Development, initial validation, and application of a visual read method for [18F]MK-6240 tau PET.

Background: The positron emission tomography (PET) radiotracer [18F]MK-6240 exhibits high specificity for neurofibrillary tangles (NFTs) of tau protein in Alzheimer's disease (AD), high sensitivity to medial temporal and neocortical NFTs, and low within-brain background. Objectives were to develop and validate a reproducible, clinically relevant visual read method supporting [18F]MK-6240 use to identify and stage AD subjects versus non-AD and controls. Methods: Five expert readers used their own methods to assess 30 scans of mixed diagnosis (47% cognitively normal, 23% mild cognitive impairment, 20% AD, 10% traumatic brain injury) and provided input regarding regional and global positivity, features influencing assessment, confidence, practicality, and clinical relevance. Inter-reader agreement and concordance with quantitative values were evaluated to confirm that regions could be read reliably. Guided by input regarding clinical applicability and practicality, read classifications were defined. The readers read the scans using the new classifications, establishing by majority agreement a gold standard read for those scans. Two naïve readers were trained and read the 30-scan set, providing initial validation. Inter-rater agreement was further tested by two trained independent readers in 131 scans. One of these readers used the same method to read a full, diverse database of 1842 scans; relationships between read classification, clinical diagnosis, and amyloid status as available were assessed. Results: Four visual read classifications were determined: no uptake, medial temporal lobe (MTL) only, MTL and neocortical uptake, and uptake outside MTL. Inter-rater kappas were 1.0 for the naïve readers gold standard scans read and 0.98 for the independent readers 131-scan read. All scans in the full database could be classified; classification frequencies were concordant with NFT histopathology literature. Discussion: This four-class [18F]MK-6240 visual read method captures the presence of medial temporal signal, neocortical expansion associated with disease progression, and atypical distributions that may reflect different phenotypes. The method demonstrates excellent trainability, reproducibility, and clinical relevance supporting clinical use. Highlights: A visual read method has been developed for [18F]MK-6240 tau positron emission tomography.The method is readily trainable and reproducible, with inter-rater kappas of 0.98.The read method has been applied to a diverse set of 1842 [18F]MK-6240 scans.All scans from a spectrum of disease states and acquisitions could be classified.Read classifications are consistent with histopathological neurofibrillary tangle staging literature.

Rates of regional tau accumulation in ageing and across the Alzheimer's disease continuum: an AIBL 18F-MK6240 PET study.

BACKGROUND: Tau positron emission tomography (PET) imaging enables longitudinal observation of tau accumulation in Alzheimer's disease (AD). 18F-MK6240 is a high affinity tracer for the paired helical filaments of tau in AD, widely used in clinical trials, despite sparse longitudinal natural history data. We aimed to evaluate the natural history of tau accumulation, and the impact of disease stage and reference region on the magnitude and effect size of regional change. METHODS: One hundred and eighty-four participants: 89 cognitively unimpaired (CU) beta-amyloid negative (Aß-), 44 CU Aß+, 51 cognitively impaired Aß+ (26 with mild cognitive impairment [MCI] and 25 with dementia) had follow-up 18F-MK6240 PET for one to four years (median 1.48). Regional standardised uptake value ratios (SUVR) were generated. Two reference regions were examined: cerebellar cortex and eroded subcortical white matter. FINDINGS: CU Aß- participants had very low rates of tau accumulation in the mesial temporal lobe (MTL). In CU Aß+, significantly higher rate of accumulation was seen in the MTL (particularly the amygdala), extending into the inferior temporal lobes. In MCI Aß+, the rate of accumulation was greatest in the lateral temporal, parietal and lateral occipital cortex, and plateaued in the MTL. Accumulation was global in AD Aß+, except for a plateau in the MTL. The eroded subcortical white matter reference region showed no significant advantage over the cerebellar cortex and appeared prone to spill-over in AD participants. Data fitting suggested approximately 15-20 years to accumulate tau to typical AD levels. INTERPRETATION: Tau accumulation occurs slowly. Rates vary according to brain region, disease stage and tend to plateau at high levels. Rates of tau accumulation are best measured in the MTL and inferior temporal cortex in preclinical AD and in large neocortical areas, in MCI and AD. FUNDING: NHMRC; Cerveau Technologies.

Plasma p217+tau versus NAV4694 amyloid and MK6240 tau PET across the Alzheimer's continuum.

Introduction: We evaluated a new Simoa plasma assay for phosphorylated tau (P-tau) at aa217 enhanced by additional p-tau sites (p217+tau). Methods: Plasma p217+tau levels were compared to 18F-NAV4694 amyloid beta (Aß) positron emission tomography (PET) and 18F-MK6240 tau PET in 174 cognitively impaired (CI) and 223 cognitively unimpaired (CU) participants. Results: Compared to Aß- CU, the plasma levels of p217+tau increased 2-fold in Aß+ CU and 3.5-fold in Aß+ CI. In Aß- the p217+tau levels did not differ significantly between CU and CI. P217+tau correlated with Aß centiloids P = .67 (CI, P = .64; CU, P = .45) and tau SUVRMT P = .63 (CI, P = .69; CU, P = .34). Area under curve (AUC) for Alzheimer's disease (AD) dementia versus Aß- CU was 0.94, for AD dementia versus other dementia was 0.93, for Aß+ versus Aß- PET was 0.89, and for tau+ versus tau- PET was 0.89. Discussion: Plasma p217+tau levels elevate early in the AD continuum and correlate well with Aß and tau PET.

Elecsys CSF biomarker immunoassays demonstrate concordance with amyloid-PET imaging.

BACKGROUND: ß-amyloid (Aß) positron emission tomography (PET) imaging is currently the only Food and Drug Administration-approved method to support clinical diagnosis of Alzheimer's disease (AD). However, numerous research studies support the use of cerebrospinal fluid (CSF) biomarkers, as a cost-efficient, quick and equally valid method to define AD pathology. METHODS: Using automated Elecsys® assays (Roche Diagnostics) for Aß (1-42) (Aß42), Aß (1-40) (Aß40), total tau (tTau) and phosphorylated tau (181P) (pTau), we examined CSF samples from 202 participants of the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of ageing cohort, to demonstrate the concordance with pathological AD via PET imaging. RESULTS: Ratios Aß42/Aß40, tTau/Aß42 and pTau/Aß42 had higher receiver operator characteristic-area under the curve (all 0.94), and greater concordance with Aß-PET (overall percentage agreement ~ 90%), compared with individual biomarkers. CONCLUSION: Strong concordance between CSF biomarkers and Aß-PET status was observed overall, including for cognitively normal participants, further strengthening the association between these markers of AD neuropathological burden for both developmental research studies and for use in clinical trials.

A model-based estimation of inter-prefectural migration of physicians within Japan and associated factors: A 20-year retrospective study.

Despite an increase in the number of physicians in Japan, misdistribution of physicians within the 47 prefectures remains a major issue. Migration of physicians among prefectures might partly explain the misdistribution. However, geographical differences and the magnitude of physicians' migration are unclear. The aim of this study was to estimate the extent of migration of physicians among prefectures and explore possible factors associated with physicians' migration patterns.Using a publicly available government database from 1995 to 2014, a quantitative estimation of physicians' migration after graduation from a medical school was performed. The inflow and outflow of physicians were ostensibly calculated in each prefecture based on the differences between the number of newly licensed physicians and the actual number of practicing physicians after an adjustment for the number of deceased or retired physicians. Simple and multiple linear regression analyses were conducted to examine socio-demographic background factors.During the 20-year study period, the mean annual numbers of newly licensed physicians, deceased or retired physicians, and increase in practicing physicians in the whole country were 7416, 3382, and 4034, respectively. Among the 47 prefectures, the median annual number of newly licensed physicians to 100,000 population ratio (PPR) was 6.4 (range 1.5-16.5), the median annual adjusted number of newly licensed physicians was 61 (range, -18 to 845; the negative and positive values denote outflow and inflow, respectively), whereas the median annual number of migrating physicians was 13 (range, -171 to 241). The minimum and maximum migration ratios observed were -68% and 245%, respectively. In the final regression model of the 8 variables examined, only "newly licensed PPR" remained significantly associated with physician's migration ratios.A significant inequality in the proportion of the migration of physicians among prefectures in Japan was observed. The multivariate analyses suggest that the newly licensed PPRs, and not from-rural-to-urban migration, might be one of the keys to explaining the migration ratios of physicians. The differences and magnitude of physicians' migration should be factored into mitigate misdistribution of physicians.

Observations of backscatter from sand and gravel seafloors between 170 and 250 kHz.

Interpreting observations of frequency-dependence in backscatter from the seafloor offers many challenges, either because multiple frequencies are used for different observations that will later be merged or simply because seafloor scattering models are not well-understood above 100 kHz. Hindering the understanding of these observations is the paucity of reported, calibrated acoustic measurements above 100 kHz. This manuscript seeks to help elucidate the linkages between seafloor properties and frequency-dependent seafloor backscatter by describing observations of backscatter collected from sand, gravel, and bedrock seafloors at frequencies between 170 and 250 kHz and at a grazing angle of 45°. Overall, the frequency dependence appeared weak for all seafloor types, with a slight increase in seafloor scattering strength with increasing frequency for an area with unimodal, very poorly to moderately well sorted, slightly granular to granular medium sand with significant amounts of shell debris and a slight decrease in all other locations.

Induction of both cellular and humoral immunity following a rational prime-boost immunization regimen that incorporates recombinant ovine atadenovirus and fowlpox virus.

Recombinant fowlpox viruses (rFPV) and ovine atadenoviruses (rOAdV) are being developed as safe, nonpathogenic, prophylactic and therapeutic vaccine vectors. There is scope, however, to improve the limited immune responses elicited by each of these vaccine vectors. Using previously determined and optimized routes of administration and viral doses, we characterized the primary adaptive immune responses elicited by recombinant variants of each virus. We demonstrate the contrasting nature of the response elicited by each recombinant virus. Whereas rFPV generates predominately cell-mediated immunity to our nominal target antigen, ovalbumin (OVA), rOAdV drives strong humoral responses. By defining the time taken to achieve maximal cytotoxic T cell responses and by studying the different patterns and kinetics of major histocompatibility complex class I-restricted OVA antigen expression postimmunization, we proposed a heterologous prime-boost regimen of immunization with rOAdV followed by rFPV. The subsequent experimental results showed that this approach produced robust cell-mediated and humoral immune responses against OVA that, importantly, were accompanied by weak anti-viral vector antibody responses. These results, therefore, represent a novel and potentially clinically applicable way to achieve broadly based and effective immunity to the antigens encoded by vectored vaccines.

Vaccine-induced IgG2 anti-HIV p24 is associated with control of HIV in patients with a 'high-affinity' FcgammaRIIa genotype.

OBJECTIVES: We have previously shown that vaccination with a recombinant fowlpox virus carrying the genes for HIV Gag-Pol and interferon-gamma (IFN-gamma) was associated with partial control of HIV replication after antiretroviral therapy (ART) was ceased but not with increased anti-HIV T-cell responses. Because IFN-gamma enhances IgG2 production, and IgG2 antibodies to HIV antigens and the 'high-affinity' polymorphism of FcgammaRIIa (the major Fc receptor for IgG2) have been associated with a favourable outcome of HIV infection, we examined the association of IgG2 antibodies to HIV p24 and 'high-affinity' polymorphisms of FcgammaRIIa with control of HIV replication in these patients. METHODS: Plasma from weeks 0 (cessation of ART 1 week after the last vaccination), 9 and 20 was available from patients who had received the full construct vaccine, a partial construct (without IFN-gamma) or placebo. IgG2 and IgG1 anti-p24 and anti-gp41 were assayed and all patients were genotyped for the FcgammaRIIa 131 R/H polymorphism that affects IgG2 binding. RESULTS: At week 0, IgG2 anti-p24 was present in five of nine full construct patients but none of 14 partial construct or placebo patients and was associated with a smaller increase in plasma HIV RNA over 20 weeks. Patients with IgG2 anti-p24 and the 'high-affinity' polymorphism of FcgammaRIIa exhibited lower HIV replication than other patients at week 20. CONCLUSION: The role of IgG2 anti-HIV antibodies and FcgammaRIIa in the control of HIV replication should be investigated further. Inclusion of an IFN-gamma gene in DNA vaccine constructs might be a means of enhancing IgG2 antibody production.