bluuebunny/crossref_metadata_2025_split huggingface dataset:
Factors associated with caregiver burden in early onset dementia: the LEAF study
Authors: Lee Sun Min , Kim Hee Jin , Jung Na‐Yeon , Park Kee Hyung , Cho Hanna , Kim Yeshin , Jang Jae‐Won , Kang Heeyoung , Lee Jin San , Kang Sung Hoon , Yoon Soo Jin , Kim Hang‐Rai , Park Kyung Won , Chung Eunjoo , Park Young Ho , Jang Hyemin , Lim Jae Sung , Kim Geon Ha , Jeong Jee Hyang , Choi Seong Hye , Cho Su Hyun , Kim Seung Joo , Kwon Jay Cheol , Lee Juyoun , Kang Kyunghun , Kim Jaeho , Kim Hee‐Jin , Kim Si Eun , Yi Hyon‐Ah , Park Ji Yoon , Kim Eun‐Joo , Moon So Young 
Published: December 2023

AbstractBackgroundEarly‐onset dementia is often predicted to have a greater care burden than late‐onset dementia. Indeed, previous studies have reported that caregivers of early‐onset dementia suffer more than those of late‐onset dementia. We explored the factors that determine care burden in early‐onset dementia.MethodCaregivers whose patients participated in a longitudinal study of early onset dementia and family members (LEAF) were asked to respond to questionnaires regarding caregiver features and care burden such as CAS‐K (Korean Version of Caregiver Activity Survey), ZBI (Zarit Burden Interview), and SF‐36v2® (Short‐Form Health Survey 36 version 2). Correlation and linear regression analyses were conducted to clarify the factors affecting care burden, using commercial software (SPSS 23.0;SPSS Inc. Chicago,IL,USA).ResultA total of 255 caregivers (54.5±25.3 years old, 54.9% female) were divided into three groups depending on the clinical diagnosis of the patients they cared for (EOAD 181; FTD 53; other EOD 21). There were no statistical differences of demographic characteristics and care burden related variables among three groups of caregivers. The general burden for caregivers and time spent in caregiving were higher in patients with shorter education years, lower mini‐mental state examination(MMSE) scores (‐0.381, p<0.001), higher clinical dementia rating(CDR) (0.359, p<0.001), higher CDR sum of boxes (0.418, p<0.001), decreased level of activities of daily living (ADL, basic ‐0.334, p<0.001; instrumental 0.527, p<0.001), higher geriatric depression scale (GDS, 0.245, p<0.001) and higher body mass index(BMI, 0.149, p<0.05). Caregivers with a high Beck depression inventory(BDI) (0.218, p<0.001) spent more time for caring patients. The general care burden was greater in younger caregivers (‐0.142, p<0.05) and in caregivers with lower average monthly income(‐0.166, p<0.001), decreased physical function (‐0.142, p<0.05), poorer mental health (‐0.150, p<0.05), and more physical/emotional role limitation (‐0.464, p<0.001).ConclusionThis study is expected to have implications in that it also reviews the economic status of caregivers and ongoing personal and social changes according to the care burden. Demographic and clinical factors of patients and caregivers predict care burden in early‐onset dementia. This suggests that it is possible and necessary to attempt to reduce care burden through adjustment and support for related factors.
Identification of CSF biomarkers for cerebral amyloid angiopathy using a targeted proteomics approach
Authors: Kuiperij H. Bea , de Kort Anna M. , Schreuder Floris H.B.M. , Klijn Catharina J.M. , Verbeek Marcel M. 
Published: December 2023

AbstractBackgroundCerebral amyloid angiopathy (CAA) is characterized by progressive vascular deposition of amyloid‐β (Aβ), and can cause cognitive decline in the elderly. Currently, the diagnosis of CAA is based on neuroimaging and includes the identification of lobar (micro‐)bleeds and cortical superficial siderosis. There is, however, a need for alternative methods as these neuroimaging methods are not optimal for detection of CAA during life. Moreover, CAA is strongly associated with the risk to develop edematous or hemorrhagic amyloid‐related imaging abnormalities (ARIA) as a consequence of anti‐Aβ immunotherapy (e.g. aducanumab and lecanemab) for Alzheimer’s disease (AD). There is a need for biomarkers that can provide an accurate and early diagnosis of CAA, and additionally help in the identification of AD patients with a high burden of CAA, who are at risk of developing ARIA due to immunotherapy. We aimed to identify novel biomarker candidates for CAA in cerebrospinal fluid (CSF) using a targeted proteomics approach.MethodWe analyzed a panel of 367 proteins in CSF samples of 34 CAA patients and 51 age‐ and sex‐matched controls using the Olink Explore multiplex immunoassay platform (Neurology panel; Olink, Uppsala, Sweden). Proteins were considered measurable when their levels were above the limit of detection of the assay in at least 70% of the samples.ResultFor 15 of the 263 proteins that could be measured in CSF, we identified significantly different (p<0.05) levels in CSF of CAA patients as compared to controls. The strongest difference was observed for neurofilament light chain (NFL). Among these 15 proteins, there were two proteins (milk fat globule‐epidermal growth factor 8 (MFG‐E8/lactadherin) and urokinase‐type plasminogen activator (uPA)) for which we previously observed a significant changed level in CSF of CAA patients compared to controls 1,2.ConclusionConfirmation of previously identified CAA biomarker candidates shows the validity and strength of our biomarker identification study using a targeted proteomics approach. The 15 candidates identified in our study, therefore, hold promise for development into biomarkers that may improve the detection of CAA.References: 1 Marazuela et al, Acta Neuropathol Commun. 2021;9(1):154.2 Vervuurt et al, Neuropathol Appl Neurobiol. 2022;48(5):e12804.
The development of therapeutic nanovaccine that elicits anti‐Aβ antibodies and Aβ‐specific regulatory T cells for the treatment of Alzheimer’s disease.
Authors: Lee Songmin , Jung Mungyo , Kim Byung‐Soo , Kim YoungSoo 
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD) is a multi‐factorial cognitive disorder with complex pathogenesis including the accumulation of beta‐amyloid (Aβ) plaque and neuroinflammation. In previous studies, active immunotherapy injecting Aβ peptide as an antigen achieved the prophylaxis of Aβ accumulation by generating anti‐Aβ antibodies. Otherwise, the adoptive transfer of regulatory T (Treg) cells attenuated neuroinflammation by secreting anti‐inflammatory cytokines in the AD brain. To combine both approaches and improve the therapeutic efficacy against AD, we developed a nanovaccine that presents Aβ peptides as antigen and simultaneously induce the differentiation of naive T cells into Aβ‐specific Treg cells.MethodA lipid nanoparticle loaded with Aβ peptides and rapamycin (LNP‐R/Aβ) was intradermally injected once a week for five weeks into a transgenic AD mouse model, 5XFAD. The generation of Aβ‐specific antibodies in the plasma and brain was measured by indirect enzyme‐linked immunosorbent assay. Induction of Treg cells in the spleen was measured by flow cytometric analysis and RT‐qPCR analysis. The accumulation of Aβ aggregates in the brain and the level of neuroinflammation were evaluated by immunohistochemical and immunoblotting assay. The cognitive function of 5XFAD was assessed through the Morris water maze test.ResultAdministration of LNP‐R/Aβ generated anti‐Aβ polyclonal antibodies detecting the N‐terminus (Aβ1‐8) of the Aβ peptide. Also, the increased level of CD4+Foxp3+Treg cells was observed in the spleen and brain. The Treg cells induced by the LNP‐R/Aβ more efficiently reduced the Aβ plaque accumulation than general Treg cells, indicating that LNP‐R/Aβ promoted the generation of Aβ‐specific Treg cells. Also, the Aβ‐specific Treg cells led to the differentiation of microglia into anti‐inflammatory form of microglia secreting anti‐inflammatory cytokines such as TGF‐β1 and IL‐10. These changes resulted in a significantly decreased amount of Aβ plaques and the attenuated proliferation of reactive microglia and astrocyte in the 5XFAD mice brains. Furthermore, LNP‐R/Aβ injected 5XFAD mice showed improved learning and memory function in the Morris water maze test.ConclusionLNP‐R/Aβ proposes a novel approach to AD treatment that achieves synergistic therapeutic efficacy by combining the mode of action of anti‐Aβ antibodies and Aβ‐specific Treg cells.
Association of waist‐to‐hip ratio with Alzheimer’s disease and neuroinflammation biomarkers in cognitively unimpaired adults
Authors: Tort‐Colet Núria , Sánchez‐Benavides Gonzalo , Minguillon Carolina , Kollmorgen Gwendlyn , Carboni Margherita , Zetterberg Henrik , Blennow Kaj , Gispert Juan Domingo , Suarez‐Calvet Marc , Grau‐Rivera Oriol 
Published: December 2023

AbstractBackgroundObesity is associated with higher risk of Alzheimer’s disease (AD) and other dementias. This association could be mediated by a pro‐inflammatory effect of abdominal adiposity. Here, we used the waist‐to‐hip ratio (WHR) as a proxy for central adiposity to explore its association with AD and neuroinflammation biomarkers, as well as its interaction with sex in cognitively unimpaired adults from the ALFA+ cohort.MethodWe analyzed data from 353 participants (61.2% females; 64.3% β‐amyloid [Aβ]+; 61.04 ± 4.77 years on average). We measured CSF p‐tau and t‐tau with the Elecsys® immunoassays and CSF Aβ42, Aβ40 and neuroinflammation biomarkers (sTREM2, GFAP, YKL40, S100 and IL‐6) with the exploratory Roche NeuroToolKit robust prototype assays. We used separated linear regression models to analyze associations of WHR with CSF AD and neuroinflammation biomarkers while adjusting by age, sex, APOE status, education years, mean blood pressure and triglycerides. We ran interaction analyses between WHR and sex.ResultWe did not find significant main effects of WHR on CSF AD or neuroinflammation biomarkers. We found a significant interaction between WHR and sex on IL‐6 (p = 0.008; correcting by multiple hypotheses, p_adjusted = 0.067). After stratifying by sex, WHR was associated with IL‐6 in the male group (p = 0.032; p_adjusted = 0.242), but not in the female group (p = 0.596).ConclusionWHR is positively associated with IL‐6 levels in males. The effect of sex, and the role of neuroinflammation as a potential mediator in the association between obesity and dementia risk warrant further research.
Concordant and antagonistic associations of genetic variants with Alzheimer’s disease and diabetes mellitus through blood glucose and body‐mass index
Authors: Kulminski Alexander M. , Feng Fan , Loika Yury , Loiko Elena , Kulminskaya Irina 
Published: December 2023

AbstractBackgroundMounting evidence suggests common etiologies of Alzheimer’s disease (AD) and diabetes mellitus (DM). Genetic mechanisms underlying the risks of AD and DM remain elusive.MethodWe used individual‐level data from four longitudinal studies,—the Atherosclerosis Risk in Communities study, Cardiovascular Health Study, Framingham Heart Study, and UK Biobank,—to examine causal mediation effects in the associations of single nucleotide polymorphisms (SNPs) with AD and DM. We selected 178 lead SNPs representing 74 previously identified AD‐ and/or DM‐associated loci on 20 chromosomes (excluding chromosomes 6 and 21). First, we used marginal structural models to perform a univariate mediation meta‐analysis considering AD or DM as an outcome and blood glucose (BG) or body mass index (BMI) measured before the onset of AD and DM as a mediator. Then, we utilized summary statistics from these univariate analyses to examine pleiotropic mediation effects on AD and DM using an omnibus test.ResultWe identified 56 SNPs in 26 loci on 12 chromosomes attaining p<0.05 in the univariate mediation meta‐analyses and genome‐wide significance (p<5×10−8) in the pleiotropic meta‐analysis of indirect effects on AD and DM through BG and BMI. BG and BMI mediated associations of 27 SNPs—14 loci on nine chromosomes; none in the APOE locus— and 33 SNPs—14 loci on eight chromosomes, including the APOE locus—, respectively. SNPs only from two of 26 loci on chromosomes 7p15.1 (JAZF1 gene) and 10q25.2 (TCF7L2 gene) showed pleiotropic effects through both BG and BMI. Directions of the mediation effects on AD and DM were the same for the same alleles through BG and the opposite through BMI. The exclusion of DM‐affected subjects explained mediation effects on AD through BG in all 14 loci. In contrast, this exclusion improved the significance of the mediation effects on AD through BMI also in all loci by decreasing p‐values 0.5 to 2 orders of magnitude.ConclusionMost of the identified genetic variants increase susceptibility to AD and DM through different mechanisms. The BG‐associated genetic mechanism is common for AD and DM, whereas the BMI‐related genetic mechanism mediates the AD and DM risks in an antagonistic manner.
Genetic screening of ANXA11 in Korean patients with Frontotemporal dementia syndrome
Authors: Kim Eun‐Joo , Ki Chang‐Seok , Kim Seung Hyun , Na Duk L , Seo Sang Won , Kim Hee Jin , Jung Na‐Yeon , Lee Sun Min , Moon So Young , Park Kyung Won , Kim Young‐Eun 
Published: December 2023

AbstractBackgroundPathogenic variants of ANXA11 have recently been identified in patients with ALS and ALS‐FTD in ALS cohorts. However, it is uncertain how prevalent the pathogenic variant of ANXA11 is in FTD syndrome. Thus, we performed genetic screening of ANXA11 in Korean patients with FTD to investigate the frequencies and clinical manifestations of ANXA11 mutations in Asian FTD population.MethodWe searched pathogenic variants of ANXA11 in whole exome database of Korean patients with FTD syndrome. Out of a total of 240 patients, 179 patients had been included in the previous Korean FTD genetic screening studies and the rest 61 patients have currently been enrolled in an ongoing longitudinal study of early onset dementia and family members‐FTD (LEAF‐FTD).ResultOne pathogenic variant in ANXA11, c.119A>G (p.D40G), was identified in three patients with right‐predominant svPPA. One of them has recently been reported elsewhere. They were all women and mean age of onset was 63 years old. Two of them had family history of dementia in first‐degree relatives. One patient showed dysarthria and motor weakness 3 years after the onset of symptoms who might have been presumed to have svPPA‐ALS, while the other two had no neurological deficits. Initial neuropsychological test results revealed selective impairments of naming and verbal memory. Brain MRIs demonstrated cortical atrophy in bilateral anterior temporal areas, worse on the right. One patient carried a pathogenic variant, p.V180I of PRNP as well as p.D40G of ANXA11, however, did not show any clinical features of CJD. Other than p.D40G variant, we found two variants of unknown significance of ANXA 11 in one patient with nfvPPA (c.1336‐6C>G) and the other with bvFTD (c.654G>A, p.T218 = ).ConclusionANXA11 mutations account for 0.8% of familial and 1.7% of sporadic ALS in European populations. The p.D40G variant identified in this study (1.25%, 3/240) had already been reported in both familial and sporadic ALS. Although the phenotypic variation of ANXA11 in FTD or FTD‐ALS syndrome remains unclear, our results suggest that right‐predominant svPPA may be a common FTD or FTD‐ALS manifestation in p.D40G variant. Further genetic screening of ANXA11 in Caucasian FTD cohort is needed.
Behavioural Deficits and Regional Cerebral Perfusion Map in Cognitively Normal and Pre‐Dementia Stages
Authors: Vipin Ashwati , Soo See Ann , Zailan Fatin Zahra , Leow Yi Jin , Kumar Dilip , Lee Faith Phemie Hui En , Ghildiyal Smriti , Kandiah Nagaendran 
Published: December 2023

AbstractBackgroundOur previous work has shown increased presence of early behavioural impairment in Asian than Western cohorts(Soo et al.,2021). Such impairments include mild behavioural changes, sleep disruptions and higher depression, anxiety and stress, in turn representing an at‐risk state which may predict later development of dementia(Müller‐Spahn,2003;Soo et al.,2021). Additionally, growing evidence illustrates that cerebrovascular changes are a key component in the pathological sequelae and may be detectable years before clinical presentation of dementia (de la Torre,2018). However, the influence of cerebral perfusion on behaviour, especially in pre‐dementia stages remains to be elucidated. Thus, we examined the association between regional grey matter perfusion and behaviour in cognitively normal(CN) and subjects with mild cognitive impairment(MCI) or subjective cognitive decline(SCD). We hypothesized that grey matter perfusion deficits would be related to behaviour impairment even in early stages of SCD/MCI.MethodWe studied 35 CN and 248 pre‐dementia (MCI/SCD) from a community‐based research cohort from the Dementia Research Centre (Singapore) with neuroimaging, neuropsychological and behavioural assessments(Table 1). We investigated the association between regional grey matter perfusion across 31 regions of interest spanning frontal, parietal, temporal and occipital lobes using 2D pulsed Arterial Spin Labelling and performance on the mild behaviour impairment‐checklist(MBI‐C), Pittsburgh Sleep Quality Index(PSQI) and Depression, Anxiety and Stress Scale(DASS). These associations were examined in CN and MCI/SCD groups separately and respective Pearson’s correlation matrices were derived.ResultOverall, greater behavioural impairment on the MBI‐C, DASS and PSQI was associated with hypoperfusion across multiple grey matter regions. This association was stronger in CN than in the pre‐dementia group. Specifically, among CN, hypoperfusion in the frontal, parietal and occipital lobes related most strongly to greater behavioural impairment, especially MBI‐C and DASS depression(Fig.1). In the MCI+SCD group, only hypoperfusion in the frontal and temporo‐occipital regions related to worse behavioural impairment across the MBI, PSQI and DASS(Fig.2).ConclusionIn this study, we illustrate differential associations between cerebral hypoperfusion and behavioural impairment in CN and MCI/SCD groups, with CN individuals showing more widespread and stronger associations between behavioural impairment and hypoperfusion across the brain. In SCD/MCI, hypoperfusion in frontal and temporo‐occipital regions were associated with behavioural impairment.
Dysbiosis of the Gut microbiota was improved after 24‐week multidomain intervention program to prevent dementia: Subgroup Analysis of SUPERBRAIN study
Authors: Kang Woorim , Park Yoo Kyoung , Jeong Jee Hyang , Moon So Young , Song Hong‐Sun , Lee Sun Min , Choi Muncheong , Park Kyung Won , Kim Byeong‐Chae , Cho Soo Hyun , Choi Seong Hye , Hong Chang Hyung , Na Hae Ri 
Published: December 2023

AbstractBackgroundThe stability of intestinal microbiota is critical to maintaining the integrity of epithelial barrier and immune homeostasis. Thereby, the disruptions to this balance and resulting dysbiosis are often associated with inflammation and compromised barrier function and may cause several kinds of diseases. There is growing evidence that people with Alzheimer’s may have different internal microorganisms than those who do not. We aimed to investigate gut microbiota changes after a 24‐week multidomain lifestyle intervention program in the SoUth Korean study to PrEvent cognitive impaiRment and protect BRAIN health through lifestyle intervention in at‐risk elderly people (SUPERBRAIN).MethodParticipants without dementia and with at least one modifiable dementia risk factor, aged 60‐79 years, were randomly assigned to the facility‐based multidomain intervention (FMI) (n = 51), the home‐based multidomain intervention (HMI) (n = 51), and the control group (n = 50). Demographic and clinical factors were assessed as well as the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) were evaluated as neuropsychological tests both at baseline and at the end of the study. Stool samples were collected for analysis of 16S rRNA gene sequencing, taxonomic profiling, and functional profiling.ResultParticipants who received either the facility‐based (5.4 ±7.7 increase) or home‐based (5.4 ±8.2 increase) intervention showed significantly increased RBANS scores compared to the control (0.03 ± 9.3 increase). The Beta‐diversity analysis showed significant differences in the microbial composition between the intervention group and control group. Also, participants who received multidomain intervention showed decreased proteobacteria abundance and increased abundance of Lachnospira, Parabacteroides.ConclusionIn conclusion, the present study suggest that multidomain intervention in elderly with high risk of dementia not only showed beneficial effect on neuropsychological status but also improving the dysbiosis of gut microbiome
Adaptive immune response in Alzheimer’s disease: untangling the role of ApoE4
Authors: Halters Sem , Vries De 
Published: December 2023

AbstractBackgroundThe strongest genetic risk factor for developing late‐onset Alzheimer’s disease (AD), ApoE4, drives inflammation in the central immune system. However, it remains largely unkown whether ApoE4 also affects the adaptive immune response.MethodFirst, we performed mass cytometry to identify an immune signature in splenocytes of human ApoE4‐TR and ApoE3‐TR mice. Following this, we used immunohistochemistry to check for brain infiltration of immune cells and BBB integrity.ResultWe identified an adaptive immune response in splenocytes of human ApoE4‐TR mice displayed by a shift from naïve and effector to memory CD8+ T cells. Futhermore, we found an increased number of CD8+ T cells in the brain of ApoE4‐TR mice. ApoE4 also has an effect on BBB integrity, as indicated by a decrease in the tight junction proteins, VE‐cadherin and claudin‐5, in ApoE4‐TR mice compared to ApoE3‐TR mice.ConclusionApoE4 induces an adaptive immune response in mouse splenocytes resulting in brain infiltration of CD8+ T cells.
Comparative Pharmacokinetic Studies of One‐Month Donepezil IM Depot and Once Daily Oral Tablet in Healthy Male Volunteers
Authors: Seol Eunyoung , Lee Jinwoo , Lee Shin‐Won , Byun Jeongsu , Chung Jae‐Yong , Lee Heeyong 
Published: December 2023

AbstractBackgroundThis study is to evaluate the safety and tolerability of single dose of one‐month donepezil IM depot (GB‐5001) in healthy male volunteers and to compare pharmacokinetic parameters of 70mg donepezil IM depot and 10mg once daily oral tablet (Aricept®) in human.MethodIn this phase 1, a randomized, double‐blind, placebo‐controlled, dose‐escalation study, 48 healthy subjects were randomized to single dose of Aricept tablet or placebo or GB‐5001 (70mg or 140mg or 280mg) for 64 days. In this study, safety and tolerability of 70mg donepezil IM depot were examined by monitoring adverse events and vital signs. PK parameters such as AUCt, AUCinf, Cmax and Tmax were compared by measuring donepezil concentration after a single dose of 70mg IM depot and 10mg oral tablet.ResultA single dose of 70mg donepezil IM depot showed no significant adverse events and was well tolerated in healthy male volunteers. In 70mg GB‐5001, all the subjects had measurable concentrations up to 1512 h post dose. The geometric mean of PK exposure parameters are 6482.82 h*ng/mL, 6604.01 h*ng/mL and 11.40 ng/mL for AUCt(0‐1512h), AUCinf, and Cmax, respectively. The median peak concentration (Tmax) was observed at 432h post dose. In 10mg oral Aricept, all the subjects had measurable concentrations up to 240 h post dose. The geometric mean of PK exposure parameters are 656.84 h*ng/mL, 751.34 h*ng/mL and 17.68 ng/mL for AUCt(0‐240h), AUCinf, and Cmax, respectively. The median peak concentration (Tmax) was observed at 2.25 h post dose.ConclusionA single dose of 70mg donepezil IM depot was found to be safe and well tolerated in healthy male volunteers. The pharmacokinetic results of 70mg donepezil IM depot showed stable donepezil blood concentration for more than one month without burst drug release, and showed comparable unit dose drug exposure not lower than that of once daily 10mg oral formulation. Through the PK results for additional higher doses and multiple PK simulations, optimal once monthly dose of donepezil IM depot could be suggested which will be bioequivalent to 10mg once daily tablet.