bluuebunny/crossref_metadata_2025 huggingface dataset:
Neighborhood Disadvantage and Its Effects on Cognitive Health and Vascular Risk in Veterans
Authors: Deering Olivia , Van Hulle Carol A. , Zylstra Hannah , Cronin Kate , Cole Aleshia , Beckman Elena , Eierman Allison C , Blazel Madeleine , Lazar Karen K , Johnson Kevin M. , Rivera‐Rivera Leonardo A. , Chapell Richard , Zetterberg Henrik , Gleason Carey E. , Johnson Sterling C. , Asthana Sanjay , Carlsson Cynthia M.
Published: January 2025

Background

Prior research has highlighted the impact of neighborhood quality on health outcomes. Given veterans' unique experiences and challenges, exploring the association between neighborhood quality on cognitive measures and vascular risk scores is crucial for guiding targeted interventions, improving overall cognitive well‐being, promoting health equity, and contributing to our understanding of Alzheimer’s Disease (AD) risk factors.

Method

The Brain Amyloid and Vascular Effects of Eicosapentaenoic Acid study (BRAVE) was an 18‐month randomized, placebo‐controlled, double‐blind, clinical trial conducted at William S. Middleton Memorial Veteran’s Hospital in Madison, Wisconsin. This analysis used cross‐sectional data on VA‐eligible Veterans between the ages of 50 and 75 with no clinical diagnosis of a memory disorder. Study analyses included N = 201 Veterans who completed pre‐study screening and N = 129 who completed a baseline visit. Cognitive outcomes were collected at the baseline visit and ASCVD scores were collected during screening. Of the Veterans who completed a pre‐study screening, live in Wisconsin (N = 164), Illinois (N = 34), Iowa (N = 2) and Minnesota (N = 1). The main outcomes are ASCVD risk score and Preclinical Alzheimer’s Cognitive Composite (PACC). The Area Deprivation Index (ADI) state decile measures neighborhood quality on 18 metrics. For this study, participants in the most disadvantaged (ADI 7‐10) were compared to participants in the least disadvantaged neighborhoods (ADI 1‐6).

Result

In the prescreening cohort, 87.7% of participants were male and 89.4% non‐Hispanic, white. In the baseline cohort, 84.5% of participants were male and 94.7% were non‐Hispanic, white. PACC scores were significantly lower (PACC; p = 0.007; Cohen’s D = 0.562) for participants living in the most disadvantaged neighborhoods (‐0.42, SD = 0.98, N = 31) compared to the least disadvantaged (0.13, SD = 0.97, N = 98). The group mean differences in ASCVD scores were not statistically significant.

Conclusion

Our findings reveal that Veterans in the most disadvantaged neighborhoods exhibit lower cognitive performance. We found no significant association between neighborhood disadvantage and cardiovascular risk scores. These findings emphasize the importance of implementing targeted interventions to address cognitive health disparities in disadvantaged areas. Further exploration with a larger and more representative sample is essential to gain a comprehensive understanding of the relationship between neighborhood disadvantage, cognitive health disparities, and cardiovascular risk factors among Veterans.
Genetic associations with amyloid, tau, and neurodegeneration: an ADSP neuroimaging study
Authors: Mamourian Elizabeth , Bao Jingxuan , Cui Yuhan , Huang Heng , Saykin Andrew J. , Thompson Paul M. , Moore Jason H. , Ritchie Marylyn D. , Kim Dokyoon , Davatzikos Christos , Shen Li
Published: January 2025

Background

The amyloid‐tau‐neurodegeneration (ATN) framework provides a valuable model for comprehending the pathophysiology and progression of Alzheimer’s disease (AD). However the relationship between and genetic interaction with these three characteristics are complex and not fully understood. Here, we use neuroimaging‐derived quantitative traits to evaluate the genetic risk for amyloid accumulation, tau pathology, and neurodegeneration.

Method

The Alzheimer’s Disease Sequencing Project (ADSP) collected and harmonized whole genome sequencing (WGS) and quantitative phenotype data. This study examines harmonized neuroimaging traits, including 3 Amyloid‐PET features in N = 1,217 participants (Age = 72.6±8.1 years, Sex = 48.9% female), 6 Tau‐PET features in N = 470 participants (Age = 74.0±8.6 years, Sex = 53.8% female), and 20 selected T1 MRI derived volumetric measures of neurodegeneration in N = 2,644 participants (Age = 72.6±8.3 years, Sex = 52.0% female). We conducted genome wide association studies (GWAS) using Plink on the QC'ed WGS data of over 7.1 million variants for each trait, correcting for the top 10 principal components, age, and sex; for volumetric measures, we also control for intracranial volume.

Result

We found associations at the genome‐wide significance threshold for all three characteristics, including N = 56 SNPs associated with Amyloid phenotypes, N = 53 SNPs associated with Tau phenotypes, and N = 77 SNPs associated with Neurodegeneration phenotypes (Fig. 1). The strongest associations to Amyloid phenotypes (amyloid positivity, centiloid values) overlap with Neurodegeneration phenotypes (hippocampal volume) in chromosome 19, with the lead SNPs located in APOE. We found an additional region on chromosome 6 significantly associated with Tau phenotypes (Braak staging), but not Amyloid or Neurodegenerative phenotypes (Fig. 2).

Conclusion

These results provide additional evidence supporting the genetic contributions to risk of ATN pathology, confirming that variants in APOE and the surrounding region of chromosome 19 are strongly associated to amyloid positivity and hippocampal atrophy. These findings also support the genetic basis of a tau‐specific AD pathway. These results yield new insights into the genetic risk for amyloid accumulation, tau pathology, and neurodegeneration using the harmonized ADSP quantitative traits.
Association of mid‐life blood pressure status with longitudinal trajectories of blood‐based biomarkers of Alzheimer’s disease neuropathology and neurodegeneration in the Atherosclerosis Risk in Communities (ARIC) Study
Authors: Chen Jinyu , Pike James Russell , Lu Yifei , Gottesman Rebecca F. , Walker Keenan A. , Gu Zhengyi , Mielke Michelle M. , Sedaghat Sanaz , Sullivan Kevin J. , Thyagarajan Bharat , Sharrett Richey , Mosley Thomas H. , Coresh Josef , Palta Priya
Published: January 2025

Background

Current blood biomarkers of Alzheimer’s disease (AD) neuropathology and neurodegeneration include the ratio of amyloid‐β 42 to 40 (Aβ42/Aβ40), phosphorylated tau at threonine 181 (p‐Tau181), neurofilament light (NfL) and glial fibrillary acidic protein (GFAP). Prior studies have reported that hypertension is cross‐sectionally associated with lower levels of Aβ42/Aβ40 and longitudinally associated with faster accumulation of NfL. In this longitudinal investigation, we expanded on prior research by examining whether mid‐life blood pressure status was associated with change in AD biomarkers from mid‐ to late‐life.

Method

In the Atherosclerosis in Communities Study (ARIC) cohort, 1424 participants had blood pressure measurements at Visit 3 (baseline, 1993‐95) and two or more measurements of AD blood biomarkers from Visit 3, Visit 5 (2011‐13), and Visit 6 or 7 (2016‐2019). Linear mixed effects models quantified the association of mid‐life blood pressure status (hypotension, SBP<90 or DBP<60; hypertension, SBP>130 or DBP>90; normotension) with the rate of change in each AD blood biomarker. Models were adjusted for age, sex, race, education, the presence of apolipoprotein ε4 (APOE ε4) alleles, time‐varying body mass index and estimated glomerular filtration rate, and baseline cardiovascular and lifestyle risk factors.

Result

The sample included 860 women (60.4%) and 364 Black participants (25.6%). At baseline, 143 participants (10.0%) had hypotension and 449 (31.5%) had hypertension. Compared to participants with normotension, mid‐life hypertension was associated with accelerated accumulation of NfL from mid‐ to late‐life (Table 2). Both mid‐life hypotension and hypertension were associated with accelerated accumulation of pTau‐181 from mid‐ to late‐life. In subgroup analyses, these associations were greater among women, Black participants, and individuals without APOE ε4 alleles.

Conclusion

Mid‐life hypotension and hypertension are associated with faster changes in both AD‐specific (pTau‐181) and neurodegenerative (NfL) biomarkers from midlife to late‐life. Future investigation is needed to determine whether hypotension and hypertension are on the causal pathway relating AD neuropathology to dementia or if abnormal blood pressure and faster accumulation of pTau‐181 are shared characteristics of other comorbidities.
The effect of gantenerumab treatment on brain functional connectivity
Authors: Gobbi Susanna , Klein Gregory , van den Heuvel Martijn , Magon Stefano
Published: January 2025

Background

Changes in brain functional connectivity obtained from resting state MRI (rs‐fMRI) have been found to be associated with cognitive decline and neurodegeneration in clinical trial participants with Alzheimer’s disease (AD). This study investigates whether and how this technique can be used in AD clinical trials to monitor treatment effects. Specifically, we analyzed changes in brain functional connectivity over a period of 116 weeks in participants with AD treated with gantenerumab, an investigational anti‐amyloid beta monoclonal antibody. Although this drug did not meet the primary clinical endpoints, some significant associations were found with exploratory biomarkers.

Method

We analyzed rs‐fMRI of participants with MCI due to AD and mild AD at screening and week 116 collected in a subgroup of the randomized, double‐blind, pivotal, Phase III trials GRADUATE I (273 patients, 52% female, 50% placebo) and GRADUATE II (335 patients, 59% female, 57% placebo) (NCT03444870, NCT04374253). Using group Independent Components Analysis (GIFT, Calhoun et al., 2001), we extracted 25 resting states components in each clinical trial and grouped them into 7 networks (Sensory Motor, Cerebellar, Visual, SubCortical, Auditory, Default Mode and Cognitive Control). Using a linear model, we investigated changes in between‐ and within‐networks brain connectivity at screening and week 116 in gantenerumab and placebo participants. The components‐wise Pearson’s correlation (Z‐Fisher score) was used as the dependent variable, group (gantenerumab vs placebo), visit (screening vs week 116) and the interaction term group‐by‐visit as covariates of interest, while controlling for sex, age and scanner magnetic field strength (1.5T vs 3T). This analysis was exploratory in nature and no adjustment for multiple components‐wise comparisons was applied.

Result

In both GRADUATE I and II, we found a significant group‐by‐visit effect (p < 0.05). Specifically, we found decreasing within‐ and between‐networks functional connectivity in the placebo group at week 116 compared to screening. Conversely, the gantenerumab group reported stable or higher connectivity at week 116 compared to screening (Fig. 1‐2).

Conclusion

These results suggest a potential relationship between amyloid removal and changes in brain functional connectivity. Due to the exploratory nature of this study further investigation is needed to confirm these findings.
A tablet‐ and virtual reality‐based training for preventing and detecting cognitive decline: a usability study
Authors: Zuschnegg Julia , Schultz Anna , Paletta Lucas , Dini Amir , Linzer Amadeus , Berger Ursula , Kratky Wolfgang , Goldgruber Judith , Koini Marisa , Russegger Silvia , Draxler Sandra , Orgel Thomas , Schneeberger Michael , Pszeida Martin , Weiss Wolfgang , Schüssler Sandra
Published: January 2025

Background

Virtual Reality (VR) is hailed as a top emerging technology for older adults in healthcare. Despite its potential, limited research exists on VR applications for individuals with cognitive decline, particularly in leisure‐based cognitive training, as opposed to traditional (instrumental) activities of daily living (I)ADL training such as shopping. The SmartAktiv project has developed immersive VR leisure experiences with (I)ADL cognitive training embedded, aiming to enhance cognition in a playful manner and detect early cognitive deficits. We assessed the usability of the SmartAktiv VR‐based intervention combined with a tablet‐based training among participants before initiating a pilot study.

Method

Healthy older adults (n = 4), people with suspected mild cognitive impairment (MCI) (n = 4), people with suspected dementia (n = 4) (according Montreal Cognitive Assessment, MoCA) and healthcare professionals (n = 4) tested the combined tablet‐ and VR‐based training (hiking tour scenario). After the intervention, qualitative focus groups were held with each group to gather insights into training’s usability from participants' experiences. Furthermore, cybersickness (Simulator Sickness Questionnaire, SSQ) was measured.

Result

Older adults (MoCA, x̅ 27.00±1.41 points), people with suspected MCI (MoCA, x̅ 23.25±1.26 points) those with suspected dementia (MoCA, x̅ 16.00±0.00 points) and healthcare professionals experienced negligible cybersickness after the training (SSQ, x̅ 6.98±5.26 points). Qualitative findings indicated positive perceptions of the intervention among all participants. Participants appreciated the variety of cognitive exercises (e.g., quiz, puzzle) in the tablet‐training program, but emphasized the need for greater sensitivity of the tablet‐PC and the necessity of a tablet pen. The immersive VR hiking tour was very well‐received, evoking a longing for nature, especially among older individuals (with/without cognitive impairment). They found the interactive cognitive (I)ADL tasks enjoyable/fun, with some even reporting feeling more alert/euphoric afterwards. However, hand tracking issues arose in certain VR tasks (e.g., picking mushrooms), and low contrast made some VR elements difficult to perceive (e.g., payment for train).

Conclusion

The findings offer insights into the usability of the combined tablet‐ and VR‐based (I)ADL cognitive training, to be considered for a pilot study. This pilot study will test four scenarios (hiking tour, beach vacation, city trip, winter outing) on individuals (n = 30) with and without cognitive decline.
“I’m worth saving”‐ a qualitative study of people with dementia considering treatment with lecanemab
Authors: Thacker Ayush , Parks Anna L , Dohan Daniel , Gomez Liliana A Ramirez , Ritchie Christine S , Paladino Joanna , Shah Sachin J
Published: January 2025

Background

As lecanemab becomes available to people living with dementia, there is a pressing need to understand how they weigh the potential benefits against costs. This study investigates how older adults perceive lecanemab’s risks and benefits and their approach to treatment decisions.

Methods

Semi‐structured interviews of older adults undergoing evaluation in Neurology clinics for lecanemab eligibility at two academic medical centers. An interdisciplinary research team used rapid thematic analysis guided by the Ottawa Decision Support Framework.

Results

22 people completed interviews (mean age 70 years, 36% women, 100% white). Preliminary themes included: 1) Hopes, expected benefits, and the existential threat of dementia driving willingness and readiness to start lecanemab. Hopes included more time with family and more time feeling like themselves by stalling the progression of cognitive decline and amyloid build‐up. Some expected benefits included “getting back to where I was” and “getting better, not worse.” Some patients pursued Lecanemab because it would be doing ‘something’ (versus nothing), given the fear and stress of dementia. 2) Patients sought and obtained information from different sources, including advocacy organizations, the Internet, and clinicians. Patients desired more information about their personal risk and wanted to hear more from patients who took the medication. 3) Individual traits and preferences, family factors, and degree of trust in expertise influence how patients balance risks and benefits. Some patients were willing to accept treatment at any cost, either due to the perceived inevitability of decline without intervention or because they tend to “look past the negatives” when making decisions. Others weighed risks (e.g., brain bleeding) and financial and logistical costs carefully, but supportive families, insurance coverage, and trust in the system helped in their decision to start treatment. A small proportion of people would not get the treatment as the costs outweighed their personal benefit.

Conclusions

This group of people with mild dementia who are at the forefront of lecanemab treatment showed variation in hopes for treatment, information sought and obtained, and contextual factors in decision‐making, supporting the need for an individualized approach. These insights can guide future interventions to improve individualized decision‐making for lecanemab treatment.
Evaluating the causal association between resting state intrinsic functional networks and the risk for neurodegeneration
Authors: Nassan Malik , Daghlas Iyas , Diamond Bram R , Martersteck Adam , Rogalski Emily J
Published: January 2025

Background

Alterations of resting state intrinsic functional networks have been associated with neurodegenerative diseases even before the onset of cognitive symptoms. Emerging hypotheses propose a role of intrinsic functional networks alterations in the risk or vulnerability to neurodegeneration. It is unknown whether intrinsic functional network alterations can be causal for neurodegenerative diseases. We sought to answer this question using two‐sample Mendelian randomization, a method able to assess causal relationships.

Methods

Using the largest genome‐wide association study of resting state intrinsic functional connectivity (n = 47,276), we generated genetic instruments (at the significance level 2.8 × 10−11) to proxy resting state intrinsic functional network features. From these, we selected 26 genetically proxied resting state intrinsic functional features from brain regions implicated in neurodegenerative diseases. We tested their association with the paired neurodegenerative outcomes: Alzheimer dementia (111,326 cases, 677,663 controls), frontotemporal dementia (2,154 cases, 4,308 controls), semantic dementia (308 cases, 616 controls), and Lewy body dementia (2,591 cases, 4,027 controls). Major depressive disorder outcome (170,756 cases, 329,443 controls) was included as a positive control. Power and sensitivity analyses were completed to assess the robustness of the results.

Results

None of the genetically proxied resting state intrinsic functional network features were significantly associated with neurodegenerative disease outcomes (adjusted P value >0.05), despite sufficient power. However, two resting state exposures in the visual cortex showed a nominal level of association with Lewy body dementia (P = 0.01), a finding that was supported using a separate visual cortex connectivity exposure (P = 0.03). For our confirmatory positive control, the global connectivity pattern in the default mode network was associated with risk of major depressive disorder (P = 0.024), supporting the validity of the selected genetic instruments. Sensitivity analyses were supportive of the main results.

Conclusion

This is the first study to comprehensively assess the potential causal effect of resting state intrinsic functional network features on risk of neurodegenerative diseases. Overall, the results do not support a causal role for intrinsic functional network connectivity in the pathogenesis of neurodegenerative disorders. However, the suggestive association between visual network connectivity and risk of Lewy body dementia requires further evaluation.
Single‐nuclei RNA‐Sequencing of Postmortem Choroid Plexus Uncovers Dysfunction Alzheimer’s disease
Authors: Philippe Tristan J , Kearns Nicola , Avey Denis R. , Saunders Devin M. , Vyas Himanshu , De Tissera Sashini L , Xu Jishu , Bennett David A. , Wang Yanling
Published: January 2025

Background

The choroid plexus (ChP) is formed by epithelial cells and stromal fibroblasts which act as a blood‐cerebrospinal fluid (CSF) barrier, play a key role in maintaining brain homeostasis, and provide a niche for immune cells. ChP dysfunction has been implicated in Alzheimer’s Disease (AD), including changes in CSF secretion, increased apoptosis, and dysregulated immune, mitochondrial, and transporter functions.

Method

Here, we performed single‐nuclei RNA‐Sequencing (snRNA‐Seq) on 965,647 ChP nuclei from 68 ROSMAP participants with no cognitive impairment (NCI), mild cognitive impairment (MCI) or Alzheimer’s Dementia (ADem).

Result

We identified 14 major cell types, including two types of epithelial cells, four types of fibroblasts, five types of border associated macrophages (BAMs), one type of T cells, and two types of vascular cells. In ciliated epithelial cells, we observed a decreased expression of genes essential for cilia formation and movement (e.g., DNAH12, CFAP100, ARL13B) in participants with ADem, but not MCI. In ADem and MCI fibroblasts and epithelial cells, we observed changes in cell adhesion (e.g., ITGA8, CEMIP, CEACAM1, ADMTS4), ion transport (e.g., SLC12A2, SLC4A5, STAEP4, SLC1A1), and metabolism (e.g., ALDH4A1, ENO4, AKR1C2, PDE10A) in addition to increased expression of pro‐inflammatory genes (e.g., IL6, CXCL8, IL12RB2). Compared to the NCI group, we also observed increased expression of lipid metabolism genes (e.g., ALOX15B, ACSL1) in phagocytic BAMs and a higher proportion of pro‐inflammatory BAMs in the ADem, but not MCI groups. Proteomics on ex‐vivo CSF and tissue, immunostaining, and RNAscope support the major cell types described herein and validate differential gene expression.

Conclusion

We show that multiple cellular and molecular functions are dysregulated in ADem, to suggest ChP dysfunction is a key contributor to AD pathogenesis. Changes to the cilia of ChP epithelial cells and ChP BAM function could contribute to differences in the degree of cognitive impairment across participants.
Experiences of Participant Burden in an Alzheimer’s Disease Research Center Longitudinal Cohort
Authors: Gierzynski Theresa F. , Reader Jonathan M , Flores Bernardo , Gadwa Renee , Bhaumik Arijit K , Rahman‐Filipiak Annalise , Heidebrink Judith L , Giordani Bruno , Hampstead Benjamin M. , Bakulski Kelly M. , Paulson Henry L , Roberts J. Scott
Published: January 2025

Background

Longitudinal studies of Alzheimer’s and related dementias (ADRD) are crucial to understanding disease progression. Retention among study participants is vital to successful longitudinal research, as dropout can skew the subject population in ways that significantly compromise study outcomes (e.g., limited generalizability). Prior research suggests that higher perceptions of burden among research volunteers are associated with an increased likelihood of attrition and missed visits. Additionally, underrepresented groups (e.g., racial minorities) may be uniquely impacted by barriers that hinder participation and sustained engagement in ADRD research. The current study aimed to measure participants’ perceived burden in a cohort of longitudinal ADRD research participants and assess for potential differences in perceived burden by race.

Methods

Participants enrolled in a study of memory and aging at the Michigan Alzheimer’s Disease Research Center (MADRC) were administered a modified, 22‐item version of the Perceived Research Burden Assessment (PeRBA) survey instrument (Keleman et al., 2023) either in‐person or via telephone. The PeRBA is a validated measure assessing overall, logistical, psychological, and physical burdens of participating in research. A series of Wilcoxon Rank Sum Tests were performed to assess for possible racial differences in the mean scores of overall burden, as well as in each subscale.

Result

A total of 76 participants completed the PeRBA; the sample was 18.8% Black/African American, 67.1% female, and 55.3% cognitively unimpaired. Overall burden ranged from 21 to 55 (110 possible) (Overall Mean (SD) = 36.23 (8.25); Black/African American Mean (SD) = 43.86 (2.07); White Mean (SD) = 34.61 (8.17)). Results indicated that Black/African American participants experienced significantly more overall burden than their White counterparts (all ps < 0.05) as well as across all subscales.

Conclusion

Further research is needed to better understand the ostensibly higher appraisals of research burden in our Black/African American participants. Future investigations should consider the role of geographic/site‐specific factors as well as structural (e.g., socioeconomic status, transportation) and psychosocial influences and their role in participant retention and recruitment. Moreover, the identification of deterrents and barriers to engagement can inform tailored strategies that support the specific needs of diverse older adult populations in ADRD studies.
Astrocyte selective insulin receptor knockout in the 5xFAD model of amyloidosis
Authors: Wright Nicholas A , Galopin Leopoldine B , Sims Sophiya L , Lin Ruei‐Lung , Rucker Edmund B , Rogers Colin B , Kraner Susan D , Norris Christopher M. , Thibault Olivier
Published: January 2025

Background

We have recently published that overexpressing a constitutively active form of the insulin receptor beta subunit (IR‐β) in hippocampal neurons ameliorates spatial memory performance in the F344 rat model of aging (Frazier et al., 2020). Because astrocytes express IRs and are central to cellular energy and information transfer in the brain, here we focus on the knockdown of IR in astrocytes of the primary somatosensory cortex (S1) in the 5xFAD animal model. Using Cre‐lox recombination, we tested the cellular expression of AAV‐Cre recombinases and serotypes to selectively excise the IR, including 1. AAV5.GFAP.Cre.WPRE.hGH (AddGene), 2. AAV5.Gfa104.C1.Cre.WPRE.SV40 (UPenn), 3. AAV5.GFAP.GFP.Cre (UNC), 4. AAV8.GFAP.GFP.Cre (UNC; gift from Dr. Weikang Cai) and 5. AAV5.Gfa104‐Cre‐4×6T (Addgene/UPenn).

Method

The 5xFAD and the IRfl/fl were used to generate unique genotypes IRfl/fl; 5xFAD−/− (WT) and IRfl/fl; 5xFAD+/− (5XFAD). Mice were injected unilaterally in S1 with five different AAVs, followed with 3‐4 week recovery prior to the extraction and processing of the brain for immunohistochemical (IHC) and immunofluorescence (IF) analyses. Coronal sections of S1 were exposed to anti‐Cre recombinase primary antibodies labeled with secondary AlexaFluor antibodies. Counter stains used included DAPI and an anti‐GFAP or anti‐NeuN primary antibodies to address selectivity. In a second set of experiments conducted in older WT and 5xFAD mice injected unilaterally with AAV#2 and AAV#3 above, we used Western blotting techniques on two separate fractions (astrocyte‐depleted [AD] and astrocyte‐enriched [AE]). Samples were separated using the magnetic cell separation techniques followed by anti‐NeuN and anti‐GFAP antibodies to monitor selectivity.

Result

Initial IHC indicates that the expression of the Cre recombinase under the GFAP promoter was surprisingly, mostly neuronal with very little expression in astrocytes. AAVs with the smaller Gfa104 promoter show improved specificity toward astrocytes (∼50%), with some expression in neurons. Our modified AAV shows higher cell‐type selectivity toward astrocytes.

Conclusion

Overall, our attempt to target astrocyte IR knockdown has proven to be difficult and current efforts using molecular remodeling and targeting to astrocytes using an miRNA‐based AAV to degrade transcription in neurons, thus, enriching expression of Cre in astrocytes, is proving to be a very valuable strategy.
A Systematic Review on the Process of Translation and Cross‐Cultural Adaptation of Functional Activity Tests for Dementia
Authors: O'Donald Freddie , Calia Clara
Published: January 2025

Background

This systematic review aims to investigate the methodologies employed in the translation and cross‐cultural adaptation of functional activity measures for dementia on a global scale. The Consensus‐based Standards for the Selection of Health Measurement Instruments (COSMIN) initiative is used as a framework, offering established criteria for assessing psychometric properties across diverse domains.

Method

A systematic search of five electronic databases (CINAHL Plus, EMBASE, PubMed, MEDLINE, PsycINFO) was conducted from inception until September 2023. Quality assessment criteria were then utilised to evaluate the process of cross‐cultural adaptation and psychometric properties of identified functional activity measures.

Result

Fifteen studies relating to adapted functional activity measures in eleven languages were identified. It was found that less than half of these studies fully adhered to established guidelines for the translation and cross‐cultural adaptation of instruments. Regarding psychometric properties, while the internal consistency and reliability of included measures were generally strong, there was variability in evaluating other psychometric properties, notably structural validity, measurement error, and cross‐cultural validity.

Conclusion

This review underscores the need for researchers and clinicians to follow standardised guidelines for translating and cross‐culturally adapting functional activity measures for dementia and ensuring the comprehensive evaluation of psychometric properties in cross‐cultural settings. Researchers and clinicians should consider whether the psychometric properties and characteristics of an adapted functional activity measure are suitable for use in their population of interest.
Increasing primary and specialty healthcare access for rural older adults: Facilitators, barriers, and opportunities of telehealth in rural community centers
Authors: Fischer Ben , Jackson Yolanda , Roberts Celeste , Robinson Celeste , Early Robert , Sprang Robert , Rhodus Elizabeth K.
Published: January 2025

Background

Shortcomings in primary and specialty healthcare access in rural communities create substantial health disparities among older adults, especially in areas of modifiable risk factors for Alzheimer’s disease and related dementias (ADRD). Telehealth stations in community centers increase healthcare access to patients thereby improving modifiable risk factors for ADRD. The objective of this project was to assess facilitators, barriers, and opportunities of telehealth use for older adults within rural community centers.

Methods

Following an implementation‐based clinical trial (NCT05552638), this study conducted in‐depth interviews with multi‐level stakeholders, including rural, community‐residing seniors, senior center administrators, and medical partners to assess use of telehealth in rural community centers. Data were analyzed using descriptive thematic analysis. Coding was conducted using HyperResearch Software.

Results

Interviews were completed with nine multi‐level stakeholders who represented of a combine population of >2000 older adults residing in rural communities. Emergent themes reveal facilitators of involvement of community centers as a strategy to promote telehealth usage, as well as involving local providers; both offering familiarity to local residents. Identified barriers include a need for increased acceptance of telehealth services possibly through education and exposure to the technology, patients’ concerns regarding costs, quality of care delivered, and patients’ need for assistance to manage scheduling. Overall, increasing acceptance and fostering positive experiences with technology provide opportunities of improving primary and specialty care via telehealth usage in rural community centers.

Conclusion

Facilitators, barriers, and opportunities for primary and specialty healthcare via telehealth among older adults in rural communities provides key considerations when developing approaches to address health disparities. Findings of this study provide future implementation strategies to improve acceptance and utilization of telehealth services. Continued research is needed to explore health beliefs of healthcare access mechanisms, as well as innovations to address critical health disparities in rural communities.
Plasma Aβ42/40, APOE4, and Ethnicity in Aβ‐PET Prediction
Authors: Taylor Steven W , Weber Darren M , Lagier Robert J , Stroh Matthew A , Clarke Nigel J , Vaillancourt David , Duara Ranjan , Racke Michael K
Published: January 2025

Background

Addition of apolipoprotein E4 (ApoE4) proteotype (as a surrogate for high‐risk APOE ɛ4 genotype) has significantly improved models that use the plasma Aβ42/40 ratio to predict Aβ PET‐positivity, but studies suggest different ethnicities may be less affected by the addition. Our objective was to assess the influence ApoE4 proteotype in a predominantly Hispanic cohort of participants.

Method

Participants in this study (n = 250) underwent neurological and neuropsychological evaluations and amyloid PET brain scans (SUVR data and visual reads) at the 1Florida ADRC; they also underwent blood draws for ApoE4 proteotyping and Aβ42/40 ratio determination by LC‐MS/MS performed at Quest Diagnostics. Ethnicity was self‐reported as Hispanic or non‐Hispanic. Using logistic regression analysis and Delong’s test, we examined the effect of incorporating ApoE4 proteotype as a categorical variable on AUCs for the overall population and for participants stratified by ethnicity: Hispanic vs non‐Hispanic. Statistical analyses were conducted using R statistical software version 4.3.3. Two‐tailed P‐values <0.05 were considered statistically significant.

Result

The ADRC cohort had roughly 3‐times the percentage of Hispanic participants (about 60% of both the Aβ PET‐positive and Aβ PET‐negative participants) compared with a previous Aβ42/40 LC‐MS/MS study that incorporated ApoE4 proteotype. Based on ApoE4 proteotype, incorporating APOE4 allele count modestly but significantly increased the AUC (95% CI) from 0.84 (0.79‐0.89) to 0.86 (0.82‐0.91), P = 0.038, Figure A. Subsetting the ADRC cohort participants into Hispanic vs non‐Hispanic ethnicity provided a contrasting effect for ApoE4 proteotype on model improvement. For Hispanic participants, the AUC (95% CI) for the ratio plus ApoE4 proteotype, 0.86 (0.80 to 0.92) and the Aβ42/40 ratio alone, 0.85 (0.78‐0.91) were not significantly different (P = 0.306), Figure B. For non‐Hispanic participants, the AUC (95% CI) for the ratio plus ApoE4 proteotype, 0.87 (0.81‐0.94) was significantly higher (P = .048) than the Aβ42/40 ratio alone, 0.83 (0.75‐ 0.91), Figure C.

Conclusion

ApoE4 proteotype did not improve prediction of PET positivity by plasma Aβ42/40 in the Hispanic subcohort, suggesting that adding APOE4 to Aβ42/40 in algorithms used in Alzheimer’s disease risk assessment may not improve PET‐prediction for all races and ethnicities.
Microglia density measured by TSPO PET across amyloid positivity and clinical variants
Authors: Houlihan Hannah M. , Johnson Aubrey S. , Smith Anna C. , Guzmán Diana S. , Okafor Amarachukwu , Heuer Lauren B. , Talmasov Daniel , Chikwem Ndubisi , Dass Dina S. , Noble James M. , Kreisl William C. , Small Scott A. , Lao Patrick J.
Published: January 2025

Background

We hypothesized that TSPO PET, which measures microglia density, would be elevated in the presence of amyloid and impairment across different clinical variants in a pattern that follows their characteristic tau distribution.

Method

Participants (n = 17 amyloid‐negative control, 3 amyloid‐positive AD, 2 amyloid‐positive PCA, 6 amyloid‐negative with impairment (1 aMCI, 1 MCI, 3 AD, 1 LATE); age = 69±7, 43% women) from the Longitudinal Imaging of Microglial Activation in Different Clinical Variants of Alzheimer’s Disease study underwent amyloid PET (Florbetaben), tau PET (MK6240), and TSPO PET (ER176). Amyloid positivity was determined by visual read. Clinical groups were determined at ADRC consensus. Partial volume corrected TSPO and tau SUVR was compared across amyloid positivity and clinical variants (amyloid‐negative controls as reference group).

Result

The amyloid‐positive AD group had elevated TSPO in amygdala (0.34, p = 0.01), prefrontal cortex (0.31, p = 0.0004), middle inferior temporal gyrus (0.29, p = 0.0003), inferior parietal lobe (0.28, p = 0.001), superior temporal lobe (0.23, p = 0.001), cingulate gyrus (0.19, p = 0.01), superior parietal lobe (0.19, 0.04), insula (0.14, p = 0.02), and lingual gyrus (0.13, p = 0.02), while the amyloid‐positive PCA group had elevated TSPO in amygdala (0.50, p = 0.001), superior parietal lobe (0.38, p = 0.04), inferior parietal lobe (0.29, p = 0.001), middle inferior temporal gyrus (0.20, p = 0.0003), prefrontal cortex (0.15, p = 0.0004), superior temporal lobe (0.14, p = 0.001), cingulate gyrus (0.13, p = 0.01), and insula (0.06, p = 0.02). The impaired amyloid‐negative group had elevated TPSO in the amygdala (0.31, p = 0.04), fusiform gyrus (0.15, p = 0.05), cingulate gyrus (0.14, p = 0.02), middle inferior temporal gyrus (0.12, p = 0.02), superior temporal lobe (0.12, p = 0.02), prefrontal cortex (0.12, p = 0.02), and inferior parietal lobe (0.11, p = 0.02). These elevations in TSPO spatially coincide with elevations in tau burden (Figure 1).

Conclusion

Microglia may respond to amyloid pathology and follow a spatial pattern similar to that of tau pathology for a given clinical variant. Interestingly, microglia were elevated to the greatest extent in key limbic regions for amyloid‐negative impaired participants. Non‐AD pathologies may be driving this limbic neuroinflammation or limbic neuroinflammation itself may be sufficient for clinical impairment in the context of low amyloid and tau burden.
SmartSocks: a new data collection paradigm for dementia and other neurological disorders
Authors: Steer Zeke , Venkatesh Prabha Thirthahalli , Mejia‐Mejia Elisa , Dennis William Wu , Ogundele Patrick Ademola , Brooking Annie , Eimontaite Iveta
Published: January 2025

Background

Distress and agitation are predictors of entry into long‐term care and health inequalities (Schulz et al., 2004, Weir et al., 2022). Physiological data has been shown to reliably predict distress (Goodwin et al., 2019), yet wearable devices have low acceptance rates (Koumpouros & Kafazis, 2019). The current study discusses findings from a multifaceted approach investigating the detection of early signs of distress via physiological sensors in a foot‐worn device.

Method

Firstly, the acceptance and concern ratings for a foot‐worn device, SmartSocks, wrist‐worn devices, Empatica E4 and Shimmer GSR+, and chest‐worn device, Equivital within a healthy population (N = 10) were assessed with a self‐report questionnaire. Secondly, data accuracy between Shimmer ECG and Polar OH1+ was compared within a healthy population (N = 12) in a standing, sitting and supine position. Finally, an ongoing ecologically valid feasibility trial (N = 2) involving participants with dementia or a learning disability is assessing the reliability of physiological data and AI‐detected stress from SmartSocks relative to subjective ratings of distress, the Abbey Pain Scale (APS), and the Neuropsychiatric Inventory (NPI).

Result

Firstly, the SmartSocks received lowest concern ratings compared to wrist‐ and chest‐worn devices (1.64 vs <1.71). Secondly, the accuracy of SmartSocks pulse rate (PR) estimates obtained using photoplethysmography (PPG) in combination with the delineator algorithm was determined by comparing estimates to a Shimmer 1‐lead ECG, recording Mean Absolute Error (MAE)<5bpm at 64HZ for participants in a supine position (Fig. 1). This led to the development of new features for classifying PPG signal quality using neural networks, achieving approximately 95% accuracy. Finally, the initial stage of the feasibility trial indicated APS and NPI scores were lower after the participant with dementia wore SmartSocks for two weeks. Physiological data collected from the participant with a learning disability using SmartSocks showed moderate correlation (χ2
= 0.45) between the reported and AI‐detected stress over the day (Fig. 2 & 3).

Conclusion

Early findings suggest SmartSocks are more comfortable than comparable wrist‐ and chest‐worn devices, and validity of the data is comparable to other devices. Preliminary data obtained from people with dementia and learning disabilities suggest SmartSocks are capable of detecting distress to alleviate user discomfort.
Correlation between MRI Visual Atrophy Scales and cognitive performance in a Brazilian Outpatient Memory Clinic
Authors: Real Ana Paula Bernardes , Engelmann Gabriela Tomé Oliveira , Moro Giovanna Correia Pereira , Vieira Carolina Portugal , Dias Bruna Fugêncio , Queiroz Thaise Vallesca , Kimoto Leonardo Ryuiti , Melgaço Marcilene Anacleto , de Souza Aline Siqueira , Burgos Ivonne Carolina Bolaños , de Paula Jonas Jardim , Romano‐Silva Marco Aurelio , Bicalho Maria Aparecida Camargos , Viana Bernardo M
Published: January 2025

Background

Brain imaging plays an important role in Alzheimer’s disease (AD) assessment. Combined with cognitive assessment, MRI helps to exclude other brain disorders and to support AD diagnosis based on the atrophy of specific regions. Visual atrophy scales are useful in clinical practice, especially in low‐income areas where access to biomarkers and automated volumetric analysis are limited.

Objective

To assess the correlation between different MRI Visual Atrophy Scales and cognitive performance in a cohort of a Memory Clinic of Brazilian older adults with heterogeneous educational background.

Methods

Data were collected from the Cog‐Aging Cohort, including participants with normal cognition, mild cognitive impairment, and Alzheimer’s Disease Dementia. Thirty‐five MRI scans were analyzed using the following visual scales: Global Cortical Atrophy (GCA), the Entorhinal Cortical Atrophy Score (ERICA), the Medial Temporal Lobe Atrophy (MTA) scale, and the KOEDAM scale, Fazekas scale for white matter lesions. They were rated by consensus of two memory specialists. These scores were correlated to sociodemographics, to Dementia Rating Scale (DRS), Mini‐Examination of State Examination (MMSE), 5‐minute recall of the CERAD word list, and immediate episodic memory recall (A6) from the of the Rey Auditory Verbal Learning Test (RAVLT).

Results

The mean age of participants was 77.15 years (SD: 74‐80), and the median education was 6.53 years (IQ: 4.48‐8.59). No difference in sex was found. The ERICA scale showed a statistically significant moderate correlation with RAVLT (Rho = ‐.454, p = .017) and a weak correlation with the 5‐minute recall from CERAD’s Word List (Rho = ‐.381, p = .026). No other visual scale demonstrated statistically significant correlations with any cognitive tests. We found strong correlations between the ERICA and MTA scores (Rho = ‐.616, p<.001), and weak but significant correlations between ERICA and KOEDAM (Rho = ‐.390, p = .023).

Conclusion

A higher ERICA score correlated to a worst memory performance. These data corroborate other studies addressing the importance of the use of this scale in research and clinical practice.
Blood Gene Expression Network Expression Strongly Relates to Brain Amyloid Burden
Authors: Janve Vaibhav A , Seto Mabel , Sperling Reisa A , Aisen Paul S. , Rissman Robert A. , Koran Mary Ellen I. , Dumitrescu Logan C. , Buckley Rachel F , Hohman Timothy J. ,   A4 and LEARN Study Group
Published: January 2025

Background

Amyloid deposition occurs during the preclinical stages of Alzheimer’s disease (AD) a decade or more before clinical symptoms emerge. We leveraged blood transcriptomics and positron emission tomography (PET) measures of amyloidosis to identify cell types and gene networks in the blood that relate to amyloid burden in the brain.

Method

Whole blood RNA sequencing and amyloid PET data were leveraged from 1771 participants (62% females, mean age 71, 32% amyloid+) in the Anti‐Amyloid Treatment in Asymptomatic Alzheimer’s Disease (A4) Study. RNAseq data were aligned with STAR, sorted, counted using Subread, and batch normalized with voom. 19,945 genes were available for analysis following quality control. Cell fractions were quantified using CIBERSORTx (LM22 used as reference) and WGCNA was used to calculate gene co‐expression modules (soft threshold = 12). Amyloid PET data were acquired using 18F‐florbetapir 50‐70 minutes post injection and a global cortical standardized uptake value ratio (SUVR) was quantified (whole cerebellum as reference). Linear regression related gene module expression or cell fraction to mean SUVR, covarying for age, sex, education, APOE ε2 and ε4 status. Correction for multiple comparisons used false discovery rate. Gene enrichment was performed using Gene Ontology.

Result

Two gene modules were associated with amyloid deposition. One included 48 genes whereby higher expression was associated with lower amyloid burden (β = ‐12.37, p = 0.0001). This module was enriched for DNA damage pathway genes and the top gene associations in the module included histone genes such as H3C3 and H2AC14. The second module included 241 genes whereby higher expression related to higher amyloid burden (β = 7.15, p = 0.001). This module was enriched for leukocyte migration and regulation of RNA pathways. The top gene association in the module was the calcium homeostasis gene CHERP. Finally, a higher proportion of CD4 positive activated memory T cells was associated with higher amyloid burden (β = ‐1.940, p = 0.04), but did not survive FDR correction.

Conclusion

Our results implicate DNA damage and activated memory T cells as contributing to amyloid deposition in preclinical AD. Future work will seek to identify modifiers of the APOE effect on amyloid and evaluate blood transcription networks as complementary biomarkers of amyloid deposition.
Association between blood‐based protein biomarkers and brain MRI in the Alzheimer’s disease continuum: A systematic review
Authors: Mitolo Micaela , Lombardi Gemma , Manca Riccardo , Nacmias Benedetta , Venneri Annalena
Published: January 2025

Background

Blood‐based biomarkers are becoming emerging tools, easily detectable and minimally invasive, to reveal neurodegeneration and neuroinflammation in Alzheimer’s disease (AD). However, a comprehensive and up‐to‐date overview of the association between blood‐based biomarkers and brain parameters as measured by MRI is not available. The aim of this review is to fill this gap and clarify the relationship between the main peripheral blood‐based protein biomarkers (i.e., Aβ, p‐tau, t‐tau, NfL and GFAP) and brain parameters derived from MRI in the AD continuum.

Method

A literature search was carried out searching the PubMed and Web of Science databases for articles published up to May 2023. Articles were excluded according to the following criteria: no data on protein biomarkers; no data on the association between biomarkers and MRI data; articles not presenting novel data; articles that included only cognitively unimpaired older adults or patients with other neurological conditions; animal studies; molecular imaging studies; non‐peer reviewed articles; non‐English language articles; case reports.

Result

A total of 33 articles were included in this systematic review. The findings revealed the following: hippocampal volume was positively correlated with Aβ42 and Aβ42/Aβ40 and negatively with Aβ40 plasma levels; p‐tau181 and p‐tau217 concentrations were negatively correlated with temporal grey matter volume and cortical thickness; NfL levels were negatively correlated with white matter microstructural integrity, whereas GFAP levels were positively correlated with myo‐inositol values in the posterior cingulate cortex/precuneus. Moreover, higher plasma GFAP levels were also negatively associated with hippocampal atrophy, lower cortical thickness, and smaller white matter volumes in temporal and parietal regions.

Conclusion

Our systematic review showed strong associations between the main blood‐based protein biomarkers and MRI markers of AD, highlighting a high degree of concordance between these measurements. This suggests a possible advantage in combining multiple AD‐related markers to improve accuracy of early diagnosis, prognosis, progression monitoring and treatment response.

Acknowledgement: This study is supported by funding obtained under the National Recovery and Resilience Plan (NRRP), Mission 4 Component 2 Investment 1.3 ‐ Project code PE0000006, CUP D93C22000930002, “A multiscale integrated approach to the study of the nervous system in health and disease” (MNESYS).