Amyloid-ß prediction machine learning model using source-based morphometry across neurocognitive disorders.

Previous studies have developed and explored magnetic resonance imaging (MRI)-based machine learning models for predicting Alzheimer's disease (AD). However, limited research has focused on models incorporating diverse patient populations. This study aimed to build a clinically useful prediction model for amyloid-beta (Aß) deposition using source-based morphometry, using a data-driven algorithm based on independent component analyses. Additionally, we assessed how the predictive accuracies varied with the feature combinations. Data from 118 participants clinically diagnosed with various conditions such as AD, mild cognitive impairment, frontotemporal lobar degeneration, corticobasal syndrome, progressive supranuclear palsy, and psychiatric disorders, as well as healthy controls were used for the development of the model. We used structural MR images, cognitive test results, and apolipoprotein E status for feature selection. Three-dimensional T1-weighted images were preprocessed into voxel-based gray matter images and then subjected to source-based morphometry. We used a support vector machine as a classifier. We applied SHapley Additive exPlanations, a game-theoretical approach, to ensure model accountability. The final model that was based on MR-images, cognitive test results, and apolipoprotein E status yielded 89.8% accuracy and a receiver operating characteristic curve of 0.888. The model based on MR-images alone showed 84.7% accuracy. Aß-positivity was correctly detected in non-AD patients. One of the seven independent components derived from source-based morphometry was considered to represent an AD-related gray matter volume pattern and showed the strongest impact on the model output. Aß-positivity across neurological and psychiatric disorders was predicted with moderate-to-high accuracy and was associated with a probable AD-related gray matter volume pattern. An MRI-based data-driven machine learning approach can be beneficial as a diagnostic aid.

Performance of plasma Aß42/40, measured using a fully automated immunoassay, across a broad patient population in identifying amyloid status.

BACKGROUND: Plasma biomarkers have emerged as promising screening tools for Alzheimer's disease (AD) because of their potential to detect amyloid ß (Aß) accumulation in the brain. One such candidate is the plasma Aß42/40 ratio (Aß42/40). Unlike previous research that used traditional immunoassay, recent studies that measured plasma Aß42/40 using fully automated platforms reported promising results. However, its utility should be confirmed using a broader patient population, focusing on the potential for early detection. METHODS: We recruited 174 participants, including healthy controls (HC) and patients with clinical diagnoses of AD, frontotemporal lobar degeneration, dementia with Lewy bodies/Parkinson's disease, mild cognitive impairment (MCI), and others, from a university memory clinic. We examined the performance of plasma Aß42/40, measured using the fully automated high-sensitivity chemiluminescence enzyme (HISCL) immunoassay, in detecting amyloid-positron emission tomography (PET)-derived Aß pathology. We also compared its performance with that of Simoa-based plasma phosphorylated tau at residue 181 (p-tau181), glial fibrillary acidic protein (GFAP), and neurofilament light (NfL). RESULTS: Using the best cut-off derived from the Youden Index, plasma Aß42/40 yielded an area under the receiver operating characteristic curve (AUC) of 0.949 in distinguishing visually assessed 18F-Florbetaben amyloid PET positivity. The plasma Aß42/40 had a significantly superior AUC than p-tau181, GFAP, and NfL in the 167 participants with measurements for all four biomarkers. Next, we analyzed 99 participants, including only the HC and those with MCI, and discovered that plasma Aß42/40 outperformed the other plasma biomarkers, suggesting its ability to detect early amyloid accumulation. Using the Centiloid scale (CL), Spearman's rank correlation coefficient between plasma Aß42/40 and CL was -0.767. Among the 15 participants falling within the CL values indicative of potential future amyloid accumulation (CL between 13.5 and 35.7), plasma Aß42/40 categorized 61.5% (8/13) as Aß-positive, whereas visual assessment of amyloid PET identified 20% (3/15) as positive. CONCLUSION: Plasma Aß42/40 measured using the fully automated HISCL platform showed excellent performance in identifying Aß accumulation in the brain in a well-characterized cohort. This equipment may be useful for screening amyloid pathology because it has the potential to detect early amyloid pathology and is readily applied in clinical settings.

Impact of Amyloid and Tau PET on Changes in Diagnosis and Patient Management.

BACKGROUND AND OBJECTIVES: Previous studies have evaluated the diagnostic effect of amyloid PET in selected research cohorts. However, these studies did not assess the clinical impact of the combination of amyloid and tau PETs. Our objective was to evaluate the association of the combination of 2 PETs with changes in diagnosis, treatment, and management in a memory clinic cohort. METHODS: All participants underwent amyloid [18F]florbetaben PET and tau PET using [18F]PI-2620 or [18F]Florzolotau, which are potentially useful for the diagnosis of non-Alzheimer disease (AD) tauopathies. Dementia specialists determined a pre- and post-PET diagnosis that existed in both a clinical syndrome (cognitive normal [CN], mild cognitive impairment [MCI], and dementia) and suspected etiology, with a confidence level. In addition, the dementia specialists determined patient treatment in terms of ancillary investigations and management. RESULTS: Among 126 registered participants, 84.9% completed the study procedures and were included in the analysis (CN [n = 40], MCI [n = 25], AD [n = 20], and non-AD dementia [n = 22]). The etiologic diagnosis changed in 25.0% in the CN, 68.0% in the MCI, and 23.8% with dementia. Overall changes in management between pre- and post-PET occurred in 5.0% of CN, 52.0% of MCI, and 38.1% of dementia. Logistic regression analysis revealed that tau PET has stronger associations with change management than amyloid PET in all participants and dementia groups. DISCUSSION: The combination of amyloid and tau PETs was associated with changes in management and diagnosis of MCI and dementia, and the second-generation tau PET has a strong impact on the changes in diagnosis and management in memory clinics. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that the combination of amyloid and tau PETs was associated with changes in management and diagnosis of MCI and dementia.

[The questionnaire survey regarding the impact of COVID-19 pandemic on Parkinson's disease patients].

We conducted the multicenter questionnaire survey targeting patients with Parkinson's disease (PD) in order to investigate the impacts on their daily lives and their requests to hospitals in the pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Mainly using open-ended questionnaire, we asked their anxiety, troubles they are facing, and requests toward hospitals in the pandemic of SARS-CoV-2. Two hundred fifth-eight PD patients answered the questionnaire. There were various opinions about anxiety such as "PD patients are susceptible and vulnerable to SARS-CoV-2" (36.8%). Concerning the troubles in the pandemic, the most frequent answer was that they couldn't participate in the rehabilitation and elderly day care (38.4%). Relatively many PD patients requested telemedicine (29.5%), whereas some people hoped face-to-face medical care (8.1%). There were demands about the delivery of medications (50.0%), the establishment of telephone consultations (43.8%), resources for rehabilitation at home (43.8%). The medical care adapted to the anxiety, trouble and requests of PD patients will be required in the era when we have to live with SARS-CoV-2.

Evaluation of [18F]PI-2620, a second-generation selective tau tracer, for assessing four-repeat tauopathies.

Tau aggregates represent a key pathologic feature of Alzheimer's disease and other neurodegenerative diseases. Recently, PET probes have been developed for in vivo detection of tau accumulation; however, they are limited because of off-target binding and a reduced ability to detect tau in non-Alzheimer's disease tauopathies. The novel tau PET tracer, [18F]PI-2620, has a high binding affinity and specificity for aggregated tau; therefore, it was hypothesized to have desirable properties for the visualization of tau accumulation in Alzheimer's disease and non-Alzheimer's disease tauopathies. To assess the ability of [18F]PI-2620 to detect regional tau burden in non-Alzheimer's disease tauopathies compared with Alzheimer's disease, patients with progressive supranuclear palsy (n = 3), corticobasal syndrome (n = 2), corticobasal degeneration (n = 1) or Alzheimer's disease (n = 8), and healthy controls (n = 7) were recruited. All participants underwent MRI, amyloid ß assessment and [18F]PI-2620 PET (Image acquisition at 60-90 min post-injection). Cortical and subcortical tau accumulations were assessed by calculating standardized uptake value ratios using [18F]PI-2620 PET. For pathologic validation, tau pathology was assessed using tau immunohistochemistry and compared with [18F]PI-2620 retention in an autopsied case of corticobasal degeneration. In Alzheimer's disease, focal retention of [18F]PI-2620 was evident in the temporal and parietal lobes, precuneus, and cingulate cortex. Standardized uptake value ratio analyses revealed that patients with non-Alzheimer's disease tauopathies had elevated [18F]PI-2620 uptake only in the globus pallidus, as compared to patients with Alzheimer's disease, but not healthy controls. A head-to-head comparison of [18F]PI-2620 and [18F]PM-PBB3, another tau PET probe for possibly visualizing the four-repeat tau pathogenesis in non-Alzheimer's disease, revealed different retention patterns in one subject with progressive supranuclear palsy. Imaging-pathology correlation analysis of the autopsied patient with corticobasal degeneration revealed no significant correlation between [18F]PI-2620 retention in vivo. High [18F]PI-2620 uptake at 60-90 min post-injection in the globus pallidus may be a sign of neurodegeneration in four-repeat tauopathy, but not necessarily practical for diagnosis of non-Alzheimer's disease tauopathies. Collectively, this tracer is a promising tool to detect Alzheimer's disease-tau aggregation. However, late acquisition PET images of [18F]PI-2620 may have limited utility for reliable detection of four-repeat tauopathy because of lack of correlation between post-mortem tau pathology and different retention pattern than the non-Alzheimer's disease-detectable tau radiotracer, [18F]PM-PBB3. A recent study reported that [18F]PI-2620 tracer kinetics curves in four-repeat tauopathies peak earlier (within 30 min) than Alzheimer's disease; therefore, further studies are needed to determine appropriate PET acquisition times that depend on the respective interest regions and diseases.

Oxidative Coupling of Terminal Alkynes with Aldehydes Leading to Alkynyl Ketones by Using Indium(III) Bromide.

An indium(III)-promoted direct acylation of terminal alkynes using aldehydes leading to ynones was developed. In contrast to the previous addition reactions of alkynes to aldehydes, which provide propargylic alcohols, the oxidative coupling proceeded exclusively to afford alkynyl ketones. The products were likely generated through an Oppenauer oxidation of the indium propargylic alkoxide species by excess amounts of aldehydes.

Effective Remote Loading of Doxorubicin into DPPC/Poloxamer 188 Hybrid Liposome to Retain Thermosensitive Property and the Assessment of Carrier-Based Acute Cytotoxicity for Pulmonary Administration.

Functional liposome administration via the pulmonary route is of interest to treat pulmonary diseases, including cancer. Here, a block copolymer used as a medical additive, Poloxamer 188 (P188), was incorporated into liposome membranes, and the thermosensitive characteristics of the DPPC/P188 hybrid liposomes were assessed. An increase in P188 incorporation in DPPC liposomes enhanced the release of calcein, a fluorescence marker, from liposomes at 42°C in vitro; calcein release was significantly slower at 37°C. The lipid composition was optimal at a DPPC/P188 ratio of 3:0.4 (molar ratio). DPPC/P188 liposomes did not exhibit in vitro cytotoxicity against A549 cells and Raw 264.7 cells used as models of pulmonary cells or trigger in vivo acute inflammation as determined by the secretion of tumor necrosis factor alpha. Next, an anticancer drug, doxorubicin (DOX), was loaded with approximately 90% efficiency into DPPC/P188 liposomes using a remote-loading method and a DOX-phospholipid ratio of 1:20 (w/w). The interior buffer of liposome has remarkably changed DOX release at 42°C. DOX released from DPPC/P188 liposomes at 42°C exhibited cytotoxic effects toward A549 cells comparable with free DOX solution. These results suggest that a DOX-loaded DPPC/P188 liposome formulation administered via the pulmonary route may be useful for treating lung cancer.