Cerebrospinal fluid biomarkers for differentiation of frontotemporal lobar degeneration from Alzheimer's disease
Open accessAbstract
Accurate ante mortem diagnosis in frontotemporal lobar degeneration (FTLD) is crucial to the development and implementation of etiology-based therapies. Several neurodegenerative disease-associated proteins, including the major protein constituents of inclusions in Alzheimer's disease (AD) associated with amyloid-beta (Aβ(1-42)) plaque and tau neurofibrillary tangle pathology, can be measured in cerebrospinal fluid (CSF) for diagnostic applications. Comparative studies using autopsy-confirmed samples suggest that CSF total-tau (t-tau) and Aβ(1-42) levels can accurately distinguish FTLD from AD, with a high t-tau to Aβ(1-42) ratio diagnostic of AD; however, there is also an urgent need for FTLD-specific biomarkers. These analytes will require validation in large autopsy-confirmed cohorts and face challenges of standardization of within- and between-laboratory sources of error. In addition, CSF biomarkers with prognostic utility and longitudinal study of CSF biomarker levels over the course of disease are also needed. Current goals in the field include identification of analytes that are easily and reliably measured and can be used alone or in a multi-modal approach to provide an accurate prediction of underlying neuropathology for use in clinical trials of disease modifying treatments in FTLD. To achieve these goals it will be of the utmost importance to view neurodegenerative disease, including FTLD, as a clinicopathological entity, rather than exclusively a clinical syndrome.
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An important challenge for routine diagnosis and clinical trials is to identify cases within the FTD spectrum and differentiate them from related diseases such as sporadic AD or non-neurodegenerative primary psychiatric disorders.
“An important challenge for both routine diagnosis and clinical trials is to identify cases within the FTD spectrum and differentiate these from those of related diseases, such as sporadic AD 55 or the non‐neurodegenerative primary psychiatric disorders.”
From New developments of biofluid‐based biomarkers for routine diagnosis and disease trajectories in frontotemporal dementia (2022) · cites this paper as [55]
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Self-citationCytoskeleton proteins in CSF distinguish frontotemporal dementia from AD
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Amyloid β(1–42) and phosphorylated tau in CSF as markers for early-onset Alzheimer disease
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Tau and Aβ42 protein in CSF of patients with frontotemporal degeneration
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Tau and p-tau as CSF biomarkers in dementia: a meta-analysis
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Cerebrospinal fluid tau levels in neurodegenerative diseases with distinct tau-related pathology
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Self-citationClinical, neuroimaging, and pathologic features of progressive nonfluent aphasia
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Self-citationNeuroanatomy of Apathy and Disinhibition in Frontotemporal Lobar Degeneration
Massimo, L., Powers, C., Moore, P., Vesely, L., Avants, B., Gee, J., Libon, D. J., & Grossman, M. (2009) · Dementia and Geriatric Cognitive Disorders · doi:10.1159/000194658 · Cited by 156 · see citing works
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Shapes of the Trajectories of 5 Major Biomarkers of Alzheimer Disease
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Self-citationNon-fluent speech in frontotemporal lobar degeneration
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Apathy in Frontotemporal Dementia: Behavioral and Neuroimaging Correlates
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Apathy in frontotemporal dementia: Behavioral and neuroimaging correlates
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Self-citationCSF neurofilament proteins in the differential diagnosis of dementia
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Self-citationMultimodal predictors for Alzheimer disease in nonfluent primary progressive aphasia
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Self-citationNovel CSF biomarkers for frontotemporal lobar degenerations
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Self-citationPattern of Tau forms in CSF is altered in progressive supranuclear palsy
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Why are patients with progressive nonfluent aphasia nonfluent?
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Cerebrospinal fluid Alzheimer's biomarker profiles in CNS infections
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Self-citationNeurochemical dementia diagnostics: a simple algorithm for interpretation of the CSF biomarkers
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CSF biomarkers in posterior cortical atrophy
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Longitudinal decline in autopsy-defined frontotemporal lobar degeneration
Grossman, M., Xie, S. X., Libon, D. J., Wang, X., Massimo, L., Moore, P., Vesely, L., Berkowitz, R., Chatterjee, A., Coslett, H. B., et al. (2008) · Neurology · doi:10.1212/01.wnl.0000303816.25065.bc · Cited by 77 · see citing works
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Self-citationNeuropsychological and behavioural correlates of CSF biomarkers in dementia
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Decreased sAβPPβ, Aβ 38 , and Aβ 40 Cerebrospinal Fluid Levels in Frontotemporal Dementia
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Self-citationCerebrospinal fluid amyloid-β 2-42 is decreased in Alzheimer’s, but not in frontotemporal dementia
Bibl, M., Gallus, M., Welge, V., Esselmann, H., Wolf, S., Rüther, E., & Wiltfang, J. (2012) · Journal of Neural Transmission · doi:10.1007/s00702-012-0801-3 · Cited by 59 · see citing works
Diagnostic Value of CSF Biomarker Profile in Frontotemporal Lobar Degeneration
Kapaki, E. N., Paraskevas, G. P., Papageorgiou, S. G., Bonakis, A., Kalfakis, N., Zalonis, I., & Vassilopoulos, D. (2008) · Alzheimer Disease & Associated Disorders · doi:10.1097/wad.0b013e3181610fea · Cited by 58 · see citing works
White matter imaging contributes to the multimodal diagnosis of frontotemporal lobar degeneration
McMillan, C. T., Brun, C., Siddiqui, S. M., Churgin, M., Libon, D. J., Yushkevich, P. A., Zhang, H. G., Boller, A., Gee, J. C., & Grossman, M. (2012) · Neurology · doi:10.1212/wnl.0b013e31825830bd · Cited by 55 · see citing works
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Self-citationRascovsky, K., Salmon, D. P., Hansen, L. A., & Galasko, D. R. (2008) · Journal of the International Neuropsychological Society · doi:10.1017/s135561770808051x · Cited by 52 · see citing works
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Self-citationFrontotemporal Lobar Degeneration Without Lobar Atrophy
Josephs, K. A., Whitwell, J. L., Jack, C. R., Parisi, J. E., & Dickson, D. W. (2006) · Archives of Neurology · doi:10.1001/archneur.63.11.1632 · Cited by 50 · see citing works
The Philadelphia Brief Assessment of Cognition (PBAC): A Validated Screening Measure for Dementia
Libon, D. J., Rascovsky, K., Gross, R. G., White, M. T., Xie, S. X., Dreyfuss, M., Boller, A., Massimo, L. M., Moore, P., Kitain, J., et al. (2011) · The Clinical Neuropsychologist · doi:10.1080/13854046.2011.631585 · Cited by 47 · see citing works
Self-citationBiomarkers in frontotemporal lobar degenerations—Progress and challenges
Hu, W. T., Trojanowski, J. Q., & Shaw, L. M. (2011) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2011.04.012 · Cited by 42 · see citing works
Self-citationCerebrospinal fluid biomarker results in relation to neuropathological dementia diagnoses
Brunnström, H., Rawshani, N., Zetterberg, H., Blennow, K., Minthon, L., Passant, U., & Englund, E. M. (2010) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2009.12.005 · Cited by 35 · see citing works
CSF tau and Aβ42 are not useful in the diagnosis of frontotemporal lobar degeneration
Pijnenburg, Y. A. L., Schoonenboom, N. S. M., Rosso, S. M., Mulder, C., van Kamp, G. J., Swieten, J. C. V., & Scheltens, P. (2004) · Neurology · doi:10.1212/01.wnl.0000123014.03499.a7 · Cited by 35 · see citing works
Additional Value of CSF Amyloid-β40 Levels in the Differentiation between FTLD and Control Subjects
Verwey, N. A., Kester, M. I., van der Flier, W. M., Veerhuis, R., Berkhof, J. H., Twaalfhoven, H. A. M., Blankenstein, M. A., Scheltens, P., & Pijnenburg, Y. A. L. (2010) · Journal of Alzheimer s Disease · doi:10.3233/jad-2010-1392 · Cited by 34 · see citing works
Novel cerebrospinal fluid biomarkers of axonal degeneration in frontotemporal dementia.
Mattsson, N., Rüetschi, U., Pijnenburg, Y., Blankenstein, M., Podust, V., Li, S., Fagerberg, I., Rosengren, L., Blennow, K., & Zetterberg, H. (2008) · Molecular Medicine Reports · doi:10.3892/mmr_00000025 · Cited by 34 · see citing works
Reduced CSF carboxyterminally truncated Aβ peptides in frontotemporal lobe degenerations
Bibl, M., Mollenhauer, B., Wolf, S., Esselmann, H., Lewczuk, P., Kornhuber, J., & Wiltfang, J. (2007) · Journal of Neural Transmission · doi:10.1007/s00702-006-0618-z · Cited by 33 · see citing works
Self-appraisal in behavioural variant frontotemporal degeneration
Massimo, L. M., Libon, D. J., Chandrasekaran, K., Dreyfuss, M., McMillan, C. T., Rascovsky, K., Boller, A., & Grossman, M. (2012) · Journal of Neurology Neurosurgery & Psychiatry · doi:10.1136/jnnp-2012-303153 · Cited by 33 · see citing works
Self-citationDecreased cerebrospinal fluid amyloid beta (1-40) levels in frontotemporal lobar degeneration
Pijnenburg, Y. A. L., Schoonenboom, S. N. M., Mehta, P. D., Mehta, S. P., Mulder, C., Veerhuis, R., Blankenstein, M. A., & Scheltens, P. (2006) · Journal of Neurology Neurosurgery & Psychiatry · doi:10.1136/jnnp.2006.105064 · Cited by 32 · see citing works
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Self-citationThe neural basis for establishing a focal point in pure coordination games
McMillan, C. T., Rascovsky, K., Khella, M. C., Clark, R., & Grossman, M. (2011) · Social Cognitive and Affective Neuroscience · doi:10.1093/scan/nsr070 · Cited by 28 · see citing works
Self-citationCould Clinical Profile Influence CSF Biomarkers in Early-onset Alzheimer Disease?
Koric, L., Félician, O., Guedj, É., Hubert, A.-M., Mancini, J., Boucraut, J., & Ceccaldi, M. P. (2010) · Alzheimer Disease & Associated Disorders · doi:10.1097/wad.0b013e3181d712d9 · Cited by 25 · see citing works
Can MRI screen for CSF biomarkers in neurodegenerative disease?
McMillan, C. T., Avants, B., Irwin, D. J., Toledo, J. B., Wolk, D. A., Deerlin, V. M. V., Shaw, L. M. J., Trojanoswki, J. Q., & Grossman, M. (2012) · Neurology · doi:10.1212/wnl.0b013e31827b9147 · Cited by 24 · see citing works
Self-citationCSF tau protein: A new prognostic marker for Guillain-Barre syndrome
Jin, K., Takeda, A., Shiga, Y., Sato, S., Ohnuma, A., Nomura, H., Arai, H., Kusunoki, S., Ikeda, M., & Itoyama, Y. (2006) · Neurology · doi:10.1212/01.wnl.0000240119.29939.c7 · Cited by 24 · see citing works
CSF TAU PROTEIN: A NEW PROGNOSTIC MARKER FOR GUILLAIN-BARRE SYNDROME
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Cognitive correlates of cerebrospinal fluid biomarkers in frontotemporal dementia
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Frontotemporal lobar degeneration: recent progress in antemortem diagnosis
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Abeta amyloid and glucose metabolism in three variants of primary progressive aphasia
Rabinovici, G. D., Racine, C. A., Mormino, E. C., O’Neil, J. P., Lal, R., Dronkers, N. F., Miller, B. L., & Gorno-Tempini, M.-L. (2008) · Cited by 15 · see citing works
Role for peroxisome proliferator-activated receptor-gamma in Alzheimer's disease.
van Geel (2001) · Open Repository and Bibliography (University of Luxembourg) · doi:10.1002/1531-8249(20010201)49:2 · Cited by 7 · see citing works
Self-citationCSF tau and Abeta42 are not useful in the diagnosis of frontotemporal lobar degeneration
Pijnenburg, Y., Schoonenboom, N., Rosso, S. M., Mulder, C., van Kamp, G., Swieten, J. C. V., & Scheltens, P. (2004) · EUR Research Repository (Erasmus University Rotterdam) · Cited by 2 · see citing works
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Frontotemporal lobar degeneration: defining phenotypic diversity through personalized medicine
Irwin, D. J., Cairns, N. J., Grossman, M., McMillan, C. T., Lee, E. B., Deerlin, V. M. V., Lee, V. M. ‐., & Trojanowski, J. Q. (2014) · Acta Neuropathologica · doi:10.1007/s00401-014-1380-1 · Cited by 262 · see citing works
Self-citationCNS-Derived Blood Exosomes as a Promising Source of Biomarkers: Opportunities and Challenges
Hornung, S., Dutta, S., & Bitan, G. (2020) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2020.00038 · Cited by 239 · see citing works
Emerging Concepts in Alzheimer's Disease
Vinters, H. V. (2014) · Annual Review of Pathology Mechanisms of Disease · doi:10.1146/annurev-pathol-020712-163927 · Cited by 232 · see citing works
Cerebrospinal fluid tau and amyloid-β1-42in patients with dementia
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CSF sAPPβ, YKL-40, and neurofilament light in frontotemporal lobar degeneration
Alcolea, D., Vilaplana, E., Suárez-Calvet, M., Illán-Gala, I., Blesa, R., Clarimón, J., Lladó, A., Sánchez-Valle, R., Molinuevo, J. L., García-Ribas, G., et al. (2017) · Neurology · doi:10.1212/wnl.0000000000004088 · Cited by 123 · see citing works
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Self-citationAdditional file 1 of Plasma proteome profiling identifies changes associated to AD but not to FTD
Mofrad, R. B., del Campo, M., Peeters, C. F. W., Meeter, L. H. H., Seelaar, H., Koel-Simmelink, M., Ramakers, I. H. G. B., Middelkoop, H. A. M., De Deyn, P. P., Claassen, J. A. H. R., et al. (2022) · Figshare · doi:10.6084/m9.figshare.21384317
Additional file 2 of Plasma proteome profiling identifies changes associated to AD but not to FTD
Mofrad, R. B., del Campo, M., Peeters, C. F. W., Meeter, L. H. H., Seelaar, H., Koel-Simmelink, M., Ramakers, I. H. G. B., Middelkoop, H. A. M., De Deyn, P. P., Claassen, J. A. H. R., et al. (2022) · Figshare · doi:10.6084/m9.figshare.21384320
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- Authors
- Irwin, D. J., Trojanowski, J. Q., & Grossman, M.
- Affiliations
- Hospital of the University of Pennsylvania (US)
- Corresponding author
- Grossman, Murray
- Venue
- Frontiers in Aging Neuroscience
- Publisher
- Frontiers Media SA
- Published
- 2013
- Volume
- 5
- Pages
- 6-6
- ISSN
- 1663-4365 (ISSN-L)
- PMC
- PMC3578350
- OpenAlex
- W2106839031
- Cited by
- 96
- References
- 142
- Citations by year
- 2026: 5 · 2025: 3 · 2024: 4 · 2023: 2 · 2022: 9 · 2021: 6 · 2020: 6 · 2019: 12 · 2018: 7 · 2017: 9 · 2016: 8 · 2015: 11 · 2014: 11 · 2013: 3
- FWCI
- 7.82
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Frontiers in Aging Neuroscience (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Wyncote Foundation
- National Institutes of Health (AG 10 124, AG000255, AG 17586)
- National Institute on Aging (P30AG010124, P01AG017586, T32AG000255)
- National Institute of Neurological Disorders and Stroke (P50NS053488, R01NS044266)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Keywords
- frontotemporal lobar degeneration, Alzheimer's disease, cerebrospinal fluid biomarkers, differential diagnosis, tau protein, amyloid-beta, neurodegenerative diseases, disease-modifying therapy, biomarker standardization
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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