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Characterization of brain mGluR5 binding in a pilot study of late-life major depressive disorder using positron emission tomography and [¹¹C]ABP688.

ABSTRACT: The metabotropic glutamate receptor subtype 5 (mGluR5) has been implicated in the pathophysiology of mood and anxiety disorders and is a potential treatment target in major depressive disorder (MDD). This study compared brain mGluR5 binding in elderly patients suffering from MDD with that in elderly healthy volunteers using positron emission tomography (PET) and [(11)C]ABP688. Twenty elderly (mean age: 63.0 ± 6.3) subjects with MDD and twenty-two healthy volunteers in the same age range (mean age: 66.4 ± 7.3) were examined with PET after a single bolus injection of [(11)C]ABP688, with many receiving arterial sampling. PET images were analyzed on a region of interest and a voxel level to compare mGluR5 binding in the brain between the two groups. Differences in [(11)C]ABP688 binding between patients with early- and late-onset depression were also assessed. In contrast to a previously published report in a younger cohort, no significant difference in [(11)C]ABP688 binding was observed between elderly subjects with MDD and healthy volunteers. [(11)C]ABP688 binding was also similar between subgroups with early- or late-onset depression. We believe this is the first study to examine mGluR5 expression in depression in the elderly. Although future work is required, results suggest potential differences in the pathophysiology of elderly depression versus depression earlier in life.

SUBMITTER: DeLorenzo C

PROVIDER: S-EPMC5068588 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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Characterization of brain mGluR5 binding in a pilot study of late-life major depressive disorder using positron emission tomography and [¹¹C]ABP688.

DeLorenzo C C Sovago J J Gardus J J Xu J J Yang J J Behrje R R Kumar J S D JS Devanand D P DP Pelton G H GH Mathis C A CA Mason N S NS Gomez-Mancilla B B Aizenstein H H Mann J J JJ Parsey R V RV

Translational psychiatry 20151208

The metabotropic glutamate receptor subtype 5 (mGluR5) has been implicated in the pathophysiology of mood and anxiety disorders and is a potential treatment target in major depressive disorder (MDD). This study compared brain mGluR5 binding in elderly patients suffering from MDD with that in elderly healthy volunteers using positron emission tomography (PET) and [(11)C]ABP688. Twenty elderly (mean age: 63.0 ± 6.3) subjects with MDD and twenty-two healthy volunteers in the same age range (mean ag ...[more]

PMID: 26645628

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Project description:ImportanceMajor depressive disorder (MDD) might involve dopamine (DA) reductions. The DA transporter (DAT) regulates DA clearance and neurotransmission and is sensitive to DA levels, with preclinical studies (including those involving inescapable stressors) showing that DAT density decreases when DA signaling is reduced. Despite preclinical data, evidence of reduced DAT in MDD is inconclusive.ObjectiveUsing a highly selective DAT positron emission tomography (PET) tracer ([11C] altropane), DAT availability was probed in individuals with MDD who were not taking medication. Levels of DAT expression were also evaluated in postmortem tissues from donors with MDD who died by suicide.Design, setting, and participantsThis cross-sectional PET study was conducted at McLean Hospital (Belmont, Massachusetts) and Massachusetts General Hospital (Boston) and enrolled consecutive individuals with MDD who were not taking medication and demographically matched healthy controls between January 2012 and March 2014. Brain tissues were obtained from the Douglas-Bell Canada Brain Bank. For the PET component, 25 individuals with current MDD who were not taking medication and 23 healthy controls recruited from McLean Hospital were included (all provided usable data). For the postmortem component, 15 individuals with depression and 14 healthy controls were considered.InterventionPET scan.Main outcomes and measuresStriatal and midbrain DAT binding potential was assessed. For the postmortem component, tyrosine hydroxylase and DAT levels were evaluated using Western blots.ResultsCompared with 23 healthy controls (13 women [56.5%]; mean [SD] age, 26.49 [7.26] years), 25 individuals with MDD (19 women [76.0%]; mean [SD] age, 26.52 [5.92] years) showed significantly lower in vivo DAT availability in the bilateral putamen and ventral tegmental area (Cohen d range, -0.62 to -0.71), and both reductions were exacerbated with increasing numbers of depressive episodes. Unlike healthy controls, the MDD group failed to show an age-associated reduction in striatal DAT availability, with young individuals with MDD being indistinguishable from older healthy controls. Moreover, DAT availability in the ventral tegmental area was lowest in individuals with MDD who reported feeling trapped in stressful circumstances. Lower DAT levels (and tyrosine hydroxylase) in the putamen of MDD compared with healthy controls were replicated in postmortem analyses (Cohen d range, -0.92 to -1.15).Conclusions and relevanceMajor depressive disorder, particularly with recurring episodes, is characterized by decreased striatal DAT expression, which might reflect a compensatory downregulation due to low DA signaling within mesolimbic pathways.

Project description:Importance:Monoamine oxidase B (MAO-B) is an important, high-density enzyme in the brain that generates oxidative stress by hydrogen peroxide production, alters mitochondrial function, and metabolizes nonserotonergic monoamines. Recent advances in positron emission tomography radioligand development for MAO-B in humans enable highly quantitative measurement of MAO-B distribution volume (MAO-B VT), an index of MAO-B density. To date, this is the first investigation of MAO-B in the brain of major depressive disorder that evaluates regions beyond the raphe and amygdala. Objective:To investigate whether MAO-B VT is elevated in the prefrontal cortex in major depressive episodes (MDEs) of major depressive disorder. Design, Setting, and Participants:This case-control study was performed at a tertiary care psychiatric hospital from April 1, 2014, to August 30, 2018. Twenty patients with MDEs without current psychiatric comorbidities and 20 age-matched controls underwent carbon 11-labeled [11C]SL25.1188 positron emission tomography scanning to measure MAO-B VT. All participants were drug and medication free, nonsmoking, and otherwise healthy. Main Outcomes and Measures:The MAO-B VT in the prefrontal cortex (PFC). The second main outcome was to evaluate the association between MAO-B VT in the PFC and duration of major depressive disorder illness. Results:Twenty patients with MDEs (mean [SD] age, 34.2 [13.2] years; 11 women) and 20 healthy controls (mean [SD] age, 33.7 [13.1] years; 10 women) were recruited. Patients with MDEs had significantly greater MAO-B VT in the PFC (mean, 26%; analysis of variance, F1,38 = 19.6, P < .001). In individuals with MDEs, duration of illness covaried positively with MAO-B VT in the PFC (analysis of covariance, F1,18 = 15.2, P = .001), as well as most other cortex regions and the thalamus. Conclusions and Relevance:Fifty percent (10 of 20) of patients with MDEs had MAO-B VT values in the PFC exceeding those of healthy controls. Greater MAO-B VT is an index of MAO-B overexpression, which may contribute to pathologies of mitochondrial dysfunction, elevated synthesis of neurotoxic products, and increased metabolism of nonserotonergic monoamines. Hence, this study identifies a common pathological marker associated with downstream consequences poorly targeted by the common selective serotonin reuptake inhibitor treatments. It is also recommended that the highly selective MAO-B inhibitor medications that are compatible for use with other antidepressants and have low risk for hypertensive crisis should be developed or repurposed as adjunctive treatment for MDEs.

Project description:BackgroundMesolimbic dopamine system dysfunction is believed to contribute to major depressive disorder (MDD), but molecular neuroimaging of striatal dopamine neurotransmission has yielded mixed results, possibly owing to limited sensitivity of antagonist radioligands used with positron emission tomography to assess dopamine release capacity. This study used an agonist radioligand with agonist challenge to assess dopamine release capacity and D2/D3 receptor availability in MDD.MethodsTwenty-six treatment-naive adults with MDD and 26 healthy comparison participants underwent functional magnetic resonance imaging during a probabilistic reinforcement task, and positron emission tomography with the D3-preferring ligand [11C]-(+)-PHNO, before and after oral dextroamphetamine. MDD participants then received pramipexole treatment for 6 weeks.ResultsMDD participants had trend-level greater dopamine release capacity in the ventral striatum, as measured by percent change in baseline binding potential relative to nondisplaceable compartment (ΔBPND) (-34% vs. -30%; p = .072, d = 0.58) but no difference in D2/D3 receptor availability (BPND). Striatal and extrastriatal BPND and percent change in baseline BPND were not significantly associated with blood oxygen level-dependent response to reward prediction error in the ventral striatum, severity of depression and anhedonia, or antidepressant response to pramipexole (response rate = 72.7%).Conclusions[11C]-(+)-PHNO demonstrated high sensitivity to displacement by amphetamine-induced dopamine release, but dopamine release capacity and D2/D3 availability were not associated with ventral striatal activation to reward prediction error or clinical features, in this study powered to detect large effects. While a preponderance of indirect evidence implicates dopaminergic dysfunction in MDD, these findings suggest that presynaptic dopamine dysregulation may not be a feature of MDD or a prerequisite for treatment response to dopamine agonists.

Dataset Information

Characterization of brain mGluR5 binding in a pilot study of late-life major depressive disorder using positron emission tomography and [¹¹C]ABP688.

Publications

Characterization of brain mGluR5 binding in a pilot study of late-life major depressive disorder using positron emission tomography and [¹¹C]ABP688.

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