Novel CSF biomarkers for frontotemporal lobar degenerations.
OBJECTIVE
To identify antemortem CSF diagnostic biomarkers that can potentially distinguish between the 2 main causes of frontotemporal lobar degeneration (FTLD), i.e., FTLD with TDP-43 pathology (FTLD-TDP) and FTLD with tau pathology (FTLD-tau).


METHODS
CSF samples were collected antemortem from 23 patients with FTLD with known pathology to form a autopsy cohort as part of a comparative biomarker study that additionally included 33 living cognitively normal subjects and 66 patients with autopsy-confirmed Alzheimer disease (AD). CSF samples were also collected from 80 living patients clinically diagnosed with frontotemporal dementia (FTD). Levels of 151 novel analytes were measured via a targeted multiplex panel enriched in neuropeptides, cytokines, and growth factors, along with levels of CSF biomarkers for AD.


RESULTS
CSF levels of multiple analytes differed between FTLD-TDP and FTLD-tau, including Fas, neuropeptides (agouti-related peptide and adrenocorticotropic hormone), and chemokines (IL-23, IL-17). Classification by random forest analysis achieved high sensitivity for FTLD-TDP (86%) with modest specificity (78%) in the autopsy cohort. When the classification algorithm was applied to a living FTD cohort, semantic dementia was the phenotype with the highest predicted proportion of FTLD-TDP. When living patients with behavioral variant FTD were examined in detail, those predicted to have FTLD-TDP demonstrated neuropsychological differences vs those predicted to have FTLD-tau in a pattern consistent with previously reported trends in autopsy-confirmed cases.


CONCLUSIONS
Clinical cases with FTLD-TDP and FTLD-tau pathology can be potentially identified antemortem by assaying levels of specific analytes that are well-known and readily measurable in CSF.
Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia 19104-4283, USA. trojanow@mail.med.upenn.edu
W T
WT
Hu
A
A
Chen-Plotkin
M
M
Grossman
S E
SE
Arnold
C M
CM
Clark
L M
LM
Shaw
L
L
McCluskey
L
L
Elman
H I
HI
Hurtig
A
A
Siderowf
V M-Y
VM
Lee
H
H
Soares
J Q
JQ
Trojanowski
D000324:Adrenocorticotropic Hormone / Q000134:cerebrospinal fluid; D000368:Aged; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid; D015415:Biomarkers / Q000134:cerebrospinal fluid*; D015331:Cohort Studies; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005260:Female; D057174:Frontotemporal Lobar Degeneration / Q000134:cerebrospinal fluid* / Q000150:complications; D006801:Humans; D020381:Interleukin-17 / Q000134:cerebrospinal fluid; D008297:Male; D008609:Mental Status Schedule; D008875:Middle Aged; D009483:Neuropsychological Tests; D018709:Statistics, Nonparametric; D024801:Tauopathies / Q000134:cerebrospinal fluid* / Q000150:complications
D015415:Biomarkers; D004268:DNA-Binding Proteins; D020381:Interleukin-17; D000324:Adrenocorticotropic Hormone