bluuebunny/crossref_metadata_2025 huggingface dataset:
NIA’s qualitative message testing: optimizing how to communicate Alzheimer’s and related dementia research with the public
Authors: Thomas Christopher G
Published: December 2023

Background

Communicating the latest advances in Alzheimer’s disease and related dementias (AD/ADRD) research to the public is part of the NIH National Institute on Aging’s mission and strategic directions plan. To further this goal, the NIA Office of Communications and Public Liaison obtained insights from focus groups and in‐depth interviews (IDIs) to optimize language used in public outreach efforts.

Method

NIA contracted the public opinion company Edge Research to conduct a qualitative study. NIA messages about AD/ADRD research were tested in five focus groups and six IDIs. Of the focus groups, three were with at‐risk Individuals (people with family history) and two were with caregivers for someone with Alzheimer’s or a related dementia. The six IDIs were with individuals who were experiencing symptoms of dementia or who had been diagnosed by their doctor with early signs of Alzheimer’s or a related dementia. The messages tested relayed information about AD/ADRD research basics, progress, future direction, and clinical trial participation.

Result

The results suggested that current NIA messaging communicates many key ideas and information as intended and that government sources of information about dementia generally are trusted. Nevertheless, even among those who are symptomatic, have a family history, or who spend their days as a caregiver, knowledge about AD/ADRD is imperfect and sometimes vague. Additionally, respondents could not recall information about the latest in dementia research; and they were hesitant to participate in clinical trials in part because of a misconception that all trials involve a medication.

Conclusion

The results reinforced the need for ongoing efforts to communicate about AD/ADRD research to the public. NIA is incorporating feedback and recommendations in current and future materials.
Evaluation of functionality after three years of subjective cognitive complaint in the elderly
Authors: Marques Fernanda Mariotti , Gonçalves Eduardo C Q , Kahtalian Lais Lundstedt , Neubern Patricia Cardoso Buchain , Ribeiz Salma Rose Imanari , Filho Geraldo Busatto
Published: December 2023

Background

Subjective cognitive decline (SCD) is defined as the self‐reported experience of cognitive decline in subjects with normal performance on neuropsychological tests, and expectedly with preserved functionality. This condition is associated with a higher risk for developing objective cognitive decline and dementia. The objective of this study is to carry out a descriptive analysis of the B‐ADL scale in elders 24 to 48 months after SCD identification.

Method

Forty‐three participants aged 60 years and over without clinically relevant depressive symptoms (CESD<16) and without cognitive impairment (MMSE≥14) were randomly selected from a group of users of basic health units in the city of São Paulo. The Clinical Memory Inventory and a questionnaire about perceived memory problems (i.e.: “have you had memory problems lately?”) were applied and 24 to 48 months later an informant answered the Bayer Activities of Daily Living Scale (B‐ADL).

Result

The mean age of the total sample was 70.7 years. There were 22 women, 45.5% of whom had SCD, and 21 men, 23.8% of whom had SCD. The group with SCD had a mean age of 70.1 years, while in the group without SCD the mean age was 71 years. The group without SCD had a mean B‐ADL score of 1.26 and the group with SCD had 1.32 . Eighteen subjects (41.9%) did not score in B‐ADL. Out of these, 12 (66,6%) were elderly without SCD while 6 (33,3%) had SCD.

Conclusion

After three years of identification, the SCD group showed no functional impairment. Other studies with larger samples may help elucidate the relationship between subjective cognitive decline and functionality.
Identification of Alzheimer’s disease in Veteran patients using clinical notes from electronic health records
Authors: Miller Donald R , Aguilar Byron J. , Li Xuyang , Shishova Ekaterina , Jasuja Guneet , Berlowitz Dan , Morin Peter J , O'Connor Maureen K. , Nguyen Andrew H. , Christiansen Cindy , Zhang Haixin , Monfared Amir Abbas Tahami , Zhang Quanwu , Xia Weiming
Published: December 2023

Background

There are challenges in studying and monitoring Alzheimer’s disease (AD) in large patient populations. Clinicians often have insufficient availability of resources to make the diagnosis (e.g. brain scanning, referral to specialists) and clinical inertia may be tied to the perception that there are no clinical benefits in making the differential diagnosis of this stigmatized disease. Consequently, diagnosis codes specifically for AD are underutilized and prevalence is generally underestimated. Our goal was to improve identification of probable AD in a large patient population with the development and application of a refined search algorithm of computerized clinical notes contained in electronic health records.

Method

Our methods were developed using records for all Veteran patients in the national Department of Veterans Affairs Healthcare System (VA) in fiscal years 2010‐2019. Starting with initial searches for “Alzheimer” and related terms in all clinical notes, the algorithm was optimized through an iterative process. Multiple references to “Alz” in notes were evaluated separately and chunks were excluded when the term referred to family history, care facilities, or negative statements, or when it was part of text in assessment instruments or medication indications. The final algorithm was validated through manual reviews of over 2,400 randomly selected patient charts (predictive value positive = 86.3%; kappa = 0.76 among 2‐4 reviewers).

Result

When the algorithm was applied to records for the nearly 5 million VA patients over 50 years of age in fiscal year (FY) 2019, we identified 141,816 with probable AD, nearly five times the count based on ICD‐10 codes (30,090). Prevalence, standardized to the 2010 census for age and sex, was 2.70%, with higher prevalence in women (3.26%) than in men (2.06%). Median age of probable AD patients was 75 years.

Conclusion

As disease modifying treatments for AD enter the market, there will be more focus on proper diagnosis of AD, particularly early in the disease process, emphasizing the importance of better identification of the disease in patient populations. This method, based on searches of clinical notes, appears to be promising to identify patients with probable AD and study its progression in large patient populations.
Ambient RNA from CSF to capture brain cell‐type signatures in AD and other neurodegenerative diseases
Authors: Kaczaral Jacqueline , Buss Jared , Eteleeb Abdallah , Novotny Brenna C , D'Oliveira Albanus Ricardo , Brase Logan , Benitez Bruno A. , Karch Celeste M. , Piccio Laura , Ter‐Ovanesyan Dima , Harari Oscar
Published: December 2023

Background

We leveraged digital deconvolution methods to determine cellular changes from brain transcriptomics of Alzheimer’s Disease(AD), and identified a change in cellular proportion between neuropathology, and severity of the disease as determined by Clinical Dementia Rating[5]. We expanded these approaches to Cerebral Spinal Fluid(CSF), to evaluate cellular changes associated with disease progresses.

Method

We used RNAseq data from published sources to test and refine a gene panel to deconvolve ambient RNA from CSF. Candidate marker genes were selected via literature search and verified using the brainseq [1] along with the human brain single‐cell gene expression [2]. We optimized gene panels using the leave‐one‐out cross‐validation method to predict proportions of neurons, astrocytes, microglia, oligodendrocytes, macrophages and endothelial cells, using bulk and ambient RNA sequenced in single‐cell transcriptomics.

Result

We leveraged our deconvolution to ascertain whether ambient RNA captured in single‐cell gene expression from the CSF captures the cellular population structure of the brain. Preliminary results show that cellular signatures for non‐immune cells are present in CSF in AD (Gate et al. (n = 9, Control = 3, MCI = 3, AD = 3)[3] and Multiple Sclerosis(MS)(Ramesh et al. (n = 15, Control = 3, MS = 12)[4]), and the proportions of those non‐immune cells change depending on the disease state. In MS, there is an increase in the proportion of Astrocytes (p = 3.4×10e‐2) in MS samples. Similar results were found for Neurons (p = 4.4×10e‐2) and Oligodendrocyte Precursor Cells (OPC) (p = 8.2×10e‐3). In AD, we identified significant differences between AD, MCI and controls (p = 0.01) in OPC.

Conclusion

These results show that ambient RNA in the CSF can capture subtle differences in cellular population structure in AD and MS. These analyses were done on a small sample size, but show the potential to analyze larger cohorts and cell‐type specific transcriptional states. We also plan to expand the process to other neurologic diseases.

References:

[1] Zhang et al. 2015

[2] Brase et al. “A landscape of the genetic and cellular heterogeneity in Alzheimer disease” In press

[3] Gate et al. “Clonally expanded CD8 T cells patrol the cerebrospinal fluid in Alzheimer’s disease” 2020

[4] Ramesh et al. “A pathogenic and clonally expanded B cell transcriptome in active multiple sclerosis” 2020

[5] Li et al. 2018
Validation of the effect of soundscape on the well‐being and behaviour of people with dementia: a randomized clinical trial
Authors: Talebzadeh Arezoo , Iaboni Andrea , Botteldooren Dick , Devos Paul , Vriendt Patricia De , de Velde Dominique Van
Published: December 2023

Background

Using the Soundscape approach to design an environment that improves people’s quality of life is crucial. This approach is more challenging for people with dementia. This project uses a personalized algorithm to play sounds at prescheduled moments throughout the night in patients’ rooms in a research hospital specializing in dementia care to evaluate the reduction in resistance to care and agitation.

Method

A single‐blind repeated measure randomized clinical trial is designed to estimate the overall or average effects of the customized soundscape on people with dementia. Twenty‐six participants were randomized into two groups of AcustiCare (n = 13) and Treatment as usual (n = 13) for six weeks for each study group.

Result

The primary outcomes of this study were the NPI‐total score and the PAS‐resisting care subscale. In a linear mixed effects model, there were improvements in the NPI‐total scores over time in both groups (‐5.9 +/‐1.3; ρ<0.001). With the PAS‐resisting care subscale, a significant group x time difference, with a greater reduction in PAS‐resisting care score in the AcustiCare group (‐0.81 +/‐ 0.4; ρ = 0.042).

Conclusion

People with dementia can benefit from augmented sonic environments since auditory stimulation can reduce agitation and anxiety and provide safety and familiarity. The outcome of a small sample size showed improvement in resistance to care and reduction in agitation; These results can also be used to calculate effect size and determine the sample size for a future RCT.
Designing Intersectoral Environments to Address Isolation/Loneliness as a Risk Factor for Dementia: A Mixed Methods Health Promotion Program
Authors: Valente Thomas W. , Yang Seiyan , Francioni Arnaud , Walsh Chesley , Belchior Patricia , Bourdais Marie Christine Le , Park Melissa
Published: December 2023

Background

Intersectoral partnerships are critical for effective and sustainable health promotion programs. The aim of our Public Health Agency of Canada Dementia Community Investment project, What Connects Us∼Ce Qui Nous Lie (2020‐2023) was to collaboratively cultivate sociocultural environments worth living in using shared activities and events. In this paper, we present initial results on the effectiveness of using shared activities and events to link academic, arts/culture, mental health, and community‐based organizations and generate a sustainable web of resources for, while positively impacting on, the quality of life and connectivity as a protective factor for persons living with Alzheimer’s and related disorders (PLWA) and their carers.

Method

We used a mixed methods ethnographic approach to describe and measure the impact of shared activities and events on the intersectoral networks by fielding pre‐/post‐partner social network surveys distributed across four social sectors using standard intersectoral network metrics such as density, clustering, centralization, and average path length; as well as measures of centrality and bridging among partners. We measured the impact of this intervention se with pre‐/post‐activity participant surveys using the UCLA Loneliness scale and the CDC health quality of life instrument. All partners and participants answered demographic questions.

Result

Network measures showed an increase from the initial number of organizations who submitted letters of support for the project (N = 16), as well as increases in network density at the intersectoral level. Patterns of centrality and bridging in the partner data are still emerging, with arts/cultural organizations being the most engaged in facilitating activities and events. For the participants in activities who completed surveys, emerging data demonstrate that those who participated in multiple activities had lower loneliness scores (N = 117 of the 370). Descriptions of context across the project support its upscaling, including the mechanisms that supported the continued growth in number, variety, and modifications of activities despite the impact of Covid‐19 on social distancing.

Conclusion

Community‐based efforts to create environments to reduce loneliness are possible but require effort to create sustainable intersectoral networks amidst structural and other leadership changes.
High Precision β‐Amyloid 1‐40, β‐Amyloid 1‐42, and Ptau181 Plasma Assay Performance in NCRAD Biomarker Assay Laboratory
Authors: Russ Kristen A. , Smith Emily , Kostadinova Ralitsa V. , Gao Sujuan , Brown Steve , Apostolova Liana G. , Risacher Shannon L , Saykin Andrew J. , Foroud Tatiana M. , Dage Jeff L.
Published: December 2023

Background

To achieve the robust and reliable implementation of assays in the National Centralized Repository for Alzheimer’s Disease and related Dementias (NCRAD), new assays and platforms must be assessed for performance characteristics. The goal of this study is to assess the [Fujirebio Lumipulse] G1200 performance in comparison to existing platforms

Method

Plasma samples utilized for assay precision measurements were collected from healthy control subjects and patients with Alzheimer’s disease (AD) by the Indiana Biobank. Five samples were chosen to span the assay range and were assayed on two separate days. Clinical utility was assessed with plasma samples (N = 179) collected by the Indiana Alzheimer’s Disease Research Center (IADRC). A subset (N = 92) of these samples were also assayed on the Neurology 4‐Plex E Advantage Kit on the [Quanterix] Simoa‐HDx platform. All samples were assayed on the [Fujirebio Lumipulse] G β‐Amyloid 1‐40, β‐Amyloid 1‐42, and Ptau181 plasma assays.

Result

[Fujirebio Lumipulse] G β‐Amyloid 1‐40, β‐Amyloid 1‐42, and Ptau181 plasma assays had an average inter‐assay coefficient of variation of 2.6%, 2%, and 2% respectively (Figure 1). In samples with both [Fujirebio Lumipulse] and Simoa‐HDx pTau181 data, linear regression showed an R^2 of 0.80 and slope of 1.67. Bland‐Altman analysis showed a consistent bias of 54%. Once results were standardized by Z‐score, slope was near one, y‐intercept near zero, demonstrating comparability of results. Area Under Receiver Operating Characteristic curve (AUC) for IADRC samples with PET data was 0.84 for Aβ 42/40 ratio alone and 0.87 including age, sex and APOE status. AUC for Ptau181 alone was 0.83 and 0.89 including age, sex and APOE status. Assays were able to detect differences in clinical diagnosis or amyloid status (Figure 2A and B).

Conclusion

The [Fujirebio Lumipulse] assays exhibited high precision. When standardized by Z‐score, the [Fujirebio Lumipulse] Ptau181 assay was comparable to the Simoa‐HDx Ptau181v2 assay allowing comparison of data between assay platforms. AUCs for amyloid PET were higher when considering age, sex and APOE status in the model. The assays were able to differentiate between clinical diagnoses and amyloid status suggesting suitability for implementation.
Detection of subclinical epileptiform discharges in Alzheimer’s disease using long‐term out‐patient EEG monitoring
Authors: Musaeus Christian Sandøe , Frederiksen Kristian Steen , Bo Andersen Birgitte , Høgh Peter , Kidmose Preben , Fabricius Martin , Hribljan Melita Cacic , Hemmsen Martin Christian , Rank Mike Lind , Waldemar Gunhild , Kjaer Troels Wesenberg
Published: December 2023

Background

In patients with Alzheimer’s disease (AD) without clinical seizures, up to half have epileptiform discharges in long‐term in‐patient electroencephalography (EEG) recordings. Long‐term in‐patient monitoring is obtrusive, and expensive as compared to out‐patient monitoring. No studies have so far investigated if long‐term out‐patient EEG monitoring is able to identify epileptiform discharges in AD. To investigate if epileptiform discharges as measured with ear‐EEG are more common in patients with AD compared to healthy elderly controls (HC). To understand the association with AD, we investigated the variability across multiple recordings.

Method

In this longitudinal observational study, 24 patients with mild to moderate AD and 15 age‐matched HC were included in the analysis. Patients with AD underwent up to three ear‐EEG recordings, each lasting up to two days, within 6 months. The first recording was defined as the baseline recording.

Result

At baseline, epileptiform discharges were detected in 75.0% of patients with AD and in 46.7% of HC (p‐value = 0.073). The spike frequency (spikes or sharp waves/24 hours) was significantly higher in patients with AD as compared to HC with a risk ratio of 2.90 (CI: 1.77‐5.01, p<0.001). Most patients with AD (91.7%) showed epileptiform discharges when combining all ear‐EEG recordings.

Conclusion

Long‐term ear‐EEG monitoring detects epileptiform discharges in most patients with AD with a three‐fold increased spike frequency compared to HC, which most likely originates from the temporal lobes. Since most patients showed epileptiform discharges with multiple recordings, elevated spike frequency should be considered a marker of hyperexcitability in AD.
Identification of rare coding variants associated with Alzheimer’s disease.
Authors: Khurshid Zainab , Farrer Lindsay A. , Zhang Xiaoling , Martin Eden R. , Kuzma Amanda B , Farrell John , Tong Tong , Zhu Congcong , Naj Adam C. , Cantwell Laura B , Valladares Otto , Wang Li‐San , Lunetta Kathryn L. , Schellenberg Gerald D. , Haines Jonathan L. , Leung Yuk Yee , Pericak‐Vance Margaret A.
Published: December 2023

Background

Previous whole exome sequencing (WES) studies of Alzheimer’s disease (AD) have identified genome‐wide significant associations with rare variants in several novel genes and highlighted the need for investigations in larger samples. We combined WES and whole genome sequencing (WGS) data assembled by the Alzheimer Disease Sequencing Project (ADSP) to increase the power for detecting associations of AD with rare variants in gene coding regions.

Method

We developed an efficient computational pipeline to perform both pre‐merging and post‐merging genotype, variant and sample‐level quality control (QC) on WGS data containing 16,905 individuals and WES data for 20,504 individuals. The resultant sample included participants from European (EA, 11,279 AD cases, 8,924 controls), African American (AA, 2,757 AD cases, 4,336 controls), and Caribbean Hispanic (CH 1,438 AD cases, 3,256 controls) ancestries. We employed GENESIS to test association of AD with 250,465 bi‐allelic QC’d variants using a logistic model including covariates for age, sex, exome capture kit, read length, and ancestry principal components (PCs).

Result

In the total sample, variants from APOE and other known AD genes including SORL1 (P = 5.30×10‐7), NECTIN2 (P = 6.94×10‐7), and TREM2 R47H (P = 2.34×10‐13) crossed or neared the study‐wide significance (SWS) threshold of P = 2.00×10‐7 (0.05/250,465). SWS or borderline significant associations were also found with variants in several novel loci including TKTL2 (P = 2.35×10‐8), D2HGDH, (P = 1.09×10‐7), CECR1 (P = 4.02×10‐7), PDHA2 (P = 2.76×10‐7), GOLGA1 (P = 1.72×10‐7), CYLD (P = 1.84×10‐7), and RP11‐243M5.4 (P = 1.37×10‐7). PSEN1 missense mutation G206A (rs63750082) previously associated with early onset AD in the CH group, was significantly associated with late onset AD in the same population (P = 1.58×10‐13). SWS association of AD with APOE was observed in all groups. Significant associations were also observed with variants in SERPINB8 (P = 3.77×10‐9) and FAM171A (P = 7.20×10‐7) in EAs and TLR4 (P = 4.58×10‐7) in CH. Associations with several top‐ranked variants were replicated in the Alzheimer’s Disease Genetics Consortium GWAS dataset that were imputed using the TOPMed reference panel and ADSP 5K WGS dataset.

Conclusion

We demonstrated that merging WGS and WES datasets can increase power to detect associations with rare coding variants in genes including ones previously implicated in AD (CYLD and TLR4) and early‐onset stroke (CECR1).
Early screening for Alzheimer’s disease (AD) in subjects with age‐related macular degeneration: Associated risk factors and impact on their quality of life
Authors: Martinez Luis E , Martinez Sara Carolina , Baracaldo Gabriela
Published: December 2023

Background

Age‐associated macular degeneration (AMD) is one of the main causes of central vision loss in one or both eyes, Multiple studies have shown that AMD and Alzheimer’s disease (AD) have risk factors and histopathological changes in common, such as the constitution of protein deposits.

Method

Case‐control type analysis study, On a sample of 236 subjects, of whom 118 present AMD (cases) from the Colombian Ophthalmology Center in the city of Bogotá and 118 non‐DMR (controls) an analytical study of biomarkers for Alzheimer’s disease (ApoE) is performed to establish the degree of association between AMD and AD. After performing anamnesis and risk factors questionnaire, the fundus of the eye is studied by means of a Topcon TRV‐50VT type non midritic camera confirming the AMD, and Neuropsychological evaluation for cognitive impairment (MMSE, MOCA, MOCA BASICA and MOCA BLIND) for detection of MCI or AD and QOLIE quality of life questionnaire.

Result

Study in progress, in the phase of recruitment of subjects to participate, in the ophthalmological center in Bogotá. Visual abnormalities are prominent in AD and are believed to develop before cognitive decline, with our study we proposed the hypothesis of correlation for biomarkers (+) especially for ApoE 4 in blood for subjects with AMD and AD/MCI. On the other hand, we propose Correlation of ApoE2 or ApoE3 for biomarkers in the control group. In addition, we hope to correct the risk factors in both pathologies, we also plan a significant impact on quality of life for subjects with AMD and AD/MCI compared to the other groups.

Conclusion

Many of the protein accumulations associated with druses have been identified as responsible for the pathogenesis of other diseases such as AD, arteriosclerosis and amyloidosis, opening the possibility of common origins. Apo E is a cholesterol‐carrying protein that is present in hard and soft druses, in the brain one of the functions of Apo E is to regulate cholesterol during the process of neuronal remodeling. The apolipoprotein E allele inheritance is involved in the pathogenesis of arteriosclerosis and AD but with a decreased risk of exudative AMD.
Design of a Phase 2, Randomized, Double‐Blind, Placebo‐Controlled, Parallel‐Group Study to Assess the Efficacy, Safety, and Tolerability of BIIB080 in Subjects with Mild Cognitive Impairment Due to Alzheimer’s Disease or Mild Alzheimer’s Disease Dementia
Authors: Ziogas Nick , Mummery Catherine J. , Rovira Mercè Boada , Cummings Jeffrey L. , Fox Nick C , Hansson Oskar , Iwata Atsushi , Salloway Stephen , Schneider Anja , Unwin Anne , Huang Ellen , Edwards Amanda , Tien Irene , Wu Shuang , Lin Lin , Shulman Melanie , Landen Jaren , Haeberlein Samantha Budd
Published: December 2023

Background

BIIB080 (formerly IONIS MAPT‐RX) is an antisense oligonucleotide (ASO) designed to bind to MAPT pre‐mRNA, promote its degradation, and prevent translation of all forms of tau protein. BIIB080 is, to our knowledge, the first tau targeting ASO to enter human clinical trials in Alzheimer’s disease (AD).

BIIB080 was evaluated in Study ISIS 814907‐CS1 (NCT03186989) a Phase 1b, placebo‐controlled, double blind, multiple ascending dose clinical trial with 13‐week treatment period and 23‐week follow‐up period followed by an open‐label long term extension in patients with mild Alzheimer’s disease. BIIB080 was generally well tolerated. Importantly, robust, time‐dependent and dose‐dependent decreases in CSF total and phosphorylated tau were observed. Additionally, BIIB080 impacted aggregated tau pathology as measured by tau PET as early as 25 weeks.

Based on the Phase 1b results, Biogen is conducting a Phase 2 study, Study 247AD201 (NCT05399888) that will evaluate the efficacy, safety, and tolerability of BIIB080 in participants with mild cognitive impairment (MCI) due to Alzheimer’s disease or mild Alzheimer’s disease dementia.

Method

Randomized, double‐blind, placebo‐controlled, parallel‐group Phase 2 study (CELIA), is enrolling approximately 735 individuals aged 50‐80 years, with MCI due to Alzheimer’s disease or mild Alzheimer’s disease dementia, Clinical Dementia Rating (CDR) global score 0.5‐1, Mini Mental State Examination (MMSE) score 22‐30, objective evidence of cognitive impairment at Screening, and evidence of amyloid pathology as measured by PET or cerebrospinal fluid (CSF) sampling.

The Phase 2 study will randomize participants to receive 1 of 3 different dose regimens of intrathecal (IT) BIIB080 or placebo every 12 or 24 weeks during the 76‐week placebo‐controlled period. The primary endpoint will assess the dose‐response in change from Baseline to Week 76 on the CDR‐SB.

The study includes a tau PET substudy to assess the effect of BIIB080 on tau aggregates with 18F‐MK6240.

Result

The Ph2 CELIA study is currently recruiting participants.

Conclusion

The ongoing Ph2 CELIA trial will assess the efficacy, safety and tolerability of BIIB080, compared to placebo in subjects with MCI due to Alzheimer’s disease or mild Alzheimer’s disease dementia.
Effect of long‐term treatment with carbonic anhydrase inhibitors on the brain microcirculation in Tg‐SwDI mice
Authors: Gutiérrez‐Jiménez Eugenio , Rasmussen Peter Mondrup , Mikkelsen Irene Klærke , Kura Sreekanth , Fruekilde Signe Kirk , Bordoni Luca , Boas David , Fossati Silvia , Østergaard Leif
Published: December 2023

Background

Alzheimer’s disease (AD) shares many risk factors with cardiovascular diseases, and much evidence shows that AD involves a cerebrovascular component. AD patients display disturbances in brain hemodynamics characterized by decreased cerebral blood flow (CBF) during steady‐state conditions. It has been suggested that capillary stalls heavily impact the CBF of AD animal models. Increased stalling time may impair capillary flow patterns, reducing oxygen availability to the brain tissue. Previous studies have shown that capillary stalling is induced by leukocyte plugging due to damage to the capillary endothelium and adhesion molecules' expression. Carbonic anhydrase inhibitors (CAIs), potent vasodilators, have been shown to reduce amyloid β (Aβ) neurovascular toxicity. We examined capillary hemodynamics in the Tg‐SwDI mouse model after long‐term treatment with CAIs.

Method

Four months old Tg‐SwDI mice were fed for 140 – 150 days with a diet supplemented with acetazolamide (ATZ), methazolamide (MTZ), or no medication (Tg‐Ctrl). A control group of wild‐type (WT) mice was also included. We performed imaging in awake head‐restrained Tg‐SwDI and WT mice through a cranial window placed onto the barrel cortex’s somatosensory area. Capillary stalls were quantified using time‐series OCT‐angiography. We examined capillary hemodynamics, morphometrics, and amyloid load using two‐photon microscopy. The distribution of flow dynamics was estimated as the coefficient of variance (CVs) of capillary scans. Amyloid load and ICAM‐1 expression were measured in the brain cortex and hippocampus using ELISA.

Result

We included 62 mice (mean 16 ± 3 per group). Both treated groups showed a decreased stalling time compared to the Tg‐Ctrl group (p < 0.05). Mice treated with MTZ showed larger capillary diameters correlated to increased cell flux and velocity (p ≤ 0.01). We observed a similar in mice treated with ATZ. Cell velocity and diameter CVs were much smaller in mice treated with ATZ than in non‐treated mice (p < 0.01), indicating more homogenous capillary flow patterns. We observed a similar tendency in the MTZ group. Hemodynamic changes were associated with decreased Ab‐42 and ICAM‐1.

Conclusion

Treatment with CAIs improves capillary flow hemodynamics and distribution, preventing amyloid accumulation in brain tissue. Improvement of capillary flow patterns is associated with better oxygen diffusion.
Longitudinal analysis in an Alzheimer’s murine model reveals sex‐specific inflammatory response
Authors: Barber Alicia J , del Genio Carmen L , Pizzi Elizabeth , Swain Anna Beth , Tapiavala Vedant N , Watson Sarah C , Mah'moud Mirelle M , Zanazzi George J , Gaur Arti B
Published: December 2023

Background

Striking sex‐related differences are observed in individuals with Alzheimer’s disease (AD). Females with AD largely present with more severe neuropathology, yet surprisingly, males with AD have an increased risk of mortality. To elucidate this dichotomy, we conducted a longitudinal study in an AD mouse model, aimed at identifying cellular and molecular based drivers of sex‐specific disease trajectories.

Method

Tissues were collected from 3xTg‐AD and control mice of both sexes across the lifespan (3‐24 months) and stained with H&E (liver, spleen, heart, lungs, kidney) or beta‐amyloid, phospho‐tau, and total tau antibodies (brain). Brain tissue was also used for RNA‐sequencing. Sex‐specific differential gene expression and ingenuity pathway analyses were conducted between age‐matched 3xTg‐AD and control brain tissue samples, in addition to clinical AD and control brain tissue samples obtained from the AD Knowledge Portal RNAseq Harmonization Study.

Result

Over the course of our longitudinal study, we confirmed that female 3xTg‐AD mice exhibit more severe Alzheimer’s related neuropathology than males. Surprisingly, 3xTg‐AD males do not develop amyloid plaque pathology within their lifespan, however, they do experience significantly worse splenomegaly, myocardial injury, and liver inflammation in old age, resulting in higher mortality, compared to females. Changes observed in gene expression across the lifespan of both sexes show significant upregulation of various inflammatory pathways in the brain, including the complement system. However, in line with pathological findings, aged female 3xTg‐AD mice exhibit sex‐specific dysregulation of synaptic and endocrine pathways in the brain, while male 3xTg‐AD mice exhibit sex‐specific dysregulation of TREM1 signaling, hepatic dysfunction, and additional immune‐related pathways. Many canonical pathways disrupted in 3xTg‐AD mice were also detected in clinical AD samples, including pathogen induced cytokine storm signaling, S100 family signaling, and hepatic fibrosis/hepatic stellate cell activation.

Conclusion

Our results show widespread inflammatory responses in the 3xTg‐AD model, that are exacerbated in male mice, suggesting a systemic impact of Alzheimer’s disease involving liver dysfunction. Furthermore, neuroinflammation is not correlated with amyloid plaque deposition in 3xTg‐AD mice, raising important questions surrounding the protein’s role in disease progression. Our analyses of clinical AD RNA‐sequencing data further validate the gene expression changes observed in 3xTg‐AD mice.
Can we use machine learning to predict cognitive performance from actigraphy data? Preliminary results from the UK Biobank Study
Authors: Falck Ryan S , Liu‐Ambrose Teresa , Galea Liisa A , Tam Roger
Published: December 2023

Background

Circadian rhythms (i.e., the ∼24‐hour biological clock) are critical to the maintenance of the sleep‐wake cycle, and sleep‐wake disturbances are common in people at risk for cognitive decline and dementia. Several studies have identified circadian factors associated with cognitive decline using actigraphy (a common field measure for indexing the sleep‐wake cycle). However, there are currently untapped opportunities to use the power of artificial intelligence, specifically machine learning (ML), to improve our ability to identify signs of cognitive decline from actigraphy data. As a first step towards this goal, we examined the utility of two supervised ML models for predicting cognitive performance using data from the UK Biobank study.

Method

A cross‐sectional analysis of participants in the UK Biobank study (40‐69 years at entry) with valid actigraphy data and complete cognitive data (N = 49,469). Participants completed computerized versions of Trail Making Test B‐A (TMT) and Digit Symbol Substitution Test (DSST). Actigraphy data were collected over 7 days, with average hourly movement being indexed. Along with 24‐hour actigraphy data, we included the following features in each model: age, biological sex, household income, educational attainment, smoking and alcohol intake, ethnicity, body mass index, and Townsend Deprivation Index. Seventy percent of participants were randomized to the training set, with the remaining 30% held out as a test set. We developed two separate ML models to predict cognitive performance: 1) a linear regression approach; and 2) a 3‐hidden layer (40 hidden units per layer) neural network. Model accuracy was compared using the coefficient of determination (R2).

Result

Mean age was 55 years (SD = 8 years) and 56% of participants were female. Average TMT time was 27.22 seconds (SD = 20.10 seconds), and mean DSST score was 20.06 (SD = 5.04). Our supervised linear regression had modest predictive ability of TMT (R2 = 8%) and DSST performance (R2 = 21%); the 3‐hidden layer neural network had similar predictive capability for both TMT (R2 = 8%) and DSST (R2 = 21%).

Conclusion

ML approaches for predicting cognitive performance using actigraphy data show modest capability. Further work is needed to identify how ML can be used to predict cognitive function from biometric data.
A comparison of the original ADAS‐cognitive subscale and a novel extended version in mild cognitive impairment and Alzheimer’s disease.
Authors: Roller Hunter R , Chaulagain Suchana , McGinity Sean , Botchway Albert , Conner Drew C , Zec Ronald F , Ala Tom , Hascup Erin R. , Trivedi Mehul Alkesh
Published: December 2023

Background

The Original Alzheimer’s disease Assessment Scale‐cognitive subscale (oADAS) is the gold standard for assessing cognition in Alzheimer’s disease (AD) medication clinical trials. One criticism is that this measure is not sensitive to pre‐dementia syndromes such as mild cognitive impairment (MCI), possibly due to ceiling effects for many of the subtests in the original ADAS‐cog (oADAS). In this study, we examined group differences between individuals with MCI, AD, and normal controls (NC) on the oADAS and a novel extended version of the ADAS (eADAS). We hypothesized the eADAS would be more sensitive than the oADAS at detecting differences between the groups after controlling for age, education, and sex.

Method

The oADAS was administered using standardized methods. The eADAS included short‐delay recall and recognition trials for the first wordlist, a short‐delay true‐false word recognition trial for the second word‐list, a letter‐digit timed psychomotor test, supermarket fluency, spontaneous clock drawing, three additional items to the object naming subtest, three additional figures to copy, and a similarities test. MCI and possible AD were diagnosed using established diagnostic criteria. The NC group was significantly younger and more educated than the MCI and AD groups. A 3×2 ANCOVA model with group as the between subject factor and ADAS type as the within subject factor was used. Total error scores from the oADAS and eADAS were converted to z‐scores.

Result

There was no main effect of ADAS type or ADAS type X education or ADAS type X group interactions. There were ADAS type x age and ADAS type x gender interactions (p’s = 0.01). Pairwise comparisons demonstrated that the NC group had lower total error scores compared to the MCI and AD groups and the MCI group had lower total error scores compared to the AD group for both the oADAS and eADAS (p’s<0.001).

Conclusion

The results of the current study indicate that oADAS and eADAS are sensitive to group differences between MCI and AD, which was contrary to our hypothesis. We suggest more rigorous diagnostic criteria for MCI in the present study may explain some of the conflicting findings in the literature.
Mild cognitive impairment in novel SPG4/SPAST mutation‐related sporadic late onset hereditary spastic paraplegia: case series
Authors: Meyyazhagan Arun , Rumore Roberto , Gaudiello Fabrizio , Miele Marialuisa , Kawarai Toshitaka , Orlacchio Antonio
Published: December 2023

Background

Mutations and deletions in the SPG4/SPAST gene cause for up to 50% of the autosomal dominant forms of hereditary spastic paraplegia (HSP) and for up to 15% of the sporadic cases. Affected individuals have pyramidal signs in the lower limbs and some present additional features. Cognitive impairment is common in late‐onset forms of HSPs.

Methods

This study examined the cognitive abilities of 20 sporadic late‐onset patients with HSP using next‐generation sequencing. We also used a combination of the Mini‐Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA) to assess their cognition.

Results

The present study led to the discovery of three new pathogenic mutations of the SPG4 gene through evolutionary conservation and analysis of structural models. We also confirmed mild cognitive impairment (MCI) with normal MMSE scores (≥27) and reduced MoCA scores (<26) in these HSP‐SPG4 mutant patients. Such individuals mainly present with impaired executive function, delayed memory, abstraction and language.

Conclusions

The results broaden the mutational space of SPG4‐associated HSP with sporadic late‐onset modality and indicate a combination of reduced MoCA and normal MMSE for diagnosis, indicating that clinicians should consider performing a MoCA to detect MCI in patients with HSP, particularly those with sporadic onset SPG4/SPAST‐HSP.
ADSP Whole Genome Sequencing (WGS) Release 4 Data Update from Genome Center for Alzheimer’s Disease
Authors: Leung Yuk Yee , Lee Wan‐Ping , Kuzma Amanda B , Gangadharan Prabhakaran , Nicaretta Heather Issen , Qu Liming , Ren Youli , Cantwell Laura B , Valladares Otto , Zhao Yi , Iqbal Taha , Schmidt Michael A. , Mena Pedro R. , Vardarajan Badri N , Dalgard Clifton L. , Kunkle Brian W. , Bush William S. , Martin Eden R. , Naj Adam C. , Haines Jonathan L. , Pericak‐Vance Margaret A. , Wang Li‐San , Schellenberg Gerald D. ,   the Alzheimer’s Disease Sequencing Project (ADSP)
Published: December 2023

Background

The Genome Center for Alzheimer’s Disease (GCAD) coordinates the integration of all available Alzheimer’s disease (AD) relevant whole genome sequencing (WGS) data with the goal of identifying AD risk or protective genetic variants and eventual therapeutic targets. The WGS datasets are generated through collaboration between investigators from the Alzheimer’s Disease Sequencing Project (ADSP) and GCAD. With the goal of minimizing data heterogeneity, introduced by different sequencing protocols and assays, GCAD processes all samples using standardized pipelines and performs quality control (QC)/quality assurance (QA) checks.

Methods

Raw sequencing data (FASTQs or BAMs) were aligned to GRCh38/hg38 by BWA, and variant calling and joint genotyping on single nucleotide variants (SNVs), insertions and deletions (indels), were done by GATK. Structural variants (SVs) were called per sample using the Smoove, Manta, and Strelka packages. Preliminary QA checks including sex check, contamination, and genotype concordance were performed followed by QC per ADSP protocol to evaluate the quality of samples and variants. To facilitate access and usage of massive joint‐genotype called VCF files, a compact version for storing variant info and sample genotypes only was released first.

Results

We dropped 275 (0.7%) samples of poor coverage (<20×), and we flagged 219 (0.6%) samples that were of borderline quality. As a result, the dataset (ADSP Release 4, 2022) includes 36,361 genomes from 40 diverse cohorts with 4 major ancestries: 16,573 Non‐Hispanic Whites, 11,358 Hispanics; 5,422 African Americans; and 2,802 Asians. Data are deeply sequenced (average genome coverage: 40x). All samples’ CRAMs and gVCFs from GATK were deposited into NIAGADS Data Sharing Service (DSS) (https://dss.niagads.org/) for public distribution. Joint‐genotyped called VCFs are undergoing a full QC/annotation process and will be made available. This joint‐genotyped called VCF contains >362M bi‐allelic variants, >58M multi‐allelic variants, with 95% of variants remaining after QC. SV calling is ongoing and data will be ready prior to the conference.

Conclusion

The ADSP and GCAD generate high quality SNVs, indels and SV calls. Currently GCAD is preparing the next release of ∼60,000 more ancestrally‐diverse WGS samples sequenced primarily through the ADSP Follow‐Up Study, which we anticipate will be released in 2023 to greatly benefit the AD genetics community.
Cognitive decline and longitudinal atrophy in successful and typical aging
Authors: Pezzoli Stefania , Giorgio Joseph , Chen Xi , Harrison Theresa M. , Jagust William J.
Published: December 2023

Background

Greater hippocampal volume (HV) and thicker mid‐cingulate cortex (MCC) are features of successful agers (SA), defined as exceptional cognitive performers, compared to typical agers (TA). This study aimed at examining whether SA experience different longitudinal change in cognition and atrophy from TA, and how baseline β‐amyloid (Aβ) affects these relationships.

Method

190 cognitively normal older adults (70+ years old) underwent 11C‐Pittsburgh compound B (PiB)‐PET to derive baseline Aβ positivity, and longitudinal structural MRI and cognitive testing. A machine learning cognitive‐age model was used to predict participants’ cognitive‐age from cognitive testing. Cognitive‐age gap (CAG = cognitive‐age – chronological age) was computed to represent individual variability in cognitive aging, wherein negative values indicate better cognitive performance than expected for age; SA were below the 20th percentile (n = 39). Linear mixed‐effects models were used to investigate the relationship between longitudinal changes in 1) Preclinical Alzheimer’s Cognitive Composite (PACC), 2) HV, and 3) MCC, with baseline CAG or SA‐status, as well as Aβ‐status as predictors.

Result

We found a significant main effect on PACC for CAG (p<0.001), but not Aβ‐status (p = 0.9), and significant CAG x time (p = 0.002) and Aβ‐status x time (p = 0.02) interactions (Figure 1). Results were similar when participants were dichotomized into SA and TA. In addition, baseline CAG showed significant main effects on 1) HV (p<0.001) and 2) MCC (p = 0.02), but the CAG x time interactions were not significant (HV: p = 0.6; MCC: p = 0.7) (Figure 2). Finally, when CAG, Aβ‐status, and HV were included in the same model to predict PACC change, we found a significant main effect for CAG (p<0.001), significant CAG x time (p = 0.01) and Aβ‐status x time (p = 0.02) interactions, and a marginally significant HV x time interaction (p = 0.06) (Figure 3).

Conclusion

Lower baseline CAG scores, indicating younger cognitive‐age, were related to greater HV and thicker MCC cross‐sectionally, but not longitudinal atrophy differences, suggesting that better cortical integrity in SA may reflect longstanding differences from TA. Lower baseline CAG and Aβ negativity were independently associated with slower cognitive decline. These findings suggest that factors underlying SA include separate contributions of both brain maintenance and reserve.
Leading Multi‐level Change to Build a Better System to Support Family Caregivers
Authors: Parmar Jasneet K , Anderson Sharon Dorothy , Pollard Cheryl , Charles Lesley , Drance Elisabeth , Penner Jamie , Lobchuk Michelle , Carforio Laurie , Leslie Myles , L'Hereux Tanya , McGhan Gwen , Huhn Arlene , Lowther Johnna , Marion Cecelia , Tarnowski Glenda , Weir Carolyn , Melenberg Denise , Pooler Charlotte
Published: December 2023

Background

Worldwide the care economy is in crisis.[1] The care economy includes both paid and unpaid services provided to populations who are unable to independently support themselves. Family caregivers (FCGs) make up the largest proportion of the care workforce, providing over 90% of care for people with dementia,[2 3] yet they remain marginalized in the existing healthcare systems.[4] While some caregiving scholars call for education to enhance the competencies of health and social care providers to partner effectively with caregivers,[3 4] other stakeholders advocate for broader systemic and policy change.

Objectives

Report on how an academic‐community partnership co‐design group focused on educating about person‐centered supports for FCGs is advocating for systemic change.

Project description

Advocacy is a critical population health strategy that emphasizes collective action to effect systemic change. The essential elements of advocacy includes: clear policy goals, solid evidence‐base, values linked to equity, broad coalition support, framing in mass media, and use of policy for change.[5]

Methods

Drawing on learning health systems and collective impact approaches, we are weaving together the actions of FCGs, researchers, health and social care providers, leaders, and management to build a No Wrong Door, seamless health & social care support system to enable FCGs to maintain their wellbeing & sustain care.

Results

Our goal is for formal recognition of the FCG role within health and social care policy. Broad consultations with stakeholders, then co‐design of the Caregiver‐Centered Care education built a robust collaborative of Caregiver Champions. While educating the health workforce is a population health approach to address known gaps in supporting and working with FCGs across the care trajectory, [3 4 6] such education is also developing FCG champions who can advocate across settings and communities. Within Alberta, this collective voice has resulted in recognition of FCGs in the new Continuing Care Act, Bill 11.

Discussion

An integrated FCG system is still a work in progress. Many FCGs do not connect with services they need until they are in a crisis.

Conclusion

Now we are working on strategy mapping to shift the collective focus from reactive problem solving to co‐creating the future.