Vascular dementia and the cholinergic pathways

Engelhardt, Eliasz; Moreira, Denise Madeira; Laks, Jerson

doi:10.1590/S1980-57642008DN10100002

Abstract

Vascular cognitive impairment/vascular dementia have been the subject of a large number of studies, due to their high prevalence and broad preventive and compensatory therapeutic potential. The knowledge of the cerebral anatomy correlated to the vascular territories of irrigation enables understanding of clinical manifestations, as well as classification into the several types of syndromic presentations. The central cholinergic system exercises important neuromodulatory functions on cerebral circuits related to cognitive and behavioral integration, as well as on vasomotor control related to cerebral blood flow adjustments. The acquisition of data on the anatomy of the cholinergic pathways, including the localization of the nuclei of the basal prosencephalon and the routes of their projections, established an important milestone. The knowledge of the vascular distribution and of the trajectories of the cholinergic pathways allows identification of the strategic points where a vascular lesion can cause interruption. The ensuing denervation leads to cholinergic hypofunction in the involved territories. This information proves important to better evaluate the sites of vascular lesions, emphasizing their strategic localizations in relation to the cholinergic pathways, and offering more robust foundations for treatment aiming at enhancing cholinergic activity.

Key words:
anatomy; vascular dementia; cognitive impairment; cholinergic fibers.

Resumo

Comprometimento cognitivo vascular/demência vascular vem sendo objeto de numerosos estudos, levando em conta sua alta prevalência e as amplas possibilidades terapêuticas preventivas e compensatórias. O conhecimento da anatomia cerebral correlacionado ao dos territórios vasculares de irrigação permite a compreensão das manifestações clínicas, assim como a classificação dos diversos tipos de apresentações sindrômicas. O sistema colinérgico central exerce funções neuromoduladoras importantes dos circuitos relacionados à integração cognitiva e comportamental, além do controle vasomotor relacionado aos ajustes do fluxo sanguíneo cerebral. A obtenção de dados sobre a anatomia das vias colinérgicas, incluindo a localização dos núcleos do prosencéfalo basal e os trajetos das suas projeções, estabeleceu um marco importante. O conhecimento da distribuição vascular e do percurso das vias colinérgicas permite identificar pontos estratégicos onde a lesão vascular pode causar sua interrupção. A desnervação que se segue causa hipofunção colinérgica dos territórios acometidos. Essas informações são importantes para melhor avaliar os locais das lesões vasculares, enfatizando suas localizações estratégicas em relação às vias colinérgicas, oferecendo, desse modo, bases mais sólidas para o tratamento que visa aumentar a atividade colinérgica.

Palavras-chave:
anatomia; demência vascular; comprometimento cognitivo; fibras colinérgicas.

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Full text available only in PDF format.

References

¹
Bartus RT, Dean RL, Beer, Lippa AS. The cholinergichypothesis of geriatric memory dysfunction. Science 1982; 217:408-417.
²
Bartus RT. On neurodegenerative diseases, models, andtreatment strategies: lessons learned and lessons forgotten a generation following the cholinergic hypothesis. Exp Neurol 2000;163:495-529.
³
Birks J. Cholinesterase inhibitors for Alzheimer's disease. Cochrane Database Syst Rev; 2006.
⁴
Engelhardt E, Brucki SM, Cavalcanti JLS, Forlenza OV, LaksJ, Vale FAC. Tratamento da doença de Alzheimer: recomendações e sugestões do Departamento Científico de Neurologia Cognitiva e do Envelhecimento da Academia Brasileira de Neurologia. Arq Neuropsiquiatr 2005;63:1104-1112.
⁵
Román GC, Kalaria RN. Vascular determinants of cholinergic deficits in Alzheimer's disease and vascular dementia. Neurobiol Aging (in press).
⁶
Mesulam MM. Structure and function of cholinergic pathways in the cerebral cortex, limbic system, basal ganglia, and thalamus of the human brain. In: Bloom FE, Kupfer DJ, editors. Psychopharmacology: The Fourth Generation of Progress. New York: Raven Press; 1995:135-146.
⁷
Mufson EJ, Ginsberg SD, Ikonomovic MD et al. Humancholinergic basal forebrain: chemoanatomy and neurological dysfunction. J Chem Neuroanat 2003;26:233-242.
⁸
Nieuwenhuys R. Chemoarchitecture of the brain. Berlin: Springer-Verlag; 1985:7-11.
⁹
Gertz HJ, Cervos-Navarro J, Ewald V. The septo-hippocampal pathway in patients suffering from senile dementia of Alzheimer's type. Evidence for neuronal plasticity? Neurosc Lett 1987;76:228-232.
¹⁰
Fujishiro H, Umegaki H, Isojima D et al. Depletion ofcholinergic neurons in the nucleus of the medial septum and the vertical limb of the diagonal band in dementia with Lewy bodies. Acta Neuropathol 2006;111:109-114.
¹¹
Arendt T, Bigl V, Tennstedt A et al. Neuronal loss in differentparts of the nucleus basalis is related to neuritic plaque formation in cortical target areas in Alzheimer's disease. Neuroscience 1985;14:1-14.
¹²
Geula C, Mesulam MM. Cholinergic Systems in Alzheimer'sDisease. In: Terry RD, Katzman R, Bick KL, Sisodia SS, editors. Alzheimer Disease, 2nd ed, Philadelphia: Lippincott Williams & Wilkins; 1999:269-292.
¹³
McGeer PL, McGeer EG, Suzuki J et al. Aging, Alzheimer'sdisease, and the cholinergic system of the basal forebrain. Neurology 1984;34:741-745.
¹⁴
Mesulam M, Geula C. Nucleus Basalis (Ch4) and corticalcholinergic innervation in the human brain: observations based on the distribution of acetylcholinesterase and choline acetyltransferase. J Comp Neurol 1988;275:216-240.
¹⁵
Page KJ, Sofroniew MV. The ascending basal forebraincholinergic system. Prog Brain Res 1996;107:513-22.
¹⁶
Everitt B, Robbins TW. Central cholinergic systems and cognition. Ann Rev Psychol 1997;48:649-684.
¹⁷
Gold PE. Acetylcholine modulation of neural systemsinvolved in learning and memory. Neurobiol Learn Mem 2003;80:194-210.
¹⁸
Mesulam M. The cholinergic lesion of Alzheimer's disease: pivotal factor or side show. Learn Mem 2004;11:43-49.
¹⁹
Minger SL, Esiri MM, McDonald B, et al. Cholinergicdeficits contribute to behavioral disturbances in patients with dementia. Neurology 2000; 55:1460-1467
²⁰
Sarter M,Bruno JP.Cognitive functions of cortical acetylcholine: toward a unifying hypothesis. Brain Res Brain Res Rev 1997; 23:28-46.
²¹
Iadecola C. Neurovascular regulation in the normal brainand in Alzheimer's disease. Nat Rev Neurosci 2004;5:347360.
²²
Claassen JAHR, Jansen WMM. Cholinergically mediatedaugmentation of cerebral perfusion in Alzheimer's disease and related cognitive disorders: The cholinergic-vascular hypothesis. J Gerontol Med Sci 2006;61:267-271.
²³
Elhusseiny A, Cohen Z, Olivier A, et al. Functional acetylcholine muscarinic receptor subtypes in human brain microcirculation: identification and cellular localization. J Cer Bl Flow Metabol 1999;19:794-802.
²⁴
Luiten PGM, de Jong Givan, der Zee EA, van Dijken H.Ultrastructural localization of cholinergic muscarinic receptors in rat brain cortical capillaries. Brain Res 1996; 720:225-229.
²⁵
Tong XK, Hamel E. Regional cholinergic denervation of cortical microvessels and nitric oxide synthase-containing neurons in Alzheimer's disease. Neuroscience 1999;92:163-174.
²⁶
Barbelivien A, Bertrand N, Besret L, et al. Neurochemicalstimulation of the rat substantia inominata increases cerebral blood flow (but not glucose use) through the parallel activation of cholinergic and non-cholinergic pathways. Brain Res 1999; 840:115-124.
²⁷
Grantham C, Geerts H. The rationale behind cholinergicdrug treatment for dementia related to cerebrovascular disease. J Neurol Sci 2002;203-4:131-136.
²⁸
Sato A, Sato Y, Uchida S. Regulation of regional cerebralblood flow by cholinergic fibers originating in the basal forebrain. Int J Dev Neuroscience 2001;19:327-337.
²⁹
Scremin OU, Li MG, Scremin AME et al. Cholinesteraseinhibition improves blood flow in the ischemic cerebral cortex. Brain Res Bull 1997;42:59-70.
³⁰
Blin J, Ivanoiu A, Coppens A, et al. Cholinergic neurotransmission has different effects on cerebral glucose consumption and blood flow in young normals, aged normals, and Alzheimer's disease patients. Neuroimage 1997;6:335-343.
³¹
Ceravolo R, Volterrani D, Tognoni G, et al. Cerebral perfusional effects of cholinesterase inhibitors in Alzheimer's disease. Clin Neuropharmacol 2004; 27:166-170.
³²
Lojkowska W, Ryglewicz D, Jedrzejczak T, et al. The effect ofcholinesterase inhibitors on the regional blood flow in patients with Alzheimer's disease and vascular dementia. J Neurol Sci 2003;216:119-126.
³³
Lipczynska-Lojowska W, Ryglewicz D, Jedrzejczak T, et al.The effect of rivastigmine on cognitive functions and regional cerebral blood flow in Alzheimer's disease and vascular dementia: follow-up for 2 years. Neurol Neuroch Polska 2004;38:471-481.
³⁴
Nobili F, Koulibaly M, Vitali P et al. Brain perfusion followup in Alzheimer's patients during treatment with acetylcholinesterase inhibitors. J Nucl Med 2002;43:983-990.
³⁵
Kitt CA, Mitchell SJ, DeLong MR et al. Fiber pathways ofbasal forebrain cholinergic neurons in monkeys. Brain Res 1987; 406:192-206.
³⁶
Mesulam MM, Hersh LB, Mash DC, Geula C. Differentialcholinergic innervation within functional subdivisions of the human cerebral cortex: a choline acetyltransferase study. J Comp Neurol 1992;318:16-28.
³⁷
Paré D, Smith Y, Parent A, Steriade M. Projections of brainstem core cholinergic and non-cholinergic neurons of cat to intralaminar and reticular thalamic nuclei. Neuroscience 1988;25:69-86.
³⁸
Selden NR, Gitelman DR, Salamon-Murayama N et al. Trajectories of cholinergic pathways within the cerebral hemispheres of the human brain. Brain 1998;121:2249-2257.
³⁹
Steriade M, Paré D, Parent A, Smith Y. Projections of cholinergic and non-cholinergic neurons of the brainstem core to relay and associational thalamic Nuclei in the cat and macaque monkey. Neuroscience 1988;25:47-67.
⁴⁰
Descarries L, Gisiger V, Steriade M. Diffuse Transmission byAcetylcholine in the CNS. Progr Neurobiol 1997; 53:603625.
⁴¹
Sykova E. Extrasynaptic volume transmission and diffusionparameters of the extracellular space. Neuroscience 2004; 129: 861-876.
⁴²
Sykova E. Glia and volume transmission during physiological and pathological states. J Neural Transm 2005;112:137147.
⁴³
Zoli M, Agnati LF. Wiring and volume transmission in thecentral nervous system: the concept of closed and open synapses. Progr Neurobiol 1996; 49:363-380.
⁴⁴
Engelhardt E, Moreira DM, Nacif MS, Moscovici M. As viascolinérgicas e a demência vascular. Rev Bras Neurol 2006; 42:43-52.
⁴⁵
Shute CC, Lewis PR. The ascending cholinergic reticularsystem: neocortical, olfactory and subcortical projections. Brain 1967; 90:497-520.
⁴⁶
Adams RD, Victor M. Cerebrovascular diseases. In: AdamsRD, Victor M. Principles of neurology. 5th ed, New York: McGraw-Hill, 1993:669-748.
⁴⁷
Biller J. Vascular syndromes of the cerebrum. In: Brazes PW,Masseur JC, Biller J, editors. Localization in clinical neurology. 2nd ed, Boston: Little, Brown and Co., 1990:429-455.
⁴⁸
Krayenbühl HÁ, Yasargil MG. Cerebral angiography. 2th ed.Londres: Butterworths; 1968:20-84.
⁴⁹
Salamon G. Atlas de la vascularisation arterielle du cerveauchez l'homme. Paris: Sandoz Editions; 1973.
⁵⁰
Serizawa T, Saeki N, Yamaura A. Microsurgical anatomy andclinical significance of the anterior communicating artery and its perforating branches. Neurosurgery 1997;40:1211-1216.
⁵¹
Woolsey AT, Hanaway J, Gado MH. The brain atlas. 2nd ed.,Hodoboken: Wiley; 2003.
⁵²
Chemerinski E, Robinson RG. The neuropsychiatry ofstroke. Psychosomatics 2000;41:5-14.
⁵³
Engelhardt E, Laks J, Cavalcanti JLS, Moreira DM, Madalen C. Demência vascular. Rev Bras Neurol 2004;40:5-26.
⁵⁴
Erkinjuntti T. Clinicopathological study of vascular dementia. In: Prohovnik I, Wade J, Knezevic S, Tatemichi T, Erkinjuntti T, editors. Vascular dementia: current concepts, Chichester: Wiley; 1996:73-112.
⁵⁵
Jellinger KA. The pathology of ischemic-vascular dementia: an update. J Neurol Sci 2002;203-204:153-157.
⁵⁶
Markus HS. Cerebral perfusion and stroke. J NeurolNeurosurg Psychiatry 2004;75:353-361.
⁵⁷
Mesulam M, Siddique T, Cohen B. Cholinergic denervationin a pure multi-infarct state. Neurology 2003; 60:1183-1185.
⁵⁸
Tomimoto H, Ohtani R, Shibata M, Nakamura N. Loss ofcholinergic pathways in vascular dementia of the Binswanger type. Dement Geriatr Cogn Disord 2005;19:282288.
⁵⁹
Román GC. Cholinergic dysfunction in vascular dementia. Curr Psychiatry Rep 2005;7:18-26.
⁶⁰
Swartz RH, Sahlas DJ, Black SE. Strategic involvement ofcholinergic pathways and executive dysfunction: does location of white matter signal hypertensities matter? J Stroke Cerebrovasc Dis 2003;12:29-36.
⁶¹
Bocti C, Swartz RH, Gao FQ, et al. A new visual rating scaleto assess strategic white matter hyperintensities within cholinergic pathways in dementia. Stroke 2005;36:21262131.

Publication Dates

Publication in this collection
Jan-Mar 2007

This is an open-access article distributed under the terms of the Creative Commons Attribution License

[1] ¹
Bartus RT, Dean RL, Beer, Lippa AS. The cholinergichypothesis of geriatric memory dysfunction. Science 1982; 217:408-417.

[2] ²
Bartus RT. On neurodegenerative diseases, models, andtreatment strategies: lessons learned and lessons forgotten a generation following the cholinergic hypothesis. Exp Neurol 2000;163:495-529.

[3] ³
Birks J. Cholinesterase inhibitors for Alzheimer's disease. Cochrane Database Syst Rev; 2006.

[4] ⁴
Engelhardt E, Brucki SM, Cavalcanti JLS, Forlenza OV, LaksJ, Vale FAC. Tratamento da doença de Alzheimer: recomendações e sugestões do Departamento Científico de Neurologia Cognitiva e do Envelhecimento da Academia Brasileira de Neurologia. Arq Neuropsiquiatr 2005;63:1104-1112.

[5] ⁵
Román GC, Kalaria RN. Vascular determinants of cholinergic deficits in Alzheimer's disease and vascular dementia. Neurobiol Aging (in press).

[6] ⁶
Mesulam MM. Structure and function of cholinergic pathways in the cerebral cortex, limbic system, basal ganglia, and thalamus of the human brain. In: Bloom FE, Kupfer DJ, editors. Psychopharmacology: The Fourth Generation of Progress. New York: Raven Press; 1995:135-146.

[7] ⁷
Mufson EJ, Ginsberg SD, Ikonomovic MD et al. Humancholinergic basal forebrain: chemoanatomy and neurological dysfunction. J Chem Neuroanat 2003;26:233-242.

[8] ⁸
Nieuwenhuys R. Chemoarchitecture of the brain. Berlin: Springer-Verlag; 1985:7-11.

[9] ⁹
Gertz HJ, Cervos-Navarro J, Ewald V. The septo-hippocampal pathway in patients suffering from senile dementia of Alzheimer's type. Evidence for neuronal plasticity? Neurosc Lett 1987;76:228-232.

[10] ¹⁰
Fujishiro H, Umegaki H, Isojima D et al. Depletion ofcholinergic neurons in the nucleus of the medial septum and the vertical limb of the diagonal band in dementia with Lewy bodies. Acta Neuropathol 2006;111:109-114.

[11] ¹¹
Arendt T, Bigl V, Tennstedt A et al. Neuronal loss in differentparts of the nucleus basalis is related to neuritic plaque formation in cortical target areas in Alzheimer's disease. Neuroscience 1985;14:1-14.

[12] ¹²
Geula C, Mesulam MM. Cholinergic Systems in Alzheimer'sDisease. In: Terry RD, Katzman R, Bick KL, Sisodia SS, editors. Alzheimer Disease, 2nd ed, Philadelphia: Lippincott Williams & Wilkins; 1999:269-292.

[13] ¹³
McGeer PL, McGeer EG, Suzuki J et al. Aging, Alzheimer'sdisease, and the cholinergic system of the basal forebrain. Neurology 1984;34:741-745.

[14] ¹⁴
Mesulam M, Geula C. Nucleus Basalis (Ch4) and corticalcholinergic innervation in the human brain: observations based on the distribution of acetylcholinesterase and choline acetyltransferase. J Comp Neurol 1988;275:216-240.

[15] ¹⁵
Page KJ, Sofroniew MV. The ascending basal forebraincholinergic system. Prog Brain Res 1996;107:513-22.

[16] ¹⁶
Everitt B, Robbins TW. Central cholinergic systems and cognition. Ann Rev Psychol 1997;48:649-684.

[17] ¹⁷
Gold PE. Acetylcholine modulation of neural systemsinvolved in learning and memory. Neurobiol Learn Mem 2003;80:194-210.

[18] ¹⁸
Mesulam M. The cholinergic lesion of Alzheimer's disease: pivotal factor or side show. Learn Mem 2004;11:43-49.

[19] ¹⁹
Minger SL, Esiri MM, McDonald B, et al. Cholinergicdeficits contribute to behavioral disturbances in patients with dementia. Neurology 2000; 55:1460-1467

[20] ²⁰
Sarter M,Bruno JP.Cognitive functions of cortical acetylcholine: toward a unifying hypothesis. Brain Res Brain Res Rev 1997; 23:28-46.

[21] ²¹
Iadecola C. Neurovascular regulation in the normal brainand in Alzheimer's disease. Nat Rev Neurosci 2004;5:347360.

[22] ²²
Claassen JAHR, Jansen WMM. Cholinergically mediatedaugmentation of cerebral perfusion in Alzheimer's disease and related cognitive disorders: The cholinergic-vascular hypothesis. J Gerontol Med Sci 2006;61:267-271.

[23] ²³
Elhusseiny A, Cohen Z, Olivier A, et al. Functional acetylcholine muscarinic receptor subtypes in human brain microcirculation: identification and cellular localization. J Cer Bl Flow Metabol 1999;19:794-802.

[24] ²⁴
Luiten PGM, de Jong Givan, der Zee EA, van Dijken H.Ultrastructural localization of cholinergic muscarinic receptors in rat brain cortical capillaries. Brain Res 1996; 720:225-229.

[25] ²⁵
Tong XK, Hamel E. Regional cholinergic denervation of cortical microvessels and nitric oxide synthase-containing neurons in Alzheimer's disease. Neuroscience 1999;92:163-174.

[26] ²⁶
Barbelivien A, Bertrand N, Besret L, et al. Neurochemicalstimulation of the rat substantia inominata increases cerebral blood flow (but not glucose use) through the parallel activation of cholinergic and non-cholinergic pathways. Brain Res 1999; 840:115-124.

[27] ²⁷
Grantham C, Geerts H. The rationale behind cholinergicdrug treatment for dementia related to cerebrovascular disease. J Neurol Sci 2002;203-4:131-136.

[28] ²⁸
Sato A, Sato Y, Uchida S. Regulation of regional cerebralblood flow by cholinergic fibers originating in the basal forebrain. Int J Dev Neuroscience 2001;19:327-337.

[29] ²⁹
Scremin OU, Li MG, Scremin AME et al. Cholinesteraseinhibition improves blood flow in the ischemic cerebral cortex. Brain Res Bull 1997;42:59-70.

[30] ³⁰
Blin J, Ivanoiu A, Coppens A, et al. Cholinergic neurotransmission has different effects on cerebral glucose consumption and blood flow in young normals, aged normals, and Alzheimer's disease patients. Neuroimage 1997;6:335-343.

[31] ³¹
Ceravolo R, Volterrani D, Tognoni G, et al. Cerebral perfusional effects of cholinesterase inhibitors in Alzheimer's disease. Clin Neuropharmacol 2004; 27:166-170.

[32] ³²
Lojkowska W, Ryglewicz D, Jedrzejczak T, et al. The effect ofcholinesterase inhibitors on the regional blood flow in patients with Alzheimer's disease and vascular dementia. J Neurol Sci 2003;216:119-126.

[33] ³³
Lipczynska-Lojowska W, Ryglewicz D, Jedrzejczak T, et al.The effect of rivastigmine on cognitive functions and regional cerebral blood flow in Alzheimer's disease and vascular dementia: follow-up for 2 years. Neurol Neuroch Polska 2004;38:471-481.

[34] ³⁴
Nobili F, Koulibaly M, Vitali P et al. Brain perfusion followup in Alzheimer's patients during treatment with acetylcholinesterase inhibitors. J Nucl Med 2002;43:983-990.

[35] ³⁵
Kitt CA, Mitchell SJ, DeLong MR et al. Fiber pathways ofbasal forebrain cholinergic neurons in monkeys. Brain Res 1987; 406:192-206.

[36] ³⁶
Mesulam MM, Hersh LB, Mash DC, Geula C. Differentialcholinergic innervation within functional subdivisions of the human cerebral cortex: a choline acetyltransferase study. J Comp Neurol 1992;318:16-28.

[37] ³⁷
Paré D, Smith Y, Parent A, Steriade M. Projections of brainstem core cholinergic and non-cholinergic neurons of cat to intralaminar and reticular thalamic nuclei. Neuroscience 1988;25:69-86.

[38] ³⁸
Selden NR, Gitelman DR, Salamon-Murayama N et al. Trajectories of cholinergic pathways within the cerebral hemispheres of the human brain. Brain 1998;121:2249-2257.

[39] ³⁹
Steriade M, Paré D, Parent A, Smith Y. Projections of cholinergic and non-cholinergic neurons of the brainstem core to relay and associational thalamic Nuclei in the cat and macaque monkey. Neuroscience 1988;25:47-67.

[40] ⁴⁰
Descarries L, Gisiger V, Steriade M. Diffuse Transmission byAcetylcholine in the CNS. Progr Neurobiol 1997; 53:603625.

[41] ⁴¹
Sykova E. Extrasynaptic volume transmission and diffusionparameters of the extracellular space. Neuroscience 2004; 129: 861-876.

[42] ⁴²
Sykova E. Glia and volume transmission during physiological and pathological states. J Neural Transm 2005;112:137147.

[43] ⁴³
Zoli M, Agnati LF. Wiring and volume transmission in thecentral nervous system: the concept of closed and open synapses. Progr Neurobiol 1996; 49:363-380.

[44] ⁴⁴
Engelhardt E, Moreira DM, Nacif MS, Moscovici M. As viascolinérgicas e a demência vascular. Rev Bras Neurol 2006; 42:43-52.

[45] ⁴⁵
Shute CC, Lewis PR. The ascending cholinergic reticularsystem: neocortical, olfactory and subcortical projections. Brain 1967; 90:497-520.

[46] ⁴⁶
Adams RD, Victor M. Cerebrovascular diseases. In: AdamsRD, Victor M. Principles of neurology. 5th ed, New York: McGraw-Hill, 1993:669-748.

[47] ⁴⁷
Biller J. Vascular syndromes of the cerebrum. In: Brazes PW,Masseur JC, Biller J, editors. Localization in clinical neurology. 2nd ed, Boston: Little, Brown and Co., 1990:429-455.

[48] ⁴⁸
Krayenbühl HÁ, Yasargil MG. Cerebral angiography. 2th ed.Londres: Butterworths; 1968:20-84.

[49] ⁴⁹
Salamon G. Atlas de la vascularisation arterielle du cerveauchez l'homme. Paris: Sandoz Editions; 1973.

[50] ⁵⁰
Serizawa T, Saeki N, Yamaura A. Microsurgical anatomy andclinical significance of the anterior communicating artery and its perforating branches. Neurosurgery 1997;40:1211-1216.

[51] ⁵¹
Woolsey AT, Hanaway J, Gado MH. The brain atlas. 2nd ed.,Hodoboken: Wiley; 2003.

[52] ⁵²
Chemerinski E, Robinson RG. The neuropsychiatry ofstroke. Psychosomatics 2000;41:5-14.

[53] ⁵³
Engelhardt E, Laks J, Cavalcanti JLS, Moreira DM, Madalen C. Demência vascular. Rev Bras Neurol 2004;40:5-26.

[54] ⁵⁴
Erkinjuntti T. Clinicopathological study of vascular dementia. In: Prohovnik I, Wade J, Knezevic S, Tatemichi T, Erkinjuntti T, editors. Vascular dementia: current concepts, Chichester: Wiley; 1996:73-112.

[55] ⁵⁵
Jellinger KA. The pathology of ischemic-vascular dementia: an update. J Neurol Sci 2002;203-204:153-157.

[56] ⁵⁶
Markus HS. Cerebral perfusion and stroke. J NeurolNeurosurg Psychiatry 2004;75:353-361.

[57] ⁵⁷
Mesulam M, Siddique T, Cohen B. Cholinergic denervationin a pure multi-infarct state. Neurology 2003; 60:1183-1185.

[58] ⁵⁸
Tomimoto H, Ohtani R, Shibata M, Nakamura N. Loss ofcholinergic pathways in vascular dementia of the Binswanger type. Dement Geriatr Cogn Disord 2005;19:282288.

[59] ⁵⁹
Román GC. Cholinergic dysfunction in vascular dementia. Curr Psychiatry Rep 2005;7:18-26.

[60] ⁶⁰
Swartz RH, Sahlas DJ, Black SE. Strategic involvement ofcholinergic pathways and executive dysfunction: does location of white matter signal hypertensities matter? J Stroke Cerebrovasc Dis 2003;12:29-36.

[61] ⁶¹
Bocti C, Swartz RH, Gao FQ, et al. A new visual rating scaleto assess strategic white matter hyperintensities within cholinergic pathways in dementia. Stroke 2005;36:21262131.

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