bluuebunny/crossref_metadata_2025 huggingface dataset:
Improving interpreting for dementia assessments: Results from the MINDSET trial
Authors: Brijnath Bianca , Cavuoto Marina G. , Markusevska Simona , Gilbert Andrew , Antoniades Josefine , Garcia Erika Gonzalez , Hlavac Jim , Low Lee‐Fay , LoGiudice Dina , Woodward‐Kron Robyn , Enticott Joanne , Hwang Kerry , White Jennifer , Lin Xiaoping
Published: January 2025

Background

The Improving Interpreting for Dementia Assessments (MINDSET) study aimed to upskill interpreters through an online co‐designed course in dementia and cognitive assessments.

Methods

A single‐blinded randomized controlled digital trial conducted between June 2022 and November 2023. Interpreters were randomized to training or waitlist control conditions with 3‐ and 6‐month follow‐up. The primary outcome was a composite Z‐score comprising dementia and cross‐cultural knowledge, translation and ethical knowledge, and observed interpreting skills. Preliminary analyses were conducted using a mixed ANOVA with assessment period as the within‐subjects factor and intervention group as the between‐subjects factor, controlling for age.

Results

126 interpreters (Mage = 44.13 years (SD = 12.71) completed baseline (22 Arabic, 14 Cantonese, 6 Greek, 14 Italian, 64 Mandarin, 6 Vietnamese), 3m follow‐up (n = 100) and 6m follow‐up (n = 101). For the primary outcome, there were no significant main effects for assessment period F (2, 178) = 0.21, p = .814 nor intervention group F (1, 89) = 0.31, p = .548, and no significant interaction between intervention group and assessment period, F (2, 178) = 0.64, p = .526. Secondary outcomes revealed significant main effects for dementia knowledge (DKAS) for the assessment period, F (2, 98) = 8.80, p <.001, and intervention group F (1, 99) = 4.59, p = .035, with significantly higher scores at the 3‐ (mean difference = 1.308, SE = .31, p <.001, 95% CI .692, 1.924) and 6‐month follow‐up (mean difference = .814, SE = .31, p = .010, 95% CI .203, 1.425); and significantly higher scores in the intervention compared to control (mean difference = .842, SE = .393, p = .035, 95% CI .062, 1.621). A significant interaction between assessment period and intervention group F (2, 98) = 3.33, p = .040 indicated that the increase in scores at the 3‐ and 6‐month periods were greater for the intervention group.

Conclusions

This is the first time a dementia training resource for interpreters has been trialled. Preliminary analyses revealed an improvement in interpreter’s dementia knowledge.
Transgenic Domestic Pigs for research in Vascular Contributions to Cognitive Impairment and Dementia
Authors: Hainsworth Atticus H , Onwuzuruike Love , Ramesh Misha , Ascione Raimondo , Berry Colin , Bridges Leslie , Cash Diana , Clutton Eddie , Daniel Carola , Gao Betty , Isaacs Jeremy D , Lillico Simon , Madigan Jeremy , Meijles Daniel , Nixon James , Osei Stephanie , Ritchie Adrian , Romanowska Monika , Tennant Peter , Warren Claire , Westaby Joseph , Whitelaw C.Bruce A , Williams Steven CR
Published: January 2025

Background

Cardiovascular disease causes vascular dementia and contributes to most clinical dementia. This is embodied in the concept of vascular contributions to cognitive impairment and dementia (VCID). The potent endogenous peptide endothelin‐1 (ET1) causes small artery vasoconstriction and fibrosis. ET1 is implicated in microvascular disease and in VCID. There are few experimental animal models relevant to VCID [Hainsworth et al. 2017]. Pigs are higher mammals with a gyrencephalic brain and extensive subcortical white matter.

Method

We engineered domestic pigs carrying additional copies of the ET1‐encoding gene EDN1 under a Tet‐ON promotor, by lentiviral injection into blastocysts. We induced transgene expression for up to 8 days using oral doxycycline in young adults.

Result

We studied ET1‐overexpressing (n = 6, 3F/3M, mean±SD age 184±61 days) and control animals (n = 5, 3F/2M, 149±41 days). Following doxycycline treatment we observed a wide range of transgene expression at mRNA level. Antibody labelling indicated a spectrum of ET1 abundance in brain and heart tissue. Heart weight was 460±106 g in ET1‐overexpressing pigs and 394±25 g in controls. Brain weight: 104±14.4 g in ET1‐overexpressing, 101±9.0 in controls. We will report phenotypes relevant to inflammation and blood vessel fibrosis.

Conclusion

Adult‐onset EDN1 induction in domestic pigs produces ET1 overexpression that is well‐tolerated to 8 days.

Reference: Hainsworth AH, et al. (2017) BMC Med.15(1):16. Translational models for vascular cognitive impairment: a review including larger species.
Pre‐diagnostic manifestations of Alzheimer’s disease: A systematic review and meta‐analysis of longitudinal studies
Authors: Zabihi Sedigheh , Jeraldo Rosario Isabel Espinoza , Anjum Rifah , Carter Christine , Roche Moïse , Bestwick Jonathan P , Morgan‐Trimmer Sarah , Cooper Claudia , Marshall Charles R , Birks Yvonne , Wilberforce Mark , Walter Fiona M
Published: January 2025

Background

Alzheimer’s disease (AD) is associated with a range of non‐cognitive symptoms that can be early or even presenting features. Better recognition of pre‐diagnostic symptoms of AD would support improved early detection and diagnosis.

Method

To identify possible prodromal symptoms of AD, we systematically searched three electronic databases for prospective longitudinal studies to March 2023, that reported the risk of AD diagnosis associated with non‐cognitive symptoms. Meta‐analyses were performed to assess the associations between a commonly reported symptom and AD. We estimated pooled odds ratios (OR) using random‐effects model.

Result

Thirty studies were included with the majority focused on neuropsychiatric symptoms. Quantitative analysis of fourteen studies showed depression to be associated with subsequent AD diagnosis (pooled OR = 1.80; 95% CI: 1.29 to 2.50; I2 = 95.8%) and individual reports of the association showed it to be stronger later in life and closer to AD diagnosis. In contrast with the literature, the evidence on the association between anxiety, sleep difficulties, personality changes and psychotic symptoms, and incident AD was inconsistent.

We found evidence that autonomic symptoms including urinary dysfunction, constipation, fatigue, syncope and collapse might be pre‐diagnostic symptoms of AD recorded up to 10 years before receiving an AD diagnosis, and there was strong evidence of an association between hypotension and incident AD (pooled OR = 1.94; 95% CI: 1.88 to 2.01; I2 = 0.0%). We were also able find evidence for the association between weight loss and subsequent AD diagnosis within 10 years (pooled OR = 1.46; 95% CI: 1.22 to 1.74; I2 = 57.5%). Furthermore, the quantitative synthesis of the evidence on hearing loss (pooled OR = 1.47; 95% CI: 1.14 to 1.89; I2 = 87.6%) and spondylosis (pooled OR = 1.55; 95% CI: 1.34 to 1.80; I2 = 68.2%) showed both to be associated with AD diagnosis up to 10 years after identification of these sensory symptoms.

Conclusion

Our findings suggest that improved recognition of early non‐cognitive presentations is key in facilitating access to timely diagnosis of AD, especially as the emergence of disease‐modifying therapies for AD increases the importance of early detection.
Dural arteriovenous fistula as a cause of reversible cognitive impairment. Case report and a literature review
Authors: Boccazzi Julian Fernandez , del Hierro Xavier Merchan , Eizaguirre Barbara , Rojas Galeno , Leis Adriana , Sayavedra Ramiro , Persi Gabriel Gustavo , Guillen Jonathan Cubas , Aldinio Victoria , Gatto Emilia
Published: January 2025

Background

Dural arteriovenous fistulas (DAVFs) are abnormal communications between dural arteries and cortical, meningeal, or dural sinus veins. They represent 10‐15% of intracranial arteriovenous malformations. In rare cases, they have been associated with potentially reversible cognitive impairment and dementia.

Method

This report presents a clinical case of reversible cognitive impairment associated with DAVF and a review of the literature. Literature research was conducted using PubMed with the following keywords: “Dementia AND Dural arteriovenous fistula”; “Reversible dementia AND dural arteriovenous fistula” and “Dural arteriovenous fistula AND cognitive impairment”.

Result

A case report was presented on a 72‐year‐old male patient who was hypertensive, a smoker, and had a history of headaches. The patient consulted for memory loss that had been ongoing for 3 years and had significantly progressed in the last year. The memory loss was associated with mild anomic aphasia and postural instability. During the examination, the patient exhibited impaired delayed recall and attention. The total score on the Mini‐Mental State Exam (MMSE) was 25 out of 30, and the clock drawing test was failed. The neuropsychological evaluation (NPE) revealed deficits in language, verbal memory, attention, executive functioning, and visuoconstruction. The magnetic resonance imaging (MRI) showed an unusual vascular pathway in the left basal temporal cortico‐subcortical region, with venous congestion mainly in the superior petrosal sinus and hyperperfusion in the left temporal‐insular area in the arterial spin‐labeling (ASL) sequence. Digital angiography confirmed the diagnosis of left petrosal DAVF with afferents from the ipsilateral round foramen, middle meningeal, and occipital arteries. The fistula was completely embolized, and the patient had a favorable outcome. The post‐treatment NEP demonstrated significant improvement, resulting in the normalization of all previously deficient cognitive domains.

Conclusion

While cognitive manifestations secondary to DAVFs are rare, they should be considered as a potentially treatable cause of cognitive impairment. Early identification and adequate treatment have a favorable prognosis and usually lead to a reversal of symptoms, improving the patient’s quality of life.
Unveiling the role of Fli‐1 in controlling astrocyte dysfunction and transformation in Alzheimer’s disease
Authors: Li Pengfei , Goodwin Andrew , Halushka Perry , Fan Hongkuan
Published: January 2025

Background

Alzheimer’s disease (AD) is associated with cognitive impairment and neuro‐inflammation. Dysregulated activation of microglia and astrocytes induces neuro‐inflammation, and reactive astrocytes have been classified into A1 neurotoxic and A2 neuroprotective phenotypes. A1 astrocytes are induced by activated neuro‐inflammatory microglia via secreting IL‐1α, TNFα and C1q, and contributing to inflammation and neuronal cell death. However, the processes that govern astrocyte transformation and their role in AD development remains unclear. Increased friend leukemia virus integration 1 (Fli‐1) levels were observed in the hippocampus of brain tissue from AD patients and 5xFAD mice, a murine model of AD. While inhibition of Fli‐1 reduced pericyte loss, Aβ deposition and BBB dysfunction in the 5xFAD mice. However, Fli‐1’s specific role in astrocyte activation in AD remains unexplored.

Method

Fli‐1 levels and A1 phenotype astrocyte number were detected in brain tissues from WT mice, 5xFAD mice and inducible Fli‐1 KO 5xFAD mice. Control or Fli‐1 antisense oligonucleotide Gapmers were injected into the hippocampus of 5xFAD mice at 3 and 4.5 months of age. A1 phenotype astrocyte number, inflammatory mediators and cognitive deficits were evaluated at 6 months of age. Cultured mouse astrocytes were transfected with control or Fli‐1 Gapmers for 24 h and followed stimulation with IL‐1α, TNFα and C1q for another 24 h. The expression levels of Fli‐1 and inflammatory mediators, and A1 phenotype astrocyte number were determined.

Result

Fli‐1 levels are higher in the astrocytes in hippocampus of 5xFAD mice, and corresponded with increased astrocyte activation, A1 astrocyte number, inflammation and cognitive impairment. While 5xFAD mice with inducible Fli‐1 KO exhibited decreased astrocyte activation, attenuated inflammation, and mitigated cognitive impairment. Knockdown of Fli‐1 in cultured mouse astrocytes with Fli‐1 Gapmers suppressed activated microglia‐induced astrocyte activation, and inhibited IL‐1α, TNFα and C1q‐indcued A1 astrocyte transformation in vitro. Moreover, injection of Fli‐1 Gapmers into the hippocampus of 5xFAD mice significantly decreased Fli‐1 levels and reduced A1 astrocyte number.

Conclusion

The elevated Fli‐1 levels contribute to astrocyte dysfunction and A1 astrocyte transformation in AD. Targeting Fli‐1 could be a therapeutic approach to prevent or mitigate AD‐induced astrocyte dysfunction and cognitive impairment, offering potential clinical applications.
Physical function and cognition in older adult women: the Study of Women’s Health Across the Nation (SWAN)
Authors: Baker Jillian , MacConnachie Lauren , Hood Michelle , Derby Carol A. , Appelhans Bradley M. , Reeves Alexis , Karvonen‐Gutierrez Carrie A.
Published: January 2025

Background

Menopause is a time of accelerated loss of physical function, illustrated by challenges to mobility, speed, strength, and performance of activities of daily living. Physical function is associated with cognitive function, but there are limited data exploring this association among older women. In a cohort of older adult women, we hypothesize better performance on measures of physical function will be associated with better cognitive performance. This paper aims to characterize the link between physical function and cognition in older women, which may suggest interventions to support health in both domains of function.

Methods

The Study of Women’s Health Across the Nation (SWAN) is a multi‐ethnic, community‐based study of women followed through and beyond the menopausal transition. At Visit 15 (V15, 2015‐16), SWAN participants completed self‐reported measures (SF‐36) and performance‐based measures (gait speed and stair climb) of physical function and tests of cognition, including symbol digit modalities test [SDMT], East Boston Memory Test‐Delayed and ‐Immediate (EBMT‐D/EBMT‐I), and digit span backwards (DSB). A global cognitive z‐score was calculated by averaging the z‐scores of the four cognitive tests.

In separate linear regressions with cross‐sectional (V15), we regressed SDMT and global z‐score on each measure of physical function (SF‐36, gait speed, stair climb), adjusting for demographic factors, socioeconomic status (SES), and health conditions.

Results

Our sample included 1703 women who had at least one measure of physical function and cognition at V15, with a mean age of 65.5 years (SD = 2.69); 47.6% were white, 26.8% Black, 10.2% Chinese, 9.9% Japanese, and 5.5% Hispanic. Almost half (48.9%) attained a college degree. All but one woman were post‐menopausal, indicating at least 12 months elapsed since the final menstrual period.

Higher SF‐36 scores and faster gait speeds were associated with faster processing speed (SDMT, β = 0.04, p = 0.005; β = 2.69, p = 0.039, respectively) and global cognition (β = 0.002, p = 0.037; β = 0.23, p = 0.006, respectively). Slower stair climbs were associated with worse processing speed (SDMT β = ‐0.18, p<0.001) and global cognition (β = ‐0.01, p<0.001).

Conclusions

In cross‐sectional analyses in SWAN, physical functioning is positively associated with cognition among older adult women. Future analyses with longitudinal data are needed to assess whether better physical performance predicts better cognition as women age.
Spatial Exploration Behavior – A Novel Cognitive Marker for Alzheimer’s Disease?
Authors: Puthusseryppady Vaisakh , Sultzer David L , Chrastil Elizabeth R
Published: January 2025

Background

Alterations to spatial navigation have been suggested by previous studies to represent an early cognitive marker for those with and at risk of Alzheimer’s Disease (AD). However, with most of these studies focusing on spatial memory (usage of formed spatial representations), very little is known about the extent to which spatial exploration (process by which spatial representations are formed) may be altered in AD. The aim of this study is to investigate how spatial exploration behavior may be altered in individuals with and at risk of AD, and the extent to which individuals can be classified into their clinical status based on their exploration behavior.

Method

10 cognitively unimpaired older adults, 10 adults with mild cognitive impairment (MCI), and 10 adults with clinical AD are recruited (all participants aged > 50 years). All participants undergo a Virtual Supermarket Learning Task using immersive walking virtual reality to measure their exploration behavior and spatial memory. In the exploration phase, participants freely explore a 13×6‐meter virtual supermarket for 7 minutes and learn the locations of 6 floating target objects. Here, various exploration behaviors (distance travelled, turning angles, object visits, etc.) are measured. In the wayfinding phase, participants are instructed to navigate from one target object to another, without feedback, and wayfinding success (proportion of correct trials) is measured. In the pointing phase, participants are instructed to point from one target object to another, without feedback, and angular error (deviation from correct location) is measured.

Result

Performance of the AD and MCI groups in all task phases are compared to that of the healthy controls to assess alterations to exploration behavior as well as wayfinding and pointing performance. Furthermore, we assess how well we can classify the AD and MCI groups from controls using their exploration behavior, and compare this with the classification accuracy obtained from using their wayfinding/pointing performance.

Conclusion

The study results will highlight the extent to which spatial exploration behavior can be considered a novel and sensitive cognitive marker for AD, having important implications for understanding early cognitive changes in AD and potentially identifying candidates for therapeutic intervention.
Effects of a cognitive and physical intervention program in older adults in Panama
Authors: Quiros Elianne S Pauli , Oviedo Diana C , Britton Gabrielle B , Rangel Giselle , Villarreal Alcibiades E , Juárez Jemila , Jones Hjalmar
Published: January 2025

Background

Dementia affects nearly 50 million people worldwide and is the leading cause of disability in older adults. According to predictions by the World Health Organization, the global population with dementia will reach 82 million by 2030, and 152 million by 2050. Currently, pharmacological interventions to delay cognitive decline are proving to be insufficient. By contrast, non‐pharmacological approaches have gained attention in recent years because they can improve clinical symptoms, are low risk and could even alleviate the burden on caregivers. The present study aims to evaluate the effect of an intervention program on cognition, subjective well‐being, and physical health in older adults in Panama.

Method

This is a randomized controlled trial study. The sample includes 60 participants aged 60‐80 years, divided into three groups: 1) a control group, which will receive informative talks about health; 2) experimental group 1, which will participate in cognitive and physical interventions, including cognitive training using the CogniFit platform, group cognitive training and weekly walks monitored with a smartwatch; and 3) experimental group 2, that will perform weekly walks only. A pre‐assessment of the participants is currently being conducted, with 42 participants evaluated so far. The assessment includes a sociodemographic interview, clinical scales, a cognitive test battery, and a physical assessment. Subsequently, a three‐month intervention program will be implemented, followed by a reinforcement program to maintain cognitive and physical training habits introduced in the intervention program. Last, a post‐test will be used to evaluate cognitive function 6 months after the beginning of the intervention program.

Results

According to existing literature, it is expected the group receiving multidomain interventions will improve significantly more than groups receiving a single intervention and the control group.

Conclusion

This study is projected to benefit the physical, cognitive, and emotional health of the participants, as well as to provide them with tools for the prevention of cognitive decline. It will also generate a new line of research that will have an impact on the treatment of older adults with cognitive impairment in Panama.
Automated Physical Performance Battery as a Digital Marker for Alzheimer’s Disease and Mild Cognitive Impairment
Authors: Adeli Ehsan
Published: January 2025

Historically, screening for incidence of AD‐related MCI or conversion from MCI to AD dementia has relied on cognitive, activities of daily living, and brain imaging measures. Limitations of this diagnostic approach include dependency on education and language, time‐consuming and costly measures, and long‐term monitoring. Emerging studies suggest that non‐tremor motor dysfunction in dementias is known to be highly associated with AD biomarkers, with signs of cognitive decline visible in gait and hand movement at various stages of the illness. With the evidence that gait and physical disturbances are early predictors of cognitive impairment and that their trajectories could readily be tracked, we utilize recent advances in computer vision (CV) to quantify mobility in a data‐driven fashion from the video‐recorded 5‐minute Short Performance Physical Battery (SPPB) tests. We use the data collected at Stanford AD Research Center and show that our CV methods can automatically reduce videos to body markers (human skeleton tracked through time) and extract several features (such as gait speed, mean torso inclination angle, double support time, gait‐summary score, etc.) and finally turn those into clinical SPPB test scores. Our initial data observed a significant difference between healthy controls (HC) and the two MCI and AD groups for the repeated chair stand test score. Similarly, an inverse correlation between the MoCa cognitive test score and the gait speed is observed. At the end of the talk, I will also discuss how this CV method for mobility can be used for detecting behavioral changes in animal AD models and implications for future human AD research.
Effects of lifestyle factors on Alzheimer’s disease symptoms in adults with Down syndrome
Authors: Schworer Emily K , Zammit Matthew D , Handen Benjamin L , Okonkwo Ozioma C , Hom Christy L. , Ances Beau , Christian Bradley T. , Hartley Sigan L
Published: January 2025

Background

Lifetime risk for symptomatic Alzheimer’s disease (AD) in people with Down syndrome (DS) is 90%, with the age of onset of symptomatic AD ranging widely. Identifying resiliency factors related to a later age of symptoms is of critical importance for the DS community. This study investigated lifestyle factors hypothesized to moderate the association between amyloid‐beta (Aβ plaques) and AD symptoms in adults with DS.

Method

Participants were 63 adults with DS (M age = 40.21 years, SD = 7.73). The majority of participants were cognitively stable (84.1%), 6.3% had dementia, and 9.6% had mild cognitive impairment. Participants completed an Aβ PET scan using [11C] Pittsburgh Compound‐B (PiB) and Aβ trajectories were modeled using a sampled iterative local approximation algorithm to assign each individual a chronicity value, centered at 18 Centiloids. Participants completed the modified Cued Recall Test (mCRT) and caregivers completed the National Task Group‐Early Detection Screen for Dementia (NTG‐EDSD). Caregivers were also asked to rate the amount of time the adult with DS participated in cognitive, social, and vocational activities. Adults with DS wore an Actigraph accelerometer for 7 days to assess daily step count. A lifestyle composite score was created.

Result

Two moderation tests were run, with Aβ chronicity as the predictor, AD symptoms (mCRT or NTG‐EDSD) as the dependent variable, and lifestyle composite as a moderator. There was a significant interaction of lifestyle composite X chronicity on mCRT, t = 3.03, p = .004 and NTG‐EDSD, t = ‐3.29, p = .002. Participants who engaged in lifestyle activities for less time than average experienced a greater effect of chronicity on mCRT (Figure 1) and NTG‐EDSD (Figure 2).

Conclusion

Lifestyle activities moderated the association between Aβ chronicity and AD symptoms. Participants who had active lifestyles with more cognitive, social, physical, and vocational activities evidenced fewer AD symptoms (i.e., less cognitive impairment) given similar Aβ chronicity values than participants who engaged in fewer activities. This study was limited to cross‐sectional associations. Future longitudinal research should tease out time‐ordered effects. Modifiable lifestyle factors may allow adults with DS to maintain cognitive functioning for longer in the face of early AD pathology.
Integrating multi‐omics data for target and biomarker discovery
Authors: Arnold Matthias ,   the Alzheimer’s Disease Metabolomics Consortium
Published: January 2025

Background

Despite recent breakthroughs, Alzheimer’s disease (AD) remains untreatable. In addition, we are still lacking robust biomarkers for early diagnosis and promising novel targets for therapeutic intervention. To enable utilizing the entirety of molecular evidence in the discovery and prioritization of potential novel biomarkers and targets, we have developed the AD Atlas, a network‐based multi‐omics data integration platform. Through recent extensions, the AD Atlas provides a comprehensive database of high‐quality multi‐omics data that can be utilized for hypothesis‐free ranking of molecular markers and disease modules, as well as prioritization of potential novel targets and drug repositioning candidates.

Method

We developed several graph‐based analysis tools from proximity searches to applications of artificial intelligence that can be applied to the AD Atlas. For prioritization of potential targets and biomarkers, we derived several network‐based metrics to score ‐omics entities for disease relevance by not only assessing evidence for a single marker but also for its functional neighborhood in the AD Atlas network. For disease module identification, we employed graph representation learning coupled with unsupervised clustering to extract functional modules as defined by the network structure. Finally, we propose an ensemble approach that enables weighted aggregation of drug repositioning predictions from both signature‐based and network‐based algorithms.

Result

We demonstrate that the AD Atlas enables complex computational analyses for target and biomarker discovery and prioritization as well as in silico drug repositioning in AD. Using the integrated scores for prioritizing single targets and biomarkers for AD, we observe significantly higher relevance scores for genes that have been nominated as promising targets by the AMP‐AD consortium. We further find that extracted disease modules are enriched for specific AD‐relevant biological domains and can be ranked by disease relevance using similar graph‐based metrics. Finally, we demonstrate that drug repositioning candidates are significantly enriched for compounds that were or are being tested in clinical trials for AD.

Conclusion

High‐quality, multi‐omics networks, such as the AD Atlas, enable exploitation of large‐scale heterogeneous data through computational applications for target, biomarker, disease module, and drug repositioning candidate discovery and prioritization.
Passively collected smartphone behaviour as a reliable and feasible measure for global cognition in Alzheimer’s Disease
Authors: Keijzer Matthijs J. , van Liere Mariska N. , Van De Glind Marie‐Christine M. A. B. J. , Muurling Marijn , de Boer Casper , Redeman Erwin G. M. , Meijer Kim A. , van der Flier Wiesje M. , Sikkes Sietske A. M.
Published: January 2025

Background

With the increasing number of potential interventions for Alzheimer’s Disease (AD), there is a growing need to detect meaningful cognitive changes early in the disease. Frequent passive monitoring of smartphone behaviour, such as typing speed and precision, can give insight into the cognitive changes in AD. In the ‘A personalized Medicine Approach for AD’ (ABOARD)‐project we investigated the reliability and validity of typing behaviour to monitor cognition in people with and without AD.

Method

In this prospective study we included forty participants (Healthy controls (N = 9), Subjective Cognitive Decline (N = 11), Mild Cognitive Impairment (N = 10) and dementia due to AD (N = 10)). Typing behaviour and sensor data during typing were collected for 28 days using a smartphone application (Neurokeys). Eight keystroke dynamics (KD) features were calculated (Figure 1a), standardized into z‐scores, and averaged over time to create a single score per feature. Test‐retest reliability was assessed by intra‐class correlations between the first and last 14 days. Concurrent validity was explored with correlations between the Mini‐Mental State Examination (MMSE), KD features and movement in three orthogonal directions (Figure 1b).

Results

All participants completed the study with an average of 640±413 keystrokes per day (Table 1). The ICC for all features range from 0.62 to 0.88, indicating good reliability. Most KD features show moderate to strong associations with MMSE performance, including the time between characters (flight time, r = ‐0.71, p<0.001), the time between the spacebar and a next character (after‐spacebar pause, r = ‐0.65, p<0.001) and the time between the backspace and a next character (post‐correction slowing, r = ‐0.63, p<0.001, Figure 2). Movement of the phone in the X (r = 0.39, p<0.05) and Z direction (r = 0.38, p<0.05) is also correlated with the MMSE (Figure 2).

Conclusion

This study provides a first indication that smartphone behaviour can be a useful and reliable tool for monitoring cognition in AD. The results suggest that individuals with worse global cognition type slower, require more time to correct an error and take more time to initiate the next word, while individuals with better cognition show more movement during typing. A larger validation study can help to confirm the potential of smartphone‐derived AD digital biomarkers.
Presynaptic mechanisms of impaired long term potentiation of lateral entorhinal cortex input to CA1 in the PS19 mouse model of tauopathy
Authors: Thangavel Mohankumar , Tian Chengju , Reyes Isabel , Masurkar Arjun V.
Published: January 2025

Background

How tauopathy disrupts direct entorhinal cortex (EC) inputs to CA1 and their plasticity is understudied, despite its critical role in memory. Moreover, dysfunction of lateral EC (LEC) input is less clear, despite its relevance to early Alzheimer’s disease pathogenesis. Here we examined how tau impacts long‐term potentiation (LTP) of LEC→CA1 input in a transgenic model of tauopathy.

Method

Acute hippocampal slices were prepared from PS19 and WT mice (8‐10 mo. old, M/F) in which LEC had been injected with an AAV expressing channelrhodopsin ChR2. Ex vivo recordings were achieved with blue LED light to excite LEC axons and an extracellular field electrode in stratum lacunosum moleculare (SLM) of distal CA1 to record field responses. Input‐output curves were established using 25‐100% LED power for field postsynaptic excitatory potentials (fEPSPs) with inhibition blocked (GABAA: 2mm SR95531, GABAB: 1mm CGP55845). LTP of fEPSPs was elicited after a 10” baseline using an LED theta burst stimulation (TBS). Paired pulse ratio (PPR) of fEPSPs was elicited with LED stimulation of 2 pulses at 20Hz. Fluorescence immunohistochemistry (IHC) was performed in separate mice using antibodies to N‐type calcium channels.

Result

All results are based on n = 4‐8/sex/genotype. The LEC fEPSP was of reduced magnitude in female PS19 versus WT mice, while unchanged across genotype in male mice. TBS induced a late‐onset LTP (147% at 45”) of the LEC fEPSP in female WT mice, which was significantly reduced in female PS19 mice (p = 0.0051). There was no LTP reduction in male mice. LTP in female WT mice was associated with a PPR reduction that was reversed by the addition of the N‐type calcium channel blocker w‐conotoxin GVIA, all of which did not occur in PS19 mice (p<0.0001). PPR was appropriately reduced in male mice across genotype. IHC of N‐type calcium channels showed reduced fluorescence in the SLM of female PS19 mice versus WT.

Conclusion

In PS19 mice, the impact of tau on LEC→CA1 input is sex‐dependent, with reduced LEC‐driven excitation and LTP only in female mice. A reduction in presynaptic N‐type calcium channels in PS19 mice may serve as a presynaptic mechanism for the reduced plasticity.
Gait Speed Reflects Cognitive Impairment in Early AD
Authors: Wu Che‐Sheng , Chou Chia‐Ju , Chang Chih‐Ting , Lee Chia‐Ying , Fang Chuang Yi‐ , Chiu Yen‐Ling , Liu Yi‐Chien
Published: January 2025

Background

Gait performance has been found to be an effective method for screening cognitive impairment in elderly. Nevertheless, the efficacy of utilizing gait speed as a marker for monitoring cognitive changes remains incompletely substantiated.

Method

From 2021 to 2023, we recruited 104 participants from the memory clinic of Cardinal Tien Hospital in Taipei, Taiwan. Individuals with organic brain lesions, joint diseases, or any other factors affecting gait speed were excluded. All participants underwent comprehensive neuropsychological tests and the Short Physical Performance Battery (SPPB) to assess physical function. The clinical diagnosis of Alzheimer disease (AD) was established using the 2021 NIA‐AA criteria. Global cognitive impairment was determined using the Cognitive Abilities Screening Instrument (CASI), and gait speed was measured through a 4‐meter walking test derived from the SPPB. Cognition in specific domains was assessed using various tests, such as the Logical Memory Test (LM) from the Wechsler Memory Scale 3rd edition, the Color Trail Making Test (CTT), and the Verbal Fluency Test (VF).

Result

This study revealed a significant difference in SPPB score (11.03 vs. 12.64, p < 0.001) and gait speed (0.78 vs. 0.95 m/s, p = 0.005) between the early AD and normal groups. Furthermore, a positive correlation was observed between gait speed and CASI scores (r = 0.421, p < 0.001) in the early AD group, while no such effect was observed in the normal group (p = 0.24). In multiple regression analysis, our study demonstrated that CASI was better predicted by gait speed (p = 0.001) rather than age, gender, or years of education. LM (r = 0.393, p = 0.001), CTT (r = ‐0.449, p = 0.001), and VF (r = 0.349, p = 0.004) also revealed a significant correlation with gait speed in the early AD group.

Conclusion

Gait speed positively correlated with cognitive impairment in the early AD, but not in normal controls. One possible explanation is the pathological changes of AD in the brain that affect gait and cognition simultaneously. Our study suggests that gait speed should be considered as a marker reflecting global cognitive function.
Discordance between self‐ and study partner‐reported cognitive decline is associated with MCI diagnosis
Authors: Aaronson Anna , Diaz Adam , Ashford Miriam T. , Jin Chengshi , Tank Rachana , Miller Melanie J. , Kang Jaemyeong , Manjavong Manchumad , Landavazo Bernard , Eichenbaum Joseph , Truran‐Sacrey Diana , Camacho Monica R. , Fockler Juliet , Flenniken Derek , Mackin Scott R. , Weiner Michael S. W. , Nosheny Rachel L. ,   the Alzheimer’s Disease Neuroimaging Initiative
Published: January 2025

Background

In Alzheimer’s disease research, subjective report of cognitive and functional decline from participant‐study partner (SP) dyads is an efficient method of assessing cognitive impairment and risk of clinical progression. The extent to which discordance (disagreement) between self‐ and SP–report is associated with diagnosis of cognitive impairment is not known.

Method

We tested the hypothesis that discordance between baseline self‐ and SP‐report Everyday Cognition Scale (ECog) scores was associated with greater probability of mild cognitive impairment (MCI) diagnosis. Dyads enrolled in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and the University of California, San Francisco Brain Health Registry (BHR), an online longitudinal aging‐related research registry, completed an online adaptation of the 39‐item ECog to assess subjective change across six cognitive domains.

We derived four metrics of discordance between participant and SP ECog scores (dyadic discordance): Raw Score Difference, Absolute Score Difference, Overreport Score, and Underreport Score (Table 1). In the ADNI cohort, we fit a logistic regression model for each of the discordance metrics to independently evaluate their association with MCI diagnosis, after adjusting for dyad relationship and sociodemographic factors. Then, to further evaluate the predictive utility of these measures, we carried out a model selection procedure using cross‐sectional data collected from ADNI dyads (N = 921; Table 1). Finally, we externally validated the model in a BHR cohort with clinically confirmed diagnoses (N = 279; Table 1).

Result

Higher Raw and Absolute Score Difference, greater Underreport scores, and lower Overreport scores were associated with greater probability of MCI in the ADNI cohort (Table 2). The model selection procedure identified a number of highly predictive variables, which were then included in a model that was externally validated in the BHR cohort. This model distinguished diagnostic groups in the BHR cohort with AUC = 0.892, Sensitivity = 0.61, Specificity = 0.95 (Figure 1) based on a restricted cubic spline regression model.

Conclusion

Results indicate that ECog score discordance is associated with MCI diagnosis. The selected model showcased good predictive performance in the validation cohort, and highlights the potential utility of subjective dyadic discordance metrics to help identify older adults with MCI in diverse settings.
The relationship between dyadic perspective in subjective reports and objective cognitive decline in preclinical Alzheimer's
Authors: López‐Martos David , Brugulat‐Serrat Anna , Cañas‐Martínez Alba , Canals‐Gispert Lidia , Marne Paula , Gramunt Nina , Suárez‐Calvet Marc , Milà‐Alomà Marta , Minguillon Carolina , Fauria Karine , Zetterberg Henrik , Blennow Kaj , Molinuevo Jose Luis , Gispert Juan Domingo , Grau‐Rivera Oriol , Sánchez‐Benavides Gonzalo ,   for the ALFA study
Published: January 2025

Background

Subjective Cognitive Decline (SCD) may represent the initial symptom of Alzheimer’s disease (AD), but SCD may be absent and/or unrelated to actual cognitive decline. Objective Subtle Cognitive Decline (obj‐SCD) can be identified through longitudinal standardized neuropsychological tests in individuals not yet meeting criteria for Mild Cognitive Impairment (MCI). We argue that the relationship between SCD and obj‐SCD might help to inform clinical and research criteria in pre‐MCI stages. This study explores the dyadic perception (participant‐informant) of SCD as an early symptomatic marker of obj‐SCD in Cognitively Unimpaired (CU) population at increased risk of (AD) dementia.

Method

Three hundred thirty‐seven CU participants from the ALFA+ prospective cohort study (with three‐year follow‐up) were included. AT(N) profiles were defined at baseline with Cerebrospinal Fluid (CSF) biomarkers. Baseline reports of SCD, “My‐Cognition” for the participant and “Their‐Cognition” for the informant, were measured with the SCD‐Questionnaire (SCD‐Q). AD biomarker‐based reliable change indices adjusted for practice effect (A‐T‐[N]‐ group’s longitudinal performance as reference) were computed for the robust measurement of cognitive trajectory. Considering the relationship between the number of neuropsychological measures and the base rate of impaired scores, obj‐SCD was defined as longitudinal biomarker‐based performance below ‐1.645 SD (<5th‐percentile) in at least 3 variables within each domain (episodic memory | global). Episodic memory and global obj‐SCD were analyzed using logistic linear regression with CSF Aβ42/40 status and SCD reports as predictors.

Result

CSF Aβ‐status was not associated with global, but with memory obj‐SCD (OR = 2.743, 95%CI = 1.013‐7.811). SCD scores in My‐Cognition and Their‐Cognition were associated with global obj‐SCD (OR = 1.096, 95%CI = 1.003‐1.192; OR = 1.228, 95%CI = 1.075‐1.394), and Their‐Cognition was further associated with memory obj‐SCD (OR = 1.183, 95%CI = 1.020‐1.354). Descriptives in Table‐1, inferential results in Table‐2 and Figure‐1.

Conclusion

Aβ‐pathology was linked to memory, but not global obj‐SCD, in participants not yet meeting MCI criteria. Subjective reports from informants showed greater effect sizes than reports from participants and were associated to memory and global obj‐SCD. The participant‐informant discrepancy observed for memory obj‐SCD and its association to AD‐related impairment suggested that participants with objective memory problems might not be fully aware of these subtle changes, highlighting the relevance of tracking dyadic reports in preclinical Alzheimer’s.
Development and validation of language as an endpoint in Alzheimer’s Disease clinical trials
Authors: Robin Jessica , Spilka Michael J , Xu Mengdan , Simpson William
Published: January 2025

Background

Changes in the structure and use of language are well established clinical characteristics of Alzheimer’s disease. In recent years, there has been a concerted effort to objectively quantify these changes using the latest advances in Natural Language Processing (NLP) tools. Much academic research has been conducted to evaluate how these speech characteristics change with the course of illness, but they have yet to be elevated beyond exploratory endpoints in trials. Through a series of studies, we apply a validation framework with the goal of creating a speech based biomarker suitable for use in trials as a language endpoint.

Method

In order to accurately capture the spectrum of disease, a biomarker should be able to 1) detect disease in case‐control samples, 2) be able to capture severity within clinical groups and 3) capture change over time. We conducted a series of studies leveraging multiple methods to assess how NLP derived speech and language features perform at each of these validation tasks.

Result

Using machine learning based approaches, we were able to accurately differentiate patients with dementia from demographically matched controls with >80% accuracy. Numerous characteristics of speech, including syntactic complexity, information content, use of nouns and pronoun:noun ratios were shown to correlate with gold standard measures of cognition and function including the CDR, ADAS‐Cog, MMSE and ADCS‐ADL. Many of these same features also showed significant change over time, in line with traditional endpoints. Analytical strategies to combine these characteristics into composite scores have yielded measures which are correlated, but not identical to gold standard endpoints, with generally similar effect sizes and acceptable test‐retest reliability.

Conclusion

Collectively, these studies indicate that speech and language can detect disease, align with severity and track clinical changes over time. While additional characteristics, including cross‐language performance, speech source optimization and precise evaluations of patient relevance are required, speech based digital biomarkers are a promising advance in the measurement of AD.
Chronic heavy alcohol intake and liver‐specific LRP‐1 reduction increase amyloidosis in Alzheimer’s disease mice
Authors: Chandrashekar Devaraj V. , Roules G. Chuli , Steinberg Ross A. , Panchal Urvashi R. , Jagadeesan Nataraj , Oyegbesan Adenike , Roselyn Trinh , Yang Joshua , Bhagwat Sharda R. , Rakholia Hiya , Mevawala Rutvi D. , Roosan Moom , Han Derick , Sumbria Rachita K.
Published: January 2025

Background

Chronic heavy alcohol drinking may be a modifiable risk factor for Alzheimer’s disease (AD), but studies in rodent AD models more closely mimic chronic moderate alcohol drinking in humans and largely focus on the brain. The role of the liver, which is significantly impacted by chronic heavy alcohol intake, in driving brain changes in alcohol‐dependent AD remains unexplored. Our study using intragastric‐ethanol feeding, which mimics chronic heavy alcohol intake in humans, in C57BL/6J mice showed significant AD‐relevant changes in the brain and liver. Therefore, we aimed to investigate how hepatic changes using this model of chronic heavy drinking drive AD pathology in AD mice, which has never been attempted.

Methods

Eight‐month‐old male APP/PS1 mice were fed ethanol or control diet intragastrically for 5 weeks (n = 7‐11/group). Brain and liver Aβ were assessed using immunoassays. Three important mechanisms of brain amyloidosis were investigated: hepatic LRP‐1 (major peripheral Aβ regulator), blood‐brain barrier (BBB) function (vascular Aβ regulator), and microglia (major brain Aβ regulator) using immunoassays. Hepatic LRP‐1 expression was confirmed using Nanostring spatial transcriptomics. To elucidate the role of hepatic LRP‐1 in brain amyloidosis, hepatic LRP‐1 was silenced by injecting LRP‐1 microRNA delivered by the adeno‐associated virus 8 (AAV8) and the hepato‐specific thyroxine‐binding globulin promoter to 4‐month‐old male APP/PS1 mice (n = 6). Control APP/PS1 mice received control AAV8 (n = 6). Spatial memory was assessed 12 weeks after LRP‐1 silencing using Y‐maze, and brains and livers were harvested to detect Aβ.

Results

Alcohol feeding increased aggregated Aβ (p<0.05) by ELISA and 6E10‐positive Aβ load (p<0.05) by immunostaining, and reduced plaque‐associated microglia in APP/PS1 mice brains. Further, alcohol‐fed APP/PS1 had liver steatosis and significantly downregulated hepatic LRP‐1 (p<0.01) at the protein and transcript level, and brain and hepatic Aβ were positively correlated (p<0.05). Hepato‐specific LRP‐1 silencing significantly increased brain Aβ load (p<0.05) and reduced entries into the novel arm of the Y‐maze (p<0.05) in APP/PS1 mice.

Conclusion

Chronic heavy alcohol intake reduced hepatic LRP‐1 expression, and hepato‐specific LRP‐1 silencing increased brain Aβ and spatial memory deficits in APP/PS1 mice. Our results place hepatic LRP‐1 as a potential key driver of brain amyloidosis in alcohol‐dependent AD.