Search

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: The increasing prevalence of Alzheimer's disease (AD) has emerged as a major challenge worldwide. China as the most populous country in the globe is amid rapid aging of its population, highlighting the need for appropriate social and medical policies to meet the challenge. The current multicenter cross-sectional observational study aims to provide understanding of the current status of caring given to AD patients in China and investigate the factors that influence the family burden as well as the choice of care given to AD patients. Methods: A total of 1,675 patients with probable AD from 30 provincial regions of mainland China were enrolled in the current study from August 2019 to December 2019. We analyzed the caregiving status and its relationship with family burden and various socio-economical and medical factors. Results: In the current study, 90.87% of the AD patients enrolled adopted family care. The choice of caregiving method was influenced by factors including age (>80 years old, OR 0.648; 95% CI, 0.427–0.983), overall family burden (high, OR 0.574; 95% CI, 0.0.373–0.884), patients' income (OR 0.511; 95% CI, 0.330–0.789) and self-care ability (OR 0.329; 95% CI, 0.183–0.588). Conclusion: Family care is the primary method of care for AD patients in China and the institutional care system for AD patients is still underprepared in China. [ABSTRACT FROM AUTHOR]

Background: Activated microglia is present in both Alzheimer's subjects (AD) and mild cognitive impairment (MCI) subjects and can be visualised by both pathological evaluation and in‐vivo imaging studies. It has been established that neuroinflammation plays a vital role in Alzheimer's trajectory and disruption in structural and functional connectivity is also a key event in Alzheimer's disease. However, the mechanism by which microglial activation influence brain structural and functional connectivity remains to be elucidated. 11C‐PBR28 PET is a marker of translocator protein (TSPO) reflecting microglial activation and 18F‐Flutematemol PET is a marker of amyloid deposition. Method: 25 amnestic MCI and 17 healthy controls (HC) were recruited and underwent T1‐weighted, diffusion tensor and resting‐state functional MRI, 11C‐PBR28 and 18F‐Flutemetamol PET scans. 11C‐PBR28 and 18F‐Flutemetamol scans were analysed using target‐to‐cerebellar ratio. Tract‐Based Spatial Statistics was performed on DTI scans. RS‐fMRI scans were analysed using medial prefrontal cortex (MPFC) as a seed. The relationship between tracer uptake and structural integrity of white matter tracts or brain functional connectivity with MPFC was analysed using linear regression corrected for age and gender. Result: MCI cohort showed significantly decreased functional connectivity between MPFC and posterior cingulate and precuneous regions. Cortical 11C‐PBR28 uptake but not 18F‐Flutemetamol was negatively correlated with FA in the corpus callosum, bilateral inferior frontal‐occipital fasciculi and inferior longitudinal fasciculi. MPFC 11C‐PBR28 uptake was correlated with increased MPFC functional connectivity to anterior frontal regions and reduced connectivity to posterior frontal, temporal, parietal and cingulate regions; while frontal amyloid load was correlated with reduced MPFC connectivity with frontal and temporal cortices. Regression analysis with both 18F‐Flutemetamol and 11C‐PBR28 demonstrated that MPFC 11C‐PBR28 was significantly associated MPFC connectivity with posterior frontal, parietal and cingulate regions. Conclusion: The findings suggest that MPFC microglial activation is associated with increased functional connectivity with the nearby regions and decreased connectivity with the distal regions to MPFC in MCI subjects. Findings from DTI analysis showed negative correlation with structural integrity of the long fibre tracts which are connecting distal regions. These findings suggest that neuroinflammation is involved in the structural and functional connectivity disruption and probably remodelling in AD trajectory. [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]

Background: The increasing prevalence of Alzheimer's disease (AD) has emerged as a major challenge worldwide. China as the most populous country in the globe is amid rapid aging of its population, highlighting the need for appropriate social and medical policies to meet the challenge. The current study aims to provide understanding of the current status of caring given to AD patients in China and the underlying factors with a large multicenter cross‐sectional observational approach. Method: A total of 1675 patients with probable AD from 30 provincial regions of mainland China were enrolled in the current study from August 2019 to December 2019. We analyzed the caregiving status and its relationship with family burden and various socioeconomical and medical factors. Result: 90.87% of the patients enrolled adopted family care. The choice of caregiving method was influenced by factors including age (>80 years old, OR 0.648; 95% CI, 0.427–0.983), overall family burden (high, OR 0.574; 95% CI, 0.0.373–0.884),patients' income (OR 0.511; 95% CI, 0.330–0.789) and self‐care ability (OR 0.329; 95% CI, 0.183–0.588). Conclusion: Family care is the primary method of care for AD patients in China and the institutional care system for AD patients is still underprepared in China. [ABSTRACT FROM AUTHOR]

Background: There is growing evidence that microglial activation plays a crucial role in the early pathological changes reported in Alzheimer's disease (AD). Multimodal neuroimaging can be used to detect micro‐ and macrostructural alterations together with molecular imaging to quantify metabolism and proteins expression. Diffusivity map, reflecting neuronal integrity, can be derived from diffusion‐weighted imaging, and is thought to be increased in AD following pathological alterations. We hypothesised that changes in diffusivity could be colocalized with microglial activation at different stages of the disease. Method: 56 patients (mean age=70.4, SD=8.5) cognitively normal (CN, n=15), with mild cognitive impairment (MCI, n=28) and with AD (n=12) were included in this study. All participants underwent diffusion tensor imaging (DTI), amyloid PET ([18F]flutemetamol) and TSPO PET ([11C]PBR28). DTI data were processed with FSL v.6.0 to compute mean diffusivity (MD) maps. Standard uptake ratio (SUVR) values were calculated in SPM12 to identify the amyloid deposition and microglial activation within cortical regions. Amyloid status (Aβ‐positive/Aβ‐negative) was determined from processed data using a cerebellar gray matter ratio with a binding value greater than the CN mean+2SD. Z score maps of MD and [11C]PBR28 SUVR were computed using CN amyloid negative participants as reference. Z score maps were then correlated using SPM8 and the BPM toolbox. Significance was set at a threshold of p<0.05 with an extended threshold of 50 voxels. Result: We found a significant positive correlation clusters between MD and PBR28‐SUVR Z score maps (higher diffusivity correlated with higher microglial activation) in MCI amyloid negative subjects in the temporal lobe (coordinates: 28 ‐3 ‐32, corrected p<0.001, k=7363). In MCI amyloid positive subjects, we found positive correlation in the parietal lobe (coordinates: ‐47 ‐41 39, corrected p=0.008, k=5712). Conclusion: We found colocalized diffusivity and microglial changes in the early stage of the disease, in the temporal lobe of MCI amyloid negative participants and in later stages of the disease, in the parietal lobe of MCI amyloid positive participants. These results suggest the potential of DTI diffusivity and microglial activation imaging in detecting early neuronal damage occurring in dementia. [ABSTRACT FROM AUTHOR]

Background: There is growing evidence that pathological changes in Alzheimer's disease (AD) begin several years before the symptom onset. Neuroimaging approaches can be used to detect microstructural alterations in the early stages of neurodegeneration using diffusion‐weighted MRI. Cortical grey matter mean diffusivity (cMD) is thought to be increased in AD following pathological alterations resulting in disrupted neuronal function, neuronal death and cellular atrophy. We hypothesised that changes in MD could be detected early in the disease progression and that they would be correlated with structural imaging biomarkers. Method: 72 patients (mean age=69.1, SD=9.2) cognitively normal (CN, n=21) and with mild cognitive impairment (MCI, n=51) were included in this study. All participants underwent T1‐weighted MPRAGE MRI, diffusion tensor imaging (DTI) and PET amyloid ([18F]flutemetamol). Regional cortical thickness was measured on T1‐MPRAGE using FreeSurfer v.6.0. DTI data were processed with FSL v.6.0 to compute MD maps. Standard uptake ratio (SUVR) values were calculated in SPM12 to identify the amyloid deposition within cortical regions. Amyloid status (Aβ‐positive/Aβ‐negative) was determined from processed data using a cerebellar gray matter reference to create target‐to‐cerebellar ratio. Subjects were considered positive with an uptake value of greater than mean+2SD of the control subjects. Student's t‐test were used to compare imaging modalities between CN and MCI participants. Pearson's correlation coefficients were calculated to assess the relationship between imaging modalities. Result: There was a significantly increased MD in MCI compared to CN participants in hippocampus (p=0.0213) and in medial temporal lobe (p=0.033). There were no significant group differences neither in whole brain mean cortical thickness (p=0.6984) nor in temporal cortical thickness (p=0.0923). Interestingly, when splitting subjects based on their amyloid status, we found that whole brain MD was significantly negatively correlated with whole brain cortical thickness in amyloid negative (CN+MCI amyloid negative, p<0.001) but not in amyloid positive (CN+MCI amyloid positive, p=0.99). Conclusion: We found that changes in gray matter diffusivity could be detected in the early stages of AD pathology. We also found that there is a direct relationship between MD and structural changes (i.e. cortical thickness) only before amyloid deposition suggesting that MD provides information about early microstructural changes before macrostructural changes. [ABSTRACT FROM AUTHOR]

Background: Neuroinflammation has been established as a key component of Alzheimer's pathology. Numerous cross‐sectional studies have found associations between neuroinflammatory markers and neuronal damage in AD, suggesting neuroinflammation as a potential drive force of disease progression. However, there have been debate on whether neuroinflammation has a causal effect on disease progression. Here we questioned whether neuroinflammation is predictive of future cognitive decline in early stage of the disease. Method: 21 MCI patients were recruited and had baseline T1‐MRI and 11C‐PBR28 scans. Patients were followed up for at least one year (mean follow‐up period 3.1±1.3 years) and had mini‐mental state examinations (MMSE) at each visit. 19 of them had baseline 18F‐Flutemetamol PET, 11 had 18F‐AV1451 scans. 18F‐AV1451 and 11C‐PBR28 SUVR in the medial temporal lobe were measured, while PCA analyses were performed to evaluate uptakes in the neocortex for all 3 tracers. Principle components of temporal lobe volumetric measurements were computed as the neurodegeneration marker. A linear growth model was fitted for each subjects using all available time points, giving the intercept and slope of individual cognition trajectory. Age, intercept, 11C‐PBR28, and T1 MRI markers were then put into linear models to predict slope, and a backward model selection procedure was conducted. To further validate that neuroinflammation is not just a mediator of amyloid and tau pathologies, we further included amyloid and tau markers in the sub‐cohorts and inspected the final model. Result: The average baseline MMSE was 28±1.9 in the study cohort and the average annual change of MMSE was ‐0.46. We found 11C‐PBR28 SUVR in neocortex and MMSE intercept, but not temporal cortical thickness, were predictive of the slope of MMSE decline. In subgroups where 18F‐Flutemetamol and 18F‐AV1451 SUVRs were included respectively, we found neocortical amyloid and tau load were also predictive of MMSE slope, while 11C‐PBR28 SUVR remained its significance in the models. Conclusion: Our findings suggest that neuroinflammation is an independent factor that drives disease progression and cognitive decline in early stage of AD. Molecular imaging biomarkers may better predict patients' outcome as they detect underlying biological processes. [ABSTRACT FROM AUTHOR]

Background: Microglial activation has been found surrounding amyloid plaques and neurofibrillary tangles in brains of Alzheimer's subjects. In‐vivo imaging using 11C‐PBR28 (a marker of translocator protein over expressed in activated microglia) has demonstrated significant correlation between both amyloid (18F‐Flutematemol PET) and tau deposition (18F‐AV1451 PET). However, it is not clear whether tau or amyloid predominantly influence microglial activation. Methods: 11C‐PBR28, 18F‐Flutematemol, 18F‐AV1451 PET scans were performed on clinically diagnosed mild cognitive impairment and Alzheimer's dementia patients (n=20). 90‐120 minute summed 18F‐Flutematemol, 80‐100 minute summed 18F‐AV1451 and 60‐90 minute summed 11C‐PBR28 images were created. Tracer uptake in cerebellar grey matter was then sampled and individual image was divided by cerebellar uptake. The images were then smoothed with 6mm FWHM and analysed. Multiple regression analysis was performed using by VoxelStats package with 11C‐PBR28 as dependent variable, and 18F‐Flutematemol, 18F‐AV1451 and age as independent variable. Correction for multiple comparison was applied based on random field theory. Results: In the current model, amyloid deposition was found to contribute to elevated microglial activation in the posterior part of the brain including bilateral temporal, occipital lobe and posterior cingulate. While tau deposition contributed to neuroinflammation in wide‐spread areas covering bilateral frontal, temporal, parietal, occipital lobe and cingulate cortex. Conclusion: In the current model tau deposition had more unique contribution to microglial activation in MCI and AD cohort, suggesting that tau formation has a stronger association with microglial activation which is independent of amyloid deposition. [ABSTRACT FROM AUTHOR]

Introduction: In China, the increasing number of people with Alzheimer's disease (AD) poses a great challenge to families and the country. Economic and cultural differences cause a urban-rural gap in medical resources. This multicenter survey aimed to investigate the real-world practice of disease treatment among people with AD., Methods: People with AD and their caregivers from 30 provincial regions in mainland China were enrolled from October 2020 to December 2020 to be surveyed for their treatment experience. Logistic regression was used to explore the factors that influence medication adherence in all areas, urban areas, and rural areas., Results: In this survey, 1,427 participants came from urban areas, and 539 participants came from rural areas. Patients in urban areas were older (mean age 74 vs. 70, p = 0.001), less frequently had mild AD (36.0 vs. 52.1%, p < 0.001), and more often were cared for at professional institutions (8.8 vs. 3.2%, p < 0.001). In terms of pharmacotherapy, 77.8% of people accepted taking lifelong medication, whereas 61.3% of patients insisted on taking medications. Although 72.0% of rural people believed in taking lifelong medication, only 30.0% adhered to drug use. The major factors that influenced medication adherence for all patients with AD were regional distribution ( p < 0.001, OR = 6.18, 95% CI: 4.93-7.74) and family earnings ( p = 0.003, OR = 1.22, 95% CI: 1.07-1.38). In rural areas, family earnings ( p = 0.008, OR = 1.44, 95% CI: 1.10-1.89) and severity of AD ( p = 0.033, OR = 1.31, 95% CI: 1.02-1.68) were the main factors. Family earnings ( p = 0.038, OR = 1.16, 95% CI: 1.01-1.34) was the only factor among urban areas. Among all non-pharmaceutical activities except for cognitive intervention, the participation rates of rural patients were significantly higher than those of urban patients ( p < 0.05)., Conclusion: Although national progress has been made in the public awareness of disease treatment, adequate diagnosis and medication adherence need to be prompted, especially in rural areas. Furthermore, lifelong treatment should be improved based on regional characteristics through the joint efforts of the government, health workers, and social volunteers., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Li, Liu, Wan, Sheng, Wang, Leng, Peng, Wang, Du, Zhu, Mima, Wang, Xie, Wang, Jin and Sun.)