bluuebunny/crossref_metadata_2025 huggingface dataset:
Fostering the delivery of non‐pharmacological nursing home dementia care: Designing and executing a multi‐site pragmatic clinical trial
Authors: Leland Natalie E , Shier Victoria , Lekovitch Cara A. , Bae‐Shaaw Yuna H. , Sood Neeraj , Day Claire E , Cass Paul , Como Dominique H. , Wong Carin M. , Chew Felicia M
Published: January 2025

Background

Nursing home (NH) staff face daily challenges caring for the residents living with dementia (e.g., management of behavioral and psychological symptoms). Research supports the delivery of team‐ and problem‐based non‐pharmacological approaches to dementia care. The team‐based approach includes dementia training for all NH staff using a common language and strategies to support continuity and sustainability. The problem‐based approach capitalizes on the discipline‐specific expertise of the professional healthcare providers (e.g., rehabilitation) to target emergent issues. Prior work has not compared the two approaches. Our objective is to determine if there is a difference between these non‐pharmacological dementia care approaches with respect to resident outcomes and satisfaction and acceptability among NH staff and family caregivers.

Method

We will describe the development and execution of a community‐engaged pragmatic clinical trial that compared team‐ and problem‐based approaches to NH dementia care. The trial leveraged a convergent mixed methods design in order to examine (a) comparative effectiveness of two dementia care approaches on long‐term NH resident outcomes (e.g., off‐label antipsychotic medications), (b) whether either approach was protective against the negative consequences of COVID‐19, and (c) NH staff and family caregiver perspectives of the care approaches (e.g., application, recommendations, sustainability). Data collection included the NH Minimum Data Set, electronic medical records, and interviews with NH staff and families of residents living with dementia.

Result

80 NHs were randomized to one of the two treatment approaches. This presentation will share considerations for designing and implementing pragmatic trials in a United States NH context. Designing this NH pragmatic trial required a multi‐level implementation framework, which accounted for variations in societal, contextual, and encounter level factors related to the approaches as well as peripheral factors impacting NH care more broadly. Successful completion of the study required the active engagement of a community‐engaged Advisory Committee.

Conclusion

The design and execution of NH implementation research should consider intervention‐specific and peripheral factors spanning levels of influence and be anchored in community‐engagement methodology. Results of the trial can provide health system leaders and policymakers with evidence on how to advance dementia care in an effort to optimize resident outcomes.
Correlating hippocampal and amygdala volumes with neuropathological burden in neurodegenerative diseases using 7T postmortem MRI
Authors: Liou Jr‐Jiun , Li Jinghang , Berardinelli Jacob , Jin Hecheng , Santini Tales , Noh Jaehoon , Farhat Nadim , Aizenstein Howard J , Yong William , Head Elizabeth , Ikonomovic Milos D , Ibrahim Tamer S , Kofler Julia
Published: January 2025

Background

High‐resolution and high‐contrast postmortem MRI can unveil structural abnormalities overlooked by antemortem MRI, making it well‐suited for targeted pathology assessments. In community cohorts, limbic‐predominant age‐related TDP‐43 encephalopathy (LATE) pathology is linked with smaller amygdala [Makkinejad 2019 Neurobiol Aging] and hippocampal volumes [Josephs 2015 Ann Neurol]. Whether a similar association exists in Down syndrome (DS) remains unexplored. This study investigates the potential correlation of amygdala and hippocampal atrophy with AD and LATE pathology in both DS and AD.

Methods

7T postmortem ex vivo MRI scans (n=67, comprising 13 DS and 54 AD) and a subset of antemortem MRI scans (n=17) were obtained. Manual segmentation of the hippocampus and amygdala was performed. The resulting volumes, normalized to fresh brain weight and adjusted for age, sex, and ApoE4, were correlated with pathological findings, including Thal phase, Braak stage, LATE stage, and the presence of hippocampal sclerosis (HS).

Results

Postmortem‐antemortem volume correlation was significant for the hippocampus (p=0.0066) but not the amygdala. Compared to AD, individuals with DS had significantly lower hippocampal (p=0.0004) and amygdala (p=0.0002) volumes. In the DS group, lower hippocampal (p=0.0051) and amygdala (p=0.0127) volumes correlated with more severe Braak stage, with no significant correlations with Thal phase. In two DS cases that exhibited LATE or HS, trends toward smaller hippocampal volume were observed. In AD, lower hippocampal volume correlated with more severe Thal phase (p=0.0020), Braak stage (p=0.0081), LATE stage (p=0.0017), and the presence of HS (p<0.0001), whereas lower amygdala volume correlated with more severe LATE stage (p=0.0160) and HS (p=0.0139) but not with Thal phase or Braak stage.

Conclusions

7T postmortem MRI protocol produced good alignment of postmortem volumes with antemortem findings and revealed correlations between volume measures and neuropathological burden. In AD, hippocampal volume is influenced by both AD and LATE pathologies, whereas amygdala volume appears to be influenced primarily by LATE. In DS, hippocampal volume is smaller than in AD and primarily influenced by tau pathology. Future investigation will also explore Lewy body pathology and its potential association with hippocampal and amygdala volume changes in DS and AD.
Relationship Between 18F‐AV‐1451 Binding in Human Brain and Tissue Alterations Defined by Quantitative Gradient Recalled Echo (qGRE) MRI Measurements
Authors: Kothapalli Satya V.V.N. , Benzinger Tammie L.S. , Gordon Brian A. , Eldeniz Cihat , Hildebolt Charles F , Goyal Manu S. , Morris John C. , Yablonskiy Dmitriy A.
Published: January 2025

Background

The 18F‐AV‐1451 radioligand enables in‐vivo identification of tau neurofibrillary tangles that are considered as biomarkers of neurodegeneration in Alzheimer Disease (AD). However, off‐target radioligand binding is also observed in basal ganglia, known as an iron‐rich region. Hence, it is important to distinguish between radioligand‐identified tissue neurodegeneration and iron‐related radioligand binding effects. Our aim is to answer this question by using previously developed quantitative Gradient Recalled Echo (qGRE) MRI technique sensitive to morphological and microstructural tissue neurodegeneration, as well as to iron deposition.

Methods

Sixty‐eight participants (ages: 72.1y ± 8.2y; 15 with amyloid status (Aβ) positive and cognitive dementia rating (CDR®)>0; 16 with Aβ‐positive and CDR®=0; and 37 with Aβ‐negative and CDR®=0) recruited by Knight ADRC underwent 18F‐AV‐1451 PET imaging and qGRE MRI imaging (3T Siemens MRI scanners). As previously demonstrated, the R2t* metric of qGRE signal is sensitive to both, pre‐atrophic neuronal loss (low R2t*, a.k.a. Dark Matter (DM), and nonheme iron accumulation (High R2t*). The histogram characterizing distribution of R2t* values across the brain (Figure 1) allows the quantification of DM (R2t*<5.8s‐1) and Iron Deposition Score (IDS, R2t*>28s‐1). 18F‐AV‐1451 binding was characterized in terms of Standardized Uptake Value Ratio (SUVR). All results were summarized in brain regions segmented using FreeSurfer.

Results

(Figures 2 and 3): Tissue volumes exhibited moderate negative associations with 18F‐AV‐1451 SUVRs in MTL (R2=0.21), temporal lobe (R2=0.17), and parietal lobe (R2=0.11). The linear model that includes IDS and DM exhibited positive association with 18F‐AV‐1451 SUVRs only in MTL (R2=0.18). The linear mixed model that includes volume, IDS and DM metrics showed the improved association between predicted and actual 18F‐AV‐1451 tracer retention in the MTL (R2=0.34), the temporal lobe (R2=0.23), and the parietal lobe (R2=0.12).

Conclusion

Our results suggest that the 18F‐AV‐1451 binding is modulated not only by neurodegeneration but also by elevated levels of iron deposition. More detail studies are required to answer the question whether the iron effect is concomitant or contributes to neurodegeneration through ferroptosis. The qGRE‐based multiparametric approach allowing simultaneous identification of pre‐atrophic neurodegeneration and iron deposition has a potential to contribute to understanding of this intricate relationship.
Dynamic Light Scattering Spectroscopy as an Early Biomarker of Alzheimer’s Disease
Authors: Weiss Jeffrey Neill
Published: January 2025

Background

The early detection of neurologic damage at the microscopic level when the disease is subclinical would facilitate intervention preventing progression or potentially reversing the condition. The early determination of drug efficacy could shorten the length of drug studies, thereby reducing research costs. The eye is the only place in the body where an artery, vein, and nerve can be directly visualized The nerve fiber layer of the retina is an outgrowth of the brain.

Method

Dynamic Light Scattering (DLS) Spectroscopy measures the thermal random movement (Brownian Motion) of particles by analyzing the temporal fluctuations of scattered light.

A proof‐of‐concept instrument for making retinal measurements provides optical power well below the maximal permissible exposure recommended by the ANSI Z136.1 standard. Scattered light is analyzed by a digital autocorrelator with an extended delay option for baseline determination. The testing duration is 5 seconds.

DLS measurements were made from the macular area of 4 patients diagnosed with mild cognitive impairment and 4 age‐matched controls with no history of neurologic disease. Both groups of patients had normal retinal examinations, including normal Optical Coherence Tomography, (OCT).

Result

Figure 1 Screenshot ‐ 62‐year‐old female recently with mild cognitive impairment, subsequently diagnosed with Alzheimer’s disease 1 year after DLS testing.

Figure 2 Screenshot ‐ Age‐matched control

Conclusion

The 4 patients with mild cognitive impairment were subsequently diagnosed with Alzheimer’s disease approximately 1 year after the abnormal DLS measurement. The differences between the patients subsequently diagnosed with Alzheimer’s disease, compared to the normal age‐matched controls, was consistent across the tested patients. Alzheimer’s measurements begin above 0.6 g 2(t)‐1 and exhibit flattening of the initial line as opposed to the curve seen in non‐Alzheimer’s patients.

The development of an early, noninvasive, quantitative test to diagnose Alzheimer’s disease will lead to breakthroughs in drug development and hopefully, to the successful treatment of patients before dementia is irreversible.
Development of ultra‐sensitive and reproducible measurement system for blood biomarkers
Authors: Tosaka Kenta , Shimizu Keisuke , Matsunaga Taichi , Satou Hiroshi
Published: January 2025

Background

Neurodegenerative diseases, such as Alzheimer’s disease(AD), have become more prevalent in aging societies. Therefore, it is important to develop a blood‐based measurement system to diagnose early‐stage AD. However, such AD‐related biomarkers in blood exist at extremely low levels and are difficult to detect precisely and reproducibly.

Method

The measurement system was constructed by using brain natriuretic peptide(BNP) as a model biomarker. The outline of the system is as follows. (1) BNP in sample is captured by anti‐BNP antibody modified magnetic beads followed by enzyme labeling. (2) Magnetic beads with capturing BNP are enclosed in a microwell array for ultra‐sensitive detection of the marker. In our method, multiple beads are enclosed in a microwell to measure as many beads as possible and improve measurement reproducibility. (3) BNP is quantified by integrating the fluorescence intensity which generated by the enzymatic reaction in each microwells. BNP standards were measured in triplicate by developed system and calculated the limit of detection (LOD).

Result

The LOD of BNP was 2.5 fM (8.6 fg/mL), which was significantly sensitive compared to the conventional immunoassay system. Furthermore, the coefficient of variation (CV) of 7.2 fM (25 fg/mL) BNP was 8.1%, so that reproducibility in the low concentration range was also satisfactory.

Conclusion

We developed ultra‐sensitive and reproducible measurement system and it can be applied to the detection of AD‐related biomarkers in blood.
What Matters Most to Informal Caregivers of Persons with Dementia? Results from the Application of Deep Learning to Twitter Posts from 2013 to 2022
Authors: Ang Li Chang , Malhotra Rahul , Chowdhury Anupama Roy , Liew Tau Ming
Published: January 2025

Background

With the advent of new media, more people – possibly including caregivers of persons with dementia – are turning to social media platforms to share their thoughts and emotions related to personal life experiences. This may potentially serve as an opportunity to leverage on social media to gain insights into the key issues faced by dementia caregivers. We examined salient concerns of dementia caregivers through Twitter posts, aiming to shed light on how to better support and engage such caregivers.

Method

English tweets related to “dementia” and “caregiver” (or related terms such as “Alzheimer’s disease” and “carer”) were extracted between 1st January 2013 and 31st December 2022. A supervised deep learning model (Bidirectional Encoder Representations from Transformers, BERT) was trained to select tweets describing individual’s accounts related to dementia caregiving. Then, an unsupervised deep learning approach (BERT‐based topic modelling) was applied to identify topics from selected tweets, with each topic further grouped into themes manually using thematic analysis.

Result

A total of 44,527 tweets were analysed, and stratified using the emergence of COVID‐19 pandemic as a threshold. Three themes were derived: challenges of caregiving in dementia, positive aspects related to dementia caregiving, and dementia‐related stigmatization. Over time, there is a rising trend of tweets relating to dementia caregiving. Post‐pandemic, challenges of caregiving remained the top discussed topic; followed by an increase in tweets related to dementia‐related stigmatization; and a decrease in tweets related to positive aspects of caregiving (p‐value<.001).

Conclusion

Social media is increasingly being used by dementia caregivers to share their thoughts. The findings uncover the worrying trend of growing dementia‐related stigmatization among the caregivers, and its manifestation in the form of devaluing others. The persistence of these issues post‐pandemic underscores the need for caregiver’s support and resources.
Visual and body perceptual disturbances in posterior cortical atrophy and Alzheimer’s disease
Authors: Yong Keir X X , Bai Yuhan , Bancroft Matthew J , Petzold Axel , Foster Paul J , Kaski Diego , Hoe Juanita , Pisella Laure , Greenwood John A , Crutch Sebastian J , Day Brian L
Published: January 2025

Background

Posterior cortical atrophy (PCA) is often considered the most common atypical Alzheimer’s disease phenotype, being characterized by progressive loss of visual and other posterior cortical functions. Early reading and other visuoperceptual difficulties prompt PCA patients presenting to eye clinics and receiving ocular misdiagnoses. Patients also report altered perception of body position‐ for example, difficulty locating ones’ arm during dressing. Disabling perceptual disturbances emerge later in typical Alzheimer’s disease (tAD) yet are poorly assessed or understood.

This project investigates visual and proprioceptive disturbances in PCA and tAD and underlying mechanisms.

Method

Participants underwent psychophysical testing of vision and body perception (UCL: PCA n=28; tAD n=16; Control n=19; UKBiobank n=1,951). To evaluate perception of a visual target, participants repeatedly identified letters under increasing degradation, or incompleteness (trial n=45). To evaluate perception of a proprioceptive target, participants repeatedly indicated the position of their non‐dominant thumb without and with vision (trial n=40). Perceptual error and thresholds were determined alongside primary sensory and visual functions (vibrotactile sensitivity, acuity).

Result

Thresholds for perceiving a visually degraded target were elevated in PCA compared to UKBiobank participants without or with documented eye conditions (Figure 1), consistent with higher‐order visual dysfunction (PCA sensitivity: 87%; specificity vs eye conditions: 91%).

Across groups, perceived location of a proprioceptive target (non‐dominant thumb) was shifted, or ‘biased’, towards non‐dominant space, consistent with previous work in healthy participants. However, proprioceptive biases were considerably elevated in both patient relative to control groups, particularly with targets positioned towards contralateral space (Figure 2). Biases were not attributable to primary sensory deficits, suggesting higher‐order disturbances.

Proprioceptive biases were attenuated by vision, especially in PCA and tAD groups (increased vision*target position interaction vs Controls: PCA p=.004; tAD p<.001). However, in the PCA group, biases arising from targets in contralateral space were evident even with vision (Figure 2i), indicating altered visual‐proprioceptive interactions.

Conclusion

Perceptual distortions may emerge from altered integration of visual and sensory information across AD phenotypes, especially in atypical presentations. Current digital vision tests offer promise to discriminate PCA from common eye conditions. Adapted tasks are available to detect dementia‐related perceptual disturbances across clinical services and research settings.
Analyzing ageism in the district of La Matanza, Province of Buenos Aires Argentina: a design for a study and interventions to reverse inequality and discrimination towards old age
Authors: Feldberg Carolina , Hermida Paula Daniela , Ofman Silvia Deborah , Tartaglini María Florencia , Natalia Irrazabal , Quian Rosario , Serrano Cecilia , Pollard Agustina
Published: January 2025

Background

The stereotypes that exist in people function as a bias that conditions their behavior. The presence of negative stereotypes towards older people has negative consequences both at an individual level and at a social level, since discriminatory practices occur towards this group. Therefore, the present project arises to respond a social problem detected by the National Institute of Social Services for Retirees and Pensioners (PAMI) of LaMatanza, Buenos Aires Argentina who had contacted a group of researchers of National Council of Scientific and Technical Research (CONICET) Argentina, to provide an answer to this problem in the region, were few studies were done about this subject. The aim of the present study is to analyze attitudes towards old age, and to design an intervention to reverse inequality and discrimination in the District of LaMatanza, Province of Buenos Aires.

Method

Design: Prospective cohort study. Universe: Adults over 18 years old. Sample: 800 adults over 18 years (400 subjects between 18 and 59 years old and 400 over 60 years old) will be interviewed.

Result

The project includes a research and intervention. It is expected to find different results that helps to work with the stereotypes in the three stages of the project 1) meetings with PAMI staff and members of the community to know their perspective, and select the data collection instruments 2) a prospective study will be carried out applying quantitative and qualitative instruments 3) Presentation of the final report and recommendations of possible interventions against ageism in the municipality.

Conclusion

The World Health Organization has postulated that prejudices and negative stereotypes towards old age can interfere in vital aspects of being such as health, social participation, and security. It recognized ageism as a public health problem. It is expected in this research and intervention study, to find heterogeneity in the social attitudes of the different actors interviewed. The results will thus make it possible to detect the population sectors that require more work in relation to negative attitudes towards old age, as well as the population sectors that present more favorable attitudes and can be allies in the face of the necessary changes.
Feasibility of Telehealth Memory Assessments for a Mild Cognitive Impairment Registry: Lessons Learned from a Clinical Coordinator
Authors: Stagge Faith , Lanzi Alyssa M , Cohen Matthew L. , Johnson Curtis L , Martens Christopher R.
Published: January 2025

Background

To create de novo infrastructure for ADRD research, The Delaware (DE) Center for Cognitive Aging Research (DECCAR) began a telehealth‐based mild cognitive impairment (MCI) registry. The registry included a dynamic recruitment plan and remote intake procedures to classify community‐dwelling adults as having MCI from probable Alzheimer’s Disease. The main goal of the registry was to match participants to DECCAR‐supported research studies. This work aims to report the feasibility of our telehealth methodology and observations from its development.

Methods

Older adults, ages 60‐90 years old, were recruited with a variety of methods. During an initial telephone pre‐screening, individuals completed the Modified Telephone Interview for Cognitive Status (TICS‐m) and a questionnaire about health conditions. Individuals were invited to participate in a lengthier telehealth‐based cognitive assessment using Zoom if (1) they produced TICS‐m scores suggestive of MCI, (2) could identify a study partner, and (3) did not report non‐ADRD conditions that can cause cognitive impairment.

Results

Between December, 2018, and December, 2023, n = 1029 individuals completed pre‐screening procedures (mean age was 70.1 (SD 6.56)). Paid online advertisements were the most effective recruitment source (79.30%, n = 816). Of the 1029 people who completed pre‐screening, 723 were eligible for cognitive assessment, and 571 (79%) scheduled a visit. Reasons for unsuccessful scheduling included loss of interest (n = 36), loss to follow‐up (n = 28), lack of a study partner (n = 19), and miscellaneous other reasons (n = 57). Of those who elected to schedule a telehealth assessment, 538 (94%) completed the session successfully. Telehealth assessors did not report technology to be a significant barrier. Overall, we have identified 139 individuals with MCI using this approach, which equates to 25.8% of those who successfully completed a Zoom‐based assessment.

Conclusion

Telehealth platforms can be used to build an MCI research registry. In our experience, individuals who are scheduled for a telehealth assessment will generally do so successfully, perhaps because inclusion of a study partner was required. Improving the follow through from telephone pre‐screening to Zoom may require clearer advertising, removing the requirement of a study partner, or more rigorous pursuit of people who were difficult to schedule.
Derivation and Validation of the Cognitive Impairment Prediction Model in Older Adults: A National Cohort Study
Authors: Hu Mingyue
Published: January 2025

Background

This prediction model quantifies the risk of cognitive impairment. This aim of this study was to develop and validate a prediction model to calculate the 6‐year risk of cognitive impairment.

Methods

Participants from the Chinese Longitudinal Healthy Longevity Survey (CLHLS) 2008‐2014 and 2011‐2018 surveys were included for developing the cognitive impairment prediction model. The least absolute shrinkage and selection operator, clinical knowledge, and previous experience were performed to select predictors. The Cox proportional hazard model and Fine‐Gray analysis adjusting for death were conducted to construct the model. The discriminative ability was measured using C‐statistics. The model was evaluated externally using the temporal validation method via the CLHLS 2002‐2008 survey. A nomogram was conducted to enhance the practical use. The population attributable fraction was calculated.

Results

A total of 10,053 older adults were included for model development. During a median of 5.68 years, 1,750 (17.4%) participants experienced cognitive impairment. Eight easy‐to‐obtain predictors were used to develop the model. The overall proportion of death was 43.3%. The effect of age on cognitive impairment reduced after adjusting the competing risk of death. The Cox and Fine–Gray models showed a similar discriminative ability, with average C‐statistics of 0.71 and 0.69 in development and external validation datasets, respectively. The model performed better in younger older adults (65‐74 years). The proportion of 6‐year cognitive impairment due to modifiable risk factors was 47.7%.

Conclusion

This model could be used to identify older adults aged 65 years and above at high risk of cognitive impairment and initiate timely interventions on modifiable factors to prevent nearly half of dementia.
Identification of PLCG2 activators for the treatment of Alzheimer’s disease
Authors: Clayton Brent , Massey Steven M , Beck Daniel E , Putt Karson S , Utsuki Tada , Visvanathan Ramya , Mesecar Andrew D. , Lendy Emma K , Kaiser Bridget L , Chu Shaoyou , Mason Emily R , Lamb Bruce T. , Palkowitz Alan D. , Richardson Timothy I.
Published: January 2025

Background

The goal of the TREAT‐AD Center is to enable drug discovery by developing assays and providing tool compounds for novel and emerging targets. The role of microglia in neuroinflammation has been implicated in the pathogenesis of Alzheimer’s disease (AD). Genome‐wide association studies, whole genome sequencing, and gene‐expression network analyses comparing normal to AD brain have identified risk and protective variants in genes essential to microglial function. among them. The P522R variant of phospholipase C gamma2 (PLCγ2) is associated with reduced risk for AD and has been characterized as a functional hypermorph. Carriers of P522R with mild cognitive impairment exhibited a slower cognitive decline rate. Conversely the M28L variant increases risk. Therefore, activation of the protein PLCγ2 with small molecules has been proposed as a therapeutic strategy to reduce the rate of disease progression and cognitive decline in AD patients.

Method

We performed a high‐throughput screen using affinity selection mass spectrometry (ASMS) to identify novel small molecules that bind to the full‐length protein PLCγ2. A Cellular Thermal Shift Assay (CETSA) was developed to confirm target engagement in cells. A liposomal‐based, fluorogenic reporter biochemical assay was implemented to evaluate activity of the enzyme. A high‐content imaging assay measuring phagocytosis, cell number, and nuclear intensity was carried out using the BV2 and HMC3 cell lines to characterize cellular pharmacology and cytotoxicity. Structure activity relationship (SAR) studies were performed to synthesize analogs and optimize for binding and cellular pharmacology. Optimized compounds have been studied in vivo to assess pharmacokinetic properties and drug likeness.

Result

Novel PLCγ2 activators have been discovered and preliminary optimization has been completed. These compounds have shown positive results for target engagement, biochemical activity, and cellular pharmacology. In silico predictions indicated the molecule structures are suitable CNS drug discovery program starting points.

Conclusion

Activation of PLCγ2 is a novel therapeutic strategy for treatment of AD. We identified structurally distinct molecular scaffolds capable of enzyme activation and cellular activity. Recommendations for use of probe molecules in target validation studies and the development of lead‐like molecules for clinical studies will be made.
Gradient Analysis for the Study of Alzheimer's Disease
Authors: Camargo Aldo , Wang Ze
Published: January 2025

Background

Dys‐connectivity has been repeatedly shown in Alzheimer’s Disease (AD) but the change of connectivity gradient across the brain is under‐studied. In this study, we used resting state fMRI (rsfMRI) from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) to build a whole brain functional connectivity matrix. We then compared the major connectivity gradients decomposed from the connectivity matrix from normal controls (NC), mild cognitive impairment (MCI), and AD patients.

Method

30 NC, 11 MCI, and 40 AD were included in the analysis. Data preprocessing including motion correction, slice time correction, normalization, and artifact component removal, was performed using SPM12 and FSL. Mean rsfMRI time series was extracted from each of the 400 segments in the Schaefer atlas. A 400x400 functional connectivity matrix was calculated for each subject. Connectivity gradients were subsequently calculated using the BrainSpace toolbox. A mean connectivity matrix and its gradients were calculated for NC, MCI, and AD separately. Individual subject’s gradients were then aligned to those population level ones and compared across groups through two‐sample t‐test. Our analysis limits to the first three gradients as the corresponding eigenvalues explained >39 % of the original matrix variance. Multiple comparison correction was performed using Bonferroni correction.

Result

Figure 1 shows the first gradient map for each sub‐group. The gradients were lowest in occipital cortex, and increased in the motor network and temporal cortex, and then gradually went down toward prefrontal cortex. Figure 2‐4 are the statistical comparison results. The first gradient map showed the largest cross‐sectional changes. Compared to NC, MCI had reduced gradients in occipital cortex, motor cortex, and temporal cortex. Gradients in occipital cortex and posterior part of temporal cortex further reduced in AD compared to MCI, and AD patient showed gradient reduction in prefrontal cortex.

Conclusion

We found consistent functional connectivity gradient reduction in the AD continuum in occipital cortex and temporal cortex, suggesting a common pathway of AD‐related impairment to functional connectivity. Gradient reduction was identified in motor cortex in MCI compared to NC and was found in prefrontal cortex in AD compared to MCI, likely related to the escalated cognitive control and working memory decline in AD.
Exploring Polygenic Risk and Neuroimaging Parameters across the Alzheimer's disease Spectrum
Authors: Pandya Snehal , Venneri Annalena , De Marco Matteo
Published: January 2025

Background

Sporadic Alzheimer’s disease (AD) accounts for >90% of AD cases, of which 70% are thought to be due to a combination of several risk genes. Of these, Apolipoprotein E (APOE) is the most studied gene. Given that the APOE ɛ4 risk variant is found in ∼14% of the general population and ∼37% of the AD population, APOE ɛ4 is neither necessary nor sufficient to cause AD on its own. Investigating polygenic scores may lead to a better predictive model of AD, by studying many genes simultaneously, and increase understanding of how gene‐gene interactions may contribute to AD. The aim of this research was to review systematically papers exploring polygenic risk and neuroimaging parameters across the AD spectrum.

Method

Literature searches were conducted on three online databases: PubMed, Scopus, and Web of Science, between January–March 2023. All articles and early access papers, written in English, and on humans, were included. Reviews and systematic reviews were excluded. Papers were cross‐checked by three independent reviewers. Selected papers were assessed with a customised set of criteria to determine quality papers for this review and to avoid biases.

Result

3264 papers were found, of which 66 were eligible for review. Some papers used more than one imaging modality, therefore, there were a total of 80 studies: 49 structural, 8 functional, and 23 neuromolecular, covering regional and whole‐brain metrics. Polygenic risk scores and polygenic hazard scores are associated with regions vulnerable to AD, e.g., hippocampi, and entorhinal cortices. These findings are consistent across the three imaging modalities, and across the AD spectrum. In some cases, significant associations between polygenic scores and neuroimaging parameters are only present when including, or excluding, APOE. There are discrepancies in whether APOE increases, or decreases, strength of associations.

Conclusion

This review demonstrates that attention must divert away from APOE since numerous genes impact brain architecture and connectivity, and it is their combined effect that is of key interest in sporadic AD. It highlights the challenges faced, and the intricacies that must be thought about, when constructing polygenic scores.
Design of A Phase 1 Trial for Safety, Tolerability, Single‐ascending Dose, Multiple‐ascending Dose, Food Effect, and Pharmacokinetic Study of TML‐6, A Novel Oral Multi‐Target Drug, in Healthy Volunteers
Authors: Lin Chien Hong , Chen Shang Hung , Yu Hsu Chia‐ , Wang Hui‐Chen , Su Ih‐Jen
Published: January 2025

Background

Alzheimer’s disease (AD) is complex in pathogenesis and related to aging biology, especially in late‐onset AD. We identified a novel synthetic curcumin analog TML‐6 through the platform of 6 biomarkers of anti‐aging, anti‐inflammation, and anti‐Aβ as the potential AD drug candidate. TML‐6 exhibits multi‐target effects on AD pathogenesis, including the activation of NrF‐2, the regulation of autophagic machinery through mTOR, the inhibition of APP synthesis and reduction of Aβ, the upregulation of ApoE, and the inhibition of microglial activation. In the past years, we conducted series of preclinical studies on TML‐6 which showed satisfactory bioavailability and sufficient safety. US pre‐IND consultation has been completed, and IND/ phase I trial is expected to be approved on February, 2024.

Method

Phase 1 trial was designed into 5 parts containing 8 cohorts on 72 healthy subjects, including single ascending doses and multiple ascending doses. The food effect, the elderly subjects, the plasma pK analysis, and the CSF pK analysis were studied.

Result

The final phase I trial protocol was shown in the flow chart. The phase 1 trial will be conducted by CRO in Glendale Adventist Medical Center, LA, USA. According to pre‐clinical data, we anticipate good tolerability and safety of phase 1 trial through TML‐6 oral administration in healthy adults. The pK data will be analyzed for the design of dosing regimens in phase 2.

Conclusion

TML‐6 exhibits a multi‐target action mechanism meeting the new era strategy to develop AD drug. The combined data of phase 1 trial and 9‐month chronic toxicology in dogs will be applied to US FDA for global phase 2a trial, with integration of blood biomarkers. We look forward to the success of TML‐6 in clinical trials that will provide an ideal therapy, with potential of combining with anti‐amyloid drug, for Alzheimer’s disease.

Key Words: TML‐6; curcumin analogue; Alzheimer’s disease; amyloid‐beta; aging biology
Sex Differences in the Associations of Cardiorespiratory Fitness with Executive function, Episodic Memory, and Global Cognition in Older Adults with Mild Cognitive Impairment
Authors: Yu Fang , Salisbury Dereck L. , Pituch Keenan A , Lin Feng Vankee
Published: January 2025

Background

A potential mechanism underpinning the cognitive benefits from physical activity and aerobic exercise is cardiorespiratory fitness (CRF). Greater cardiorespiratory fitness (CRF) was associated with better executive function, short‐term memory, and global cognition in older adults without cognitive impairment. Sex differences in CRF has been established in adults. However, sex differences in the associations between CRF and cognition have been limitedly studied among older adults with mild cognitive impairment (MCI).

Method

This study examined sex differences in the associations of CRF with executive function, episodic memory, and global cognition in community‐dwelling older adults with amnestic MCI. Baseline data from the Aerobic exercise and Cognitive Training (ACT) Trial that tests the cognitive effects and mechanisms of 6‐month combined aerobic exercise and cognitive training were used. CRF was measured by peak oxygen consumption (VO2peak) in a laboratory‐based symptom‐limited peak cycle‐ergometer test. Executive function was measured with the EXAMINER that calculates 3 sub‐domain composite scores on working memory, cognitive control, and fluency, episodic memory with the Brief Visuospatial Memory Test‐Revised learning and delayed recall, and global cognition with Montreal Cognitive Assessment. Covariates included demographics, body‐mass index, comorbidities, activities of daily living, depression, and premorbid intellect. Regressions were performed.

Result

On average, the participants (N = 142) were 73.8±5.8 years of age with 16.9±2.9 years of education, 87.3% White, 51.4% male, and 69.7% married. Their VO2peak was 17.1±5.0 mL/kg/min. After controlling for covariates, VO2peak was related to executive function (β = 0.037, SE = .015, p<.05) and episodic memory (b = .590, SE = .226, p<.05), but not global cognition (b = .074, SE = .055, p > .05). The associations of VO2peak with executive function (b = .063, SE = .024, p<.05) and episodic memory (b = 1.008, SE = .312, p<.01) were significant for males only.

Conclusion

Our findings show that VO2peak was associated with executive function and working memory in the overall sample and males. Future studies need to examine longitudinal changes of CRF in preclinical AD and MCI to better understand of its sex‐differential impact on cognition and personalize exercise interventions on targeted cognitive domains based on sex.
Assessment of Interest and Resources Needed for the Development of Scalable Healthcare Professionals Facilitated Strategies to Diversify Alzheimer’s Disease Research Participation
Authors: Parker Monica W , Glover Crystal M , Johnson David K , Rentería Miguel Arce , Biber Sarah A , Wang Sophia
Published: January 2025

Background

Increasing underrepresented racial and ethnic minority group (URG) participation in early‐stage Alzheimer’s disease and related dementias (ADRD) research is critical to inclusive characterization of underlying pathology and testing of disease‐modifying treatments. One promising recruitment strategy to accelerate URG participation is for healthcare professionals (HCPs) to facilitate referrals. The use of HCP‐facilitated recruitment strategies across the Alzheimer’s Disease Research Center (ADRC) network, a major referral source for ADRD multisite observational and clinical trials, has not been examined. We hypothesized that there would be interest in the development of scalable HCP‐facilitated recruitment strategies to accelerate URG participation across the ADRC network.

Methods

We emailed Outreach, Recruitment and Engagement (ORE) Cores within the NIA‐funded ADRC network to complete a web‐based REDCap™ survey on their current HCP‐facilitated recruitment strategies for URG participants, resources enhancing use of these strategies, and their interest in strategy development. We conducted descriptive statistics using SPSS 29.0.

Results

Out of 37 ADRCs, 27 (73.0%) completed the survey. Although the majority of ADRCs (66.7%, N = 18) reported HCPs referring URG participants (Table 1), they mostly relied on HCP faculty based at the ADRC (48.1%, N = 13) or the ADRC affiliated academic medical center (51.9%, N = 14) (Table 2). Nearly all (92.5%, N = 25) ORE Cores expressed interest in participating in or learning more about future efforts to develop HCP‐facilitated recruitment strategies for increasing URG participation. Resources which would increase use of HCP‐facilitated strategies for URG referrals included guidance on outreach and engagement strategies (70.4%, N = 19), culturally tailored resources for HCPs to refer participants (59.3%, N = 16), technology and informatic recruitment strategies (63.0%, N = 17), and staff effort (63.0%, N = 17) (Table 3).

Conclusions

Our survey identified key opportunities to develop novel scalable HCP‐facilitated recruitment strategies to accelerate URG participation. Although most ORE Cores expressed interest in expanding their HCP‐facilitated recruitment strategies to have more inclusive research participation, there is need for both higher‐level strategic guidance and ready‐to‐use resources to implement these strategies. Future studies will need to develop and test scalable HCP‐facilitated strategies and resources to systematically accelerate URG research participation.
DA‐7503, a novel tau aggregation inhibitor, ameliorates tau pathology and reduces CSF tau in transgenic mouse models of Alzheimer’s disease and primary tauopathies
Authors: Lee Min Jung , Choi Song‐hyen , Moon Jun‐Hwan , Lee Hyangsoo , Kim Eunjin , Lee Dae Young , Lim Sungsu , Kim Yun Kyung , Pae Ae Nim
Published: January 2025

Background

Elevation of cerebrospinal fluid (CSF) tau is a feature of Alzheimer’s disease (AD) and is being explored as a biomarker of AD and other tauopathies. The aim of this study was to elucidate the in vivo effects of DA‐7503, a potent and selective tau aggregation inhibitor, and its pharmacodynamics on CSF tau in transgenic mouse models of Alzheimer’s disease and primary tauopathies.

Method

TauP301L‐BiFC mice expressing full‐length human tau with the P301L mutation were orally administrated with DA‐7503 for 1 month. CSF, plasma, and brain homogenates were collected at 4 time points from the last dosing. Total tau in CSF was measured using an AlphaLISA, and the concentrations of DA‐7503 in CSF and plasma by time were determined using LC‐MS/MS. To further evaluate the effectiveness of DA‐7503, neurobehavior and tau pathology were investigated after oral administration of DA‐7503 in TauP301L‐BiFC mice. The effect of DA‐7503 on tau pathology was also determined in human Tau (hTau) transgenic mice expressing all six isoforms of human tau combined with a knockout of murine tau.

Result

In a TauP301L‐BiFC AD mouse model, DA‐7503 showed not only a significant reversal of memory and recognition deficits but also an attenuation of tau aggregation and phosphorylation in the cortex and hippocampus. In these mice, DA‐7503 caused a significant reduction of CSF tau in a drug concentration‐dependent manner. DA‐7503 also reduced phosphoSer202‐tau in the brain cortex of hTau transgenic mice.

Conclusion

DA‐7503 restores the impairments of memory and recognition, and ameliorates the aggregation and hyperphosphorylation of tau in transgenic mouse models of AD and other tauopathies. The inverse correlation between total Tau in CSF and DA‐7503 exposure in plasma suggests that DA‐7503 induces an increase of tau clearance from the brain and CSF tau may be explored as a biomarker in clinical development of DA‐7503. Our findings indicate DA‐7503 is a promising agent for the treatment of AD and primary tauopathies.
Predictors of Life Expectancy in Community‐Dwelling People with Dementia – The Role of Social Support
Authors: Blotenberg Iris , Boekholt Melanie , Michalowsky Bernhard , Platen Moritz , Rodriguez Francisca S , Teipel Stefan , Hoffmann Wolfgang , Thyrian Jochen René
Published: January 2025

Background

The aim of the present study was twofold: First, to examine the validity of previously reported sociodemographic (age, sex) and clinical predictors (cognitive status, functional status, comorbidities) for the life expectancy in people with dementia in a community sample. Second, to investigate the role of social support beyond individual predictors.

Method

The study utilizes data from 500 individuals living in the community who were diagnosed with dementia. These participants were monitored over a period of up to eight years. The research focused on assessing life expectancy in connection with established sociodemographic factors (such as age and sex), clinical predictors (including cognitive status, functional status, and comorbidities), and also considered the impact of social support. This was analyzed using Cox regression.

Result

Advanced age increased the risk of mortality (hazard ratio [HR], 1.08; 95% CI, 1.05–1.11), while being female was associated with a lower mortality risk (HR, 0.65; 95% CI, 0.49–0.87). Higher cognitive (HR, 0.95; 95% CI, 0.93–0.98) and functional status at baseline (HR, 0.91; 95% CI, 0.86–0.97) were linked to increased life expectancy. Greater support from the social environment reduced the risk of mortality (HR, 0.79; 95% CI, 0.64–0.99), even after accounting for clinical variables.

Conclusion

Previously reported sociodemographic and clinical predictors were confirmed within a community sample. Additionally, social support was found to predict life expectancy in individuals with dementia. Our findings highlight the crucial role of the social environment for the well‐being of individuals with dementia and emphasise the need for interventions that specifically address these factors.
Association and multimodal model of retinal and blood‐based biomarkers for detection of preclinical Alzheimer’s disease
Authors: Ravichandran Swetha , Snyder Peter J. , Alber Jessica , Jeromin Andreas , Chaby Lauren E , Arthur Edmund
Published: January 2025

Background

The potential of plasma Aβ42/Aβ40 ratio, NfL, p‐tau 181, and p‐tau 217 has been extensively discussed in the literature. Our previous study explored the association between retinal biomarkers and preclinical AD. The goal of this study was to evaluate the association and a multimodal model of retinal and plasma biomarkers for detection of preclinical AD.

Methods

We included 81 cognitively unimpaired (CU) participants (139 eyes; mean age: 67 years; range: 56‐80) from the Atlas of Retinal Imaging in Alzheimer's Study (ARIAS). Blood samples were assessed for concentrations of Aβ42/Aβ40 ratio, NfL, p‐tau 181, and p‐tau 217 (ALZpath, Inc.) using SIMOA technology. Spectralis II instrument was used to acquire macular centered SD‐OCT images for evaluation of putative retinal gliosis surface area and macular retinal nerve fiber layer (RNFL) thickness. A subgroup cohort of 57 eyes (32 preclinical, 25 controls; mean age: 69 vs 66, p = 0.06) were included for assessment of a multimodal model to distinguish between preclinical AD (PET Aβ+ve) and controls (PET Aβ‐ve). For all participants, partial correlations (accounting for age) were assessed between retinal and blood‐based biomarkers. For the subgroup cohort, an ROC analysis was performed to compare a multimodal model of the retinal and plasma biomarkers vs. each biomarker alone to distinguish between the two groups.

Result

Significant positive partial correlation was found between putative retinal gliosis and p‐tau 217 (ρ = 0.27, p = 0.001) but not for the other plasma biomarkers. The multimodal ROC model based on retinal (gliosis area, inner inferior RNFL thickness, inner superior RNFL thickness, and inner nasal RNFL thickness) and plasma biomarkers (p‐tau 217 and Aβ42/Aβ40 ratio) had an excellent AUC of 0.97 (95% CI = 0.93 – 1.01; p < 0.001) compared to unimodal models of gliosis and RNFL thickness; AUC = 0.68 (95% CI = 0.54 – 0.82, p = 0.01), ptau 217; AUC = 0.87 (95% CI = 0.78 ‐ 0.97, p < 0.001), and Aβ42/Aβ40 ratio; AUC = 0.54 (95% CI = 0.38 – 0.70, p = 0.67).

Conclusion

Our analysis shows the potential of integrating retinal and blood‐based biomarkers for improved detection and screening of preclinical AD.