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| Role of Personalized Medicine in the Identification and Characterization
of Parkinson’s Disease in Asymptomatic Subjects |
| Giulio Maria Pasinetti* |
| Department of Neurology, The Mount Sinai School of Medicine, New York, USA |
| *Corresponding author: |
Giulio Maria Pasinetti,
Department of Neurology
The
Mount Sinai School of Medicine
NY 10029, USA
E-mail: giulio.pasinetti@mssm.edu |
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| Received June 28, 2012; Accepted June 28, 2012; Published June 30, 2012 |
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| Citation: Pasinetti GM (2012) Role of Personalized Medicine in the Identification
and Characterization of Parkinson’s Disease in Asymptomatic Subjects. J
Alzheimers Dis Parkinsonism 2:e118. doi:10.4172/2161-0460.1000e118 |
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| Copyright: © 2012 Pasinetti GM . This is an open-access article distributed under
the terms of the Creative Commons Attribution License, which permits unrestricted
use, distribution, and reproduction in any medium, provided the original author and
source are credited. |
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| Medical physicians and scientists alike have traditionally viewed
and interpreted diseases at the ‘visual’ clinical level. With the advent of
genomics and proteomics technologies, personalized medicine offers
the promise and potential of uncovering the largely ‘unseen’ details
of disease causality, onset and progression [1]. We hypothesized that
changes in the expression profile of biological indices (biomarkers)
in the plasma and in circulating Peripheral Blood Mononuclear Cells
(PBMC) may provide an ideal and clinically assessable “window” into
the brain, reflecting molecular alterations associated with the onset
and progression of Parkinson’s disease (PD). The objective of our
subsequent study was to test whether the differential expression of
micro (mi) RNAs in PBMCs could be used to distinguish true PD from
non-PD cases at baseline, prior to any definitive clinical diagnosis. |
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| We explored whether specific changes in microRNA (miRNA)
[2] from circulating PBMCs might reflect central nervous system
neuropathology, such as in PD. We analyzed miRNA expression
profiles in PBMC specimens that were collected at the baseline visit
(recruitment) from 23 randomly chosen subjects with suspected PD,
but whose mild clinical phenotypes precluded definitive PD diagnoses.
Follow-up assessments conducted one year later, when patients had
developed sufficiently robust clinical symptoms for unambiguous
disease diagnosis, confirmed that thirteen of the patients met the
clinical criteria for true PD (ten were deemed not to have PD). The
objective of this study was then to test whether differential expression of
miRNAs in PBMCs could be used to distinguish true-PD from non-PD
cases at baseline, prior to definitive clinical diagnosis. |
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| Results from our high throughput miRNA expression profile
analyses of baseline PBMC specimens using the Agilent miRNA
platform led to the identification of three candidate miRNA biomarker
species (hsa-mir-29C, hsa-mir-424 and hsa-mir-30e5p) that were
expressed at significantly higher levels in baseline PBMC specimens
from true-PD compared to non-PD cases. In follow-up analyses, we
used independent quantitative real-time Polymerase Chain Reaction
(qPCR) techniques to examine the differential regulation of the three
candidate miRNAs in the PBMCs of true-PD versus non-PD cases.
Consistent with our high-throughput miRNA expression profile
analyses, results from our qPCR studies confirmed that hsa-mir-29c,
hsa-mir-424 and hsa-mir-30e5p expression levels were significantly
higher (by more than two- to four-fold) in baseline PBMC specimens
of true-PD compared to non-PD cases (data not shown). Thus, our
studies demonstrated for the first time that the regulation of specific
peripheral molecular indices (e.g., miRNA biomarkers in PBMCs) is
associated with the onset and/or progression of PD. Using receiver
operating characteristics (ROC) analyses, we assessed the predictive
accuracy of using miRNA biomarker contents in PBMCs to correctly
identify true PD cases among patients with suspected PD. We found
that the combination of the hsa-mir-29c, hsa-mir-30e-5p, and hsamir-
424 miRNA biomarker species (the three miRNA model) provided
95% accuracy in correctly diagnosing “true” PD. Moreover, this
model resulted in 92% sensitivity, missing 8% of true PD cases (false negatives), and 100% specificity, not incorrectly identifying any of the
non-PD cases as true PD (false positives) (Table 1). |
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Table 1: The 3 miRNA model provides a sensitive and specific criterion for
distinguishing true PD from non-PD among patients with suspected PD. |
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| Based on the efficacy of miRNA biomarker contents in PBMCs in
distinguishing true-PD from non-PD cases among our study cohort,
we continued to explore potential changes in the regulation of the
three miRNA biomarkers in the brains of PD cases. In recent ongoing
feasibility studies, we found higher contents of the three miRNA
biomarkers in substantia nigra specimens of PD compared to normal
cases (data not shown). Our observation suggests that the content of
hsa-mir-29c, hsa-mir-30e-5p, and hsa-mir-424 miRNA biomarker
species in clinically accessible PBMCs provides a “window to the brain”,
reflecting molecular changes in the PD brain. More importantly, our
new feasibility evidence suggests that hsa-mir-29c, hsa-mir-30e-5p,
and hsa-mir-424 miRNA might have potential roles in PD onset and/
or progression. Based on this, we used the Diana-mirPath Software
(http://diana.cslab.ece.ntua.gr/?sec=home) to assess the potential
roles of the identified PD biomarker miRNAs in biological processes
relevant to PD. We conducted the Diana-mirPath analysis using 2 of
the miRNA biomarkers (hsa-mir-29C and hsa-mir-424) that are part of
the Diana-mirPath database; hsa-mir-30e5p is not part of the database
and was therefore excluded from this analysis. Interestingly, we found
that potential target genes that might be regulated by hsa-mir-29C
and hsa-mir-424 are significantly (p<5.1E-06) enriched in a cellular
pathway relevant to PD pathophysiology, particularly in relation to
cellular dopamine metabolism/release. Our observations suggest that
these biomarkers might have direct pathological relevance to PD onset/
progression. |
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| Collectively, our findings suggest that changes in miRNA
biomarker contents in PBMCs reflect biological features relevant to PD
and provide a means to help identify true-PD from non-PD cases at
early stages of the disease, prior to definitive clinical diagnoses. Future
studies will continue searching for potential relationships between
miRNA biomarker contents in PBMCs and indices of dopamine uptake
in the brain. Outcomes will test the potential value of PBMC miRNA
biomarker contents as an index of brain dopaminergic function in
PD. The development of biomarkers in personalized medicine will
provide impetus for future investigations aimed at the early detection
of disease, possibly at asymptomatic stages of PD and other age-related
neurodegenerative disorders, and will help to devise future preventative
therapeutic interventions. |
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| Acknowledgements |
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| These studies were supported by discretional funding to GMP and in part by
the National Institutes of Health (grant AG037504). |
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| References |
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- Maglo KN (2012) Group-Based and Personalized Care in an Age of Genomic
and Evidence-Based Medicine: A Reappraisal. Perspect Biol Med 55:137-154.
- Persengiev SP, Kondova II, Bontrop RE (2012) The Impact of MicroRNAs on
Brain Aging and Neurodegeneration. Curr Gerontol Geriatr Res 359369.
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