Risk factors for post-stroke depression in patients with mild and moderate strokes.

To determine the possible risk factors for post-stroke depression in patients with mild and moderate acute strokes. A cross-sectional descriptive study was conducted involving 129 patients with mild and moderate acute strokes. The patients were divided into post-stroke depression and non-depressed stroke groups according to the Hamilton Depression Rating Scale for Depression-17 item and Patient Health Questionnaire-9 item assessments. All participants were evaluated based on clinical characteristics and a battery of scales. Patients with post-stroke depression had an increased stroke frequency, severe stroke symptoms and poor performance in activities of daily living (ADL), cognitive function, sleep quality, interest in pleasurable activities, negative life events, and utilization of social support compared to stroke patients without depression. The Negative Life Event Scale (LES) score was significantly and independently associated with an increased probability of depression in stroke patients. Negative life events were shown to be independently associated with the incidence of depression in patients with mild and moderate acute strokes, likely mediating the influence of other predictors of depression, such as a history of stroke, decreased ADL ability, and utilization of support.

Altered intrinsic default mode network functional connectivity in patients with remitted geriatric depression and amnestic mild cognitive impairment.

OBJECTIVES: Patients with geriatric depression exhibit a spectrum of symptoms ranging from mild to severe cognitive impairment which could potentially lead to the development of Alzheimer's disease (AD). The aim of the study is to assess the alterations of the default mode network (DMN) in remitted geriatric depression (RGD) patients and whether it could serve as an underlying neuropathological mechanism associated with the risk of progression of AD. DESIGN: Cross-sectional study. PARTICIPANTS: A total of 154 participants, comprising 66 RGD subjects (which included 27 patients with comorbid amnestic mild cognitive impairment [aMCI] and 39 without aMCI [RGD]), 45 aMCI subjects without a history of depression (aMCI), and 43 matched healthy comparisons (HC), were recruited. MEASUREMENTS: All participants completed neuropsychological tests and underwent resting-state functional magnetic resonance imaging (fMRI). Posterior cingulate cortex (PCC)-seeded DMN functional connectivity (FC) along with cognitive function were compared among the four groups, and correlation analyses were conducted. RESULTS: In contrast to HC, RGD, aMCI, and RGD-aMCI subjects showed significant impairment across all domains of cognitive functions except for attention. Furthermore, compared with HC, there was a similar and significant decrease in PCC-seed FC in the bilateral medial superior frontal gyrus (M-SFG) in the RGD, aMCI, and RGD-aMCI groups. CONCLUSIONS: The aberrations in rsFC of the DMN were associated with cognitive deficits in RGD patients and might potentially reflect an underlying neuropathological mechanism for the increased risk of developing AD. Therefore, altered connectivity in the DMN could serve as a potential neural marker for the conversion of geriatric depression to AD.

Predicting conversion to Alzheimer's disease among individual high-risk patients using the Characterizing AD Risk Events index model.

AIMS: Both amnestic mild cognitive impairment (aMCI) and remitted late-onset depression (rLOD) confer a high risk of developing Alzheimer's disease (AD). This study aims to determine whether the Characterizing AD Risk Events (CARE) index model can effectively predict conversion in individuals at high risk for AD development either in an independent aMCI population or in an rLOD population. METHODS: The CARE index model was constructed based on the event-based probabilistic framework fusion of AD biomarkers to differentiate individuals progressing to AD from cognitively stable individuals in the aMCI population (27 stable subjects, 6 progressive subjects) and rLOD population (29 stable subjects, 10 progressive subjects) during the follow-up period. RESULTS: AD diagnoses were predicted in the aMCI population with a balanced accuracy of 80.6%, a sensitivity of 83.3%, and a specificity of 77.8%. They were also predicted in the rLOD population with a balanced accuracy of 74.5%, a sensitivity of 80.0%, and a specificity of 69.0%. In addition, the CARE index scores were observed to be negatively correlated with the composite Z scores for episodic memory (R2  = .17, P < .001) at baseline in the combined high-risk population (N = 72). CONCLUSIONS: The CARE index model can be used for the prediction of conversion to AD in both aMCI and rLOD populations effectively. Additionally, it can be used to monitor the disease severity of patients.

Withaferin A alleviates traumatic brain injury induced secondary brain injury via suppressing apoptosis in endothelia cells and modulating activation in the microglia.

Traumatic brain injury (TBI) is a major public health concern with high rates of morbidity and mortality worldwide. Currently used medications, though effective, are also associated with several adverse effects. Development of effective neuroprotective agents with fewer side-effects would be of clinical value. Previous studies have shown that withaferin compounds have a potential neuroprotective effect in nervous system disorders. However, the effect of withaferin compounds, especially withaferin A (WFA), on traumatic brain injury is unclear. In the present study, both in vivo and in vitro models were used to assess whether WFA could exert a neuroprotective effect after TBI and were used to explore the associated mechanisms. The results showed that WFA significantly improved neurobehavioral function in a dose-dependent fashion and alleviated histological alteration of injury to tissues in TBI mice. In vitro models of TBI revealed that dose-dependent WFA treatment increased the viability of SH-SY5Y cells. In addition, WFA treatment could attenuate blood-brain barrier disruption and brain edema via suppressing apoptosis in endothelial cells. Furthermore, both our in vivo and in vitro results reveal that WFA treatment could significantly reduce levels of several neuroinflammation cytokines (IL-1ß, IL-6, and TNF-α), which correlate with an overall reduction in microglial activation. These data suggest that the neuroprotection by WFA is, at least in part, related to regulation of microglial activation and inhibition of vascular endothelial cell apoptosis. Taken together, these findings support further investigation of WFA as a promising therapeutic agent for promoting functional recovery after traumatic brain injury.

Cerebral blood flow changes in remitted early- and late-onset depression patients.

Abnormal cerebral blood flow (CBF) is reportedly associated with major depressive disorder (MDD). We have investigated CBF changes in early-onset depression (EOD) and late-onset depression (LOD), and their impact on cognitive function. Thirty-two remitted EOD patients, 32 remitted LOD patients, and 43 age-matched healthy controls were recruited, and the pulsed arterial spin labeling data were scanned under 3.0T MRI and processed through voxel-by-voxel statistical analysis. Compared to healthy controls, LOD patients had decreased normalized CBF in the bilateral precuneus, cuneus, right fronto-cingulate-striatal areas, and right temporal, occipital and parietal lobes, but increased normalized CBF in the left frontal and temporal cortices and the cingulate gyrus. EOD patients had decreased normalized CBF in the left cerebellum and right calcarine/lingual/fusiform gyrus, and increased normalized CBF in right angular gyrus. LOD patients displayed hemispheric asymmetry in CBF, and had more regions with abnormal CBF than EOD patients. A significant correlation between abnormal CBF and impaired cognitive function was detected in LOD patients, but not EOD patients. These results demonstrate greater CBF abnormalities in LOD patients than EOD patients, and suggest these CBF changes may be associated with progressive degradation of cognitive function in LOD patients.

Divergent Roles of Vascular Burden and Neurodegeneration in the Cognitive Decline of Geriatric Depression Patients and Mild Cognitive Impairment Patients.

Both geriatric depression and mild cognitive impairment (MCI) confer an increased risk for the development of dementia. The mechanisms underlying the development of cognitive impairment in geriatric depression patients remain controversial. The present study aimed to explore the association of cognitive decline with vascular risk, white matter hyperintensity (WMH) burden and hippocampal volume in both remitted geriatric depression (RGD) subjects and amnestic mild cognitive impairment (aMCI) subjects. Forty-one RGD subjects, 51 aMCI subjects, and 64 healthy elderly subjects underwent multimodal MRI scans and neuropsychological tests at both baseline and a 35-month follow-up. According to the changing patterns (declining or stable) of global cognitive function during the follow-up period, each group was further divided into a declining subgroup and a stable subgroup. The Framingham 10-year cardiovascular risk, WMH volume and hippocampal volume were measured to assess vascular pathology and neurodegeneration, respectively. The RGD declining group displayed a higher vascular risk and greater WMH volume than the RGD stable group, whereas no such difference was found in the aMCI subjects. In contrast, the aMCI declining group displayed a smaller left hippocampal volume than the aMCI stable group, whereas no such difference was found in the RGD subjects. Furthermore, greater increases in the WHM volume correlated with greater decreases in global cognitive function in the RGD declining group, and greater decreases in the left hippocampal volume correlated with greater decreases in global cognitive function in the aMCI declining group. In conclusion, the cognitive decline in RGD patients is associated with vascular burden, whereas the cognitive decline in aMCI patients is associated with neurodegeneration. These findings could contribute to a better understanding of the specific mechanisms of the development of dementia in each condition.

The characteristic of cognitive dysfunction in remitted late life depression and amnestic mild cognitive impairment.

Remitted late life depression exhibits persistent cognitive impairments and enhances the risk of dementia. This study aimed to examine the characteristics of cognitive dysfunction in remitted late life depression and amnestic mild cognitive impairment (MCI). Remitted late life depression (n=61), amnestic MCI (n=61) and age-education-matched controls (n=65) were evaluated with a battery of neuropsychological tests grouped into executive function, memory, processing speed, attention and visuospatial domains. Compared with control subjects, amnestic MCI individuals showed more severe cognitive impairments in all domains, while remitted late life depression individuals performed worse in executive function and memory. The pattern of cognitive profiles significantly differed between remitted late life depression and amnestic MCI groups, which might be mainly attributed to worse impairments in memory and executive function in amnestic MCI individuals. Executive function was the core impaired cognitive domain mediating the influence of predictors on other cognitions in both remitted late life depression and amnestic MCI groups, which indicated a possible etiopathogenic mechanism underlying the conversion to dementia.

Differential Effects of APOE Genotypes on the Anterior and Posterior Subnetworks of Default Mode Network in Amnestic Mild Cognitive Impairment.

BACKGROUND: The apolipoprotein E (APOE) ɛ4 carriers are at increased risk of developing Alzheimer's disease (AD) while the ɛ2 carriers appear to be protected against the disease. The default mode network (DMN), based in ventromedial prefrontal cortex (vmPFC) and posterior cingulate cortex (PCC), consists of functionally differentiable anterior and posterior subnetworks. OBJECTIVE: This study was to investigate whether there are differential effects of APOE polymorphisms on DMN subnetworks in amnestic mild cognitive impairment (aMCI). METHODS: Functional connectivity (FC) analyses were performed in DMN subnetworks in 74 aMCI (9 APOE ɛ2ɛ3, 44 ɛ3ɛ3, and 21 ɛ3ɛ4) and 105 healthy controls (HC; 32 APOE ɛ2ɛ3, 39 ɛ3ɛ3, and 34 ɛ3ɛ4). Logistic regression analysis was performed to obtain a model for classifying aMCI and HC. RESULTS: Significant interactions of APOE by aMCI on FCs were found in right cerebellum posterior lobe, left lingual gyrus, and right middle cingulate cortex in the vmPFC subnetwork, and bilateral fusiform gyrus, left inferior frontal gyrus, and left precuneus in the PCC subnetwork. The impairment of episodic memory for ɛ4-carriers in aMCI negatively correlated with altered FC between vmPFC and right middle cingulate cortex, while positively correlated with altered FC between PCC and left fusiform gyrus. A model composed of episodic memory and FCs dexterity correctly classified 89.4% of aMCI and HC. CONCLUSIONS: APOE ɛ4 and ɛ2 alleles differentially mediate anterior and posterior DMN subnetworks. Furthermore, it further suggests that the anterior and posterior DMN subnetworks in aMCI play an opposing role on the impairment of episodic memory.

Mediation of episodic memory performance by the executive function network in patients with amnestic mild cognitive impairment: a resting-state functional MRI study.

Deficits in episodic memory (EM) are a hallmark clinical symptom of patients with amnestic mild cognitive impairment (aMCI). Impairments in executive function (EF) are widely considered to exacerbate memory deficits and to increase the risk of conversion from aMCI to Alzheimer's disease (AD). However, the specific mechanisms underlying the interaction between executive dysfunction and memory deficits in aMCI patients remain unclear. Thus, the present study utilized resting-state functional magnetic resonance imaging (fMRI) scans of the EF network and the EM network to investigate this relationship in 79 aMCI patients and 119 healthy controls (HC). The seeds were obtained from the results of a regional homogeneity (ReHo) analysis. Functional connectivity (FC) within the EM network was determined using a seed in the right retrosplenial cortex (RSC), and FC within EF network was assessed using seeds in the right dorsolateral prefrontal cortex (DLPFC). There was a significant negative correlation between EM scores and EF scores in both the aMCI and HC groups. Compared to the HC group, aMCI patients had reduced right RSC connectivity but enhanced right DLPFC connectivity. The overlapping brain regions between the EM and EF networks were associated with FC in the right inferior parietal lobule (IPL) in the right RSC network, and in the bilateral middle cingulate cortex (MCC) and left IPL in the right DLPFC network. A mediation analysis revealed that the EF network had an indirect positive effect on EM performance in the aMCI patients. The present findings provide new insights into the neural mechanisms underlying the interaction between impaired EF and memory deficits in aMCI patients and suggest that the EF network may mediate EM performance in this population.

Convergent and divergent intranetwork and internetwork connectivity patterns in patients with remitted late-life depression and amnestic mild cognitive impairment.

INTRODUCTION: Both remitted late-life depression (rLLD) and amnesiac mild cognitive impairment (aMCI) alter brain functions in specific regions of the brain. They are also disconnection syndromes that are associated with a high risk of developing Alzheimer's disease (AD). OBJECTIVES: Resting-state functional connectivity magnetic resonance imaging (rs-fcMRI) was performed to define the shared and distinct aberrant patterns in intranetwork and internetwork connectivity between rLLD and aMCI and to determine how knowledge of these differences might contribute to our essential understanding of the altered sequences involved in functional systems both inside and outside of resting-state networks. METHODS: We used rs-fcMRI to investigate in five functionally well-defined brain networks in two large cohorts of subjects at high risk for AD (55 rLLD and 87 aMCI) and 114 healthy controls (HC). RESULTS: A reduced degree of functional connectivity was observed in the bilateral inferior temporal cortex and supplemental motor area, and reduced correlations were observed within the sensory-motor network (SMN) and in the default mode network (DMN)-control network (CON) pair in the rLLD group than the HC group. The aMCI group showed only focal functional changes in regions of interest pairs, a trend toward increased correlations within the salience network and SMN, and a trend toward a reduced correlation in the DMN-CON pair. Furthermore, the rLLD group exhibited more severely altered functional connectivity than the aMCI group. Interestingly, these altered connectivities were associated with specific multi-domain cognitive and behavioral functions in both rLLD and aMCI. The degree of functional connectivity in the right primary auditory areas was negatively correlated with Hamilton Depression Scale scores in rLLD. Notably, altered connectivity between the right middle temporal cortex and the posterior cerebellum was negatively correlated with Mattis Dementia Rating Scale scores in both rLLD and aMCI. CONCLUSIONS: These results demonstrate that rLLD and aMCI may share convergent and divergent aberrant intranetwork and internetwork connectivity patterns as a potential continuous spectrum of the same disease. They further suggest that dysfunctions in the right specific temporal-cerebellum neural circuit may contribute to the similarities observed in rLLD and aMCI conversion to AD.

Differential contributions of subregions of medial temporal lobe to memory system in amnestic mild cognitive impairment: insights from fMRI study.

Altered function of the medial temporal lobe (MTL) is a valuable indicator of conversion from amnestic mild cognitive impairment (aMCI) to Alzheimer's disease. This study is to delineate the functional circuitry of multiple subdivisions of parahippocampal gyrus and hippocampus (HIP) and to examine how this knowledge contributes to a more principled understanding of the contributions of its subregions to memory in aMCI. The functional connectivity (FC) analysis was performed in 85 aMCI and 129 healthy controls. The aMCI demonstrated the distinct disruptive patterns of the MTL subregional connectivity with the whole-brain. The right entorhinal cortex (ERC) and perirhinal cortex (PRC) showed increased connectivity with the left inferior and middle occipital gyrus, respectively, which potentially indicated a compensatory mechanism. Furthermore, the right altered MTL subregional FC was associated with episodic memory performance in aMCI. These results provide novel insights into the heterogeneous nature of its large-scale connectivity in MTL subregions in memory system underlying the memory deficits in aMCI. It further suggests that altered FC of MTL subregions is associated with the impairment of the differential encoding stages of memories and the functional changes in the specific right HIP-ERC-PRC-temporal circuitry may contribute to the impairment of episodic memory in aMCI.