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Label-free, live optical imaging of reprogrammed bipolar disorder patient-derived cells reveals a functional correlate of lithium responsiveness.

Wang JL, Shamah SM, Sun AX, Waldman ID, Haggarty SJ, Perlis RH - Transl Psychiatry (2014)

Bottom Line: However, efficiently identifying and characterizing relevant neuronal phenotypes in the absence of well-defined pathophysiology remains a challenge.In this study, we collected fibroblast samples from patients with bipolar 1 disorder, characterized by their lithium response (n=12), and healthy control subjects (n=6).We identified a cellular phenotype in reprogrammed neurons using a label-free imaging assay based on a nanostructured photonic crystal biosensor and found that an optical measure of cell adhesion was associated with clinical response to lithium treatment.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Psychiatry, Center for Experimental Drugs and Diagnostics, Massachusetts General Hospital, Boston, MA, USA [2] Center for Human Genetics Research, Massachusetts General Hospital, Boston, MA, USA [3] Stanley Center for Psychiatric Research, Broad Institute of MIT & Harvard, Cambridge, MA, USA.

ABSTRACT
Development of novel treatments and diagnostic tools for psychiatric illness has been hindered by the absence of cellular models of disease. With the advent of cellular reprogramming, it may be possible to recapitulate the disease biology of psychiatric disorders using patient skin cells transdifferentiated to neurons. However, efficiently identifying and characterizing relevant neuronal phenotypes in the absence of well-defined pathophysiology remains a challenge. In this study, we collected fibroblast samples from patients with bipolar 1 disorder, characterized by their lithium response (n=12), and healthy control subjects (n=6). We identified a cellular phenotype in reprogrammed neurons using a label-free imaging assay based on a nanostructured photonic crystal biosensor and found that an optical measure of cell adhesion was associated with clinical response to lithium treatment. This cellular phenotype may represent a useful biomarker to evaluate drug response and screen for novel therapeutics.

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Correlation of cellular BIND metrics to clinical features. (a) The four plots illustrate marginal means and 95% confidence intervals for the four cellular phenotypes identified using the BIND Scanner, with adjustment for age, sex and experiment. The asterisk denotes a significant difference in ΔPWV between BD Li Non-responders and BD Li Responders as indicated by Bonferroni corrected post hoc pairwise testing (P=0.02). (b) Marginal means and 95% confidence intervals for change in cell fraction, cell perimeter and PWV, with adjustment for change in cell count. (c) Results for change in PWV, adjusted as in b, by Alda score (degree of improvement with lithium) group. BD, bipolar disorder; PWV, peak wavelength value.
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fig3: Correlation of cellular BIND metrics to clinical features. (a) The four plots illustrate marginal means and 95% confidence intervals for the four cellular phenotypes identified using the BIND Scanner, with adjustment for age, sex and experiment. The asterisk denotes a significant difference in ΔPWV between BD Li Non-responders and BD Li Responders as indicated by Bonferroni corrected post hoc pairwise testing (P=0.02). (b) Marginal means and 95% confidence intervals for change in cell fraction, cell perimeter and PWV, with adjustment for change in cell count. (c) Results for change in PWV, adjusted as in b, by Alda score (degree of improvement with lithium) group. BD, bipolar disorder; PWV, peak wavelength value.

Mentions: Figure 3a illustrates marginal means and 95% confidence intervals for each cellular metric, by subject group, drawn from GLM. There was a significant overall difference between patient groups for ΔPWV (x2=9.64, P=0.008) but not for Δcell count (x2=0.93, P=0.63), Δcell fraction (x2=2.26, P=0.32) or Δcell perimeter. After controlling for plate date, sex and age, the significant overall difference between patient groups persisted for ΔPWV (x2=7.02, P=0.03) but not for Δcell count (x2=2.88, P=0.24), Δcell fraction (x2=3.54, P=0.17) or Δcell perimeter (x2=2.45, P=0.29). For ΔPWV, Bonferroni-corrected post hoc pairwise tests indicated significant differences between BD lithium responsive and nonresponsive cells (z=2.65, P=0.02); neither group differed significantly from healthy controls (z=−1.48, P=0.42 for controls (n=6) versus BD lithium nonresponders (n=6) and z=1.36, P=0.51 for controls versus BD Li responders (n=6)).


Label-free, live optical imaging of reprogrammed bipolar disorder patient-derived cells reveals a functional correlate of lithium responsiveness.

Wang JL, Shamah SM, Sun AX, Waldman ID, Haggarty SJ, Perlis RH - Transl Psychiatry (2014)

Correlation of cellular BIND metrics to clinical features. (a) The four plots illustrate marginal means and 95% confidence intervals for the four cellular phenotypes identified using the BIND Scanner, with adjustment for age, sex and experiment. The asterisk denotes a significant difference in ΔPWV between BD Li Non-responders and BD Li Responders as indicated by Bonferroni corrected post hoc pairwise testing (P=0.02). (b) Marginal means and 95% confidence intervals for change in cell fraction, cell perimeter and PWV, with adjustment for change in cell count. (c) Results for change in PWV, adjusted as in b, by Alda score (degree of improvement with lithium) group. BD, bipolar disorder; PWV, peak wavelength value.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4150245&req=5

fig3: Correlation of cellular BIND metrics to clinical features. (a) The four plots illustrate marginal means and 95% confidence intervals for the four cellular phenotypes identified using the BIND Scanner, with adjustment for age, sex and experiment. The asterisk denotes a significant difference in ΔPWV between BD Li Non-responders and BD Li Responders as indicated by Bonferroni corrected post hoc pairwise testing (P=0.02). (b) Marginal means and 95% confidence intervals for change in cell fraction, cell perimeter and PWV, with adjustment for change in cell count. (c) Results for change in PWV, adjusted as in b, by Alda score (degree of improvement with lithium) group. BD, bipolar disorder; PWV, peak wavelength value.
Mentions: Figure 3a illustrates marginal means and 95% confidence intervals for each cellular metric, by subject group, drawn from GLM. There was a significant overall difference between patient groups for ΔPWV (x2=9.64, P=0.008) but not for Δcell count (x2=0.93, P=0.63), Δcell fraction (x2=2.26, P=0.32) or Δcell perimeter. After controlling for plate date, sex and age, the significant overall difference between patient groups persisted for ΔPWV (x2=7.02, P=0.03) but not for Δcell count (x2=2.88, P=0.24), Δcell fraction (x2=3.54, P=0.17) or Δcell perimeter (x2=2.45, P=0.29). For ΔPWV, Bonferroni-corrected post hoc pairwise tests indicated significant differences between BD lithium responsive and nonresponsive cells (z=2.65, P=0.02); neither group differed significantly from healthy controls (z=−1.48, P=0.42 for controls (n=6) versus BD lithium nonresponders (n=6) and z=1.36, P=0.51 for controls versus BD Li responders (n=6)).

Bottom Line: However, efficiently identifying and characterizing relevant neuronal phenotypes in the absence of well-defined pathophysiology remains a challenge.In this study, we collected fibroblast samples from patients with bipolar 1 disorder, characterized by their lithium response (n=12), and healthy control subjects (n=6).We identified a cellular phenotype in reprogrammed neurons using a label-free imaging assay based on a nanostructured photonic crystal biosensor and found that an optical measure of cell adhesion was associated with clinical response to lithium treatment.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Psychiatry, Center for Experimental Drugs and Diagnostics, Massachusetts General Hospital, Boston, MA, USA [2] Center for Human Genetics Research, Massachusetts General Hospital, Boston, MA, USA [3] Stanley Center for Psychiatric Research, Broad Institute of MIT & Harvard, Cambridge, MA, USA.

ABSTRACT
Development of novel treatments and diagnostic tools for psychiatric illness has been hindered by the absence of cellular models of disease. With the advent of cellular reprogramming, it may be possible to recapitulate the disease biology of psychiatric disorders using patient skin cells transdifferentiated to neurons. However, efficiently identifying and characterizing relevant neuronal phenotypes in the absence of well-defined pathophysiology remains a challenge. In this study, we collected fibroblast samples from patients with bipolar 1 disorder, characterized by their lithium response (n=12), and healthy control subjects (n=6). We identified a cellular phenotype in reprogrammed neurons using a label-free imaging assay based on a nanostructured photonic crystal biosensor and found that an optical measure of cell adhesion was associated with clinical response to lithium treatment. This cellular phenotype may represent a useful biomarker to evaluate drug response and screen for novel therapeutics.

Show MeSH
Related in: MedlinePlus