SciELO - Scientific Electronic Library Online

 
vol.72 issue3Clinical features and management of hereditary spastic paraplegiaAdult onset sporadic ataxias: a diagnostic challenge author indexsubject indexarticles search
Home Pagealphabetic serial listing  

Services on Demand

Journal

Article

Indicators

Related links

Share


Arquivos de Neuro-Psiquiatria

Print version ISSN 0004-282X

Arq. Neuro-Psiquiatr. vol.72 no.3 São Paulo Mar. 2014

http://dx.doi.org/10.1590/0004-282X20130233 

Views and Reviews

Biological markers of Alzheimer’s disease

Biomarcadores da doença de Alzheimer

Leonardo Cruz de Souza1  3 

Marie Sarazin1  4 

Antônio Lúcio Teixeira Júnior2  3 

Paulo Caramelli3 

Antônio Emanuel dos Santos1 

Bruno Dubois1 

1Institut de la Mémoire et de la Maladie d’Alzheimer, département de Neurologie, Hôpital de la Pitié-Salpêtrière, Paris, France;

2Grupo de Neuroimunologia, Laboratório Interdisciplinar de Investigação Médica, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte MG, Brazil;

3Grupo de Pesquisa em Neurologia Cognitiva e do Comportamento, Departamento de Clínica Médica, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte MG, Brazil;

4Centre de Psychiatrie et des Neurosciences, INSERM UMR S894, Université Paris Descartes, Sorbonne Paris Cité, Hôpital Sainte-Anne, Paris, France.

ABSTRACT

The challenges for establishing an early diagnosis of Alzheimer’s disease (AD) have created a need for biomarkers that reflect the core pathology of the disease. The cerebrospinal fluid (CSF) levels of total Tau (T-tau), phosphorylated Tau (P-Tau) and beta-amyloid peptide (Aβ42) reflect, respectively, neurofibrillary tangle and amyloid pathologies and are considered as surrogate markers of AD pathophysiology. The combination of low Aβ42 and high levels of T-tau and P-Tau can accurately identify patients with AD at early stages, even before the development of dementia. The combined analysis of the CSF biomarkers is also helpful for the differential diagnosis between AD and other degenerative dementias. The development of these CSF biomarkers has evolved to a novel diagnostic definition of the disease. The identification of a specific clinical phenotype combined with the in vivo evidence of pathophysiological markers offers the possibility to make a diagnosis of AD before the dementia stage with high specificity.

Key words: CSF biomarkers; Alzheimer’s disease

RESUMO

O desafio de se estabelecer o diagnóstico precoce de doença de Alzheimer (DA) levou ao desenvolvimento de biomarcadores que reflitam os aspectos patológicos centrais da doença. As dosagens no líquor da proteína Tau total (T-Tau), Tau fosforilada (P-Tau) e peptídeo beta-amiloide (Aβ42) no líquido cefalorraquidiano (LCR) refletem, respectivamente, as patologias Tau e amiloide, sendo consideradas como marcadores da fisiopatologia da DA. Os biomarcadores do LCR podem identificar acuradamente pacientes com DA em estágios precoces da doença, mesmo antes do desenvolvimento da demência. A análise combinada dos biomarcadores permite também fazer o diagnóstico diferencial entre DA e outras demências degenerativas. O desenvolvimento dos biomarcadores de DA conduziu a uma nova definição diagnóstica da doença. A identificação de um fenótipo clínico específico associado a uma evidência fisiopatológica in vivo provida por um biomarcador possibilita estabelecer, com alta especificidade, o diagnóstico de DA antes do estágio demencial.

Palavras-Chave: biomarcadores do LCR; doença de Alzheimer

Biological markers of Alzheimer’s disease

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that is the most common form of dementia, accounting for approximately 50-60% of all cases 1 . The most prominent feature of AD is the decline in cognitive function, with an early impairment of episodic memory 2 . The incidence of AD increases with age and, due to the increasing aging of populations and life expectancy, the prevalence of AD continues to rise worldwide. In this scenario, AD represents a major public health concern, with important social and economic outcomes 3 .

There is still no curative treatment for AD, but many ongoing trials are actually evaluating new therapeutic strategies on different molecular targets. Among several factors, the efficacy of these disease-modifying treatments will depend of early and accurate diagnosis 4 . These treatments should be more efficient if they are administered at early stages of the disease and in well-defined groups of patients, which requires accurate tools for the early diagnosis.

The challenges for establishing an early and accurate diagnosis have created a need for biomarkers, which may be defined as “an objective measure of a biological or pathogenic process that can be used to evaluate disease risk or prognosis, to guide clinical diagnosis or to monitor therapeutic interventions” 5 . These biomarkers for AD include both neuroimaging and biological parameters. In this review, we will only focus on cerebrospinal fluid (CSF) biomarkers and present data demonstrating their added-value when they are applied to the clinical diagnosis and evaluation of AD.

CSF biomarkers as evidence of the pathological process

Ideally, a biological marker of AD should detect with high accuracy a fundamental feature of AD’s pathology early in the course of the disease 6 . The core pathological hallmarks of the AD are the extracellular deposits of Aβ peptide and the intracellular accumulation of abnormally hyperphosphorylated tau protein. As the CSF is in direct contact with the extracellular space of the brain and also considering that the CSF usually reflects pathological changes in the brain, the CSF is an optimal source of pathophysiological markers 5 , 7 . Currently, the main biological biomarkers employed in AD diagnosis are total Tau (Tau), the isoforms of phosphorylated Tau (P-Tau181 and P-Tau231) and β-amyloid peptide (Aβ42).

Some studies investigated the correlations between antemortem CSF biomarker levels (Tau, P-Tau and Aβ proteins) and AD-type neuropathologic changes in the brain 6 , 8 - 10 . Data from these clinico-pathological studies showed that CSF levels of total Tau reflect the intensity of neuronal degeneration, while P-tau reflects tangle pathology. It has also been demonstrated that antemortem42 is inversely correlated with Aβ plaque counts at post-mortem examination 9 . Moreover, there is an inverse correlation between CSF Aβ42 levels and the overall retention of the amyloid tracer Pittsburgh compound B (PiB) with positron-emission tomography investigation 11 , 12 .

These findings have been recently confirmed by a study that analyzed relationships between AD pathology in cortical brain biopsy and AD biomarkers in a series of 182 patients 13 , showing that the amount of amyloid plaques and hyperphosphorylated Tau in cortical brain biopsies are associated with low CSF Aβ42 and high CSF levels of Tau markers, respectively. It was also demonstrated a concordance of 94% between CSF markers and neuropathological diagnosis in a sample of patients from a memory clinic 14 .

Taken together, data from clinico-pathological studies support the view of CSF biomarkers as surrogate markers of the pathophysiological process of AD 5 .

Sensitivity and specificity of CSF biomarkers for Alzheimer’s disease

During the last two decades, a multitude of studies has consistently demonstrated that AD patients exhibit a decrease in CSF Aβ42 and an increase in CSF Tau and P-tau when compared with healthy controls 5 , 7 , 15 . Data provided by these studies confirm that each of these biomarkers differentiates AD patients from age-matched controls with 80-90% sensitivity and specificity 5 , 7 .

The CSF Aβ42 levels are around 50% lower in AD patients than in aged-matched normal subjects 16 . The aggregation of Aβ protein in amyloid plaques and the consequent reduction of its availability in the CSF are the suggested mechanisms to explain the reduction of CSF Aβ42 levels in AD patients 5 . It should be noted, however, that a reduction of CSF Aβ42 levels may also occur in other diseases, such as Lewy body dementia, vascular dementia and cerebral amyloid angiopathy 14 , 17 , 18 . Hence, although a decreased level of Aβ42 is characteristic of AD, it is not sufficient for an etiologic diagnosis of AD.

Tau is considered to be a non-specific marker of neuronal lesion associated to a variety of biological processes 7 . In AD patients, total Tau CSF levels are about three times higher than in age-matched controls 16 . Isolated high total Tau protein levels can also be detected in other acute neurodegenerative diseases and brain lesions, such as head trauma, stroke, and in Creutzfeldt-Jakob disease 5 , 7 , 14 . On the contrary, P-Tau protein (subtypes P-Tau181 and P-Tau231) is the most specific biomarker of AD, being normal in non-AD diseases, including those in which Tau protein levels may be increased, such as Creutzfeldt-Jakob disease and stroke 14 .

It is well established that the best accuracy in the differential diagnosis between AD patients and controls is obtained with the combined analysis of two or more of the three main AD CSF markers (total Tau, P-Tau and Aβ42). Association of Aβ42 with Tau or P-Tau improves both sensitivity and specificity of AD diagnosis when compared to any of the markers alone. The value of the combined approach of CSF biomarkers was demonstrated by a study with neuropathological confirmation of the diagnosis, which showed that the ratio P-Tau/Aβ42 has a sensitivity of 91.6% and a specificity of 85.7% for AD diagnosis 6 . In order to consider the combined analysis of biomarkers, some ratios have been proposed, as the Innotest Amyloid-Tau Index (IATI), defined by the ratio Aβ42/(240+1.18 x Tau) 19 , 20 , the AD-CSF-Index 21 , and the ratios Tau/Aβ42 and P-Tau/Aβ42. An IATI score inferior to 1 has been proposed as suggestive of AD but, given the high prevalence (31%) of control subjects without cognitive impairment with this profile 22 , this cut-off does not seem to be specific.

CSF biomarkers in the prodromal stage (pre-dementia) of Alzheimer's disease

The pathophysiological process of AD starts decades before the clinical onset of the disease, with a gradual loss of synapses, axons and neurons that progress before the appearance of the first cognitive symptoms, most often episodic memory impairment 23 . The dementia that characterizes the severe stage of the disease is thus preceded by a clinical phase in which the patients present memory impairment in an intermediate degree between age-matched normal controls and patients fulfilling clinical criteria for AD. This symptomatic predementia phase is characterized by a preserved autonomy and may be referred as mild cognitive impairment (MCI) 24 .

During the last decade, large cohort studies have consistently shown that an AD biomarker profile distinguishes with high accuracy (up to 95% sensitivity) MCI patients who will progress to AD from healthy controls and from MCI patients who will remain cognitively stable during the follow-up. These longitudinal studies showed that “MCI-converters” have a biological profile characterized by low Aβ42 associated with high levels of CSF total Tau and P-Tau, while “MCI-stable” patients have a normal biomarker profile 22 , 25 - 27 . Taken together, these data support the validity of CSF markers for identifying incipient AD among patients with mild cognitive impairment 5 . These patients with objective memory deficit, preserved autonomy and an AD signature at CSF analysis may be referred as “prodromal AD” 28 .

Besides predementia stages of AD, abnormalities on CSF measures can be eventually observed in subjects without cognitive complaints 22 , 23 , which is in line with the current knowledge on AD pathophysiology. According to it, the first clinical symptoms of AD are preceded by a long pathophysiological process. It should be noted, however, that the accumulated data from clinical studies do not allow the assumption of progression from normal cognition to AD in asymptomatic subjects with any specific biomarker of AD 29 . Therefore, at this time, the concept of “preclinical AD” is restricted only for research, and cannot be translated into a recommendation for the clinical practice 29 .

The prognostic value of CSF biomarkers

A series of studies investigated whether CSF biomarkers are correlated to clinical and imaging markers of AD severity. Data from a longitudinal study suggested that low Aβ42, elevated Tau level and high Tau/Aβ42 are predictive of a faster cognitive decline during a follow-up of one year 30 . Patients with extreme alterations in CSF biomarkers (Aβ42 reduction and increased total Tau and P-Tau) appear to progress unfavorably, with a more severe cognitive decline, poor response to anticholinesterase treatment and higher mortality 31 . CSF markers may also be useful to identify subgroups of AD patients with distinctive clinical and neuropsychological profiles which may be associated with more severe cognitive impairment 32 , 33 .

Neuroimaging studies with structural brain MRI have also reported a significant positive correlation between the increased levels of Tau markers (total Tau and P-Tau) and the severity of hippocampal atrophy 34 - 39 . High levels of CSF total Tau and P-Tau seem also to be related to a faster progression of hippocampal atrophy 36 - 38 .

These data suggest that CSF markers may be predictive of the clinical severity in specific groups of AD patients. These findings, however, need further validation.

CSF biomarkers for the differential diagnosis between Alzheimer's disease and other dementias

The analysis of CSF biomarkers has been increasingly employed in the differential diagnosis between AD and other dementias 14 , 40 - 44 . Data from different centers consistently confirmed that the combined analysis of the CSF biomarkers provides the best accuracy in the differential diagnosis between AD and other degenerative dementias 14 , 40 , 42 . Particularly, the P-Tau/Aβ42 was the best biomarker for differentiating AD from the behavioral variant of frontotemporal lobar degeneration and from semantic dementia, with a sensitivity of 91.7% and 98.3%, respectively, and a specificity of 92.6% and 84.2%, respectively 42 . These results in terms of performance for the differential diagnosis between AD and frontotemporal lobar degeneration are in agreement with previous findings showing a specificity of 96.6% in a series of patients with diagnostic confirmation either by genetics or by post-mortem examination 40 .

CSF biomarkers are also useful for identifying patients with focal atypical presentations of AD. In contrast to the typical amnestic profile “of the hippocampal type”, atypical focal forms of AD include non-amnestic focal cortical syndromes 45 , such as posterior cortical atrophy (PCA), logopenic aphasia and the frontal variant of AD 28 , 46 - 50 which exhibit characteristic histological lesions of AD-type pathology at post-mortem examination. For instance, AD-type pathology is the retained diagnosis in more than 80% of PCA cases at post-mortem examination 46 , 51 and in almost 60% of patients with primary progressive aphasia (PPA) 52 , 53 . In these groups of patients, data on biomarker assays are consistent with the pathological studies, as it was observed that 60% of PCA patients (9/15) and 61.5% (16/26) of aphasic subjects had an AD biological profile, with both altered Tau/Aβ42 and P-Tau/Aβ42 ratios 42 . Moreover, a concordance between CSF markers and amyloid imaging with PiB was reported in a group of patients with PCA 54 . Also interestingly, in a series of 34 patients with PPA who underwent both brain perfusion SPECT and lumbar puncture for CSF biomarkers, two distinct brain perfusion profiles were observed: PPA patients with an AD CSF profile presented a perfusion pattern similar to that observed in logopenic aphasia, and those PPA patients without an AD CSF biomarker profile showed a brain perfusion pattern similar to that has been described in semantic dementia 55 . Indeed, other studies demonstrated that logopenic aphasia is associated with significant PiB uptake, while semantic dementia and non-fluent aphasia do not exhibit amyloidosis on molecular imaging 56 , 57 , in agreement with the classification of logopenic aphasia as a focal variant of AD, and non-fluent APP and semantic dementia as language variants of frontotemporal lobar degeneration 58 . AD pathology may also be observed in patients with behavioral presentation mimicking behavioral variant of frontotemporal lobar degeneration, the so-called frontal variant of AD 46 , 48 , 59 .

Taken together, these data support using CSF biomarkers for identifying AD pathology in patients with atypical presentations. By identifying an underlying AD pathology in these patients, CSF biomarkers are useful as their positivity may reorient the diagnosis and, hence, the therapeutics 14 .

Final remarks

The development of CSF biomarkers of AD led to a new diagnostic definition of the disease. The use of biological markers in association with the clinical approach opens the possibility to establish a diagnosis of AD before the dementia stage, differently from the previous National Institute of Neurological and Communication Disorders and Stroke - Alzheimer Disease and Related Disorders Association (NINCDS-ADRDA) criteria 60 . The core clinical criteria remain the main landmark of the diagnosis of AD in the clinical practice, but biological evidence provided by CSF increases the specificity of the diagnosis. By using CSF markers, it is now possible to establish an etiological diagnosis in vivo , which enables identifying patients at predementia stages of the disease and patients with atypical focal presentations of AD 52 . This is crucial in the perspective of new disease-modifying drugs that will tackle specific pathophysiological targets.

References

. Querfurth HW, LaFerla FM. Alzheimer's disease. N Engl J Med 2010;362:329-344. [ Links ]

. Ballard C, Gauthier S, Corbett A, Brayne C, Aarsland D, Jones E. Alzheimer's disease. Lancet 2011;377:1019-1031. [ Links ]

. Wimo A, Winblad B, Jonsson L. The worldwide societal costs of dementia: Estimates for 2009. Alzheimers Dement 2010;6:98-103. [ Links ]

. Sarazin M, Dorothee G, de Souza LC, Aucouturier P. Immunotherapy in Alzheimer's disease: do we have all the pieces of the puzzle? Biol Psychiatry 2013;74:329-332. [ Links ]

. Blennow K, Hampel H, Weiner M, Zetterberg H. Cerebrospinal fluid and plasma biomarkers in Alzheimer disease. Nat Rev Neurol 2010;6:131-144. [ Links ]

. Tapiola T, Alafuzoff I, Herukka SK, et al. Cerebrospinal fluid {beta}-amyloid 42 and tau proteins as biomarkers of Alzheimer-type pathologic changes in the brain. Arch Neurol 2009;66:382-389. [ Links ]

. Forlenza OV, Diniz BS, Gattaz WF. Diagnosis and biomarkers of predementia in Alzheimer's disease. BMC Medicine 2010;8:89. [ Links ]

. Buerger K, Ewers M, Pirttila T, et al. CSF phosphorylated tau protein correlates with neocortical neurofibrillary pathology in Alzheimer's disease. Brain 2006;129:3035-3041. [ Links ]

. Strozyk D, Blennow K, White LR, Launer LJ. CSF Abeta 42 levels correlate with amyloid-neuropathology in a population-based autopsy study. Neurology 2003;60:652-656. [ Links ]

. Tapiola T, Overmyer M, Lehtovirta M, et al. The level of cerebrospinal fluid tau correlates with neurofibrillary tangles in Alzheimer's disease. Neuroreport 1997;8:3961-3963. [ Links ]

. Grimmer T, Riemenschneider M, Forstl H, et al. Beta amyloid in Alzheimer's disease: increased deposition in brain is reflected in reduced concentration in cerebrospinal fluid. Biol Psychiatry 2009;65:927-934. [ Links ]

. Tolboom N, van der Flier WM, Yaqub M, et al. Relationship of cerebrospinal fluid markers to 11C-PiB and 18F-FDDNP binding. J Nucl Med 2009;50:1464-1470. [ Links ]

. Seppala TT, Nerg O, Koivisto AM, et al. CSF biomarkers for Alzheimer disease correlate with cortical brain biopsy findings. Neurology 2012;78:1568-1575. [ Links ]

. Schoonenboom NS, Reesink FE, Verwey NA, et al. Cerebrospinal fluid markers for differential dementia diagnosis in a large memory clinic cohort. Neurology 2012;78:47-54. [ Links ]

. De Meyer G, Shapiro F, Vanderstichele H, et al. Diagnosis-independent Alzheimer disease biomarker signature in cognitively normal elderly people. Arch Neurol 2010;67:949-956. [ Links ]

. Hampel H, Burger K, Teipel SJ, Bokde AL, Zetterberg H, Blennow K. Core candidate neurochemical and imaging biomarkers of Alzheimer's disease. Alzheimers Dement 2008;4:38-48. [ Links ]

. Hall S, Ohrfelt A, Constantinescu R, et al. Accuracy of a panel of 5 cerebrospinal fluid biomarkers in the differential diagnosis of patients with dementia and/or parkinsonian disorders. Arch Neurol 2012;69:1445-1452. [ Links ]

. Parnetti L, Tiraboschi P, Lanari A, et al. Cerebrospinal fluid biomarkers in Parkinson's disease with dementia and dementia with Lewy bodies. Biol Psychiatry 2008;64:850-855. [ Links ]

. Hulstaert F, Blennow K, Ivanoiu A, et al. Improved discrimination of AD patients using beta-amyloid(1-42) and tau levels in CSF. Neurology 1999;52:1555-1562. [ Links ]

. Visser PJ, Knopman DS. Amyloid imaging in the prediction of Alzheimer-type dementia in subjects with amnestic MCI. Neurology 2009;73:744-745. [ Links ]

. Molinuevo JL, Gispert JD, Dubois B, et al. The AD-CSF-Index discriminates Alzheimer's disease patients from healthy controls: a validation study. J Alzheimers Dis 2013;36:67-77. [ Links ]

. Visser PJ, Verhey F, Knol DL, et al. Prevalence and prognostic value of CSF markers of Alzheimer's disease pathology in patients with subjective cognitive impairment or mild cognitive impairment in the DESCRIPA study: a prospective cohort study. Lancet Neurol 2009;8:619-627. [ Links ]

. Jack CR, Jr., Knopman DS, Jagust WJ, et al. Hypothetical model of dynamic biomarkers of the Alzheimer's pathological cascade. Lancet Neurol 2010;9:119-128. [ Links ]

. Albert MS, Dekosky ST, Dickson D, 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;7:270-279. [ Links ]

. Shaw LM, Vanderstichele H, Knapik-Czajka M, et al. Cerebrospinal fluid biomarker signature in Alzheimer's disease neuroimaging initiative subjects. Ann Neurol 2009;65:403-413. [ Links ]

. Hansson O, Zetterberg H, Buchhave P, Londos E, Blennow K, Minthon L. Association between CSF biomarkers and incipient Alzheimer's disease in patients with mild cognitive impairment: a follow-up study. Lancet Neurol 2006;5:228-234. [ Links ]

. Mattsson N, Zetterberg H, Hansson O, et al. CSF biomarkers and incipient Alzheimer disease in patients with mild cognitive impairment. Jama 2009;302:385-393. [ Links ]

. Dubois B, Feldman HH, Jacova C, et al. Revising the definition of Alzheimer's disease: a new lexicon. Lancet Neurol 2010;9:1118-1127. [ Links ]

. Sperling RA, Aisen PS, Beckett LA, 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;7:280-292. [ Links ]

. Kester MI, van der Vlies AE, Blankenstein MA, et al. CSF biomarkers predict rate of cognitive decline in Alzheimer disease. Neurology 2009;73:1353-1358. [ Links ]

. Wallin AK, Blennow K, Zetterberg H, Londos E, Minthon L, Hansson O. CSF biomarkers predict a more malignant outcome in Alzheimer disease. Neurology 2010;74:1531-1537. [ Links ]

. Koric L, Felician O, Guedj E, et al. Could clinical profile influence CSF biomarkers in early-onset Alzheimer disease? Alzheimer Dis Assoc Disord 2010;24:278-283. [ Links ]

. van der Vlies AE, Verwey NA, Bouwman FH, et al. CSF biomarkers in relationship to cognitive profiles in Alzheimer disease. Neurology 2009;72:1056-1061. [ Links ]

. Apostolova LG, Hwang KS, Andrawis JP, et al. 3D PIB and CSF biomarker associations with hippocampal atrophy in ADNI subjects. Neurobiol Aging 2010;31:1284-1303. [ Links ]

. de Souza LC, Chupin M, Lamari F, et al. CSF tau markers are correlated with hippocampal volume in Alzheimer's disease. Neurobiol Aging 2012;33:1253-1257. [ Links ]

. Fjell AM, Walhovd KB, Fennema-Notestine C, et al. CSF biomarkers in prediction of cerebral and clinical change in mild cognitive impairment and Alzheimer's disease. J Neurosci 2010;30:2088-2101. [ Links ]

. Hampel H, Burger K, Pruessner JC, et al. Correlation of cerebrospinal fluid levels of tau protein phosphorylated at threonine 231 with rates of hippocampal atrophy in Alzheimer disease. Arch Neurol 2005;62:770-773. [ Links ]

. Henneman WJ, Vrenken H, Barnes J, et al. Baseline CSF p-tau levels independently predict progression of hippocampal atrophy in Alzheimer disease. Neurology 2009;73:935-940. [ Links ]

. Leow AD, Yanovsky I, Parikshak N, et al. Alzheimer's disease neuroimaging initiative: a one-year follow up study using tensor-based morphometry correlating degenerative rates, biomarkers and cognition. Neuroimage 2009;45:645-655. [ Links ]

. Bian H, Van Swieten JC, Leight S, et al. CSF biomarkers in frontotemporal lobar degeneration with known pathology. Neurology 2008;70:1827-1835. [ Links ]

. Bibl M, Mollenhauer B, Lewczuk P, et al. Cerebrospinal fluid tau, p-tau 181 and amyloid-beta38/40/42 in frontotemporal dementias and primary progressive aphasias. Dement Geriatr Cogn Disord 2011;31:37-44. [ Links ]

. de Souza LC, Lamari F, Belliard S, et al. Cerebrospinal fluid biomarkers in the differential diagnosis of Alzheimer's disease from other cortical dementias. J Neurol Neurosurg Psychiatry 2011;82:240-246. [ Links ]

. Grossman M, Farmer J, Leight S, et al. Cerebrospinal fluid profile in frontotemporal dementia and Alzheimer's disease. Ann Neurol 2005;57:721-729. [ Links ]

. Kapaki E, Paraskevas GP, Papageorgiou SG, et al. Diagnostic value of CSF biomarker profile in frontotemporal lobar degeneration. Alzheimer Dis Assoc Disord 2008;22:47-53. [ Links ]

. Warren JD, Fletcher PD, Golden HL. The paradox of syndromic diversity in Alzheimer disease. Nat Rev Neurol 2012;8:451-464. [ Links ]

. Alladi S, Xuereb J, Bak T, et al. Focal cortical presentations of Alzheimer's disease. Brain 2007;130:2636-2645. [ Links ]

. Kas A, de Souza LC, Samri D, et al. Neural correlates of cognitive impairment in posterior cortical atrophy. Brain 2011;134:1464-1478. [ Links ]

. Mendez MF, Joshi A, Tassniyom K, Teng E, Shapira JS. Clinicopathologic differences among patients with behavioral variant frontotemporal dementia. Neurology 2013;80:561-568. [ Links ]

. Murray ME, Graff-Radford NR, Ross OA, Petersen RC, Duara R, Dickson DW. Neuropathologically defined subtypes of Alzheimer's disease with distinct clinical characteristics: a retrospective study. Lancet Neurol 2011;10:785-96. [ Links ]

. Snowden JS, Thompson JC, Stopford CL, et al. The clinical diagnosis of early-onset dementias: diagnostic accuracy and clinicopathological relationships. Brain 2011;134:2478-2492. [ Links ]

. Renner JA, Burns JM, Hou CE, McKeel DW, Jr., Storandt M, Morris JC. Progressive posterior cortical dysfunction: a clinicopathologic series. Neurology 2004;63:1175-1180. [ Links ]

. Cummings J. Primary progressive aphasia and the growing role of biomarkers in neurological diagnosis. Ann Neurol 2008;64:361-364. [ Links ]

. Deramecourt V, Lebert F, Debachy B, et al. Prediction of pathology in primary progressive language and speech disorders. Neurology 2010;74:42-49. [ Links ]

. de Souza LC, Corlier F, Habert MO, et al. Similar amyloid-{beta} burden in posterior cortical atrophy and Alzheimer's disease. Brain 2011;134:2036-2043. [ Links ]

. Kas A, Uspenskaya O, Lamari F, et al. Distinct brain perfusion pattern associated with CSF biomarkers profile in progressive aphasia J Neurol Neurosurg Psychiatry 2012;83:695-698. [ Links ]

. Leyton CE, Villemagne VL, Savage S, et al. Subtypes of progressive aphasia: application of the international consensus criteria and validation using {beta}-amyloid imaging. Brain 2011;134: 3030-3043. [ Links ]

. Rabinovici GD, Jagust WJ, Furst AJ, et al. Abeta amyloid and glucose metabolism in three variants of primary progressive aphasia. Ann Neurol 2008;64:388-401. [ Links ]

. Gorno-Tempini ML, Hillis AE, Weintraub S, et al. Classification of primary progressive aphasia and its variants. Neurology 2011;76:1006-1014. [ Links ]

. de Souza LC, Bertoux M, Funkiewiez A, et al. Frontal presentation of Alzheimer's disease: a series of patients with biological evidence by CSF biomarkers Dement Neuropsychol 2013;7:66-74. [ Links ]

. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology 1984;34:939-944. [ Links ]

Support: This work was partly funded by CNPq, Brazil.

Received: October 03, 2013; Accepted: October 10, 2013

Correspondence: Leonardo Cruz de Souza; Universidade Federal de Minas Gerais, Laboratório Interdisciplinar de Investigação Médica, sala 281; Avenida Professor Alfredo Balena, 190 Centro; 30130-100 Belo Horizonte MG – Brasil; E-mail: leocruzsouza@hotmail.com

Conflict of interest: There is no conflict of interest to declare.

Creative Commons License This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.