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Mixed dementia: A review of the evidence

DEMÊNCIA MISTA: REVISÃO DAS EVIDÊNCIAS

ABSTRACT.

Mixed dementia is the coexistence of Alzheimer's disease and cerebrovascular disease (CVD) in the same demented patient. Currently, its diagnosis and treatment remains a challenge for practitioners. To provide an overview of the epidemiology, pathogenesis, natural history, diagnosis, and therapy of Mixed Vascular-Alzheimer Dementia (MVAD). The literature was reviewed for articles published between 1990-2016 by using the keywords linked to MVAD. Neuropathological studies indicate that MVAD is a very common pathological finding in the elderly with a prevalence about of 22%. The distinction between Alzheimer's dementia and vascular dementia (VD) is complex because their clinical presentation can overlap. There are international criteria for the MVAD diagnosis. The pharmacologic therapy shows modest clinical benefits that are similar among all drugs used in patients with Alzheimer's dementia and VD. The non-pharmacologic therapy includes the rigorous management of cardiovascular risk factors (especially hypertension) and the promotion of a healthy diet. The diagnosis and treatment of MVAD cannot be improved without further studies. Currently available medications provide only modest clinical benefits once a patient has developed MVAD. In subjects at risk, the antihypertensive therapy and healthy diet should be recommend for preventing or slowing the progression of MVAD.

Key words:
mixed dementia; Alzheimer's disease; vascular dementia; cerebrovascular disease

RESUMO.

Demência mista é denominação usual para a coexistência da doença de Alzheimer e doença cerebrovascular (DCV) no mesmo paciente demente. Atualmente, seu diagnóstico e tratamento continuam sendo um desafio. Fornecer uma visão geral da epidemiologia, patogênese, história natural, diagnóstico e terapia da Demência Mista Alzheimer-Vascular (DMAV). Foi realizada revisão da literatura buscando por artigos publicados entre 1990 e 2016 usando palavras-chave relacionadas ao DMAV. Estudos neuropatológicos indicam que DMAV é um achado patológico muito comum em idosos, com uma prevalência de cerca de 22%. A distinção entre demência de Alzheimer e demência vascular (DV) é complexa porque suas apresentações clínicas podem se sobrepor. Existem critérios internacionais para o diagnóstico DMAV. A terapia farmacológica mostra benefícios clínicos modestos que são semelhantes para todos os medicamentos utilizados em pacientes com demência de Alzheimer e DV. A terapia não-farmacológica inclui o manejo rigoroso dos fatores de risco cardiovascular (especialmente a hipertensão) e a promoção de uma dieta saudável. O diagnóstico e o tratamento do DMAV não podem ser melhorados sem outros estudos. Os medicamentos atualmente disponíveis fornecem apenas benefícios clínicos modestos, depois que DMAV instalou-se. Em indivíduos em risco, a terapia anti-hipertensiva e uma dieta saudável devem ser recomendadas para prevenir ou retardar a progressão da DMAV.

Palavras-chave:
demência mista; doença de Alzheimer; demência vascular; doença cerebrovascular

INTRODUCTION

According to the American Heart Association/American Stroke Association (AHA/ASA), the vascular and neurodegenerative disorders are common in the elderly and it could coexist in the same patient. These processes underlying dementia are mutually potentiated for developing cognitive impairment and dementia, generating overlapped clinical phenotypes and neuroimaging.11 Gorelick PB, Scuteri A, Black SE, arli C, Greenberg SM, Iaola C, et al. Vascular Contributions to Cognitive Impairment and Dementia. Stroke. 2011;42(9):2672-713. Thus, the mixed dementia occurs in patients with a neurodegenerative disorder (such as Alzheimer's disease (AD), Lewy body disease, or Pick body disease) and, additionally, a cerebrovascular disease (CVD).22 Zekry D, Hauw J-J, Gold G. Mixed dementia: epidemiology, diagnosis, and treatment. J Am Geriatr Soc. 2002;50(8):1431-8.

The mixed dementia, the Alzheimer's dementia, and the vascular dementia (VD) are the most frequent types of dementia,33 Chui HC, Ramirez-Gomez L. Clinical and imaging features of mixed Alzheimer and vascular pathologies. Alzheimers Res Ther. 2015;7:21. which could be related to each other. There is evidence of the near linkage between AD and the CVD. For example, CVD lesions such as lacunes and white matter lesions (WML), are common in patients with AD. Likewise, typical pathological changes of AD, as extracellular amyloid plaques (“senile senile”) and intracellular neurofibrillary tangles (NFT), are observed in elderly patients with VD.44 Hanyu H. Diagnosis and treatment of mixed dementia. Brain Nerve. 2012;64(9):1047-55. Finally, the brain lesions of AD and VD often occur together55 Lim A, Tsuang D, Kukull W, Nochlin D, Leverenz J, McCormick W, et al. Clinico-neuropathological correlation of Alzheimer’s disease in a community-based case series. J Am Geriatr Soc. 1999 ;47(5):564-9.

6 Massoud F, Devi G, Stern Y, Lawton A, Goldman JE, Liu Y, et al. A clinicopathological comparison of community-based and clinic-based cohorts of patients with dementia. Arch Neurol. 1999 ;56(11): 1368-73.
-77 Neuropathology Group. Medical Research Council Cognitive Function and Aging Study. Pathological correlates of late-onset dementia in a multicentre, community-based population in England and Wales. Neuropathology Group of the Medical Research Council Cognitive Function and Ageing Study (MRC CFAS). Lancet. 2001;357(9251):169-75. and interact in several ways to increase the likelihood of clinically significant cognitive decline.88 Snowdon DA, Greiner LH, Mortimer JA, Riley KP, Greiner PA, Markesbery WR. Brain infarction and the clinical expression of Alzheimer disease. The Nun Study. JAMA. 1997;277(10):813-7.,99 Torre JC. Vascular basis of Alzheimer’s pathogenesis. Ann N Y Acad Sci. 2002;977(1):196-215.

For an optimal treatment of dementia, the adequate diagnosis of each dementia type is essential. However, recognizing the distinction between these diseases can be difficult in clinical practice. This review provides an overview of the Mixed Vascular-Alzheimer Dementia (MVAD, addressing the epidemiological, pathogenic, clinical, diagnostic and therapeutic aspects of this medical condition.

METHODS

Search strategy.

Studies published between 1990 and 2016 were obtained from the following databases: Medline, Biomed Central, Embase, Scopus, Scirus, PsychInFO, LILACS and IBECS. Scholar Google, Ovid, Ebsco, Proquest, Cochrane Library, Cochrane Library Plus and WHO/PAHO databases was reviewed too. All languages were considered. The authors independently searched in specific fields (title, abstract and, if available, subject) for the following terms: (Dementia) AND (“Alzheimer Disease”) AND (“Cerebrovascular Disorders” OR ”Brain Ischemia” OR “Carotid Artery Diseases” OR “Cerebral Small Vessel Diseases” OR “Cerebrovascular Trauma” OR “Intracranial Arterial Diseases” OR “Intracranial Arteriovenous Malformations” OR “Intracranial Embolism and Thrombosis” OR “Intracranial Hemorrhages” OR “Stroke” OR “Central Nervous System Vasculitis”). Abstracts of articles in any language were independently reviewed by the authors. The only inclusion criterion was that the study should be available as full text in any bibliographic or academic databases. We did secondary search of reference lists of identified studies and received additional references from international experts. The latest date of publication for inclusion of articles in the study was 31th July 2017.

Ethics.

No approval from the ethics committee was required since the study was carried out solely with published data from the world literature.

EVIDENCE SYNTHESIS

Selection of studies.

In the consulted databases our search strategy identified 357 scientific documents (original articles, reviews and conference papers), which 26 articles addressed the topic of “mixed dementia” and 8 key articles were selected for this study, including a previous review about mixed dementia.1010 Langa KM, Foster NL, Larson EB. Mixed dementia: emerging concepts and therapeutic implications. JAMA. 2004;292(23):2901-8. Additional references were selected through of expert suggestions (3 articles) and secondary search of the mentioned documents. Finally, the total of references of this study were completed according the required information for each section (epidemiology, pathogenesis, etc.).

Epidemiology.

Several autopsy-based studies reported a dementia prevalence of 39.5%-44.4%,1111 Petrovitch H, White LR, Ross GW, Steinhorn SC, Li CY, Masaki KH, et al. Accuracy of clinical criteria for AD in the Honolulu-Asia Aging Study, a population-based study. Neurology. 2001 24;57(2):226-34.

12 White L, Petrovitch H, Hardman J, Nelson J, Davis DG, Ross GW, et al. Cerebrovascular pathology and dementia in autopsied Honolulu-Asia Aging Study participants. Ann N Y Acad Sci. 2002 ;977:9-23.
-1313 Suemoto CK, Ferretti-Rebustini REL, Rodriguez RD, Leite REP, Soterio L, Brucki SMD, et al. Neuropathological diagnoses and clinical correlates in older adults in Brazil: A cross-sectional study. PLOS Med. 2017;14(3):e1002267. corresponding 36%-50% to Alzheimer's dementia,1212 White L, Petrovitch H, Hardman J, Nelson J, Davis DG, Ross GW, et al. Cerebrovascular pathology and dementia in autopsied Honolulu-Asia Aging Study participants. Ann N Y Acad Sci. 2002 ;977:9-23.

13 Suemoto CK, Ferretti-Rebustini REL, Rodriguez RD, Leite REP, Soterio L, Brucki SMD, et al. Neuropathological diagnoses and clinical correlates in older adults in Brazil: A cross-sectional study. PLOS Med. 2017;14(3):e1002267.

14 Matsui Y, Tanizaki Y, Arima H, Yonemoto K, Doi Y, Ninomiya T, et al. Incidence and survival of dementia in a general population of Japanese elderly: the Hisayama study. J Neurol Neurosurg Psychiatr. 2009; 80(4):366-70.
-1515 Troncoso JC, Zonderman AB, Resnick SM, Crain B, Pletnikova O, O’Brien RJ. Effect of infarcts on dementia in the Baltimore longitudinal study of aging. Ann Neurol. 2008;64(2):168-76. 30%-43.0% to DV,1111 Petrovitch H, White LR, Ross GW, Steinhorn SC, Li CY, Masaki KH, et al. Accuracy of clinical criteria for AD in the Honolulu-Asia Aging Study, a population-based study. Neurology. 2001 24;57(2):226-34.,1313 Suemoto CK, Ferretti-Rebustini REL, Rodriguez RD, Leite REP, Soterio L, Brucki SMD, et al. Neuropathological diagnoses and clinical correlates in older adults in Brazil: A cross-sectional study. PLOS Med. 2017;14(3):e1002267.,1414 Matsui Y, Tanizaki Y, Arima H, Yonemoto K, Doi Y, Ninomiya T, et al. Incidence and survival of dementia in a general population of Japanese elderly: the Hisayama study. J Neurol Neurosurg Psychiatr. 2009; 80(4):366-70. and 20%-22% to MVAD.1313 Suemoto CK, Ferretti-Rebustini REL, Rodriguez RD, Leite REP, Soterio L, Brucki SMD, et al. Neuropathological diagnoses and clinical correlates in older adults in Brazil: A cross-sectional study. PLOS Med. 2017;14(3):e1002267.,1616 Brayne C, Richardson K, Matthews FE, Fleming J, Hunter S, Xuereb JH, et al. Neuropathological correlates of dementia in over-80-year-old brain donors from the population-based Cambridge city over-75s cohort (CC75C) study. J Alzheimers Dis. 2009;18(3):645-58. Other studies have found that 5%,1414 Matsui Y, Tanizaki Y, Arima H, Yonemoto K, Doi Y, Ninomiya T, et al. Incidence and survival of dementia in a general population of Japanese elderly: the Hisayama study. J Neurol Neurosurg Psychiatr. 2009; 80(4):366-70. 28%1717 Schneider JA, Aggarwal NT, Barnes L, Boyle P, Bennett DA. The Neuropathology of Older Persons with and With Dementia from Community versus Clinic Cohorts. J Alzheimers Dis. 2009;18(3):691-701. and 35%1515 Troncoso JC, Zonderman AB, Resnick SM, Crain B, Pletnikova O, O’Brien RJ. Effect of infarcts on dementia in the Baltimore longitudinal study of aging. Ann Neurol. 2008;64(2):168-76. of the demented subject's autopsies had mixed lesions of CVD-AD. Communities based studies have showed a dementia prevalence of 12.4% (73/590), with a proportion of CVD lesions of 67.1%. In this study the prevalence of MVAD and AD with CVD were 1.7% and 4.7%, respectively.1818 Meguro K, Ishii H, Yamaguchi S, Ishizaki J, Shimada M, Sato M, et al. Prevalence of dementia and dementing diseases in Japan: the Tajiri project. Arch Neurol. 2002;59(7):1109-14.

Other autopsy-based studies showed that the dementia proportion increases from 57% to 75% due to the presence of large artery infarctions and up to 93% due to the presence of lacunar infarcts.1919 Snowdon DA, Greiner LH, Mortimer JA, Riley KP, Greiner PA, Markesbery WR. Brain infarction and the clinical expression of Alzheimer disease. The Nun Study. JAMA. 1997;277(10):813-7. Likewise, the presence of single and multiple infarctions multiplies the dementia risk by 2.12 and 2.67 times, respectively. In autopsies with few neuritic plaques (mature plaques or amyloid plaques) Petrovitch et al. demonstrated that the synergistic effect of CVD-AD through finding a very high proportion of dementia among those with coexisting vascular lesions.2020 Petrovitch H, Ross GW, Steinhorn SC, Abbott RD, Markesbery W, Davis D, et al. AD lesions and infarcts in demented and non-demented Japanese-American men. Ann Neurol. 2005;57(1):98-103.

Pathogenesis.

The MVAD, as well as other dementias, starts several years before the symptoms display, which allow their diagnosis.2121 Jack CR, Knopman DS, Jagust WJ, Petersen RC, Weiner MW, Aisen PS, et al. Update on hypothetical model of Alzheimer’s disease biomarkers. Lancet Neurol. 2013;12(2):207-16.,2222 Villemagne VL, Burnham S, Bourgeat P, Brown B, Ellis KA, Salvado O, et al. Amyloid b deposition, neurodegeneration, and cognitive line in sporadic Alzheimer’s disease: a prospective cohort study. Lancet Neurol. 2013;12(4):357-67. The pathogenesis of Alzheimer's dementia is unclear. However, there are two theories that attempt to explain their origin: amyloid theory and vascular theory. Taking into account the theme of this review, we consider pertinent to discuss the last theory.

According to vascular theory, the chronic non-communicable diseases (hypertension, diabetes mellitus, dyslipidemia, obesity, and cardiac disease) and the sedentary lifestyle produce several vascular changes2323 Mehlig K, Skoog I, Waern M, Miao Jonasson J, Lapidus L, Björkelund C, et al. Physical activity, weight status, diabetes and dementia: a 34-year follow-up of the population study of women in Gothenburg. Neuroepidemiology. 2014;42(4):252-9.,2424 de Bruijn RF, Ikram MA. Cardiovascular risk factors and future risk of Alzheimer's disease. BMC Med. 2014; https://doi.org/10.1186/s12916-014-0130-5
https://doi.org/10.1186/s12916-014-0130-...
such as the thickening of the capillary basal membrane and the accumulation of collagen in the vascular endothelium, which both generate vascular atrophy of the vascular terminations, as well as a decrease in the number of terminal blood vessels. These changes affect the cerebral microvasculature and reduces the cerebral blood flow,99 Torre JC. Vascular basis of Alzheimer’s pathogenesis. Ann N Y Acad Sci. 2002;977(1):196-215.,2525 Zhao Y, Gong C-X. From chronic cerebral hypoperfusion to Alzheimer-like brain pathology and neurodegeneration. Cell Mol Neurobiol. 2015;35(1):101-10. which especially observed in untreated hypertensive patients and those treated irregularly or insufficiently.2626 Iaola C. Hypertension and Dementia. Hypertension. 2014;64(1):3-5.

There have been reports of different mechanisms of vascular damage such as small vessel atherosclerosis, large vessel arteriosclerosis, cortical and subcortical infarcts, lacunar infacts with gray/white matter lesions, WML (leukoaraoisis), demyelination, gliosis, amyloid angiopathy, and small brain hemorrhages.33 Chui HC, Ramirez-Gomez L. Clinical and imaging features of mixed Alzheimer and vascular pathologies. Alzheimers Res Ther. 2015;7:21.,2727 O’Brien JT, Thomas A. Vascular dementia. Lancet. 2015;386(10004): 1698-706.,2828 Chui HC, Brown NN. Vascular cognitive impairment. CONTINUUM: Lifelong Learning in Neurology. 2007;13:109-43. All these damages would progressively accumulate it, producing hypoperfusion, neuronal death and cerebral atrophy, and accumulating beta-amyloid and phosphorylated tau proteins. Considering that neurovascular dysfunction seems to play a key role in the pathogenesis of AD, some researchers have suggested that AD is a primary vascular-cerebral disorder.2929 Torre JC de la. Alzheimer Disease as a Vascular Disorder: Nosological Evidence. Stroke. 2002;33(4):1152-62.,3030 Snyder HM, Corriveau RA, Craft S, Faber JE, Greenberg S, Knopman D, et al. Vascular Contributions to Cognitive Impairment and Dementia Including Alzheimer’s Disease. Alzheimers Dement. 2015 ;1(6):710-7.

According several epidemiological studies, the main vascular risk factors are the age,3131 Breteler MM, van den Ouweland FA, Grobbee DE, Hofman A. A community-based study of dementia: the Rotterdam Elderly Study. Neuroepidemiology. 1992;11 Suppl 1:23-8. hypertension,3232 Launer LJ, Ross GW, Petrovitch H, Masaki K, Foley D, White LR, et al. Midlife blood pressure and dementia: the Honolulu-Asia aging study. Neurobiol Aging. 2000;21(1):49-55.,3333 Skoog I, Lernfelt B, Landahl S, Palmertz B, Andreasson LA, Nilsson L, et al. 15-year longitudinal study of blood pressure and dementia. Lancet. 1996;347(9009):1141-5. hyperhomocysteinemia,3434 Morris MS, Jacques PF, Rosenberg IH, Selhub J, National Health and Nutrition Examination Survey. Hyperhomocysteinemia associated with poor recall in the third National Health and Nutrition Examination Survey. Am J Clin Nutr. 2001;73(5):927-33.,3535 Duron E, Hanon O. Vascular risk factors, cognitve line, and dementia. Vasc Health Risk Manag. 2008;4(2):363-81. and WML that are shown as hyperintensities (hypersignals) in brain magnetic resonances.3636 Doddy RS, Massman PJ, Mawad M, Nance M. Cognitive consequences of subcortical magnetic resonance imaging changes in Alzheimer’s disease: comparison to small vessel ischemic vascular dementia. Neuropsychiatry Neuropsychol Behav Neurol. 1998;11(4):191-9.,3737 Modrego PJ, Rios C, Pérez Trullen JM, Errea JM, García-Gómara MJ, Sanchez S. The cerebrovascular pathology in Alzheimer’s disease and its influence on clinical variables. Am J Alzheimers Dis Other Demen. 2008;23(1):91-6. The presence of these factors increases the injury risk to the cerebral blood vessels, leading to CVD, which can progress to cerebral vascular injury (CVI), whether large or small arteries. With the CVD establishment can emerge manifestations of cognitive deficits that exceed those of normal aging, classified as vascular cognitive impairment (VCI), and progressing to affect daily living activities and social/occupational functioning, i.e. VD.22 Zekry D, Hauw J-J, Gold G. Mixed dementia: epidemiology, diagnosis, and treatment. J Am Geriatr Soc. 2002;50(8):1431-8.

3 Chui HC, Ramirez-Gomez L. Clinical and imaging features of mixed Alzheimer and vascular pathologies. Alzheimers Res Ther. 2015;7:21.
-44 Hanyu H. Diagnosis and treatment of mixed dementia. Brain Nerve. 2012;64(9):1047-55.

In the case of AD, some studies reported a set of brain changes during the presymptomatic phase, which includes accumulation of beta-amyloid protein, tau protein and phosphorylated tau protein, alterated glucose metabolism,3838 Jack CR, Knopman DS, Jagust WJ, Petersen RC, Weiner MW, Aisen PS, et al. Update on hypothetical model of Alzheimer’s disease biomarkers. Lancet Neurol. 2013 ;12(2):207-16.

39 Vlassenko AG, Benzinger TL, Morris JC. PET Amyloid-Beta Imaging in Preclinical Alzheimer’s Disease. Biochim Biophys Acta. 2012;1822(3): 370-9.
-4040 Okamura N, Furumoto S, Fodero-Tavoletti MT, Mulligan RS, Harada R, Yates P, et al. Non-invasive assessment of Alzheimer’s disease neurofibrillary pathology using 18F-THK5105 PET. Brain. 2014;137(Pt 6):1762-71. and cortical thinning4141 Dickerson BC, Wolk DA. MRI cortical thickness biomarker predicts AD-like CSF and cognitive line in normal adults. Neurology. 2012;78(2): 84-90. and cortical atrophy,4242 Tondelli M, Wilcock GK, Nichelli P, De Jager CA, Jenkinson M, Zamboni G. Structural MRI changes detectable up to ten years before clinical Alzheimer's disease. Neurobiol Aging. 2012;33(4):825.e25-36. which occurs 10 years before the onset of symptoms. All these changes have a deleterious and irreversible effect on the brain, and accumulate over time until triggering the clinical manifestations.

Diagnosis

Clinical diagnosis.

There is no consensus for the diagnosis of MVAD. Thus, international referents such as the Alzheimer's Disease Diagnostic and Treatment Centers (ADDTC)4343 Chui HC, Victoroff JI, Margolin D, Jagust W, Shankle R, Katzman R. Criteria for the diagnosis of ischemic vascular dementia proposed by the State of California Alzheimer’s Disease Diagnostic and Treatment Centers. Neurology. 1992;42(3 Pt 1):473-80. and the National Institute of Neurological Disorders and Stroke and Association Internationale pour la Recherche et l'Enseignement en Neurosciences (NINDS-AIREN)4444 Román GC, Tatemichi TK, Erkintti T, Cummings JL, Masdeu JC, Garcia JH, et al. Vascular dementia: diagnostic criteria for research studies. Report of the NINDS-AIREN International Workshop. Neurology. 1993; 43(2):250-60. have proposed diagnostic criteria that differ from each other. A third organization, the Consortium to Establish a Registry for Alzheimer's Disease (CERAD), has not considered MVAD in its classification system.4545 Morris JC, Heyman A, Mohs RC, Hughes JP, van Belle G, Fillenbaum G, et al. The Consortium to Establish a Registry for Alzheimer’s Disease (CERAD). Part I. Clinical and neuropsychological assessment of Alzheimer’s disease. Neurology. 1989;39(9):1159-65.

According to the ADDTC criteria, the diagnosis of MVAD requires the existence of a typical AD and closely dementia related CVD.4343 Chui HC, Victoroff JI, Margolin D, Jagust W, Shankle R, Katzman R. Criteria for the diagnosis of ischemic vascular dementia proposed by the State of California Alzheimer’s Disease Diagnostic and Treatment Centers. Neurology. 1992;42(3 Pt 1):473-80. The NINDS-AIRRN criteria include evidence of: 1) memory compromise and ³ 2 other cognitive areas; 2) CVI (focal neurological signs and detection of WML in brain images); and 3) dementia onset during the first 3 months after the cerebral stroke.4444 Román GC, Tatemichi TK, Erkintti T, Cummings JL, Masdeu JC, Garcia JH, et al. Vascular dementia: diagnostic criteria for research studies. Report of the NINDS-AIREN International Workshop. Neurology. 1993; 43(2):250-60.

Additionally, we recommend an approach aimed to identify the dominant component (CVI or AD). Thus, in the majority of patients with predominance of CVI lesions, the initial clinical phenotype should be as VD (i.e., impairment in frontal-executive functions, rather than memory),4646 Looi JC, Sachdev PS. Differentiation of vascular dementia from AD on neuropsychological tests. Neurology. 1999;53(4):670-8. with a later deterioration of attention/concentration.4747 Sachdev P, Kalaria R, O’Brien J, Skoog I, Alladi S, Black SE, et al. Diagnostic criteria for vascular cognitive disorders: a VASCOG statement. Alzheimer Dis Assoc Disord. 2014;28(3):206-18. Otherwise, in patients with predominance of AD, the initial clinical phenotype is episodic memory impairment, with a progressively addition of sub-cortical dementia and a step-by-step evolution of disease (which differs with the typical gradual evaluation of the AD).4848 Snowdon DA, Greiner LH, Mortimer JA, Riley KP, Greiner PA, Markesbery WR. Brain infarction and the clinical expression of Alzheimer disease. The Nun Study. JAMA. 1997;277(10):813-7.,4949 Skoog I. Vascular aspects in Alzheimer’s disease. J Neural Transm Suppl. 2000;59:37-43.

Neuroimaging.

The neuroimaging studies is useful for increasing the diagnostic certainty, particularly in silent lesions such as lacunar infarcts and WML.4747 Sachdev P, Kalaria R, O’Brien J, Skoog I, Alladi S, Black SE, et al. Diagnostic criteria for vascular cognitive disorders: a VASCOG statement. Alzheimer Dis Assoc Disord. 2014;28(3):206-18.,5050 Tullberg M, Fletcher E, arli C, Mungas D, Reed BR, Harvey DJ, et al. White matter lesions impair frontal lobe function regardless of their location. Neurology. 2004;63(2):246-53. However, there are not pathognomonic imaging signs of VCI/VD and the findings should be interpreted based on individual clinical context. According the VASCOG statement, a near temporal relationship between vascular event and the cognitive symptoms/signs must be present to suspect VCI/VD (ideally, 3 months), especially if previous imaging has been undertaken.4747 Sachdev P, Kalaria R, O’Brien J, Skoog I, Alladi S, Black SE, et al. Diagnostic criteria for vascular cognitive disorders: a VASCOG statement. Alzheimer Dis Assoc Disord. 2014;28(3):206-18.,5151 Brown WR, Moody DM, Thore CR, Challa VR, Anstrom JA. Vascular dementia in leukoaraiosis be a consequence of capillary loss not only in the lesions, but in normal-appearing white matter and cortex as well. J Neurol Sci. 2007;257(1-2):62-6.

Pathologic diagnosis.

A definitive diagnosis warrants a neuropathologic verification. Regarding the clinical-pathological diagnosis of MVAD, we suggest to use the recommendations for the AD diagnosis based on morphological changes (Table 1).5252 Jellinger KA, Attems J. Neuropathological evaluation of mixed dementia. J Neurol Sci. 2007;257(1-2):80-7. According to the guides of the National Institute of Aging (NIA) and the Ronald and Nancy Reagan Institute from the Alzheimer's Association, the postmortem diagnosis of AD can be performed by combining the criteria of CERAD and Braak NFT staging.5353 Braak H, Braak E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 1991;82(4):239-59. Thus, this method allows to estimate the probability that the AD is the cause of dementia through the following rule: low (CERAD = 0-A and Braak = 1-2), medium (CERAD B and Braak 3-4); or high (CERAD C and Braak 5-6).5454 Hyman BT, Troowski JQ. Consensus recommendations for the postmortem diagnosis of Alzheimer disease from the National Institute on Aging and the Reagan Institute Working Group on diagnostic criteria for the neuropathological assessment of Alzheimer disease. J Neuropathol Exp Neurol. 1997;56(10):1095-7.

Table 1
Rules for the pathological diagnosis of AD.

There are no specific recommendations for the pathological diagnosis of VCI/VD. However, its importance lies in that allows to identify the type of underlying CVD. Additionally, it also allows to identify injuries in cases of non-detectable lesions by current neuroimaging technologies, such as small cystic infarctions, selective neuronal loss, and microinfarcts.

In this context, Jellinger and Atems proposed as a criterion for pathological diagnosis of MVAD the combination of AD (confirmed by autopsy) with presence of multiple lacunar infarcts or CVI lesions located in the cortex, basal ganglia, thalamus, hippocampus and white matter, with an infarcted cerebral volume of 30 - 50 ml, approximately.5252 Jellinger KA, Attems J. Neuropathological evaluation of mixed dementia. J Neurol Sci. 2007;257(1-2):80-7.

Diagnosis in investigation studies.

For the research purposes, the AD diagnosis requires the evidence of: 1) amyloid deposition in the autopsy study, low b-amyloid concentrations in cerebrospinal fluid (CSF), or b-amyloid deposition in positron emission tomography; and 2) neuro-degeneration in the autopsy study, high concentrations of phosphorylated Tau in CSF, or pattern of EA atrophy in the cerebral images.5555 Sperling RA, Aisen PS, Beckett LA, Bennett DA, Craft S, Fagan AM, et al. Toward defining the preclinical stages of Alzheimer’s disease: Recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 2011;7(3):280-92.

56 Albert MS, DeKosky ST, Dickson D, Dubois B, Feldman HH, Fox NC, et al. The diagnosis of mild cognitive impairment due to Alzheimer’s disease: Recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 2011;7(3):270-9.
-5757 Jack CR, Albert M, Knopman DS, McKhann GM, Sperling RA, Carillo M, et al. Introduction to Revised Criteria for the Diagnosis of Alzheimer’s Disease: National Institute on Aging and the Alzheimer Association Workgroups. Alzheimers Dement. 2011;7(3):257-62. However, amyloid and tau biomarkers are not required in usual clinical practice. On the other hand, the diagnosis of VCI/VD is under discussion due to the heterogeneity of the clinical-neuropsychological phenotype produced by several CVI types. The AHA/ASA recommended establishing a clear causal relationship between the occurrence of vascular event and the onset of cognitive impairment, and between both the location and severity of CVI, clinically detected or identified by brain imaging, with the pattern and severity of cognitive impairment.11 Gorelick PB, Scuteri A, Black SE, arli C, Greenberg SM, Iaola C, et al. Vascular Contributions to Cognitive Impairment and Dementia. Stroke. 2011;42(9):2672-713.

Diagnostic challenges.

The AHA/ASA highlighted that there are several factors that affect diagnostic accuracy. For example, current imaging technologies are unable to detect microscopic infarctions (≤ 3 mm) and alterations in small vessels such as arteriosclerosis.11 Gorelick PB, Scuteri A, Black SE, arli C, Greenberg SM, Iaola C, et al. Vascular Contributions to Cognitive Impairment and Dementia. Stroke. 2011;42(9):2672-713. Evenly, there are findings in neuroimaging studies that are not pathognomonic of VCI/VD such as microbleeds,5858 Kirsch W, McAuley G, Holshouser B, Petersen F, Ayaz M, Vinters HV, et al. Serial susceptibility weighted MRI measures brain iron and microbleeds in dementia. J Alzheimers Dis. 2009;17(3):599-609.

59 Cordonnier C, van der Flier WM, Sluimer JD, Leys D, Barkhof F, Scheltens P. Prevalence and severity of microbleeds in a memory clinic setting. Neurology. 2006;66(9):1356-60.
-6060 Lee DY, Fletcher E, Martinez O, Ortega M, Zozulya N, Kim J, et al. Regional pattern of white matter microstructural changes in normal aging, MCI, and AD. Neurology. 2009;73(21):1722-8. white matter degeneration11 Gorelick PB, Scuteri A, Black SE, arli C, Greenberg SM, Iaola C, et al. Vascular Contributions to Cognitive Impairment and Dementia. Stroke. 2011;42(9):2672-713. and hippocampal atro­phy,6161 Jagust WJ, Zheng L, Harvey DJ, Mack WJ, Vinters HV, Weiner MW, et al. Neuropathological Basis of Magnetic Resonance Images in Aging and Dementia. Ann Neurol. 2008;63(1):72-80.,6262 Zarow C, Sitzer TE, Chui HC. Understanding hippocampal sclerosis in the elderly: epidemiology, characterization, and diagnostic issues. Curr Neurol Neurosci Rep. 2008;8(5):363-70. which may also occur in patients with AD.

Cognitive phenotypes. Due to the lack of consensus on the diagnostic criteria and the heterogeneous neuropathological characteristic of the MVAD, this entity has not been widely studied. However, establishing a cognitive profile in relation to AD can be useful for measuring the contribution of CVD/CVI to cognitive impairment and establishing clinical management and therapeutic strategies in patients with MVAD.2828 Chui HC, Brown NN. Vascular cognitive impairment. CONTINUUM: Lifelong Learning in Neurology. 2007;13:109-43.,5252 Jellinger KA, Attems J. Neuropathological evaluation of mixed dementia. J Neurol Sci. 2007;257(1-2):80-7.,6363 Jellinger KA. The enigma of mixed dementia. Alzheimers Dement. 2007; 3(1):40-53.

There are studies showing that the cognitive performance of patients with MVAD is lower than that observed in patients with Alzheimer's dementia,6464 Reed BR, Mungas DM, Kramer JH, Ellis W, Vinters HV, Zarow C, et al. Profiles of neuropsychological impairment in autopsy-defined Alzheimer’s disease and cerebrovascular disease. Brain. 2007;130(Pt 3):731-9.,6565 Dong Y, Gan DZQ, Tay SZ, Koay WI, Collinson SL, Hilal S, et al. Patterns of neuropsychological impairment in Alzheimer’s disease and mixed dementia. J Neurol Sci. 2013;333(1-2):5-8. particularly in the attention,6565 Dong Y, Gan DZQ, Tay SZ, Koay WI, Collinson SL, Hilal S, et al. Patterns of neuropsychological impairment in Alzheimer’s disease and mixed dementia. J Neurol Sci. 2013;333(1-2):5-8. memory,6666 Bowler JV, Eliasziw M, Steenhuis R, Munoz DG, Fry R, Merskey H, et al. Comparative evolution of Alzheimer disease, vascular dementia, and mixed dementia. Arch Neurol. 1997;54(6):697-703. denomination6666 Bowler JV, Eliasziw M, Steenhuis R, Munoz DG, Fry R, Merskey H, et al. Comparative evolution of Alzheimer disease, vascular dementia, and mixed dementia. Arch Neurol. 1997;54(6):697-703. visuoconstruction6565 Dong Y, Gan DZQ, Tay SZ, Koay WI, Collinson SL, Hilal S, et al. Patterns of neuropsychological impairment in Alzheimer’s disease and mixed dementia. J Neurol Sci. 2013;333(1-2):5-8. and executive functions.6464 Reed BR, Mungas DM, Kramer JH, Ellis W, Vinters HV, Zarow C, et al. Profiles of neuropsychological impairment in autopsy-defined Alzheimer’s disease and cerebrovascular disease. Brain. 2007;130(Pt 3):731-9. Similarly, in patients with Alzheimer's dementia, the subgroup that developed cerebral infarction showed a greater involvement of memory,88 Snowdon DA, Greiner LH, Mortimer JA, Riley KP, Greiner PA, Markesbery WR. Brain infarction and the clinical expression of Alzheimer disease. The Nun Study. JAMA. 1997;277(10):813-7.,6666 Bowler JV, Eliasziw M, Steenhuis R, Munoz DG, Fry R, Merskey H, et al. Comparative evolution of Alzheimer disease, vascular dementia, and mixed dementia. Arch Neurol. 1997;54(6):697-703.,6767 Song I-U, Kim J-S, Kim Y-I, Eah K-Y, Lee K-S. Clinical Significance of Silent Cerebral Infarctions in Patients With Alzheimer Disease. Cogn Behav Neurol. 2007;20(2):93-98. language,6767 Song I-U, Kim J-S, Kim Y-I, Eah K-Y, Lee K-S. Clinical Significance of Silent Cerebral Infarctions in Patients With Alzheimer Disease. Cogn Behav Neurol. 2007;20(2):93-98. denomination,88 Snowdon DA, Greiner LH, Mortimer JA, Riley KP, Greiner PA, Markesbery WR. Brain infarction and the clinical expression of Alzheimer disease. The Nun Study. JAMA. 1997;277(10):813-7.,6666 Bowler JV, Eliasziw M, Steenhuis R, Munoz DG, Fry R, Merskey H, et al. Comparative evolution of Alzheimer disease, vascular dementia, and mixed dementia. Arch Neurol. 1997;54(6):697-703. verbal fluency,88 Snowdon DA, Greiner LH, Mortimer JA, Riley KP, Greiner PA, Markesbery WR. Brain infarction and the clinical expression of Alzheimer disease. The Nun Study. JAMA. 1997;277(10):813-7. and constructive praxis.88 Snowdon DA, Greiner LH, Mortimer JA, Riley KP, Greiner PA, Markesbery WR. Brain infarction and the clinical expression of Alzheimer disease. The Nun Study. JAMA. 1997;277(10):813-7.,6666 Bowler JV, Eliasziw M, Steenhuis R, Munoz DG, Fry R, Merskey H, et al. Comparative evolution of Alzheimer disease, vascular dementia, and mixed dementia. Arch Neurol. 1997;54(6):697-703.

Therapeutic guidelines.

Currently, the treatment is basically symptomatic and preventive. The use of acetylcholinesterase inhibitor drugs such as donepezil, galantamine and rivastigmine and antidemential drugs such as memantine can be used in patients with Alzheimer's dementia and VD.6868 Román GC, Salloway S, Black SE, Royall DR, arli C, Weiner MW, et al. Randomized, placebo-controlled, clinical trial of donepezil in vascular dementia: differential effects by hippocampal size. Stroke. 2010; 41(6): 1213-21.,6969 Auchus AP, Brashear HR, Salloway S, Korczyn AD, De Deyn PP, Gassmanner C, et al. Galantamine treatment of vascular dementia: a randomized trial. Neurology. 2007;69(5):448-58.

Studies in patients with MVAD have shown a mild improvement, especially in ​​cognition function, with contradictory results in daily living activities and global status, and showing no statistical superiority in the efficacy of either agent.7070 Ballard C, Sauter M, Scheltens P, He Y, Barkhof F, van Straaten ECW, et al. Efficacy, safety and tolerability of rivastigmine capsules in patients with probable vascular dementia: the VantagE study. Curr Med Res Opin. 2008;24(9):2561-74. Considering the potential adverse effects of medication, it is necessary to carefully evaluate its use in these patients.7070 Ballard C, Sauter M, Scheltens P, He Y, Barkhof F, van Straaten ECW, et al. Efficacy, safety and tolerability of rivastigmine capsules in patients with probable vascular dementia: the VantagE study. Curr Med Res Opin. 2008;24(9):2561-74. Memantine, for example, has demonstrated a cognitive effect similar to acetylcholinesterase inhibitors in patients with VD, although with less adverse effects.7171 National Institute for Health and Care Excellence. Dementia: supporting people with dementia and their carers in health and social care. 2016 [cited 2017 12]. Available from: https://www.nice.org.uk/guidance/cg42
https://www.nice.org.uk/guidance/cg42...
,7272 Wilcock G, Möbius HJ, Stöffler A, MMM 500 group. A double-blind, placebo-controlled multicentre study of memantine in mild to moderate vascular dementia (MMM500). Int Clin Psychopharmacol. 2002;17(6): 297-305.

Although effective blood pressure control seems to decrease the progression rate of WML in hypertensive patients,3333 Skoog I, Lernfelt B, Landahl S, Palmertz B, Andreasson LA, Nilsson L, et al. 15-year longitudinal study of blood pressure and dementia. Lancet. 1996;347(9009):1141-5. there is no evidence that adequate control of blood pressure or levels of glucose, cholesterol and triglyceride modify the dementia progression.7373 Orgogozo J-M, Rigaud A-S, Stöffler A, Möbius H-J, Forette F. Efficacy and safety of memantine in patients with mild to moderate vascular dementia: a randomized, placebo-controlled trial (MMM 300). Stroke. 2002;33(7):1834-9.,7474 Pearce LA, McClure LA, Anderson DC, Jacova C, Sharma M, Hart RG, et al. Effects of long-term blood pressure lowering and dual antiplatelet therapy on cognition in patients with recent lacunar stroke: Secondary Prevention of Small Subcortical Strokes (SPS3) trial The SPS3 Investigators. Lancet Neurol. 2014;13(12):1177-85. We suspect that both the early and continue use of these measures could generate the necessary evidence for its inclusion in the clinical protocols.

A healthy diet includes a greater amount of vegetables, fruits, nuts, soy proteins, grains and fish, as well as lower consumption of red meat. Longitudinal studies have shown that this dietary regimens can decrease both the progression rate of cognitive impairment and the risk of developing AD.7575 Ngandu T, Lehtisalo J, Solomon A, Levälahti E, Ahtiluoto S, Antikainen R, et al. A 2 year multidomain intervention of diet, exercise, cognitive training, and vascular risk monitoring versus control to prevent cognitive line in at-risk elderly people (FINGER): a randomised controlled trial. Lancet. 2015;385(9984):2255-63.,7676 Lourida I, Soni M, Thompson-Coon J, Purandare N, Lang IA, Ukoumunne OC, et al. Mediterranean diet, cognitive function, and dementia: a systematic review. Epidemiology. 2013;24(4):479-89. Likewise, regular exercise (≥ 30 minutes for ≥ 3 times per week) showed to decrease the progression of cognitive symptoms associated with AD and VD,7777 Safouris A, Tsivgoulis G, Sergentanis TN, Psaltopoulou T. Mediterranean Diet and Risk of Dementia. Curr Alzheimer Res. 2015;12(8):736-44. improving the independence and maintaining the daily living activities.

Finally, psychological and social support is critical, particularly when the patient is working. This support should also cover the family, who must understand the progressive loss of independence of the patient.

Conclusions.

There is a public health need for new studies that address the diagnosis and treatment of MVAD. Currently, the available medications offer only a modest clinical benefits once a patient has developed MVAD, without any modification of its evolution. In subjects at risk, the antihypertensive therapy and healthy diet should be both recommend and promoted for preventing or slowing the progression of MVAD.

Recommendations.

For improving the health outcomes, we recommend thinking in MVAD as probable diagnosis in all demented patients with an atypical presentation of AD and coexistence of risk factors for CVD/CVI.

For improving the value of image studies in the diagnosis of dementia, we recommend to assess the concordance between neuroimaging patterns and postmortem findings.22 Zekry D, Hauw J-J, Gold G. Mixed dementia: epidemiology, diagnosis, and treatment. J Am Geriatr Soc. 2002;50(8):1431-8. According the current evidence, it is necessary conduct further studies to develop a better understanding of MVAD.

  • This study was conducted at the Unidad de Diagnóstico de Deterioro Cognitivo y Prevención de Demencia. Instituto Peruano de Neurociencias. Lima, Perú.

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Publication Dates

  • Publication in this collection
    Oct-Dec 2017

History

  • Received
    16 Sept 2017
  • Accepted
    16 Nov 2017
Academia Brasileira de Neurologia, Departamento de Neurologia Cognitiva e Envelhecimento R. Vergueiro, 1353 sl.1404 - Ed. Top Towers Offices, Torre Norte, São Paulo, SP, Brazil, CEP 04101-000, Tel.: +55 11 5084-9463 | +55 11 5083-3876 - São Paulo - SP - Brazil
E-mail: revistadementia@abneuro.org.br | demneuropsy@uol.com.br