Positive Scan Research Articles

Significance of a positive tau pet scan with a negative amyloid pet scan

AbstractBackgroundThe implications of a positive tau (T) Positron Emission Tomography (PET) with a negative beta amyloid (A) PET are not well understood. We investigated cognitive performance in participants who were positive on tau PET but negative on beta amyloid PET.MethodWe evaluated 98 participants from the Mayo Clinic Study of Aging (MCSA) and the Mayo Clinic Alzheimer’s Disease Research Center (ADRC) who were positive for Flortaucipir (FTP) and negative for PiB PET. Participants were classified as A‐ and T+ based on Standardized Uptake Value Ratios (SUVr) of FTP and PiB PET scans, and were matched 2:1 to amyloid negative and tau negative cognitively unimpaired controls from the MCSA. Cognitive test scores were compared between the combined ADRC/MCSA group and MCSA only group. We also examined clinical diagnoses in our cohort. The most common were Alzheimer’s Disease, mild cognitive impairment (MCI), Dementia with Lewy Bodies (DLB) and Frontotemporal dementia (FTD) amongst others.ResultThere were no significant differences in demographic features or PiB SUVr between groups. There were significant differences in APOE genotype between groups. In the combined ADRC/MCSA group, 25% of A‐T‐ and 13% of A‐T+ were APOE e4 carriers (p = 0.016), and in the MCSA only group, 27% of A‐T‐and 10% of A‐T+ were APOE e4 carriers (p = 0.010). In the combined ADRC/MCSA group, the A‐T+ group demonstrated lower performance than the A‐T‐ group on the Mini Mental Status Exam (MMSE) (p<0.001), Wechsler Memory Scale‐Revised Logical Memory I (p<0.001) and Logical Memory II (p<0.001), Auditory verbal Learning Test Delayed Recall (AVLT) (p = 0.004), Category fluency animals (p = 0.005), Category fluency vegetables (p = 0.021), Trailmaking test A (p<0.001), Trail making test B (p<0.001), Wechsler Adult Intelligence Scale‐IV (WAIS‐IV) (p = 0.002), and Unified Parkinson’s Disease Rating Scale part III (UPDRS III) (p = 0.003). In the MCSA only group, the A‐T+ group had lower scores on Logical Memory II (p = 0.022), AVLT delated recall (p = 0.04), and WAIS‐R block design (p = 0.035) compared to the A‐T‐group.ConclusionPositive tau PET in the absence of beta‐amyloid positivity is associated with lower cognitive performance.

Quantification supports visual assessment of challenging amyloid‐PET images

AbstractBackgroundIn clinical practice, amyloid‐PET images are visually assessed to determine the presence or absence of amyloid pathology. The expected arrival of disease‐modifying treatments warrants the need for objective quantification of amyloid burden to further support treatment decisions. Here, we investigated whether quantification increases reader confidence and influences visual read (VR) classification in patients with challenging or ambiguous amyloid information sampled across the clinical continuum.MethodsFrom the AMYPAD‐DPMS trial (N = 840), we selected a subsample of 85 amyloid‐PET scans ([18F]flutemetamol, N = 48/[18F]florbetaben, N = 53), for which 1) visual assessment was discordant with amyloid status based on Centiloid (CL) (cut‐off = 21) and/or 2) were assessed with a low confidence (i.e. ≤3 on a 5‐point scale) by the local reader. In addition, concordant negative and positive (N = 8/8) scans across tracers were included to balance the dataset (N = 101, Table‐1). PET images were processed using GEHCs AMYPYPE PET‐only pipeline, providing global CL and regional z‐scores for 7 cortical ROIs. VR classification and corresponding confidence was assessed for 3 independent certified assessors before and after disclosure of the quantification results. In addition, readers stated whether CL quantification and/or the regional z‐scores supported their assessment. Reader agreement was assessed using Fleiss Kappa. Changes in reader confidence after disclosure was assessed using paired t‐test.ResultsOverall, readers reported global CL and regional z‐score quantification to be VR‐supportive in 76.2% and 49.7% of assessments, respectively. After disclosure of quantitative results, concordance between readers (Kbaseline= 0.60; Kpost‐disclosure= 0.79), concordance between majority‐VR and CL‐status (agreementbaseline = 75.2%; agreementpost‐disclosure = 81.2%), and reader confidence (Mbaseline= 4.0 vs. Mpost‐disclosure= 4.37, t = ‐5.8, p<0.001) significantly improved. Classification changed for 26 (8.6%) assessments, with 8 (30.8%) changing to VR‐ and 18 (69.2%) to VR+. In these cases, CL was considered supportive in 16 (61.5%) cases, regional z‐scores were considered supportive for 8/10 remaining cases, and most often for the posterior cingulate/precuneus region. The 2 remaining cases had a low confidence at both time‐points. Example cases are shown in Figure 1.ConclusionIn a dataset enriched with challenging amyloid‐PET scans for visual assessment, quantification resulted in a significantly increased agreement and confidence across readers. We further aim to determine in which cases quantification was considered most supportive.

A systematic review of the impact of amyloid PET scan disclosure on psychological and behavioral outcomes for persons with cognitive impairment and their caregivers

AbstractBackgroundAmyloid‐β PET scans are a potentially useful diagnostic tool, however there is limited understanding of the impact of amyloid disclosure on persons with cognitive impairment and their caregivers. This study aimed to systematically review the impact of amyloid scan disclosure on patient and caregiver psychological and behavioral outcomes.MethodWe searched Medline, Embase and PsychInfo to identify relevant articles. Studies of any design including persons with subjective cognitive impairment, MCI and dementia and their caregivers were included. Outcomes were limited to psychological and behavioral outcomes recorded following disclosure. All articles were screened for eligibility by two reviewers.ResultWe identified 9 papers from 6 studies. Depression, anxiety and test‐related distress were the most common psychological outcomes and recall and knowledge of the scan result were the most common behavioral outcomes. The psychological impact of amyloid disclosure varied depending on the scan recipient’s level of impairment and scan result. Higher test related distress was observed in persons with MCI and elevated amyloid and higher levels of anxiety were found in their caregivers. Most persons with cognitive impairment and their caregivers were able to recall the scan result. However, one study found that gains in knowledge regarding the scan recipients diagnosis following disclosure were comparable to receiving psychoeducation.ConclusionPsychological responses to amyloid PET scan disclosure depends on the recipient’s level of impairment and the scan result itself. Persons with MCI and a positive scan result, and their caregivers were at greater risk of distress or anxiety and may benefit from additional post‐diagnostic support. Participants were able to correctly recall their scan results and reported an increase in knowledge regarding their diagnosis. However, psychoeducation may be equally effective at enhancing patient and caregiver knowledge, at a lower cost.

Comparison of Expert Reads vs. Local Clinical Reads of Amyloid PET Scans in IDEAS

AbstractBackgroundAmyloid‐directed therapies will increase the clinical use of amyloid PET. IDEAS captured >17,000 clinical scan interpretations from local radiologists and nuclear medicine physicians. This study aimed to establish accuracy of these interpretations by comparison to expert readers across identical scans.MethodRandomly selected amyloid PET/CT scans performed using one of three FDA‐approved agents [18F‐Florbetaben (FBB), 18F‐Florbetapir (FBP), 18F‐Flutemetamol (FMM)] and previously interpreted by local readers from the Imaging Dementia ‐ Evidence for Amyloid Scanning (IDEAS) study were assigned to vendor‐selected panels of 3 expert readers for interpretation; 500 scans per agent and 1 panel per agent. Scans were stratified to match frequencies observed in the overall study by 1) participant age; 2) MCI vs dementia; 3) positive/negative interpretation; and 4) type of PET facility. Respective vendors performed quality control on attenuation‐corrected PET/CT images. Visual interpretations (positive or negative for Aß cortical deposition) were performed according to agent‐specific validated interpretation criteria. Expert panel readers were blinded to clinical and demographic data. Cohen’s kappa statistic with two‐sided 95% confidence interval estimates examined agreement between local reader and majority expert panel visual interpretation.ResultExpert panel readers’ visual interpretations totaled 4489. Median age for scanned participants was 75 (range 65‐96), 51.4% were female and 60.5% had MCI. Local readers interpreted 60.9% of scans positive and 39.1% negative (Table 1). Across all radiotracers, agreement between majority expert read and local readers was excellent (k coefficient 0.76; 95% CI 0.73 – 0.80, p<.0001) with 86.6% (791/913) agreement for positive scans and 90.9% (532/585) agreement for negative scans (Figure 1). Agreement by individual radiopharmaceuticals was good to excellent: k coefficient 0.78 (95% CI 0.72 – 0.83, p<.001) for FBB, k coefficient 0.72 (95% CI 0.66 – 0.78, p<.001) for FBP, and k coefficient 0.78 (95% CI 0.73 – 0.84) for FMM (Figure 1). Agreement levels between local readers and individual experts varied from good to excellent (Figure 2).ConclusionWe found good to excellent agreement between local readers and majority assessment of three‐member expert panels for all combined scans and scans by individual agents. Visual interpretation of Aß PET can be performed in a clinical setting with high reliability.

Comparison of Expert Reads vs. Local Clinical Reads of Amyloid PET Scans in IDEAS

AbstractBackgroundAmyloid‐directed therapies will increase the clinical use of amyloid PET. IDEAS captured >17,000 clinical scan interpretations from local radiologists and nuclear medicine physicians. This study aimed to establish accuracy of these interpretations by comparison to expert readers across identical scans.MethodRandomly selected amyloid PET/CT scans performed using one of three FDA‐approved agents [18F‐Florbetaben (FBB), 18F‐Florbetapir (FBP), 18F‐Flutemetamol (FMM)] and previously interpreted by local readers from the Imaging Dementia ‐ Evidence for Amyloid Scanning (IDEAS) study were assigned to vendor‐selected panels of 3 expert readers for interpretation; 500 scans per agent and 1 panel per agent. Scans were stratified to match frequencies observed in the overall study by 1) participant age; 2) MCI vs dementia; 3) positive/negative interpretation; and 4) type of PET facility. Respective vendors performed quality control on attenuation‐corrected PET/CT images.Visual interpretations (positive or negative for Aβ cortical deposition) were performed according to agent‐specific validated interpretation criteria. Expert panel readers were blinded to clinical and demographic data. Cohen’s kappa statistic with two‐sided 95% confidence interval estimates examined agreement between local reader and majority expert panel visual interpretation.ResultExpert panel readers’ visual interpretations totaled 4489. Median age for scanned participants was 75 (range 65‐96), 51.4% were female and 60.5% had MCI. Local readers interpreted 60.9% of scans positive and 39.1% negative (Table 1).Across all radiotracers, agreement between majority expert read and local readers was excellent (k coefficient 0.76; 95% CI 0.73 – 0.80, p<.0001) with 86.6% (791/913) agreement for positive scans and 90.9% (532/585) agreement for negative scans (Figure 1). Agreement by individual radiopharmaceuticals was good to excellent: k coefficient 0.78 (95% CI 0.72 – 0.83, p<.001) for FBB, k coefficient 0.72 (95% CI 0.66 – 0.78, p<.001) for FBP, and k coefficient 0.78 (95% CI 0.73 – 0.84) for FMM (Figure 1). Agreement levels between local readers and individual experts varied from good to excellent (Figure 2).ConclusionWe found good to excellent agreement between local readers and majority assessment of three‐member expert panels for all combined scans and scans by individual agents. Visual interpretation of Aβ PET can be performed in a clinical setting with high reliability.

Developing Topics.

Both 11C-Pittsburgh compound-B (PiB) and 18F-Flutemetamol (FMT) have off-target white matter (WM) signal that increases with age, but WM uptake is stronger with FMT than PiB. Although their WM patterns are comparably associated with age, the difference between them may impact visual and quantitative assessments of cortical amyloid-β uptake. Our objective was to determine whether PiB PET and FMT PET visual assessments agree with quantitative cortical amyloid-β evaluations. A cohort of cognitively unimpaired (CU) younger adults with median (range) of 39 (30, 48) years (N = 30), CU older adults with age of 67 (61, 83) years (N = 30) and older adults with AD dementia with age of 67 (54-84) years (N = 23) underwent MRI, PiB PET and FMT PET. PiB-PET and FMT PET scans were evaluated visually by two nuclear medicine specialists blinded to participant information. Disagreements were reconciled with a second, joint round of visual reads. Readers applied standard visual assessment criteria using the absence of regional gray matter (GM) and WM contrast as an indication of a positive scan. The global cortical PiB standard uptake value ratio (SUVr) was obtained referencing to cerebellar crus uptake and converted to centiloid values. Participants were classified as PiB positive/negative using a centiloid cut-off of 22. PiB and FMT visual positivity agreed with quantitative positivity on PiB-based centiloid values in 69/83 for PiB and 78/83 for FMT. There were 10 disagreements with PiB, 1 disagreement with FMT and 4 disagreements with both. Few disagreements occurred near the centiloid threshold. Interestingly, all disagreements between visual reads (amyloid-β positive) and centiloid (amyloid-β negative) in the CU younger were with PiB. FMT disagreements were always in the CU older and AD groups. Disagreements between amyloid-β positivity on visual reads and quantitative measurements (centiloid) may depend on age and tracer. PiB WM uptake is lower than FMT WM uptake, which may lead to reduced contrast between GM and WM (part of the standard criteria for visual reads), especially in younger ages. In contrast, WM uptake increases at older ages, and increased WM signal may bleed more into cortical regions, hiding subtle, near-threshold cortical uptake, especially with FMT.

Low-dose CT screening among never-smokers with or without a family history of lung cancer in Taiwan: a prospective cohort study

In Taiwan, lung cancers occur predominantly in never-smokers, of whom nearly 60% have stage IV disease at diagnosis. We aimed to assess the efficacy of low-dose CT (LDCT) screening among never-smokers, who had other risk factors for lung cancer. The Taiwan Lung Cancer Screening in Never-Smoker Trial (TALENT) was a nationwide, multicentre, prospective cohort study done at 17 tertiary medical centres in Taiwan. Eligible individuals had negative chest radiography, were aged 55-75 years, had never smoked or had smoked fewer than 10 pack-years and stopped smoking for more than 15 years (self-report), and had one of the following risk factors: a family history of lung cancer; passive smoke exposure; a history of pulmonary tuberculosis or chronic obstructive pulmonary disorders; a cooking index of 110 or higher; or cooking without using ventilation. Eligible participants underwent LDCT at baseline, then annually for 2 years, and then every 2 years up to 6 years thereafter, with follow-up assessments at each LDCT scan (ie, total follow-up of 8 years). A positive scan was defined as a solid or part-solid nodule larger than 6 mm in mean diameter or a pure ground-glass nodule larger than 5 mm in mean diameter. Lung cancer was diagnosed through invasive procedures, such as image-guided aspiration or biopsy or surgery. Here, we report the results of 1-year follow-up after LDCT screening at baseline. The primary outcome was lung cancer detection rate. The p value for detection rates was estimated by the χ2 test. Univariate and multivariable logistic regression analyses were used to assess the association between lung cancer incidence and each risk factor. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of LDCT screening were also assessed. This study is registered with ClinicalTrials.gov, NCT02611570, and is ongoing. Between Dec 1, 2015, and July 31, 2019, 12 011 participants (8868 females) were enrolled, of whom 6009 had a family history of lung cancer. Among 12 011 LDCT scans done at baseline, 2094 (17·4%) were positive. Lung cancer was diagnosed in 318 (2·6%) of 12 011 participants (257 [2·1%] participants had invasive lung cancer and 61 [0·5%] had adenocarcinomas in situ). 317 of 318 participants had adenocarcinoma and 246 (77·4%) of 318 had stage I disease. The prevalence of invasive lung cancer was higher among participants with a family history of lung cancer (161 [2·7%] of 6009 participants) than in those without (96 [1·6%] of 6002 participants). In participants with a family history of lung cancer, the detection rate of invasive lung cancer increased significantly with age, whereas the detection rate of adenocarcinoma in situ remained stable. In multivariable analysis, female sex, a family history of lung cancer, and age older than 60 years were associated with an increased risk of lung cancer and invasive lung cancer; passive smoke exposure, cumulative exposure to cooking, cooking without ventilation, and a previous history of chronic lung diseases were not associated with lung cancer, even after stratification by family history of lung cancer. In participants with a family history of lung cancer, the higher the number of first-degree relatives affected, the higher the risk of lung cancer; participants whose mother or sibling had lung cancer were also at an increased risk. A positive LDCT scan had 92·1% sensitivity, 84·6% specificity, a PPV of 14·0%, and a NPV of 99·7% for lung cancer diagnosis. TALENT had a high invasive lung cancer detection rate at 1 year after baseline LDCT scan. Overdiagnosis could have occurred, especially in participants diagnosed with adenocarcinoma in situ. In individuals who do not smoke, our findings suggest that a family history of lung cancer among first-degree relatives significantly increases the risk of lung cancer as well as the rate of invasive lung cancer with increasing age. Further research on risk factors for lung cancer in this population is needed, particularly for those without a family history of lung cancer. Ministry of Health and Welfare of Taiwan.

Post-Transplant Nivolumab Plus Unselected Autologous Lymphocytes in Truly Refractory Hodgkin Lymphoma Patients Is Highly Effective and Responses Are Mediated By NK Cells

Background In the relapsed/refractory Hodgkin Lymphoma (HL) setting (RHL), the achievement of complete remission (CR) is fundamental in order to proceed with allogeneic stem cell transplantation (HSCT) consolidation. Immune checkpoint inhibitors (CI) have demonstrated clinical activity in patients relapsing after ASCT, although only 20% CR rate is observed. In order to improve the efficacy of CI in RHL, we previously reported a salvage treatment based on early CI therapy following post-autologous stem cell transplantation (ASCT) with the reinfusion of unselected autologous lymphocytes infusions (ALI). The rationale of this approach is based on the achievement of a disease debulking through ASCT conditioning. Early administration of CI (nivolumab) is performed on a minimal disease burden, while reinfusions of ALI reduce post ASCT immune depression eliciting CI efficacy. Aims The aim of this study was to evaluate the efficacy of the procedure in terms of CR rates and overall survival (OS) after an extended follow up. Biological endpoint was to investigate the lymphocyte subpopulations involved in the mechanism of response and investigate the role of NK-cells mediating anti tumor responses in HL. Methods Patient were eligible to this study after failure to respond to first line treatment (i.e. positive PET2 or PET6 scan) and underwent autologous lymphocyte apheresis upon enrollment. All patients received conventional 2nd line chemo followed by 3rd line chemo-immunotherapy with Brentuximab-Vedotin (BV) in non-responding patients. Patient failing to achieve CR after BV were enrolled in the treatment arm and proceeded to ASCT + CI and ALI, whereas patients responding to 2nd- or 3rd treatment received ASCT followed by ALI alone, as a control cohort (figure 1A). NK cell degranulation assay was evaluated by staining for CD107a (LAMP-1) expression on healthy-donors derived NK cells exposed to HL cell lines (L428 and L250), in the presence or absence of monoclonal antibodies targeting inhibitory or activating receptors. Surface and intracellular staining was performed prior to flow cytometry and analysis was performed on the CD3-/CD56+ gated population. Results Twenty-one patients with RHL (median age 32 years; range 18-65) underwent lymphocyte apheresis after failure of 1st line chemo and then proceeded to salvage therapy. Thirteen patients failed to respond to 2nd and 3rd line therapy and thus received early post-transplant CI supported with four ALI. Eight patients responded to 2nd line chemo (n=6) or 3rd line BV (n=2) and received ASCT followed by ALI alone. No adverse events were recorded, specifically, no immune-related toxicity was observed. All patients receiving ALI + CI (treated patients) achieved negative PET scan CR. Eight of them received HSCT consolidation. One patient refusing HSCT after achieving CR in this study relapsed and responded to CI re treatment followed by HSCT. All patients in the treatment arm are alive and disease-free after a median follow-up of 32 months (95% CI 26.4-51.0). Median disease-free survival (DFS) was not reached in treatment arm (Fig 1B). Four of the patients in the control arm relapsed (50%). Three of them responded to 3rd line therapy and proceeded to HSCT. One patient achieved CR with conventional CI treatment but refused HSCT and the other relapsing patient died because of progressive lymphoma after failure to achieve CR with conventional single agent CI. Median DFS in the control arm was 22 months (Fig 1B). NK cells showed higher expansion and a faster maturation in the treatment arm, compared to the control arm (p<0.05). As expected, HL cells lines do not express HLA class I and II, but express activating NK cells receptors (aNKG2D, aNKp30, aNKp46, aDNAM-1). In vitro, the activation of each of those receptors was able to trigger NK cells degranulation. Similarly, PD-L1 and PD-L2 blockade on HL cell lines significantly increased NK cell degranulation (p<0.05). Taken together, those observations support the role of NK cells in this setting. Conclusions Our data show very high anti-tumor activity of ALI + CI for RHL, allowing most patients to proceed to HSCT. RHL patients in the treatment arm had an excellent outcome if compared to the control arm, which included patient who did respond to conventional treatment. Biological data suggests that this approach may accelerate NK cell development/maturation and suggest that NK cells may mediate response to CI in HL.

Preclinical In Vivo Imaging of Multiple Myeloma with [ 18f]Fluorohomoleucine (FHL) PET/CT

Purpose: Imaging of patients with multiple myeloma (MM) remains challenging due to its multi-focal nature affecting bone marrow, bone structures and soft tissue. As a result, current diagnostic methods like X-rays, CT and MRI scans only provide a partial understanding of disease activity and treatment response, lacking a comprehensive overview. Although 2-deoxy-2-[ 18F]fluoro-D-glucose (FDG) positron emission tomography (PET) has become the standard for detecting multifocal cancer spread, its use in MM patients is limited due to metabolic heterogeneity of MM and limited sensitivity in detecting extramedullary disease leading to false negative and false positive scans. To overcome these limitations, we developed a novel radiopharmaceutical L-[ 18F]Fluorohomoleucine (FHL) targeting LAT1 amino acid transporter. LAT1 has been significantly correlated with the proliferative activity of MM cells, poor prognosis and response to treatment in MM patients, presenting an appealing molecular target for assessing disease activity. Methods: FHL was synthesized as described by Nodwell et al. (J Nucl Med, 2019) and FDG was obtained from BC Cancer. LAT1 expression in multiple myeloma (MM) cell lines was confirmed by flow cytometry. Cell uptake assays were conducted using luciferase-transfected MM1S, L363, NCI H929 and AMO1 MM cells, and 2-amino-bicyclo[2.2.1]heptanes-2-carboxylic acid (BCH) was used as a blocking agent. For in vivo studies, male NRG mice were injected either with 1 x 10 6 MM cells intravenously (i.v.) via the caudal vein or subcutaneously (SQ) with 1 x 10 7 cells. Tumor engraftment was monitored weekly on an in vivo bioluminescence imager Perkin Elmer's IVIS Ilumina 5, starting at 2 weeks post-injection (p.i.). Biodistribution and PET/CT imaging studies were conducted at 4-6 weeks p.i. Results: All MM cells tested exhibited LAT1-specific FHL uptake in vitro with L363 and NCI H929 demonstrating the highest tracer uptake and average blocking efficacy over 83% and 93%, respectively. We were able to observe weekly progression of disease in the i.v. cohort using IVIS imaging. Biodistribution and PET imaging studies revealed FHL accumulation in the SQ xenografts, pancreas and excretion via the urinary tract. The SQ tumor uptake values were 4.53±0.82 %ID/g in AMO1 xenografts, 5.55±0.82 %ID/g in NCI H929, and 6.37±0.70 %ID/g in L363 tumors. In the i.v. cohort, the mouse intravenously injected with L363 cells demonstrated accumulation of radioactivity in the skull and vertebrae, as anticipated from the IVIS images. Furthermore, preliminary data suggests that FHL was able to detect a more extensive bone and lymphatic involvement than FDG in MM xenografts. Conclusion: We have demonstrated the ability of FHL for in vivo imaging of three human multiple myeloma tumors in SQ murine models, with the tumor uptake ranging from 4.53±0.82 %ID/g in AMO1 xenografts to 6.37±0.70 %ID/g in L363 tumors. Work is underway to establish the utility of this tracer in detecting disease dissemination in the orthotopic murine models of multiple myeloma, with promising preliminary results presented herein.

Minor head injury in anticoagulated patients: Outcomes and analysis of clinical predictors. A prospective study

BackgroundThe optimal management of patients taking oral anticoagulants who experience minor head injury (MHI) is unclear. The availability of validated protocols and reliable predictors of prognosis would be of great benefit. We investigated clinical factors as predictors of clinical outcomes and intracranial injury (ICI). MethodsWe conducted a single-cohort, prospective, observational study in an ED. Our structured clinical pathway included a first head CT scan, 24 h observation and a second CT scan. The primary outcome was the occurrence of MHI-related death or re-admission to ED at day +30. The secondary outcome was the rate of delayed ICI (dICI), defined as second positive CT scan after a first negative CT scan. We assessed some clinical predictors derived from guidelines and clinical prediction rules as potential risk factors for the outcomes. Results450 patients with a negative first CT scan who underwent a second CT scan composed our ‘study population’. The rate of the primary outcome was 4%. The rate of the secondary outcome was 4.7%. Upon univariate and multivariate analysis no statistically significant predictors for the outcomes were found. ConclusionsPrevious retrospective studies showed a lot of negative predictive factors for anticoagulated patients suffering a minor head injury. In our prospective study no clinical factors emerged as predictors of poor clinical outcomes and dICI. So, even if we confirmed a low rate of adverse outcomes, the best management of these patients in ED remains not so clear and future trials are needed.

Improved resistive switching performance of amorphous InGaZnO-based memristor with the TiO2 insertion layer

A stable I–V repeatability memristor based on amorphous InGaZnO (a-IGZO) with a TiO2 insertion layer was investigated. Two memristive structures composed of Pt/a-IGZO/Pt and Pt/TiO2/a-IGZO/Pt were manufactured on SiO2/Si substrate by the magnetron sputtering method. The crystallization of IGZO thin films was analyzed by the XRD process under different annealing temperatures, and the results show that the thin films remain in a stable amorphous state. The resistive switching performance of the two structures was tested by the semiconductor parameter analyzer 4200-SCS at room temperature. After 30 cyclic scans, the Pt/a-IGZO/Pt structure shows signs of degeneration in its I–V cyclic characteristics. However, in the Pt/TiO2/a-IGZO/Pt structure, the cyclic characteristics of I–V are highly stable (cycles >105 sweeps) with a limiting operating current of 0.01 A. Its rectification ratio is approximately 20 at low operating voltages (±1.0 V), and conductance increases (or decreases) progressively with continuous positive (or negative) voltage scans. Further analysis of the experimental energy band diagram was measured by UV–vis spectra and ultraviolet photoemission spectroscopy (UPS). The results demonstrate that the operational mechanism is the modulation of the barrier at the TiO2/a-IGZO interface, which is conducive to the stable I–V cyclic characteristic of Pt/TiO2/a-IGZO/Pt memristor.

Pilot study of lung cancer screening for survivors of Hodgkin lymphoma.

Hodgkin lymphoma (HL) treatment increases the risk of lung cancer. Most HL survivors are not eligible for lung cancer screening (LCS) programs developed for the general population, and the utility of these programs has not been tested in HL survivors. We ran a LCS pilot in HL survivors to describe screening uptake, participant characteristics, impact of a decision aid and screen findings. HL survivors treated ≥5 years ago with mustine/procarbazine and/or thoracic radiation, were identified from a follow-up database and invited to participate. Participants underwent a low-dose computed tomography (LDCT) reported using protocols validated for the general population. Two hundred and eighteen individuals were invited, 123 were eligible, 102 were screened (58% response rate): 58% female, median age 52 years, median 22 years since HL treatment; 91.4% were deemed to have made an informed decision; participation was not influenced by age, sex, years since treatment or deprivation. Only three of 35 ever-smokers met criteria for LCS through the program aimed at the general population. Baseline LDCT results were: 90 (88.2%) negative, ten (9.8%) indeterminate, two (2.0%) positive. Two 3-month surveillance scans were positive. Of four positive scans, two patients were diagnosed with small-cell lung cancer; one underwent curative surgery. Coronary artery calcification was detected in 36.3%, and clinically significant incidental findings in 2.9%. LDCT protocols validated in ever-smokers can detect asymptomatic early-stage lung cancers in HL survivors. This finding, together with screening uptake and low false positive rates, supports further research to implement LCS for HL survivors (clinicaltrials gov. Identifier: NCT04986189.).

NIMG-88. THALLIUM 201 SINGLE PHOTON EMISSION CT (TI-SPECT) FOR DIFFERENTIATION OF MALIGNANT VERSUS BENIGN NERVOUS SYSTEM SPACE OCCUPYING LESIONS: A RETROSPECTIVE STUDY, SYSTEMATIC REVIEW, AND META-ANALYSIS

Abstract Importance Thallium-201 single-photon emission computed tomography (TI-SPECT) imaging has been used historically to distinguish malignant cerebral neoplasms from infectious etiologies. Objectives Our study aims to review existing literature and conduct a retrospective study and meta-analysis on the use of TI-SPECT to differentiate malignant from non-malignant nervous system lesions. Data Sources A retrospective study on use of TI-SPECT in differentiating malignant versus benign nervous system masses was conducted in two tertiary hospitals in the Philippines. Systematic review of relevant studies regarding TI-SPECT for brain and spinal cord lesions was also done. Meta-analysis was performed to generate pooled sensitivity and specificity. Study Selection All study types published in the English language were included – randomized controlled trials (RCTs), prospective/retrospective cohort studies, and case series and reports; abstract only studies were excluded. Studies that involved either pediatric and adult cases were considered. Data Extraction and Synthesis The study complied with the Meta-analysis of Observational Studies in Epidemiology (MOOSE) and Preferred Reporting Items for Systematic reviews and Meta-analyses (PRISMA) Guidelines. Main Outcome and Measure The primary outcome was sensitivity and specificity of TI-SPECT. This involved getting correlation of positive and negative thallium scan uptake with either biopsy results (if available) or diagnosis via clinical response to treatment (i.e. whether cases that were managed as infection or demyelination showed improvement on follow-up). RESULTS: Thirty-two (32) articles were qualitatively described and 25 datasets were subjected to meta-analysis. Pooled sensitivity and specificity were 0.89 (95% CI: 0.82-0.94) and 0.82 (95% CI: 0.74-0.88), respectively with an area under the curve (AUC) for diagnostic accuracy of 0.92. CONCLUSION: and Relevance Thallium scans may be utilized to discriminate malignant from benign nervous system lesions, especially, in cases with a >80% pre-test probability. Further studies are needed to validate this findings.

Non-hyperaemic coronary flow velocity acceleration indices correlate with hyperaemic microvascular resistance in patients with INOCA

Abstract Background Coronary microvascular dysfunction (CMD) is associated with an overall worse prognosis. While the diagnosis and endo-typing of CMD currently rely on hyperaemic physiological indices, the search for accurate non-hyperaemic techniques continues. Flow velocity acceleration pattern is mechanistically associated with changes in shear stress, endothelial function, arterial stiffness and pressure in pulsatile flow systems (1-3). Purpose We aim to interrogate whether resting flow velocity acceleration indices correlate with hyperaemic microvascular resistance (HMR) in patients with Ischemia and no obstructive coronary artery disease (INOCA). Methods In 21 Patients with INOCA (all of whom had presented with typical angina pectoris, had no significant epicardial stenoses but positive myocardial perfusion scan test for ischemia) invasive physiological assessment was performed by means of intracoronary Doppler. Hyperaemia was induced with intracoronary adenosine administration. Coronary flow reserve (CFR) and HMR were calculated per their definitions. Flow velocity acceleration indices were derived from the first derivative of the averaged resting flow velocity waveforms with respect to time. We have defined 6 wave peaks of interest in all patients (peak diastolic acceleration (initial prominent peak with ventricular relaxation, referred as A), early diastolic deceleration (B), early re-acceleration wave (C), peak presystolic deceleration (seen just before initial systolic acceleration peak, J), initial systolic acceleration peak (X) and pre-diastolic deceleration nadir (Z)) and calculated the ratios between them as well as adjusted them with respect to resting mean flow velocity (Figure 1). Results The mean age was 59 ± 8 years and the majority of the study group was female (%81). Cardiovascular risk factors were common amongst the study group.All patients had CFR < 2.5. Mean CFR and HMR were 2.05 ± 0.32 and 2.20 ± 0.60 mmHg.cm.sec-1 respectively. Raw C peak magnitude was significantly correlated with APVh (rho:-0.457 p:0.037) and HMR (rho:0.612 p:0.004). Adjusting the C magnitudes with APVb at patient level yielded better correlations (APVh rho:-0.496 p:0.022 ; HMR:0.642 p:0.002). The ratio between diastolic reacceleration peak (C) and presystolic peak deceleration (J), C/J , adjusted with the APVb ((C/J)/APVb) showed the most pronounced correlation with HMR (rho: 0.758 p < 0.001) (unadjusted C/J – HMR rho: 0.718 p<0.001)(Figure 2). Conclusion(s) Acceleration characteristics of resting coronary flow velocity correlate with hyperaemic microvascular resistance indicating structurally impaired coronary microcirculation, hence their utilisation may aid developing non-hyperaemic physiological markers for coronary microvascular dysfunction in patients with INOCA.Derived Acceleration WaveformsCorrelations between HMR and C/J Ratio

Abstract 17577: Cardiomyopathy With Positive ATTR Mutation but Negative Tc-PYP Scan: A Conundrum

Background: Cardiac amyloidosis (CA) is a Hypertrophic Cardiomyopathy (HCM) mimic. Technetium labeled pyrophosphate (Tc-PYP) scan provides a rapid & non-invasive means for identifying ATTR-type CA with 99% sensitivity and specificity. We present 2 patients who were referred to HCM clinic but were found to have genetic testing positive for hTTR. In both cases, Tc-PYP scan was negative. Case Presentation: Outlined in Figure 1. Discussion: Both cases present a diagnostic and management dilemma. Neither of these two patients can be strictly considered asymptomatic carriers of the ATTR gene as both had phenotypic expression in the form of cardiomyopathy & massive LVH on imaging. Yet, in both Tc-PYP scan was negative. Neither had the ATTR mutations (Phe64Leu and Val30Met) that have reported association with negative Tc-PYP scan. Another possibility is early CA, which maybe rarely associated with negative Tc-PYP scan. Patient 1 refused endomyocardial biopsy, so early CA remains on the differential for her. Patient 2 had a negative endomyocardial biopsy. Her case is unique due to history of liver transplant 20 years prior to presentation making phenotypic CA less likely, but not impossible as there have been prior reports of cardiac disease progressing even after liver transplantation in familial ATTR. She also had tacrolimus exposure, which is known to cause LVH in rare cases. Both patients had hypertension, which could have also contributed to LVH. This case series serves to highlight the importance of maintaining a broad differential diagnosis in patients undergoing evaluation for HFpEF and severe LVH, particularly in cases of positive genetic testing but negative PYP scan for CA. From a management standpoint, it is unclear if early initiation of tafamidis might have a role in preventing cardiomyopathy progression in such patients with diagnostic uncertainty & ongoing concern for early CA.

End-of-Treatment Response Assessment after Frontline Therapy for Aggressive B-Cell Lymphoma: Landmark Comparison of a Singular PET/CT Scan Versus Ultrasensitive Circulating Tumor DNA

Background : Lymphoma response criteria rely on PET/CT scans at end of therapy (EOT) to determine complete response (CR), which is necessary for cure. ~25% of patients achieve <CR by response criteria, but PET/CT scans have imperfect specificity and the positive predictive value of a single PET/CT scan at EOT is only ~50% (Kostakoglu 2021). To overcome this limitation, clinicians use additional tests including tissue biopsies or repeat PET/CT scans prior to salvage therapy to adjudicate positive results, but it remains unclear how often this occurs. Circulating tumor DNA (ctDNA) has improved tumor specificity that may reduce reliance on additional tests. We addressed these questions within a clinical trial delivering 1L therapy to pts with aggressive B-cell lymphoma. Methods : Pts were enrolled in a phase 2 study of DA-EPOCH-R or R-CHOP +/- acalabrutinib for treatment naïve DLBCL or high-grade B-cell lymphoma (HGBCL) [NCT04002947]. All pts were >18yrs old, stage II-IV, with adequate organ function. Pts completing induction therapy with available EOT PET/CT scans and EOT plasma samples were studied. PET/CT scans were interpreted by 2 nuclear medicine (NM) radiologists blinded to clinical outcomes using the 5-point Deauville Score (DS) with DS4/5 considered positive. Tissue biopsies and unplanned PET scans after the EOT PET/CT scan to determine remission status were recorded. Measurable residual disease (MRD) in plasma cfDNA was evaluated by Phased Variant Enrichment & Detection Sequencing (PhasED-Seq) at Foresight Diagnostics blinded to clinical outcomes. Tumor derived Phased Variants (PVs) were identified from baseline pretreatment plasma samples or baseline tumor tissue, with matched constitutional DNA from paired PBMCs used to censor germline variants and CHIP. PVs were used to assess EOT MRD. Results were reported as MRD positive when ctDNA levels exceeded an analytical detection threshold (~1:10 6 cfDNA molecules) corresponding to 98% specificity. The prognostic utility of MRD was compared to standardized PET/CT scan at EOT to freedom-from-progression (FFP) and progression-free survival (PFS). Results : 55 enrolled pts completing planned therapy had EOT PET/CT and MRD analyzed. 54 (98%) pts were successfully genotyped and comprised the study population. Median age was 61 (range 26-85), including 22 (41%) female, 44 (81%) with advanced stage, and 26 (48%) with IPI score ³3. Pathologic subtypes included 24 (44%) GCB, 21 (39%) non-GCB, 8 (15%) HGBL-DH, and 1 (2%) THRLBCL. 43 (80%) pts received DA-EPOCH-R and 11 (20%) pts received R-CHOP. Twenty-six (48%) pts received acalabrutinib with R-chemotherapy. After 26 months median follow-up, the 2-year FFP and PFS of the cohort was 89% and 84%. Fourteen (26%) pts had a positive EOT PET/CT scan and 40 (74%) were negative. The concordance rate between the 2 NM radiologists on positive scans was 100%. Only 2 of 14 patients with a positive EOT PET/CT had clinical progression requiring salvage therapy (14% PPV). Nine (64%) of these pts required additional tests to determine remission status including 5 repeat PET/CT scans and 4 tissue biopsies. The 2-year PFS for pts with a positive vs negative EOT PET/CT was 66% vs 90% (p=0.08, Fig.A). Twelve (22%) pts had detectable EOT MRD and 42 (78%) were undetectable. 7 pts with detectable EOT MRD had clinical progression requiring salvage therapy or have died. While no pt with undetectable EOT MRD progressed, 1 (2%) died in remission of sudden cardiac death. Of 14 pts with positive EOT PET/CT, 7 (50%) had undetectable ctDNA and none progressed, suggesting MRD testing could have potentially rendered additional tests unnecessary. Conversely, patients with positive PET/CTs who progressed invariably had detectable ctDNA at EOT, suggesting utility of MRD for adjudicating PET/CT results. The 2-yr PFS for pts with detectable vs undetectable EOT MRD was 33% vs 98% (p<0.0001, Fig.B). At EOT, the PFS hazard ratio for MRD was 35.7, as compared with 3.1 for PET/CT. Conclusions : Response evaluations relying on PET/CT scans often require additional tests and procedures to assess remission status in aggressive B-cell lymphomas. Initiation of salvage therapy without adjudication in patients not achieving CR by EOT PET/CT scans will result in overtreatment. Given the higher specificity and PPV of EOT MRD, we propose an integrated response evaluation strategy combining these methods to reduce unnecessary additional tests and overtreatment.

50 Effects of Cerebrovascular Risk Factors and Alzheimer’s Disease Pathology on Executive Function and Memory Changes: Analysis of the National Alzheimer’s Coordinating Center Cohort

Objective:A common assumption in clinical neuropsychology is that cerebrovascular risk is adversely associated with executive function, while Alzheimer’s disease (AD) primarily targets episodic memory. The goal of the present study was to determine the cross-sectional and longitudinal validity of these assumptions using validated markers of cerebrovascular and AD burden.Participants and Methods:19271 longitudinally-followed participants from the National Alzheimer Coordinating Center (NACC) database (Mean age= 72.25; SD age= 10.42; 58% women; 51.6% CDR= 0, 33.7% CDR= 0.5, 14.7% CDR> 1) were included. Cognitive outcomes were a composite memory score and an executive function composite score (UDS3-EF; Staffaroni et al., 2020). Baseline presence of cerebrovascular disease was indexed by the presence of moderate to severe white matter hyperintensities or lacunar infarct on brain MRI (yes/no), while baseline AD pathology was indexed by the presence of a positive amyloid PET scan or elevated CSF AD biomarkers (yes/no). We used linear mixed effect models to assess the effects of baseline cerebrovascular disease, baseline AD pathology, and their interactions with time in study (years post baseline) controlling for baseline age, sex, education, and baseline MoCA score.Results:Baseline cerebrovascular disease was significantly associated with a lower intercept on executive functioning (between-person effect) (p < -0.001, 95% CI -0.37, -0.14) but not memory, while presence of AD biomarkers was associated with a lower memory intercept (p < -0.001, 95% CI -0.52, -0.39) but not executive function. However, only presence of AD pathology at baseline was associated with faster longitudinal decline on both memory and executive functioning over time. Baseline cerebrovascular disease did not independently relate to rate of cognitive decline.Conclusions:Consistent with widely held assumptions, our between-person analyses showed that MRI evidence of cerebrovascular disease was associated with worse executive functioning but not memory, while biomarker evidence of AD pathology was associated with worse memory but not executive function. Longitudinally, however, AD is the primary driver of decline in both executive and memory function. These results extend our understanding of how pathology impacts cognition in aging cohorts and highlight the importance of using longitudinal models.

5 Intraindividual Variability in Processing Speed on Digital Cognitive Assessments Differs by Amyloidosis Status in Cognitively Normal Older Adults

Objective:Intraindividual variability (IIV) is defined as fluctuations in an individual’s cognitive performance over time1. IIV has been identified as a marker of neurobiological disturbance making it a useful method for detecting changes in cognition among cognitively healthy individuals as well as those with prodromal syndromes2. IIV on laboratory-based computerized tasks has been linked with cognitive decline and conversion to mild cognitive impairment (MCI) and/or dementia (Haynes et al., 2017). Associations between IIV and AD risk factors including apolipoprotein (APOE) ε4 carrier status, neurodegeneration seen on brain imaging, and amyloid (Aß) Positron emission tomography (PET) scan status have also been observed1. Recent studies have demonstrated that evaluating IIV on smartphone-based digital cognitive assessments is feasible, has the capacity to differentiate between cognitively normal (CN) and MCI individuals, and may reduce barriers to cognitive assessment3. This study sought to evaluate whether such differences could be detected in CN participants with and without elevated AD risk.Participants and Methods:Participants (n=57) were cognitively normal older adults who previously received an Aß PET scan through the Butler Hospital Memory and Aging Program. The sample consisted of primarily non-Hispanic (n=49, 86.0%), White (n=52, 91.2%), college-educated (M=16.65 years), females (n=39, 68.4%). The average age of the sample was 68 years old. Approximately 42% of the sample (n=24) received a positive PET scan result. Participants completed brief cognitive assessments (i.e., 3-4 minutes) three times per day for eight days (i.e., 24 sessions) using the Mobile Monitoring of Cognitive Change (M2C2) application, a mobile app-based cognitive testing platform developed as part of the National Institute of Aging’s Mobile Toolbox initiative (Sliwinski et al., 2018). Participants completed visual working memory, processing speed, and episodic memory tasks on the M2C2 platform. Intraindividual standard deviations (ISDs) across trials were computed for each person at each time point (Hultsch et al., 2000). Higher ISD values indicate more variability in performance. Linear mixed effects models were utilized to examine whether differences in IIV existed based on PET scan status while controlling for age, sex at birth, and years of education.Results:n interaction between PET status and time was observed on the processing speed task such that Aß- individuals were less variable over the eight assessment days compared to Aß + individuals (B= -5.79, SE=2.67, p=.04). No main or interaction effects were observed on the visual working memory task or episodic memory task.Conclusions:Our finding that Aß- individuals demonstrate less variability over time on a measure of processing speed is consistent with prior work. No associations were found between IIV in other cognitive domains and PET status. As noted by Allaire and Marsiske (2005), IIV is not a consistent phenomenon across different cognitive domains. Therefore, identifying which tests are the most sensitive to early change is crucial. Additional studies in larger, more diverse samples are needed prior to widespread clinical use for early detection of AD.

Three linked variants have opposing regulatory effects on isovaleryl-CoA dehydrogenase gene expression.

While genome-wide association studies (GWAS) and positive selection scans identify genomic loci driving human phenotypic diversity, functional validation is required to discover the variant(s) responsible. We dissected the IVD gene locus-which encodes the isovaleryl-CoA dehydrogenase enzyme-implicated by selection statistics, multiple GWAS, and clinical genetics as important to function and fitness. We combined luciferase assays, CRISPR/Cas9 genome-editing, massively parallel reporter assays (MPRA), and a deletion tiling MPRA strategy across regulatory loci. We identified three regulatory variants, including an indel, that may underpin GWAS signals for pulmonary fibrosis and testosterone, and that are linked on a positively selected haplotype in the Japanese population. These regulatory variants exhibit synergistic and opposing effects on IVD expression experimentally. Alleles at these variants lie on a haplotype tagged by the variant most strongly associated with IVD expression and metabolites, but with no functional evidence itself. This work demonstrates how comprehensive functional investigation and multiple technologies are needed to discover the true genetic drivers of phenotypic diversity.

Idiopathic Normal Pressure Hydrocephalus: The Real Social and Economic Burden of a Possibly Enormous Underdiagnosis Problem.

Normal Pressure Hydrocephalus (iNPH) typically affects the elderly and can cause cognitive decline, resulting in its differential diagnosis with other neurodegenerative conditions. Moreover, it is probably underdiagnosed; such under- and misdiagnosis prevents the patient from receiving the right treatment and significantly affects the quality of life and life expectancy. This investigation is an in-depth analysis of the actual incidence of iNPH in the population of the province served by our hospital (circa 580,000 individuals). The first phase of this study was conducted by visualizing a total of 1232 brain CT scans performed in the Emergency Departments of the four hospitals of our network on patients who were admitted for different complaints yet screened as suspicious for iNPH. Subsequently, corresponding Emergency Department medical records were investigated to understand the medical history of each patient in search of elements attributable to an alteration of CSF dynamics. The cohort of positive CT scans, according to the radiological and clinical inclusion criteria, included 192 patients. Among the reasons to require acute medical care, "Fall" was the most common. The cumulative incidence of CT scans suggestive of iNPH among the patients undergoing CT scans was as high as 15.58%, and the period prevalence calculated for the total amount of patients accessing the Emergency Departments was 1.084%. The real incidence of iNPH in the population may be underestimated, and the social burden linked to the assistance of patients suffering from such untreated conditions could be significantly relieved.