Depression is a highly heterogeneous psychiatric disorder, and it is considered as late life depression (LLD) when depressive episode in elderly (age ≥ 60 years). Currently, with the coming of aging society, LLD has become a public health problem. According to the age of first depressive episode, LL could be divided into early onset depression (EOD) and late onset depression (LOD). Compared with LOD patients, EOD patients show more symptoms including somnolence, anxiety, suicidal ideation and suicidal behavior, and more family history of depression. In addition, LOD patients are more likely to have anhedonia and vascular pathology. Furthermore, LOD patients exhibit greater cognitive function impairments, aberrant changes of brain and risk of dementia.
LLD patients always have multiple cognitive impairments, and these cognitive functions do not improve to normal level even after the depressive symptom has remitted. Information processing speed is the core cognitive impairment followed by executive function in the acute phase of LLD, meaning that it could mediate the influences of clinical variables on other cognitive domains. However, prior studies reported that information processing speed had improved to normal level after the depressive symptom remitted, and it became non-core cognitive function. LOD patients show greater memory, processing speed, executive function impairments than EOD patients. It is not clear whether information processing speed has returned to normal level and whether it is still the core cognitive function in remitted LOD.
In recent years, imaging technology has become important tool in neuroscience and psychiatry research. The hypothesis of “dysfunction of brain neural network” is associated with a close attention in depression research. However, there is no consistent result of abnormal brain changes to explain the depression pathogenesis, which may be due to heterogeneity of depression. Prior study has reported greater hippocampal atrophy in LOD patients relative to EOD patients. However, we did not found the functional imaging research in both EOD and LOD patients. There are different alterations of brain function between young depression and late life depression, the differences of age may be contributed to these brain differences. Therefore, it is necessary to investigate the brain function between EOD and LOD in elderly. Blood oxygenation level-dependent (BOLD) and arterial spin labeling (ASL) are magnetic resonance techniques to investigate the brain function. The BOLD could explore the functional integration of brain by functional connectivity, and determine the network alterations between brain regions. ASL could be used to calculate the regional cerebral blood flow (CBF) values, which reflect the regional function of brain.
This study recruited remitted EOD, LOD patients and age-match health controls. For all participants, we assessed their cognitive function using multi-domain neurocognitive tests and analysis brain function using resting-state functional magnetic resonance imaging data. The present study yielded three main research directions: (1) To investigate the severity and characteristic of cognitive impairments in remitted EOD and LOD patients and their relationship with clinical variables. (2) We aimed to elaborate the neurobiological markers of remitted LOD and EOD in the default mode network (DMN), executive control network (ECN) and salience network (SN) by using BOLD data. (3) We sought to investigate the CBF alterations and their relations with cognitive deficits in remitted EOD and LOD by using ASL data. Finally, this study is expected to advance the current understanding of neurobiological mechanism underlying the cognitive dysfunction in EOD and LOD patients, and shed lights on exploring the direction and mechanism of cognitive progressive degeneration in the future.
Part1. The characteristic of cognitive dysfunction in remitted early onset and late onset depression
Objective: To investigate the severity and characteristic of cognitive impairments in remitted EOD and LOD patients and their relationship with clinical variables.
Methods: Remitted EOD (n=36), LOD (n=38) and age-matched controls (n=65) were canned with fMRI and evaluated with a battery of neuropsychological tests grouped into executive function, memory, information processing speed, attention and visuospatial domains. A series of statistical analyses were used including analysis of variance (ANOVA), profile analysis and multiple linear stepwise regression analysis.
Results: Remitted EOD patients performed memory impairment and remitted LOD patients showed poor performances on executive function, memory and information processing speed relative to controls. There was no significantly different cognitive function between remitted EOD and LOD patients. Profile analysis found no significantly different patterns of cognitive domains between remitted EOD and LOD patients. While the significantly different patterns of neuropsychological tests between two patient groups mainly due to their differences in executive function and memory. Multiple linear stepwise regression analysis revealed that executive function was the core cognitive domain which mediated the influence of age on memory, but not the influence of education on attention in remitted EOD patients. Similarly, remitted LOD patients showed that executive function was the core cognitive domain followed by information processing speed. The executive function mediated the influence of grey matter volume on memory, and the information processing speed mediated the influence of age on attention.
Conclusion: Remitted LOD patients have more widely cognitive impairments than remitted EOD patients. Executive function is the core cognitive function in remitted EOD patients, while executive function and information processing speed are the core cognitive functions in remitted LOD patients.
Key words: early onset depression, late onset depression, core cognitive function, executive function, information processing speed.
Part2. Aberrant resting-state functional connectivity between early and late onset depression
Objective: This research aimed to elaborate the neurobiological markers of remitted LOD and EOD in the default mode network (DMN), executive control network (ECN) and salience network (SN).
Methods: A total of 33 remitted LOD, 31 remitted EOD and 43 matched healthy controls (HC) underwent a battery of neuropsychological tests and scanned by fMRI. The three networks were explored using a seed based ROI approach. After functional image preprocessing, selected five ROIs as seeds to analysis the functional connectivity. The analysis of covariance was used to explore the differences of the seed functional connectivity in remitted EOD, LOD and HC groups. The partial correlation analysis was used to investigate the relationship between aberrant functional connectivity and cognitive domains.
Results: Significantly different resting-state functional connectivity of frontal, temporal cortex, cingulate cortex and left angular within the DMN were found among the 3 groups. Similarly, there was significantly different connectivity of frontal, temporal cortex and cingulate cortex within the ECN and different connectivity of bilateral fronto-insula-striatum (FIS), frontal cortex and middle cingulate cortex/supplementary motor area (MCC/SMA) within the SN among 3 groups. The significantly low connectivity was found in DMN, ECN and SN in the remitted EOD patients compared with the remitted LOD patients. The impaired memory was significantly correlated with the decreased connectivity of ECN in remitted LOD patients.
Conclusion: Both remitted EOD and LOD patients have significantly decreased functional connectivity of DMN, ECN and SN. Remitted EOD patients show greater disruptions of connectivity than remitted LOD patients. The aberrant functional connectivity of ECN is associated with memory deficit in remitted LOD patients.
Key words: early onset depression, late onset depression, default mode network, executive control network, salience network.
Part3. Characteristic of CBF changes in remitted early and late onset depression
Objective: This research aimed to investigate the CBF alterations and their relations with cognitive deficits in remitted EOD and LOD.
Methods: This study included 32 remitted EOD, 32 remitted LOD patients and 43 age-matched healthy controls (HC). All the participants underwent 3-T MRI with pulsed arterial spin labeling (pASL). The pASL data were processed by voxel-by-voxel statistical analysis.
Results: There were significant hypoperfusion in bilateral precuneus, cuneus, right fronto-cingulate- striatal areas, right temporal, occipital and parietal lobes, and hyperperfusion in left frontal, temporal cortex and cingulate gyrus in LOD patients relative to healthy controls. In patients with EOD, a significant hypoperfusion was observed in left cerebellum and right calcarine/lingual/fusiform gyrus, and hyperperfusion in right angular gyrus. LOD patients demonstrated more serious CBF changes than EOD patients. Significant correlations between CBF and cognitive function were detected in LOD patients, but not EOD patients.
Conclusion: These results suggest that hemispheric asymmetry of CBF may be a unique characteristic in remitted LOD patients. These alterations of CBF are likely to provide a biomarker for cognitive impairments in LOD patients.
Key words: early onset depression, late onset depression, cerebral blood flow.