PET Status Research Articles

The Child and the Animal in Times of War: Halahmy’s The Emergency Zoo and Contemporary News Reports on the War in Ukraine

This article looks at both Miriam Halahmy’s historical novel for children, The Emergency Zoo, set during several days of mass pet culling in London prior to World War II and Hilda Kean’s published research on the somewhat conveniently forgotten phenomenon, entitled The Great Dog and Cat Massacre. In both these works we observe the strong connection between child and pet, emphasised all the more in a period of uncertainty brought on by impending conflict. The reader is also presented with a detailed exploration of the child’s worldview as compared to that of the adults’ largely hierarchical humanistic perceptions, a way of thinking which is taken as one of the key contributory causes of the terrible pet cull of 1939. Comparisons are then drawn with the treatment of the child–animal relationship and that of household pets during the current Russo-Ukrainian War (the largest European conflict since World War II) as broadly represented in newspaper articles and photographic reports. These reports not only recognise the importance of the child–animal relationship (especially in terms of alleviating trauma and providing a sense of well-being) but also demonstrate that animals are both perceived as refugees and rightly given refugee status. Through an analysis of the strong contemporary media focus on the child and animal refugee, along with the comparison drawn with both Halahmy’s novel and Kean’s historical study, the article concludes that there is clear evidence showing that more recent perceptions of the child–animal relationship and the improved status of pets have been specifically shaped by both posthumanist thinking and the various debates concerning the nature and consequences of the Anthropocene.

3T sodium-MRI as predictor of neurocognition in nondemented older adults: a cross sectional study.

Dementia is a burgeoning global problem. Novel magnetic resonance imaging (MRI) metrics beyond volumetry may bring new insight and aid clinical trial evaluation of interventions early in the Alzheimer's disease course to complement existing imaging and clinical metrics. To determine whether: (i) normalized regional sodium-MRI values (Na-SI) are better predictors of neurocognitive status than volumetry (ii) cerebral amyloid PET status improves modelling. Nondemented older adult (>60 years) volunteers of known Alzheimer's Disease Assessment Scale (ADAS-Cog11), Mini-Mental State Examination (MMSE) and Consortium to Establish a Registry for Alzheimer's Disease (CERAD) neurocognitive test scores, ApolipoproteinE (APOE) e4 +/- cerebral amyloid PET status were prospectively recruited for 3T sodium-MRI brain scans. Left and right hippocampal, entorhinal and precuneus volumes and Na-SI (using the proportional intensity scaling normalization method with field inhomogeneity and partial volume corrections) were obtained after segmentation and co-registration of 3D-T1-weighted proton images. Descriptive statistics, correlation and best-subset regression analyses were performed. In our 76 nondemented participants (mean(standard deviation) age 75(5) years; woman 47(62%); cognitively unimpaired 54/76(71%), mildly cognitively impaired 22/76(29%)), left hippocampal Na-SI, not volume, was preferentially in the best models for predicting MMSE (Odds Ratio (OR) = 0.19(Confidence Interval (CI) = 0.07,0.53), P-value = 0.001) and ADAS-Cog11 (Beta(B) = 1.2(CI = 0.28,2.1), P-value = 0.01) scores. In the entorhinal analysis, right entorhinal Na-SI, not volume, was preferentially selected in the best model for predicting ADAS-Cog11 (B = 0.94(CI = 0.11,1.8), P-value = 0.03). While right entorhinal Na-SI and volume were both selected for MMSE modelling (Na-SI OR = 0.23(CI = 0.09,0.6), P-value = 0.003; volume OR = 2.6(CI = 1.0,6.6), P-value = 0.04), independently, Na-SI explained more of the variance (Na-SI R 2 = 10.3; volume R 2 = 7.5). No imaging variable was selected in the best CERAD models. Adding cerebral amyloid status improved model fit (Akaike Information Criterion increased 2.0 for all models, P-value < 0.001-0.045). Regional Na-SI were more predictive of MMSE and ADAS-Cog11 scores in our nondemented older adult cohort than volume, hippocampal more robust than entorhinal region of interest. Positive amyloid status slightly further improved model fit.

18FFlutemetamol-PET Aided Classification of Cerebral Amyloid Angiopathy: A Multicenter Study.

Cerebral amyloid angiopathy (CAA)-related features on neuroimaging often coexist with signs of arteriolosclerosis-small vessel disease on neuroimaging in people with intracranial hemorrhage (ICH). This study aimed at defining the value of amyloid pathology detected by 18Fflutemetamol PET in reclassification and stratification of risk of bleeding in people with mixed CAA-arteriolosclerosis features. We included consecutive patients admitted to 2 institutions (2018-2023) with spontaneous symptomatic ICH, subarachnoid hemorrhage (SAH), transient focal neurologic episodes (TFNE), or cognitive impairment and MRI showing CAA hallmarks. All patients underwent brain magnetic resonance imaging (MRI) with susceptibility weighted imaging and 18Fflutemetamol PET imaging and were followed up for at least 1 year. We compared cases with CAA and arteriolosclerosis + CAA features and defined long-term outcomes (composite outcome including death, ICH, ischemic stroke, SAH, TFNE) depending on PET status (CAA/amyloid pathology vs arteriolosclerosis-predominant groups). Among 47 patients, according to PET and MRI imaging, 38 patients were reclassified in the CAA/amyloid pathology group and 9 in the arteriolosclerosis-predominant group, with similar cardiovascular risk factors but a significantly higher lobar microbleed burden for the former group. The CAA/amyloid pathology group had higher rates of composite outcome (43.9 vs 11.1 events per 100 patient-year; p = 0.039) and ICH (36.5 vs 5.6 events per 100 patient-years; p = 0.04) compared with the arteriolosclerosis-predominant group. 18FFlutemetamol PET imaging can help in reclassification of mixed arteriolosclerosis + CAA into CAA/amyloid pathology and arteriolosclerosis-predominant, with implications on long-term risk of recurrent events. This study provides Class IV evidence that 18Fflutemetamol PET can distinguish between CAA + arteriolosclerosis and arteriolosclerosis-predominant pathology.

Longitudinal Phospho-tau217 Predicts Amyloid Positron Emission Tomography in Asymptomatic Alzheimer’s Disease

BackgroundBlood-based AD biomarkers such as plasma P-tau217 are increasingly used in clinical trials as a screening tool.ObjectivesTo assess the utility of an electrochemiluminescence (ECL) immunoassay in predicting brain amyloid PET status in cognitively unimpaired individuals.SettingPlasma samples collected at baseline, week 12, and week 240 or endpoint originated from the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s Disease (A4) trial and the companion Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) study.ParticipantsBoth A4 and LEARN enrolled eligible cognitively unimpaired persons 65 to 85 years. Individuals with elevated brain amyloid PET levels were eligible for the A4 Study, while those without elevated brain amyloid PET levels were eligible for the LEARN Study.InterventionParticipants in the A4 Study received intravenous solanezumab (up to 1600 mg) or placebo every 4 weeks. The LEARN Study is an observational study without intervention.MeasurementsPlasma P-tau217 concentration levels from A4 Study participants were measured using an ECL immunoassay. Receiver Operating Characteristic (ROC) curve analysis was performed for each biomarker against amyloid positivity, defined by ≥22 CL and ≥ 33 CL.ResultsReceiver operating characteristic curve (ROC) analysis indicates high diagnostic value of P-tau217 in individuals with amyloid PET ≥ 20 (Area under the ROC (AUROC): 0.87) and ≥ 33 CL (AUROC: 0.89). Repeated testing with the placebo group taken 12 weeks apart (range: 68 to 143 days) and the LEARN participants taken between 1.4 and 1.75 years resulted in a strong positive correlation (Corr. 0.91 (0.90 to 0.92)).ConclusionAn ECL immunoassay testing plasma P-tau217 accurately predicts amyloid PET positivity in cognitively unimpaired individuals. Our future analyses aim to determine if use of this assay may reduce the screening burden of preclinical individuals into anti-amyloid clinical trials.

Acceptable performance of blood biomarker tests of amyloid pathology - recommendations from the Global CEO Initiative on Alzheimer's Disease.

Anti-amyloid treatments for early symptomatic Alzheimer disease have recently become clinically available in some countries, which has greatly increased the need for biomarker confirmation of amyloid pathology. Blood biomarker (BBM) tests for amyloid pathology are more acceptable, accessible and scalable than amyloid PET or cerebrospinal fluid (CSF) tests, but have highly variable levels of performance. The Global CEO Initiative on Alzheimer's Disease convened a BBM Workgroup to consider the minimum acceptable performance of BBM tests for clinical use. Amyloid PET status was identified as the reference standard. For use as a triaging test before subsequent confirmatory tests such as amyloid PET or CSF tests, the BBM Workgroup recommends that a BBM test has a sensitivity of ≥90% with a specificity of ≥85% in primary care and ≥75-85% in secondary care depending on the availability of follow-up testing. For use as a confirmatory test without follow-up tests, a BBM test should have performance equivalent to that of CSF tests - a sensitivity and specificity of ~90%. Importantly, the predictive values of all biomarker tests vary according to the pre-test probability of amyloid pathology and must be interpreted in the complete clinical context. Use of BBM tests that meet these performance standards could enable more people to receive an accurate and timely Alzheimer disease diagnosis and potentially benefit from new treatments.

Longitudinal Assessment of Cognitive Decline: Distinguishing Features and Trends in Cognitive Challenge Test among Older Adults with Mild Cognitive Impairment and Amyloid PET Status

Longitudinal Assessment of Cognitive Decline: Distinguishing Features and Trends in Cognitive Challenge Test among Older Adults with Mild Cognitive Impairment and Amyloid PET Status

Clinical utility of plasma Aβ42/40 ratio by LC-MS/MS in Alzheimer's disease assessment.

Plasma Aβ42/40 ratio can help predict amyloid PET status, but its clinical utility in Alzheimer's disease (AD) assessment is unclear. Aβ42/40 ratio was measured by LC-MS/MS for 250 specimens with associated amyloid PET imaging, diagnosis, and demographic data, and for 6,192 consecutive clinical specimens submitted for Aβ42/40 testing. High diagnostic sensitivity and negative predictive value (NPV) for Aβ-PET positivity were observed, consistent with the clinical performance of other plasma LC-MS/MS assays, but with greater separation between Aβ42/40 values for individuals with positive vs. negative Aβ-PET results. Assuming a moderate prevalence of Aβ-PET positivity, a cutpoint was identified with 99% NPV, which could help predict that AD is likely not the cause of patients' cognitive impairment and help reduce PET evaluation by about 40%. High-throughput plasma Aβ42/40 LC-MS/MS assays can help identify patients with low likelihood of AD pathology, which can reduce PET evaluations, allowing for cost savings.

Association between PET/CT Scan Findings, Treatment, and Cancer Incidence in a Cohort of AAA Patients.

Background: Abdominal aortic aneurysm (AAA) is a chronic inflammatory disease that poses several challenges. Given the increasing evidence that AAA patients are more likely to develop cancer and the importance of its early detection, we strived to develop a non-invasive tool based on serial FDG-PET/CT scan examinations to identify, among AAA patients, those at risk of cancer. Methods: Between 2006 and 2011 we recruited 149 AAA patients, free of cancer at baseline, and followed them until the end of 2021. All patients underwent an FDG-PET/CT scan at inclusion and possibly more scans during follow-up. At each medical imaging examination, the aneurysmal FDG uptake was recorded. Patients were stratified based on their aortic wall PET status (negative/positive). Any occurrence of cancer was reported. A Cox regression analysis and competing-risk modeling were applied to the data. Results: The proportion of AAA patients who developed cancer was 31.5% (mean time to diagnosis was 5.7 ± 3.4 years) and the death rate was 59%. A difference in cancer incidence between PET+ and PET- patients was detected (46.8% vs. 27.3%; HR = 1.96, 95%CI: 1.07-3.57, p = 0.028). Moreover, AAA patients undergoing surgical treatment had a lower risk of cancer than unoperated patients (28% vs. 50%; HR = 0.41, 95%CI: 0.21-0.80, p = 0.009). Conclusions: In AAA patients, diagnostic imaging with an FDG-PET/CT scan can help identify those patients at a higher risk of developing cancer. Moreover, the higher cancer risk in non-surgically treated patients calls for further analysis of associations between aneurysm growth and malignant disease.

Comparison of cerebrospinal fluid, plasma and neuroimaging biomarker utility in Alzheimer's disease.

Alzheimer's disease biomarkers are crucial to understanding disease pathophysiology, aiding accurate diagnosis and identifying target treatments. Although the number of biomarkers continues to grow, the relative utility and uniqueness of each is poorly understood as prior work has typically calculated serial pairwise relationships on only a handful of markers at a time. The present study assessed the cross-sectional relationships among 27 Alzheimer's disease biomarkers simultaneously and determined their ability to predict meaningful clinical outcomes using machine learning. Data were obtained from 527 community-dwelling volunteers enrolled in studies at the Charles F. and Joanne Knight Alzheimer Disease Research Center at Washington University in St Louis. We used hierarchical clustering to group 27 imaging, CSF and plasma measures of amyloid beta, tau [phosphorylated tau (p-tau), total tau t-tau)], neuronal injury and inflammation drawn from MRI, PET, mass-spectrometry assays and immunoassays. Neuropsychological and genetic measures were also included. Random forest-based feature selection identified the strongest predictors of amyloid PET positivity across the entire cohort. Models also predicted cognitive impairment across the entire cohort and in amyloid PET-positive individuals. Four clusters emerged reflecting: core Alzheimer's disease pathology (amyloid and tau), neurodegeneration, AT8 antibody-associated phosphorylated tau sites and neuronal dysfunction. In the entire cohort, CSF p-tau181/Aβ40lumi and Aβ42/Aβ40lumi and mass spectrometry measurements for CSF pT217/T217, pT111/T111, pT231/T231 were the strongest predictors of amyloid PET status. Given their ability to denote individuals on an Alzheimer's disease pathological trajectory, these same markers (CSF pT217/T217, pT111/T111, p-tau/Aβ40lumi and t-tau/Aβ40lumi) were largely the best predictors of worse cognition in the entire cohort. When restricting analyses to amyloid-positive individuals, the strongest predictors of impaired cognition were tau PET, CSF t-tau/Aβ40lumi, p-tau181/Aβ40lumi, CSF pT217/217 and pT205/T205. Non-specific CSF measures of neuronal dysfunction and inflammation were poor predictors of amyloid PET and cognitive status. The current work utilized machine learning to understand the interrelationship structure and utility of a large number of biomarkers. The results demonstrate that, although the number of biomarkers has rapidly expanded, many are interrelated and few strongly predict clinical outcomes. Examining the entire corpus of available biomarkers simultaneously provides a meaningful framework to understand Alzheimer's disease pathobiological change as well as insight into which biomarkers may be most useful in Alzheimer's disease clinical practice and trials.

Impacto do período de lockdown da COVID-19 na saúde dos animais de companhia na Argélia

ABSTRACT The COVID-19 pandemic and the measures established by governments to protect populations have caused significant harm to humanity, not only regarding public health but also in terms of economic and social welfare. This study aims to assess the health status and behavior of pets during the total lockdown period in Algeria from March to June 2020. An online questionnaire consisting of 20 questions was published. A total of 200 pet owners across various departments participated. The lockdown had a negative impact on the physical health of 19.5% of individuals, with weight gain, allergies, and diabetes being predominant (51.8%, 27.7%, and 20.5%, respectively). 38.5% of cases report behavioral disorders, with hyper attachment, aggressiveness, and disobedience being predominant (47.3%, 27.6%, and 18.4%, respectively). The study helped estimate the negative impact of the lockdown on the physical and psychological health of animals. This information will aid in preventing similar damage in case of future pandemics or epidemics.

Remote and in‐clinic digital cognitive screening tools outperform the MoCA to distinguish cerebral amyloid status among cognitively healthy older adults

AbstractBackgroundExisting cognitive screening measures fall short in capturing preclinical AD, and cognitive impairment is unrecognized or misdiagnosed in 27‐81% of older adult primary care patients. Digital assessment technology has the potential to deliver more efficient and sensitive cognitive screening, but requires rigorous validation first. We aimed to determine the accuracy of remote (M2C2 mobile app) and clinic‐based (TabCAT and DCTclockTM) digital tests to distinguish between older adults with and without AD pathologic change. We used the Montreal Cognitive Assessment (MoCA) as a reference standard comparison test.MethodWe recruited 73 cognitively normal participants with Aß PET status (Aß+, n = 25; Aß‐, n = 48, determined by clinical read) from the Butler Hospital Alzheimer’s Prevention Registry (mean age = 69.2 and education = 16.5; 71% female; 89% White). Participants completed M2C2 tasks at home 3 times per day for 8 days, followed by the TabCAT tasks, DCTclockTM, and MoCA at an in‐person study visit. We calculated the area under the curve (AUC) to compare cognitive task accuracy to distinguish Aß status. Multi‐day learning curves were used to examine differences in M2C2 task performance by Aß status over time.ResultAmong the M2C2 tasks, average performance on the Prices task (episodic memory) over 8 days showed the highest accuracy (AUC = .77) to distinguish Aß status. The Aß+ group tended to perform worse than the Aß‐ group on the Prices task over time (Figure 1). On in‐person screening measures (single time‐point), accuracy to distinguish Aß was greatest for the TabCAT Favorites task (AUC = .76), relative to the DCTclockTM (AUC = .72) and the MoCA (AUC = .71).ConclusionWe showed that several brief digital screening approaches (memory‐specific tasks on the M2C2 and TabCAT) outperform the MoCA in distinguishing between cognitively healthy individuals with and without elevated cerebral Aβ. Although further validation in community and clinic‐based samples is needed, these results suggest that these digital cognitive assessments may be suitable for more widespread screening to detect early pathological changes in neurodegenerative disorders. Figure 1. M2C2 task performance over time (3 sessions daily for 8 days) by Aβ status.

Remote and in‐clinic digital cognitive screening tools outperform the MoCA to distinguish cerebral amyloid status among cognitively healthy older adults

AbstractBackgroundExisting cognitive screening measures fall short in capturing preclinical AD, and cognitive impairment is unrecognized or misdiagnosed in 27‐81% of older adult primary care patients. Digital assessment technology has the potential to deliver more efficient and sensitive cognitive screening, but requires rigorous validation first. We aimed to determine the accuracy of remote (M2C2 mobile app) and clinic‐based (TabCAT and DCTclockTM) digital tests to distinguish between older adults with and without AD pathologic change. We used the Montreal Cognitive Assessment (MoCA) as a reference standard comparison test.MethodsWe recruited 73 cognitively normal participants with Aß PET status (Aß+, n = 25; Aß‐, n = 48, determined by clinical read) from the Butler Hospital Alzheimer’s Prevention Registry (mean age = 69.2 and education = 16.5; 71% female; 89% White). Participants completed M2C2 tasks at home 3 times per day for 8 days, followed by the TabCAT tasks, DCTclockTM, and MoCA at an in‐person study visit. We calculated the area under the curve (AUC) to compare cognitive task accuracy to distinguish Aß status. Multi‐day learning curves were used to examine differences in M2C2 task performance by Aß status over time.ResultsAmong the M2C2 tasks, average performance on the Prices task (episodic memory) over 8 days showed the highest accuracy (AUC = .77) to distinguish Aß status. The Aß+ group tended to perform worse than the Aß‐ group on the Prices task over time (Figure 1). On in‐person screening measures (single time‐point), accuracy to distinguish Aß was greatest for the TabCAT Favorites task (AUC = .76), relative to the DCTclockTM (AUC = .72) and the MoCA (AUC = .71).ConclusionsWe showed that several brief digital screening approaches (memory‐specific tasks on the M2C2 and TabCAT) outperform the MoCA in distinguishing between cognitively healthy individuals with and without elevated cerebral Aβ. Although further validation in community and clinic‐based samples is needed, these results suggest that these digital cognitive assessments may be suitable for more widespread screening to detect early pathological changes in neurodegenerative disorders. Figure 1. M2C2 task performance over time (3 sessions daily for 8 days) by Aβ status.

Mastermind of the Alzheimer’s blood‐based biomarkers: development of cutoffs and a visualization tool for use in clinical practice

AbstractBackgroundPhosphorylated (P‐)tau, amyloid‐beta (Abeta)1‐42/1‐40, glial fibrillary acidic protein (GFAP) and neurofilament light (NfL) are the current key Alzheimer’s disease (AD) blood‐based biomarkers. Interpreting results of the four biomarkers simultaneously in a clinical context is challenging. A decision algorithm could aid in the interpretation, tailored to clinically relevant questions: 1) identify positive amyloid status among preclinical and prodromal AD stages, 2) discriminate AD‐dementia from frontotemporal dementia (FTD), 3) discriminate AD‐dementia from dementia with Lewy bodies (DLB). We aimed to develop such an interpretation tool.MethodWe included 1199 participants from the Amsterdam Dementia Cohort (table 1) with subjective cognitive decline (SCD), mild cognitive impairment (MCI), AD‐dementia, FTD (mixed pathologies) or DLB. Plasma P‐tau181, Abeta1‐42/1‐40, GFAP and NfL were measured with Simoa. NfL levels were adjusted for age (method: https://doi.org/10.1002/acn3.51676). We used LASSO regression with bootstrap (1000 iterations) to identify which plasma markers robustly contribute to the prediction of the outcomes of our clinically relevant questions. When a marker was selected in &gt;95% of the iterations in at least one of the clinical scenarios, we qualified it as a contributing marker. Subsequently, we constructed UpSet plots applying Youden’s cutoffs as interpretation tool for the plasma results.ResultP‐tau181, GFAP and NfL were selected as contributing biomarkers. Abeta1‐42/1‐40 was not selected. The panel of P‐tau181, GFAP and NfL had an AUC = 83% (95%CI: 76‐90%) to identify amyloid positivity in SCD+MCI, AUC = 87% (95%CI: 79‐94%) to differentiate AD‐dementia from FTD, and AUC = 73% (95%CI: 62‐84%) to differentiate AD‐dementia from DLB. The UpSet plots show the simultaneous interpretation of P‐tau181, GFAP and NfL results for each clinically relevant question (figure 1): e.g., when all three biomarkers are abnormal in participants with SCD+MCI, there is 83% agreement with an abnormal PET or CSF amyloid status, and when all three plasma markers are normal, there is 88% agreement with a normal amyloid status.ConclusionThe combination of P‐tau181, GFAP and NfL in plasma could support decision making in different clinical contexts. UpSet plots enable easy interpretation of a combination of the markers, and could serve as a tool to support both detection and differential diagnosis of Alzheimer’s disease.

Plasma Alzheimer biomarkers in the 1946 British birth cohort: predicting conversion to amyloid PET positivity over a two‐year follow‐up period

AbstractBackgroundIn the Insight 46 sub‐study of the 1946 British birth cohort we investigated concordance of baseline plasma biomarkers (age 71) with cerebral amyloid PET status at two time‐points (ages 71 and 73).MethodBaseline plasma samples were tested using Simoa (Quanterix) commercial (NfL, GFAP, Aβ42, Aβ40, p‐tau181V2) and homebrew digital immunoassays (p‐tau181, p‐tau231: University of Gothenburg; NT1 tau: Harvard University). Logistic regression and ROC analysis were used to assess concordance of single biomarkers with cerebral amyloid PET status at each timepoint, defined as 18F‐florbetapir SUVR&gt; = 1.071 normalized to whole cerebellum without partial volume correction (13 centiloids). Areas under the curve were compared to that from the base model (age, sex, APOE ε4 carrier status) using De Long tests. Combinations of the top five biomarkers that had singly significantly improved on the base model were compared using Akaike Information Criteria (AIC). Differences between biomarker values across the three amyloid PET groups (both scans negative, baseline negative and follow‐up positive, both positive) were assessed using Kruskal‐Wallis ANOVA and post hoc Dunn’s tests with Bonferroni correction.ResultBaseline assessment of 502 individuals (mean age 70.7 years (s.d. 0.7), 51% male, 29.6% APOE ε4 carriers) yielded 432 individuals with plasma and amyloid PET available at the first timepoint (19.4% PET‐positive) and 336 at the second timepoint (25.3% PET‐positive). No single biomarker outperformed the base model in predicting amyloid PET status at either timepoint. However, each of Aβ40/42, all the p‐tau biomarkers, NT1 tau, and GFAP improved base model performance at both timepoints (Table 1). A model combining base model covariates with Aβ40/42, p‐tau181 homebrew and GFAP gave the best fit for follow‐up amyloid PET status, (AIC 292, compared with the base model AIC of 355 ‐ Table 2). Individuals who converted from PET‐negative to positive had higher median values of p‐tau181 (both assays) and p‐tau231 at baseline than those who remained amyloid PET‐negative (Figure 1).ConclusionCombining baseline plasma Aβ40/42, p‐tau181 and GFAP gave the best prediction of amyloid PET status over 2‐year follow‐up. Individuals who converted from amyloid PET‐negative to positive had higher values of p‐tau181 and p‐tau231 than those who remained PET‐negative.

Blood‐based biomarkers of Alzheimer disease as measured by a mass spectrometry assay are as accurate as CSF tests

AbstractBackgroundEspecially because disease‐modifying treatments (DMTs) for Alzheimer disease (AD) are likely to become more available soon, highly accurate AD blood tests for use in clinical diagnosis are critically needed. Although amyloid PET scans and cerebrospinal fluid (CSF) tests are highly accurate in the identification of individuals with brain amyloidosis, blood tests are likely the only test modality that will enable an adequate scale of AD biomarker testing. Mass spectrometry‐based AD blood tests have consistently demonstrated very high performance.MethodsResearch participants enrolled in studies at the Knight Alzheimer Disease Research Center who underwent amyloid PET and measurement of established CSF biomarkers of AD with Lumipulse automated assays were included. The presence and severity of dementia was evaluated with the Clinical Dementia Rating® (CDR®) and Clinical Dementia Rating Sum of Boxes (CDR‐SB). Plasma samples collected at the same session as CSF underwent analysis for specific phosphorylated and non‐phosphorylated tau species with an immunoprecipitation‐mass spectrometry assay. Plasma T217 occupancy was calculated as the percent of phosphorylated to non‐phosphorylated tau at threonine 217.ResultsThe study cohort included 337 individuals with an average age of 69.8 ± 8.3 years (mean ± standard deviation); 175 (52%) were female, 128 (38%) were APOE ε4 carriers, 112 (33%) were amyloid PET positive, and 50 (15%) were cognitively impaired. Classification accuracy of amyloid PET status was equivalent for plasma T217 occupancy (AUC 0.973) and CSF Aβ42/Aβ40 (AUC 0.970), (p = 0.72 for the difference). Interestingly, plasma T217 occupancy more accurately classified individuals as cognitively impaired (CDR&gt;0) or cognitively unimpaired (CDR 0), with an AUC of 0.876 versus 0.814 for CSF Aβ42/Aβ40 (p = 0.006 for the difference). Further, plasma T217 occupancy was better correlated with dementia severity as measured by the CDR‐SB (Spearman ρ = 0.455 versus ‐0.338 for CSF Aβ42/Aβ40, p = 0.02).ConclusionPlasma T217 occupancy as measured by mass spectrometry had equivalent classification accuracy of amyloid PET status compared to Lumipulse CSF Aβ42/Aβ40. Notably, plasma T217 occupancy was more strongly associated with cognitive impairment and dementia severity than CSF Aβ42/Aβ40. Overall, these data suggest that some AD blood tests have equivalent or better performance characteristics than clinically used CSF tests.

Alzheimer’s disease blood tests of amyloid‐β 42/40, p‐tau217, p‐tau181 and p‐tau205 ratios in a diverse community‐based population: Preliminary results from SEABIR

AbstractBackgroundAlzheimer’s disease (AD) blood tests that can identify and quantify amyloid plaques, tau tangles, and cognitive and clinical decline are needed in clinical practice, including primary care. However, these tests require validation in diverse groups and real‐world settings. The goals of the Study to Evaluate Amyloid in Blood and Imaging Related to Dementia (SEABIRD) were to enroll 1120 participants to determine the accuracy and validity of blood amyloid‐β (Aβ) and phosphorylated tau (p‐tau) tests in a diverse, community‐based sample of older adults compared with amyloid PET, and to explore the impact of key factors (age, race, years of education, cognition, APOE genotype, and medical conditions) on validity estimates.MethodSEABIRD measured blood plasma Aβ42/40 ratio and ratios of phosphorylated to non‐phosphorylated p‐tau217, p‐tau181, and p‐tau205 (%p‐tau) in a diverse population of older adults. In addition, cognitive screening with the AD8® dementia screen and Montreal Cognitive Assessment (MoCA) were obtained. Approximately 25% of participants were selected for amyloid PET and CDR as a reference standard.ResultOf the 859 participants enrolled in this ongoing study, 20.6% self‐identified as Black or African American and the percentage of APOE ε4 carriers was 30.2%, as expected for a population‐based sample (Table 1). For a subset of 76 participants with completed amyloid PET and all blood measures, plasma Aβ42/40 had ROC‐AUC with amyloid PET status of 0.85, %p‐tau217 of 0.97, %p‐tau181 of 0.83, and %p‐tau205 of 0.81 (Figure 1). Spearman correlations with amyloid PET SUVR were ‐0.59 for plasma Aβ42/40, 0.69 for p‐tau217 ratio, 0.43 for p‐tau181 ratio and 0.48 for p‐tau205 ratio.ConclusionThese preliminary results demonstrate that AD blood tests have similar accuracies in a diverse population‐based sample to those reported in AD research cohorts. These findings suggest that rapid screening and diagnosis of amyloid pathology with AD blood tests is possible in a broader population with higher comorbid disease burden and greater diversity than typical AD research cohorts. Screening with AD blood tests could accelerate clinical trial recruitment and increase the representativeness of clinical trial populations, which may improve the generalizability of clinical trial results.

Production pathway of APP669‐x peptides in the cultured cells

AbstractBackgroundWe have identified APP669‐711 (a.k.a. Aβ(‐3)‐40) in human plasma using immunoprecipitation combined with matrix‐assisted laser desorption ionization time‐of‐flight mass spectrometry (IP‐MALDI‐MS), and revealed that the composite biomarker using APP669‐711/Aβ1‐42 ratio correlates with amyloid PET status (Kaneko et al., 2014; Nakamura et al., 2018). We also recently found that A Disintegrin and Metalloproteinase with a Thrombospondin type 1 motif, type 4 (ADAMTS4) is responsible for the APP669‐site cleavage of APP (Matsuzaki et al., Mol Psychiatry 2023). Here, we analyzed the production pathway APP669‐x peptides from the C‐terminal stub c102 of APP, which is c99 with 3 extra N‐terminal amino acid residues (i.e., the cleaved APP fragment at APP669‐site).MethodWe established the endo‐specific antibody against the N terminus of APP669‐x peptide, an anti‐c102 antibody. We analyzed the effect of ADAMTS4 on the production of Aβ‐related peptides from the APP‐expressing HEK293 cells using IP‐MALDI‐MS.ResultWe successfully detected the endogenous C‐terminal fragment of APP specifically reacted with anti‐c102 antibody in A549 cells. We found that the overexpression of the recombinant c102 resulted in the production of a series of APP669‐x peptides by the γ‐secretase. No Aβ starting at the 1st nor 4th position was generated from c102‐expressing cells irrespective of ADAMTS4 expression. Co‐expression of ADAMTS4 with APP increased the production of both APP669‐711 and Aβ4‐40. However, the addition of extracellular ADAMTS4 to HEK293 cells expressing APP resulted in the increase in the Aβ4‐40, but not APP669‐711 nor Aβ1‐40, suggesting that no further N‐terminal trimming of c102 is occurred within the cells after ADAMTS4‐mediated APP669 cleavage.ConclusionThese results indicated that ADAMTS4 cleaves APP in the secretory pathway to generate c102, which is a direct substrate for the γ‐secretase.

Developing Topics.

A previous comparative analysis of plasma Aβ42/40 immunoassays and mass spectrometry-based assays conducted in 2021 found that several assays had strong performance in predicting amyloid PET status (Zicha et al., 2022). In the spirit of enabling the National Institute on Aging and the Alzheimer's Association framework for classifying Alzheimer's disease (AD) utilizing measures of pathology for amyloid, tau, and neurodegeneration (ATN), we have added to this comparative analysis a newly developed immunoassay on an automated, scalable platform. Robustly validated plasma Aβ assays represent a non-invasive and cost-effective alternative to CSF or neuroimaging for early detection of Alzheimer's disease pathology and screening participants for enrollment into clinical trials. The project team consists of pharmaceutical industry, patient advocacy, governmental, and academic representatives. The current study utilized an additional aliquot of the same 130 plasma samples provided by ADNI that were previously tested on three immunoassays and three mass spectrometry-based assays. The statistical analysis plan was performed as published previously to determine if the measurement of plasma Aβ with age and APOE ε4 status performs better than age and APOE ε4 status alone in determining amyloid PET status. In this sample cohort, the new automated immunoassay with age and APOE genotype had similar prediction of amyloid status compared to mass spectrometry-based assays, with an ROC AUC of 85.7 (95% CI: 79.1 - 92.4) for the immunoassay and 84.2 (95% CI: 77.0 - 91.3) for the best- performing mass spectrometry-based assay. The Spearman correlation of plasma Aβ42/40 with amyloid PET (florbetapir standardized uptake value ratio) for the new immunoassay was -0.567 (p < 0.001) compared to -0.536 (p < 0.001) for the best performing mass spectrometry-based assay. The new immunoassay significantly improved the prediction of amyloid positivity beyond age and APOE ε4 genotype (p = 0.003). Results from this comparative analysis together with the continued advancement in plasma assay technology identify a potential use for plasma Aβ42/40 measurement in addressing the amyloid component of the ATN framework. Further evaluation of plasma Aβ42/40 in addition to p-tau in plasma is planned using longitudinal samples to determine the ability of plasma biomarkers to detect amyloidosis.

The use of Event Related Potentials to predict amyloid PET status among patients from a memory disorders clinic

AbstractBackgroundAmyloid PET scans provide in vivo evidence of Alzheimer’s Disease (AD) however, due to high cost and limited insurance coverage, they are not available as part of standard clinical care. Event Related Potentials (ERPs) are inexpensive, and non‐invasive method to directly measure brain physiology that may allow an alternative method for detection of AD pathology.MethodWe investigated whether ERPs together with neuropsychological data are predictors of amyloid PET status in patients with memory complaints. Older veterans aged 50‐100 were recruited from a memory disorders clinic at VA Boston Healthcare System. Participants underwent a standard neuropsychological battery and an ERP auditory oddball protocol. Twenty‐eight patients had a positive amyloid PET scan, and thirty‐nine patients had a negative amyloid PET scan.ResultsTwo neuropsychological measures (CERAD Delayed Recall and MMSE) were predictors of amyloid PET status. Increased P200 target amplitude (Figure 1B), and decreased P200 standard latency (Figure 1A) in patients with amyloid PET positive scan were found. ERP‐P200 amplitude in response to target tones and ERP‐P200 latency in response to standard tones were also predictors of amyloid PET status. The highest classification accuracy was obtained when combining CERAD Delayed Recall, MMSE and ERP‐P200 standard latency.ConclusionERP‐P200, especially when combined with cognitive measures of delayed memory and overall cognitive function, was predictive of amyloid beta (Aβ) load in the brain of patients from a memory disorder clinic. Increased P200 amplitude, and decreased P200 latency in patients with amyloid PET positive scan might suggest hyperactivation of perceptual bottom‐up processes to compensate for AD‐related synaptic loss in the fronto‐parietal networks.

Ownership and Health Care Status of Pets in Osun State, Nigeria

Demographic survey of pets’ ownership and the health status of pets within Osogbo metropolis, Osun State was conducted between April and October, 2020. This was done by preparing a structured demographic survey questionnaire which was randomly administered, retrieved and analyzed using descriptive statistics. Majority of pets owners in the study area fall within 21 - 30 years, representing 43.7% of respondents. Three types of breeds - exotic, crossed and local- were identified. A significant number of respondents indicated pets were kept for sustenance and livelihood probably due to the fact that certain category of pets was crossbred with exotic species for preferred traits. Goat owners represent 52.9% of the surveyed population. Most pets’ owners (67.4%) did not register their pets with State’s Animal Husbandry and Veterinary Services Department. Only 35.4% of pet owners admitted that their pets were ectoparasite infested. About 65.7% of respondents vaccinated their pets, 59.9% treated their pets against helminthic infections while 43.0% admit to regular veterinary clinical check-up. Findings from this survey suggests the likelihood for pets to be registered with relevant authority is low but pet owners are more likely to treat and vaccinate their pets.