bluuebunny/crossref_metadata_2025 huggingface dataset:
Toward standardizing family caregiving competencies based on the stage of dementia
Authors: Kim Jinju , Jung Jihye , Doan Thao , Park Myonghwa
Published: December 2023

Background & Purpose

Despite of the introduction of the formal care system such as long term care insurance system, informal family caregiving still takes an important part in caring for people with dementia. In an environment where family caregiving is not performed properly, the quality of life of both the dementia patient and the family caregiver deteriorates, leading to early admission to a facility and an increase in social costs. This study aimed to identify the importance of family caregiving competencies in different dementia stages from the perspective of the family caregiver.

Methods

This study recruited 210 family caregivers of people with dementia. Data collection was conducted by using a self‐report questionnaire. The participant scored the extent of the importance of dementia caregiving competency according to stages of dementia: early, middle, and advanced stage. The data were illustrated as frequency, percentage, mean, and standard deviation.

Results

The importance of family caregiving competency was statistically different according to age, gender, education level, and relationship between people with dementia and family caregivers. The family caregivers refer to the following items as critical competencies: using cognitive programs for people with dementia in the early stage; creating a safe living environment in the middle stage; and managing the physical symptoms such as bedsores, incontinence, and diseases of the people with dementia, and properly utilizing necessary long‐term care services in the advanced stage.

Conclusion

This study indicated the differences of the importance of family caregiving competencies between each stage of dementia from the perspective of family caregivers. The results of this study are valuable data to standardize effective programs for family caregivers during the different stage of dementia.
Frontal versus temporal type memory deficit in amnestic mild cognitive impairment; predictive value in the diagnosis of Alzheimer disease
Authors: Kim Yong Bum
Published: December 2023

Background

Retention‐deficit in verbal learning test is attributed to the medial temporal lobe dysfunction and retrieval‐deficit to the frontal lobe. We tried to determine whether memory deficit patterns (the retention‐deficit amnestic mild cognitive impairment (rtn‐aMCI) vs. retrieval‐deficit aMCI (rtv‐aMCI)) can differentiate amyloid positive Alzheimer disease (AD) from non‐AD neurodegenerative diseases.

Method

One hundred and seventy‐four MCI patients were enrolled who underwent a set of neuropsychological assessments, brain MRI and flutemetamol amyloid PET. All MCI patients were diagnosed using the Petersen criteria. They were divided into the rtn‐aMCI (below ‐1.0SD on both delayed recall and recognition test) and rtv‐aMCI (below ‐1.0SD on delayed recall, above ‐1.0SD on recognition test) based on the results of Seoul Verbal Learning Test (SVLT).

Result

Of 174 patients, 106 were classified as rtn‐aMCI group and 68 were as rtv‐aMCI. There was no significant difference in amyloid PET positivity between two groups (50.0% in rtn‐aMCI vs. 47.1% in rtv‐aMCI; χ2 = 0.143, p = 0.705). Forward digit span (6.06 ± 1.4 vs. 5.25 ± 1.6, p < 0.001) & backward digit span (3.68 ± 1.2 vs. 3.29 ± 1.4, p < 0.05) were lower in the rtv‐aMCI group. Word fluency and Stroop tests were not different between them.

Conclusion

This study revealed that the temporal type memory deficit pattern in rtn‐aMCI patients is not predictive of AD pathology in amyloid PET scan. We should be aware that temporal type memory deficit can also be observed in patients with other non‐AD neurodegenerative disorders.
Prevalence and Severity Distribution of Alzheimer’s Disease in the United States from the Health and Retirement Study
Authors: Monfared Amir Abbas Tahami , Chandak Aastha , Khachatryan Artak , De Benedetti Laura , Hummel Noemi , Zhang Quanwu
Published: December 2023

Background

There is limited data regarding Alzheimer’s disease (AD) prevalence by severity across the AD continuum. This study aimed to estimate prevalence of mild cognitive impairment (MCI) and mild, moderate, and severe AD in a representative sample of the United States (US) population.

Method

Data from the Health and Retirement Study (HRS), a bi‐annual national survey of older adults in the US, were analyzed (2014‐2018), applying cluster sampling weights. AD ascertainment from HRS was based on patient report of a clinical diagnosis (physician diagnosis‐based), or the test score of Modified Telephone Interview of Cognitive Status (TICS‐m) (cognitive performance‐based). Patients with MCI were identified with the cognitive performance‐based method only. MCI and AD severity stages were ascertained using a crosswalk between the scores of TICS‐m and the mini‐mental state examination (MMSE).

Result

The diagnosis‐based method identified 1.2%, 1.2%, 1.3% patients with AD in 2014, 2016 and 2018, respectively (2.2% pooled). The mean (SD) age was 79.4 (10.3) years, with 61% women and 22% had passed college education (combined across surveys). The cognitive performance‐based method identified 23%, 23%, 21% patients with MCI in 2014, 2016 and 2018, respectively (24% pooled), and 27%, 22%, 17% patients with AD in 2014, 2016 and 2018, respectively (30% pooled). For patients with MCI, the mean age was 67.3 (10.1) years, with 51% women and 36% passed college education; for patients with AD, the mean age was 72.8 (11.1) years, with 53% women and 28% had passed college education. Severity distributions are shown in Figure 1. Unweighted results were similar.

Conclusion

The cognitive performance‐based method identified a substantially higher prevalence of AD than the diagnosis‐based method and enabled identification of MCI prevalence using HRS data. The prevalence of MCI was consistently higher than AD dementia severity categories over the years (2014, 2016, and 2018). The discordance in AD prevalence estimation between cognitive performance‐based and diagnosis‐based methods underscores a need for better understanding of clinical practice patterns in AD diagnosis, use of clinical assessment tools, and severity classification in the US.
Clinical Validation and Correlates of the Cingulate Island Sign Visual Rating Scale for the Diagnosis of Dementia with Lewy Bodies
Authors: Feng Linda Ruohua , Vogel Asmus , Jensen Clara Mellergaard , Waldemar Gunhild , Hasselbalch Steen G. , Law Ian , Henriksen Otto Mølby , Frederiksen Kristian Steen
Published: December 2023

Background

The cingulate island sign (CIS) is a metabolic pattern on [18F]fluorodeoxyglucose ([18F]FDG) positron emission tomography (PET) associated with dementia with Lewy bodies (DLB). The aim of this study was to validate the visual CIS rating scale (CISRs) for the diagnosis of DLB and to explore the clinical correlates.

Method

This single‐center, retrospective study included 166 consecutive patients with DLB and 161 patients with Alzheimer’s disease (AD). The CIS on [18F]FDG‐PET scans was rated using the CISRs (0‐4) independently by three readers blinded to other patient data.

Result

The optimal cut‐off to differentiate DLB from AD was a CISRs score ≥ 1 (sensitivity = 66%, specificity = 84%) whereas a CISRs score ≥ 2 (sensitivity = 58%, specificity = 92%) was optimal to differentiate amyloid positive DLB (n = 43 (82.7%)) and AD. To identify DLB with abnormal (n = 53 (72.6%)) versus normal (n = 20 (27.4%)) dopamine transporter imaging (DaT), a CISRs cut‐off of 4 had a specificity of 95% for abnormal DaT. DLB patients with a CISRs score of 4 performed significantly better in tests of free verbal recall and picture based cued recall, but worse in test of processing speed compared with DLB with a CISRs score of 0.

Conclusion

This study confirms the CISRs as a valid marker for the diagnosis of DLB with a high specificity and a lower, but acceptable, sensitivity. Concomitant AD pathology does not influence diagnostic accuracy of the CISRs. In DLB patients, presence of CIS is associated with relative preserved memory function and impaired processing speed.
Program providers’ perception of caregiving competency of family caregivers according to dementia stage
Authors: Jung Jihye , Park Myonghwa , Kim Jinju , Doan Thao
Published: December 2023

Purpose

Family caregivers take significant roles in helping their relatives with dementia to meet daily life needs. Various support programs have been developed to decrease family caregivers’ stress and burden. Among the studies conducted so far, there is a lack of programs developed based on caregiving competencies according to each stage of dementia. To prepare for the development of a program based on caregiving competencies for stages of dementia, this study aimed to investigate the appropriateness and importance of family caregivers’ caregiving competency from the perspectives of the program providers.

Method

175 program providers who participated in a support program for family caregivers of people with dementia were recruited in this study. We used a 40‐item questionnaire, which consisted of caregiving competencies according to stages of dementia: 14 items for the early stage, 14 items for the middle stage, and 12 items for the advanced stage. For each item, the participants were asked to score its appropriateness and importance using 5 Likert scale.

Result

Study findings indicated dementia caregiving competencies that scored as most appropriateness and importance in different dementia stages. Specifically, “Eliminating prejudice against dementia” (4.07±0.75, 4.14±0.74, respectively) were identified in the early stage, “Managing family caregivers’ stress” (4.07±0.76, 4.15±0.74, respectively) in the middle stage, and “Properly utilizing necessary long‐term care services” (4.19±0.77, 4.26±0.72, respectively) and “Decision making with other family members so that people with dementia can end their lives comfortably” (4.09±0.74, 4.14±0.73, respectively) in the advanced stage. Whereas, care competencies that gained the lowest scores of appropriateness and importance comprised: “Medical and legal documents required after diagnosis of dementia” (3.80±0.78, 3.87±.077, respectively) in the early stage, “Participating in self‐support groups” (3.79±0.79, 3.90±.078, respectively) in the middle stage, and “Share valuable memories with dementia” (3.75±0.77, 3.83±.078, respectively) in the advanced stage.

Conclusion

This study figured out the importance of the caregiving competencies that should be delivered to the family caregivers of people with dementia from the perspectives of the program providers. Findings from this work would be valuable resources in developing effective family support programs to improve the dementia caregiving competency of family caregivers during their caregiving journey.
Developing an immersive gamification technology system for the management of patients with behavioral and psychological symptoms of dementia (Phase 1 trial)
Authors: Anlacan Veeda Michelle M. , Jamora Roland Dominic G. , Panganiban Angelo Cedric F. , Galecio Bryan Andrei C. , Concepcion Florinda P. , Gonzales Juan Raphael , Salido Isabel Teresa O. , Tee Michael L. , Aguila Maria Eliza R. , Tee Cherica A. , Caro Jaime D. L.
Published: December 2023

Background

Virtual reality (VR) technology has been increasingly used in the management of people living with dementia, serving as a novel and important non‐pharmacologic approach to address the complex behavioral and psychological symptoms. The objective of this phase 1 study was to develop an immersive gamification technology system (ImGTS), specifically, a VR application, and describe its acceptability, usability, and safety in a cohort of healthy adults.

Method

The development of ImGTS included software and hardware designs appropriate for the local context and tested using two distinct set‐ups: head‐mounted display (HMD) and the Semi‐Cave automatic virtual environment (Semi‐CAVE). Qualitative and quantitative data questionnaires, with responses analyzed using thematic analysis and descriptive statistics were used to measure the sense of place, usability and safety of the two set‐ups.

Result

Participants who used the HMD (n = 15) and the Semi‐CAVE (n = 15) had positive impressions and clear recollections of the VR experience. Incidence of VR sickness symptoms was low, and the mean total VR sickness scores decreased across sessions. Participants in both groups were able to perform key tasks in the VR experience, and the majority performed these actions with ease by the final testing session (n = 15 for the HMD, n = 13 for the Semi‐CAVE). The three main activities were given a ‘neutral to positive’ description in terms of satisfaction.

Conclusion

The technology we developed had a considerable level of impact in eliciting important aspects of cognition and emotion. Through self‐reported measures and researcher observations, we found that the HMD and Semi‐CAVE VR setups were safe, acceptable and usable by healthy adult participants.
SGLT2 and DPP4 inhibitors improve Alzheimer’s disease‐like pathology and cognitive function through distinct mechanisms in T2D‐AD mouse model
Authors: Sim A Young , Kim Jong Youl , Lee Yong‐Ho , Lee Jong Eun
Published: December 2023

Background

There are common mechanisms between Alzheimer’s disease (AD) and type 2 diabetes mellitus (T2D), such as insulin resistance. As insulin signaling has important roles in regulation of neuronal functions in the brain, the hypotheses and theories regarding the pathogenesis of AD implicate brain insulin resistance as a key factor. Also, recent studies demonstrated that sodium‐glucose cotransporter 2 inhibitor (SGLT2‐i) and dipeptidyl peptidase‐4 inhibitor (DPP4‐i) which are T2D drugs have been shown to exert beneficial effects on insulin sensitivity and neuroprotection beyond glucose‐lowering actions. However, in relation to the two drugs, the brain metabolic dysfunction and its mechanisms impaired by insulin resistance have never been investigated.

Method

We developed T2D‐AD mice model using 60% high‐fat diet for 12 weeks and a single dose of streptozotocin (100 mg/kg/i.p) at week 4 of the diet. Subsequently treated with SGLT2‐i (empagliflozin, 25 mg/kg/day/po) and DPP4‐i (sitagliptin, 100 mg/kg/day/po) for 7 weeks. After behavior tests, expression properties of brain insulin signaling, AD related proteins and drugs action‐associated proteins were examined by using western blotting and immunohistochemistry.

Result

T2D‐AD mice not only increased blood glucose and body weight, but also had insulin resistance through insulin tolerance test and glucose tolerance test. SGLT2‐i and DPP4‐i were effective in ameliorating insulin sensitivity and reducing body weight gain. In addition, as a result of evaluating hippocampus‐dependent spatial learning and preference memory through behavioral tests, SGLT2‐i and DPP4‐i were found to improve learning, memory, and cognitive functions. Interestingly, SGLT2‐i and DPP4‐i reduced AD‐associated hyperphosphorylated tau (pTau) and amyloid β (Aβ) accumulation in different ways, respectively, along with enhancing brain insulin signaling. SGLT2‐i reduced pTau accumulation through ACE2/Ang(1‐7)/MasR, and DPP4‐i showed an effect of reducing Aβ accumulation by increasing IDE.

Conclusion

These findings suggested that SGLT2‐i and DPP4‐i prevented AD‐like pathology and cognitive decline by affecting brain insulin signaling through different mechanisms.
The associations of socioeconomic status with structural brain damage and connectivity and cognition: The Maastricht Study
Authors: Geraets Anouk F.J. , Schram Miranda T. , Köhler Sebastian , Jansen Jacobus F.A. , van Boxtel Martin P.J. , Koster Annemarie , Stehouwer Coen D.A. , Bosma Hans , Leist Anja K.
Published: December 2023

Background

Socioeconomic inequalities in the risk for cognitive impairment have been reported, which might partly act through structural brain damage or differential numbers of brain connections (structural connectivity). This study investigated the extent to which the association of early‐life socioeconomic status (SES) with later‐life cognitive performance is mediated by later‐life SES, and whether the association of SES with later‐life cognitive performance can be explained by structural brain damage and connectivity.

Method

We used cross‐sectional data from the population‐based Maastricht study (n = 4,839; mean age 59.2±8.7 years, 49.8% women). Early‐life SES was assessed retrospectively by self‐reported poverty and parental education. Later‐life SES included education, occupation, and household income. Participants underwent cognitive testing and 3 T magnetic resonance imaging to measure volumes of white matter hyperintensities, gray matter, white matter, cerebrospinal fluid, and structural connectivity. Multiple linear regression analyses tested the associations between SES, brain markers and cognition. Analyses were adjusted for age, sex, and type 2 diabetes (because of oversampling). Structural equation modeling tested mediation.

Result

Higher SES was associated with higher grey matter volume, lower white matter volume, and higher structural connectivity. Structural brain damage and lower structural connectivity were associated with lower overall cognitive performance. Both higher early‐life and later‐life SES were associated with overall higher cognitive performance (B [95% CI] medium versus low early‐life SES = 0.17[0.12;0.23]; B high versus low early‐life SES = 0.26[0.20;0.32]; B medium versus low later‐life SES = 0.46[0.41;0.52]; B high versus low later‐life SES = 0.72[0.67;0.78]). The association of early‐life SES with later‐life cognitive performance was partly mediated by later‐life SES (73.8%). The extent to which the association of SES with cognitive performance could be explained by structural brain damage or connectivity was marginal (up to 5.9%).

Conclusion

Though there was an association between early‐life SES and later‐life cognitive performance independent of later‐life SES, a large part of this association could be explained by later‐life SES. Structural brain damage and connectivity marginally explained socioeconomic inequalities in cognitive performance. More research is needed to investigate alternative pathways that explain associations of life‐course SES with later‐life cognition.
Sensory‐Evoked 40Hz Gamma Oscillation: A Feasible and Promising Treatment Option for Alzheimer’s Disease
Authors: Hajos Mihaly , Boasso Alyssa , Cimenser Aylin , Shpokayte Monika , Hempel Evan , Da Xiao , Seshagiri Chandran , Megerian Jonathan Thomas , Vaughan Brent , Malchano Zach
Published: December 2023

Background

Developing safe and disease modifying therapies for Alzheimer’s disease (AD) is still challenging, in spite of recent advancements in the understanding of AD pathophysiology. A fundamentally different therapeutic approach under development at Cognito Therapeutics targets abnormal neuronal activities using the company’s Gamma Sensory Stimulation System. This treatment is based on the recent breakthrough, demonstrating that 40Hz neuronal network oscillation evoked via optogenetic, or sensory stimulation profoundly reduces AD pathologies in AD‐related transgenic mice.

Method

This presentation will provide an overview of the main findings from a clinical trial (NCT03556280) which evaluated Cognito Therapeutics Gamma Sensory Stimulation System as a potential novel therapeutic intervention for AD, evaluating feasibility, safety, tolerability, and efficacy of this treatment. In the 6‐month long, double‐blinded, randomized, controlled, clinical trial, participants with clinical presentation on the AD spectrum, were randomized 2:1 (active:sham) to receive daily, one‐hour 40Hz audio‐visual stimulation treatment using Cognito’s Gamma Sensory Stimulation System or sham stimulation.

Result

A total of 135 subjects were screened, of whom 74 were randomized and 53 completed (20 sham arm, 33 active arm). Daily use of the Gamma Sensory Stimulation System was confirmed to be safe with minimal side effects. MRI data confirmed the absence of ARIA in participants. High adherence to daily therapy was established based on device‐recorded usage. In assessing cognitive and functional abilities, changes in ADCS‐ADL and MMSE scores were statistically significant between the sham and treatment arms, demonstrating a significant slowing in functional and cognitive decline in the treatment group. Further, quantitative MRI analysis revealed a significantly reduced whole brain, white matter, and occipital lobe volume loss, along with a significantly attenuated reduction in occipital cortical thickness in the active arm relative to sham. These clinical benefits were achieved independent of a reduction in amyloid plaque loads.

Conclusion

Our results demonstrate that daily 40Hz sensory stimulation delivered by Cognito’s Gamma Sensory Stimulation System is safe and well tolerated; patients in the active arm maintained their functional and cognitive abilities, showed reduced brain atrophy. The upcoming pivotal clinical trial will further evaluate the clinical efficacy of this treatment, also evaluating its most relevant downstream mechanisms in AD patients.
Precuneus magnetic stimulation for Alzheimer’s disease: a novel TMS‐EEG based peronsalized therapeutic strategy
Authors: Koch Giacomo
Published: December 2023

Background

Repetitive transcranial magnetic stimulation (rTMS) may improve cognition in patients with Alzheimer’s disease (AD). rTMS therapy is currently limited by the relative short duration and the uncertainty on the most appropriate brain target area. AD patients primarily show alterations of the default mode network (DMN), a brain functional network for which the precuneus (PC) is a key node.

Method

We hypothesized that a long‐term 6 month course of rTMS applied over the precuneus could modify cognitive functions in patients with mild‐to‐moderate AD, by restoring cortical activity in the target network. To test this hypothesis we performed a randomized, double‐blind, sham‐controlled, phase II, 24‐weeks trial (NCT03778151). The primary outcome measure was change from baseline to week 24 of the Clinical Dementia Rating Scale–Sum of Boxes (CDR‐SOB). Secondary outcomes included score changes in the Alzheimer’s Disease Assessment Scale– Cognitive Subscale (ADAS‐Cog)11, Mini Mental State Examination (MMSE) and Alzheimer’s Disease Cooperative Study–Activities of Daily Living scale (ADCS‐ADL).Personalization of treatment and monitoring of cortical activity changes were refined by combining TMS and electroencephalography (TMS‐EEG).

Result

We found that AD patients treated with PC‐rTMS showed almost no decline in the CDR‐SB score, showing a clear advantage in terms of cognitive functions and functional abilities as compared to the sham group. rTMS induced in parallel remarkable changes in cortical activity, as demonstrated by TMS‐EEG recordings.

Conclusion

24 weeks of PC‐ rTMS may slow down cognitive and functional decline in AD patients by enhancing brain plasticity. Non‐invasive brain stimulation of the DMN could represent a novel therapeutic approach in AD patients.
Towards an EEG/ERP Test Battery for the Neurophysiological Assessment in Alzheimer’s Disease Patients
Authors: Meixner Johannes M , Scheibner Hannah , Heinze Martin , Behr Joachim , Babiloni Claudio , Jost Kerstin , Dahling Volker
Published: December 2023

Background

Previous studies have shown that resting‐state electroencephalographic (rsEEG) and event‐related potential (ERP) biomarkers reflect the neurophysiological mechanisms underpinning vigilance dysfunctions and cognitive decline in persons with mild cognitive impairment (MCI) and dementia due to Alzheimer’s disease (ADD). However, their best combination as inputs to artificial intelligence tools for clinical applications is unknown. This study aimed at identifying the most promising rsEEG and ERP biomarkers by their comparison among MCI, ADD, and cognitively normal (NOLD) persons towards their future use of those tools.

Method

At present, fifty (12 ADD, 16 MCI, and 22 NOLD) participants aged between 58 and 88 (mean age 76) were recruited at the memory clinics of the Brandenburg Medical School to take part in a multi‐session longitudinal study. Clinical, neuropsychological, neuroradiological, rsEEG, and ERP data probing attention (oddball task), working memory (n‐back task) and episodic memory (face name association task) were collected and analyzed with a cross‐sectional design.

Results

Compared to the NOLD group, the MCI and ADD groups showed the following abnormalities (more significant in the ADD than the MCI group): (1) slowing of the individual alpha frequency, reduction in the alpha power, and diffuse increase in the delta power from rsEEG activity; (2) delayed latency peak and reduced amplitude of the posterior ERP‐P3 peak from the oddball task; and (3) reduced amplitude of the ERP‐PN complex from the memory n‐back task.

Conclusion

The results showed increased impairment in the cortical neurophysiological underpinnings of vigilance regulation (rsEEG “slowing"), attention (oddball P3), and working memory (n‐back task PN complex) in the MCI and ADD patients, respectively. These components will be used as inputs to artificial intelligence tools to test the accuracy of their combination for classification and identifying persons at‐risk for developing MCI or ADD.
Effectiveness of a digitally supported care management program for family and other informal dementia caregivers: baseline data and first results from the GAIN randomized controlled trial
Authors: Kilimann Ingo , Boekholt Melanie , Klein Olga A. , Thyrian Jochen René , Teipel Stefan , Hoffmann Wolfgang
Published: December 2023

Background

Almost two‐thirds of people with dementia (PwD) living at home receive care from informal caregivers. The caregiver’s work load can be comparable or above a full‐time employment. Evidence shows that family caregivers have a higher risk for psychiatric and non‐psychiatric diseases compared to non‐caregivers. A dyadic approach on disease management can help to reduce the burden of care and increase the quality of life (QoL) of caregivers and PwD.

Methods

The cluster randomized controlled trial “Gesund Angehörige Pflegen” (GAIN; ClinicalTrials.gov Identifier NCT04037501) conducted in general practitioner (GP) practices and memory clinics in Northern Germany aimed to evaluate the effectiveness of a 6‐months digitally supported care management program delivered by specifically qualified study nurses to reduce unmet needs of informal caregivers of PwD. Primary outcomes were the number of self‐reported unmet needs, regarding the caregiver and the PwD, assessed with a modified version of the Camberwell Assessment of Need for the Elderly (CANE) and the health‐related quality of life with the EQ‐5D‐5L questionnaire. A generalized linear mixed effects model was used with intercept as random effect.

Results

The recruitment for the GAIN trial (October 2020 to January 2022) yielded n = 192 participants (mean age: 65 years, women 75%). The number of identified unmet needs was on average 8.66 (range 1 – 30). Analyses of the primary endpoints revealed a statistically significantly higher reduction of unmet needs of caregivers in the intervention group compared to the control group. Evaluation of the EQ‐5D‐5L showed no significant difference between groups.

Conclusion

The GAIN care management program was able to lower the number of unmet needs for informal dementia caregivers. Health related quality of life showed a major ceiling effect (high scoring at baseline), which might explain the lack of an effect. The study shows the benefit of a computerized self‐assessment system in primary care and should be further developed as an entry point to the existing health care system.
Isomerization and phosphorylation significantly influence the effect of beta amyloid on blood‐brain barrier endothelial cells
Authors: Petrovskaya Aleksandra , Tverskoi Artem , Barykin Evgeny , Varshavskaya Kseniya , Dalina Alexandra , Mitkevich Vladimir , Makarov Alexander , Petrushanko Irina
Published: December 2023

Background

The blood‐brain barrier (BBB) is typically compromised in Alzheimer’s disease (AD): its permeability and intracellular parameters of the endothelial cells are affected. AD‐related amyloid isoforms –Aβ42, isoD7‐Aβ42 and pS8‐Aβ42, inducing amyloidogenesis in a different mode – may have peripheral origin and affect the BBB cells. This study aimed to assess this effect.

Method

Mouse brain endothelial cells bEnd.3 underwent incubation with 10 µM of Aβ42, isoD7‐Aβ42 and pS8‐Aβ42 for 4, 24 and 48 hours to assess nitric oxide (NO), glutathione (GSH), reactive oxygen species (ROS), mitochondrial potential, Ca2+, cell viability by flow cytometry and mitochondrial functioning by Seahorse technology. To analyze the integrity of the cellular monolayer, the expression level of tight junction proteins and permeability of bEnd.3 monolayer to fluorescent tracers were assessed by Western Blotting and transwell‐modeling, correspondingly .

Result

pS8‐Aβ42 and isoD7‐Aβ42 effects on the redox status of the cells and mitochondria functioning differ from the effects of Aβ42. Even at 4 hours, Aβ42 and isoD7‐Aβ42 induce immense changes in mitochondrial potential and NO level but pS8‐Aβ42 does not. Prolonged incubation with three isoforms leads to an increase in ROS, and greater increase is observed after incubation with isoD7‐Aβ42. pS8‐Aβ42 induces ROS increase later than other isoforms. Above all, incubation with pS8‐Aβ42 results in a less pronounced NO и GSH growth compared with Aβ42 и isoD7‐Aβ42 which induce activation of mitochondrial respiration and increase in mitochondrial potential, compared with pS8‐Aβ42. IsoD7‐Aβ42 is mostly toxic to bEnd.3 cells. Although Aβ42 and isoD7‐Aβ42 significantly affect redox parameters of bEnd.3 cells, their effects on BBB permeability and tight junction protein expression are less pronounced. Our data demonstrate that inhibition of NO synthases and NMDA receptors induces changes in BBB cells’ response to Aβ peptides.

Conclusion

Amyloid isoforms differently affect redox parameters of BBB cells significantly modulating mitochondria functioning. Iso‐Aβ42 induces higher cytotoxicity, thus, being a more pathogenic form. Post‐translational modifications of Aβ42 alter the amyloid effect on the BBB cells. It may result in different changes in BBB functioning and its permeability under amyloid isoforms.

This research was funded by Russian Science Foundation (Grant No. #19‐74‐30007).
Investigating the impact of treatment timing on urinary tract infections in dementia at the population level
Authors: Lai Helen , Kolanko Magdalena A , Li Lucia , Tzoulaki Ioanna , Sharp David J , Soreq Eyal
Published: December 2023

Background

Urinary tract infections (UTIs) are common causes of avoidable emergency hospitalisation in people living with dementia (PLWD). PLWD are at higher risk of UTIs, which can often cause death. Previous research in older adults has suggested that survival following infection is reduced by delays in antibiotic treatment (Gharbi et al., 2019). Here we investigate the incidence of UTIs in people with and without dementia and test whether delays in antibiotic treatment particularly increase mortality in PLWD.

Method

Data were extracted for 2.47 million people aged 50 and living in Wales from 2000‐2021 using the SAIL Databank (Figure 1). UTI incidence was calculated as the number of cases identified in GP and hospital records using diagnostic codes. Temporal clustering was applied to remove redundant coding occurring within 90 days. Eligible PLWD and paired non‐dementia (ND) groups were selected monthly using propensity sampling, matching for age, sex, and socioeconomic deprivation. Cox regression was used to study the effects of immediate and deferred treatment (1‐7 days after diagnosis) on survival, focusing on the last recorded UTI in a subset of patients diagnosed and treated at the primary care level.

Result

UTI incidence was higher in PLWD compared to ND (11.21.85 vs 4.30.75, 1:1000) over 22 years (Figure 2). We also observed an increase in UTIs leading to death within 60 days of the infection (1.560.4 vs 0.60.2, 1:1000). We performed Cox regression survival analysis on 76,283 last UTIs with 2,973 observed events (deaths). Age, sex, dementia, and treatment timing were used as predictors. Mortality risk was significantly increased in PLWD relative to ND (***HR = 2.06,[1.91,2.23],z = 18.2) (Figure 3). Mortality was also increased in older adults (***HR = 1.07,[1.07,1.08],z = 36.4) and in males (***HR = 1.50,[1.40,1.61],z = 11.3). Furthermore, deferred treatment was associated with increased mortality (***HR = 1.58,[1.43,1.74],z = 8.93), replicating previous findings. The interaction between dementia and treatment timing was not significant.

Conclusion

Our study found increased UTI incidence and mortality rates in PLWD. Deferred treatment was associated with higher mortality, regardless of dementia diagnosis. Early intervention and frequent screening may reduce adverse health outcomes. Further research is needed to determine the best strategies to prevent and manage UTIs in PLWD.
What influence does self‐reported history of single or repeated mild TBI have on cognitive performance and brain volume at mid‐life?
Authors: Thayanandan Tony , Filippini Nicola , Griffanti Ludovica , Dounavi Maria‐Eleni , Mak Elijah , Low Audrey , O'Brien John T , Mackay Clare , Ritchie Craig W. , Raymont Vanessa
Published: December 2023

Background

The long‐term consequences of mild traumatic brain injury (mTBI) are poorly understood. Prior studies have shown that a history of mTBI is associated with a 2 fold increase of dementia diagnosis. However, the precise mechanisms for increased dementia risk which could start in mid‐life remain unclear. TBI can cause varying degrees of damage to different regions of the brain, and as a result, may affect distinct subdomains of cognitive function in distinct ways. This study investigated cognitive performance and brain volume among individuals at risk of Alzheimer’s Disease (AD) in mid‐life with a history of self‐reported mTBI.

Method

578 participants (118 no head injury, 116 single mTBI & 344 repeated mTBI) aged 40‐60 years participating in the PREVENT study, a large cohort study examining the risk of AD in mid‐life, underwent structural 3T MRI and neuropsychometric evaluation (ACE‐III and COGNITO) at baseline. Self‐reported, cross‐sectional data on head injury were collected through the Brain Injury Screening Questionnaire (BISQ). FSL (version 6.0.1) was used to calculate brain volume (correcting for head size). Comparisons between participants with no history of head injury and single or repeated mTBI were done using a one‐way ANOVA.

Result

There was no statistically significant difference in total brain volume between participants with or without a history of mTBI (F(2,576) = 1.24, p = 0.29). There was also no significant difference between self‐reported mTBI and ACE‐III total scores F(2,579) = 0.0112, p = 0.99) or performance on memory (p = 0.87), language (p = 0.24), visuospatial abilities (p = 0.61) and attention (p = 0.14) in the COGNITO battery.

Conclusion

We found no evidence that a history of mTBI (single or repeated) is associated with cognitive impairment in this cohort. Future longitudinal studies are necessary to further evaluate self‐reported mTBI and how the aging process might interact with cognitive outcome post‐injury. Future analysis of covariates such as lower socioeconomic status, gender, physical health and history of alcohol/drug use, that are known to impact cognitive performance and are related to greater rates of TBI, will be studied to determine the influence of a history of mTBI on dementia risk.
Tear biomarkers for Alzheimer’s disease screening and diagnosis (The TearAD study): design and rationale of an observational longitudinal multicenter study
Authors: van de Sande Nienke , Ramakers Inez H.G.B. , Visser Pieter Jelle , Verhey Frans R.J. , Verbraak Frank D. , Bouwman Femke H. , Berendschot Tos T.J.M. , Nuijts Rudy M.M.A. , Webers Carroll A.B. , Gijs Marlies
Published: December 2023

Background

Early diagnosis of Alzheimer’s disease (AD) is important to promote timely and optimal management. Currently, the diagnosis of AD involves the use of amyloid PET scan or biomarker‐based cerebrospinal fluid analyses. These tests are invasive and expensive therefore limiting their usage as a front‐line screener. Thus, there is a need for non‐invasive and cost‐effective tools to diagnose subjects in early stages of the disease. With the TearAD study, we propose using the eye as the window to the brain. The eye is closely connected to the brain through the optic nerve. Tears contain thousands of molecules and protein secretion in the lacrimal gland is regulated by (para‐)sympathetic innervation. A study performed by our group demonstrated that proteins associated with AD (Aβ38, Aβ40 and Aβ42, total‐tau and phosphor‐tau) are detectable in tear fluid (Gijs et al., 2021, Scientific reports). Tear total‐tau levels were significantly elevated in dementia patients compared to people with subjective cognitive decline (SCD). Besides changes in tear protein content, retinal abnormalities have been observed in AD patients, which include retinal nerve fiber thinning and optic nerve degeneration. This observational longitudinal multicenter study aims to evaluate diagnostic accuracy measures of tear and retinal biomarkers to discriminate individuals with and without neurodegeneration.

Methods

A total of 200 subjects will be included, of which 100 with and 100 without neurodegeneration. The study includes three visits (baseline, 12 months, and 24 months). The tear fluid will be collected non‐invasively with a Schirmer strip. Retinal images will be obtained by a standard, ultra‐wide field (Optos) and hyperspectral (Optina) fundus camera. Additionally, cross‐sectional images of the retina will be obtained through optical coherence tomography. Protein levels in tear fluid will be determined using multiplex immunoassays.

Results

Inclusion for baseline started in June 2022 and is expected to complete in June 2023. Currently (Jan, 2023) we included a total of 115 participants. Which consist of 50 cognitively healthy controls, 25 patients with SCD, 17 patients with mild cognitive impairment and 13 patients with dementia.

Conclusion

The TearAD study will provide insight into the diagnostic accuracy of using tear and retinal biomarkers for screening and diagnosis of AD.
Episodic memory decline symptoms are strong predictors of Alzheimer’s disease defined by Positron Emission Tomography in participants with amnestic mild cognitive impairment and mild dementia
Authors: Booncharoen Kittithatch , Hiransuthikul Akarin , Thanapornsangsuth Poosanu , Thanprasertsuk Sekh , Sarutikriangkri Yuthachai , Tangnimitchoke Suchart , Rattanawong Wanakorn , Phanthumchinda Kammant , Likitjaroen Yuttachai
Published: December 2023

Background

The diagnosis of Alzheimer’s disease (AD) has been shifted from clinical to biomarker‐based approach. However, the disease‐specific biomarker investigations are either invasive, expensive, or unavailable. Episodic memory decline symptoms (EMDS) have been recognized as an early manifestation of AD. We aimed to determine the performance of integrating EMDS in predicting AD among participants with amnestic mild cognitive impairment (MCI) or mild dementia.

Method

Amnestic MCI and mild dementia participants were recruited from memory clinic at King Chulalongkorn Memorial Hospital, Thailand. In‐house informant‐based questionnaire was used to interview participants’ caregivers, which comprise of (A) 7 questions on changes in EMDS during the past 10 years and (B) 6 questions on the average daily frequency of EMDS in the previous month. Amyloid (Florbetaben) and Tau (PI‐2620) Positron Emission Tomography (PET) were performed. The result with A+T+ was defined as AD, the result with A+T‐ or A‐T‐ were define as other cognitive impairments. Multivariable logistic regression models were employed to construct the predictive model. The likelihood ratio test and area under the curve of receiver operating characteristic curve (AUC‐ROC) were used to identify the best model.

Result

Among 50 participants enrolled (median [interquartile range] age 72 [65‐77] years), 24 (48%) had AD. A comparison of AD and other cognitive impairments is shown in Table 1. The combination of 3 symptoms, including (1) consistently worse in remembering events during the past 10 years; (2) at least once daily momentary confabulation; and (3) at least once daily repetitive questioning, had the best diagnostic performance in parsimonious model for predicting AD with AUC‐ROC of 0.77 (95% confidence interval [CI]: 0.64‐0.90). (Figure 1)

Conclusion

EMDS are still a valuable clinical marker for predicting AD in participants with amnestic MCI and mild dementia. The combination of selected EMDS might be a useful screening tool for selecting patients for further AD specific biomarker investigations.
Metabolic Syndrome‐Associated Oligodendrocyte Dysfunction and Cognitive Impairment
Authors: Noureldein Mohamed , Elzinga Sarah E , Kim Bhumsoo , Savelieff Masha G , Rigan Diana M , Feldman Eva L
Published: December 2023

Background

One in nine people aged 65 and older in the United States suffer from cognitive decline, including dementias such as Alzheimer’s disease (AD) and AD‐related Dementias (ADRD). A major risk factor for cognitive impairment is midlife metabolic syndrome (MetS). MetS‐associated cognitive impairment progresses in a non‐cell autonomous manner and implicates a breakdown in metabolic support. This breakdown in metabolic support is likely due to disruption of metabolic crosstalk between neurons and glia, especially oligodendrocytes. Our aim was therefore to elucidate midlife MetS effects on oligodendrocytes and subsequent impact on oligodendrocyte metabolism and cognition.

Method

To accomplish this aim, middle‐aged mice (12‐month old) were fed either standard diet (SD, 10% fat) or high‐fat diet (HFD, 60% fat) for 13 weeks, followed by full assessment of metabolic parameters and cognitive function. Oligodendrocytes were then isolated for single cell RNA‐sequencing (scRNA‐seq), and protein expression of monocarboxylate transporters (MCTs).

Result

We observed that, as expected, HFD mice gained more weight and had higher blood glucose and fat mass versus SD controls. Middle‐aged HFD mice also performed worse in puzzle box and social recognition tests, reflecting impaired executive function and impaired short‐ and long‐term memory responses. scRNA‐seq analysis identified multiple oligodendrocyte clusters. One cluster of interest contained genes involved in cognition (Fam171a2, Nrsn1, Dlgap4) and metabolism (Ldhb, Slc25a5, Cox7c, Cox17), which were differentially expressed in HFD versus SD mice. This was coupled with downregulated MCT1 protein expression in HFD mouse oligodendrocytes versus oligodendrocytes from their SD counterparts. In vitro, human oligodendrocytes treated with palmitate to mimic MetS developed insulin resistance and had downregulated MCT1 protein expression.

Conclusion

Collectively, these results suggest that midlife MetS impairs oligodendrocyte metabolic function, suggesting a novel mechanism underlying MetS‐associated cognitive impairment.
Investigating two pore potassium channel THIK‐1 expression in Alzheimer’s disease
Authors: Tang Hao , Sun Yuhong , Fachim Helene A , Cheung To Ka Dorcas , Reynolds Gavin P , Harte Michael K
Published: December 2023

Background

The neuroinflammatory response, particularly the activation of the NLRP3 pathway, has been suggested as one of the key mechanisms of the pathological process in neurodegenerative diseases. Tandem pore domain halothane‐inhibited K+ channel 1 (THIK‐1) provides an upstream regulation of this neuroinflammatory response by modulating intracellular K+. While in vitro and in vivo model systems provide strong support for these mechanisms, unequivocal evidence from neurodegenerative disorders has been lacking.

Method

This research project investigated gene expression of markers in the THIK‐1/NLRP3 pathway by studying post‐mortem brain tissue of animal model representing Alzheimer’s disease (AD). In addition, THIK‐1 gene and protein expression in human post‐mortem brains of AD and Parkinson’s disease (PD) was investigated. Furthermore, DNA methylation of THIK‐1 gene in human post‐mortem brains of AD was analysed to explore a potential underlying mechanism of the changes of THIK‐1 gene expression.

Result

A rat model of AD pathogenesis by intrahippocampal Aβ oligomer injection showed substantial up regulation of THIK‐1, glial activation markers, NLRP3 inflammasome components and IL‐1β. Changes in cortical gene expression for THIK‐1 support an inflammatory glial cell activation in both advanced AD and PD with dementia, not observed in the substantia nigra of the latter group. The increase in THIK‐1 expression was also supported by down‐regulation in DNA methylation of its corresponding gene in AD.

Conclusion

The association between THIK‐1 expression and pathology changes observed in this study indicate a THIK‐1‐induced activation of this glial subtype in AD and PD. Therefore, specific blocks of the microglial THIK‐1 K+ channels at the early stage of AD and PD provides a potential therapeutic target.
Risk architecture for altered hippocampal connectivity in normal aging differ between men and women
Authors: Schweitzer Noah , Li Jinghang , Lopresti Brian J , Klunk William E , Snitz Beth E. , Tudorascu Dana , Cohen Ann D. , Kamboh M. Ilyas , Halligan Edye , Thurston Rebecca C , Villemagne Victor L , Iordanova Bistra , Aizenstein Howard J , Wu Minjie
Published: December 2023

Background

Functional MRI (fMRI) studies have associated impaired memory networks with increase in AD pathology. Recently, cross‐sectional analyses found b‐amyloid (Aβ) deposition associated with different patterns of hippocampal connectivity in a memory task based on sex and white matter hyperintensity volume (WMHV). However, cross‐sectional studies don’t provide insight into the driving mechanisms of network change. In this longitudinal study, we identify risk factors based on sex that are associated with memory network connectivity changes.

Method

Our study included 54 cognitively normal older adults (N = 34 female, mean age 74.6 years) with MRI scans on average 2.43 (SD 0.82) years apart. T1w, T2‐FLAIR MRI, and PiB PET were collected to quantify cortical volume, WMHV and Aβ deposition, respectively. Task fMRI was collected while participants performed face‐name associative memory tasks. Left and right hippocampus seeds were used to estimate functional connectivity between hippocampus and voxels in the brain. Second‐level analyses were performed to determine regions of interest (ROI) with significant differences in sex by time interaction (p<0.001). The mean beta values were extracted from the significant ROIs for post‐hoc analysis where we performed multivariate linear regression analyses to find correlations with connectivity change (follow‐up minus baseline).

Result

Three ROIs presented significant sex by time interactions: left‐right hippocampus, hippocampus‐anterior cingulate cortex (ACC), and hippocampus‐medial frontal gyrus. The change in left‐right hippocampus connectivity increased for women and decreased for men (Fig.1). For the other ROIs, connectivity increased for men and decreased for women (Fig.2). Left‐right hippocampal connectivity change had a significant sex‐WMHV interaction effect (p<0.01), where only women had a positive association between connectivity change and baseline WMHV. Hippocampus‐ACC connectivity change had a significant sex‐Aβ interaction (p<0.01), with greater baseline Aβ associated with increased connectivity change for men and decreased for women.

Conclusion

We observed sex‐differences in risk architecture for altered hippocampal connectivity. In the presence of vascular pathology and Aβ, women appear to experience local hippocampal connectivity and decrease hippocampal‐frontal connectivity. Meanwhile, men experienced hippocampal‐frontal connectivity with increased Aβ burden. Characterizing these sex differences in memory network alterations can help guide the development of sex‐specific prevention and treatment strategies.