bluuebunny/crossref_metadata_2025 huggingface dataset:
The Pattern of Hippocampus and Entorhinal Cortex Subregion Atrophy in Early Alzheimer’s Disease
Authors: Laczó Jan , Lerch Ondrej , Martinkovic Lukas , Laczó Martina , Vyhnalek Martin , Hort Jakub
Published: December 2023

Background

Atrophy of the hippocampus and entorhinal cortex (EC) develops early in Alzheimer’s disease (AD). The nature of atrophy along the anterior‐posterior longitudinal axis of the hippocampus and EC in individuals with amnestic mild cognitive impairment (aMCI) with positive AD biomarkers (AD aMCI) has been less researched. We aimed to reveal a possible different pattern of atrophy in longitudinal axis of the hippocampus and EC between AD aMCI individuals and those with AD biomarker negative aMCI (non‐AD aMCI).

Method

In total, 100 older adults with AD aMCI (n = 26), non‐AD aMCI (n = 23), mild AD dementia (n = 22) and cognitively normal (CN; n = 29) from the Czech Brain Aging Study (CBAS) underwent clinical and cognitive testing, and brain MRI with the 3‐dimensional T1‐weighted high‐resolution magnetization‐prepared rapid gradient echo sequences. An automated processing pipeline using the Advanced Normalization Tools based on the CBAS population template and a manual segmentation protocol were used to measure left and right subregional hippocampus and EC volumes including hippocampus head (HH), body (HB) and tail (HT), and anterolateral (alEC) and posteromedial (pmEC) entorhinal cortex volumes, respectively. Volumes were normalized to estimated total intracranial volume.

Result

Compared to the CN group, the AD aMCI group had lower subregional hippocampus and EC volumes (p<0.05) except for right and left HH volumes. Compared to the non‐AD aMCI group, the AD aMCI group had lower right HB (p<0.05), right and left HT (p<0.01), right alEC (p<0.05), and right (p<0.01) and left (p<0.05) pmEC volumes. The mild AD dementia group had lower all subregional hippocampus and EC volumes compared to the CN group (p<0.05).

Conclusion

These results are in line with previous research that demonstrated atrophy of the hippocampus and EC in early AD and indicate that atrophy of the posterior hippocampus and EC subregions may reflect AD pathology in aMCI individuals. Volumetric differences along the anterior‐posterior axis of the hippocampus and EC could serve as a potential biomarker to identify the underlying pathology in different neurodegenerative diseases.
Investigating epigenetic regulation of microglia in a human‐mouse chimera model of Alzheimer’s disease
Authors: Marzi Sarah
Published: December 2023

Background

Microglia, the resident macrophages of the brain, are implicated in Alzheimer’s disease (AD). The genetic risk for AD is significantly enriched near microglial genes and enhancers. In the human brain, APOE is the strongest genetic risk factor for late onset AD and is primarily expressed in microglia and astrocytes. The “disease associated microglia” (DAM) state, in which inflammatory pathways are upregulated in amyloid plaque‐associated microglia, is a characteristic pathological response in AD.

Method

Here, we studied how amyloid pathology interacts with genetic risk for AD to regulate the DAM state.We profiled gene regulation in human iPS‐derived microglia. We xenotransplanted the microglia into the APPNL‐G‐F mouse model of AD using isogenic APOE2/3/4 and APOE knockout (KO) microglia (n = 5 animals per microglial APOE genotype). We characterized dissociated iPS‐derived microglia from each animal by RNA‐seq, CUT&Tag for H3K27ac, and ATAC‐seq. We performed quantitative analyses of the epigenetic landscapes of microglial populations across heterogeneous activation states. This allowed us to infer the regulatory pathways that are responsible for the differential microglia response to amyloid aggregation, depending on APOE.

Result

We observed widespread differences in gene regulation across microglia related to APOE genotype. While we observed upregulation of chemokine and interferon response signalling in AD‐risk variant e4, we observed corresponding downregulation in the AD‐protective variant e2. Additional analyses identified increased chromatin accessibility at vitamin D receptor binding motifs in e2 through motif analysis. Finally, we identified gene expression networks and modules underlying differential microglial activation states.

Conclusion

Our findings are important for understanding microglia and their activation in AD and neurodegenerative diseases. Here, we profiled comprehensive epigenetic landscapes in a human‐mouse chimera in the context of APOE genotype. This enabled us to leverage the realistic biological environment for the microglia offered by this model, and dissect genetic effects underlying microglial responses for the first time.
"Caregiving made me grateful:” The unexpected blessings of dementia caregiving for Alaska Natives when given a second chance to care for a family member
Authors: Kim Steffi M , Asquith‐Heinz Zayla , Lewis Jordan P.
Published: December 2023

Background

There is a cultural value among Alaska Natives to care for their Elders and this commitment applies to all Elders, regardless of health status or cognitive health. Caregiver duties can lead to stress, isolation, and depression that negatively impact their overall health and wellbeing. Despite the challenges, these caregivers emphasized the unexpected blessings, which served as coping mechanisms and providing meaning and purpose to their caregiver role.

Method

Interviews were conducted with 22 Alaska Native caregivers for Alaska Natives with Alzheimer’s Disease and Related Disorders (ADRD) in rural and urban communities across Alaska. Interviews lasted approximately 60 min and were transcribed verbatim. We employed directed content analysis to examine the caregivers’ experiences of ADRD and the unexpected blessings associated with being a caregiver.

Result

Alaska Native caregivers shared the challenges associated with caregiving duties, and the lack of education, awareness, and available resources exacerbated their stress and challenges. As their family member experienced changes related to the ADRD, the blessings took different forms and served different purposes. Spending more time with their family member, remembering family history, engaging in generative behaviors, and strengthening intergenerational relationships were the most frequently discussed blessings. Focusing on these blessings enabled caregivers to continue to find meaning in this role and carry on their cultural values and traditions.

Conclusion

This study shifts the focus of caregiving research to highlight the unexpected blessings. The focus on strengths of caregiving and sharing these stories has the potential to provide current and future caregivers to step into this role with a different perspective, or at least not just hear of the challenges and barriers associated with ADRD caregiving.
Individualised prognostic models using plasma biomarkers for clinical progression to Alzheimer’s disease dementia in non‐demented elderly
Authors: Honey Madison I. J. , van Maurik Ingrid S. , van Harten Argonde C. , Gouda Mariam , Kroeze Lior A. , van Leeuwenstijn Mardou S. S. A. , Mank Arenda , Trieu Calvin , Pijnenburg Yolande A.L. , van der Flier Wiesje M. , Wilson David , Teunissen Charlotte E. , Verberk Inge M.W.
Published: December 2023

Background

Blood‐based biomarkers can provide a low‐invasive and accessible way to identify neurodegenerative diseases before the clinical onset of dementia. We aimed to construct prognostic models for personalized risk of developing Alzheimer’s disease (AD) dementia in a memory clinic population of individuals with either subjective cognitive decline (SCD) or mild cognitive impairment (MCI), using plasma phosphorylated‐tau‐181 (pTau181), amyloid beta1‐42/1‐40 (Aβ42/40), glial fibrillary acidic protein (GFAP) and/or neurofilament light (NfL).

Method

From the Amsterdam Dementia Cohort and SCIENCe project we included 303 individuals with SCD (age 61±9 years, n = 126(42%) female, MMSE 28±1) and 250 with MCI (age 65±7 years, n = 89(36%) female, MMSE 27±2), who had annual follow‐up visits for re‐evaluation of diagnosis (average follow‐up duration: 2.7±1.7 years.) Our outcome measure was progression to AD dementia. Plasma biomarkers were measured at baseline using SiMoa. Concentrations were then Z‐transformed for the statistical analysis and split into tertiles for risk chart visualisation. We evaluated adding the biomarkers individually, or as a panel, to a basic prognostic model including age, sex and baseline diagnosis. We selected a final model by its discrimination (Harrell’s C‐index, a value above 0.7 indicates a good model) and accuracy (Brier score, a value below 0.2 indicates a good model) and used it to calculate 5‐year risk scores for progression to AD dementia.

Result

During follow‐up, 86 individuals developed AD dementia (8 with SCD, 78 with MCI at baseline, average time to progression: 2.8±1.7 years). Adding any of the biomarkers to the basic model improved the model discrimination (Table 1). The prognostic model with all four plasma biomarkers had the best discrimination and accuracy, followed by the model with GFAP only, and the model with pTau181 only (Table 1). Using the model with all four biomarkers, 5‐year individual progression risks to AD dementia varied from 1.9% (lowest tertiles for GFAP, pTau181 and NfL, highest tertile for Aβ42/40 ratio) to 40.6% (highest tertiles for GFAP, pTau181 and NfL, lowest tertile for Aβ42/40 ratio) (Figure 1).

Conclusion

Plasma biomarkers, particularly plasma GFAP, can be utilized to provide prognostic risk information about progression to AD dementia for individuals presenting at a memory clinic.
Development of Behavioural and Psychological Symptoms of Dementia(BPSD) App for use in a hospital setting
Authors: Soong Mei Min , Barrett Tomiko
Published: December 2023

Introduction

Previous quantitative audits at Wyong Hospital, a 300 bed regional and teaching hospital in the Central Coast Local Health District (CCLHD) showed that the majority of Clinical Aggression Response Team (CART) calls occurred in the geriatric population.

Results suggested that often BPSD guidelines which were on the CCLHD intranet were not adhered to. It was suggested that medical officers need ready access to local guidelines and more education. Interviews with staff who were participating in CART calls found that medical staff were not confident in when to and what to prescribe and what was the most appropriate management.

These audits, which involved interviewing participants of CART calls, plus evidence about implementing practice change, suggests that mobile phone apps are used more frequently and are more effective than intranet documents.

Objective

Develop a BPSD app with the potential to make evidence based recommendations and local guidelines accessible to the user at the bedside using a mobile device particularly during CART calls and enables the user to manage BPSD with ease.

Methods

1. Content of the app is based on BPSD guidelines published on the CCLHD intranet geriatric medicine webpages.

2. A prototype of the app was developed on Marvel designs and provided to the IT and e‐health New South Wales department who provided suggestions, guidance on the app development and integration of the app onto the hospital IT system. Training sessions were provided via drop in sessions and online videos using Microsoft teams. Targeted education sessions on app usage was provided to medical personnel. Costs for the development of the app was funded by the Department of Geriatric medicine, Wyong and Gosford Hospital.

3. Ethics approval was obtained from the Central Coast Local Health District Human Research Ethics Committee.

Results

There has been more than 100 downloads of the app with levels of usage ranging from 1 to 38 on a daily basis.

Conclusion

The development of the app allows ease of access to concise evidenced based information and supports clinicians in their role in managing BPSD.
Angiotensin Receptor Blockers as an Alternative Strategy for Addressing Neurodegeneration in a LPS Mice Model
Authors: Gouveia Filipa , Fonseca Carla , Silva Ana , Camins Antonio , Cruz M. Teresa , Arriola Miren Ettcheto , Fortuna Ana
Published: December 2023

Background

To identify new therapeutic strategies that impair the development of Alzheimer’s disease (AD), angiotensin receptor blockers (ARB) were investigated as promising candidates to reduce the risk of developing AD in hypertensive patients. However, the mechanism by which they are able to induce this effect remains unclear. On the other hand, it has been described that neuroinflammation plays an important role in neurodegenerative diseases, including AD, being key in the cognitive decline process. Therefore, the aim of this study is to evaluate the neuroprotective effect of ARB in in vivo and in vitro models of neuroinflammation induced by Lipopolysaccharide (LPS) and to disclose their mechanism of action.

Method

BV‐2 microglia cell line was exposed to LPS and treated with the ARB. Meanwhile, 7–8‐week‐old C57/BL6 male exposed to LPS were used as a neuroinflammation model. Animals were treated with saline or intranasal ARB (40 mg/kg/day) for 10 days and LPS (1 mg/kg) was injected in last day, 24h before sacrifice. Before euthanizing, long‐term memory was evaluated by Novel Object Recognition test (NORT). Afterwards, analysis of the dendritic spines, neuroinflammation and molecules related to neurodegeneration and cognitive decline was performed.

Result

Our results show a beneficial effect of ARB in neuroinflammation by reverting the memory loss observed in mice that received a LPS injection. This beneficial effect is also correlated to an amelioration of the synapsis dysfunction by the activation of pathways involved in neuroprotection, namely the PI3K/AKT pathway and by differences in spine density. Moreover, molecular studies show that previous treatment with ARB is able to stimulate the anti‐oxidant defense system by increasing SOD2 and Gpx‐1. Also, LPS increased neuroinflammatory markers that were significantly reduced in the ARB group as well as apoptotic factors that were decreased with the treatment. Therefore, contributing to the maintenance of cognitive function avoiding the development of neurodegenerative processes.

Conclusion

In conclusion, results demonstrate that intranasal administration of ARB prevents LPS‐induced cognitive decline, through the reduction of neuroinflammation and the activation of neuroprotective pathways, highlighting the potential of ARB in the prevention of AD and other neurodegenerative diseases.
Association between neutrophil to lymphocyte ratio and Alzheimer’s Disease in large biobank cohorts
Authors: Drzymalla Emily , Avery Christy , Raffield Laura
Published: December 2023

Background

Neutrophil to lymphocyte ratio (NLR) is used as a marker for systematic inflammation and innate immune system activation; NLR has been associated with Alzheimer’s disease (AD) in previous literature, but mostly in relatively small case control studies. The goal of this study is to investigate the association between AD and NLR in two large biobanks, the UK Biobank and the United States based All of Us.

Method

AD was defined using inpatient ICD10/9 codes and death certificates (UK Biobank) or inpatient ICD10/9 codes and Systematized Nomenclature of Medicine (All of Us). Cox proportional hazards models were used to estimate hazard ratios (HR) adjusting for age, sex, race, and recruitment center (UK Biobank). Because the UK Biobank had extensive covariate data available, we also estimated HRs further adjusting for hypertension, hypercholesterolemia, education, body mass index, and smoking.

Result

With complete covariate data, 233,173 UK Biobank (mean age = 58; 56% female; 2,049 incident AD cases) and 68,382 All of Us (mean age = 59; 65% female; 239 incident AD cases) participants were included. In the UK Biobank, every 1 standard deviation (SD) increase in NLR was associated with a 3% increase in AD risk (HR = 1.03, 95% CI = 1.01‐1.05, p‐value = 0.001) and this relationship was robust to lifestyle and clinical factor adjustment. NLR per 1 SD increase was not associated with AD (HR = 1.03, 95% CI = 0.81‐1.17, p‐value = 0.755) in All of Us.

Conclusion

NLR was associated with AD in UK Biobank but not in All of Us, however, we note that power is lower in All of Us due to fewer AD cases. We plan to repeat this analysis as more cases accrue in All of Us and explore the neutrophil‐associated Duffy null variant for potential modification of this AD/NLR association. These findings provide further evidence for the association between NLR and AD as well as the possible role of systemic inflammation in AD pathology.
External causes of death from death certificates in patients with dementia
Authors: Mo Minjia , Xu Hong , Hoang Minh Tuan , Jurado Pol Grau , Mostafaei Shayan , Kåreholt Ingemar , Johnell Kristina , Eriksdotter Maria , Garcia‐Ptacek Sara
Published: December 2023

Background

The external causes of death, including unintentional injuries, falls, suicide, and complications of medical and surgical care, in dementia are not well‐established, particularly in rare dementias. We compared risk of death from specific external causes in patients with dementia and control participants.

Method

This was a nationwide population‐based cohort study in Sweden integrating 6 national registers from May 1, 2007, through December 31, 2018. We included all dementia patients aged 40 years or older identified from the Swedish Dementia Register‐SveDem and the national patient registry during the period and up to four control participants who were matched on the year of birth (± 3 years), sex and region of residence. Causes of death were obtained from death certificates compiled in the death registry. Hazard ratios (HRs) and 95% confidence intervals (CIs) of dementia on external cause‐specific mortality were calculated using Cox proportional models, adjusted for sociodemographic variables, comorbidity, and psychiatric disorders.

Result

The study cohort included 241 569 patients with dementia (99 380 men [41.1%]; mean [SD] age, 81.5 [8.5] years) and 794 562 control participants (352 295 men [44.3%]; mean [SD] age, 79.9 [8.6] years), over 3 871 433 person‐years. People with dementia presented higher incident rates for unintentional injuries and falls during old age, and suicide in middle aged dementia patients, while the reverse trend for suicide in dementia was observed after 75 years. The association varied according to time since diagnosis. Compared with control participants, people diagnosed with dementia had an adjusted HR of 2.66 (95% CI, 2.58‐2.74) for unintentional injuries, 2.10 (95% CI, 2.01‐2.20) for falls, 0.48 (95%CI, 0.40‐0.58) for suicide, 0.94 (95%CI, 0.89‐1.00) for complications of medical and surgical care, and 2.61 (95%CI, 2.04‐3.34) for other external causes. Compared with control participants, patients with frontotemporal dementia had the highest risk of unintentional injuries and falls, while participants with mixed dementia were less likely to die from suicide and complications of medical and surgical care.

Conclusion

Suicide risk screening in early‐onset dementia and early interventions for unintentional injuries and falls prevention in older patients with dementia should be provided.
CSF ADAM10 levels in AD patients in relationship to ADAM10 gene variants
Authors: Agüero Pablo , Cremades‐Jimeno Lucía , García‐Ayllón María‐Salud , Gea‐González Adriana , Sainz María José , Téllez Raquel , Cárdaba Blanca , Sáez‐Valero Javier , Pérez‐Pérez Julián , Gómez‐Tortosa Estrella
Published: December 2023

Background

The disintegrin metalloproteinase 10 (ADAM10) is the main α‐secretase acting in the non‐amyloidogenic processing of APP. Some ADAM10 gene variants (Q170H, R181G) have been associated with higher susceptibility to develop late‐onset AD and have been shown to promote AD‐type changes in mice models. We tested the hypothesis that some ADAM10 rare variants could increase the risk for AD through conferring an earlier age‐related downregulation of a‐secretase activity.

Method

ADAM10 gene was sequenced in 103 AD cases (78% with family history) with positive CSF biomarkers, and 96 cognitively preserved nonagenarians. ADAM10 in CSF of the AD cases was analyzed by means of ELISA (total levels) and western blot (segregated by isoforms of 50 kDa, 55 kDa, and 80 kDa) in comparison with controls and non‐AD dementia cases. We examined whether there was an increase of rare gene variants (MAF < 0.01) in the AD group and their potential association with lowers CSF protein levels.

Result

Rare variants were found in 15,5% of AD cases (in 23% of early‐onset versus 7,8% in late‐onset, p = 0.058) and in 12,5% of nonagenarians, and several of them were exclusive of the group. However, all were intronic variants except the Q170H change found in three AD cases and one nonagenarian. The SNP rs74016945 (3’UTR), with MAF close to 0.01, was found in 6% of the nonagenarians (OR 0.146, Fisher exact test p = 0.057). ELISA ADAM10 levels were not significantly different comparing AD cases with controls, carriers of rare variants versus non‐carriers, and did not differ consistently according to age at onset or APOE genotype. The three ADAM10 species were also similar in AD cases and controls, and did not differ according to genetic variants or age at onset.

Conclusion

Rare ADAM10 exonic variants are uncommon in AD cases and the presence of rare intronic variants (more frequent in early versus late‐onset cases) is not associated with decreased ADAM10 levels in CSF.
Assessment of cognition in Chinese older population from a digital game‐based mobile applet: an observational study
Authors: Huang Lin , Li Yatian , Wu Jingnan , Xia Huanhuan , Li Kun , Wang Ziming , Guo Qihao
Published: December 2023

Background

A rapid and reliable digital instrument is needed to improve the efficiency of dementia screening. We developed a digital game‐based mobile applet, Game‐based Cognitive Assessment – 3‐minute Version (G3), and aimed to summarize the demographic characteristics and cognitive performance of the online users in a large‐scale Chinese population.

Method

The G3 instrument is self‐administered, and includes cognitive tasks designed as interesting games to automatically assess individuals’ performance on six cognitive domains, i.e., calculation, executive function, visual perception, abstraction, memory and attention. We used an observational design to review all participants who registered for G3 assessment between Feb 28, 2020, and Oct 31, 2022. We restricted our analysis to a population of middle aged and older adults aged 45 to 89, as the focus of our study population. We descriptively analyzed the demographics, global cognitive scores, and the six domain scores of G3 users stratified by sex, education and geographic location.

Result

A total of 12,113,327 individuals were enrolled in this study, of which 1,273,521 were 45∼89 years old. Among the population aged 45∼89, the mean G3 total score was 61.7±13.1 for women (n = 575490) and 60.1±13.2 for men (n = 698031). There was a tendency for the G3 scores in all cognitive domains to decrease with age and women were observed to achieve significantly higher scores than men in almost all age groups. When classified by education level, the G3 scores tended to decline with age in all groups, whereas those with relative low education level (below primary school) and advanced age (80‐89 years old) were heterogeneous. When classified by geographic locations, significant increases in G3 scores were observed among those aged 65‐69 years old in central China.

Conclusion

Our findings characterized the demographic characteristics and cognitive performance of Chinese older population via G3 instrument in a large sample and support the application of G3 for cognitive screening in a community‐based population with different ages and education levels in all regions of China. However, interpretation should be cautious in a population with low education and advanced age.
Association of kidney function with dementia and structural brain differences: a large population‐based cohort study
Authors: Wang Shuqi , Wang Jiao , Dove Abigail , Guo Jie , Miao Yuyang , Qi Xiuying , Xu Weili
Published: December 2023

Background

The association between kidney function (KF) and dementia risk and the mechanisms underlying this relationship remain unclear. We aimed to examine the association of impaired KF with dementia and structural brain differences on magnetic resonance imaging (MRI).

Method

Within the UK biobank, 191,970 dementia‐free participants aged ≥60 (mean age: 64.1 ± 2.9 years) were followed for 16 years to detect incident dementia. Serum creatinine and cystatin C were measured at baseline to calculate estimated glomerular filtration rate (eGFR, mL/min/1.73 m2) using the Chronic Kidney Disease Epidemiology Collaboration equation. KF was categorized as normal (eGFR ≥ 90), mildly impaired (60 £ eGFR < 90), or moderately to severely impaired (eGFR < 60). Dementia was assessed based on self‐reported medical history and medical records. During the follow‐up, a subsample of 12,637 participants underwent brain MRI scans. Volumes of total brain, gray matter, white matter, hippocampus, and white matter hyperintensities were assessed. Data were analyzed using Cox regression, Laplace regression, and linear regression.

Result

Of all participants, 122,463 (63.8%) had mildly impaired KF and 8,670 (4.5%) had moderate to severely impaired KF at baseline. Over the follow‐up (median [interquartile range]: 12.8 [11.9‐13.5] years), 5,327 (2.8%) participants developed dementia. In multi‐adjusted Cox regression, eGFR was dose‐dependently associated with dementia (per 1‐standard‐deviation decrease in eGFR; hazard ratio [HR] 95% confidence interval [CI]: 1.10 [1.07‐1.14]). Compared to normal KF, there was an increased risk of dementia with moderate to severely impaired KF (HR 1.53, 95% CI 1.32‐1.76) but not mildly impaired KF. In Laplace regression, dementia onset among people with moderate to severely impaired KF occurred 1.53 (95% CI: 0.98–2.08) years earlier than those with normal KF. Moderate to severely impaired KF was related to significantly lower gray matter volume (β = ‐0.11, 95% CI: ‐0.19– ‐0.03), but not to other brain MRI measures.

Conclusion

Impaired KF is associated with about 50% increased risk of dementia and anticipates dementia onset by more than 1.5 years. Brain neurodegeneration may underlie the KF‐dementia association.
Clinical effects of Lewy body pathology in clinically unimpaired and cognitively impaired individuals – A prospective longitudinal study
Authors: Hansson Oskar , Palmqvist Sebastian , Parchi Piero
Published: December 2023

Background

Aggregates of misfolded α‐synuclein are the underlying pathology of Lewy body (LB) disease. Little is known about the early effects of LB pathology in preclinical (i.e., pre‐symptomatic) individuals. Further, there is poor knowledge about the independent clinical effects of Lewy body (LB) pathology in patients with cognitive decline, especially when coexisting with Alzheimer’s disease (AD) pathology.

Method

Here, we examined the effects of LB pathology using a cerebrospinal fluid α‐synuclein seeding aggregation assay in 1,182 cognitively and neurologically unimpaired participants as well as 882 participants with mild cognitive impairment or dementia from the BioFINDER‐1 and BioFINDER‐2 studies.

Result

In clinically unimpaired individuals, we found that 8% were LB‐positive, 26% Aβ‐positive (12% of those were also LB‐positive), and 16% tau‐positive. LB pathology had independent and significant negative effects on cross‐sectional and longitudinal global cognition and memory. These were similar in magnitude to the effects of tau pathology and more pronounced than those of Aβ pathology. Participants with both LB and AD (Aβ and tau) pathology exhibited faster cognitive decline than those with just LB or AD pathology. LB, but not AD, pathology was associated with reduced sense of smell.

In cognitively impaired individuals, we found that 23% of participants had LB pathology, of whom only 32% fulfilled clinical criteria of Parkinson’s disease or dementia with Lewy bodies, and 54% exhibited AD pathology (amyloid‐β+ and tau+). Within the LB‐positive group, 48% also had AD‐pathology. In the AD‐positive group, 17% of patients with mild cognitive impairment and 24% of those with dementia were also LB‐positive. LB pathology was associated with worse attention/executive, visuospatial, and motor function independently of AD pathology. Moreover, LB pathology was also independently associated with a faster longitudinal decline in all examined cognitive functions.

Conclusion

This study highlights the cognitive effects of LB pathology, independent from AD pathology, in clinically unimpaired individuals, which will be important to consider for prognosis and design of both preclinical AD and LB disease trials.

Further, analyzing LB status, in addition to amyloid‐β and tau, in cognitively impaired individuals provides a better precision medicine approach identifying patient subgroups with different clinical trajectories.
A systematic review of measures of social connection for people living in long‐term care homes
Authors: Dewan Neha , Chapman Hannah , Sommerlad Andrew , Liougas Madalena , Livingston Gill , McGilton Katherine S , Bethell Jennifer
Published: December 2023

Background

Social connection is important for quality of life and care in long‐term care (LTC) homes. However, measuring social connection in LTC residents is challenging due to the high prevalence of dementia and the distinct care environment and activities, so research is limited by a lack of consensus on best approaches to measurement. The objective of our study is to systematically review measures of social connection developed for LTC residents, including those with dementia, by evaluating their measurement properties including structural validity, internal consistency, reliability and construct validity.

Method

We are following COnsensus‐based Standards for the selection of health Measurement INstruments (COSMIN) systematic review methods. We searched multiple bibliographic databases to November 2021 for studies conducted in LTC residents, which quantified any aspect(s) of social connection, and reported at least one psychometric property for the measure(s) of social connection. We conducted a second targeted search in April 2022 using our list of identified measures, supplemented with a list of measures used in previous research in this population. We are using COSMIN guidelines to evaluate the measurement properties reported for each identified measure.

Result

We identified 68 studies reporting on 35 measures that assess social connection in LTC homes. Twenty‐five were measures of quality of life, wellbeing or life satisfaction and included a social connection subdomain. Only 10 measures specifically targeted social connection. From our pooled evaluation of 20 measures to date, we found that 20% (n = 4) have sufficient structural validity, 15% (n = 3) have sufficient internal consistency, 25% (n = 5) have sufficient reliability, and 15% (n = 3) have sufficient construct validity.

Conclusion

Many measures have assessed social connection in LTC settings for people living with dementia, but few are designed for this purpose and they often have insufficient psychometric properties. This review will provide detailed evidence of the quality of these measures to enable researchers to prioritize valid and reliable tools. Our results will inform our development of a new person‐centred social connection measurement tool for LTC residents in the Alzheimer’s Association/Brain Canada‐funded Social Connection in Long‐Term Care Home Residents (SONNET) study.
The visibility of retinal amyloid deposits as a biomarker of Alzheimer’s disease when imaged in polarized light through the cornea
Authors: Campbell Melanie CW , Potsiluienko Yurii , Mason Erik L , Redekop Rachel , Kitor Monika , Emptage Laura , Hirsch‐Reinshagen Veronica , Hsiung Ging‐Yuek Robin , MacKenzie Ian R
Published: December 2023

Background

We previously reported a novel, dye‐free method to image amyloid deposits in the retina. Using polarized light interactions to create deposit contrast, the number of deposits in ex vivo retinas predicted the severity of brain amyloid found in association with Alzheimer’s disease (AD). Here we describe the effect of the potential range of corneal interactions with polarized light on the visibility of these retinal deposits when imaged in vivo.

Method

52 retinal amyloid deposits, positive for thioflavin (Fig 1) and with a range of visibility in polarized light were imaged ex vivo in retinas of 12 participants with a moderate (2) or high (10) likelihood of Alzheimer’s disease, based on brain pathology. New images of each deposit were created by combining the polarized light interactions of the deposit and surrounding retina with the known range of interactions of human corneas with polarized light. The varying contrasts of each deposit with 45 different sets of corneal properties (a total of 2340 deposit images) were compared to the initial ex vivo images.

Result

As a function of the modelled corneal properties, the root mean square (RMS) contrast of each deposit both increased and decreased from that without a cornea (Fig 2). On average, RMS contrast across deposits combined with a cornea decreased 12% from that without a cornea. For 3% of deposit images, there was a corneal property that reduced the deposit contrast by over 50% (Fig 2). However, even in these cases, because of the variation in interaction with polarized light across the deposit (Fig 3), the deposit remained visible against the background retina.

Conclusion

Although the cornea interaction with polarized light will affect images of amyloid deposits in the retina taken with our non‐invasive method, all cases investigated are predicted to remain visible against the background retina. In addition, during in vivo imaging, an established method of compensating for an individual’s corneal interaction with polarized light, would guarantee 100% visibility. Thus, in vivo, our retinal imaging method is predicted to give a biomarker of the severity of amyloid in the brain found in association with Alzheimer’s disease.
Distribution of APP in endo‐lysosomal system induced by Aβ is modulated by Gβγ signaling
Authors: Antonino Magdalena , Marmo Paula , Almirón Romina , Lorenzo Alfredo , Bignante Elena Anahi
Published: December 2023

Background

Alzheimer´s disease is characterized by the deposition of aggregated species of amyloid beta (Aβ) in the brain, which leads to progressive cognitive deficits and dementia. We recently found that Aβ assemblies, oligomers and fibrils, increase APP and BACE1 interaction in recycling endosomes and accumulation of intracellular Aβ42 in human neurons derived from iPSCs by a mechanism dependent of APP/Go/Gβγ signaling (Antonino et al 2022, https://doi.org/10.3389/fcell.2022.852738). Now, we are interested on deepen in the APP trafficking in the endo‐lysosomal pathway in order to understand the mechanism underlying such effect.

Method

N2a and human neurons derived from iPSc cultures were transfected with fluorescently tagged proteins (APP‐YFP, BACE‐CH, Rab11‐RFP, LAMP1‐CH, Rab7‐CH, APP‐VN, BACE‐VC). Cultures were treated with vehicle or the Gβγ inhibitor gallein and 30 minutes later with vehicle or 1 µM of Aβ oligomeric or fibrillar. After 24 h of treatment quantitative colocalization analysis and bimolecular fluorescence complementation assays were performed.

Result

We found that Aβ induced an enrichment of APP in recycling endosomes at the expense of a decrement of its levels in lysosomes. This change in APP intracellular distribution is drive by Gβγ signaling. Moreover, we found that the changes on APP distribution correlate with an increase in its interaction with BACE1 and with an increase in the number of recycling endosomes, both events modulated by Gβγ signaling (Figure 1,2).

Conclusion

Together, these results suggest that Aβ pathological assemblies induce a re‐direction of APP from its physiological route to lysosomes, to recycling endosomes which favors its encounter with BACE1 and its amyloidogenic processing. These finding elucidate the intracellular process which sustain the feed‐forward mechanisms implicated in the amyloidogenesis induced by pathological assemblies of Aβ.
Relationship between Physical Activity, Handgrip Strength, Depressive Symptoms, and Cognitive Impairment in Korean older adults
Authors: Jin Youngyun , Kim Donghyun , Kim Sehwan , Kim Mingeun , Kim Taewan
Published: December 2023

Background

Physical activity, muscle strength, depressive symptoms, and cognitive function are intertwined in later life. This study aimed to investigate the association physical activity (PA), relative handgrip strength (RHGS), depressive symptoms, and cognitive impairment in Korean older adults.

Method

This study consisting of 512 community‐dwelling Korean older adults (417 female, 95 male) aged 65 years and older (74.8±5.4 years) in S‐city, Gyeonggi‐do. PA and handgrip strength were assessed with the Global Physical Activity Questionnaire and using a dynamometer (GRIP‐D; Takei Ltd, Niigata, Japan). Depressive symptoms were evaluated using the Korean form of the Center for Epidemiologic Studies Depression (CES‐D) Scale. Cognitive impairment was assessed with the Mini‐Mental State Examination for Dementia Screening (MMSE‐DS) of Korean version. The PROCESS V3.4 macro for SPSS based on the bootstrap method was used to determine the mediating effects of PA and RHGS on the relationship between depressive symptoms and cognitive impairment.

Result

Multiple logistic regression showed that insufficient PA was associated with high odds of a cognitive impairment ((OR = 2.972, 95%CI = 1.749‐5.052, p = .002) compared with sufficient PA (OR = 1). Weak RHGS (OR = 3.540, 95%CI = 2.156‐5.814, p<.001) was associated with high odds of the cognitive impairment compared with normal RHGS (OR = 1). Depressive symptoms (OR = 2.676, 95%CI = 1.594‐4.492, p<.001) were associated with higher odds of the cognitive impairment compared with normal depression status (OR = 1). Particularly, depressive symptoms were found to have both direct and indirect effects on cognitive impairment. As predicted, PA and RHGS partially mediated the relationship between depressive symptoms and cognitive impairment (PA: B = –0.017, 95%CI = –0.028 ‐ –0.009, p<.001; RHGS: B = –0.005, 95%CI = –0.007 ‐ –0.003, p<.001). In addition, serial mediation analysis indicates that the association between depressive symptoms and cognitive impairment was partially mediated by PA and RHGS in a sequential manner (B = –0.004, 95%CI = –0.006 ‐ –0.002, p<.001).

Conclusion

According to the results of the serial multiple mediation model, the elderly should be encouraged to continue their physical activity in daily life, which not only improves and maintaining muscular strength but also reduces the negative impact of depressive symptoms on cognitive impairment.
Effect of resistance exercise on secondary inflammatory insult in Alzheimer’s disease models
Authors: Wong Alvin Ka‐Wai , Chang Raymond Chuen‐Chung
Published: December 2023

Background

Physical exercise improves cognition in human and animal studies associated with Alzheimer’s Disease (AD). However, resistance‐type regimes remain poorly investigated. Acute illness or injury can influence the rate AD progression and trigger accelerated cognitive decline.

Method

To evaluate the role of RE in modulating pre‐existing cognitive impairment, female 3xTg and 5xFAD mice underwent a five‐week RE training protocol. An acute systemic inflammatory insult: laparotomy or intraperitoneally‐injected LPS, was performed to investigate the effect of RE under these challenges. Behavior tests was used to probe for cognition and learning. Brain homogenates were harvested for western blot analysis, qPCR, or post‐fixed in neutral‐buffered formalin solution for immuno‐histochemical exploration.

Result

RE showed improved cognitive function, reduced P‐S396‐tau, decreased ionized calcium‐binding adapter molecule 1 (Iba‐1), and decreased inflammatory cytokine transcripts compared to sedentary controls. RE significantly reduced anxiety‐like behavior and cognitive deficit stimulated by acute systemic inflammation episode.

Conclusion

RE attenuates exaggerated cellular responses and improves cognitive functions in AD and accelerated cognitive impairment triggered by secondary inflammation insult.
Caregiving for a spouse with cognitive impairment: Effects on serum homocysteine level
Authors: Jeon So Yeon , Kim Jeong Lan
Published: December 2023

Background

Among older adults, being a spousal caregiver (SCG) for a patient with cognitive impairment is well known to be associated with increased risk for cognitive decline and cardiovascular disease. It is important to understand the caregiving‐related risk factor for caregiver’s health outcome. Elevated total serum homocysteine also has been linked to cognitive impairment and is a risk factor for cardiovascular disease. Therefore, this study aims to examine the relationship between caregiver burden with serum homocysteine level in older adults couples.

Method

From May 2020 to December 2022, clinical evaluation and blood tests were conducted for patients who visited Chungnam National University Geriatric Neuropsychiatric clinic with their spouse. A total of 92 individuals were included in the analysis. As clinical assessment, we evaluated the care burden using Zarit burden interview and blood samples were collected from the subjects after overnight fasting.

Result

In linear regression analysis adjusted for age, sex, care‐recipient’s clinical diagnosis, vascular risk score and apolipoprotein E ε4 positivity. The SCG’s burden was significantly associated with the level of homocysteine (β = 0.289, t = 2.670, p = 0.009). As SCG’s burden increased, the serum homocysteine level also increased. The results were unchanged after excluding care‐recipient with normal cognition (n = 8) (β = 0.266, t = 2.432, p = 0.018)

Conclusion

This finding suggest that SCG’s burden for patients with cognitive impairment might raise homocysteine levels among SCGs which can further affect cardiovascular disease and cognitive decline. As such, homocysteine level should be well monitored among SCGs for patient with cognitive impairment.
Incorporating Mindfulness Based Strategies in CarePRO‐Virtual Spanish (CarePRO‐VS): A Multicomponent Intervention for the Latino Community
Authors: Manzo Alma A , Coon David W. , Gonzalez Maria S , Glinka Allison , Carbajal Berta , Gómez‐Morales Abigail
Published: December 2023

Background

A recent report estimates Latinos in the U.S. living with Alzheimer’s Disease (AD) could reach as high as 3.5 million by 2060 and are 1.5 times more likely to develop AD than non‐Latino Whites. Consequently, Latino caregivers of people with Alzheimer’s Disease or other related dementias (ADRD) face significant risks to their physical and mental well‐being. Due to the immense increase of ADRD in Latinos, it is important for research to highlight the ways in which caregivers can learn mindfulness based skills to support challenges they may face.

Method

U.S. Latina caregivers of people with ADRD (n = 18) were analyzed from the CarePRO‐VS program. CarePRO‐VS is a multicomponent skill‐focused intervention conducted in Spanish that manages stress, tension and frustration associated with caregiving. This pilot project was conducted over ten weeks via telephone and Zoom including: (1) screening to determine eligibility, (2) pre‐ and post‐ intervention assessments conducted within approximately two weeks of the intervention, (3) individual “coach calls” and (4) the five‐week CarePRO‐VS program.

Result

By week five, 60% of caregivers used mindful breathing 3 or more times a day. In comparison to week one, only 18.8% of caregivers used mindful breathing 3 or more times a day. As an example of a frequent user, coach call notes showed that one participant in particular self‐reported use of the relaxing techniques every week with an average of 3‐4 times a day. Mindful breathing helped her destress, stay positive, and focus on the present moment. Body scans helped her bring awareness to how she felt during stressful situations involving her father, the care recipient. She also extended the use of mindful breathing to situations beyond caregiving. At five weeks, she used mindful breathing with her father to ease his anxiety.

Conclusion

These Latina caregivers implemented a new strategy that shows promising results and future research can expand on aspects of mindfulness as an equitable and accessible strategy to increase relaxation for caregivers and care recipients. To date, there are few published studies incorporating mindfulness techniques that also included Latino caregivers of people with ADRD in the U.S.
How Do Event‐Related Gamma Oscillations Differ in Alzheimer’s Disease From Other Types of Dementia ?
Authors: Güntekin Bahar , Bölükbaş Burcu , Duygun Rümeysa , Kuloğlu Hikmet Buse , Yemeniciler İrem , Yıldırım Ebru , Aktürk Tuba , Yener Görsev
Published: December 2023

Background

Although recent studies showed that gamma frequency entrainment might have therapeutic effects on Alzheimer’s Disease (AD) (Iaccarino et al. 2016), the gamma band abnormalities in AD patients are still poorly understood, while some studies presented increased gamma responses in AD, others showed reduced gamma responses (Güntekin et al., 2022). The differentiation of gamma responses between different dementia types is also not known. The present study aims to analyze the event‐related gamma responses in AD patients and to find out how the event‐related gamma responses differentiate between AD, Parkinson’s disease dementia (PDD), and Lewy Body dementia (DLB).

Method

EEG of 17 DLB, 19 PDD, 20 AD patients, and 20 healthy controls was recorded with a 32‐channel EEG device. Subjects had performed visual oddball paradigm during EEG recordings. Event‐related phase locking and Event‐related power were analyzed in three gamma frequency bands (25‐30 Hz, 30‐35 Hz, 35‐48 Hz) in three different time windows (0 200 ms, 200 400 ms, 400‐600 ms) for target and non‐target stimuli. Repeated measures of ANOVA were used with the between‐subjects and within‐subjects factors.

Result

Target responses elicited higher gamma phase locking than the non‐target responses (p<0.05). Healthy subjects had higher gamma phase locking than AD, PDD, and DLB patients (p<0.05). The healthy control group had increased gamma power in the 0‐200 ms time window at frontal and central locations (p<0.05); however, patient groups did not have this early time window increase of gamma responses. Furthermore, although it was non‐significant, gamma phase locking values of PDD and DLB patients were worse than AD.

Conclusion

The present study showed that AD, PDD, and DLB patients had reduced event‐related gamma phase locking and power in the early time window compared to healthy elderly controls. The gamma phase locking values of PDD and DLB patients were worse than those of AD patients. The present study showed that similar to AD patients and other dementia types could also have deficits in the gamma frequency band. Since the PDD and DLB patients had even more abnormal gamma band activities, the gamma entrainment could also have positive effects in these groups of patients.