bluuebunny/crossref_metadata_2025 huggingface dataset:
A cross‐linguistic test of automated speech and language analysis for detecting Alzheimer’s disease: Machine learning evidence from English and Spanish speakers
Authors: Perez‐Toro Paula Andrea , Ferrante Franco Javier , Pérez Gonzalo Nicolás , Slachevsky Andrea , Nöth Elmar , Schuster Maria , Maier Andreas , Arroyave Juan Rafael Orozco , Garcia Adolfo M.
Published: January 2025

Background

Digital health research on Alzheimer’s disease (AD) points to automated speech and language analysis (ASLA) as a globally scalable approach for diagnosis and monitoring. However, most studies target uninterpretable features in Anglophone samples, casting doubts on the approach’s clinical utility and cross‐linguistic validity. The present study was designed to tackle both issues.

Method

The study included 178 native English speakers from the Pitt corpus (134 with AD, 44 controls) and 39 native Spanish speakers from a Chilean cohort (21 with AD, 18 controls). Participants were audio‐recorded as they described the Cookie Theft picture. Recordings were used to extract speech timing features (reflecting semantic memory retrieval effort), whereas their transcriptions were used to derive vocabulary selection features (revealing lexicon navigation patterns). We first trained classifiers with English‐speaking AD patients and controls, and then tested them in (a) a within‐language setting (with English‐speaking patients and controls as testing folds) and (b) a between‐language setting (with Spanish‐speaking patients and controls as testing folds). To discriminate between groups, in each case, we ran a separate classifier per modality (timing, vocabulary) and then another combining both modalities via early fusion. Finally, we explored whether the most sensitive features in each setting could predict patients’ clinical severity, as indexed through the Mini‐Mental Status Examination (MMSE).

Result

Within‐language analysis showed that discrimination between AD patients and controls was good when based on speech timing (AUC = 0.75) and vocabulary (AUC = 0.79) features alone, and excellent when upon combining both modalities (AUC = 0.91). Between‐language analyses yielded maximal discrimination for the speech timing classifier (AUC = 0.79), surpassing vocabulary features (AUC = 0.60), and the fusion of both dimensions (AUC = 0.66). Patients’ MMSE scores were robustly predicted by speech timing features in both the within‐language (ρ = 0.41, p < .001) and the between‐language (ρ = 0.60, p < .001) settings.

Conclusion

Interpretable ASLA features capturing semantic memory processes can robustly identify AD patients, with speech timing measures showing greater potential for cross‐linguistic generalization and severity prediction. Our approach paves the way for novel studies bridging the gap between ASLA and global approaches to dementia.
Clinical Characteristics of Progressive Supranuclear Palsy Subtypes Defined by AT(N) CSF Biomarkers
Authors: Ishiguro Takanobu , Kasuga Kensaku , Tsukie Tamao , Onodera Osamu , Ikeuchi Takeshi
Published: January 2025

Background

Progressive supranuclear palsy (PSP) may show concomitant neuropathological findings such as Alzheimer's disease (AD)‐related pathologies. Recent advances in CSF biomarkers enabled the estimation of neuropathological changes in brains in various neurodegenerative diseases. Clinical characteristic of subtypes of PSP defined by CSF biomarkers have not been well understood.

Methods

Nineteen PSP patients (11 males and 8 females, age at the examination: 72.9±7.9 years) who diagnosed by board‐certified neurologists were included in this study. They all met the criteria for 'probable,' 'possible,' or 'suggestive' PSP according to the MDS PSP criteria (2017). CSF AT(N) biomarkers including Aβ42 and Aβ42/40 ratio as A marker, p‐tau181 as T marker, and total tau [t‐tau] and neurofilament light chain [NfL]) as N marker were quantified. The positivity/negativity of each biomarker was determined based on the cutoff value defined in an independent cohort. PSP patients were classified into subgroup defined by AT(N) CSF biomarkers. Clinical characteristics were compared between the AD continuum (A+ profile) group and the non‐AD continuum (suspected non‐AD pathophysiology, SNAP) group. The activities of daily living (ADL) in PSP patients were evaluated using the Barthel Index.

Results

Fourteen patients (74%) met the criteria for probable PSP‐Richardson syndrome. CSF AT(N) biomarker analysis revealed that the AD continuum pattern (A+ pattern) (AD [n=4] and, A+T‐N+ [n=8]) was observed in 12 PSP patients, and the SNAP pattern was observed in 7 PSP patients. The AD continuum group exhibited later onset (p=0.0009), lower MMSE scores (p=0.0177), and a higher frequency of axial rigidity (p=0.0379). CSF NfL showed a significant negative correlation with the Barthel Index in the entire PSP patients (r= ‐0.7281, p=0.001).

Conclusions

Different clinical characteristics were observed in subgroups of PSP patients defined by AT(N) CSF biomarkers. PSP patients with the AD continuum had later onset and more impaired cognition than those without AD continuum. CSF NfL may be a valuable marker reflecting ADL in PSP patients.
Additive and interactive roles of alcohol use disorder and anxiety disorder on higher risk of Alzheimer’s disease and related dementias amongst hypertensive patients in high‐volume claims data: a retrospective study
Authors: Lundin Sori Kim , Hu Xinyue , Feng Jingna , Chen Yong , Schulz Paul E , Tao Cui
Published: January 2025

Background

Alcohol use disorder (AUD) among elderly population is a strong risk factor for dementia. Anxiety disorder also poses a great toll on cognitive health and is commonly diagnosed among individuals with AUD. However, the additive and interactive roles of AUD‐anxiety disorder comorbidities on cognitive disorders such as Alzheimer’s disease and related dementias (ADRD) is poorly studied.

Method

6,390,826 individuals with hypertension were selected from US‐based Optum de‐identified Clinformatics® Data Mart. Baseline characteristics were compared between groups by the Chi‐square test for categorical variables and the Kruskal‐Wallis test for continuous variables. Kaplan‐Meier and adjusted cox proportional hazards (PH) model were used to study the additive and interactive associations of AUD and anxiety disorder in relation to the time from hypertension to ADRD.

Result

318,163 individuals with AUD and 6,072,663 without AUD were identified. Almost 70% of the AUD patients were male. Incidence of anxiety disorder, depression, substance use disorder, tobacco use, and COPD were significantly higher in AUD patients compared to non‐AUD patients (all P < 0.0001). In the Kaplan‐Meier plot, hypertensive individuals with AUD‐anxiety disorder comorbidity showed the highest cumulative hazards of ADRD, followed by those with anxiety disorder but no AUD. Individuals without AUD and anxiety disorder had the least cumulative hazards of ADRD. These four groups had a significant difference in their risk of ADRD (P < 0.0001). Using Cox PH analyses with additive terms, individuals with AUD comorbidity showed a 33% and 41% higher adjusted hazard ratio (aHR) of ADRD development than those without, among patients with and without anxiety disorder, respectively. Interactive terms of AUD and anxiety disorder were associated with 3% increase in aHR (P=0.012).

Conclusion

In conclusion, our study found that AUD‐anxiety disorder comorbidities were associated with a higher risk of ADRDs from large‐volume claims data. We also found that the interaction of AUD‐anxiety disorders was linked to harmful effects against ADRD development. These results strongly suggest a critical need for combining medical and psychological efforts to fight dementia through integrative intervention on AUD and anxiety disorder.
The effect of social interaction intervention on cognitive functions among non‐demented older adults: A systematic review and meta‐analysis
Authors: Wei Chi chuan , Xie Ming‐Jia , Chuang Yi‐Fang
Published: January 2025

Background

Previous systemic reviews, predominantly including observational studies, have shown that participation in social activities is a protective factor against cognitive decline. However, this association is subject to potential reverse causality, creating a knowledge gap in our understanding of the effect of social interaction interventions on cognitive function. Therefore, this study aims to conduct a systematic review and meta‐analysis of randomized‐controlled trials to examine the effects of social interaction interventions on cognitive decline among non‐demented older adults.

Method

This systematic review was registered in PROSPERO (CRD42022367828), and we systematically searched six databases from inception to May 6, 2022, to identify relevant articles on the effects of activities with social interaction components on cognitive function in community‐dwelling non‐demented older adults over 60. Two independent reviewers performed study selection, data extraction, and bias assessment, and RevMan5.3 was used to conduct the meta‐analysis. Subgroup analysis was conducted to explore potential sources of heterogeneity and assess variation in intervention effects across subgroups.

Result

We included 11 studies for qualitative analysis and eight studies for the meta‐analysis. The result showed that social interaction intervention had a significant effect on executive function (SMD = 1.63; 95% CI, 0.55 to 2.70), but not attention (SMD = 0.09; 95% CI, ‐0.09 to 0.26) and memory (SMD = ‐0.03; 95% CI, ‐0.32 to 0.25). The subgroup analysis showed a greater cognitive benefit among normal older adults but not older adults with mild cognitive impairment. Additionally, when considering different social interaction modes, in‐person social interaction positively affected global cognition, while online interaction did not.

Conclusion

Social interaction interventions have a limited impact on cognitive function in non‐demented older adults but showed potential effects on executive function. This finding offers insights for implementing social intervention in the community. Future efforts should focus on conducting more rigorous clinical trials to investigate the effects of different types of social interaction interventions on specific cognitive domains.
Five year trajectories of the mental and physical SF‐36 summary scores in men: results from the PREADViSE trial
Authors: Ding Xiuhua , Charnigo Richard , Schmitt Frederick A , Kryscio Richard J , Abner Erin L.
Published: January 2025

Background

Previous studies have shown that SF36 summary scores predict incident dementia. However, it is unclear whether SF36 summary scores follow different temporal trajectories. Thus, the goal of this study is to examine possible trajectories for SF36 summary scores.

Method

A subset of 2,746 Prevention of Alzheimer’s Disease (AD) by Vitamin E and Selenium (PREADViSE) participants who completed SF‐36 assessments at annual visits was included in the current analysis. First, group‐based trajectory modeling (GBTM) was applied to fit SF‐36 Mental Component summary (MCS) scores and Physical Component Summary (PCS) scores. The final models were selected based on perceptions of interpretability and reproducibility with the assistance of the Bayesian information criterion (BIC). Then joint trajectory modeling was used to examine overlaps between trajectory groups based on MCS scores and trajectory groups based on PCS scores.

Result

Four trajectories were identified for each of MCS and PCS, when examined separately. In terms of shape, MCS trajectories were described as stable (∼81.3% of subjects), curvilinear decline (∼ 4.3%), linear decline (∼ 11.2%) and slight increase (∼ 3.2%), while PCS trajectories were described as stable (∼48.7%) and slight decline (∼51.3% encompassing three groups). Joint trajectory modelling showed overlaps suggesting that MCS and PCS trajectories are not independent.

Conclusion

Both MCS scores and PCS scores showed multiple trajectories over time; some were stable, and some exhibited decline. We were also able to estimate how many subjects belonged to each group and to quantify overlaps in group membership for MCS and PCS scores.
Longitudinal loneliness changes are associated with cognitive decline and brain structure alterations: evidence from the Whitehall II cohort study
Authors: Zhang Ye , Tatewaki Yasuko , Liu Yingxu , Tomita Naoki , Thyreau Benjamin , Taki Yasuyuki
Published: January 2025

Background

Loneliness has been linked to cognitive decline and an elevated risk of Alzheimer’s disease (AD). Previous studies measured loneliness at a single point time, which may not accurately capture the longitudinal changes of different loneliness types (e.g., recover form loneliness; persistent loneliness) and their impact in the neuropathology of AD. This study investigates five‐year longitudinal changes of loneliness and their associations with cognitive function and brain structure alterations using data from the Whitehall II cohort study.

Method

This study included 5346 participants with mean age = 65 year (Female:26.68%) at baseline (2007‐2009). Loneliness was measured using one item form the Center for Epidemiologic Studies Depression Scale, and longitudinal loneliness changes were defined from two time points (2002‐2004; 2007‐2009). Linear mixed‐effect models were used to examine the association between different loneliness types and eight‐year changes of different cognitive domains (global cognition, reasoning, verbal fluency, and verbal memory). Robust linear regression models were employed to assess loneliness types and gray matter volumes (GMVs) in selected brain regions five‐year later (2012‐2012) using the Whitehall IIMRI substudy (N = 711).

Result

We defined four types of loneliness changes: “No loneliness”, “Transient loneliness”, “Incident loneliness” and “Persistent loneliness”. Compared to no loneliness, persistent loneliness was associated with decline in cognitive function (global cognition: b = ‐0.20, p<0.001; reasoning: b = ‐0.29, p<0.001; verbal memory: b = ‐0.11, p<0.007; verbal fluency: b = ‐0.15, p = 0.001;) after controlled for age, sex, education, and objective social isolation. Compared to no loneliness, persistent loneliness was associated with decreased GMVs in right posterior cingulate cortex (b = ‐0.17, pFDR‐corrected = 0.041); transient loneliness was associated with increased GMVs in rostral anterior cingulate cortex (b = ‐0.48, pFDR‐corrected = 0.025).

Conclusion

Persistent loneliness was associated with both longitudinal cognitive decline and decreased brain regions involved in emotional regulation, suggesting persistent loneliness feelings, no incident loneliness, could be a risk factor in the neuropathology of AD. Moreover, recovery from loneliness feeling (transient loneliness) could be protective in future brain structure alterations. Our study suggests that identifying participants has long‐term loneliness and developing strategies to overcome loneliness feeling could be important for AD prevention.
Heart rate fragmentation during a Stroop task reveals cognitively healthy individuals with pathological CSF amyloid/tau
Authors: Choy Elizabeth H. , Al‐Ezzi Abdulhakim , Buennagel David P , Nolty Anne , Fonteh Alfred N. , Kloner Robert A , Kleinman Michael T. , Arakaki Xianghong
Published: January 2025

Background

Stroop task is used to evaluate inhibition, a core executive function. Alpha Event‐Related Desynchronization (ERD) from analysis of electroencephalogram (EEG) during Stroop task reflects brain interference processing. We previously reported different relationships between heart rate variability (HRV) and alpha ERD during Stroop task. However, HRV proxied autonomic function can be confounded by increasing erratic rhythm with age, quantified by heart rate fragmentation (HRF). The knowledge of HRF is limited in a Cognitively Healthy (CH) cohort. To fill this gap, we studied these measurements in CH participants who underwent a Stroop task.

Method

We studied HRF in an established EEG dataset during Stroop task from CH participants when their CSF amyloid/tau ratio were normal (≥2.71, CH‐NATs) or pathological (<2.71, CH‐PATs). Heart rate fragmentation (HRF) was analyzed from 5‐minute electrocardiogram (ECG) during resting or task. HRF was classified into three categories: hard inflection point, soft inflection point, and non‐inflection. Hard inflection point represents an acceleration‐to‐deceleration (AD) in heart rate and vice versa (DA). Soft inflection point describes heart rate transitions from acceleration or deceleration‐to‐zero acceleration (AZ or DZ) and vice versa (ZA or ZD). Non inflection means heart rates are accelerating (NA), decelerating (ND), or no change (NZ).

Result

We previously reported that alpha ERD during incongruent trials were negatively correlated with heart rate (HR) in CH‐NATs but not in CH‐PATs (Figure 1). In CH‐NATs, there was a decrease in a subcategory of non‐inflection during task compared to resting (Figure 2A). We observed a significant increase in hard inflection points and a decrease in non‐inflections during Stroop task compared to resting in CH‐PATs (Figure 2B).

Conclusion

These pilot results suggest: 1) from resting to task, CH‐PATs presented increase of HRF hard inflection points, which was not observed in CH‐NATs; 2) our previous analysis show that HR was negatively correlated with alpha ERD in CH‐NATs (higher HR related to more brain activation ‐ more negative alpha ERD), which was not observed in CH‐PATs. Although a larger sample size is needed, these results support a potential heart‐brain dysregulation using non‐invasive EEG and ECG in cognitively healthy individuals at higher risk of cognitive decline.
Classification of Apolipoprotein E ϵ4 Allele Carriers in Alzheimer Disease Patients and Healthy Controls using Event‐Related Potentials and Event‐Related Spectral Perturbation
Authors: Frassão Kauê O. , Filho Sandro M. S. , Pedroso Renata Valle , Nascimento Carla , Junior Henrique Pott , Cominetti Marcia Regina , Fraga Francisco J.
Published: January 2025

Background

Understanding the genetic etiology of Alzheimer's disease (AD) has been a major focus of research in neurodegenerative diseases. Amid the three common allelic variants of the apolipoprotein E (APOE) gene in humans, called APOE ε2, ε3 and ε4, the ε4 allele is the most common genetic risk factor for late‐onset AD, being found in 20% of the world population.

Method

We used Event‐Related Potentials (ERP) and Event‐Related Spectral Perturbation (ERSP) as features for classification of apolipoprotein E ϵ4 (APOE ε4) allele carriers in AD patients and healthy controls. The study participants were 37 healthy older adults (9 APOE ε4 carriers) and 47 AD patients (15 APOE ε4 carriers), which underwent an auditory oddball task (with Target and Frequent trials) using an electroencephalographic (EEG) equipment with 21 channels. A leave‐one‐subject‐out (LOSO) cross‐validation approach was used to perform feature selection and classification with Support Vector Machine (SVM) classifiers.

Result

After feature extraction and selection, we achieved a classification accuracy of 86,90% in the APOE ε4 carriers versus non‐carriers comparison (regardless diagnosis) and 85,71% in the Alzheimer disease patients versus healthy controls comparison (regardless APOE ε4 status). When combining the results of all participants we reached a global accuracy of 73,81% in the four‐class classification (Alzheimer disease patients carriers and non‐carriers, healthy elderly carriers and non‐carriers).

Conclusion

We hope our work could help clinicians to make a more accurate and earlier AD diagnosis, considering the presence of the APOE ε4 allele.
Sex‐specific risk profiles associated with Alzheimer’s disease markers in cognitively unimpaired older adults
Authors: Touron Edelweiss , Wirth Miranka , Binette Alexa Pichet , Demnitz‐King Harriet , Collette Fabienne , Poisnel Géraldine , Vivien Denis , la Sayette Vincent De , Marchant Natalie L , Chételat Gael , Gonneaud Julie ,   the Medit‐Ageing Research Group
Published: January 2025

Background

Despite evidence that sex can modulate Alzheimer’s disease (AD) risk, whether risk factors are similarly related to AD markers in women and men remains largely unexplored. We aimed to assess how a combination of potentially modifiable risk factors are associated with cognitive and pathological markers of AD in older women and men.

Method

We included 135 cognitively unimpaired older adults (≥65 years old, 83 women; Table 1) from the Age‐Well trial (NCT02977819; baseline data) with multidomain assessments of modifiable risk factors, including cardiovascular (body mass index, systolic blood pressure, LDL cholesterol), lifestyle (complex mental activity throughout life, physical activity, diet), and psychological (quality of life, depressive and anxiety symptoms, rumination, worry). AD markers included the Preclinical Alzheimer Cognitive Composite‐5 (PACC‐5), a measure of global cognition sensitive to AD‐related decline, and multimodal neuroimaging and blood sampling providing measures of hippocampal volume (MRI), brain perfusion in temporo‐parietal regions, neocortical amyloid burden (PET) and p‐tau181 (plasma). Multivariate partial least squares analyses were used to assess relationships between combinations of risk factors and AD hallmarks (cognition, neurodegeneration, amyloid and tau) in women and men separately.

Result

In women, a combination of lower quality of life and complex mental activity throughout life and higher levels of anxiety and worry, was associated with lower PACC‐5 scores and higher p‐tau181 levels (p = .002, 60.5% of variance explained; Fig. 1). In men, two significant latent variables emerged. Lower systolic blood pressure, adherence to a Mediterranean diet and quality of life, and higher levels of anxiety and worry, were associated with higher hippocampal volume and lower brain perfusion in regions sensitive to AD (p = .022, 45.2% of the variance explained; Fig. 2A); while lower levels of quality of life and complex mental activity throughout life were associated with worse PACC‐5 scores and higher neocortical amyloid deposition and p‐tau181 levels (p = .023, 35.9% of the variance explained; Fig. 2B).

Conclusion

These preliminary findings suggest that the modifiable factors that could influence AD markers may differ by sex in cognitively unimpaired older adults. Pending replication in larger and independent cohorts, these results highlight the need to consider sex specificities in prevention strategies.
How short peptides can disassemble ultra‐stable tau fibrils extracted from Alzheimer’s disease brain by a strain‐relief mechanism
Authors: Hou Ke , Ge Peng , Sawaya Michael R , Dolinsky Joshua L. , Yang Yuan , Jiang Yi Xiao , Lutter Liisa , Boyer David , Cheng Xinyi , Pi Justin , Zhang Jeffrey , Lu Jiahui , Yang Shixin , Yu Zhiheng , Feigon Juli , Eisenberg David S.
Published: January 2025

Background

Reducing fibrous aggregates of protein tau is a possible strategy for halting progression of Alzheimer’s disease (AD). Previously we found that in vitro the D‐peptide D‐TLKIVWC fragments tau fibrils from AD brains (AD‐tau) into benign segments, whereas its six‐residue analog D‐TLKIVW cannot. However, the underlying fragmentation mechanism remains unknown, preventing the further development of this type of drug candidate for AD.

Method

To understand the necessity of the cysteine residue of D‐TLKIVWC in fragmenting AD‐tau, we designed a series of peptides of sequence D‐TLKIVWX varying only at the seventh residue, X. To better understand the fragmentation process of AD‐tau, we conducted a time‐course dot blot and EM experiment. We determined the structures of D‐TLKIVWX amyloid‐like fibrils by atomic force microscopy and cryo‐electron microscopy. We studied the complexes of D‐TLKIVWX (X = I, S, R) with AD‐tau by cryo‐electron microscopy and confirmed the binding site between D‐TLKIVWX and Tau through NMR.

Result

These D‐TLKIVWX candidates showed various efficacies in fragmenting AD‐tau in vitro, in which X = Ile was the best performer. From electron microscopy, we discovered that D‐TLKIVWX peptides form amyloid‐like fibrils themselves, and from atomic force microscopy we learned that these fibrils have a right‐handed helical twist, in contrast to the left‐handed helical twist of AD‐tau. From cryo‐EM we learned that D‐TLKIVWX protofilaments bind to tau fibrils of opposing twist.

Conclusion

We find that the amyloid‐like, fibril‐forming property of D‐TLKIVWX contributes to the fragmentation of AD‐tau fibrils. We propose the strain‐relief mechanism of fragmentation and believe the fragmentation of AD‐tau fibrils is driven by the release of torsion in D‐TLKIVWX protofilaments.
Looking beyond efficacy: The implementation science exploration of the Australian PITCH study, a national stepped‐wedge cluster RCT evaluating a dementia training program for home care workers
Authors: Goh Anita M Y , Gaffy Ellen , Engel Lidia , Belay Yared , Peters Sanne , Dang Christa , Doyle Colleen , Savvas Steven , Batchelor Frances , Low Lee‐Fay , Ames David , Malta Susan , Cooper Claudia , Livingston Gill , Panayiotou Anita , Loi Samantha M , Fairhall Anne , Roth Cathy , Dow Briony
Published: January 2025

Background

The Promoting Independence Through quality Care at Home (PITCH) project aimed to improve outcomes for people with dementia and their carers via a co‐designed training intervention for home care workers (HCWs). The results of the primary efficacy analysis of the successful stepped‐wedge cluster RCT (n = 172 HCWs in 18 clusters in 7 Australian service providers) were presented at AAIC 2023.

Method

This presentation goes beyond efficacy and discusses the implementation science (process evaluation and behavioural change) and health economic analysis of the intervention.

Result

Process Evaluation: Many intervention trials only focus on specific outcomes, with little consideration of the processes behind intervention effectiveness. However, solely focusing on outcomes in intervention trials without exploring the underlying processes limits understanding of what works, and hinders knowledge translation. Process evaluation allows the consideration of the mechanisms of change or lack of change. We present the process evaluation of the PITCH intervention, barriers and facilitators to implementation, and factors that related to unexpected problems and variation in intervention delivery, using the Theoretical Domains Framework of behaviour change.

Behaviour Change Techniques (BCTs): Linking BCTs with theories of behaviour change allows investigation of mechanisms underlying intervention effects, and extends process evaluations. To understand how interventions may result in behaviour change, this presentation reports our findings of BCTs used in all published RCTs in HCWs (including PITCH), using the Behaviour Change Technique Taxonomy (v1). Results presented include robust evidence synthesis about which BCTs are effective (and ineffective) within HCW interventions and how they vary as a function of contextual variables (e.g. setting, population).

Health economics: This presentation reports the economic evaluation of the PITCH intervention, adopting a cost‐consequences analysis discussing whether PITCH provides good value for money. We found that integrating health economics provided additional key information, ensuring efficient use of resources, benefiting care‐recipients and healthcare systems.

Conclusion

Using newly‐analyzed results from a large RCT in HCWs, this presentation goes beyond the traditional efficacy results of RCTs and reports on the importance, methods, and results of analyzing other key intervention characteristics: 1) process of intervention delivery, 2) effective (and ineffective) behavioural change techniques, and 3) health economic analysis.
Improved precision of Alzheimer’s disease fluid biomarkers when using Amyloid‐β40 or non‐phosphorylated tau as a reference
Authors: Karlsson Linda , Janelidze Shorena , Horie Kanta , Barthélemy Nicolas R. , Vogel Jacob W. , Arvidsson Ida , Åström Kalle , Ovod Vitaliy , Bollinger James G. , He Yingxin , Palmqvist Sebastian , Stomrud Erik , Salvadó Gemma , Binette Alexa Pichet , Blennow Kaj , Bateman Randall J. , Mattsson‐Carlgren Niklas , Hansson Oskar
Published: January 2025

Background

Fluid biomarkers represent an informative and cost‐effective way to detect and monitor Alzheimer’s disease (AD). However, as we recently showed, the overall proteome average in CSF exhibits a non‐disease related average signal (inter‐individual variability), which can reduce the precision of concentration based CSF AD biomarkers.1 Now, we therefore investigate if several already high performing CSF and plasma AD biomarkers can be improved by normalizing their concentration to a reference protein (e.g. Aβ40 and non‐phosphorylated mid‐region tau [nP‐tau]).

Methods

Using the BioFINDER‐2 (BF2) cohort (n=1908), we compared the associations between amyloid/tau‐PET load and CSF biomarkers (MTBR‐tau243, P‐tau217, P‐tau181, P‐tau205, Aβ42) alone versus in a ratio with a reference protein (e.g. CSF Aβ40 or nP‐tau) in linear regression models. We repeated this analysis for plasma biomarkers (P‐tau217, P‐tau181, P‐tau205, Aβ42) alone versus in a ratio with plasma Aβ40 or nP‐tau. Assays included mass spectrometry based (WashU) and immunoassays (Lilly and Elecsys).

Results

All concentration based CSF biomarkers, including MTBR‐tau243, showed significantly stronger association with tau‐PET load when applied in a ratio with CSF Aβ40 compared to alone (ΔR‐squared=0.0639‐0.213), Table 1 and Figure 1a‐1b. Similar results (but not all significant) were seen for associations with amyloid‐PET (ΔR‐squared=0.0161‐0.278), Figure 1c. A ratio with CSF nP‐tau significantly increased biomarker concordance with amyloid‐PET for all except MTBR‐tau243 (ΔR‐squared=‐0.0059‐0.188), but not tau‐PET (ΔR‐squared=‐0.044‐0.0626). For plasma biomarkers, ratios with both Aβ40 and nP‐tau led to stronger associations with tau‐PET (ΔR‐squared=0.0039‐0.120), while associations with amyloid‐PET mainly were improved in ratios with nP‐tau (ΔR‐squared=0.018‐0.123), Figure 1d‐1f. When comparing all biomarkers (Figure 2), highest correlation with tau PET was seen for MTBR‐tau243/Aβ40 in CSF (R‐squared=0.770) and P‐tau217/nP‐tau in plasma (R‐squared=0.666), and with amyloid‐PET for P‐tau217/nP‐tau in both CSF (R‐squared=0.689) and plasma (R‐squared=0.652).

Conclusions

CSF and plasma biomarkers show stronger association with tau‐PET and amyloid‐PET loads when applied in a ratio with a reference protein (e.g. Aβ40 or nP‐tau). Ongoing work involves validation in external cohorts, and longitudinal analyses to assess if a ratio approach also can reduce biomarker fluctuations within an individual.

Karlsson, L. et al. Cerebrospinal fluid reference proteins increase accuracy and interpretability of biomarkers for brain diseases. BioRxiv (preprint) (2023) doi:10.1101/2023.06.08.544222.
Measuring metabolic decrement with repeat FDG‐PET for the early diagnosis of neurodegenerative diseases
Authors: de Luca e Tuma Raphael , Coutinho Artur Martins , Carneiro Camila de Godoi , Tres Eduardo Sturzeneker , Rodrigues Júlia Chartouni , Buchpiguel Carlos Alberto , Brucki Sonia Maria Dozzi
Published: January 2025

Background

The diagnostic capability of fluorine‐18‐fluorodeoxyglucose positron emission tomography (FDG‐PET) is well established, but few studies have explored the utility of repeating scans, especially when using semi‐quantification methods to analyze the decrement between them.

Methods

We retrospectively selected all patients at our clinic submitted to two or more FDG‐PETs. The initial and final FDG‐PET of each patient underwent semi‐quantitative analysis using the CortexID® Suite software (GE Healthcare) for 26 pre‐determined regions normalized for global cortical uptake. We subtracted the initial standardized uptake value ratio (SUVr) from the final SUVr to calculate the total variation. Patients with at least 3 years of clinical follow‐up were categorized based on their final diagnosis for comparison. Lastly, in patients with at least 1 year between exams, each total variation was then divided by the number of years between exams, to reach a value termed the “rate of metabolic decrement”.

Results

We found 144 cases with two or more FDG‐PETs in our database, and 9 were excluded. There was a significant Pearson correlation coefficient between the total metabolic variation and the time between scans in 23 of the 26 regions. 103 cases could be clinically categorized: 16 were diagnosed with Alzheimer’s disease (AD) and 53 were cognitively stable (Table 1 & 2). All 26 regions were compared (Figure 1). Of note, analyzing only cases with at least 1 year between exams (83 cases), the posterior left cingulate of AD patients (14 patients) and cognitively stable cases (40 cases) had, respectively, an absolute variation of – 4.1% (IQR –5.6% ‐ –1.2%) versus +1.8 (IQR 0.0% ‐ +2.8%) and a rate of metabolic decrement per year of –1.1% (IQR –2.0% ‐ –0.6%) versus +0.4% (IQR 0.0% ‐ +0.7%), with a significant difference in both comparisons. 34 patients with other diagnoses (including 4 with behavioral‐variant frontotemporal dementia), were analyzed separately. 28 patients also had amyloid PETs available for analysis.

Conclusions

Repeating an FDG‐PET may have a significant diagnostic benefit over a single scan. The rate of metabolic decrement could be a useful clinical tool for the early diagnosis of AD or in complex cases.
OVERTURE Phase 2 Clinical Trial MRI Outcomes Demonstrate Consistent Treatment Benefits in Subgroup Analysis
Authors: Kern Ralph , Kuang Colin , Seshagiri Chandran , Konisky Alexandra , Galley Alyssa , Boasso Alyssa , Hempel Evan , Malchano Zach , Vaughan Brent , Cimenser Aylin , Da Xiao , Shpokayte Monika , Hajos Mihaly
Published: January 2025

Background

The OVERTURE (NCT03556280) randomized controlled trial (RCT) evaluated evoked gamma oscillation therapy using Cognito’s medical device (CogTx‐001) in mild‐moderate Alzheimer’s disease (AD). Brain atrophy, as measured by whole brain volume (WBV), is a key indicator of neurodegeneration in AD1 and may be influenced by baseline covariates such as age2, disease stage3, APOE4 carrier status4, and PET amyloid levels5, as well as treatment6. We analyzed OVERTURE MRI whole brain volume outcomes across these key baseline subgroups.

Method

Neuroimaging data were collected in the Overture phase 2 clinical trial (NCT03555280), comparing one‐hour, daily, at‐home, 40Hz gamma sensory stimulation vs. sham stimulation for six months (2:1 randomization). 76 participants were randomized, 74 were treated and 53 completed the 6‐month RCT. Magnetic resonance imaging (1.5 T‐MRI and FLAIR) data were collected at baseline (N=56) and month 6 (N=53). Brain amyloid was evaluated with [18F]‐florbetapir PET at baseline and 6 months. APOE4 carrier status was evaluated at baseline.

Result

Baseline WBV (mean, SD) in active (1060.7,129.35) and sham‐treated participants (1017.7,122.80) and baseline PET SUVR in active (1.3,0.23) and sham‐treated participants (1.2,0.25) were similar. We observed a 69% reduction in MRI whole brain volume loss in participants who received active treatment compared to sham treatment (p=0.005). Treatment outcomes were similar across subgroups: baseline age (>70, ≤70), Mild vs. moderate AD (MMSE 20‐26, 14‐19), APOE4 genotype (carrier, non‐carrier), and PET amyloid values (SUVR ≥1.12, <1.12).

Conclusion

The OVERTURE clinical trial demonstrated consistent treatment‐related slowing of brain atrophy across key baseline subgroups (age, AD stage, APOE4 carrier status, and PET amyloid). We are evaluating WBV as a key indicator of neurodegeneration in the ongoing phase 3 HOPE study (NCT05637801).

References:

Jack, Alzheimer Dement. 2018

Coupé, Sci Rep. 2019

Wei X, Cereb Cortex 2023

Löwe, PLOSOne 2016

La Joie, Sci Transl Med. 2020

Ten Kate M et al. J Prev Alz Dis 2023;92
The Effect of Healing Gardens among Care Residents with and Without Dementia in Nigeria
Authors: Akindejoye Funmi , Ezedinma Uchenna , Rorh Susanne
Published: January 2025

Background

A healing garden is a non‐pharmacological approach that supports the interaction of humans and elements of nature towards improving well‐being and quality of life. It has gained increased utilization in managing the health outcomes of older persons with and without dementia. However, there is a paucity of evidence of its use and benefits in African countries with increasing prevalence of dementia, such as Nigeria. This study aims to co‐design a low‐maintenance healing garden intervention and measure its impact on the psychosocial measures and quality of life of participating residents and caregivers, from two care home facilities in Lagos state, Nigeria.

Method

The study co‐designed and developed a healing garden in two selected care facilities and employed validated tools to measure the quality of life, agitation, and depression at baseline and three months after the intervention. Also, surveys were used to elicit further information from caregivers, three months after the co‐design, and development of individual healing gardens.

Results

The study revealed that the low‐maintenance healing garden improved the quality of life and experiences of agitation but no significant change in depression measures among residents with and without dementia. Further, caregivers reported a positive benefit of the healing garden on their work‐life experience and the residents’ well‐being.

Conclusion

Evidence from this study on the benefits of healing gardens to older persons with or without dementia in Nigeria is preliminary. Future research using a more multidimensional and broad research design is warranted.
Validation of the Chinese Brief Ageing Perceptions Questionnaire (C‐BAPQ)
Authors: Lai Frank Ho‐yin , Siu Andrew Man‐hong , Yip Ben Chi‐bun , Hai Eddie Yip‐kuen , Lowe Julie‐anne , Chan Stella Kai‐wui , Chui Vivian Wai‐yin , Yu Kathy Ka‐ying
Published: January 2025

Background

Understand individuals’ self‐perception of aging is crucial for promoting a positive aging experience, better health with good quality of life, addressing activities participation, and can help by advocating policies and interventions that support the diverse needs of an aging population. This study aims to examine the validity and reliability of the Chinese version of BAPQ (C‐BAPQ) for the healthy older people by assessing the content validity, test‐retest reliability, and correlational analyses with mental health by Depression, Anxiety, and Stress Scale (DASS‐21), quality of life by the Short Form 36 Health Survey (SF‐36) and activity participation by the Model of Human Occupation Screening Tool (MOHOST). Moreover, to study the factor structure of the Chinese version of BAPQ (C‐BAPQ) by using exploratory factor analysis.

Method

A two‐phase study was conducted. Phase 1 included reviews by a panel of experts and a panel of caregivers to evaluate the clarity, understandability and relevance of C‐BAPQ items. Phase 2 field testing examined test‐retest reliability, internal consistency, factor structure, and correlation with the SF36, DASS‐21, and MOHOST in a sample of Chinese older adults who are community dwellers.

Result

Inter‐rater reliability analysis demonstrated moderate agreement in clarity, understandability, and cultural relevance for the C‐BAPQ. With a group of 120 older adults from snow‐ball sampling, the C‐BAPQ demonstrated a high level of internal consistency, with Cronbach’s alpha of 0.99, F = .005, p = .831. The C‐BAPQ was moderately correlated with mental health (r = ‐ .52, p < .001), health status and quality of life (r = .45, p < .001) and activity participation (r = .54, p < .001). Factor analysis yielded a five‐factor structure of the C‐BAPQ which was consistent with the original version.

Conclusion

The C‐BAPQ demonstrates sensitivity in assessing self‐perception of ageing in older adults. Further longitudinal research utilizing a larger, more representative sample would serve to enhance the psychometric rigor and properties of the C‐BAPQ.
Assessment of Financial Toxicity in an ADRC Cohort: a Pilot Study
Authors: Choate Radmila , Barber Justin M , Jicha Gregory A , Abner Erin L.
Published: January 2025

Background

Alzheimer’s disease and related dementias (ADRD) are associated with substantial direct healthcare costs, including specialist care, medication, and indirect costs related to loss of productivity and informal caregiving. The economic burden of ADRD on families and caregivers often threatens the financial security of entire households. The consequences of this financial burden are linked to a worsened quality of life and treatment compliance, rapid disease progression, and lower survival. The term “financial toxicity” is widely used in cancer research to describe the impact of financial hardship due to cancer treatment. However, financial toxicity remains understudied in people living with ADRD, their families, and caregivers.

Methods

We used the 12‐item Comprehensive Score for Financial Toxicity v.2 (COST‐FACIT) instrument to measure financial distress related to receiving care. 11 of the 12 items are used to create a financial toxicity score (range 0‐44), with higher scores indicating better financial well‐being (Figure 1). The instrument used in this study was adapted for use in individuals with normal cognition and cognitive impairment. The data were collected electronically from the University of Kentucky Alzheimer’s Disease Research Center cohort, a convenience sample of community‐based older adults across the spectrum of cognition followed longitudinally until death. We used descriptive statistics to characterize the survey respondents and evaluate their self‐perceived financial distress.

Results

These preliminary analyses include data from 153 adults who responded to the emailed survey. The mean age of the cohort was 79.4 years (SD = 6.3), 70% female, 93% white, with an average of 17 years of education; 138 (90%) had normal cognition, and 15 (10%) had MCI. The average COST‐FACIT score (range 0‐44) was 32.6 (SD = 7.7) in the overall cohort, indicating a low grade of financial toxicity. We did not observe an association between self‐perceived financial burden and age, sex, years of education, or cognitive status in this cohort of older adults.

Conclusions

Further and larger studies are needed to evaluate financial toxicity across the cognition spectrum and to assess factors associated with high financial burden, including cost‐coping behaviors and health‐related quality of life of people living with ADRD and their families.
Association between plasma neurofilament light chain (NfL) concentrations and renal impairment
Authors: Ashrafzadeh‐Kian Susan , Larson Bethany , Bornhorst Joshua A , Algeciras‐Schimnich Alicia
Published: January 2025

Background

Neurofilament Light Chain (NfL) is a blood biomarker of axonal injury and neurodegeneration that can be used in a variety of neurological disorders. Despite the potential clinical use of plasma NfL across multiple neurological disorders, there is increasing evidence that underlying comorbidities such as renal impairment associated with chronic kidney disease (CKD) and cardiovascular diseases can increase NfL concentrations. The objective of this study was to determine the relationship between plasma NfL concentrations and renal function (CKD staging) in individuals without known neurological conditions.

Methods

Individuals (n=62) seen in an outpatient setting at Mayo Clinic who had various stages of renal impairment (stages 1‐5 by CKD‐EPI 2021 estimated glomerular filtration rate (eGFR) equation) and did not have co‐existing conditions that are known to elevate plasma NfL were retrospectively identified through electronic medical record review. EDTA plasma from these patients collected within +/‐ 30 days of the eGFR determination was identified and stored frozen (‐80°C) until the time of testing. Samples were tested using the Simoa® NF‐light™ V2 Advantage Kit (Quanterix). NfL concentrations in pg/mL were used to calculate age‐adjusted Z‐scores (https://shiny.dkfbasel.ch/baselnflreference/) using an online calculator. Correlation analysis was performed to assess associations of continuous eGFR (mL/min/ 1.73 m2) with plasma NfL age‐adjusted Z‐scores.

Results

A strong negative correlation between NfL Z‐score and eGFR was observed (Spearman’s ρ= ‐0.806). Mean NfL Z‐scores (ranges) in each CKD stage were ‐0.4(‐2.3‐1.4) for stage 1 (N=9), 0.9(‐0.8‐1.9) for stage 2 (N=10), 1.9(‐1.2‐3.4) for stage 3 (N=29), 2.9(2.7‐3.5) for stage 4 (N=6), and 3.2(1.6‐3.7) for stage 5 (N=8); with all groups showing significant differences (P>0.05) except between groups 4 and 5 (P=0.09).

Conclusions

Plasma NfL concentrations were increased in individuals with a decreased eGFR. Kidney impairment is an important potential confounding factor to consider when utilizing NfL as a biomarker of neurodegeneration in the clinical setting.
Development of pyroptosis inhibitors for Alzheimer’s disease
Authors: Xu Yiming , Biby Savannah , Zhang Shijun
Published: January 2025

Background

Pyroptosis is a type of inflammasome‐dependent cell death, in which gasdermin D (GSDMD) plays key roles as the executor. Neuroinflammation and pyroptosis have been indicated critical roles in neurodegenerative disorders including Alzheimer’s disease (AD). Therefore, novel GSDMD inhibitors represent valuable probes to understand and validate GSDMD as a viable drug target for AD.

Method

Biophysical screening and rational design were employed to design novel GSDMD inhibitors. Cellular testing using iBMDMs to examine membrane pore formation, LDH and Il‐1 release, and GSDMD cleavage.

Result

A series compounds based on a scaffold identified via biophysical screening against recombinant mouse GSDMD were designed and synthesized to optimize the potency and selectivity. Among the tested compounds, several lead compounds were identified with nanomolar binding affinity to GSDMD and in vitro GSDMD and pyroptosis inhibition.

Conclusion

Novel GSDMD inhibitors were successfully identified and functional evaluation demonstrated promising and selective inhibition on GSDMD. The results encourage further characterization of the lead compounds as novel probes.