This is the first report to demonstrate a relationship between severity of depressive and anxiety symptoms and FDDNP binding values in non-demented middle age and older people. Our findings support previous work suggesting a relationship between more severe forms of geriatric depression and brain amyloid deposition (4
). We also report the patterns of associations in the two groups that underscores the importance of the MCI diagnosis in relation to the underlying pathophysiology of mood and anxiety symptoms. Surprisingly, the depression scores showed correlation only with the lateral temporal FDDNP binding in the MCI group, while the medial temporal FDDNP binding values correlated with the severity of depression in the comparison subjects
. However, the severity of anxiety symptoms correlated with the FDDNP binding in posterior cingulate region in the MCI group and with frontal and medial temporal regions in the comparison subjects
. Our preliminary
findings suggest differences in the neural circuitry involvement in the pathogenesis of mood and anxiety symptoms in relation to the cognitive status. In other words, mood and anxiety states with and without MCI may represent two endophenotypes with different underlying neural mechanisms and gene expression. Although at this time we have only limited evidence to support this hypothesis, we plan to explore the relationships between such clinical phenotypes of mood and anxiety disorders with and without MCI to the FDDNP-PET and genetic markers in future prospective studies that will include larger samples.
Although major depression can cause cognitive symptoms in younger and older adults, the relationship between late-life major depression and cognitive impairment is particularly complex. For example, not all studies find the neuropathological link between depression and dementia (39
). Significant cognitive impairment occurs in more than half of elderly depressed patients during an episode of depression (40
). Impaired cognition does not completely normalize with successful treatment of depression, especially in the areas of memory, executive function and information-processing speed (41
). Nearly 50% of those with cognitive impairment during a depressive episode or “pseudodementia” go on to develop dementia in the next 5 years (43
A number of studies have found an association between late-life major depression and increased risk for clinically diagnosed AD (7
). Thus, a diagnosis of late-life major depression similar to the MCI diagnosis may serve to identify a high-risk group that would benefit from initiation of therapies with the goal of delaying or preventing the onset of dementia (42
). Sweet and colleagues recently (2004) demonstrated a neuropathological link in 10 subjects initially diagnosed with major depression who were followed in a longitudinal study. Seven (70%) subjects had evidence of onset of a dementia prior to death. Major depression with dementia was significantly associated with a neuropathological diagnosis of AD. Therefore, current evidence suggests that AD is the predominant neuropathological condition in geriatric major depression subjects with dementia. In search of antemortem surrogate diagnostic markers of risk for dementia, Pomara et al (26
) analyzed plasma amyloid beta 1-42 (Aβ42) levels because elevated plasma amyloid beta 1-42 (Aβ42) level has been linked to increased risk for incident AD in cognitively-intact elderly. Results indicated that plasma Aβ42 levels and the Aβ42/40 ratios were elevated in the depressed group relative to control subjects, suggesting that increased plasma Aβ42 and Aβ42/40 ratios are present in geriatric depression.
Our results presented in suggest that the relationship between depression symptoms and FDDNP binding is mainly driven by subjects with GDS scores above the cutoff for mild depression. This finding is supported by the work of Sweet et al (2004) (4
) showing an increase in amyloid load in patients with geriatric depression, as well as the reports by Rapp et al (2006, 2008) (50
) showing an increase in plaques and tangles in Alzheimer's disease patients with depression co-morbidity (50
). Rapp et al (2008) (51
) demonstrated in patients with AD that the presence of depression comorbidity corresponds to increases in AD-related neuropathologic changes with accumulation of neurofibrillary tangles beyond age, gender, level of education, and cognitive status, suggesting an interaction between depression and the neuropathologic processes in AD. In another report, a life time prevalence of major depression was associated with increased hippocampal plaques and tangles in patients with Alzheimer disease (50
Although much less is known about the link between generalized anxiety and AD, recent studies indicate that the relationship may be even stronger than that with major depression (19
), and anxiety may represent an additional risk for progression from MCI to AD (20
). Interestingly, in patients with MCI, anxiety but not depressive symptoms were associated with conversion to AD, while in cognitively normal subjects depression was associated with AD diagnosis at follow up (52
). No other surrogate biological markers or autopsy data have been used to support this link. Similarly, there are no studies linking less severe forms of depression or anxiety to dementia and cognitive impairment, particularly, using biological markers.
Autopsy confirmation is seen as the “gold standard” for a diagnosis of AD; however, in most clinical research settings, a clinical diagnosis of AD is a reasonable proxy, with autopsy confirmation rates generally reported between 85 and 100% (53
). As has been demonstrated recently, the use of biological markers and in vivo neuroimaging can further improve the accuracy of early detection of dementia in these high-risk populations (27
We are not able to compare our results to other studies because of the unique design and methodology of our study. The differences that we observed in the correlations between the regional FDDNP binding and depression and anxiety scores in the two cognitive groups may be important as predictors of future development of mood and anxiety disorders, or dementia. This will need to be tested in a longitudinal follow up. However, several recent conceptual papers indicated the importance of application of integrative approaches combining genetics and in-vivo neuroimaging methods using biological markers to understand such complex issues as the potential overlap between depression and dementia, especially for the development of early diagnosis tools and preventive interventions (65
With regard to the localization of the FDDNP binding and potential neurocircuits involved, our findings are consistent with the findings in the literature identifying neurocircuitry of mood and anxiety disorders, evidenced by the association of neuroticism and anticipatory anxiety with smaller anterior and posterior cingulate volumes (68
), and negative association with brain activity on fMRI in the posterior cingulate gyrus in younger adults (69
). A magnetization transfer (MTR) study of geriatric depression reported reduced myelin integrity in specific aspects of frontostriatal and limbic networks that indicate decreased organization of white matter fibers in specific frontal and temporal regions including dorsolateral prefrontal, anterior and posterior cingulate regions (70
). However, a recent study demonstrated the relationship between depressive symptoms and medial temporal lobe atrophy to conversion to Alzheimer's disease in a prospective study (71
). Atrophy of the medial temporal lobe and left lateral temporal were predictors of conversion from MCI to Dementia (72
). A recent SPECT study demonstrated different patterns of blood flow in subjects with AD compared to subjects with depression. Depressed subjects had reductions in blood flow in the lateral frontal, left thalamus and bilateral medial frontal regions, and AD subjects had reduced blood flow to the lateral parietal, lateral temporal, bilateral precuneus and bilateral posterior cingulate gyrus (74
). However, no prior studies demonstrated that the pathophysiolgy of mood and anxiety symptoms in older adults is affected by the accumulation of amyloid and tau-protein in the regions of interest using PET imaging. It is possible that long-standing trait anxiety or mood disorders would contribute to the neural damage and overproduction of amyloid and tau in the structures that are involved in the pathogenesis of anxiety and depression. For example, our recent report identified such a link by showing changes in 5-HT1A
receptor densities in the living brain of AD patients (ADs). Mild cognitive impairment patients (MCI) were also correlated with global and regional measures of glucose metabolic activity, with the extent and spatial distribution of the NFT/ -amyloid senile plaque deposition (75
). However, we need to be careful about overinterpreting this data due to a relatively small sample size, and expect replication of the findings in future studies. This particularly refers to our finding of the different association between the GDS scores and the FDDNP binding in the medial temporal in the MCI and comparison subjects that was found to be statistically significant (). It may have to do with the accumulation of plaques and tangles initially in the medial temporal cortex and spreading to the lateral temporal cortex in the MCI subjects compared to normal subjects who may only show the association in the medial temporal cortex (76
), or this may be entirely due to a relatively small sample size.
Our findings suggest that this relationship between mood and anxiety symptoms and biomarkers of cerebral amyloid and tau deposition may vary on the basis of comorbid mild cognitive impairment. However, the major limitations of the study are its exploratory nature that may result in a type 1 error, a relatively small sample size and mild severity of depression and anxiety. Future studies should assess the presence of biomarkers of cerebral amyloid and tau deposition in more severe forms of mood and anxiety disorders in middle-aged and older individuals with and without cognitive impairment.