Abstract | Importance: Objective: To develop an algorithm based on core AD CSF measures to exclude cases with AD pathology and then differentiate between FTLD-tau and FTLD transactive response DNA-binding protein of approximately 43kDa ( FTLD-TDP). Design, Setting, and Participants: A case-control study at the University of Pennsylvania. Participants were selected from a database of 1796 patients included between 1992 and 2016 with different neurodegenerative diseases with available CSF. Three patient cohorts were included: a cohort of patients with sporadic, autopsy-confirmed FTLD and AD (n = 143); a cohort of patients with frontotemporal degeneration (FTD) with TDP-associated or tau-associated mutations (n = 60); and a living cohort of patients with syndromes highly predictive of FTLD ( progressive supranuclear palsy and FTD- amyotrophic lateral sclerosis; n = 62). Main Outcomes and Measures: Cerebrospinal fluid values of amyloid β1-42 (Aβ1-42), total tau (t-tau), and p-tau obtained using the INNO-BIA AlzBio3 (xMAP; Luminex) assay or INNOTEST enzyme-linked immunosorbent assay transformed using a previously validated algorithm. Sensitivities and specificities for differentiating AD from FTLD groups were calculated. Results: This autopsy cohort included FTLD-tau (n = 27; mean [SD] age at onset, 60.8 [9.7] years), FTLD-TDP (n = 13; mean [SD] age at onset, 62.4 [8.5] years), AD (n = 89, mean [SD] age at onset, 66.5 [9.7] years); and mixed FTLD-AD (n = 14, mean [SD] age at onset, 70.6 [8.5] years).The p-tau/Aβ1-42 ratio showed an excellent diagnostic accuracy to exclude AD cases in the autopsy cohort with single neurodegenerative pathologies (area under the curve [AUC], 0.98; 95% CI, 0.96-1.00). Cerebrospinal fluid p-tau levels showed a good AUC (0.87; 95% CI, 0.73-1.00) for discriminating pure FTLD-TDP from pure FTLD-tau. The application of an algorithm using cutpoints of CSF p-tau to Aβ1-42 ratio and p-tau allowed a good discrimination of pure FTLD-TDP cases from the remaining FTLD-tau and mixed FTLD cases. The diagnostic value of this algorithm was confirmed in an independent cohort of living patients with progressive supranuclear palsy and FTD- amyotrophic lateral sclerosis (AUC, 0.9; 95% CI, 0.81-0.99). However, the algorithm was less useful in FTD cases carrying a pathogenic mutation (AUC, 0.58; 95% CI, 0.38-0.77) owing to elevated p-tau levels in TDP-associated mutation carriers. Conclusions and Relevance:
Alzheimer disease CSF core biomarkers can be used with high specificity for the in vivo identification of patients with pure FTLD-TDP and FTLD-tau when accounting for comorbid AD and genetic status.
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Authors | Alberto Lleó, David J Irwin, Ignacio Illán-Gala, Corey T McMillan, David A Wolk, Edward B Lee, Vivianna M Van Deerlin, Leslie M Shaw, John Q Trojanowski, Murray Grossman |
Journal | JAMA neurology
(JAMA Neurol)
Vol. 75
Issue 6
Pg. 738-745
(06 01 2018)
ISSN: 2168-6157 [Electronic] United States |
PMID | 29554190
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- Amyloid beta-Peptides
- Biomarkers
- Peptide Fragments
- amyloid beta-protein (1-42)
- tau Proteins
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Topics |
- Aged
- Aged, 80 and over
- Algorithms
- Amyloid beta-Peptides
(cerebrospinal fluid)
- Biomarkers
(cerebrospinal fluid)
- Case-Control Studies
- Databases, Factual
(trends)
- Female
- Frontotemporal Lobar Degeneration
(cerebrospinal fluid, classification, pathology)
- Humans
- Male
- Peptide Fragments
(cerebrospinal fluid)
- tau Proteins
(cerebrospinal fluid)
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