Highlights
- •A large single-center cohort of FTLD and AD patients was studied.
- •Equally reduced CSF Aβ40 levels were seen in both dementia groups.
- •No added value of Aβ40, along with Aβ42, t-Tau and p-Tau, in FTLD/AD distinction
- •Aβ40 can however be useful in discriminating dementia groups from controls.
- •Diagnostic accuracy between FTLD and AD was still sub-optimal.
Abstract
Cerebrospinal fluid (CSF) biomarkers have been increasingly studied for dementia diagnosis,
however the accuracy to distinguish between different forms of dementia is still unsatisfactory.
In this study, the added value of another CSF Aβ-peptide (Aβ40), along with the core
CSF markers t-Tau, p-Tau, and Aβ42, in the discrimination between two large dementia
groups of Frontotemporal Lobar Degeneration (FTLD; n = 107), Alzheimer's Disease (AD; n = 107) and non-demented subjects (n = 33) was evaluated.
In FTLD, t-Tau and p-Tau were significantly increased in relation to controls, but
lower than in AD, while Aβ42 was similar in FTLD and controls, but higher than in
AD. Equally reduced Aβ40 levels were seen in both dementia groups, and therefore the
combination of Aβ40 with core CSF biomarkers optimally discriminated FTLD and AD patients
from controls. Aβ42 and t-Tau were selected as the best biomarker subset to differentiate
FTLD from AD, with no added value of Aβ40 to the model. Diagnostic accuracy between
FTLD and AD was still sub-optimal, with a significant percentage (23%) of FTLD patients,
in particularly women, carrying an ApoE-ε4 allele, showing a CSF-AD biomarkers profile.
Although CSF Aβ40 does not appear to have an additional value in the distinction between
FTLD and AD, it increases the discrimination between subjects with dementia from controls.
A CSF-AD biomarker profile can be seen in patients with a clinical phenotype of FTLD,
reinforcing the need for autopsy confirmation.
Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Journal of the Neurological SciencesAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- p62 positive, TDP-43 negative, neuronal cytoplasmic and intranuclear inclusions in the cerebellum and hippocampus define the pathology of C9orf72-linked FTLD and MND/ALS.Acta Neuropathol. 2011; 122: 691-702
- Diagnostic and Statistical Manual of Mental Disorders, 4 rd ed.American Psychiatric Association, Washington, DC1994
- Diagnostic value of CSF protein profile in a Portuguese population of sCJD patients.J. Neurol. 2009; 256: 1540-1550
- Clinical dementia rating (CDR).Psychopharmacol. Bull. 1988; 24: 637-639
- CSF biomarkers in frontotemporal lobar degeneration with known pathology.Neurology. 2008; 70: 1827-1835
- Cerebrospinal fluid Tau, p-Tau 181 and Amyloid-β38/40/42 in frontotemporal dementias and primary progressive aphasias.Dement. Geriatr. Cogn. Disord. 2011; 31: 37-44
- Cerebrospinal fluid Ab42 is decreased in Alzheimer's, but not in frontotemporal dementia.J. Neural Transm. 2012; 119: 805-813
- Reduced CSF carboxyterminally truncated Ab peptides in frontotemporal lobe degenerations.J. Neural Transm. 2007; 114: 621-628
- TDP-43 pathology in primary progressive aphasia and frontotemporal dementia with pathologic Alzheimer disease.Acta Neuropathol. 2010; 120: 43-54
- Cerebrospinal fluid and plasma biomarkers in Alzheimer's disease.Nat. Rev. Neurol. 2010; 6: 131-144
- Links between frontotemporal lobar degeneration, corticobasal degeneration, progressive supranuclear palsy, and amyotrophic lateral sclerosis.Alzheimer Dis. Assoc. Disord. 2007; 21: S31-S38
- CSF p-tau181/tau ratio as biomarker for TDP pathology in frontotemporal dementia.Amyotroph. Lateral Scler. Frontotemporal Degener. 2015; 16: 86-91
- Cerebrospinal fluid tau in frontotemporal lobar degeneration: clinical, neuroimaging, and prognostic correlates.J. Alzheimers Dis. 2010; 23: 505-512
- Cerebrospinal fluid biomarker results in relation to neuropathological dementia diagnosis.Alzheimers Dement. 2010; 6: 104-109
- Single-day apolipoprotein E genotyping.J. Neurosci. Methods. 1994; 53: 125-127
- The neuropsychiatric inventory: assessing psychopathology in dementia patients.Neurology. 1997; 48: 10-16
- Prediction of MCI to AD conversion, via MRI, CSF biomarkers, and pattern classification.Neurobiol. Aging. 2011; 32 (2322.e.19-2322.e.27)
- Research criteria for the diagnosis of Alzheimer's disease: revising the NINCDS-ADRDA criteria.Lancet Neurol. 2007; 6: 734-746
- Advancing research diagnostic criteria for Alzheimer's disease: the IWG-2 criteria.Lancet Neurol. 2014; 13: 614-629
- CSF biomarkers for the differential diagnosis of Alzheimer's disease. A large-scale international multicenter study.Alzheimers Dement. 2015; https://doi.org/10.1016/j.jalz.2014.12.006
- In vivo amyloid imaging with PET in frontotemporal dementia.Eur. J. Nucl. Med. Mol. Imaging. 2008; 35: 100-106
- Apolipoprotein E e4 is a risk factor for Alzheimer's disease: the central region of Portugal (Coimbra) as a case study.Eur. Neurol. 1999; 42: 183-184
- Mini-mental state: a practical method for grading the cognitive state of patients for the clinician.J. Psychiatry Res. 1975; 12: 189-198
- Frontotemporal dementia: clinicopathological correlations.Ann. Neurol. 2006; 59: 952-962
- Decreased sAβPPβ, Aβ38, and Aβ40 cerebrospinal fluid levels in frontotemporal dementia.J. Alzheimers Dis. 2011; 26: 553-563
- Development of a functional measure for persons with Alzheimer's Disease: the disability assessment for dementia scale.Am. J. Occup. Ther. 1999; 53: 471-481
- Inhibition of APP trafficking by tau protein does not increase the generation of amyloid-beta peptides.Traffic. 2006; 7: 873-888
- Cognition and anatomy in three variants of primary progressive aphasia.Ann. Neurol. 2004; 55: 335-346
- Increased tau in the cerebrospinal fluid of patients with frontotemporal dementia and Alzheimer's disease.Neurosci. Lett. 1999; 259: 133-135
- Cerebrospinal fluid profile inFrontotemporal dementia and Alzheimer's Disease.Ann. Neurol. 2005; 57: 721-729
- Contribution of neuropsychology to the study of dementias.(Ph.D. thesis) Faculty of Medicine of Lisbon, Lisbon, Portugal1988
- Escalas e testes na demência.Grupo de Estudos de Envelhecimento Cerebral e Demência. 2003; : 33-49
- Avaliação breve do estado mental: escalas e testes na demência.Grupo de Estudos de Envelhecimento Cerebral e Demência. 2003; : 27-32
- A method of comparing the areas under receiver operating characteristic curves.Radiology. 1983; 148: 839-843
- 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
- Evaluation of CSF biomarkers as predictors of Alzheimer's disease: a clinical follow-up study of 4.7 years.J. Alzheimers Dis. 2010; 21: 1119-1128
- Semantic dementia: a unique clinicopathological syndrome.Lancet Neurol. 2007; 6: 1004-1014
- Multimodal predictors for Alzheimer disease in nonfluent primary progressive aphasia.Neurology. 2010; 75: 595-602
- Tau in Alzheimer disease and related tauopathies.Curr. Alzheimer Res. 2010; 7: 656-664
- Frontotemporal lobar degeneration: defining phenotypic diversity through personalized medicine.Acta Neuropathol. 2015; 129: 469-491
- Recent advances in our understanding of neurodeneration.J. Neural Transm. 2009; 116: 1111-1162
- Clinical and pathological evidence for a frontal variant of Alzheimer's disease.Arch. Neurol. 1999; 56: 1233-1239
- Cerebrospinal fluid biomarkers for Alzheimer's disease in patients with frontotemporal lobar degeneration and amyotrophic lateral sclerosis with the C9ORF72 repeat expansion.Dement. Geriatr. Cogn. Disord. 2015; 39: 287-293
- Diagnostic value of CSF biomarker profile in frontotemporal lobar degeneration.Alzheimer Dis. Assoc. Disord. 2008; 22: 47-53
- The corticobasal degeneration syndrome overlaps progressive aphasia and frontotemporal dementia.Neurology. 2000; 55: 1368-1375
- The evolution and pathology of frontotemporal dementia.Brain. 2005; 128: 1996-2005
- Cognitive correlates of cerebrospinal fluid biomarkers in frontotemporal dementia.Alzheimers Dement. 2013; 9: 269-275
- Escalas e testes na demência.Grupo de Estudos de Envelhecimento Cerebral e Demência, 2003: 67-86
- Escalas e testes na demência.Grupo de Estudos de Envelhecimento Cerebral e Demência, 2008: 107-110
- Neurochemical diagnosis of Alzheimer's dementia by CSF Aβ42, Aβ42/Aβ40 ratio and total tau.Neurobiol. Aging. 2004; 25: 273-281
- The overlap of amyotrophic lateral sclerosis and frontotemporal dementia.Neurology. 2002; 59: 1077-1079
- Amyloid beta protein deposition in patients with frontotemporal lobar degeneration: relationship to age and apolipoprotein E genotype.Neurosci. Lett. 2001; 304: 161-164
- The Alzheimer's Association external quality control program for cerebrospinal fluid biomarkers.Alzheimers Dement. 2011; 7: 386-395
- CSF biomarker variability in the Alzheimer's Association quality control program.Alzheimers Dement. 2013; 9: 251-261
- Age and diagnostic performance of Alzheimer disease CSF biomarkers.Neurology. 2012; 78: 68-476
- Lessons from multicenter studies on CSF biomarkers for Alzheimer's Disease.Int. J. Alzheimers Dis. 2010;
- CSF biomarkers and incipient Alzheimer disease in patients with mild cognitive impairment.JAMA. 2009; 302: 385-393
- 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; 4: 939-944
- Clinical and pathological diagnosis of frontotemporal dementia: report of the work group on frontotemporal dementia and pick's disease.Arch. Neurol. 2001; 58: 1803-1809
- The diagnosis of dementia 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: 263-269
- Primary progressive aphasia.Ann. Neurol. 2001; 49: 425-432
- Slowly progressive aphasia without generalized dementia.Ann. Neurol. 1982; 11: 592-598
- The Alzheimer's Disease assessment scale: an instrument for assessing treatment efficacy.Psychopharmacol. Bull. 1983; 19: 448-450
- Frontotemporal dementia.Lancet Neurol. 2005; 4: 771-780
- Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria.Neurology. 1998; 51: 1546-1554
- Pathological correlates of late-onset dementia in a multicentre, community-based population in England and Wales.Lancet. 2001; 357: 169-175
- Overlap between frontotemporal dementia and Alzheimer's disease: cerebrospinal fluid pattern and neuroimaging study.J. Alzheimers Dis. 2013; 36: 49-55
- CSF neurofilaments in frontotemporal dementia compared with early onset alzheimer's disease and controls.Dement. Geriatr. Cogn. Disord. 2007; 23: 225-230
- CSF biomarkers in frontotemporal lobar degeneration: relations with clinical characteristics, apolipoprotein E genotype, and neuroimaging.J. Neurol. Neurosurg. Psychiatry. 2006; 77: 246-248
- Decreased cerebrospinal fluid amyloid beta (1–40) levels in frontotemporal lobar degeneration.J. Neurol. Neurosurg. Psychiatry. 2007; 78: 735-737
- Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia.Brain. 2011; 134: 2456-2477
- Tau and Abeta42 protein in CSF of patients with frontotemporal degeneration.Neurology. 2002; 58: 1622-1628
- A new rating scale for Alzheimer's Disease.Am. J. Psychiatry. 1984; 141: 1356-1364
- Total tau and phophorylated tau 181 levels in the cerebrospinal fluid of patients with frontotemporal dementia due to P301L and G272V tau mutations.Arch. Neurol. 2003; 60: 1209-1213
- Medical research council cognitive function and ageing study. Age, neuropathology, and dementia.N. Engl. J. Med. 2009; 360: 2302-2309
- Association of GSK3B with Alzheimer disease and frontotemporal dementia.Arch. Neurol. 2008; 65: 1368-1374
- CSF neurofilament concentration reflects disease severity in frontotemporal degeneration.Ann. Neurol. 2014; 75: 116-126
- Cerebrospinal fluid markers for differential dementia diagnosis in a large memory clinic cohort.Neurology. 2012; 78: 47-54
- Clinical, genetic and pathological heterogeneity of frontotemporal dementia: a review.J. Neurol. Neurosurg. Psychiatry. 2011; 82: 476-486
- CSF levels of tau, β-amyloid1–42 and GAP-43 in frontotemporal dementia, other types of dementia and normal aging.J. Neural Transm. 2000; 107: 563-579
- Cerebrospinal fluid Abeta1-40 improves differential dementia diagnosis in patients with intermediate P-tau181P levels.J. Alzheimers Dis. 2013; https://doi.org/10.3233/JAD-130107
- Linking Abeta and tau in late-onset Alzheimer's disease: a dual pathway hypothesis.Neuron. 2008; 60: 534-542
- Semantic dementia: a form of circumscribed cerebral atrophy.Behav. Neurol. 1989; 2: 167-182
- The cerebrospinal fluid amyloid beta42/40 ratio in the differentiation of Alzheimer's disease from non-Alzheimer's dementia.Curr. Alzheimer Res. 2010; 7: 470-476
- Tau blocks traffic of organelles, neurofilaments, and APP vesicles in neurons and enhances oxidative stress.J. Cell Biol. 2002; 156: 1051-1063
- Diagnostic accuracy of cerebrospinal fluid amyloid-β isoforms for early and differential dementia diagnosis.J. Alzheimers Dis. 2015; 45: 813-822
- Assessment of CSF Aβ42 as an aid to discriminating Alzheimer's disease from other dementias and mild cognitive impairment: a meta-analysis of 50 studies.J. Neurol. Sci. 2014; 345: 26-36
- Does CSF p-tau181 help to discriminate Alzheimer's disease from other dementias and mild cognitive impairment? A meta-analysis of the literature.J. Neural Transm. 2014; https://doi.org/10.1007/s00702-014–1226-y
- Cerebrospinal fluid (beta)-amyloid 42 and tau proteins as biomarkers of Alzheimer-type pathologic changes in the brain.Arch. Neurol. 2009; 66: 382-389
- Clinical and neuropathological criteria for frontotemporal dementia.J. Neurol. Neurosurg. Psychiatry. 1994; 57: 416-418
- CSF biomarkers cutoffs: the importance of coincident neuropathological diseases.Acta Neuropathol. 2012; 124: 23-35
- Additional value of CSF amyloid-β40 levels in the differentiation between FTLD and control subjects.J. Alzheimers Dis. 2010; 20: 445-452
- Quantification of amyloid-beta 40 in cerebrospinal fluid.J. Immunol. Methods. 2009; 348: 57-66
- Preclinical Alzheimer's disease and its outcome: a longitudinal cohort study.Lancet Neurol. 2013; 12: 957-965
- Definite behavioral variant of frontotemporal dementia with C9ORF72 expansions despite positive Alzheimer's disease cerebrospinal fluid biomarkers.J. Alzheimers Dis. 2012; 32: 19-22
Article info
Publication history
Published online: September 09, 2015
Accepted:
September 8,
2015
Received in revised form:
August 11,
2015
Received:
June 8,
2015
Identification
Copyright
© 2015 Elsevier B.V. Published by Elsevier Inc. All rights reserved.
