Abstract
Major depressive disorder (MDD), common in the elderly, is a risk factor for dementia. Abnormalities in glutamatergic neurotransmission via the N-methyl-d-aspartate receptor (NMDA-R) have a key role in the pathophysiology of depression. This study examined whether depression was associated with cerebrospinal fluid (CSF) levels of NMDA-R neurotransmission-associated amino acids in cognitively intact elderly individuals with MDD and age- and gender-matched healthy controls. CSF was obtained from 47 volunteers (MDD group, N=28; age- and gender-matched comparison group, N=19) at baseline and 3-year follow-up (MDD group, N=19; comparison group, N=17). CSF levels of glutamine, glutamate, glycine, l-serine and d-serine were measured by high-performance liquid chromatography. CSF levels of amino acids did not differ across MDD and comparison groups. However, the ratio of glutamine to glutamate was significantly higher at baseline in subjects with MDD than in controls. The ratio decreased in individuals with MDD over the 3-year follow-up, and this decrease correlated with a decrease in the severity of depression. No correlations between absolute amino-acid levels and clinical variables were observed, nor were correlations between amino acids and other biomarkers (for example, amyloid-β42, amyloid-β40, and total and phosphorylated tau protein) detected. These results suggest that abnormalities in the glutamine–glutamate cycle in the communication between glia and neurons may have a role in the pathophysiology of depression in the elderly. Furthermore, the glutamine/glutamate ratio in CSF may be a state biomarker for depression.
Highlights
Late-life depression, one of the most common psychiatric disorders in older adults, is associated with significant functional impairment, variable treatment response, high recurrence rates, chronicity and high rates of medical comorbidity and mortality.[1,2] Multiple lines of evidence suggest that late-life depression is a risk factor for the development of dementia, including Alzheimer’s disease (AD) and vascular dementia.[2,3,4] the precise molecular mechanisms underlying the relationship between latelife depression and dementia risk remain unknown
As the abnormalities in N-methyl-D-aspartate receptor (NMDA-R) neurotransmission by altered glutamine–glutamate cycle in the brain may be involved in the pathophysiology of major depressive disorder (MDD),[5,6] it is of great interest to examine cerebrospinal fluid (CSF) levels of amino acids related with NMDA-R in elderly patients with MDD, and age- and gender-matched no differences in amyloid-β42 levels were observed within the MDD group as a function of antidepressant treatment.[26]
We found that older individuals with MDD showed an increased CSF glutamine/glutamate ratio compared with controls, CSF levels of the individual amino acids were not different
Summary
Late-life depression, one of the most common psychiatric disorders in older adults, is associated with significant functional impairment, variable treatment response, high recurrence rates, chronicity and high rates of medical comorbidity and mortality.[1,2] Multiple lines of evidence suggest that late-life depression is a risk factor for the development of dementia, including Alzheimer’s disease (AD) and vascular dementia.[2,3,4] the precise molecular mechanisms underlying the relationship between latelife depression and dementia risk remain unknown. Abnormality of glutamine–glutamate cycle in elderly depression K Hashimoto et al communication.[5,6,8,23,24] As the abnormalities in NMDA-R neurotransmission by altered glutamine–glutamate cycle in the brain may be involved in the pathophysiology of MDD,[5,6] it is of great interest to examine CSF levels of amino acids related with NMDA-R in elderly patients with MDD, and age- and gender-matched no differences in amyloid-β42 levels were observed within the MDD group as a function of antidepressant treatment.[26] Clinical data, including physical examination, routine laboratory tests, psychiatric evaluations, HAM-D rating scale, cognitive functions and CSF samples, were collected at 3-year follow-up.
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