Tiantian Qiu

Associations between APOE genotype and cerebral small-vessel disease: a longitudinal study

Objective It remains unclear if and how the interactions between APOE genotypes and cerebral small-vessel diseases (CSVD) lead to cognitive decline in the long term. Based on ADNI cohort, this longitudinal study aimed to clarify the potential relationship among APOE genotype, CSVD and cognition by integrating multi-level data. Method There were 135 healthy elderly (including ε2, ε4 allele carriers and ε3 homozygotes) who had completed two years’ follow-up. MRI markers of CSVD, including white matter hyperintensities (WMH), dilated perivascular space (dPVS), microbleeds and lacune, were assessed. Besides, neuropathological factors including Alzheimers disease-related pathology measured by CSF and PiB-PET were assessed. Repeated measurements ANOVAs were performed to test impact of different APOE genotypes on CSVD. Results We found that APOE ε4 carriers had significantly more frontal WMH burden and basal ganglia dPVS at baseline and faster progression of frontal WMH burden during follow-up. Furthermore, our results showed that APOE ε4 carriers had significantly decreased Aβ1-42 level, and its level was negatively related with baseline and progressive total WMH burden. Then, general linear modals indicated interaction between basal frontal WMH burden and ε4 allele was related with declining trend of cognition. Conclusion Our findings suggested APOE ε4 allele was associated with increased Aβ deposition, which may lead to the formation and progression of WMH, especially in frontal lobe. Besides, interaction between the increased frontal WMH burden and ε4 allele can exert long-term detrimental effects on individuals trajectory of cognition.

Decreased Inter-Hemispheric Functional Connectivity in Cognitively Intact Elderly APOE ɛ4 Carriers: A Preliminary Study

The apolipoprotein E (APOE) ɛ4 allele is the best-known genetic risk factor for developing sporadic Alzheimers disease (AD). According to neuroimaging studies, the APOE ɛ4 allele is associated with localized altered brain function. However, in long-range circuitry, APOE ɛ4 allele-related alterations in functional communication between hemispheres have rarely been directly investigated. We examined the alteration of resting-state functional connectivity (RSFC) between inter-hemispheric homotopic regions in cognitively intact, elderly APOE ɛ4 carriers. The voxel-mirrored homotopic connectivity method was used to assess the inter-hemispheric RSFC. The current study included 13 cognitively intact, elderly APOE ɛ4 carriers (with at least one copy of APOE ɛ4 allele) and 22 well-matched ɛ3 homozygotes. Comparisons between the two groups were conducted, and subsequently, the correlation between the differential inter-hemispheric RSFC and cognitive ability was analyzed. Compared with ɛ3 homozygotes, APOE ɛ4 carriers showed decreased inter-hemispheric RSFC in the bilateral medial temporal lobe (MTL) and orbital frontal cortex (OFC). Moreover, in APOE ɛ4 carriers, the inter-hemispheric RSFC of the MTL correlated with the Wechsler Memory Scale-Logical Memory (WMS-LM) (immediate and delayed performance, r = 0.64, p <  0.05; r = 0.65, p <  0.05, respectively), and the inter-hemispheric RSFC of the OFC correlated with the WMS-LM delayed performance (r = 0.71, p <  0.05). In our study, the presence of the APOE ɛ4 allele was linked with decreased inter-hemispheric RSFC, which was attributed to memory performance in carriers.

Alteration of regional homogeneity and white matter hyperintensities in amnestic mild cognitive impairment subtypes are related to cognition and CSF biomarkers

Amnestic mild cognitive impairment can be further classified as single-domain aMCI (SD-aMCI) with isolated memory deficit, or multi-domain aMCI (MD-aMCI) if memory deficit is combined with impairment in other cognitive domains. Prior studies reported these clinical subtypes presumably differ in etiology. Thus, we aimed to explore the possible mechanisms between different aMCI subtypes by assessing alteration in brain activity and brain vasculature, and their relations with CSF AD biomarkers. 49 healthy controls, 32 SD-aMCI, and 32 MD-aMCI, who had undergone structural scans, resting-state functional MRI (rsfMRI) scans and neuropsychological evaluations, were identified. Regional homogeneity (ReHo) was employed to analyze regional synchronization. Periventricular white matter hyperintensities (PWMH) and deep WMH (DWMH) volume of each participant was quantitatively assessed. AD biomarkers from CSF were also measured. SD-aMCI showed decreased ReHo in medial temporal gyrus (MTG), and increased ReHo in lingual gyrus (LG) and superior temporal gyrus (STG) relative to controls. MD-aMCI showed decreased ReHo, mostly located in precuneus (PCu), LG and postcentral gyrus (PCG), relative to SD-aMCI and controls. As for microvascular disease, MD-aMCI patients had more PWMH burden than SD-aMCI and controls. Correlation analyses indicated mean ReHo in differenced regions were related with memory, language, and executive function in aMCI patients. However, no significant associations between PWMH and behavioral data were found. The Aβ level was related with the ReHo value of STG in SD-aMCI. MD-aMCI displayed different patterns of abnormal regional synchronization and more severe PWMH burden compared with SD-aMCI. Therefore aMCI is not a uniform disease entity, and MD-aMCI group may show more complicated pathologies than SD-aMCI group.

Affect of APOE on information processing speed in non-demented elderly population: a preliminary structural MRI study

APOE is one of the strongest genetic factors associated with information processing speed (IPS). Herein, we explored the neural substrates underlying APOE-related IPS alteration by measuring lobar distribution of white matter hyperintensities (WMH), cortical grey matter volume (GMV) and thickness. Using the ADNI database, we evaluated 178 cognitively normal elderly individuals including 34 APOE ε2 carriers, 54 APOE ε4 carriers and 90 ε3 homozygotes. IPS was determined using Trail Making Tests (TMT). We quantified lobar distribution of WMH, cortical GM lobar volume, cortical thickness among three groups. Finally, we used Pearson’s correlation and general linear models to examine structural MRI markers in relation to IPS. There were significant differences of IPS among groups, with ε4 carriers displaying the worst performance. Across groups, significant differences in frontal and parietal WMH load were observed (the highest in ε4 carriers); however, no significant differences in cortical GMV and thickness were found. Pearson’s correlation analysis showed parietal WMH volume was significantly related with IPS, especially in ε4 carriers. Subsequently a general linear model demonstrated that parietal WMH volume, age and the interaction between parietal WMH volume and age, was significantly associated with IPS, even after adjusting total intracranial volume (TIV), gender and vascular risk factors. Disruption of WM structure, rather than atrophy of GM, plays a more critical role in APOE ε4 allele-specific IPS. Moreover, specific WMH loci are closely associated with IPS; increased parietal WMH volume, especially in ε4 carriers, was independently contributed to slower IPS.

Disrupted Brain Network in Progressive Mild Cognitive Impairment Measured by Eigenvector Centrality Mapping is Linked to Cognition and Cerebrospinal Fluid Biomarkers

Mild cognitive impairment (MCI) is a heterogeneous condition associated with a high risk of progressing to Alzheimers disease (AD). Although functional brain network alterations have been observed in progressive MCI (pMCI), the underlying pathological mechanisms of network alterations remain unclear. In the present study, we evaluated neuropsychological, imaging, and cerebrospinal fluid (CSF) data at baseline across a cohort of: 21 pMCI patients, 33 stable MCI (sMCI) patients, and 29 normal controls. Fast eigenvector centrality mapping (fECM) based on resting-state functional MRI (rsfMRI) was used to investigate brain network organization differences among these groups, and we further assessed its relation to cognition and AD-related pathology. Our results demonstrated that pMCI had decreased eigenvector centrality (EC) in left temporal pole and parahippocampal gyrus, and increased EC in left middle frontal gyrus compared to sMCI. In addition, compared to normal controls, patients with pMCI showed decreased EC in right hippocampus and bilateral parahippocampal gyrus, and sMCI had decreased EC in right middle frontal gyrus and superior parietal lobule. Correlation analysis showed that EC in the left temporal pole was related to Wechsler Memory Scale-Revised Logical Memory (WMS-LM) delay score (r = 0.467, p = 0.044) and total tau (t-tau) level in CSF (r = -0.509, p = 0.026) in pMCI. Our findings implicate EC changes of different brain network nodes in the prognosis of pMCI and sMCI. Importantly, the association between decreased EC of brain network node and pathological changes may provide a deeper understanding of the underlying pathophysiology of pMCI.

Abnormal of inter-hemispheric functional connectivity in elderly subjects with overweight/obesity

BACKGROUND There is a growing literature documenting a variety of brain abnormalities associated with obesity. However, little is known about the effects of obesity on inter-hemispheric connectivity in aging people. METHODS Participants included 61 cognitively intact elderly (including people with obesity, overweight, and lean controls) who underwent structural MRI, resting-state functional magnetic resonance imaging (rsfMRI) and standard neuropsychological batteries. Techniques including FreeSurfer and Voxel-mirrored Homotopic Connectivity (VMHC) were employed to evaluate inter-hemispheric structural and functional connectivity respectively. RESULTS There were no differences of cognitive abilities and vascular risks among groups. When compared to lean controls, obese group had greater VMHC in fusiform gyrus (FG); while overweight group had greater VMHC in FG, calcarine gyrus, inferior temporal gyrus (ITG), and postcentral gyrus (PCG). Moreover, the obesity group had lower VMHC in calcarine gyrus and PCG than overweight group (p<0.05, corrected). CONCLUSIONS The present study suggested, increased inter-hemispheric information transmission in networks supporting visual and sensorimotor function may lead to gain in weight, by possibly mediating diet behaviours of individuals.

A Comparison Study of Single-Echo Susceptibility Weighted Imaging and Combined Multi-Echo Susceptibility Weighted Imaging in Visualizing Asymmetric Medullary Veins in Stroke Patients.

Background Asymmetric medullary veins (AMV) are frequently observed in stroke patients and single-echo susceptibility weighted imaging (SWIs) is the main technique in detecting AMV. Our study aimed to investigate which echo time (TE) on single-echo susceptibility is the optimal echo for visualizing AMV and to compare the ability in detecting AMV in stroke patients between SWIs and multi-echo susceptibility weighted imaging (SWIc). Materials and Methods Twenty patients with middle cerebral artery stroke were included. SWI was acquired by using a multi-echo gradient-echo sequence with six echoes ranging from 5 ms to 35.240 ms. Three different echoes of SWIs including SWIs1 (TE = 23.144 ms), SWIs2 (TE = 29.192 ms) and SWIs3 (TE = 35.240 ms) were reconstructed. SWIc was averaged using the three echoes of SWIs. Image quality and venous contrast of medullary veins were compared between SWIs and SWIc using peak signal-to-noise ratio (PSNR), mean opinion score (MOS), contrast-to-noise ratio (CNR) and signal-to-noise ratio (SNR). The presence of AMV was evaluated in each SWIs (1–3) and SWIc. Results SWIs2 had the highest PSNR, MOS and CNR and SWIs1 had the highest SNR among three different echoes of SWIs. No significant difference was found in SNR between SWIs1 and SWIs2. PSNR, MOS and CNR in SWIc were significantly increased by 27.9%, 28.2% and 17.2% compared with SWIs2 and SNR in SWIc was significantly increased by 32.4% compared with SWIs1. 55% of patients with AMV were detected in SWIs2, SWIs3 and SWIc, while 50% AMV were found in SWIs1. Conclusions SWIs using TE around 29ms was optimal in visualizing AMV. SWIc could improve image quality and venous contrast, but was equal to SWIs using a relative long TE in evaluating AMV. These results provide the technique basis for further research of AMV in stroke.

Decreased Bilateral FDG-PET Uptake and Inter-Hemispheric Connectivity in Multi-Domain Amnestic Mild Cognitive Impairment Patients: A Preliminary Study

Background: Amnestic mild cognitive impairment (aMCI) is a heterogeneous condition. Based on clinical symptoms, aMCI could be categorized into single-domain aMCI (SD-aMCI, only memory deficit) and multi-domain aMCI (MD-aMCI, one or more cognitive domain deficit). As core intrinsic functional architecture, inter-hemispheric connectivity maintains many cognitive abilities. However, few studies investigated whether SD-aMCI and MD-aMCI have different inter-hemispheric connectivity pattern. Methods: We evaluated inter-hemispheric connection pattern using fluorine-18 positron emission tomography – fluorodeoxyglucose (18F PET-FDG), resting-state functional MRI and structural T1 in 49 controls, 32 SD-aMCI, and 32 MD-aMCI patients. Specifically, we analyzed the 18F PET-FDG (intensity normalized by cerebellar vermis) in a voxel-wise manner. Then, we estimated inter-hemispheric functional and structural connectivity by calculating the voxel-mirrored homotopic connectivity (VMHC) and corpus callosum (CC) subregions volume. Further, we correlated inter-hemispheric indices with the behavioral score and pathological biomarkers. Results: We found that MD-aMCI exhibited more several inter-hemispheric connectivity damages than SD-aMCI. Specifically, MD-aMCI displayed hypometabolism in the bilateral middle temporal gyrus (MTG), inferior parietal lobe, and left precuneus (PCu) (p < 0.001, corrected). Correspondingly, MD-aMCI showed decreased VMHC in MTG, PCu, calcarine gyrus, and postcentral gyrus, as well as smaller mid-posterior CC than the SD-aMCI and controls (p < 0.05, corrected). Contrary to MD-aMCI, there were no neuroimaging indices with significant differences between SD-aMCI and controls, except reduced hypometabolism in bilateral MTG. Within aMCI patients, hypometabolism and reduced inter-hemispheric connectivity correlated with worse executive ability. Moreover, hypometabolism indices correlated to increased amyloid deposition. Conclusion: In conclusion, patients with MD-aMCI exhibited the more severe deficit in inter-hemispheric communication than SD-aMCI. This long-range connectivity deficit may contribute to cognitive profiles and potentially serve as a biomarker to estimate disease progression of aMCI patients.

Altered effective connectivity anchored in the posterior cingulate cortex and the medial prefrontal cortex in cognitively intact elderly APOE ε4 carriers: a preliminary study

The APOE ε4 allele is associated with impaired intrinsic functional connectivity in neural networks, especially in the default mode network (DMN). However, effective connectivity (EC) reflects the direct causal effects of one brain region to another, which has rarely been investigated. Recently, Granger causality analysis (GCA) proved suitable for the study of directionality in neuronal interactions. Using GCA, we examined the differences in the EC between the anterior medial prefrontal cortex/posterior cingulate cortex (aMPFC/PCC) and the whole brain in 17 ε4 carrying and 32 non-carrying cognitively intact elderly individuals. Furthermore, correlation analyses were performed between the abnormal EC and cognition/neuropathological indices. Compared with the non-carriers, the results showed that the ε4 carriers exhibited decreased EC from the PCC to the whole brain in the middle temporal gyrus (MTG), the anterior cingulate cortex (ACC), and the precuneus (PCu). Meanwhile, the ε4 carriers demonstrated increased EC from the whole brain to the aMPFC in the inferior parietal lobe (IPL) and the postcentral gyrus (PCG). The correlation analyses suggested that the EC from the IPL/PCG to the aMPFC was related to episodic memory in non-carriers, while the decreased EC from the PCC to the ACC was associated with increased levels of t-tau in the ε4 carriers. In ε4 carriers, a negative influence can be traced from the PCC to both the anterior and posterior DMN subsystems; meanwhile, the anterior DMN subsystem receives compensatory effects from the parietal cortex. Early increases in AD-related pathologies in the PCC may act as first factors during this pathological process.

Altered function but not structure of the amygdala in nicotine-dependent individuals

ABSTRACT Tobacco use disorder is frequently comorbid with emotional disorders, each exerting reciprocal influence on the other. As an important hub for emotional processing, amygdala may also play a critical role in tobacco addiction. Therefore, we aimed to investigate the volume and spontaneous activity of the amygdala in nicotine‐dependent individuals and their relationships with cigarette use. A total of 84 smokers (aged 22–54 years) and 41 nonsmokers (aged 26–56 years) were enrolled in the present study. 3D‐T1 weighted images and resting‐state fMRI images were acquired from all participants. We used ROI‐wise volume, fractional amplitude of low frequency fluctuation (fALFF) and resting‐state functional connectivity (FC) to assess structural and functional changes of the amygdala in the smokers. There was no significant difference between smokers and nonsmokers on amygdala volume (p > 0.05). When compared to nonsmokers, increased fALFF in the right amygdala was observed in smokers (p = 0.024). In addition, increased FC between the left amygdala and the right precuneus and decreased FC between the right amygdala and the right orbitofrontal cortex (OFC) was found in smokers. In smokers, these amygdala measures did not correlate with any measures of cigarette use. The results revealed that the amygdala function but not volume was affected in nicotine addiction. When considering the fALFF and FC results, we propose that the OFC top‐down control may regulate the amygdala activity in nicotine addicts. The pattern of amygdala‐based FC in smokers revealed in our study may provide new information about the brain circuitry of tobacco dependence. HIGHLIGHTSAmygdala volume and function were compared between smokers and nonsmokers.Different patterns of amygdala‐based functional connectivity (FC) in smokers.Reduced amygdala‐OFC FC top‐down control induced high fALFF in amygdala in smokers.