. Possible therapeutic implication of Abeta disturbances in depression. Int J Geriatr Psychiatry. 2007 Sep;22(9):931-2; author reply 930. PubMed.

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  1. The major idea of this letter is that there may be a subtype of treatment-resistant, recurrent depression caused by brain elevation of synaptotoxic oligomeric forms of Aβ, especially Aβ42, that would respond to therapeutic strategies with emerging Aβ-lowering compounds.

    It is clear that the results of the only two studies that have examined plasma Aβ42 levels in elderly depressives are conflicting (Pomara et al., 2006, and Qiu et al., 2007). However, these findings could both be reflective of a disturbance in central Aβ levels, which is the focus of some ongoing investigations. For example, I am aware of ongoing in vivo studies in depressed elderly using PET ligands for Aβ. My own R01 is a longitudinal study looking at plasma and CSF Aβ levels in cognitively intact depressed elderly and controls and their relationship to progressive cognitive decline and AD.

    As you know, there are compelling data from several lines of evidence, including epidemiological and postmortem studies, linking depressive symptoms to increased risk for AD. There are also data suggesting that depressive symptoms may represent a prodromal phase of AD. Since Aβ disturbances may develop decades before the actual manifestation of dementia, it is possible that the neurotransmitter and synaptic dysfunction associated with elevation in Aβ could contribute to the development of depressive symptoms.

    However, recent work by Kang and colleagues (2007) suggests that stress-induced elevation in CRF can also result in increases in interstitial Aβ. Since stress is a well-established risk factor for depression and since depression is known to be accompanied by elevation in CRF, these findings suggest that there could be elevations in brain Aβ in depression secondary to increases in CRF and independent of incipient AD. Thus, both groups might respond to a therapeutic strategy that would lower brain Aβ or attenuate its neurotoxic effects.

    References:

    . Elevation in plasma Abeta42 in geriatric depression: a pilot study. Neurochem Res. 2006 Mar;31(3):341-9. PubMed.

    . Depression is associated with low plasma Abeta42 independently of cardiovascular disease in the homebound elderly. Int J Geriatr Psychiatry. 2007 Jun;22(6):536-42. PubMed.

    . Acute stress increases interstitial fluid amyloid-beta via corticotropin-releasing factor and neuronal activity. Proc Natl Acad Sci U S A. 2007 Jun 19;104(25):10673-8. PubMed.