bluuebunny/crossref_metadata_2025 huggingface dataset:
A machine‐learning approach to biomarker evaluation for AD precision medicine
Authors: Climer Sharlee
Published: December 2023

Background

Late‐onset Alzheimer disease (AD) is a heterogeneous disease, as demonstrated by its wide range of genetic and environmental risk factors, as well as diversity of clinical manifestations. Cognizant of the futility of a one‐size‐fits‐all approach for heterogeneous diseases, precision medicine aims to treat each subtype appropriately, but methods for successful diagnosis of AD subtypes has been limited. Real‐valued biomarkers, such as omics measurements in plasma or CSF, frequently are evaluated based on fold change (FC) and/or the area under the receiver operating characteristic curve (AUC) metric. We previously demonstrated the inability for FC and AUC to capture signals for subtypes that comprise less than 50% of the diseased individuals due to inherently low true positive rates and proposed an alternative approach based on the bimodality of the data [Smith and Climer, https://doi.org/10.1101/2022.02.14.22270972]. This approach is based on statistical characteristics of the data, including skewness, cardinality, and kurtosis. k‐medians clustering, a machine learning approach to identify natural clusters in data, removes these statistical assumptions, but optimally solving k‐medians is generally NP‐hard, yielding computational intractability for datasets of interest. Lloyd’s approximation algorithm is commonly used in practice, however, its accuracy is highly sensitive to the random start state, thus is not suitable when accuracy is paramount.

Method

Owing to the nature of the problem, we present an evaluation metric based on the optimal k‐medians objective with k = 2. Additionally, due to the single dimensionality of the data, we introduce a dynamic programming algorithm to improve computational performance.

Result

Although optimally solving k‐medians is NP‐hard, our 2‐medians objective over 1‐dimensional data using dynamic programming has an average time complexity of O(n log n), and worst‐case complexity of O(n
2) where n is the number of data values. This objective has no reliance upon false positive rate, skewness, or kurtosis, making it robust for real‐valued data drawn from heterogeneous AD subtypes.

Conclusion

Biomarker data drawn from heterogeneous AD subtypes will have inherently low true positive rates, resulting with low FC and AUC values. Our machine‐learning based approach for evaluating potential biomarkers efficiently produces optimal clustering of the data and scales well to large datasets.
Classification of patients with dementia in a late life depression cohort using structural MRI
Authors: Hadji Mohammad , Weinstein Andrea M. , Jeyachandra Jerrold , Brown Patrick , Butters Meryl A. , Lavretsky Helen , Lenze Eric J. , Miller J. Philip , Mulsant Benoit H. , Voineskos Aristotle N. , Shimony Joshua S.
Published: December 2023

Background

Late life depression (LLD) is a risk factor for cognitive impairment, with up to 40% of depressed older adults showing persistent cognitive deficits even after symptom remission. Over 20% of Alzheimer’s disease patients exhibit depression‐like symptoms which can represent an early marker of disease (Tsuno et Homma., 2009). We hypothesized that automated classification algorithms trained on structural MRI could predict adjudicated diagnosis of cognitive impairment (CI) in this cohort.

Method

Our study evaluated 295 patients with LLD. An adjudication committee consisting of two board‐certified psychiatrists and a clinical neuropsychologist determined ground‐truth labels for patient diagnostic results of CI (N = 145) or No CI (N = 150). Patients underwent T1‐weighted scans, which were segmented with Freesurfer 6.0.1 (freesurfer.net) packaged with fMRIPrep 1.5.8 (fmriprep.org) using the Desikan‐Killiany atlas. Cortical thickness and volumetric data were obtained along with demographic parameters. Freesurfer data was then regressed against estimated total intracranial volume. 11 classifications algorithms implemented in R were trained and tested on 209 and 88 patients, respectively, to classify if a patient has CI. All continuous‐valued data were normalized with respect to the training set mean and standard deviation.

Result

Table 1 shows results from multiple classifications algorithms, including high sensitivity, specificity, and accuracy from adaptive boosting algorithms. The latter algorithms iteratively optimize a set of binary classification tree algorithms (Freund et Schapire., 1996).

Conclusion

Volumetric structural MRI biomarkers trained with machine learning classifiers can adequately categorize depressed older adults with CI which could assist the adjudication process. Future work incorporating structural MRI biomarkers with gold standard clinical data may improve earlier detection of cognitive impairment stemming from a neurodegenerative etiology.

References

:

1. Tsuno, N., & Homma, A. (2009). What is the association between depression and Alzheimer’s disease?. Expert review of neurotherapeutics, 9(11), 1667‐1676.

2. Freund, Y., & Schapire, R. E. (1996, July). Experiments with a new boosting algorithm. In icml (Vol. 96, pp. 148‐156).
Model‐EyeD: Harnessing the potential of the eye as a biomarker for Alzheimer’s disease and related dementias
Authors: Howell Gareth R , Marola Olivia J , Maclean Michael , Cossette Travis L , Hewes Amanda , Morgan James , Singer Cliff , Risacher Shannon L. , Onos Kristen D , Reagan Alaina M ,   MODEL‐AD consortium
Published: December 2023

Background

Disease‐modifying treatments for Alzheimer’s disease and related dementias (ADRD) will be most effective early in the disease process. Clinical use of these therapies will require practical, widely accessible biomarkers. Plasma‐based protein biomarkers hold promise for identifying core AD pathology, but this complex disease likely requires other markers to identify people at highest risk of progression to dementia. Studies support eye exams as a synergistic strategy since retinal imaging would be cost effective, but significant hurdles remain. The timing and subtypes of retinal biomarkers have not yet been determined and the identification of ADRD‐specific biomarkers independent of common ocular diseases is challenging. Here, we introduce a new program, Model‐EyeD, to evaluate the eye as an accessible biomarker in the mouse model and human subjects.

Method

For familial AD and mixed dementia, we have backcrossed the APPSAA
knock‐in allele (humanized Abeta with Swedish, Artic, Austrian, mutations) from C57BL/6J (B6) to genetically diverse NZO/HILtJ (prone to obesity and diabetes), and WSB/EiJ (susceptible to cerebrovascular deficits) strains. To study late‐onset AD (LOAD), we are using strains created by the IU/JAX/PITT MODEL‐AD Center, including the common 677C>T variant in methylene tetrahydrofolate reductase gene (Mthfr677C>T
), a cardiovascular and cerebrovascular risk factor. A battery of ocular assays (pattern electroretinograms, fluorescence angiography, optical coherence tomography) are performed on four to 24 months old male and female mice. Results are being compared to MRI, PET/CT, cognition and blood biomarkers.

Result

Unlike previous transgenic amyloid models, B6.APPSAA
and WSB.APPSAA
mice show no retinal amyloid deposition or retinal vascular deficits at 12 months. NZO (in the absence of amyloid deposition) show retinopathy lesions (cotton wool spots, vascular leakage), suggesting NZO.APPSAA
are ideal to study interactions between metabolic syndrome retinopathy and mixed dementia. Young B6.Mthfr677C>T
mice show cerebral and retinal vascular deficits. Aging studies are ongoing. Results will be confirmed in human subjects with clinical and biomarker‐confirmed AD and mixed AD/small vessel vascular disease.

Conclusion

Our extensive collection of genetically diverse mouse models, coupled with our alignment to data from human subjects, show promise in developing eye‐based protocols to identify early stages of different clinical phenotypes of ADRD in humans.
Low‐resource long‐term dementia care settings: Identifying key features and strategies for research recruitment
Authors: Holmes Sarah D , Davie Laura , Kusmaul Nancy , Rataj Alison , Curbeam Deanna , Crary Kate , Corazzini Kirsten , Lepore Michael
Published: December 2023

Background

Low‐resource long‐term care (LTC) settings serve older adults who are at high risk for health inequities in dementia care, including individuals who are socioeconomically disadvantaged and live in rural areas. With the growing demand for dementia care and increasing diversity of LTC residents, identifying and partnering with low‐resource LTC settings is critical for dementia care research. However, low‐resource LTC settings are not well defined or understood. Drawing on data from a larger study of person‐centered dementia care, this study describes key features of low‐resource long‐term dementia care settings in two U.S. states and processes for identifying and recruiting these settings for research engagement.

Method

Primary and secondary data and purposive sampling with maximum variation were used to identify low‐resource LTC settings that serve residents with dementia in two states and to target sites for recruitment. Input from local ombudsmen and publicly available data were used to identify sites that served residents with dementia, accepted Medicaid, and were located in federally designated medically underserved areas. Sites were recruited via phone and email contacts. Following study orientation site visits, researchers developed site descriptions which were verified by each site.

Result

Four LTC settings (two nursing home; two assisted living) that serve residents with dementia participated. All four settings were in federally designated medically underserved areas with two settings each in rural and urban areas. Facility size ranged from 19 to 105 residents. The assisted living settings accepted Medicaid waivers and at least one‐third of their residents received financial assistance through Medicaid or other subsidies. Most residents in the nursing homes were Medicaid beneficiaries. Residents at the sites had a wide range of socio‐demographic characteristics and physical and cognitive impairments. All settings noted staffing challenges and considerable variation in retention strategies were reported.

Conclusion

Identifying and partnering with low‐resource LTC settings is critical for research on equity in dementia care. This presentation describes key features of low‐resource LTC settings that serve residents with dementia and strategies for identifying and recruiting them for research. Additional work is needed to expand on these descriptive findings and to broaden generalizability to other LTC settings.
Exploratory Factor Analysis of Neuropsychological Test Data as Measured by the Original and Extended Version of the Alzheimer’s Disease Assessment Scale in the SIU Longitudinal Cognitive Aging Study
Authors: Unnam Pavani P , Patel Dhara S , Bhatt Margi , McGinity Sean , Botchway Albert , Zec Ronald F , Ala Tom , Hascup Erin R. , Trivedi Mehul Alkesh
Published: December 2023

Background

The original Alzheimer’s disease Assessment Scale (oADAS) has been used to measure cognitive aging in Alzheimer’s disease (AD) since the 1980s and is considered the gold standard for assessing the efficacy of novel treatments for AD. However, the oADAS has been criticized for not being sensitive to predementia syndromes such as mild cognitive impairment (MCI) due to the ceiling effects of many of the ADAS subtests. In the present study, we used Exploratory Factor Analysis (EFA) to determine the underlying factor structure of the oADAS and a novel extended version of this measure (eADAS).

Method

We included data from 978 participants who were enrolled in the SIU LCAS as controls. The majority of the cohort was White/Non‐Hispanic (97.2%) and female (66.4%). Participants had a mean age of 66.1 years and a mean education of 14.6 years. The oADAS was administered using standardized methods. All of the subtest data was converted back from error scores to raw scores and standardized using z‐score transformation. EFA with oblimin rotation was used. The sum of examiner ratings was excluded because it was the only measure not performance‐based.

Result

For the oADAS, we identified two factors: A general factor (including 2 memory measures, naming, commands, and orientation) and a praxis factor (including constructional and ideational praxis). For the eADAS, we also identified two factors: A memory/speed factor (including 5 memory measures, orientation, word generation, and the letter‐digit test) and a general factor (including naming, constructional and ideational praxis, clock to command, and similarities). The commands subtest did not load onto either factor for the eADAS EFA. After controlling for education and sex, linear regression analysis confirmed previous findings that increasing age was associated with decreased factor scores (p < 0.001).

Conclusion

The results of the present study provide novel information regarding the underlying factor structure of the oADAS and eADAS. Our results also confirm previous research demonstrating that increasing age is associated with reduced cognition after controlling for education and sex. Future directions include using these factor scores to examine the influence of risk factors for cognitive decline in predementia syndromes.
Novel CSF tau biomarkers can be used for disease staging of sporadic Alzheimer’s
Authors: Salvadó Gemma , Horie Kanta , Barthélemy Nicolas R. , Vogel Jacob W , Binette Alexa Pichet , Chen Charles D. , Gordon Brian A. , Benzinger Tammie L.S. , Holtzman David M. , Morris John C , Palmqvist Sebastian , Stomrud Erik , Janelidze Shorena , Ossenkoppele Rik , Schindler Suzanne E. , Bateman Randall J. , Hansson Oskar
Published: December 2023

Background

Staging Alzheimer’s disease (AD) allows for the identification of key milestones and inflection points in the disease course. However, most current in vivo disease staging methods rely on costly and low‐accessible measures such as PET. Our objective was to generate and evaluate a staging model based on multiple cerebrospinal fluid (CSF) biomarkers.

Method

We created a staging model using the Subtype and Stage Inference (SuStaIn) algorithm in 426 participants covering the whole AD spectrum (Table 1) by evaluating CSF Ab42/40 and 5 CSF tau markers: the proportion of tau phosphorylated at three threonine residues (pT205/T205, pT217/T217, and pT231/T231), and the concentrations of microtubule‐binding region of tau at residue 243 [MTBR‐tau243] and total‐tau [mid‐domain containing T212‐221]). We investigated associations between CSF stages and cross‐sectional and longitudinal changes in amyloid and tau pathologies, neurodegeneration and cognition using linear regression models. ROC curves were used to identify the optimal stage for predicting positivity in imaging biomarkers and to separate AD vs non‐AD cognitive symptoms. We also tested the relative risk of progression from cognitively unimpaired or MCI to AD‐type dementia using Kaplan‐Meier curves and Cox‐proportional Hazard models. Creation of the model and cross‐sectional analyses were replicated in an independent cohort (n = 222, Table 1).

Result

SuStaIn revealed that only one subtype was present and that five CSF biomarkers (ordered: Ab42/40, pT217/T217, pT205/T205, MTBR‐tau243, T212‐221) were sufficient to create an accurate disease staging model (Fig.1A‐B). Increasing stages (0‐5) were associated with increased abnormality in other AD‐related biomarkers (Fig.1C). In both cohorts, stage ≥2 accurately predicted amyloid‐PET positivity (AUC≥0.89), stage ≥4 predicted tau‐PET (AUC≥0.94) and neurodegeneration positivity (AUC≥0.81). In the main cohort, stage≥2 separated non‐AD from AD‐related cognitive impairment (AUC = 0.96). Longitudinal changes for several AD‐biomarkers by stages are presented in (Fig.2A). Higher stages (4‐5) at baseline were associated with higher hazard ratios (HR) of progressing to AD‐type dementia (CU&MCI: HR = 4.6[2.0,10.9], MCI: HR = 3.5[1.5,8.1], Fig.2B‐C).

Conclusion

Our results suggest that the AD continuum can be accurately staged with a single CSF sample, which may be useful in the clinical setting for patient management but also as a tool in clinical trials for selection and monitoring of study participants.
Recruitment Strategies in the LatAm FINGERS Trial: A Multicultural Effort to Prevent Dementia Across Latin America
Authors: Crivelli Lucía , Calandri Ismael Luis , Suemoto Claudia Kimie , Caramelli Paulo , Lopera Francisco , Nitrini Ricardo , Sosa‐Ortiz Ana Luisa , Salinas‐Contreras Rosa Maria , Velilla Lina M , Yassuda Monica Sanches , Brucki Sonia Maria Dozzi , Sevlever Gustavo , Allegri Ricardo Francisco , Kivipelto Miia , Carrillo Maria C. ,   LatAm FINGERS Consortium
Published: December 2023

Background

LatAm‐FINGERS is the first non‐pharmacological multicenter randomized clinical trial to prevent cognitive impairment in Latin America (LA). The trial congregates the effort of 12 Countries, including Argentina, Bolivia, Brazil, Chile, Colombia, Costa Rica, Dominican Republic, Ecuador, Mexico, Peru, Puerto Rico, and Uruguay. The main aim is to investigate the feasibility of a 24‐month multi‐domain lifestyle intervention and its efficacy on the cognition of 1200 participants.

Method

Recruitment strategies differed across countries and regions because they were adapted to the idiosyncrasies of the local populations. Recruitment from medical center databases was found insufficient to provide a diverse cohort. Alternative strategies included social media posts with infographics and videos. A novel and successful strategy was in‐person talks in local city halls and local nongovernmental organizations for older adults. The use of positive colloquial language was found to be much more effective in reaching underserved populations than scientific language (e.g., focusing on brain health vs. clinical trials). A significant recruitment source in low‐income regions of Peru, Bolivia, and Ecuador was the promotion within non‐Catholic religious organizations. Appealing to the religious leaders’ endorsement was crucial for generating trust and interest in different communities. In Mexico, one successful recruitment strategy involved performing physical exercises in local parks in low‐income neighborhoods to demonstrate the intervention in‐vivo, which attracted interested people from the area. Overall, in‐person contact with participants and time dedicated to explaining the trial’s rationale in lay language was the most important strategy.

Result

As of January 2023, we have enrolled 948 participants in the study. The mean (SD) age is 67.5 (4.8) years, 75% are female, the level of education is 12.6 (3.8) years, and the MMSE score is 27.3 (1.7). To date, 58% of the population self‐reports as mestizo (mixed race), and 28% as Caucasian. Other ethnicities represented include Native American (1.5%), Mulato (5%), Black (2%), Asian (0.7%), and other (5%).

Conclusion

The LatAm‐FINGERS trial recruited participants from a wide range of diverse populations. Our results support that using tailored and idiosyncratic strategies is decisive in reaching different communities and ensuring the representativeness of the study sample.
Building a neuropsychiatric testing database for veterans with mild cognitive impairment and Alzheimer’s disease with unstructured electronic health records
Authors: Li Xuyang , Chen Jinying , Aguilar Byron J. , Shishova Ekaterina , Morin Peter J , Berlowitz Dan , Miller Donald R , O'Connor Maureen K. , Nguyen Andrew Huy , Zhang Raymond , Monfared Amir Abbas Tahami , Zhang Quanwu , Xia Weiming
Published: December 2023

Background

Information on clinical decision making and disease severity assessments for mild cognitive impairment (MCI) or Alzheimer’s dementia (AD) typically only exists in medical notes. In this study, we present the methodology of constructing a database from unstructured electronic health records (EHR), which enables enriched population studies when combined with structured administrative databases.

Method

A multidisciplinary team with expertise in neurology, epidemiology, biology, and health informatics designed and created the relational database. The database was established with three tables for patient demographics, neurocognitive and neuropsychiatric test results, and clinical judgment of AD severity. Patient cohorts were identified by searching keywords ("Alz*” or “Mild Cognitive Impairment”) from electronic clinical notes and excluding false positives using expert‐designed rules. The most frequently used six neuropsychiatric tests (MMSE, MoCA, SLUMS, Mini‐cog, BNT, BVRT) and their corresponding testing results were extracted in addition to clinicians’ judgment on disease severity. The test scores were extracted using a rule‐based natural language processing (NLP) system.

Result

A patient cohort with MCI (N = 74,444) or probable AD (N = 141,816) was identified in the VA database for the fiscal year of 2019 (Table 1), with 18,173 patients having both MCI and AD diagnosis among their clinical notes of the year. A total of 1,529,897 neuropsychiatric testing scores were extracted from the patients’ clinical notes across all years, with 388,253 MMSE scores, 614,400 MoCA scores, 462,646 SLUMS scores, 18,868 Mini‐cog scores, 45,259 BNT scores, and 471 BVRT scores. A total of 57,879 (77.75%) MCI patients and 82,656 (58.28%) AD patients had at least one test score extracted. A total of 18,939 (13.35%) AD patients had at least one documented severity categorization made by a clinician.

Conclusion

We established a database of neuropsychiatric testing scores for patients with MCI or AD based on electronic medical notes from the VA healthcare system, aided by NLP tools. Our approach demonstrated a scalable pipeline to integrate with structured EHR in support of enriched population level analysis in AD.
The impact of art therapy on the relationships between individuals diagnosed with Alzheimer’s disease and their care partners
Authors: Dodson Danielle B. , Sujata Katharine K. , Gitelman Darren R. , Liao Yunqi
Published: December 2023

Background

Individuals with dementia have long reported negative social and psychological experiences. The current study employed a small group art therapy intervention; the intra‐ and inter‐personal impact was assessed through patient and care partner self‐report.

Method

Thirty patient / care partner dyads were enrolled. Patients had an Alzheimer’s disease diagnosis, MMSE score of 18‐26, and insight into their condition. For each 4‐week session, 3 to 4 dyads jointly participated in a 90‐minute, weekly art therapy intervention, facilitated by a Registered Art Therapist. A pre‐test post‐test design was employed, with patients completing the Dyadic Relationship Scale, Rosenberg Self‐Esteem Scale, and Stigma Impact Scale; care partners completed the Dyadic Relationship Scale and Dementia Attitudes Scale.1,2,3,4 During each study visit, subjects viewed and discussed artwork, created art, and were encouraged to share their artwork with the group.

Result

Analysis was performed using Wilcoxon signed rank test. Scores for both subscales of the Dyadic Relationship Scale – Positive Dyadic Interaction and Dyadic Strain – revealed a significant improvement (p = 0.002 and p = 0.001, respectively) after art therapy. A significant increase in care partner scores was also apparent on the Dementia Knowledge subscale of the Dementia Attitudes Scale. Patient data showed a significant shift towards better self‐esteem scores after intervention.

Conclusion

This study fills a gap in research targeting intra‐ and inter‐personal experiences of individuals with dementia. Results indicate that art therapy may improve relationship dynamics between individuals with Alzheimer’s disease and their care partners, and may improve patients’ self‐esteem.

References

1. Sebern, M. D., & Whitlatch, C. J. (2007). Dyadic relationship scale: a measure of the impact of the provision and receipt of family care. The Gerontologist, 47(6), 741‐51.

2. Rosenberg, M. (1965). Society and the adolescent self‐image. Princeton, NJ: Princeton University Press.

3. Fife, B. L., & Wright, E. R. (2000). The dimensionality of stigma: a comparison of its impact on the self of persons with HIV/AIDS and cancer. Journal of Health and Social Behavior, 41(1), 50– 67.

4. O’Connor, M. L., & McFadden, S. H. (2010). Development and Psychometric Validation of the Dementia Attitudes Scale. International Journal of Alzheimer’s Disease, 2010, 1‐10.
Screening of Cognitive Impairment in patients with Rheumatoid arthritis
Authors: Berrios Waleska , Reyes Andres , Marin Nicolas , Scolnik Marina , Soriano Enrique , Rosa Javier , Salinas Camila Sanchez , Rugiero Marcelo , Golimstok Angel , Fernandez Maria Cecilia
Published: December 2023

Background

Rheumatoid arthritis (RA) is a chronic inflammatory disease that affects 0.5‐1% of the population, mainly women and older adults. There is increasing evidence of the presence of cognitive impairment in patients with RA, with a prevalence of around 30%. Some underlying mechanisms involved could be inflammation within the brain, high cardiovascular comorbidity, and the use of immunosuppressive agents that can be neurotoxic with prolonged use, among others. The Montreal Cognitive Assessment (MoCA) is a validated tool for detecting cognitive impairment in our country. The objective of this study is to determine the frequency of cognitive impairment in patients with RA compared to a group of patients with osteoarthritis.

Method

We assessed adult patients diagnosed with RA (2010 ACR/EULAR criteria) and osteoarthritis (ACR criteria) according to selection criteria. Demographic and clinical data were collected. The MoCA test was administered to all patients considering the cut‐off value <26 points to define the presence of cognitive impairment. The study was approved by the institutional ethics and research committee.

Result

A total of 60 patients were included: 40 with RA (G1) and 20 with osteoarthritis (G2), the majority being women in both groups, mean age was 66.9 (SD 11.7) years and 71.4 (SD 10.6) years, respectively. There were no statistically significant differences in education, socioeconomic status, or vascular risk factors among groups. The frequency of cognitive impairment was significantly higher in G1 compared to G2: 42.5% (95% CI 28‐58.5) versus 15% (95% CI 4‐40)(p 0.026). Regarding MoCA domains, attention and memory were more affected in G1 compared to G2. In the multivariate analysis, the diagnosis of RA and older age were factors significantly associated with cognitive impairment.

Conclusion

In our RA population, the frequency of cognitive impairment was 42.5%. RA diagnosis and older age were factors related to cognitive impairment. A substantial number of patients and the administration of a standard neuropsychological test will help us to validate these results.
Genomics and Biomarkers in older Latinos: Challenges and Opportunities
Authors: Llibre‐Guerra Jorge J
Published: December 2023

There are fundamental knowledge gaps about normal aging, cognitive decline, and the roles of Alzheimer’s Disease (AD) biomarkers in the Latino population. Previous studies report, ethno‐racial differences in amyloid (A), tau (T), and neurodegeneration (N) biomarkers and genetics of AD. However, most studies including Latino populations consider those as a monolithic group while ignoring the genetic and environmental diversity of this group. Latinos are racially and ethnically diverse, and often reflect a mix of culture, environment, and genetic ancestries drawn from African, Amerindian, and European backgrounds. Research suggest that Latinos are both less likely to carry an APOE‐ε4 allele and have less of a risk for AD due to the ε4 allele than White non‐Latinos. Further, epidemiology, biomarker, and neuroimaging data suggest that vascular risk factors are prevalent in Latinos and may increase risk in midlife, thus impacting dementia rates later in life. The interaction of genetic and environmental factors in the development and progression of AD is complex in Latinos due to the influence of different levels of education, acculturation, socioeconomic conditions, immigration, language proficiency, and bilingualism, among others. In this session, the US Consortium of Aging, Dementia & Latino Studies (CADLAS) Genomics and Biomarkers Special Interest Group (SIG) will discuss recent developments, current challenges and opportunities in this area of research. The SIG was created in 2022 with the main goal of promoting collaborations among investigators to accelerate research and discovery of biomarkers and new diagnostics that work for US Latino populations. Research priorities include validation of biomarkers of proteinopathies and neurodegeneration, as well as vascular contributions to cognitive impairment and dementias, and development of novel and most sensitive biomarkers. Explorations of the unique genomic ancestry of diverse Latinos will also be considered as they are likely to provide new insights into cognitive decline and dementia in this population.
Dementia care and psychosocial interventions for US Latino populations
Authors: Rodriguez Miriam J. , Perales Jaime
Published: December 2023

Latinos are the fastest growing older adult group in the US and are impacted disproportionately by dementia. Compared to non‐Latino Whites, Latinos are at a higher risk of developing dementia, dementia‐related behavioral symptoms and caregiver depression. These disparities are compounded by Latinos’ lower access to a diagnosis, treatment, and caregiver support. After decades of awareness of these disparities, Latinos continue to be underrepresented in behavioral and psychosocial interventions that can address these outcomes. Since outcomes in dementia behavioral and psychosocial interventions vary widely by ethnicity, the exclusion of Latinos may be widening these disparities. Studies are desperately needed that increase the participation of Latinos in dementia behavioral and psychosocial interventions, and tailor their components to their background and context (e.g., language, beliefs, culture or insurance status). In this session, the CADLAS Dementia Care and Psychosocial Interventions Special Interest Group (SIG) will discuss recent developments, current challenges and opportunities, as well as future research direction in this area. The SIG aims to promote collaborations among investigators working on dementia care and psychosocial interventions with US Latino/Hispanic populations to accelerate research and the development of interventions, scales and biomarkers. This SIG meets monthly and currently includes 13 members. Since its creation, SIG members continually share relevant educational and funding opportunities, and have been working on a state‐of‐the‐art review manuscript on dementia caregiver interventions among Latinos.
The diagnostic utility of picture description task in english, chinese and italian speaking individuals with primary progressive aphasia
Authors: Santi Gaia Chiara , Tee Boon Lead , Catricalà Eleonora , Agosta Federica , Canu Elisa , Filippi Massimo , Cappa Stefano F , Tempini Maria Luisa Gorno
Published: December 2023

Background

Primary progressive aphasia (PPA) is a language‐predominant dementia syndrome (Mesulam et al.., 201) that impacts speakers of all languages. Despite there are more than 7,000 living languages, the diagnostic model is mainly tailored for English‐language speakers. Cross‐linguistic comparisons are called for, especially considering the heterogeneities of linguistic features in the different languages (Blasi et al., 2022). We intend to study the speech and language markers of English‐, Mandarin‐, Cantonese‐ and Italian‐speaking individuals with PPA when completing verbal picture description test. The goal is to (1) characterize the speech profiles of semantic(sv), logopenic(lv), nonfluent/agrammatic(nfv) PPA for each specific language, identifying key linguistic markers for the diagnosis; (2) identify similarities/differences in terms of markers across languages.

Method

We collected the oral picture description, based on the PicNic Scene from WAB battery (Schewan & Kertesz, 1980), of 30 English‐, 30 Chinese‐ (Mandarin and Cantonese), and 30 Italian‐ speaking PPA patients (equally distributed across the three variants) with 45 matched healthy controls (HC). Collected speech samples underwent CLAN and Whisper software analysis to characterize informativeness, lexico‐semantic, morpho‐syntactic, phonological and prosody features. We standardized PPA data relatively to their respective. Differences between PPA variants and with HC for the different features were only carried out for the Italian group, using non parametric tests. Performances across different language groups will be investigated as well.

Result

Analysis on Italian sample revealed that mean length of utterances, number of empty, filled pauses, abandoned words, and words repetition significantly distinguished PPA from HC. svPPA produced more irrelevant words and adverbs than other PPA groups. nfvPPA produced more sentences without verbs compared to HC and PPA. lvPPA produced more abandoned words than other PPA. svPPA and lvPPA produced less nouns and noun‐verbs ratio compared to HC and nfvPPA, meanwhile lvPPA and nfvPPA produced less words, open class words and more determiners‐noun ratio compared to HC. svPPA and nfvPPA showed reduced idea density compared to HC.

Conclusion

Those results are consistent with previous literature on PPA oral production. However, future comparisons across languages are extremely important and needed to ensure equitable assessment and minimize disparities globally.
Longitudinal retinal changes in mild cognitive impairment and Alzheimer’s Disease
Authors: Ma Xiaoxi , Wei Shuang , Wang Xi , Wu Jie , Xiao Zhenxu , Wu Wanqing , Liang Xiaoniu , Zheng Li , Ding Ding , Lu Zhaozeng , Xiao Yiqin , Zhao Qianhua
Published: December 2023

Background

Previous studies have shown retinal thickness and vascular alterations in Alzheimer’s disease (AD), even in patients with mild cognitive impairment (MCI), suggesting that retinal parameters are potential biomarkers for AD. However, the prospective observation of retinal markers is still insufficient. In this study, we aimed to observe longitudinal retinal thickness and vascular changes in patients with AD and MCI, and to identify critical retinal markers that significantly change over time.

Method

Patients with AD (N = 22) and MCI (N = 21) were recruited from the Shanghai Memory Study. Age‐ and gender‐matched cognitively normal (NC) participants (N = 26) were included from the Shanghai Aging Study. Optical coherence tomography (OCT) and OCT angiography were performed in all participants at baseline and after an average 19.2 months follow‐up to assess changes in peripapillary retinal nerve fiber layer thickness (p‐RNFL), ganglion cell layer thickness (GCC), macular thickness and volume divided by the Early Treatment Diabetic Retinopathy Study grid, retinal vessel density, and fovea avascular zone (FAZ). Differences of monthly variation rate of retinal parameters between NC, MCI, and AD individuals were evaluated.

Result

The monthly variation rates among groups showed significant differences in thickness and volume of full temporal para‐fovea sector, inner temporal peri‐fovea sector, outer temporal para‐fovea sector, and thickness of outer superior hemisphere para‐fovea sector (all P<0.05). There was no difference in the rate of change of p‐RNFL, GCC, retinal vessel density, and FAZ among all groups. Post hoc analysis revealed that the monthly change in thickness and volume of the full‐temporal and outer sectors were significantly faster in AD than in NC, whereas the inner‐temporal sectors changed faster in MCI than in NC groups (all P<0.05). Furthermore, the monthly changes in inner temporal peri‐fovea thickness were faster in MCI than in NC and AD participants (all P<0.05).

Conclusion

During follow‐up, retinal temporal thinning was faster in patients with AD, whilst inner retina‐temporal sector thinning was faster in participants with MCI. Accelerated thinning of temporal sectors of the retina, especially the inner‐temporal sector may be an early marker of AD disease progression.
Epigenome‐wide association study of Aβ42/Aβ40 in a sample of U.S. middle‐aged twins
Authors: Beam Christopher R. , Bakulski Kelly M , Alishahi Farshad , Pilgrim Matthew JD , Zandi Ebrahim , Turkheimer Eric , Higdon Kristin , Sikes Kendra , Ryan Lesa , Davis Deborah Winders
Published: December 2023

Background

DNA methylation may affect expression of genes that promote the accumulation of amyloid‐β (Aβ). Although prior studies suggest that DNA methylation correlates with Aβ in older adults (Levine et al. (2018). An epigenetic biomarker of aging for lifespan and healthspan. Aging, 10(4), 573.), Aβ begins to accumulate earlier than when clinical symptoms associated with Aβ are evident. The purpose of the current study is to present novel results on whether differentially methylated CpG sites (i.e., regions of DNA where methylation occurs) correlate with higher Aβ42/Aβ40 ratios across a sample of middle‐aged individuals.

Method

Data from 193 individual twins from the Louisville Twin Study were used in the current analysis. Genomic DNA was extracted from venipuncture blood samples, and bisulfite‐converted DNA samples were assessed with the Illumina Infinium EpicArray BeadChip. Quality control and analyses were performed in R using the minfi package, and gene ontology analyses were performed using the MissMethyl package. Aβ42/Aβ40 was estimated using a capture sandwich immunoassay methodology that measures AD biomarkers in whole‐blood plasma. Differential DNA methylation was estimated using multivariable linear regression with an empirical Bayes estimator.

Result

Estimation of differential DNA methylation was adequate (λ = 1.38), although some Type I inflation of p‐values was observed among CpG sites with higher p‐values. Although no CpG sites reached genome‐wide statistical significance, the top four CpG sites suggested differential methylation ranging between 2.8–4.8% per unit increase in the ratio of Aβ42/Aβ40. The top gene sets associated with differential methylation were response to glucocorticoids, response to corticosteroids, and response to Aβ.

Conclusion

Despite no statistically significant CpG probes identified, likely due to the small sample size, the findings from the gene ontology analysis suggest that identification of epigenetic biomarkers may clarify the biological pathways through which the epigenome may regulate expression of Aβ proteins. As data collection is ongoing, we expect detected of genome‐wide significant probes with larger sample sizes.
Transient forgetting of early formed memory in drosophila
Authors: Chiang HsuehCheng
Published: December 2023

Background

Forgetting is a natural biological process not only to remove the stored memory but also to offer flexibility for future behaviors. Based on the retrievability of forgotten memory, forgetting could be subcategorized into permeant forgetting and transient forgetting. Compared to permeant forgetting, the cellular mechanism of transient forgetting is largely unknown. Early‐formed memory is mostly unconsolidated and sensitive to interruption; therefore, it is unclear if transient forgetting could be induced during the early stage of memory formation, and if acquired information remains intact after external stimulation‐induced forgetting.

Method

The current study used Drosophila as a model system with genetic behavioral settings to investigate the cellular mechanism of transient forgetting of early‐formed memory.

Result

We found that transient forgetting only temporally blocks memory retrieval and learned information was preserved. The lost memory spontaneously recovered after 30‐40 minutes. Our results showed that dopamine plays an important role in meditating transient forgetting. We also demonstrated that transient forgetting is different from extinction as the underlying cellular mechanism is different and the induction protocol is not the same. External stimulation recruits dopaminergic neurons to modify the behavior output to temporally interrupt memory recall. Further study showed that the encoding remains functional during transient forgetting, suggesting animals' basal cognitive functions are largely unaffected.

Conclusion

As transient forgetting is often observed during neurodegenerative diseases, the current study not only reveals the detailed cellular mechanism of transient forgetting of early‐formed memory but also how transient forgetting affects disease progression.
Polysomnography results and cognitive performance in early‐stage Parkinson’s disease
Authors: Young Vanessa M. , Pollet Erin , Serrano‐Rubio Luis Humberto , Velarde Angel G. , Gaona Carlos A. , Horn Sarah , Ramirez‐Castaneda Juan , Coss Pablo , Vaou Okeanis E. , Saklad Amy R. , Shipp Eric L. , Seshadri Sudha , Gonzalez David A. , Gonzales Mitzi M.
Published: December 2023

Background

Parkinson’s disease (PD) is a progressive neurological disorder that involves a range of motor and non‐motor symptoms. About 66% of individuals with PD report sleep disturbance impacts their quality of life. Sleep disorders may precede the cardinal motor features in PD and can influence motor and non‐motor symptom severity, including cognition. Yet current evidence of this association with objective assessments remains limited. The goal of this pilot study was to evaluate the associations between cognition and overnight polysomnography results in early‐stage PD.

Methods

Participants completed neuropsychological assessments and an overnight in‐clinic polysomnography. Associations between polysomnography results and cognitive performance were evaluated using partial correlations controlling for age and education.

Results

Twenty participants (mean age 69±8; 25% female) without dementia and with a diagnosis of early‐stage PD (Hoehn and Yahr stage 1‐2) were enrolled (Table 1). Table 2 displays the associations between polysomnography results and cognitive assessments. Greater percentage time in stage N1 sleep and increased duration of wakefulness time after sleep onset (WASO) were associated with poorer phonemic fluency (r = ‐0.626, p = .005 and r = ‐0.512, p = .030, respectively); whereas increased time spent in stage N2 sleep and higher sleep efficiency index were correlated with better phonemic fluency (r = 0.829, p < .001 and r = 0.513, p = .029, respectively). Greater percentage in stage N2 was associated with better verbal learning (Hopkins Verbal Learning Test–Revised (HVLT‐R) Immediate Recall, r = 0.521, p = .027). Higher percent time in REM sleep was correlated with increased basic attention (Digit Span Forward, r = 0.483, p = .042). No associations were found between total sleep time and cognitive performance.

Conclusion

While total sleep time was not associated with cognition, higher percent time spent in Stage N2, Stage N3, and REM sleep were associated with better cognitive performance. In contrast, higher percentage of Stage N1 sleep and increased duration of WASO were associated with poorer verbal fluency. The preliminary results highlight the importance of increased time in deeper stages of sleep for cognition in adults with early‐stage PD. Future longitudinal studies will be necessary to evaluate long‐term cognitive trajectories and transition to dementia in association with diminished sleep quality in Parkinson’s disease.
Characteristics of cerebrospinal fluid biomarkers/imaging findings in ptaients with amyloid PET‐negative dementia
Authors: Takenoshita Naoto , Yamamoto Ryo , Hanyu Haruo , Kasuga Kensaku , Ikeuchi Takeshi , Ishii Kenji , Shimizu Soichiro
Published: December 2023

Background

In daily clinical practice, we often encounter cases with atypical clinical symptoms and imaging findings, even amoung those diagnosed with Alzheimer’s disease.

Method

Forty‐nine cases of undiagnosed patients with atypical clinical symptoms or imaging findings underwent both amyloid PET and cerebrospinal fluid(CSF) examinations.They were divided into amyloid‐positive group(n = 25) and amyloid‐negative group(n = 24).The cerebrospinal fluid findings,neuropsychological examination findings,MRI findings,and SPECT findings were compared between the two groups.

Result

CSF findings showed significant differences in amyloid‐β42,amyloid‐β42/40, and P‐tau between the two groups.There was no significant difference in MRI findings.SPECT findings showed a significant difference in decreased blood flow in the right parietal lobe and bilateral precuneus.

Conclusion

In dementia patients with atypical clinical symptoms and imaging findings, CSF findings and decreased blood flow in the right parietal lobe and bilateral precuneus are suggested to be useful indicators to distinguish whether amyloid is involved in the back ground pathology.
Plasma oligomer βeta‐amyloid associated with disease severity and cerebral amyloid deposition in Alzheimer’s disease spectrum
Authors: Lim Hyun Kook , Wang Sheng‐Min , Um Yoo Hyun , Kang Dong Woo
Published: December 2023

Background

Multimer detection system‐oligomeric amyloid‐ß (MDS‐OAß) measures plasma OAß level and is associated pathology of Alzheimer’s disease (AD). However, no study investigated MDS‐OAß and cerebral Aß deposition among difference stages within AD spectrum.

Method

We studied 40 normal control (CN), 30 amyloid‐PET (A‐PET) negative mild cognitive impairment (MCI), 31 A‐PET positive MCI, and 22 A‐PET positive dementia.

Result

The one‐way analysis of variance showed group difference in MDS‐OAß. Post‐hoc analysis showed that MDS‐OAß was lowest in CN group and highest in A‐PET positive MCI group. Both A‐PET negative MCI and A‐PET positive dementia groups showed lower MDS‐OAß than A‐PET positive group dementia group (MDS‐OAß: CN < A‐PET negative MCI = A‐PET positive dementia < A‐PET positive MCI) (Figure 1). MDS‐OAß showed a positive correlation with global and regional cerebral Aß deposition measure using A‐PET.

Conclusion

Our results suggest that MDS‐OAβ shows a reverse U‐shape: increase with disease onset or when clinical symptoms appear, even before Aß pathology is evident in A‐PET, and then elevate as disease progresses but lower down as the disease becomes severe.