bluuebunny/crossref_metadata_2025 huggingface dataset:
A normative study of the Trail Making Test‐Black and White
Authors: Suh Jeewon , Baek Min Jae , Kang Yeonwook , Kim SangYun
Published: December 2023

Background

The Trail Making Test (TMT) is a neuropsychological test to measure frontal and executive function. Although it is a widely used test in identifying dementia, TMT has limited utility in cross‐culture contexts because of the use of the English alphabet in a subset of the test. TMT‐Black and white (TMT‐B&W) is a newly developed version of TMT which uses only black and white circles to overcome the performance bias among non‐English speaking and illiterate elderly. The objective of this study is to provide the initial normative data of TMT B&W and investigate the influence of age, gender and education level on the time to complete the test.

Method

The TMT‐B&W was administered to 1,012 cognitively normal participants (430 males and 582 females) from age 19 to 90 and the time in seconds taken to complete the test was measured.

Result

Age, education level and gender were significantly associated with TMT‐B&W part A and part B scores. Based on these results, normative data of TMT‐B&W part A and part B for male and female were stratified for age and education level.

Conclusion

This study provide normative data for the new version of TMT, the TMT‐B&W which can be used in a cross‐cultural context without language translation. TMT‐B&W could be a useful neuropsychological test for illiterate or low‐educated people without the ability to understand the written letter. Age, education level and gender had significant influences on both TMT‐B&W part A and B.
Xenografted human microglia in response to Alzheimer’s disease Aβ pathology
Authors: Martinez‐Muriana Anna , Mancuso Renzo , Fattorelli Nicola , Davis Emma , Wolfs Leen , Daele Johanna Van Den , Geric Ivana , Preman Pranav , Serneels Lutgarde , Poovathingal Suresh Kumar , Balusu Sriram , Verfaillie Catherine , Fiers Mark , De Strooper Bart
Published: December 2023

Background

Neuroinflammation is a pathological hallmark of Alzheimer’s disease (AD). Murine studies have revealed that mouse microglia can adopt several cell states in response to disease insults. However, single‐nuclei RNA sequencing studies have found divergent results when recalling those cell states in human post‐mortem tissue.

Method

To overcome this limitation, we have sequenced 127,000 single cell human microglia isolated from an AD xenotransplantation model.

Result

In response to plaques, human microglia can adopt several cell states including a disease‐associated microglia (DAM) and an antigen‐presenting response (HLA). When reacting to Aβ soluble aggregates, human microglia produces a pro‐inflammatory response cytokine response (CRM). TREM2 and APOE polymorphisms affect the development of the DAM‐HLA response, suggesting an important role of this response in AD.

Conclusion

Overall, this multi‐faceted response to amyloid pathologies highlights a complex scenario where these distinct phenotypes might influence the outcome on the disease.
A user‐friendly calculator to estimate length of time from initial presentation to need for full‐time care or death in individual patients with Alzheimer’s disease
Authors: Stern Yaakov , Stallard Eric , Ryu Hyunnam , Kociolek Anton J , Lee Seonjoo , Cosentino Stephanie , Zhu Carolyn W , Hernandez Michelle , Kinosian Bruce , Gu Yian
Published: December 2023

Background

Alzheimer’s disease (AD) exhibits substantial variability in its initial presentation and rate of progression. Our goal was to understand AD progression well enough to create a calculator that uses presented clinical features to estimate the length of time from initial presentation to major disease outcomes in individual patients with AD.

Method

The variability in rate of AD progression is strongly related to the variability in specific disease signs and symptoms identified at initial presentation. We developed a longitudinal Grade of Membership prediction algorithm and demonstrated its ability, based on initial presentation of six fixed covariates and 73 time‐varying clinical signs and/or symptoms, to accurately predict time to need for full‐time care (FTC) and death in two groups: a mainly white, clinic‐based group of AD patients (N = 229), and a statistically representative community‐based sample of Hispanic (N = 211) and non‐Hispanic (N = 62) older adults with MCI or AD. We then created an online calculator for use by physicians, relatives, or patients to generate these predictions.

Result

The calculator is implemented as an online, freely available R Shiny web app: https://cnd‐columbia.shinyapps.io/AD_Calc/. The user is prompted for current clinical information about the patient. Most of this information can be gleaned from patient observation, healthcare providers, or medical records. Unknown items can be skipped or sensibly approximated. The calculator generates individual‐specific survival‐probability curves, including median survival time, over the next 10 years. It also generates conditional probabilities of need for FTC in a way that allows the overall survival time to be decomposed into time free of need for FTC and time in need of FTC. The calculator does not predict which specific individuals would die before the median versus after the median; that prediction cannot be done.

Conclusion

Given the substantial variability over individuals in rate of disease progression, knowing the statistics of the individual‐specific survival times as well as the times to need for FTC can be of great value to patients with AD, their caregivers, and health care providers. The new calculator meets this need. In the future, the calculator also can be extended to predict time to other important disease milestones.
Normative data on the CERAD Word List in a robustly intact sample of older adults
Authors: Duff Kevin , Hanna Elise J , Mattek Nora , DeCapo Madison , Hantke Nathan , Pierce Aimee , Kaye Jeffrey A
Published: December 2023

Background

List learning and memory tests are frequently used to evaluate older adults for late life cognitive disorders, such as Alzheimer’s disease. The Word List subtest of the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) neuropsychological battery has been widely‐used in clinical research, including clinical trials, to identify and track such disorders. It is also freely‐available, as it is in the public domain. However, normative data, especially in robustly intact older adults, is lacking.

Method

CERAD Word List data from 897 older adults (age in years: M = 81.1, SD = 8.1, range 55‐100; 67% women; education in years: M = 14.8, SD = 2.8, range = 7‐24) deemed to be cognitively intact at two annual visits in a longitudinal observational study from the Uniform Data Set of the National Alzheimer’s Coordinating Center were used to generate predicted Word List scores based on age, sex, and education. Predicted scores were compared to observed scores to preliminarily validate these normative values.

Result

For six primary scores from the Word List subtest (Trial 1, Trial 2, Trial 3, Total Acquisition, Delay Recall, Recognition Total Correct), the three demographic variables significantly predicted test scores, with R2s ranging from 0.03 – 0.18 (p‐values<0.001). When these predicted scores were compared to observed scores, there were no significant differences (p‐values>0.40), indicating preliminary support for these prediction scores.

Conclusion

Although further validation is needed in independent intact and impaired samples, the current demographically‐based prediction scores provide normative data for the CERAD Word List subtest for older adults being evaluated for cognitive complaints. The inclusion of additional variables needs to be examined to improve the accuracy of these prediction scores. Nonetheless, normative data allows providers and researchers to be confident in using this learning and memory test in clinics and clinical trials.
Secondary School Quality and Midlife Cognition: Evidence from High School and Beyond
Authors: Chung Hyeran , Brickman Adam M. , Grodsky Eric , Manly Jennifer J. , Muller Chandra , Warren John Robert
Published: December 2023

Background

Research on the association between education and later‐life cognitive outcomes usually only considers the quantity of schooling that people complete. However, people with the same level of completed schooling are highly diverse with respect to the quality of schooling they experienced. Using a unique new data resource, we ask how secondary school quality is associated with cognitive functioning at age ∼60—net of school quantity and confounders.

Method

We use data from the High School and Beyond cohort—a large, diverse, nationally representative probability sample of American high school sophomores and seniors in 1980. HSB panelists were interviewed many times between 1980 and 2022, with high rates of participation; HSB has been supplemented with administrative data (e.g., school transcripts, mortality records) and the 2021/2022 follow‐up gathered fluid biomarkers useful for studying markers of risk for cognitive impairment. Measures from the 1980s provide extraordinarily detailed information about educational contexts, opportunities, and outcomes. We measure secondary school quality using value‐added models, which estimate each school’s contribution to student academic achievement conditional on students’ baseline achievement and family socioeconomic background. Our analyses assess the degree to which attending a high value‐added secondary school is associated with better cognitive outcomes at age ∼60 net of educational attainment. Our main dependent variables—assessed in 2021/2022—include self‐reported memory complaints and self‐reported conditions of relevance to risk of cognitive impairment (e.g., diabetes, hypertension).

Result

Net of educational attainment and demographic factors, we find that individuals who attended a high value‐added secondary school experience fewer cognitive complaints (as assessed using the AD8). They are also less likely to have been diagnosed with diabetes or hypertension. In the next few months, we will have assessed heterogeneity in results across demographic and socioeconomic groups.

Conclusion

The quality of the schooling that people experience matters for later‐life cognitive outcomes even net of the quantity of schooling they complete.
Survival and pharmacotherapy delay in young onset Alzheimer’s disease
Authors: Stojkovic Tanja , Stojmenovic Gorana Mandic , Šarčević Maksim , Stefanova Elka , Obradovic Dragan , Kostic Vladimir S
Published: December 2023

Introduction

Specific feature of young onset Alzheimer’s disease (YOAD) patients is that their diagnosis and therefore their treatment is usually delayed. Firstly, they present atypically, secondly, they have a higher cognitive reserve and symptoms are later recognized and finally at that age, the family, and the patients themselves, do not think about the possibility of dementia, which prolongs the time period to seeking medical help (on average 2‐3 years).

Aim

To examine the association of survival in YOAD with time elapsed from the onset of symptoms to the initiation of pharmacotherapy.

Material and methods

This is a retrospective study on 135 patients from Memory Center of Neurology Clinic, Clinical Center of Serbia, with clinical diagnosis of YOAD. We included outpatients that had first visit to our clinic from 01.04.2012. do 01.04.2017. The association of survival with time elapsed from onset of symptoms to initiation of therapy was examined by Kaplan Meier survival analysis with log rank test.

Results

From 2012, when the registry was created, till 2019, 89 out of 135 included patients died. Kaplan Meier survival analysis showed that patients with lower MMSE score (from 15 points and below) and who could not dress themselves or perform personal hygiene at the time of inclusion in our registry have a shorter expected survival than those who had MMSE 16 and above (p = 0.019) and who functioned independently in terms of these activities of daily living (p = 0.041 for dressing and p = 0.018 for performing personal hygiene). Patients in whom the introduction of therapy was delayed 3 or less years survived for a year longer than patients in whom therapy was introduced 4 or more years after the onset of dementia symptoms (p = 0.004).

Conclusion

Our study clearly showed that certain clinical parameters (degree of cognitive and functional damage at the time of therapy introduction), but also delay in introducing therapy from symptoms onset determine the length of survival in YOAD.
Cataloging the role of brain cell types on suppressing the effect of APOE ε4 on Alzheimer’s disease risk
Authors: Ma Yiyi , Chen Kevin W , Fujita Masashi , Yu Lei , Menon Vilas , Schneider Julie A , Bennett David A. A , De Jager Philip L
Published: December 2023

Background

We have previously developed a research pipeline to identify potential suppressors of APOE ε4 risk on Alzheimer’s disease (AD), and we have successfully identified an epigenomic factor which may act as ε4 suppressor. However, it is unknown which cell type is more important to contain this ε4 suppressor on the transcriptome level.

Method

We included single‐nucleus RNA sequencing (snRNAseq) data of the postmortem human brains from 424 subjects of the Religious Orders Study or the Rush Memory and Aging Project (ROSMAP). Based on this snRNAseq data, we have derived the estimate of the percentage and transcriptomic profiles of different types of brain cells including excitatory neurons, inhibitory neurons, endothelial cells, pericytes, oligodendrocytes, astrocytes, and microglia. Besides the main cell types, we further derived the estimates on the cell subtype level. With the generalized linear regression model, the final prioritized cell types and genes should fulfill two criteria: (1) be associated with AD pathologies (pTAU and neuritic plaque) in all subjects; and (2) reduce the effect of ε4 on AD susceptibility.

Result

Based on the transcriptome‐wide association study (TWAS) of the main brain cells, almost all the brain cell types contain at least one genome‐wide significant (P≤6.5×10−6) gene which can act as the APOE ε4 suppressor on AD risk. However, the subtype cellular analysis suggested that neuronal subtypes are more important than the other cell types because almost all the subtypes of the excitatory neuronal cells (15 out of 16) contain the genome‐wide significant ε4 suppressor while this percentage for microglia is only 25% (4 out of 16). The pathway analysis suggested that the top 179 genes expressed in the neuronal cells were involved in the trans‐synaptic signaling by trans‐synaptic complex and synapse assembly.

Conclusion

On the transcription level, APOE ε4 suppressor effects are present across a variety of different brain cell types but enriched in neurons where synapse pathways appear to play a predominant role in suppressing the effect of APOE ε4.
Baseline differences of cognition and psychiatric symptoms according to plasma amyloid‐status in the SILCODE study
Authors: Shao Kai , Kuhn Elizabeth , Hu Xiaochen , Yu Xianfeng , Li Yuxia , Zhang Mingkai , Wei Min , Liu Lin , Yang Jie , Guo Tengfei , Jessen Frank , Wagner Michael , Han Ying
Published: December 2023

Background

Subjective cognitive decline (SCD) is supposed to appear early in the course of Alzheimer’s Disease (AD). Although subtle cognitive deficits and psychiatric symptoms have been described in SCD, their association with amyloid pathology is still unclear.

Method

We collected SCD and normal controls (NC) from Sino Longitudinal Study on Cognitive Decline (SILCODE), a Chinese longitudinal observational study, which aims to develop risk prediction models of conversion to mild cognitive impairment in individuals with SCD. Subjects with memory complaints and concerns, recruited by public outreach or memory clinics, were considered as SCD. Subjects without concerns but with or without memory complaints were deemed NC. The assessment consisted of a neuropsychological test battery, an SCD‐interview, an SCD questionnaire (SCD Q9), an Ecog test and a determination of the Aβ 42/40 ratio in blood plasma. A z‐standardized composite score including the global cognition, memory, language, and executive function was created to describe the objective cognition in general. General linear model of baseline cognition and psychiatric symptoms according to group and amyloid status was performed.

Result

130 SCD (age 65.89 ± 5.37y, 60% Aβ+) and 92 NC (age 65.85 ± 5.17y, 66% Aβ+) were analyzed. No proportional differences of plasma Aβ+ were detected in the two groups. Aβ status makes little difference for cognition in NC, but is associated with cognition in SCD. There was a significant association of plasma Aβ with overall cognition (p = 0.01) and memory function (p = 0.03) only in SCD, after regression of age, sex, education and the interaction between plasma Aβ and the group. Both Aβ+ and Aβ‐ SCD showed a higher score of SCD Q9, Ecog, more SCD complain domains, more SCD plus features, more serious depression and anxiety symptoms compared to NC subjects.

Conclusion

Plasma Aβ pathology is more strongly associated with subtle cognitive deficits in SCD as compared to NC. This replicates results from other studies and suggests that, across different cultural and recruitment settings, current SCD criteria can capture stage 2 of Alzheimer’s Disease in amyloid‐positive individuals, when subtle cognitive impairments due to AD first become visible.
Cross‐omics integration analysis revels synaptic dysregulation across brain regions at later stages of Alzheimer disease
Authors: Eteleeb Abdallah M , Novotny Brenna C , Soriano‐Tarraga Carolina , Sohn Christopher , Dhungel Eliza , Brase Logan , Nallapu Aasritha , Buss Jared , Farias Fabiana H.G. , Bergmann Kristy , Norton Joanne , Gentsch Jen , Wang Fengxian , Davis Albert A , Morris John C , Karch Celeste M. , Perrin Richard J. , Benitez Bruno A. , Harari Oscar
Published: December 2023

Background

The clinical and molecular heterogeneity of Alzheimer disease (AD) is increasingly recognized as a major factor impacting diagnosis accuracy, the design of therapeutic interventions and clinical trials, and the development of effective treatments for AD. Recently, research efforts have leveraged molecular data to characterize AD patients into subgroups. However, the influence that such AD molecular profiles may have on cognitive decline trajectories remains poorly understood. Comprehensive studies that aggregate multiple modalities of omics have proven to be a powerful way to identify molecular profiles for human diseases including cancer. Here, we sought to determine whether cross‐omics integration can reveal molecular profiles of AD that have clinical and biological relevance.

Method

We leveraged machine learning approaches, digital deconvolution, and traditional statistical approaches to integrate and analyze multiple high‐throughput omics data from different cortical regions and cohorts, including the parietal cortex (N = 278) from the Knight Alzheimer Disease Research Center (Knight ADRC), the dorsolateral prefrontal cortex (N = 237) from the Religious Orders Study and Memory and Aging Project (ROSMAP) cohort, and the parahippocampal gyrus (BM36; N = 116) from The Mount Sinai Brain Bank (MSBB) study.

Result

We identified four distinct molecular profiles, one of which was associated with significantly worse Clinical Dementia Rating (CDR) at death, shorter survival after symptom onset, more severe neurodegeneration and astrogliosis, and unique metabolomic profiles. This profile, present in multiple cortical regions affected at distinct stages of AD progression, showed significant dysregulation of synaptic genes and pathways, indicating neuron/synapse losses and dysfunction at later stages of AD and associated with worse cognitive function. Among other molecules, we found that the expression of alpha‐synuclein (SNCA) and SNAP25 were downregulated in this profile. The synaptic dysregulation associated with this profile was further validated in a mouse model of pathological aSyn aggregation.

Conclusion

Together, our results demonstrate that cross‐omics approaches can reveal multiple molecular pathways associated with AD progression, and reinforce that, in AD, prominent synaptic loss and dysfunction are closely associated with worse cognition. This may open the possibility for new biomarkers for the molecular staging of AD and cognition, as well as potential therapeutic targets to ameliorate cognitive decline and AD progression.
Preliminary validation of a dual‐task gait assessment in early Alzheimer’s Disease
Authors: Wolfer Arnaud M , Kurniawan Irma T , Lipsmeier Florian , Taylor Kirsten I , Perumal Thanneer M
Published: December 2023

Background

Early stages of Alzheimer’s disease (eAD) are marked by changes in gait characteristics that may be measured using simple smartphone‐based gait tasks. Here we present an assessment of cognitive‐motor‐interference where participants walk for 30 seconds with a smartphone placed in a running belt while counting backwards, called the 30‐Second Walk Test Dual Task (30sWTDT). We report the preliminary reliability and validation of the 30sWTDT in a cohort of healthy individuals (HC), individuals with subjective cognitive decline amyloid‐PET negative and positive (SCDn and SCDp, respectively) and eAD.

Method

123 participants (32 HC, 31 SCDn, 30 SCDp and 30 eAD) were recruited as a part of a Proof‐of‐Concept study of the Alzheimer’s Disease Digital Assessment Suite (AD‐DAS) (https://www.isrctn.com/ISRCTN17035495). Participants performed 9 sessions of 30sWTDT over 28 days on provisioned smartphones. Feasibility was evaluated as the proportion of completed 30sWTDT relative to the total number of expected sessions. Two gait characteristic metrics were estimated: variability in step frequency (VSF) and the 25th percentile in step power (25SP). Intraclass correlation coefficients (ICC) tested the metrics’ reliability. Convergent validity was established as partial correlation between VSF/25SP and adjusted mean duration in Timed 25 foot Walk Test (T25WT). Clinical validity was evaluated using a proportional odds logistic regression model to differentiate between groups.

Result

Among the 97.5% of participants who completed the study (i.e., n = 120), participants completed 88.9% of all assigned 30sWTDT tasks, with no group difference in adherence. VSF and 25SP metrics showed moderate (ICC = 0.74) and good (ICC = 0.79) reliability, respectively. Both metrics significantly distinguished between HC and all other study groups (odds ratio = [0.012,0.029]), and were associated with T25WT adjusted mean duration (adjusted r2 = [0.09,0.069]).

Conclusion

Preliminary findings demonstrate that a smartphone‐based 30sWTDT can be successfully self‐administered by cognitively healthy participants and individuals on the eAD continuum. Participants show high adherence in an ecologically valid environment. 30sWTDT differentiated HC from all other groups with subjective or objective cognitive problems, indicating a lack of specificity of gait characteristics to differentiate between increasing levels of cognitive impairment. These findings require replication in larger independent datasets.
Closing the sex/gender gap in dementia: homing in on the vasculature (animal models)
Authors: Carare Roxana O. O
Published: December 2023

Females are more at risk of Alzheimer’s disease compared to males. The deposition of amyloid‐beta in the extracellular spaces of the brain as plaques and as cerebral amyloid angiopathy is more frequent in females. It is only in the recent years that experimental work on mice has embraced resting hypotheses in both sexes. Results show that cerebral microbleeds, spatial working memory and fear conditioning are more frequent in old Tg‐SwDI females compared to males (Michael E. Maniskas et al). While the rodent vasculature does not develop arteriolosclerosis with ageing as human vasculature does, the administration of a high fat diet to adult wild‐type mice impaired the spatial memory in females only and experimental hypoperfusion reduced cerebral blood flow mostly in females (Abigail E Salinero). Failure of clearance of fluids and solutes such as Abeta from the brain along Intramural Periarterial Drainage Pathways (IPAD) is a key pathogenic factor in CAA. All future experimental studies should include both sexes when analysing the clearance and other mechanisms that underlie the pathogenesis of ADRD and CAA.
Spatial gradients of gene expression, amyloid PET and functional connectome for predicting regional rates of tau‐PET increase: towards tau‐PET outcome ROIs in clinical trials.
Authors: Luan Ying , Zheng Lukai , Rubinski Anna , Franzmeier Nicolai , Ewers Michael
Published: December 2023

Background

In clinical trials, an important question is which brain regions show high tau accumulation within 1‐2 years. Building upon our previous epicenter‐connectivity‐based distance model for predicting the progression of tau‐PET accumulation from initial seed regions of high tau (epicenters) to other regions (Franzmeier et al. Sci Adv. 2020), we incorporate here epicenter‐based distance within spatial gradients of gene expression and amyloid‐PET to enhance the predictive power.

Method

We included 351 participants encompassing Ab(+) non‐demented subjects (controls & MCI), characterized by cross‐sectional 11‐F florbetaben amyloid‐PET and longitudinal 11‐F flortaucipir tau‐PET (longitudinal, n = 172, mean/range = 1,7 yrs (0.7 – 5.2 yrs)) from ADNI. For transcriptomic gene expression maps obtained from the Allen Human Brain Atlas, we computed for each of the 18,686 genes maps spatial correlations with the average tau‐PET map in a randomly selected training sample (n = 106), and retained the top 5% of positively/inversely tau‐correlating gene maps. For each imaging modality, spatial gradients were subsequently computed across amyloid‐PET scans in the training sample, the subset of gene expression maps, and functional connectivity (FC) matrices from Human Connectome project. In the test sample (n = 245), tau‐PET epicenters at baseline (Franzmeier et al. Sci Adv 2020) were projected onto the gradient maps and epicenter‐based gradient distance was computed. In step‐wise spatial regression analyses, we tested which gradient distances predicted the spatial patterns of cross‐sectional and longitudinal tau‐PET accumulation, accounting for spatial autocorrelations.

Result

For cross‐sectional tau‐PET (Fig. 1A), a total of 54.6% (p < 0.0001) of the spatial tau pattern could be explained, where an amyloid‐PET gradients and a FC gradient (spanning the transmodal axis from primary sensory to DMN regions) showed the strongest effects (Fig. 2, upper row & Fig. 3A). For longitudinal tau‐PET (Fig. 1B), a total of 47.8% (p < 0.0001) of tau increases could be explained, where gene‐expression gradients showed the strongest effects (Fig. 2 lower row & Fig. 3B).

Conclusion

Epicenter‐based gradient distances of connectivity and molecular brain properties show additive, high predictive accuracy for predicting regions of high future tau‐accumulation, providing an attractive approach to define tau‐PET outcome ROIs in clinical trials.
Alzheimer’s disease clinical management is determined by presence and severity of apathy
Authors: Oliveros‐Cid Antonio , Martinez Esther Sierrra , Moreno Lisbed Rondon , Oliveros‐Juste Antonio , Lopez Maria Angeles Cid , Hojas Sarai Garcia , Lorente Victoria Celorrio , Luque Laura Cano , Catalan Claudia Ovejas , Carrasco Ana Chacon
Published: December 2023

Background

Apathy and agitation influence daily life and care in dementia. We believe it may also influence the diagnosis, especially in early stages. We intend to examine apathy among the symptoms and the relationship with the referral schedule and early diagnosis.

Method

Outpatients referred for possible cognitive impairment included in a database of “apathy and cognitive impairment”. Clinical history, complete neuropsychological battery, MRI, MRI, laboratory, and treatment. In addition, some patients also undergo EEG, CSF and/or amyloid PET scans. Neuropsychological battery with special attention to the assessment of apathy and behavioral symptoms. Additionally, semi‐structured rating of the severity of apathy when patients were referred for the first time.

Result

64 finally diagnosed as Alzheimer’s disease (CDR 0.5 to 2). Group differences according to the frequency and severity of apathy. Those who showed apathy or depression (Independently) as a predominant symptom when referred were more often treated with psychopharmacological therapy by Primary Physician or referred to Psychiatry, where AD was generally less considered. The level of apathy showed negative correlations with MMSE, for the same group (CDR) of patients. Significantly higher levels of apathy higher levels of apathy associated with intake of antidepressants and cognitive enhancers.

Conclusion

We observed different patterns of apathy in outpatients with MCI and patients with dementia; significant negative effect on early neurological assessment of those patients, and therefore deleterious effect on their opportunities for a correct approach in the early stages of the disease.
Prospective cohort of elderly patients after hospitalization due to COVID‐19: preliminary results
Authors: da Cunha Cintra Fabiana Carla Matos , Cintra Marco Túlio , de Barros Simão Gabriel Rabelo , de Souza Campos Brenda Flaviano , Rodrigues Fabricio Groppo , Almeida Daniella Cristina Brites , de Moraes Edgar Nunes , de Faria Fortini Iza , de Mattos Viana Bernardo , Bicalho Maria Aparecida Camargo ,   Aging and neurodegenerative diseases
Published: December 2023

Background

Post Covid‐19 syndrome can cause cognitive impairment and may be associated with a higher risk of developing dementia in older people.

Method

This is a cohort study that is evaluating over 12 months the functional status and cognition of elderly people after hospital discharge. One group is composed of elderly people admitted to the hospital for Covid‐19 and the other group is composed of elderly people hospitalized for other clinical reasons. The groups are evaluated with The Mattis (DRS), AD8, ADCS‐ADL, PCL‐C, GDS‐15, FIM, COPM, CFS, FSS, mMRC and SARC‐calf. We will describe the preliminary results of the first 31 patients included in the COVID‐19 group on functional status, cognition, mood and quality of life.

Result

Thirty‐one patients with COVID‐19 were evaluated three months after hospital discharge. One was excluded due to previous mental disorder and another due to a request to be excluded from the study. We found a mean age of 69.55 ± 7.72 years, schooling 7.14 ± 4.48 years, 51.7% female, Charlson Comorbidity Index 2.21 ± 1.84, 48.3% with smoking history and 62.9% had incomplete vaccine protection for COVID‐19. Considering cognition, 13.9% of the sample had no impairment, 55.1% had mild cognitive impairment (MCI) (17.2% amnestic MCI and 37.9% non‐amnesic MCI) and 31% had dementia. 24.1% declared their health status and quality of life as fair or poor. Mean CFS was 4.45 ± 1.18, GDS‐15 4.28 ± 3.38, FSS 30.76 ± 19.24, PCL‐c 29.34 ± 10.41, SARC‐calf 4.03 ± 4.61. All had mMRC dyspnea classified between 1 and 4.

Conclusion

There was a high prevalence of mild cognitive impairment and dementia among patients after three months of discharge, with a predominance of mild frailty due to CFS and the presence of fatigue. It is noteworthy that a quarter of the sample reported low quality of life.
Applying Implementation Frameworks to Health IT Development in Dementia Care: Lessons from the CareHeroes Project
Authors: Ruggiano Nicole , Brown Ellen L , Clarke Peter J , Roberts Lisa , Framil C Victoria , Chevez Hamilton , Hurley Shannon , Kopcsik Chrystine , Allala Sai Chaithra , Hristidis Vagelis , Agronin Marc , Geldmacher David S.
Published: December 2023

Background

Caregiving and clinical care for people living with dementia (PLWD) is complex and complicated by communication challenges among caregivers and providers (Gaugler et al., 2022; Ruggiano et al. 2012; 2019). These challenges can constrain decision making about treatment options (Hinton et al., 2007; Miller et al., 2016; Wolff et al., 2020) and may contribute to negative mental health outcomes often reported by family caregivers (Gaugler et al., 2022), which disproportionately impact vulnerable caregivers (e.g., underserved racial/ethnic groups, rural caregivers (Abner et al., 2016; Fabius et al., 2020)). Health information technology (HIT) has been identified as a potential solution to communication challenges in dementia care (Ruggiano et al., 2019; Vedel et al., 2013). However, few studies have reported how to effectively integrate new HIT into practice to support provider‐caregiver communication. In this study, a four‐stage implementation science framework (Meyers et al., 2012) was used to integrate a newly developed web‐based application (app) technology, called CareHeroes (Brown et al., 2016), into clinical practice at two memory clinics to promote caregiver‐physician communication. CareHeroes is multi‐functional and allows secure sharing of patient‐related clinical information between caregivers and providers. It also provides education and support, including an educational chatbot that provides tailored, expert feedback to caregiver questions.

Method

Early stages of implementation involved interviews with caregivers and focus groups with clinic providers to develop a clinical workflow integration plan for the new app. Then, the research team collected user data collected through the app during implementation as well as caregiver psychosocial outcome data (e.g., depression, burden) at baseline and 3‐month follow‐up to evaluate implementation.

Result

Thirty‐six caregivers and eight clinic providers provided qualitative data that informed the clinical workflow integration plan. The same providers and 21 additional caregivers enrolled in the CareHeroes implementation demonstration study. While user data demonstrated that it was feasible for caregivers to share clinical information and engage in self‐support using CareHeroes, expected outcomes were confounded by complications during the COVID‐19 pandemic.

Conclusion

Through using the implementation framework, several lessons were learned regarding potential success and challenges in integrating new HIT into clinical care to support dementia care and caregiving.
Discrepancies Between Informant vs. Patient Ratings of Functional Abilities: Association with Objective Cognitive Performance in Mild Cognitive Impairment and mild dementia
Authors: De Wit Liselotte
Published: December 2023

Background

Self‐ and informant‐ratings of functional abilities are used to diagnose mild cognitive impairment (MCI) versus dementia and are a common outcome measure in clinical trials. These ratings are assumed to be accurate, yet they are subject to biases. Biases in patient ratings of daily function have been found in individuals with dementia who are older and more depressed (Martyr et al., 2012, 2019, 2022). Biases in informant ratings have been found in caregivers with higher distress and burden (Mangone et al., 1993; Martyr et al., 2014, 2022) and higher education (Hackett et al., 2020). The current study examined discrepancies in informants’ ratings of daily functioning in individuals with MCI/mild dementia.

Method

Participants were 118 patients clinically diagnosed with MCI or mild dementia and their care partners/informants who were referred to the Emory Cognitive Empowerment Program. Table 1 shows details regarding all measured constructs and variables. The discrepancy between informant rating of daily function and patients’ cognition (i.e., informant daily function rating and patient cognition discrepancy) and the informant‐ and patient discrepancy in ratings of daily function (i.e., informant/patient daily function rating discrepancy) served as dependent variables. Two forward linear regression models were run.

Result

Table 2 shows demographic information. For the informant daily function rating and patient cognition discrepancy, informants with higher perceived stress reported worse patient functioning. For the informant/patient daily function discrepancy score, worse ratings of daily function by the informant than the patient were found for informants with higher caregiver burden, worse communicative effectiveness, and patients with higher self‐efficacy.

Conclusion

This study highlights the potential for biases in patient and informant ratings of functional abilities in MCI/mild dementia. The risk for underreporting functional abilities in informants with higher burden and stress levels and lower communicative effectiveness aligns with previous research indicating that ratings can be biased by individual factors. Worse ratings by informants than patients for patients with higher self‐efficacy may also be due to individual factors in patients such as presence of anosognosia. These findings have implications for the use of perceived functional ratings for diagnostic purposes and as outcome measures in clinical trials.
FAD mutants decrease brain neovascularization and neuronal survival by targeting angiogenic mechanisms of PS1/γ‐secretase
Authors: Robakis Nikolaos K. R K , Pandey Rukmani , Yoon Yonejung , Zarrouk Amira , Dey Poylomi , Georgakopoulos Anastasios
Published: December 2023

Background

The cerebrovascular system is central to neuronal survival and function and emerging evidence suggests that vascular brain abnormalities are involved in the development of neurodegenerative disorders such as Alzheimer’s disease (AD). Angiogenesis, the generation of new blood vessels from existing vasculature, is crucial throughout adult life for maintaining brain blood circulation and for reparative mechanisms of toxic insults such as ischemia. Angiogenesis is controlled by growth factors including the Vascular Endothelial Growth Factor (VEGF). By binding to its receptor (VEGFR2), VEGF regulates extension of new blood vessels in damaged areas and maintains blood supply to tissues and organs. FAD variants of Presenilin1 (PS1), the catalytic subunit of γ‐secretase induce Familial AD (FAD) and can serve as systems where mechanisms of AD‐like neurodegeneration can be studied.

Methods

Mouse brain endothelial cells (ECs) expressing knock‐in PS1 FAD mutants were isolated and cultured and effects of PS1/γ‐secretase on angiogenic functions and processing of VEGFR2 were performed as in literature. VEGF‐induced phosphorylation of kinases downstream of VEGFR2 were determined on WBs. Middle cerebral artery occlusion (MCAO) was performed in mice as in literature. Isolated brains were sectioned using a mouse brain matrix and slices were stained with TTC and fixed with 4% PFA to detect infarct area. Cerebral blood flow (CBF) was assessed using perfusion MRI (pMRI) as in literature. Neurons were stained with anti‐NeuN and positive neurons in lesioned and contralateral areas were counted

Results

PS1/γ‐secretase process VEGFR2 and regulate crucial functions of the brain VEGF/VEGFR2 system including receptor dimerization, internalization and downstream angiogenic signaling. Importantly, PS1 FAD mutants decrease the VEGF‐induced activation and angiogenic signaling of VEGFR2 and reduce brain neovascularization suggesting mechanisms by which PS1 FAD mutants may cause neuronal dysfunction and death. In this presentation we discuss the importance of the PS1/γ‐secretase on the VEGFA/VEGFR2‐mediated angiogenenic signaling and brain neovascularization and test effects of PS1FAD mutants in brain neoangiogenesis and neuronal survival.

Conclusions

The PS1/γ‐secretase system regulates brain angiogenesis and neovascularization by activating properties of the VEGF/VEGFR2 system. PS1 FAD mutants decrease brain angiogenesis, neovascularization and neuronal survival by targeting angiogenic mechanisms of PS1 and γ‐secretase.
Utilization of the novel adeno‐associated virus PHP.eB serotype to modulate Intersectin 1 expression in the Ts65Dn mouse model of Down syndrome
Authors: Tallino Savannah L , Vural Austin , Espinosa Oscar Villareal , Velazquez Ramon
Published: December 2023

Background

Down Syndrome (DS) and Alzheimer’s disease (AD) include cholinergic neurodegeneration which parallels cognitive decline. Triplicated genes in DS are thought to play a role in basal forebrain cholinergic neuron (BFCN) pathology; one avenue to assess triplicated genes’ role is to normalize their expression in DS mouse models by stereotaxic injection of adeno‐associated viruses (AAVs) carrying silencing constructs such as single hairpin mRNA (shRNA). However, stereotaxic surgeries have drawbacks particularly when targeting areas lying deep within the brain. The introduction of the AAV‐PHP.eB serotype, which can cross the blood‐brain‐barrier when introduced into peripheral vasculature, has been shown to vary in efficiency depending on mouse background. Here, we investigated tropism of the AAV‐PHP.eB serotype in the Ts65Dn mouse, the most commonly used DS mouse model. We then used AAV‐PHP.eB to assess our ability to globally modulate expression of intersectin 1 (ITSN1), a protein triplicated in DS that may relate to BFCN dysfunction and memory impairments.

Methods

We retro‐orbitally injected N = 16 4‐4.5 month‐old male mice, (C57Bl, Ts65Dn trisomic and normosomic) with AAV‐PHP.eB‐CamKII‐GFP‐scrmble‐shRNA, to assess tropism and optimize virus concentration (2, 5, and 10µL). Four weeks post injection we imaged for GFP expression in 50µm coronal sections. To knock down ITSN1 globally, we injected N = 58 Ts65Dn mice (3 months, balanced by sex, genotype, virus) with either 5μl AAV‐PHP.eB‐U6‐scrmble‐GFP (control) or AAV‐PHP.eB‐U6‐shITSN1‐GFP (ITSN1); mice were behaviorally tested at 7 months and euthanized at 8 months followed by tissue collection.

Results

Mice injected with AAV‐PHP.eB‐CamKII‐GFP‐scrmble‐shRNA showed GFP expression 4 weeks following injection, with robust expression visible with 5µL virus. Mice subsequently injected with control and ITSN1 AAVs showed significant effects of ITSN1 knockdown, including increased tremors, increased latency in the radial arm water maze – suggesting impaired spatial reference learning and memory – decreased brain weight, and altered weight change.

Conclusion

The AAV‐PHP.eB serotype shows successful CNS tropism in the Ts65Dn mouse model, with 5µL of AAV providing the best efficiency throughout key brain regions affected in DS and AD. Furthermore, the AAV‐PHP.eB serotype can be used to modulate expression of genes triplicated in DS to investigate their mechanistic role in neurodegeneration both molecularly and behaviorally.
The Effects of 3‐month Aerobic‐Strength Training on Cognitive Functions and Adiponectin Levels in Cerebrospinal Fluid and Blood in the Elderly
Authors: Ukropcová Barbara , Tomkova Maria , Schön Martin , Slobodova Lucia , Straka Igor , Matejička Peter , Tsai Chia‐Liang , Bogner Wolfgang , Krssak Martin , Valkovič Peter , Ukropec Jozef
Published: December 2023

Background

Exercise improves physical fitness, cognitive functions & metabolism in the elderly. Evidence from animal models suggests the role for mediators from muscle or adipose tissue in the exercise‐induced brain plasticity (1). Knowledge on the regulation of these potentially neuroprotective molecules by exercise in humans is limited (2,3). We investigated effects of 3‐month supervised aerobic‐strength training on serum & cerebrospinal fluid/CSF adiponectin in the elderly, in association with cognitive functions & brain volumetry.

Method

The population consisted of sedentary elderly (n = 38, 10M/28F; 66.1±5.9yrs; BMI 26.3±3.7kg/m2). Body composition (MRI), physical fitness (Rockport test), muscle strength (dynamometry), motor tests (walking speed & chair stand tests), resting energy expenditure & substrate preference (REE, RQ, indirect calorimetry), insulin sensitivity & metabolic flexibility (euglycemic hyperinsulinemic clamp/EHC), cognitive functions (cognitive tests), brain volumetry (MRI), serum glucose & insulin were assessed.

Result

Training reduced BMI, blood pressure and insulinemia, while improving insulin sensitivity & metabolic flexibility (EHC), maximal aerobic capacity (VO2max), motor performance, and memory (ACE‐R). Improvements in cognitive functions were more pronounced in patients with MCI (p<0.05). Training led to a small but consistent increase of CSF adiponectin in cognitively healthy seniors (p<0.05), while no change was observed in MCI (p>0.1). CSF adiponectin was positively associated with psychomotor attention score (CogState), and it strongly correlated with the volume of corpus callosum normalized to intracranial volume. Training did not regulate serum adiponectin.

Conclusion

Relatively short‐term aerobic‐strength training can improve cognitive functions together with a spectrum of anthropometric, metabolic and fitness parameters, which may slow down the ageing‐related cognitive decline. Exercise modulated levels of adiponectin in CSF which correlated with cognitive functions and volume of specific brain areas. This might indirectly indicate the role for adiponectin in the exercise‐related brain plasticity in the elderly.

Funding: APVV 20‐0466, VEGA‐2/0076/22, COST DePASS, APVV 15‐0253

References

(1) Cooper, Moon, van Praag. Cold Spring Harb Perspect Med. 2018 Apr; https://doi.org/10.1101/cshperspect.a029736

(2) Effects of running on adiponectin, insulin & cytokines in CSF in healthy young individuals. M Schön, B Ukropcová et al. Sci Rep.2019Feb. https://doi.org/10.1038/s41598-018-38201-2.

(3) CSF & plasma metabolomics of acute endurance exercise. Li, Schön, Ukropcová et al. FASEB 2022 Jul. https://doi.org/10.1096/fj.202200509R.
Chronic disease patterns and associated characteristics in an ADRC cohort: a latent class analysis
Authors: Choate Radmila , Kucharska‐Newton Anna M. , Jicha Gregory A , Abner Erin L
Published: December 2023

Background

About 70% of American older adults report multiple chronic conditions (CC). The disease combinations are complex and often lead to adverse health outcomes, reduced quality of life, and require tailored treatment plans. Our study aimed to identify patterns of chronic diseases, define disease clusters and evaluate associated participant characteristics.

Method

Included in these analyses were adults ≥50 years with normal cognition at baseline and available history of 11 measured CC, demographic, and quality of life data from the University of Kentucky Alzheimer’s Disease Research Center cohort, a convenience sample of community‐based older adults followed longitudinally until death. Persons not reporting any of the 11 measured CC were assigned to a separate class. A latent class analysis (LCA) among those with ≥1 measured CC was used to identify subgroups of individuals with distinct patterns of CC. A series of LCA models with 2‐7 latent classes were assessed, and the best‐fitting model was selected based on the lowest adjusted BIC, highest entropy, and plausible clinical interpretation. Demographic and clinical characteristics of each of the latent classes were evaluated.

Result

The 772 participants were mean age 73.1±6.7 years, 66.6% female, 89.0% white, mean CDR Sum of boxes score was 0.04±0.2, and MMSE score 29.0±1.2. N = 99 (12.8%) reported none of the measured 11 CC (class 0). LCA identified 4 latent disease patterns among those with ≥1 measured CC: class 1‐prevalent hypertension, hypercholesterolemia, and diabetes; class 2‐prevalent thyroid disease; class 3‐low/moderate complexity; and class 4‐high complexity/cardiovascular and cerebrovascular conditions. Item‐response probability plots are displayed in Figure 1. Class‐specific probabilities of reporting each of the 11 CC for the 4‐class model are shown in Figure 2. On average, participants in class 4 had 5.3±1.0 CC, were older, more likely to be male, and had poorer physical quality of life than other classes (Table 1).

Conclusion

Four clusters of CC were identified in this cohort of elderly adults with normal cognition. Latent class analysis can provide additional insights into the complex relations across CC, in addition to a widely used count of comorbidities. Future longitudinal studies are needed to evaluate health outcomes in individuals assigned to the identified disease clusters.