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INTRODUCTION: Assessing the potential sources of bias and variability of the Centiloid (CL) scale is fundamental for its appropriate clinical application. METHODS: We included 533 participants from AMYloid imaging to Prevent Alzheimer's Disease (AMYPAD DPMS) and Alzheimer's Disease Neuroimaging Initiative (ADNI) cohorts. Thirty‐two CL pipelines were created using different combinations of reference region (RR), RR and target types, and quantification spaces. Generalized estimating equations stratified by amyloid positivity were used to assess the impact of the quantification pipeline, radiotracer, age, brain atrophy, and harmonization status on CL. RESULTS: RR selection and RR type impact CL the most, particularly in amyloid‐negative individuals. The standard CL pipeline with the whole cerebellum as RR is robust against brain atrophy and differences in image resolution, with 95% confidence intervals below ± 3.95 CL for amyloid beta positivity cutoffs (CL < 24). DISCUSSION: The standard CL pipeline is recommended for most scenarios. Confidence intervals should be considered when operationalizing CL cutoffs in clinical and research settings. Highlights: We developed a framework for evaluating Centiloid (CL) variability to different factors.Reference region selection and delineation had the highest impact on CL values.Whole cerebellum (WCB) and whole cerebellum plus brainstem (WCB+BSTM) as reference regions yielded consistent results across tracers.The standard CL pipeline is robust against atrophy and image resolution variation.Estimated within‐ and between‐pipeline variability (95% confidence interval) in absolute CL units. [ABSTRACT FROM AUTHOR]

Background: Clinical practitioners may have become familiar with the rapid transformation of dental composites. However, they may not scientifically understand the factors influencing the mechanical and physical properties. Scientific knowledge of filler‐resin interaction can significantly improve clinical understanding of resin composites. Several independent studies have examined the mechanical and physico‐mechanical properties of dental resin composites; however, no comprehensive study has examined the influence of fillers and resin materials on the physico‐mechanical properties of both self‐cure and dual‐cure composites. Methods: This study performed investigations on the physico‐mechanical behaviour of four commercially available dual‐cure dental composites (Bioactive, Fill Up!, Surefil One, Cention N) and two commercially available self‐cure dental composites (Stela Capsule and Stela Automix). Test specimens for flexural and compressive strength, microhardness, fracture toughness, and hydrolytic behaviour were prepared and tested as per respective standards. The data sets were statistically analysed using one‐way ANOVA and Tukey's post‐hoc comparison. Results: There was a substantial variation in flexural strength and modulus values in this study, ranging from 32.0 to 113.4 MPa and 2.36 to 12.07 GPa, respectively. Similarly, there were significant differences in compressive strength between the materials in this study, ranging from 119.3 to 223.5 MPa. The highest fracture toughness value was found to be 1.41 MPa.m0.5, while the lowest value was 0.43 MPa.m0.5. Variations in surface microhardness were significant (24.11–68.0 N/mm2), which correlated with the filler content. Water sorption and solubility demonstrated high variations among materials, with Surefil One exceeding ISO 4049 thresholds significantly. Conclusions: A linear correlation can be established between surface microhardness (HV) and flexural and compressive moduli, as well as filler content (wt.%). However, both flexural and compressive strengths are impacted by the resin's constituent monomers and the resin‐filler matrix's cross‐linking capability. Additionally, factors such as filler size, shape, and the cross‐linking ability of the resin‐filler matrix play a crucial role in fracture toughness and the propagation of cracks within the restoration. Also, resin monomers and filler particle size affect the hydrolytic degradation characteristics of composites, which can also affect their mechanical properties. © 2023 Australian Dental Association. [ABSTRACT FROM AUTHOR]

Background: The Centiloid scale is a well‐established standardized metric for estimating amyloid load in clinical and research settings. In this study, we evaluated the stability of Centiloid to pipeline design options, tracer, and image harmonization. Method: A total of 670 participants of the AMYPAD DPMS and PNHS multicenter studies with either [18F]flutemetamol or [18F]florbetaben PET scans and T1‐weighted MRI were included (Table1). PET images were harmonized to achieve an 8 mm Full‐Width‐at‐Half‐Maximum(FWHM) effective image resolution. Using SPM12, 32 Centiloid pipelines were created, calibrated and validated, based on combinations of four reference regions (Whole Cerebellum[WCB], Cerebellar Gray[CG], Whole Cerebellum+Brainstem[WCB+BSTM], Pons), two target VOI types (standard GAAIN vs subject‐based), two reference region types (standard GAAIN vs subject‐based) and two analysis spaces (native vs MNI). Generalized Estimating Equations (GEE) were used to evaluate the impact of the different factors on Centiloid. First, a base model including only the pipeline design factors was defined. Then, harmonization status (original vs harmonized PET images), tracer, and grey matter volume, as a measure of cerebral atrophy, were added to the base GEE model. Analyses were performed in the two cohorts separately and changes >5 Centiloid were considered relevant. Result: Quantification space, target VOI, and reference region type had a small impact on Centiloid. Selection of reference region had the largest impact on Centiloid as using the Pons resulted in ∆Centiloid∼‐12.00 compared with using the standard reference region, WCB (Table2). Harmonization status affected Centiloid only for some reference regions: CG and Pons were sensitive to harmonization status (∆Centiloid∼ 5.45 and ‐5.70 respectively). In contrast, Centiloid was minimally affected by harmonization when using WCB and WCB+BSTM (Table3). Tracer and atrophy had a minimal effect on Centiloid for both DPMS and PNHS cohorts. Conclusion: Centiloid quantification is robust against differences in analysis space, reference region type, target VOI, tracer and the presence of atrophy. However, choice of reference region can significantly influence Centiloid, with the Pons having the largest impact on Centiloid relative to other reference regions. Centiloid is stable against harmonization status and image resolution heterogeneities while using WCB as reference region. [ABSTRACT FROM AUTHOR]

Background: Amyloid‐β (Aβ) PET is commonly used for studying the earliest phases of Alzheimer's disease (AD) in cognitively unimpaired (CU) individuals. In this group, the expected changes in Aβ pathology are small, which emphasizes the importance of selecting a method with the highest possible precision for measuring these changes. This study compared several methods for quantifying Aβ pathology longitudinally in mostly CU individuals from the AMYPAD‐PNHS cohort. Method: Participants were scanned with either [18F]flutemetamol (baseline N = 360, follow‐up N = 243) or [18F]florbetaben (N = 66 baseline, N = 49 follow‐up), according to a dual‐time window protocol(Table 1). A subset of participants had ≥2 timepoints available (N = 206, N = 43, respectively). SUVRs were calculated, and parametric modelling was performed using RPM, SRTM2, RLogan, MRTM0, MRTM and MRTM2 using PPET software to generate parametric BPND or DVR images for a global cortical region, all with cerebellar cortex as reference tissue. Annual percentage change (APC) was calculated and compared between methods using an ANOVA. To check for changes in Aβ pathology over time, a linear mixed effects model was used. Bland‐Altman analyses were used to explore agreement between SUVR, and the outcome parameter from the parametric methods. All analyses were run per tracer, separately for visual Aβ‐positive and Aβ‐negative individuals, with a p‐value threshold of p<0.05. Result: For both tracers, there were no differences in APC between methods. However, method‐dependent differences in interquartile range of the APC were observed(Figure 1,2). For [18F]flutemetamol, only the Aβ‐negative group showed a significant change in Aβ pathology for SUVR and SRTM2 (both ‐0.004/year). For [18F]florbetaben, only the Aβ‐positive group showed a significant change in Aβ pathology for all methods except MRTM2 (range: +0.020‐0.032/year). No significant bias was observed between APC in SUVR and the other methods for either tracer or Aβ‐group. Conclusion: There were no significant differences in APC between methods, despite method‐dependent variability. In the [18F]flutemetamol‐cohort, two methods showed a minimal decrease in Aβ pathology in the Aβ‐negative‐group, possibly related to measurement variability, which requires further investigation. In the [18F]florbetaben‐cohort, which included more participants with a very mild cognitive impairment, a significant increase in Aβ pathology was observed in the Aβ‐positive‐group, except for MRTM2. [ABSTRACT FROM AUTHOR]

Background: Discordance between cerebrospinal fluid (CSF) and positron emission tomography (PET) biomarkers of amyloid‐β (Aβ) occurs in up to 20% of individuals. Generally, Aβ discordance is defined using binary cut‐offs. Given the methodological limitations of this approach, we propose a continuous Aβ CSF/PET imbalance model. We investigated biological and methodological factors underlying discrepancy in these amyloid biomarkers and associations with longitudinal cognition. Method: We included 383 non‐demented subjects (Nunimpaired = 326, Nmildly‐impaired = 57) from the AMYPAD‐PNHS cohort. Z‐scored CSF Aβ42 and amyloid‐PET (Centiloids [CL]) units were fitted to a hyperbolic regression model by minimizing the Euclidian distance of the observed datapoints to the fitted line. Subject‐specific standardized residuals were derived as a measure of continuous imbalance (Zimbalance), with Zimbalance<0 reflecting greater Aβ abnormality in CSF relative to PET and Zimbalance>0 greater Aβ abnormality in PET relative to CSF (Figure‐1). Linear models adjusted for relevant covariates (Figure‐2) were run between Zimbalance and (1) methodological factors (CSF‐PET interval, CSF kit, PET tracer, and PET injected dose); (2) demographics (age, sex, education, APOE genotype) and CSF p‐tau biomarker; (3) vascular burden (white matter hyperintensities measured as Fazekas scores). Linear mixed models were used to investigate the predictive value of Zimbalance on longitudinal cognition in several domains. Result: Sample characteristics are shown in Table‐1. Methodological factors were not significantly associated with Zimbalance. Increased CSF p‐tau levels were significantly associated with a higher Zimbalance (i.e. greater Aβ abnormality in PET relative to CSF) (β = 0.06±0.03, p =.033) (Figure‐2). In addition, a lower Zimbalance (i.e. greater Aβ abnormality in CSF relative to PET) was associated with a higher Fazekas score (n = 189, β = ‐0.55±0.26, p =.038) and predictive of faster cognitive decline on a language categorical fluency test (β = ‐0.03±0.02, p =.038) (Figure‐2). Conclusion: We found that methodological factors did not contribute to a continuous model of Aβ CSF/PET imbalance, suggesting that this imbalance reflects distinct biological profiles. Indeed, continuous CSF/PET imbalance showed differential associations, with greater pathological levels of aggregated Aβ relative to soluble Aβ being related to increased CSF p‐tau levels and excess pathological levels of soluble Aβ relative to aggregated Aβ to increased white matter hyperintensities and steeper cognitive decline. [ABSTRACT FROM AUTHOR]

Background: The relationship between cerebrospinal fluid (CSF) biomarkers for Alzheimer's disease (AD), APOE‐ε4 and longitudinal cortical amyloid deposition in preclinical AD is relevant for AD trial design but remains unclear. Thus, we aimed to investigate longitudinal cortical amyloid accumulation on PET as predicted by baseline CSF AD biomarker profiles and APOE‐ε4 carriership in cognitively unimpaired individuals. Method: We selected 330 cognitively unimpaired individuals from 6 cohorts of the AMYPAD study. All had available baseline data on CSF aß1‐42 (A), p‐tau181 (T), APOE‐ε4 carriership (yes/no), and baseline and follow‐up amyloid PET data. To evaluate different AD stages, individuals were classified as A‐T‐, A‐T+, A+T‐, or A+T+ based on CSF biomarker abnormality using center‐specific cut‐offs. We used a continuous outcome measure of global cortical amyloid deposition on PET expressed in centiloids. Analyses were performed in the total sample and stratified for APOE‐ε4, using generalized linear mixed models with random intercepts and slopes, adjusted for age and sex. Result: 58% were female, 49% APOE‐ε4 carriers, and mean age was 64+‐6.1 years, with an average follow‐up of 3 years. 170 individuals were A‐T‐, 70 A‐T+, 59 A+T‐, and 31 A+T+. Baseline cortical amyloid deposition was different between all groups, with A+T+ having the highest deposition, followed by A+T‐, A‐T+ and A‐T‐ (Figure 1, Table 1). Longitudinally, all groups showed increased amyloid deposition, except A‐T‐. Moreover, A+ groups showed greater increases in longitudinal amyloid deposition than A‐ groups. In APOE‐ε4 carriers, all AT groups showed increased longitudinal amyloid deposition, while in non‐carriers, A‐T+ and A‐T‐ did not (Figure 2, Table 1). Only in APOE‐ε4 carriers, A+T+ showed greater increases in longitudinal amyloid deposition than A+T‐, with A+T‐ showing a similar longitudinal deposition as A‐T+. Conclusion: APOE‐ε4 impacts the association between CSF AD biomarkers and longitudinal amyloid PET deposition in cognitively unimpaired persons. Amyloid‐negative APOE‐ε4 carriers could be at an early AD stage, as they showed increased cortical amyloid longitudinally, independent of baseline p‐tau status. In amyloid‐positive persons, p‐tau abnormality related to higher baseline cortical amyloid, but only in APOE‐ε4 carriers to steeper increases in cortical amyloid longitudinally. This has important implications for AD trial design. [ABSTRACT FROM AUTHOR]

Deposition of amyloid and tau pathology can be quantified in vivo using positron emission tomography (PET). Accurate longitudinal measurements of accumulation from these images are critical for characterizing the start and spread of the disease. However, these measurements are challenging; precision and accuracy can be affected substantially by various sources of errors and variability. This review, supported by a systematic search of the literature, summarizes the current design and methodologies of longitudinal PET studies. Intrinsic, biological causes of variability of the Alzheimer's disease (AD) protein load over time are then detailed. Technical factors contributing to longitudinal PET measurement uncertainty are highlighted, followed by suggestions for mitigating these factors, including possible techniques that leverage shared information between serial scans. Controlling for intrinsic variability and reducing measurement uncertainty in longitudinal PET pipelines will provide more accurate and precise markers of disease evolution, improve clinical trial design, and aid therapy response monitoring. [ABSTRACT FROM AUTHOR]

Background: In 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. Methods: From 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. Results: Overall, 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. Conclusion: In 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. [ABSTRACT FROM AUTHOR]

Background: Wider use of amyloid PET in clinical routine requires validated and standardized quantification methods. Therefore, the impact of pipeline design and post‐processing smoothing on Centiloid(CL) quantification was evaluated. Methods: This study has been performed using 725 amyloid PET scans from the two AMYPAD trials(PNHS and DPMS) that were acquired with either [18F]flutemetamol or [18F]florbetaben(Table1). Using SPM12, 32 pipelines were created and calibrated to render CL with combinations of: • 4 reference regions (Whole Cerebellum, Cerebellar Gray, Whole Cerebellums+Brainstem, Pons) • target VOI (standard GAAIN vs subject‐based) • reference region type (standard GAAIN vs subject‐based) • analysis spaces (native vs MNI) The impact of the pipeline design factors on CL values assessed using Generalized Estimating Equation(GEE) analyses. Individual morphometric variables including total intracranial volume(TIV), and grey/white matter volumes in the reference and target regions implemented in the model. To mimic differences in image resolution, PET scans were smoothed by 3mm and 6mm Gaussian filters. CL was calculated for original and corresponding smoothed PET scans. The agreement between CL values with/without smoothing evaluated using the intra‐class correlation coefficient(ICC). Bland‐Altman plots were used to demonstrate mean absolute differences between CL values after smoothing. Differences above 5CL were considered relevant. Results: There was no statistically significant relationship for CL as a function of tracer, analysis space or target region, while RR selection and its definition did have a significant impact on CL values(Table2). More specifically, the pons provided the lowest mean CL(25.06±4.51) compared to the whole‐cerebellum(35.04±4.25) and the cerebellum grey‐matter(36.99±4.16)(Table3). Using GAAIN RR provided slightly higher mean CL values (ΔCL:4.15±1.04) compared to a subject‐based method (Table4). ICC between CL values of non‐smoothed vs smoothed PET images was 0.99 for both post‐smoothing filters(p<0.001). Differences in image resolution had minimal effect on CL values for individuals with low to moderate levels of amyloid while the effect became higher for individuals with the higher amyloid burden(Figure1) Conclusion: CL quantification is robust against differences in individual morphometric measures, analysis space, image resolution, tracer and target VOI. However, reference region choice can significantly influence CL values, with the pons showing the highest discrepancies relative to other reference regions. [ABSTRACT FROM AUTHOR]

Background: In clinical practice, visual assessment of amyloid‐PET images results in a binary classification (negative or positive) of amyloid status. While this approach has shown high clinical utility, the expected approval of disease‐modifying treatments warrants the need for objective amyloid burden quantification, to further support a high‐confidence diagnosis of Alzheimer's disease (AD) and treatment decisions. We investigated two widely available quantification methods, i.e. Centiloid (CL) and z‐scores to optimize clinical use of amyloid‐PET. Methods: Patients with subjective cognitive decline plus (SCD+; N=220), mild cognitive impairment (MCI; N=293) or dementia (N=216) enrolled in the AMYPAD‐DPMS that have undergone amyloid‐PET imaging and passed quality control were included in the study. Acquired static (i.e. 90‐110 min. post‐injection) [18F]flutemetamol (N=380) or [18F]florbetaben (N=349) PET images were processed using GE Healthcare's AMYPYPE PET‐only pipeline, providing global CL, z‐scores, and z‐scores for 7 cortical ROIs. Local readers provided visual read (VR) status and regional assessments. Results: Demographics are shown in Table 1. In total, 364 (49.9%) patients were assessed as amyloid VR‐positive and showed significantly higher CL (U=3954, p<0.001) and global z‐score (U=4197, p<0.001) values across clinical stages compared to VR‐negative patients (Figure 1A). The proportion of VR‐positive patients increased with clinical stage (SCD+: 30.0%, MCI: 48.8%, dementia: 71.8%) and global amyloid burden (CL: H=24.97, p<0.001; z‐score: H=24.43, p<0.001) was also associated with disease severity (Figure 1B). VR‐positive patients with a primary etiological diagnosis of AD showed higher overall higher amyloid burden (CL: H=6.93, p=0.008; z‐score: H=5.54, p=0.019) and specifically in the pre‐frontal cortex (H=8.18, p=0.004) compared to patients with a non‐AD primary etiological diagnosis, though percentage of frontal VR‐positivity was highly similar between groups (AD: 97.2% vs. non‐AD: 96.6%). Global CL and z‐scores were highly correlated (ρ=.987, p<0.001), by a factor of 10 (Figure 1C). Conclusion: Our results demonstrate high agreement between CL and z‐scoring quantitative measures in a clinical population. While initial results do not indicate differences in patterns of regional positivity between AD and non‐AD subjects, differences in global amyloid burden seem to be driven by known AD‐related early accumulating regions. Additional analyses comparing other etiological groups will be presented at the conference. [ABSTRACT FROM AUTHOR]

Background: Higher educated patients with MCI can tolerate more neuropathology than lower educated patients with similar clinical impairment. It is not known whether this observation also accounts for potential preclinical stages of AD, namely subjective cognitive decline plus (SCD+). Method: Data of 197 SCD+ individuals, 227 MCI and 157 AD patients were included, which were collected as part of the AMYPAD‐DPMS cohort (https://amypad.eu/). First, median education in years was computed across the AD‐spectrum groups for each of the 8 European sites. Next, using a median split, the SCD+, MCI and AD cohort were separately categorized into a higher and lower educated group, excluding subjects with median education. Afterwards, the higher and lower educated AD‐spectrum groups were matched for age, sex and cognitive function (MMSE) using propensity score matching in R, leading to the following sample (low/high education): 54/54 SCD+, 70/81 MCI and 56/65 AD patients. Global amyloid load was compared between education groups using Centiloid (CL) information derived from Flutemetamol and Florbetaben PET scans. To confirm the results of the stringent group comparison, partial correlations between years of education and CL values correcting for age, sex and tracer type were performed for each AD‐spectrum group. All analyses were conducted in SPSS 28 and significance level was set to p <.05. Result: Higher educated SCD+ subjects presented significantly (p <. 001) lower CL values (M(CL) = 16.48) than lower educated SCD+ subjects (M(CL) = 32.17), whereas the opposite effect (p <.046) was observed in the MCI cohort with higher educated MCI patients presenting greater CL values (M(CL) = 57.08) compared to the lower educated MCI group (M(CL) = 41.74). No difference was found in the AD group. Results were further confirmed by the correlation approach across the unmatched sample yielding a negative association between years of education and CL values in the SCD+ group (r = ‐.159, p =.027) and a positive association in the MCI group (r =.153, p =.022). Conclusion: These results indicate that sensitivity to early amyloid accumulation may possibly increase with higher education in potential preclinical stages of AD, whereas in clinical stages of AD higher education may support compensatory mechanisms against amyloid burden. [ABSTRACT FROM AUTHOR]

Evaluating the efficacy of management actions to control invasive species is crucial for maintaining funding and to provide feedback for the continual improvement of management efforts. However, it is often difficult to assess the efficacy of control methods due to limited resources for monitoring. Managers may view effort on monitoring as effort taken away from performing management actions. We developed a method to estimate invasive species abundance, evaluate management effectiveness, and evaluate population growth over time from a combination of removal activities (e.g., trapping, ground shooting) using only data collected during removal efforts (method of removal, date, location, number of animals removed, and effort). This dynamic approach allows for abundance estimation at discrete time points and the estimation of population growth between removal periods. To test this approach, we simulated over 1 million conditions, including varying the length of the study, the size of the area examined, the number of removal events, the capture rates, and the area impacted by removal efforts. Our estimates were unbiased (within 10% of truth) 81% of the time and were correlated with truth 91% of the time. This method performs well overall and, in particular, at monitoring trends in abundances over time. We applied this method to removal data from Mingo National Wildlife Refuge in Missouri from December 2015 to September 2019, where the management objective is elimination. Populations of feral swine on Mingo NWR have fluctuated over time but showed marked declines in the last 3–6 months of the time series corresponding to increased removal pressure. Our approach allows for the estimation of population growth across time (from both births and immigration) and therefore, provides a target removal rate (above that of the population growth) to ensure the population will decline. In Mingo NWR, the target monthly removal rate is 18% to cause a population decline. Our method provides advancement over traditional removal modeling approaches because it can be applied to evaluate management programs that use a broad range of removal techniques concurrently and whose management effort and spatial coverage vary across time. [ABSTRACT FROM AUTHOR]

Background: Performance‐based tests of functional cognition (FC) use simulated instrumental activities of daily living (IADL) performed under rule constraint to evaluate ability to perform actual IADL. Because the test characteristics and the test‐takers daily activities are similar, the test‐takers need to avoid becoming "derailed" by habits or personal preferences that are not relevant to the test, a phenomenon referred to as loss of set (Burgess, 2005; Schneider, 1984). The Menu Task, a sensitive FC screening test, was designed to provoke loss of set by having the format of a food selection activity, in which test‐takers own food preferences may disrupt actual task requirements. However, there has until now been no examination of whether test‐takers approach and strategies to maintain set are associated with cognitive abilities and FC abilities. Method: A convenience sample of 93 adults living independently in the community were administered a battery of cognitive screening measures, a self‐report IADL measure, and assessments of FC including the Menu Task, and the After Menu Task Interview. Responses to the After Menu Task Interviews were qualitatively categorized according to 1. loss of set 2. calorie counting as a strategy, or 3. self‐reported planning. Independent t‐tests were used to compare the categorized group performance on cognitive, FC, and IADL measures. Result: Individuals who lost set on the Menu Task performed significantly poorer on the MoCA (p =.012), the ADCS‐MCI (p <.001), and FC assessments (p <.01) than those who did not lose set. Those who reported counting calories as a strategy scored significantly better on the MoCA (p =.012), TMT A (p =.023), TMT B (p =.012), the ADCS‐MCI (p =.044), and FC assessments (p <.05). No significant group differences were observed for those who reported planning compared to those who did not report planning. Conclusion: Clinicians using the Menu Task may wish to incorporate an After Task Interview focusing on the client's reported way of approaching the Menu Task. Individuals who focus on their own food preferences or show other indications of loss of set while completing the Menu Task may benefit from further cognitive or FC assessment. [ABSTRACT FROM AUTHOR]

Background: Early identification of mild cognitive impairment (MCI) is critical, as MCI precipitates disability and may be a precursor to major neurocognitive disorder. The Clock Drawing Test (CDT) is a widely adopted screening measure for dementia however it is not known whether paper‐and‐pencil CDT scoring rubrics are sensitive to subtle losses consistent with MCI. We examined the reliability and sensitivity to MCI of two free‐drawn Clock Drawing Test rubrics ‐ the 10‐point Rouleau, and the 20‐point Clock Drawing Interpretation Scale (CDIS) in community‐dwelling older adults. Method: 345 adults enrolled in a study of functional cognition completed the Montreal Cognitive Assessment (MoCA), the Alzheimer's Disease Cooperative Study Scale (ADCS‐ADL), and freely‐drawn clocks scored with CDIS and Roleau rubrics. We computed Cronbach's alpha, receiver operating characteristic (ROC) analyses using the MoCA as the index measure, and one‐way ANOVAs with the ADCS‐ADL for each rubric. Result: Our sample was 74% female, 83.2% white. Mean age was 70.01 ±8.89, and mean education was 15.5 ±3.735 years. Average scores were 24.28 ±3.44 (MoCA), 74.85 ±4.16 (ADCS), 8.8 ±1.68 (Rouleau) and 18.17 ±2.09 (CDIS). alphas were.65 for the CDIS and.479 for the Rouleau. ROC analyses using MoCA scores consistent with any impairment (<26) resulted in a CDIS AOC of.677, with sensitivity of.681 and specificity of.58 at a cut score of 19. The Rouleau AOC was.684, with sensitivity of.542 and specificity of.76 at a cut score of 9. ANOVAs indicated that individuals classified as impaired by the CDIS ((F = 13.095, p<.001) or the Rouleau (F = 22.2, p<.001) rubrics reported significantly more ADL/IADL difficulties than those classified as unimpaired with either rubric. Differences between impaired and unimpaired groups were larger for the CDIS, suggesting this rubric is more sensitive to ADL/IADL deficits. Conclusion: Both rubrics produced generally similar results when compared to the MoCA and adequately identified individuals needing further evaluation given reported functional problems. The CDIS produced more robust differences suggesting that it may be more appropriate for community screening to identify individuals in need of comprehensive cognitive and functional evaluation. [ABSTRACT FROM AUTHOR]

Background: Reduced injected doses in PET examinations result in lower radiation exposure, reduced acquisition times, reduced costs for institutions and ethically allow for additional scans within the same subject. Previous research has demonstrated that the injected dose of several different PET tracers can be reduced without substantial effects on quantitative outcome measures. Here, we studied the effect of reduced injected doses on signal‐to‐noise ratios (SNRs) and standardised uptake value ratios (SUVRs) for the FDA‐approved amyloid‐β (Aβ) PET tracer [18F]flutemetamol. Method: Thirty [18F]flutemetamol PET scans from previously classified Aβ‐positive and Aβ‐negative individuals were included in this study (Table 1). Amyloid positivity was derived using a validated centiloid pipeline. Subsets of the PET data containing 70%, 50%, 40% 30% and 20% of the total events was extracted randomly from the list‐mode data to generate sinograms and reconstructed using e7 tool. SUVRs were computed for a whole brain region‐of‐interest from an intracranial volume mask using whole cerebellum as a reference region. Reference and target ROIs were derived in MNI space. Next, group separation between Aβ‐positive (A+) and Aβ‐negative (A‐) using mean SNRs was computed using formula 1. Additionally, the differences in SUVR and SNR for true and the respective reduced injected dose were calculated. Group Separation= (meanA+ ‐ meanA‐)/(0.5√((SDA+)2+(SDA‐)2) (1) Result: Initial results (Table 2) show an absolute change in group separation from 0.65 to 0.62 (4.8% change) for original injected dose and a reduction of injected dose to 20% respectively. Whole cortical SUVRs changed by a maximum of 0.01 (<1% change) in both Aβ‐positive and ‐negative individuals. Figure 1 shows scans of a representative Aβ‐positive individual derived from true and different simulated reduced injected doses. Conclusion: Preliminary findings in our pilot sample suggest that lower injected tracer‐doses for [18F]flutemetamol yield robust SUVRs at injected doses as low as 20% of the original dose. We will report further validation in a larger dataset. In addition, a whole cortex region was used for SUVR derivation, and investigations of smaller ROIs will be added. The effect of scanner and reconstruction settings as well as the effect of reduced injected doses on separating Aβ‐positive from ‐negative individuals will be investigated. [ABSTRACT FROM AUTHOR]

Background: Positron emission tomography (PET) provides in vivo quantification of amyloid‐β (Aβ) pathology. The most common method for assessing PET is standardized uptake value ratio (SUVr), which can be affected by physiological and technical factors. Novel, data‐driven metrics have been developed to address these sources of variability. We evaluate cross‐sectional and longitudinal performance of four data driven metrics. Method: Three cohorts were used for evaluation: Insight 46, a neuroimaging sub‐study of the 1946 British birth cohort, Australian Imaging, Biomarker & Lifestyle Flagship Study of Ageing, and a test‐retest flutemetamol dataset (Table 1). Data from participants were included if good quality volumetric MRI and amyloid PET, using florbetapir (Insight 46) or flutemetamol (AIBL and test‐retest data), was available. No partial volume correction was applied. Four data driven metrics were extracted: the Centiloid derived from non‐negative matrix factorisation (CLNMF), the Aβ PET pathology accumulation index (Aβ‐index), amyloid load (Aβ‐load), and amyloid pattern similarity score (AMPSS). These data‐driven metrics were compared to a global composite SUVr, with either a pons (flutametamol) or cerebellar grey matter (florbetapir) reference region, and a Centiloid (CL) score. They were evaluated by measures of repeatability in test‐retest data, associations with non‐displaceable binding potential (BPND, computed from Logan graphical analysis), sample size estimates to detect a 20% slowing in Aβ accumulation with 95% significance and 80% power, and accuracy in predicting the second follow‐up visit. Result: All metrics show good to excellent reliability. The repeatability is highly influenced by the amyloid burden, the range, and the offset of each metric. (Table 1) All metrics are strongly correlated to the BPND (R2: 0.8 to 0.94), with SUVr and CL explaining more variance in BPND than the data‐driven metrics. (Figure) Sample size estimates were lowest in CL and CLNMF compared to the SUVr. (Table 2) The Aβ‐index had the best predictive power over ∼3 years while the other metrics were comparable. (Table 3) Conclusion: Novel data driven metrics provide comparable performance in terms of accuracy and performance to more established quantification methods of Aβ PET tracer uptake, but with additional benefits, such as being MRI‐free, reference region independent, or more robust to change in tracer. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) diagnostics is evolving rapidly, moving toward biomarker‐based diagnoses characterized by amyloid, tau, and neurodegeneration. To clarify benefits and risks of using this framework with cognitively unimpaired adults, particularly those from groups under‐represented in AD biomarker research, we developed a 30‐minute telephone survey to identify factors predicting willingness to enroll in biomarker studies and hypothetical disclosure‐related outcomes. Method: Existing scales were modified for telephone administration to assess experience/concern about AD, perceived health, health locus of control, brain health social norms, trust in medical research, and experiences of discrimination. Five hypothetical scenarios assessed willingness to participate in biomarker studies with or without results disclosure. Three open‐ended items provided qualitative data on willingness to participate and share results with others. Forty‐one items assessed reasons for learning results and potential reactions following a hypothetical elevated result. Descriptive statistics were used to evaluate response patterns. Thematic analysis of open‐ended items was conducted using an inductive coding method. Result: Cognitively unimpaired participants (N=334) included 148 Black/African Americans and 186 non‐Hispanic Whites; aged 45‐89; Table 1). Most participants had cared for someone with dementia (73%), desired to know if they will develop AD (82%) and trust medical research (mean RAQ‐7 = 30/35) (Table 2). Approximately 50% were very or extremely willing to participate in biomarker studies regardless of results disclosure; however, African Americans were less willing to participate if results were not disclosed. Common themes related to willingness to participate and learn results included wanting to know if at personal risk or to prevent/plan for AD and wanting to support science or help others. Misgivings/anxiety about knowing biomarker and concerns about invasiveness or lack of a cure for AD were common themes for those less willing (Table 3). Conclusion: This survey assesses AD‐relevant, health, and experiential factors, willingness to participate in biomarker research, and disclosure‐related outcomes. Initial results suggest understanding risk, prevention/planning behaviors, and helping others are reasons for participating and learning biomarker results. Results may also inform recruitment of African Americans into biomarker studies. Future analyses will investigate factors predicting potential positive (e.g., planning, risk‐reducing behavior) and negative (psychological distress/stigma) disclosure outcomes. [ABSTRACT FROM AUTHOR]

Background: The binding substrates of [18F]flutemetamol and [11C]PiB PET consist of fibrillar amyloid‐β (Aβ) aggregates in morphologically and structurally distinct diffuse plaques (DP) and cored plaques (CP) which are present at different proportions across brain regions in Alzheimer's disease (AD). To account for this heterogeneity, an unbiased quantitative measure integrating plaque size and density of amyloid‐β (Aβ) fibrils in plaques could help avoid false positive results, improve imaging‐to‐autopsy correlations, and further advance our understanding of pathological substrates for binding of amyloid PET tracers. Method: Sixteen subjects underwent [18F]flutemetamol PET imaging in the pivotal Phase III end‐of‐life study (Study GE067‐007 and GE067‐026) and later came to autopsy (mean imaging‐to‐autopsy interval was 111 ± 87.6 days). [18F]flutemetamol SUVRpons values in four neocortical regions were correlated with region‐matched postmortem measures of cyano‐flutemetamol labeling of all plaques, as well as CP and DP separately, using percent area coverage, mean grayscale intensity of fluorescence, or a combination of the two measures referred to as integrated density. Result: In the analysis of all cyano‐flutemetamol‐labeled plaques, [18F]flutemetamol SUVRpons values were more closely associated with integrated density measures than percent area coverage and mean grayscale values. Similarly, when CP and DP were analyzed separately, the integrated density values showed the closest association with neocortical region‐matched [18F]flutemetamol SUVRpons values. When area coverage of CP and DP were each expressed as a fraction of total plaque area coverage with or without integrating fluorescence intensity values, [18F]flutemetamol SUVRpons values within each region of interest were associated with the DP, but not the CP, area coverage measure. Conclusion: The association of antemortem [18F]flutemetamol PET and region‐matched postmortem integrated density measurements of cyano‐flutemetamol labeled plaques further supports the hypothesis that amyloid PET signal is influenced both by plaque size and Aβ fibril density within DP and CP. Further elucidating the relative contributions of each plaque type to the retention of amyloid PET radioligands could influence how a positive amyloid PET signal is interpreted in relation to postmortem pathology data. [ABSTRACT FROM AUTHOR]

Background: CSF biomarkers are well characterised as surrogate markers for amyloid deposition and neurofibrillary tau tangles reflecting pathological features of Alzheimer's disease. Amyloid PET images provide a visual and quantitative assessment of brain amyloid burden. In diagnostic workup these biomarkers are considered interchangeable, however their relationship is not fully understood. Methods: Centiloid (CL) values for 387 [18F]flutemetamol images from the Swedish BioFINDER I study were derived following the methods of Klunk et.al. (Alzheimer's & Dementia, 2015). Subjects, comprising Controls, SCD and MCI (Table 1), were ranked by Centiloid values (lowest to highest) and the average for each consecutive group of 30 subjects calculated. Corresponding CSF biomarker values (Aβ42/40 and pTau181) were plotted for each group. Results: Subjects in groups averaging ‐7.7 CL to 29.0 CL had a mean(±SD) Aβ 42/40 ratio of 0.144 (±0.033, range 0.051 to 0.236, n = 240) with no statistically significant differences between groups (Fig. 1A). A statistically significant fall in CSF Aβ42/40 ratio between the 29.0 CL and 47.3 CL groups (from 0.134 (±0.041, 0.066 to 0.236) to 0.088(±0.031, 0.045 to 0.183), p<0.0001) was observed. The average CSF Aβ42/40 ratio value for all subjects ranging from 66.3 Cl to129.8 CL was 0.072 (±0.017, 0.030 to 0.127, n = 117) with no statistically significant difference in CSF levels across these CL bands. Subjects in the groups averaging ‐7.7 CL to 29.0 CL had a mean(±SD) pTau181 value of 48.9 pg/mL (±15.9, 22 to 138) with no statistically significant difference between groups (Fig. 1B). A statistically significant (p<0.05) increase between 29.0 CL (47.3±19.3, 24 to 116 pg/mL) and 47.3 CL groups (67.8±29.4, 24 to 175 pg/mL) was observed. For all Subjects from 66.3 CL to129.8 CL mean pTau181 levels were 79.6 (±30.3, 32 to 209 pg/mL) with no statistically significant difference across these CL bands. Conclusions: Comparison of [18F]flutemetamol image quantitation and CSF biomarkers indicates CSF Aβ42/40 and pTau181 starts to show amyloid positivity at approximately 30‐40 CL units. Recent comparisons between visual rating and Centiloids from PET imaging indicate visual positivity from approximately 20 CL units indicating sensitivity of amyloid PET imaging for the detection of early amyloid deposition. [ABSTRACT FROM AUTHOR]

Background: The binding substrates of [18F]flutemetamol and [11C]PiB PET consist of fibrillar amyloid‐ß (Aß) aggregates in morphologically and structurally distinct diffuse plaques (DP) and cored plaques (CP) which are present at different proportions across brain regions in Alzheimer's disease (AD). To account for this heterogeneity, an unbiased quantitative measure integrating plaque size and density of amyloid‐ß (Aß) fibrils in plaques could help avoid false positive results, improve imaging‐to‐autopsy correlations, and further advance our understanding of pathological substrates for binding of amyloid PET tracers. Method: Sixteen subjects underwent [18F]flutemetamol PET imaging in the pivotal Phase III end‐of‐life study (Study GE067‐007 and GE067‐026) and later came to autopsy (mean imaging‐to‐autopsy interval was 111 ± 87.6 days). [18F]flutemetamol SUVRpons values in four neocortical regions were correlated with region‐matched postmortem measures of cyano‐flutemetamol labeling of all plaques, as well as CP and DP separately, using percent area coverage, mean grayscale intensity of fluorescence, or a combination of the two measures referred to as integrated density. Result: In the analysis of all cyano‐flutemetamol‐labeled plaques, [18F]flutemetamol SUVRpons values were more closely associated with integrated density measures than percent area coverage and mean grayscale values. Similarly, when CP and DP were analyzed separately, the integrated density values showed the closest association with neocortical region‐matched [18F]flutemetamol SUVRpons values. When area coverage of CP and DP were each expressed as a fraction of total plaque area coverage with or without integrating fluorescence intensity values, [18F]flutemetamol SUVRpons values within each region of interest were associated with the DP, but not the CP, area coverage measure. Conclusion: The association of antemortem [18F]flutemetamol PET and region‐matched postmortem integrated density measurements of cyano‐flutemetamol labeled plaques further supports the hypothesis that amyloid PET signal is influenced both by plaque size and Aß fibril density within DP and CP. Further elucidating the relative contributions of each plaque type to the retention of amyloid PET radioligands could influence how a positive amyloid PET signal is interpreted in relation to postmortem pathology data. [ABSTRACT FROM AUTHOR]

Background: CSF biomarkers are well characterised as surrogate markers for amyloid deposition and neurofibrillary tau tangles reflecting pathological features of Alzheimer's disease. Amyloid PET images provide a visual and quantitative assessment of brain amyloid burden. In diagnostic workup these biomarkers are considered interchangeable, however their relationship is not fully understood. Method: Centiloid (CL) values for 387 [18F]flutemetamol images from the Swedish BioFINDER I study were derived following the methods of Klunk et.al. (Alzheimer's & Dementia, 2015). Subjects, comprising Controls, SCD and MCI (Table 1), were ranked by Centiloid values (lowest to highest) and the average for each consecutive group of 30 subjects calculated. Corresponding CSF biomarker values (Aß42/40 and pTau181) were plotted for each group. Result: Subjects in groups averaging ‐7.7 CL to 29.0 CL had a mean(±SD) Aß 42/40 ratio of 0.144 (±0.033, range 0.051 to 0.236, n = 240) with no statistically significant differences between groups (Fig. 1A). A statistically significant fall in CSF Aß42/40 ratio between the 29.0 CL and 47.3 CL groups (from 0.134 (+0.041, 0.066 to 0.236) to 0.088(+0.031, 0.045 to 0.183), p<0.0001) was observed. The average CSF Aß42/40 ratio value for all subjects ranging from 66.3 Cl to129.8 CL was 0.072 (±0.017, 0.030 to 0.127, n = 117) with no statistically significant difference in CSF levels across these CL bands. Subjects in the groups averaging ‐7.7 CL to 29.0 CL had a mean(±SD) pTau181 value of 48.9 pg/mL (±15.9, 22 to 138) with no statistically significant difference between groups (Fig. 1B). A statistically significant (p<0.05) increase between 29.0 CL (47.3±19.3, 24 to 116 pg/mL) and 47.3 CL groups (67.8±29.4, 24 to 175 pg/mL) was observed. For all Subjects from 66.3 CL to129.8 CL mean pTau181 levels were 79.6 (±30.3, 32 to 209 pg/mL) with no statistically significant difference across these CL bands. Conclusion: Comparison of [18F]flutemetamol image quantitation and CSF biomarkers indicates CSF Aß42/40 and pTau181 starts to show amyloid positivity at approximately 30‐40 CL units. Recent comparisons between visual rating and Centiloids from PET imaging indicate visual positivity from approximately 20 CL units indicating sensitivity of amyloid PET imaging for the detection of early amyloid deposition. [ABSTRACT FROM AUTHOR]

Introduction: The association between cerebral amyloid‐β accumulation and downstream CSF biomarkers is not fully understood, particularly in asymptomatic stages. Methods: In 318 cognitively unimpaired participants, we assessed the association between amyloid‐β PET (Centiloid), and cerebrospinal fluid (CSF) biomarkers of several pathophysiological pathways. Interactions by Alzheimer's disease risk factors (age, sex and APOE‐ε4), and the mediation effect of tau and neurodegeneration were also investigated. Results: Centiloids were positively associated with CSF biomarkers of tau pathology (p‐tau), neurodegeneration (t‐tau, NfL), synaptic dysfunction (neurogranin) and neuroinflammation (YKL‐40, GFAP, sTREM2), presenting interactions with age (p‐tau, t‐tau, neurogranin) and sex (sTREM2, NfL). Most of these associations were mediated by p‐tau, except for NfL. The interaction between sex and amyloid‐β on sTREM2 and NfL was also tau‐independent. Discussion: Early amyloid‐β accumulation has a tau‐independent effect on neurodegeneration and a tau‐dependent effect on neuroinflammation. Besides, sex has a modifier effect on these associations independent of tau. [ABSTRACT FROM AUTHOR]

Background: The Centiloid method has been proposed to enhance the comparability of amyloid PET quantification across different amyloid tracers and to provide a reference metric. In this study, we first quantified the impact of reconstruction parameters on Centiloid values for different reference regions, then we evaluated the reduction of this source of bias after PET image harmonization. Method: A total of 71 cognitively unimpaired participants from ALFA+ cohort were included in this study. For each participant a 18F‐flutemetamol PET scan and a T1‐weighted MRI scan were acquired. A Hoffman 3D‐brain phantom filled with 0.5 mCi of 18F‐FDG was scanned in the same tomograph. Participant and phantom PET data were reconstructed with 4 different protocols used in the clinical and research settings (Table1). The reconstruction with the coarsest spatial resolution was selected as the reference. The remaining 3 were harmonized to yield the same effective spatial resolution using the protocol used in the ADNI study. All images were quantified with a validated Centiloid pipeline using an AAL composite and different reference regions (Whole Cerebellum, Cerebellar Gray, Pons and White Matter). The mean absolute difference in Centiloids (CL) between different reconstructions of the same scan was calculated using the coarsest resolution as reference. Differences below 2.5 CL were considered to be irrelevant based on published test‐retest data. Result: Respectively, Figures 1 and 2 show the Hoffman phantom and the amyloid PET scans before and after harmonization. While mean absolute differences were below the test‐retest threshold for the Cerebellar Gray and whole cerebellum, differences up to 9 CL were observed for the Pons (Table2). White matter as reference region showed the biggest sensitivity to reconstruction parameters and the bias was dependent on the amyloid load (Figure 3c). After harmonization differences were always below the test‐retest threshold. Conclusion: Reconstruction parameters impact the Centiloid values as a function of reference region. While the impact using Cerebellar gray and the Whole Cerebellum was minor, important differences were observed when using the pons and white matter as reference regions. In all cases, harmonization of the effective spatial resolution was able to bring these biases below the test‐retest threshold. [ABSTRACT FROM AUTHOR]

Background: The pathophysiological events associated with the earliest cerebral amyloid deposition are not fully understood. Here, we describe, in cognitively unimpaired individuals, the association between amyloid load and cerebrospinal fluid (CSF) biomarkers of the pathogenic events described in Alzheimer's disease (AD): core AD biomarkers (Aβ42/40 and pTau), synaptic dysfunction (neurogranin), neurodegeneration (neurofilament light [NfL]), microglial and astroglial‐related response (sTREM2, YKL‐40, GFAP, S100b), neuroinflammation (IL‐6) and α‐synuclein. Method: The first consecutive 293 participants of the ALFA+ study with both valid CSF biomarker determination and [18F]flutemetamol amyloid PET scans acquired within one year time were included. We measured the CSF biomarkers using the Roche NeuroToolkit robust prototype assays and the commercially available Elecsys® Phospho‐Tau CSF assay. Centiloid (CL) values and SUVr images were derived from [18F]flutemetamol scans using the whole cerebellum as reference region. We sought for correlations between CSF biomarkers and cerebral amyloid deposition both globally, using the Centiloids as outcome variable, and regionally, using a voxel‐wise approach. The final model used for both analyses included: main effects of all CSF biomarkers and also interaction effects between CSF biomarkers with age, sex and APOE‐ε4 status. Interactions were only included if they showed a trend effect (p<0.10) in the global analysis. Neurogranin and pTau were included in the model as a unique vector due to their high collinearity (r>0.9). Result: In the global analysis, pTau‐neurogranin, NfL, GFAP and YKL‐40 showed a positive correlation with global amyloid burden (Table 1). Significant interaction effects were found between: age*pTau‐neurogranin (older participants show higher amyloid deposition with higher pTau‐neurogranin); sex*sTREM2 (women with higher sTREM2 had higher amyloid deposition); APOE‐ε4*NfL (carriers with higher NfL had higher amyloid deposition) and APOE‐ε4*α‐synuclein (carriers with higher α‐synuclein had lower amyloid deposition), which are shown in Table 1 and Figure 1. Regional main effects are shown in Figure 2 while interactions are shown in Figure 3. Conclusion: Neurodegeneration and inflammation pathways are associated to early amyloid deposition. The fact that biomarkers of these pathways show interactive effects with the main AD risk factors (age, sex and APOE‐ε4) also suggests that they play different roles in the early stage of the Alzheimer's continuum. [ABSTRACT FROM AUTHOR]

Background: Unrecognized deficits in complex instrumental activities of daily living, termed "preclinical disability", have been identified in individuals experiencing mild cognitive impairment (MCI: Fieo & Stern, 2018; Peterson et al., 2017). Screening for difficulties in the performance of cognitively demanding complex IADLs may facilitate earlier identification of people on the threshold of MCI and can facilitate earlier intervention (Rodakowski et al., 2014). We examined the ability of three cognitive screening tests to identify individuals reporting IADL problems on the ADCS‐ADL‐MCI scale. Methods: A sample of 87 adults living independently in the community were assessed with the Menu Task, Mini‐Cog, Montreal Cognitive Assessment (MoCA), the ADCS‐ADL, and the 18 and 24 item versions of the ADCS‐MCI‐ADL scale. Established cut‐off scores for each cognitive screen identified impaired and unimpaired groups. Mann‐Whitney U tests compared differences between unimpaired and impaired groups for each cognitive screen on the 18 and 24 item ADCS‐MCI‐ADL composite scores. Between group differences were also examined for each of the ADCS‐MCI‐ADL‐24 individual items. Results: Sample demographics are presented in Table 1. Individuals impaired on the Menu Task had significantly lower composite scores on both the ADCS‐MCI‐ADL‐18 and the ADCS‐MCI‐ADL‐24 (p <.01), although no significant composite score differences were found for the Mini‐Cog (p =.061, p =.155) or the MoCA (p =.053, p =.099). Individual ADCS MCI items were also analyzed to explore the types of IADL impairments identified by each of the three cognitive screens scales. Different patterns of IADL impairment emerged for each of the cognitive screening measures. Individuals impaired on the Mini‐Cog had significantly lower ADCS‐ADL composite scores (p <.05). Conclusion: Individuals living in the community who score as impaired on the Menu Task demonstrated significantly lower ADCS‐MCI‐ADL‐18 and ADCS‐MCI‐ADL‐24 composite scores, but no significant difference on ADCS‐ADL. Impairment on each of the cognitive screening measures was associated with lower scores on individual ADCS‐ADL‐MCI complex IADL items. Cognitive screening measures that detect early and subtle changes in function may lead to earlier diagnosis and interventions for cognitively complex IADL deficits. [ABSTRACT FROM AUTHOR]

Background: Several reports have described higher gray matter volumes and glucose consumption in cognitively unimpaired individuals with abnormal amyloid biomarkers, typically interpreted to be caused by inflammatory or compensatory mechanisms. In this study, we investigated structural and metabolic differences in cognitively unimpaired individuals with mismatching amyloid cerebrospinal fluid (CSF) and PET biomarkers (CSF+/PET‐), thought to be the earliest detectable Alzheimer's disease (AD) pathologic change. Additionally, we investigated whether inflammatory CSF biomarkers could explain such differences. Method: In 302 cognitively unimpaired participants of the ALFA study, we measured CSF Aβ42/40, phosphorylated tau (p‐tau), total tau (t‐tau), neurofilament light (NfL), neurogranin, sTREM2, YKL40, GFAP, IL6, S100b and α‐synuclein using the exploratory Roche NeuroToolKit assays, a panel of robust prototype immunoassays (Roche Diagnostics International Ltd). Participants also underwent T1 MRI, [18F]flutemetamol amyloid PET, [18F]FDG PET and cognitive assessment (PACC). Amyloid PET was quantified with a validated pipeline to render Centiloid (CL) values. Individuals were classified into three groups: CSF‐/PET‐, CSF+/PET‐ and CSF+/PET+ using previously determined thresholds for positivity (Aβ42/40<0.071 and CL>30). Between‐group differences in Gray Matter volume (GMv) and [18F]FDG uptake were evaluated voxel‐wise with SPM12 (p<0.005, k>100) including age and sex as covariates. Additional models were implemented to measure possible mediation effects by inflammatory biomarkers (sTREM2, YKL40, GFAP, IL6, S100). Between‐group differences in cognition were also studied (p<0.05). Result: A total of 195 participants were CSF‐/PET‐, 82 were CSF+/PET‐ and 25 were CSF+/PET+ (Table 1). CSF+/PET‐ individuals displayed widespread higher GMv with respect to the reference CSF‐/PET‐ group as well as the CSF+/PET+ group (Fig. 1A). These differences were not mediated by inflammatory biomarkers. No significant between‐group differences were found in [18F]FDG uptake. PACC values were significantly higher in CSF+/PET‐ than the other groups (Fig. 1B) Conclusion: In cognitively unimpaired individuals, increases in GMv and cognitive functioning were observed in participants ]with abnormal amyloid CSF but PET negative. These increases could not be explained by measured neuroinflammatory CSF biomarkers. Even at the earliest stages of the AD continuum, factors enhancing resistance to amyloid plaque deposition might have a beneficial impact on cognition and could be used to inform prevention strategies. [ABSTRACT FROM AUTHOR]

Background: A lumbar puncture (LP) is required to study cerebrospinal fluid (CSF) based biomarkers in preclinical Alzheimer's Disease (AD). However, participants are often reluctant to undergo an LP due to fear. Insufficient data on the experiences of participants from underrepresented groups may contribute to their greater reluctance to agree to LP procedures, impacting diversity in AD studies. This analysis explores racial differences in intra‐procedural and post‐procedural complications rates. Methods: 870 LP procedures were performed on 606 participants in the Wisconsin Alzheimer's Disease Research Center, using a standardized technique with 24 or 25 gauge atraumatic needles. Up to 22 milliliters of CSF was obtained using gentle syringe aspiration of fluid. The clinician performing the procedure documented any intraprocedural complications experienced, including: headache, pain, vasovagal response, and radiculopathy. A follow‐up phone call the next day was used to assess any side effects following the procedure. Statistical analysis was performed using IBM‐SPSS version 27. Chi‐square tests were performed to compare complication rates between non‐Hispanic white, African American, and American Indian participants. Logistic regression analysis helped determine if BMI and waist‐to‐hip ratio also influenced complication rates. Results: Sample characteristics are shown in Table 1. LP success rates varied significantly by race (11.370, p=0.001). 90% of White, 77.5% of African American, and 66.6% of American Indian participants had a successful LP (Table 2); 61.1% of White, 48.8% of African American, and 52.4% of American Indian participants experienced zero complications (Figure 1). African American and American Indian participants experienced higher rates of total intraprocedural complications (9.642, p=0.022; 0.975, p=0.807 respectively). There was a significant group difference in reports of pain and headache during the procedure. However, few participants experienced any post‐procedural side effects. Overall, 5.5% experienced a headache and 8.5% experienced low back pain and no significant differences were seen between racial groups. Conclusion: LPs are relatively safe with limited intraprocedural complications and few post‐procedural side effects. These results can help re‐evaluate potential disparities, alter LP procedures, and provide accurate information to potential participants to increase recruitment and study diversity. [ABSTRACT FROM AUTHOR]

Background: Visual assessment of [18F]flutemetamol amyloid PET images, performed regionally (frontal, lateral temporal, posterior cingulate/precuneus, temporo‐parietal, striatum), is recommended, with a positive (abnormal) classification if any one of these regions is clearly positive. Changes in the striatum, known to contain extensive fibrillar amyloid deposits in AD, could identify likely converters in Subjective Cognitive Decline (SDC) or Mild Cognitive Impairment (MCI) subjects. CSF biomarkers are proven to detect abnormal amyloid metabolism in early stages of AD, with Aβ42/40 more reliable than Aβ42 alone. We applied a novel regional Centiloid Atlas, based on standard Centiloid (CL) cortical VOIs with additional striatal , aiming to better stratify amyloid abnormalities. Correlation between CL and Aβ42/40 was also investigated. Methods: The regional Centiloid atlas, developed by overlaying standard CL cortical VOI on AAL atlas and incorporating additional striatal regions, was applied to 394 [18F]flutemetamol subjects from the Swedish BioFINDER I study following the methods of Klunk et.al. (Alzheimer's & Dementia, 2015). In total, 387 Subjects with CSF Aβ42/40 information from the ADx analysis platform available, were included for analysis. Results: Average Aβ42/40 and CL values are presented (Table 1). Statistically significant differences in Aβ42/40 between control and MCI (p=0.0004), and SCD and MCI (p=0.0031) were observed (Fig. 1). Statistically significant differences in CL were also found in the cortical (p=0.007 or less) and striatal (p=0.028 or less) regions across all groups. Correlation between CL and Aβ42/40 for controls was moderate in both cortical (R2=0.35, Fig. 1) and striatal (R2=0.33, Fig. 2) regions. Similar correlations were found for SCD (Cortical: R2=0.52, Striatal: R2=0.48) and MCI (Cortical: R2=0.52, Striatal: R2=0.54). Conclusions: Standard Centiloid PET quantification provides global values across the cortical region. Identifying combined striatal differences in [18F]flutemetamol retention may provide additional information, aiding. Detecting these abnormalities and understanding their relationship to CSF biomarker changes may be useful in identifying those subjects for progression to AD. Further work to identify differences between cortical and striatal uptake in within subjects is ongoing. [ABSTRACT FROM AUTHOR]

Background: The Centiloid method enables direct quantitative comparison of amyloid‐PET scans acquired with different amyloid tracers. However, it does not explicitly model differences in image resolution which may have an impact on quantification, particularly in multicenter studies. This study evaluated the stability of the Centiloid scale with or without post‐processing smoothing to simulate distinct reconstruction settings. In addition, the effect of reference region selection was assessed. Methods: A total of 318 [18F]flutemetamol PET scans from the ADC and EMIF‐AD Twin 60++ cohorts are included in this study (Table 1). Scans were reconstructed with LOR‐Ramla algorithm. Additionally, images were smoothed to get an effective resolution of 8mm. All images were quantified with a validated Centiloid (CL) pipeline using the GAAIN cortical composite and five different reference regions (whole cerebellum, cerebellum gray, pons, whole cerebellum+brainstem and eroded white‐matter). To assess the impact of reconstruction settings on CL values, we calculated the mean absolute difference between CL values of the original reconstructions vs the smoothed images. Differences above 5CL were considered as relevant. Finally, Bland‐Altman plots were used to assess whether any proportional bias was present between these outcome measures. Results: Figure 1 displays image quality differences between local reconstruction settings and post‐smoothed images. CL values were not significantly affected by reconstruction methods using either whole cerebellum, whole cerebellum+brainstem, or white‐matter as reference region (Table 2). However, for the images with a higher level of amyloid, ΔCL was higher than 5 using whole cerebellum. On the contrary, the CL was highly affected by image resolution when using the pons as reference region, introducing constant bias for all ranges of amyloid burden. Using cerebellum gray, ΔCL has an inverse linear relationship with amyloid burden, though it was below 5CL for subjects with low to moderate amyloid burden, and differences above 5 were observed for images with CL above 80 (Figure 2). Conclusion: Whole cerebellum and whole cerebellum+brainstem, the standard reference regions in CL quantification, are capable of providing stable CL values irrespective of image resolution for a wide range of amyloid burden. Other reference regions were less stable. [ABSTRACT FROM AUTHOR]

Background: Childhood dementia is a devastating and under‐recognised group of conditions with a high level of unmet need. Typically monogenic in origin, this collective of neurodegenerative conditions are defined by a progressive impairment of neurocognitive function, presenting in infancy, childhood or adolescence. Method: We undertook a scoping review and burden of illness study to understand the spectrum of childhood dementia conditions and their impact. A literature review identified conditions that met the case definition and an expert clinical working group reviewed and ratified inclusion. Epidemiological data were extracted from published literature and collective incidence, prevalence and life expectancy were modelled. Result: Over 140 individual genetic conditions were identified that can be consistently defined as childhood dementia with the largest proportion of births belonging to the lysosomal disease and mitochondrial disease categories. Collectively the incidence is surprisingly high at 1 in 2,900 births and the life expectancy is low, with most affected children not surviving into adulthood. A relational database of the childhood dementia disorders has been created and will be continually updated as new disorders are identified (https://knowledgebase.childhooddementia.org/). Conclusion: This scoping review highlights the importance of grouping these conditions as a phenotypic syndrome, rather than individually rare diseases, in keeping with the approach to adult dementia. Opportunities exist to address overlapping disease mechanisms and utilise therapeutic platforms for multiple childhood dementia conditions to tap into significant economies of scale. Collaboration with adult dementia researchers on common disease attributes is also expected to be mutually beneficial. By unifying these conditions, we have highlighted the many unmet needs of this significantly disadvantaged group of children and young people and the data presented here will enable advocacy for systemic change in treatment, care, and support for them and their families. [ABSTRACT FROM AUTHOR]

Introduction: Reimbursement of amyloid–positron emission tomography (PET) is lagging due to the lack of definitive evidence on its clinical utility and cost‐effectiveness. The Amyloid Imaging to Prevent Alzheimer's Disease–Diagnostic and Patient Management Study (AMYPAD‐DPMS) is designed to fill this gap. Methods: AMYPAD‐DPMS is a phase 4, multicenter, prospective, randomized controlled study. Nine hundred patients with subjective cognitive decline plus, mild cognitive impairment, and dementia possibly due to Alzheimer's disease will be randomized to ARM1, amyloid‐PET performed early in the diagnostic workup; ARM2, amyloid‐PET performed after 8 months; and ARM3, amyloid‐PET performed whenever the physician chooses to do so. Endpoints: The primary endpoint is the difference between ARM1 and ARM2 in the proportion of patients receiving a very‐high‐confidence etiologic diagnosis after 3 months. Secondary endpoints address diagnosis and diagnostic confidence, diagnostic/therapeutic management, health economics and patient‐related outcomes, and methods for image quantitation. Expected Impacts: AMYPAD‐DPMS will supply physicians and health care payers with real‐world data to plan management decisions. [ABSTRACT FROM AUTHOR]

Background: When and how to communicate effectively the results of genetic and biomarker based prediction, detection, and quantification of the brain substrates of dementia involve important ethical and legal issues critical for precision medicine. The urgency of the issue has increased as People Living with Dementia (PLwD) and with Risk for Dementia (PwRD) can access direct to consumer genetic testing, amyloid targeting drugs, and clinical amyloid PET scans. To address the need for effective dissemination and consultation, an advisory group was convened that welcomes all interested members. Method: Members attend two meetings monthly via phone/computer/WebEx. One meeting is a targeted working group that focuses on the following: 1. Symptomatic (PLwD), 2. Asymptomatic (PwRD), 3. Research, 4. Ethics/Healthcare Law, 5. Trainee/Mentorship. These discussion groups hear from and present to stakeholders (PLwD/PwRD/caregivers, professional organizations, companies) to solicit feedback on the efficacy of their efforts. Members also attend a monthly "all hands" meeting where they receive updates from other groups and hear presentations on emerging research and resources. Result: The advisory group is composed of 104 members who represent advocacy/stakeholders (21%, e.g. professional organization representatives, (PLwD/PwRD/caregivers, FDA), academia (78%, e.g. university, funders, foundations), and healthcare law (1%). Professions include geneticists, genetic counsellors, researchers, clinicians, ethicists, and lawyers. Motivations for joining include improving communication in research and clinical contexts, mitigating potential negative impacts (e.g.emotional distress or discrimination), and protecting rights to know. Topics have included DTC genomics, the impact of APOE disclosure, genetics and personalized medicine, ecological momentary assessment of response to disclosure, and ethical issues in national and international research registries (EPAD). Activities included a survey on disclosure practices in NIA funded ADCs and collaborations with ADEAR. Stakeholders varied in concerns ranging from a need to protect patients from disclosure to a need to protect the right of access. Conclusion: Membership is increasing and is engaging diverse specialties and stakeholders who provide education and consultation around communication and use of genetic and biomarkers related to dementia. The group structure and inclusion of members from multiple organizations supports open and free collaboration. Future efforts will be developing structured education for stakeholders and publications. [ABSTRACT FROM AUTHOR]

Background: Weight loss is common in Alzheimer's disease (AD) and may start before cognitive impairment, but little is known about the relationship between weight change and AD biomarkers in the preclinical Alzheimer's continuum. We aimed to assess the association between weight change and AD biomarkers and cognitive performance in cognitively unimpaired (CU) adults from the ALFA+ study. Method: We analyzed data from 295 CU middle‐aged adults with two consecutive (mean interval 3.7 years) weight measures and neuropsychological assessments (n=267). Preclinical Alzheimer's Cognitive Composite (PACC) was computed as an average of z‐scores of episodic memory, semantic fluency and processing speed measures. We measured cerebrospinal fluid (CSF) levels of Aβ42, Aβ40, p‐tau, t‐tau, neurofilament light (NfL) and neurogranin using the Roche NeuroToolKit and Elecsys® immunoassays (n=280), and performed a [18F]flutemetamol PET scan in the follow‐up visit (n=252). PET results were dichotomized (Aβ positive or negative) based on visual read. Using established CSF cutoffs, we grouped participants in three biomarker categories: A‐T‐ (both Aβ and tau negative), A+T‐ (Aβ positive only) and A+T+ (both Aβ and tau positive). Linear and logistic regression and Kernel‐weighted local polynomial smoothing were used for analyses, which were adjusted by age, sex, body mass index, APOE genotype and years of education, as appropriate. Result: Weight loss predicted amyloid PET positivity (odds ratio 1.1, p=0.028) and was associated with significantly higher CSF levels of p‐tau (p=0.005), t‐tau (p=0.005) and neurogranin (p=0.002) (Table 1). Weight loss ≥5% (a standard cutoff for clinically relevant weight change) yielded 87% specificity and 30% sensitivity for amyloid PET positivity. Participants from the A+T+ group experienced significantly higher weight loss compared to A+T‐ (p=0.0029) and A‐T‐ (p=0.0005) groups (Figure 1). Weight loss was not associated with longitudinal changes in cognitive performance and preceded cognitive decline when using Aβ42/40 as a proxy of AD change progression (Table 1, Figure 2). Conclusion: Weight loss predicts amyloid PET positivity in CU middle‐aged adults. Our results suggest that weight loss is mainly related with changes in tau‐related and synaptic dysfunction biomarkers and may precede cognitive decline in the preclinical stage of the Alzheimer's continuum. [ABSTRACT FROM AUTHOR]

Background: Although a dichotomous and visual interpretation of amyloid PET is sufficient in clinical routine, regional image assessment may yield additional opportunities in the research setting. Understanding the regional‐temporal evolution of amyloid pathology may enable earlier pathological identification, as well as a more fine‐grained assessment of the extent and associated risk of amyloid pathology beyond traditional dichotomous measures. This multi‐study analysis of neuropathology and PET studies assessed the potential for the detection of regional amyloid deposition patterns and its utility for staging amyloid pathology in vivo. Method: A total of 15 studies (neuropathology and PET imaging based) have been included for review. First, an overall assessment of the similarities and discrepancies in the described ordering of amyloid pathology was performed in view of the methodological differences and limitations. Secondly, a multi‐tracer amyloid PET staging system was performed with a variety of cohorts to demonstrate the utility of such a methodology in comparison with traditional global dichotomous measures of pathology. The chosen system has been developed based on cross‐sectional PET data from 400 subjects (100 per tracer, including [11C]PiB, [18F]florbetapir, [18F]florbetaben, and [18F]flutemetamol), applied to >3000 scans and related to clinical and biological markers of Alzheimer's disease. Result: Although methodological discrepancies between studies need to be considered, it can be observed that 1) cortical generally precedes striatal accumulation, 2) medial neocortical regions are seen to accumulate amyloid earlier than lateral regions in PET studies (influenced by signal distortion), and 3) the placement of temporal regions in the pathological ordering is remarkably variable across studies (Figure 1). Multiple PET‐based staging systems have been successfully applied to various cohorts, but a multi‐tracer approach demonstrated that between‐tracer discrepancies influence the observed regional ordering and should be taken into account (Figure 2). Finally, PET‐based amyloid stage strongly relates to demographic and clinical measures, detects pre‐global amyloid burden, characterizes distinct levels of pathology beyond a CSF plateau phase, and predicts future cognitive decline (Figure 3). Conclusion: With modest agreement to neuropathology, models for staging amyloid pathology using PET imaging could improve subject selection into secondary prevention trials and potentially guide visual assessment in clinical routine. [ABSTRACT FROM AUTHOR]

Background: Determining the presence of amyloid pathology in vivo is possible by visual read (VR) and quantification. VR is the method of reference for clinically assessing amyloid pathology, and guidelines are based on distinguishing positive scans from Alzheimer's dementia patients from healthy controls negative scans. More quantitative approaches using cut‐off values also focused on identification of early amyloid pathology in preclinical populations. This study investigated whether a VR‐defined cut‐off would perform similarly to recently proposed Centiloid (CL) cut‐offs. Methods: [18F]flutemetamol PET images of 352 cognitively unimpaired (CU) participants from the ALFA+ and 145 patients from the ADC cohort were included (Table 1). Scans were read by an experienced reader according to the product guidelines, collecting the number of positive regions (0‐5) and the final positive/negative classification. Tracer uptake was quantified with the standard CL pipeline. Using VR as the reference standard, previously proposed CL=12/30 cut‐offs were tested for sensitivity and specificity. In addition, a data‐driven cut‐off was determined using ROC analysis and the Youden Index. Results: 152 (30.6%) scans were read as positive. The CL=30 cut‐off resulted in 80.3% sensitivity and 100% specificity, while the CL=12 cut‐off greatly improved the sensitivity to 95.2% and kept a high specificity at 95.9%. Based on the ROC analysis, a CL=16 cut‐off was found, with both excellent sensitivity (93.9%) and specificity (98.2%) (AUC of.99, 95% CI:.989‐.998) (Figure 1). Mean CL values significantly increased with increasing number of visually positive regions (F=568.10, η2=.85, p<.01, Figure 2, Table 2). Number of visually positive regions was related to age in the ALFA+ CU population (F=9.17, η2=.12, p<.01). Conclusion: Using VR as reference standard, we found a similar CL cut‐off to that proposed by previous work using independent amyloid biomarkers (post‐mortem and CSF). These results illustrate that CL can be as sensitive as VR to early amyloid pathology. Importantly, these results could (at least partially) be attributed the level of experience of the reader and the inclusion of mainly cognitively unimpaired subjects. In addition, our results suggests that it can be of value to visually capture the extent of amyloid burden in addition to negative/positive classifications. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the tolerability and safety of cannabidiol for treating drug-resistant epilepsy in children, and to describe adverse events associated with such treatment. Study design: Prospective, open label cohort study. Setting: Three tertiary NSW referral centres with paediatric neurology services. Participants: First 40 children enrolled in the NSW Compassionate Access Scheme for children with drug-resistant epilepsy and uncountable daily seizures. Intervention: Children received cannabidiol as an adjunct anti-epileptic drug, titrated to a maximum of 25 mg/kg/day, for up to 12 weeks. Outcome measures: Adverse events, withdrawals, and caregiver and physician Global Impression of Change assessments were recorded at 4, 8 and 12 weeks. Seizure frequency could not be reliably recorded because of disease severity. Results: Thirty-nine patients reported at least one adverse event; many were deemed unrelated to cannabidiol treatment. The most frequent treatment-related adverse event was somnolence (15 participants), which resolved spontaneously in ten patients; it was particularly frequent in patients taking higher clobazam doses. Gastrointestinal effects (nausea, vomiting, diarrhoea) were each reported by seven to nine participants. Four children were withdrawn from treatment, including one with elevated transaminase levels. The caregivers of 12 children felt the overall health of their children had much or very much improved; clinicians assessed seven children as being much or very much improved. Conclusion: Cannabidiol as an adjunct treatment had some subjective benefit for overall health, with a manageable adverse event profile. Monitoring changes in liver function and awareness of potential drug interactions is essential. Whether the reported benefit is attributable to cannabidiol cannot be established in an open label study of participants with severe intractable epilepsy. [ABSTRACT FROM AUTHOR]

Research is expanding for the use of cannabidiol as an anticonvulsant drug. The mechanism of cannabidiol in paediatric epilepsy is unclear but is thought to play a role in modulation of synaptic transmission. Evidence for its efficacy in treating epilepsy is limited but growing, with a single pharmaceutical company-funded randomised double-blind controlled trial in children with Dravet syndrome. Progress towards the use of medicinal cannabinoids incorporates a complex interplay of social influences and political and legal reform. Access to unregistered but available cannabidiol in Australia outside of clinical trials and compassionate access schemes is state dependent and will require Therapeutic Goods Administration approval, although the cost may be prohibitive. Further clinical trials are needed to clearly define efficacy and safety, particularly long term. [ABSTRACT FROM AUTHOR]

Background: The informed consent (IC) process offers an opportunity for researchers to promote participant autonomy and facilitate decision making. However, the traditional IC experience is often tedious, requiring study coordinators to present information in long IC documents. Paper IC documents can be difficult to understand and do not necessarily meet the needs of participants or study coordinators. The COVID‐19 pandemic underscores the need to provide an alternative to the in‐person, paper‐based IC process to minimize person‐to‐person contact. We worked with IRBs to revise how we engage and consent people in Alzheimer's Disease Research Centers at the University of Wisconsin‐Madison and Emory University. Method: In an ongoing effort to improve the IC process for adults at risk of developing memory and cognitive deficit, our team has been building and testing an electronic IC experience. We interviewed a total of 63 participants with a median age of 72. Participants underwent both the eConsent prototype and the paper consent. Seventy (70) percent of those participants preferred the eConsent over the traditional paper copy. We adapted into REDCap the electronic IC experience (eConsent). We collected input on the project from IRBs and study coordinators, and measured participant's understanding of key elements of the IC through questions distributed throughout the eConsent. Results: Each interested study participant received a unique link to the eConsent in REDCap. We observed which participants selected to review the eConsent information on their own, and which ones preferred to be guided remotely with the Study coordinators. We evaluated level of engagement with the eConsent and scored comprehension. The insights provided by this informed consent approach were used to determine whether it would be well suited for at‐home self‐administration across a diverse population. Conclusion: Study participants and study coordinators alike prefer an electronic consent process and participants retain information better as opposed to the typical paper consent form. While the REDCap consent survey is a temporary solution for our study team, it is a cost‐effective solution that facilitates a better experience for the participants. We believe that this REDCap eConsent could be a beneficial solution for the virtual recruitment and consent process at other ADRC sites. [ABSTRACT FROM AUTHOR]

Background: COVID19 forced cessation of in‐person recruitment accelerating reliance on social media and other communication strategies. New strategies are needed to reach healthy controls who are typically recruited outside of clinical settings. Engaging diverse communities is also a priority given the disproportionate burden of AD and related dementias. Understanding the general and differential appeal of recruitment messaging to diverse groups will facilitate more effectively tailored messaging. Methods: The Voices Heard Survey designed to identify factors associated with willingness to participate in biomedical research requesting biospecimens was administered to a diverse sample of 406 Wisconsin residents. Respondents include White (n=100), African American (n=105), Latino (n=100) and American Indian (n=101) adults. The 96 item survey assessed trust in medical research, along the continuum of study complexity and invasiveness relevant to AD studies, factors positively or negatively affecting willingness to participate in biomedical studies and clinical trials. Response frequencies indicated likelihood of participation were calculated for the full sample and by racial/ethnic group. Chi‐Square analyses were computed to determine significant differences across groups. Results: Sample characteristics are presented in Table 1. The factors most highly associated with willingness to volunteer for a study for the total sample were: Invited to Participate (85%), Research Goal (83%), Family Member with Disease (74%) and factors less likely to promote participation were: Share Results (48%), Paid for Participation (35%) and Transportation (34%) (see Figure 1). Significant differences were observed between the White and minority groups for the following factors: Black, Latino and American Indian respondents were: Significantly more likely to volunteer if asked by a a person of the same race (p<.0001), and more concerned than Whites about Disruption of work and family responsibilities (p<.001),Availability of transportation(p<.01), and If the results are used to help others (p<.01), and Childcare (p<.02). Remuneration for participation (p<.06) and sharing results with community (p<.07) approached significance. Specific priorities by racial and ethnic group will be presented. Conclusion: AD study recruitment requires strategic communication and innovative methods of reaching groups traditionally underrepresented in biomedical research. We identified information opportunities for tailored messaging designed to increase awareness of the value and opportunities afforded of research participation. [ABSTRACT FROM AUTHOR]

This paper is a discussion and elaboration of a paper by Prenner & al. (2010), entitled " Floral formulae updated for routine inclusion in formal taxonomic descriptions". The aim of the Prenner paper was to promote the use of floral formulae in botany and to reach a consensus among botanists for best practice. An important purpose of floral formulae is to induce users to observe and describe flowers accurately. It is proposed that additional information on anther, ovule, style and stigma should be included. Also, only visible organs should be included in a formula and theoretical speculations should be illustrated with floral diagrams, which are complementary to formulae, unless there is good reason to include absent organs. We propose a universal, standardized method to accurately shorthand a description of a flower. The level of detail given in the formula can be highly flexible and depends on the intentions of the user. [ABSTRACT FROM AUTHOR]

Background: Amyloid pathology can be detected using cerebrospinal fluid (CSF) biomarkers and positron emission tomography (PET) imaging, even though they measure two distinct beta‐amyloid (Aβ) pools. While CSF Aβ concentrations reflect the clearance of soluble amyloid species from the brain, PET imaging informs on the presence of insoluble fibrillary plaques in the brain tissue. Many studies have shown the concordance between the two measures in individuals along the Alzheimer's continuum. Here, we assessed whether APOE‐ε4, the major genetic risk factor for Alzheimer's disease (AD), affects the pattern of cerebral Aβ load as a function of CSF Aβ levels. Method: The first consecutive 276 cognitively unimpaired (CDR = 0) individuals of the ALFA+ study, aged between 48 and 74, with valid structural MRI and [18F]flutemetamol (FTM) PET, APOE genotyping and CSF samples were included. Aβ40 and Aβ42 concentrations were determined with the Roche NeuroToolKit (Roche Diagnostics) and parametric standardized uptake value ratio images (SUVr) were calculated with the whole cerebellum as reference region. A voxel‐wise regression was performed to predict FTM uptake, with the following independent variables: age, sex, APOE‐ε4, and CSF Aβ42/40 ratio. Statistical threshold was set to p < 0.001 with a cluster extent correction of 100 voxels. Result: As expected, CSF Aβ42/40 ratio was negatively associated with cerebral FTM uptake (Figure 1a‐1b). Age and APOE‐ε4 gene dose mapped onto distinct spatial patterns of FTM‐binding across the whole sample (Figure 2b‐2c). Importantly, we found a significant interaction between CSF Aβ42/40 and APOE‐ε4 indicating that carriers had a negative association between fluid and imaging Aβ measures in the bilateral hippocampus, as well as the bilateral middle temporal and temporo‐parietal junction (Figure 3). Conclusion: Compared to non‐carriers, APOE‐ε4 carriers showed higher cerebral Ab load for any given level of CSF Aβ42/40 in areas that are not typically vulnerable to Aβ deposition yet undergoing neurodegeneration early in the Alzheimer's continuum, such as the hippocampus. This suggests that APOE‐ε4 may influence the biological mechanisms regulating the equilibrium between soluble and deposited amyloid, which may transcend the hindering effect caused by Aβ fibrillary plaques and render medial temporal lobe structures particularly vulnerable when Aβ metabolism becomes deficient. [ABSTRACT FROM AUTHOR]

Background: Study partners are required for all ADC Clinical Core participants, they provide valuable information about cognitive and functional status of enrolled participants, which is essential for CDR ratings and documentation of perceived cognitive changes over time. Retention of participants and their SPs is essential for unbiased longitudinal data, yet little is known of SP attitudes and beliefs and how these attitudes influence missed visits or overall attrition. This mixed methods study identified SPs perceived barriers and facilitators related to participant retention in longitudinal ADC studies Method: Methods: A 57 item survey with 2 open ended questions was administered by telephone to randomly selected study partners (N=210) from four NIA funded Alzheimer's disease Centers. The Perceived Research Burden Assessment (PeRBA) was included in the survey. Respondents were 51% female, mean age was 72±8.6 (52‐92yrs), 92% were spouses. Response frequencies were computed for each item, open ended responses were transcribed, and thematically coded. Result: Study partners report high levels of trust in medical researchers (88%), high levels of altruism they believe their participation is valuable (96%) and society benefits from their research participation (98%). Low levels of overall burden were associated with ADC participation. Most negative attitudes were associated with travel (14%), inconvenience reaching the research center (15%) and length of study visits (17%). They also reported that their last LP (18%) and memory testing (19%) visits were difficult, with physical pain (13%) and fatigue (16%) as most common post‐assessment problems. A substantial number (83%) had difficulty keeping track of different study procedures. Only 37% reported being invited to participate in additional ADC‐sponsored studies. Thematic analyses identified common concerns/suggestions across ADC sites including: more frequent feedback and information about study results, evidence‐based caregiving advice, more complete disclosure of individual findings, better coordination and communication around multiple study visits and high praise for research staff. Conclusion: Study partners are critical to longitudinal retention of ADC participants. SP loss accounts for a significant proportion of missed visits or outright attrition. Changing study partners contributes to greater variability in longitudinal data. Our findings emphasize the importance of attending to the concerns of study partners in retention programs. [ABSTRACT FROM AUTHOR]

Background: There is a rising interest in machine learning for classification of images and lesions in medicine. A hurdle is the necessity for enough labeled cases based on an independent standard‐of‐truth. Here we applied linear support vector machine (SVM) to the phase 3 18F‐flutemetamol end‐of‐life study (GE067‐007), where 18F‐flutemetamol PET scans were available in close proximity to the time of autopsy and where brains were characterized in a standardized manner. Method: As our primary analysis, we trained a leave‐one‐out SVM to discriminate between normal vs abnormal cases based on Bielschowsky silver staining (BSS) (the primary outcome measure of GE067‐007). As a secondary analysis, we also trained a classifier to discriminate between Aβ (Thal) phase 0‐1 vs phase 5. The dataset contained 29 normal and 72 abnormal cases according to BSS SoT and 17 phase 0‐1 and 44 phase 5 cases. To avoid bias, the number of cases was equated between classes (29 per class for BSS and 17 per class for Aβ). Selection of cases per class was performed randomly 50 times. Result: Compared to the BSS SoT, the classifier had a sensitivity of 84% and a specificity of 90% (accuracy 87%) (Figure 1). Compared to Aβ phase, the sensitivity and specificity was, respectively, 97% and 100% (accuracy 98%). The three discordant BSS SoT normal cases, all had Aβ phase 3 or higher. Overall, highest feature weights were in striatum, middle frontal gyrus, precuneus, middle temporal, and cingulate. When we selected the voxels with the 10% highest amplitudes of feature weights (Figure 2) and re‐ran the analysis against the BSS SoT, performance increased to 95% sensitivity and 98.8% specificity. When we trained the algorithm to distinguish Aβ phase 4 (n=21) or 3 (n=14) from 0‐1, accuracy decreased to 88.8% and 71.9% respectively. In a further analysis, Aβ phase 3 vs 4 classification had an accuracy of 62.4% (95% CI 60.8, 63.9) and for phase 4 vs 5 an accuracy of 60.3% (95% CI 58.4, 62.1). Conclusion: This study shows that SVM is able to classify 18F‐flutemetamol scans in a binary manner (normal vs abnormal) which closely corresponds to the neuropathology measures. [ABSTRACT FROM AUTHOR]

Background: [18F]flutemetamol PET scanning provides information on brain amyloid load and has been approved for routine clinical use based upon visual interpretation of scans as either negative (equating to none or sparse amyloid plaques in pathology SoT), or amyloid positive (equating to moderate or frequent plaques). Quantitation is however fundamental to the practice of Nuclear Medicine and hence can be used to supplement amyloid reading methodology especially in unclear cases. Data was collected from multiple sources to assess comparability of the two methods of image interpretation. Method: 9 separate studies where visual reading of [18F]flutemetamol and quantitative analysis of images was available were combined to form a single cohort to measure the percentage agreement between the two methods of image interpretation. Scans covered a wide range of cases (eg from cognitively unimpaired subjects to patients attending the memory clinics see table). Methods of quantifying amyloid ranged from using CE marked/510K cleared software (eg Cortex ID), to other research tools (eg PMOD, CapAIBL) as well as newer methods such as AmyloidIQ. Concordance between visual and quantiative imaging used thresholds robustly established using pathology as the standard of truth Result: A total of 2,566 [18F] flutemetamol images were collected from 9 clinical studies, visually interpreted by readers using the approved reading methodology and compared to quantitative measures using thresholds which had a binary delineation of amyloid. The mean concordance between visual read and quantitation was 95.01% (SD 3.00%), the median was 95.0%, and the range of the 9 studies was from 89.7% to 99.0%. A total of 379 images were compared using CE marked/510k cleared amyloid quantitation software and the percent agreement in these studies was 98.8% to 99.0%. Conclusion: Given the high concordance of visual and quantitation from over 2500 scans, users are able apply quantitative amyloid PET software methods to supplement visual inspection. The decision to use these methods as an adjunct to visual reading is left to the choice of the physician as both methods of image interpretation are comparable. The European Medicines Agency (EMA) have agreed to update the prescribing instructions for [18F]flutemetamol (Vizamyl) based upon this analysis. [ABSTRACT FROM AUTHOR]

Background: Amyloid pathology can be quantified both in the cerebro‐spinal fluid (CSF) and in positron emission tomography (PET) images, even though they measure two distinct amyloid pools. While CSF Aβ reflects the clearance of soluble amyloid species from the brain, PET imaging informs on the presence of insoluble fibrillary plaques. Many studies have shown the concordance of the two measures in individuals along the Alzheimer's disease (AD) continuum. Here, we assessed whether APOE‐ε4, the major genetic risk factor for AD, affects the pattern of cerebral Aβ‐load as a function of CSF Aβ levels. Method: The first consecutive 276 cognitively unimpaired (CDR=0) individuals of the ALFA+ study, aged between 48 and 74, with valid structural MRI and [18F]Flutemetamol (FTM) PET, APOE genotyping and CSF samples were included. Aβ‐40 and Aβ‐42 concentrations were determined with the NeuroToolKit (Roche Diagnostics International Ltd.) on a Elecsys cobas e‐411 instrument and parametric standardized uptake value ratio images (SUVr) were calculated with the whole cerebellum as reference region. A voxelwise regression to predict FTM uptake was performed, with the following independent variables: Age, Sex, APOE‐ε4, and CSF Aβ‐42/40. Statistical threshold was set to p<0.001 with a cluster extent correction of 100 voxels. Result: As expected, CSF Aβ‐42/40 was strongly and negatively associated to cerebral FTM uptake (Fig. 1a‐1b). Age and APOE‐ε4 gene dose mapped onto distinct spatial patterns of FTM binding across the whole sample (Fig. 2b‐2c). Importantly, we found a significant interaction between Aβ‐42/40 and APOE‐ε4 indicating that carriers had a negative association between fluid and imaging Aβ measures in the bilateral hippocampus, as well as the bilateral middle temporal and temporo‐parietal junction (Fig. 3). Conclusion: Compared to non‐carriers, APOE‐ε4 carriers show higher cerebral amyloid load for any given level of CSF Aβ 42/40 in areas which are not typically vulnerable to Aβ deposition yet undergoing neurodegeneration early in the AD continuum, such as the hippocampus. This suggests that APOE‐ε4 may influence the biological mechanisms regulating the equilibrium between soluble and deposited amyloid, which may transcend the hindering effect caused by Aβ fibrillary plaques and render medial temporal lobe structures particularly vulnerable when Aβ metabolism becomes deficient. [ABSTRACT FROM AUTHOR]

Background: AMYPAD‐DPMS is the largest European, multicenter, prospective and randomized study assessing clinical utility and cost‐effectiveness of amyloid‐PET in a controlled but realistic clinical setting. In the present abstract we report preliminary results on the baseline features of the first study participants. Method: A total of 900 participants (300 with subjective cognitive decline plus [SCD+], 300 with mild cognitive impairment [MCI], and 300 with dementia) will be enrolled and randomized into 3 study arms: ARM‐1, amyloid‐PET performed early in the diagnostic workup; ARM‐2, amyloid‐PET performed late in the diagnostic work‐up; and ARM‐3, amyloid‐PET performed if and when the physician chooses to. Result: As of January 23rd 2020, 617 participants (154 SCD+, 303 MCI, and 160 dementia) have been enrolled from 8 centers. Baseline features are reported in Table 1. SCD+ participants are younger than MCI (p=0.006) and dementia (p<0.001) participants. SCD+ are more highly educated than MCI and dementia (p<0.001), and MCI are more highly educated that dementia (p=0.008). As expected, worse global cognition is observed in dementia (p<0.001) compared to MCI and SCD+, and in MCI compared to SCD+ (p<0.001). Among those who already underwent amyloid‐PET, 34% (30/88) of SCD+, 58% (90/155) of MCI, and 74% (60/81) of dementia patients were amyloid‐positive based on visual PET scan assessment. Conclusion: The socio‐demographic and cognitive features of the first 68% of AMYPAD‐DPMS participants are as expected for a memory clinic population, confirming the inclusion/exclusion criteria resulted in a representative sample. These results support the generalizability of the final study results. The end of participants' enrolment is expected by mid‐2020. [ABSTRACT FROM AUTHOR]

Background: Amyloid‐PET is increasingly used for diagnostic purposes in patients with cognitive impairment due to suspected Alzheimer's disease. However, cognitively unimpaired individuals are frequently included in research studies involving amyloid‐PET scan. Even if amyloid‐PET is not clinically recommended in these cases, these patients often want to know their amyloid status, a strong risk factor for incident dementia. Currently, evidence on the impact of the disclosure of amyloid‐PET results on patients' psychological well‐being is scanty. The aim of this sub‐study is to assess how a positive amyloid‐PET result affects the psychological well‐being of patients with subjective cognitive decline plus (SCD+) enrolled in a prospective study on the diagnostic utility of amyloid PET (AMYPAD‐DPMS). Method: The impact of the disclosure of amyloid‐PET results on patient's psychological well‐being was investigated using the Impact of Event Scale–Revised (IES‐R). IES‐R is used to detect potential changes from the current time point and a previous time point preceding up to 7 days an event (the amyloid‐PET result disclosure in this case). IES‐R was administered 1‐3 days post‐disclosure, and consists of one total score (0‐88) and three sub‐scores (0‐4): avoidance (avoidance of thoughts, feelings, memories or situations), intrusions (intrusive memories, thoughts, or feelings causing distress), and hyperarousal (hypervigilance, feeling watchful and on guard, difficulty concentrating). IES‐R total score between 12‐32: symptoms of post‐traumatic stress, patient monitoring is required; ≥33: probable presence of a post‐traumatic stress disorder. Result: So far, 36 SCD+ participants of AMYPAD‐DPMS, who received their amyloid‐PET results, have accepted to participate in this sub‐study. Amyloid‐positive patients (n=9) had higher IES‐R total score (median=10, lower‐upper quartiles=1‐14) than amyloid‐negatives (1, 0‐6), albeit at trend level (p=0.052). We also observed higher avoidance scores in amyloid‐positives compared to amyloid‐negatives (0, 0.00‐0.62 vs. 0, 0.00‐0.00, p=0.004), but no differences in the other two sub‐scores (p>0.05). Conclusion: These preliminary data on 36 participants suggests that the disclosure of positive amyloid scan to an SCD+ patient is associated with the avoidance of thoughts and memories of the news. Future analyses will address additional outcome measures (e.g. post‐disclosure anxiety and depression) and factors associated with a milder psychological impact in amyloid‐positive patients. [ABSTRACT FROM AUTHOR]