bluuebunny/crossref_metadata_2025 huggingface dataset:
Speech characteristics and their association with neuroimaging and CSF biomarkers of AD pathology
Authors: Simpson William , Spilka Michael J , Xu Mengdan , Robin Jessica
Published: January 2025

Background

Digital speech assessment shows promise as an objective and low burden measure of progressive speech and language changes in AD. While associations with clinical endpoints are well established, less is known about how computational speech features align with biomarkers of AD pathology. The current analysis sought to examine these associations both cross‐sectionally and longitudinally.

Method

Speech samples were collected during a Phase 2/3 clinical trial in mild‐to‐moderate AD. Participants completed clinical assessments at baseline, 3‐month, 6‐month, and 12‐month intervals. Participants completed two picture description speech tasks at each timepoint. Clinical symptoms were assessed using the CDR, ADAS‐cog and MMSE. Biomarkers included neuroimaging markers (cortical thickness and volume) and CSF measurements of tau, p‐tau and AB40/42 ratio. Participants were grouped into terciles for each biomarker and group differences in speech characteristics were assessed. We also explored sensitivity to change by examining whether changes in speech were correlated with changes in biomarker values.

Result

In the cross‐sectional analysis, several speech features showed significant group differences. The strongest associations were for cortical thickness, where average word length, frequency, use of nouns and pronoun:noun ratio showed stepwise differences across biomarker terciles. A similar, stepwise association with biomarker terciles was observed across all three clinical endpoints. Associations with CSF measures were notably weaker, with only 1 significant association (syntactic depth and p‐tau levels). Longitudinally, correlations between cortical thickness and speech characteristics were significant but weaker in magnitude (r<0.2) compared to correlations with clinical endpoints (r>0.4). One modest significant correlation was observed between speech and p‐tau (use of particles, r=‐0.17), while no significant correlations were observed between changes in p‐tau and changes in clinical endpoints.

Conclusion

We found converging evidence for stepwise associations between neuroimaging markers and speech features previously shown to track clinical progression in AD. Associations with speech generally appeared weaker than associations with clinical endpoints, consistent with the different level of specificity of each measure (speech vs. general cognition and function). Results highlight a disease‐level association between speech parameters and neuroimaging markers of AD. Future work will help understand how these findings can be leveraged in screening and monitoring settings.
Genetic evidence supports therapeutic hypothesis of increasing progranulin levels for Alzheimer’s Disease
Authors: Robins Chloe , Eicher John , Wang Qin , Liu Jimmy , Liu Dongjing , Richardson Thomas , Davitte Jonathan , Pulford David J. , Gormley Padhraig , Ingelsson Erik D. , Scott Robert A. , Kumar Sanjay , Fang Xu Chun‐
Published: January 2025

Background

Genetic variants in GRN, the gene encoding progranulin, are causal for or are associated with the risk of multiple neurodegenerative diseases. Modulating progranulin has been considered as a therapeutic strategy for neurodegenerative diseases including Frontotemporal Dementia (FTD) and Alzheimer’s Disease (AD). Here, we integrated genetics with proteomic data to determine the causal human evidence for the therapeutic benefit of modulating progranulin in AD.

Method

Using AD genome‐wide association studies (GWAS) summary statistics, we performed colocalization and Mendelian randomization (MR) analyses with plasma cis‐pQTL data in UK Biobank and CSF pQTL data from neurodegeneration‐focused cohorts. We additionally performed rare variant analyses using UK Biobank whole genome sequencing data to examine the association of GRN rare variants with AD and dementia. Finally, we characterized common genetic determinants of progranulin levels genome‐wide in UK Biobank.

Result

We observe consistent supporting genetic evidence that increased progranulin levels associate with reduced AD/dementia risk through GWAS (rs5848, OR = 0.93, p = 2.4e‐20), aggregated rare variant associations (p = 9.18e‐14), pQTL colocalization, and MR evidence. Genome‐wide associations with plasma progranulin levels identify several potential modulators (e.g., SORT1, PSAP, APOE), with SORT1 showing the strongest common variant association (p<1e‐300). Given the receptor‐ligand relationship between SORT1 and progranulin, we re‐scaled MR analyses to estimate the therapeutic effect of modulating progranulin with sortilin inhibitors. Our MR analyses suggest that a genetically predicted 2‐fold increase in CSF progranulin levels, as observed in phase 1 clinical trials of a sortilin inhibitor, associates with a ∼46% lower odds of developing AD (OR = 0.54, p = 2.2e‐12).

Conclusion

Our work demonstrates consistent causal associations of GRN with AD risk. These data provide causal human evidence supporting the potential therapeutic benefits on AD/dementia of inhibiting sortilin to increase progranulin levels.
Examination of GFAP Among a Racial and Ethnically Diverse Community‐Based Cohort: An HABS‐HD Study
Authors: Petersen Melissa , Zhang Fan , Hall James , O'Bryant Sid E. ,   the HABS‐HD Study Team
Published: January 2025

Background

Rates of Alzheimer’s disease (AD) Dementia are expected to grow considerably among certain ethnic/racial groups, including Blacks and Hispanics. Glial fibrillary acidic protein (GFAP) has been examined as a biomarker of AD; however, limited research has been conducted examining this particular marker among diverse populations. Therefore, this study sought to address this gap and provide an initial examination among a diverse community‐based cohort.

Method

Participants included n= 326 (n=125 Black; n=26 Hispanic; n=175 non‐Hispanic white) from the Health and Aging Brain Study‐Health Disparities. Clinical information, including age, education, and medical history, was derived via a clinical interview. Cognitive diagnosis of Mild Cognitive Impairment and Dementia were determined by consensus review. Plasma samples were assayed for GFAP using Quanterix kits and run on an HD‐X imager. PET Tau neuroimaging included the 18F‐PI‐2620 tracer. PET Tau positivity was determined based on a clinical read. Statistical analyses were run across racial/ethnic groups and included a correlational analysis between GFAP and PET Tau positivity. Additional analyses included examining the relationship between GFAP, demographic factors, medical comorbidities, and cognitive diagnosis. Statistical significance was set at p<0.05.

Result

A significant correlation was found between GFAP and a clinical read of PET Tau positivity only among Blacks (p‐value =0.002). Black participants were also found to have a significant relationship between GFAP and age (p‐value<0.001) as well as a cognitive diagnosis of Dementia (p‐value=0.002). Among non‐Hispanic whites, GFAP was found to be significantly related to age (p‐value=0.03) and a medical diagnosis of Diabetes (p‐value=0.003). No significant findings were found between GFAP and variables such as education, hypertension, dyslipidemia, or a cognitive diagnosis of Mild Cognitive Impairment. There were no significant findings identified among Hispanics.

Conclusion

The link between GFAP and select demographic and cognitive factors was found to be greater among Blacks and non‐Hispanic whites; however, findings were likely limited among Hispanics due to the relatively small sample size. Although there was a limited number of participants who were PET Tau positive, the only significant correlation found was among Blacks, highlighting the further need examine such AD biomarkers among diverse populations.
The cross‐sectional association of White Matter Hyperintensities, CAIDE Dementia Risk Score, and cognition in Mexican American elders from the HABS‐HD Study
Authors: Vintimilla Raul
Published: January 2025

Background

Associations between CAIDE scores and white matter hyperintensities (WMH) have been reported, and research have shown that both can impact cognition. The cognitive correlates of high CAIDE scores and WMH load in minorities like Mexican Americans (MA) remain unclear.

Method

Cognitively normal MA from the Health and Aging Brain Study (HABS‐HD) (n = 112), were classified as high or low risk for dementia according to a CAIDE cutoff score of 9. WMH volume was measured from FLAIR using the Statistical Parametric Mapping Lesion Segmentation Tool. After comparing global cognition, memory, executive function (EF), verbal fluency, and processing speed (PS) scores between groups, generalized linear models were used to explore the associations of WMH, CAIDE score and cognition. To better understand the association of WMH and CAIDE score with cognitive performance, we conducted a mediation analysis using PROCESS Macro (Hayes 2013). Age, sex, and education were entered as covariates in the models.

Result

Participants in the high‐risk group were older, less educated, and had lower scores in all cognitive measures. CAIDE score was not associated with any cognitive measures. WMH were associated with memory (B = ‐.14, p <0.001), EF (B = ‐.13, p = .002), and PS (B = .89, p = .02), and the three measures were also associated with the interaction high risk x WMH. In mediation analysis, the regression of WMH on the mediator, CAIDE, was significant (b = ‐.57, p <.001). The analysis showed that the mediator (CAIDE), controlling for WMH, was significant for executive function (b = ‐.09, p <0.001), and processing speed (b = ‐.03, p = .002). The analyses also revealed that, controlling for the mediator (CAIDE), WMH was still a significant predictor of executive function (b = ‐.18, p <0.001), and processing speed (b = ‐.15, p <0.001), but the effects were smaller.

Conclusion

These results suggest that MA with higher WMH perform worse in measures of executive function and processing speed, and that association is partially mediated by higher CAIDE scores. Further studies are needed to investigate if cognitive performance in normal individuals with WMH and high CAIDE scores.
Association between plasma angiotensin converting enzyme 1 level and cognition over 12‐years: The Look AHEAD Study
Authors: Yasar Sevil , Anderson Andrea , Hayden Kathleen M. , Espeland Mark A. , Carmichael Owen T. , Clark Jeanne M , Carlson Michelle C , Asby Daniel , Kehoe Patrick Gavin , Miners James Scott
Published: January 2025

Background

The renin angiotensin system (RAS) has been proposed as a potential modifier of the development of Alzheimer’s disease (AD). However, prospective studies of RAS are sparse especially among cognitively normal individuals with type 2 diabetes mellitus (T2DM) and other vascular risk factors. We aimed to determine whether plasma levels or activity of the RAS marker ACE‐1 predicts cognitive decline over an 8‐year period in this population.

Method

We performed a secondary data analysis of the Action for Health in Diabetes (Look AHEAD) study among community‐dwelling, non‐demented adults with overweight/obesity and T2DM aged 45‐76 years at baseline observed over a 12‐year period. Of 5,145 participants, we included 310 participants who were not using medications affecting the RAS system, had blood available at years 1, 4 and 10 and had undergone cognitive testing at least once and up to 4 times between years 8 and 16. Plasma ACE‐1 was measured using by ELISA (R&D systems) and ACE‐1 activity using immunocapture fluorogenic peptide assay. Cognitive tests included the Modified Mini‐Mental State Examination (3MSE), the Trail Making Test Parts A and B, the Stroop Color‐Word Test, the Digit Symbol Substitution Test, and the Rey Auditory Verbal Learning (RAVLT) Immediate and Delayed test. A cognitive composite score was derived by averaging standardized cognitive test scores. Mixed effects models were used to relate log converted ACE‐1 levels and activity to performance in cognitive test scores after adjusting for potential confounders.

Result

Participants included in the analyses were more likely to be female (65%), White (76%), and were more likely to have obesity (34%), have lower HgbA1C, LDL and systolic blood pressure control compared to the excluded particpants. Higher mean ACE‐1 levels measured at Y1, 4 and 10 was significantly associated with 3MSE (β=0.1774; p=0.02) and RAVLT‐delayed recall (β=0.1600; p=0.05). The cognitive composite score was not associated with ACE‐1 level. There was no association between ACE‐1 activity and cognitive function.

Conclusion

In this sample with T2DM and dementia free at baseline, we observed longitudinal associations between mean ACE‐1 levels and global cognition and memory.
Cerebrospinal Fluid Proteomics in Down Syndrome Identifies Common and Unique Pathological Changes Compared to Late‐Onset and Autosomal Dominant Alzheimer’s Disease
Authors: Bian Shijia , Montoliu‐Gaya Laia , Dammer Eric B. , Sauer Mathias , Alcolea Daniel , Blennow Kaj , Zetterberg Henrik , Fortea Juan , Johnson Erik C.B.
Published: January 2025

Background

Nearly all people with Down Syndrome (DS) develop Alzheimer’s dementia (AD) by the 7th decade of life. However, whether the alterations in fluid biomarker levels associated with DS follow the same pattern to those observed in other forms of AD is not well understood.

Method

We used mass spectrometry‐based proteomics to measure 1116 proteins in cerebrospinal fluid (CSF) across euploid controls (n=130), sporadic late‐onset AD (LOAD, n=89), asymptomatic DS (n=117), prodromal DS (n=57), and dementia DS (n=80) cases, and compared the protein changes observed in DS to those in LOAD and to those recently described in autosomal dominant AD (ADAD).

Result

We observed both common and unique CSF proteomic alterations in DS compared to LOAD and ADAD. Common changes included increased levels of 14‐3‐3 proteins, glucose metabolism, immune activation, and decreased levels in neurosecretory and neuropentraxin synaptic markers. Common changes were strongly correlated to tau and Aβ pathology, and like ADAD, most CSF protein changes occurred prior to the onset of cognitive symptoms. Compared to LOAD, DS showed markedly early elevations in complement, immunoglobulins, extracellular matrix and plasma proteins, suggesting early dysfunction in immune‐related processes and blood‐brain barrier function. These DS‐related changes were observed to occur prior to the onset of Aβ or tau pathology. In contrast to the progression observed in ADAD, in DS neurofilament light was increased prior to total tau levels, which were in turn increased prior to pTau levels, suggesting relatively earlier white matter and axonal dysfunction in DS. Neuronal and neurosecretory proteins were also decreased earlier in DS than in ADAD, consistent with early neuronal dysfunction in DS. Compared to LOAD, DS demonstrated more significant elevations in endosome/lysosome markers in symptomatic phases of the disease.

Conclusion

Early pathological alterations in immune function and the blood‐brain barrier associated with trisomy 21 may contribute to the onset of AD pathology in DS. While most pathological alterations are shared between DS, ADAD, and LOAD, the temporal ordering of these pathological changes in DS has unique features.
Outdoor air pollution as a risk factor for Alzheimer’s disease: A systematic review
Authors: Dhillon Gurneet , Hassan Nehal , Wilson Sarah , Ardle Ríona Mc , Su Li , Slight Sarah
Published: January 2025

Background

Outdoor air pollution is a global issue which poses a significant health risk. Modern neuroimaging techniques have revealed the detrimental impact of air pollution on brain health, in particular the development and progression of neurodegenerative diseases such as Alzheimer’s disease (AD).(1) We conducted a systematic review to evaluate the effects of long‐term (months to years) exposure to outdoor air pollutants on the development and progression of AD using neuroimaging data.

Method

This review followed PRISMA guidelines and registered in PROSPERO (CRD42023482979). Four large databases (MEDLINE, Embase, Scopus, and CINAHL) were systematically searched using words relating to “air pollution”, “neuroimaging”, and “Alzheimer’s disease”. The population researched was kept broad to include all ages. There were no geographical limits applied, and so included all countries. Articles were exported to Endnote (Endnote X9.3.3, Clarivate US), where duplicate articles were removed. Remaining articles were uploaded to the Rayyan and screened for eligibility. The Newcastle Ottawa Scale was used to assess the quality of included papers. A narrative synthesis was conducted, which involved grouping papers that focused on the same neuroimaging outcome and comparing and contrasting between studies.

Result

Our search yielded 397 results, after removing duplicated (n=172), articles were removed at the title (n=192), abstract (n=8), and full text (n=17) stages. Eight articles met our inclusion criteria and focused on changes to white matter (n= 5), cortical thickness (n= 6), and grey matter (n= 2). Specific air pollutants (e.g., PM2.5) were associated with white matter reductions, and PM10 and NO2 with reduced cortical thickness. However, higher exposure to NOx and NO2 was linked to better performance in cognition tests. Exposure to PM2.5 was associated with reduced grey matter, with study participants showing greater cognitive impairment. Air pollution exposure was associated with brain structure changes which are commonly seen in AD‐related pathology.

Conclusion

Our results highlighted significant associations between specific air pollutant exposure and changes in different brain structures. Future research is needed to further investigate the relationship between air pollution exposure and cognitive decline.

References:

Block ML, Calderón‐Garcidueñas L. Air pollution: mechanisms of neuroinflammation and CNS disease. Trends Neurosci. 2009;32(9):506‐16.
Exploring a weighted composite score for harmonization of 18F‐MK6240 and 18F‐ Flortaucipir: linearity and correlations with cognitive measures in a head‐to‐head tau PET dataset – The HEAD Study
Authors: Finn Quentin , Povala Guilherme , Bauer‐Negrini Guilherme , Franco Andrea , Vo Tam , Lussier Firoza Z , Amaral Livia , Gordon Brian A. , Klunk William E , Lowe Val J. , Oh Hwamee , Rosa‐Neto Pedro , soleimani‐meigooni David N. , Baker Suzanne L. , Masdeu Joseph C. , Pascoal Tharick , Pascual Belen
Published: January 2025

Background

Harmonization of the two most commonly used Tau PET tracers, 18F‐Flortaucipir and 18F‐MK6240 has proven to be complex. Unlike the centiloid scale for amyloid tracers, Tau PET SUVRs of the two tracers are not linearly comparable and vary markedly in dynamic range and sensitivity.

Method

Tau PET SUVRs for Braak stage (1‐6) in 18F‐MK6240 and 18F‐Flortaucipir were obtained from the Longitudinal multicenter head‐to‐head harmonization of tau‐PET tracers (HEAD) project. For training, we used 13 amyloid confirmed AD, 24 amyloid confirmed MCI and 66 amyloid negative controls. To assess linearity and correlations with neuropsychological tests, we included the training data as well as 74 subjects of unknown or inconsistent amyloid status. Two methods of generating outcome measures were used. (1) As a stand‐in for Tau load, similar to the centiloid scale, a score of 100, 50 or 0 was given to participants of the training set by multiplying CDR score by 100. Hierarchical and ridge regression were performed for each tracer using PET‐Braak SUVRs as predictive variables. Regression coefficients were used to calculate an outcome measure for all participants. (2) Principal component analysis (PCA) was applied for each tracer to the vectors of PET‐Braak regional SUVR of the training subset. Projections along the principal axis were calculated for both modalities

Result

Hierarchical, ridge regression and PCA all yielded composite measures with good linear dependence between the two tracers (r2 for hierarchical, ridge and PCA were 0.84, 0.80, 0.80, respectively). Regions remaining in the hierarchical regression analyses varied between tracers: predictive regions for 18F‐MK6240 were PET‐Braak 1, 4 and 5, while 18F‐Flortaucipir used only PET‐Braak 1 and 5. Composite measures correlated well with MMSE and total MOCA score with all composite measures r < ‐0.61.

Conclusion

While both tracers may have different sensitivities to regional Tau distributions and disease stages, weighting multiple regions differently for each tracer gives a composite score linearly comparable across tracers that correlates with neuropsychological measures. This study is limited by the low total tau load and impairment level of all participants and would benefit from the inclusion of patients with more disease progression.
Acceptance of wearable technology for the early detection of dementia‐causing diseases: perspectives from the CODEC II cohort
Authors: Wilson Sarah , Beswick Emily , Morrell Rachel , Bhogal Sharandeep , Tolley Clare , Whitfield Tim , Wing Kieran , Ardle Ríona Mc , Walker Zuzana , Slight Sarah
Published: January 2025

Background

With global dementia prevalence estimated to reach 139 million by 2050,(1) early detection of dementia‐causing diseases is crucial for promoting preventative interventions. Wearable technologies have the potential to detect early signs; however, they need to be acceptable amongst users. We explored user’s perspectives on the acceptability of wearable devices.

Method

A sub‐group of participants from a research cohort, Predictors of COgnitive DECline using digital devices (CODEC‐II), were recruited. Participants used four wearables (smartwatch, EEG headband, active and passive smartphone app) for two weeks every three‐months over a year. Semi‐structured interviews were conducted with participants after the first two weeks. A framework thematic analysis approach was used, assisted by N‐Vivo (QSR, version 14.23.2). The Intelligent Systems Technology Acceptance Model(2) aided in refining key themes.

Result

Twenty‐one participants were interviewed, including those with subjective cognitive decline (n=10), mild cognitive impairment (MCI) (n=7), dementia with Lewy bodies (n=1), and caregivers (n=3). Key themes included ease of use, data security, usefulness, intention of use. Many participants expressed low digital self‐efficacy, relying on the research team for support with technology setup and troubleshooting. Those with MCI needed more assistance with synching data, and experience difficulty with some cognitive testing games in the active smartphone app. Some participants expressed concerns surrounding the potential for someone to hack data generated from their device. Others questioned the accuracy of the study smartwatch, as they compared its outputs to their personal ones. Participants with professional or caregiving responsibilities described how their busy lifestyle hindered their ability to use the active smartphone app every day; this was not expressed by retired individuals.

Conclusion

Acceptance of using different wearable technologies for the early detection of dementia‐causing diseases varied amongst participants. Researchers should consider the difficulty level of cognitive testing games for those with cognitive impairment. Future work must explore ways to support individuals with low digital self‐efficacy, ensuring digital health equity is supported.

References:

Prince et al., 2015, The global impact of dementia, World Alzheimer report

Vorm and Combs, 2022, Integrating transparency, trust, and acceptance: The intelligent systems technology acceptance model (ISTAM). International Journal of Human–Computer Interaction.
Application of a Plasma Amyloid Beta Test in Clinical Practice
Authors: Pavlik Valory , Yu Melissa , Lin Chi‐Ying Roy , Yonce Shayla
Published: January 2025

Background

The gold standard Alzheimer’s disease (AD) diagnosis with amyloid PET or CSF sampling is costly and not widely available. There is growing interest in utilizing plasma biomarker tests to provide etiologic clarity in the earliest symptomatic phases. We report the uptake, and biomarker results in relation to clinical diagnosis, of a brain amyloid probability score (APS) with the Precivity AD™ test (C2N Diagnostics) offered to clinician‐selected eligible patients during their clinical workup in a memory clinic.

Method

Eligibility criteria included: MMSE>=22, a CDR global score <=1.0, and a diagnosis of subjective memory complaint (SMC), mild cognitive impairment (MCI) or early AD. Consensus clinical diagnoses were assigned according to NIA‐AA criteria prior to obtaining PrecivityAD™ results. The APS, derived from a regression equation including plasma Aß42/ 40, age, and APOE genotype, has a reported accuracy of 86%. To identify selection factors for referral, we used logistic regression to assess the independent association of age, sex, race/ethnicity, years of education, MMSE score, number of APOE e4 alleles, and diagnosis between participants and a sample of non‐participating patients meeting the same eligibility criteria.

Result

Sixty patients were consented over 9 months. Average age was 70.8±8.06, 60.0% were male, and 11.3% persons of color. Fifty‐five percent of those with MCI received a high APS, compared to 15.4% of those with SMC. Forty‐one percent of MCI patients had a low APS compared to 61.5% with SMC (Table 1). Only a diagnosis of probable AD was associated with enrollment (less likely).

Conclusion

PrecivityAD™ probability scores were generally consistent with the clinical diagnosis. An intermediate or high APS required clinician counselling regarding the implications of and indications for further testing given the clinical diagnosis. The high representation of SMC patients may reflect provider and/or patient desire for additional information on prognosis. The low usage in patients with probable AD may reflect a greater degree of provider certainty in clinical diagnosis. Longitudinal follow‐up of cognitive changes, and analysis of PET imaging results in those referred for additional testing will clarify the clinical utility of this plasma biomarker.
Intranasal lithium in Ryanodex formulation vehicle inhibits inflammation and pyroptosis in aged 5XFAD mice brains
Authors: Bhuiyan Piplu , Zhang Wenjia , Chae Rebecca , Kim Kyelee , St. Louis Lauren , Wang Ying , Liang Ge , Liu Jia , Wei Huafeng
Published: January 2025

Background

This study investigates the therapeutic versus side effects of intranasal lithium chloride (LiCl) in Ryanodex formulation vehicle (RFV) to inhibit inflammation and pyroptosis and to ameliorate on cognitive dysfunction and depressive behavior in 5XFAD mice.

Method

5XFAD and wild type (WT) B6SJLF1/J mice were treated with intranasal or oral LiCl (3 mM/kg) dissolved in RFV starting at 2 or 9 months old and the continuous treatment lasted for 12 weeks. Behavior was examined for depression, cognition, olfaction, and motor function at the ages of 5 or 12 months. Body weights were monitored monthly. At 6 or 13 months old, blood and brain were harvested. Blood biomarkers for thyroid (TSH: thyroid stimulating hormone) and kidney (creatinine) function were measured by ELISA. Immunoblotting determined the proteins expression levels of type 1 InsP3 receptors (InsP3R‐1), oxidative stress (4‐HNE, MDA), pyroptosis activation pathway regulatory proteins, proinflammatory versus neuroprotective cytokines, and synaptic proteins in aged mice brains.

Result

Compared to WT mice, significant memory loss and depression behavior existed in both adult and aged 5XFAD mice, and both were abolished by intranasal LiCl in RFV Intranasal LiCl in RFV significantly inhibited the pathological proteins increase of InsP3R‐1, MDA‐modified proteins by pyroptosis pathway activation proteins (NLRP3, cleaved caspase‐1, N‐terminal GSDMD) in aged 5XFAD mice brains, in comparison with aged WT mice brains. Furthermore, intranasal LiCl in RFV significantly reduced protein levels of cytotoxic cytokines (IL‐1β, IL‐18, IL‐6, TNF‐α), alleviated the activation of astrogliosis and microgliosis, and increased cytoprotective cytokine IL‐10 and inhibited PSD‐95 synapse protein loss in aged 5XFAD mice brain. Intranasal LiCl did not affect blood TSH but significantly inhibited abnormal age‐dependent increase of blood creatinine in 5XFAD mice. Intranasal LiCl in RFV did not affect body weight, smell, or motor function significantly in either WT or 5XFAD mice.

Conclusion

Intranasal LiCl in RFV ameliorates memory loss and depressive behavior in 5XFAD mice without side effects or organ toxicity, with chronic use. Intranasal LiCl in RFV effectively inhibited, oxidative stress, inflammation and pyroptosis in aged 5XFAD brains.
MRI Correlates of Executive Function in Cognitively Normal Older Subjects
Authors: Shakibajahromi Banafsheh , Dolui Sudipto , Brown Christopher , Taghvaei Mohammad , Khandelwal Pulkit , Wu Qichao , Sadaghiani Shokufeh , Yushkevich Paul A. , Wolk David A , Detre John A.
Published: January 2025

Background

Cerebral small vessel disease (CSVD) is the most prevalent cause of vascular cognitive impairment. Executive function impairment and white matter (WM) lesions occur early in CSVD, the latter typically in periventricular WM (PVWM) ‐ the least perfused brain region. Accounting for vascular risk factors (VRF) and amyloid status in cognitively normal older subjects, we assessed the relationship between Trail‐making test (TMT) performance and MRI measures preceding WM lesions: arterial spin labeling (ASL)‐derived cerebral blood flow (CBF) and diffusion tensor imaging (DTI) indices in normal‐appearing WM (NAWM) and normal‐appearing PVWM (NAPVWM).

Method

133 cognitively normal adults (>50y) from Penn Alzheimer’s Disease Research Center were included. TMT:B minus TMT:A (TMT:B‐A) was used as a metric of executive function. We categorized participants into amyloid‐positive (A+) and amyloid‐negative (A‐) groups based on PET. VRFs included hypertension, diabetes, obesity, hypercholesteremia and smoking. WM hyperintensity (WMH) masks were derived from FLAIR MRI using a deep‐learning model to calculate WMH volume and to mask WMH voxels. We extracted mean CBF and DTI indices (fractional anisotropy (FA) and mean diffusivity (MD)) in NAWM and NAPVWM using a perfusion‐based PVWM mask. NAPVWM relative CBF (rCBF) was defined relative to global CBF. Using linear regression, we assessed the associations of TMT:B‐A with VRF presence and imaging metrics in each group adjusting for age, sex and education. The relative importance of these variables was measured through random forest regression.

Result

The mean (SD) age was 70 (6) with 64% females. 23 subjects were A+ and 79 were A‐. Neither VRF presence nor imaging metrics were significantly associated with TMT:B‐A in A+ group. In A‐ group, after adjustment for covariates, VRF (Beta= 0.319, P=0.009), NAPVWM rCBF (Beta= ‐0.240, P=0.035)), NAWM MD (Beta=0.266, P=0.022) and NAPWM MD (Beta=0.255, P=0.029) were significantly associated with TMT:B‐A. WMH volume was not associated with TMT:B‐A (P= 0.668). In A‐ group, NAPWM MD and NAPWM rCBF were the most important determinants of TMT:B‐A relative to the other variables in the random forest model (Figure 1).

Conclusion

CBF and MD in NAPVWM are associated with executive function in normal aging and might be an early biomarker of CSVD.
Acceptance of using digital technologies to aid the timely detection of dementia: perspectives from Boston University Alzheimer’s Disease Research Centre
Authors: Beswick Emily , Wilson Sarah , Popp Zachary T , Rahman Salman , Khan Raiyan R , Tolley Clare , Low Spencer , Slight Sarah
Published: January 2025

Background

Using digital technologies to detect the early signs of dementia‐causing diseases could improve the timely detection of these diseases. To support this approach, we explored users’ perspectives on the acceptability of using a variety of digital technologies.

Method

A sub‐group of participants from Boston University’s Alzheimer’s Disease Research Centre were recruited. Participants used up to nine study technologies (active smartphone apps (n=3), passive apps (n=2), wrist worn activity monitor (n=2), EEG headband (n=1), Oximeter ring (n=1)) for two weeks, every three‐months, over a year. Semi‐structured interviews were conducted after the first two weeks. A framework thematic analysis approach was applied to the interview transcripts, assisted by N‐Vivo (QSR, version 14.23.2). The Technology Acceptance Model(1) aided in refining key themes.

Result

Twenty‐four individuals were interviewed: 13 with mild cognitive impairment (MCI) and 11 without cognitive impairments. Three key themes emerged; perceived usefulness, intention to use and enjoyment of use. Participants were excited about the possibility of using digital technologies to remotely monitor their brain health, but some raised concerns that this could reduce personal interaction with their healthcare professional. Participants with pre‐existing health conditions, questioned the accuracy of the technology. For example, a participant wondered what effect an oxygen mask used for sleep apnoea would have on the data collected from the oximeter ring, reducing their perceived usefulness of the devices. Many participants using seven or more devices reflected on the burden of using multiple devices, finding it was challenging to familiarise themselves with them and then remember to use them all. Participants with MCI enjoyed the cognitive stimulation they felt after using the gamified cognitive tasks in the active smartphone apps, whereas participants without cognitive impairment wanted more variety to improve engagement.

Conclusion

Results highlight the acceptability of a variety of digital technologies for the timely detection of dementia‐causing diseases and discussed the burden of using multiple devices. Future research should explore how pre‐existing health conditions could affect the accuracy of digital technologies to improve real world applicability.

References

Davis FD. Perceived usefulness, perceived ease of use, and user acceptance of information technology. MIS quarterly. 1989 Sep 1:319‐40.
Genome‐wide mediation analysis reveals amyloid and tau imaging genetics patterns in Alzheimer’s Disease
Authors: Mu Shizhuo , Rathore Saima , Bao Jingxuan , Yang Shu , Hooli Basavaraj , Shen Li ,   for the ADNI
Published: January 2025

Background

Alzheimer’s disease (AD) is a progressive neurological disorder with an unclear cause, and its amyloid and tau hypotheses need deeper investigation to understand their link to genetic variants and AD outcomes. To bridge this gap, we conduct a mediation analysis using the genotyping, amyloid and tau imaging, and cognitive data from Alzheimer’s Disease Neuroimaging Initiative (ADNI) to delineate specific mediation pathways from genetic variants such as single nucleotide polymorphisms (SNPs), to regional amyloid/tau protein aggregation in the brain, and to cognitive outcomes.

Method

ADNI provides genotyped data and harmonized phenotypes. We further imputed, harmonized, annotated the genotyping data. Post‐quality control and subject matching resulted in 1,051 individuals for amyloid and 525 for tau imaging measurements. We first conducted genome‐wide association study (GWAS) on 5,302,064 variants to prioritize SNPs significantly associated with cognitive scores. Subsequently, we employed a mediation model to explore how regional amyloid and tau imaging measures mediate the genetic effects on cognitive scores. Specifically, we used prioritized SNPs from GWAS as exposure, two cognitive scores (ADAS‐Cog13 and MMSE) as outcomes, and amyloid and tau imaging measures from 68 cortical regions as mediators. Additionally, we contrasted results from GWAS‐identified SNPs with five candidate AD SNPs.

Result

We assessed amyloid and tau aggregation in 68 cortical brain regions as mediators for SNP effects on cognitive scores; see Figure 1 for top findings. After Bonferroni correction, we found 9,551, 34,402, 5,636, and 193,002 mediation relationships for SNP‐amyloid‐ADAS13, SNP‐amyloid‐MMSE, SNP‐tau‐ADAS13, and SNP‐tau‐MMSE respectively. Tau aggregation demonstrated a broader impact on AD across cortical regions compared to amyloid. Although 4 of the candidate AD SNPs showed no signal, one of them, rs429358, demonstrated strong amyloid and tau mediated genetic effects on cognitive outcomes. Our results also showed that amyloid and tau hypotheses have different regional mediation patterns (Figure 2). For example, bankstss region only influences the tau pathway, while caudal anterior cingulate only affects the amyloid pathway.

Conclusion

Our genome‐wide mediation analysis has identified top cortical regions and SNPs associated with amyloid‐ and tau‐mediated cognitive declines in AD. These results yield new insights into AD etiology linking genetic determinants, cellular hallmarks, and phenotypic outcomes.
First GPR39‐imaging radiotracer to track zinc homeostasis in a rodent model of Alzheimer’s disease
Authors: Gollepalli Krishna Kumar , Bhoopal Bhuvanachandra , Damuka Naresh , Krizan Ivan , Miller Mack , Kumar JV Shanmukha , Bashetti Nagaraju , Whitlow Christopher T , Lockhart Samuel N. , Jadiya Pooja , Sai Kiran K. Solingapuram
Published: January 2025

Background

The G protein‐coupled receptor GPR39 is heavily associated with the pathogenesis of neurologic disorders, including Alzheimer’s disease (AD) and related dementia (ADRD). Its dysregulation of zinc 2+ (Zn2+) processes triggers metallic dyshomeostasis, oxidative stress, neuroinflammation, microtubule destabilization, synaptic dysfunction, and tau phosphorylation—all hallmarks of neurodegeneration. Hence, pharmacologic modulation of GPR39 could offer an effective treatment against AD and ADRD. With the right radiotracer, PET could be used to quantify GPR39 in brains in vivo and track distribution, target engagement, and dose occupancy of novel GPR39‐based agonistic drugs to regulate Zn2+ (dys)homeostasis function. In this abstract we report the development and validation of the first PET radiotracer, [11C]TMN‐1324 to image GPR39 in rodent models of AD.

Method

GPR39 agonist TM‐N1324, was selected as the lead compound for its brain penetration and high GPR39 affinity—acts with and without Zn2+ to both human and rodent GPR39s. To validate [11C]TM‐N1324 imaging potential, we performed 0‐60 min dynamic PET imaging and post‐PET biodistribution with [11C]TM‐N1324 in (a) normal C57BL/J mice (4 mo, n=4) and (b) male Aβ‐overexpressing APP/PS1 transgenic (TG) mice and age‐matched wild‐type (WT) mice (12 mo, n=4/group). Brain autoradiography investigated regional uptake in the same cohort. TM‐N1324 blocking studies (n=4) confirmed in vivo GPR39 specificity of the radioligand

Result

Radiochemistry was fully optimized for high radiochemical purity (>98%) and molar activity (>48635 MBq/µmol) decay corrected to end‐of‐synthesis. PET imaging of rodents showed brain penetration and ∼65±4% blocking with TM‐N1324 pretreatment. It demonstrated ∼22±3% lower brain uptake in APP/PS1 TG mice compared to WT littermates (Figure 1). Autoradiography showed significant uptake in cortical regions (high GPR39‐expressing regions). Biodistribution showed ∼33±1% lower brain uptake in TG mice than WTs.

Conclusion

Our pilot study here with the first GPR39‐imaging PET radiotracer, [11C]TM‐N1324 demonstrated brain penetration, differential uptake in mouse model of AD, and regional specificity. By validating our highly specific GPR39 PET radiotracer for studying Zn2+‐based dyshomeostasis, we will elucidate GPR39 PET imaging strategies to monitor target responses to potential novel therapeutics.
Critical Modifying Effect of APOE 4 Allele and Sex on the Prospective Associations between Lipid Species and 10‐year Cognitive Decline in Biracial Community‐dwelling Older Adults: the Chicago Health and Aging Project (CHAP)
Authors: Ng Ted K.S. , Beck Todd , Liu Xiaoran , Desai Pankaja , Holland Thomas Monroe , Dhana Klodian , Krueger Kristin R , Wilson Robert S. , Evans Denis A , Rajan Kumar B
Published: January 2025

Background

There have been contradictory findings on the associations between lipids and cognitive decline, which could have been attributed to heterogeneity in APOE allele and sex.

Method

We analyzed a subset of the Chicago Health and Aging Project, comprising 3,496 biracial community‐dwelling older adults (58% African American & 64% women; mean follow‐up=4.6 years) with lipid panel and longitudinal cognitive tests. We ran adjusted mixed‐effects models and examined APOE allelic and sex differences.

Result

Total cholesterol and triglycerides, independently, was associated with longitudinal cognitive decline only in ε4 carriers. The associations of total cholesterol and, independently, triglycerides with longitudinal cognitive decline was driven by men and women ε4 carriers, respectively. LDL was associated with cognitive decline only in men ε4 carriers.

Conclusion

The associations of lipids and cognitive decline were only present in ε4 carriers and are further dependent on and diverged according to sex, highlighting their importance in risk prediction and treatment. Hence, apart from examining lipid panel, it is critical to simultaneously consider APOE 4 status and sex to better inform precision medicine, particularly risk prediction and treatment.
Application of High‐Resolution Diffusion‐MRI in Neurotrauma Accelerated Alzheimer's Disease
Authors: Hua Ning , Minaeva Olga , Parsons Douglas , Moncaster Juliet A , Jara Hernan , Goldstein Lee E
Published: January 2025

Background

Traumatic brain injury (TBI) is a risk factor for earlier onset of Alzheimer’s disease (AD)( Graves AB, et al., 1990), and the more severe the injury, the greater the risk of developing AD(Johnson VE, et al.,2010). Given the prevalence of AD in modern society, the possibility that TBI may predispose individuals to develop AD has significant social and economic implications. Therefore, it is important to understand how TBI triggers accelerated AD progression. In this study, we explored how neurotrauma accelerated white matter degeneration in a transgenic mouse model of AD using high‐resolution (60mm3) ex vivo diffusion MRI.

Method

3xTg‐AD mice were pretreated with a non‐sedating dose of the analgesic buprenorphine (0.2mg/kg, i.p.) prior to TBI. 3xTg‐AD mice were subjected to left‐lateral closed‐head impact injury at 10‐12 weeks of age (Tagge CA, et al.,2018). At six months post‐TBI, mice were sacrificed using transcardial perfusion. The harvested brains were submerged in 10% formalin for 24 hours and stored in Gadavist‐doped PBS (1:400 dilution) until MRI. MRI data were acquired using a 9.4T Bruker scanner and a 2‐element cryoprobe. Key parameters are TR=300ms, TE=27.7ms, b=3000 and 5000 s/mm2 (64 directions), FOV=13.92x10.20x7.20mm3, Matrix=232x170x120, resolution=60mm3. Diffusion MRI was analyzed in DSI Studio (http://dsistudio.labsolver.org). Age‐ and gender‐matched 3xTg‐AD mice without TBI were used as controls.

Result

Figure 1 shows the representative quantitative anisotropy (QA) maps obtained from a mouse with TBI. At 6 months post‐TBI, decreased QA values were observed in the brain regions ipsilateral to the injury (arrows) compared to the corresponding contralateral regions. Figure 2 shows the representative QA maps of the regions around the hippocampus in mice with and without TBI. Compared to the control mouse, the mouse with neurotrauma showed decreased QA values in the corpus callosum and bilateral hippocampus, especially in the CA1 subregion.

Conclusion

Our results demonstrated that ultra‐high resolution diffusion MRI can capture subtle alterations of white matter integrity in different brain sub‐regions. Using this technique, we were able to detect subtle white matter degeneration in a mouse model of Alzheimer’s disease. The observed white matter deterioration may contribute to the worsening of Alzheimer’s disease after neurotrauma.
MMSE and CDR Score Changes and Potential Score Inflation in Multinational Alzheimer’s Disease Trials
Authors: Hackebeil Amanda , Barbati Gila , Machizawa Sayaka , Stenclik Jessica , Appleman Erica R. , Iacob Andrei , Massa Jacqueline
Published: January 2025

Background

In Alzheimer’s Disease trials, the Mini‐Mental State Examination (MMSE) and Clinical Dementia Rating (CDR) are commonly utilized as inclusionary criteria at screening. These measures, however, do not always reaffirm inclusionary status at baseline. Score changes between screening and baseline visits may imply potential score inflation at screening leading to inappropriate participant enrollment. This study compared score changes in global AD trials when MMSE and CDR scores were used as inclusionary measures at screening only versus screening and baseline visits.

We hypothesized greater score changes would be observed in trials utilizing these inclusionary measures at screening alone.

Method

This study incorporated electronic scale (eScale) data from three global Phase 3 trials comprised of MCI to Mild AD participants, where the MMSE and CDR were used as inclusionary criteria. Two studies applied inclusion scoring criteria at screening, while one study applied inclusion scoring criteria at both screening and baseline. All raters completed Signant Health standardized rater training and certification programs. eScales and data quality monitoring programs increased rater scoring accuracy. Mann‐Whitney U tests and t‐tests were conducted comparing score changes on MMSE total score and CDR Domain and Global Scores.

Result

Both Mann‐Whitney U and t‐tests revealed significant differences in score changes between screening and baseline visits for the two trial designs, including all domain and total scale scores, except for the CDR Personal Care domain (p<0.001), as seen in Table 1. Increased scores for the CDR domain/Global scores and reduced scores on MMSE were observed when inclusionary criteria were required at screening alone.

Conclusion

The present study found greater score changes in the CDR and MMSE for participants who met inclusion criteria at screening only compared to both screening and baseline. These findings suggest potential score inflation at inclusionary visits when inclusionary scoring is required only at screening. To reduce inclusionary bias and inappropriate participant enrollment, a data quality surveillance program is recommended at inclusionary and subsequent visits throughout the study. Future studies should explore additional factors contributing to score change.