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Background: Tau‐first cognitive proteinopathy (TCP) denotes a clinical phenotype of Alzheimer disease (AD) showing Florzolotau(18F) positron emission tomography (PET) positivity but a negative amyloid status. Aim: We explored the biological property of tau using longitudinal cognitive and neuroimaging data in TCP and compared with late‐onset AD (LOAD). Method: We enrolled 56 patients with LOAD, 34 patients with TCP, and 26 cognitive unimpaired controls. All of the participants had historical data of 2 to 4 three‐dimensional T1 images and 2 to 6 annual cognitive evaluations over a follow‐up period of 7 years. Tau topography was measured using Florzolotau(18F) PET. In the LOAD and TCP groups, we constructed tau or gray matter clusters covarying with the cognitive measurements. We used mediator analysis to explore the regional tau load as predictor, gray matter partitions as mediators, and significant cognitive test scores as outcomes. Longitudinal cognitive decline and cortical thickness degeneration pattern were analyzed using a linear mixed‐effects model. Results: The TCP group had longitudinal declines in nonexecutive domains. The deterministic factor predicting the short‐term memory score in TCP was the hippocampal volume and not directly via the medial and lateral temporal tau load. These features formed the conceptual differences with LOAD. Discussion: The biological properties of tau and the longitudinal cognitive‐imaging trajectory support the conceptual distinction between TCP and LOAD. TCP represents one specific entity featuring salient short‐term memory impairment, declines in nonexecutive domains, a slower gray matter degenerative pattern, and a restricted impact of tau. [ABSTRACT FROM AUTHOR]

The change in hypometabolism affects the regional links in the brain network. Here, to understand the underlying brain metabolic network deficits during the early stage and disease evolution of AD (Alzheimer disease), we applied correlation analysis to identify the metabolic connectivity patterns using 18F-FDG PET data for NC (normal control), sMCI (stable MCI), pMCI (progressive MCI) and AD, and explore the inter- and intra-hemispheric connectivity between anatomically-defined brain regions. Regions extracted from 90 anatomical structures were used to construct the matrix for measuring the inter- and intra-hemispheric connectivity. The brain connectivity patterns from the metabolic network show a decreasing trend of inter- and intra-hemispheric connections for NC, sMCI, pMCI and AD. Connection of temporal to the frontal or occipital regions is a characteristic pattern for conversion of NC to MCI, and the density of links in the parietal-occipital network is a differential pattern between sMCI and pMCI. The reduction pattern of inter and intra-hemispheric brain connectivity in the metabolic network depends on the disease stages, and is with a decreasing trend with respect to disease severity. Both frontal-occipital and parietal-occipital connectivity patterns in the metabolic network using 18F-FDG PET are the key feature for differentiating disease groups in AD.

Background: Tau pathology plays a crucial role in neurodegeneration diseases including Alzheimer's disease (AD) and non-AD diseases such as progressive supranuclear palsy. Tau positron emission tomography (PET) is an in-vivo and non-invasive medical imaging technique for detecting and visualizing tau deposition within a human brain. In this work, we aim to investigate the biodistribution of the dosimetry in the whole body and various organs for the [18F]Florzolotau tau-PET tracer. A total of 12 healthy controls (HCs) were enrolled at Chang Gung Memorial Hospital. All subjects were injected with approximately 379.03 ± 7.03 MBq of [18F]Florzolotau intravenously, and a whole-body PET/CT scan was performed for each subject. For image processing, the VOI for each organ was delineated manually by using the PMOD 3.7 software. Then, the time-activity curve of each organ was acquired by optimally fitting an exponential uptake and clearance model using the least squares method implemented in OLINDA/EXM 2.1 software. The absorbed dose for each target organ and the effective dose were finally calculated. Results: From the biodistribution results, the elimination of [18F]Florzolotau is observed mainly from the liver to the intestine and partially through the kidneys. The highest organ-absorbed dose occurred in the right colon wall (255.83 μSv/MBq), and then in the small intestine (218.67 μSv/MBq), gallbladder wall (151.42 μSv/MBq), left colon wall (93.31 μSv/MBq), and liver (84.15 μSv/MBq). Based on the ICRP103, the final computed effective dose was 34.9 μSv/MBq with CV of 10.07%. Conclusions: The biodistribution study of [18F]Florzolotau demonstrated that the excretion of [18F]Florzolotau are mainly through the hepatobiliary and gastrointestinal pathways. Therefore, a routine injection of 370 MBq or 185 MBq of [18F]Florzolotau leads to an estimated effective dose of 12.92 or 6.46 mSv, and as a result, the radiation exposure to the whole-body and each organ remains within acceptable limits and adheres to established constraints. Trial registration: Retrospectively Registered at Clinicaltrials.gov (NCT03625128) on 12 July, 2018, https://clinicaltrials.gov/study/NCT03625128. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) and vascular dementia (VaD) are the two most common forms of dementia. However, their neuropsychological and pathological features often overlap, making it difficult to distinguish between AD and VaD. In addition to clinical consultation and laboratory examinations, clinical dementia diagnosis in Taiwan will also include Tc-99m-ECD SPECT imaging examination. Through machine learning and deep learning technology, we explored the feasibility of using the above clinical practice data to distinguish AD and VaD. We used the physiological data (33 features) and Tc-99m-ECD SPECT images of 112 AD patients and 85 VaD patients in the Taiwanese Nuclear Medicine Brain Image Database to train the classification model. The results, after filtering by the number of SVM RFE 5-fold features, show that the average accuracy of physiological data in distinguishing AD/VaD is 81.22% and the AUC is 0.836; the average accuracy of training images using the Inception V3 model is 85% and the AUC is 0.95. Finally, Grad-CAM heatmap was used to visualize the areas of concern of the model and compared with the SPM analysis method to further understand the differences. This research method can quickly use machine learning and deep learning models to automatically extract image features based on a small amount of general clinical data to objectively distinguish AD and VaD. [ABSTRACT FROM AUTHOR]

Synaptic dysfunction is an important pathological hallmark and cause of Alzheimer’s disease (AD). High-frequency stimulation (HFS)-induced long-term potentiation (LTP) has been widely used to study synaptic plasticity, with impaired LTP found to be associated with AD. However, the exact molecular mechanism underlying synaptic plasticity has yet to be completely elucidated. Whether genes regulating synaptic plasticity are altered in AD and contribute to disease onset also remains unclear. Herein, we induced LTP in the hippocampal CA1 region of wildtype (WT) and AD model mice by administering HFS to the CA3 region and then studied transcriptome changes in the CA1 region. We identified 89 genes that may participate in normal synaptic plasticity by screening HFS-induced differentially expressed genes (DEGs) in mice with normal LTP, and 43 genes that may contribute to synaptic dysfunction in AD by comparing HFS-induced DEGs in mice with normal LTP and AD mice with impaired LTP. We further refined the 43 genes down to 14 by screening for genes with altered expression in pathological-stage AD mice without HFS induction. Among them, we found that the expression of Pygm, which catabolizes glycogen, was also decreased in AD patients. We further demonstrated that down-regulation of PYGM in neurons impaired synaptic plasticity and cognition in WT mice, while its overexpression attenuated synaptic dysfunction and cognitive deficits in AD mice. Moreover, we showed that PYGM directly regulated energy generation in neurons. Our study not only indicates that PYGM-mediated energy production in neurons plays an important role in synaptic function, but also provides a novel LTP-based strategy to systematically identify genes regulating synaptic plasticity under physiological and pathological conditions. [ABSTRACT FROM AUTHOR]

Background: The diffusion tensor imaging analysis along the perivascular space (ALPS)‐index can be used to model the glymphatic system in vivo. Aim: This study explores putative mechanisms between prediction of ALPS‐index and cognitive outcomes in young‐onset Alzheimer's disease (YOAD) and age‐matched controls (CTLs) and analyzes whether the link was mediated by the integrity of ALPS‐index‐anchored cerebral gray matter (GM). Methods: We enrolled 130 patients with YOAD and 137 CTLs. All participants underwent three‐dimensional T1‐weighted MRI, diffusion tensor imaging and cognitive tests. We constructed GM regions correlated with the ALPS‐index in the YOAD and CTL groups. For the GM regions significantly correlated with the ALPS‐index and cognitive measures, we extracted a 4‐mm radius sphere. In the YOAD and CTL groups, we used mediator analysis to explore the ALPS‐index as predictor, GM partitions as mediators, and significant cognitive test scores as outcomes. Results: Patient group had significantly lower ALPS‐index. The ALPS‐index was associated with GM volume in the cerebellar gray, dorsolateral prefrontal, thalamus, superior frontal, amygdala and hippocampus, and these coherent regions coincided with those showing GM atrophy in the YOAD group. Mediation analysis of the YOAD group suggested that the relationships between the ALPS‐index and cognitive performance were fully mediated by the integrity of ALPS‐index coherent GM areas. Discussion: Reserved GM mediates the link between the glymphatic system and cognition. Our findings suggest that GM integrity rather than the glymphatic system could serve as a direct cognitive test scores predictor in patients with YOAD. [ABSTRACT FROM AUTHOR]

Objective: The glymphatic system cleans amyloid and tau proteins from the brain in animal studies of Alzheimer disease (AD). However, there is no direct evidence showing this in humans. Methods: Participants (n = 50, 62.6 ± 5.4 years old, 36 women) with AD and normal controls underwent amyloid positron emission tomography (PET), tau PET, structural T1‐weighted magnetic resonance imaging, and neuropsychological evaluation. Whole‐brain glymphatic activity was measured by diffusion tensor image analysis along the perivascular space (DTI‐ALPS). Results: ALPS‐indexes showed negative correlations with deposition of amyloid and tau on PET images and positive correlations with cognitive scores even after adjusting for age, sex, years of education, and APOE4 genotype covariates in multiple AD‐related brain regions (all p < 0.05). Mediation analysis showed that ALPS‐index acted as a significant mediator between regional standardized uptake value ratios of amyloid and tau images and cognitive dysfunction even after correcting for multiple covariates in AD‐related brain regions. These regions are responsible for attention, memory, and executive function, which are vulnerable to sleep deprivation. Interpretation: Glymphatic system activity may act as a significant mediator in AD‐related cognitive dysfunction even after adjusting for multiple covariates and gray matter volumes. ALPS‐index may provide useful disease progression or treatment biomarkers for patients with AD as an indicator of modulation of glymphatic activity. ANN NEUROL 2023;93:164–174 [ABSTRACT FROM AUTHOR]

Background and Purpose: Pyroglutamate-modified β-amyloid peptide (AβpE) is crucial for AD pathophysiological process. The potential associations of plasma AβpE and total tau (t-tau) with brain Aβ burden and cognitive performance remain to be clarified. Methods: Forty-six subjects with unimpaired cognition, mild cognitive impairment, or very mild dementia were enrolled. Plasma levels of AβpE3−40, t-tau, and Aβ42 were quantified by immunomagnetic reduction (IMR) assays. We analyzed individual and combined biomarker correlations with neuropsychological scores and Aβ positivity determined by 18F-florbetapir positron emission tomography (PET). Results: Both plasma AβpE3−40 levels and AβpE3−40/t-tau ratios correlated negatively with short-term memory and global cognition scores, while correlating positively with PET standardized uptake value ratios (SUVRs). Among the biomarkers analyzed, the combination of AβpE3−40 in a ratio with t-tau had the best discriminatory ability for Aβ PET positivity. Likewise, logistic regression analysis showed that AβpE3−40/t-tau was a highly robust predictor of Aβ PET positivity after controlling for relevant demographic covariates. Conclusion: Plasma AβpE3−40/t-tau ratios correlate with cognitive function and cerebral Aβ burden. The suitability of AβpE3−40/t-tau as a candidate clinical biomarker of AD pathology in the brain should be examined further in larger studies. [ABSTRACT FROM AUTHOR]

Objective: To develop a practical method to rapidly utilize a deep learning model to automatically extract image features based on a small number of SPECT brain perfusion images in general clinics to objectively evaluate Alzheimer's disease (AD). Methods: For the properties of low cost and convenient access in general clinics, Tc-99-ECD SPECT imaging data in brain perfusion detection was used in this study for AD detection. Two-stage transfer learning based on the Inception v3 network model was performed using the ImageNet dataset and ADNI database. To improve training accuracy, the three-dimensional image was reorganized into three sets of two-dimensional images for data augmentation and ensemble learning. The effect of pre-training parameters for Tc-99m-ECD SPECT image to distinguish AD from normal cognition (NC) was investigated, as well as the effect of the sample size of F-18-FDG PET images used in pre-training. The same model was also fine-tuned for the prediction of the MMSE score from the Tc-99m-ECD SPECT image. Results: The AUC values of w/wo pre-training parameters for Tc-99m-ECD SPECT image to distinguish AD from NC were 0.86 and 0.90. The sensitivity, specificity, precision, accuracy, and F1 score were 100%, 75%, 76%, 86%, and 86%, respectively for the training model with 1000 cases of F-18-FDG PET image for pre-training. The AUC values for various sample sizes of the training dataset (100, 200, 400, 800, 1000 cases) for pre-training were 0.86, 0.91, 0.95, 0.97, and 0.97. Regardless of the pre-training condition ECD dataset used, the AUC value was greater than 0.85. Finally, predicting cognitive scores and MMSE scores correlated (R2 = 0.7072). Conclusions: With the ADNI pre-trained model, the sensitivity and accuracy of the proposed deep learning model using SPECT ECD perfusion images to differentiate AD from NC were increased by approximately 30% and 10%, respectively. Our study indicated that the model trained on PET FDG metabolic imaging for the same disease could be transferred to a small sample of SPECT cerebral perfusion images. This model will contribute to the practicality of SPECT cerebral perfusion images using deep learning technology to objectively recognize AD. [ABSTRACT FROM AUTHOR]

Introduction: Metabolic brain network analysis based on graph theory using FDG PET imaging is potentially useful for investigating brain activity alternation due to metabolism changes in different stages of Alzheimer's disease (AD). Most studies on metabolic network construction have been based on group data. Here a novel approach in building an individual metabolic network was proposed to investigate individual metabolic network abnormalities. Method: First, a weighting matrix was calculated based on the interregional effect size difference of mean uptake between a single subject and average normal controls (NCs). Then the weighting matrix for a single subject was multiplied by a group-based connectivity matrix from an NC cohort. To study the performance of the proposed individual metabolic network, inter- and intra-hemispheric connectivity patterns in the groups of NC, sMCI (stable mild cognitive impairment), pMCI (progressive mild cognitive impairment), and AD using the proposed individual metabolic network were constructed and compared with those from the group-based results. The network parameters of global efficiency and clustering coefficient and the network density score (NDS) in the default-mode network (DMN) of generated individual metabolic networks were estimated and compared among the disease groups in AD. Results: Our results show that the intra- and inter-hemispheric connectivity patterns estimated from our individual metabolic network are similar to those from the group-based method. In particular, the key patterns of occipital-parietal and occipital-temporal inter-regional connectivity deficits detected in the groupwise network study for differentiating different disease groups in AD were also found in the individual network. A reduction trend was observed for network parameters of global efficiency and clustering coefficient, and also for the NDS from NC, sMCI, pMCI, and AD. There was no significant difference between NC and sMCI for all network parameters. Conclusion: We proposed a novel method in constructing the individual metabolic network using a single-subject FDG PET image and a group-based NC connectivity matrix. The result has shown the effectiveness and feasibility of the proposed individual metabolic network in differentiating disease groups in AD. Future studies should include investigation of inter-individual variability and the correlation of individual network features to disease severities and clinical performance. [ABSTRACT FROM AUTHOR]

Introduction: Due to the high cost and high failure rate of ascertaining amyloid positron emission tomography positivity (PET+) in patients with earlier stage Alzheimer's disease (AD), an effective pre-screening tool for amyloid PET scans is needed. Methods: Patients with mild cognitive impairment (n = 33, 24.2% PET+, 42% females, age 74.4 ± 7.5, MMSE 26.8 ± 1.9) and mild dementia (n = 19, 63.6% PET+, 36.3% females, age 73.0 ± 9.3, MMSE 22.6 ± 2.0) were recruited. Amyloid PET imaging, Apolipoprotein E (APOE) genotyping, and plasma amyloid β (Aβ)1–40, Aβ1–42, and total tau protein quantification by immunomagnetic reduction (IMR) method were performed. Receiver operating characteristics (ROC) analysis and Youden's index were performed to identify possible cut-off points, clinical sensitivities/specificities, and areas under the curve (AUCs). Results: Amyloid PET+ participants had lower plasma Aβ1–42 levels than amyloid PET-negative (PET−) subjects. APOE ε4 carriers had higher plasma Aβ1–42 than non-carriers. We developed an algorithm involving the combination of plasma Aβ1–42 and APOE genotyping. The success rate for detecting amyloid PET+ patients effectively increased from 42.3 to 70.4% among clinically suspected MCI and mild dementia patients. Conclusions: Our results demonstrate the possibility of utilizing APOE genotypes in combination with plasma Aβ1–42 levels as a pre-screening tool for predicting the positivity of amyloid PET findings in early stage dementia patients. [ABSTRACT FROM AUTHOR]

Background: Visual association memory test (VAMT) is a brief 6-point cognition test that has been shown to be effective in differentiating Alzheimer's disease (AD) from other types of dementia. This study aimed to investigate the correlation of the VAMT performance with amyloid plaque burden and hippocampal atrophy.Methods: Fourteen patients with AD, 29 with amnestic mild cognitive impairment (aMCI), and 11 normal cognition (NC) subjects were recruited. Brain magnetic resonance imaging (MRI) and [18F]AV-45 positron emission tomography (PET) were performed to evaluate hippocampal atrophy and amyloid plaque burden.Results: The VAMT median score and interquartile range of the NC, aMCI and AD groups were 6 (6-6), 2 (0-4), and 0 (0-1), respectively (p < 0.001). The hippocampal atrophy was correlated with VAMT results across each group. The VAMT score was correlated with the occipital and parietal cortical [18F]AV-45 uptake in the NC group, and with the frontal, parietal and precuneus uptake in the aMCI group. However, no correlation between VAMT score and [18F]AV-45 uptake was found in the AD group.Conclusion: The VAMT can be an adjunctive cognitive test to identify patients with AD, and the early amyloid plaque accumulation is correlated with VAMT scores in patients with aMCI and even NC subjects. [ABSTRACT FROM AUTHOR]

Objective: This study aims to identify metabolites with altered levels of expression in patients with early and progressive stages of Alzheimer's disease (AD). Methods: All participants of the study underwent genetic screening and were diagnosed using both neuropsychological assessment and amyloid imaging before metabolome analysis. According to these assessments, the patients were classified as normal (n = 15), with mild cognitive impairment (n = 10), and with AD (n = 15). Results: Using a targeted metabolomic approach, we found that plasma levels of C3, C5, and C5‐DC acylcarnitines, arginine, phenylalanine, creatinine, symmetric dimethylarginine (SDMA) and phosphatidylcholine ae C38:2 were significantly altered in patients with early and progressive stages of AD. We created a predictive model based on the decision tree that included three main parameters: age, arginine and C5 plasma concentrations. The model distinguished AD patients from other participants with 60% sensitivity and 86.7% specificity. For healthy controls, the sensitivity was 85.7% and specificity was 61.5%. Multivariate ROC analysis to develop a decision tree showed that our model reached moderate diagnostic power in differentiating between older adults who are cognitively normal (AUC = 0.77) and those with AD (AUC = 0.72). Interpretation: The plasma levels of arginine and valeryl carnitine, together with subject age, are promising as biomarkers for the diagnosis of AD in older adults. [ABSTRACT FROM AUTHOR]

Background: The amyloid AV-45 (florbetapir) positron emission tomography (PET) has been used in the study of the familial Alzheimer's disease (FAD) with the D678H amyloid precursor protein (APP) mutation. In addition, the progress of the disease remains unknown.Objective: We aim to investigate the progression rate of amyloid accumulation in FAD patients with this mutation by neuroimages analysis.Methods: The clinical course, changes in cognitive function, brain magnetic resonance imaging (MRI) and 18F-AV-45 PET scan were investigated in FAD patients and sporadic AD (sAD) patients. We compared the amyloid deposition pattern in serial brain 18F-AV-45 PET scan among the FAD, familial mild cognitive impairment (FMCI), and sMCI and sAD patients.Results: Seven familial patients received a follow-up survey. The follow up duration for brain AV-45 PET was from 1.54 to 3.61 years. In 4 FMCI patients, an increased regional SUVR was noted, and the annual change rates were increased from 1.03% to 18.82%. However, a decreased regional SUVR was noted in 3 FAD patients and the annual change rates were from -2.62% to -16.03%. As compared with the sAD and sMCI patients, the annual change rate is statistically significant in FAD and FMCI patients respectively.Conclusions: The data indicate a biphasic course with an initial increase and then a decrease of SUVR in brain amyloid PET scan in familial APP mutation patients. The data also reveal that the novel Taiwan APP (D678H) mutation has a more amyloid burden than the sAD patients, particularly in an MCI stage. [ABSTRACT FROM AUTHOR]

Abstract: Background: Patients with late‐life depression may be at the preclinical stage of dementia. However, the neurodegenerative processes in late‐life depression are poorly understood. This study aimed to investigate the distribution patterns of amyloid pathology and neurodegeneration in a depressive population without dementia. Methods: The study recruited 63 middle‐aged and elderly patients with major depressive disorder (MDD) and 22 control subjects. The MDD patients were further subdivided into those with mild cognitive impairment (MCI) (n = 24) and non‐MCI (n = 39) patients. We used the global standardized uptake value ratio of 18F‐florbetapir (AV‐45/Amyvid) positron emission tomography imaging as a biomarker of cerebral amyloidosis and the hippocampal volume as a biomarker for neurodegeneration. Cutoff points of brain amyloid positivity and hippocampal atrophy were determined using independent data obtained from clinically diagnosed Alzheimer's disease (AD) patients in a previous study. Results: Most of the control subjects (81.8%) were biomarker‐negative, in contrast to the MCI MDD patients (37.5%). A relatively high proportion of the MCI MDD patients (12.5%) exhibited both amyloid positivity and hippocampal atrophy as compared to the control subjects (4.5%) and non‐MCI patients (5.1%). However, a considerable proportion of the MCI MDD patients (29.2%) were categorized into the group with hippocampal atrophy alone, and negative amyloid deposition, as compared to the control subjects (0%) and non‐MCI patients (5.1%). Conclusions: This study highlights the expected heterogeneity of the processes of neurodegeneration in MDD patients. The diverse neurodegenerative processes may have important etiologic and therapeutic implications regarding neurodegenerative pathophysiology in late‐life depression. [ABSTRACT FROM AUTHOR]

Background/purpose: To determine whether dual-phase 18F-florbetapir positron emission tomography imaging with perfusion-like and amyloid deposition information can distinguish among primary progressive aphasia (PPA), Alzheimer's disease (AD), and healthy controls (HCs).Methods: Patients diagnosed with PPA, including four semantic dementia (SD) and two progressive nonfluent aphasia (PNFA), as well as one logopenic variant (LV) of PPA, were studied. All PPA patients, and age-/sex-matched patients with probable AD (n=8) and HCs (n=8) were subjected to dual-phase 18F-florbetapir imaging. Atlas-based quantitative volumes of interest (VOIs) analysis for six cortical areas and whole cerebellum was performed. The standardized uptake value ratios were calculated by normalizing the dual-phase-integrated activities of the six VOIs to whole cerebellum counts.Results: Early phase 18F-florbetapir image showed significantly lower global perfusion index in six PPA patients as compared with HCs. According to VOI analysis, the hypoperfusion lesions were identified in the frontal, anterior cingulate, parietal, precuneus, and temporal regions. Similar findings were confirmed by voxel-base image comparison. 18F-florbetapir late-phase image showed significantly increased amyloid burden in the global cortex index and all six brain regions of eight AD and LV patients when compared with the other six PPA patients and eight HCs. There was no apparent uptake of amyloid tracer in both six PPA patients and eight HCs.Conclusion: Dual-phase 18F-florbetapir images of six PPA (SD and PNFA) patients showed hypoperfusion in the frontotemporal cortex, and little global amyloid uptake, which may be a distinct image pattern for differentiation among HC, AD, and PPA patients. [ABSTRACT FROM AUTHOR]

Purpose: We investigated dual-phase F-florbetapir (AV-45/Amyvid) PET imaging for the concomitant detection of brain perfusion deficits and beta-amyloid deposition in patients with Alzheimer's disease (AD) and amnestic mild cognitive impairment (MCI), and in cognitively healthy controls (HCs). Methods: A total of 82 subjects (24 AD patients, 44 MCI patients and 14 HCs) underwent both dual-phase F-AV-45 PET and MRI imaging. Dual-phase dynamic PET imaging consisted of (1) five 1-min scans obtained 1 - 6 min after tracer injection (perfusion F-AV-45 imaging, pAV-45), and (2) ten 1-min scans obtained 50 - 60 min after tracer injection (amyloid F-AV-45 imaging). Amyloid-negative MCI/AD patients were excluded. Volume of interest analysis and statistical parametric mapping of pAV-45 and F-AV-45 images were performed to investigate the perfusion deficits and the beta-amyloid burden in the three study groups. The associations between Mini-Mental State Examination (MMSE) scores and global perfusion deficits and amyloid deposition were investigated with linear and segmental linear correlation analyses. Results: HCs generally had normal pAV-45 findings, whereas perfusion deficits were evident in the hippocampus, and temporal, parietal and middle frontal cortices in both MCI and AD patients. The motor-sensory cortex was relatively preserved. MMSE scores in the entire study cohort were significantly associated with the degree of perfusion impairment as assessed by pAV-45 imaging ( r = 0.5156, P < 0.0001). F-AV-45 uptake was significantly higher in AD patients than in the two other study groups. However, the correlation between MMSE scores and F-AV-45 uptake in MCI patients was more of a binary phenomenon and began in MCI patients with MMSE score 23.14 when F-AV-45 uptake was higher and MMSE score lower than in patients with early MCI. Amyloid deposition started in the precuneus and the frontal and temporal regions in early MCI, ultimately reaching the maximum burden in advanced MCI. Conclusion: Our results indicate that brain perfusion deficits and beta-amyloid deposition in AD follow different trajectories that can be successfully traced using dual-phase F-AV-45 PET imaging. [ABSTRACT FROM AUTHOR]

Purpose: The objective of this study was to evaluate the amyloid burden, as assessed by F-florbetapir (AV-45/Amyvid) positron emission tomography PET, in patients with major depressive disorder (MDD) with different subtypes of mild cognitive impairment (MCI) and the relationship between amyloid burden and cognition in MDD patients. Methods: The study included 55 MDD patients without dementia and 21 healthy control subjects (HCs) who were assessed using a comprehensive cognitive test battery and F-florbetapir PET imaging. The standardized uptake value ratios (SUVR) in eight cortical regions using the whole cerebellum as reference region were determined and voxel-wise comparisons between the HC and MDD groups were performed. Vascular risk factors, serum homocysteine level and the apolipoprotein E (ApoE) genotype were also determined. Results: Among the 55 MDD patients, 22 (40.0 %) had MCI, 12 (21.8 %) non-amnestic MCI (naMCI) and 10 (18.2 %) amnestic MCI (aMCI). The MDD patients with aMCI had the highest relative F-florbetapir uptake in all cortical regions, and a significant difference in relative F-florbetapir uptake was found in the parietal region as compared with that in naMCI subjects ( P < 0.05) and HCs ( P < 0.01). Voxel-wise analyses revealed significantly increased relative F-florbetapir uptake in the MDD patients with aMCI and naMCI in the frontal, parietal, temporal and occipital areas ( P < 0.005). The global cortical SUVR was significantly negatively correlated with MMSE score ( r = −0.342, P = 0.010) and memory function ( r = −0.328, P = 0.015). The negative correlation between the global SUVR and memory in the MDD patients remained significant in multiple regression analyses that included age, educational level, ApoE genotype, and depression severity ( β = −3.607, t = −2.874, P = 0.006). Conclusion: We found preliminary evidence of brain beta-amyloid deposition in MDD patients with different subtypes of MCI. Our findings in MDD patients support the hypothesis that a higher amyloid burden is associated with a poorer memory performance. We also observed a high prevalence of MCI among elderly depressed patients, and depressed patients with MCI exhibited heterogeneously elevated F-florbetapir retention as compared with depressed patients without MCI. The higher amyloid burden in the aMCI patients suggests that these patients may also be more likely to develop Alzheimer's disease than other patients diagnosed with major depression. [ABSTRACT FROM AUTHOR]

Purpose: The literature suggests that a history of depression is associated with an increased risk of developing Alzheimer's disease (AD). The aim of this study was to examine brain amyloid accumulation in patients with lifetime major depression using F-florbetapir (AV-45/Amyvid) PET imaging in comparison with that in nondepressed subjects. Methods: The study groups comprised 25 depressed patients and 11 comparison subjects who did not meet the diagnostic criteria for AD or amnestic mild cognitive impairment. Vascular risk factors, homocysteine and apolipoprotein E (ApoE) genotype were also examined. The standard uptake value ratio (SUVR) of each volume of interest was analysed using whole the cerebellum as the reference region. Results: Patients with a lifetime history of major depression had higher F-florbetapir SUVRs in the precuneus (1.06 ± 0.08 vs. 1.00 ± 0.06, p = 0.045) and parietal region (1.05 ± 0.08 vs. 0.98 ± 0.07, p = 0.038) than the comparison subjects. Voxel-wise analysis revealed a significantly increased SUVR in depressed patients in the frontal, parietal, temporal and occipital areas ( p < 0.01). There were no significant associations between global F-florbetapir SUVRs and prior depression episodes, age at onset of depression, or time since onset of first depression. Conclusion: Increased F-florbetapir binding values were found in patients with late-life major depression relative to comparison subjects in specific brain regions, despite no differences in age, sex, education, Mini Mental Status Examination score, vascular risk factor score, homocysteine and ApoE ε4 genotype between the two groups. A longitudinal follow-up study with a large sample size would be worthwhile. [ABSTRACT FROM AUTHOR]

Purpose: Amyloid positron emission tomography (PET) is an important noninvasive method for detecting amyloid burden in Alzheimer's disease (AD) patients. As amyloid PET images have limited anatomical information, magnetic resonance (MR) imaging is usually acquired to perform reliable spatial normalization needed for large-scale analysis. This work proposed and evaluated the performance of new MR-free spatial normalization methods using a perfusion-like template for amyloid PET imaging. Methods: Amyloid PET and MR images were collected in 35 subjects (cohort 1: 8 AD patients and 6 controls; cohort 2: 15 AD patients and 6 controls). Three ligand-related templates (AD, control, mixed group) and a perfusion-like template (pAV-45) from early time frames of amyloid PET images were constructed from cohort 1. The variations of F-AV-45 standardized uptake value ratios (SUVRs) among AD patients, controls, and all subjects were tested with repeated two-way (template × brain region) analysis of variance (ANOVA) in cohort 2. F-AV-45 SUVRs by region of interest analysis and voxelwise analysis between MR-based and MR-free approaches were compared and correlated to clinical and image parameters. Effect size (group mean SUVR difference between AD and control/standard deviation) was also evaluated for each template method. Results: Significantly different F-AV-45 SUVRs between MR-free spatial normalization and MR-based reference images were found among AD patients, controls, and all subjects by the effect of template and brain regions. The highest correlation ( r=0.991) of F-AV-45 SUVR to MR-based reference was found in the pAV-45 group. The SUVR percentage difference to MR-based reference showed the least variation and bias (control: −1.31±3.47 %; AD: −0.36±2.50 %) in the pAV-45 group as well. The voxelwise analysis showed the smallest t statistic value in pAV-45 followed by mixed, control, and AD groups when compared to MR-based reference images. Moreover, an overall larger effect size but compatible to that of MR-based reference result was observed in the pAV-45 group as compared to those of the other MR-free template. Conclusion: The novel MR-free template based on the early-phase perfusion images pAV-45 approach for amyloid imaging showed significantly better performance in quantitation accuracy, effect size, and stability when compared with other MR-free PET templates and thus has potential for large-scale clinical applications. [ABSTRACT FROM AUTHOR]

Purpose: F-Florbetapir (AV-45/Amyvid) is a novel positron emission tomography (PET) tracer for imaging plaque pathology in Alzheimer's disease (AD), while PET images of fluorodeoxyglucose (FDG) for cerebral glucose metabolism can provide complementary information to amyloid plaque images for diagnosis of AD. The goal of this preliminary study was to investigate the perfusion-like property of relative cerebral blood flow estimates (R) and summed early-phase AV-45 images [perfusion AV-45 (pAV-45)] and optimize the early time frame for pAV-45. Methods: Dynamic AV-45 PET scans (0-180 min) were performed in seven subjects. pAV-45, late-phase AV-45, and FDG images were spatially normalized to the Montreal Neurological Institute template aided by individual MRI images, and the corresponding standardized uptake value ratio (SUVR) was computed. The R images were derived from a simplified reference tissue model. Correlations between regional and voxelwise R and the corresponding FDG images were calculated. An optimization of time frames of pAV-45 was conducted in terms of correlation to FDG images. The optimal early time frame was validated in a separate cohort. Results: The regional distribution in the R images correlated well ( R = 0.91) to that of the FDG within subjects. Consistently high correlation was noted across a long range of time frames. The maximal correlation of pAV-45 to FDG SUVR of R = 0.95 was observed at the time frame of 1-6 min, while the peak correlation of R = 0.99 happened at 0-2 min between pAV-45 and R. A similar result was achieved in the validation cohort. Conclusion: Preliminary results showed that the distribution patterns of R and pAV-45 images are highly correlated with normalized FDG images, and the initial 5-min early time frame of 1-6 min is potentially useful in providing complementary FDG-like information to the amyloid plaque density by late-phase AV-45 images. [ABSTRACT FROM AUTHOR]

Abstract: We report herein the Good Manufacturing Practice (GMP)-compliant automated synthesis of 18F-labeled styrylpyridine, AV-45 (Florbetapir), a novel tracer for positron emission tomography (PET) imaging of β-amyloid (Aβ) plaques in the brain of Alzheimer’s disease patients. [18F]AV-45 was prepared in 105min using a tosylate precursor with Sumitomo modules for radiosynthesis under GMP-compliant conditions. The overall yield was 25.4±7.7% with a final radiochemical purity of 95.3±2.2% (n=19). The specific activity of [18F]AV-45 reached as high as 470±135TBq/mmol (n=19). The present studies show that [18F]AV-45 can be manufactured under GMP-compliant conditions and could be widely available for routine clinical use. [Copyright &y& Elsevier]

Abstract: Purpose: The compound (E)-4-(2-(6-(2-(2-(2-18F-fluoroethoxy)ethoxy)ethoxy) pyridin-3-yl)vinyl)-N-methylbenzenamine ([18F]AV-45) is a novel radiopharmaceutical capable of selectively binding to β-amyloid (Aβ) plaques. This pilot study reports the safety, biodistribution, and radiation dosimetry of [18F]AV-45 in human subjects. Methods: In vitro autoradiography and fluorescent staining of postmortem brain tissue from patients with Alzheimer''s disease (AD) and cognitively healthy subjects were performed to assess the specificity of the tracer. Biodistribution was assessed in three healthy elderly subjects (mean age: 60.0±5.2 years) who underwent 3-h whole-body positron emission tomography (PET)/computed tomographic (CT) scans after a bolus injection of 381.9±13.9 MBq of [18F]AV-45. Another six subjects (three AD patients and three healthy controls, mean age: 67.7±13.6 years) underwent brain PET studies. Source organs were delineated on PET/CT. All subjects underwent magnetic resonance imaging (MRI) for obtaining structural information. Results: In vitro autoradiography revealed exquisitely high specific binding of [18F]AV-45 to postmortem AD brain sections, but not to the control sections. There were no serious adverse events throughout the study period. The peak uptake of the tracer in the brain was 5.12±0.41% of the injected dose. The highest absorbed organ dose was to the gallbladder wall (184.7±78.6 μGy/MBq, 4.8 h voiding interval). The effective dose equivalent and effective dose values for [18F]AV-45 were 33.8±3.4 μSv/MBq and 19.3±1.3 μSv/MBq, respectively. Conclusion: [18F]AV-45 binds specifically to Aβ in vitro, and is a safe PET tracer for studying Aβ distribution in human brain. The dosimetry is suitable for clinical and research application. [Copyright &y& Elsevier]

Dementia is a complex human disease. The incidence of dementia among the elderly population is rising rapidly worldwide. In the United States, Alzheimer''s disease (AD) is the leading type of dementia and was the fifth and eighth leading cause of death in women and men aged ≥ 65 years, respectively, in 2003. In Taiwan and many other counties, dementia is a hidden health issue because of its underestimation in the elderly population. In Western countries, the prevalence of AD increases from 1–3% among people aged 60–64 years to 35% among those aged > 85 years. In Taiwan, the prevalence of dementia for people aged ≥ 65 years was 2–4% by 2000. Therefore, it is important to identify protective and risk factors for dementia to prevent this disease at an early stage. Several factors are related to dementia, e.g. age, ethnicity, sex, genetic factors, physical activity, smoking, drug use, education level, alcohol consumption, body mass index, comorbidity, and environmental factors. In this review, we focus on studies that have evaluated the association between these factors and the risk of dementia, especially AD and vascular dementia. We also suggest future research directions for researchers in dementia-related fields. [Copyright &y& Elsevier]

The correct differential diagnosis of dementia has an important impact on patient treatment and follow-up care strategies. Tc-99m-ECD SPECT imaging, which is low cost and accessible in general clinics, is used to identify the two common types of dementia, Alzheimer's disease (AD) and Lewy body dementia (LBD). Two-stage transfer learning technology and reducing model complexity based on the ResNet-50 model were performed using the ImageNet data set and ADNI database. To improve training accuracy, the three-dimensional image was reorganized into three sets of two-dimensional images for data augmentation and ensemble learning, then the performance of various deep learning models for Tc-99m-ECD SPECT images to distinguish AD/normal cognition (NC), LBD/NC, and AD/LBD were investigated. In the AD/NC, LBD/NC, and AD/LBD tasks, the AUC values were around 0.94, 0.95, and 0.74, regardless of training models, with an accuracy of 90%, 87%, and 71%, and F1 scores of 89%, 86%, and 76% in the best cases. The use of transfer learning and a modified model resulted in better prediction results, increasing the accuracy by 32% for AD/NC. The proposed method is practical and could rapidly utilize a deep learning model to automatically extract image features based on a small number of SPECT brain perfusion images in general clinics to objectively distinguish AD and LBD. [ABSTRACT FROM AUTHOR]

Misfolding, aggregation, and cerebral accumulation of tau deposits are hallmark features of Alzheimer's disease. Positron emission tomography study of tau can facilitate the development of anti-tau treatment. Here, we investigated a novel tau tracer 18F-PM-PBB3 (18F-APN-1607) in a mouse model of tauopathy. Dynamic PET scans were collected in groups of rTg4510 transgenic mice at 2–11 months of age. Associations between distribution volume ratios (DVR) and standardized uptake value ratios (SUVR) with cerebellum reference were used to determine the optimal scanning time and uptake pattern for each age. Immunohistochemistry staining of neurofibrillary tangles and autoradiography study was performed for ex vivo validation. An SUVR 40–70 min was most consistently correlated with DVR and was used in further analyses. Significant increased 18F-PM-PBB3 uptake in the brain cortex was found in six-month-old mice (+28.9%, p < 0.05), and increased further in the nine-month-old group (+38.8%, p < 0.01). The trend of increased SUVR value remained evident in the hippocampus and striatum regions except for cortex where uptake becomes slightly reduced in 11-month-old animals (+37.3%, p < 0.05). Radioactivity distributions from autoradiography correlate well to the presence of human tau (HT7 antibody) and hyperphosphorylated tau (antibody AT8) from the immunohistochemistry study of the adjacent brain sections. These findings supported that the 40–70 min 18F-PM-PBB3 PET scan with SUVR measurement can detect significantly increased tau deposits in a living rTg4510 transgenic mouse models as early as six-months-old. The result exhibited promising dynamic imaging capability of this novel tau tracer, and the above image characteristics should be considered in the design of longitudinal preclinical tau image studies. [ABSTRACT FROM AUTHOR]

With the great extension of the human lifespan in recent times, many aging diseases have inevitably followed. Dementia is one of the most-commom neurodegenerative aging diseases, in which inflammation-related Alzheimer's disease (AD) is the most prevalent cause of dementia. Amyloid accumulation in the brain, which occurs before any clinical presentations, might be the first and key step in the development of AD. However, many clinical trials have attempted to remove amyloid from brains of AD patients, but none has so far been successful. Negatively charged plasmon-activated water (PAW) is created by resonantly illuminated gold (Au) nanoparticles (NPs), which reduce the hydrogen-bonded (HB) structure of water. PAW was found to possess anti-oxidative and anti-inflammatory effects. Herein, we report on an innovative strategy to retard the progression of AD by the daily consumption of PAW instead of normal deionized (DI) water. APPswe/PS1dE9 transgenic mice were treated with PAW or DI water from the age of 5 months for the next 9 months. Encouragingly, compared to DI water-treated mice, mice treated with PAW presented better memory performance on a test of novel object recognition and had a significantly lower amyloid burden according to 18F-florbetapir amyloid-PET and phosphorylated (p)-tau burden according to Western blotting and immunohistochemistry measurements. There were no obvious side effects in PAW-treated mice. Collectively, our findings support that PAW was able to reduce the amyloid and p-tau burden and improve memory in an AD mouse model. However, the protein levels of molecules involved in amyloid metabolism and oligomeric amyloid did not change. We propose that the effects of PAW of reducing the amyloid burden and improving memory function cannot be attributed to synthesis/degradation of amyloid-βprotein but probably in preventing aggregation of amyloid-β proteins or other mechanisms, including anti-inflammation. Further applications of PAW in clinical trials to prevent the progression of AD are being designed. [ABSTRACT FROM AUTHOR]

Abstract Introduction The novel D678H amyloid precursor protein (APP) gene mutation has been called the "Taiwan mutation". The study aims to identify amyloid deposition patterns and clinical features associated with this mutation. Methods we analyzed the clinical manifestations, brain neuroimages and 18F-AV-45 positron emission tomography (PET) findings in symptomatic patients and asymptomatic subjects with the autosomal-dominant Alzheimer's disease (AD). We compared the amyloid deposition pattern among 10 patients with genetically-positive familial cognitive decline (CD), 18 patients with sporadic CD, and 19 healthy controls. Results The clinical features were the early onset of memory impairment in all 10 patients and cerebral amyloid angiopathy in 3 patients. The characteristic results of brain 18F-AV-45 PET included the highest standard uptake value ratio (SUVR) in the occipital and cerebellar cortical areas in the genetically-positive CD patients. In subgroup analysis, the familial AD patients had a decreased amyloid SUVR trend in most areas except for cerebellar cortex compared to those with familial mild cognitive impairment. Conclusion Our data indicate that the familial D678H gene mutation have resulted in a more potent amyloid burden than in the patients with sporadic AD patients. The high amyloid uptake in the occipital area is characteristic of the specific Taiwan APP gene. Highlights • The study evaluated the amyloid patterns and clinical features in the Taiwan familial AD with D678H APP mutation. • Early onset of memory impairment and cerebral amyloid angiopathy in 2 patients. • The highest stardand uptake value ratio in the occipital and cerebellar cortical areas in the gCD patients. • The familial D678H gene mutation patients have a more potent amyloid burden than the sporadic AD patients [ABSTRACT FROM AUTHOR]

Abstract: Aim: Recently, the feasibility of detecting amyloid plaques in the living brain by positron emission tomography (PET) imaging has been successfully demonstrated. As such, imaging β-amyloid (Aβ) plaques in the brain may further advance the differential diagnosis of the disease and allow clinicians to measure the effectiveness of therapeutic drugs aimed at lowering plaques in the brain. We report herein the preclinical validation of a potential 18F-labeled biphenylalkyne, AV-138, as a preliminary step toward developing the imaging agent for patients suspected of having Alzheimer''s disease. Methods: In vitro binding was carried out in the homogenates prepared from postmortem AD brains with [125I]IMPY as the radioligand. [18F]AV-138 was successfully prepared using a tosylate precursor and Sumitomo modules for radiosynthesis. Similarly, specific binding of [18F]AV-138 (0.02–0.05 nM) to homogenates, prepared from gray and white matters of pooled AD patients and control subjects, was performed. Specific binding to Aβ plaques was measured by autoradiography in AD brain sections (n=11), and the same brain sections were fluorescently stained with thioflavin-S (TF-S). Images of both radiolabeling and fluorescent staining of plaques obtained by a phosphor imager were used for correlation image analysis. Results: As expected, AV-138 displayed a high binding affinity (K i=2.4±0.7 nM) in AD gray matter homogenates (due to its high level of Aβ plaque accumulation). Specific binding can be clearly measured in the AD gray matter homogenates, but not in the AD white matters. Control brain homogenates, due to a lack of Aβ plaques, also showed no specific binding. Furthermore, in vitro autoradiography of postmortem AD brain sections showed that the high binding signal of [18F]AV-138 was specifically due to Aβ plaques. Fluorescent staining of plaques with TF-S correlated well with the radiolabeling of [18F]AV-138 in AD brain sections (r>0.90). Conclusion: Taken together, these preliminary results strongly suggest that [18F]AV-138 is potentially useful for imaging Aβ plaques in the living human brain. [Copyright &y& Elsevier]

Recent epidemiology studies have indicated that traumatic brain injury (TBI) can increase the risk of developing neurodegenerative diseases such as Alzheimer's disease (AD). Amyloid-β (Aβ) plaques and neurofibrillary tangles are pathological indicators of AD. The accumulation of Aβ is considered the first step of AD pathophysiology. Compelling studies have supported the hypothesis that TBI accelerates the formation and accumulation of Aβ. These findings could link TBI with AD, although the research that reported these findings had limitations, particularly regarding mild TBI (mTBI) patients. The effects of mTBI on Aβ accumulation remain uncertain because of a lack of mTBI pathology data. Using amyloid-positron emission tomography (amyloid-PET), researchers can help to determine whether mTBI increases the accumulation of Aβ, which might be involved in the pathophysiological mechanisms of mTBI in AD, and could be a target for the treatment of neurodegenerative diseases associated with TBI. In this study, we recruited 27 mTBI patients with mTBI in mean 6 years before this study (21 mTBI patients without cognitive impairment, 6 mTBI patients with cognitive impairment,) and 10 controls. All of them underwent mini-mental state examination, apolipoprotein E (APOE) genotyping, and amyloid-PET. The results show an increase of amyloid accumulation and allele frequency of APOE4 in the mTBI patients with cognitive impairment. These findings indicate that amyloid accumulation is an important indicator of cognitive impairment, and amyloid-PET should be a safe and useful tool for diagnosing amyloid-related cognitive impairment. APOE allele might play a role in the occurrence of cognitive impairment after mTBI. The contribution of mTBI to the amyloid accumulation requires further study, and mTBI patients should be recruited for longitudinal research with repeated amyloid-PET studies. [ABSTRACT FROM AUTHOR]

Abstract: A series of novel rutaecarpine derivatives and related alkaloid derivatives 3-aminoalkanamido-substituted rutaecarpine 4a–f and 7,8-dehydrorutaecarpine 5a–c, and 6-aminoalkanamido-substituted 3-[2-(3-Indolyl)ethyl]-4(3a)-quinazolinones 8a–c, were synthesized and subjected to pharmacological evaluation as acetylcholinesterase (AChE) inhibitors. The synthetic compounds exhibited strong inhibitory activity for AChE and high selectivity for AChE over BuChE. The structure–activity relationships were discussed and their binding conformation and simultaneous interactions mode were further clarified by kinetic characterization and the molecular docking studies. [Copyright &y& Elsevier]