Neuroimaging biomarkers of glial activation for predicting the annual cognitive function decline in patients with Alzheimer's disease.

BACKGROUND: Glial activation is central to the pathogenesis of Alzheimer's disease (AD). However, researchers have not demonstrated its relationship to longitudinal cognitive deterioration. We aimed to compare the prognostic effects of baseline positron emission tomography (PET) imaging of glial activation and amyloid/tau pathology on the successive annual cognitive decline in patients with AD. METHODS: We selected 17 patients diagnosed with mild cognitive impairment or AD. We assessed the annual changes in global cognition and memory. Furthermore, we assessed the predictive effects of baseline amyloid and tau pathology indicated by cerebrospinal fluid (CSF) concentrations and PET imaging of glial activation (11C-DPA-713-binding potential in the area of Braak 1-3 [11C-DPA-713-BPND]) on global cognition and memory using a stepwise regression analysis. RESULTS: The final multiple regression model of annual changes in global cognition and memory scores included 11C-DPA-713-BPND as the predictor. The CSF Aß42/40 ratios and p-tau concentrations were removed from the final model. In stepwise Bayesian regression analysis, the Bayes factor-based model comparison suggested that the best model included 11C-DPA-713-BPND as the predictor of decline in global cognition and memory. CONCLUSIONS: Translocator protein-PET imaging of glial activation is a stronger predictor of AD clinical progression than the amount of amyloid/tau pathology measured using CSF concentrations. Glial activation is the primary cause of tau-induced neuronal toxicity and cognitive deterioration, thereby highlighting the potential of blocking maladaptive microglial responses as a therapeutic strategy for AD treatment.

Involvement of inflammation in the medial temporal region in the development of agitation in Alzheimer's disease: an in vivo positron emission tomography study.

BACKGROUND: The evaluation of 11 C-DPA-713 binding using positron emission tomography for quantifying the translocator protein can be a sensitive approach in determining the level of glial activation induced by neuroinflammation. Herein, we aimed to investigate the relationship between regional 11 C-DPA713-binding potential (BPND ) and neuropsychiatric symptoms (NPS) in amyloid-positive Alzheimer's disease (AD) patients. METHODS: Fifteen AD patients were enrolled in this study. Correlations were evaluated between the 11 C-DPA713-BPND and Neuropsychiatric Inventory Questionnaire (NPI-Q) scores, including scores in its four domains: agitation, psychosis, affective, and apathy. 11 C-DPA713-BPND values were compared between groups with and without the neuropsychiatric symptoms for which a relationship was observed in the abovementioned correlation analysis. RESULTS: A positive correlation was found between the severity of agitation and 11 C-DPA713-BPND in the Braak 1-3 area, including the amygdala, hippocampal and parahippocampal regions, and lingual and fusiform areas. An increase in the 11 C-DPA713-BPND was observed in AD patients with agitation. We did not find any significant effects of possible confounding factors, such as age, duration of illness, education, gender, Mini-Mental State Examination score, cerebrospinal fluid amyloid ß 42/40 ratio, and apolipoprotein E4 positivity, on either the 11 C-DPA713-BPND or agitation score. CONCLUSIONS: Neuroinflammation in the medial temporal region and its neighbouring area was shown to be associated with the development of agitation symptoms in AD patients. Our findings extend those of previous studies showing an association between some NPS and inflammation, suggesting that immunologically based interventions for agitation can serve as an alternative treatment for dementia.

Iodinated Contrast Media Substitution to Prevent Recurrent Hypersensitivity Reactions: A Systematic Review and Meta-Analysis.

Background Changing iodinated contrast media (ICM) may reduce the risk of recurrent ICM-induced hypersensitivity reactions in patients with a prior reaction. Purpose To perform a systematic review on the effectiveness of ICM change in comparison with no change to prevent recurrent ICM immediate hypersensitivity reactions. Materials and methods Multiple data bases were searched without language restriction between January 1990 and August 2021 to identify comparative studies of any design that included patients with a prior ICM hypersensitivity reaction to low-osmolality ICM and re-exposure to intravascular ICM. The methods used included a duplicate assessment of eligibility, double extraction of quantitative data, validity assessment, and random-effects meta-analysis. The primary outcome was the incidence of all-grade immediate recurrent hypersensitivity reactions. Secondary outcomes were the incidence of severe immediate recurrent hypersensitivity reactions and other adverse events associated with ICM change. Results Six retrospective observational studies at moderate to severe risk of bias assessed 7155 adult patients (4329 in the ICM change group and 2826 in the no-change group). Studies adopted nonstandardized switching methods, and the proportions of the ICM change group ranged between 19% (five of 27 examinations) and 80% (3104 of 3880 examinations). A Bayesian meta-analysis revealed that changing ICM was associated with a reduced risk of recurrent hypersensitivity reaction by 61% (risk ratio = 0.39; 95% credible interval [CrI]: 0.24, 0.58). The wide-ranging estimates of risk reduction were not explained by the risk of bias ratings, the event rates in the no-change group, the index-reaction severity, or the co-administered nonstandard premedication. Rare severe recurrent reactions (five studies with five events) precluded a conclusion (risk ratio = 0.34, favoring ICM change; CrI: 0.01, 3.74). Adverse events associated with ICM change were not reported. Conclusion In observational evidence of limited quality, iodinated contrast media (ICM)-change was associated with a reduced risk of recurrent immediate hypersensitivity reaction in patients with a prior ICM-induced hypersensitivity reaction. © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by McDonald in this issue.

Diagnostic accuracy of DAT-SPECT and MIBG scintigraphy for dementia with Lewy bodies: an updated systematic review and Bayesian latent class model meta-analysis.

PURPOSE: Imperfect clinical reference standards can preclude accurately estimating the diagnostic accuracy of DAT-SPECT and MIBG myocardial scintigraphy for diagnosing DLB. To investigate the validity of unadjusted accuracy, we updated our previous meta-analysis. METHODS: Literature search was updated to March 18, 2018. We also examined published systematic review reports. Two investigators extracted data and rated study validity using the QUADAS-2 tool. We performed a Bayesian latent class model meta-analysis accounting for imperfect reference standards. RESULTS: We evaluated 27 studies including 2236 patients. With the exception of two DAT-SPECT studies that involved postmortem neuropathological verification, studies were susceptible to bias from imperfect reference standards. Compared with the unadjusted accuracy estimates, the adjusted sensitivity values were similar, whereas the adjusted specificity values were generally lower for detecting α-synuclein pathology in the brain. The adjusted summary sensitivity and specificity were 0.86 (95% credible interval [CrI], 0.76-0.95) and 0.81 (CrI, 0.70-0.92), and 0.93 (CrI, 0.74-1.00) and 0.75 (CI, 0.47-0.94) for visual and semi-quantitative assessments of DAT-SPECT, respectively; 0.92 (CrI, 0.81-0.99) and 0.80 (CrI, 0.67-0.93), and 0.87 (CrI, 0.74-0.98) and 0.80 (CrI, 0.69-0.93), for delayed- and early-phase scans of MIBG scintigraphy, respectively. When diagnosing the typical clinical syndrome, the adjusted accuracy values were similar to the unadjusted estimates. The adjusted sensitivity and specificity were 0.89 (CrI, 0.75-0.98) and 0.87 (CrI, 0.72-0.97), and 0.97 (CrI, 0.78-1.0) and 0.70 (CrI, 0.43-0.92) for visual and semi-quantitative assessments of DAT-SPECT, respectively; and 0.93 (CrI, 0.81-0.98) and 0.90 (CrI, 0.73-0.97), and 0.85 (CrI, 0.66-0.96) and 0.96 (95% CI, 0.83-1.0) for delayed- and early-phase scans of MIBG scintigraphy, respectively. CONCLUSIONS: In our adjusted analyses, both imaging biomarkers had high diagnostic accuracy for detecting the hallmark pathology in the brain and for diagnosing the typical clinical syndrome.

[Comparison of Kinetic Curve between Gadodiamide Hydrate and Gadobutrol on Breast Dynamic Contrast-enhanced Magnetic Resonance Imaging in Invasive Ductal Carcinoma].

The shape of the kinetic curve for gadobutrol is reportedly different compared with that for other conventional contrast agents. We speculate that the shape of gadobutrol kinetic curve may be influenced by different magnetic resonance imaging (MRI) protocols and evaluation methods. The purpose of our study was to assess the influence between gadobutrol and other conventional contrast agent (gadodiamide hydrate) on the kinetic curve in invasive ductal carcinoma (IDC). We assessed 139 women of IDC in this study. Gadodiamide hydrate (2 ml/s) was administered to 69 women, and gadobutrol (1 ml/s) was administrated to 70 women, both contrast agents at 0.1 mmol/kg BW. When the kinetic curves of contrast agents were evaluated between by Breast Imaging Reporting and Data System (BI-RADS) 4th edition and BI-RADS 5th edition, suggested that the analysis method of BI-RADS may affect. Patient group who were administered gadobutrol demonstrated a lower washout rate when compared with patient group who were administered gadodiamide hydrate administration (P<0.01). These results suggest that the kinetic curve characteristics of gadobutrol are an important consideration in diagnosis. Therefore, it is necessary to perform image diagnosis by considering the influence of the contrast agent and the analysis method, when image diagnostic doctor perform image diagnosis.

MRI and FDG-PET for assessment of response to neoadjuvant chemotherapy in locally advanced rectal cancer.

BACKGROUND: The purpose of this study was to assess the value of magnetic resonance imaging (MRI) and additional (18)F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) for tumor response to neoadjuvant chemotherapy (NAC) in patients with locally advanced rectal cancer (LARC). METHODS: Data on 40 patients with LARC, who were treated with NAC and underwent MRI and FDG-PET/CT before and after NAC, were analyzed retrospectively. Surgery was performed at a median of 6 weeks after NAC and the images were compared with the histological findings. The tumor regression grade 3/4 was classified as a responder. RESULTS: Sixteen patients were pathological responders. Receiver operating characteristic (ROC) analysis revealed that MRI total volume after NAC (MRI-TV2) and ΔMRI-TV had the highest performance to assess responders (area under the ROC curve [AUC] 0.849 and AUC 0.853, respectively). The reduction rate of the maximum standardized uptake value (ΔSUVmax) was also an informative factor (AUC 0.719). There seems no added value of adding FDG-PET/CT to MRI-TV2 and ΔMRI-TV in assessment of NAC responders judging from changes in AUC (AUC of ΔSUVmax and MRI-TV2 was 0.844, and AUC of ΔSUVmax and ΔMRI-TV was 0.846). CONCLUSIONS: MRI-TV2 and ΔMRI-TV were the most accurate factors to assess pathological response to NAC. Although ΔSUVmax by itself was also informative, the addition of FDG-PET/CT to MRI did not improve performance. Patients with LARC who were treated by induction chemotherapy should receive an MRI examination before and after NAC to assess treatment response. A more than 70 % volume reduction shown by MRI volumetry may justify the omission of subsequent radiotherapy.

Blood levels of glial fibrillary acidic protein for predicting clinical progression to Alzheimer's disease in adults without dementia: a systematic review and meta-analysis protocol.

BACKGROUND: There is urgent clinical need to identify reliable prognostic biomarkers that predict the progression of dementia symptoms in individuals with early-phase Alzheimer's disease (AD) especially given the research on and predicted applications of amyloid-beta (Aß)-directed immunotherapies to remove Aß from the brain. Cross-sectional studies have reported higher levels of cerebrospinal fluid and blood glial fibrillary acidic protein (GFAP) in individuals with AD-associated dementia than in cognitively unimpaired individuals. Further, recent longitudinal studies have assessed the prognostic potential of baseline blood GFAP levels as a predictor of future cognitive decline in cognitively unimpaired individuals and in those with mild cognitive impairment (MCI) due to AD. In this systematic review and meta-analysis, we propose analyzing longitudinal studies on blood GFAP levels to predict future cognitive decline. METHODS: This study will include prospective and retrospective cohort studies that assessed blood GFAP levels as a prognostic factor and any prediction models that incorporated blood GFAP levels in cognitively unimpaired individuals or those with MCI. The primary outcome will be conversion to MCI or AD in cognitively unimpaired individuals or conversion to AD in individuals with MCI. Articles from PubMed and Embase will be extracted up to December 31, 2023, without language restrictions. An independent dual screening of abstracts and potentially eligible full-text reports will be conducted. Data will be dual-extracted using the CHeck list for critical appraisal, data extraction for systematic Reviews of prediction Modeling Studies (CHARMS)-prognostic factor, and CHARMS checklists, and we will dual-rate the risk of bias and applicability using the Quality In Prognosis Studies and Prediction Study Risk-of-Bias Assessment tools. We will qualitatively synthesize the study data, participants, index biomarkers, predictive model characteristics, and clinical outcomes. If appropriate, random-effects meta-analyses will be performed to obtain summary estimates. Finally, we will assess the body of evidence using the Grading of Recommendation, Assessment, Development, and Evaluation Approach. DISCUSSION: This systematic review and meta-analysis will comprehensively evaluate and synthesize existing evidence on blood GFAP levels for prognosticating presymptomatic individuals and those with MCI to help advance risk-stratified treatment strategies for early-phase AD. TRIAL REGISTRATION: PROSPERO CRD42023481200.

Comparison of consistency in centiloid scale among different analytical methods in amyloid PET: the CapAIBL, VIZCalc, and Amyquant methods.

OBJECTIVE: The Centiloid (CL) scale is a standardized measure for quantifying amyloid deposition in amyloid positron emission tomography (PET) imaging. We aimed to assess the agreement among 3 CL calculation methods: CapAIBL, VIZCalc, and Amyquant. METHODS: This study included 192 participants (mean age: 71.5 years, range: 50-87 years), comprising 55 with Alzheimer's disease, 65 with mild cognitive impairment, 13 with non-Alzheimer's dementia, and 59 cognitively normal participants. All the participants were assessed using the three CL calculation methods. Spearman's rank correlation, linear regression, Friedman tests, Wilcoxon signed-rank tests, and Bland-Altman analysis were employed to assess data correlations, linear associations, method differences, and systematic bias, respectively. RESULTS: Strong correlations (rho = 0.99, p < .001) were observed among the CL values calculated using the three methods. Scatter plots and regression lines visually confirmed these strong correlations and met the validation criteria. Despite the robust correlations, a significant difference in CL value between CapAIBL and Amyquant was observed (36.1 ± 39.7 vs. 34.9 ± 39.4; p < .001). In contrast, no significant differences were found between CapAIBL and VIZCalc or between VIZCalc and Amyquant. The Bland-Altman analysis showed no observable systematic bias between the methods. CONCLUSIONS: The study demonstrated strong agreement among the three methods for calculating CL values. Despite minor variations in the absolute values of the Centiloid scores obtained using these methods, the overall agreement suggests that they are interchangeable.

Trait-anxiety and glial-related neuroinflammation of the amygdala and its associated regions in Alzheimer's disease: A significant correlation.

Background: Positron emission tomography, which assesses the binding of translocator protein radiotracers, 11C-DPA-713, may be a sensitive method for determining glial-mediated neuroinflammation levels. This study investigated the relationship between regional 11C-DPA713 binding potential (BPND) and anxiety in patients with Alzheimer's disease (AD) continuum. Methods: Nineteen patients with AD continuum determined to be amyloid-/p-tau 181-positive via cerebrospinal fluid analysis were included in this cross-sectional study (mild cognitive impairment [MCI, n = 5] and AD [n = 14]). Anxiety was evaluated using the State-Trait Anxiety Inventory (STAI). A whole-brain voxel-based analysis was performed to examine the relationship between 11C-DPA-713-BPND values at each voxel and the STAI score. Stepwise multiple regression analysis was performed to determine the predictors of STAI scores using independent variables, including 11C-DPA-713-BPND values within significant clusters. 11C-DPA-713-BPND values were compared between patients with AD continuum with low-to-moderate and high STAI scores. Results: Voxel-based analysis revealed a positive correlation between trait anxiety severity and 11C-DPA713-BPND values in the centromedial amygdala and the left inferior occipital area [P < 0.001 (uncorrected) at the voxel-level]. 11C-DPA713-BPND values in these regions were a strong predictor of the STAI trait anxiety score. Specifically, patients with AD continuum and high trait anxiety had increased 11C-DPA713-BPND values in these regions. Conclusions: The amygdala-occipital lobe circuit influences the control of emotional generation, and disruption of this network by AD pathology-induced inflammation may contribute to the expression of anxiety. Our findings suggest that suppression of inflammation can help effectively treat anxiety by attenuating damage to the amygdala and its associated areas.

PET in the clinical management of glioma: evidence map.

OBJECTIVE: Several studies have assessed PET to complement the anatomic information obtained from other imaging modalities in various clinical contexts for the management of glioma. We constructed an evidence map of clinical evidence on the use of PET in glioma and identified research gaps. MATERIALS AND METHODS: We searched PubMed and Scopus (from inception through June 30, 2011) to identify studies assessing the use of PET for glioma regardless of setting of care or indication. We extracted test objectives, study characteristics, and phases of diagnostic evidence and then assessed research diversity and temporal trends in the literature. We excluded studies assessing only technical feasibility and optimization of PET. RESULTS: A total of 129 studies were considered eligible; the number of articles published annually has greatly increased over time (p for trend < 0.001). Most studies (n = 118, 91%) assessed diagnostic or prognostic performance; fewer studies reported on the impact of PET on diagnostic thinking (n = 4, 3%), therapeutic decisions (n = 4, 3%), or patient-relevant clinical outcomes (n = 3; 2%). Fluorine-18 FDG (n = 73, 57%) or (11)C-methionine (n = 44, 34%) were the two most commonly evaluated PET tracers. Pretherapy assessment (n = 72, 56%) and monitoring of treatment response (n = 48, 37%) were the most common settings of test use assessed in the research studies. CONCLUSION: More primary studies, particularly studies of newer tracers focusing on biopsy or treatment planning, are needed to better characterize the role of PET in specific contexts.

Comparison of liquid crystal display monitors calibrated with gray-scale standard display function and with γ 2.2 and iPad: observer performance in detection of cerebral infarction on brain CT.

OBJECTIVE: The purpose of the study was to compare observer performance in the detection of cerebral infarction on a brain CT using medical-grade liquid crystal display (LCD) monitors calibrated with the gray-scale standard display function and with γ 2.2 and using an iPad with a simulated screen setting. MATERIALS AND METHODS: We amassed 97 sample sets, from 47 patients with proven cerebral infarction and 50 healthy control subjects. Nine radiologists independently assessed brain CT on a gray-scale standard display function LCD, a γ 2.2 LCD, and an iPad in random order over 4-week intervals. Receiver operating characteristic (ROC) analysis was performed by using the continuous scale, and the area under the ROC curve (A(z)) was calculated for each monitor. RESULTS: The A(z) values for gray-scale standard display function LCD, γ 2.2 LCD, and iPad were 0.875, 0.884, and 0.839, respectively. The difference among the three monitors was very small. There was no significant difference between gray-scale standard display function LCD and γ 2.2 LCD. However, the A(z) value was statistically significantly smaller for the iPad than the γ 2.2 LCD (p < 0.05). CONCLUSION: Observer performance for detecting cerebral infarction on the LCD with γ 2.2 calibration was found to be similar to the LCD with gray-scale standard display function calibration. Although observer performance using the iPad was poorer than that using the other LCDs, the difference was small. Therefore, the iPad could not substitute for other LCD monitors. However, owing to the promising potential advantages of tablet PCs, such as portability, further examination is needed into the clinical use of tablet PCs.

An open competition involving thousands of competitors failed to construct useful abstract classifiers for new diagnostic test accuracy systematic reviews.

There are currently no abstract classifiers, which can be used for new diagnostic test accuracy (DTA) systematic reviews to select primary DTA study abstracts from database searches. Our goal was to develop machine-learning-based abstract classifiers for new DTA systematic reviews through an open competition. We prepared a dataset of abstracts obtained through database searches from 11 reviews in different clinical areas. As the reference standard, we used the abstract lists that required manual full-text review. We randomly splitted the datasets into a train set, a public test set, and a private test set. Competition participants used the training set to develop classifiers and validated their classifiers using the public test set. The classifiers were refined based on the performance of the public test set. They could submit as many times as they wanted during the competition. Finally, we used the private test set to rank the submitted classifiers. To reduce false exclusions, we used the Fbeta measure with a beta set to seven for evaluating classifiers. After the competition, we conducted the external validation using a dataset from a cardiology DTA review. We received 13,774 submissions from 1429 teams or persons over 4 months. The top-honored classifier achieved a Fbeta score of 0.4036 and a recall of 0.2352 in the external validation. In conclusion, we were unable to develop an abstract classifier with sufficient recall for immediate application to new DTA systematic reviews. Further studies are needed to update and validate classifiers with datasets from other clinical areas.

Age-related increase of monoamine oxidase B in amyloid-negative cognitively unimpaired elderly subjects.

OBJECTIVE: Monoamine oxidase B (MAO-B) is highly abundant in reactive astrocytes and upregulated in neuroinflammatory processes. However, the age-related change of MAO-B in amyloid-negative cognitively unimpaired elderly subjects has not yet been sufficiently evaluated on positron emission tomography (PET). 18F-THK5351 is a radiotracer with high affinity to MAO-B, which may potentially serve as an imaging biomarker for detecting neuroinflammation. The purpose of this study was to investigate the age-related topographic change of 18F-THK5351 PET in amyloid-negative cognitively unimpaired elderly subjects. METHODS: The age-related change of 18F-THK5351 retention was evaluated on the visual analysis, voxel and region of interest (ROI)-based analyses using Statistical Parametric Mapping and PETSurfer tool of FreeSurfer in 31 amyloid-negative cognitively unimpaired elderly subjects. RESULTS: On visual inspection, elderly groups showed the spread of 18F-THK5351 accumulation from the medial to inferolateral temporal and basal frontal lobes, and cingulate gyrus. Additionally, voxel- and ROI-based analysis demonstrated the correlation between 18F-THK5351 accumulation and participants' age, especially in the inferior temporal lobes. CONCLUSIONS: This study demonstrated age-dependent increase of 18F-THK5351 retention in amyloid-negative cognitively unimpaired subjects, which suggests an increase in MAO-B positive reactive astrocytes with aging.

Kinetic modeling and non-invasive approach for translocator protein quantification with 11C-DPA-713.

INTRODUCTION: 11C-DPA-713 is a positron emission tomography (PET) radiotracer developed for imaging the expression of the translocator protein (TSPO) in glial cells, which is considered to be a marker of the neuroinflammatory burden. This study investigated the pharmacokinetic profile of 11C-DPA-713 and evaluated kinetic modeling and non-invasive TSPO quantification using dynamic PET imaging data in the Alzheimer's disease (AD) and cognitive normal (CN) participants. METHODS: Eleven patients with AD and 6 CN participants were examined using dynamic 11C-DPA-713 PET imaging for 60 min with arterial blood sampling. Time-activity curves were calculated from the cerebellum and three composite regions of interest (ROIs), according to the anatomical definitions of Braak's stages 1 to 3, stage 4, stage 5, and stage 6 that correspond to the pathological stages of tangle deposition. The total distribution volume (VT) was evaluated using compartmental modeling and graphical analysis. Reference region-based methods were implemented using an optimal area that was assumed to be void of the radiotracer target as reference tissue. RESULTS: The concentration of radioactivity in plasma demonstrated rapid clearance. 11C-DPA-713 peaked rapidly in the gray matter. Compartmental modeling resulted in a good fit, and the one-tissue model with estimated blood volume correction (1Tv) showed the best performance. The estimated VT obtained from the graphical plasma methods was highly correlated with that obtained from 1Tv. Reference region-based analysis was conducted using the Braak 6 area as the reference region, and the estimated non-displaceable binding potential was highly correlated with that obtained from 1Tv. CONCLUSION: 11C-DPA-713 possesses properties suitable for TSPO quantification with PET imaging. The Braak 6 area was shown to be a useful reference region in the patients with AD and the CN participants, and non-invasive reference tissue models using the Braak 6 area as a reference region can be employed for TSPO quantification with 11C-DPA-713-PET imaging as an alternative to the invasive compartmental model.

Patterns of Distribution of 18F-THK5351 Positron Emission Tomography in Alzheimer's Disease Continuum.

BACKGROUND: Alzheimer's disease (AD) is conceptualized as a biological continuum encompassing the preclinical (clinically asymptomatic but with evidence of AD pathology) and clinical (symptomatic) phases. OBJECTIVE: Using 18F-THK5351 as a tracer that binds to both tau and monoamine oxidase B (MAO-B), we investigated the changes in 18F-THK5351 accumulation patterns in AD continuum individuals with positive amyloid PET consisting of cognitively normal individuals (CNp), amnestic mild cognitive impairment (aMCI), and AD and cognitively normal individuals (CNn) with negative amyloid PET. METHODS: We studied 69 individuals (32 CNn, 11 CNp, 9 aMCI, and 17 AD) with structural magnetic resonance imaging, 11C-Pittsburgh compound-B (PIB) and 18F-THK5351 PET, and neuropsychological assessment. 18F-THK5351 accumulation was evaluated with visual analysis, voxel-based analysis and combined region of interest (ROI)-based analysis corresponding to Braak neurofibrillary tangle stage. RESULTS: On visual analysis, 18F-THK5351 accumulation was increased with stage progression in the AD continuum. On voxel-based analysis, there was no statistical difference in 18F-THK5351 accumulation between CNp and CNn. However, a slight increase of the bilateral posterior cingulate gyrus in aMCI and definite increase of the bilateral parietal temporal association area and posterior cingulate gyrus/precuneus in AD were detected compared with CNn. On ROI-based analyses, 18F-THK5351 accumulation correlated positively with supratentorial 11C-PIB accumulation and negatively with the hippocampal volume and neuropsychological assessment. CONCLUSION: The AD continuum showed an increase in 18F-THK5351 with stage progression, suggesting that 18F-THK5351 has the potential to visualize the severity of tau deposition and neurodegeneration in accordance with the AD continuum.

Estimation of blood-based biomarkers of glial activation related to neuroinflammation.

Background: Neuroinflammation is a well-known feature of Alzheimer's disease (AD), and a blood-based test for estimating the levels of neuroinflammation would be expected. In this study, we examined and validated a model using blood-based biomarkers to predict the level of glial activation due to neuroinflammation, as estimated by 11C-DPA-713 positron emission tomography (PET) imaging. Methods: We included 15 patients with AD and 10 cognitively normal (CN) subjects. Stepwise backward deletion multiple regression analysis was used to determine the predictors of the TSPO-binding potential (BPND) estimated by PET imaging. The independent variables were age, sex, diagnosis, apolipoprotein E4 positivity, body mass index and the serum concentration of blood-based biomarkers, including monocyte chemotactic protein 1 (MCP-1), fractalkine, chitinase 3-like protein-1 (CHI3L1), soluble triggering receptor expressed on myeloid cells 2 (sTREM2), and clusterin. Results: Sex, diagnosis, and serum concentrations of MCP1 and sTREM2 were determined as predictors of TSPO-BPND in the Braak1-3 area. The serum concentrations of MCP1 and sTREM2 correlated positively with TSPO-BPND. In a leave one out (LOO) cross-validation (CV) analysis, the model gave a LOO CV R2 of 0.424, which indicated that this model can account for approximately 42.4% of the variance of brain TSPO-BPND. Conclusions: We found that the model including serum MCP-1 and sTREM2 concentration and covariates of sex and diagnosis was the best for predicting brain TSPO-BPND. The detection of neuroinflammation in AD patients by blood-based biomarkers should be a sensitive and useful tool for making an early diagnosis and monitoring disease progression and treatment effectiveness.

Diagnostic accuracy, yield, and comparative effectiveness of whole-body computed tomography in blunt trauma: A protocol for systematic review and meta-analysis.

OBJECTIVES: Controversies emerge over routine performances of whole-body computed tomography (WBCT) in patients with blunt polytrauma. The existing randomized and non-randomized evidence is inconclusive, and during observations of non-trauma, incidental findings, detected by WBCT, have left uncertainty regarding their consequences and optimal management. Additionally, previous meta-analyses have failed to address the limitations of primary studies and issues associated with incidental findings. Therefore, we planned a new systematic review to address these points. METHODS: We will search the PubMed, EMBASE, and Cochrane Central databases from inception to December 31, 2020, with no language restriction and perform full-text evaluation of potentially relevant articles. We will include prospective and retrospective studies with a single-gate design that assessed diagnostic accuracy and/or yield of WBCT to detect traumatic injuries, and studies that assessed incidental findings detected by WBCT. Additionally, we will include randomized controlled trials and non-randomized comparative studies that assessed the effectiveness of WBCT against conventional care, including selective computed tomography (CT). Studies of patients of all ages with blunt traumatic injuries, assessed at an emergency department, will be included. Two reviewers will extract data and rate the study validity via standard quality assessment tools. The primary outcome of interest will be reduction in mortality. Our secondary outcomes will include diagnostic accuracy and yield, detection of incidental findings and clinical outcomes associated with these detections, and improvement in other non-mortality clinical outcomes. We will qualitatively assess study, patient, and intervention characteristics and clinical outcomes. If appropriate, we will perform random-effects model meta-analyses to obtain summary estimates. Finally, we will assess the certainty of evidence by the grading the quality of evidence and strength of recommendations. ETHICS AND DISSEMINATION: Ethics approval is not applicable, as this is a secondary analysis of publicly available data. The review results will be submitted for publication in peer-reviewed journals. PROSPERO REGISTRATION: CRD42020187852.

Sloping Shoulders Sign: A Practical Radiological Sign for the Differentiation of Alzheimer's Disease and Argyrophilic Grain Disease.

BACKGROUND: Although hippocampal atrophy is a well-known imaging biomarker of Alzheimer's disease (AD), this finding is not useful to differentiate AD from argyrophilic grain disease (AGD) which is a common AD mimicker presenting with similar amnestic symptoms and medial temporal atrophy. Instead, we propose use of the "sloping shoulders sign", defined as a distinct configuration of the bilateral hippocampal heads showing lateral and downward slopes on axial magnetic resonance imaging (MRI). OBJECTIVE: We investigated the diagnostic utility of the "sloping shoulders sign" as a simple radiological discriminator of AD from AGD. METHODS: Using axial and coronal three-dimensional MRI, our newly proposed "sloping shoulders sign", other quantitative indices including the axial hippocampal head angle (AHHA), and well-known medial temporal atrophy (MTA) score were evaluated in pathologically-proven 24 AD and 11 AGD patients. RESULTS: Detection rate of the "sloping shoulders sign" was significantly higher in all AD groups (83%; 20/24) and AD with Braak neurofibrillary tangle V/VI stage subgroup (88%; 15/17) than in AGD patients (18% - 2/11; p < 0.001 and p < 0.001, respectively). In contrast to the MTA score, this sign as well as AHHA demonstrated higher diagnostic performance and reproducibility, especially to differentiate all AD patients from AGD ones (accuracies of 71.4% , 82.9% and 82.9%; Cohen's kappa of 0.70 and 0.81, and intraclass correlation coefficient of 0.96, respectively). CONCLUSION: The "sloping shoulders sign" is useful to differentiate advanced-stage AD from AGD. Its simplicity and reproducibility based on visual inspection using axial MRI make it suitable for routine clinical practice.

Simple Quantitative Indices for the Differentiation of Advanced-Stage Alzheimer's Disease and Other Limbic Tauopathies.

BACKGROUND: The differentiation of Alzheimer's disease (AD) from age-related limbic tauopathies (LT), including argyrophilic grain disease (AGD) and senile dementia of the neurofibrillary tangle type (SD-NFT), is often challenging because specific clinical diagnostic criteria have not yet been established. Despite the utility of specific biomarkers evaluating amyloid and tau to detect the AD-related pathophysiological changes, the expense and associated invasiveness preclude their use as first-line diagnostic tools for all demented patients. Therefore, less invasive and costly biomarkers would be valuable in routine clinical practice for the differentiation of AD and LT. OBJECTIVE: The purpose of this study is to develop a simple reproducible method on magnetic resonance imaging (MRI) that could be adopted in daily clinical practice for the differentiation of AD and other forms of LT. METHODS: Our newly proposed three quantitative indices and well-known medial temporal atrophy (MTA) score were evaluated using MRI of pathologically-proven advanced-stage 21 AD, 10 AGD, and 2 SD-NFT patients. RESULTS: Contrary to MTA score, hippocampal angle (HPA), inferior horn area (IHA), and ratio between HPA and IHA (i.e., IHPA index) demonstrated higher diagnostic performance and reproducibility, especially to differentiate advanced-stage AD patients with Braak neurofibrillary tangle stage V/VI from LT patients (the area under the receiver-operating-characteristic curve of 0.83, 089, and 0.91; intraclass correlation coefficients of 0.930, 0.998, and 0.995, respectively). CONCLUSION: Quantitative indices reflecting hippocampal deformation with ventricular enlargement are useful to differentiate advanced-stage AD from LT. This simple and convenient method could be useful in daily clinical practice.

Can Medial Temporal Impairment Be an Imaging Red Flag for Neurodegeneration in Disproportionately Enlarged Subarachnoid Space Hydrocephalus?

BACKGROUND: The differentiation of idiopathic normal pressure hydrocephalus (iNPH) from neurodegenerative diseases such as Alzheimer's disease (AD) and dementia with Lewy bodies (DLB) is often challenging because of their non-specific symptoms. Therefore, various neuroradiological markers other than ventriculomegaly have been proposed. Despite the utility of disproportionately enlarged subarachnoid-space hydrocephalus (DESH) for the appropriate selection of shunt surgery candidates, the specificity and neuropathology of this finding have not been sufficiently evaluated. OBJECTIVE: Investigation of the clinicopathological features and comparison of the neuroradiological findings between DESH with postmortem neuropathological diagnoses (pDESH) and clinically-diagnosed iNPH (ciNPH) patients are the main purposes of this study. METHOD: In addition to the retrospective evaluation of clinicopathological information, quantitative, semiquantitative, and qualitative magnetic resonance imaging (MRI) indices were compared between pathologically-investigated 10 patients with pDESH and 10 patients with ciNPHResults:Excluding one patient with multiple cerebral infarctions, the postmortem neuropathological diagnoses of the pathologically-investigated patients were mainly neurodegenerative diseases (five AD, one DLB with AD pathologies, one DLB, one argyrophilic grain disease, and one Huntington's disease). In addition to the common neuroradiological featuresConclusion:Hippocampal atrophy and deformation with temporal horn enlargement seem to be characteristic neuroradiological findings of long-standing severely demented patients with DESH and neurodegenerative diseases, mainly advanced-stage AD.