Magnetic Resonance Images Implicate That Glymphatic Alterations Mediate Cognitive Dysfunction in Alzheimer Disease.

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.

Investigation of reactive astrogliosis effect on post-stroke cognitive impairment.

BACKGROUND: The aim of this study is to investigate the associations between post-stroke cognitive impairment (PSCI) severity and reactive astrogliosis (RA) extent on normalized 18F-THK-5351 positron-emission tomography (PET) imaging in amyloid-negative patients with first-ever stroke. METHODS: We prospectively enrolled 63 amyloid-negative patients with first-ever stroke. Neurocognitive evaluation, MRI, 18F-THK-5351, and 18F-florbetapir PET were performed around 3 months after stroke. The 18F-THK-5351 uptake intensity was normalized using a signal distribution template to obtain the Z-SUM scores as the RA extent in the whole brain and cerebral hemisphere ipsilateral to stroke lesion. We evaluated stroke volume, leukoaraiosis, and brain atrophy on MRI. We used a comprehensive neurocognitive battery to obtain composite cognitive scores, and defined PSCI as a general cognitive function score < - 1. We analyzed the influence of Z-SUM scores on PSCI severity after adjusting for demographic, vascular, and neurodegenerative variables. RESULTS: Twenty-five of 63 stroke patients had PSCI. Patients with PSCI had older age, lower education, and more severe cortical atrophy and total Z-SUM scores. Total Z-SUM scores were significantly associated with general cognitive and executive functions at multiple regression models. Path analyses showed that stroke can exert cognitive influence directly by stroke itself as well as indirectly through RA, including total and ipsilateral Z-SUM scores, in patients with either right or left hemisphere stroke. CONCLUSION: The patterns and intensity of 18F-THK-5351 uptake in amyloid-negative patients with first-ever stroke were associated with PSCI manifestations, which suggests that RA presents a modulating effect in PSCI development.

Characterization of 18F-PM-PBB3 (18F-APN-1607) Uptake in the rTg4510 Mouse Model of Tauopathy.

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.

Correlation between visual association memory test and structural changes in patients with Alzheimer's disease and amnestic mild cognitive impairment.

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.

New Digital Plug and Imaging Sensor for a Proton Therapy Monitoring System Based on Positron Emission Tomography.

One of the most challenging areas of sensor development for nuclear medicine is the design of proton therapy monitoring systems. Sensors are operated in a high detection rate regime in beam-on conditions. We realized a prototype of a monitoring system for proton therapy based on the technique of positron emission tomography. We used the Plug and Imaging (P&I) technology in this application. This sensing system includes LYSO/silicon photomultiplier (SiPM) detection elements, fast digital multi voltage threshold (MVT) readout electronics and dedicated image reconstruction algorithms. In this paper, we show that the P&I sensor system has a uniform response and is controllable in the experimental conditions of the proton therapy room. The prototype of PET monitoring device based on the P&I sensor system has an intrinsic experimental spatial resolution of approximately 3 mm (FWHM), obtained operating the prototype both during the beam irradiation and right after it. The count-rate performance of the P&I sensor approaches 5 Mcps and allows the collection of relevant statistics for the nuclide analysis. The measurement of both the half life and the relative abundance of the positron emitters generated in the target volume through irradiation of 10 10 protons in approximately 15 s is performed with 0.5% and 5 % accuracy, respectively.

Dual-phase 18F-florbetapir positron emission tomography in patients with primary progressive aphasia, Alzheimer's disease, and healthy controls: A preliminary study.

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.

Imaging characteristic of dual-phase (18)F-florbetapir (AV-45/Amyvid) PET for the concomitant detection of perfusion deficits and beta-amyloid deposition in Alzheimer's disease and mild cognitive impairment.

PURPOSE: We investigated dual-phase (18)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 (18)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 (18)F-AV-45 imaging, pAV-45), and (2) ten 1-min scans obtained 50 - 60 min after tracer injection (amyloid (18)F-AV-45 imaging). Amyloid-negative MCI/AD patients were excluded. Volume of interest analysis and statistical parametric mapping of pAV-45 and (18)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). (18)F-AV-45 uptake was significantly higher in AD patients than in the two other study groups. However, the correlation between MMSE scores and (18)F-AV-45 uptake in MCI patients was more of a binary phenomenon and began in MCI patients with MMSE score 23.14 when (18)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 (18)F-AV-45 PET imaging.

Beta-amyloid deposition and cognitive function in patients with major depressive disorder with different subtypes of mild cognitive impairment: (18)F-florbetapir (AV-45/Amyvid) PET study.

PURPOSE: The objective of this study was to evaluate the amyloid burden, as assessed by (18)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 (18)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 (18)F-florbetapir uptake in all cortical regions, and a significant difference in relative (18)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 (18)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 (ß = -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 (18)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.

Increased brain amyloid deposition in patients with a lifetime history of major depression: evidenced on 18F-florbetapir (AV-45/Amyvid) positron emission tomography.

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 (18)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 (18)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 (18)F-florbetapir SUVRs and prior depression episodes, age at onset of depression, or time since onset of first depression. CONCLUSION: Increased (18)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.

Human biodistribution and radiation dosimetry for the tau tracer [18F]Florzolotau in healthy subjects.

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 .

The application of machine learning on brain imaging features of different narcolepsy subtypes.

STUDY OBJECTIVES: Narcolepsy is a central hypersomnia disorder, and differential diagnoses between its subtypes can be difficult. Hence, we applied machine learning to analyze the positron emission tomography (PET) data of patients with type 1 or type 2 narcolepsy, and patients with type 1 narcolepsy and comorbid schizophrenia, to construct predictive models to facilitate the diagnosis. METHODS: This is a retrospective and prospective case-control study of adolescent and young adult patients with type 1 or type 2 narcolepsy, and type 1 narcolepsy and comorbid schizophrenia. All participants received 18-F-fluorodeoxy glucose PET, sleep studies, neurocognitive tests, sleep questionnaires, and human leukocyte antigen typing. The collected PET data were analyzed by feature selections and classification methods in machine learning to construct predictive models. RESULTS: A total of 314 participants with narcolepsy were enrolled; 204 had type 1 narcolepsy, 90 had type 2 narcolepsy, and 20 had type 1 narcolepsy and comorbid schizophrenia. We used three filter methods for feature selection followed by a comparative analysis of classification methods. To apply a small number of regions of interest (ROI) and high classification accuracy, the Naïve Bayes classifier with the Term Variance as feature selection achieved the goal with only three ROIs (left basal ganglia, left Heschl, and left striatum) and produced an accuracy of higher than 99%. CONCLUSIONS: The accuracy of our predictive model of PET data are promising and can aid clinicians in the diagnosis of narcolepsy subtypes. Future research with a larger sample size could further refine the predictive model of narcolepsy.

Classification Prediction of Alzheimer's Disease and Vascular Dementia Using Physiological Data and ECD SPECT Images.

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.

Dominance of Tau Burden in Cortical Over Subcortical Regions Mediates Glymphatic Activity and Clinical Severity in PSP.

BACKGROUND: Progressive supranuclear palsy (PSP) is a tauopathy that involves subcortical regions but also extends to cortical areas. The clinical impact of different tau protein sites and their influence on glymphatic dysfunction have not been investigated. PATIENTS AND METHODS: Participants (n = 55; 65.6 ± 7.1 years; 29 women) with PSP (n = 32) and age-matched normal controls (NCs; n = 23) underwent 18 F-Florzolotau tau PET, MRI, PSP Rating Scale (PSPRS), and Mini-Mental State Examination. Cerebellar gray matter (GM) and parametric estimation of reference signal intensity were used as references for tau burden measured by SUV ratios. Glymphatic activity was measured by diffusion tensor image analysis along the perivascular space (DTI-ALPS). RESULTS: Parametric estimation of reference signal intensity is a better reference than cerebellar GM to distinguish tau burden between PSP and NCs. PSP patients showed higher cortical and subcortical tau SUV ratios than NCs ( P < 0.001 and <0.001). Cortical and subcortical tau deposition correlated with PSPRS, UPDRS, and Mini-Mental State Examination scores (all P 's < 0.05). Cortical tau deposition was further associated with the DTI-ALPS index and frontal-temporal-parietal GM atrophy. The DTI-ALPS indexes showed a significantly negative correlation with the PSPRS total scores ( P < 0.01). Finally, parietal and occipital lobe tau depositions showed mediating effects between the DTI-ALPS index and PSPRS score. CONCLUSIONS: Cortical tau deposition is associated with glymphatic dysfunction and plays a role in mediating glymphatic dysfunction and clinical severity. Our results provide a possible explanation for the worsening of clinical severity in patients with PSP.

Perfusion-like template and standardized normalization-based brain image analysis using 18F-florbetapir (AV-45/Amyvid) PET.

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 (18)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. (18)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 (18)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 (18)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.

Atrophy, hypometabolism and implication regarding pathology in late-life major depression with suspected non-alzheimer pathophysiology (SNAP).

BACKGROUND: A substantial proportion of individuals with late-life major depression could be classified as having a suspected non-Alzheimer disease pathophysiology (SNAP), as indicated by a negative test for the biomarker ß-amyloid (Aß-) but a positive test for neurodegeneration (ND+). This study investigated the clinical features, characteristic patterns of brain atrophy and hypometabolism, and implications regarding pathology in this population. METHODS: Forty-six amyloid-negative patients with late-life major depressive disorder (MDD) patients, including 23 SNAP (Aß-/ND+) and 23 Aß-/ND- MDD subjects, and 22 Aß-/ND-healthy control subjects were included in this study. Voxel-wise group comparisons between the SNAP MDD, Aß-/ND- MDD and control subjects were performed, adjusting for age, gender and level of education. For exploratory comparisons, 8 Aß+/ND- and 4 Aß+/ND + MDD patients were included in the Supplementary Material. RESULTS: The SNAP MDD patients had atrophy extending to regions outside the hippocampus, predominately in the medial temporal, dorsomedial and ventromedial prefrontal cortex; hypometabolism involving a large portion of the lateral and medial prefrontal cortex in addition to the bilateral temporal, parietal and precuneus cortex within typical Alzheimer disease regions were observed. Metabolism ratios of the inferior to the medial temporal lobe were significantly elevated in the SNAP MDD patients. We further discussed the implications with regards to underlying pathologies. CONCLUSION: The present study demonstrated characteristic patterns of atrophy and hypometabolism in patients with late-life major depression with SNAP. Identifying individuals with SNAP MDD may provide insights into currently unspecified neurodegenerative processes. Future refinement of neurodegeneration biomarkers is essential in order to identify potential pathological correlates while in vivo reliable pathological biomarkers are not forthcoming.

Gold-Nanoparticles-Enhanced Production of Reactive Oxygen Species in Cells at Spread-Out Bragg Peak under Proton Beam Radiation.

This study investigates the radiobiological effects of gold nanoparticles (GNPs) as radiosensitizers for proton beam therapy (PBT). Specifically, we explore the enhanced production of reactive oxygen species (ROS) in GNP-loaded tumor cells irradiated by a 230 MeV proton beam in a spread-out Bragg peak (SOBP) zone obtained by a passive scattering system. Our findings indicate that the radiosensitization enhancement factor is 1.24 at 30% cell survival fraction, 8 days after 6 Gy proton beam irradiation. Since protons deposit the majority of their energy at the SOBP region and interact with GNPs to induce more ejected electrons from the high-Z GNPs, these ejected electrons then react with water molecules to produce excessive ROS that can damage cellular organelles. Laser scanning confocal microscopy reveals the excessive ROS induced inside the GNP-loaded cells immediately after proton irradiation. Furthermore, the damage to cytoskeletons and mitochondrial dysfunction in GNP-loaded cells caused by the induced ROS becomes significantly severe, 48 h after proton irradiation. Our biological evidence suggests that the cytotoxicity of GNP-enhanced ROS production has the potential to increase the tumoricidal efficacy of PBT.

Visual reading for [18F]Florzolotau ([18F]APN-1607) tau PET imaging in clinical assessment of Alzheimer's disease.

Introduction: Tau-targeted positron emission tomography (tau-PET) is a potential tool for the differential diagnosis of Alzheimer's disease (AD) and to clarify the distribution of tau deposition. In addition to the quantitative analysis of tau-PET scans, visual reading supports the assessment of tau loading for clinical diagnosis. This study aimed to propose a method for visually interpreting tau-PET using the [18F] Florzolotau tracer and investigate the performance and utility of the visual reading. Materials and methods: A total number of 46 individuals with 12 cognitively unimpaired subjects (CU), 20 AD patients with mild cognitive impairment (AD-MCI), and 14 AD with dementia (AD-D) patients with both [18F]Florbetapir amyloid PET and [18F]Florzolotau tau PET scans were included. Clinical information, cognitive assessment, and amyloid PET scan results were recorded. For visual interpretation, a modified rainbow colormap was created and a regional tau uptake scoring system was proposed to evaluate the degree of tracer uptake and its spatial distribution within five cortical regions. Each region was scored on a scale of [0, 2] as compared to the background, and that resulted in a global scale range of [0, 10]. Four readers interpreted [18F]Florzolotau PET using the visual scale. The global and regional standardized uptake value ratios (SUVr) were also calculated for analysis. Results: The result indicates the average global visual scores were 0 ± 0 in the CU group, 3.43 ± 3.35 in the AD-MCI group, and 6.31 ± 2.97 in the AD-D group (p < 0.001). The consensus among the four observers on image scores was high with an intraclass correlation coefficient of 0.880 (95% CI: 0.767-0.936). The average global visual score was significantly associated with global SUVr (r = 0.884, p < 0.0001) and with the CDR-sum of box (r = 0.677, p < 0.0001). Conclusion: The visual reading method generated a visual score of [18F]Florzolotau tau-PET with good sensitivity and specificity to identify AD-D or CU individuals from the other patients. The preliminary result also showed that the global visual scores are significantly and reliably correlated with global cortical SUVr, and associated well with the clinical diagnosis and cognitive performance.

A Radiotherapy Dose Map-Guided Deep Learning Method for Predicting Pathological Complete Response in Esophageal Cancer Patients after Neoadjuvant Chemoradiotherapy Followed by Surgery.

Esophageal cancer is a deadly disease, and neoadjuvant chemoradiotherapy can improve patient survival, particularly for patients achieving a pathological complete response (ypCR). However, existing imaging methods struggle to accurately predict ypCR. This study explores computer-aided detection methods, considering both imaging data and radiotherapy dose variations to enhance prediction accuracy. It involved patients with node-positive esophageal squamous cell carcinoma undergoing neoadjuvant chemoradiotherapy and surgery, with data collected from 2014 to 2017, randomly split into five subsets for 5-fold cross-validation. The algorithm DCRNet, an advanced version of OCRNet, integrates RT dose distribution into dose contextual representations (DCR), combining dose and pixel representation with ten soft regions. Among the 80 enrolled patients (mean age 55.68 years, primarily male, with stage III disease and middle-part lesions), the ypCR rate was 28.75%, showing no significant demographic or disease differences between the ypCR and non-ypCR groups. Among the three summarization methods, the maximum value across the CTV method produced the best results with an AUC of 0.928. The HRNetV2p model with DCR performed the best among the four backbone models tested, with an AUC of 0.928 (95% CI, 0.884-0.972) based on 5-fold cross-validation, showing significant improvement compared to other models. This underscores DCR-equipped models' superior AUC outcomes. The study highlights the potential of dose-guided deep learning in ypCR prediction, necessitating larger, multicenter studies to validate the results.

Correlation of early-phase 18F-florbetapir (AV-45/Amyvid) PET images to FDG images: preliminary studies.

PURPOSE: (18)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(1)) 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(1) images were derived from a simplified reference tissue model. Correlations between regional and voxelwise R(1) 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(1) 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(1). A similar result was achieved in the validation cohort. CONCLUSION: Preliminary results showed that the distribution patterns of R(1) 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.

Quantitative analysis of binding sites for 9-fluoropropyl-(+)-dihydrotetrabenazine ([¹8F]AV-133) in a MPTP-lesioned PD mouse model.

UNLABELLED: [¹8F]AV-133 is a novel PET tracer for targeting the vesicular monoamine transporter 2 (VMAT2). The aim of this study is to characterize and quantify the loss of monoamine neurons with [¹8F]AV-133 in the MPTP-lesioned PD mouse model using animal PET imaging and ex vivo quantitative autoradiography (QARG). METHODS: Optimal imaging time window of [¹8F]AV-133 was first determined in normal C57BL/6 mice (n = 3) with a 90-min dynamic scan. The reproducibility of [¹8F]AV-133 PET imaging was evaluated by performing a test-retest study within 1 week for the normal group (n = 6). For MPTP-lesioned studies, normal, and MPTP-treated [25 mg mg/kg once (Group A) and twice (Group B), respectively, daily for 5 days, i.p., groups of four normal and MPTP-treated] mice were used. PET imaging studies at baseline and at Day 4 post-MPTP injections were performed at the optimal time window after injection of 11.1 MBq [¹8F]AV-133. Specific uptake ratio (SUr) of [¹8F]AV-133 was calculated by [(target uptake-cerebellar uptake)/cerebellar uptake] with cerebellum as the reference region. Ex vitro QARG and immunohistochemistry (IHC) studies with tyrosine hydroxylase antibody were carried out to confirm the abundance of dopaminergic neurons. RESULTS: The variability between [¹8F]AV-133 test-retest striatal SUr was 6.60 ± 3.61% with less than 5% standard deviation between animals (intervariability). The percentages of MPTP lesions were Group A 0.94 ± 0.29, -42.1% and Group B 0.65 ± 0.09, -60.4%. By QARG, specific binding of [¹8F]AV-133 was reduced relative to the control groups by 50.6% and 60.7% in striatum and by 30.6% and 46.4% in substantia nigra (Groups A and B, respectively). Relatively small [¹8F]AV-133 SUr decline was noted in the serotonin and norepinephrine-enriched regions (7.9% and 9.4% in mid-brain). Results obtained from IHC consistently confirmed the sensitivity and selectivity of dopaminergic neuron loss after MPTP treatment. CONCLUSIONS: [¹8F]AV-133 PET SUr displayed a high test-retest stability. The SUr significantly declined in the caudate putamen but not in the hypothalamus and midbrain regions after MPTP treatment in the mouse brain. The results obtained for QARG and IHC were consistent and correlated well with the PET imaging studies. On the basis of these concordant results, we find that [¹8F]AV-133 should serve as a useful and reliable PET tracer for evaluating nigrostriatal degeneration.