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HOT TOPICS
252

treatment-refractory anorexia nervosa: a phase 1 consistent with earlier CSF studies,
pilot trial. Lancet 381: 1361–1370.
supporting the potential of plasma
Lozano AM, Lipsman N (2013). Probing and regulat-
ing dysfunctional circuits using deep brain stimula- markers as a screening tool (Soares
tion. Neuron 77: 406–424. et al, 2012). Unfortunately, variability
Mayberg HS, Lozano AM, Voon V, McNeely HE,
in inter-assay performance can lead to
Seminowicz D, Hamani C et al (2005). Deep brain
stimulation for treatment-resistant depression. nonreplicable findings. CSF findings
Neuron 45: 651–660. from the same ADNI subjects using a
subset of the same multiplex panel,
Neuropsychopharmacology Reviews (2014) 39, 250–252;
doi:10.1038/npp.2013.244 replicated only a few previously repor-
ted protein differences (Siuciak et al,
2012). Comparisons of plasma vs CSF
profiles using the same platform make
Proteomic Biomarkers clear that only in a few instances are
for Brain Disorders: analytes sufficiently correlated to allow
the use of plasma as a proxy for CSF
Technical
(Potter et al, 2012). Thus, even with the
Considerations and ADNI studies, where standardized sam-
Challenges ple and proteomic protocols were used,
standards for replication and verification
of assay findings to advance promising
markers to clinical application. In
December of 2013, the Biomarkers
Consortium will sponsor a workshop
(https://www.signup4.net/public/ap.aspx?
EID=CSFP11E&TID=WhpjeshOarRyJD
UAXwZjKg%3d%3d) focused on char-
acterizing the CSF proteome and
developing guidelines for use of tech-
nologies platforms to better identify
reliable markers of brain disease.
Linda S Brady1 and William Z Potter2
1
Division of Neuroscience and Basic Behavioral
Science, National Institute of Mental Health, Bethesda,
MD, USA; 2Senior Advisor to the Director, National
Institute of Mental Health, Bethesda, MD, USA
Email: lbrady@mail.nih.gov

variation in specific multiplex immu-

Proteomic technologies are being used noassay analyte findings limits the FUNDING AND DISCLOSURE
The authors declare that, except for income received
to identify fluid-based biomarkers for interpretation of the results.
from the NIMH, LSB has no financial interests to disclose.
detection, progression, and thera- An emerging strategy views broad WZP currently receives compensation from NIMH as a
peutic response in brain disorders. proteomic profiling of samples as senior consultant, serves on Advisory Boards for
AgeneBio, Amgen, Ironwood, Lilly, MedAvante, Taisho,
This commentary focuses on the tech- ‘exploratory’ to be followed by highly
Takeda, and Theravance and has personal financial
nical obstacles and challenges invol- sensitive, specific and reproducible holdings from his previous employment at Merck.
ved in the discovery, evaluation, and assays targeted to one or more specific
validation of such markers. analytes. At the current stage of deve- ...........................................................................................
Craft GE, Chen A, Nairn AC (2013). Recent advances in
Following the initial excitement in lopment, no multiplex immunoassay- quantitative neuroproteomics. Methods 61: 186–218.
the mid-90s that proteomics would based approaches that target 410 Kang JH, Vanderstichele H, Trojanowski JQ, Shaw LM
yield definitive blood patterns to char- analytes have proved sufficiently (2012; Simultaneous analysis of cerebrospinal fluid
biomarkers using microsphere-based xMAP multi-
acterize tumor types, the proteome was sensitive to detect beta-amyloid and plex technology for early detection of Alzheimer’s
explored in brain disorders, using tau in CSF at the level achieved when disease. Methods 56: 484–493.
cerebrospinal fluid (CSF) and plasma, optimizing conditions to simulta- Mattsson N, Andreasson U, Persson S, Carrillo MC,
Collins S, Chalbot S et al (2013). CSF
with the expectation that these bio- neously measure these analytes (Kang biomarker variability in the Alzheimer’s Association
fluids would reflect disease state and et al, 2012). Mass spectrometric-based quality control program. Alzheimers Dement 9:
evidence of drug action. Conflicting assays offer an unbiased discovery 251–261.
Potter WZ, Pickering EH, Immerman F, Kuhn M,
results from a decade of studies and an approach (Craft et al, 2013); studies Siuciak J, Shaw L. Alzheimer’s Disease Neuroima-
international Human Proteome Project are underway with the same CSF ADNI ging Initiative (ADNI), the Foundation for NIH
(http://www.thehpp.org/) highlight the samples allowing for a unique con- Biomarkers Consortium CSF Proteomics Project
Team (2012). Cerebrospinal fluid (CSF) vs plasma-
need to revisit basic principles: stan- trast to the multiplex immunoassay based biomarkers in Alzheimer’s disease (AD), mild
dardization of protocols and sample approach. Informatics and pathway cognitive impaired (MCI) and age-matched healthy
collection, reproducibility of technol- analysis approaches can also be used controls (HC) from the Alzheimer’s Disease
Neuroimaging Initiative (ADNI) cohort. Alzheimers
ogy platforms (Mattsson et al, 2013) to analyze proteomic data, but there is Dement 8: P217.
and controlling for false positives. a tension between application of such Siuciak JA, Pickering EH, Immermann F, Kuhn M,
The Neuroscience Steering Commit- methodologies and reproducibility of Shaw L, Potter WZ. Alzheimer’s Disease Neuro-
imaging Initiative (ADNI), the Foundation for NIH
tee of the Biomarkers Consortium measures within a proteomic platform. Biomarkers Consortium CSF Proteomics Project
(http://www.biomarkersconsortium.org/) High costs (4$500 per sample) and Team (2012). Cerebrospinal fluid (CSF) biomarkers
undertook a proteomic analysis of limited aliquots (especially for CSF) are in Alzheimer’s disease (AD), mild cognitively
impaired (MCI) and age-matched healthy controls
plasma and CSF samples collected in factors to consider in further attempts (HC) from the Alzheimer’s Disease Neuroimaging
the Alzheimer’s Disease Neuroimaging to replicate or rule out findings, which Initiative (ADNI) cohort. Alzheimers Dement 8:
(ADNI) study. A multiplex Luminex- if true, could prove important. P216–P217.
Soares HD, Potter WZ, Pickering E, Kuhn M,
based immunoassay panel was used to To realize the potential of proteo- Immermann FW, Shera DM et al (2012). Plasma
analyze plasma and CSF samples from mics, it is critical to understand biomarkers associated with the apolipoprotein E
AD, mild cognitively impaired and the limitations of the technology plat- genotype and Alzheimer disease. Arch Neurol 69:
1310–1317.
control subjects at baseline and 1 year. forms (eg, its analytical performance—
Several markers differentiated patients sensitivity, specificity, precision, sta- Neuropsychopharmacology Reviews (2014) 39, 252;
from controls; three proteins were bility, and reproducibility) and set doi:10.1038/npp.2013.202

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Neuropsychopharmacology