bluuebunny/crossref_metadata_2025 huggingface dataset:
Ethical considerations for participatory action research involving people with potential cognitive impairment
Authors: Kenny Danelle
Published: December 2023

Background

This case study aims to stimulate discussion around ethics approvals for research involving humans that is classified as high‐risk. Emerging research paradigms like participatory action research (PAR) advocate for the inclusion of stakeholders in research design, conduct, and analysis, but ethics approval requires development of the research and analysis plan prior to submission of the application, and approval is needed for all research materials, including consent forms, participant information sheets, and recruiting and marketing materials. How is it then possible to involve consumers in the research design and development phase prior to ethical approval of consent documentation?

Method

This investigation is part of the overall analysis of the COM‐IC SRG (Core Outcome Measures for Improving Care in Dementia Stakeholder Reference Group), the consumer arm of the COM‐IC study. It is a case study investigating the ethical approval process for participatory action research involving people with potential cognitive impairment. Data is sourced through the activities of the COM‐IC investigation team and the subsidiary interim SRG, as well as their communication and interaction with HREC teams from supporting institutions. Documentation pertaining to and reflections on the ethics approval process for the stakeholder reference group are critically analysed within the context and purpose of ethical review.

Result

Analysis of the ethics approval process suggests a paradigm shift is needed if true participatory action research is the goal. Lengthy delays, inconsistencies in panel decisions, poor communication, and different perceptions of rights and capabilities of people labelled high‐risk complicates an already highly emotive process. That said, it remains critical to the integrity of the overall system to have checks and balances against unethical research and ensure the rights of participants are truly protected.

Conclusion

It is important for people with cognitive impairment to have the opportunity to contribute to research that is about them. Current ethical approval processes, while advocating for protection of vulnerable groups, are inadvertently impeding and complicating their capacity to be involved. Moving forward requires a collaborative rethink around ways of working that both protect and enhance opportunities for people with cognitive impairment.
A Phase 1 Clinical Trial of IL‐2 in Patients with Alzheimer’s Disease: A Regulatory T Cell Expansion Strategy Targeting Inflammation
Authors: Faridar Alireza , Eid Abdulmunaim M , Thome Aaron D , Zhao Weihua , Beers David , Pascual Belen , Nakawah Mohammad O , Roman Gustavo C , Davis Charles S. , Grundman Michael , Masdeu Joseph C. , Appel Stanley H
Published: December 2023

Background

Regulatory T cells (Tregs) play a neuroprotective role by suppressing inflammation. We previously documented that Treg immunomodulatory mechanisms are compromised in people with Alzheimer’s disease (AD) and are associated with activation of peripheral monocytes and upregulation of inflammatory mediators. In this original study, we investigated the feasibility and potential impact of low‐dose IL‐2 immunotherapy on restoring Tregs and modifying inflammation in an AD clinical setting.

Method

Eight patients with mild‐to‐moderate AD dementia (MMSE:12‐25) were enrolled in a phase 1, open‐label, feasibility study of IL‐2 treatment. The presence of elevated brain amyloid, as demonstrated by either CSF or amyloid positron emission tomography (PET) scan, was confirmed in all participants. Enrolled individuals received monthly five‐day‐courses of subcutaneous IL‐2 (1 million units/day) for four months and were followed for an additional two months post‐treatment. Treg immunophenotype and functional analysis were obtained serially at screening, day 1 (before IL‐2 treatment) and day 8 (three days after the fifth dose) of each treatment cycle during therapy, and then at weeks 17 and 24. Two‐sided paired t‐tests were used to assess the statistical significance of changes in each analyte or clinical outcome at each timepoint.

Result

Overall, low‐dose IL‐2 immunotherapy was well‐tolerated and all patients received the treatment as planned. The number of CD4+CD25highFoxP3+ Tregs increased two to three‐fold after each IL‐2 treatment cycle (p<0.01) and returned to baseline before the next cycle. Treg suppressive function on responder T cell (Tresp) proliferation also progressively increased through the four‐month IL‐2 treatment phase (p<0.01). IL‐2 treatment down‐regulated IL‐1β, IL‐6 and TNFa transcripts in circulating monocytes and modulated plasma pro‐inflammatory chemokines and cytokines (IL‐15, CCL2, CCL4, CCL11 and FLT3LG; p<0.01). Clinical benefits (mean change ± SE) were observed on the Mini‐Mental State Exam (+2.25 ± 0.59, p = 0.007) and the Clinical Dementia Rating Sum of Boxes (‐0.56 ± 0.24; p = 0.051).

Conclusion

IL‐2 immunotherapy restored peripheral Treg function and ameliorated systemic pro‐inflammatory mediators in AD patients. The results of this study warrant conducting a well‐controlled clinical study to further evaluate the safety and efficacy of low‐dose IL‐2 as a potential treatment for AD.
Testing bidirectional relationships between functional brain networks and preclinical Alzheimer disease biomarkers
Authors: Millar Peter R , Singhe Nawang , Macharia Kiana Angela , Metcalf Nicholas V , Roman June , Morris John C , Benzinger Tammie L.S. , Ances Beau
Published: December 2023

Background

Resting‐state functional connectivity (RSFC) provides estimates of brain networks using fMRI. There are conflicting reports regarding the effects of amyloid‐β (Aβ) and tau on RSFC networks in cognitively normal participants. These inconsistencies might be explained by a recently‐proposed theoretical model that Aβ and tau have an interactive effect on RSFC, marked first by hyper‐connectivity in association with Aβ, then by hypo‐connectivity in association with tau. Although there is preliminary support for this model, independent validations and further characterizations of the effects of Aβ and tau on RSFC are needed.

Method

We analyzed RSFC, Aβ PET, and tau PET data from the Knight Alzheimer Disease Research Center (ADRC). All participants were cognitively normal (Clinical Dementia Rating®: 0). RSFC was collected on two scanners in partly‐overlapping samples (PETMR N: 190, TRIO N: 149). RSFC data were processed with framewise censoring and global signal regression. RSFC networks were defined using 298 regions of interest. Aβ was measured with PET PiB and AV‐45 tracers, which were harmonized using a Centiloid conversion. Tau was measured with a PET AV‐1451 tracer and was summarized in pre‐defined regions. Main effect and interaction relationships between Aβ, tau PET, and RSFC were tested with linear regression models, controlling for age, sex, education, and head motion as covariates, with a false discovery rate correction.

Result

We did not observe a bidirectional interaction effect in any of the hypothesized networks (default mode [DMN], salience [SAL], frontoparietal [FPN]). Aβ was positively associated with RSFC, independent of tau, in the DMN and SAL, while tau was negatively associated with RSFC, independent of Aβ, in the SAL only. Exploratory analyses of FC within and between all networks did not identify clear patterns of interactive biomarker effects, nor consistent patterns of main effect relationships within any of the other networks.

Conclusion

These results do not support an interactive model of RSFC in preclinical AD. Inconsistencies with previous interactions may be driven by sample‐specific or methodological differences, or the low reliability of FC and brain‐behavior relationships. Prominent biomarker relationships in the DMN and SAL are consistent with regional overlap with Aβ deposition in early AD.
The role of capillary and pericyte associated microglia in health and Alzheimer’s disease
Authors: Morris Gary P , Foster Catherine G , Courtney Jo‐Maree , Collins Jessica M , Cashion Jake M , Brown Lachlan S , Howells David W , Deluca Gabriele C , Canty Alison J , King Anna E , Ziebell Jenna M , Sutherland Brad A
Published: December 2023

Background

The majority of individuals with Alzheimer’s disease (AD) exhibit vascular damage in the brain including reduced cerebral blood flow (CBF) and blood‐brain‐barrier (BBB) breakdown. Growing evidence suggests pericytes, a vessel‐residing cell able to modulate CBF and BBB integrity, are a major contributor to vascular dysfunction in AD. The close spatial relationship between microglia and capillaries led us to explore the hypothesis that microglia and pericytes functionally interact to influence vessel function in the healthy brain and that this interaction may become pathological in AD.

Methods

We first characterized the spatial and functional relationship between microglia, capillaries and pericytes in the healthy central nervous system (CNS) in fixed tissue and using in vivo two‐photon microscopy through cranial windows in adult NG2DsRed x CX3CR1+/GFP mice. We then assessed the spatial relationship between microglia, capillaries and pericytes in the human superior frontal gyrus (SFG) of 12 control and 11 AD cases.

Results

We discovered a subset of microglia dynamically interacting with pericytes in the healthy CNS, which we termed pericyte‐associated microglia (PEM). PEM are present throughout the capillary tree, often maintain their position for at least 28 days and frequently were found to associate with pericytes lacking astroglial endfeet coverage. The loss of PEM alters capillary width beneath pericytes, but deletion of the microglial fractalkine receptor (CX3CR1), which regulates the recruitment of microglia to sites of neuroinflammation, does not reduce the proportion of microglia that are PEM. In AD, we found the proportion of microglia associated with capillaries and pericytes declines in the superior frontal gyrus (SFG) and that this decline is exacerbated by the APOE ε3/ε4 genotype. This reduction occurs despite an overall increase in pericyte numbers in AD cases.

Conclusion

We identify microglia specifically associating with pericytes in the healthy CNS and find these associations are reduced in AD. The changing relationship between microglia, capillaries and pericytes may be a novel mechanism contributing to vascular dysfunction in AD.
Association between childhood experiences and mental health in later‐life: Findings from the National Social life, Health, and Aging Project
Authors: Lim Seungju , Park Sang‐Mi , Han Yebin , Kim Kiwoong , Jee Sujeong , Hong Ickpyo , Park Ji‐Hyuk
Published: December 2023

Background

Middle age is the central period of life, and it is a time when people face various mental health problems. It has been reported that the experience of childhood has a lifelong effect on mental health in middle age. However, research on positive childhood effects is insufficient, compared to negative childhood.

Objectives

To investigate associations between childhood experiences and a latent construct of mental health in midlife adults.

Methods

The participants included 770 adults aged 50‐64 who retrospectively reported childhood events, including family life happiness, parent’s education, family’s financial status, childhood health status, family structure, experience of violence, and witness of violence. Second‐order structural equation modelling was used with mental health modelled as a second‐order latent variable with depression, anxiety, loneliness, and stress as first‐order components.

Results

The study found that family life happiness and healthy childhood were associated with better mental health of midlife, in both the crude (β = −.221, p < 0.001; β = −.201, p < 0.01) and adjusted models (β = −0.128, p < 0.001; β = −0.095, p < 0.05).

Conclusion

This is the first study confirming the associations of family life happiness and childhood health with mental health of midlife using second‐order structural equation modeling. Future work would benefit from a prospective investigation of these associations.

Keywords:

Mental health, Midlife, Childhood, Second‐order structural equation model
Biomarker Profiling for Alzheimer‐like Dementia in Aged Non‐human Primates
Authors: Yu Ying , Wang Mingyue , Tan Maoyun , Jiang Zhichao , Xu Gaorui , Zhou Jiawen , Gan Xue , Peng Yanlai , Zhong Qian , Wen Rongchen , Fan Yuqing , Zhang Guodong , Xu Deming
Published: December 2023

Background

Alzheimer’s disease (AD) places increasingly burdens on global healthcare. Non‐human primates (NHPs) have been used in preclinical pharmacology for AD drug discovery and they were mainly based on induction by amyloid plaque. However, previous strategies focused on clearance and prevention of amyloid plaques and neurofibrillary inclusions have mostly yielded discouraging results in clinical trials for AD. More fitting NHP models reflective of natural ageing of brain with an AD‐related clinical profile would be most desirable for translational pharmacology. To address this, the pilot study herein profiled a group of aged NHPs for biomarkers characteristic of AD‐like dementia, including cognitive behavior, diagnostic neuroimaging, EEG, and amyloid beta 42 (Aβ42) in cerebrospinal fluid (CSF).

Method

Two groups of male Macaca fascicularis (adult: 9‐11 years, n = 4; aged: 20‐25 years, n = 10) were trained to perform a delayed response task (DRT) to assess their short term memory. Meanwhile, their CSF levels of Aβ42 were determined. EEG signals at rest were captured with Neuroscan EEG System and data processed with customized Matlab code. The volume of hippocampus in eight selected animals were analyzed through a 3‐D reconstruction with MRI imaging.

Result

Six (6) out of 10 aged animals showed lower DRT performance (successful rate < 80%) than the remaining 4 and those in the adult group. The overall DRT performance was positively correlated with the CSF levels of Aβ42 in all animals. Moreover, we observed the slowing of EEG activity (increased δ & θ activity and decreased β activity) in the frontal lobe and smaller average volume of hippocampus in the low DRT performers vis‐à‐vis the rest of the animals.

Conclusion

We identified a group of aged NHPs with spontaneous dementia, with cognitive, electrophysiological and brain structural characteristic of mild cognitive impairment in the humans. Their CSF levels of Aβ42 inversely correlated with the memory function. Most notably, EEG and neuroimaging showed promising potential as non‐invasive approaches for the evaluation of aging‐related dementia of NHP in the longitudinal studies. The translational value of such animals could provide important insight to the disease progress and the therapeutic efficacy of AD treatment in the preclinical stages.
A community‐based program for older women living alone: a systematic review
Authors: Kim Inhye , Lee Hamin , Kim Mi Kyeong , Yun Sohyeon , An Hyun Seo , Park Hae Yean
Published: December 2023

Background

Life expectancy has been increasing over the decades, while there is a gap between the genders. Women are more likely to live longer than men, resulting in older women living alone. Older adults living alone could be at risk of physical or mental health and well‐being. Therefore, this systematic review aimed to identify which interventions affected older women living alone and suggest community programs to improve their health and well‐being.

Method

This study was conducted using three databases, including PubMed, Archives of Physical Medicine and Rehabilitation, and Scopus. This review followed Preferred Reporting Items for Systematic Reviews and Meta‐Analysis (PRiSMA) guidelines, and studies were assessed based on inclusion and exclusion criteria. The Standardised Critical Appraisal Tool from Joanna Briggs Institute Meta‐Analysis of Statistics Assessment and Review Instrument (JBI‐MAStARI) was used to appraise the methodological quality of these studies.

Result

Of the 2003 articles, three of them met inclusion and exclusion criteria and were reviewed. The articles are clinical trials, and the interventions were psychosocial support, reminiscence therapy, and a well‐being enhancement program. As a result of the interventions, self‐efficacy, cognitive function, and quality of life were improved, and the level of loneliness was decreased in older women living alone.

Conclusion

The findings indicated that a community intervention such as psychosocial support, reminiscence therapy, and a well‐being enhancement program positively affected self‐efficacy, cognitive function, quality of life, and the level of loneliness for older women living alone. However, further studies are required with sufficient sample sizes and diverse intervention programs.
Admixture mapping of cognitive function in diverse Hispanic and Latino adults
Authors: Fornage Myriam , Sofer Tamar , Satizabal Claudia L. , Seshadri Sudha , Mosley Thomas H. , Decarli Charles , Tarraf Wassim , Thornton Timothy A , González Hector M
Published: December 2023

Background

Genome‐wide association studies (GWAS) conducted primarily in populations of European ancestry have revealed the polygenic nature of cognitive abilities [1, 2] but genetic discoveries in other populations, including Hispanics/Latinos, are lagging. Genetically, US Hispanics/Latinos have uniquely admixed genomes, encompassing African, Amerindian, and European ancestries.[3] Admixture patterns in genomic regions (local ancestry) can be leveraged in gene mapping when frequencies of trait‐associated genetic variants located within these regions differ between ancestries.

Method

We conducted genome‐wide admixture mapping analyses followed by fine mapping to identify genetic variants associated with cognitive function in 7,140 Hispanic and Latino adults (mean age 55 years; 60.5% women) from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). Five measures of cognitive function were investigated: Six‐Item Screener (SIS), Brief Spanish English Verbal Learning Test (SEVLT), Word Fluency Test (WFT), Digit Symbol Substitution Test (DSST), and a measure of general cognitive function (PC1). We tested the identified variants for replication in independent samples with similar neurocognitive measures.

Result

We identified 9 significant local ancestry‐associated regions for the 5 cognitive tests. Counts of African ancestry on at 13q12.11, 4q14, 10p12.2 and 9p22.1 were associated with DSST, PC1, SIS, and WFT, respectively. Counts of Amerindian ancestry at 1q25.2 were associated with DSST; and at 12q14.2 and 12q15 with SIS. Counts of European ancestry at 8p22 were associated with SEVLT; and at 13q12.13 with, both, DSST and PC1. Fine mapping via SNP association testing in each region identified genetic variants that partially or totally explained the admixture signal. While statistical evidence of independent replication of the prioritized variants was generally weak, with only two replicated associations at chr8p22 and chr13q12.13, there was strong biological support for the observed associations to cognitive function. For example, the prioritized variant at 8q22 is an eQTL for CNOT7, which regulates synaptic plasticity and is essential for hippocampal‐dependent learning and memory [4].

Conclusion

Our admixture mapping analyses identified multiple novel loci associated with measures of cognitive function. This demonstrates the effectiveness of admixture mapping in complementing GWAS [5] and provides an opportunity to identify genetic loci that may be particularly relevant in underrepresented populations.
B cell and T cell populations are altered in the brain‐draining lymph nodes of the senescence accelerated mouse prone 8 (SAMP8)
Authors: Sun Jiaqi , Huang Xin , Ma Liwei , Chu Chenyin , Takechi Ryu , Mamo John CL , Trevaskis Natalie , Masters Colin L , Jin Liang , Pan Yijun
Published: December 2023

Background

Recent studies have (re)‐discovered lymphatic vessels in the meninges and other sites that flow from the brain to deep cervical lymph nodes (dcLNs). Like elsewhere in the body, these lymphatic vessels play a critical role in the clearance of fluid and macromolecules from the brain including Aβ (a toxic protein that accumulates in the brain in Alzheimer’s disease) and in trafficking immune cells to the dcLNs, where immune activation occurs. The current study examined whether the immune cell populations are altered in the dcLNs of SAMP8 mice (a mouse model of accelerated aging with spontaneous overproduction of amyloid precursor protein in the brain) compared to the healthy control mice (SAMR1).

Method

In this study, dcLNs were collected from 12‐month‐old SAMP8 and SAMR1 mice (n = 6). Cells were isolated from the dcLNs, and the B cell and T cell populations (CD19 for B cells, PNA for germinal centre B cells, CD93 for early B cells, CD138 for antibody secreting B cells; CD3 for T cells, CD8a for cytotoxic T cells, CD4 for helper T cell) were studied using flow cytometry.

Result

A significant 1.4‐fold increase in CD3+ T cells (p = 0.04) and a trend toward a decrease in CD19+ B cells (p = 0.06) was observed in the SAMP8 dcLNs compared with SAMR1 dcLNs. For B cell sub‐populations, a 77.9 ± 26.9% decrease (p = 0.0078) in geminal center B cells was observed in SAMP8 dcLNs. The T/B cell ratio was significantly increased in SAMP8 dcLNs (2.74 ± 0.14) comparing to SAMR1 dcLNs (2.10 ± 0.16). Such alteration was not observed in mesenteric lymph nodes.

Conclusion

The B cell and T cell populations were altered in the brain‐draining dcLNs of SAMP8 mice, suggesting that the dcLNs responded to pathological changes in the brain. The reduced B cells, especially the germinal centre B cells, indicate a possible impairment in the production of antibody‐secreting B cells in SAMP8 mice. We will confirm these observations in APP/PS1 and 5xFAD mice in future studies, and investigate whether such alteration in B cells contributes to Alzheimer’s disease pathology.
INPP5D modulates TREM2 loss‐of‐function phenotypes in a β‐amyloidosis mouse model
Authors: Tomita Taisuke
Published: December 2023

Background

The genetic associations of TREM2 loss‐of‐function variants with Alzheimer disease (AD) indicate the protective roles of microglia in AD pathogenesis. Functional deficiencies of TREM2 disrupt microglial clustering around amyloid β (Aβ) plaques, impair their transcriptional response to Aβ, and worsen neuritic dystrophy. However, the molecular mechanism underlying these phenotypes remains unclear.

Methods

In this study, we investigated the pathological role of another AD risk gene, INPP5D, encoding a phosphoinositide PI(3,4,5)P3 phosphatase expressed in microglia by crossing Tyrobp knockout, Inpp5d knockout and human mutant APP knockin mice.

Result

In a Tyrobp‐deficient TREM2 loss‐of‐function mouse model, Inpp5d haplodeficiency restored the association of microglia with Aβ plaques, partially restored plaque compaction and astrogliosis, and reduced phosphorylated tau+ dystrophic neurites. RNA‐sequencing of isolated microglia demonstrated that the expression of “disease‐associated microglia” genes is not responsible for these beneficial effects.

Conclusion

Our results suggest that INPP5D acts downstream of TREM2/TYROBP to regulate the microglial barrier against Aβ toxicity, thereby modulates Aβ‐dependent pathological conversion of tau.
INPP5D inhibition attenuates amyloid pathology through the regulation of microglial functions
Authors: Oblak Adrian L
Published: December 2023

Background

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by accumulated beta‐amyloid (Aβ) deposits and robust microgliosis. Recent genome‐wide association studies have identified genetic risk factors in late‐onset AD (LOAD) which are largely microglia. Among the risk factors, Inositol polyphosphate‐5‐phosphatase D (INPP5D) confers an increased risk of developing AD and is associated with increased plaque deposition. As a microglia‐specific lipid phosphatase, INPP5D negatively regulates signaling via several microglial cell surface receptors, including TREM2; however, the impact of INPP5D inhibition on AD pathology remains unclear.

Methods

To determine the impact of Inpp5d on disease pathogenesis and microglial phenotypes, we utilized the 5xFAD model expressing Inpp5d haplodeficiency.

Results

Inpp5d deficiency perturbs microglial intracellular signaling pathways that regulate the immune response, including phagocytosis, microglia‐plaque engagement, and Aβ clearance. Importantly, Inpp5d haploinsufficiency leads to the preservation of cognitive function in 5xFAD mice. Furthermore, a novel spatial transcriptomic analysis revealed genetic profiles altered by Inpp5d haploinsufficiency are related to microglial functions, synaptic regulation, and immune cell activation.

Conclusion

These data demonstrate that Inpp5d deficiency enhances microglial functions by increasing plaque clearance and preserves cognitive abilities in 5xFAD mice. Inhibition of INPP5D may serve as a potential therapeutic strategy targeting microglia for AD.
Voice Analysis of People with Dementia:Toward to AI‐based Emotion Detection for People with Dementia
Authors: Kim Dongseon , Lee Bongwon
Published: December 2023

Background

There is lack of evidence‐based research concerning the emotion expression of people with dementia even though it is important to detect their emotional state because emotion plays an important influence on the quality of life and communication in dementia care. Emotion detection is further important in developing AI conversation intervention programs as emotion detection could be a mediator for better Human‐machine interface.

Method

Researchers interview people with dementia on their emotion‐related topic (good and bad memories, their wishes, and other everyday topics) and record the dialogue. Besides, their caregivers record the dialogue with them when they show psychological and behavioral symptoms. Participants vary in gender, location of living(dialects), seriousness of the disease from mild cognitive impairment (MCI) to severe dementia. Recording is done for months long enough to collect various emotions from a person who has his or her individual voice characteristics. Researchers extract and classify the emotion into 5 categories of anger, sadness, agitation (expressed as BPSD), happiness and neutral based on the content and mood of PWD during the interview. Analysis will be done with Praat program, voice analysis program, on changes of pitch, shimmer, jitter. formant, intensity, HNR(harmony and noise ratio), and other characteristics. Verification of differences by emotions is confirmed by ANOVA, SPSS23.0.

Result

Statistically significant speech parameters for classifying the emotional groups are mainly related to speech characteristics such as jitter, shimmer, basic formant, intensity and HNR. For agitation and anxiety expressed by shouting, swearing, and repetition, voice features have different characteristics of intensity and HNR from ones of other emotions.

Conclusion

This research is useful in establishing labeling systems for future artificial intelligence modeling. At the same time, it has humanistic implications. Emotions expressed by people with dementia are various against the prejudice which their emotions are monotonous. Thus, emotion expression of people with dementia needs further analysis based on the understanding of context‐ and care method‐dependent changes. On the other hand, this data is collected in the natural settings while most data for voice‐emotion study is collected in the experimental setting. Accordingly, both limitations and merits of this unstructured data should be discussed.
Efficacy of Common Ingredients in Over‐the‐Counter Memory Supplements
Authors: Hersant Haley , He Sean , Maliha Peter , Grossberg George T
Published: December 2023

Background

The Global Brain Health Supplement Industry Market size was valued at 7.6 billion U.S. dollars. It is predicted to increase to 15.59 billion U.S. dollars by 2030. Memory and enhancement is a segment of the market that comprised the highest global revenue share in 2021.

Method

An extensive review of current supplements on the market was performed by surveying products for sale at local and national pharmacies and grocery stores. A list of 103 supplements was compiled and the most common ingredients in these supplements were identified. Scientific data relative to these ingredients was searched using PubMed and Cochrane library databases.

Result

There is not currently strong evidence that supports the clinical use of apoaequorin, ashwagandha, carnitine, choline, coenzyme q10, coffee extract, ginger, ginkgo biloba, Huperzine A, lion’s mane, l‐theanine, omega‐3 fatty acids, phosphatidylserine, polyphenol, turmeric, vitamin B9, vitamin B12, vitamin D, or vitamin E supplementation for memory improvement.

Conclusion

Dietary supplements geared toward improving cognition are a billion‐dollar industry that continues to grow despite lacking a solid scientific foundation for their marketing claims. More rigorous studies are needed relative to the long‐term use of these supplements in homogenous populations with standardized measurements of cognition.
Investigating the effect of hearing loss on genetic susceptibility to AD‐related neuropathology and cognitive impairment in a rodent model
Authors: Patel Salonee V , Schormans Ashley L , Myers Sarah J , Malouf Layya Al , Book Shae A , Hayes Sarah H , Allman Brian L , Whitehead Shawn N
Published: December 2023

Background

Dementia affects 55 million people worldwide; a staggering statistic which highlights the need to limit its risk factors (WHO 2022). Importantly, epidemiological studies have reported that hearing loss significantly increases the risk of developing dementia, including Alzheimer’s disease (AD) (Lin et al., 2011; Hung et al., 2015). Furthermore, preclinical studies have identified that noise‐induced hearing loss causes molecular changes in the hippocampus that are consistent with AD‐related neuropathology (Cui et al., 2015; Saljo et al., 2002). However, the effect of noise exposure on AD‐related neuropathology and cognitive impairment in models of genetic susceptibility to AD is not well explored.

Method

To investigate the interplay between noise‐induced hearing loss and genetic susceptibility to AD, we utilized transgenic Fischer 344 (TgAPP) rats that overexpress pathogenic human amyloid precursor protein, but do not spontaneously develop β‐amyloid plaques (Agca et al., 2008). Adult male and female, TgAPP and wildtype, Fischer 344 rats were noise (100 dB SPL; 4 hours/day; 30 days) or sham‐exposed at 12 months of age. Afterward, hippocampal cognitive function was assessed with the Morris water maze task and striatal‐dependent visuomotor associative learning was tested using an operant conditioning‐based task. Lastly, microglial activation and cholinergic function post‐noise/sham exposure were examined using immunohistochemical analysis of Iba1 and choline acetyltransferase (ChAT) expression, respectively.

Results

Consistent with hearing loss often experienced by humans, our protocol resulted in high‐frequency hearing loss in the rats. As expected, TgAPP rats showed impaired reference memory and increased Iba1‐positive cells in the hippocampus; however, in contrast to our prediction, noise exposure did not exacerbate these results. We also identified a differential effect between the sexes and genotypes for how noise exposure affected visuomotor associative learning. While noise‐exposed wildtype male rats exhibited a faster reaction time than their sham‐exposed counterparts, noise‐exposed TgAPP males showed a significantly slower reaction time; an effect not observed in female rats.

Conclusion

These findings point to a complex relationship between noise‐induced hearing loss, visuomotor associative learning, and genetic susceptibility to AD. Thus, future studies should investigate the molecular underpinnings of the differential changes in reaction time following noise exposure in models of genetic susceptibility.
Phenotypic Status Explored in Parietal Cortex of Alzheimer’s Patients and Non‐Demented Controls that Vary on the Spectrum of Neuropathological AD
Authors: Melnik Mikhail , Bilousova Tina , Ma Ricky , Matsuo Yuriko , Atluri Swetha , Kodavatikanti Achyutha , Knitowski Nina , Gylys Karen H
Published: December 2023

Background

Genetic studies of Alzheimer’s disease (AD) have shown association with microglia in the brain. We probed microglia with markers against amyloid‐associated (Clec7a, Axl), inflammatory M1 (CD86), alternatively activated M2 (CD206, CD163), and homeostatic (P2ry12, TMEM119) phenotypes in low plaque/tangle pathology controls (A‐T‐), high plaque/low tangle pathology controls (A+,T‐), high plaque/high tangle pathology controls (HPCs) and late AD samples. We sought to determine how these microglial markers changed with clinical and neuropathological AD. APOE status was also explored as its associated with increased inflammation (suggesting M1 effects) and APOE is highly expressed by amyloid‐associated microglia.

Method

Samples of parietal cortex from AD patients were cryopreserved in 0.32M sucrose + inhibitors and obtained from the UC Irvine ADRC. The tissue was later thawed, homogenized in 0.32M sucrose + inhibitors and then slow frozen to ‐80°C. These samples were then processed and probed against targets of interest by western blotting.

Result

Preliminary data shows a 64.7% decrease in P2ry12 signal in late AD compared to A‐T‐ controls that approaches significance, although TMEM119 shows no changes. A similar pattern is seen in APOE4+(APOE3/4 and 4/4) samples compared to ones that are APOE3/3, with P2ry12 showing a significant decrease while TMEM119 showing no change. CD206 shows a 44.8% decrease in late AD samples relative to A‐T‐ controls, though CD163 shows no difference. CD206 and CD163 do not differ between HPC and late AD samples, nor are they modulated by APOE genotype.

Conclusion

Preliminary data suggests a decrease of homeostatic microglial signature with the presence of neuropathological, not clinical, AD, although one of the markers, TMEM119, showed no change. TMEM119 and P2ry12 are interesting markers of homeostasis that were characterized in mouse models of AD yet may have a more complicated connection to human disease (Zhou et. al., 2020). M2 microglial marker CD206 shows an increase with neuropathological, but not clinical, AD. Again, a complicated picture of M2 markers is seen, with CD206 showing change but not CD163. APOE genotype differences modulated the P2ry12 homeostatic signal, although no M2 changes were seen.
The Relationship Between Inner Retinal Thickness, Cognition, and Frailty in Community‐dwelling Older Adults: findings from a 6‐year follow‐up study
Authors: Lee Yung‐Sung , Hsieh Yi‐Ting , Chiou Jen‐Ming , Chen Jen‐Hau , Chen Yen‐Ching
Published: December 2023

Background

Thinning of the inner retinal thickness, including ganglion cell‐inner plexiform layer (GC‐IPL) and retinal nerve fiber layer (RNFL), has been related to cognitive decline. However, the relationship between GC‐IPL/RNFL thickness, physical frailty, and cognitive frailty remains unclear. Therefore, this longitudinal study aims to investigate the association of these retinal markers with cognition, frailty, and cognitive frailty.

Method

This is a 7‐year cohort study including 221 community‐dwelling elders in the ongoing Taiwan Initiate for Geriatric Epidemiological Research (TIGER) between 2015 and 2017 and received biennial assessments for cognition and physical frailty three consecutive times. The global and domain‐specific (memory, attention, executive function, and language) cognition were assessed using the Taiwanese version of the Montreal Cognitive Assessment and a series of neuropsychological tests. Physical frailty was assessed by modified Fried frailty phenotypes. The generalized linear mixed model was used to analyze the association between GC‐IPL/RNFL thickness and global/domain‐specific cognitive frailty adjusted for age, sex, years of education, apolipoprotein E ε4 status carriers, cigarette smoking status, presence of depressive symptoms, hypertension or diabetes mellitus, years of follow‐up, and practice effect.

Result

The performance of global cognition decreased as the mean GC‐IPL thickness of bilateral eyes deviated from the sample mean (76.6 µm) (quadratic GC‐IPL: β = ‐0.4×10−2; 95% confidence interval: ‐0.7×10−2 to ‐0.2×10−2). Similar associations were also found for logical memory with RNFL/GC‐IPL thickness. No significant association was observed between RNFL/GC‐IPL thickness and physical frailty. An increased odds of impaired logical memory‐physical frailty was found for GC‐IPL (quadratic GC‐IPL: adjusted odds ratio = 1.005; 95% confidence interval: 1.001 to 1.005), but no significant association was found between cognitive frailty and RNFL thickness.

Conclusion

Change in the GC‐IPL thickness was associated with impaired cognition and poor logical memory‐frailty performance. The inner retinal thickness may serve as a biomarker for cognition or cognitive frailty in non‐demented elders.
PSEN2 poison exon inclusion is common across brain regions in late‐onset Alzheimer’s disease
Authors: Course Meredith M , Somberg Jenna , Child Daniel D , Gudsnuk Kathryn , Latimer Caitlin S , Kraemer Brian C , Keene C Dirk , Bird Thomas D. , Jayadev Suman , Liachko Nicole F , Valdmanis Paul N
Published: December 2023

Background

Pathogenic variants in APP, PSEN1 and PSEN2 can cause early‐onset familial Alzheimer’s disease (AD). The molecular events leading to AD in individuals with late‐onset sporadic AD are still unclear even though they share the same clinical and pathological features of AD.

Method

Using targeted PacBio long read isoform sequencing (Iso‐Seq), we recently reported the characterization of tens of thousands of complete PSEN1 and PSEN2 transcripts in the prefrontal cortex of individuals with sporadic AD, familial AD (carrying PSEN1 and PSEN2 pathogenic variants), and controls.

Result

We found several alternative splicing differences in PSEN2 that are significantly elevated in sporadic AD including inclusion of a human‐specific cryptic exon present in intron 9 of PSEN2 (termed exon 9B) present in 11.8% of full‐length reads in sporadic AD samples relative to 1.9% of controls (p = 0.002) and 3.4% of PSEN variant carriers (p = 0.005) as well as a 77bp intron retention product prior to exon 6. These PSEN2 splice products are predicted to generate a prematurely truncated PSEN2 protein and were confirmed in an independent RNA‐seq dataset of ∼80 AD cases and ∼80 controls from cerebellum tissue (Course et al., Brain 2022). To extend these findings we analyzed PSEN2 exon 9B isoform levels in parietal and temporal lobe tissue samples. We found exon 9B was significantly elevated in sporadic AD relative to controls in the parietal lobe (p = 0.02) as well as the temporal lobe (p = <0.001). However, levels of exon 9B were independent of TDP‐43 pathology or MSUT2 protein levels, which is intriguing given their roles as RNA binding proteins implicated in AD. We are working to establish the consequence of exon 9B inclusion in APP processing, Aβ and PSEN2 protein products in addition to possible cell autonomous roles for PSEN2 splice variants in microglia by leveraging single cell sequencing data.

Conclusion

Collectively, our findings expand our understanding of PSEN2 splice variants in the development of late‐onset sporadic AD, which can point to novel therapeutic strategies for AD.
Association of geriatric depressive symptoms and government‐initiated senior employment program: a community based cross‐sectional study in Korea
Authors: Roh Hyun Woong , Park Soyeon , Park Sunghong , Cho Yong Hyuk , Nam You Jin , Hong Sunhwa , Hong Chang Hyung , Son Sang Joon
Published: December 2023

Background

The association between geriatric depressive symptoms and government‐initiated senior employment program (GSEP) according to the income level has not been thoroughly investigated. Identifying it may provide insights into executing senior employment programs and interventions.

Method

Participants were 9287 adults, 65 or older, who participated in Living Profiles of Older People Survey (LPOPS) 2020. Korean version of the 15‐item Geriatric Depression Scale (SGDS‐K) was used to measure the main outcome, which was geriatric depressive symptoms and its three factors. The main exposure was employment status, GSEP, and the income level. A multiple linear regression analysis was performed.

Result

Compared to being unemployed, being employed was associated with lower geriatric depressive symptoms regardless of income. In non‐GSEP jobs, higher income was proportionately associated with lower geriatric depressive symptoms but also higher life dissatisfaction. A group of GSEP jobs whose income level belonged to the first tertile (β of geriatric depressive symptoms = ‐1.027, β of life dissatisfaction = ‐0.510) was associated with lower geriatric depressive symptoms and life dissatisfaction compared to all tertiles of non‐GSEP jobs (β of geriatric depressive symptoms of first, second, and third tertile = ‐0.463, ‐0.542, ‐0.576; β of life dissatisfaction of first, second, and third tertile = ‐0.258, ‐0.176, ‐0.142).

Conclusion

The group of GSEP jobs, whose income level belonged to the first tertile, was associated with lower geriatric depressive symptoms and lower life dissatisfaction compared to all tertiles of non‐GSEP jobs. We expect this result to give insights into implementing government policies and community‐based interventions.
Alzheimer’s Disease Dementia Classification Through Residual Network and QEEG Image representations
Authors: Jeong Taegyun , Park Ukeob , Hong Yuseong , Youn Young Chul , Kang Seung Wan
Published: December 2023

Background

Our everyday actions and decisions involve a complex coordination of various cognitive functions. Severe deterioration of such functions, commonly referred to as dementia, adversely affects quality of our lives. However, through early screening of the disease at its pre‐clinical stage and appropriate treatment, they can be reverted. Current diagnostic criteria for dementia utilize questionnaire‐based cognitive function assessments, such as the mini‐mental state examination. However, it is statistically less robust, where further tests such as positron emission tomography are required for accurate diagnosis. This is laborious, expensive and expose patients to harmful radiation. Therefore, we propose a quantitative electroencephalography (QEEG) based approach that distinguishes Alzheimer’s disease dementia (ADD) from a non‐ADD group that include mild cognitive impairment and subjective cognitive decline data.

Method

19 channel EEG data employed in the present study were clinically acquired from Chung‐Ang university hospital, in eyes‐closed resting state. Artefacts were eliminated through independent component analysis and bad epoch rejection. Through spectral analysis, the powers of a frequency spectrum (1‐45Hz) were computed with 0.25Hz resolution. Henceforth, the Z‐score of each value were calculated through iMediSync’s age‐ and sex‐differentiated normative database and were mapped into a rectangular arrangement in accordance with channel locations on the scalp. The rearranged Z‐score matrices were visualized, clearly exhibiting both spectral and spatial information. Gamma spectrum (30‐45Hz) was excluded due to its vulnerability to contaminations induced by external noises and muscle movements. The final dataset (N = 732; 137 ADD, 595 non‐ADD) was established, where the 75% of non‐ADD were first excluded as test data due to data imbalance. The remaining data were split into 2 to 8 ratio for testing (N = 503; 27 ADD; 476 non‐ADD) and training (N = 229; 110 ADD; 119 non‐ADD).

Result

The final 18‐layer Residual network model showed test accuracy at 88.5% with ADD sensitivity at 88.9% and specificity at 88.4%. Explainable artificial intelligence algorithm was utilized for the inference and verification of classification criteria.

Conclusion

The outstanding classification results of the established model upholds QEEG utility in the distinguishment of dementia from its pre‐clinical stages. Continuous refinement will bolster its potential in the diagnosis several other neurological diseases.
Differences in the proteomic profile of the brain in Alzheimer’s disease in Down syndrome and early‐onset Alzheimer’s disease
Authors: Farrell Clíona , Mumford Paige , Hällqvist Jenny , Heywood Wendy , Fisher Elizabeth , Mills Kevin , Toomey Christina E. , Wiseman Frances K
Published: December 2023

Background

Down syndrome (DS) is caused by trisomy of chromosome 21 (Hsa21) and is a leading genetic cause of Alzheimer’s disease (AD‐DS). People with DS have a third copy of amyloid precursor protein (APP) which causes the increased risk to develop AD neuropathology and dementia, decades earlier than in the general population. However, other genes on Hsa21 have been shown to modify AD‐DS development compared to the development of AD in the general population. Here, we aim to understand how AD‐DS differs to EOAD at end‐stage disease.

Method

Label‐free mass spectrometry was performed using a SYNAPT G2‐Si High‐Definition machine with 2D fractionation on prefrontal cortex tissue (BA10) from individuals with AD‐DS, early‐onset AD (EOAD) (both Braak‐stage VI), and healthy age‐matched controls. Proteins identified were ranked by significance (p < 0.05) and a fold‐change of difference between groups was calculated. qPCR was used to measure transcript levels of altered proteins in the same samples and to assess if transcript levels of raised proteins were altered in the Dp1Tyb (MGI:5703798) mouse model of DS which has three‐copies of ∼148 Hsa21 orthologous genes.

Result

Raised abundance of Hsa21 encoded proteins, including PDXK, APP and S100B, were identified in individuals with AD‐DS compared to EOAD. Importantly, non‐chromosome 21 encoded proteins were also shown to be raised in individuals with AD‐DS compared to EOAD, including APOE, NLRP8 and PTN. Raised APOE protein in AD‐DS compared to EOAD brain tissue is Apolipoprotein E genotype independent. Apoe is not raised in the Dp1Tyb hippocampus or cortex at 6‐months of age.

Conclusion

People with AD‐DS exhibit an altered proteomic profile compared to people with EOAD, likely driven by having three‐copies of Hsa21 genes. Raised APOE may be driven by an interaction of trisomy 21 and AD pathogenesis, as this phenotype is not seen in the Dp1Tyb mouse model. Understanding the differences in AD pathogenesis is key for including people with DS in future AD clinical trials. Future work will validate protein expression of candidates of interest in an independent cohort of human post‐mortem brain samples, as well as determine the cell types in which proteins of interest are expressed.