An Association Study Of Imaging Genetics With The Cognitive Impairment And Psychomotor Retardation In Depression

BackgroundMajor depressive disorder (MDD) is a complicated mental disorder with various manifestations involving emotion, cognition as well as motor behavior. The pathogenesis of MDD is supposed to be multifactorial. And the underlying pathology of MDD is also likely to involve various neuronal systems. To understand the various pathologies, it is better to disintegrate the MDD into different phenotypes.Psychomotor retardation (PMR) is one of the core phenotypes of MDD, with the traits of both bradyphrenia and bradykinesia involving gait, facial movements, gestures,speech, fine motor behavior. MDD patients with PMR demonstrate longer duration,higher suicide, more onset frequency, and more family history, which are significantly affect the prognosis of MDD. However, the biological mechanism of PMR is still ambiguous. Over the past decade, functional magnetic resonance imaging (fMRI)provided a wealth of evidence of the cerebral functional changes for neuropsychiatric disorders. Previous studies mainly reported structural, functional, and blood flow alterations of the basal ganglia, prefrontal cortex, primary motor cortex (PMC) and supplemental motor area (SMA) in PMR, suggesting the PMR might mainly associated with the dysfunction of these brain regions involved in motor regulation.However, these studies have yielded discrepant results that may be related to differences in sample size,subject selection,imaging protocol,and image analysis.The decreased plasma dopamine (DA) and homovanillic acid (a dopamine metabolite)in cerebrospinal fluid have been reported. fMRI studies also found increased dopamine receptor in striatum. It is reasonable to infer that the genetic polymorphism of DA pathway might affect the imaging changes in PMR. Therefore, the first part of this study investigated PMR from two levels, i.e. the imaging changes and the imaging genetics. There are two aims in our study: Firstly,a voxel-wised data-driven analysis of the cerebral blood flow (CBF) was performed to explore the brain regions with abnormal CBF associated with PMR. Then a mass univariate modeling analysis was applied to identify the dopaminergic genotype-by- PMR associations with the CBF differences; Secondly, a regions of interest (ROI)-wised hypothesis-driven analysis of the functional connectivity (FC) of cortico-striato-thalamo-cortical (CSTC)circuitry was conducted. We selected three pivotal ROI of the indirect pathway in the left and right hemisphere respectively, i.e. striatum, thalamus, and subthalamic nucleus (STN) in the present study. The hypothesis was that MDD patients with PMR would manifest increased striato-thalamo-STN FC,and these unbalanced FC should conspicuously pertain to the PMR severity. Then the genetic polymorphisms of DA pathway might modulate the striato-thalamo-STN FC associated with PMR.Late-onset depression (LOD) is often characterized by cognitive impairment (CI)which brings a heavy burden of disability to patients. Although LOD has a low prevalence, the number of patients is rising perpendicularly with the aggravated aging problem. Patients with LOD were certified to have poor outcomes, including poor response to antidepressant treatment, greater illness severity, higher relapse rate, and greater duration of illness. But even worse,LOD is considered as a clinical syndrome associated with an increased risk of developing Alzheimer's disease due to the cognitive impairment. Despite the notorious actuality, the cerebral malfunction underlying the cognitive impairment in LOD is still ambiguous. The default mode network (DMN) is a group of well-established areas involving in self-referential function, as well as emotional and cognitive processing. The dysfunction of the DMN has been widely reported in MDD. The hippocampi is central to the episodic memory formation and vital to the dorsal-cognitive system. Previous studies have demonstrated that hippocampi was implicated in the memory deficit of LOD.Hippocampal volume was also influenced by Val66Met polymorphism in the brain derived neurotrophic factor (BDNF) gene. Therefore, in the second part of the present study, we analyzed the functional connectivity of the DMN and the hippocampus in LOD patients. Besides, the influence of the BDNF Val66Met polymorphism on the functional connectivity of the DMN and the hippocampus were also investigated.Part 1 The dopaminergic polymorphisms in psychomotor retardation of depression: A pathway-based imaging genetics association studyChapter 1 Dopaminergic genotype-by-PMR associations with the CBFObjective: To investigate the association of the polymorphisms throughout the dopaminergic pathway with the cerebral blood flow (CBF) of PMR in MDD.Methods: 107 antidepressant-free MDD patients and 48 (normal control, NC)were collected in this study. Patients were divided into PMR group (N=72) and NPMR group (N=35) according to the Salpetriere Retardation Rating Scale (SRRS) score and underwent resting-state functional magnetic resonance imaging (fMRI). The blood sample of 63 patients (23 PMR, 40 NPMR) were collected for genotyping the dopaminergic polymorphisms (92 SNP from 10 genes). After quality controlling, 15 SNP in 8 candidate genes were entered into the mass univariate modeling analysis.Arterial spin labeling (ASL) data were collected for the CBF and calculation. After the first scan, patients began to receive antidepressant treatment, and 39 patients (15 PMR, 24 NPMR) who were remitted after 8 weeks participated in the follow-up fMRI scan. For the statistical analysis, patients with unqualified fMRI image and unmatched demographic data were ruled out. Consequently 30 NC and 60 patients (30 PMR, 30 NPMR) at baseline and 22 patients (11 PMR, 11 NPMR) at follow-up were taken into the statistical analysis. 56 patients (23 PMR, 33 NPMR) were taken into the genotype-by-PMR interaction analysis. One-way ANOVA was used to compare the CBF of NC?NPMR and PMR groups at baseline,independent two-sample t tests were applied for the comparison at follow-up,and paired samples t-test were performed to compare the CBF of PMR group between baseline and follow-up. The mass univariate modeling analysis was applied for assessing the genotype-by-PMR interaction on the CBF.Results: PMR group showed significantly decreased CBF in the right motor cortex and bilateral middle cingulate cortex at baseline. The CBF of the right motor cortex was increased in PMR group at follow-up. PMR group also displayed significant decreased CBF in the right motor cortex at baseline compared with follow-up.Genotype-by-PMR associations with the CBF differences were identified for 7 SNP with the lowest significant P values. The brain regions predominately distributed in bilateral prefrontal cortex (PFC), temporal cortex, and striatum, the left thalamus, the right primary motor cortex, insular cortex, fusiform gyri, and lingual gyri. The genotype-by-PMR interactions at the CBF of these brain regions were similar. For most SNP, while the non-rare allele significantly increased the CBF of the brain areas,the rare allele played an opposite role for the PMR group. Only the DRD3_rs 6280 and the SLC6A3_rs6347 showed different effect, the rare allele significantly increased the CBF of the brain areas, but the non-rare allele decreased the CBF. There were significant negative correlation between the CBF of the PFC and the PMR severity.However, the CBF of the striatum and the thalamus were positively correlated with the PMR severity.Conclusions: Increased CBF of the motor cortex might be considered as a robust biomarker of PMR in MDD. The polymorphisms of dopaminergic pathway are associated with not only CSTC circuitry, but also some other brain regions involving in cognition and emotion control. The rare alleles of the dopaminergic gene are responsible for the increased CBF of these regions in PMR. While the increased CBF of PFC might suppress PMR, the increased CBF of striatum and thalamus adversely aggravate PMR.Chapter 2 Dopaminergic genotype-by-PMR associations with the cortico-striato-thalamo-cortical functional connectivityObjective: To investigate the association of the dopaminergic polymorphisms with the cortico-striato-thalamo-cortical (CSTC) functional connectivity of the PMR in MDD.Methods: The enrollment of the participants and the blood sample collections were the same as Chapter 1, BOLD fMRI was used to analyze the FC of CSTC circuitry.The preprocess of the fMRI data was the same as Chapter 1.Three pivotal ROI of the indirect pathway in the left and right hemisphere respectively were selected, i.e.striatum, thalamus, and STN in the present study. For the genotype-by-PMR interaction analysis, the screening process of the candidate genes was the same as Chapter 1. For the statistical analysis, the screening process of the sample and the compare of the CSTC functional connectivity were the same as Chapter 1. General linear model was applied for assessing the genotype-by-PMR interaction on the CSTC functional connectivity.Results: NPMR group showed significant increased thalamo-striatum functional connectivity. There was a significant correlation between PMR severity and thalamo-STN FC. DRD5 gene had an interaction on the left thalamo-STN FC, while SLC6A3 gene affected right thalamo-STN FC. However, the genotype-by-PMR interactions were no longer significant after Bonferroni correction for multiple comparisons.Conclusions: Our findings suggested the increased thalamo-STN FC could be identified as the predictor of the PMR severity for MDD patients. The genetic polymorphism of DA pathway might not influence the FC of CSTC circuitry in PMR.Part 2 The dysfunction of default mode network and hippocampal network underlying the cognitive impairment in late-onset depressionChapter 1 The BDNF Val66Met polymorphism and Functional Connectivity of Default Mode Network underlying the Cognitive Impairment in Late-onset DepressionObjectives: To identify the association between the functional and structural changes of DMN underlying the cognitive impairment in Late-onset depression (LOD), and the influence of BDNF Val66Met polymorphism on the functional connectivity of DMN.Methods: 32 LOD patients and 39 NC were recruited and underwent resting-state fMRI, DTI scans, and cognitive assessments. The blood sample of 26 LOD patients and 36 NC were collected for genotyping the BDNF Val66Met polymorphisms.HAMD was used to evaluate the depression severity. Cognition measurements were performed using a neuropsychological battery that consisted of MMSE, AVLT, DST,VFT, TMT and SDMT. Seed-based correlation analysis was conducted to explore the functional connectivity (FC) of the DMN. Deterministic tractography between FC-impaired regions was performed to examine the structural connectivity (SC).Partial correlation analyses were employed to evaluate the cognitive association of those altered FC and SC. Two-way ANOVA was performed to evaluate the interaction of BDNF Val66Met polymorphism and LOD on the FC of DMN.Results: Compared with controls, LOD patients showed decreased FC between DMN and the cingulo-opercular network (CON), as well as the thalamus. Decreased FA and increased RD of these fiber tracts connecting DMN with CON were found in LOD patient. The DMN-CON FC and the FA, RD of the fiber tracts were both significantly correlated with the cognitive performance. BDNF Val66Met polymorphism and LOD have interaction on the FC of DMN and right angular guri. The FC of DMN and right angular guri in LOD patients who carried Val/Val homozygote was significant enhanced.Conclusions: the cognitive impairment in LOD might be associated with the decreased FC between the DMN and the CON, which probably resulted from the demyelination of the white matter. Val/Val homozygote may play a protect role for the FC of the DMN in LOD patient.Chapter 2 The BDNF Val66Met polymorphism and hippocampal functional connectivity underlying cognitive deficits in late-onset depressionObjectives: To investigate the relationship between hippocampal functional connectivity (HFC), cognitive deficits, and the influence of BDNF Val66Met polymorphism on the HFC in acute late-onset depression (LOD).Methods: The enrollment of the participants, the clinical assessment, and the genotyping of BDNF Val66Met polymorphism were the same as Chapter 1. The LOD and NC groups were further divided into four groups according to BDNF Met allele carrier or not (LOD Met- (n=8); LOD Met+ (n=18); NC Met- (n=9); NC Met+(n=24)). Then, seed-based correlation analyses and two-way analysis of covariance(ANCOVA) were performed to explore the main effects and interactive effects of LOD and BDNF Val66Met polymorphism on the HFC. Spearman correlation was applied to examine the cognitive and emotional significance of these altered HFC networks.Results: Compared with NC, bilateral positive HFC with the right insula, left positive HFC with bilateral orbit-frontal cortex (OFC) and left precuneus, right positive HFC with right dorsolateral prefrontal cortex (dlPFC) were decreased, and bilateral negative HFC with right postcentral gyrus were reversed in LOD patients. BDNF Met allele mainly decreased bilateral positive HFC with the cerebellum. The interaction of LOD and BDNF Met allele primarily influenced the bilateral HFC with the temporal cortex and dorsal nexus. The changed HFC with the OFC, postcentral gyrus,cerebellum and temporal cortex significantly correlated to the cognitive deterioration.There was no significant association between the depressive severity and any altered HFC networks.Conclusions: The cognitive deterioration in LOD patients, BDNF Met allele carriers,and LOD patients carrying Met allele were associated with the changed HFC networks in the OFC/postcentral gyrus, cerebellum and temporal cortex respectively.