bluuebunny/crossref_metadata_2025 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

Background

Neurodegenerative 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

Method

The 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

Result

The 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

Conclusion

The 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

Background

To assess the efficacy of benfotiamine plus donepezil treating mild‐to‐moderate Alzheimer’s disease (AD).

Method

Design: 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.

Result

In 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.

Conclusion

Compared 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

Background

Epidemiological 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.

Method

A 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.

Result

After 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.

Conclusion

In 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

Background

The 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.

Method

We 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.

Result

Compared 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).

Conclusion

We 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

Introduction

In 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.

Objectives

This 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.

Methodology

Thirty 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.

Results

The 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.

Conclusions

The 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

Background

Disturbances 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.

Method

A 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.

Result

In 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.

Conclusion

Subjects 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

Background

In 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.

Method

We 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.

Result

Based 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.

Conclusion

Using 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

Background

Neuroinflammation 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.

Method

MiR‐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).

Result

Our 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.

Conclusion

Our 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

Background

The 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).

Method

Older 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.

Result

Among 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.

Conclusion

Taken 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.
Fragility and its relationship with geriatric syndromes in a mexican population of elderly adults in a third‐level hospital
Authors: Ruiz‐Castillo Karla Paulina , Cuautle Karina Arellano , Reyes Brandon Alexis Reyes , Silva Itzel Alejandra Hernandez , Chable Adiel Eleazar Dzul
Published: December 2023

Background

Frailty refers a term which describes general state of health that is characterized by an increased susceptibility or vulnerability for stressors as a consequence a deterioration of physiological reserves. Frailty have been associated to multiple Geriatric syndromes, higher rates on mortality and increased risks for poor outcomes, including Alzheimer’s Disease (AD) and Mild Cognitive Impairment (MCI), which are conditions that may be common in older adults.

Method

This report is a secondary analysis from a transversal study, the inclusion criteria include adults from 60 or older, who complete evaluations at the baseline in a from a dementia clinic at a tertiary care center in Mexico. We exclude pre‐fragile and robust participants at the baseline, the analytical simple comprised 700 older adults. Frailty was established using the FRAIL criteria the presence of 3 or more remaining criteria was considered frailty. Sociodemographic variables, comorbidities, and geriatric syndromes were considered for the analysis.

Result

A total of 700 older adults were evaluated and 242 (34.5%) were diagnose with Frailty. Comorbidities such as diabetes (41.7%), high blood pressure (64%) and osteoarthritis (50%) were prevalent with frailty. Female sex (63.6%) and marital status marriage (55%) were prevalent with frailty. The incidence of mild dementia was 35.1% and 28.9% for mild cognitive impairment. Multiple logistic regression was performed finding an OR (95% CI) P <.001 in the association of frail patients in the 60‐70 age group, the association of the female sex with frailty present in OR (95% CI). P .023 and being married OR (95% CI) P < .001.

Conclusion

In Mexican older adults from the clinical population, the results demonstrated that frailty was associated with mild cognitive impairment and mild dementia as well as female sex, married marital status, and age. It would be necessary to compare with other groups without frailty to demonstrate the consistency of these findings as potential risk factors.
Reduction of Hippocampal Atrophy and Lateral Ventricle Enlargement Correlates with Clinical Benefit in APOE4 Carriers with Early AD: 1‐Year Results from a Phase 2 Biomarker Study with Oral Anti‐Amyloid Oligomer Inhibitor ALZ‐801
Authors: Hey John A. , Abushakra Susan , Kesslak Patrick , Yu Jeremy , Schaefer Jean , Bracoud Luc , Suhy Joyce , Power Aidan , Tolar Martin
Published: December 2023

Background

ALZ‐801 is an oral inhibitor of amyloid oligomer formation in development as a disease‐modifying Alzheimer’s treatment, including a Phase 3 trial in APOE4/4 homozygotes and a Phase 2 biomarker study in APOE4 carriers. We analyzed correlations between brain volume and cognitive effects of ALZ‐801 after 1 year in the Phase 2 study. We previously reported that at 1‐year timepoint, plasma p‐tau181 (primary outcome) was significantly reduced by 41% from baseline, and hippocampal volume (HV) showed ∼20% less atrophy compared to external matched controls.

Method

The study is conducted at 7 European sites and enrolled 84 APOE4 carriers (MMSE 22‐30) with positive amyloid/tau biomarkers who receive ALZ‐801 265 mg BID for 104 weeks. Primary outcome is plasma p‐tau181 at 104 weeks, and primary imaging outcome is hippocampal volume (HV) atrophy. Volumetric vMRI measures (baseline, 52 and 104 weeks) are performed by Clario, and MMSE conducted. A PK sub‐study was conducted at 65 weeks (n = 23) with bioanalysis at DDS (UK) and non‐compartmental PK analyzed by WinNonlin. Pearson correlations of MMSE changes to BSI changes of HV and lateral ventricle volume (LVV) were conducted, with two‐sided p‐values reported.

Result

At 52 and 65 weeks, changes of MMSE from baseline showed significant correlations to HV (r = 0.32 and 0.34; p<0.01, n = 66) and LVV changes (r = ‐0.42 and ‐0.44; p<0.001, n = 65). Correlations between DMMSE and DLVV were significant for both genders (range r = ‐0.54 to ‐0.42, p<0.02); correlations were observed for DHV in females (range r = 0.39‐0.47; p<0.05) and males (range r = 0.26‐0.23; p<0.18, ns). PK/PD analysis in 23 subjects showed trends (r = 0.21‐0.16, ns) between decreased HV atrophy/LVV expansion and plasma AUC24h of tramiprosate+3‐SPA (active and primary metabolite). ALZ‐801 exhibited favorable safety; main treatment‐related adverse event was mild nausea. No ARIA‐E was observed.

Conclusion

Early AD subjects treated with ALZ‐801 for 65 weeks in the Phase 2 biomarker study showed strong correlations between MMSE stability, HV reduction, and decreased ventricular enlargement in overall group, and by genders. The significant correlations between cognitive and brain volume effects support the clinical benefits of ALZ‐801 in APOE4 carriers with early AD. Oral ALZ‐801 showed favorable safety and no brain edema/ARIA‐E.
Interferon regulatory factor 5 modulates microglia response to tau by interfering with phagocytosis
Authors: Giliberto Luca , d'Abramo Cristina , Cicalo Julia , Hou Jianwei , Matta Bharati , Barnes Betsy
Published: December 2023

Background

The role of the immune system in responding to neurodegenerative pathology is well established. Microglia are at the center of such response, conveying on one end a positive protective effect, but on the other end, as with senescence, contributing to the hyperinflammation that is a core feature of neurodegeneration. We have identified the transcription factor interferon regulatory factor 5 (IRF5) as a mediator of microglia activation in response to pathological tau, described its specific activation by human‐derived PHF tau and its over‐representation in AD brains. We are now proposing that IRF5 can control the phagocytic activity of microglia, hence modulating their tau‐directed activity.

Method

We utilized age‐ and sex‐matched Irf5+/+
(WT) and Irf5−
/
−
littermate mice for the analysis of ex vivo phagocytic activity of primary microglia, at steady‐state and triggered by tau. We examined microglia morphology and numbers under these conditions and with ageing. Last, we injected PHF tau intracranially to WT and Irf5−
/
−
mice, monitoring tau accumulation and IRF5 response.

Result

1) Irf5−
/
−
microglia have higher baseline phagocytic activity compared to WT microglia, which may be modulated by tau. 2) Microglia numbers are reduced in ageing Irf5−
/
−
3) PHF tau‐injected Irf5−
/
−
mice show significant soluble tau accumulation, but a different pattern of oligomeric and insoluble tau accumulation with age. 4) In WT mice, the PHF tau‐injected hemisphere showed significantly higher levels of IRF5 compared to the contralateral, confirming a specific response of IRF5 to tau.

Conclusion

Tau is a specific activator of microglia and of the IRF5 pathway, which can modulate microglia response to pathology. Ageing is an active variable in the process, affecting the pattern of microglia response to tau, differentially in WT and Irf5−
/
− mice. Modulating the IRF5 pathway may be a viable therapeutic approach in tauopathies.
Multidimensional poverty increases dementia risk in South Africa, Afghanistan, and Pakistan among adults age 50 and older
Authors: Trani Jean‐Francois , Zhu Yiqi , Babulal Ganesh M. , Moodley Jacqueline , Fazal Monib Rahim , Azami Rahim , Park Soobin
Published: December 2023

Background

Low‐and‐middle‐income countries (LMICs) face a crisis with a higher prevalence of dementia and cognitive impairment. It is projected that 68% of dementia cases worldwide will reside in LMICs in 2050. This differential risk is exacerbated by social and environmental determinants of health (SEDOH) and in settings with war, class division, and terrorism. There is no dementia research being conducted within these LMIC settings.

Methods

Data from three cross‐sectional fieldwork studies was used. In South Africa, 227 adults were from two wards of Thulani and Doornkop (11/11/19‐2/28/20). In Afghanistan, 478 adults were from 43 villages of Badakhshan and Ghazni provinces (2/15/22‐4/20/22). In Pakistan, 817 adults were from 43 villages of Punjab and Sindh provinces (4/22/22‐7/7/22). We examined the relationship between dementia and SEDOH via multidimensional poverty among adults ≥ 50 years of age adjusting for sex, marital status, age, and household size.

Results

In South Africa, Afghanistan, and Pakistan, respectively, men were more likely to be dementia‐free (32.1%, 60.8%, 65.49%) than women (24.7%, 32.5%, 34.51%). Across all countries, a higher proportion of older adults with moderate‐to‐severe dementia lived alone without a partner. In South Africa, Afghanistan, and Pakistan, adults with moderate‐to‐severe dementia were significantly more deprived of education, health status, and employment and were more often distressed, compared to adults without dementia in each country. The risk of dementia was higher for multidimensionally poor older adults. In South Africa, the odds of dementia were 2.31X (95%CI, 1.08‐4.95) for those who were multidimensionally poor. In Afghanistan, it was 10.2X higher (95% CI,1.97‐52.62) for poor adults ≥ 70 years. In Pakistan, there was a 5.02X higher risk (95% CI, 2.07‐12.16) for poor older adults at age ≥ 50 years.

Conclusion

The prevalence and depth of poverty were greater among older adults with dementia. A lack of education, poor health, and psychosocial distress are major dimensions of poverty associated with higher dementia risk. More importantly, dementia risk was significantly higher for women in all three countries compared to men. These findings support improvement in SEDOH through targeted structural policies, particularly for quality and free education and healthcare, to prevent dementia in later life.
Artificial intelligence‐driven algorithm to detect and count cerebral microbleeds on Susceptibility Weighted Imaging
Authors: Lee Kijeong , Lee Minho , Kim Regina EY , Jo Sang‐Yeong , Kim JeeYoung , Lee Kyung Mi , Lee Ji Young , Kim Donghyeon , Kim Hye Weon
Published: December 2023

Background

Amyloid‐related imaging abnormalities (ARIA)‐H, characterized by cerebral microbleeds (CMB) and superficial siderosis, is an important Magnetic Resonance Imaging(MRI) finding observed in the patients with Alzheimer’s disease, especially receiving the anti‐amyloid immunotherapy. Because the severity of CMB can potentially lead to discontinuation of the therapy, the detection and counting of the CMB would be critical tasks in MRI analysis. We present an algorithm which can detect CMBs and count the number of them, automatically and accurately.

Method

We employed datasets of both SWI and phase images, developed in collaboration with Eunpyeong St. Mary’s Hospital, Kyung Hee, and HanYang University Medical Center. The data set comprises 463 participants with CMBs (N = 247) and without CMBs (N = 116). Experts denoted gold standard of each CMBs as bounding boxes. A localizer is trained by selecting 2D axial slices, including expert‐confirmed annotations. A modified recurrent layer was applied for weight‐sharing between two images. An optimized region proposal network was then applied. To reduce FP regions across entire slices, we developed a classifier with attention‐based 3D convolution blocks. From the CMB localizer, candidate 3D CMB patches were used in the classifier.

Result

CMB prediction was performed on the test set including 140 participants (CMB:24; Non‐CMB:116), with 263 expert‐confirmed gold standard (Figure 1). The lesion‐wise sensitivity was 0.913 [95% Confidence interval (CI), 0.863‐0.963] and the average FP rate was 0.672 per patient [95% CI, 0.290‐1.154]. Patient‐wise sensitivity and specificity were 0.862 [95% CI, 0.792‐0.932] and 0.907 [95% CI, 0.880‐0.934], respectively. When we divided the patients into four groups according to the number of gold standard, the model predicted the groups correctly by the sensitivity of 0.879 [95% CI, 0.851‐0.907] (Table 1).

Conclusion

Our model outperformed the results of recent studies by reducing FP rate with comparable sensitivity. Moreover, our model may suggest additional clinical benefit, because it can automatically count the number of CMB and classify the participants into 4 groups, used in the clinical investigation of anti‐amyloid therapy, according to the number of CMB. We expect this model may improve the workflow of the time‐consuming reading task and act as a failsafe for the detection of CMBs.
White Matter Lesion Asymmetry: A Potential Indicator of Amyloid Positivity in Patients with Mild Cognitive Impairment
Authors: Kim Hye Weon , Rieu ZunHyan , Lee Hyunji , Jeong Eui Seok , Lee Min‐Woo , Lee Minho , Kim Donghyeon , Lim Hyun Kook
Published: December 2023

Background

Assessing amyloid‐positivity in patients with mild cognitive impairment (MCI) is crucial as amyloid‐positive individuals have a higher risk of dementia conversion than amyloid‐negative patients. This study aimed to investigate whether the asymmetry of white matter lesions (WML) on T2‐fluid attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI), measured by artificial intelligence (AI) hyperintensity segmentation, could be a potential indicator for amyloid positron emission tomography (PET) positivity in patients with MCI.

Method

This retrospective cohort study included MCI patients who visited the memory clinic of Yeouido St. Mary’s Hospital. All participants underwent a set of clinical and neuropsychological assessments, brain MRI, and amyloid PET using [18F]‐Flutemetamol. Our in‐house AI software was utilized on paired T1 and T2‐FLAIR MRIs to process to segment and separate WML into left and right hemispheres. From the processed segmentation, we measured the subjects' individual WML differences through a volumetric assessment.

Results

Total 122 subjects were enrolled in this study. By the amyloid‐PET positivity, 53 and 69 patients were in the amyloid‐negative and amyloid‐positive groups, respectively. The two groups were comparable with no significant differences of age (p = 0.189), sex (p = 0.057), education years (p = 0.411) and MMSE scores (p = 0.861). However, the amyloid‐positive group had a significantly higher frequency of having an e4 allele of APOE genotype (p = 0.033) and Clinical Dementia Rating scale (p = 0.024). The average volume between hemispheres significantly differed in the amyloid‐negative group (p = 0.020) but not in the amyloid‐positive group (p = 0.220). Both groups had a larger WML volume in the left hemisphere, which did not differ significantly between groups.

Conclusion

Our findings suggest that evaluating the asymmetry of WML rather than the total hyperintensity lesion load is necessary in MCI patients, particularly in those without amyloid pathology. In conclusion, WML asymmetry may serve as a potential indicator of amyloid positivity in MCI patients.
Revolutionizing memory improvement: KIT‐13, a novel Plasmalogen analog, inhibits neuroinflammation and boosts memory in mice
Authors: Chung Eunhee , Hossain Md Shamim , Mawatari Shiro , Honsho Masanori , Fujino Takehiko
Published: December 2023

Background

A decrease in cell plasmalogens often links with an inflammatory state. Our previous study discovered that natural plasmalogens (specific types of phospholipids) extracted from scallops inhibited neuroinflammation and improved memory function in mice1. The subsequent randomized clinical trials also showed significant improvements in patients with Alzheimer’s disease by natural plasmalogens2. In order to increase the stability and achieve greater cellular plasmalogens, we developed a new plasmalogen derivative and examined if it would produce similar effects in mice.

Method

In our current study, we investigated the alkyl‐type plasmalogen analog, KIT‐13 (1‐0‐octadecyl‐2‐arachidonoyl‐sn‐glycerol‐3‐phosphoethanolamine), to evaluate its potential effect on neuroinflammation (in vitro, in vivo), neurogenesis (in vitro), and memory improvement (in vivo).

In our in vitro studies, mice microglial cell lines (BV2 and MG6) were used for evaluation of the anti‐inflammatory effects, and neuronal‐like cells (SH‐SY5Y) were used to assess the effect of KIT‐13 on the regulation of brain‐derived neurotrophic factor (BDNF) and the neurogenesis marker DCX.

In in vivo studies, learning and memory were assessed by Morris Water Maze (MWM) tests. The neuroinflammation was induced by LPS injection (i.p.), which increased activated glial cells and reduced memory in 12‐week‐old adult male (B6) mice.

KIT‐13 (0.2 mg/kg/day) was administered orally for four weeks before LPS injection.

Result

In vitro experiments demonstrated that KIT‐13 attenuated the LPS‐induced upregulation of NOS2 expression in microglial cells and increased BDNF and DCX expression in neuronal‐like cells.

Also, KIT‐13 pre‐treatment reduced LPS‐induced neuroinflammation and memory disturbance in mice, indicating that, similar to natural plasmalogens, KIT‐13 may improve memory by decreasing neuroinflammation and increasing BDNF‐mediated neurogenesis in the mouse brain.

Conclusion

These findings suggested that KIT‐13 can be a therapeutic drug candidate for diseases associated with plasmalogen reduction, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and rhizomelic chondrodysplasia punctata (RCDP).

Reference:

1. Ifuku et al. J Neuroinflammation 2012, 9:197

2. Fujino et al. EBioMedicine 2017, 17:199‐205

3. Fujino et al. J Alzheimers Dis Parkinsonism 2019, 9:4

4. Hossain et al. Front Cell Dev Biol 2022, 10:828282
Prevalence of Cerebral Microhemorrhages and Cortical Superficial Siderosis in APOE4/4 Homozygotes with Early Alzheimer’s disease: Baseline Findings from Phase 3 Trial of Oral ALZ‐801 in APOE4/4 Homozygotes (APOLLOE4)
Authors: Abushakra Susan , McLaine Rosalind , Barakos Jerome , Porsteinsson Anton P. , Watson David , MacSweeney Emer , Liang Earvin , Kesslak Patrick , Suhy Joyce , Power Aidan , Hey John A. , Tolar Martin
Published: December 2023

Background

Plaque clearing amyloid antibodies show an increased risk of amyloid‐related imaging abnormalities with edema or hemorrhages (ARIA‐E or ARIA‐H). ARIA risk increases with number of APOE4 alleles, with APOE4/4 homozygotes showing the highest risk related to high burden of Aβ plaque in microvessels (cerebral amyloid angiopathy, CAA). To decrease the risk of ARIA, amyloid antibody trials exclude subjects with CAA‐related lesions such as >4 microhemorrhages (MH) or superficial siderosis. ALZ‐801 (valiltramiprosate), an oral drug that inhibits formation of neurotoxic Aβ oligomers, shows promising efficacy in APOE4 carriers with no observed ARIA‐E (Abushakra 2017, 2022). Two ALZ‐801 trials are currently ongoing in APOE4 carriers with Early AD. A Phase 2 study enrolled APOE4 carriers, and a Phase 3 trial enrolled APOE4/4 patients. Both studies allow >10 MH and/or some siderosis lesions at baseline.

Method

The fully‐enrolled Phase 3 trial (APOLLOE4) included 325 homozygotes with Early AD (MMSE ≥22). We evaluated prevalence of microhemorrhages (MH), macrohemorrhages and superificial siderosis (CAA lesions). Baseline MRIs acquired from 1.5T/3T scanners were centrally evaluated by Clario, and the number/location of these CAA lesions is reported.

Result

Subjects had mean age 69 years, 51% female, MMSE 26, 82% white, 65% with MCI. Of 325 subjects, 313 had baseline MRIs that showed > 1 MH in 32%, including 9% with > 4 MH. A total of 9% had ≥ 1 superficial siderosis, and 2 subjects had macrohemorrahages. Occipital and frontal lobes were most common locations of CAA lesions. Most subjects had white matter disease (Fazekas = 1).

Conclusion

APOE4/4 homozygotes show high prevalence of CAA lesions with 32% and 9% having lobar microhemorrhages and superificial siderosis respectively. This high burden of CAA lesions most likely underlies the high incidence of ARIA in APOE4/4 patients treated with the approved amyloid antibodies (30%‐60%). ARIA‐E is also reported in APOE4/4 patients treated with placebo in lecanemab & gantenerumab trials (4%‐6%). This background ARIA likely reflects spontaneous CAA‐related inflammation commonly reported in APOE4 carriers (CAA‐RI, Regendhardt 2020). Oral ALZ‐801 in the ongoing studies has not shown increased ARIA risk, and has safety advantage over amyloid antibodies especially for APOE4/4 homozygous patients.
Exploring needs and wishes regarding sleep support from people with dementia and their informal caregiver at home
Authors: Huisman Chantal , Huisman Emelieke , Kort Helianthe
Published: December 2023

Background

Most people with dementia live in community with an informal caregiver (IC) for primary support (Greenwoord & Smith, 2019). Caring for someone with dementia can be emotionally and cognitively demanding and can influence the overall health and wellbeing negatively (Fonareva & Oken, 2014; Vasileiou et al., 2017). Behavioural and psychological symptoms of dementia (BPSD) are very common in people with dementia (PwD) and are one of the main factors that cause strain on an IC (Chiao et al., 2015). BPSD is related to sleep, for example, supporting sleep can improve cognitive function and BPSD (Shin et al., 2014). In all types of dementia sleep rhythms are changing. Sleep problems of a person with dementia can affect the sleep of an IC. Sleep disturbances can exacerbate changes in mental, physical, and cognitive health (Petrovsky et al., 2018), and may lead to nursing home admission (e.g. Livingston et al., 2017). This qualitative study explored the experiences around sleep and the wishes and needs of PwD and their IC to improve their sleep quality. This is a starting point for working toward appropriate sleep support using non‐pharmacological interventions.

Method

A total of 28 interviews are performed with 31 person (PwD, IC, and professionals) comprising three duos. Thematic analysis (Braun & Clarke, 2006) is used to identify patterns within and across data in relation to participants’ lived experiences, views, perspectives, behaviour, and practices.

Results

The first preliminary results show the following themes that are relevant: personal situation including other diseases and personal characteristics, day structure and daily activities, sleep behaviour including sleep rhythm, problems while sleeping, sleeping/naps during the day and caregiver experiences and supporting tools. The results show that these themes are related to the sleep of PwD and IC.

Conclusion

The findings of this study contribute to giving insight into the experience flow and are helpful to determine the priority of subjects in order to support the IC and PwD. This study show that within the target group there are many diverse experiences and that this can vary greatly from one situation to another and from one person to another.
Usability evaluation of a knowledge graph‐based dementia care intelligent recommender system: A mixed‐methods study
Authors: Leng Minmin
Published: December 2023

Background

Knowledge graph‐based recommender systems offer the possibility of meeting the personalized needs of people with dementia and their caregivers. However, the usability of such a recommender system remains unknown.

Objective

This study aimed to evaluate the usability of a knowledge graph‐based dementia care intelligent recommender system (DCIRS).

Methods

A convergent mixed‐methods design was employed to conduct the usability evaluation, including the collection of quantitative and qualitative data. Participants were recruited via social media advertisements. After two weeks of DCIRS use, feedback was collected with the Computer System Usability Questionnaire and semi‐structured interviews. Descriptive statistics were used to describe sociodemographic characteristics and questionnaire scores. Qualitative data were analyzed systematically using inductive thematic analysis.

Results

A total of 56 caregivers were recruited. Quantitative data suggested that the DCIRS was easy for caregivers to use, and the mean questionnaire score was 2.14. Qualitative data showed that caregivers generally believed that the content of the DCIRS was professional, easy to understand, instructive and could meet users’ personalized needs; they were willing to continue to use it. However, the DCIRS also had some shortcomings. Functions that enable interactions between professionals and caregivers and that provide caregiver support and resource recommendations might be added to improve the system’s usability.

Conclusions

The recommender system provides a solution to meet the personalized needs of people with dementia and their caregivers and has the potential to substantially improve health outcomes. The next step will be to optimize and update the recommender system based on caregivers' suggestions and evaluate the effect of the application.