bluuebunny/crossref_metadata_2025 huggingface dataset:
Transcriptomic Differences in Endothelial Cells Across Five Brain Regions in Normal Aging and Alzheimer's Disease
Authors: Bryant Annie G , Li Zhaozhi , Serrano‐Pozo Alberto , Woodbury Maya E. , Wachter Astrid , Lin Gen , Kwon Taekyung , Talanian Robert V. , Biber Knut , Karran Eric H , Hyman Bradley T. , Das Sudeshna , Bennett Rachel E
Published: December 2022

Background

Altered cerebral vasculature is recognized as a key feature of Alzheimer’s disease (AD) neuropathology, with current evidence suggesting a diverse collection of changes including aberrant angiogenesis, vascular pruning, inflammation, senescence, and other remodeling events. Previous studies examining the endothelial cell transcriptome in AD have been limited to 1‐2 brain regions and hampered by low numbers of isolated endothelial cell nuclei, potentially missing relevant regional heterogeneity. We hypothesized that such regional heterogeneity in endothelial cell gene expression in the normal aging brain may contribute to the varied vascular responses to AD neuropathology.

Method

Nuclei were isolated from five brain areas in subjects with increasing AD pathology (n=32 donors). The five brain areas chosen represent the hierarchical accumulation of tau pathology in AD: entorhinal cortex > inferior temporal gyrus > prefrontal cortex > secondary visual cortex > primary visual cortex. All subjects had detailed p‐tau, in vitro tau seeding, and amyloid‐beta plaque measurements available. Nuclei were FACS sorted to exclude NeuN+ and Olig2+ cells, and the resulting neuron‐ and oligodendrocyte‐depleted fraction was subject to single‐nucleus RNAseq. Endothelial cell nuclei were identified based on high von Willebrand factor expression and filtered to exclude contaminating glia, yielding a dataset comprised of 51,586 total nuclei.

Result

Transcriptomic analysis confirmed that endothelial cells share a core set of commonly upregulated genes across the five brain regions compared to other cell types. However, there is also regional heterogeneity with 193‐311 differentially upregulated genes expressed in endothelial cells within each brain area relative to all other areas. Compared to normal aging brain, endothelial cells from AD donors downregulated 962 genes and upregulated 936 genes that are enriched in vasculogenesis, blood‐brain barrier maintenance, senescence, and leukocyte interactions. Further analysis indicates regional differences in upregulation of these pathways and highlights the relationship to disease burden.

Conclusion

This dataset demonstrates a previously unrecognized regional heterogeneity in endothelial cell transcriptome in the normal aging human brain. These regional differences may impact the endothelial cell response to the local AD pathology. This dataset will inform ongoing research efforts to unravel the molecular underpinnings of AD‐induced endothelial cell dysfunction.
Modifying adult life course dementia risk: results from the Framingham Heart Study
Authors: Hwang Phillip H , Ang Ting Fang Alvin , Liu Xue , Liu Yulin , Gurnani Ashita S , Mez Jesse B. , Auerbach Sandford H , Joshi Prajakta S. , Yuan Jing , Devine Sherral A. , Au Rhoda , Liu Chunyu
Published: December 2022

Background

Modifiable risk factors of dementia identified by the 2020 Lancet Commission, including less education, high alcohol intake, smoking, obesity, physical inactivity, social isolation, diabetes, and hypertension, measured at early adult life, midlife, and late‐life were analyzed for their associations with risk of incident dementia.

Method

Participants from the Framingham Heart Study Offspring cohort who attended the fourth examination cycle (1987‐1991) and were free of prevalent dementia were included in the study sample (n = 4,015). They were stratified into three age epochs: early adult life (<45 years, n = 1,079); midlife (45‐65 years, n = 2,476); and late‐life (>65 years, n = 460). Information on alcohol intake, smoking, body mass index, physical activity, and social network, as well as diabetes and hypertension status, were ascertained at the fourth examination cycle, while information on education was ascertained from the second examination cycle. Dementia diagnoses, including all‐cause dementia and Alzheimer’s disease (AD) dementia, were adjudicated by a multi‐disciplinary consensus committee through 2019. Cox proportional hazards models were used to examine associations between each risk factor and incident all‐cause dementia and Alzheimer’s disease (AD) dementia, stratified by age epoch.

Result

Over an average of 21 years of follow‐up (early adult life = 24.0 years; midlife = 20.9 years; late‐life = 13.9 years), increased risk of all‐cause dementia was significantly associated with diabetes (HR = 1.62; 95% CI = 1.07‐2.46; p = 0.023) and physical inactivity (HR = 1.57; 95% CI = 1.12‐2.20; p = 0.009) in midlife, and with obesity (HR = 1.76; 95% CI = 1.08‐2.87; p = 0.024) in late‐life. Obesity in late‐life was associated with increased risk of AD dementia (HR = 2.19; 95% CI = 1.27‐3.77; p = 0.005). All other risk factors examined in early adult life, midlife, and late‐life were not significantly associated with risk of all‐cause dementia (Figure 1) or AD dementia (Figure 2).

Conclusion

Results suggest that modifiable risk factors individually may have modest to no impact across the adult life course on dementia risk. Additional studies are needed to determine if these risk factors in combination may have a more synergistic effect.
Identification of cognitive resilience through neuropsychological tests in the Framingham Heart Study
Authors: Hwang Phillip H , Amini Samad , Karjadi Cody , Lin Honghuang , Andersen Stacy L. , Paschalidis Ioannis , Au Rhoda , Mez Jesse B.
Published: December 2022

Background

To examine the predictive abilities of 1) traditional neuropsychological (NP) test summary scores, and 2) error and process scores in separating cognitively resilient individuals from those who exhibit cognitive decline.

Method

A total of 69 participants from the Framingham Heart Study (FHS) Offspring and Omni 1 cohorts who had ≥1 NP assessment from 2011–2014 and at high risk for dementia were included in the sample. Participants also had to be ≥60 years of age and dementia‐free at the time of NP assessment. Being at high risk for dementia was determined using a cutoff score of ≥23 based on a published FHS dementia risk score algorithm. Dementia diagnosis was adjudicated based on DSM‐IV criteria by consensus. Participants completed 10 NP tests, which were scored using 11 traditional scores and 75 error and process scores. Supervised machine learning algorithms were used to classify individuals who were cognitively resilient, defined as not progressing to dementia within ≥5 years after the NP evaluation.

Result

Among the 69 participants in our sample, 10 were cognitively resilient while 59 developed dementia. Average area under the curve when using traditional NP metrics to predict cognitive resilience ranged from 90.5% to 95.7% across each supervised machine learning algorithm (logistic regression, random forest, support vector machines, and light gradient boosting machine) (Figure 1). Average accuracy ranged from 85.3% to 92.6%, while average sensitivity was 100% across all models and average specificity ranged from 82.7% to 91.4% (Table 1). Average area under the curve when using the error and process scores to predict cognitive resilience ranged from 93.2% to 98.3% across each supervised machine learning algorithm (Figure 2). Average accuracy ranged from 89.9% to 97.0%, while average sensitivity was also 100% across all models and average specificity ranged from 88.2% to 96.5% (Table 2). All performance metrics were calculated based on five‐fold cross‐validation.

Conclusion

Results from this pilot study suggest that use of NP tests may serve as an accurate method to identify individuals who are cognitive resilient, allowing for the study of genetic, lifestyle, and other factors that confer resilience among individuals with an elevated risk for dementia.
How e‐solutions can help to improve the AD diagnostic pathway
Authors: van der Flier Wiesje M.
Published: December 2022

Background

The AD diagnostic pathway is complex, with diagnosis often made in a relatively late stage. The field is moving quickly, with knowledge about the disease increasing and options for prevention by lifestyle modification and/or medication at the horizon. We need a paradigm shift, with a focus on stages before dementia, and taking into account that both underlying biology and preferences&wishes differ between patients. This will profoundly affect the patient journey.

Methods

In this presentation, I discuss examples of how e‐solutions can help to make the next step throughout different aspects of the patient journey.

Results

Online cognitive tests, such as cCOG, could help in early detection of cognitive decline. cCOG was strongly correlated to paper&pencil tests, allowing for use in different contexts, and easy repeated assessment. ADappt.health provides a conversation starter which could be used to facilitate shared decision making in the context of AD diagnosis. Animations and a print page provide easily accessible information about the diagnostic pathway. Artificial intelligence solutions can help to combine and visualize different data sources and diagnostic tests. Such tools can provide automatic quantification of MRI images, integrating them with other sources of information, and support differential diagnosis of different types of dementia and promote individualized risk profiling for an individuals risk of future dementia. Finally, e‐solutions could provide easily accessible and easily scalable platforms for intervention, such as lifestyle interventions. In the Netherlands, the FINGER‐NL study is ongoing, entailing a hybrid lifestyle interventions, combining both on site and online meetings. Finally, when we surveyed end users, we found that the majority of both clinicians and patients and their partners is positive about the use of e‐solutions in the diagnostic pathway, provided they increase accuracy and are simple and easy to understand.

Conclusion

E‐solutions can help to improve the AD diagnostic pathway, by providing information, and tailor individually. They can help to make use of the increasing amount of available data, and create alignment across the entire patient journey. Finally, this type of solutions can help to keep healthcare affordable and accessible, and engage patients and their families more actively.
A Professional Musician with Sight‐Reading Difficulties: A Case Study
Authors: Tun Samantha M , Ficek‐Tani Bronte , Frolov Alexander , Sharp Emily , Fredericks Carolyn A
Published: December 2022

Background

There have been few reports of musical alexia in neurodegeneration. In this case report, we describe a professional orchestral musician who presented with a chief complaint of decline in performance accuracy. While he had previously been exceptional in sight‐reading, he was now making frequent mistakes and falling behind. He stated that performing a familiar piece was, “like reading it for the first time.” He later developed difficulties with visuospatial abilities and language.

Methods

We aimed to characterize his musical and cognitive symptoms using a battery that consisted of the Montreal Battery of Evaluation of Amusia, novel tasks to assess accuracy of music reading and music production, standard neuropsychological testing, and review of clinical imaging and CSF.

Results

The patient completed the Montreal Battery of Evaluation of Amusia (MBAE) with no errors. His pitch, interval, auditory memory, rhythm perception, as well as basic note names and values were unaffected. (Fig.1). We had designed two novel measures to assess his ability to play unfamiliar music using a key signature task and a performance piece. (Fig 2,3,4). Results indicated that he was able to sight read familiar excerpts but not unfamiliar excerpts. On unfamiliar pieces, his sight reading, comprehension, and production showed marked impairment. He was unable to accurately reproduce note sequences in musical passages. On standard neuropsychological measures, he demonstrated impairment on tasks requiring mental rotation and figure discrimination as well as language measures including reading comprehension (BDAE), and confrontation naming (MINT). MRI (Fig 5) showed atrophy in the patient’s parietal lobes and CSF fluid analysis was positive for abnormal Aβ‐42 and normal tau (Aβ‐42:521.55, ptau:25.55).

Conclusion

Our novel tasks revealed specific deficits in music sight reading, echoed in impairment in visuospatial abilities and language on neuropsychological measures. The patient’s imaging, positive CSF amyloid testing and cognitive testing suggest that amusia was an early stage of a probable parietal variant of Alzheimer’s disease (i.e., PCA). His case highlights the importance of considering a neurodegenerative process in patients presenting with isolated deficits in music reading. Future studies will be needed for normative and validation studies of our novel tasks.
Sex differences in dementia risk and gray matter volume associated with hearing impairment
Authors: Fitzhugh Megan C , Pa Judy
Published: December 2022

Background

Hearing impairment is highly prevalent in older adults and was recently recognized as a modifiable risk factor for dementia. However, it is unknown if risk differs by sex and whether other issues associated with hearing, like social engagement or depression, impact these associations.

Method

UK Biobank data was used to identify 165,471 participants (57±8 years, 55% female) without dementia who had a hearing assessment at baseline. Hearing was assessed using a speech reception threshold task, with scores grouped into good, insufficient, and poor severity levels based on previously derived cut‐offs (Dawes et al., 2014). Cox proportional‐hazard models were used to investigate sex differences in the association between hearing impairment and dementia risk. Sensitivity analyses were conducted to determine if social engagement or depressive symptoms mediated these associations. In a subset of participants with MRI data (n = 2,322, 62±7 years, 52% female), linear mixed models stratified by sex were conducted to examine if development of impaired hearing from baseline was associated with gray matter atrophy in auditory and limbic regions.

Result

Insufficient and poor hearing were associated with increased risk for dementia compared to good hearing (HR = 1.76, 95%CI 1.43‐2.18 and HR = 2.13, 95%CI 1.46‐3.11, respectively), but differed by sex. Women with insufficient (HR = 1.73, 95% CI 1.25‐2.40) and poor (HR = 3.08, 95%CI 1.80‐5.28) hearing had the greatest risk of dementia, whereas only men with insufficient hearing had increased risk (HR = 1.78, 95%CI 1.34‐2.35; poor HR = 1.60 95%CI 0.94‐2.73). These relationships were not mediated by social engagement or depression. In the MRI subset, women who developed or maintained impaired hearing had greater atrophy over 2.29 years in auditory pathway (e.g., primary auditory cortex, thalamus) and limbic (e.g., hippocampus, parahippocampus, amygdala) regions compared to women with good hearing. Men who developed impairment exhibited decreases over 2.30 years in a secondary auditory region only.

Conclusion

Women with impaired hearing have greater risk of dementia compared to men. These sex differences are not mediated by social engagement or depression. Women with impaired hearing exhibit greater atrophy in auditory and limbic regions, while men do not. Sex differences in gray matter atrophy may explain why women with impaired hearing are at greater risk of dementia.
Usability and acceptability of wearable technology in the early detection of dementia
Authors: Wilson Sarah , Ardle Ríona Mc , Tolley Clare , Slight Sarah
Published: December 2022

Background

The Early Detection of Neurodegeneration (EDoN) is a global initiative that aims to explore the potential of wearable technologies and smartphone applications to detect preclinical dementia, with aspirations to validate a digital toolkit for clinical practice. To enhance the development of an inclusive digital toolkit, we conducted a study to assess the usability and acceptability of different digital devices in people with cognitive impairments and their carers.

Method

Recruitment was conducted across various UK networks such as Join Dementia Research. Participants received the EDoN toolkit, which includes a smartwatch (Fitbit Charge 4), EEG headband (Dreem 3) and two smartphone applications (Longevity and Mezurio). Guides were provided to support the setup process. Initial interviews were conducted approximately three days after the participant received the devices, to explore initial perspectives regarding the toolkit and experiences of the setup process. Follow‐up interviews were conducted two weeks later to explore the acceptability and usability of the toolkit. NVivo was used to thematically analyse the interview transcripts. Emerging themes were discussed and refined by the research group.

Result

Sixteen semi‐structured interviews were conducted with nine participants, at two‐time points. Four participants had mild cognitive impairment, two had frontotemporal dementia, one had Alzheimer’s and two were carers. We identified three key themes, which centred around usability, acceptability and inequity. Participants expressed the wearable devices were comfortable but individuals with physical disabilities or cognitive impairments struggled to use some devices. Participants valued the feedback the devices provided such as information on sleep and heart rate, although some information was not fully understood. Participants also shared their concerns around detecting preclinical dementia and the increased anxiety around the consequences of this such as "being put in a home”. Various inequities of the toolkit were uncovered such as digital exclusion relating to a lack of access to strong WiFi connection, compatible smartphones and poor digital literacy.

Conclusion

These results are informative for the further development of user‐friendly digital tools for the early detection of dementia. Further work is required to ensure a digital toolkit is inclusive and provides information that can be understood by the user.
Functional profiles of older adults from the dementia continuum: Analyzing critical errors that occurred during an IADL ecological evaluation
Authors: Yaddaden Amel
Published: December 2022

Background

Older adults with Alzheimer disease (AD) or mild cognitive impairment (MCI) experience challenges that affect their independence. Instrumental activities of daily living (IADLs) are critical in assessing the independence. Single errors can have considerable impact, as they can lead to institutionalization. Thus, optimal recommendations regarding independence depends on an accurate analysis of IADL, including a fine grain analysis of the type of critical errors. Our study aim to describe the errors produced by older adults from the dementia continuum (AD, MCI and older adults living in the community with no dementia) when performing IADL. More specifically, our objectives are to understand: (1) What are the main types of errors occurring during IADL and (2) When are these errors more likely to occur.

Method

We conducted a performance based IADL assessment with older adults (n = 24), including 7 with AD, 8 with MCI, and 9 without dementia. We used the IADL Profile[1], which is a standardized assessment based on ecological observation of 8 IADL tasks. For each task, observations of performance are grouped into 4 operations: (1) formulate a goal, (2) plan, (3) execute, and (4) achieve the goal. Based on video recordings of the sessions, participants performances were transcribed into verbatim reports of all the errors that occurred. Deductive qualitative analysis and descriptive statistical analysis (standard deviation and correlation) were used to categorize/count the main type of errors for each task.

Result

Our results highlighted that (1) older adults make several errors while performing IADLs, with a higher occurrence according to the advancement along the dementia continuum and some of which may be crucial to the person’s independence; (2) the most frequent errors for all participants were in formulating a goal and in planning a task and (3) these errors are likely to occur during grocery shopping and meal preparation.

Conclusion

The fine grain analysis of errors during the performance of IADL allows us to better identify the needs of older adults from the dementia continuum that can service to guide the selection of effective strategies that can optimize their safety and functional independence.

[1] Bottari et al. (2009)
The potentially protective role of an understudied tau isoform in Alzheimer’s disease
Authors: Chung Dah‐eun Chloe , Revelli Jean‐Pierre , Richman Ronald , Yalamanchili Hari K. , Kang Myoung‐Goo , Han Alexander , Zoghbi Huda Y.
Published: December 2022

Background

As Alzheimer’s disease (AD) progresses, tau becomes abnormally aggregated and hyperphosphorylated in selective brain regions such as the cortex and hippocampus. Surprisingly, the cerebellum remains spared from tau pathology. Given this observation, we proposed to examine possible differences in the level of various tau isoforms in the cerebellum compared to the forebrain.

Methods

We first compared the transcript and protein levels of tau isoforms between the cerebellum and other brain regions (e.g., the cortex and hippocampus) using both mouse and human brain samples. Here, we discovered that “big tau”, an understudied tau isoform previously reported to be specifically expressed in the periphery, is highly elevated in the cerebellum compared to other brain regions. Next, we performed detergent fractionation using cells expressing mutant big tau or tau441 (the longest one of six major tau isoforms) to compare the aggregation propensity between the two tau isoforms. Lastly, to test this in an animal model, we injected a newborn wild‐type mice with adeno‐associated viruses (AAV) that express either mutant big tau or tau441. After aging the mice for 6 to 9 months, we examined their brains to analyze pathological changes associated with either of these two tau isoforms.

Results

We found that the transcript level of big tau is significantly higher in the mouse cerebellum compared to the cortex and hippocampus. Using the total tau antibody and the novel mouse big tau‐specific antibody that we generated, we confirmed that big tau protein level is also significantly elevated in the cerebellum. We obtained similar results in human tissues as both the transcript and protein levels of big tau were higher in the cerebellum than the cortex. Interestingly, our fractionation experiment using cells revealed that big tau protein is significantly less likely to aggregate compared to tau441. Consistent with these results, big tau did not become pathologically aggregated or phosphorylated compared to tau441 in the AAV‐based mouse model.

Conclusion

Big tau has a substantially lower tendency to become pathologically aggregated or hyperphosphorylated. The higher level of big tau in the cerebellum may potentially protect this brain region from developing tau pathology in AD.
Immigration and Cognitive Change after age 90: findings from the LifeAfter90 Study
Authors: Meunier Claire C. , Corrada Maria M. , Gilsanz Paola , Kawas Claudia H. , Mungas Dan M. , DeCarli Charles S. , Meyer Oanh L. , Whitmer Rachel A.
Published: December 2022

Background

Prior studies have suggested immigration may be associated with different cognitive decline; however, this has not been explored in those aged 90+ years. This study examined the association between United States (US) born vs non‐US born and cognitive decline in a diverse cohort of oldest‐old.

Method

We followed 641 participants of the LifeAfter90 study, an ongoing cohort study to evaluate aging and incident dementia in individuals aged 90+ recruited from Kaiser Permanente Northern California. Verbal episodic memory (VEM), semantic memory (SM), and executive function (EF) were measured using the Spanish and English Neuropsychological Assessment Scale every six months and domain‐specific scores were z‐scored to baseline. Self‐reported birthplace was collected at baseline or visit 2 (if previously not asked due to changes in the survey). Linear mixed models with random intercepts and slopes were adjusted for baseline age, gender, race/ethnicity, education, years since baseline, and practice effects.

Result

The sample was comprised of 60% women, 30% White, 18% Latino, 22% African American, 22% Asian, and 8% multiracial individuals (Table 1). Nineteen percent (n = 123) of the participants was born outside of the US, of those, 74% identified as Asian or Latino. Average baseline age was 93 years without differences between US‐born and non‐US born participants. Participants were followed for up to 7 waves (3.5 years with a mean of 2 visits). At baseline, participants born outside of the US had lower EF z‐scores (β = ‐0.39; 95% CI:‐0.57,‐0.21) and lower SM z‐scores (β = ‐0.69; 95% CI:‐0.87,‐0.51) than US‐born counterparts after adjustments (Table 2, Model 3). Participants had similar rates of cognitive change in the EF and VEM domains over the 7 waves. Participants born outside the US had a faster rate of decline in SM (β = ‐0.14; 95% CI:‐0.26,‐0.03) after adjusting for covariates.

Conclusion

In oldest‐old individuals, we found that those born outside of the US had lower baseline EF and SM; a faster rate of decline in SM and a similar, though not quite significant, effect on VEM decline. Further comprehensive data on immigration, such as age of immigration and educational opportunities, may help explain the relationship between cognitive function and immigration
Awareness Creation of Neurotoxins‐induced Wallerian‐type degeneration causing brain Acetylcholine‐imbalance and frank Alzheimer disease
Authors: Olughor Vincent Oghenekevbe
Published: December 2022

Background

Presence Environmentally Mediated Intellectual Decline Neurotoxins ('presence‐EMIDN') threats from 'bounded', 'unbounded' and 'pervasive' sources puts everyone at risk of developing neurodegenerative diseases (eg. Alzheimer) once specific lipophilic‐neurotoxins breach the blood‐brain and nose‐brain barriers to reach the brain and build up to harmful thresholds. Such neurotoxins exist; how they provoke Wallerian‐type degeneration to cause FAD have been threaded together from experimental evidenced‐based reviews. My intent/interest is to create awareness and establish the aetiology for FAD, which has remained idiopathic since 1906, when the German Neurologist, Alois Alzheimer, discovered the disease.

Method

Through threaded literature reviews from multiple sources

Results

Many neurotoxins produce Wallerian‐type degeneration: organophosphorus compounds (DFP, TOCP), acrylamide, n‐hexane and some of its metabolites. Wallerian‐type degeneration have been demonstrated in animals: hens, cats, rats, rabbits. Changes during Wallerian‐type degeneration can be grouped into two (Histopathological and Biochemical): it describes the cascade of events taking place in the distal part of an axon that has been cut or crushed. The histopathological changes occur in stages in the following order of succession: stage a: primary degeneration of axon followed by secondary degeneration of myelin in these order: axon swelling; axon disintegration; loss of normal myelin structures with swelling; tumefaction; and breakdown of myelin sheaths; followed by stage b: Cellular proliferation; and then stage c: Fibrosis. The biochemical changes result from liberations of normal biochemical constituents of axon and myelin. There is specifically a decrease in the CNS neurotransmitter's Acetylcholine content, in stage a (causing deficiency‐imbalance), increase in collagen in stage c, and other stage b changes.

Conclusion

There are evidences showing that symptoms of FAD is due to 'Acetylcholine deficiency‐imbalance in the brain' where it exercises Excitatory and Inhibitory effects which progressively kick‐starts FAD with fatalities after 5 years. Establishing this aetiology brings vistas of new hope/challenges for possible therapeutic interventions developments.
Myeloid cell bioenergetics regulate cognitive function in aging
Authors: Andreasson Katrin I. , Minhas Paras Singh , Wang Congcong
Published: December 2022

Background

A hallmark of aging is the appearance of sustained pro‐inflammatory responses and reduced clearance of pathogenic materials. Systemically, aging is accompanied by a skewing of the immune system towards the myeloid cell lineage and an increase in circulating pro‐ inflammatory factors. In the aging brain, functional degradation of microglia leads to the accumulation of neurotoxic misfolded proteins, a loss of trophic factors that support neurons, and a failure to maintain a homeostatic microenvironment. However, the underlying mechanisms that initiate and sustain maladaptive inflammation with aging are not well defined.

Method

To maintain homeostatic responses, immune cells require robust glycolytic and mitochondrial metabolism to meet demand for energy and biosynthetic precursors. In this study, we investigated metabolic and immune effects of inflammatory prostaglandin E2 (PGE2) signaling in age‐associated inflammation and cognitive decline.

Result

We demonstrate that PGE2 signaling via its EP2 receptor suppresses healthy peripheral myeloid and microglial cell glucose metabolism by driving sequestration of glucose into glycogen through the AKT/GSK3ß/GYS1 pathway and away from generation of ATP. This energy‐deficient state in turn promotes maladaptive, neurotoxic immune responses in vivo. Using genetic and pharmacological modeling, we demonstrate that inhibition of EP2 signaling restores youthful myeloid bioenergetics and immune responses and rescues synaptic mitochondrial function, hippocampal plasticity and spatial memory.

Conclusion

Inhibition of EP2‐dependent disruption of myeloid metabolism may represent a new approach to disorders of aging, with greater specificity than the use of non‐steroidal anti‐inflammatory drugs that target COX‐2 and COX‐1 and suppress both beneficial and toxic prostaglandin signaling pathways.
The Impact of COVID‐19 on Family Dementia Caregivers: Insights from a Memory Clinic in Germany
Authors: Klein Olga A. , Karras Antonia , Teipel Stefan , Hoffmann Wolfgang , Kilimann Ingo ,   DZNE GAIN research group
Published: December 2022

Background

Family dementia caregiving is associated with a high burden on the caregiving relatives. With the worldwide spread of coronavirus SARS‐CoV‐2, new stress factors were added for both the caregivers and the PwD, as they had to further limit their social contacts due to statutory restrictions and they belong to the groups of people with a higher risk of a severe COVID‐19 disease course. Our aim was therefore, to investigate the impact of the COVID‐19 pandemic on the care situation and well‐being of family dementia caregivers.

Method

Semi‐structured telephone interviews with family dementia caregivers (n = 20) were conducted, recorded, transcribed and analysed thematically. This study was embedded within a larger randomised controlled trial (RCT) assessing the effectiveness of a digitally supported care management programme.

Result

Negative consequences reported were a decrease in support for caregiving responsibilities, adverse consequences for the PwD, and problems in connection with organising a COVID‐19 vaccination. New care requirements included the responsibility to ensure that the PwD complies with the corona security measures as well as the additional care tasks for the family caregivers that could no longer be guaranteed by third parties. Positive changes that were highlighted by some participants were that they had more time for their care responsibilities due to fewer visits from family or friends and as well as reduced perceived stress for the PwD. For the majority of participants, the impact was primarily reduced by the persistence of private and professional support services and their own coping strategies.

Conclusion

Despite some negative consequences, the results showed that the COVID‐19 pandemic had little overall impact on the caregiving situation of family dementia caregivers. These were surprising results as they stand in contrast to previous research findings. The overall low impact reported could be due to several factors. The interviews took place around the time of the second lockdown in Germany, which was generally described as a “light version” with back‐up measurements in place ensuring healthcare services operating almost as usual. In addition, an already restricted lifestyle as well as the fact that some caregivers received a care management programme at the time could have mitigated the impact.
Meta‐Analysis of Animal Fluency Performance in Amnestic Mild Cognitive Impairment and Cognitively Unimpaired Older Adults.
Authors: Sharma Vivek Attri , Malek‐Ahmadi Michael H.
Published: December 2022

Background

Animal fluency is a commonly used neuropsychological measure that is used in the diagnosis of mild cognitive impairment (MCI) and Alzheimer’s disease (AD). Although most individuals with MCI have clinically normal scores on this test, several studies have shown the MCI individuals’ performance is significantly lower than that of cognitively unimpaired (CU) individuals. The aim of this meta‐analysis will be to characterize the effect size of animal fluency performance differences between MCI and CU individuals.

Method

Literature search with search terms used were: “animal fluency and mild cognitive impairment”, “semantic fluency and mild cognitive impairment”, “category fluency and mild cognitive impairment”. Data was extracted only from studies that met the following criteria: 1. It was to be an observational study (interventional studies were excluded; 2. Peterson criteria was used for diagnosis of the MCI individuals; 3. The study had raw data available animal fluency performance. Both the standardized mean difference (SMD) and the raw mean difference (RMD) were derived from random effects analyses. Demographically adjusted z‐scores for Animal fluency performance for the MCI groups were obtained to determine normative performance.

Result

Twenty studies were included in the analysis. The SMD for animal fluency performance between CU and MCI was 0.89 (95% confidence interval: [0.73; 1.04], p<0.001), I^2 = 68.6% [50.2%; 80.2%], which reflects a large effect size with moderate heterogeneity. The RMD was ‐4.09 [‐4.78; ‐3.40], p<0.001 indicating that MCI individuals generated significantly fewer animals than CU individuals. The mean z‐score for MCI groups’ animal fluency scores was z = ‐0.75 indicating performance in the Low Average range.

Conclusion

This study found a large effect size for differences on animal fluency performance between MCI and CU individuals. On average, the MCI groups’ normative performance did not fall into the Impaired range indicating that there are important sub‐clinical differences on animal fluency performance between CU and MCI individuals. These findings are relevant to the use of composite efficacy measures for AD prevention trials. Specifically, the inclusion of animal fluency in these composite scores may help increase their sensitivity to change and yield greater statistical power for these trials.
The Impact of COVID‐19 on Family Dementia Caregivers in Vietnam ‐ Insights from A Memory Clinic in Ho Chi Minh City
Authors: Tam Pham Thi Thanh , Nam Vu Hai , Huong Tran Thi Thu , Liem Do Thanh , Luu Phan Thi , Thang Tran Cong , Weschke Sarah , Kilimann Ingo , Klein Olga A.
Published: December 2022

Background

The COVID‐19 pandemic has unprecedented consequences on stress, isolation, and financial well‐being for family caregivers of people with dementia globally. In Vietnam, soaring COVID‐19 cases have led to widespread social distancing, isolation, and quarantine orders from the government. To date, limited evidence exists about the situation of persons with dementia and their family caregivers during the pandemic in Vietnam.

Objectives

The study aimed to provide insights into the impact of the COVID‐19 pandemic on family caregivers of people with dementia.

Methods

Mixed methods were used, and data collection took place in two rounds. In the first round during the first wave of infections at Ho Chi Minh City, semi‐structured interviews with caregivers and health care workers (n = 16) were conducted and analysed thematically. In the second round, this data will be complemented with survey data from family caregivers of people with dementia (n = 30). The survey includes a combination of closed‐ and open‐ended questions on the impact of the pandemic on the caregivers’ health and caregiving responsibilities.

Results

Results of the first round of data collection showed a high impact of the pandemic on caregivers resulting in negative psychosocial and emotional consequences of caregivers such as worry, stress, frustration as well as restrictions in time and place. Caregivers had reduced access to counselling services needed. At the same time, treatment services for people with dementia were reduced or even halted. The results from the survey will give additional insights into the impact of the COVID‐19 pandemic on family caregivers of people with dementia, including their challenges and concerns. These results will help to adapt counselling and treatment services for dementia family caregivers and will be presented in detail.

Conclusion

The study will lead to a better understanding of the impact of the COVID‐19 pandemic on family caregivers of people with dementia and will facilitate the adaptation of the existing as well as integration of new topics into our caregiver counselling program. Additionally, the development of (digital) self‐help groups for caregivers could be another option to prevent disruption of the health care system and to ensure ongoing service provision despite pandemic‐related restrictions.
Altered L‐carnitine and acylcarnitine profiles in APOE e4 carriers with Alzheimer’s disease reflect impaired fatty acid oxidation.
Authors: Abdullah Laila
Published: December 2022

Background

Abnormal lipid metabolism is now considered one of the key biological features of Alzheimer’s disease (AD). The L‐carnitine system plays an important role in lipid metabolism, particularly fatty acid (FA) transport and metabolism in mitochondria. Blood and tissue acylcarnitine accumulation reflects incomplete fatty acid beta‐oxidation (FAO), corresponding with insulin resistance, oxidative stress and inflammation. We hypothesized that changes in blood and brain markers of the L‐carnitine system would indicate dysfunctional FAO in aging e4 carriers, thereby influencing AD pathogenesis.

Method

Plasma and brain L‐carnitine, L‐carnitine metabolites and acylcarnitine were analyzed in controls and patients with early or moderate AD stratified by APOE genotypes. The L‐carnitine system was examined over a range of ages (10 to 50 weeks) in plasma and brains from transgenic mice expressing different human APOE isoforms and EFAD mice with human APOE and 5 x AD mutations.

Result

Among e4 carriers, plasma L‐carnitine decreased, but its metabolite, Trimethylamine N‐oxide, increased in patients with early or moderate AD. Among non‐e4 carriers these changes are detected only in moderate AD patients. Among e4 carriers, plasma long chain acylcarnitines (LCA) and very‐LCA (VLCA) were lowest in moderate AD patients. In e4 carriers, plasma acylcarnitines correlated with cerebrovascular, amyloid and tau pathologies. Whereas in e2 carriers, both brain and plasma acylcarnitines were correlated with amyloid, tau and cerebrovascular pathologies. In APOE4‐TR mice, medium chain acylcarnitines (MCA) and LCA decreased with age within the cerebrovasculature. Parenchymal acylcarnitines increased at an earlier age (25 weeks) among APOE4‐TR mice compared to mice with other APOE genotypes (50 weeks).

Conclusion

These data suggest that among e4 carriers, the L‐carnitine system‐mediated FAO is dysregulated early in the disease process of AD. Age‐dependent decreases in MCA and LCA in the cerebrovasculature in APOE4‐TR compared to APOE3‐TR mice indicate FAO deficits at an earlier age in APOE4‐TR. Understanding the role of APOE4 in impaired FAO with age in relation to the L‐carnitine system is required for developing novel preventative/therapeutic strategies for AD.
Pathological tau interactors and their role in propagation and neurodegeneration
Authors: Martínez Pablo , Patel Henika , You Yanwen , Garfe Nur Jury , Perkins Abigail , You Yingjian , Huang Xiaoqing , Dutta Sayan , Wijeratne Aruna , Redding Javier , Mosley Amber L. , Rochet Chris , Zhang Jie , Troncoso Juan C , Reeves Cristian A Lasagna
Published: December 2022

Background

Tau aggregates are critical pathological features of Alzheimer’s disease (AD) and other tauopathies. An important focus of research has been to understand the pathological tau propagation in AD patient brains that follow neuronal networks. Despite the knowledge acquired, the cellular mechanism involved in tau propagation and seeding are still unclear. Unfortunately, the nature of the tau species involved in the spreading and the precise seeding/template remains unknown. Despite this uncertainty, some studies suggest that a high molecular weight tau (HMW‐tau) is the form of tau involved in trans‐synaptic propagation. It remains unresolved whether these HMW‐tau particles are made exclusively of tau or contain other constituents such as proteins necessary for propagation.

Method

3‐months‐old PS19 mice (n=3). TBS‐soluble PS19 brain extracts were passed through a Size Exclusion Chromatography (SEC) column. We then measured the tau seeding activity of each SEC‐fraction using a well‐described bio sensor cell line that relies on flow cytometry detection of FRET signal. To identify other constituents or interactors of this tau‐ seed, we IP human tau using the HT7 antibody from the fraction with highest tau seeding activity and subjected it to TMT‐tag quantitative Mass Spectrometry. Through quantitative Mass Spectrometry, we were able to identify the protein‐interactome of the tau‐ seed and the interactome of monomeric tau isolated from the same brains.

Result

We determined that tau from fraction‐9 (F9) forms an HMW‐tau complex in vivo (>2,000KDa) with the strongest seeding activity. Interestingly, the tau present in F9 is less than 4.4% of the total tau in the brain of PS19 mice and adopt a protofibrillar morphology. Bioinformatics from both interactomes revealed an enrichment of a specific set of proteins in the tau‐seed in comparison with monomeric tau.

Conclusion

HMW‐Tau, which represent the 4% of total tau in PS19 brains, has the highest seeding activity. The protein interactome of this HMW‐tau also differs from the monomeric tau interactome.
Investigating the use of an autonomous robot assistant to improve the wellbeing of institutionalized older adults in Armenia
Authors: Mahakian Jane
Published: December 2022

Background

Researchers investigated the use of an emotional support robot to improve the well‐being of institutionalized older adults in Armenia. The autonomous assistant called Robin the Robot assessed the cognitive and psychosocial needs of elders in a nursing home in Armenia. Robin the Robot is a semi‐autonomous robot that interprets facial expressions and conversational contextual clues to understand emotions from individuals, and then uses artificial intelligence to guide its responses and develop a therapeutic interaction with patients

Method

The twelve‐week study was a randomized control trial of using Robin the Robot as an intervention to improve well‐being of older individuals in long‐term nursing care facilities in Armenia. Upon enrollment, participants completed a brief demographics interview. Evaluation of study participants, both pre and post‐test included: the International Short‐Form of the Positive and Negative Affect Schedule (I‐PANAS‐SF)2; Montreal Cognitive Assessment (MoCA)8 and the Geriatric Anxiety Scale (GAS‐10)9 and Geriatric Depression Scale (GDS)10,11

Result

The results of the study revealed Robin the Robot’s interventions improved the elder’s cognitive functioning. On the Montreal Cognitive Assessment test (MoCA), the elder’s score improved an average of 3.29 points per person. Their word recall had the largest numerical improvement. On the Geriatric Depression Test, Geriatric Anxiety Test and the PANAS Test (positive and negative affect test) there were no significant differences between the pre and post intervention, although a slight improvement on the Geriatric Depression Test, however no statistical difference.

Conclusion

The use of emotional support robots improved memory and cognitive functions of the elders, as well as slight improvement in mood. This project made a significant contribution in improving health outcomes for the elderly, bringing more attention to nursing facilities, and contributing to research on health and prevention.
Characterisation of D409V/WT mice as a novel dementia model
Authors: Sander Millie , Brown Jonathan T , Ballard Clive G , Lunnon Katie
Published: December 2022

Background

Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB) share various pathological and symptomatic traits. Such overlap complicates diagnosis, ultimately impacting the level of care and treatment options available to patients. The development of novel models to further understand DLB is therefore imperative. Recent research indicates mice with heterozygous mutations (D409V/WT) in the GBA gene to be a viable option, presenting DLB‐associated characteristics such as age‐related cognitive decline, an increase in monomeric α‐synuclein deposition and cholinergic dysfunction (Clarke et al., 2019).

Methods

To further characterise D409V/WT mice, we looked at measures of brain atrophy, patterns of neuronal firing, and transcriptomic changes. Global brain atrophy was assessed using six different measures surrounding cortical thickness and ventricle size from cresyl violet stained coronal sections. Neuronal activity in the medial septum was recorded through a series of multi‐electrode array (MEA) studies, and RNA was extracted from the same region in order to investigate transcriptional changes. All studies used WT littermates as controls.

Results

At 12 months of age, D409V/WT mice exhibited both ventricle enlargement and cortical thinning when compared with WT controls. All six measures used were significant at the p < 0.05 level. Neuronal firing appeared to be disrupted among D409V/WT mice compared to WT controls, but this was not found to be significant. Further analysis is currently being undertaken to determine the effects of both cell and slice variation upon these results. We anticipate all further MEA analysis, and transcriptomic analysis to be complete by 31st May 2022.

Conclusions

These findings support D409V/WT mice to be a candidate model for DLB. Following further characterisation, we suggest this model may be useful in better understanding DLB and developing novel diagnostic tools.