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Background: Neuroinflammation in Alzheimer's disease is known as an important process in the disease, yet how microglial activation affects disease progression remains unclear. Objective: The current study aims to interrogate the predictive value of neuroinflammation biomarker (11C-PBR28 PET), together with A/T/N imaging markers on disease deterioration in a cognitively impaired patient cohort. Methods: The study included 6 AD and 27 MCI patients, who had MRI, 11C-PBR28, 18F-flutemetamol (amyloid marker), 18F-AV1451 (tau marker) PET scans, and were followed up with multiple neuropsychological assessments for at least one year (1.6 and 2.8 years on average for AD and MCI). The predictive values of imaging biomarkers on baseline and longitudinal cognition were interrogated using linear regression to identify the biomarkers that could explain disease progression. Results: Linear mixed models found the average intercepts (baseline) MMSE were 23.5 for AD and 28.2 for MCI patients, and the slope of MMSE (annual change) were –0.74 for AD and –0.52 for MCI patients. White matter microstructural integrity was predictive of baseline cognition, while PET markers of amyloid, tau and neuroinflammation were predictive of longitudinal cognitive decline. Both amyloid and neuroinflammation PET markers were predictors independent of each other. And a sub-group analysis showed the predictive effect of neuroinflammation on cognitive decline is independent of amyloid and tau. Conclusions: Our study highlights the prognostic value of disease specific markers (amyloid, tau and neuroinflammation) in clinically diagnosed AD and MCI patients and suggests that the effects of these molecular markers are mediated by structural damage to the brain. [ABSTRACT FROM AUTHOR]

Background: Recently it has been proposed that microglial response has a stage-dependent effect on the progression of Alzheimer's disease (AD). Cerebrospinal fluid (CSF) sTREM2 has emerged as a promising microglial activation marker.Objective: To test the stage-dependent role of microglia by studying the association between baseline sTREM2 and dynamic brain structural changes in AD and mild cognitive impairment (MCI) patients.Methods: 22 amyloid-β-positive (A+) and tau-positive (T+) AD and 24 A+T+MCI patients were identified from the Alzheimer's Disease Neuroimaging Initiative. The patients had baseline CSF amyloid-β, phosphorylated-tau, and sTREM2, and were followed up for at least one year by T1-weighted and diffusion tensor imaging scans. Gray matter volumes and white matter microstructural integrity were evaluated. Linear mixed models were applied to analyze how baseline sTREM2 may influence the rate of brain structural changes while adjusting for the effects of age, APOE4 status, and the CSF core markers.Results: In A+T+AD patients, baseline CSF sTREM2 was associated with faster mean diffusivity increase in the bilateral posterior corona radiata and right superior longitudinal fasciculus. In A+T+MCI patients, baseline CSF sTREM2 was associated slower gray matter volumetric loss in parahippocampal gyrus, left fusiform cortex, left middle temporal gyrus, and left lateral occipital cortex. Baseline CSF sTREM2 also had a protective effect against mean diffusivity increase in right inferior fronto-occipital fasciculus, left superior longitudinal fasciculus, left forceps minor, and left uncinate fasciculus.Conclusion: Microglial activation at early stage might have a protective effect against neurodegeneration, while at late stage it might facilitate AD. Future efforts on modulating microglial activation could be promising, given a carefully selected time window for intervention. [ABSTRACT FROM AUTHOR]

Background: To investigate whether neuroinflammation and β‐amyloid (Aβ) deposition influence brain structural and functional connectivity in Alzheimer's spectrum, we conducted a cross‐sectional multimodal imaging study and interrogated the associations between imaging biomarkers of neuroinflammation, Aβ deposition, brain connectivity and cognition. Method: 58 participants (25 MCI, 16 AD dementia and 17 healthy controls) were recruited and scanned with 11C‐PBR28 and 18F‐flutemetamol PET, T1‐weighted, diffusion tensor and resting‐state functional MRI. Brain structural and functional connectivity were assessed by global white matter integrity and functional topology metrics, while neuroinflammation and Aβ deposition were evaluated by 11C‐PBR28 and 18F‐flutemetamol uptake, respectively. Changes of the biomarkers were compared between diagnostic groups and robust regression analyses at both voxel and regional level were performed on Aβ positive patients, who were considered to be representative of Alzheimer's continuum. Result: Increased 11C‐PBR28 and 18F‐flutemetamol uptake, decreased FA values, impaired small‐worldness and local efficiency of functional network were observed in the AD cohort. In Aβ‐positive patients, cortical 11C‐PBR28 uptake correlated with decreased structural integrity and network local efficiency independent of 18F‐flutemetamol uptake and cortical thickness. Network structural integrity and cortical thickness correlated with functional metrics, including small‐worldness and local efficiency, which were all associated with cognition. Conclusion: Our findings suggest that cortical neuroinflammation may lead to disruption of structural and functional brain network independent of amyloid deposition and cortical atrophy, which in turn can lead to cognitive impairment in AD. [ABSTRACT FROM AUTHOR]

Background: The role of neuroinflammation in the pathogenesis of Alzheimer's disease (AD) is still controversial. Recent studies proposed that microglial response may have a stage‐dependent effect on disease progression. Considering the CSF soluble triggering receptor expressed on myeloid cells 2 (sTREM2) has emerged as a promising marker of microglial activation, we aimed to further test this hypothesis by studying the association between baseline sTREM2 with dynamic brain structural changes in different stage of AD. Method: 22 amyloid‐positive (A+) and tau‐positive (T+) AD patients and 24 A+T+ MCI patients were identified from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. The patients had baseline measurements of CSF A‐beta, P‐Tau, sTREM2, baseline and follow‐up T1‐weighted and diffusion tensor imaging (DTI) scans, and were followed up for at least one year. Voxel‐based morphometry (VBM) analysis was performed to assess grey matter volumetric change, while fractional anisotropy (FA) and mean diffusivity (MD) were derived from DTI scans to evaluate white matter microstructural integrity. Linear mixed effect models were then applied to model the longitudinal change of grey and white matter integrity, and to analyze the influence of baseline sTREM2 on the rate of brain structural changes. Result: In A+T+ AD patients, baseline CSF sTREM2 was associated with faster FA decline and MD increase in association fibers including corpus callosum, inferior longitudinal fasciculus, cingulum, inferior fronto‐occipital fasciculus, and superior longitudinal fasciculus. In A+T+ MCI patients, baseline CSF sTREM2 was associated slower grey matter volumetric loss in regions including Alzheimer's signature cortices such as angular gyrus and precuneus, while mixed findings were found regarding white matter integrity, with a protective effect with regard to MD but a potential negative effect against FA values in association fibers. Conclusion: The current study suggests that microglial activation at early AD stage might have a protective effect against neurodegeneration, while at late stage, it might facilitate neurodegenerative process. These observations support the hypotheses that microglial response is an active factor in the process of Alzheimer's pathogenesis, and that it has stage‐dependent effects on disease progression. Future efforts on modulating microglial activation could be promising, given a carefully selected time window for intervention. [ABSTRACT FROM AUTHOR]

Aim: To investigate the features of skip lesions and evaluate value of top‐hat procedure in management of squamous intraepithelial lesion. Methods: We reviewed the records of patients who underwent loop electrosurgical excision procedure (LEEP) in Peking University First Hospital between 2011 and 2016. Patients were confirmed to have CIN1–3. The term 'skip lesion' refers to lesion lying deep in cervical canal discontiguous with other lesions in transformation zone and was confirmed by top‐hat. We compared their lesion grade in patients with or without skip lesion using logistic regression. We further reviewed patients who underwent subsequent hysterectomy within 6 months following LEEP and evaluated if top‐hat procedure led to less residual lesions or was able to predict residual lesions. Results: A total of 2260 patients were included and 595 underwent top‐hat procedure. Thirty‐nine out of 595 patients had skip lesions (6.5%), among whom two patients had CIN1 (5.1%), eight had CIN2 (20.5%) and 29 had CIN3 (74.4%). Logistical regression showed CIN3 was associated with higher risk of skip lesions compared to CIN1 (OR = 4.433, 95%CI: 1.036–18.964), while CIN2 was not (OR = 1.762, 95%CI: 0.366–8.471). Sixty‐two patients underwent hysterectomy within 6 months following LEEP (CIN1–3), 24 underwent top‐hat. Analysis revealed top‐hat procedure did not result in less residual lesions. Colposcopy impression or prior HPV test was unable to predict skip lesions. Conclusion: About 9.4% patients with CIN3 had skip lesions in the study, which is associated with elevated risk for residual lesion. Top‐hat procedure is able to detect skip lesions, but should not be performed on routinely because its prognostic value is not proved. [ABSTRACT FROM AUTHOR]