Our study shows that, when compared with non-depressed, non-demented elderly, subjects with LLD have significantly reduced volumes of multiple areas of the brain, predominantly in the frontal orbital and medial regions, as well as in the entire temporal lobe and the limbic system (hippocampus, amygdala, parahippocampal area). The parietal area adjacent to the temporal cortex is also significantly smaller in subjects with LLD. These results are congruent with previous reports from the literature (Bremner, 2005
), describing changes in orbito-frontal cortex (Ballmaier et al, 2004
; Coffey et al, 1993
), inferior parietal (Ballmaier et al, 2004
), hippocampus (Bell-McGinty et al, 2002
; Sheline et al, 1996
; Videbech and Ravnkilde, 2004
), amygdala (Sheline et al, 1998
) and putamen (Husain et al, 1991
The distribution of changes is concordant with a recent hypothesis implicating a limbic–cortical–striatal–pallidal– thalamic (LCSPT) circuit described in association with early-onset recurrent depression (Sheline, 2003
). Similarly, a functional circuit involving these limbic-cortical regions has also been described (Mayberg, 2007
). Our study suggests that these circuits, documented through the convergent findings of functional and structural imaging approaches, are also involved in LLD (Mayberg, 2007
Our findings indicate an extensive neuroanatomical substrate, with multiple areas involved in the morphologic changes associated with LLD. These results can be interpreted according to the two most prevalent hypotheses, the toxic stress, and the dementia prodrome. According to the toxic-stress hypothesis of depression, high levels of glucocorticoids (McEwen, 1997
; Sapolsky, 1993
) induce shrinking of the highly sensitive hippocampal gray matter (Sapolsky et al, 1985
; Sheline et al, 1999
; Steffens et al, 2000
; Videbech and Ravnkilde, 2004
). According to the prodromal dementia hypothesis of LLD, a subgroup of subjects develops LLD as a very early clinical presentation of dementia (Alexopoulos et al, 1993
; O’Brien et al, 2004
; Steffens et al, 2000
). In this case, lower volumes would be interpreted as a marker of neuronal loss related to an as yet undeclared neurodegenerative or vascular process (Alexopoulos et al, 1993
; Greenwald et al, 1997
). Most findings supporting this theory have been described in left medial temporal lobe (Greenwald et al, 1997
), left caudate (Greenwald et al, 1997
; Krishnan et al, 1992
), anterior cingulate (Drevets et al, 1997
), and putamen (Husain et al, 1991
Both hypotheses predict smaller hippocampal volumes, but diverge when predicting the relationship between hippocampus and age of onset/duration of illness. According to the toxic-stress hypothesis, a younger age of onset and a longer duration of illness would be associated with smaller hippocampal volume due to longer exposure to toxic levels of cortisol (Sheline et al, 1996
). By contrast, according to the dementia prodrome hypothesis, an older age of onset and a shorter duration of illness would be associated with smaller hippocampal volumes due to atrophy related to neurodegeneration or vascular lesions (Steffens et al, 2000
While the differences in our sample between LLD subjects and comparison subjects do not conclusively demonstrate the validity of either the toxic or the prodromal theory of depression, the correlation with the total shorter duration of illness/later age of onset of depression would be more consistent with the prodromal dementia hypothesis of depression rather than the toxic-stress hypothesis in this group of subjects.
Our findings regarding the correlation with age of onset/ duration of illness contrast with previous reports from our group (Bell-McGinty et al, 2002
). These differences may be related to several factors including our 2.3 times larger sample and the different sample profile. Our sample has a different gender ratio (more women) and contains older subjects with a slightly worse cognitive performance. Also, we used a different MR analytic paradigm—ALP, while the previous report used voxel-based morphometry. Nevertheless, the volumetric differences between LLD subjects and comparison subjects confirm the previous report (Bell-McGinty et al, 2002
For this group of LLD subjects, these findings do not support toxic stress as the predominant mechanism of volumetric changes because the reduced volumes of ROIs were correlated with a shorter duration of the total illness and/or a later age of onset. This pattern is the opposite expected as a result of chronic exposure to high levels of cortisol. In other words, subjects who develop depression de novo at an older age seem to be more likely to have an underlying process, either vascular or degenerative or both, that may trigger the onset of depression through affecting one or several stations on the limbic–cortical– striatal–pallidal–thalamic circuit.
It is important to emphasize that we do not consider these two models as the only two compelling etiopathogenic hypotheses for LLD. Biological pathways of LLD occur in the specific psychosocial context of old age (including increased medical burden and social support network diminution). Our intention was to characterize brain volumetric changes in relation to these two hypotheses regarding the neurobiological substrate of LLD. Also, the toxic stress hypothesis and the dementia prodrome hypothesis are not mutually exclusive, as these two phenomena can operate in parallel and/or in sequence. Our study’s design did not allow us to identify the cases with both toxic stress and vascular/neurodegenerative changes.
Our study has several strengths, including a relatively large group of participants compared with other structural MRI analyses in late life depression, which typically have samples of 20–50 participants (Ballmaier et al, 2004
; Lavretsky et al, 2007
). This allowed us to control for age-related structural changes of the gray matter. We used a phenotypically homogenous sample (subjects were all selected by strictly defined inclusion and exclusion criteria), which reduced the variance due to differences in clinical presentations. We used the ALP volumetric method, which is ideal for assessing neuroanatomical correlates of dementia risk in large epidemiological studies, because of its fully automated design. We have recently shown that ALP can detect significantly smaller global and focal gray matter volumes in demented compared to cognitively normal, even in small study groups (Rosano et al, 2005
). The ALP technique has several advantages: (1) it can analyze the entire brain, utilizing previously published, and validated neuroanatomical boundaries; (2) the fully automated design allows for quality control interventions in extreme cases, such as massive brain atrophy or focal brain tumors; (3) ALP provides individual volumetric measures of single ROI’s, as well as group differences for either single or multiple ROI’s.
Our study, however, has some limitations. We did not compare gender-related volumetric changes and there is variability in time between study entry and the MRI scanning. It is highly unlikely that significant changes in the volumes would emerge during the several weeks between enrolment and scanning. Some patients were receiving psychotropic medications at baseline, including benzodiazepines (see ). However, we have no data regarding the chronicity of benzodiazepine use or the compliance with treatment. Moreover, neuroimaging studies failed to report any brain abnormalities in subjects treated long term with benzodiazepines (Busto et al, 2000
). Also, at this time, we chose not to analyze the laterality of the changes, mainly to protect against Type I Error inflation, but also because most studies do not report lateralized findings (Ballmaier et al, 2004
) or they suggest an attenuation of the ‘normal’ volumetric asymmetry (Kumar et al, 2000
). Also, albeit significantly statistic, some of the correlations we report are not very strong—the only regions that have correlations >0.3 with age of onset are frontal superior, parahippocampal, and parietal inferior. Overall, the variable strength of these correlations might suggest rather subtle and uneven changes of volumetric gray matter in LLD. Another possible limitation concerns the reliability of determining the actual age of lifetime onset of major depression in 70- and 80-year-old subjects, who are prone to errors of recall and suggestions. To overcome this we used structured interviews and we corroborated information from family members and past medical record, when available. However, given this limitation, our findings should be regarded with caution.
Further research is needed with large groups of depressed subjects using a lifespan approach to identify characteristics that may confer individual vulnerability to toxic stress, and/or a vascular or degenerative process. Further, research is also needed to obtain more precise associations between clinical presentation, longitudinal evolution of LLD, and mapping of the specific volumetric changes in different areas of the brain.