Longitudinal associations between ß-amyloid and cortical thickness in mild cognitive impairment.

How beta-amyloid accumulation influences brain atrophy in Alzheimer's disease remains contentious with conflicting findings. We aimed to elucidate the correlations of regional longitudinal atrophy with cross-sectional regional and global amyloid in individuals with mild cognitive impairment and no cognitive impairment. We hypothesized that greater cortical thinning over time correlated with greater amyloid deposition, particularly within Alzheimer's disease characteristic regions in mild cognitive impairment, and weaker or no correlations in those with no cognitive impairment. 45 patients with mild cognitive impairment and 12 controls underwent a cross-sectional [11C]-Pittsburgh Compound B PET and two retrospective longitudinal structural imaging (follow-up: 23.65 ± 2.04 months) to assess global/regional amyloid and regional cortical thickness, respectively. Separate linear mixed models were constructed to evaluate relationships of either global or regional amyloid with regional cortical thinning longitudinally. In patients with mild cognitive impairment, regional amyloid in the right banks of the superior temporal sulcus was associated with longitudinal cortical thinning in the right medial orbitofrontal cortex (P = 0.04 after False Discovery Rate correction). In the mild cognitive impairment group, greater right banks amyloid burden and less cortical thickness in the right medial orbitofrontal cortex showed greater visual and verbal memory decline over time, which was not observed in controls. Global amyloid was not associated with longitudinal cortical thinning in any locations in either group. Our findings indicate an increasing influence of amyloid on neurodegeneration and memory along the preclinical to prodromal spectrum. Future multimodal studies that include additional biomarkers will be well-suited to delineate the interplay between various pathological processes and amyloid and memory decline, as well as clarify their additive or independent effects along the disease deterioration.

Cerebral microinfarcts affect brain structural network topology in cognitively impaired patients.

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.

Distinct BOLD variability changes in the default mode and salience networks in Alzheimer's disease spectrum and associations with cognitive decline.

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.

Mechanisms Linking White Matter Lesions, Tract Integrity, and Depression in Alzheimer Disease.

OBJECTIVE: Late-life depression involves the disconnection of white matter tracts that regulate mood. A pathogenic link between poor tract integrity and depressive symptoms is believed to be white matter lesions (WML), however the mechanisms linking tract integrity, WML, and depression remains unexplored. The authors sought to identify whether the association between reduced tract integrity and depressive symptoms is mediated by WML in patients with Alzheimer disease (AD), and whether individual characteristics moderate this effect. METHODS: This was a cross-sectional study in a tertiary memory clinic. A total of 91 patients with mild AD and 79 healthy elderly, comparable in depressive symptoms, white matter hyperintensities (WMH) volume, cardiovascular risk, age, and sex were chosen. Tract integrity was assessed using diffusion tensor imaging, WML were indexed as WMH, measured using fluid-attenuation inversion recovery imaging, and depressive symptoms were measured with the informant-based Geriatric Depression Scale. RESULTS: In patients with mild AD, reduced tract integrity in right hemispheric cortical-subcortical tracts and the genu of the corpus callosum was moderately associated with depressive symptoms. This association was fully mediated by WML. Moderation analysis indicated that old age strengthened the association between all tracts and depressive symptoms, as mediated by WML. In cognitively healthy elderly, neither tracts nor WML were related to depressive symptoms. CONCLUSION: Reduced tract integrity may be important but not sufficient for the manifestation of depressive symptoms in mild AD. Instead, WML may drive the pathogenic link between reduced tract integrity and depressive symptoms.

White matter microstructural abnormalities and default network degeneration are associated with early memory deficit in Alzheimer's disease continuum.

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.

Amyloid burden accelerates white matter degradation in cognitively normal elderly individuals.

Alterations in parietal and temporal white matter microstructure derived from diffusion tensor imaging occur in preclinical and clinical Alzheimer's disease. Amyloid beta (Aß) deposition and such white matter alterations are two pathological hallmarks of Alzheimer's disease. However, the relationship between these pathologies is not yet understood, partly since conventional diffusion MRI methods cannot distinguish between cellular and extracellular processes. Thus, we studied Aß-associated longitudinal diffusion MRI changes in Aß-positive (N = 21) and Aß-negative (N = 51) cognitively normal elderly obtained from the Alzheimer's Disease Neuroimaging Initiative dataset using linear mixed models. Aß-positivity was based on Alzheimer's Disease Neuroimaging Initiative amyloid-PET recommendations using a standardized uptake value ratio cut-off of 1.11. We used free-water imaging to distinguish cellular and extracellular changes. We found that Aß-positive subjects had increased baseline right uncinate fasciculus free-water fraction (FW), associated with worse baseline Alzheimer's disease assessment scale scores. Furthermore, Aß-positive subjects showed faster decrease in fractional anisotropy (FW-corrected) in the right uncinate fasciculus and faster age-dependent right inferior longitudinal fasciculus FW increases over time. Right inferior longitudinal fasciculus FW increases were associated with greater memory decline. Importantly, these results remained significant after controlling for gray and white matter volume and hippocampal volume. This is the first study to illustrate the influence of Aß burden on early longitudinal (in addition to baseline) white matter changes in cognitively normal elderly individuals at-risk of Alzheimer's disease, thus underscoring the importance of longitudinal studies in assessing microstructural alterations in individuals at risk of Alzheimer's disease prior to symptoms onset.

Cerebrovascular disease influences functional and structural network connectivity in patients with amnestic mild cognitive impairment and Alzheimer's disease.

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.

Heat shock protein 90 facilitates formation of the HBV capsid via interacting with the HBV core protein dimers.

The mechanism by which host factors contribute to hepatitis B virus (HBV) capsid formation during the viral life cycle remains unclear. This study analyzed the interaction between heat shock protein 90 (Hsp90), a host factor, and the HBV core protein. Hsp90 was found to bind to HBV core protein dimers, which was then encapsidated into the HBV capsid. Furthermore, activated Hsp90 may facilitate the formation of the human HBV capsid by catalyzing core assembly and reducing the degree of capsid dissociation at various temperatures, both in vitro and in vivo, and when subjected to detergent treatments in vitro. In addition, inhibition or downregulation of Hsp90 reduced HBV production in HepG2.2.15 cells. These results showed that Hsp90 plays an important role in HBV capsid stabilization and HBV formation.

Hepatitis B virus core interacts with the host cell nucleolar protein, nucleophosmin 1.

Hepatitis B virus (HBV) genome replication requires the packaging of viral factors (pregenomic RNA and polymerase) as well as host factors, including heat shock proteins and protein kinase C. Previous reports have suggested that there are several unidentified host factors that affect this encapsidation step. In this study, we identified a new host factor, nucleophosmin (B23) that interacts with the HBV core protein 149 (Cpl49). We analyzed this factor using NHS-activated sepharose resin and MALDI-TOF MS. Using the BIAcore analysis system, we were also able to deduce that the B23.1 residues 259-294 were required for the interaction between Cpl49 and B23.1 in vitro.