bluuebunny/crossref_metadata_2025 huggingface dataset:
Problems using structural MRIs from the oldest‐old, and some solutions: Lessons learned from The 90+ Study and ADNI
Authors: Woodworth Davis C. , Nguyen Hannah L. , Li Janice X. , Nguyen Katelynn M. , Greenia Dana E. , Kawas Claudia H. , Corrada Maria M. , Sajjadi S. Ahmad
Published: December 2022

Background

The oldest‐old (≥85 years) have the highest rates of dementia. However, because of pronounced brain atrophy, standard neuroimaging programs face unique challenges in this cohort. Here, using data from both The 90+ Study and Alzheimer’s Disease Neuroimaging Initiative (ADNI), we report the prevalence of errors when processing brain MRIs from oldest‐old participants using standard approaches and present some strategies for ameliorating these issues.

Method

First, we analyzed image quality issues and segmentation errors (FreeSurfer) for the last available scans by age‐groups (oldest‐old, ≥85 years, vs younger‐old, 55 to 85 years) in ADNI. Second, we evaluated the utility of an age‐specific template (the 90+ T1w Template) for realigning MRIs from the oldest‐old compared to a standard template (Montreal Neurological Institute T1w template, MNI) using linear and nonlinear registration (FSL) and evaluating alignment quality using visual and deformation (Jacobian) measures for oldest‐old participants (≥90 years) in both The 90+ Study and ADNI. Lastly, we evaluated whether stringent preprocessing (bias field removal, denoising, brain extraction, intensity normalization using Computational Anatomy Toolbox (CAT12)) helped reduce FreeSurfer segmentation errors in frontal, parietal, and temporal regions in MRIs from the oldest‐old. Comparisons were performed using Chi‐square tests.

Result

In ADNI data (Table‐1), MRIs from oldest‐old participants (∼10% of cohort) were around twice as likely to have image quality issues (20% vs 13%, P<0.001) and brain segmentation errors (45% vs 29%, P<0.001) compared to younger‐old participants. Figure‐1 shows a histogram of image quality issues and segmentation errors, which become more common with greater age. Compared to the MNI template, MRIs from participants aged 90 and older from both The 90+ Study (N=163, Table‐2) and ADNI (N=75) had fewer registration errors (∼5% vs ∼23%, P<0.001 for all) and less severe deformation when using the 90+ T1w Template (Figure‐2). Our proposed preprocessing pipeline (see Figure‐3 for example) roughly halved segmentation errors in the oldest‐old (P<0.001 for all regions, Figure‐4).

Conclusion

Our results show that adapting pipelines specifically for processing brain MRIs of oldest‐old participants minimizes errors, enabling more effective use of neuroimaging to study neural correlates of neurodegeneration and dementia in this important portion of our aging population.
Associations between a biological marker of resilience, brain pathology, and cognitive functioning
Authors: Marseglia Anna , Dartora Caroline , Skoog Johan , Mårtensson Gustav , Muehlboeck J‐Sebastian , Ferreira Daniel , Kern Silke , Zettergren Anna , Skoog Ingmar , Westman Eric
Published: December 2022

Background

Dementia is the end‐product of decades of accumulating neuropathology. Resilience mechanisms can help sustaining the brain structure (brain maintenance, BM) and/or compensating for neuropathology (cognitive reserve, CR), preserving cognition. Measuring such mechanisms, however, has been challenging with traditional approaches as they fail to capture the complex biological dimension. Using deep learning (DL), we recently developed a biological measure of brain age from raw brain MRI images. Here, we tested whether differences between predicted brain age and the chronological age (PBA‐CA) can be used as marker of BM/CR following the latest framework from the NIH‐supported Collaboratory on Research Definitions for Reserve and Resilience.

Method

Within the Gothenburg H70‐Birth cohort 1944, we included 728 septuagenarians with available brain MRI and without cognitive impairments/neuropsychiatric disorders. We applied the DL algorithm (developed in 15115 healthy individuals from four other cohorts) to the participants’ MRI images to predict brain age and compute PBA‐CA, which was categorized in 4 groups according to distribution: Q1 (younger‐appearing brain) to Q4 (older‐appearing brain). Brain pathology included measures of Alzheimer‐neurodegeneration (average cortical thickness in signature areas), small vessel disease (SVD, i.e. presence of lacunes, microbleeds, white‐matter lesions, perivascular spaces), and microstructural white‐matter changes. A global cognitive score was generated by averaging z‐scores from ten tests. Sex‐adjusted regressions were used in data analysis.

Result

Participants with younger‐appearing brains (reference=older‐appearing) were more likely to have less SVD burden (reference: ≥2 SVD; OR=2.75 [95% CI 1.41–5.37] for no‐SVD; OR=2.55 [95% CI 1.20–5.45] for one‐SVD), white‐matter microstructural alterations, or AD‐related atrophy. Younger‐appearing brains were also associated with better cognitive performance (β‐coefficient=0.19 [95% CI 0.04–0.30]).

Conclusion

Preliminary findings indicate that negative differences between PBA and CA (PBA<CA) were associated with less AD‐ and cerebrovascular pathology, and better cognitive functioning. This suggests that PBA<CA indicate preserved brain structure and could be used as marker of BM.
Prevalence and longitudinal clinical outcomes of negative, moderate, and advanced [18F]flortaucipir PET visual patterns across the Alzheimer's disease spectrum
Authors: Moscoso Alexis , Heeman Fiona , Camacho Valle , van Essen Martijn , Grothe Michel J. , Lin Li , Mainta Isminni , Ribaldi Federica , Devous Michael D. , Pontecorvo Michael J. , Frisoni Giovanni B , Garibotto Valentina , Schöll Michael
Published: December 2022

Background

The advent of positron emission tomography (PET) imaging with tracers such as [18F]flortaucipir (FTP) has allowed in‐vivo visualization of aggregated tau in Alzheimer’s disease (AD). Recently, a clinically applicable visual interpretation method for FTP PET yielding negative, moderate, and advanced AD visual patterns was developed, leading to its subsequent approval by the US Food and Drug Administration (FDA). Yet, the prevalence and longitudinal clinical outcomes of the different AD‐associated visual patterns, in particular the moderate AD pattern, have not been investigated systematically across the clinical spectrum of AD.

Method

We included cognitively normal individuals and patients with mild cognitive impairment and AD dementia from five observational cohort studies — Alzheimer’s Disease Neuroimaging Initiative (ADNI), Harvard Aging Brain study (HABS), A4 study, AVID’s A05 study and Geneva Memory Clinic cohort — all of which had available FTP PET scans. Furthermore, Aβ status, established with Aβ PET, was available in 1924 participants (98%), and longitudinal clinical and cognitive data was obtained for 968 participants over an average follow‐up time of 2.2 years. Three readers, blinded to clinical and imaging information, will independently evaluate each FTP PET scan, and an individual’s FTP uptake pattern will be interpreted as negative, moderate, or advanced AD tau pattern, based on the majority read of the three readers. Multinomial generalized additive models (GAM) will be fitted to provide prevalence estimates of each FTP AD pattern. Mixed models for repeated measures (MMRM) will be used to estimate cognitive decline trajectories.

Result

A total of 1963 participants had available FTP PET scans. We will investigate the prevalence of the different FTP AD patterns as a function of age per diagnostic group, stratifying participants by β‐amyloid status and APOE genotype. Further, in the subset of participants with available longitudinal clinical data, we will explore how the different FTP patterns associate with clinical decline across the aforementioned diagnostic groups.

Conclusion

Our large‐scale study will contribute significantly to elucidating the clinical relevance of FTP visual reads across the AD spectrum, potentially widening its applicability and promoting its use in patient assessment and in clinical prevention trials.
Role of APOE ε gene in cognitive performance among cognitively healthy participants of TLSA cohort
Authors: Lingegodwa Abhishek Mensegere , Kommaddi Reddy Peera , Giridhar Varsha , Ravindranath Vijayalakshmi ,   TLSA Collaborators
Published: December 2022

Background

APOE ε4 is a major genetic risk factor for Alzheimer’s Disease (AD), however, effect of APOE ε4 on cognitive decline is not well understood. TATA Longitudinal Study of Aging (TLSA) is a longitudinal study in healthy aging individuals in Bangalore, India.

Method

We analyzed the performance on global cognition, processing speed, working memory, auditory attention, verbal short‐term memory, and visuospatial skills, to ascertain between APOE ε4 carriers and non‐carriers among healthy participants of TLSA.

Result

Generalized linear models were constructed which showed that APOE ε4 carriers showed a faster cognitive decline in auditory attention and verbal short‐term memory as measured by digit forward test (B = ‐0.79; p = 0.001) compared to non‐carriers at two years of follow up. The presence of APOE ε4 allele didn’t affect the rate of cognitive decline on other cognitive domains.

Conclusion

The presence of specific cognitive deficits in APOE ε4 carriers could potentially be a composite biomarker for early cognitive decline in people carrying this allele.
Transcriptomic Analysis of Whole Blood in Admixed Latinx Alzheimer Disease Cohorts
Authors: Griswold Anthony J. , Gu Tianjie , Van Booven Derek , Whitehead Patrice L. , Hamilton‐Nelson Kara L. , Contreras Maricarmen , Sanchez Jose Javier , Tejada Sergio , Adams Larry D. , Mena Pedro Ramon , Bush William S. , Silva‐Vergara Concepcion , Cornejo‐Olivas Mario , Illanes‐Manrique Maryenela , Cuccaro Michael L. , Vance Jeffery M. , Feliciano‐Astacio Briseida E. , Beecham Gary W. , Pericak‐Vance Margaret A.
Published: December 2022

Background

Identifying the genes and biological pathways involved in Alzheimer disease (AD) is critical in the effort to develop effective therapies. Significant work has identified genetic variants conferring risk and protection for AD in individuals of diverse ancestries, but identification of downstream functional effects including modulation of gene regulation is lacking, particularly in individuals of diverse ancestries. Therefore, to explore transcriptional changes between clinically diagnosed AD and cognitively intact age‐matched controls, herein we analyzed RNA sequencing data from peripheral blood collected from individuals of admixed genetic backgrounds.

Method

Total RNA was extracted from peripheral whole blood stored in PAXGene tubes from 47 Cubans (22 AD and 25 controls), 85 Peruvians (41 AD and 44 controls), and 168 Puerto Ricans (88 AD and 80 controls). PolyA selected mRNA was sequenced to more than 40 million paired end read per sample on the Illumina NovaSeq 6000. The bioinformatic pipeline included mapping to the human reference genome (GRCh38), gene quantifications against the GENCODE v35 annotation set, and differential expression was calculated using DESeq2 with sex, age at blood draw, and count of APOEe4 alleles as covariates. Functional categorization was performed by gene set enrichment of gene ontology and KEGG pathways.

Result

Across the cohorts, a total of 358 protein‐coding genes (FDR ≤ 0.05, Fold change ≥ 1.25) were differentially expressed with 238 down‐regulated and 120 up‐regulated in AD relative to controls. Despite the few genes overlapping between ethnicities, pathway analysis revealed common pathways including up‐regulation of genes involved in inflammation and RNA processing and down‐regulation of genes involved in cellular detoxification and lipid transport, among others. Interestingly, while few specific genes overlap in differential expression overlap with a published set of genes from non‐Hispanic Europeans and African Americans (Griswold et al, 2018), the pathways identified are similar.

Conclusion

Our analysis reveals a signature of gene expression that implicates increased inflammation and decreased cellular detoxification based on gene expression analysis in admixed Latinx AD. Convergence of pathways across these and African American and European cohorts supports the idea of distinct genes but similar underlying pathological processes contributing to AD across individuals of diverse ancestries.
Multidisciplinary collaboration to develop a digital health solution for early detection of cognitive decline in primary care
Authors: Hilsabeck Robin C. , Keller Jeffrey N. , Henry Maya L , Toprac Paul , Rathouz Paul , Sreekanth Varshinee , Largent Avery , Chang Joshua , Li Jessy , Pugalenthi Lokesh , Parsons Thomas , Cuevas Heather E , Schmitz Suzanne
Published: December 2022

Background

Developing digital healthcare solutions that facilitate rapid identification and effective management of patients with Alzheimer disease and related disorders (ADRD) is an area of intense study. A critical juncture for these efforts involves the early detection of cognitive decline. Because primary care providers (PCPs) are the first line of medical care, they are often the first to hear concerns about cognitive decline. However, under‐diagnosis of ADRD in primary care settings is widely recognized, as are the many barriers to routine cognitive screening. While information about brief cognitive screening tools for detecting ADRD is plentiful, PCPs remain uncertain about which patients to assess, which tools to use and how to use them, and how to communicate results. The goal of this project was to design a risk assessment and cognitive screening (RACS) application that specifically addressed the needs and concerns of PCPs to facilitate identification of cognitive decline in primary care settings.

Method

We employed a multi‐modal assessment approach in designing the RACS app, which first assesses risk for cognitive impairment and then assesses cognitive functioning using a working memory/processing speed task in combination with four speech/language tasks. We assembled a multidisciplinary team with the following expertise to develop and test the app: biostatistics, computational linguistics, computer science, computerized cognitive assessment, gaming/app development, engineering, neurology, neuropsychology, neuroscience, primary care, psychometrics, and speech‐language pathology.

Result

Programming of app features and pilot testing with people with ADRD was completed in 3 months. Initial development of the connected speech analysis pipeline was completed in 4 months with ongoing testing. Data collection of 50 cognitively normal, 50 mild cognitive impairment, and 50 mild dementia participants is approximately 50% completed within 6 months. Preliminary results based on cognitive performance alone show good ability to discriminate groups. Reduction of speech‐language variables for inclusion in a final cognitive performance score is underway using a variety of machine learning techniques, including the elastic net and random forests.

Conclusion

The RACS app shows promise as a digital health solution to facilitate early detection of cognitive decline in primary care and may prove useful in other busy clinical settings.
Development and Co‐Design of a Digital Intervention for People Affected by Dementia who are Fearful of Disclosing the Diagnosis to Their Social Networks
Authors: Kohl Gianna , Bhatt Jem , Scior Katrina , Charlesworth Georgina
Published: December 2022

Background

Receiving a diagnosis of dementia can affect all aspects of an individual’s life, including their sense of identity. As a consequence, some people with dementia may socially withdraw due to stigma, embarrassment or fear of what might happen if other people were to find out about the diagnosis. The “Who to tell, how and when” intervention, a group‐based face‐to‐face intervention, has been developed for people affected by dementia who are fearful of disclosing the diagnosis to others. This study aims to adapt the existing intervention for online delivery, in light of the ongoing COVID‐19 pandemic.

Methods

A co‐created, user‐centred design in three phases is applied. In phase 1, focus groups conducted with people with dementia and informal caregivers will inform the platform, features and adaptation of pre‐existing material. Phase 2 consists of the development of the digital prototype. In phase 3, the feasibility and usability are tested with end users to inform prototype v. 2.0.

Results

Research has indicated that peer support in the disclosure decision‐making process is especially important for participants. Results from phase 1 and 2, including findings from the discussions with the focus groups and options appraisals for the peer support elements of the digital intervention will be discussed. We will discuss general principles of adaptation from paper manual to digital intervention.

Conclusion

Online access to this intervention may be especially valuable for people who wish to maintain anonymity and privacy, for example people from cultural or ethnic groups where the stigma of dementia is high. Online versions of face‐to‐face interventions improve overall accessibility by providing choice.
Feasibility of Intentional Technology Pairing in Fostering Connections Among Dementia Caregivers
Authors: Fields Julie A. , Forsberg Leah K. , Knutson Matthew , Seifert Sara J. , Melius Jodi L. , Kramer Kevin M. , Lunde Angela
Published: December 2022

Background

To gather user input iteratively to develop a matching algorithm for peer‐to‐peer support and to assess the feasibility and usability of a web‐based program to conduct matching.

Method

32 caregivers of persons with dementia (PwD) participated in semi‐structured focus groups and completed surveys to provide input regarding characteristics deemed valuable in someone they would choose to be connected with for emotional support. Through an iterative process as new information emerged, a web‐based prototype and matching algorithm were developed. Caregivers interacted with the prototype and provided feedback indicating ease of accessibility and use, initial impression, and comfort/satisfaction with profile content.

Result

All 32 caregivers (age 40‐90, education 12/GED‐20, sex 88% female, 31% Black/African‐American) completed online profiles. Of those who interacted with the prototype, 23 completed the feedback survey, on which 87% had no or only mild difficulty accessing the site, 91% had no difficulty with technology once there, 86% had a very or quite positive initial impression, 91% found it very or quite easy to navigate, 87% rated a very or quite high level of comfort with completing the personal profile questions, and 82% felt very or quite confident the questions asked would lead to a good match.

Conclusion

A large majority of caregivers of PwD demonstrated the web‐based platform was easy to access and navigate, provided a positive experience, and gathered information that would lead to a good supportive relationship with another caregiver. Phase II will optimize the design and algorithm and evaluate the matching process in 350 caregivers.
Evaluating the sensitivity of Centiloid quantification to pipeline design and image resolution
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 ,   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.

Methods

This study has been performed using 725 amyloid PET scans from the two AMYPAD trials(PNHS and DPMS) that were acquired with either [18F]flutemetamol or [18F]florbetaben(Table1). Using SPM12, 32 pipelines were created and calibrated to render CL with combinations of:

• 4 reference regions (Whole Cerebellum, Cerebellar Gray, Whole Cerebellums+Brainstem, Pons)

• target VOI (standard GAAIN vs subject‐based)

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

• analysis spaces (native vs MNI)

The impact of the pipeline design factors on CL values assessed using Generalized Estimating Equation(GEE) analyses. Individual morphometric variables including total intracranial volume(TIV), and grey/white matter volumes in the reference and target regions implemented in the model. To mimic differences in image resolution, PET scans were smoothed by 3mm and 6mm Gaussian filters. CL was calculated for original and corresponding smoothed PET scans. The agreement between CL values with/without smoothing evaluated using the intra‐class correlation coefficient(ICC). Bland‐Altman plots were used to demonstrate mean absolute differences between CL values after smoothing. Differences above 5CL were considered relevant.

Results

There was no statistically significant relationship for CL as a function of tracer, analysis space or target region, while RR selection and its definition did have a significant impact on CL values(Table2). More specifically, the pons provided the lowest mean CL(25.06±4.51) compared to the whole‐cerebellum(35.04±4.25) and the cerebellum grey‐matter(36.99±4.16)(Table3). Using GAAIN RR provided slightly higher mean CL values (ΔCL:4.15±1.04) compared to a subject‐based method (Table4). ICC between CL values of non‐smoothed vs smoothed PET images was 0.99 for both post‐smoothing filters(p<0.001). Differences in image resolution had minimal effect on CL values for individuals with low to moderate levels of amyloid while the effect became higher for individuals with the higher amyloid burden(Figure1)

Conclusion

CL quantification is robust against differences in individual morphometric measures, analysis space, image resolution, tracer and target VOI. However, reference region choice can significantly influence CL values, with the pons showing the highest discrepancies relative to other reference regions.
Racial and Ethnic Disparities in Measures of Consumer Assessment of Healthcare Providers and Systems among ADRD Patients
Authors: Chen Jie , Albaroudi Asmaa
Published: December 2022

Background

This study examines the consumer reported health care quality and racial and ethnic disparities among ADRD patients.

Method

The main datasets included 2017 Medicare inpatient claims data, Medicare Beneficiary Summary File, and the Medicare Shared Savings Program ACO data. Consumer Assessment of Healthcare Providers and Systems (CAHPS) scores were used to measure the quality of physician‐patient relationship among ADRD patients enrolled in ACOs.

Result

Whites reported higher CAHPS total score compared to Black, Hispanic, and Asian ADRD patients, and social determinants of health explained 11% ‐13% of disparities between White vs. Black and White vs. Hispanic. Compared to Whites, Black, Hispanic, and Asian ADRD patients reported significantly lower CAHPS measures on access, communication, and rating, Hispanics reported higher scores on the measure of health promotion, and Hispanics and Asians reported higher scores on shared decision making.

Conclusion

Our results demonstrated significant variations of CAHPS score by race and ethnicity among ADRD patients who were enrolled in ACOs.
Monitoring abnormal nocturnal behaviour in the homes of patients living with dementia
Authors: Soreq Eyal , Kolanko Magdalena A , Monica Ciro della , Ravindran Kiran K.G. , Revell Victoria Louise , de Villèle Paul , Barnaghi Payam , Dijk Derk‐Jan , Sharp David J ,   CRT group
Published: December 2022

Background

People living with dementia (PLWD) often exhibit marked sleep disturbances. These cause substantial care challenges and may be causally related to dementia progression. Collecting ecologically valid data on sleep disturbance in naturalistic settings has been difficult. As a result, sleep assessments in PLWD are generally limited to short studies in sleep laboratories or data collection from wearables, where compliance is problematic. Here, we demonstrate how passive internet of things (IoT) sensors can be used to monitor the effects of dementia on nocturnal behaviour and physiology.

Method

Using the Withings under‐mattress pressure sensor, we validated bed occupancy and physiological measures in 35 older adults tested both at home and in the laboratory. We then examined data collected between 2019 and 2021 from the general population (N=13,663) and from a cohort of PLWD taking part in the UK DRI study of home monitoring for PLWD (N=46). More than 4 million unique bed mat observations were analysed.

Result

Arise time across all subjects was negatively correlated with time to bed (Fig.1a, r(13,617)=‐0.5, p<.0001). Bed occupancy increased with age, but PLWD spent more time in bed than age‐matched controls (Fig.1b) and had more nocturnal awakenings (Fig.1c). Explainable gradient boosting machine learning was successfully used to classify data from individual nights (PLWD vs. general population). PLWD probability was related to specific changes, such as increased awakenings, high or low time spent in bed, high heart rate and low breathing rate (Fig.2). We also explored variations in night‐time behaviour and physiology over time for individual PLWD (Fig.3a). High within‐subject variability was present, which related to disease progression, intercurrent illness and changes in medication. Data from each night was transformed into a risk score for each metric (Fig.3b) and a compound risk score. These quantify the risk of abnormal night‐time behaviour and physiology produced by dementia (Fig.3c) and reflect clinically relevant changes in PLWD.

Conclusion

Taken together our work demonstrates how digital biomarkers collected passively using under mattress technology can be used to automatically monitor the nocturnal effects of dementia across large populations. The approach is also potentially applicable for preclinical screening and the evaluation of treatments effects.
Overestimation of performance after a memory task in cognitively unimpaired individuals is related to lower cortical thickness in Alzheimer’s disease vulnerable regions and to executive decline, particularly in men.
Authors: Sánchez‐Benavides Gonzalo , Arenaza‐Urquijo Eider M , Brugulat‐Serrat Anna , Operto Grégory , Garcia Marina , Shekari Mahnaz , Gispert Juan Domingo , Suárez‐Calvet Marc , Milà‐Alomà Marta , Minguillón Carolina , Fauria Karine , Molinuevo Jose Luis , Grau‐Rivera Oriol ,   ALFA study
Published: December 2022

Background

Low awareness of cognitive decline is a common feature in Alzheimer’s disease (AD) dementia, and it relates to higher risk of progression in individuals with Mild Cognitive Impairment. Previous research suggests that, in cognitively unimpaired individuals, it has prognostic value and is related to AD biomarkers. We aimed at exploring the associations between the ability to judge performance after a memory task and demographic, clinical (cognitive complaints), structural neuroimaging, cognitive and amyloid status variables in cognitively unimpaired individuals.

Methods

We analyzed data from 225 ALFA+ study participants (mean[SD] age = 68.9[4.9], 63.6% female). We defined a discrepancy score between objective and subjective memory measures by subtracting the self‐ratings of performance in the delayed recall of the Memory Binding Test (range 0–100) from the percentage of words actually recalled. Structural MRI (AD signature cortical thickness), amyloid (PET visual read), and Subjective Cognitive Decline (SCD) status measures were available. We classified individuals as decliners vs non decliners (change >‐0.5 z‐score after 3 years) using executive and memory composites. Linear models with the discrepancy score as dependent variable and age, sex, education, AD signature, amyloid and SCD status as predictors, and with decline/non decline in executive and memory composites as predictors, were constructed.

Results

Males overestimate their memory performance more than females (p = 0.003, Figure 1). Lower cortical thickness in the AD signature was also related to overestimation (p = 0.035, Table 1). Age, education, amyloid and SCD were not significant predictors and did not interact with sex or AD signature. Decline in the executive composite was related to overestimation of performance (p = 0.048), being this association driven by men (men p = 0.032, women p = 0.403, Figure 2). We did not find associations with decline in memory performance.

Conclusions

Our results suggest that, in cognitively unimpaired individuals, the overestimation of objective memory performance relates to lower cortical thickness in AD vulnerable regions and to a subtle decline in executive abilities. Men seem to overestimate their ability more than women, particularly those that have decline in executive scores. Future research to define the value of altered self‐judgment of cognitive ability in presymptomatic stages of AD and its relationship with SCD is granted.
Progression of white matter signal abnormalities in predementia frontotemporal dementia mutation carriers
Authors: Lee Hyunwoo , Chatterjee Atri , Gibson Erin , Beg Mirza Faisal , Popuri Karteek , Mackenzie Ian R , Rosen Howard J. , Kantarci Kejal , Boeve Bradley F. , Boxer Adam L , Tartaglia Carmela , Hsiung Ging‐Yuek Robin ,   ALLFTD Consortium
Published: December 2022

Background

White matter signal abnormalities (WMSA) are frequently observed on magnetic resonance imaging (MRI) scans of people with frontotemporal dementia (FTD). We hypothesized that carriers of mutations in progranulin (GRN+), chromosome 9 open reading frame 72 (C9orf72+) and microtubule associated protein tau (MAPT+) have increased rates of progression of WMSA compared to non‐carrier individuals prior to onset of dementia, and that different mutations may have different rates of WMSA accumulation.

Method

Participants were recruited through the ARTFL‐LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) Study. We selected participants with Clinical Dementia Rating scale (CDR) scores of 0 and 0.5. If a participant developed FTD during the follow‐up, we only analyzed observations collected before the conversion. WMSA were defined as hyperintensities on FLAIR MRI. Total WMSA volumes were normalized to the respective intracranial volumes. We used a linear mixed effects model, with random intercepts and slopes, to compare the baseline burden and the longitudinal progression of total WMSA volumes between mutation carriers and controls. The model was adjusted for baseline age, sex, education, baseline Montreal Cognitive Assessment (MoCA) scores, and MRI acquisition sites.

Result

We analyzed MRI data from 199 participants who had at least two MRI visits (46 C9orf72+, 17 GRN+, 35 MAPT+, 101 non‐carrier controls; up to five years of follow‐up). We did not find significant group differences in baseline demographic features, except that MAPT+ was younger than non‐carrier controls (average age: C9orf72+=47, GRN+=56, MAPT+=40, controls=47). Baseline WMSA volumes were not significantly different between mutation carriers and controls. Longitudinally, the rates of WMSA volume increase in C9orf72+ and MAPT+ were comparable to controls; whereas, GRN+ had higher rates of WMSA volume increases compared to controls (p=0.01).

Conclusion

WMSA may accumulate at higher rates in GRN+ prior to the onset of FTD, which is consistent with the frequent presence of white matter diseases observed in symptomatic FTD patients with GRN mutations. Future work is warranted to investigate the association between white matter structural changes and cognitive/psychiatric changes in FTD mutation carriers.
Disparities in Recruitment and Screen Failure by Race and Ethnicity in the Harvard Aging Brain Study (HABS)
Authors: Levin Raina , Vila‐Castelar Clara , Samaroo Aubryn H , Muniz Martha C. , Martinez Jairo E. , Gonzalez Christopher , Garza‐Naveda Ana Paola , Quiroz Yakeel T. , Rentz Dorene M. , Johnson Keith A. , Sperling Reisa A.
Published: December 2022

Background

Despite progress, disparities in Alzheimer’s Disease (AD) research participation continue to be a problem. Underrepresentation of certain racial and ethnic groups can result from several factors, including narrow recruitment strategies and strict exclusion criteria, and hinders our understanding of AD. We examined racial/ethnic differences in recruitment and screen failure in the Harvard Aging Brain Study (HABS), a longitudinal observational study, to elucidate these discrepancies.

Method

We analyzed HABS screening data from September 2010 to December 2021. Eligible participants were 50‐90 years old, cognitively intact (based on CDR, Logical Memory, and MMSE scores), in stable physical health, and had a study partner who could answer questions about their daily functioning. Participants were categorized into four mutually exclusive racial/ethnic groups based on self‐report data: Hispanic/Latino, White, Black, and other (Asian, American Indian/Alaskan Native, >1 Race, or did not disclose). Screen fail reasons were divided into clinical/cognitive, MRI/PET contraindications, medical and psychiatric history, and other. Statistical analyses included chi‐square, odds ratio, and t‐tests.

Result

The racial/ethnic breakdown of the 514 screened participants was 72.0% White, 14.0% Black, 10.9% Hispanic/Latino, and 3.1% other. Black participants had lower mean years of education than White participants (p < .05; Black, Mean [SD] = 14.28 [2.76]; White, 16.00 [2.96]). A total of 18.7% of participants screen failed with 17.8% of White, 19.4% of Black, and 28.6% of Hispanic/Latino participants (p > .05). Clinical/cognitive test scores were the most common reason for screen failure across all participants (41.7%), followed by medical history (26.0%). There were differences across racial/ethnic groups; compared with White participants, Black (odds ratio (OR), 2.6, 95% CI, 1.1‐5.6; p < .05) and Hispanic/Latino (OR, 2.7; 95% CI, 1.0‐6.1; p < .05) were more likely to meet exclusion criteria for cognition.

Conclusion

While efforts have been made to broaden recruitment strategies, create a Spanish‐language cohort, and revise exclusion criteria, racial/ethnic differences in recruitment and screen failure of HABS participants persist. This reflects a continued need to identify more culturally appropriate cognitive tests, norms, and cutoffs. Discovering and analyzing disparities by race/ethnicity will inform future efforts to create inclusive cohorts, leading to more representative AD research.
The CDR‐SB and other clinical trial mistakes made due to regulatory momentum
Authors: Dickson Samuel P. , Hogan Nathaniel J. , Nicodemus‐Johnson Jessie , Knowlton Newman , Hennessey Sean , Hendrix Suzanne B.
Published: December 2022

Background

In 2013 the FDA released a draft guidance for developing drugs for the treatment of early stage Alzheimer’s disease (AD) with the CDR‐SB suggested as a suitable scale for a primary outcome. Since that time, this suggestion has been treated as a regulatory requirement, but a single endpoint is preferable to the co‐primary endpoints necessary in mild‐to‐moderate populations or when using an outcome besides the CDR‐SB. Although it is true that AD progression is mostly represented by a single dimension, the FDA incorrectly claimed that CDR‐SB represents this dimension, when this would be true only for an empirically‐derived composite outcome, like ADCOMS. Years of damaging regulatory momentum surrounding clinical trial outcomes has resulted in equivocal results in nearly all development programs. The only major approval in almost two decades (aducanumab) was granted without definitive success in the primary outcome (CDR‐SB) partially because of this.

Method

Public FDA statements and documents were analyzed. Historical data from ADCS, ADNI, and publicly‐available clinical trial results were used to provide performance metrics for outcomes including CDR‐SB, ADAS‐Cog, ADCS‐ADL, ADCS‐CGIC, ADCOMS, and iADRS.

Result

Despite regulatory pressure to use CDR‐SB in early AD and co‐primary endpoints in mild‐to‐moderate populations, these endpoints are suboptimal methods for assessing the efficacy of treatments in slowing disease progression. CDR‐SB represents a 23 degree departure from the axis of disease progression. While being a composite of cognitive and functional domains itself, other proposed composite outcomes are required to demonstrate independent effects on cognition and function, despite a greater than 70% correlation between the cognitive and functional domains of CDR‐SB. The alternative of using co‐primary endpoints for a disease‐modifying treatment may require as much as a tenfold increase in sample size compared to a composite endpoint.

Conclusion

The use of CDR‐SB as the primary outcome already cost Biogen (aducanumab) credibility, will likely cost Eisai (Ban2401) around 500 patients, and will continue to cost the AD community effective treatments for years to come. Those suffering from AD are failing to benefit from treatment advances because regulatory momentum surrounding clinical trial outcomes has made it nearly impossible for clinical trials of otherwise effective treatments to succeed.
Inflammatory biomarkers are associated with changes in cerebral large artery thickness and lumen diameter in older adults
Authors: Cambronero Francis E. , Liu Dandan , Bown Corey W. , Kresge Hailey A. , Moore Elizabeth E. , Pechman Kimberly R. , Khan Omair A. , Davis L. Taylor , Gifford Katherine A. , Hohman Timothy J. , Blennow Kaj , Zetterberg Henrik , Jefferson Angela L.
Published: December 2022

Background

Age‐associated remodeling of cerebral large arteries contributes to worse systemic and brain health in older adults. Vessel wall imaging (VWI) is a neuroimaging technique that offers the critical ability to quantify thickness and lumen diameter across arterial segments of the circle of Willis (CoW). Inflammation, a well‐known feature of aging, cerebrovascular disease, and Alzheimer’s disease, may be a central driver of age‐related changes in CoW morphology. We investigate if fluid biomarkers of inflammation predict key features of intracranial arterial aging, including CoW thickening and dilatation over time.

Methods

Vanderbilt Memory and Aging Project participants were studied (n=96, 73±7 years, 80% male, mean follow‐up=3.0 years). Baseline systemic inflammatory biomarkers (TNF‐α, IL‐6) were quantified from blood plasma samples. Baseline neuroinflammatory biomarkers (sTREM2, YKL‐40, MMP‐2, MMP‐3, MMP‐9) were quantified from cerebrospinal fluid samples. Intracranial artery lumen diameter and thickness were manually measured across the basilar artery (BA) and bilateral segments of the internal carotid artery (ICA), anterior cerebral artery (ACA), and middle cerebral artery (MCA) using serial VWI MRI. Linear mixed effects regressions related time x inflammatory biomarker (one predictor per model) to longitudinal VWI lumen diameter and thickness outcomes, adjusting for baseline age, sex, race/ethnicity, education, Framingham Stroke Risk Profile, cognitive status, apolipoprotein ε4 status, T1‐weighted intracranial volume, and time.

Results

Higher CSF sTREM2 levels related to faster luminal narrowing (right ACA, p‐value=0.001). Higher CSF YKL‐40 levels related to faster luminal narrowing (right ACA, p‐value=0.07). Lower CSF MMP‐2 levels related to faster wall thickening (left MCA, p‐value<0.05). Lower CSF MMP‐3 levels related to luminal narrowing, while higher CSF MMP‐3 levels related to luminal widening (left ICA, p‐value=0.05). TNF‐α, IL‐6, and MMP‐9 were unrelated to any VWI changes (p‐values>0.14).

Conclusion

Results suggest neuroinflammatory biomarkers are largely related to longitudinal intracranial artery narrowing and thickening. However, additional associations between MMPs and luminal widening may reflect the mixed nature of MMP activity on cerebrovascular remodeling. Immune responses mediated by astroglial and microglial activity as well as MMPs may be key pathophysiological mechanisms underlying age‐related cerebral arterial remodeling.
Developing a new clinical interview to assess awareness in dementia.
Authors: Alexander Catherine Maria , Martyr Anthony , Clare Linda ,   in collaboration with the IDEAL programme research team
Published: December 2022

Background

People with dementia differ in degree of awareness of difficulties. Awareness can influence well‐being, communication and relationships, and impact on personal safety and decision‐making in everyday and clinical situations. Evaluating awareness could facilitate person‐centered care. A scoping review identified the lack of a brief, multidimensional clinical tool. We aimed to develop and test a new awareness interview for clinical use.

Method

Measure development was informed by scoping review findings, available evidence about awareness phenomena in dementia, and considerations of suitability for remote as well as in‐person administration. Some items were drawn from existing validated measures, covering awareness of functional ability, memory, and socio‐emotional functioning, and new items were developed to assess awareness of medication management and mobility, providing a profile of awareness across these domains. Scoring was based on calculation of discrepancies between self‐rating and either informant ratings or objective memory task performance, as well as self‐reported acknowledgement of specific symptoms. The interview was tested for feasibility and acceptability in a remotely‐administered pilot study. The interview was administered to 31 community‐dwelling people with mild‐to‐moderate dementia recruited in England in 2020‐2021, via telephone or Zoom video‐call. A caregiver, acting as an informant, completed a corresponding questionnaire in advance. Cognitive ability of the participant with dementia was assessed with the Montreal Cognitive Assessment‐5 minute protocol (MoCA‐5 min). Structured and open‐ended feedback was obtained from participants and caregivers

Result

The interview was completed by 29 participants with MoCA‐5 min scores ranging from 9.5 to 29.Two participants with lower MoCA‐5 min scores were unable to complete the interview. Remote administration was straightforward with few challenges, taking on average under 11 minutes. Awareness profiles showed a spectrum of awareness across domains. Feedback indicated that interview questions were acceptable and understandable, but certain aspects, such as the memory task, could be somewhat upsetting as they highlighted current difficulties.

Conclusion

The new Healthcare Awareness Profile Interview (HAPI) shows potential as an evidence‐based brief clinical tool for assessing awareness in people with mild‐to‐moderate dementia. Following discussions with clinical advisory and patient and public involvement groups, a final version will be prepared for a larger validation study.
Elucidating Multi‐Stage Progression of Neuro‐degeneration Process in Alzheimer’s Disease
Authors: Ma Haixu , Liu Yufeng , Wu Guorong
Published: December 2022

Background

Mounting evidence shows that an individual’s neurodegeneration process exhibits wide heterogeneity in clinical manifestation. Since early symptomatic interventions may ultimately constitute the best long‐term therapeutic strategy, it is vital to disentangle the diverse neurodegeneration process into several distinct progression stages and understand the stage‐specific interaction between AD biomarkers and risk factors.

Method

We aim to understand the pathophysiological mechanism of multi‐stage disease progression as well as the role of risk factors that contribute to the diversities of neurodegeneration in the development of AD. Our statistical inference is performed on 2,352subjects with amyloid‐PET scans, 836 subjects with tau‐PET scans, 2,546 subjects with FDG‐PET scans. The cognitive decline is measured by MMSE score.

Result

(1) Both amyloid and tau pathologies contribute to cognitive decline at a constant pace in the APOE4 carrier cohort. In contrast, APOE4 non‐carriers show more diversities in the time course of the neurodegenerative process. The multi‐stage cognitive decline in APOE4 non‐carrier populations suggests the necessity of adjusting treatment as the disease progresses. (2) The decline pattern with respect to tau pathology shows more diversity in terms of progression stages (three transition points have been detected) than amyloid pathology (no transition has been detected) in the aging population. As the neurodegenerative process is most likely non‐linear, this result provides lateral evidence that measuring the tau level in a longitudinal manner is more beneficial than using the amyloid biomarker in tracking cognitive decline. (3) We find the pathological process that AD pathology (measured by CSF tau/Aβ ratio) leads to the reduction of metabolism level exhibits three progression stages. In addition, such multi‐stage progression pattern of pathology‐to‐neurodegeneration relationship only exists in males instead of females. (4) We find APOE4 status is a predominant risk factor deeply involved in the critical transition points of disease progression. Regarding the modifiable variable, education level plays a significant role in modulating the disease progression in AD.

Conclusion

We disentangle the heterogeneous temporal behavior of pathophysiological mechanisms in AD, which allows us to advance our understanding of disease diversity in AD. These findings provide a new window to manage the priority of risk factors more effectively in AD treatment.
Resistance training improves white matter structural connectivity in older adults at‐risk for cognitive decline
Authors: Lien Ryu , Furlano Joyla , Nagamatsu Lindsay ,   Exercise, Mobility, and Brain Health Lab
Published: December 2022

Background

Diabetes is a global health concern that impacts 415 million people worldwide. Individuals who are at‐risk for diabetes (characterized by high blood glucose and/or being overweight) have white matter atrophy, decreased cognitive function, and an increased risk of Alzheimer’s disease (AD). Recently, resistance training (RT) has been shown to lower white matter atrophy and white matter lesion volume. However, investigating changes in white matter tracts is complex, hence previous findings remain inconclusive. Diffusion tensor imaging (DTI) serves as a highly sensitive tool that enables visualization and characterization of white matter tracts and has the potential to combat this complexity. The study aimed to measure the effects of RT on structural connectivity in older adults at‐risk for cognitive decline using DTI.

Method

We conducted a 6‐month, thrice‐weekly randomized controlled trial. Twenty‐four participants (aged 60‐80 years, sedentary; body mass index ≥25) were randomized into one of two groups: 1) progressive resistance (weight) training (RT), or 2) balance and tone (BAT; control group). High resolution DTI images were obtained using a 3T Siemens MRI scanner at both baseline and endpoint for 17 (RT:11, BAT:6) participants. Images were analyzed using FSL’s tract based spatial statistics (TBSS) to evaluate structural connectivity between groups based on fractional anisotropy (FA), a measure reflecting fiber density, axonal diameter, and myelination in white matter tracts.

Results

Six months of RT led to higher FA values in the splenium of the corpus callosum, right posterior thalamic radiation, right and left superior corona radiata (+0.56%, +0.90%, +0.64% and +0.66%, respectively) compared to BAT (+0.16%, ‐0.72%, ‐0.28% and ‐0.24%).

Conclusion

These findings suggest that RT is associated with improvements in WM fiber microstructural integrity related to motor functions and visual short term memory capacity (vSTM). Thus, resistance training may be a promising intervention for patients with AD as the literature suggests that motor function deficits and vSTM dysfunction are early markers of AD pathology.