Yamada M, Hayakawa M et al (1993) Cerebral amyloid angiopathy: a significant cause of cerebellar as well as lobar cerebral hemorrhage in the elderly. J Neurol Sci 116:135–141
Jellinger KA (2002) Vascular-ischemic dementia: an update. J Neural Transm (Suppl) 62:1–23
Jellinger KA, Attems J (2010) Prevalence of dementia disorders in the oldest-old: an autopsy study. Acta Neuropathol 119:421–433
Jin F, Hagemann N, Schäfer ST et al (2013) SDF-1 restores angiogenesis synergistically with VEGF upon LDL exposure despite CXCR4 internalization and degradation. Cardiovasc Res 100:481–491
Kamino K, Orr HT, Payami H et al (1992) Linkage and mutational analysis of familial Alzheimer disease kindreds for the APP gene region. Am J Hum Genet 51:998–1014
Laurent S, Briet M, Boutouyrie P (2009) Large and small artery cross-talk and recent morbidity-mortality trials in hypertension. Hypertension 54:388–392
Lehmann M, Ghosh PM, Madison C et al (2013) Greater medial temporal hypometabolism and lower cortical amyloid burden in ApoE4-positive AD patients. J Neurol Neurosurg Psychiatry. doi:10.1136/jnnp-2013-305858
Li ZG, Zhang W, Sima AA (2007) Alzheimer-like changes in rat models of spontaneous diabetes. Diabetes 56:1817–1824
Marini C, Totaro R, De Santis F et al (2001) Stroke in young adults in the community-based L’Aquila registry: incidence and prognosis. Stroke 32:52–56
Mawuenyega KG, Sigurdson W, Ovod V et al (2010) Decreased clearance of CNS beta-amyloid in Alzheimer’s disease. Science 330:1774
McNay EC, Ong CT, McCrimmon RJ, Cresswell J, Bogan JS, Sherwin RS (2010) Hippocampal memory processes are modulated by insulin and high-fat-induced insulin resistance. Neurobiol Learn Mem 93:546–553
Merlini M, Meyer EP, Ulmann-Schuler A, Nitsch RM (2011) Vascular β-amyloid and early astrocyte alterations impair cerebrovascular function and cerebral metabolism in transgenic arcAβ mice. Acta Neuropathol 122:293–311
Meyer-Luehmann M, Coomaraswamy J, Bolmont T et al (2006) Exogenous induction of cerebral beta-amyloidogenesis is governed by agent and host. Science 313:1781–1784
Miravalle L, Tokuda T, Chiarle R et al (2000) Substitutions at codon 22 of Alzheimer’s abeta peptide induce conformational changes and diverse apoptotic effects in human cerebral endothelial cells. J Biol Chem 275:27110–27116
Mosconi L, Tsui WH, De Santi S et al (2005) Reduced hippocampal metabolism in MCI and AD: automated FDG-PET image analysis. Neurology 64:1860–1867
Nagy Z, Esiri MM, Jobst KA et al (1997) The effects of additional pathology on the cognitive deficit in Alzheimer disease. J Neuropathol Exp Neurol 56:165–170
O’Sullivan M (2008) Leukoaraiosis. Pract Neurol 8:26–38
Patil SP, Ballard R, Sanchez S, Osborn J, Santangelo D Jr (2012) ApoE: the link between Alzheimer’s-related glucose hypometabolism and Aβ deposition? Med Hypotheses 78:494–496
Paulson OB, Hasselbalch SG, Rostrup E, Knudsen GM, Pelligrino D (2010) Cerebral blood flow response to functional activation. J Cereb Blood Flow Metab 30:2–14
Pelligrino DA (2006) Regulation of the cerebral circulation. J Appl Physiol 100:3–4
Pluta R, Jolkkonen J, Cuzzocrea S, Pedata F, Cechetto D, Popa-Wagner A (2011) Cognitive impairment with vascular impairment and degeneration. Curr Neurovasc Res. 8:342–350
Popa-Wagner A, Schroeder E, Walker LC, Kessler Ch (1998) ß-amyloid precursor protein and Aß peptide immunoreactivity in the rat brain following middle cerebral artery occlusion: effect of age. Stroke 29:2196–2202
Popa-Wagner A, Pirici D, Zagrean AM et al (2010) Cerebral circulation: anatomy, distribution and physiopathology, advances in medicine and biology. pp 1–45
Price JM, Chi X, Hellermann G, Sutton ET (2001) Physiological levels of beta-amyloid induce cerebral vessel dysfunction and reduce endothelial nitric oxide production. Neurol Res 23:506–512
Rensink AA, de Waal RM, Kremer B et al (2003) Pathogenesis of cerebral amyloid angiopathy. Brain Res Brain Res Rev 43:207–223
Roman GC, Tatemichi TK, Erkinjuntti T et al (1993) Vascular dementia: diagnostic criteria for research studies: report of the NINDS-AIREN international workshop. Neurology 43:250–260
Sadowski M, Pankiewicz J, Scholtzova H et al (2004) Amyloid-beta deposition is associated with decreased hippocampal glucose metabolism and spatial memory impairment in APP/PS1 mice. Neuropathol Exp Neurol 63:418–428
Schneider JA, Bennett D (2010) Where vascular and neurodegenerative diseases meet. Stroke 41(10 Suppl):S144–S146
Schneider JA, Wilson RS, Bienias JL, Evans DA, Bennett DA (2004) Cerebral infarctions and the likelihood of dementia from Alzheimer disease pathology. Neurology 62:1148–1155
Selnes OA, Vinters HV (2006) Vascular cognitive impairment. Nat Clin Pract Neurol 2:538–534
Siegel GJ, Chauhan NB (2000) Neurotrophic factors in Alzheimer’s and Parkinson’s disease brain. Brain Res Brain Res Rev 33:199–227
Takeda S, Sato N, Rakugi H, Morishita R (2011) Molecular mechanisms linking diabetes mellitus and Alzheimer disease: beta-amyloid peptide, insulin signaling, and neuronal function. Mol BioSyst 7:1822–1827
Talbot K, Wang HY, Kazi H et al (2012) Demonstrated brain insulin resistance in Alzheimer’s disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline. J Clin Invest 122:1316–1338
Thal DR, Ghebremedhin E, Orantes M et al (2003) Vascular pathology in Alzheimer disease: correlation of cerebral amyloid angiopathy and arteriosclerosis/lipohyalinosis with cognitive decline. J Neuropathol Exp Neurol 62:1287–1301
van Beek AH, Claassen JA, Rikkert MG, Jansen RW (2008) Cerebral autoregulation: an overview of current concepts and methodology with special focus on the elderly. J Cereb Blood Flow Metab 28:1071–1085
Vinters HV, Ellis WG, Zarow C et al (2000) Neuropathologic substrates of ischemic vascular dementia. J Neuropathol Exp Neurol 59:931–945
Vlassenko AG, Vaishnavi SN, Couture L et al (2010) Spatial correlation between brain aerobic glycolysis and amyloid-β (Aβ) deposition. Proc Natl Acad Sci USA 107:17763–17767
Weller RO, Boche D, Nicoll JA (2009) Microvasculature changes and cerebral amyloid angiopathy in Alzheimer’s disease and their potential impact on therapy. Acta Neuropathol 118:87–102
Wolburg H, Noell S, Mack A et al (2009) Brain endothelial cells and the glio-vascular complex. Cell Tissue Res 335:75–96
Zechariah A, ElAli A, Hagemann N, Jin F, Doeppner TR, Helfrich I, Mies G, Hermann DM (2013) Hyperlipidemia attenuates vascular endothelial growth factor-induced angiogenesis, impairs cerebral blood flow, and disturbs stroke recovery via decreased pericyte coverage of brain endothelial cells. Arterioscler Thromb Vasc Biol 33:1561–1567
Zlokovic BV (2008) The blood-brain barrier in health and chronic neurodegenerative disorders. Neuron 57:178–201
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This work was supported by UEFISCDI, PN-II-ID-PCE-2011-3-0848 and UEFISCDI FLARE2 (to A.M.B.).
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Popa-Wagner, A., Buga, AM., Popescu, B. et al. Vascular cognitive impairment, dementia, aging and energy demand. A vicious cycle. J Neural Transm 122 (Suppl 1), 47–54 (2015). https://doi.org/10.1007/s00702-013-1129-3
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DOI: https://doi.org/10.1007/s00702-013-1129-3