bluuebunny/crossref_metadata_2025 huggingface dataset:
The impact of neuropsychiatric symptoms in in PSP. An overview of quality of life and functionality
Authors: Morales‐Rivero Alonso , Khoja Abeer , Cordero Indira Ruth Garcia , Couto Blas , Monteiro Marta , Tsang Michelle , Antwi Jeffrey , Sasitharan Johnathan , Bhakta Puja , Alwazan Batoul , Kovacs Gabor G. , Fox Susan , Tang‐Wai David F. , Lang Anthony E , Tartaglia Carmela
Published: December 2023

Background

Progressive supranuclear paralysis (PSP) is an atypical parkinsonian disorder associated with oculomotor features, motor disturbances, postural instability along with cognitive problems and neuropsychiatric symptoms. Functional impairment and quality of life (QOL) are often related to the motor symptoms. Our aim was to investigate the contribution of neuropsychiatric symptoms such as depression, anxiety and sleep disturbance to functionality and QOL.

Method

We used data from 69 patients meeting criteria for probable PSP from the Rossy PSP Centre. Neuropsychiatric symptoms, severity and functionality were examined using validated rating scales including the Hamilton Anxiety Rating Scale (HAM‐A) for anxiety, Geriatric Depression Scale (GDS) for depression, Epworth sleepiness scale (ESS) for sleep and Neuropsychiatry Inventory (NPI) total scores. To examine function, we used the Schwab and England Activities of Daily Living Scale (SEADL), severity of disease we used PSP rating scale and for QOL the (EQ‐5D‐5L). Cognition was examined using the Montreal Cognitive Assessment (MOCA). We investigated the relationships between neuropsychiatric symptoms and function and QOL using Pearson correlations controlling for multiple comparisons with false discovery test.

Result

In our sample (37.7% female, mean age 71.2+/‐ 6.5) 26.9% had depression, 13% had anxiety, 97.3% had scores compatible with cognitive impairment. Mean QOL‐EQ‐5D‐5L score was 50.4 +/‐ 25.3, mean PSP‐RS 39.5 +/‐ 12.7. Subgroups were made for QOL and functionality analysis. We found negative correlations between SEADL and HAM‐A (r ‐0.32 p = 0.01), and GDS (r ‐0.32 p = 0.01); between QOL‐EQ‐5D‐5L and GDS (r‐0.51 p = 0.014) and HAM‐A (r‐0.49 p = 0.014). Positive correlations were found between SEADL and QOL‐EQ‐5D‐5L (r = 0.61 p = 0.005) and between PSP‐RS and ESS (r 0.35 p = 0.004). The SEADL and PSP‐RS were negatively correlated (r‐0.39 p = 0.002).

Conclusion

Consistent with apriori hypotheses we found anxiety, depression and PSP‐RS are related to function as measured by the SEADL and quality of life of PSP patients. Sleep disturbance was related to PSP‐RS. These results emphasize the importance of comprehensive evaluations to better capture the multi‐faceted impairments seen in PSP that have a meaningful impact on the patient’s life.
A new home‐based cognitive test using phone calls in mild cognitive impairment
Authors: Hong Yun Jeong , Lee Kyung Won
Published: December 2023

Background

Mild cognitive impairment (MCI) is a risk group of dementia. Despite of plethora of hospital‐based neuropsychological tests, assessment tools that can be performed at home to detect cognitive progression are lacking. We thought that a home‐based cognitive test (HCT) is useful for regular cognitive monitoring without visiting the hospital. Our study aimed to validate the HCT by assessing relationships with existing hospital‐based neuropsychological tests scores.

Method

This pilot study was conducted in a university‐affiliated dementia clinic from July 2019 to December 2021. We had developed a new HCT that can be examined using phone calls without visiting the hospital. The newly developed HCT is composed of 20 questions (score ranges 0‐30), a higher score indicates better general cognition. Participants with MCI were enrolled and underwent regular HCT during 6 months. Brain MRI, plasma amyloid, baseline and endpoint neuropsychological tests, and assessment for clinical progression were performed. Associations between HCT scores and in‐person neuropsychological tests were investigated. We additionally assessed whether the HCT scores are correlated with Alzheimer’s disease (AD)‐related biomarkers including plasma amyloid values and regional brain volumes. To assess relevance, partial correlation coefficient adjusted by age, sex, and education was performed.

Result

HCT had good intraclass correlation coefficient values (test‐retest Cronbach’s alpha 0.839 & inter‐rater reliability Cronbach’s alpha 0.627). Totally 38 participants were enrolled and 32 completed the endpoint evaluations at 6 months. Seven participants progressed to mild dementia. Baseline HCT score showed good correlations with Mini‐Mental State Examination (MMSE) score, verbal memory delayed recall scores, and stroop test scores after adjustment for age, sex, and education. However, HCT scores did not show significant associations with AD‐biomarkers. MCI with higher risk of progression (APOE4 carrier or positivity in plasma amyloid values) showed numerical trends of faster HCT declines compared with MCI with lower risk of progression, although it did not reach statistical significance (p>0.05).

Conclusion

We demonstrated good reliability and correlations of the newly developed HCT with existing in‐person neuropsychological tests. It also showed good applicability on the elderly with MCI. Hence, HCT could be a promising and alternative option to monitor cognitive declines without visiting the hospital.
ADSP Phenotype Harmonization Consortium
Authors: Hohman Timothy J.
Published: December 2023

Background

The Alzheimer’s Disease Sequencing Project Phenotype Harmonization Consortium (ADSP‐PHC) was assembled in 2021 to provide large‐scale harmonization of 40+ deeply phenotyped cohorts included in the ADSP. Harmonization spans from markers of amyloid, tau, neurodegeneration, concomitant pathways of injury, and cognitive decline. This presentation will provide an overview of the methods and results of our first data release (October 2022) and provide a preview for upcoming data release in the coming years.

Method

A team of domain experts was established to provide statistical harmonization. The outcome of these specialized harmonization procedures includes longitudinal composite measures of executive function, language, and memory performance leveraging latent variable modeling, longitudinal biomarker measurement of Aβ42, total tau, and phosphorylated tau leveraging a distribution based harmonization, longitudinal amyloid positron emission tomography (PET) harmonization accounting for different ligands and scanner protocols across sites, longitudinal magnetic resonance imaging (MRI) harmonization including diffusion imaging leveraging image‐based harmonization and statistical harmonization with COMBAT, and both vascular risk factor and neuropathology harmonization leveraging a detailed variable mapping approach. All data, scripts, and documentation are made freely available to qualified investigators on dss.niagads.org.

Result

The first data release (October of 2022) and is described in detail here: https://dss.niagads.org/datasets/ng00067/#phenotype-harmonization. This release included longitudinal cognitive data from >50k individuals covering more than 100k longitudinal data points, with more than 15k individuals also having full sequencing data. Moreover, the release included >6k individuals with harmonized neuropathology and genetic data, and >3k individuals with harmonized fluid biomarker and genetic data. Full data dictionaries and data availability are publicly available here: https://vmacdata.org/adsp-phc. In our next release coming late summer 2023 we will extend the available data in all three of these domains while also including longitudinal neuroimaging (released jointly by NIAGADS and LONI) and vascular risk factor data from 17 cohorts in the ADSP.

Conclusion

The deeply phenotyped cohort studies within the ADSP provide an unprecedented opportunity to explore the genetic architecture of amyloid, tau, neurodegeneration, and cognitive decline. The ADSP‐PHC will deliver an unparalleled resource of harmonized data across domains to facilitate novel genomic discovery and provide AI‐ready resources to better understand drivers of disease heterogeneity.
Association between lifestyle at different life periods and brain integrity in older adults
Authors: Turpin Anne‐Laure , Felisatti Francesca , Ourry Valentin , Mézenge Florence , Landeau Brigitte , Vivien Denis , la Sayette Vincent De , Chetelat Gael , Gonneaud Julie ,   Medit‐Ageing Research Group
Published: December 2023

Background

Increasing evidence suggests that lifestyle factors are related to cerebral markers of aging and Alzheimer’s disease (AD) in older individuals. However, most studies addressed the association between current lifestyle and neuroimaging, providing little information on the relative effect of lifestyle at different life periods on older adults’ brain integrity. We proposed to determine the life period(s) at which lifestyle factors have the greatest influence on older adults’ brain health.

Method

We included baseline data of 135 cognitively unimpaired older adults (aged>65) from the Age‐Well study (NCT02977819). They underwent multimodal neuroimaging providing measures of Gray Matter volume (GMv), glucose metabolism, perfusion (early‐Florbetapir‐PET) and beta‐amyloid burden. The Lifestyle Experiences Questionnaires (LEQ) was used to assess complex mental activities during early‐ (13‐30y), mid‐ (30‐65y) and late‐life (>65y). To evidence the effect of activities at each life period controlling for the others, multiple regressions were conducted including the three LEQ sub‐scores to predict each neuroimaging modality, both 1) focusing on AD‐signature regions and 2) voxel‐wise. In the presence of significant associations, complementary analyses were realized to directly compare the effect of life periods between them. All analyses were controlled for age and sex.

Results

LEQ scores were not associated with AD‐signature regions. Voxel‐wise analyses revealed that higher LEQ score at midlife were positively associated with GMv, including the anterior cingulate cortex (Fig.1a), and negatively associated with amyloid burden, notably in the precuneus (Fig.1b). When compared with the other periods, these associations were statistically stronger for midlife. On the other hand, late‐life activities were positively associated with perfusion (Fig.2a) and glucose metabolism (Fig.2b), mainly in medial frontal regions, and these associations were stronger for late‐life than for any other life period.

Conclusion

Our study suggests that complex mental activities at midlife are more strongly associated with structural and molecular markers of brain integrity in older adults, while late‐life (i.e. current) activities are more strongly correlated with brain function. Interestingly, these associations were not found on AD‐signature regions but in brain regions relevant to reserve and aging. Lifestyle at different life periods might have an influence on distinct markers of brain health in late‐life.
Neuro‐immune markers, socioeconomic inequalities, and neurodegenerative disorders in older age
Authors: Gireesh Aswathikutty , Sacker Amanda , McMunn Anne , Cadar Dorina
Published: December 2023

Background

Accumulating evidence suggests that the neuro‐immune markers of inflammation may be involved in the onset of neurodegenerative disorders (Bostancıklıoğlu, 2019; Park et al., 2020). However, immune mechanisms linking socioeconomic adversities in later life and neurodegenerative disorders have yet to be fully explored. This study has used a large longitudinal study to investigate the mediating effects of neuro‐immune markers in the socioeconomic disparities of neurocognitive disorders in older adults.

Method

Data of 4815 participants aged 50 and above from the English Longitudinal Study of Ageing (ELSA) across three waves of data collection. Socioeconomic position was assessed in 2008/9 and neuro‐immune markers in 2012/2013. Neurocognitive disorders were ascertained using cognitive variables available in 2018/2019 using a well‐accepted consensus criterion (Richardson et al., 2019). It was categorised into no cognitive impairment, cognitive impairment, no dementia (CIND) and dementia. Mediation analysis was carried out to investigate the mediation effect of c‐reactive protein (CRP), fibrinogen and white blood cell (WBC) count in the association between socioeconomic position and different subtypes of neurocognitive disorders. All models were adjusted for age, sex, marital status and baseline cognitive status.

Result

After accounting for potential confounders, CRP, fibrinogen, and WBC partly mediated the association of education, occupation, and wealth with cognitive impairment. Results on dementia were all non‐significant.

Conclusion

Adverse socioeconomic environment were related to early stages of neurocognitive disorders partly via elevated biomarker levels in later life. Neuroinflammation might be one of the immunobiological mechanisms underlying socioeconomic disparities in cognitive impairment. Further research should explore other plausible biological mechanisms to develop interventions to delay the onset of neurodegeneration.
Predictive value of BMI in Cognitive Outcome in Mild Cognitive Impairment
Authors: Jeong Jee Hyang , Lee Eun Hye , Kim Geon Ha , Choi Seong Hye
Published: December 2023

Background

This study aimed to determine the association between neuropsychological performance and body mass index (BMI) in patients with mild cognitive impairment (MCI). In addition, this study investigated the effects of the APOE genotype and sex in the relationship between the BMI and cognition in MCI.

Methods

A total of 3,038 subjects with MCI aged 65‐90 were enrolled from the Clinical Research Center for Dementia of South Korea (CREDOS) cohort and a dementia cohort of the Ewha Womans University Mokdong Hospital (EUMC). MCI patients were classified into three subgroups (normal‐weight, overweight and obesity) according to the Asian standard of BMI. Cognitive performances between groups were compared by one way analysis of variance. To investigate the effects of the age, education, APOE genotype and sex, multivariate linear regression models after adjusting for possible confounders were used.

Results

Even‐though normal BMI groups were younger, had more males and less comorbidities, higher BMI groups (Overweigh and Obese) were associated with better performance in cognitive functions, scores of all neurocognitive tests were significantly increased (RCFT copy, p = 0.047; animal fluency, p = 0.039; phonemic fluency, p = 0.013; SVLT delay recall, p = 0.005; RCFT delay recall, K‐MMSE, p = 0.001; K‐BNT and Stroop test, p<0.001), and CDR‐SB (p = 0.001) was decreased. The APOE ε4 carriers showed positive relationship between the BMI and the memory tasks: SVLT delay recall (p = 0.017) and RCFT delay recall (p = 0.002). And comparing between APOE ε4 carrier gender groups, significant positive relationship was shown only with visual memory task as BMI increases.

Conclusions

Our findings suggested that higher BMI in patients with MCI were associated with better cognitive performance. The effects of the APOE genotype and sex in the associations between BMI and cognition were distinguishing. Therefore, according to physical status, APOE ε4 genotype, and sex‐specific strategies in the assessments and treatments may be necessary in elderly patients with MCI.
Identifying Cognitive Resilience Related Genes Among Genetic Risk Loci of Alzheimer’s Disease
Authors: Carrigan Maria , Van der Lee Sven J , van Loenhoud Anna C. , Bocancea Diana I. , Groot Colin , Barkhof Frederik , Krugers Harm J. , Lucassen Paul J. , van der Flier Wiesje M. , Ossenkoppele Rik
Published: December 2023

Background

Cognitive resilience (CR) in the context of Alzheimer’s disease (AD) describes the ability to maintain cognitive function despite the presence of neuropathology (Hohman et al., 2016). While most studies have focused on investigating genetic risk factors for developing AD, we here examined the association of most robust risk loci (Bellenguez et al., 2021) with CR using a neuroimaging‐based approach that incorporates measures of brain atrophy and cognition into a quantitative CR metric (van Loenhoud, 2017).

Method

We performed magnetic resonance imaging (3T) and DNA testing on n = 440 amyloid‐positive individuals in different clinical stages of AD. Employing a global cognitive composite score, we predicted gray matter volume (GM) in each voxel, adjusted for sex, age, premorbid intracranial volume, disease stage, and scanner type. To operationalize CR, W‐scores were computed for each individual based on the standardized individual difference between predicted and observed GM within temporoparietal (TP) and whole brain (WB) masks. In this approach, positive W‐scores reflect low CR, while negative W‐scores reflect high CR. A total of 83 genetic risk variants for AD (Bellenguez et al., 2021) were each tested for their association with W‐scores in a linear regression model corrected for population substructure (PC1‐5).

Result

We found an association for 6 genetic loci, of which variants rs113706587 in gene RASGEF1c and rs6943429 in gene UMAD1 were associated with higher CR (TP: p<0.01, p<0.02; WB: p<0.02, p<0.01). As expected, APOEe4 was associated with low CR (TP: p<0.01, WB: p<0.01), as were genetic markers of genes CLU, MINDY2 (WB: p<0.04, p<0.04), and BCKDK (WB: p<0.05, TP: p<0.04). Importantly, no association was found between APOEe2 and CR (WB: p = 0.195, TP: p = 0.139).

Conclusion

Among genetic risk‐loci for AD, we identified two genetic variants associated with cognitive resilience in amyloid‐positive individuals. Interestingly, APOEe4 associated with low CR, as did genes CLU, MINDY2, and BCKDK, indicating anti‐resilience – possibly through accelerating mechanisms. In addition, our results suggest that CR against AD is independent of the protective relationship found between APOEe2 and developing AD, highlighting the relevance of investigating the mechanisms behind CR.
Realizing the Representative Reach: How Digital is Enabling Engagement of Hispanic Participants from a Semi Rural County in the United States
Authors: Cantú Jessica A. , Falcon James A , Gonzalez Daniella , Garcia Laura , Falcon Cindy , Griffith Dora Y , Devine Sherral A. , Ume Chisom , Ames Hailey Grace , Jain Shubhi , Sunderaraman Preeti , Brown Christina M. , Low Spencer , Au Rhoda
Published: December 2023

Background

Early detection of brain‐related disorders is key to prevention of Alzheimer’s disease (AD), and research on Hispanic populations is severely lacking. Obstacles to recruitment include the lack of trust in research and researchers and requirements for English proficiency, which excludes many potential Hispanic participants.

Methods

Researchers from El Faro Health and Therapeutics in Starr County, Texas and the Framingham Heart Study are teaming up on a digital phenotyping study and incorporating “trust” as a central theme for recruitment/retention of Hispanic participants. Study materials are in both English and Spanish. The smartphone tasks are presented in two formats: “in‐clinic” using an iPad and “remote” utilizing participants’ smartphones. Activities include voice tasks, gait and balance, and game‐like cognitive tasks. Longitudinal data will be collected every three months for one year.

Participants

Recruitment is for anyone aged 18+ in Starr County, which is approximately 98% Hispanic. To maximize inclusivity, there are no other inclusion/exclusion criteria. Study procedures are customized to accommodate individuals. Recruitment goal is 500 participants within one year, with planned expansion to 5,000+ over 5 years.

Results

Recruitment approach includes several components: (1) El Faro investigators have been providing clinical services to community members for decades, and are respected and trusted members of the community. (2) All participant‐facing study materials are available in both English and Spanish, with most translated into the specific local dialect. (3) Community fliers include text in both English and Spanish. (4) Social media outreach has sparked a great deal of interest for participating in research, and the team attends community events to further spread the word. (5) Multi‐generational families are encouraged given family decision‐making culture; (6) Word‐of‐mouth within the Starr County community is expected to be an important contributor to recruitment.

Conclusions

Although data collection will begin in February 2023, already more than 150 participants have expressed interest in being involved. Leveraging resources to enable highly respected and trusted local researchers to conduct the research, and using participant‐centric design approaches will result in greater success in recruitment and retention of this underrepresented population.
Carers' perspective on adapting the iSupport in New Zealand
Authors: Sani Tara P , Cheung Gary , Peri Kathy , Yates Susan , Whaanga Hēmi , Cullum Sarah J
Published: December 2023

Background

The World Health Organisation (WHO) has developed ‘iSupport for Dementia’, a self‐paced training for family carers of people with dementia. Empowering Dementia Carers in an iSupport Virtual Assistant (e‐DIVA) project aims to develop a website based on iSupport to support carers in Aotearoa New Zealand (NZ), Australia, Indonesia, and Vietnam. We aim to understand carers’ perspectives on iSupport to inform the NZ adaptation.

Method

We recruited primary unpaid carers through a local non‐government dementia support organisation. We included carers who were aged 18 years old or over, caring for a person living with dementia for at least six months, able to speak English and use internet for video conference. Participants were provided with the original iSupport manual to review for a month. We conducted online focus group discussions with the carers (3‐4 per group) who provided feedback on the original manual. Each group met twice for two hours. The meetings were recorded, transcribed verbatim, and analysed thematically. We then used the results of the thematic analysis to inform the development of the iSupport‐VA NZ website and supporting materials such as videos.

Result

Seven carers participated in this study. We identified common feedback which could be grouped into content, delivery, and potential use beyond immediate family carers. Based on the feedback, we split Module 1 into four sections, adding contents on optimising brain health, person‐centred care, and planning for the future. We also rearranged Modules 4 and 5 to start with information that all carers need then moving on to information more relevant to mid‐to‐late stage dementia. We also made changes in the illustration and language used. We amended the school‐like features (right‐or‐wrong approach), but kept the reflective activities. Carers also discussed the possibility of using iSupport as resources for extended family not involved in care and for care professionals.

Conclusion

Several changes were required to adapt iSupport for use in NZ. This tool has some potentials for wider use beyond unpaid family carers. A separate research with Māori carers using a similar method started in 2023.
Establishing National Social Exposome Alzheimer’s Disease and Related Dementias (ADRD) Infrastructure
Authors: Kind Amy J.
Published: December 2023

The exposome, comprising the variety of life‐course exposures and influenced by structural inequities such as systematic racism, is theorized to interact with biological, behavioral, sociocultural, and economic mechanisms as a modifiable factor influencing Alzheimer’s Disease and Related Dementias (ADRD) risk and resilience. The disparities‐aligned exposome is optimally linked to biologic health outcomes using participant residential history– denoted by US privacy law as ‘protected health information’ or PHI and subject to stringent regulation. The complicated legal, administrative, and technical research infrastructure challenges with multi‐site PHI‐data have formed substantial barriers to ADRD‐aligned exposome study, leading to a present state in which most national biologic repositories and resources curate only non‐PHI data thus prohibiting direct disparities‐aligned exposome metric linkage. Due to data security concerns including the substantial cybersecurity risk an institution assumes in storage of PHI‐data from outside the home institution, there are few existing resources to link geo‐specific exposures to ADRD outcomes on a national scale. This project will remove barriers in exposome science by addressing the infrastructure expansion needed to connect key NIA national data and biorepository resources to PHI‐requiring exposome metrics while shielding these NIA research infrastructures from the burden of PHI management. Our goal is to build infrastructure across the 22 ADRCs in the Neighborhoods Study (R01AG070883), including developing data intake and linkage processes for new exposome metrics. The project is directly responsive to the Congressional language that led to the allocation of these funds; specifically, to support infrastructure that enables the linkage of life‐course exposure factors to biological outcomes, characterized through a mechanistic health disparities lens. In this presentation we will outline the specific plans to enhance, refine and establish enduring, ethical and community‐aligned administrative and legal agreement, process and coordination infrastructure for on‐going PHI and exposome data flow intake and non‐PHI exposome data outflow; and to enact data acquisition, intake, linkage and management processes for additional ADRD disparities‐aligned exposome metrics (e.g., pollution).
The speech‐to‐song illusion in frontotemporal dementia and Alzheimer’s disease
Authors: Jiang Jessica , Requena‐Komuro Mai‐Carmen , Benhamou Elia , Johnson Jeremy , Sivasathiaseelan Harri , Chokesuwattanaskul Anthipa , Hardy Chris JD , Warren Jason D
Published: December 2023

Background

Perceptual plasticity depends on dynamic, coordinated synaptic tuning across neural circuits and is therefore likely to be vulnerable to neurodegenerative pathologies. However, the nature and limits of perceptual plasticity in dementia are largely unknown. Here we addressed this issue using a dramatic instance of auditory perceptual plasticity ‐ the speech‐to‐song illusion discovered by Diana Deutsch (2011), whereby a spoken phrase is perceived as sung after a few repetitions.

Method

We studied patients representing all major syndromes of frontotemporal dementia (FTD) (N = 22) and Alzheimer’s disease (AD) (N = 25) versus healthy age‐matched controls (N = 21). We asked each participant whether they experienced the Deutsch illusion, and separately assessed their ability to discriminate spoken and sung phrases. In patients who reported experiencing the illusion, we verified this using a forced‐choice procedure.

Result

The Deutsch illusion was reported by 76% of healthy controls, and by 44.4% with progressive non‐fluent aphasia (PNFA), 42.9% of patients with semantic dementia (SD), 20% with typical AD, 20% with logopenic aphasia (LPA), and none with behavioural variant FTD (bvFTD). Mean scores for speech/song discrimination were as follows: healthy controls, 99%; SD, 97.6%; AD, 95%; LPA, 94.7%; PNFA, 94%; bvFTD, 87%. bvFTD performed significantly lower than healthy controls at discrimination.

Conclusion

Perception of the speech‐to‐song illusion is reduced in canonical FTD and AD syndromes compared with healthy older people and stratifies dementia syndromes disproportionately to any underlying perceptual deficit. The illusion presents an interesting new model for assessing perceptual plasticity in these diseases.
Recruitment and retention of US Latinos in biomedical research and clinical trials
Authors: Portacolone Elena
Published: December 2023

Latinos/Hispanics are underrepresented in clinical trials for Alzheimer’s disease and related dementias (ADRD).This underrepresentation reduces the generalizability of research findings, widening health disparities. These are significant public health concerns, because Latinos have a higher risk than non‐Latino Whites to develop ADRD and represent 19% of the US population.

Taking lessons from the micro‐meso‐macro framework of Maria Aranda et al., in this session the Recruitment and Clinical Trials Special Interest Group (SIG) of the US Consortium of Aging, Dementia & Latino Studies (CADLAS) will discuss opportunities, challenges and future directions across multiple lenses of analysis. We argue that to increase Latino representation it is essential a far‐reaching perspective sensitive to the interplay among subjective/community (i.e., micro) factors, meso factors pertaining to the domain of clinical trials and researchers, as well as macro factors such as policies of funders and regulatory agencies such as the Food and Drug Administration (FDA).

The SIG aims to promote collaborations among investigators working to improve participation and retention of US Latino/Hispanic populations into clinical research. Building on the expertise of SIG members, key opportunities range from fostering career advancements while offering job opportunities to Latino outreach specialists, to playing Loteria to engage Latino audiences. Opportunities also include new ways of designing participants’ incentives moving beyond financial compensations to include ad‐hoc medical services, and caregiving and transportation supports. Challenges range from funders not requiring comprehensive and culturally‐relevant recruitment plans (and related budgets), to limited awareness of clinical trials in Latino communities. Promising directions include emerging partnerships between national organizations trusted by Latino communities and the Alzheimer’s Clinical Trial Consortium, and the recent plan of the FDA to recommend diversity plans. The session will end with a set of recommendations leveraging on opportunities and promising directions.
Soluble Abeta produces an increase in cytosolic and mitochondrial calcium in astrocytes in vivo, in part by direct effect in astroglial cells
Authors: Sanchez‐Mico Maria V. , Calvo‐Rodriguez Maria , Kelly Patricia H. , Whiteman Sara , Kharitonova Elizabeth K. , Hou Steven S. , Bacskai Brian J.
Published: December 2023

Background

By using in vivo multiphoton microscopy, we have previously reported that astrocytic cytosolic resting calcium (Ca2+) is globally elevated in a transgenic mouse model of cerebral β‐amyloidosis (APPswe/PS1dE9) (PMID:19251629). However, this phenomenon is independent of the proximity of astrocytes to amyloid β (Aβ) plaques. In addition, soluble Aβ oligomers (Aβo) are thought to mediate neuronal toxicity by increasing neuronal calcium and causing synapse loss. For those reasons, we hypothesized that Aβo, rather than Aβ plaques, contribute to the Ca2+ insult in astroglial cytosol and mitochondria in vivo.

Method

To test this hypothesis, we topically applied naturally secreted soluble Aβo (conditioned medium from cultured transgenic primary neurons) onto the brain surface of 4‐6‐month old wild‐type mice. We investigated changes on astrocyte and mitochondrial Ca2+ levels relative to baseline via intravital multiphoton imaging, by using a ratiometric genetically‐encoded FRET‐based Ca2+ indicator (Yellow Cameleon 3.6) targeted to astroglial cytosol or mitochondria.

Result

We observed that Ca2+ levels dramatically increased upon topical soluble Aβo application, in all cytosolic astrocyte compartments (soma, branches and end feet), but also in astrocyte mitochondria. Aβ‐immunodepleted transgenic conditioned media and wild‐type conditioned media did not alter astrocyte cytosolic or mitochondrial Ca2+, supporting the specificity of the observed effects. Furthermore, we have also seen this effect in cultured astrocytes, suggesting that Aβo is directly interacting with astroglial cells, and not through an effect on other cell types, such as neurons or microglia. In addition, we previously reported that upon blocking the mitochondrial calcium uniporter (MCU) with Ru360, calcium levels in neuronal mitochondria were restored (PMID:32358564). However, there was still an increase of mitochondrial calcium in astrocytes in presence of soluble Aβo and Ru360 in vivo. Thus, soluble Aβo is disrupting calcium levels in astrocytes through a different mechanism.

Conclusion

Ultimately, these results together support a detrimental role of Aβo which leads to astrocyte Ca2+ dyshomeostasis in vivo, implying that Aβo are involved in the astrocytic dysfunction observed in AD. Future studies will continue to explore the source of soluble Aβo‐induced Ca2+ increase, including intracellular Ca2+ stores and channels involved, which could have therapeutic value.
Major changes in AD brain gene expression caused by the T9861C mtDNA mutation
Authors: Castora Frank J , Pflanzer Haley K , Alvarez Nehemiah S
Published: December 2023

Background

Evidence of mitochondrial dysfunction in Alzheimer’s Disease (AD) has accumulated over the years. We have previously identified a mutation in mitochondrial DNA (mtDNA) that is strongly associated with AD. This T9861C mutation changes a phenylalanine into a leucine at amino acid position 219 of cytochrome c oxidase subunit 3, resulting in a significant reduction of cytochrome oxidase activity. We report the effect of this mutation on the expression of genes involved in mitochondrial function in AD brains.

Method

Total RNA sequencing with ribosome depletion was performed on frozen archival tissue from parietal cortex of three control and eight sporadic AD (four AD, and four AD+ (AD patients possessing the T9861C mtDNA mutation)) brains. Reads were aligned to a transcriptome reference (Ensemble, GCRh38) containing all annotated mRNA and noncoding RNA using kallisto bus (v0.48). Read counts were calculated for genes using bustools (v0.41). Count data were analyzed using RNAfuzzyApp. Read count normalization was performed using TMM and differential gene expression was determined using edgeR. Pathway enrichment was performed using Gene Ontology (GO).

Result

The heatmap shown identifies a total of 472 deferentially expressed genes (DEGs, p value <0.05, FDR <0.05) in the comparison of control vs AD vs AD+ samples. Principal component analysis shows that gene expression in AD samples is significantly different from that in controls and that a more striking difference exists between the AD+ samples and both control and AD samples. The 472 DEGs can be grouped into five clusters. These clusters impact a variety of mitochondrial functions related to synaptic signaling, cell junctions, neuron projections, the HIF‐1 signaling pathway, voltage‐gated channel activity and carbohydrate metabolism.

Conclusion

The presence of the T9861C mutation in the brains of AD patients has a significant effect on expression of the brain transcriptome in the parietal cortex. There is a general and robust decrease in expression of the majority of DEGs relative to control and non‐mutation containing AD brains. There is also a smaller number of DEGs that are upregluated compared to control and non‐mutation containing AD brains. These gene expression changes impact mitochondrial function resulting in neuronal failure and neurodegeneration.
Relationship between a novel virtual reality test of mild functional difficulties and cerebrovascular disease
Authors: Holmqvist Sophia L. , Jobson Katie , DeSalme Dennis , Simone Stephanie M. , Tassoni Molly , Mckniff Moira , Yamaguchi Takehiko , Olson Ingrid , Martin Nadine , Giovannetti Tania
Published: December 2023

Background

It is well known that mild cognitive impairment (MCI) is associated with subtle functional decline. However, standardized and cost‐effective methods for the objective quantification of mild functional difficulties are lacking. Here we report preliminary validity data for a novel, non‐immersive virtual‐reality task (Virtual Kitchen Challenge [VKC]) against brain markers of cerebrovascular disease and in contrast to a conventional, self‐report measure of function.

Method

Twenty (n = 14 healthy control, n = 6 MCI) community‐dwelling older adults aged 60+ completed neuropsychological testing, including the Functional Activities Questionnaire (FAQ), and the VKC, which requires completion of simulated breakfast and lunch tasks on a touch‐screen computer. White matter hyperintensity (WMH) volumes from Fluid Attenuation Inversion Recovery (FLAIR) MRI sequences were derived using the UBO detector, a cluster‐based WMH extraction pipeline based on k‐nearest neighbors (k‐NN) algorithm. WMH volumes were calculated in SPM’s DARTEL space, precluding the need to adjust for intracranial volume (ICV).

Result

MCI participants reported significantly more functional difficulties than healthy controls (FAQ U = 76.50 p = .002) and obtained marginally slower completion times on the VKC (U = 60.00, p = .138). VKC completion time was moderately associated with age (r = .441, p = .059) but relations with sex, race, and IQ were weak and not significant (all rs<.195). VKC completion time significantly and strongly correlated with all WMH measures, even after controlling for age, sex, race, and IQ (total WMH r = .649, p = .031; deep WMH r = .615, p = .044; periventricular WMH r = .623, p = .041). By contrast, FAQ was not associated with WMH (rs<.2, p>.05 for all) or VKC completion time (r<.1, p>05) after controlling for age, sex, race, and IQ.

Conclusion

Our naturalistic, performance‐based measure of function (VKC) was not associated with race, sex, or premorbid IQ, but was strongly associated with neuroimaging markers of cerebrovascular disease (WMH). By contrast, a conventional self‐report measure of everyday functioning (FAQ) was not associated with neuroimaging measures (WMH). These results offer preliminary support for the VKC as a valid measure of early, subtle functional difficulties associated with cerebrovascular pathology that is not vulnerable to bias associated with race, sex, or premorbid IQ.
Neuropathology in the LifeAfter90 Study: 2023 update on an Ethnically Diverse Cohort Study of Oldest‐Old
Authors: Dugger Brittany N , Jin Lee‐Way , Ortega Krystle , Decarli Charles , Gilsanz Paola , Mungas Dan M. , Kawas Claudia H. , Corrada María M. M. , Whitmer Rachel A.
Published: December 2023

Background

Neuropathology studies of the oldest‐old have significantly advanced our understanding of the multiple etiologies late in very late life. Most studies, however, have limited ethnoracial diversity with almost exclusively White decedents. Our goal was to characterize neuropathology in a cohort of ethnically and racially diverse oldest‐old decedents.

Method

The LifeAfter90 study is an ongoing cohort study of Kaiser Permanente Northern California members, aged 90+ with targeted recruitment of individuals across different racial/ethnic groups with no prior diagnosis of dementia in their medical record. Interviews and cognitive assessments occur approximately every 6 months. Brain donation was available to all interested consenting participants. Neuropathology was assessed using the National Alzheimer’s Coordinating Center Neuropathology form v.10 and used NIA‐AA guidelines for Alzheimer’s diagnoses. As of January 2023, 304 participants (40%) were enrolled in autopsy (20% Asian, 18% African American, 17% Latino, 9% Multiracial/Other, and 36% White).

Result

Of the 304 participants, 59 had died and neuropathological evaluations were completed. The median age of death was 93 years (range 90‐105), 33 (56%) were female, 8 Asian, 5 Black, 10 Latino, 31 White, and 5 Multiracial/Other. At final clinical exam, 17 participants had dementia (29%), 25 questionable/mild cognitive impairment (42%), and 16 were cognitively normal (27%). Alzheimer disease (AD) and vascular pathologies were the most frequent findings (Figure). Twenty two percent of participants did not have AD, one lacked neurofibrillary tangles (NFT). The most severe distributions/densities of NFTs and plaques were infrequent, with high likelihood of AD in two participants. For vascular pathologies, 98% had some level of arteriolosclerosis, 97% had atherosclerosis, 70% had amyloid angiopathy, and 26% had at least one old microinfarct. Other pathologies were less common: 27% had Lewy bodies, 18% had TDP‐43 deposits, and only one had Hippocampal sclerosis. Although data is sparse to test for associations, the proportion of individuals with dementia tended to increase with increasing pathology severity especially for AD pathologies.

Conclusion

This diverse cohort of oldest‐old individuals reveal numerous brain pathologies are present with advanced age, with AD and select vascular pathologies being the most common. Future analyses will investigate their role with cognitive impairment.
SLEEP MICROARCHITECTURE IN MILD COGNITIVE IMPAIRMENT: A HIGH‐DENSITY EEG STUDY
Authors: D’Rozario Angela L , Kao Chien‐Hui , Haroutonian Carla , Grunstein Ronald R , Naismith Sharon L
Published: December 2023

Background

Sleep disturbance and sleep disorders are potential risk factors for dementia. Adults with mild cognitive impairment (MCI) are at increased risk of developing dementia and many report disturbed sleep. Altered sleep neurophysiology including deficits in sleep spindles and slow wave activity (SWA) during NREM sleep have been reported in MCI, though studies are sparse. These NREM EEG oscillations are crucial for overnight memory consolidation and optimal daytime functioning. Abnormal EEG activity during sleep in MCI may adversely impact sleep‐dependent memory processes and cognitive trajectory. This study is the first to examine sleep microarchitecture using high‐density EEG technology in MCI.

Method

Older adults with multi‐domain MCI (n = 19, mean age 68.5 years) and cognitively‐intact controls (n = 22, 69 years) had 256‐channel high‐density EEG recordings during overnight polysomnography and resting wakefulness. Declarative (word paired associates) and procedural (finger tapping) memory tasks were administered before and after sleep. Neuropsychological testing and brain MRI scans were also performed. After artefact processing, spectral analysis was performed for high‐density EEG recordings. Topographical power maps were calculated for standard frequency ranges for NREM sleep (N2 and N3 (slow wave sleep)). Maps were compared between groups using normalized power (z‐scores computed for each subject).

Result

The MCI group had worse declarative (% retention, MCI vs Controls: 84.2 ± 16.6 vs. 94.5 ± 7.8, p = 0.024) and procedural (% early improvement: 92.9 ± 11.0 vs. 103.0 ± 12.0%, p = 0.017) overnight memory consolidation than the controls. Topographic analysis of high‐density EEG data revealed a regional increase in SWA (1‐4.5Hz) EEG power during N3 in a cluster of 18 electrodes overlying the centroparietal cortex in the MCI group (cluster mean t‐value = 3.11, p = 0.0036, uncorrected) and a regional reduction in SWA in the left frontal (5 channels, t = ‐3.75, p<0.001) and right temporal areas (5 channels, t = ‐3.46, p = 0.001), Figure 1.

Conclusion

Overnight memory consolidation was impaired in this MCI population. Regional differences in SWA during deep sleep were present in distinct brain regions and may indicate pathology. Future analysis exploring associations between EEG abnormalities with underlying brain structures may provide mechanistic insights into the impact of altered sleep neurophysiology on cognitive outcomes in MCI.
Fear and avoidance of memory loss: associations with cognitive, psychological and lifestyle factors in mid‐ and later life
Authors: Farina Francesca R , Wells Katie , Marquez Melissa , An Hosanna , Koychev Ivan , Malhotra Paresh A , O'Brien John T , Ritchie Craig W , Naci Lorina , Griffith James W , Lawlor Brian
Published: December 2023

Background

Alzheimer’s disease and related dementias (ADRD) are among the most feared conditions. Some level of fear can motivate healthy behaviors. However, intense fears can have the opposite effect, leading to avoidance behaviors such as withdrawal from cognitively or socially demanding activities. In this way, fears and avoidance behaviors have potential to influence modifiable ADRD risk. Here, we investigated if fear and avoidance are associated with cognitive, psychological and lifestyle factors in mid‐ and later life.

Methods

Participants were middle‐aged (n = 188, 40‐59 years, mean = 51.4 ± 5, 52.7% female) and older adults (n = 746, 60‐90 years, mean = 65 ± 7.2, 61.5% female). Fears and avoidance behaviors were measured using Fear and Avoidance of Memory Loss scale. Linear regression examined the contribution of fear and avoidance to cognitive, psychological and lifestyle factors. Mid‐life factors included cognition (COGNITO), stress (Perceived Stress Scale), depressive symptoms (Center for Epidemiologic Studies Depression Scale), loneliness (UCLA Loneliness Scale) and lifestyle activities (Lifetime of Experiences Questionnaire). Later life factors included cognition (MoCA) and depression (Geriatric Depression Scale). Models were adjusted for age, gender, education, ADRD family history and anxiety.

Results

Middle‐aged and older women reported higher fear compared to men (ps < .028). Older individuals with a family history of ADRD also reported higher fear (p < .001). Avoidance behaviors were significantly associated with worse cognitive performance in later life (β = ‐0.10, p = .020), but not in mid‐life. Greater avoidance in mid‐life was associated with higher stress (β = .83, p = .001), loneliness (β = 1.22, p < .001) and depressive symptoms (β = 1.09, p < .001), and lower engagement in lifestyle activities (β = ‐0.19, p = .02). Avoidance was also associated with depressive symptoms in later life (β = .28, p < .001).

Conclusions

Avoidance behaviors were associated with lower engagement in healthy lifestyle activities in mid‐life, worse cognitive performance in later life, and reduced psychological well‐being in both mid‐ and later life. While causation cannot be determined, it is likely that these factors interact recursively over time. Thus, targeting avoidance early on may be beneficial for ADRD risk reduction.