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Cerebral microinfarcts (CMIs), a novel cerebrovascular marker, are prevalent in Alzheimer's disease (AD) and associated with cognitive impairment. Nonetheless, the underlying mechanism of how CMIs influence cognition remains uncertain. We hypothesized that cortical-CMIs disrupted structural connectivity in the higher-order cognitive networks, leading to cognitive impairment. We analyzed diffusion-MRI data of 92 AD (26 with cortical-CMIs) and 110 cognitive impairment no dementia patients (CIND, 28 with cortical-CMIs). We compared structural network topology between groups with and without cortical-CMIs in AD/CIND, and tested whether structural connectivity mediated the association between cortical-CMIs and cognition. Cortical-CMIs correlated with impaired structural network topology (i.e. lower efficiency/degree centrality in the executive control/dorsal attention networks in CIND, and lower clustering coefficient in the default mode/dorsal attention networks in AD), which mediated the association of cortical-CMIs with visuoconstruction dysfunction. Our findings provide the first in vivo human evidence that cortical-CMIs impair cognition in elderly via disrupting structural connectivity.

Optimal levels of intrinsic Blood-Oxygenation-Level-Dependent (BOLD) signal variability (variability hereafter) are important for normative brain functioning. However, it remains largely unknown how network-specific and frequency-specific variability changes along the Alzheimer's disease (AD) spectrum and relates to cognitive decline. We hypothesized that cognitive impairment was related to distinct BOLD variability alterations in two brain networks with reciprocal relationship, i.e., the AD-specific default mode network (DMN) and the salience network (SN). We examined variability of resting-state fMRI data at two characteristic slow frequency-bands of slow4 (0.027-0.073 Hz) and slow5 (0.01-0.027 Hz) in 96 AD, 98 amnestic mild cognitive impairment (aMCI), and 48 age-matched healthy controls (HC) using two commonly used pre-processing pipelines. Cognition was measured with a neuropsychological assessment battery. Using both global signal regression (GSR) and independent component analysis (ICA), results generally showed a reciprocal DMN-SN variability balance in aMCI (vs. AD and/or HC), although there were distinct frequency-specific variability patterns in association with different pre-processing approaches. Importantly, lower slow4 posterior-DMN variability correlated with poorer baseline cognition/smaller hippocampus and predicted faster cognitive decline in all patients using both GSR and ICA. Altogether, our findings suggest that reciprocal DMN-SN variability balance in aMCI might represent an early signature in neurodegeneration and cognitive decline along the AD spectrum.

Instead of assuming a constant relationship between brain abnormalities and memory impairment, we aimed to examine the stage-dependent contributions of multimodal brain structural and functional deterioration to memory impairment in the Alzheimer's disease (AD) continuum. We assessed grey matter volume, white matter (WM) microstructural measures (free-water (FW) and FW-corrected fractional anisotropy), and functional connectivity of the default mode network (DMN) in 54 amnestic mild cognitive impairment (aMCI) and 46 AD. We employed a novel sparse varying coefficient model to investigate how the associations between abnormal brain measures and memory impairment varied throughout disease continuum. We found lower functional connectivity in the DMN was related to worse memory across AD continuum. Higher widespread white matter FW and lower fractional anisotropy in the fornix showed a stronger association with memory impairment in the early aMCI stage; such WM-memory associations then decreased with increased dementia severity. Notably, the effect of the DMN atrophy occurred in early aMCI stage, while the effect of the medial temporal atrophy occurred in the AD stage. Our study provided evidence to support the hypothetical progression models underlying memory dysfunction in AD cascade and underscored the importance of FW increases and DMN degeneration in early stage of memory deficit.

Chronic postsurgical pain (CPSP) occurs in up to 50% of individuals after surgeries and 32% after hysterectomy, leading to major adverse effects on quality of life and socioeconomic burden. Little is known about whether and how large-scale neural networks being affected in CPSP, particularly with regard to the functional connectivity (FC) of insula which is known to be the hub of the intrinsic neural network playing a critical role in pain processing. Here, we sought to examine the dynamics of insular FC in the context of noxious stimuli in CPSP patients. To this aim, resting state fMRI data were acquired, before and after acute heat pain stimulation, from 11 individuals with chronic post-hysterectomy pain (CPHP) and 22 age-matched healthy controls (HCs) who had a hysterectomy but without chronic post-surgical pain. We examined whole-brain FC were mapped by seeding at the sensorimotor and chemosensory subfields of the insula and found significant group × stimulation interaction effects. Specifically, the HC group had increased FC between the left sensorimotor insula and right angular and middle occipital gyrus (MOG) and increased FC between the left chemosensory insula and bilateral angular and MOG following pain stimulation. In contrast, such pain stimulation related FC changes were absent in the CPHP group. Furthermore, higher insular FC at baseline and smaller increased insular FC after pain stimulation correlated with clinical pain scores in CPHP patients. Our findings suggest that CPSP is associated with altered dynamics of large-scale functional networks anchored in the insula.

Background: Patients with amnestic mild cognitive impairment (aMCI) and Alzheimer's disease (AD) show functional and structural connectivity alterations in the default mode network (DMN) while cerebrovascular disease (CeVD) shows functional and structural connectivity changes in the executive control network (ECN). Such disruptions are associated with memory and executive function impairment, respectively. Concurrent AD and CeVD pathology is associated with a higher rate of cognitive decline and differential neurodegenerative patterns. Together, such findings are likely reflective of different underlying pathology in AD with and without CeVD. However, few studies have examined the effect of CeVD on network functional connectivity (task-free functional magnetic resonance imaging (fMRI)) and structural connectivity (diffusion MRI) of the DMN and ECN in aMCI and AD using a hypothesis-driven multiple seed-based approach., Methods: We examined functional and structural connectivity network changes in 39 aMCI, 50 aMCI+CeVD, 47 AD, 47 AD+CeVD, and 65 healthy controls (HCs) and their associations with cognitive impairment in the executive/attention and memory domains., Results: We demonstrate divergent DMN and ECN functional connectivity changes in CeVD and non-CeVD subjects. Compared with controls, intra-DMN hippocampal functional connectivity reductions were observed in both AD and AD+CeVD, while intra-DMN parietal and medial prefrontal-parietal functional connectivity was higher in AD+CeVD and aMCI+CeVD, but lower in AD. Intra-ECN frontal functional connectivity increases and fronto-parietal functional connectivity decreases occurred in CeVD but not non-CeVD subjects. Such functional connectivity alterations were related with cognitive impairment in a dissociative manner: intra-DMN functional connectivity changes were associated with worse cognition primarily in non-CeVD groups, while intra-ECN functional connectivity changes were associated with worse cognition primarily in CeVD groups. Additionally, CeVD and non-CeVD groups showed overlapping and distinct alterations in inter-network DMN-ECN functional connectivity depending on disease severity. In contrast to functional connectivity, CeVD groups had greater network structural connectivity damage compared with non-CeVD groups in both aMCI and AD patients. Network structural connectivity damage was associated with worse cognition., Conclusions: We demonstrate differential functional and structural network changes between aMCI and AD patients with and without CeVD through diverging and deleterious network-based degeneration underlying domain-specific cognitive impairment.

Spatial working memory (SWM) relies on the interplay of anatomically separated and interconnected large-scale brain networks. EEG studies often observe load-associated sustained negative activity during SWM retention. Yet, whether and how such sustained negative activity in retention relates to network-specific functional activation/deactivation and relates to individual differences in SWM capacity remain to be elucidated. To cover these gaps, we recorded concurrent EEG-fMRI data in 70 healthy young adults during the Sternberg delayed-match-to-sample SWM task with three memory load levels. To a subset of participants (N = 28) that performed the task properly and had artefact-free fMRI and EEG data, we employed a novel temporo-spatial principal component analysis to derive load-dependent negative slow wave (NSW) from retention-related event-related potentials. The associations between NSW responses with SWM capacity were divergent in the higher (N = 14) and lower (N = 14) SWM capacity groups. Specifically, larger load-related increase in NSW amplitude was associated with greater SWM capacity for the higher capacity group but lower SWM capacity for the lower capacity group. Furthermore, for the higher capacity group, larger NSW amplitude was related to greater activation in bilateral parietal areas of the fronto-parietal network (FPN) and greater deactivation in medial frontal gyrus and posterior mid-cingulate cortex of the default mode network (DMN) during retention. In contrast, the lower capacity group did not show similar pattern. Instead, greater NSW was linked to higher deactivation in right posterior middle temporal gyrus. Our findings shed light on the possible differential EEG-informed neural network mechanism during memory maintenance underlying individual differences in SWM capacity., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Network-sensitive neuroimaging methods have been used to characterize large-scale brain network degeneration in Alzheimer's disease and its prodrome. However, few studies have investigated the combined effect of Alzheimer's disease and cerebrovascular disease on brain network degeneration. Our study sought to examine the intrinsic functional connectivity and structural covariance network changes in 235 prodromal and clinical Alzheimer's disease patients with and without cerebrovascular disease. We focused particularly on two higher-order cognitive networks-the default mode network and the executive control network. We found divergent functional connectivity and structural covariance patterns in Alzheimer's disease patients with and without cerebrovascular disease. Alzheimer's disease patients without cerebrovascular disease, but not Alzheimer's disease patients with cerebrovascular disease, showed reductions in posterior default mode network functional connectivity. By comparison, while both groups exhibited parietal reductions in executive control network functional connectivity, only Alzheimer's disease patients with cerebrovascular disease showed increases in frontal executive control network connectivity. Importantly, these distinct executive control network changes were recapitulated in prodromal Alzheimer's disease patients with and without cerebrovascular disease. Across Alzheimer's disease patients with and without cerebrovascular disease, higher default mode network functional connectivity z-scores correlated with greater hippocampal volumes while higher executive control network functional connectivity z-scores correlated with greater white matter changes. In parallel, only Alzheimer's disease patients without cerebrovascular disease showed increased default mode network structural covariance, while only Alzheimer's disease patients with cerebrovascular disease showed increased executive control network structural covariance compared to controls. Our findings demonstrate the differential neural network structural and functional changes in Alzheimer's disease with and without cerebrovascular disease, suggesting that the underlying pathology of Alzheimer's disease patients with cerebrovascular disease might differ from those without cerebrovascular disease and reflect a combination of more severe cerebrovascular disease and less severe Alzheimer's disease network degeneration phenotype., (© The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background: Mixed vascular and neurodegenerative dementia, such as Alzheimer's disease (AD) with concomitant cerebrovascular disease, has emerged as the leading cause of age-related cognitive impairment. The brain white matter (WM) microstructural changes in neurodegeneration well-documented by diffusion tensor imaging (DTI) can originate from brain tissue or extracellular free water changes. The differential microstructural and free water changes in AD with and without cerebrovascular disease, especially in normal-appearing WM, remain largely unknown. To cover these gaps, we aimed to characterize the WM free water and tissue microstructural changes in AD and mixed dementia as well as their associations with cognition using a novel free water imaging method., Methods: We compared WM free water and free water-corrected DTI measures as well as white matter hyperintensity (WMH) in patients with AD with and without cerebrovascular disease, patients with vascular dementia, and age-matched healthy control subjects., Results: The cerebrovascular disease groups had higher free water than the non-cerebrovascular disease groups. Importantly, besides the cerebrovascular disease groups, patients with AD without cerebrovascular disease also had increased free water in normal-appearing WM compared with healthy control subjects, reflecting mild vascular damage. Such free water increases in WM or normal-appearing WM (but not WMH) contributed to dementia severity. Whole-brain voxel-wise analysis revealed a close association between widespread free water increases and poorer attention, executive functioning, visual construction, and motor performance, whereas only left hemispheric free water increases were related to language deficits. Moreover, compared with the original DTI metrics, the free water-corrected DTI metric revealed tissue damage-specific (frontal and occipital) microstructural differences between the cerebrovascular disease and non-cerebrovascular disease groups. In contrast to both lobar and subcortical/brainstem free water increases, only focal lobar microstructural damage was associated with poorer cognitive performance., Conclusions: Our findings suggest that free water analysis isolates probable mild vascular damage from WM microstructural alterations and underscore the importance of normal-appearing WM changes underlying cognitive and functional impairment in AD with and without cerebrovascular disease. Further developed, the combined free water and tissue neuroimaging assays could help in differential diagnosis, treatment planning, and disease monitoring of patients with mixed dementia.

Both healthy and pathological aging due to Alzheimer's disease (AD) are associated with decreased brain grey matter volume (GMV) and disrupted white matter (WM) microstructure. Thinner macular ganglion cell-inner plexiform layer (GC-IPL) measured by spectral-domain optical coherence tomography has been reported in patients with AD and mild cognitive impairment. Emerging evidence suggested a link between thinner GC-IPL and lower GMV in subjects with no dementia using region-of-interest-based approach. However, it remains unknown whether GC-IPL thickness is associated with brain WM microstructure and how such association differed between normal and cognitively impaired subjects. Here, for subjects with no cognitive impairment (NCI), thinner GC-IPL was associated with lower WM microstructure integrity in the superior longitudinal fasciculus, inferior fronto-occipital fasciculus, corticospinal tracts, anterior thalamic radiation, and cingulum regions, while it was weakly associated with lower GMV in visual cortex and cerebellum. Nevertheless, these retina-brain associations were disrupted in the presence of cognitive impairment. Correlations between GMV and GC-IPL were lost in patients with cognitive impairment but no dementia (CIND) and AD patients. GC-IPL was related to WM microstructural disruption in similar regions with decreased significance. In contrast, lower WM microstructure integrity in the fornix showed a trend of correlation with thinner GC-IPL in both CIND and AD but not NCI. Collectively, our findings suggest the possible physiological retina-brain relationship in healthy aging, which might be disrupted by disease-induced changes in patients with cognitive impairment. Longitudinal study with larger patient sample should follow to confirm the disease mechanism behind these retina-brain relationship changes.

Evidences suggested that both corpus callosum (CC) degeneration and alternations of homotopic inter-hemispheric functional connectivity (FC) are present in Alzheimer's disease (AD). However, the associations between region-specific CC degeneration and homotopic inter-hemispheric FC and their relationships with memory deficits in AD remain uncharacterized. We hypothesized that selective CC degeneration is associated with memory impairment in AD and amnestic mild cognitive impairment (aMCI), which is mediated by homotopic inter-hemispheric functional dysconnectivity. Using structural magnetic resonance imaging (MRI) and task-free functional MRI, we assessed the CC volume and inter-hemispheric FC in 66 healthy controls, 41 aMCI and 41 AD. As expected, AD had CC degeneration and attenuated inter-hemispheric homotopic FC. Nevertheless, aMCI had relatively less severe CC degeneration (mainly in mid-anterior, central, and mid-posterior) and no reduction in inter-hemispheric homotopic FC. The degeneration of each CC sub-region was associated with specific inter-hemispheric homotopic functional disconnections in AD and aMCI. More importantly, impairment of inter-hemispheric homotopic FC partially mediated the association between CC (particularly the central and posterior parts) degeneration and memory deficit. Notably, these results remained after controlling for hippocampal volume. Our findings shed light on how CC degeneration and the related inter-hemispheric FC impact memory impairment in early stage of AD.

It is known that Interferon (IFN) is present in normal body fluids and tissues during pregnancy. Using an immunohistochemical technique and a panel of monoclonal antibodies we have localized IFN-alpha, -beta and -gamma directly on formalin-fixed paraffin-embedded normal human placentae at different stages of pregnancy and in the hydatidiform mole. The results show that IFNs is mostly localized in villous syncytiotrophoblast and in extravillous interstitial-trophoblast. No reactivity was observed in villous cytotrophoblast or in cytotrophoblast cell columns. The most intense staining was observed for IFN-alpha and -beta, while IFN-gamma was rather weak. There is then a gradual diminution in IFN reactivity with increasing gestation age being almost imperceptible at term. These results suggest that IFN may deploy antiviral, immunomodulator and differentiation activities during normal human pregnancy.