³¹Phosphorus magnetic resonance spectroscopy study of tissue specific changes in high energy phosphates before and after sertraline treatment of geriatric depression

Abstract

SUMMARYIntroduction We investigated tissue specific differences in markers of energy metabolism, including high energy phosphate compounds (beta and total NTP, PCr) and pH, in older adults with depression compared with healthy controls, before and after a 12-week treatment trial of sertraline. Methods Thirteen older adults, age !55, with Major Depressive Disorder (HAMD 17 score of !18) were recruited along with ten age-matched controls. The depression subjects had a pre-and post-treatment 4T 31 P-MRS scan using a threedimensional chemical shift imaging sequence. The extracted brain images were segmented into white matter (WM), gray matter (GM) and CSF. A linear mixed effects model analyzed the effects of pre-treatment and post-treatment depression on phosphorus metabolite concentration estimates (including calculated pH and Mg þþ ). Results Total tissue beta-NTP (À8%, t(18.66) ¼ 3.50; p ¼ 0.0024) and total tissue total NTP (À6%, t(17.41) ¼ 2.68; p ¼ 0.0156) were lower in subjects with geriatric depression compared with healthy controls. Total tissue levels of total-NTP changed significantly with treatment (À2%, t(14.84) ¼ À2.47; p ¼ 0.0259). Total NTP was reduced in the WM, but not the GM, in the pre-treatment depression group (t(51.65) ¼ 4.02; p ¼ 0.0002). Intracellular pH was higher in the GM of subjects with pre-treatment depression (t(1133.84) ¼ À2.10; p ¼ 0.0353) and decreased to approximate control levels after treatment (t(648.86) ¼ À2.53; p ¼ 0.0115). Discussion These findings demonstrate bioenergetic changes including tissue specific differences in 31 P-MRS metabolites in geriatric depression. Decreased white matter total NTP may reflect alterations in white matter function.

Tissue Type-Specific Bioenergetic Abnormalities in Adults with Major Depression

“…Phosphorus 31 P 3D-CSI was done using the following acquisition parameters: TR = 500 ms; tip-angle = 32 degrees; Rx bandwidth = ± 2 kHz; complex-points = 1024; readout duration = 256 ms; pre-pulses = 10; pre-acquisition delay = 1.905 ms; FOV (x,y,z) = 330 mm; nominal volume = 13.1 cc; maximum phase-encode matrix dimension (x,y,z) 14 × 14 × 14 (zero-filled out to 16 × 16 × 16 prior to reconstruction) as described in our prior publications (Forester et al, 2009;Harper et al, 2014).…”

“…Briefly, the spatially resolved, 31 P 3D-CSI grid was co-registered with the axial T1-weighted images such that the grid was centered midsagittally inside the brain according to anatomical landmarks in both the sagittal and axial planes and a 4 × 7 × 3 matrix of voxels was centered within the brain as described in our prior publications (Forester et al, 2009;Harper et al, 2014).…”

“…For 31 P 3D-CSI spectral fitting, we used a spectral time-domain fitting program, based on the Marquardt-Levenberg non-linear, least squares algorithm, incorporating prior knowledge of spectral peak assignments, chemical-shifts, and J-coupling constants as described in our prior publications (Forester et al, 2009;Harper et al, 2014;Jensen et al, 2002). Representative data are shown in Figure 1.…”

“…This factor could partially explain discrepant findings in PCr as different sampling regions likely have different tissue compositions. 3-dimensional chemical shift imaging (3D-CSI) allows for quantification of energetic metabolites in a three-dimensional matrix of voxels over the whole brain allowing for the use of segmentation information to derive gray matter and white matter metabolite estimates (Forester et al, 2009;Hetherington et al, 2001;Mason et al, 1998).…”

“…We hypothesized, based on our previous data (Forester et al, 2009), that differences in bioenergetic metabolites between depressed and normal subjects would be tissue class specific (white vs gray matter). We further hypothesized a reduction in β-NTP (which in the brain largely represents ATP), and a compensatory increase in PCr in adult MDD subjects, consistent with our previous results (Iosifescu et al, 2008).…”