The molecular mechanisms leading to resistance to PD-1 blockade are largely unknown. Here, we characterize tumor biopsies from a patient with melanoma who displayed heterogeneous responses to ...anti-PD-1 therapy. We observe that a resistant tumor exhibited a loss-of-function mutation in the tumor suppressor gene
, whereas a sensitive tumor from the same patient did not. Consistent with a functional role in immunotherapy response, inactivation of
in murine tumor cell lines caused resistance to anti-PD-1 in immunocompetent animals. Loss of
was associated with altered immune microenvironment, decreased tumor-intrinsic expression of the double-stranded RNA (dsRNA) sensors MDA5 and RIG1, and diminished induction of type I IFN and MHC-I expression. In contrast, restoration of dsRNA sensing in
-deficient cells was sufficient to sensitize them to anti-PD-1. Our results thus establish a new role for the commonly inactivated tumor suppressor
in viral sensing and sensitivity to immunotherapy. SIGNIFICANCE: Our findings establish a role of the commonly inactivated tumor suppressor
as a genomic driver of response to anti-PD-1 therapy.
loss promotes resistance to anti-PD-1 through the downregulation of viral sensing pathways, suggesting that therapeutic reactivation of these pathways could improve clinical responses to checkpoint inhibitors in genomically defined cancer patient populations.
.
Purpose
The PET tracer 18Fflorbetapir is a specific fibrillar amyloid-beta (Aβ) biomarker. During the late scan phase (> 40 min), it provides pathological information about Aβ status. Early scan ...phase (0–10 min) can provide FDG-‘like’ information. The current investigation tested the feasibility of using florbetapir as a dual-phase biomarker in behavioural variant frontotemporal dementia (bvFTD).
Methods
Eight bvFTD patients underwent 18Fflorbetapir and 18FDG-PET scans. Additionally, ten healthy controls and ten AD patients underwent florbetapir-PET only. PET data were acquired dynamically for 60-min post-injection. The bvFTD PET data were used to define an optimal time window, representing blood flow-related pseudo-metabolism (‘pseudo-FDG’), of florbetapir data that maximally correlated with the corresponding real FDG SUVR (40–60 min) in a composite neocortical FTD region.
Results
A 2 to 5-min time window post-injection of the florbetapir-PET data provided the largest correlation (Pearson’s
r
= 0.79,
p
= 0.02) to the FDG data. The pseudo-FDG images demonstrated strong internal consistency with actual FDG data and were also visually consistent with the bvFTD patients’ hypometabolic profiles. The ability to identify bvFTD from blind visual rating of pseudo-FDG images was consistent with previous reports using FDG data (sensitivity = 75%, specificity = 85%).
Conclusions
This investigation demonstrates that early phase florbetapir uptake shows a reduction of frontal lobe perfusion in bvFTD, similar to metabolic findings with FDG. Thus, dynamic florbetapir scans can serve as a dual-phase biomarker in dementia patients to distinguish FTD from AD and cognitively normal elderly, removing the need for a separate FDG-PET scan in challenging dementia cases.
Purpose
To provide percentage depth dose (PDD) data along the central axis for dosimetry calculations in small‐animal radiation biology experiments performed in cabinet irradiators. The PDDs are ...provided as a function of source‐to‐surface distance (SSD), field size, and animal size.
Methods
The X‐ray tube designs for four biological cabinet irradiators, the RS2000, RT250, MultiRad350, and XRAD320, were simulated using the BEAMnrc Monte Carlo code to generate 160, 200, 250, and 320 kVp photon beams, respectively. The 320 kVp beam was simulated with two filtrations: a soft F1 aluminium filter and a hard F2 thoraeus filter made of aluminium, tin, and copper. Beams were collimated into circular fields with diameters of 0.5–10 cm at SSDs of 10–60 cm. Monte Carlo dose calculations in 1–5‐cm diameter homogeneous (soft tissue) small‐animal phantoms as well as in heterogeneous phantoms with 3‐mm diameter cylindrical lung and bone inserts (rib and cortical bone) were performed using DOSXYZnrc. The calculated depth doses in three test‐cases were estimated by applying SSD, field size, and animal size correction factors to a reference case (40‐cm SSD, 1‐cm field, and 5‐cm animal size), and these results were compared with the specifically simulated (i.e., expected) doses to assess the accuracy of this method. Dosimetry for two test‐case scenarios of 160 and 250 kVp beams (representative of end‐user beam qualities) was also performed, whereby the simulated PDDs at two different depths were compared with the results based on the interpolation from reference data.
Results
The depth doses for three test‐cases calculated at 200, 320 kVp F1, and 320 kVp F2 with half value layers (HVLs) ranging from ∼0.6 to 3.6 mm Cu, agreed well with the expected doses, yielding dose differences of 1.2%, 0.1%, and 1.0%, respectively. The two end‐user test‐cases for 160 and 250 kVp beams with respective HVLs of ∼0.8 and 1.8 mm Cu yielded dose differences of 1.4% and 3.2% between the simulated and the interpolated PDDs. The dose increase at the bone‐tissue proximal interface ranged from 1.2 to 2.5 times the dose in soft tissue for rib and 1.3 to 3.7 times for cortical bone. The dose drop‐off at 1‐cm depth beyond the bone ranged from 1.3% to 6.0% for rib and 3.2% to 11.7% for cortical bone. No drastic dose perturbations occurred in the presence of lung, with lung‐tissue interface dose of >99% of soft tissue dose and <3% dose increase at 1‐cm depth beyond lung.
Conclusions
The developed dose estimation method can be used to translate the measured dose at a point to dose at any depth in small‐animal phantoms, making it feasible for preclinical calculation of dose distributions in animals irradiated with cabinet‐style irradiators. The dosimetric impact of bone must be accurately quantified as dramatic dose perturbations at and beyond the bone interfaces can occur due to the relative importance of the photoelectric effect at kilovoltage energies. These results will help improve dosimetric accuracy in preclinical experiments.
First-degree relatives of people with dementia (FH+) are at increased risk of developing Alzheimer's disease (AD). Here, we investigate “estimated years to onset of dementia” (EYO) as a surrogate ...marker of preclinical disease progression and assess its associations with multi-modal neuroimaging biomarkers.
89 FH+ participants in the PREVENT-Dementia study underwent longitudinal MR imaging over 2 years. EYO was calculated as the difference between the parental age of dementia diagnosis and the current age of the participant (mean EYO = 23.9 years). MPRAGE, ASL and DWI data were processed using Freesurfer, FSL-BASIL and DTI-TK. White matter lesion maps were segmented from FLAIR scans. The SPM Sandwich Estimator Toolbox was used to test for the main effects of EYO and interactions between EYO, Time, and APOE-ε4+. Threshold free cluster enhancement and family wise error rate correction (TFCE FWER) was performed on voxelwise statistical maps.
There were no significant effects of EYO on regional grey matter atrophy or white matter hyperintensities. However, a shorter EYO was associated with lower white matter Fractional Anisotropy and elevated Mean/Radial Diffusivity, particularly in the corpus callosum (TFCEFWERp < 0.05). The influence of EYO on white matter deficits were significantly stronger compared to that of normal ageing. APOE-ε4 carriers exhibited hyperperfusion with nearer proximity to estimated onset in temporo-parietal regions. There were no interactions between EYO and time, suggesting that EYO was not associated with accelerated imaging changes in this sample.
Amongst cognitively normal midlife adults with a family history of dementia, a shorter hypothetical proximity to dementia onset may be associated with incipient brain abnormalities, characterised by white matter disruptions and perfusion abnormalities, particularly amongst APOE-ε4 carriers. Our findings also confer biological validity to the construct of EYO as a potential stage marker of preclinical progression in the context of sporadic dementia. Further clinical follow-up of our longitudinal sample would provide critical validation of these findings.
Analysis of 772 complete severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genomes from early in the Boston-area epidemic revealed numerous introductions of the virus, a small number of ...which led to most cases. The data revealed two superspreading events. One, in a skilled nursing facility, led to rapid transmission and significant mortality in this vulnerable population but little broader spread, whereas other introductions into the facility had little effect. The second, at an international business conference, produced sustained community transmission and was exported, resulting in extensive regional, national, and international spread. The two events also differed substantially in the genetic variation they generated, suggesting varying transmission dynamics in superspreading events. Our results show how genomic epidemiology can help to understand the link between individual clusters and wider community spread.
Amyloid-beta (Aβ) deposition is common in cognitively unimpaired (CU) elderly >85 years. This study investigated amyloid distribution and evaluated three published in vivo amyloid-PET staging schemes ...from a cognitively unimpaired (CU) cohort aged 84.9 ± 4.3 years (n = 75). SUV-based principal component analysis (PCA) was applied to
F-flutemetamol PET data to determine an unbiased regional covariance pattern of tracer uptake across grey matter regions. PET staging schemes were applied to the data and compared to the PCA output. Concentration of p-tau181 was measured in blood plasma. The PCA revealed three distinct components accounting for 91.2% of total SUV variance. PC1 driven by the large common variance of uptake in neocortical and striatal regions was significantly positively correlated with global SUVRs, APOE4 status and p-tau181 concentration. PC2 represented mainly non-specific uptake in typical amyloid-PET reference regions, and PC3 the occipital lobe. Application of the staging schemes demonstrated that the majority of the CU cohort (up to 93%) were classified as having pathological amount and distribution of Aβ. Good correspondence existed between binary (+/-) classification and later amyloid stages, however, substantial differences existed between schemes for low stages with 8-17% of individuals being unstageable, i.e., not following the sequential progression of Aβ deposition. In spite of the difference in staging outcomes there was broad spatial overlap between earlier stages and PC1, most prominently in default mode network regions. This study critically evaluated the utility of in vivo amyloid staging from a single PET scan in CU elderly and found that early amyloid stages could not be consistently classified. The majority of the cohort had pathological Aβ, thus, it remains an open topic what constitutes abnormal brain Aβ in the oldest-old and what is the best method to determine that.
Background The panel of fluid- and imaging-based biomarkers available for neurodegenerative disease research is growing and has the potential to close important gaps in research and the clinic. With ...this growth and increasing use, appropriate implementation and interpretation are paramount. Various biomarkers feature nuanced differences in strengths, limitations, and biases that must be considered when investigating disease etiology and clinical utility. For example, neuropathological investigations of Alzheimer's disease pathogenesis can fall in disagreement with conclusions reached by biomarker-based investigations. Considering the varied strengths, limitations, and biases of different research methodologies and approaches may help harmonize disciplines within the neurodegenerative disease field. Purpose of review Along with separate review articles covering fluid and imaging biomarkers in this issue of Alzheimer's Research and Therapy, we present the result of a discussion from the 2019 Biomarkers in Neurodegenerative Diseases course at the University College London. Here, we discuss themes of biomarker use in neurodegenerative disease research, commenting on appropriate use, interpretation, and considerations for implementation across different neurodegenerative diseases. We also draw attention to areas where biomarker use can be combined with other disciplines to understand issues of pathophysiology and etiology underlying dementia. Lastly, we highlight novel modalities that have been proposed in the landscape of neurodegenerative disease research and care. Keywords: Biomarkers, Neurodegenerative diseases, Alzheimer's disease, Tau, Amyloid, Neurofilament light chain, Magnetic resonance imaging, Positron emission tomography, Cerebrospinal fluid, Plasma biomarkers
BackgroundMarkers of cerebrovascular disease are common in dementia, and may be present before dementia onset. However, their clinical relevance in midlife adults at risk of future dementia remains ...unclear. We investigated whether the Cardiovascular Risk Factors, Ageing and Dementia (CAIDE) risk score was associated with markers of cerebral small vessel disease (SVD), and if it predicted future progression of SVD. We also determined its relationship to systemic inflammation, which has been additionally implicated in dementia and SVD.MethodsCognitively healthy midlife participants were assessed at baseline (n=185) and 2-year follow-up (n=158). To assess SVD, we quantified white matter hyperintensities (WMH), enlarged perivascular spaces (EPVS), microbleeds and lacunes. We derived composite scores of SVD burden, and subtypes of hypertensive arteriopathy and cerebral amyloid angiopathy. Inflammation was quantified using serum C-reactive protein (CRP) and fibrinogen.ResultsAt baseline, higher CAIDE scores were associated with all markers of SVD and inflammation. Longitudinally, CAIDE scores predicted greater total (p<0.001), periventricular (p<0.001) and deep (p=0.012) WMH progression, and increased CRP (p=0.017). Assessment of individual CAIDE components suggested that markers were driven by different risk factors (WMH/EPVS: age/hypertension, lacunes/deep microbleeds: hypertension/obesity). Interaction analyses demonstrated that higher CAIDE scores amplified the effect of age on SVD, and the effect of WMH on poorer memory.ConclusionHigher CAIDE scores, indicating greater risk of dementia, predicts future progression of both WMH and systemic inflammation. Findings highlight the CAIDE score’s potential as both a prognostic and predictive marker in the context of cerebrovascular disease, identifying at-risk individuals who might benefit most from managing modifiable risk.
Purpose
Amyloid PET tracers have been developed for in vivo detection of brain fibrillar amyloid deposition in Alzheimer’s disease (AD). To serve as an early biomarker in AD the amyloid PET tracers ...need to be analysed in multicentre clinical studies.
Methods
In this study 238
11
CPittsburgh compound-B (PIB) datasets from five different European centres were pooled. Of these 238 datasets, 18 were excluded, leaving
11
CPIB datasets from 97 patients with clinically diagnosed AD (mean age 69 ± 8 years), 72 patients with mild cognitive impairment (MCI; mean age 67.5 ± 8 years) and 51 healthy controls (mean age 67.4 ± 6 years) available for analysis. Of the MCI patients, 64 were longitudinally followed for 28 ± 15 months. Most participants (175 out of 220) were also tested for apolipoprotein E (ApoE) genotype.
Results
11
CPIB retention in the neocortical and subcortical brain regions was significantly higher in AD patients than in age-matched controls. Intermediate
11
CPIB retention was observed in MCI patients, with a bimodal distribution (64 % MCI PIB-positive and 36 % MCI PIB-negative), which was significantly different the pattern in both the AD patients and controls. Higher
11
CPIB retention was observed in MCI ApoE ε4 carriers compared to non-ApoE ε4 carriers (
p
< 0.005). Of the MCI PIB-positive patients, 67 % had converted to AD at follow-up while none of the MCI PIB-negative patients converted.
Conclusion
This study demonstrated the robustness of
11
CPIB PET as a marker of neocortical fibrillar amyloid deposition in brain when assessed in a multicentre setting. MCI PIB-positive patients showed more severe memory impairment than MCI PIB-negative patients and progressed to AD at an estimated rate of 25 % per year. None of the MCI PIB-negative patients converted to AD, and thus PIB negativity had a 100 % negative predictive value for progression to AD. This supports the notion that PIB-positive scans in MCI patients are an indicator of prodromal AD.
PDF
![Dual-phase [18F]florbetapir...](http://api.summon.serialssolutions.com/2.0.0/image/issn/XR4PS5YY4K/1619-7070/small "Dual-phase [18F]florbetapir in frontotemporal dementia")
