bluuebunny/crossref_metadata_2025 huggingface dataset:
Multigraph Cluster Analysis of AD Candidate Genes via Human Brain Mapping
Authors: Wu Ruiming Ray , Bao Jingxuan , Kim Mansu , Saykin Andrew J. , Moore Jason H , Shen Li ,   for the ADNI
Published: December 2022

Background

Brain imaging genetics examines associations between imaging quantitative traits (QTs) and genetic factors such as single nucleotide polymorphisms (SNPs) to provide important insights into the pathogenesis of Alzheimer’s diseases (AD). Given the high dimensionality, the individual level SNP‐QT signals typically have small effect sizes and are hard to be detected and replicated. To overcome this limitation, this work proposes a new approach to identify high‐level imaging genetic associations through applying multi‐graph clustering to SNP‐QT association maps.

Methods

Participants include 255 cognitive normal (CN) and 218 late mild cognitive impairment (LMCI) subjects from the ADNI data. Linear regression is performed to regress regional AV‐45 measures on each of the 54 AD SNPs to obtain a brain association map across 116 AAL‐ROIs. To quantify the similarity between each SNP pair, 5 scoring functions are used to calculate 5 different similarity measures between the respective brain maps of the two SNPs. Each scoring function yields a similarity graph of all 54 SNPs. Multigraph min‐max clustering is applied to 5 different graphs simultaneously to group similar SNPs together. Functional annotation is performed on each SNP cluster and the corresponding average brain association map to provide high level interpretations.

Results

Figure 1 shows the genetic effect on regional AV‐45 measures for each pair of SNP and ROI. The multi‐graph clustering result is shown in Figure 2, where 54 AD‐related SNPs are clustered into two groups. Figure 3a shows the results of Enrichr Elsevier pathway analysis. SNP group 1 is associated with pathways such as amyloid beta clearance, while SNP group 2 is associated with pathways including amyloid beta formation and APP processing in AD. Figure 3b shows the NeuroSynth annotation of the average brain effect maps associated with the two SNP clusters, respectively.

Conclusion

We proposed an approach that transforms individual level imaging genetic associations (SNP vs ROI) to high‐level associations (i.e., SNP cluster vs brain association map), and applied it to an LMCI study. These high‐level findings have the potential to provide valuable insights into relevant genetic pathways and brain circuits, which can help form new hypotheses for more detailed imaging and genetics studies in independent cohorts.
ACT‐AD: Fosgonimeton in mild‐to‐moderate Alzheimer’s disease – first results of a randomized, placebo‐controlled, 26‐week Phase 2 proof‐of‐concept trial
Authors: Moebius Hans J. , Bernick Charles B. , Winner Paul , Maalouf Joyce , Ooi Kai‐Bin , Dickson Samuel P. , Hendrix Suzanne B. , Church Kevin , Olichney John M.
Published: December 2022

Background

Fosgonimeton (ATH‐1017) is a positive modulator of HGF/MET, a key neurotrophic pathway impaired in Alzheimer’s disease (AD). Neuronal MET expression is decreased in the cortex and hippocampus, which may contribute to synaptic loss, neurodegeneration, and functional decline. ACT‐AD seeks to replicate and extend the previously shown improvement of event‐related potential (ERP) P300 latency in AD patients demonstrated in an 8‐day randomized, placebo‐controlled, double‐blind Phase 1 trial. ERP P300 latency is a noninvasive, objective, quantitative biomarker of cognitive performance without learning effects.

Method

ACT‐AD is a Phase 2, 26‐week, randomized, double‐blind, placebo‐controlled, parallel group trial in patients with a clinical diagnosis of mild to moderate AD. Patients enrolled were aged 55‐85 years, had a mini‐mental state examination (MMSE) score of 14‐24, a Clinical Dementia Rating global score of 1 or 2 at screening, a syndromal clinical diagnosis of probable AD according to McKhann et al. (Alzheimers Dement. 2011), and were treatment‐naïve or receiving stable acetylcholinesterase inhibitor therapy. Patients were randomized (1:1:1) to placebo or fosgonimeton at doses of 40 or 70 mg, administered subcutaneously once daily. The trial is powered for the primary endpoint, change in ERP P300 latency. Secondary endpoints include ADAS‐Cog11, ADCS‐CGIC and ADCS‐ADL23. The relationship of ERP P300 latency with cognition, memory and executive function, as well as pharmacokinetics, and safety will also be analyzed.

Result

In total, 77 patients with mild to moderate AD were randomized, with a mean (SD) age of 71.4 (7.3) years, 50.6% female, and mean (SD) baseline MMSE score of 19.5 (3.1). ApoE4 carriers made up 56% of the population, with 42% as noncarriers and 2% unknown.

Conclusion

The double‐blind period of ACT‐AD is ongoing and estimated to complete in May 2022, with results available in June 2022. First analyses will be presented at the annual 2022 AAIC congress.

This study is sponsored by Athira Pharma, registered at Clinicaltrials.gov: NCT04491006, and supported by a grant from the National Institute on Aging of the National Institutes of Health under Award Number R01AG06268.
Lexical markers from paragraph recall predict cognitive status
Authors: Park Seho , Roth Nicole , Cosentino Stephanie , Perls Thomas T. , Au Rhoda , Sebastiani Paola , Andersen Stacy L.
Published: December 2022

Background

Cognitive tests that require a spoken response, such as paragraph recall, are rich in cognitive‐related information that is not captured using traditional scoring methods. This study aimed to determine whether linguistic features embedded in spoken responses can differentiate between individuals who are and are not cognitively impaired.

Method

We used linguistic text analysis software (Linguistic Inquiry Word Count) to identify lexical and grammatical features from manually transcribed recordings of Logical Memory immediate (IR) and delayed recall (DR) from a subset (N = 169) of Long Life Family Study participants. We used regression models with Generalized Estimating Equations adjusted by age, sex, education, and within‐family correlation to select features associated with cognitive status (normal cognition [NC] versus cognitive impairment [CI]; threshold p<0.1). We developed a “polyfeature score” (PFS) for both immediate and delayed recall, each calculated as a weighted sum of the selected lexical features for each recall condition. We then built a logistic regression model to evaluate the predictive value of the PFSs for identifying cognitively impaired individuals.

Result

The sample included 133 participants with NC and 36 with CI (mean age = 75.8±11.7 years, 56% female). The regression identified 11 features for IR (e.g., percent of prepositions, words > = 6 letters) and 13 features for DR (e.g., percent of perceptual process words, percent of conjunctions) that significantly predicted cognitive status. Only 45% of features selected in IR were also selected in DR. Both PFSs were highly associated with cognitive status (PFS_IR β = 1.48, p < 0.001; PFS_DR β = 0.67, p = 0.001). The PFS yielded high discriminative value for cognitive status (PFS_IR AUC = 0.96, sensitivity = 0.73, specificity = 0.86; PFS_DR AUC = 0.90, sensitivity = 0.82, specificity = 0.86). Combining lexical features from both recall conditions did not increase the predictive value of the models.

Conclusion

Lexical features from immediate paragraph recall alone provide sufficient information for classifying cognitive status increasing its potential as a cognitive screener in clinical settings. Additionally, each recall condition identified unique lexical features associated with cognitive impairment which may help elucidate processes underlying deficits in learning and recall.
Scoping Review for Establishing an Effective Lifestyle Intervention Education Model
Authors: Kim Mi Kyeong , Park Kang‐Hyun , Park Sun Ha , Lee Ha Min , Park Hae Yean
Published: December 2022

Background

In order to face a socially healthy aging society, research on successful aging and lifestyles is being actively conducted. However, there are many studies reporting the positive effects of lifestyle interventions, but studies on educational models that ultimately train experts who perform lifestyle interventions are insufficient. Therefore, this study was conducted to prepare basic data for establishing an effective lifestyle intervention expert training model, suitable for the future domestic situation by analyzing lifestyle intervention expert training programs in progress at home and abroad.

Method

This study was conducted according to the five research stage of the scoping review suggested by Arskey and O'Malley. Through literature search, only programs that can clearly identify the educational purpose, target, method, and process were selected from among the lifestyle intervention specialist education programs conducted by 28 organizations that have established ties with the Lifestyle Medicine Global Alliance (LMGA).

Result

As a result of the study, six programs were selected. By country, the United States had the highest number of four, which had two cases of qualifications for education limited to medical, health, and health workers and other two cases of anyone interested could participate without any special restrictions. It was confirmed that 5 programs had an online‐based untacted education delivery method, and most of the educational contents were focused on physical activity, diet, mental health (sleep and stress management), and drug management.

Conclusion

This study confirmed the need to develop a new lifestyle intervention specialist education program. Therefore, based on the results of this study, it is considered that it is necessary to develop a new professional curriculum for multilateral lifestyle interventions with contents that can develop activity participation and digital literacy competency in consideration of the future domestic situation.
Conversations and decision‐making about nutrition and hydration for people with severe dementia in acute hospitals: a qualitative study
Authors: Anantapong Kanthee , Davies Nathan , Sampson Elizabeth
Published: December 2022

Background

In acute hospitals, care for nutrition and hydration for people with severe dementia is often suboptimal and requires shared decision‐making between family carers and hospital professionals. This study aims to gain an in‐depth understanding of the shared decision‐making process about nutrition and hydration from the perspectives and experiences of family cares and hospital professionals.

Method

Semi‐structured interviews were conducted with 29 participants (12 family carers and 17 hospital professionals). Data were analysed using thematic analysis.

Result

We identified five themes: 1) getting the decision‐making process started, 2) assessing the problems and exchanging information, 3) emotional‐ and value‐sensitive conversations, 4) making the decisions, and 5) discharge planning and post‐discharge support. Overall, eating and drinking decisions for an individual with severe dementia required person‐centred care and a best‐interests decision‐making approach. Decision‐making in acute hospitals was demanding and often poorly supported. Due to the busy environment and rapid staff rotation, hospital professionals might make assumptions about the individual’s ability to eat and drink and adapt their eating and drinking without adequate consultations with family carers. Most hospital professionals wanted to gather information about the overall dementia progression before talking to family carers. This can be perceived as delaying by family carers. The decisions required a multidisciplinary team approach, which was not regularly used. Poor sharing of information meant family carers often felt confused and frustrated to repeat conversations with different professionals and needed to act as information coordinators in the acute hospitals. Different approaches across hospital wards and professionals made the decisions and conversations even more confusing. Most participants perceived artificial nutrition and hydration as not beneficial for the individual, but temporary uses of intravenous fluids and nasogastric tubes might be unavoidable for very specific situations. Decisions and conversations should cover post‐discharge support and advance care plans to prevent readmission.

Conclusion

Family carers and hospital professionals often found the conversations and decisions about eating and drinking difficult and insufficiently supported in acute hospitals. A multidisciplinary team approach, clear procedures and better information support may improve the decision‐making processes to enhance the person‐centred care and best‐interests decision‐making for the individual with severe dementia.
Blood‐based biomarker prescreening in the SKYLINE secondary prevention study with gantenerumab
Authors: Rabe Christina , Bittner Tobias , Mertes Michaela , Riley Kellie , Jethwa Alexander , Schrurs Isabelle , Babitzki Galina , Stomrud Erik , Palmqvist Sebastian , Sperling Reisa A. , Aisen Paul , Rissman Robert A. , Masters Colin L , Fontoura Paulo , Ostrowitzki Susanne , Hansson Oskar , Doody Rachelle S.
Published: December 2022

Background

SKYLINE is a new secondary prevention study in Alzheimer's disease (AD) enrolling amyloid‐positive, cognitively normal individuals at risk for clinical AD between 60 and 80 years and treating them with gantenerumab or placebo for 4 years. Based on available data from other studies, we expect only 15% of individuals to be amyloid‐positive in this screening population. We developed a blood‐based biomarker (BBBM) prescreening test to screen out participants who have a low likelihood of amyloid positivity by positron emission tomography (PET) or cerebrospinal fluid (CSF) testing before entering the main screening of SKYLINE.

Method

We explored multiple individual key AD BBBMs (measured with Elecsys® prototype assays) and combinations in three large cohorts (BioFINDER‐1, AIBL, A4) of cognitively unimpaired and subjective cognitive decline/mild cognitive impairment participants. We used predefined thresholds for amyloid PET and/or CSF pTau/Abeta42 as the reference standard for amyloid positivity. The performance of the BBBM was assessed by evaluating the positive and negative predictive value (PPV and NPV) for amyloid positivity, and screen‐out proportions based on a range of potential thresholds. Those metrics were translated into the total number of participants that need to be screened and the reduction of the number of participants that need to be screened with PET or CSF testing to reach the target sample size.

Result

We identified a combination of two key AD biomarkers expected to enable a high NPV at moderate PPV, screening out 40–50% of participants, amongst whom are only 3–5% true amyloid positives (falsely ruled out). This BBBM prescreening would reduce the need for PET or CSF testing by 40% while requiring screening of 8% more participants to compensate for the wrongly excluded amyloid positives.

Conclusion

The implementation of Elecsys® blood‐based prescreening in SKYLINE will significantly reduce site and participant burden, accelerate the study enrollment, and save screening costs by reducing unnecessary downstream screening assessments such as cognitive batteries, magnetic resonance imaging, and PET or CSF testing.
Underlying clusters of NIA‐AA Research Framework stage 2 criteria and their relationship with AD biomarkers in the DELCODE study
Authors: Sannemann Lena , Meiberth Dix U. , Schild Ann‐Katrin , Bürger Katharina , Heneka Michael T. , Christoph Laske , Perneczky Robert , Peters Oliver , Priller Josef , Schneider Anja , Spottke Annika , Teipel Stefan , Wiltfang Jens , Wolfsgruber Steffen , Wagner Michael , Duzel Emrah , Jessen Frank ,   DELCODE Study Group
Published: December 2022

Background

As part of the updated NIA‐AA Research Framework for Alzheimer’s disease (AD), a numeric clinical staging scheme, applicable only to individuals in the Alzheimer’s continuum, has been introduced. “Stage 2” is defined as a transitional stage, characterized by subtle or subjective decline in cognition or neuropsychiatric symptoms (NPS) that might reflect underlying AD pathology (Jack et al., Alzheimers Dement. 2018). Here, we aimed to cluster a sample of cognitively healthy participants based on stage 2 criteria and compare the emerging clusters with regard to differences in CSF biomarker status.

Method

For this analysis, we included baseline data of N = 349 cognitively healthy participants with available CSF biomarker information from the DZNE Longitudinal Cognitive Impairment and Dementia (DELCODE) study. A two‐step cluster analysis (TSCA) was applied based on CSF Aß42/40 status and stage 2 criteria, which included a) subtle objective cognitive impairment (<0.5SD) in any of five factor scores from DELCODE’s neuropsychological test battery, b) subjective cognitive decline (SCD) with concern in any of the five SCD‐Interview domains and c) the presence of agitation, depression, anxiety, disinhibition, irritability or sleep disturbances on the Neuropsychiatric Inventory Questionnaire [NPI‐Q]. The TSCA identifies the optimal number of clusters by grouping cases into preclusters first and then clustering those using a hierarchical algorithm.

Result

The TSCA yielded three clusters. Cluster 1 (n = 114) was characterized by subtle cognitive impairment in memory, language, executive function and working memory as well as SCD in the memory and language domain. In contrast, cluster 2 (n = 104) was predominantly formed by participants that reported SCD and NPS without subtle objective impairment. In cluster 3 (n = 121), none of the stage 2 criteria were prominent. In comparison to clusters 2 and 3, participants in cluster 1 had lower levels of Aß42/40 (H(2) = 11.58, p = .003) and Aß42/ptau‐181 (H(2) = 12.06, p = .002). We observed no significant differences between clusters 2 and 3.

Conclusion

Our analysis resulted in three distinct clusters of cognitively healthy participants with different distributions of stage 2 criteria. The criteria prominent in participants of cluster 1 seem most promising to identify individuals at risk of progression due to underlying AD pathology.
The impact of COVID‐19 restrictions after one year on modifiable risk factors related to brain health in older adults in The Netherlands
Authors: Waterink Lisa , Bakker Els D. , Visser Leonie N.C. , Mangialasche Francesca , Kivipelto Miia , Deckers Kay , Köhler Sebastian , Sikkes Sietske A.M. , Prins Niels D. , Scheltens Philip , van der Flier Wiesje M. , Zwan Marissa D.
Published: December 2022

Background

COVID‐19‐restrictions impact the lifestyle and mental health of people, which then might affect brain health and increase risk of cognitive decline particularly in older adults. Thereby, COVID‐19 might indirectly contribute to cognitive decline. We aimed to investigate changes in modifiable risk factors related to brain health in older adults after one year of COVID‐19‐restrictions.

Method

An online questionnaire was disseminated between February and March 2021 to registrants of the Dutch Brain Research Registry, aged ≥50, without a self‐reported diagnosis of mild cognitive impairment or dementia. Participants reported potential changes in behaviors during COVID‐19 pandemic concerning modifiable risk factors in eight domains (physical activity, sleep, memory, stress, feeling of loneliness, diet, alcohol consumption and smoking) compared to before the COVID‐19‐outbreak. We counted the number of reported detrimental and beneficial changes, and used multiple regression analyses to relate (socio)demographics, subjective memory complaints and COVID‐19 related aspects to increasing number of reported detrimental and beneficial changes, separately.

Result

3943 participants (66±8 years old, 76% female) completed the questionnaire. After one year of COVID‐19‐restrictions, 74% reported one or more detrimental changes and 60% reported at least on beneficial change. More specifically, participants reported more often detrimental changes for loneliness, sleep, physical activities, stress, memory complaints and smoking, while beneficial changes were more often reported for diet and alcohol consumption. More detrimental changes was associated lower age, (B = 0.02; 95%confidence interval = ‐0.03‐ ‐0.01), female sex (0.28;0.15–0.41), living alone (0.35;0.22–0.48), the presence of subjective memory complaints (0.69;0.54–0.84), a current or past COVID‐19 infection (0.35;0.14–0.56) and a fear of a COVID‐infection (0.54;0.42–0.65). In addition, those who were less satisfied with their income were more likely to report more detrimental changes (0.66;0.34‐1.00). More beneficial changes were only associated with female sex (0.16;0.06‐0.27).

Conclusion

The COVID‐19 pandemic appears to have a differentially impact on older adults in the Netherlands, with people who are relatively younger, female, living alone, experiencing subjective memory complaints and those with a past or current or fear of a COVID‐19‐infection seem more vulnerable for more detrimental changes in modifiable risk factors related to brain health. Thus providing an opportunity for targeted prevention and health education.
Evaluating the sensitivity of Centiloid quantification to pipeline design and image resoloution
Authors: Shekari Mahnaz , García David Vállez , Collij Lyduine E. , Heeman Fiona , Roé‐Vellvé Núria , Bullich Santiago , Buckley Christopher , Barkhof Frederik , Farrar Gill , Pemberton Hugh , Gispert Juan Domingo ,   the AMYPAD consortium
Published: December 2022

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.

Method

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)

2 target VOI (standard GAAIN vs subject‐based)

2 reference region type (standard GAAIN vs subject‐based)

2 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.

Result

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.
Mechanisms by which culturally‐informed narratives may promote ADRD research enrollment among African American adults
Authors: Lingler Jennifer H , Ren Dianxu , Cameron Judy L , Knox Melissa L , Mbawuike Uchenna J , Robinson Renã AS , Terry Melita H , Tamres Lisa K , Williams Ishan Canty
Published: December 2022

Background

Insufficient racial and ethnic diversity is a pervasive challenge in clinical research on Alzheimer’s disease (AD). The Recruitment Innovations for Diversity Enhancement (RIDE) in AD research study is grounded in the premise that culturally informed narratives of research participation can inspire other individuals from a given culture‐sharing group (in this case, African Americans) to consider enrolling in research. RIDE involved developing and disseminating narrative materials to share the research participation experiences of African American adults who are enrolled in AD research with those who are not. The current analysis aims to examine factors associated with interest in AD research following exposure to RIDE narrative campaign materials.

Method

A community‐based sample of 500 individuals, primarily in mid to late life, identifying as Black or African American adults were invited to view a RIDE study video (∼2 minute story of AD research participation) online and complete a survey of perceptions about research and researchers, AD risk, and likelihood of enrolling in AD research. Logistic regression models were used to identify predictors of self‐reported likelihood of participating in AD research and potential mediators were tested to examine the causal pathway between predictors and likelihood of enrollment.

Result

Most (n = 376; 72%) participants reported interest in being contacted to learn more about local AD research opportunities. After controlling for demographic variables and perceived AD risk, prior experience with clinical research and trust in medical researchers emerged as independent predictors of likelihood of enrolling in AD research. Mediation analysis revealed that perceived burdens of AD research mediated 40.5% of the effect of prior research experience and 25.3% of the effect of trust on likelihood of enrollment (P<0.05). Perceived benefits of AD research also played a mediating role, accounting for 35.3% of the effect of trust on likelihood of enrollment (P = 0.006).

Conclusion

This study is a first step to understand the mechanisms by which narrative may function to enhance diversity in AD research. Findings suggest that participant narratives should address experiences that speak to the burdens and potential benefits of AD research participation as these factors may influence decisions leading to subsequent research enrollment.
evoke and evoke+: design of two large‐scale, double‐blind, placebo‐controlled, phase 3 studies evaluating the neuroprotective effects of semaglutide in early Alzheimer’s disease
Authors: Atri Alireza , Feldman Howard H. , Hansen Charlotte Thim , Honore Julie Broe , Johannsen Peter , Knop Filip Krag , Poulsen Pernille , Raket Lars Lau , Sano Mary , Soininen Hilkka , Cummings Jeffrey
Published: December 2022

Background

Preclinical, clinical, and real‐world evidence suggest benefits in Alzheimer’s disease (AD)‐related symptoms and reduced risk of dementia in type 2 diabetes following treatment with glucagon‐like peptide 1 receptor agonists (GLP‐1RA; Figure 1). The phase 3 evoke and evoke+ trials (NCT04777396 and NCT04777409, respectively) will assess the efficacy and safety of the oral GLP‐1RA semaglutide versus placebo in participants with early AD. Here, we present the design of these trials.

Method

evoke and evoke+ are two randomized, double‐blind, placebo‐controlled trials (Figure 2) recruiting across 38 countries, with 2 further countries pending (Figure 3). In each trial, a planned 1,840 amyloid‐positive participants (aged 55 to 85 years) with mild cognitive impairment (MCI) due to AD (Clinical Dementia Rating [CDR] global = 0.5) or mild AD dementia (CDR global = 1.0) will be randomized (1:1) to oral semaglutide 14 mg once‐daily (escalated via 3‐ and 7‐mg doses over 8 weeks) or placebo for 156 weeks. Participants may use approved AD treatments if on a stable dose ≥3 months before screening. Other key inclusion criteria are: Mini‐Mental State Examination score ≥22 and Repeatable Battery for the Assessment of Neuropsychological Status delayed memory index score ≤85. The key difference between the trials is the inclusion of ≥20% of participants with significant small vessel co‐pathology in evoke+. The primary endpoint is change in the CDR – Sum of Boxes score from baseline to week 104. Confirmatory secondary endpoints are change in Alzheimer’s Disease Cooperative Study‐Activities of Daily Living‐MCI score, and time to progression to dementia among participants with MCI at baseline. Exploratory endpoints include effects on neurodegeneration and neuroinflammation assessed by changes in plasma and cerebrospinal fluid biomarkers. After week 104, participants will continue their original randomized, double‐blind, placebo‐controlled treatment for a 52‐week extension phase followed by a 5‐week follow‐up, allowing assessment of the long‐term effects of semaglutide. A full list of endpoints is provided in Figure 4.

Result

The evoke and evoke+ read‐outs are expected in 2025.

Conclusion

evoke and evoke+ will be the first large‐scale phase 3 trials (Ntotal = 3,680) to investigate the hypothesized neuroprotective disease‐modifying effect of semaglutide in early AD.
Early striatal amyloid signal in Down Syndrome: Comparison of PiB and Florbetapir PET
Authors: McLachlan Max , Price Julie C , Laymon Charles M , Garimella Arun , Keator David B. , Kreisl William Charles , Klunk William E , Fryer Tim D , McVea Andrew K , DiFilippo Alexandra H , Christian Bradley T ,   Alzheimer’s Biomarker Consortium – Down Syndrome Investigators
Published: December 2022

Background

PET amyloid [11C]PiB imaging has revealed early detection of Ab in the striatum in individuals with Down Syndrome (DS), a group carrying genetic risk for AD. The goal of this investigation is to examine striatal binding of [11C]PiB and [18F]florbetapir (FBP) to determine if similar striatal uptake profiles are observed in individuals with DS.

Methods

PET scans were acquired as part of the Alzheimer’s Biomarker Consortium – Down Syndrome (ABC‐DS) study. DS participants were scanned with either PiB (n=204; ages 25‐56 yrs) or FBP (n=84; ages 40‐85 yrs) at seven academic sites. SUVR images were created with acquisition times of 50‐70min for both radiotracers, using a cerebellar reference region. ROIs were defined for the anterior ventral striatum (AVS) and the full cortex (CTX). SUVR was then converted to centiloids (CL) using published methods (Klunk 2015) with DS‐specific modifications, including AVS extraction and approximate CL_AVS. Aβ(+) was defined using a threshold of 18.1 CL in CTX ROI, categorizing Aβ(‐) and Aβ(+) groups. Comparisons across PiB and FBP examined 1) the proportion of CL_AVS values exceeding the threshold in the Aβ(‐) group and 2) the difference between SUVR_AVS and SUVR_CTX in the Aβ(+) group.

Results

58/204 subjects (PiB) and 72/84 subjects (FBP) were Aβ(+), with differences in Aβ(+) presumably due to greater age and advanced neurodegeneration in the FBP group. For the Aβ(‐) comparison, elevated CL_AVS was detected in 16/146 (PiB) and 0/12 (FBP). The average CL_AVS of those that exceeded the threshold was 37.0±12.7 CL (PiB) (mean±SD). For the Aβ(+) comparison, 52/58 (PiB) and 52/72 (FBP) had CL_AVS greater than their CL_CTX. The average difference between SUVR_AVS and SUVR_CTX for the Aβ(+) group was 0.50±0.39 SUVR (46.9±36.8 CL) (PiB) and 0.08±0.18 SUVR (14.2±31.0 CL) (FBP).

Conclusions

PiB PET exhibited higher uptake in the striatum during early stages of amyloid deposition. PiB revealed a 6x greater difference than FBP between striatal to cortical SUVR in the Aβ(+) group. Neuropathological investigation is ongoing to characterize these differences in striatal binding in DS. Despite this difference in early‐stage binding, both PiB and FBP demonstrate sensitivity for determining the presence of Aβ in DS.
Drug repurpose screening identifies regorafenib as potential amyloid‐beta aggregation inhibitor
Authors: Eby Blake , Chaapel Skye , Kasper Evan , Mancini Gabriella , Miller Isaiah , Fisher Liam , McKell Carmen , Martino Paul A
Published: December 2022

Background

Regorafenib is an FDA‐approved multikinase inhibitor used to treat cancer. Drug repurposing may allow for indications as an Alzheimer’s therapeutic targeting inhibition of amyloid‐beta aggregation.

Method

Regorafenib was one of several FDA‐approved drug candidates uncovered in a literature search. Initial in‐silico tests implemented [AutoDock Vina] to model the peptide‐ligand interactions between regorafenib and amyloid‐beta. Thioflavin T assays were used to measure regorafenib’s impact on amyloid‐beta aggregation relative to other small molecule candidates. Circular dichroism spectroscopy was performed to determine the dose‐response impact of regorafenib.

Result

Computational analysis revealed strong binding between regorafenib and amyloid‐beta 42. Aggregation assays and CD spectroscopy data provide evidence for the effectiveness of regorafenib as an amyloid‐beta aggregation inhibitor.

Conclusion

Regorafenib inhibits amyloid‐beta 42 aggregation and may be repurposed as an Alzheimer’s Disease therapeutic. The structural activity of regorafenib as a kinase inhibitor could be used as a model for future drug repurposing.
Increased Dementia Incidence among Black and Hispanic Veterans across Regions of the United States
Authors: Kornblith Erica S , Bahorik Amber L , Boscardin W John , Xia Feng , Barnes Deborah E , Yaffe Kristine
Published: December 2022

Background

Although the US military is increasingly diverse, the association of race/ethnicity and geographical region with incidence of dementia diagnosis among older Veterans is unknown.

Method

We identified a random sample of 1,869,090 patients age ≥ 55 years [mean age: 69.4 (standard deviation 7.9), 2% female] who received care at the Veterans Health Administration (VHA), the largest integrated health care system in the United States, between October 1, 1999 and September 30, 2019. Participants self‐reported race/ethnicity: White: 88.6% (n = 1,655,376); Black, 9.5% (n = 176,795); Hispanic (1.0%, n = 20,663), Asian (0.5%, n = 9,391), or American Indian/Alaska Native [AIAN (0.4%, n = 6,895). US region was derived using residential ZIP codes and categorized based on 10 Center for Disease Control and Prevention Health Promotion regions. Incident dementia was defined using International Classification of Diseases, 9th (ICD‐9) and 10th (ICD‐10) edition codes; age‐adjusted dementia incidence was estimated using direct standardization to compare rates by race/ethnicity overall and by US region.

Result

Over a mean follow‐up of 10.1 years, 243,272 (13%) participants received a diagnosis of dementia. Age‐adjusted incidence per 1,000 person‐years was 14.2 [95% confidence interval (CI), 13.3‐15.1] for AIAN participants, 12.4 (95% CI, 11.7‐13.1) for Asian participants, 19.4 (95% CI, 19.2‐19.6) for Black participants, 20.7 (95% CI, 20.1‐21.3) for Hispanic participants, and 11.5 (95% CI, 11.4‐11.6) for White participants. Across US regions, a similar pattern was observed; compared to White participants, rates were significantly higher for Black participants across all regions (15.5 to 20.7, p values <0.001), and for Hispanic participants in all regions except the Southeast (14.0 to 21.7, p values ≤ 0.03). Across most regions, AIAN (8.6 to 16.2,) and Asian participants (8.4 to 15.6,) showed a pattern of rates that was similar to or slightly higher than for White participants (9.8 to 12.0, p values >0.05).

Conclusion

Among older Veterans receiving care at VHA, where access to care for enrollees is held relatively equal, differences in dementia incidence were observed based on race/ethnicity. Across US regions, rates varied, but incidence was consistently higher for Black and Hispanic Veterans. Further research is needed to elucidate drivers of these differences.
OPTICAL COHERENCE TOMOGRAPHY AND COGNITIVE IMPAIRMENT IN BUENOS AIRES, ARGENTINA
Authors: Fernandez Maria Cecilia , Berrios Waleska , Campora Nuria , Golimstok Angel , Basso Tomas Ortiz , Challiol Camila Fernanda , Cagnasso Juan Ignacio
Published: December 2022

Background

The search for biomarkers for the early detection of mild cognitive impairment (MCI) and dementia continues, including ocular markers.

An association between neurodegenerative diseases with thinning of optic nerve fiber layers (NFL), macular thickness (MT) and choroidal vessels has been shown by means of optical coherence tomography (OCT), since these structures correspond embryologically to the same origin.

In this research we present our data from a population with mild cognitive impairment and dementia and the OCT findings.

Method

We carried out an observational, analytical, cross‐sectional study, comparing the OCT parameters (macular thickness and choroidal thickness) between people with cognitive impairment and a control group of patients treated in the Neurology and Ophthalmology services of the Italian Hospital from Buenos Aires between the years 2009 and 2019. The results were analyzed using the Kruskal‐Wallis and Wilcoxon test using the STATA v14 software

Result

We included 26 patients with MCI, 21 with dementia and a control group of 30 patients. Regarding the main objective, the measurement of macular thickness, we found statistically significant differences only in the quadrants according to ETDRS (Early Treatment Diabetic Retinopathy Study) greater than 3 mm and in the nasal one, 6 mm, both in the right eye (p < 0.02), finding very similar thickness values in the remaining quadrants. We were also unable to find differences in choroidal thickness between the groups under study (p0.27 in RE and p0.25 in LE)

Conclusion

In our study, we were unable to determine the association of cognitive impairment with significant thinning of the retinal macular thickness and choroidal thickness, either in early stages or in dementia, not knowing if this result derives from the way in which patients were selected or if there is another factor. It seems relevant to us to present these negative data and to propose future studies to clarify these results
Cognitively Assistive Robots at Home: Translating Clinical Interventions to Robots
Authors: Kubota Alyssa , Cruz‐Sandoval Dagoberto , Kim Soyon , Twamley Elizabeth W. , Riek Laurel D
Published: December 2022

Background

Much research in healthcare robotics explores extending rehabilitative interventions to the home. However, for adults, little guidance exists on how to translate human‐delivered, clinic‐based interventions into robot‐delivered, home‐based ones to support longitudinal interaction. This is particularly problematic for neurorehabilitation, where adults with cognitive impairments require unique styles of interaction to avoid frustration or overstimulation.

Method

For the past several years, our team has worked with neuropsychologists to develop cognitively assistive robots (CARs) that administer compensatory cognitive training (CCT) autonomously and longitudinally to people with mild cognitive impairment (PwMCI) at home. Our system helps users practice cognitive strategies to strengthen skills such as attention, learning/memory, and executive functioning.

We explore the design of robot‐delivered neurorehabilitation interventions for PwMCI. We used these prototypes as design probes to understand how neuropsychologists (n=6) envision translating CCT to a CAR, and features the robot intervention needs to be successful, such as supporting goal setting, content personalization, encouragement for real‐world transfer, and ways to longitudinally maintain engagement. We also conducted interviews with PwMCI (n=3), the end users of the robot‐administered intervention.

Result

We report our findings and specify design patterns and considerations for translating neurorehabilitation interventions to robots. First, we provide insights for translating neurorehabilitation interventions to CARs in order to contextualize them to the lives of PwMCI. Second, we present new interaction design patterns for robot‐delivered neurorehabilitation interventions to maintain longitudinal engagement and intervention efficacy. Finally, we propose design considerations for developing robots for PwMCI, a population with unique needs and abilities distinct from those of people with dementia and older adults [1].

Conclusion

This work will serve as a basis for future endeavors to translate cognitive training and other clinical interventions onto a robot, support longitudinal engagement with home‐deployed robots, and ultimately extend the accessibility of longitudinal health interventions for people with cognitive impairments.

[1] Kubota, A., Cruz‐Sandoval, D., Kim, S., Twamley, E., and Riek, L.D. “Cognitively Assistive Robots at Home: HRI Design Patterns for Translational Science.” In Proceedings of the 17th Annual ACM/IEEE Conference on Human Robot Interaction (HRI). 2022.
Alteration of Fatty Acid Metabolism is Associated with Alzheimer’s Disease in People with Down Syndrome
Authors: Mapstone Mark ,   The Alzheimer's Biomarker Consortium‐ Down Syndrome (ABC‐DS)
Published: December 2022

Background

People with Down syndrome (DS) are at high risk for Alzheimer’s disease (AD) in part because nearly all carry an extra copy of the APP gene which results in overexpression of amyloid. However, other factors are likely to interact with this genetic risk to produce individual pathobiological and clinical trajectories. We sought to examine the impact of diverse physiological pathways on AD risk in people with DS using plasma metabolomics.

Method

We studied the plasma metabolome of 744 people with DS (mean age =49) using mass spectrometry (MS). A total of 144 individuals from our cohort met criteria for MCI or AD (DS‐AD, mean age= 55.0) and 600 were cognitively stable (DS‐NAD, mean age = 47.4). We quantified the relative abundance of over 7000 putative metabolites. We performed differential expression (DE) analysis and constructed group classification models (DS‐AD vs DS‐NAD) using Regularized Logistic Regression with age included as a covariate. We evaluated the classification models using Receiver Operating Characteristic (ROC) analysis.

Result

We found 20 DE features between the DS‐AD and DS‐NAD groups (q < 0.05), of which we definitively identified 11 through tandem mass spectrometry. Of the 11 metabolites, 5 were naturally occurring unique human metabolites involved in fatty acid metabolism, including two diacylglycerides, one monoglyceride, one lysophosphatidycholine, and one acylcarnitine. When combined, this set of lipids classified the DS‐AD and DS‐NAD groups with ROC area under the curve of 0.796 [95% CI: 0.784‐ 0.808] across resamples (Sensitivity 29%, Specificity 97%). The addition of participant sex or APOE status did not significantly alter classification performance.

Conclusion

Here, we find depletion of lipids in the plasma of people with DS who also have AD compared to people with DS who are not demented. While the overall number of DE metabolites is small, it is remarkable that from over 7000 putative metabolites measured, all are lipids involved in fatty acid metabolism. These results are consistent with an emerging picture of dysregulated lipid metabolism in AD, both in the people with DS and in the neurotypical population.
How many is enough? Sample size estimation for imaging‐based outcomes in clinical trials of neurodegenerative disease
Authors: Cash David M , Frost Christopher , Fox Nick C ,   Dominantly Inherited Alzheimer Network (DIAN)
Published: December 2022

Background

Effective treatments for neurodegenerative diseases are a global health priority. Appropriately powered clinical trials are critical to showing evidence of efficacy ‐ these are expensive and take years to complete. Depending on the study aims, imaging biomarkers can provide high precision measurements that reflect underlying pathology or downstream effects and may help in reducing the number of participants and/or duration of the trial. Identifying how to design trials that make the most efficient use of imaging endpoints, while maintaining sufficient statistical power to detect the desired therapeutic effect, will be critical to reduce approval time for effective therapies.

Method

Sample size estimates were computed for a wide range of imaging biomarkers, trial designs, and target therapeutic effects. We examined how sample size estimates were affected by the target population (inclusion/exclusion criteria), visit schedule, and the rate of participant dropout. From the resulting trial designs, appropriate formulae for sample size estimation were derived. These formulae require estimates of a number of parameters including both the mean rate of change over time in the outcome measure and the related variances. These were obtained from natural history studies, including ADNI, DIAN, and TRACK‐HD. The precision of these estimates is calculated by bootstrap resampling.

Result

Across target populations, imaging biomarkers produced lower sample sizes to detect a clinically relevant slowing of change compared to conventional primary endpoints, particularly in shorter duration (i.e. 1‐2 years) trials. Imaging biomarkers that incorporated longitudinal information into the measurements were often the best performers. If the participant dropout rate is non‐negligible, this can result in noticeable increases in sample size, which can be partially mitigated by including interim visits into the analysis. The precision of sample sizes estimates can vary substantially between biomarkers and should be considered when making decisions on trial design.

Conclusion

Imaging based outcomes can play an important role in providing evidence of disease modification in trials, particularly in primary and secondary prevention studies. Accurate sample size estimates for the desired treatment effect are critical for the success of these studies.