Dataset Information

Levothyroxine effects on depressive symptoms and limbic glucose metabolism in bipolar disorder: a randomized, placebo-controlled positron emission tomography study.

ABSTRACT: Adding supraphysiologic doses of levothyroxine (L-T4) to standard treatment for bipolar depression shows promise, but the mechanisms underlying clinical improvement are unknown. In a previous pilot study, L-T4 treatment reduced depression scores and activity within the anterior limbic network. Here we extended this work in a randomized, double-blind, placebo-controlled study of patients with bipolar depression. Cerebral glucose metabolism was assessed with positron emission tomography and [F-18]fluorodeoxyglucose before and after 6 weeks of treatment with L-T4 (n=15) or placebo (n=10) in 12 volumes of interest (VOIs): the bilateral thalamus, amygdala, hippocampus, dorsal striatum and ventral striatum, and midline cerebellar vermis and subgenual cingulate cortex. Radioactivity in the VOIs, normalized to whole-brain radioactivity was taken as a surrogate index of glucose metabolism, and markers of thyroid function were assayed. Changes in brain activity and their association with clinical response were assessed using statistical parametric mapping. Adjunctive L-T4 treatment produced a significant decline in depression scores during the 6-week treatment. In patients treated with L-T4, we found a significant decrease in regional activity at P<0.05 after Bonferroni correction in the left thalamus, right amygdala, right hippocampus, left ventral striatum and the right dorsal striatum. Decreases in the left thalamus, left dorsal striatum and the subgenual cingulate were correlated with a reduction in depression scores (P<0.05 after Bonferroni correction). Placebo treatment was associated with a significant decrease in activity only in the right amygdala, and no region had a change in activity that was correlated with change in depression scores. The groups differed significantly in the relationship between the changes in depression scores and in activity in the thalamus bilaterally and the left ventral striatum. The findings provide evidence that administration of supraphysiologic thyroid hormone improves depressive symptoms in patients with bipolar disorder by modulating function in components of the anterior limbic network.

SUBMITTER: Bauer M

PROVIDER: S-EPMC4790155 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Levothyroxine effects on depressive symptoms and limbic glucose metabolism in bipolar disorder: a randomized, placebo-controlled positron emission tomography study.

Bauer M M Berman S S Stamm T T Plotkin M M Adli M M Pilhatsch M M London E D ED Hellemann G S GS Whybrow P C PC Schlagenhauf F F

Molecular psychiatry 20150120 2

Adding supraphysiologic doses of levothyroxine (L-T4) to standard treatment for bipolar depression shows promise, but the mechanisms underlying clinical improvement are unknown. In a previous pilot study, L-T4 treatment reduced depression scores and activity within the anterior limbic network. Here we extended this work in a randomized, double-blind, placebo-controlled study of patients with bipolar depression. Cerebral glucose metabolism was assessed with positron emission tomography and [F-18] ...[more]

PMID: 25600111

Similar Datasets

Project description:Fluorine-18-fluoro-2-deoxy-D-glucose (FDG) is widely used as positron-emission-tomography (PET) radiotracer for the detection and staging of human cancer. Tumor uptake of FDG varies substantially between different cancer types and between patients with the same tumor type. The molecular basis for this heterogeneity is unknown. Using cancer cell lines and primary human tumors of distinct histologic origins, we here show that increased FDG uptake is universally associated with coordinate upregulation of genes within the glycolysis, pentose-phosphate, and other related metabolic pathways. In primary human breast cancers, this FDG signature shows significant overlap with established breast cancer signatures for the “basal-like” disease subtype and “poor prognosis”. FDG high breast cancer showed significantly more gene copy number alterations genome wide than FDG low cancers. About 50 % of primary breast cancers with high FDG uptake and FDG gene expression signature show DNA copy gain encompassing the c-myc gene locus and express gene sets regulated by the transcription factor MYC. Our data shows that FDG-PET marks a distinct subset of “basal-like” human breast cancer which is characterized by MYC and prognostically unfavorable gene expression signatures, suggesting that FDG-PET imaging may be useful to risk-stratify patients with locally advanced breast cancer. Our general strategy to identify molecular determinants of FDG-retention through a genome-wide approach consisted of FDG uptake measurements in cancer cell lines and primary human tumors, the selection of samples with particularly high versus low FDG-retention, and subsequent pathway-based analysis of RNA expression data collected from these samples. Cell line RNA was extracted from a 10 cm plate seeded simultaneously and at the same density as the wells for FDG-uptake assays. For primary human tumor samples, RNA was extracted from macrodissected frozen tumor tissue. All cell line RNA samples and the astrocytoma RNA aliquots were hybridized to Affymetrix U133 Plus 2.0 arrays. All primary breast cancer RNA samples were hybridized to Affymetrix U133A arrays.

Project description:Subthalamic nucleus (STN) deep brain stimulation (DBS) can improve motor symptoms in Parkinson's disease (PD), as well as potentially improving otherwise intractable comorbid depressive symptoms. To address the latter issue, we evaluated the severity of depressive symptoms along with the severity of motor symptoms in 18 PD patients (mean age, 58.4 ± 5.4 years; 9 males, 9 females; mean PD duration, 9.4 ± 4.4 years) with treatment-resistant depression (TRD) before and after approximately 1 year of STN-DBS treatment. Moreover, to gain more insight into the brain mechanism mediating the therapeutic action of STN-DBS, we utilized 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) to assess cerebral regional glucose metabolism in the patients at baseline and 1-year follow-up. Additionally, the baseline PET data from patients were compared with PET data from an age- and sex-matched control group of 16 healthy volunteers. Among them, 12 PD patients underwent post-operative follow-up PET scans. Results showed that the severity of both motor and depressive symptoms in patients with PD-TRD was reduced significantly at 1-year follow-up. Also, patients used significantly less antiparkinsonian medications and antidepressants at 1-year follow-up, as well as experiencing improved daily functioning and a better quality of life. Moreover, relative to the PET data from healthy controls, PD-TRD patients displayed widespread abnormalities in cerebral regional glucose metabolism before STN-DBS treatment, which were partially recovered at 1-year follow-up. Additionally, significant correlations were observed between the patients' improvements in depressive symptoms following STN-DBS and post-operative changes in glucose metabolism in brain regions implicated in emotion regulation. These results support the view that STN-DBS provides a promising treatment option for managing both motor and depressive symptoms in patients who suffer from PD with TRD. However, the results should be interpreted with caution due to the observational nature of the study, small sample size, and relatively short follow-up.

Project description:KEY POINTS:The goal was to determine the importance of the sodium-glucose cotransporter SGLT1 and the glucose uniporter GLUT2 in intestinal glucose absorption during oral glucose tolerance tests (OGTTs) in mice. Glucose absorption was determined in mice using positron emission tomography and three non-metabolizable glucose probes: one specific for SGLTs, one specific for GLUTs, and one a substrate for both SGLTs and GLUTs. Absorption was determined in wild-type, Sglt1-/- and Glut2-/- mice. Gastric emptying was a rate-limiting step in absorption. SGLT1, but not GLUT2, was important in fast glucose absorption. In the absence of SGLT1 or GLUT2, the oral glucose load delivered to the small intestine was slowly absorbed. Oral phlorizin only inhibited the fast component of glucose absorption, but it contributed to decreasing blood glucose levels by inhibiting renal reabsorption. ABSTRACT:The current model of intestinal absorption is that SGLT1 is responsible for transport of glucose from the lumen into enterocytes across the brush border membrane, and GLUT2 for the downhill transport from the epithelium into blood across the basolateral membrane. Nevertheless, questions remain about the importance of these transporters in vivo. To address these questions, we have developed a non-invasive imaging method, positron emission tomography (PET), to monitor intestinal absorption of three non-metabolized glucose tracers during standard oral glucose tolerance tests (OGTTs) in mice. One tracer is specific for SGLTs (α-methyl-4-[18 F]fluoro-4-deoxy-d-glucopyranoside; Me-4FDG), one is specific for GLUTs (2-deoxy-2-[18 F]fluoro-d-glucose; 2-FDG), and one is a substrate for both SGLTs and GLUTs (4-deoxy-4-[18 F]fluoro-d-glucose; 4-FDG). OGTTs were conducted on adult wild-type, Sglt1-/- and Glut2-/- mice. In conscious mice, OGTTs resulted in the predictable increase in blood glucose that was blocked by phlorizin in both wild-type and Glut2-/- animals. The blood activity of both Me-4FDG and 4-FDG, but not 2-FDG, accompanied the changes in glucose concentration. PET imaging during OGTTs further shows that: (i) intestinal absorption of the glucose load depends on gastric emptying; (ii) SGLT1 is important for the fast absorption; (iii) GLUT2 is not important in absorption; and (iv) oral phlorizin reduces absorption by SGLT1, but is absorbed and blocks glucose reabsorption in the kidney. We conclude that in standard OGTTs in mice, SGLT1 is essential in fast absorption, GLUT2 does not play a significant role, and in the absence of SGLT1 the total load of glucose is slowly absorbed.

Project description:ImportanceThe recent proliferation of phosphorylated tau (p-tau) biomarkers has raised questions about their preferential association with the hallmark pathologies of Alzheimer disease (AD): amyloid-β plaques and tau neurofibrillary tangles.ObjectiveTo determine whether cerebrospinal fluid (CSF) and plasma p-tau biomarkers preferentially reflect cerebral β-amyloidosis or neurofibrillary tangle aggregation measured with positron emission tomography (PET).Design, setting, and participantsThis was a cross-sectional study of 2 observational cohorts: the Translational Biomarkers in Aging and Dementia (TRIAD) study, with data collected between October 2017 and August 2021, and the Alzheimer's Disease Neuroimaging Initiative (ADNI), with data collected between September 2015 and November 2019. TRIAD was a single-center study, and ADNI was a multicenter study. Two independent subsamples were derived from TRIAD. The first TRIAD subsample comprised individuals assessed with CSF p-tau (p-tau181, p-tau217, p-tau231, p-tau235), [18F]AZD4694 amyloid PET, and [18F]MK6240 tau PET. The second TRIAD subsample included individuals assessed with plasma p-tau (p-tau181, p-tau217, p-tau231), [18F]AZD4694 amyloid PET, and [18F]MK6240 tau PET. An independent cohort from ADNI comprised individuals assessed with CSF p-tau181, [18F]florbetapir PET, and [18F]flortaucipir PET. Participants were included based on the availability of p-tau and PET biomarker assessments collected within 9 months of each other. Exclusion criteria were a history of head trauma or magnetic resonance imaging/PET safety contraindications. No participants who met eligibility criteria were excluded.ExposuresAmyloid PET, tau PET, and CSF and plasma assessments of p-tau measured with single molecule array (Simoa) assay or enzyme-linked immunosorbent assay.Main outcomes and measuresAssociations between p-tau biomarkers with amyloid PET and tau PET.ResultsA total of 609 participants (mean [SD] age, 66.9 [13.6] years; 347 female [57%]; 262 male [43%]) were included in the study. For all 4 phosphorylation sites assessed in CSF, p-tau was significantly more closely associated with amyloid-PET values than tau-PET values (p-tau181 difference, 13%; 95% CI, 3%-22%; P = .006; p-tau217 difference, 11%; 95% CI, 3%-20%; P = .003; p-tau231 difference, 15%; 95% CI, 5%-22%; P < .001; p-tau235 difference, 9%; 95% CI, 1%-19%; P = .02) . These results were replicated with plasma p-tau181 (difference, 11%; 95% CI, 1%-22%; P = .02), p-tau217 (difference, 9%; 95% CI, 1%-19%; P = .02), p-tau231 (difference, 13%; 95% CI, 3%-24%; P = .009), and CSF p-tau181 (difference, 9%; 95% CI, 1%-21%; P = .02) in independent cohorts.Conclusions and relevanceResults of this cross-sectional study of 2 observational cohorts suggest that the p-tau abnormality as an early event in AD pathogenesis was associated with amyloid-β accumulation and highlights the need for careful interpretation of p-tau biomarkers in the context of the amyloid/tau/neurodegeneration, or A/T/(N), framework.

Dataset Information

Levothyroxine effects on depressive symptoms and limbic glucose metabolism in bipolar disorder: a randomized, placebo-controlled positron emission tomography study.

Publications

Levothyroxine effects on depressive symptoms and limbic glucose metabolism in bipolar disorder: a randomized, placebo-controlled positron emission tomography study.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets