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In this paper, two complementary chemistry model reduction methods for combustion simulations are further developed and combined. A progress variable model (PVM), which follows the idea of trajectory generated manifolds (TGLDM), is tailored for describing auto-ignition in situations where the influence of molecular transport on chemical reaction is weak, like auto-ignition in media with weak scalar gradients. The other model using the reaction diffusion manifold approach (REDIM) is designed for situations where the interaction of chemistry with molecular transport is essential. The formulation of both models is discussed and implementational issues of each single model are given. Also, each model is tested in its respective range of applicability (quasi-homogeneous combustion under steady/unsteady physical boundary conditions for the PVM, combustion in fields with essential scalar gradients for REDIM). The coupling of the two models into a unified model, which covers combustion in both regimes and during the transitions between regimes, is discussed, based on the global quasi-linearization concept (GQL).

Introduction: As Alzheimer's disease (AD) biomarkers rapidly develop, tools are needed that accurately and effectively communicate risk of AD dementia. Methods: We analyzed longitudinal data from >10,000 cognitively unimpaired older adults. Five‐year risk of AD dementia was modeled using survival analysis. Results: A demographic model was developed and validated on independent data with area under the receiver operating characteristic curve (AUC) for 5‐year prediction of AD dementia of 0.79. Clinical and cognitive variables (AUC = 0.79), and apolipoprotein E genotype (AUC = 0.76) were added to the demographic model. We then incorporated the risk computed from the demographic model with hazard ratios computed from independent data for amyloid positron emission tomography status and magnetic resonance imaging hippocampal volume (AUC = 0.84), and for plasma amyloid beta (Aβ)42/Aβ40 (AUC = 0.82). Discussion: An adaptive tool was developed and validated to compute absolute risks of AD dementia. This approach allows for improved accuracy and communication of AD risk among cognitively unimpaired older adults. [ABSTRACT FROM AUTHOR]

Amyloid imaging plays an important role in the research and diagnosis of dementing disorders. Substantial variation in quantitative methods to measure brain amyloid burden exists in the field. The aim of this work is to investigate the impact of methodological variations to the quantification of amyloid burden using data from the Dominantly Inherited Alzheimer's Network (DIAN), an autosomal dominant Alzheimer's disease population. Cross-sectional and longitudinal [11C]-Pittsburgh Compound B (PiB) PET imaging data from the DIAN study were analyzed. Four candidate reference regions were investigated for estimation of brain amyloid burden. A regional spread function based technique was also investigated for the correction of partial volume effects. Cerebellar cortex, brain-stem, and white matter regions all had stable tracer retention during the course of disease. Partial volume correction consistently improves sensitivity to group differences and longitudinal changes over time. White matter referencing improved statistical power in the detecting longitudinal changes in relative tracer retention; however, the reason for this improvement is unclear and requires further investigation. Full dynamic acquisition and kinetic modeling improved statistical power although it may add cost and time. Several technical variations to amyloid burden quantification were examined in this study. Partial volume correction emerged as the strategy that most consistently improved statistical power for the detection of both longitudinal changes and across-group differences. For the autosomal dominant Alzheimer's disease population with PiB imaging, utilizing brainstem as a reference region with partial volume correction may be optimal for current interventional trials. Further investigation of technical issues in quantitative amyloid imaging in different study populations using different amyloid imaging tracers is warranted.

[This corrects the article DOI: 10.1371/journal.pone.0152082.].

Background: The balance between production, clearance, and toxicity of Ab peptides is central to AD pathobiology. Though highly variable in terms of age of symptom onset (AAO), hundreds of pathogenic variants in Presenilin‐1 (PSEN1) cause autosomal dominant forms of AD (ADAD). PSEN1 forms the catalytic core of the γ‐secretase complex and thereby directly mediates the production of longer, aggregation‐prone Aβ peptides relative to shorter, non‐aggregating peptides. We hypothesized that the broad AAO and biomarker heterogeneity seen across ADAD would be predictable based on mutation‐specific differences in γ‐secretase function, as measured by a ratio of production of shorter vs. longer Aβ species. Methods: Aβ‐37, 38, 40, 42, and 43 production was quantified from 162 unique PSEN1 variants expressed in HEK293 cells engineered to lack endogenous wild‐type PSEN1/2 (Figure 1). Prediction of AAO was carried out in 107 PSEN1 variants (characterized by Liu et al, 2022) and then replicated with a set 55 unique PSEN1 variants represented in the Dominantly Inherited Alzheimer Network (DIAN; n = 190 corresponding variant carriers with detailed cognitive and biomarker data; Figure 2). Results: Mutation‐level variations in Aβ production, including a novel composite representing γ‐secretase function (lower score = less g‐processivity), from the cellular model were highly predictive of actual AAO across the 162 mutants examined (Non‐DIAN variants [N = 107]: r = 0.71, p <2.2e‐16; DIAN variants [N = 55]: r = 0.61, p = 6.10e‐07). Our cell‐based γ‐secretase function composite was strongly associated with cerebral PiB‐PET β‐amyloid burden (B[SE] = ‐0.03[0.01], p = 4.06e‐07), MRI gray matter volume (B[SE] = 44.22[6.4], p = 5.15e‐01), cerebrospinal fluid Aβ42/40 (B[SE] = 6.3e‐04[1.5e‐04], p = 4.46e‐05) and phosphorylated tau‐217 (B[SE] = ‐0.01[0.002], p = 1.98e‐05), Clinical Dementia Rating®‐ Sum of Boxes (B[SE] = ‐0.07[0.02], p = 4.86e‐05), and Mini‐Mental State Exam (B[SE] = 0.11[.03], p = 2.17e‐04). Conclusions: Biochemical variations in γ‐secretase function across PSEN1 pathogenic variants broadly predicted the cross‐sectional clinical, cognitive, and biomarker course of ADAD, including AAO. These findings elucidate the critical link between γ‐secretase function, Aβ production, and severity of AD. The novel approach designed here also represents a tool to account for heterogeneity in ADAD clinical trials and to assess the pathogenicity of PSEN1 variants of unknown significance or with limited family history. [ABSTRACT FROM AUTHOR]

Background: Alzheimer disease (AD) is a slowly progressive neurodegenerative disorder characterized by the presence of amyloid plaques that can be measured in vivo with positron emission tomography (PET). PET quantifies the lifetime accumulation of amyloid plaques, while cerebrospinal fluid (CSF) biomarkers reflect the production and clearance of Aβ and tau peptides at time of CSF collection. Previous work has demonstrated a relative plateau of CSF values at higher levels of amyloid burden. Our objective was to identify the range of amyloid PET values predicted by CSF measures of tau phosphorylation, which have been found to be strongly associated with amyloid PET burden. Method: CSF was collected within two years of an amyloid PET scan from 417 (63 cognitively impaired) participants enrolled in studies of memory and aging at the Knight Alzheimer Disease Research Center (mean age 69.8 years, standard deviation 8.9 years). PET imaging was performed with Pittsburgh Compound B (PiB). CSF Aβ42, p‐tau181 and Aβ40 were measured with Lumipulse automated immunoassays. The CSF tau phosphorylation occupancies (percent of tau phosphorylated) at T111, T153, T175, T181, S199, S202, T205, S208, T217, and T231 were evaluated with an immunoprecipitation‐mass spectrometry (IPMS) assay. We applied a neural network to generate a simulated PET‐PiB scan and cortical summary estimates using the fluid biomarkers as modeled inputs. We used asymptotic regression to evaluate the range of amyloid PET values predicted by each CSF measure (Figure 1). Result: Combining fluid biomarkers generated a cortical amyloid burden estimate within 12.6% mean average percent error (MAPE). Four of the assessed fluid biomarkers individually generated estimates within 20% MAPE (Figure 2). Of these, CSF Lumipulse p‐tau181/Aβ42, pS208/S208 (%), and pT231/T231 (%) predicted amyloid PET burden up until a high level (3.08 SUVR/91.1 Centiloids; 3.01 SUVR/88.0 Centiloids; 2.79 SUVR/78.1 Centiloids, respectively) (Figure 3). CSF pT217/217 (%) also had high accuracy but a slightly lower prediction threshold (2.65 SUVR/71.8 Centiloids). Conclusion: CSF measures including phosphorylated tau predict amyloid PET over different ranges. Combining different measures of CSF tau phosphorylation can generate estimates of cortical amyloid burden. Future work will evaluate the prediction of tau PET by CSF measures. [ABSTRACT FROM AUTHOR]

Background: Obesity and adiposity at midlife, evidenced by high body mass index (BMI), are increasingly understood as a risk factor for Alzheimer's disease (AD). Importantly, visceral fat is known to be associated with insulin resistance and proinflammatory state, the mechanisms involved in AD pathology. Herein, we aimed to assess the association between brain MRI volumes as well as amyloid and tau uptake with obesity, insulin resistance, and abdominal adipose tissue in cognitively normal midlife population. Method: A total of 34 middle‐aged (age: 51.27 ± 6.12 years, BMI: 32.28 ± 6.39 kg/m2), cognitively normal participants, underwent bloodwork, brain and abdominal MRI, as well as amyloid and tau PET scan. Homeostatic Model Assessment for Insulin Resistance (HOMAIR) > 1.9 was used as a measure of insulin resistance. Visceral and subcutaneous adipose tissue (VAT, SAT) were semi‐automatically segmented using VOXel Analysis Suite (Voxa). FreeSurfer 7.1.1 was used for automatic segmentation of cortical and subcortical brain regions using a probabilistic atlas. Dynamic amyloid imaging was performed with a bolus injection of ∼15 mCi of [11C]PiB, followed by a 60‐min scan. A single intravenous bolus of between 7.2‐10.8 mCi of AV‐1451 was administered. Data from the 30‐60 minute, and 80‐100 minute post‐injection window for PiB and AV‐1451 were used for the analysis, respectively. The association of brain volumes and PiB and AV‐1451 SUVRs within the default mode network areas with BMI and VAT/SAT ratio were assessed using linear regression models. Result: We observed lower right entorhinal white matter volumes in obese participants with insulin resistance compared to metabolically normal non‐obese group (p = 0.004), without any significant difference in PiB or AV‐1451 SUVRs. Regression models with sex, age and education as covariates showed a significant positive association between VAT/SAT ratio and left precuneus white matter PiB SUVRs (R2 = 0.31, p = 0.005), but no significant associations with AV‐1451 SUVRs. Conclusion: In our midlife obese sample with insulin resistance, there were lower right entorhinal white matter volume, which is involved in relaying information to the hippocampus. We also demonstrate higher early amyloid pathology in AD‐signature areas such as the precuneus in mid‐life persons with high VAT/SAT ratio, a marker of visceral obesity. [ABSTRACT FROM AUTHOR]

Background: Studies suggest distinct differences in the development, presentation and longitudinal progression of Alzheimer's Disease (AD) between women and men. However, most of these sex‐specific differences have been explored in symptomatic stages of sporadic AD. We investigated cross‐sectional sex differences in clinical‐cognitive assessments as well as fluid and imaging biomarkers in the spectrum of dominantly inherited AD (DIAD). Method: 319 DIAD mutation carriers of the Dominantly Inherited Alzheimer Network‐Observational study (DIAN‐OBS) were included in the analysis and, according to Clinical Dementia Rating® (CDR®) scores, classified as presymptomatic (CDR = 0, 66,1%) or symptomatic (CDR>0). All participants underwent clinical and neuropsychological assessment; lumbar puncture, structural MRI and 11C‐PiB‐PET imaging for amyloid‐β detection were conducted. Mann‐Whitney‐U‐test, Fisher's Exact and linear mixed models with fixed effects for sex, estimated age of onset (EYO) and their interaction, a random effect for family, and years of education and CDR Sum of Boxes as covariates (where appropriate) were used to explore cross‐sectional sex differences. Result: Demographics showed no significant sex differences in presymptomatic (pMC, 56.4% women, p>0.05) or symptomatic mutation carriers (sMC, 52,7% women, p>0.05). In pMC, men showed a worse performance on the Digit Symbol test (p<0.01, Fig.1) than women, and, in interaction with EYO, a better performance in immediate (p<0.05) and delayed (p<0.05) prose recall. In contrast, sMC men performed better on the Animal Naming test (p<0.05), but, in interaction with EYO, worse on the Digit Span forward (p<0.01). CSF analysis did not indicate sex‐related differences in Aβ42/Aβ40‐Ratio, phosphorylated Tau‐181 or total Tau levels (all p>0.05) in either group. In pMC men, PET imaging revealed significantly less tracer binding in the medial orbitofrontal cortex, the frontal pole and the rostral & caudal anterior cingulate in interaction with EYO (all p<0.05, Fig. 2). Furthermore, MRI volume analysis showed a significant reduction in the amygdala in women compared to men (p<0.01) in sMC. Conclusion: We report preliminary results suggesting cross‐sectional sex differences in presymptomatic and symptomatic DIAD mutation carriers regarding episodic, verbal and working memory; processing speed; as well as differential patterns of PiB‐PET burden within cerebral areas related to emotion, decision making and cognitive flexibility. [ABSTRACT FROM AUTHOR]

Background: Imaging transcriptomics is a rapidly developing field that combines neuroimaging with genomics to study mechanisms that influence the organization and activity of the nervous system. Using whole‐brain microarray mRNA expression data from the Allen Human Brain Atlas (AHBA), we examined spatial gradients of gene expression in the brain. We then related these gradients to known spatial patterns of brain function. Method: We mapped regional mRNA expression data from more than 21,000 genes to the 200‐parcel Schaeffer atlas. Principle components analysis (PCA) was used to reduce the dimensionality of the data to ten principle components (PCs). This was done for all genes for the whole brain (WBExp) as well as those specific to Alzheimer Disease (ADExp). We additionally mapped eight other properties: functional connectivity gradients (Fig. 2A), myelin, cortical thickness, cerebral blood volume, cerebral blood flow, glucose consumption, and evolutionary expansion (Fig. 2B) to this atlas to explore their relationships with genetic patterns. Region weights from the PCs were predicted from these eight maps. Result: The majority of variance for both WBExp (Fig. 1A & 1C) and ADExp (Fig. 1B & 1D) expression was explained by three PCs. Functional connectivity gradients one (β = ‐0.38, β = 0.14), two (β = 0.33, β = ‐0.45), and five (β = ‐0.44, β = 0.32) were moderately related to the first PC of WBExp (Fig. 3A) and ADExp (Fig. 3C) expression patterns (p < 0.05), respectively. Cortical thickness (β = ‐0.32, β = 0.19), cerebral brain volume (β = 0.10, β = ‐0.13), cerebral blood flow (β = 0.42, β = ‐0.52), and evolutionary expansion (β = 0.08, β = ‐0.20) were additionally moderately related to the the WBExp PC1 (Fig. 3B, p < 0.05) and the ADExp PC1 (Fig. 3D, p < 0.05), respectively. Conclusion: Our results highlighted that gradients in genetic expressions are related to functional gradients seen using rs‐fMRI as well as biological properties such as cortical thickness, cerebral blood volume, cerebral blood flow, and evolutionary expansion. These findings shed light on mechanisms that influence the structure and function of the brain. Understanding the relationship between genetic patterns and these properties can give insight into healthy and diseased‐brain states such as Alzheimer disease. [ABSTRACT FROM AUTHOR]

Background: The Centiloid (CL) project was developed to harmonise the quantification of Aβ‐PET scans to a unified scale. The CL neocortical mask was defined using 11C‐PiB, overlooking potential differences in regional distribution among Aβ tracers. We created a universal mask using an independent dataset of 5 Aβ tracers, and investigated its impact on inter‐tracer agreement, tracer variability and group separation. Method: Using data from the ADOPIC study (AIBL, ADNI and OASIS3), age‐matched pairs of mild Alzheimer's disease (AD) (MMSE = 20‐24;CL>25) and healthy controls (MMSE> = 28;CDR = 0;CL<15) were selected: 18F‐Florbetapir (FBP:147 pairs), 18F ‐Florbetaben (FBB:22 pairs), 18F ‐Flutemetamol (FLT:10 pairs), 18F ‐NAV (NAV:42 pairs), 11C‐PiB (PIB:63 pairs). The PET images were smoothed to a uniform 8mm resolution to reduce the influence of different scanner sharpness on the derived masks. The images were then spatially normalised using the SPM CL pipeline and transformed into SUVR (whole cerebellum). For each tracer, the mean AD‐HC difference image was computed and mirrored. The threshold for each difference image was optimised to maximise the overlap with the standard CL mask. The Universal mask was defined as the intersection of all 5 masks. It was then used to recalibrate each tracer into Centiloids. The Universal mask and associated transforms were evaluated on the GAAIN head‐to‐head calibration datasets in terms of inter‐tracer agreement and variance in the young controls (YC). They were also evaluated on the baseline ADOPIC dataset (N = 3565) with the effect‐size between HC/AD and HC/MCI. Result: The overlap between each tracer specific mask was high (mean Dice = 0.82). The Universal mask was 26% smaller than the Standard one, but the overlap was high (Dice = 0.74). The Universal mask led to a small reduction in the variance of the YC in most tracers (‐3.4%) and a small increase in the R2 between each of the 11C‐PiB/18F‐tracer pairs (+0.24%). In ADOPIC, it led to a higher effect‐size between HC/AD (1.43 vs 1.42) and HC/MCI (0.71 vs 0.70). Conclusion: The universal CL mask led to an increase in inter‐tracer agreement and group separation. Those increases were however relatively small indicating that the existing standard CL mask is suitable for the quantification of all Aβ tracers. [ABSTRACT FROM AUTHOR]

Background: The Alzheimer's Association and Society for Nuclear Medicine and Molecular Imaging convened a Workgroup to update previous Appropriate Use Criteria (AUC) for amyloid PET (Johnson 2013) and develop the first AUC for tau PET. The AUC represent general guidelines and should not be considered a substitute for clinical judgment exercised in the care of individual patients. Method: The Workgroup included 14 researchers with multidisciplinary expertise. Meetings were held between June 2020 and August 2021. Key research questions were identified using the PICOTS framework, triggering an independent systematic literature review. Using established methods (Fitch 2001), the Workgroup identified 17 clinical scenarios in which amyloid/tau PET may be considered. Appropriateness of amyloid and tau PET as independent, stand‐alone modalities were ranked for each scenario using a 9‐point scale (Table 1). Consensus was achieved using a modified Delphi process. Online surveys were completed iteratively by Workgroup members, followed by discussion, until all votes for each scenario fell within one of the following categories: Appropriate/Uncertain/Rarely Appropriate. Result: As an over‐arching principle, amyloid/tau PET should be considered in patients who: (1) have undergone a comprehensive assessment by a dementia expert; (2) Alzheimer's disease (AD) is a diagnostic possibility but uncertainty remains; and (3) knowledge of amyloid/tau PET results is expected to help establish diagnosis and guide patient management. Consensus ratings for clinical scenarios are shown in Table 2. More evidence was available to inform recommendations for amyloid than tau PET. Amyloid PET was considered "Appropriate" to inform diagnosis of MCI or dementia due to suspected AD; clarify diagnosis when CSF biomarkers are equivocal; to inform prognosis in MCI; and to determine eligibility for amyloid‐targeting therapies. Tau PET was considered "Appropriate" to clarify diagnosis in patients with MCI/dementia under age 65 or those with atypical presentations; and to inform prognosis in MCI or dementia due to suspected AD. Conclusion: The updated AUC highlight a growing role for amyloid PET and an emerging role for tau PET in the clinical evaluation of cognitively impaired patients. AUC are expected to further evolve based on data from ongoing studies of clinical utility and a rapidly developing therapeutic landscape. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) blood tests are needed to aid in the evaluation of dementia, but the performance of these tests should be evaluated in diverse groups and real‐world settings. The goals of the Study to Evaluate Amyloid in Blood and Imaging Related to Dementia (SEABIRD) were to enroll 1120 participants to determine the participant acceptability and validity (relative to amyloid PET) of a plasma amyloid‐β 42/40 test in a diverse, community‐based sample of older adults, and explore the impact of important factors (age, race, education, cognition, APOE genotype, and medical conditions) on the blood test's performance. Method: SEABIRD measured plasma amyloid‐β 42/40 in a diverse population of older adults in the Saint Louis, Missouri, USA area. Participants completed a blood collection, cognitive screening (AD8® dementia screening interview and Montreal Cognitive Assessment [MoCA]), and a survey about their study experience and perceptions of the blood test. A subset of participants completed additional blood collection for reproducibility, amyloid PET and MRI for validation of the blood test, and the Clinical Dementia Rating® (CDR) for validation of the cognitive screening measures. Result: Of the 859 participants enrolled in this ongoing study, 20.6% self‐identified as Black or African American and the percentage of APOE ε4 carriers was 30.2% (Table 1). Compared to the general population, SEABIRD participants were more likely to be female, aged 70‐79 years, and highly educated. They were less likely to report high cholesterol, diabetes, kidney disease, and stroke, and more likely to report depression. The receiver operating characteristic area under the curve for distinguishing cognitively unimpaired (CDR = 0) from cognitively impaired (CDR>0) individuals was 0.72 for the informant‐rated AD8, 0.46 for the self‐rated AD8, 0.70 for the MoCA, and 0.79 for the AD8/MoCA composite (Table 2). Survey results indicated that the blood test was well accepted (Figure 1), but it was perceived more positively by white and highly educated individuals. Conclusion: A study of an AD blood test achieved rapid enrollment, broader diversity than typical AD cohorts, and high rates of participation. These results suggest that an AD blood test could be used for screening in a diverse clinical population. [ABSTRACT FROM AUTHOR]

The A/T/N classification system is the foundation of the 2018 NIA-AA Research Framework and is intended to guide the Alzheimer disease (AD) research agenda for the next 5–10 years. Driving is a widespread functional activity that may be particularly useful in investigation of functional changes in pathological AD before onset of cognitive symptoms. We examined driving in preclinical AD using the A/T/N framework and found that the onset of driving difficulties is most associated with abnormality of both amyloid and tau pathology, rather than amyloid alone. These results have implications for participant selection into clinical trials and for the application time of interventions aimed at prolonging the time of safe driving among older adults with preclinical AD.

Amyloid PET imaging is an indispensable tool widely used in the investigation, diagnosis and monitoring of Alzheimer's disease (AD). Currently, a reference region based approach is used as the mainstream quantification technique for amyloid imaging. This approach assumes the reference region is amyloid free and has the same tracer influx and washout kinetics as the regions of interest. However, this assumption may not always be valid. The goal of this work is to evaluate an amyloid imaging quantification technique that uses arterial region of interest as the reference to avoid potential bias caused by specific binding in the reference region. 21 participants, age 58 and up, underwent Pittsburgh compound B (PiB) PET imaging and MR imaging including a time-of-flight (TOF) MR angiography (MRA) scan and a structural scan. FreeSurfer based regional analysis was performed to quantify PiB PET data. Arterial input function was estimated based on coregistered TOF MRA using a modeling based technique. Regional distribution volume (VT) was calculated using Logan graphical analysis with estimated arterial input function. Kinetic modeling was also performed using the estimated arterial input function as a way to evaluate PiB binding (DVRkinetic) without a reference region. As a comparison, Logan graphical analysis was also performed with cerebellar cortex as reference to obtain DVRREF. Excellent agreement was observed between the two distribution volume ratio measurements (r>0.89, ICC>0.80). The estimated cerebellum VT was in line with literature reported values and the variability of cerebellum VT in the control group was comparable to reported variability using arterial sampling data. This study suggests that image-based arterial input function is a viable approach to quantify amyloid imaging data, without the need of arterial sampling or a reference region. This technique can be a valuable tool for amyloid imaging, particularly in population where reference normalization may not be accurate.

Key summary points: Aim: To describe the evidence on the usefulness of a Comprehensive Geriatric Assessment (CGA)-based approach during the COVID-19 pandemic. Findings: The multidimensional, CGA-based approach allows better identification of individual risk profiles and frailty status of infected, recovered but with a post-COVID-19 condition, and non-infected older adults. Message: Capturing older patients' needs through CGA may offer the possibility to guide clinical decision and implement personalized medicine. Purpose: The COVID-19 pandemic has been a dramatic trigger that has challenged the intrinsic capacity of older adults and of society. Due to the consequences for the older population worldwide, the Special Interest Group on Comprehensive Geriatric Assessment (CGA) of the European Geriatric Medicine Society (EuGMS) took the initiative of collecting evidence on the usefulness of the CGA-based multidimensional approach to older people during the COVID-19 pandemic. Methods: A narrative review of the most relevant articles published between January 2020 and November 2022 that focused on the multidimensional assessment of older adults during the COVID-19 pandemic. Results: Current evidence supports the critical role of the multidimensional approach to identify older adults hospitalized with COVID-19 at higher risk of longer hospitalization, functional decline, and short-term mortality. This approach appears to also be pivotal for the adequate stratification and management of the post-COVID condition as well as for the adoption of preventive measures (e.g., vaccinations, healthy lifestyle) among non-infected individuals. Conclusion: Collecting information on multiple health domains (e.g., functional, cognitive, nutritional, social status, mobility, comorbidities, and polypharmacy) provides a better understanding of the intrinsic capacities and resilience of older adults affected by SARS-CoV-2 infection. The EuGMS SIG on CGA endorses the adoption of the multidimensional approach to guide the clinical management of older adults during the COVID-19 pandemic. [ABSTRACT FROM AUTHOR]

Introduction: As knowledge about neurological examination findings in autosomal dominant Alzheimer disease (ADAD) is incomplete, we aimed to determine the frequency and significance of neurological examination findings in ADAD. Methods: Frequencies of neurological examination findings were compared between symptomatic mutation carriers and non mutation carriers from the Dominantly Inherited Alzheimer Network (DIAN) to define AD neurological examination findings. AD neurological examination findings were analyzed regarding frequency, association with and predictive value regarding cognitive decline, and association with brain atrophy in symptomatic mutation carriers. Results: AD neurological examination findings included abnormal deep tendon reflexes, gait disturbance, pathological cranial nerve examination findings, tremor, abnormal finger to nose and heel to shin testing, and compromised motor strength. The frequency of AD neurological examination findings was 65.1%. Cross‐sectionally, mutation carriers with AD neurological examination findings showed a more than two‐fold faster cognitive decline and had greater parieto‐temporal atrophy, including hippocampal atrophy. Longitudinally, AD neurological examination findings predicted a significantly greater decline over time. Discussion: ADAD features a distinct pattern of neurological examination findings that is useful to estimate prognosis and may inform clinical care and therapeutic trial designs. [ABSTRACT FROM AUTHOR]

This work applies Large Eddy Simulation (LES) to the combustion process within a CAI engine. The chemical reaction is treated with a pre-tabulation approach based on homogeneous reactor simulations. At this juncture, a five-dimensional chemistry database is employed where the thermo-chemical properties are a function of the unburnt gas temperature, the air–fuel ratio, the exhaust gas ratio, the pressure, and the reaction progress variable. Statistical quantities are gathered for 20 simulated cycles and the averaged pressure curves get compared to measurements. The simulation data are then used to provide further insight into the auto-ignition process. It will be shown how thermo-chemical states are distributed within the cylinder and how the ignition quality depends on them. A statistical analysis is conducted to identify manifolds in the multi-dimensional scalar space along which the conditions leading to ignition evolve. Furthermore the strong influence in between consecutive cycles caused by the exhaust gas is investigated to identify the mechanism of cycle-to-cycle variations.

BackgroundFalls and fall-related injuries pose a major threat to older peoples’ health, and are associated with increased morbidity and mortality. In the course of demographic changes, development and implementation of fall prevention strategies have been recognized as an urgent public health challenge. Various risk factors for falls and a number of effective interventions have been recognized. A substantial proportion of falls occur for people who are neither frail nor at high risk. Therefore, population-based approaches reaching the entire older population are needed. ObjectiveThe objective of the study presented is the development, implementation, and evaluation of a population-based intervention for the prevention of falls and fall-related injuries in a medium sized city in Germany. MethodsThe study is designed as a population-based approach. The intervention community is a mid sized city named Reutlingen in southern Germany with a population of 112,700 people. All community dwelling inhabitants 65 years and older are addressed. There are two main measures that are defined: (1) increase of overall physical activity, and (2) reduction of modifiable risk factors for falls such as deficits in strength and balance, home and environmental hazards, impaired vision, unsafe footwear, and improper use of assistive devices. The implementation strategies are developed in a participatory community planning process. These might include, for example, training of professionals and volunteers, improved availability of exercise classes, and education and raising awareness via newspaper, radio, or lectures. ResultsThe study starts in September 2010 and ends in December 2013. It is evaluated primarily by process evaluation as well as by telephone survey. ConclusionsPhysical activity as a key message entails multiple positive effects with benefits on a range of geriatric symptoms. The strength of the design is the development of implementation strategies in a participatory community planning. The problems that we anticipate are the dependency on the stakeholders’ willingness to participate, and the difficulty of evaluating population-based programs by hard end points.

BACKGROUND:Impaired balance is a major problem in patients with idiopathic Parkinson's disease (PD) resulting in an increased risk of falls and fall-related fractures. Most studies which analyzed the risk of femoral fractures in patients with idiopathic PD were performed either in specialized centers or excluded very frail patients. The current study used a large population-based dataset in order to analyze the risk of femoral fractures in patients with idiopathic PD. METHODS:Data from more than 880.000 individuals aged 65 years or older and insured between 2004 and 2009 at a large German health insurance company were used for the analyses. Persons with idiopathic PD were identified by the dispensing of Parkinson-specific medication and by hospital diagnoses, if available. People without PD served as the reference group. Incident femoral fractures were obtained from hospital diagnoses. Analyses were stratified by gender and information on severe functional impairment (care need) as provided by reimbursement claims. RESULTS:Compared with the reference group, persons with idiopathic PD had a more than doubled risk to sustain a femoral fracture. The risk was higher in men (HR = 2.61; 95%-CI: 2.28-2.98) than in women (HR = 1.79; 95%-CI: 1.66-1.94). The increased risk was only observed in people without severe functional impairment. The sensitivity analysis using a refined definition of idiopathic PD patients yielded similar results. CONCLUSION:The findings confirm the increased risk of femoral fractures in patients with idiopathic PD. The relative risk is particularly high in male PD patients and in patients without severe functional impairment.

The amyloid-β (Aβ) protein is diurnally regulated in both the cerebrospinal fluid and blood in healthy adults; circadian amplitudes decrease with aging and the presence of cerebral Aβ deposits. The cause of the Aβ diurnal pattern is poorly understood. One hypothesis is that the Amyloid Precursor Protein (APP) is diurnally regulated, leading to APP product diurnal patterns. APP in the central nervous system is processed either via the β-pathway (amyloidogenic), generating soluble APP-β (sAPPβ) and Aβ, or the α-pathway (non-amyloidogenic), releasing soluble APP-α (sAPPα). To elucidate the potential contributions of APP to the Aβ diurnal pattern and the balance of the α- and β- pathways in APP processing, we measured APP proteolytic products over 36 hours in human cerebrospinal fluid from cognitively normal and Alzheimer's disease participants. We found diurnal patterns in sAPPα, sAPPβ, Aβ40, and Aβ42, which diminish with increased age, that support the hypothesis that APP is diurnally regulated in the human central nervous system and thus results in Aβ diurnal patterns. We also found that the four APP metabolites were positively correlated in all participants without cerebral Aβ deposits. This positive correlation suggests that the α- and β- APP pathways are non-competitive under normal physiologic conditions where APP availability may be the limiting factor that determines sAPPα and sAPPβ production. However, in participants with cerebral Aβ deposits, there was no correlation of Aβ to sAPP metabolites, suggesting that normal physiologic regulation of cerebrospinal fluid Aβ is impaired in the presence of amyloidosis. Lastly, we found that the ratio of sAPPβ to sAPPα was significantly higher in participants with cerebral Aβ deposits versus those without deposits. Therefore, the sAPPβ to sAPPα ratio may be a useful biomarker for cerebral amyloidosis.

Background: Variants in the apolipoprotein E (APOE) gene represent the greatest genetic risk factor for Alzheimer disease (AD). Carriers of the ε4 allele have an increased risk of developing AD pathology and a lower age of symptom onset. While prior work has focused on the sporadic form of AD, little is known about how the ε4 allele impacts AD‐specific pathology in autosomal dominant AD (ADAD). Method: 430 participants from the Charles and Joanne F. Knight Alzheimer Disease Research Center and 276 ADAD mutation‐carriers from the Dominantly Inherited Alzheimer Network, were included in these analyses. Participants were classified as ε4‐positive or ‐negative, and further grouped using Clinical Dementia Rating® (CDR®) scores as cognitively impaired or –unimpaired (Table 1). All participants completed magnetic resonance imaging (MRI), beta‐amyloid positron emission tomography (Ab‐PET), and cognitive testing within a 12‐month period. Result: Using regression models, we replicated prior work demonstrating that the ε4 allele is associated with an increase in AD pathology measured by Ab‐PET and MRI in a sporadic AD cohort. Furthermore, the ε4 allele was also associated with a decline in cognitive performance. Follow‐up pairwise comparisons revealed that within the sporadic‐AD cohort, the influence of the ε4 allele was most pronounced in individuals who were cognitively impaired. In contrast, in a cohort of individuals possessing autosomal dominant mutations, the ε4 allele was not associated with increases in pathology measured by Ab‐PET and MRI, nor was it associated with a decrease in cognition (Table 1; Figure 1). Conclusion: We present quantitative evidence that the APOE‐ ε4 allele differentially impacts the pathology and cognitive outcomes of sporadic‐ and autosomal dominant AD. In those with sporadic AD, possession of at least one copy of the ε4 allele is associated with increased amyloid deposition and cortical thinning, as well as decreased cognition, particularly in individuals who are cognitively impaired. However, in ADAD mutation‐carriers, these same patterns are not evident. We propose that this is due to the overwhelming influence of the autosomal dominant genetic mutations that drive this unique and rare form of AD. [ABSTRACT FROM AUTHOR]

Background: Given the triplication of chromosome 21 and the location of the amyloid precursor protein gene on chromosome 21, almost all adults with Down syndrome (DS) develop Alzheimer disease (AD)‐like pathology and dementia during their lifetime. Comparing amyloid accumulation in DS to autosomal dominant AD (ADAD), another genetic form of AD, may improve our understanding of early AD pathology development. Method: We assessed amyloid positron emission tomography (PET) imaging in 192 participants with DS and 33 sibling controls from the Alzheimer's Biomarker Consortium‐Down Syndrome (ABC‐DS) and 265 mutation‐carriers (MC) and 169 familial controls from the Dominantly Inherited Alzheimer Network (DIAN) (Table 1). We calculated regional standard uptake value ratios (SUVR) using a cerebellar cortex reference region and converted global amyloid burden SUVR to centiloids. We compared amyloid PET by cognitive status and estimated‐years‐to‐symptom‐onset (EYO). EYO was calculated for DIAN participants by subtracting their age from parental age of symptom onset and for ABC‐DS participants by subtracting their age from 50.2 years, a published average age of symptom onset in a large sample of individuals with DS (Fortea et al., 2020). In a subset of participants, we assessed the relationship between amyloid PET and CSF Aβ42/40. Result: The relationship between CSF Aβ42/40 and amyloid PET was similar in DS and MC participants (Figure 1). We did not observe significant differences between MC and DS grouped by cognitive status (Figure 2). However, when assessed over EYO, global amyloid burden was significantly elevated in MC at EYO ≥ ‐23 but was not elevated in DS until EYO ≥ ‐15 (Figure 3). We observed early cortical and subcortical amyloid PET increases in both groups, but we also measured some regional differences in amyloid PET changes between MC and DS, specifically in the medial occipital region (Figure 4 and 5). Conclusion: These results demonstrate similarities in the relationship between amyloid biomarkers and the levels of amyloid accumulation in ADAD and DS. However, we also observed a 5‐10 year delay and some regional differences in amyloid accumulation in DS. This is important for future clinical trials to consider when recruiting participants and determining treatment efficacy. [ABSTRACT FROM AUTHOR]

Background: Binding of 18F‐Flortaucipir (FTP) has qualitatively been noted in the skull. We investigate the characteristics of this off‐target signal, as well as its impact on regional PET analyses. Method: FTP tau PET, 18F‐Florbetapir (FBP) amyloid PET, head CT, and T1‐weighted MR images were acquired for 313 cognitively unimpaired and impaired older participants. A subset (n=152) also received a 11C‐PiB PET scan. Another subset (n=14) received longitudinal FTP scans. MR images were segmented into ROIs using FreeSurfer and a skull ROI for each participant was defined from the head CT after removing non‐skull bone and tissue. Standard uptake value ratios (SUVRs) were calculated for all ROIs. Skull binding was correlated across FTP, FBP, and PiB to determine if binding is radioisotope specific. Longitudinal persistence of FTP skull signal was tested in the subset with longitudinal data. Finally, participants were grouped by amyloid positivity based on FBP and linear models controlling for age and sex predicted regional non‐partial volume corrected (non‐PVC) and PVC SUVR from skull SUVR to assess the regional impact of skull signal. Result: FTP skull binding was significantly correlated with both FBP (ρ=0.48, p<0.001, Figure 1A) and PiB (ρ=0.34, p<0.001, Figure 1B), suggesting the binding is not due to tracer defluorination. In the longitudinal subset, baseline SUVR was significantly correlated with follow‐up SUVR (Figure 2). Higher skull SUVR resulted in erroneously elevated regional SUVRs for areas in the frontal, parietal, and temporal lobes in amyloid negative individuals. After applying PVC, only medial temporal, inferior parietal, and lateral occipital continued to show significant positive relationships with skull SUVR (Figure 3). Decreased skull bone density was significantly related to higher skull SUVR in women but not men (see Figure 4). Conclusion: Skull signal from FTP is a stable, subject‐specific phenomenon that can persist across longitudinal visits and tracers. This off‐target signal can potentially bias quantitative PET measurements in AD tauopathy regions in amyloid negative but not positive individuals even after PVC is applied. The bone binding was overwhelmingly driven by women, suggesting at least some proportion of previously observed sex effects may be driven by bone uptake. [ABSTRACT FROM AUTHOR]

Introduction: Longitudinal changes in Alzheimer's disease (AD) biomarkers, including cerebrospinal fluid (CSF) analytes, amyloid uptakes from positron emission tomography (PET), structural outcomes from magnetic resonance imaging (MRI), and cognition, have not been compared between Blacks and Whites. Methods: A total of 179 Blacks and 1180 Whites who were cognitively normal at baseline and had longitudinal data from at least one biomarker modality were analyzed for the annual rates of change. Results: CSF amyloid beta (Aβ)42/Aβ40 declined more slowly (P =.0390), and amyloid (PET) accumulated more slowly (P =.0157), in Blacks than Whites. CSF Aβ42 changed in opposite directions over time between Blacks and Whites (P =.0039). The annual increase in CSF total tau and phosphorylated tau181 for Blacks was about half of that for Whites. Discussion: Longitudinal racial differences in amyloid biomarkers are observed. It will be important to comprehensively and prospectively examine the effects of apolipoprotein E genotype and sociocultural factors on these differences. [ABSTRACT FROM AUTHOR]

Introduction: Multiple positron emission tomography (PET) tracers are available for amyloid imaging, posing a significant challenge to consensus interpretation and quantitative analysis. We accordingly developed and validated a deep learning model as a harmonization strategy. Method: A Residual Inception Encoder‐Decoder Neural Network was developed to harmonize images between amyloid PET image pairs made with Pittsburgh Compound‐B and florbetapir tracers. The model was trained using a dataset with 92 subjects with 10‐fold cross validation and its generalizability was further examined using an independent external dataset of 46 subjects. Results: Significantly stronger between‐tracer correlations (P <.001) were observed after harmonization for both global amyloid burden indices and voxel‐wise measurements in the training cohort and the external testing cohort. Discussion: We proposed and validated a novel encoder‐decoder based deep model to harmonize amyloid PET imaging data from different tracers. Further investigation is ongoing to improve the model and apply to additional tracers. [ABSTRACT FROM AUTHOR]

In vivo quantification of β-amyloid deposition using positron emission tomography is emerging as an important procedure for the early diagnosis of the Alzheimer's disease and is likely to play an important role in upcoming clinical trials of disease modifying agents. However, many groups use manually defined regions, which are non-standard across imaging centers. Analyses often are limited to a handful of regions because of the labor-intensive nature of manual region drawing. In this study, we developed an automatic image quantification protocol based on FreeSurfer, an automated whole brain segmentation tool, for quantitative analysis of amyloid images. Standard manual tracing and FreeSurfer-based analyses were performed in 77 participants including 67 cognitively normal individuals and 10 individuals with early Alzheimer's disease. The manual and FreeSurfer approaches yielded nearly identical estimates of amyloid burden (intraclass correlation = 0.98) as assessed by the mean cortical binding potential. An MRI test-retest study demonstrated excellent reliability of FreeSurfer based regional amyloid burden measurements. The FreeSurfer-based analysis also revealed that the majority of cerebral cortical regions accumulate amyloid in parallel, with slope of accumulation being the primary difference between regions.