bluuebunny/crossref_metadata_2025_split huggingface dataset:
Investigating the effect of hearing loss on genetic susceptibility to AD‐related neuropathology and cognitive impairment in a rodent model
Authors: Patel Salonee V , Schormans Ashley L , Myers Sarah J , Malouf Layya Al , Book Shae A , Hayes Sarah H , Allman Brian L , Whitehead Shawn N 
Published: December 2023

AbstractBackgroundDementia affects 55 million people worldwide; a staggering statistic which highlights the need to limit its risk factors (WHO 2022). Importantly, epidemiological studies have reported that hearing loss significantly increases the risk of developing dementia, including Alzheimer’s disease (AD) (Lin et al., 2011; Hung et al., 2015). Furthermore, preclinical studies have identified that noise‐induced hearing loss causes molecular changes in the hippocampus that are consistent with AD‐related neuropathology (Cui et al., 2015; Saljo et al., 2002). However, the effect of noise exposure on AD‐related neuropathology and cognitive impairment in models of genetic susceptibility to AD is not well explored.MethodTo investigate the interplay between noise‐induced hearing loss and genetic susceptibility to AD, we utilized transgenic Fischer 344 (TgAPP) rats that overexpress pathogenic human amyloid precursor protein, but do not spontaneously develop β‐amyloid plaques (Agca et al., 2008). Adult male and female, TgAPP and wildtype, Fischer 344 rats were noise (100 dB SPL; 4 hours/day; 30 days) or sham‐exposed at 12 months of age. Afterward, hippocampal cognitive function was assessed with the Morris water maze task and striatal‐dependent visuomotor associative learning was tested using an operant conditioning‐based task. Lastly, microglial activation and cholinergic function post‐noise/sham exposure were examined using immunohistochemical analysis of Iba1 and choline acetyltransferase (ChAT) expression, respectively.ResultsConsistent with hearing loss often experienced by humans, our protocol resulted in high‐frequency hearing loss in the rats. As expected, TgAPP rats showed impaired reference memory and increased Iba1‐positive cells in the hippocampus; however, in contrast to our prediction, noise exposure did not exacerbate these results. We also identified a differential effect between the sexes and genotypes for how noise exposure affected visuomotor associative learning. While noise‐exposed wildtype male rats exhibited a faster reaction time than their sham‐exposed counterparts, noise‐exposed TgAPP males showed a significantly slower reaction time; an effect not observed in female rats.ConclusionThese findings point to a complex relationship between noise‐induced hearing loss, visuomotor associative learning, and genetic susceptibility to AD. Thus, future studies should investigate the molecular underpinnings of the differential changes in reaction time following noise exposure in models of genetic susceptibility.
Phenotypic Status Explored in Parietal Cortex of Alzheimer’s Patients and Non‐Demented Controls that Vary on the Spectrum of Neuropathological AD
Authors: Melnik Mikhail , Bilousova Tina , Ma Ricky , Matsuo Yuriko , Atluri Swetha , Kodavatikanti Achyutha , Knitowski Nina , Gylys Karen H 
Published: December 2023

AbstractBackgroundGenetic studies of Alzheimer’s disease (AD) have shown association with microglia in the brain. We probed microglia with markers against amyloid‐associated (Clec7a, Axl), inflammatory M1 (CD86), alternatively activated M2 (CD206, CD163), and homeostatic (P2ry12, TMEM119) phenotypes in low plaque/tangle pathology controls (A‐T‐), high plaque/low tangle pathology controls (A+,T‐), high plaque/high tangle pathology controls (HPCs) and late AD samples. We sought to determine how these microglial markers changed with clinical and neuropathological AD. APOE status was also explored as its associated with increased inflammation (suggesting M1 effects) and APOE is highly expressed by amyloid‐associated microglia.MethodSamples of parietal cortex from AD patients were cryopreserved in 0.32M sucrose + inhibitors and obtained from the UC Irvine ADRC. The tissue was later thawed, homogenized in 0.32M sucrose + inhibitors and then slow frozen to ‐80°C. These samples were then processed and probed against targets of interest by western blotting.ResultPreliminary data shows a 64.7% decrease in P2ry12 signal in late AD compared to A‐T‐ controls that approaches significance, although TMEM119 shows no changes. A similar pattern is seen in APOE4+(APOE3/4 and 4/4) samples compared to ones that are APOE3/3, with P2ry12 showing a significant decrease while TMEM119 showing no change. CD206 shows a 44.8% decrease in late AD samples relative to A‐T‐ controls, though CD163 shows no difference. CD206 and CD163 do not differ between HPC and late AD samples, nor are they modulated by APOE genotype.ConclusionPreliminary data suggests a decrease of homeostatic microglial signature with the presence of neuropathological, not clinical, AD, although one of the markers, TMEM119, showed no change. TMEM119 and P2ry12 are interesting markers of homeostasis that were characterized in mouse models of AD yet may have a more complicated connection to human disease (Zhou et. al., 2020). M2 microglial marker CD206 shows an increase with neuropathological, but not clinical, AD. Again, a complicated picture of M2 markers is seen, with CD206 showing change but not CD163. APOE genotype differences modulated the P2ry12 homeostatic signal, although no M2 changes were seen.
The Relationship Between Inner Retinal Thickness, Cognition, and Frailty in Community‐dwelling Older Adults: findings from a 6‐year follow‐up study
Authors: Lee Yung‐Sung , Hsieh Yi‐Ting , Chiou Jen‐Ming , Chen Jen‐Hau , Chen Yen‐Ching 
Published: December 2023

AbstractBackgroundThinning of the inner retinal thickness, including ganglion cell‐inner plexiform layer (GC‐IPL) and retinal nerve fiber layer (RNFL), has been related to cognitive decline. However, the relationship between GC‐IPL/RNFL thickness, physical frailty, and cognitive frailty remains unclear. Therefore, this longitudinal study aims to investigate the association of these retinal markers with cognition, frailty, and cognitive frailty.MethodThis is a 7‐year cohort study including 221 community‐dwelling elders in the ongoing Taiwan Initiate for Geriatric Epidemiological Research (TIGER) between 2015 and 2017 and received biennial assessments for cognition and physical frailty three consecutive times. The global and domain‐specific (memory, attention, executive function, and language) cognition were assessed using the Taiwanese version of the Montreal Cognitive Assessment and a series of neuropsychological tests. Physical frailty was assessed by modified Fried frailty phenotypes. The generalized linear mixed model was used to analyze the association between GC‐IPL/RNFL thickness and global/domain‐specific cognitive frailty adjusted for age, sex, years of education, apolipoprotein E ε4 status carriers, cigarette smoking status, presence of depressive symptoms, hypertension or diabetes mellitus, years of follow‐up, and practice effect.ResultThe performance of global cognition decreased as the mean GC‐IPL thickness of bilateral eyes deviated from the sample mean (76.6 µm) (quadratic GC‐IPL: β = ‐0.4×10−2; 95% confidence interval: ‐0.7×10−2 to ‐0.2×10−2). Similar associations were also found for logical memory with RNFL/GC‐IPL thickness. No significant association was observed between RNFL/GC‐IPL thickness and physical frailty. An increased odds of impaired logical memory‐physical frailty was found for GC‐IPL (quadratic GC‐IPL: adjusted odds ratio = 1.005; 95% confidence interval: 1.001 to 1.005), but no significant association was found between cognitive frailty and RNFL thickness.ConclusionChange in the GC‐IPL thickness was associated with impaired cognition and poor logical memory‐frailty performance. The inner retinal thickness may serve as a biomarker for cognition or cognitive frailty in non‐demented elders.
PSEN2 poison exon inclusion is common across brain regions in late‐onset Alzheimer’s disease
Authors: Course Meredith M , Somberg Jenna , Child Daniel D , Gudsnuk Kathryn , Latimer Caitlin S , Kraemer Brian C , Keene C Dirk , Bird Thomas D. , Jayadev Suman , Liachko Nicole F , Valdmanis Paul N 
Published: December 2023

AbstractBackgroundPathogenic variants in APP, PSEN1 and PSEN2 can cause early‐onset familial Alzheimer’s disease (AD). The molecular events leading to AD in individuals with late‐onset sporadic AD are still unclear even though they share the same clinical and pathological features of AD.MethodUsing targeted PacBio long read isoform sequencing (Iso‐Seq), we recently reported the characterization of tens of thousands of complete PSEN1 and PSEN2 transcripts in the prefrontal cortex of individuals with sporadic AD, familial AD (carrying PSEN1 and PSEN2 pathogenic variants), and controls.ResultWe found several alternative splicing differences in PSEN2 that are significantly elevated in sporadic AD including inclusion of a human‐specific cryptic exon present in intron 9 of PSEN2 (termed exon 9B) present in 11.8% of full‐length reads in sporadic AD samples relative to 1.9% of controls (p = 0.002) and 3.4% of PSEN variant carriers (p = 0.005) as well as a 77bp intron retention product prior to exon 6. These PSEN2 splice products are predicted to generate a prematurely truncated PSEN2 protein and were confirmed in an independent RNA‐seq dataset of ∼80 AD cases and ∼80 controls from cerebellum tissue (Course et al., Brain 2022). To extend these findings we analyzed PSEN2 exon 9B isoform levels in parietal and temporal lobe tissue samples. We found exon 9B was significantly elevated in sporadic AD relative to controls in the parietal lobe (p = 0.02) as well as the temporal lobe (p = <0.001). However, levels of exon 9B were independent of TDP‐43 pathology or MSUT2 protein levels, which is intriguing given their roles as RNA binding proteins implicated in AD. We are working to establish the consequence of exon 9B inclusion in APP processing, Aβ and PSEN2 protein products in addition to possible cell autonomous roles for PSEN2 splice variants in microglia by leveraging single cell sequencing data.ConclusionCollectively, our findings expand our understanding of PSEN2 splice variants in the development of late‐onset sporadic AD, which can point to novel therapeutic strategies for AD.
Association of geriatric depressive symptoms and government‐initiated senior employment program: a community based cross‐sectional study in Korea
Authors: Roh Hyun Woong , Park Soyeon , Park Sunghong , Cho Yong Hyuk , Nam You Jin , Hong Sunhwa , Hong Chang Hyung , Son Sang Joon 
Published: December 2023

AbstractBackgroundThe association between geriatric depressive symptoms and government‐initiated senior employment program (GSEP) according to the income level has not been thoroughly investigated. Identifying it may provide insights into executing senior employment programs and interventions.MethodParticipants were 9287 adults, 65 or older, who participated in Living Profiles of Older People Survey (LPOPS) 2020. Korean version of the 15‐item Geriatric Depression Scale (SGDS‐K) was used to measure the main outcome, which was geriatric depressive symptoms and its three factors. The main exposure was employment status, GSEP, and the income level. A multiple linear regression analysis was performed.ResultCompared to being unemployed, being employed was associated with lower geriatric depressive symptoms regardless of income. In non‐GSEP jobs, higher income was proportionately associated with lower geriatric depressive symptoms but also higher life dissatisfaction. A group of GSEP jobs whose income level belonged to the first tertile (β of geriatric depressive symptoms = ‐1.027, β of life dissatisfaction = ‐0.510) was associated with lower geriatric depressive symptoms and life dissatisfaction compared to all tertiles of non‐GSEP jobs (β of geriatric depressive symptoms of first, second, and third tertile = ‐0.463, ‐0.542, ‐0.576; β of life dissatisfaction of first, second, and third tertile = ‐0.258, ‐0.176, ‐0.142).ConclusionThe group of GSEP jobs, whose income level belonged to the first tertile, was associated with lower geriatric depressive symptoms and lower life dissatisfaction compared to all tertiles of non‐GSEP jobs. We expect this result to give insights into implementing government policies and community‐based interventions.
Alzheimer’s Disease Dementia Classification Through Residual Network and QEEG Image representations
Authors: Jeong Taegyun , Park Ukeob , Hong Yuseong , Youn Young Chul , Kang Seung Wan 
Published: December 2023

AbstractBackgroundOur everyday actions and decisions involve a complex coordination of various cognitive functions. Severe deterioration of such functions, commonly referred to as dementia, adversely affects quality of our lives. However, through early screening of the disease at its pre‐clinical stage and appropriate treatment, they can be reverted. Current diagnostic criteria for dementia utilize questionnaire‐based cognitive function assessments, such as the mini‐mental state examination. However, it is statistically less robust, where further tests such as positron emission tomography are required for accurate diagnosis. This is laborious, expensive and expose patients to harmful radiation. Therefore, we propose a quantitative electroencephalography (QEEG) based approach that distinguishes Alzheimer’s disease dementia (ADD) from a non‐ADD group that include mild cognitive impairment and subjective cognitive decline data.Method19 channel EEG data employed in the present study were clinically acquired from Chung‐Ang university hospital, in eyes‐closed resting state. Artefacts were eliminated through independent component analysis and bad epoch rejection. Through spectral analysis, the powers of a frequency spectrum (1‐45Hz) were computed with 0.25Hz resolution. Henceforth, the Z‐score of each value were calculated through iMediSync’s age‐ and sex‐differentiated normative database and were mapped into a rectangular arrangement in accordance with channel locations on the scalp. The rearranged Z‐score matrices were visualized, clearly exhibiting both spectral and spatial information. Gamma spectrum (30‐45Hz) was excluded due to its vulnerability to contaminations induced by external noises and muscle movements. The final dataset (N = 732; 137 ADD, 595 non‐ADD) was established, where the 75% of non‐ADD were first excluded as test data due to data imbalance. The remaining data were split into 2 to 8 ratio for testing (N = 503; 27 ADD; 476 non‐ADD) and training (N = 229; 110 ADD; 119 non‐ADD).ResultThe final 18‐layer Residual network model showed test accuracy at 88.5% with ADD sensitivity at 88.9% and specificity at 88.4%. Explainable artificial intelligence algorithm was utilized for the inference and verification of classification criteria.ConclusionThe outstanding classification results of the established model upholds QEEG utility in the distinguishment of dementia from its pre‐clinical stages. Continuous refinement will bolster its potential in the diagnosis several other neurological diseases.
Differences in the proteomic profile of the brain in Alzheimer’s disease in Down syndrome and early‐onset Alzheimer’s disease
Authors: Farrell Clíona , Mumford Paige , Hällqvist Jenny , Heywood Wendy , Fisher Elizabeth , Mills Kevin , Toomey Christina E. , Wiseman Frances K 
Published: December 2023

AbstractBackgroundDown syndrome (DS) is caused by trisomy of chromosome 21 (Hsa21) and is a leading genetic cause of Alzheimer’s disease (AD‐DS). People with DS have a third copy of amyloid precursor protein (APP) which causes the increased risk to develop AD neuropathology and dementia, decades earlier than in the general population. However, other genes on Hsa21 have been shown to modify AD‐DS development compared to the development of AD in the general population. Here, we aim to understand how AD‐DS differs to EOAD at end‐stage disease.MethodLabel‐free mass spectrometry was performed using a SYNAPT G2‐Si High‐Definition machine with 2D fractionation on prefrontal cortex tissue (BA10) from individuals with AD‐DS, early‐onset AD (EOAD) (both Braak‐stage VI), and healthy age‐matched controls. Proteins identified were ranked by significance (p < 0.05) and a fold‐change of difference between groups was calculated. qPCR was used to measure transcript levels of altered proteins in the same samples and to assess if transcript levels of raised proteins were altered in the Dp1Tyb (MGI:5703798) mouse model of DS which has three‐copies of ∼148 Hsa21 orthologous genes.ResultRaised abundance of Hsa21 encoded proteins, including PDXK, APP and S100B, were identified in individuals with AD‐DS compared to EOAD. Importantly, non‐chromosome 21 encoded proteins were also shown to be raised in individuals with AD‐DS compared to EOAD, including APOE, NLRP8 and PTN. Raised APOE protein in AD‐DS compared to EOAD brain tissue is Apolipoprotein E genotype independent. Apoe is not raised in the Dp1Tyb hippocampus or cortex at 6‐months of age.ConclusionPeople with AD‐DS exhibit an altered proteomic profile compared to people with EOAD, likely driven by having three‐copies of Hsa21 genes. Raised APOE may be driven by an interaction of trisomy 21 and AD pathogenesis, as this phenotype is not seen in the Dp1Tyb mouse model. Understanding the differences in AD pathogenesis is key for including people with DS in future AD clinical trials. Future work will validate protein expression of candidates of interest in an independent cohort of human post‐mortem brain samples, as well as determine the cell types in which proteins of interest are expressed.
Developing an occupational telerehabilitation program for caregivers of people with dementia to increase their ability to care and reduce burden
Authors: Giovanni Orientina Miriam Di , Chinaglia Cinzia Negri , Petrucci Bianca Maria , Fritzsching Daniela Matilde , Fabbo Andrea 
Published: December 2023

AbstractBackgroundPeople with dementia (PwD) require high levels of care, most of which is provided by either family or informal caregivers. Psychosocial interventions have been demonstrated to reduce caregiver burden and delay nursing home admission. Telemedicine could provide caregivers access to such interventions, increasing their sense of competence and resilience.MethodThrough a co‐design process involving geriatricians, psychologists, neurologists, nurses, occupational therapists and 25 dyads, a telerehabilitation program has been developed and tested through a 12‐months Beta Test protocol. The program comprises a multidimensional clinical assessment and a telerehabilitation plan. Whilst occupational therapists act as care manager interface towards caregivers through a telemedicine platform, a multidisciplinary team including nurses, psychologists and geriatricians, regularly oversees each plan and delivers interventions whenever required.ResultsAlmost all caregivers were spouses or children (22 out of 25). 79% were female and 59% lived with the care recipient in the same household. The average age of caregivers was 63,72 and Zarit index 36,88. On average PwD’s age was 83,75, Barthel Index 61,27, IADL 0,97, NPI Index 24,86 with 4,8 BPSD. The program has required on average 18,8 sessions per caregiver: which comprised of 4,5 sessions for multidimensional evaluation of both PwD and caregiver, 9,1 sessions for the execution of the telerehabilitation plan and 5,2 sessions for follow up. Sessions could range from 45 minutes (clinical scales‐based assessment) to 10 minutes (follow up). 48% of telerehabilitation sessions addressed BPSD, 17% provided emotional support, 14% supported caregivers in ADL activities, 11% addressed comorbidities and 10% addressed other issues (communication and cognition). A self‐developed caregivers' reported outcome questionnaire (24 responders out of 25) reported that 88% of caregivers improved their health literacy, 87% their sense of competence and 97% felt emotionally supported. After at least 6 months, a follow up analysis on 13 PwD and 10 family caregivers, NPI Index has improved on average by 41% while Zarit Index by 16%. Average yearly cost of the program reached 2 euro per day per dyad.ConclusionsThe beta test showed encouraging outcomes in terms of caregivers’ satisfaction that require further investigation in terms of clinical outcomes and cost‐effectiveness.
Chronic Exposure of 5‐Alpha Reductase Inhibitor in Young Male Rats Induces Not Only Metabolic Disturbance, But Also Depressive‐Like Behaviors as Similar with Obese Condition
Authors: Saengmearnuparp Thiraphat , Pintana Hiranya , Apaijai Nattayaporn , Chunchai Titikorn , Lojanapiwat Bannakij , Chattipakorn Nipon , Chattipakorn Siriporn C 
Published: December 2023

AbstractBackgroundFinasteride (FIN), a 5‐alpha reductase inhibitor (5‐ARIs), is one of the drugs approved for the treatment of androgenetic alopecia (AGA) and benign prostatic hyperplasia (BPH). AGA has been found to be associated with obesity. Obesity and AGA themselves often co‐occurs with anxiety and depression. Nevertheless, several studies reported adverse effects of FIN on anxiety and depression, especially in young men. A previous study also reported that FIN caused anxiety and depression in male rats; however, the effects of chronic FIN exposure in young obese condition has not been investigated.MethodTwenty male Wistar rats (8‐week‐old) were divided into two groups (N = 10/group) to feed with either normal diet (ND) or high‐fat diet (HFD) for 18 weeks. At week 13, rats in each dietary group were subdivided into two subgroups to treat with either vehicle as control or FIN (5 mg/kg/day) via oral gavage. At the end of the experimental protocol, the anxiety/depression‐like behaviors were measured using the Elevated‐Plus Maze (EPM) and the Splash Test (ST), while the Open‐Field Test (OFT) was examined for locomotor activity. In addition, blood in each rat was collected for determining the metabolic profiles.ResultHFD‐fed rats developed obesity and hypercholesterolemia, with an increase in systemic oxidative stress (Figure 1A‐C). Anxiety and depressive‐like behaviors were observed in vehicle‐treated HFD‐fed rats, as indicated by decreasing % preference index in the open arm of EPM and grooming time in ST (Figure 1D‐E). FIN treated ND‐fed rats also showed depression‐like behaviors, similar to those in vehicle‐treated HFD‐fed rats (Figure 1E). Although FIN increased plasma cholesterol levels in HFD‐fed rats, it did not aggravate anxiety and depression‐like behaviors in HFD‐fed rats. Regarding the locomotor activity, no significant difference was found among all groups. (Figure 1F).ConclusionAll of these findings suggest that FIN exposure induced metabolic disturbance, and depression‐like behaviors as similar to obesity without the aggravating effects of FIN and obesity on depressive‐like behaviors.