To our knowledge, this is the first study to use a volumetric MRI-based parcellation method of the prefrontal cortex to examine the patterns of neuroanatomical changes associated with apathy in older patients with major depression and age-matchednormal comparison group. We found an association between depression and gray matter volumes in the right and left orbitofrontal cortex. However, the severity of apathy was associated with reduced gray matter volumes in the anterior cingulate.
Overall, our findings are consistent with the expected alteration in the anterior cingulate and prefrontal cortex implicated in the pathophysiology of apathy9,16,18,35
in older adults. Unfortunately, prior reports included only subjects with Alzheimer disease and related dementias,35-37,47
which complicates the comparison of our results to other studies.
Interestingly, we did not find an association between the AES scores and orbitofrontal volume. This suggests that the orbitofrontal cortex is involved in the mediation of depressed mood but not apathy, and the anterior cingulate cortices involvement in the mediation of apathy.34
We doubt that this result can be attributed to the interaction between the apathy and depression because we combined the two study groups and controlled for the diagnosis. It is possible that having decreased anterior cingulate volumes can predispose one to the development of apathy in the context of a depressive syndrome.
In our prior study of a subset of depressed elderly subjects with early-onset depression, we reported significant bilateral reduction in the gray matter volumes in the anterior cingulate and the orbitofrontal cortex.30
However, the overlap in the clinical features of depression and apathy was not addressed in the previous reports.30,43
Our current findings are consistent with our previous reports in smaller samples implicating dorsolateral prefrontal and orbital fron-tal cortex (OFC) in the pathophysiology of depression.15,48,49
However, we did not find group differences in the anterior cingulate volumes that could be due to combining subjects with early- and late-onset depression, or those with a single episode and recurrent depression in the current sample.
In geriatric depression, marked volumetric reductions in the prefrontal cortex and OFC were observed in MRI data.50
Moreover, two studies demonstrated a reduction in whole prefrontal cortical volume in elderly minor and major depression,51,52
with volumes of prefrontal lobe decreasing with increasing severity of illness. Using voxel-based morphometry, another study in geriatric depression found smaller gray matter volumes bilaterally in the middle frontal gyrus.53
Studies focused on elderly depressed patients have repeatedly suggested a potential involvement of the OFC in the disorder. Reduced OFC volume,54
a significant association between smaller OFC gray matter and functional impairment,55
as well as increased lesion density in orbitofrontal white matter, have been specifically reported in elderly depression.56
We report a reduction in the white matter volume in the orbitofrontal regions in depressed subjects compared to the normal comparison group (), which lost its statistical significance after correction for multiple comparisons. This could be supported by postmortem findings indicating glial density reduction in distinct areas of the OFC in major depression.48,49
Possible mechanisms for tissue loss include neuronal loss and decreased neuronal density through exposure to repeated episodes of hypercortisolemia; glial cell loss, resulting in increased vulnerability to glutamate neurotoxicity; stress-induced reduction in neurotrophic factors; and stress-induced reduction in neurogenesis.57
Despite the lack of the neuroimaging studies to identify neuroanatomical substrates of the late-life neuropsychiatric syndromes in older subjects without dementia, a similar conceptual approach has been used in the neuroimaging studies of behavioral manifestations of dementia, including apathy and depression. Sultzer47
summarized disparate findings from the existing structural and functional neuroimaging studies in identifying behavioral substrates expressed in regional cerebral pathology in dementia. Depressed mood, apathy, and blunted affect were associated with structural lesions in subcortical nuclei and resulting frontal cortical dysfunction. Paul et al.58
studied MRI correlates of apathy and depression in patients with human immunodeficiency virus. Apathy, but not depression, was correlated with lower volume of the nucleus accumbens. Several recent positron emission tomography studies identified correlates of depression and apathy in Alzheimer disease. Holthoff and colleagues36
reported significant decreases in left orbitofrontal regions in subjects with apathy in the context of early Alzheimer disease when compared with patients free of apathy, whereas clinical depression was associated with hypometabolism in dorsolateral prefrontal regions. Mega and colleagues37
used the same approach in evaluating correlates of response to galantamine in behavioral subgroups of patients with Alzheimer disease. Right cingulate metabolic change significantly correlated with improvement in depression and right ventral putamen metabolic change with improvement in apathy. Rosen et al.35
reported an association of apathy with tissue loss in the ventral portion of the right anterior cingulate cortex and adjacent ventromedial superior frontal gyrus in subjects with dementia. None of these findings are identical to ours, which can be explained by the difference in the clinical populations with underlying neurodegenerative changes and comorbid cognitive symptoms in dementia.
The limitations of our study were the exploratory nature, the lack of matching by sex, and unavailability of the analyses of lacunar and deep white matter lesions, which are typically prevalent in this age group. However, we examined sex differences directly and found no group differences. Despite all subjects being free of psychotropic medications at the time of the study, we did not control for the prior medication exposure. Although we controlled for the severity of medical burden in the analyses, we did not address the potential contribution of psychomotor retardation or executive cognitive dysfunction to mediate the relationship between the AES scores and the regional MRI volumes. We combined the depressed and nondepressed subjects under the assumption that the all subjects will have the same neuroanatomical correlates of apathy controlling for diagnosis, which was supported by the similar correlation coefficients between the brain regions and the apathy scores in both group. Only postmortem studies, however, may elucidate the biological mean-ing of brain tissue changes in elderly depressed patients. Finally, our depressed outpatients suffered from moderate major depression, thus the results may not generalize to a more severely depressed population. With this caveat in mind, our findings offer the first important insights into the neuroanatomical correlates of apathy in an elderly clinical sample.
In summary, this is the first study to examine neuroanatomical correlates of apathy in older adults with and without major depression, which yielded intriguing results warranting replication in the future studies. We examined neuroanatomical features of apathy and depression using the MRI parcellation analyses of the frontal lobes in depressed elderly patients and age-matched controls. We observed different patterns of neuroanatomical substrates of depression and apathy, supporting the role of these regions in the mediation of late-life depression and apathy.
Neuroimaging can serve as a tool for redefining the endophenotypes of late-life neuropsychiatric disorders. Further development of neuroimaging techniques, more focused neuroimaging study designs, and corroboration with neuropathologic studies will help clarify the pathophysiologic mechanisms involved in neuropsychiatric and cognitive symptoms and will suggest opportunities for therapeutic intervention.