We investigated the relationship between brain lithium levels and the metabolites N-acetyl aspartate (NAA) and myo-inositol (myo-Ino) in the anterior cingulate cortex of a group of older adults with bipolar disorder (BD).
This cross-sectional assessment included nine subjects (six males and three females) with bipolar I disorder and currently treated with lithium, who were examined at McLean Hospital's Geriatric Psychiatry Research Program and Brain Imaging Center. The subjects' ages ranged from 56 to 85 years (66.0 +/- 9.7 years) and all subjects had measurements of serum and brain lithium levels. Brain lithium levels were assessed using lithium magnetic resonance spectroscopy. All subjects also had proton magnetic resonance spectroscopy to obtain measurements of NAA and myo-Ino.
Brain lithium levels were associated with higher NAA levels [df = (1, 8), Beta = 12.53, t = 4.09, p < 0.005] and higher myo-Ino levels [df = (1, 7), F = 16.81, p < 0.006]. There were no significant effects of serum lithium levels on any of the metabolites.
Our findings of a relationship between higher brain lithium levels and elevated NAA levels in older adult subjects with BD may support previous evidence of lithium's neuroprotective, neurotrophic, and mitochondrial function-enhancing effects. Elevated myo-Ino related to elevated brain lithium levels may reflect increased inositol monophosphatase (IMPase) activity, which would lead to an increase in myo-Ino levels. This is the first study to demonstrate alterations in NAA and myo-Ino in a sample of older adults with BD treated with lithium.
"Structural neuroimaging studies have demonstrated that short- and long-term lithium treatment was associated with increased hippocampal and amygdala volume, and cortical thickness.73–76 In addition, lithium treatment was associated with increased N-acetylaspartate and myo-inositol levels in magnetic resonance spectroscopy.77,78 These neuroimaging findings suggest that long-term lithium treatment may have a significant effect on synaptic density and neuronal vitality in bipolar patients. "
[Show abstract][Hide abstract] ABSTRACT: In the last two decades, a growing body of evidence has shown that lithium has several neuroprotective effects. Several neurobiological mechanisms have been proposed to underlie these clinical effects. Evidence from preclinical studies suggests that neuroprotection induced by lithium is mainly related to its potent inhibition of the enzyme glycogen synthase kinase-3β (GSK-3β) and its downstream effects, ie, reduction of both tau protein phosphorylation and amyloid-β42 production. Additional neuroprotective effects include increased neurotrophic support, reduced proinflammatory status, and decreased oxidative stress. More recently, neuroimaging studies in humans have demonstrated that chronic use is associated with cortical thickening, higher volume of the hippocampus and amygdala, and neuronal viability in bipolar patients on lithium treatment. In line with this evidence, observational and case registry studies have shown that chronic lithium intake is associated with a reduced risk of Alzheimer's disease in subjects with bipolar disorder. Evidence from recent clinical trials in patients with mild cognitive impairment suggests that chronic lithium treatment at subtherapeutic doses can reduce cerebral spinal fluid phosphorylated tau protein. Overall, convergent lines of evidence point to the potential of lithium as an agent with disease modifying properties in Alzheimer's disease. However, additional long-term studies are necessary to confirm its efficacy and safety for these patients, particularly as chronic intake is necessary to achieve the best therapeutic results.
"This decrease in NAA has been reported in several brain regions, extending from sub-cortical brain areas such as the hippocampus and thalamus, through to cortical brain regions (Bertolino et al., 2003; Cecil et al., 2002; Winsberg et al., 2000). Several studies also report no changes in NAA (Brambilla et al., 2004, 2005; Frey et al., 2005; Hamakawa et al., 1998) or find that NAA changes are related to medication status (Forester et al., 2008; Moore et al., 2000; Silverstone et al., 2003). (2) Choline metabolites, detected by 1 H-MRS, include phosphocholine (PCh), glycerophosphocholine (GPC), phosphatidylcholine, sphingomyeline, choline and acetylcholine, which contribute marginally. "
[Show abstract][Hide abstract] ABSTRACT: Background:
Bipolar disorder is characterised by changes in brain metabolites, as measured by (1)H-MRS. However, there is no consistent metabolic profile for bipolar disorder, which includes changes in N-acetyl-aspartate (NAA), choline metabolites and myo-inositol. The aim of the present paper is to add to this literature of (1)H-MRS, the metabolite profiles in bipolar disorder.
Nineteen individuals with euthymic bipolar I disorder and eight control participants were recruited for the present study. (1)H-MRS chemical shift imaging (CSI) was used to measure NAA, choline metabolites and myo-inositol of several bilateral brain areas potentially involved in bipolar disorder: hippocampal complexes, brain stem including the locus coeruleus, and thalami.
Compared with healthy controls, individuals with bipolar I disorder showed increased choline metabolites in bilateral thalami and increased NAA in left hippocampus. The (1)H-MRS data were not influenced by age, symptom severity, or medication status.
Our present findings suggest that individuals with bipolar I disorder have increased phospholipid concentration in the thalami and increased NAA concentration in the left hippocampus. While MRS data on bipolar data remain somewhat inconsistent, the findings here are consistent with other evidence supporting the hypothesis that dysfunctional thalamocortical gating plays a role in bipolar disorder.
Progress in Neuro-Psychopharmacology and Biological Psychiatry 11/2012; 41. DOI:10.1016/j.pnpbp.2012.10.026 · 3.69 Impact Factor
"In the same study, a positive correlation was observed between the clinical improvement and the increment in myo-inositol levels (Zheng et al., 2010). In another study, increased myo-inositol levels were reported after lithium treatment of older adults with bipolar disorder (Forester et al., 2008). There are also negative findings in the literature and further studies are necessary to clarify the usefulness of myo-inositol concentration measurements as a biomarker in patients with mood disorders. "
[Show abstract][Hide abstract] ABSTRACT: Post-mortem histopathological studies report on reduced glial cell numbers in various frontolimbic areas of depressed patients implying that glial loss together with abnormal functioning could contribute to the pathophysiology of mood disorders. Astrocytes are regarded as the most abundant cell type in the brain and known for their housekeeping functions, but as recent developments suggest, they are also dynamic regulators of synaptogenesis, synaptic strength and stability and they control adult hippocampal neurogenesis. The primary aim of this review was to summarize the abundant experimental evidences demonstrating that antidepressant therapies have profound effect on astrocytes. Antidepressants modify astroglial physiology, morphology and by affecting gliogenesis they probably even regulate glial cell numbers. Antidepressants affect intracellular signaling pathways and gene expression of astrocytes, as well as the expression of receptors and the release of various trophic factors. We also assess the potential functional consequences of these changes on glutamate and glucose homeostasis and on synaptic communication between the neurons. We propose here a hypothesis that antidepressant treatment not only affects neurons, but also activates astrocytes, triggering them to carry out specific functions that result in the reactivation of cortical plasticity and can lead to the readjustment of abnormal neuronal networks. We argue here that these astrocyte specific changes are likely to contribute to the therapeutic effectiveness of the currently available antidepressant treatments and the better understanding of these cellular and molecular processes could help us to identify novel targets for the development of antidepressant drugs.
European neuropsychopharmacology: the journal of the European College of Neuropsychopharmacology 05/2012; 23(3). DOI:10.1016/j.euroneuro.2012.04.017 · 4.37 Impact Factor
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