bluuebunny/crossref_metadata_2025 huggingface dataset:
Improving the global understanding of CADASIL‐ a monogenic cause of vascular dementia
Authors: Saks Danit G , Sachdev Perminder S. , Group AusCADASIL Study ,   the Global CADASIL Consortium (GCC)
Published: January 2025

Background

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a rare, hereditary cerebrovascular disease which causes stroke, complex migraine, and cognitive impairment. Given its monogenic nature, CADASIL is considered a ‘pure’ model of small vessel disease and vascular dementia. CADASIL is caused by NOTCH3 pathogenic variants with a broad resulting phenotypic spectrum. There are few CADASIL cohort studies worldwide, often with small or moderate samples, such that any study protocol variation limits the comparability of conclusions across populations. Our recently established Global CADASIL Consortium (GCC) will collate current research and develop guidelines for harmonised protocols and minimum datasets. Further, we have begun the first Australian cohort study of CADASIL, AusCADASIL, to determine the phenotypic presentation, progression, and pathogenic variants in this population.

Method

Literature search, publicising at the 2023 VASCOG conference, and chain‐referrals were used to identify CADASIL researchers and experts who may be interested in contributing to the global collaborative effort. Study meta‐data sharing is ongoing including demographics, clinical, genetic, and imaging outcomes.

AusCADASIL will include 150 participants with genetically‐confirmed CADASIL, family history of CADASIL or suspected CADASIL symptoms, and 150 NOTCH3‐negative controls; to be assessed at six main sites. Participants will complete a comprehensive medical, neuropsychological, neurological, ocular, blood biomarker and genetic assessment, including annual follow‐up for 4 years to monitor progression. Data from this cohort will contribute to the international consortium.

Result

The GCC, comprised of 75 individuals from 18 countries, has begun by sharing meta‐data from 10 cohorts based in Australia, East Asia, Netherlands, USA, Spain, France, United Kingdom, and Finland with recruited sample sizes ranging from 20‐520 individuals, and discussing development of working groups. Recruitment for AusCADASIL opened in November 2023 and assessments will begin in early 2024.

Conclusion

There is increased global interest in CADASIL as a model for small vessel disease and vascular dementia. This recently established international body is committed to improving the understanding of CADASIL, harmonising assessment protocols and pooling data for larger analyses of biomarkers. AusCADASIL is the first Australian cohort study of CADASIL and will contribute to international efforts.
TMEM106B C‐terminal fragments drive a distinct neurodegenerative proteinopathy in C. elegans.
Authors: Kraemer Brian C. , Riordan Ruben
Published: January 2025

Background

Genetic variation of lysosomal protein, transmembrane protein 106B (TMEM106B) has long been known as a risk factor for a diverse range of neurodegenerative disorders, especially FTLD with progranulin (GRN) haplo‐insufficiency, though the mechanisms involved are not yet understood. Recently, through advances in cryo‐electron microscopy (cryo‐EM), aggregates of the C‐Terminal domain of TMEM106B (TMEM CT) were shown to make up previously unidentifiable protein aggregates in the brains of human FTLD, AD, progressive supranuclear palsy (PSP), and dementia with Lewy Bodies (DLB) patients.

Methods

To determine the TMEM CT aggregation propensity and neurodegenerative potential, we generated a new transgenic C. elegans proteinopathy model pan‐neuronally expressing the TMEM CT fragment constituting the fibrillar core in FTLD‐TDP cases.

Results

We found that C. elegans pan‐neuronal expression of TMEM CT causes neuronal dysfunction as evidenced by behavioral analysis. TMEM c‐terminal fragments accumulate as detergent insoluble material. Behavioral dysfunction was accompanied by neurodegeneration as illustrated by loss of GABAergic neurons. To investigate the mechanisms driving TMEM106B proteinopathy, we aimed to explore the impact of GRN loss on the neurodegenerative effect of TMEM CT expression. To this end, we generated TMEM CT expressing C. elegans with PRGN loss of function. We found that loss of PGRN did not alter TMEM phenotypes confirming PGRN loss of function is upstream of TMEM aggregation. We also observed TMEM neurodegenerative phenotypes exhibit a distinct set of genetic modifiers as strong suppressors of tauopathy such as spop‐1, sut‐2 sut‐6 show only modest modification of TMEM proteinopathy.

Conclusions

Taken together, our data suggest expression of TMEM CT in C. elegans neurons provides a useful model for the functional characterization of TMEM106B proteinopathy in neurodegenerative disease. Comparison with other proteinopathy models will inform potential disease mechanisms.
Accuracy of intact performance on measures of odor identification, global cognition, and amyloid imaging for identifying lack of cognitive decline and dementia in the Mayo Clinic Study of Aging cohort
Authors: Motter Jeffrey N , Lee Seonjoo , Knopman David S. , Vassilaki Maria , Devanand Davangere
Published: January 2025

Background

Previous studies have linked impaired odor identification and global cognition with increased risk of cognitive decline and transition to dementia. However, the reverse question remains: if individuals have intact performance on these measures, are they at reduced risk for transition? We aimed to examine the accuracy of intact odor identification and global cognition for identifying lack of transition to dementia/cognitive decline using the population‐based Mayo Clinic Study of Aging and compare their accuracy against and in combination with amyloid PET (Positron Emission Tomography).

Method

n = 647 participants age≥55 without dementia completed at baseline the Brief Smell Identification Test (BSIT; ‘Intact’ = 9‐12), Blessed Information‐Memory‐Concentration Test (BIMCT; ‘Intact’ = 18‐20,), and amyloid PET (‘Normal/Intact’ SUVR<1.48). We calculated sensitivity, specificity, positive predictive value, and negative predictive value for these measures, with “lack of transition to dementia” as the gold standard/target. “Lack of cognitive decline” (cognitively unimpaired to mild cognitive impairment [MCI]; cognitively unimpaired to dementia; or MCI to dementia) was a secondary target.

Result

94.7% of participants (613/647) did not transition to dementia and 84.2% (545/647) did not cognitively decline over 11.25‐year‐follow‐up. The combination of intact BSIT+BIMCT had high rates of lack of transition to dementia (98.3%, 355/361) and lack of cognitive decline (93.1%, 336/361). This combination yielded mixed sensitivity (0.579) and specificity (0.824) though had high positive predictive value (0.983) for identifying lack of transition to dementia. Intact amyloid PET alone exhibited comparable rates of lack of transition to dementia (99.0%, 418/423) and lack of cognitive decline (92.4%, 391/423). When evaluated conjointly, the combination of all three intact measures also had mixed sensitivity (0.421) and specificity (0.962) though higher positive predictive value (PPV = 0.996) for lack of transition to dementia. 99.6% (258/259) of participants with intact/normal status on all three did not transition to dementia and 96.5% (250/259) did not cognitively decline.

Conclusion

This replicates prior reports that intact olfaction/global cognition have strong utility for identifying individuals unlikely to develop MCI/dementia. Intact/normal amyloid PET further enhances the positive predictive value. Clinically, identifying individuals at low risk of transition can shorten diagnostic workups, reduce need for early follow‐up visits, and screen patients in‐or‐out of clinical trials.
Voice Problems and Depression: Findings from the 2022 National Health Interview Survey
Authors: Hong Ickpyo , LEE HOKYUNG
Published: January 2025

Background

In contemporary society, essential for quality of life and professional success, is impacted by voice problems affecting 3∼9% of the population. These issues, leading to significant health and economic burdens, can alter voice frequency and tone, impacting self‐esteem, social interactions, and professional outcomes. Voice problems are linked to social isolation and depression, a major emotional disorder causing lethargy and loss of hope. Studies, including the 2012 National Health Interview Survey, show higher depression rates in individuals with voice issues. Our study aimed to use the most recent national survey data and examine this link, and also provide insights for better treatment strategies.

Method

This study utilized the 2022 National Health Interview Survey to explore the relationship between voice problems and depression in U.S. adults. The independent variable is self‐reported voice problems, while the dependent variable is depression, measured using the PHQ‐8 questionnaire. Covariates included sex, age, race, education, income, comorbidities, body weight, and anxiety disorders. Propensity score matching techniques and multivariate logistic regression were used to control for selection bias between the comparison groups. Subgroup analysis investigated the link between the severity of voice problems and depression.

Result

The study found that 12.24% of U.S. adults reported voice problems in 2022. Demographics and health conditions significantly differed between those with and without voice problems. Depression was 1.6 times more likely in individuals with voice problems, and lower in men and non‐white ethnicities (OR = 1.655, 95% CI [1.495, 1.832]). After propensity score matching, covariates were balanced, confirming a consistent, significant association between voice problems and depression across various adjustment models. Subgroup analysis showed a stronger association of depression severity with voice problems severity and anxiety disorders, with women exhibiting a negative correlation(β = 0.89, p <.0001; β = ‐0.13, p <.0001).

Conclusion

The study highlights a strong association between voice problems and increased depression risk, especially in women and those with anxiety disorders. These findings emphasize the importance of specialized intervention strategies to address these issues.
Exposure to melamine exacerbates D‐galactose‐induced aging‐type toxicity in neuronal SH‐SY5Y cells
Authors: Rai Nitish
Published: January 2025

Background

Various investigations have elucidated the impact of diet and environmental toxins on the aging process. Melamine (Mel) is a widely recognized and infamous food adulterant with documented toxicity in various organs, including the brain. Nevertheless, there is currently a dearth of reports on the neurotoxic effects of Mel in aging neurons. This study aims to fill this knowledge gap by exploring the in‐vitro neurotoxicity induced by Mel in a D‐galactose (DG) induced aging model, utilizing neuronal SH‐SY5Y cells.

Method

In this current investigation, the neuronal SH‐SY5Y cells underwent separate and combined treatments with D‐galactose (DG) and Melamine (Mel) to evaluate their neurotoxic potential. The assessment involved employing the MTT assay for cell viability and measuring neurite length. Additionally, we examined the activities of superoxide dismutase (SOD), catalase (CAT), and total antioxidant levels. Subsequent analyses included determining intracellular reactive oxygen species (ROS), mitochondrial membrane potential (MMP), and caspase‐3 (Casp3) activity.

Result

When Melamine (Mel) and D‐galactose (DG) were co‐administered to neuronal SH‐SY5Y cells, a notable increase in cell death was observed compared to cells treated with DG or Mel individually, as well as untreated control cells. The co‐treated cells exhibited the most significant shrinkage in neurite length and the highest production of reactive oxygen species (ROS), indicating an exacerbated toxicity from Mel. Furthermore, the combined treatment (Mel + DG) led to a decrease in the activity of superoxide dismutase (SOD), catalase (CAT), and total antioxidants compared to cells treated with Mel or DG alone and untreated cells. Additionally, the co‐toxicity of Mel and DG significantly elevated the activity of caspase‐3 (Casp3) compared to all other groups, underscoring an enhanced apoptotic response.

Conclusion

This study represents the initial exploration into the heightened neurotoxic potential of Melamine (Mel) within an aging model of neuronal SH‐SY5Y cells. These findings suggest that Mel consumption by the elderly could potentially contribute to elevated occurrences of neurodegenerative conditions such as Alzheimer’s disease and Parkinson’s disease.
A non‐canonical Receptor tyrosine kinase DDR2 resides inside the nuclear speckles and regulates alternative splicing in Alzheimer’s
Authors: Das Russa , Mukhopadhyay Debashis
Published: January 2025

Background

Receptor Tyrosine kinase‐mediated signaling is indispensable for the cell’s normal functioning, the perturbation of which leads to disease conditions. The altered expression and activity of several Receptor Tyrosine kinases (RTKs) are known to regulate the pathophysiology of Alzheimer’s disease (AD). However, the mechanistic details remain illusive. Discoidin Domain Receptor 2 (DDR2) is a unique set of RTKs that gets significantly upregulated in an Alzheimer’s disease (AD) cell model and AD brain lysate.

Method

The AD cell model was prepared using SH‐SY5Y cells and treated with AICD and Aß for 48 hours and was checked for the activity and expression level of DDR2. The expression level of the collagens was also checked. Molecular docking studies were performed to predict the interaction between DDR2 and Amyloid beta. ICC followed by nuclear fractionation studies was performed to confirm the compartmental distribution of DDR2 in the AD model. Immunoprecipitation followed by mass‐spectrometry was done to confirm the interactors of DDR2 in AD.

Result

The mRNA and protein levels and activity of DDR2 were significantly upregulated in the AD cell model. There were no significant changes in the mRNA expression level of collagens. Molecular docking followed by ICC studies confirms the interaction between DDR2 and amyloid beta. Again, for the first time, we showed that DDR2 translocates to the nucleus in an untreated condition in SH‐SY5Y cells, and also the DDR2 level increases in AD nucleus compared to control using ICC and nuclear fractionation. Moreover, we observed that DDR2 forms a punctate structure inside the nucleus that strongly colocalizes with SRSF2 a nuclear speckle protein. Immunoprecipitation of DDR2 followed by Mass spectrometry (MS) in the AD cell model revealed some important proteins like HNRNPH1, HNRNPU, PCBP2, and SRSF7 as binding partners of DDR2, implicating a role of DDR2 in mRNA splicing.

Conclusion

DDR2 which is a receptor tyrosine kinase, in the absence of its endogenous ligand collagen gets activated in AD by interacting with amyloid beta and translocates to the nucleus. DDR2 resides inside the nuclear speckles, and interacts with several splicing factors, thereby regulating alternative splicing in AD.
Uncovering the association between dysphagia and depression: Insights from the 2022 National Health Interview Survey
Authors: Yoo Sanghee , Hong Ickpyo
Published: January 2025

Background

Dysphagia can increase fear of swallowing, reduce self‐esteem, and hinder social relationships. Such factors can also increase anxiety and degrade the quality of life. This study aimed to elucidate the association between dysphagia and depressive symptoms.

Method

This study conducted an assessment of 26,810 U.S. adults using the 2022 National Health Interview Survey (NHIS) database. Multiple regression analysis and five different propensity score matching approaches were used to account for sex, race/ethnicity, educational attainment, household income, number of comorbid chronic diseases, and presence of anxiety disorder.

Result

Utilizing the 2022 NHIS database, 26,810 American adults were assessed. Of the weighted population demographics, 51.88% reported having dysphagia, with 43.64% being females and an average age of 46.17 (SD 0.22). The study findings revealed that individuals reporting dysphagia had an elevated likelihood of presenting depressive symptoms (OR = 1.875, p < .0001). Several factors influencing depressive symptoms were identified, including sex, race, educational attainment, household income, the number of accompanying chronic diseases, and the presence of an anxiety disorder. Females exhibited a higher likelihood of depression (OR = 1.441; 95%CI 1.354, 1.533) compared to males. Individuals with educational levels of ‘some college’ or higher demonstrated elevated odds ratios for depressive symptoms relative to those who did not complete high school (OR = 1.141; 95%CI 1.018, 1.279). The presence of two‐plus chronic diseases significantly upped depression risks (OR = 1.902; 95%CI 1.725, 2.097), with anxiety disorders further amplifying this (OR = 5.147; 95%CI 4.676, 5.664).

Conclusion

This study demonstrated the intricate interplay between dysphagia and various demographic and health factors, emphasizing the critical need for individualized management strategies for depression in patients with dysphagia.
Alzheimer’s Disease and Lewy Body Co‐Pathology Presenting with Corticobasal Syndrome
Authors: Nouh Claire Delpirou , Vallejo Kristen , Tan Simon , Zeineh Michael , Sha Sharon J , Nirschl Jeffrey
Published: January 2025

Background

Corticobasal syndrome (CBS) corresponds to a clinical phenotype with heterogeneous neuropathology, including corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), Alzheimer’s disease (AD), and synucleinopathies such as Lewy Body Disease (LBD), in rare cases. Previous reports of CBS‐LBD describe patients with diffuse LBD, a younger age of onset and occasionally lacking core features like REM sleep Behavior Disorder (RBD).

Method

We present a young patient with CBS who had a rapid progression and was found to have a high burden of limbic LBD and high AD co‐pathology at autopsy.

Result

A 58‐year‐old right‐handed woman consulted for progressively worsening apraxia, writing, and visuospatial difficulties over the year prior to presentation. She had minimal short‐term memory loss initially, did not have RBD nor visual hallucinations and remained independent in activities of daily living. She scored 20/30 on the Montreal Cognitive Assessment, with difficulties in visuospatial and executive tasks. The neurological exam showed predominant apraxia, asymmetric parkinsonism and sensory neglect, all left‐sided. The brain MRI confirmed striking asymmetric atrophy affecting the right parieto‐temporal lobes. Cerebrospinal fluid (CSF) demonstrated decreased Abeta 42/tau index and elevated total and phosphorylated tau. Her condition progressed quickly over the next year, and she passed away four years after diagnosis. Brain autopsy showed asymmetric moderate‐severe cortical atrophy with abundant phospho‐synuclein positive Lewy bodies extending to the temporal but not frontal/parietal cortices, consistent with limbic (transitional) LBD and high Alzheimer’s disease co‐pathology (A3, B3, C3). There was severe Lewy body pathology in the hippocampal CA2 subfield, prominent phospho‐tau in the substantia nigra, severe neuron loss in the locus coeruleus, and severe gliosis in the motor cortex.

Conclusion

AD and LBD commonly occur together, but the frequency of AD and LBD as a cause of CBS is unknown. Here, we add to the literature of co‐pathology in CBS and consider that early age and rapid progression could suggest dual pathology and potential synergistic effects. CSF testing limited to AD biomarkers will miss this dual pathology. Thus, CSF α‐synuclein seeding amplification may help identify patients with dual AD‐LBD pathology and assist prognostication.
Contrasting Manual and Automatic Approaches for Extracting Linguistic Features in Predicting Alzheimer’s Disease through Chinese Speech
Authors: Wang Yi‐Hsuan , Fang Cheng Chia‐ , Chou Chia‐Ju , Liu Yi‐Chien , Lee Chia‐Ying , Chang Ya‐Ning
Published: January 2025

Background

Continuous speech analysis is considered as an efficient and convenient approach for early detection of Alzheimer’s Disease (AD). However, the traditional approach generally requires human transcribers to transcribe audio data accurately. This study applied automatic speech recognition (ASR) in conjunction with natural language processing (NLP) techniques to automatically extract linguistic features from Chinese speech data. Machine learning (ML) models were then used to predict early AD. The obtained results were compared with those derived from manual processes.

Method

Continuous speech samples were obtained from 81 native Chinese speakers in Taiwan performing a picture description task. The participants included 34 normal controls (61‐89 yrs) and 47 patients diagnosed with amnestic mild cognitive impairment (aMCI) and early AD (59‐89 yrs). Fifteen linguistic features (Table 1) were measured via both manual and automatic processes. In the automatic extraction process, an ASR model transcribed the speech automatically, followed by the application of NLP techniques for automatic extraction of linguistic features. To classify AD, six ML models were trained with the two sets of features, and their performance was compared. The training‐to‐testing data ratio was 7:3, and cross‐validation was employed to mitigate overfitting.

Result

The Random Forest classifier achieved the best prediction accuracy and F1 score in both the datasets processed manually (acc = 0.92, F1 score = 0.908) and automatically (acc = 0.88, F1 score = 0.857) (see Table 2). Figure 1 illustrates the top five linguistic features for both the manually‐processed (Figure 1A) and auto‐processed (Figure 1B) datasets. The results showed an overlap in three out of five key features were overlapped including mean length of utterance (MLU), long pause ratio and pronoun ratio.

Conclusion

Our automatic approach for extracting linguistic features achieved comparable accuracy (88%) with those extracted through human judgment in Random Forest classifiers (92%). Importantly, MLU emerged as the predominant feature in both manually‐ and automatically‐processed datasets. This outcome suggests a noteworthy decline in syntactic complexity during the early stages of AD in Chinese‐speaking patients.
Chimeric hippocampal organotypic slices enable the in vitro investigation of human iPSC‐derived microglia in a three‐dimensional environment with preserved neural network activity
Authors: Devoght Jens , Nonneman Annelies , Swijsen Sofie , Wuyts Dirk , Van den Daele Johanna , Maurin Hervé , De Vos Winnok H , Ebneth Andreas , Yu Shih Pei‐ , Almenar Juan Diego Pita
Published: January 2025

Background

Microglial cells have emerged as key players in the pathogenesis of Alzheimer’s disease (AD). They act as a first line defense and fulfil a crucial role during brain development and circuit homeostasis. Microglia are involved in the removal of debris, control neural activity, regulate synaptic plasticity, and synapse pruning. Normal microglial functioning can be impaired by aging, stress, and genetic predisposition, provoking a pathophysiological turnover towards excessive neuroinflammation, neurodegeneration and synaptic loss, all hallmarks of AD. Despite similarities between human and mouse microglia, major discrepancies exist across species regarding gene expression and functionality. Even more, a variety of human microglial risk genes lack the proper murine orthologues, urging for the use of human cell‐based assays. Although in vitro (human) cell culture systems provide useful insights of microglial functionality, they lack a functional three‐dimensional brain environment.

To investigate human microglia in a functional brain network, we developed an easy‐to‐manipulate chimeric platform of murine hippocampal organotypic slice cultures (OSCs) with integrated human iPSC‐derived microglia.

Method

OSCs depleted from endogenous mouse microglia were engrafted with human iPSC‐derived microglia to develop a chimeric OSC model which was validated using electrophysiology, immunostaining, RT‐qPCR and MSD.

Result

The intact neural network activity of OSCs and effects of microglial depletion and activation were verified using a high‐density multielectrode array. Further evaluation of endogenous microglial effects on synaptic signaling within OSCs was measured using whole‐cell patch‐clamp. A co‐immunostaining with STEM121 (human) and IBA1 (microglia) validated the engraftment and presence of mature human iPSC‐microglia. Morphological analysis of the engrafted human iPSC‐microglia revealed a larger cell body, a higher number of ramifications per microglia and an increase in length of these ramifications, when compared to monocultures. Besides validation of the expression of microglial markers and morphological assessment, proper functioning of these human iPSC‐microglia engrafted cells was confirmed. The engrafted human iPSC‐microglia revealed damage‐induced migratory responses and release of human‐specific proinflammatory cytokines upon LPS stimulation.

Conclusion

The developed chimeric OSCs model with engrafted human iPSC‐microglia provides an ex vivo platform to investigate human iPSC‐derived microglia within a physiologically relevant and functional brain network.
Association between self‐reported SCD‐plus criteria and Alzheimer’s disease biomarkers in cognitively unimpaired older adults: meta‐analyses
Authors: Kuhn Elizabeth , Klinger Hannah M , Amariglio Rebecca E , Jessen Frank , Wagner Michael , Chételat Gael , Rentz Dorene M , Sperling Reisa A , Ebenau Jarith L. , Butterbrod Elke , van der Flier Wiesje M. , Sikkes Sietske A.M , Rami Lorena , Sánchez‐Benavides Gonzalo , Gifford Katherine A. , Van Hulle Carol A. , Buckley Rachel F ,   the Alzheimer’s Disease Neuroimaging Initiativethe Australian Imaging Biomarkers and Lifestyle flagship study of ageingthe A4 study team, the DELCODE study groupthe Harvard Aging Brain Study
Published: January 2025

Background

In cognitively unimpaired (CU) older adults, the presence of a subjective cognitive decline (SCD) combined with evidence of abnormal b‐amyloid (Ab) is proposed as stage 2 of Alzheimer’s disease (AD) by the NIA‐AA framework (Jack et al., 2018). However, the associations found between SCD and preclinical AD are inconsistent across studies, highlighting the importance of better understanding which specific SCD features are associated with either Ab or tau burden.

Methods

The present study includes cross‐sectional data from 9 independent cohorts with a total of 7217 CU older adults (57% female), aged 69.34 (1.20) years, recruited from general and memory‐clinic populations. Ab and tau biomarkers were measured by positron emission tomography (PET) or cerebrospinal fluid (CSF). Using established cut‐offs, 28% of participants were Aβ+, and 12% were Aβ+T+ (approximately one‐third of the sample had available tau data). We examined four SCD‐plus criteria as well as the mean number of SCD criteria met (i.e., mean SCD‐severity) in relation to both biomarker status and levels in logistic/linear regressions adjusted for age and sex for each cohort. Summary statistics were extracted for meta‐analyses.

Results

The overall frequency of stage 2 AD varied from 7‐16% [4‐26%] according to each SCD‐plus criterion endorsement. Only 1‐5% [0‐8%] of participants meeting the SCD‐plus criteria also had both high Aβ and tau burden (Fig.1). The presence of self‐reported memory decline (SMD), an associated concern/worry, and a higher mean SCD‐severity were each associated with high Ab (status and continuous). Only the latter was associated with high tau status (Fig.2). Onset of SCD within the last 5 years, and feeling of worse performance than same‐age peers, were not associated with AD biomarkers at a Bonferroni‐corrected threshold.

Conclusions

Our results suggest that widespread endorsement of multiple SCD features is more powerful than a single criterion alone in identifying both Aβ and tau in CU older adults. We found that the isolated SCD criterion was particularly sensitive to elevated Aβ, even after adjustment for tau, supporting the power of SCD as a very early behavioral marker of preclinical AD.
Remote cognitive testing in Insight46: relationship to standard cognitive assessments and biomarkers of neurodegeneration
Authors: Giovane Martina Del , Leoni Marguerite , Giunchiglia Valentina , Cai Ziyuan , Street Rebecca E , Lu Kirsty , Wong Andrew , Popham Maria ,   Insight 46 study Team, Murray‐Smith Heidi , Richards Marcus , Crutch Sebastian J , Hampshire Adam , Schott Jonathan M
Published: January 2025

Background

Dementia‐related biomarkers can detect pathology years before clinical diagnostic criteria are met. Understanding the relationship between biomarkers and early cognitive changes is crucial as disease‐modifying therapies may have maximum benefits when delivered early. We aimed to demonstrate the utility of remote computerised cognitive tests in a large cohort of cognitively normal older individuals, comparing these to standard in‐person assessments and investigating their associations with biomarkers.

Methods

Using the Cognitron platform, we remotely deployed 11 computerised tests (Figure 1) in 255 members of the Insight46 study. Participants had previously completed biomarker and in‐person standard cognitive assessments at age 71‐73 (1). We generated brain, hippocampal, and white matter hyperintensity volumes, rates of brain and hippocampal volume change between age 71‐73, amyloid load (SUVR) and positivity as previously described (1). General linear models (GLMs) assessed the relationship between the Cognitron tests and biomarkers. Principal component analysis was used for dimensionality reduction, and bivariate correlations compared the standard tests total composite score with the Cognitron accuracy and response time (RT) composite scores. Canonical Correlation Analysis (CCA) further quantified these associations.

Results

Of 255 participants (132 males, 234 right‐handed, age at assessment 77), 66 were amyloid positive. Amyloid positivity was significantly predicted by RT for the Objects memory test (delayed recognition) (OR = 1.58 (95% CI 0.09,0.85)). We found an association between the Cognitron Objects memory tests and biomarkers (Table 1). Immediate recognition was significantly associated with hippocampal volume change (F(2,204) = 4.34; CI: ‐7.78, ‐7.74), while the amount of amyloid positivity was significantly predicted by delayed recognition (F(2,225) = 4.48; CI: ‐0.06, ‐0.04) and retention (F(2,204) = 3.47; CI: 0.01, 0.1). Both Cognitron accuracy and RT composites significantly correlated with the standard composite (r = 0.56, p<0.001; r = ‐0.32, p<0.001) (Figure 2). CCA indicated shared variance with significant canonical variables between the standard tests and the Cognitron accuracy (M1:r = 0.73, p<0.001; M2:r = 0.54, p<0.001; M3:r = 0.49, p = 0.01) and RT (M1:r = 0.54, p<0.001) scores.

Conclusions

Remote computerised cognitive testing correlates with standard supervised assessments and holds potential for studying early cognitive changes associated with neurodegenerative biomarkers at scale and longitudinally.

Reference

1. Lane et al. (2017) ‐ BMC Neurol, 17(75). https://doi.org/10.1186/s12883‐017‐0846‐x
Association of Sleeping Pills on Anxiety Symptoms in Dementia and Borderline Groups: Insights from the 2022 National Health and Aging Trends Study
Authors: Yoo Sanghee , Hong Ickpyo
Published: January 2025

Background

Old adults' sleep patterns change during the aging process1. Among old adults, 40% of individuals experience insufficient sleep and complain of sleeping disorder, including a decline in the quality of sleep2. Patients with dementia also experience sleep disorders, and the most common intervention for this is pharmacotherapy3,4. This study aims to investigate the relationship between anxiety and sleeping pills in patients with dementia and borderline groups.

Method

In this study, the 2022National Health and Aging Trends Study was used to examine the association between anxiety symptoms and sleeping pill use in patients with dementia and borderline groups. The analysis was conducted using a multiple regression model by accounting for demographics.

Result

This study analyzed a sample of 1,189 and there were 351 (29.52%) patients with dementia and borderline groups who reported taking sleeping pills. As a result of multiple regression analysis, the group that took drugs for sleep showed a significantly higher risk of anxiety symptoms than the group that did not take drugs (odds ratio [OR] 2.999; 95% confidence interval [CI] 2.235, 4.023). Compared to men, the risk of showing anxiety symptoms was significantly higher in women (OR 1.666; 95% CI 1.224, 2.267). Compared to whites, blacks had a significantly lower risk of anxiety (OR 0.770; 95%CI 0.535, 1.108).

Conclusion

This study showed a strong association between sleep medication use and anxiety symptoms in American patients with dementia and a borderline group. This suggests the need for treatment that addresses the mental health of dementia and borderline groups who experience sleep disorders.
Exploring an Audio‐based Approach for Early Detection of Alzheimer’s Disease using Chinese Speech Data
Authors: Lee Hung‐Wei , Fang Cheng Chia‐ , Wang Yi‐Hsuan , Chang Ya‐Ning
Published: January 2025

Background

Alzheimer’s disease (AD) has been associated with speech and language impairment. Recent progress in the field has led to the development of automated AD detection using audio‐based methods, because it has a great potential for cross‐linguistic detection. In this investigation, we utilised a pretrained deep learning model to automatically detect AD, leveraging acoustic data derived from Chinese speech.

Method

Speech samples from a picture description task were obtained from 81 native Chinese speakers in Taiwan. This group included 34 normal controls (NC) (14 females; age range: 61‐89 years; average age: 73.9 years; SD: 6.7) and 47 patients diagnosed with early AD (24 females; age range: 59‐89 years; average age: 76.8 years; SD: 7.6). The audio data were first segmented into 6‐second clips, resulting in a total of 1117 clips for the NC group and 1770 for the AD group. Due to the data imbalance, we equalized the groups by randomly selecting 1117 clips from the AD group. The dataset was then divided into a training‐to‐testing ratio of 8 to 2. The training clips were initially processed using a pre‐trained Wav2vec2 model to generate internal acoustic representations. Subsequently, these acoustic representations, now serving as feature data, were input into a two‐layer fully connected neural network for additional training and classification.

Result

The model achieved a training accuracy of 83%. Notable metrics for test performance were observed as follows: Accuracy ‐ 81.25%, Precision ‐ 80.92%, Recall ‐ 81.79%, and F1 Score ‐ 81.35%. These findings suggest a promising capability of wav2vec2 in Alzheimer’s Disease detection, demonstrating a commendable balance between precision and recall.

Conclusion

The pre‐trained Wav2vec2 model emerges as a promising tool for AD detection through Chinese speech data. This research sets the foundation for additional investigation into the model’s potential for cross‐linguistic detection using speech data. Additionally, future work can also be conducted to investigate what acoustic features are used and their significances in classification process.
Discrepancy between Apolipoprotein E genotyping and proteotyping as a result of a nonsense mutation
Authors: Vandenbroucke Ina , Yuri Tatsushi , Dobbels Caroline , Minczakiewicz Dagmara , Kamada Jo , Nojima Hisashi , Aoyagi Katsumi , Van Dongen Jasper , Kucukali Fahri , Sleegers Kristel , Degrieck Rosina
Published: January 2025

Background

Apolipoprotein E (APOE) ε4 is a significant genetic risk factor for late‐onset Alzheimer’s Disease and appears to be closely related with brain amyloidosis. Current identification methods for APOE ε4 carriers are mostly based on genotyping which cannot always predict the specific ApoE protein isoform. We present a case study of a sample with a discordant result for genotype compared to the protein isoform (proteotype) and we reflect on possible implications for future applications.

Method

Proteotyping was performed on plasma using the Lumipulse® G Pan‐ApoE and Lumipulse® G ApoE4  immunoassays on the LUMIPULSE G platform (Fujirebio, Japan). Isoelectric focusing electrophoresis (IEF) was performed using the Phenotyping ApoE IEF system (Joko Inc., Japan). Amplicon‐based sequencing of APOE on genomic DNA was performed by targeted long‐read sequencing on the Flongle platform using SQK‐LSK110 chemistry (Oxford Nanopore Technologies).

Result

Previous comparison of genotyping (by real‐time PCR) with proteotyping on 230 paired blood /plasma samples revealed one discordant result (ε2/ε4 genotype versus negative E4 proteotype), achieving a 99.6% concordance rate. The proteotype of this discordant sample was confirmed to be E2 with absence of E4 using IEF. Long‐read gDNA sequencing of the discordant sample revealed a nonsense mutation (c.745G > T; p.E249X) in phase with the APOE ε4 allele. This stop codon could either lead to a truncated protein, with a loss of function or altered function, or lead to degradation of the mRNA via the Nonsense Mediated Decay (NMD) pathway. Since the E4 isoform was not detected by the detecting antibody on the LUMIPULSE G platform, the most likely pathway is the degradation of the RNA by NMD, unless the E4 epitope was altered in the truncated protein.

Conclusion

ApoE4 proteotyping offers advantages over genotyping by determining the effective presence of the protein in plasma, especially in case of mutations affecting the expression or function of the protein. Also, quantifying ApoE protein levels via immunoassays could yield insights into the relation of ApoE protein levels with pathology. Moreover, in case of potential future applications in a laboratory workflow, molecular testing could possibly be avoided, offering advantages in terms of turn‐around‐time and logistics.
TRIDENT cognitive substudy: preliminary results from a Brazilian cohort
Authors: de Souza Ana Cláudia , Borelli Wyllians Vendramini , Miyamoto Kendi Nishino , Alves Ana Claudia , Almudi Mariana , Hess Adriana Binsfeld , Kochhann Renata , Carbonera Leonardo Augusto , Martins Sheila O , Anderson Craig S.
Published: January 2025

Background

Intracerebral hemorrhage (ICH) is the most severe and disabling stroke, accounting for up to 50% of the cases in low‐to‐middle‐income countries. High rates of cognitive decline and dementia follow acute ICH, due to the common underlying vasculopathy of cerebral small vessel disease (CSVD). The international clinical trial, TRIDENT (Triple therapy prevention of Recurrent Intracerebral Disease EveNts Trial), aims to determine the effectiveness of the fixed low‐dose Triple Pill combination of blood pressure‐lowering agents (telmisartan 20 mg, indapamide 1.25 mg, and amlodipine 2.5 mg) versus placebo on recurrent stroke and additionally on the secondary outcomes of cognitive decline and dementia. The aim of the Brazilian substudy is to assess the Triple Pill effectiveness on memory, cognition, and CSVD progression in ICH patients.

Method

This substudy is part of the TRIDENT international, multicenter, double‐blind, placebo‐controlled, parallel‐group, randomized controlled trial led by The George Institute for Global Health in Australia. A subset of participants recruited from Brazilian local sites are offered the opportunity to undergo additional cognitive assessments through gold‐standard neuropsychological tests at baseline (until up to 6 weeks post‐randomization), and 12 months. MRI evaluation of these patients will be performed to assess CSVD progression through specific parameters at baseline and 12 months.

Primary Outcome (MRI) ‐ Changes in T2 FLAIR WMH volume between baseline and 12 months will be assessed.

Secondary Outcomes (MRI)

1. Whole brain atrophy measured by percentage brain volume change between baseline and 12 months on HIRES‐T1.

2. Substructure change (cortical grey matter, white matter, and CSF) between baseline and 12 months.

3. Change in the number of CMBs between baseline and 12 months on SWI.

Result

The study recruitment is ongoing.

Conclusion

The substudy could potentially evaluate Triple Pill’s effectiveness on cognitive decline, dementia, and CSVC progression.
Omega 3 fatty acid alleviates sleep deprivation‐induced oxidative stress, inflammation, and cognitive impairment in the hippocampus of Male Wistar rats
Authors: Ochai Joy , Umana Uduak Emmanuel , Musa Sunday Abraham , Oladele Samuel B
Published: January 2025

Background

Sleep deprivation leads to an increase in oxidative stress and activation of inflammatory response and both could increase the production and accumulation of toxic beta‐amyloid in the hippocampus which is considered one of the molecular drivers of Alzheimer’s pathogenesis and progression. Despite these findings, obtaining sleep is still challenging in our modern society that values work around the clock. Omega‐3 fatty acids represents an active biological agent with vital antioxidant and anti‐inflammatory activities that could protect memory in the face of insufficient sleep. This study evaluated the anti‐oxidative, anti‐inflammatory, and neurocognitive effect of omega‐3 fatty acids on memory impairment caused by sleep deprivation in male Wistar rats.

Method

Thirty male Wistar rats were randomly divided into five groups of six rats each. Group I received 2ml/kg distilled water, Group II, III IV and V were sleep deprived for 18 hours daily for a 21 days duration using the modified multiple platform method. Additionally, group III, IV and V received 100mg/kg, 200mg/kg and 400mg/kg of omega‐3 fatty acids respectively via oral route. Neurobehavioral assay for spatial learning and memory using the Morris water maze (MWM) test was carried out. The animals were euthanised and the brain tissues excised, fixed, and processed for β‐amyloid study using Congo red stain. Tissue homogenate was used for assessment of malondialdehyde (MDA), superoxide dismutase (SOD), interleukin‐6 (IL‐6) and tumor necrosis factor‐alpha (TNF‐α) levels.

Result

The result revealed a marked increase in the time‐spent in locating the escape platform in the MWM test, and an increased in β‐amyloid burden in the sleep deprived only group. Biochemical assessment also showed significant increase in MDA, IL‐6 and TNF‐ α and decrease in SOD level within this group. However, significant improvement in memory retention ability, decreased β‐amyloid accumulation, MDA, IL‐6, TNF‐ α and increase in SOD level were observed in the omega‐3 fatty acid treated groups. The observed changes were dose dependent.

Conclusion

Omega‐3 fatty acids protects the hippocampus against memory impairment caused by sleep deprivation.
Cell type‐specific signatures of resilience to cognitive decline in the presence of brain pathologies
Authors: Luquez Tain , Sreenivas Dhwani , Bennett David A. , De Jager Philip L. , Menon Vilas
Published: January 2025

Background

To identify discrete and continuous cell type signatures in brain tissue from donors with minimal cognitive decline despite harboring substantial proteinopathies associated with Alzheimer’s Disease and Alzheimer’s Disease‐related dementias.

Method

Three large‐scale single‐nucleus RNA‐seq studies on Alzheimer’s Disease post‐mortem human tissue were re‐annotated and integrated to identify cell type composition associations with cognitive resilience to various neuropathologies. Cell type signatures were defined in two ways: using an integrated clustering approach and using a continuous factor‐based analysis. Cognitive resilience was also defined in two ways: using a categorical grouping of donors as well as a continuous definition based on the slope of decline across each of five cognitive domains.

Result

We report two microglial cell types associated with resilience to Alzheimer’s and alpha‐synuclein proteinopathies. Individuals cognitively resilient to substantial cortical alpha‐synuclein aggregates have higher levels of a microglial subset enriched for redox genes and overexpressing APOE, TYROBP and SPP1. By contrast, cognitively resilient individuals with high amyloid burden show lower proportions of a microglial subset marked by TMEM163+. On the neuronal side, a subset of glutamatergic layer 2/3 neurons was higher in individuals resilient to visuospatial decline despite harboring alpha‐synucleinopathy. A different L2/3 excitatory neuron cluster is depleted in the same individuals, thus highlighting preferential loss or preservation of neuronal subclasses in individuals with cognitive resilience. Finally, we find lower levels of committed oligodendrocyte precursor cells and FTH1+/CRYAB1+ oligodendrocytes in individuals with amyloid and alpha‐synuclein aggregates with better preserved visuospatial, semantic memory and global cognition.

Conclusion

Using a combination of categorical and continuous definitions of resilience, together with existing single‐nucleus RNA‐sequencing data on cortical tissue from >600 human donors, we uncovered cell‐type compositional changes in microglia, neurons and oligodendrocytes that are associated with global and domain‐specific cognitive resilience to amyloid, tau and alpha‐synuclein proteinopathies.
Localized Proteomics of Amyloid Plaque Tissue in Down Syndrome and Alzheimer’s Disease
Authors: Ariza Mitchell Marta , Leitner Dominique , Suazo Jianina , Pedrosa Ana Giusti , Kanshin Evgeny , Ueberheide Beatrix , Fortea Juan , Lleo Alberto , Wisniewski Thomas
Published: January 2025

Background

Down syndrome (DS) is strongly associated with Alzheimer’s disease (AD), attributable to APP overexpression, displaying common features with early‐onset AD (EOAD) and late‐onset AD (LOAD) like Amyloid‐β (Aβ) and tau pathology. Here, we evaluated the Aβ plaques proteome of DS, EOAD and LOAD.

Method

We used unbiased localized proteomics to analyze amyloid plaques and the adjacent plaque‐devoid tissue (‘AD non‐plaque’) from post‐mortem paraffin‐embedded tissues in three subtypes of AD (n = 20/group): DS (59.8 ±4.99 y/o), EOAD (63 ±4.07 y/o), and LOAD (82.1 ±6.37 y/o). Functional associations were analyzed using Gene Ontology (GO) enrichment and protein interaction networks.

Result

We identified 132, 192 and 128 differentially abundant proteins in DS, EOAD and LOAD Aβ plaques (FDR<5%, fold‐change<1.5). Common plaque‐associated proteins constituted 14% across all groups, with 15% only in DS, 32% in EOAD, and 17% in LOAD. Significant correlations (p<0.0001) existed between DS and EOAD (R2 = 0.77) and DS and LOAD (R2 = 0.73), compared to EOAD and LOAD (R2 = 0.67). Top BP GO terms (p<0.0001) were lysosomal transport, regulation of the immune system process and lysosome organization for DS, EOAD and LOAD, respectively. Protein networks revealed a characteristic signature across all AD subtypes involving APP metabolism, immune response, and lysosomal pathways. We identified 263, 269, and 301 differentially abundant proteins in DS, EOAD and LOAD non‐plaques. Common differentially abundant proteins constituted 12% across AD subtypes, with 24% only in DS, 14% in EOAD and 26% in LOAD. DS correlated significantly (p<0.0001) with EOAD (R2 = 0.59) and with LOAD (R2 = 0.33), compared to EOAD and LOAD (R2 = 0.79). The top BP GO term for all three subtypes was chromatin remodeling (p = 0.0013, p = 5.79 × 10‐9, and p = 1.69 × 10‐10, respectively). Additional GO terms for DS included extracellular matrix and integrin‐mediated signaling (p = 0.0068), while EOAD and LOAD were associated with protein‐DNA complexes and regulation of gene expression (p<0.0001).

Conclusion

We identified proteome differences in Aβ plaques across AD subtypes. Correlation and functional analyses revealed that DS and LOAD plaque‐associated proteins primarily participate in lysosomal pathways, while EOAD proteins are linked to immune response. In contrast, EOAD and LOAD non‐plaque proteins correlated better compared to DS, with functional differences reflected in the top GO terms.