Uncovering distinct progression patterns of tau deposition in progressive supranuclear palsy using [18F]Florzolotau PET imaging and subtype/stage inference algorithm.

BACKGROUND: Progressive supranuclear palsy (PSP) is a primary 4-repeat tauopathy with diverse clinical phenotypes. Previous post-mortem studies examined tau deposition sequences in PSP, but in vivo scrutiny is lacking. METHODS: We conducted [18F]Florzolotau tau positron emission tomography (PET) scans on 148 patients who were clinically diagnosed with PSP and 20 healthy controls. We employed the Subtype and Stage Inference (SuStaIn) algorithm to identify PSP subtype/stage and related tau patterns, comparing clinical features across subtypes and assessing PSP stage-clinical severity association. We also evaluated functional connectivity differences among subtypes through resting-state functional magnetic resonance imaging. FINDINGS: We identified two distinct subtypes of PSP: Subtype1 and Subtype2. Subtype1 typically exhibits a sequential progression of the disease, starting from subcortical and gradually moving to cortical regions. Conversely, Subtype2 is characterized by an early, simultaneous onset in both regions. Interestingly, once the disease is initiated, Subtype1 tends to spread more rapidly within each region compared to Subtype2. Individuals categorized as Subtype2 are generally older and exhibit less severe dysfunctions in areas such as cognition, bulbar, limb motor, and general motor functions compared to those with Subtype1. Moreover, they have a more favorable prognosis in terms of limb motor function. We found significant correlations between several clinical variables and the identified PSP SuStaIn stages. Furthermore, Subtype2 displayed a remarkable reduction in functional connectivity compared to Subtype1. INTERPRETATION: We present the evidence of distinct in vivo spatiotemporal tau trajectories in PSP. Our findings can contribute to precision medicine advancements for PSP. FUNDING: This work was supported by grants from the National Natural Science Foundation of China (number 82272039, 81971641, 82021002, and 92249302); Swiss National Science Foundation (number 188350); the STI2030-Major Project of China (number 2022ZD0211600); the Clinical Research Plan of Shanghai Hospital Development Center of China (number SHDC2020CR1038B); and the National Key R&D Program of China (number 2022YFC2009902, 2022YFC2009900), the China Scholarship Council (number 202006100181); the Deutsche Forschungsgemeinschaft (DFG) under Germany's Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (EXC 2145 SyNergy, ID 390857198).

Improved interpretation of 18F-florzolotau PET in progressive supranuclear palsy using a normalization-free deep-learning classifier.

While 18F-florzolotau tau PET is an emerging biomarker for progressive supranuclear palsy (PSP), its interpretation has been hindered by a lack of consensus on visual reading and potential biases in conventional semi-quantitative analysis. As clinical manifestations and regions of elevated 18F-florzolotau binding are highly overlapping in PSP and the Parkinsonian type of multiple system atrophy (MSA-P), developing a reliable discriminative classifier for 18F-florzolotau PET is urgently needed. Herein, we developed a normalization-free deep-learning (NFDL) model for 18F-florzolotau PET, which achieved significantly higher accuracy for both PSP and MSA-P compared to semi-quantitative classifiers. Regions driving the NFDL classifier's decision were consistent with disease-specific topographies. NFDL-guided radiomic features correlated with clinical severity of PSP. This suggests that the NFDL model has the potential for early and accurate differentiation of atypical parkinsonism and that it can be applied in various scenarios due to not requiring subjective interpretation, MR-dependent, and reference-based preprocessing.

The heterogeneity of asymmetric tau distribution is associated with an early age at onset and poor prognosis in Alzheimer's disease.

PURPOSE: Left-right asymmetry, an important feature of brain development, has been implicated in neurodegenerative diseases, although it's less discussed in typical Alzheimer's disease (AD). We sought to investigate whether asymmetric tau deposition plays a potential role in AD heterogeneity. METHODS: Two independent cohorts consisting of patients with mild cognitive impairment due to AD and AD dementia with tau PET imaging were enrolled [the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort with 18F-Flortaucipir, the Shanghai Memory Study (SMS) cohort with 18F-Florzolotau]. Based on the absolute global tau interhemispheric differences, each cohort was divided into two groups (asymmetric versus symmetric tau distribution). The two groups were cross-sectionally compared in terms of demographic, cognitive characteristics, and pathological burden. The cognitive decline trajectories were analyzed longitudinally. RESULTS: Fourteen (23.3%) and 42 (48.3%) patients in the ADNI and SMS cohorts showed an asymmetric tau distribution, respectively. An asymmetric tau distribution was associated with an earlier age at disease onset (proportion of early-onset AD: ADNI/SMS/combined cohorts, p = 0.093/0.026/0.001) and more severe pathological burden (i.e., global tau burden: ADNI/SMS cohorts, p < 0.001/= 0.007). And patients with an asymmetric tau distribution were characterized by a steeper cognitive decline longitudinally (i.e., the annual decline of Mini-Mental Status Examination score: ADNI/SMS/combined cohorts, p = 0.053 / 0.035 / < 0.001). CONCLUSIONS: Asymmetry in tau deposition, which may be associated with an earlier age at onset, more severe pathological burden, and a steeper cognitive decline, is potentially an important characteristic of AD heterogeneity.

Health insurance system and resilience to epidemics.

We theoretically analyze the resilience (efficiency) of health insurance systems and diverse factors including trace and test technology, infection and contagion rates, and social distancing/lockdown policy, in coping with contagious diseases like COVID-19. Our findings can be summarized as follows. First, public insurance is more resilient than market insurance, as the former's investment in test technology is made at the social optimum, whereas the latter's investment is less. The decentralized behavior of competing insurers leads to a less resilient outcome. Second, resilience decreases as the market becomes more competitive because the externality effect becomes more severe. Third, a higher contagion rate, a more cost-efficient test technology or a higher initial infection rate unless it is not too high, leads to a higher test accuracy level. Fourth, the socially optimal social distancing/lockdown policy is determined by comparison between its relative costs and the benefit from contagion reduction.

Assessment of perfusion deficit with early phases of [18F]PI-2620 tau-PET versus [18F]flutemetamol-amyloid-PET recordings.

PURPOSE: Characteristic features of amyloid-PET (A), tau-PET (T), and FDG-PET (N) can serve for the A/T/N classification of neurodegenerative diseases. Recent studies showed that the early, perfusion-weighted phases of amyloid- or tau-PET recordings serve to detect cerebrometabolic deficits equally to FDG-PET, therefore providing a surrogate of neuronal injury. As such, two channels of diagnostic information can be obtained in the setting of a single PET scan. However, there has hitherto been no comparison of early-phase amyloid- and tau-PET as surrogates for deficits in perfusion/metabolism. Therefore, we undertook to compare [18F]flutemetamol-amyloid-PET and [18F]PI-2620 tau-PET as "one-stop shop" dual purpose tracers for the detection of neurodegenerative disease. METHODS: We obtained early-phase PET recordings with [18F]PI-2620 (0.5-2.5 min p.i.) and [18F]flutemetamol (0-10 min p.i.) in 64 patients with suspected neurodegenerative disease. We contrasted global mean normalized images (SUVr) in the patients with a normal cohort of 15 volunteers without evidence of increased pathology to ß-amyloid- and tau-PET examinations. Regional group differences of tracer uptake (z-scores) of 246 Brainnetome volumes of interest were calculated for both tracers, and the correlations of the z-scores were evaluated using Pearson's correlation coefficient. Lobar compartments, regions with significant neuronal injury (z-scores < - 3), and patients with different neurodegenerative disease entities (e.g., Alzheimer's disease or 4R-tauopathies) served for subgroup analysis. Additionally, we used partial regression to correlate regional perfusion alterations with clinical scores in cognition tests. RESULTS: The z-scores of perfusion-weighted images of both tracers showed high correlations across the brain, especially in the frontal and parietal lobes, which were the brain regions with pronounced perfusion deficit in the patient group (R = 0.83 ± 0.08; range, 0.61-0.95). Z-scores of individual patients correlated well by region (R = 0.57 ± 0.15; range, 0.16-0.90), notably when significant perfusion deficits were present (R = 0.66 ± 0.15; range, 0.28-0.90). CONCLUSION: The early perfusion phases of [18F]PI-2620 tau- and [18F]flutemetamol-amyloid-PET are roughly equivalent indices of perfusion defect indicative of regional and lobar neuronal injury in patients with various neurodegenerative diseases. As such, either tracer may serve for two diagnostic channels by assessment of amyloid/tau status and neuronal activity.

Decoding the dopamine transporter imaging for the differential diagnosis of parkinsonism using deep learning.

PURPOSE: This work attempts to decode the discriminative information in dopamine transporter (DAT) imaging using deep learning for the differential diagnosis of parkinsonism. METHODS: This study involved 1017 subjects who underwent DAT PET imaging ([11C]CFT) including 43 healthy subjects and 974 parkinsonian patients with idiopathic Parkinson's disease (IPD), multiple system atrophy (MSA) or progressive supranuclear palsy (PSP). We developed a 3D deep convolutional neural network to learn distinguishable DAT features for the differential diagnosis of parkinsonism. A full-gradient saliency map approach was employed to investigate the functional basis related to the decision mechanism of the network. Furthermore, deep-learning-guided radiomics features and quantitative analysis were compared with their conventional counterparts to further interpret the performance of deep learning. RESULTS: The proposed network achieved area under the curve of 0.953 (sensitivity 87.7%, specificity 93.2%), 0.948 (sensitivity 93.7%, specificity 97.5%), and 0.900 (sensitivity 81.5%, specificity 93.7%) in the cross-validation, together with sensitivity of 90.7%, 84.1%, 78.6% and specificity of 88.4%, 97.5% 93.3% in the blind test for the differential diagnosis of IPD, MSA and PSP, respectively. The saliency map demonstrated the most contributed areas determining the diagnosis located at parkinsonism-related regions, e.g., putamen, caudate and midbrain. The deep-learning-guided binding ratios showed significant differences among IPD, MSA and PSP groups (P < 0.001), while the conventional putamen and caudate binding ratios had no significant difference between IPD and MSA (P = 0.24 and P = 0.30). Furthermore, compared to conventional radiomics features, there existed average above 78.1% more deep-learning-guided radiomics features that had significant differences among IPD, MSA and PSP. CONCLUSION: This study suggested the developed deep neural network can decode in-depth information from DAT and showed potential to assist the differential diagnosis of parkinsonism. The functional regions supporting the diagnosis decision were generally consistent with known parkinsonian pathology but provided more specific guidance for feature selection and quantitative analysis.

Differential Diagnosis of Parkinsonism Based on Deep Metabolic Imaging Indices.

The clinical presentations of early idiopathic Parkinson disease (IPD) substantially overlap with those of atypical parkinsonian syndromes such as multiple system atrophy (MSA) and progressive supranuclear palsy (PSP). This study aimed to develop metabolic imaging indices based on deep learning to support the differential diagnosis of these conditions. Methods: A benchmark Huashan parkinsonian PET imaging (HPPI, China) database including 1,275 parkinsonian patients and 863 nonparkinsonian subjects with 18F-FDG PET images was established to support artificial intelligence development. A 3-dimensional deep convolutional neural network was developed to extract deep metabolic imaging (DMI) indices and blindly evaluated in an independent cohort with longitudinal follow-up from the HPPI and an external German cohort of 90 parkinsonian patients with different imaging acquisition protocols. Results: The proposed DMI indices had less ambiguity space in the differential diagnosis. They achieved sensitivities of 98.1%, 88.5%, and 84.5%, and specificities of 90.0%, 99.2%, and 97.8%, respectively, for the diagnosis of IPD, MSA, and PSP in the blind-test cohort. In the German cohort, they resulted in sensitivities of 94.1%, 82.4%, and 82.1%, and specificities of 84.0%, 99.9%, and 94.1%, respectively. Using the PET scans independently achieved a performance comparable to the integration of demographic and clinical information into the DMI indices. Conclusion: The DMI indices developed on the HPPI database show the potential to provide an early and accurate differential diagnosis for parkinsonism and are robust when dealing with discrepancies between populations and imaging acquisitions.

Image-level trajectory inference of tau pathology using variational autoencoder for Flortaucipir PET.

PURPOSE: Alzheimer's disease (AD) studies revealed that abnormal deposition of tau spreads in a specific spatial pattern, namely Braak stage. However, Braak staging is based on post mortem brains, each of which represents the cross section of the tau trajectory in disease progression, and numerous studies were reported that do not conform to that model. This study thus aimed to identify the tau trajectory and quantify the tau progression in a data-driven approach with the continuous latent space learned by variational autoencoder (VAE). METHODS: A total of 1080 [18F]Flortaucipir brain positron emission tomography (PET) images were collected from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. VAE was built to compress the hidden features from tau images in latent space. Hierarchical agglomerative clustering and minimum spanning tree (MST) were applied to organize the features and calibrate them to the tau progression, thus deriving pseudo-time. The image-level tau trajectory was inferred by continuously sampling across the calibrated latent features. We assessed the pseudo-time with regard to tau standardized uptake value ratio (SUVr) in AD-vulnerable regions, amyloid deposit, glucose metabolism, cognitive scores, and clinical diagnosis. RESULTS: We identified four clusters that plausibly capture certain stages of AD and organized the clusters in the latent space. The inferred tau trajectory agreed with the Braak staging. According to the derived pseudo-time, tau first deposits in the parahippocampal and amygdala, and then spreads to the fusiform, inferior temporal lobe, and posterior cingulate. Prior to the regional tau deposition, amyloid accumulates first. CONCLUSION: The spatiotemporal trajectory of tau progression inferred in this study was consistent with Braak staging. The profile of other biomarkers in disease progression agreed well with previous findings. We addressed that this approach additionally has the potential to quantify tau progression as a continuous variable by taking a whole-brain tau image into account.

The Effects of Anthocyanin-Rich Bilberry Extract on Transintestinal Cholesterol Excretion.

Hypercholesterolemia is one of the modifiable and primary risk factors for cardiovascular diseases (CVD). Emerging evidence suggests the stimulation of transintestinal cholesterol excretion (TICE), the nonbiliary cholesterol excretion, using natural products can be an effective way to reduce CVD. Bilberry (Vaccinium myrtillus L.) has been reported to have cardioprotective effects by ameliorating oxidative stress, inflammation, and dyslipidemia. However, the role of bilberry in intestinal cholesterol metabolism is not well understood. To examine the effects of bilberry in intestinal cholesterol metabolism, we measured the genes for cholesterol flux and de novo synthesis in anthocyanin-rich bilberry extract (BE)-treated Caco-2 cells. BE significantly decreased the genes for cholesterol absorption, i.e., Niemann-Pick C1 Like 1 and ATP-binding cassette transporter A1 (ABCA1). In contrast, BE significantly upregulated ABCG8, the apical transporter for cholesterol. There was a significant induction of low-density lipoprotein receptors, with a concomitant increase in cellular uptake of cholesterol in BE-treated cells. The expression of genes for lipogenesis and sirtuins was altered by BE treatment. In the present study, BE altered the genes for cholesterol flux from basolateral to the apical membrane of enterocytes, potentially stimulating TICE. These results support the potential of BE in the prevention of hypercholesterolemia.

Towards Understanding Complex Human Dexterous Manipulation Strategies: Kinematics of Gaiting-based Object Rotations.

This paper presents a novel method for tracking gaiting-based (changing contacts, reciprocal, cyclical) withinhand manipulation strategies of a human hand. We present a kinematic model that relies on data collected from 6-DOF magnetic sensors attached to 7 external sites on the hand. The sensors are calibrated by three procedures-sensor-to-fingertip, constrained fingertip workspace limits, and flat hand configuration. Subjects rotated two cubes of different sizes around the 3 object-centric axes, while a synchronized camera recorded the object motion. Hand motions were segmented and then averaged using dynamic time warping (DTW) to yield a representative time-series motion primitive for the given task. The hand movements of two subjects during cube rotation tasks were reconstructed using a 22-degree of freedom (DOF) hand kinematic model. Based on a qualitative evaluation of the joint movements, intrasubject correlations of joint angles were found.

Purification of 2,3-butanediol from fermentation broth: process development and techno-economic analysis.

BACKGROUND: 2,3-Butanediol (2,3-BDO) is a synthetic chemical compound that also can be produced by biomass fermentation, which is gaining share in the global market as an intermediate product for numerous applications, i.e. as liquid fuel or fuel additive. Several metabolic engineering fermentation strategies to enhance the production of 2,3-BDO were developed. However, the recovery of 2,3-BDO from its fermentation broth remains a challenge due to its low concentration and its solubility in water and other components. Thus, a cost-effective recovery process is required to deliver the required purity of 2,3-BDO. This paper presents a new process development and techno-economic analysis for 2,3-BDO purification from a fermentation broth. RESULTS: Conventional distillation and hybrid extraction-distillation (HED) processes are proposed in this study with detailed optimization and economic analysis. Particularly, a systematic solvent selection method was successfully implemented to determine a good solvent for the proposed HED configuration based on numerous experimental data obtained with each solvent candidate. NRTL and UNIQUAC property methods were evaluated to obtain binary interaction parameters of 2,3-BDO through rigorous Aspen Plus regression and validated using experimental data. Total annual cost (TAC)-based optimization was performed for each proposed configuration. Even though the HED configuration required 9.5% higher capital cost than conventional distillation, placing an extraction column before the distillation column was effective in removing water from the fermentation broth and significantly improved the overall process economics. CONCLUSIONS: Oleyl alcohol was found to be the most suitable solvent for the HED of 2,3-BDO due to its high distribution coefficient and high selectivity. The proposed HED drastically reduced reboiler duty consumption and TAC by up to 54.8 and 25.8%, respectively. The proposed design is expected to be used for the commercial scale of 2,3-BDO production from fermentation process.

Improvement of anti-cancer drug efficacy via thermosensitive hydrogel in peritoneal carcinomatosis in gastric cancer.

Peritoneal carcinomatosis (PC) of gastric origin has a poor prognosis with short survival due to lack of effective therapeutic modalities. Here, we evaluated the therapeutic efficacy of an injectable thermosensitive poly (organophosphazene) (PPZ) hydrogel with docetaxel (DTX-gel) to develop an effective therapeutic agent for patient with PC. Three days after inoculation of highly metastatic 44As3Luc cells into peritoneal cavity, the mice were intravenously or intraperitoneally administered with docetaxel alone (DTX-sol IV or IP), and intraperitoneally injected with DTX-gel. The anti-tumor activity was monitored by bioluminescence live imaging system. Compared to DTX-sol IV or IP, the tumor growth was significantly reduced in the DTX-gel treated mice (p<0.0001, p=0.0001). Furthermore, the survival rate was significantly increased in the DTX-gel treated mice compared to DTX-sol IV or IP treated mice (p<0.0001, p=0.0068). Our results demonstrated that DTX-gel suppresses peritoneal metastasis by continuing release of chemotherapy agent, which leads to increase the survival rate in a PC model. Therefore, biodegradable thermosensitive hydrogel with docetaxel system can be a good anti-cancer agent for PC.

Eight-year experience of using HTA in drug reimbursement: South Korea.

This study describes the process and results of drug reimbursement decision-making in South Korea and evaluates its performance from the perspectives of the various stakeholders involved. Data were retrieved from the evaluation report posted on the Health Insurance Review and Assessment Service (HIRA) website. As of 2014, 253 new drugs had been submitted to the HIRA for appraisal. Of these, 175 (69.2%) were recommended in favor of listing and 78 (30.8%) were rejected. Furthermore, 68 of these drugs were deemed clinically improved relative to existing drugs. For those drugs that did not demonstrate clinical superiority (which was most of them), a simple price comparison to the existing drug was utilized as a gate toward listing. On top of the base-line analysis, 104 stakeholders from the industry, academia, public office, and civic society responded to a questionnaire designed to obtain their opinions on the South Korean positive list system (PLS). Stakeholders agreed that the consistency of reimbursement decision-making has improved since 2007, while accessibility to new drugs has apparently decreased. Respondents also indicated a preference toward improved public access to decision-making information. This examination of reimbursement decisions in South Korea will illuminate critical issues for countries that are considering the introduction of similar policies.

Price cuts and drug spending in South Korea: the case of antihyperlipidemic agents.

OBJECTIVE: To identify the effect of price control policies on drug expenditure in South Korea. METHODS: We retrospectively examined the effects of price-reduction policies on drug expenditures, in particular regarding anti-hyperlipidemic drugs. The National Health Insurance claims data for a 60-month period between 2006 and 2010 were analysed. A segmented regression analysis was conducted with three intervention variables: July 2008, April 2009, and January 2010. RESULTS: Despite three rounds of price cuts, monthly drug expenditures increased by KRW 599.67 million (USD 523,726) after the third intervention (p=0.0781). The trend in volume increased consistently, but not significantly. The unit prices showed a steady downward trend over time, but rebounded after the third price cut. The number of patients with hyperlipidemia more than doubled to 3729 (p=0.0801) per month after the entry of generics for atorvastatin in July 2008. CONCLUSION: Extensive price controls did not effectively suppress the growth of pharmaceutical expenditures. The increased number of patients, attributable to the newly launched generic drug atorvastatin, and the increased use of expensive drugs were major factors affecting the increase in drug spending. Policies that regulate both drug prices and utilisation, and that reduce financial burdens via enhanced use of generics need to be introduced.

Cost-utility analysis for platinum-sensitive recurrent ovarian cancer therapy in South Korea: results of the polyethylene glycolated liposomal doxorubicin/carboplatin sequencing model.

OBJECTIVE: We performed a cost-utility analysis to assess the cost-effectiveness of a chemotherapy sequence including a combination of polyethylene glycolated liposomal doxorubicin (PLD)/carboplatin versus paclitaxel/carboplatin as a second-line treatment in women with platinum-sensitive ovarian cancer. METHODS: A Markov model was constructed with a 10-year time horizon. The treatment sequence consisted of first- to sixth-line chemotherapies and best supportive care (BSC) before death. Cycle length, a time interval for efficacy evaluation of chemotherapy, was 9 weeks. The model consisted of four health states: responsive, progressive, clinical remission, and death. At any given time, a patient may have remained on a current therapy or made a transition to the next therapy or death. Median time to progressions and overall survivals data were obtained through a systematic literature review and were pooled using a meta-analytical approach. If unavailable, this was elicited from an expert panel (eg, BSC). These outcomes were converted to transition probabilities using an appropriate formula. Direct costs included drug-acquisition costs for chemotherapies, premedication, adverse-event treatment and monitoring, efficacy evaluation, BSC, drug administration, and follow-up tests during remission. Indirect costs were transportation expenses. Utilities were also derived from the literature. Costs and utilities were discounted at an annual rate of 5% per cycle. RESULTS: PLD/carboplatin combination as the second line in the sequence is more effective and costly than paclitaxel/carboplatin combination, showing an additional US$21,658 per quality-adjusted life years. This result was robust in a deterministic sensitivity analysis except when median time to progression of second-line therapies and administration cost of PLD/carboplatin per administration cycle were varied. The probability of cost-effectiveness for PLD/carboplatin combination was 49.4% at a willingness to pay $20,000. CONCLUSION: A PLD/carboplatin combination is an economically valuable option as second-line chemotherapy for the treatment of platinum-sensitive ovarian cancer in South Korea.