Abnormality in serum levels of mature brain-derived neurotrophic factor (BDNF) and its precursor proBDNF in mood-stabilized patients with bipolar disorder: a study of two independent cohorts.
BACKGROUND
Early detection and diagnosis of bipolar disorder can be difficult. Tools are needed to help clinicians detect bipolar disorder earlier, which would ameliorate the prognosis.


METHODS
ELISA kits that distinguish between mature brain derived neurotrophic factor (BDNF) and proBDNF, we compared serum levels of mature BDNF, proBDNF, and matrix metalloproteinase-9 (MMP-9) in two independent cohorts (Sahlgrenska cohort and Karolinska cohort) of mood-stabilized bipolar patients and healthy controls. The total sample size in both cohorts consisted of 263 (48+215) bipolar patients and 155 (43+112) healthy controls.


RESULTS
Levels of mature BDNF and the ratio mature BDNF/proBDNF were significantly higher in patients than in controls. Serum levels of proBDNF were significantly lower in patients compared to controls. Serum levels of MMP-9 did not differ between the groups but MMP-9 correlated positively and significantly with mature BDNF. Mature BDNF, proBDNF, the ratio of mature BDNF/proBDNF and interactions with MMP-9 explained the diagnostic dichotomy in both cohorts with high significance, using multivariate logistic ANCOVA (gender, age, and BMI were covaried out). The model explained 41% of the diagnostic variance in the Sahlgrenska cohort (p<0.0001) and 15% in the Karolinska cohort (p<0.0001). In both cohorts, the equations provided good power for diagnostic classification. The diagnostic sensitivity was 89% in the Sahlgrenska and 74% in the Karolinska cohort, and specificity 77% and 64%, respectively.


CONCLUSIONS
The study is cross-sectional with no longitudinal follow up. The cohorts are relatively small with no medication-free patients. There are no "ill patient controls".


CONCLUSIONS
Abnormalities in the conversion of proBDNF to mature BDNF may be associated with pathogenesis of bipolar disorder. Clinical use of these biomarkers may provide opportunities for earlier detection and correct treatment.
Institute of Neuroscience and Physiology, Section of Psychiatry and Neurochemistry, University of Gothenburg, Gothenburg SE-416 85, Sweden. Electronic address: kristoffer.sodersten@gu.se.
Kristoffer
K
Södersten
Institute of Neuroscience and Physiology, Section of Psychiatry and Neurochemistry, University of Gothenburg, Gothenburg SE-416 85, Sweden.
Erik
E
Pålsson
Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan.
Tamaki
T
Ishima
Sahlgrenska Cancer Center, University of Gothenburg, Gothenburg, Sweden.
Keiko
K
Funa
Institute of Neuroscience and Physiology, Section of Psychiatry and Neurochemistry, University of Gothenburg, Gothenburg SE-416 85, Sweden; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
Mikael
M
Landén
Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan.
Kenji
K
Hashimoto
Institute of Neuroscience and Physiology, Section of Psychiatry and Neurochemistry, University of Gothenburg, Gothenburg SE-416 85, Sweden.
Hans
H
Ågren
D000328:Adult; D015415:Biomarkers / Q000097:blood; D001714:Bipolar Disorder / Q000097:blood* / Q000175:diagnosis / Q000523:psychology; D019208:Brain-Derived Neurotrophic Factor / Q000097:blood*; D016022:Case-Control Studies; D015331:Cohort Studies; D003430:Cross-Sectional Studies; D005260:Female; D006801:Humans; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000097:blood; D008875:Middle Aged
D015415:Biomarkers; D019208:Brain-Derived Neurotrophic Factor; D020780:Matrix Metalloproteinase 9
Biomarker; Bipolar disorder; Diagnosis; Mature BDNF; Serum; proBDNF