bluuebunny/crossref_metadata_2025_split huggingface dataset:
A structure‐based fluid biomarker for the differential diagnosis of early‐stage neurodegenerative diseases measured by the immuno‐infrared‐sensor (iRS)
Authors: Schuler Martin , Mann Marvin , Langenhoff Lennart Carl , Budde Brian , Beyer Léon , Woitzik Nathalie , Gerwert Grischa , Wanka Robin , Hoeveler Adrian , Dreier Max‐Aylmer , Hubert Diana , Galkowski Sandy , Güldenhaupt Jörn , Kötting Carsten , Gerwert Klaus Bernhard 
Published: December 2023

AbstractBackgroundNeurodegenerative diseases like Alzheimer’s (AD) and Parkinson’s disease (PD) are accompanied by misfolding of the key proteins into beta‐sheet enriched structures resulting in high neurotoxicity in early phases. We have developed a diagnostic immuno‐infrared‐sensor (iRS) that monitors the secondary structure distribution of these key proteins (Abeta for AD, alpha‐synuclein for PD) as an early detectable biomarker before the clinical manifestation, which is shown exemplarily for AD.1
MethodThe iRS combines the secondary‐structure‐specific infrared spectroscopy in a flow system based attenuated total reflection (ATR) set‐up with methods of immuno‐detection by surface‐immobilized antibodies. The antibodies specifically capture disease‐related target proteins (e.g., Abeta) from complex media (cerebrospinal fluid or blood plasma) for measurements. The readout is the amide‐I band, which directly reflects the secondary structure distribution of the captured proteins in body fluids and thus, indicates the protein misfolding: The lower the amide‐I frequency, the higher the content of misfolded Abeta species in the sample present.2
ResultThe structure biomarker for Abeta has been validated in multiple independent clinical studies with strong correlation to CSF biomarkers and PET scans.1,3‐5 Especially, very early preclinical AD could be identified in symptom‐free individuals before plaque formation, up to 17 years before the diagnosis.6
ConclusionThe results demonstrate a highly specific and sensitive immune‐assay capable of tracking structural changes of Abeta before clinical manifestation of AD. In addition, alpha‐synuclein and TDP‐43 misfolding indicate PD and ALS in current discovery studies, providing a tool for differential diagnosis at early stages.
References:
1Nabers, A. et al. 2016. Analytical chemistry 88.5: 2755‐2762.
2Nabers, A. et al. 2016. Journal of biophotonics 9.3: 224‐234.
3Nabers, A. et al. 2018. EMBO molecular medicine 10.5.
4Nabers, A. et al. 2019. Alzheimers Dement. Diagn. Assess. Dis. Monit. 11: 257‐263.
5Stocker, H., Nabers, A. et al. 2020. Alzheimer’s Dement. 16: 283‐291.
6Beyer, L., et al. 2023. Alzheimer’s Dement. 19: 1020‐1028
Efficacy of benfotiamine plus donepezil treatment for patients with mild‐to‐moderate Alzheimer’s disease: multicenter, randomized, phase II clinical trial
Authors: Pan Xiaoli , Sang Shaoming , Zhong Chunjiu 
Published: December 2023

AbstractBackgroundTo assess the efficacy of benfotiamine plus donepezil treating mild‐to‐moderate Alzheimer’s disease (AD).MethodDesign: Multicenter, randomised, double‐blind, phase II clinical trial. Setting: 21 cognitive clinics of tertiary hospitals affiliated Medical Colleges or Universities in China. Participants: 434 patients who took donepezil (5 mg daily) continuously for more than 6 months (inclusive) were screened. Intervention: 302 patients entered this study and were randomly assigned (1:1:1 allocation) to high‐dose benfotiamine (600 mg daily, n = 99) plus donepezil (5 mg daily, the same below), low‐dose benfotiamine (300 mg daily, n = 104) plus donepezil or the only donepezil (n = 99) groups. Main outcomes measures: The primary efficacy outcome was the change of Assessment Scale‐Cognitive Subscale 11(ADAS‐cog) score at week 52 from baseline.ResultIn the overall population, the primary efficacy outcome did not reach significant difference, but tended to be beneficial to benfotiamine plus donepezil treatment with a dose‐effect relationship. Post hoc analyses showed that for the moderate AD subgroup in the full analysis set, the increases of ADAS‐cog scores at week 52 from baseline were the least in high‐dose benfotiamine plus donepezil (‐3.07, p = 0.027) and the second least in low‐dose benfotiamine plus donepezil (‐1.49, p > 0.05) as compared with that in only donepezil. There were no significant differences in the primary efficacy outcome among three subgroups of mild cases.ConclusionCompared to only donepezil, benfotiamine plus donepezil treatment tends to have beneficial effects on delaying cognitive decline of mild to moderate AD. Post hoc analyses showed that the efficacy of benfotiamine plus donepezil treatment with a dose‐effect relationship is better than that of only donepezil treatment for moderate AD, but not for mild AD. The current proof of concept study showed that the combination treatment of correcting TDP reduction with acetylcholinesterase inhibitor is an effective therapeutic way for AD. Future studies should further expand the sample to verify these results.
Exploring the link between mood disorders and Alzheimer’s disease in the Australian Imaging, Biomarker & Lifestyle Study of Ageing (AIBL)
Authors: Ma Liwei , Zhuo Yuanhao , Low Yi Ling Clare , Chu Chenyin , Masters Colin L , Jin Liang , Pan Yijun 
Published: December 2023

AbstractBackgroundEpidemiological studies have demonstrated a positive association between mood disorders (anxiety and depression) and mild cognitive impairment (MC)/ Alzheimer’s disease (AD). However, the relationship between anxiety/depression and the progression of cognitive decline (PCD, i.e. cognitively unimpaired [CU] to MCI, and MCI to AD) in AD is not clearly understood.MethodA total of 2129 AIBL participants with data collected at 10 longitudinal timepoints were included in this study. The logistic regression model was employed to calculate the crude and adjusted odds ratios (OR), to assess the association between the anxiety/depression and MCI/AD. To determine the correlation between anxiety/depression and PCD, only participants who had anxiety/depression diagnosed prior to PCD was included for analysis. Potential confounders (smoking, alcohol, marital status, education, or sex) were adjusted for in the analysis.ResultAfter adjusting for all potential confounders, anxiety and depression were associated with an increased risk of MCI (anxiety OR:1.54, 95% confidence interval (CI): [1.00 ‐ 2.37], p = 0.049 / depression OR: 1.94, 95%CI: [1.30 ‐ 2.92], p = 0.001) or AD (anxiety OR: 2.43, 95%CI: [1.74 ‐ 3.39], p < 0.001 / depression OR: 2.27, 95%CI: [1.63 ‐ 3.16], p < 0.001). Both anxiety and depression were positively associated with a higher risk of progression from CU to MCI, though not statistically significant. After adjusting for all potential confounders, anxiety showed a high positive association with the progression from CU to AD (OR:2.25, 95%CI:[1.12 ‐ 4.53], p = 0.023) and MCI to AD (OR: 1.93, 95%CI: [1.15 ‐ 3.24], p = 0.013). Participants with anxiety also formed 1.53‐fold increased odds of PCD compared to those without anxiety. Similar calculations were performed for depression, but all associations observed in each condition were not statistically significant.ConclusionIn AIBL, we demonstrated a positive association between anxiety/depression and MCI/AD. Interestingly, anxiety but not depression was found to be a risk factor for PCD.
Trend in dementia mortality in an older Chinese population over two decades
Authors: Ding Ding 
Published: December 2023

AbstractBackgroundThe Shanghai Epidemiological Survey of Dementia and Alzheimer’s Disease (SESD)[1] and the Shanghai Aging Study (SAS)[2] are geographically defined population‐based studies established in the same resident district in 1987 and 2010. We attempted to explore the secular trend of dementia mortality through these two cohort studies conducted two decades apart.MethodWe examined the changes in 5‐year mortality of dementia (i.e. Alzheimer’s disease [AD], vascular dementia [VD], and all dementia) by analyzing survival data of participants aged≥65 years from the prospective stages of SESD (1987‐1992) [1] and SAS (2010‐2015). Mortality rate (MR), case fatality rate (CFR), and standardized mortality ratio (SMR) in SAS were adjusted by the sex, age, and education‐structured population data in SESD.ResultCompared to SESD (n = 3531), participants in SAS (n = 2342) were older and more educated, and with a higher prevalence of hypertension, diabetes, stroke, cancer, and kidney disease. The adjusted 5‐year MRs of AD (0.76% vs. 2.24%; OR, 95%CI 0.34, 0.20‐0.57), VD (0.37% vs. 1.16%; OR 0.33,0.16‐0.68), and all dementia (1.23% vs. 3.74%; OR 0.32, 0.22‐0.48) in SAS were lower than that in SESD. The same trend of the 5‐year CFRs was also observed in AD (23.3% vs. 62.2%; OR 0.19, 0.10‐0.35), VD (48.7% vs. 77.4%; OR 0.29, 0.10‐0.90), and all dementia (61.0% vs. 70.6%; OR 0.21, 0.12‐0.35). When taking into account that the 5‐year all‐cause mortality rate in total participants also decreased from 20.33% in SESD to 9.14% in SAS (OR 0.39, 0.34‐0.46), the SMRs of all dementia (3.30 vs. 3.20) and AD (3.06 vs. 2.54) in SAS were similar with that in SESD, while an increasing trend was shown in VD (3.81 vs. 5.32).ConclusionWe observed a decreasing trend of dementia mortality, and vascular dementia still induced a higher threat to life loss over 20 years in this older Chinese population.References: 1. Katzman R, et al. The malignancy of dementia. Predictors of mortality in clinically diagnosed dementia in a population survey of Shanghai, China. Arch Neurol. 1994;51:1220‐1225.2. Ding D, et al. The Shanghai Aging Study: study design, baseline characteristics, and prevalence of dementia. Neuroepidemiology.2014;43:114‐122. 3.
Effects of Cognitive‐motor Rhythmic Training on Executive Functions and Motor Performance in Older Adults with Mild Cognitive Impairment: A Randomized Controlled Trial
Authors: Lo Cheuk Wing Cherry , Tam Kui Fu Stanley , Chan Yuk Piu 
Published: December 2023

AbstractIntroductionIn recent years, prevalence of mild cognitive impairment (MCI) has increased in older adults, exacerbating the potential impact on global health. Cognitive‐motor training is an emerging treatment modality with proven benefits in enhancing both physical and cognitive functions. In recent research findings, training of musical rhythmic skills with auditory‐motor synchronization is beneficial to reactivate the brain’s sensorimotor and perceptual regions as well as to improve cognition. However, there is limited research on combining these modalities.ObjectivesThis pilot study aims to develop a pioneer program on cognitive‐motor rhythmic training (CMRT), and to investigate whether the program would improve the executive functions (EF) and hand functions of patients with MCI.MethodologyThirty patients recruited from the Hong Kong Buddhist Hospital were randomized into two groups: (i) an intervention group receiving a 6‐week training program and (ii) a waitlist control group. The program was designed with reference to the rhythm game “Taiko no Tatsujin”, in which precise timed motor responses were required to hit the circular cues against the target zone. The game was designed with progression of difficulty levels and instant feedback. Classical Cantopop songs that were familiar to Hong Kong older adults were selected. Mental flexibility, inhibitory control, working memory, visuospatial memory, verbal fluency, processing speed and problem‐solving were assessed using domain‐specific cognitive tests, while hand dexterity was measured by the Purdue Pegboard Test. Paired t‐test and ANOVA were used to examine the within group difference and the comparison between groups. The level of significance was set at P<0.05.ResultsThe analysis showed significant Time x Group interaction effects in Color Trail Test (p = 0.001), Color Word Stroop Test (P = 0.002), Digit Span Test (P<0.001), Corsi Block‐Tapping Test (P<0.001), Verbal Fluency Test (P<0.001), Symbol Digit Modalities Test (P = 0.015), Maze Test (P<0.001) and the Purdue Pegboard scores (P<0.001) compared to the control group after training.ConclusionsThe 6‐week CMRT program is effective in improving the executive functions and motor performance in patients with MCI. This innovation can serve as an affordable and quality intervention in early stages of cognitive decline.
Relationship Between Memory and Brain Metabolism is Markedly Disordered in non‐Demented Patients Who Have Worsening Sleep Over Time
Authors: Hogue Anne E. , Silverman Daniel H. 
Published: December 2023

AbstractBackgroundDisturbances in circadian rhythm often emerge during disease progression in patients with dementia. We recently reported that subjects with worsening sleep experienced significantly faster cerebral decline compared to subjects with improved sleep over comparable timeframes. Here we describe relationships between brain metabolism and memory as a function of changing sleep status.MethodA consecutive series of 2,005 cognitively normal and mildly impaired subjects from more than 50 North American sites participating in the first three phases of the Alzheimer’s Disease Neuroimaging Initiative was studied. Changes in cognition assessed through formal neuropsychological testing, and in regional cerebral metabolism assessed through brain PET using the radiotracer [F‐18]fluorodeoxyglucose (FDG), were examined. Activities in 47 standardized volumes of interest (sVOI’s), as normalized to each subject’s whole brain activity, were longitudinally measured, and significance of changes in memory were evaluated using a Pearson correlational analysis and two‐sided one‐sample t tests.ResultIn this consecutive series of 2005 subjects, 211 were documented to have had a change in insomnia status during their participation: 83 who were documented to have insomnia at baseline that was subsequently alleviated (“improving sleep”), and 128 who were documented to have no insomnia at baseline but developed it during the study period (“worsening sleep”); among them, 62 (29%) underwent FDG‐PET scans during both baseline insomnia and subsequent insomnia‐free status, or both baseline normal sleep and subsequent insomnia status periods. In subjects with improving sleep, baseline metabolism of posterior cingulate cortex, the brain region with metabolism that declines most significantly in the earliest stages of Alzheimer’s disease, was strongly associated with memory domain performance (r = 0.65, p = 0.00003). In marked contrast, this relationship was severely degraded in subjects who had worsening sleep (r = 0.20, p = 0.18). Similar relative relationships, though somewhat less statistically dramatic, were also observed with respect to global cognition, as assessed by both ADAS‐COG and MMSE scores in both groups of subjects.ConclusionSubjects with worsening sleep over time showed a highly disordered relationship between their baseline regional brain metabolism and cognitive function, and this effect was most dramatic with respect to their memory domain performance.
Single‐molecule Analysis of Protein Glycosylation Patterns for Early Detection of Alzheimer’s Disease Biomarkers
Authors: de Lannoy Carlos Victor , Filius Mike , Joo Chirlmin 
Published: December 2023

AbstractBackgroundIn recent years, it has become apparent that protein glycosylation plays a variety of roles in the development of Alzheimer’s disease (AD). For instance, characteristic glycosylation patterns of tau and APP have been found in AD patient samples, and O‐GlcNAcylation of alpha‐synuclein (aSyn) has been indicated as a therapeutic anti‐AD target. By extension, the presence of specific glycoforms in patient samples could constitute an important biomarker for early detection purposes (Zhou et al., 2023, Alzheimer’s Dement., https://doi.org/10.1002/alz.13024). However current state‐of‐the‐art methods using mass spectrometry (MS) typically detect proteins starting at millions of copies, thus they lack the sensitivity to perform detection in early disease stages. Moreover, they are prohibitively expensive for routine clinical analysis.MethodWe have developed an ultra‐sensitive protein analysis method that can be used to localize post‐translational modifications in full‐length proteins, including glycans, at single‐molecule resolution (Filius et al., 2021, Nano letters, https://doi.org/10.1021/acs.nanolett.1c00725). Using Förster resonance energy transfer (FRET), a fluorescence‐based distance measurement approach with sub‐nanometer resolution, our method can determine both presence and approximate location of glycans on the protein. Contrary to MS, it does not require complex sample preparation, such as enzymatic digestion or peptide enrichment. We validated this approach by detecting O‐GlcNAcylation on aSyn.ResultBased on measured fluorescence intensities and without using prior information on aSyn’s O‐GlcNAcylation tendencies, we deduced that molecules are doubly O‐GlcNAcylated. Using a calibration construct, we then inferred that the modified residues are in between residues 42 and 78. This is in accordance with MS measurements on bulk samples, which indicate that double glycosylation had taken place at Thr54 and Thr64 respectively. Our results demonstrate for the first time that O‐GlcNAc can be localized on full‐length proteins with single molecule sensitivity.ConclusionUsing our highly sensitive protein analysis approach, we have demonstrated the detection and location of glycans on full‐length aSyn at single‐molecule resolution. We believe that the high resolution of our method will allow for the detection of biomarkers in patient samples in early stages of disease. In future work, we will expand the proof‐of‐concept presented here for such usage by detecting AD‐associated tau and APP glycoforms.
Emerging role of miR‐223‐3p in regulating sex dimorphic neuroinflammation and cognitive function in mice following controlled cortical impact
Authors: Wang Wang‐Xia , Geleta Urim , Prajapati Paresh , Macheda Teresa , Bachstetter Adam D , Springer Joe E 
Published: December 2023

AbstractBackgroundNeuroinflammation is a key feature of many neurodegenerative diseases, however its regulation is not well understood. MicroRNAs (miRNAs) are small, non‐coding RNAs that involve in the regulation of many biological and pathological pathways including inflammation. MiR‐223‐3p is macrophage/microglia enriched miRNA that involves in inflammation and immunity. However, the role of miR‐223‐3p in neurodegeneration is unknown.MethodMiR‐223‐3p knockout (KO) and genetic background matched wildtype (WT), female and male young (12‐14‐week) or aged (18‐20‐month) mice were used in the studies. CD11b+ cells were isolated from brain tissues of KO and WT, female and male naïve mice and RT‐qPCR was used to quantify inflammatory markers. Immunofluorescent studies using anti‐IBA1 was used to determine the number of activated microglia in brain sections of aged KO and WT female mice following a CCI. To evaluate the impact of miR‐223‐3p on cognitive and behavior, young (12‐14‐week) or old (18‐20‐month) mice were subjected to CCI followed by a radio arm water maze (RAWM) test (young mice) or Y‐maze test (aged mice) 2 weeks after controlled cortical impact (CCI).ResultOur preliminary studies reveal that deficiency of miR‐223‐3p resulted in a female‐biased elevation of inflammatory transcripts including such as NLRP3, TRAF6, TNFα, NFκB, and ITGAM in brain CD11b+ cells. In addition, immunofluorescent analysis demonstrated that a greater number of IBA1 staining microglia in KO than that of WT mice brains. Furthermore, deficiency of miR‐223‐3p seemed to associate with a deficit in cognitive function in aged female mice following CCI. We also examined the level of CCAAT‐enhancer‐binding protein beta (CEBPβ), an important transcription factor regulating inflammation and a validated target of miR‐223‐3p. Our preliminary data showed that CEBPβ protein was increased in the brain of miR‐223‐3p KO mice brain tissue relative to that of WT.ConclusionOur preliminary data suggest that miR‐223‐3p may regulate a sexually dimorphic neuroinflammation and cognitive function, likely via regulating inflammation transcription factor CEBPβ.
Alzheimer’s disease‐driven microbiome dysbiosis is a strong predictor of cognitive performance in humans
Authors: Zeamer Abigail L , Bucci Vanni , Haran John P 
Published: December 2023

AbstractBackgroundThe association between Alzheimer’s Disease (AD) and dysbiosis of the gastrointestinal (GI) microbiome has been demonstrated in several studies. Here, we aimed to expand on our previous findings that in nursing home residents the microbiome and clinical variables are predictive of AD compared to no dementia (ND) by expanding our study population to include those residing in the general community. We sought to identity microbiota characteristics that stratify AD from ND individuals across environments. Further, in our community residing population, we assessed the longitudinal microbiome’s ability to predict cognitive performance (ADAS‐Cog‐13).MethodOlder individuals residing in Massachusetts nursing homes (n = 79) or in the general community (n = 71) were enrolled in our study. At each visit, fecal samples and clinical variables were collected. For those residing in the community, ADAS‐Cog‐13 testing was done. Metagenomic profiling was performed on longitudinal fecal samples. Random forest classification models were used to identify associations between residency, AD diagnosis and microbial features and metabolic pathways. Mixed‐effect random forest regression models were created to identify metagenome features informative of cognitive performance.ResultAmong AD and ND individuals residing in both the NH and community, microbial abundance and basic clinical variables were informative of AD status (F1‐score = 0.827±0.03), with Clostrida, Blautia and Neglecta species associating with AD diagnosis. In specifically the community residing individuals, increase in Bacteroidetes (F1‐score = 0.906 ± 0.03) and pathways (F1‐score = 0.885±0.03) involved in amino acid catabolism and nucleotide synthesis was informative of AD diagnosis. Additionally, mixed‐effect random forest machine learning models determined that variability in the abundance of these bacteria and pathways accurately predicts the cognitive performance (ADAS‐Cog‐13) in community residing individuals.ConclusionTaken together our study describes that the AD microbiome from both nursing home and community‐dwelling older adults is depleted in health‐associated Clostridia and that the abundance of these bacteria and their metabolites not only optimally discriminates older human according to disease status, but it also accurately reflects their cognitive ability.