bluuebunny/crossref_metadata_2025 huggingface dataset:
Association of APOE/TOMM40 Haplotypes and Limbic System White Matter Microstructure in Black and White Individuals
Authors: Mooney Katelyn Elizabeth , Archer Derek B. , Hohman Timothy J. , Sathe Aditi , Kadiri Ose , Barnes Lisa L. , Deters Kacie
Published: January 2025

Background

APOE is in linkage disequilibrium with the length of poly‐T repeats at the rs10524523 (‘523) locus of the TOMM40 gene. APOE‐ε3 is associated with short (S) and (VL) variants of ‘523 in white and Black individuals. In white individuals, APOE‐ε4 is associated with the long (L) ‘523 variant, but is associated with ‘523‐S, ‘523‐L, and ‘523‐VL variants in Black individuals. Black ε3‐’523‐S carriers have faster rates of cognitive decline while Black ε4‐’523‐S carriers have slower rates of cognitive decline. Little is known about the association of these haplotypes with white matter integrity. This study aims to determine the association between APOE/TOMM40 haplotypes and white matter microstructure (WMM) in tracts important for cognition and risk of AD.

Methods

Data comes from participants without cognitive impairment from the Rush Memory and Aging Project and the Minority Aging Research Study who self‐identified as non‐Hispanic white (N=500) and non‐Hispanic Black (N=144). WMM was measured using diffusion MRI (dMRI). dMRI was preprocessed using PreQual and microstructural metrics were calculated in DTIFIT and MATLAB. Data was harmonized using Longitudinal ComBat. We assessed free‐water (FW; higher values are abnormal) and FW‐corrected fractional anisotropy (FAFW‐corr; lower values are abnormal) in five limbic tracts that are associated with AD: the inferior longitudinal fasciculus, cingulum, fornix, inferior temporal gyrus, and uncinate fasciculus. The effect of 0, 1, or 2 copies of ‘523‐S on FW and FAFW‐corr was assessed using linear regression models, controlling for age, sex/gender, and education.

Results

White ε3/ε3 participants with two copies of ‘523‐S had lower FAFW‐corr in the cingulum (β=−0.006, SE=0.003, P=0.031) and inferior temporal gyrus (β=−0.007, SE=0.003, P=0.042) (Table). Black ε4+ participants with one‐‘523‐S had lower FW in cingulum (β=−0.024, SE=0.01, P=0.020) and inferior longitudinal fasciculus (β=−0.0304, SE=0.013, P=0.026) (Table).

Conclusions

This is the first study examining APOE/‘523 variation on WMM in Black participants, and the first to examine this association using FW‐corrected metrics. These results support prior findings that ‘523‐S copy‐number is deleterious in White‐ε3/ε3 participants, but protective in Black‐ε4+ participants. These findings suggest a differential effect by racialized background of APOE on brain microstructural integrity in older adults.
Investigation of blood‐brain barrier water exchange rate as a novel early indicator of neurovascular dysfunction and Alzheimer’s disease
Authors: Rowsthorn Ella , Sim Ming Ann , O'Brien William , McDonald Stuart , Vivash Lucy , O'Brien Terence J , Law Meng , Chong Trevor T.‐J. , Shao Xingfeng , Wang Danny JJ , Pase Matthew P. , Harding Ian H
Published: January 2025

Background

Growing evidence shows neurovascular dysfunction occurs early in Alzheimer’s disease (AD) and may be a useful early marker of pathology. Blood‐brain barrier water exchange rate (BBB kw) is a novel measure of fluid transport through the neurovascular unit. Lower BBB kw has been associated with vascular risk factors, but its relationship with age, vascular brain health and biomarkers of AD remains equivocal. The present study investigated the relationships between BBB kw, age, MRI measures of neurovascular integrity, and cerebrospinal fluid amyloid‐beta (Aβ).

Method

The Brain and Cognitive Health (BACH) Cohort Study recruited 108 participants without dementia, aged 55‐80 (68.5% female; mean age=67 years) from the general community. Participants underwent a suite of MRI scans (3T Siemens Prisma) that allowed for quantification of BBB kw, enlarged perivascular space volume (ePVS), diffusion free water (FW), cerebral blood flow (CBF), and white matter hyperintensity volume (WMH). A subsample of 35 individuals also completed an optional lumbar puncture for Aβ42 and Aβ40 quantification. Linear regression models and linear mixed‐effects models were used to investigate the association between BBB kw and the outcomes. We also investigated whether there was an interaction effect of age on MRI measure relationships. All analyses were adjusted for age, sex and intracranial volume.

Result

BBB kw was negatively associated with age (B(SE)=‐44.74(20.91), R2
partial =.04, p=.04), negatively associated with FW (B(SE)=‐87.86(29.03), R2
marginal=.128, p=.006; Figure 1), and positively associated with CBF (B(SE)=0.02(0.08), R2
marginal=.128, p=.018; Figure 2). BBB kw was not associated with ePVS or WMH (p>.05). The association between BBB kw and CBF was modified by age (R2
partial=.06, p=.047), such that the relationship was stronger in younger participants (Figure 3). BBB kw was not associated with Aβ42/Aβ40 ratio (B(SE)=59.89(205.30), R2
partial=<.01, p=.773) in the small subsample.

Conclusion

Lower efficiency of fluid transport through the neurovascular unit was associated with markers of neurovascular health, including cerebral perfusion and fluid accumulation/white matter integrity. These findings suggest BBB kw as a useful imaging tool for studying neurovascular unit integrity in the context of brain aging. Associations of BBB kw across the continuum of AD requires further investigation.
First Comprehensive Intranasal PET imaging of Insulin using the Aptar device in Nonhuman Primates
Authors: Sai Kiran K. Solingapuram , Gollepalli Krishna Kumar , Erichsen Jennifer M. , Krizan Ivan , Miller Mack , Jorgensen Matthew J. , Craft Suzanne
Published: January 2025

Background

Insulin resistance (IR) is associated with abnormal tau‐phosphorylation and IR markers in AD brain co‐localize with neurofibrillary tangles. One strategy to overcome brain IR is to increase brain insulin is via intranasal insulin (INI) administration using specialized intranasal devices that deliver insulin to the brain. Our recent INI vs. placebo‐controlled double‐blinded clinical trial in MCI/AD showed that INI improved CSF biomarkers and slowed symptom progression over the placebo group treated with one type of delivery device (with no benefit with another). While these studies highlight the potential of INI for therapeutic applications, methods are needed to verify the successful INI delivery with specific devices. Here we report our novel [68Ga]‐NOTA‐insulin‐based brain PET imaging and whole‐body dosimetry through intranasal route in healthy vervets using the Aptar Cartridge Pump System (CPS) device for the first time.

Method

Human‐grade insulin was chelated with NOTA and radiolabeled with [68Ga]. 0‐90min and 0‐3h PET scans were conducted for brain and whole‐body dosimetry in healthy vervets (n=4/sex, 9‐12 y) after intranasal administration (2 puffs per nostril) of [68Ga]‐NOTA‐insulin (25‐37 MBq) through the Aptar device. Blood glucose, oxygen, heartbeat, and temperature were collected throughout the scan. Standard uptake values (SUVs), time‐activity curves (TACs), and standard dosimetry organ doses were calculated.

Result

[68Ga]‐NOTA‐insulin radiochemistry was fully‐optimized: shorter reaction times (∼6‐7min), lower insulin mass (2‐4 units), high radiochemical purity (>99%), and molar activity (108 GBq/µmol). No significant changes were observed in vitals recorded. PET/MRI images showed brain penetration; SUV whole‐brain=0.29±0.11, hippocampus=0.18±0.05, cortex=0.21±0.08, choroid plexus=0.38±0.11, and cerebellum=0.09±0.01. TACs showed that radioactivity peaked in brain within 15‐20min of radiotracer administration and washed out by 90 min. Dosimetry showed nasal cavity and eyes as critical organs and effective dose=0.11 mSv/MBq. No sex differences were seen in brain uptake or dosimetry parameters.

Conclusion

Brain PET and whole‐body dosimetry PET scans of [68Ga]‐NOTA‐insulin in vervets demonstrate brain penetration and favorable distribution of INI respectively. This preliminary data provides critical information for translating [68Ga]‐NOTA‐insulin PET with intranasal delivery to humans using the Aptar device. This strategy will create a new paradigm for understanding the INI in AD pathogenesis and advance novel therapeutic platforms.
Associations between basal forebrain volume and cognitive decline in GBA and LRRK2 mutation carriers from asymptomatic stages to Parkinson’s disease
Authors: Schumacher Julia , Teipel Stefan , Storch Alexander
Published: January 2025

Background

In people with Parkinson’s disease (PD), mutations in GBA and LRRK2 are associated with different clinical phenotypes which might be related to differential involvement of the cholinergic system. We aimed to investigate cholinergic basal forebrain (cBF) volume in asymptomatic and symptomatic mutation carriers in comparison to idiopathic PD and healthy controls and associations with cognitive decline.

Method

This study included 149 asymptomatic GBA and 169 asymptomatic LRRK2 mutation carriers, 112 LRRK2 carriers and 60 GBA carriers with PD, 492 idiopathic PD, and 180 healthy controls from the Parkinson’s Progression Markers Initiative (PPMI). cBF volumes were extracted using an established automated MRI volumetry approach based on a stereotactic atlas (Figure 1A). We also estimated hippocampal volumes as a control analysis. Bayesian ANCOVAs were used to compare volumes between (1) asymptomatic carriers and controls including covariates for age, sex, and years of education and (2) mutation carriers with PD and idiopathic PD with an additional covariate for disease duration.

Result

We found evidence for an increase in cBF volume in asymptomatic GBA (Bayes Factor against the null hypothesis (BF10)=75.2) and LRRK2 mutation carriers (BF10=57.0) compared to controls and for no group differences between the two mutation groups (BF10=0.17) (Figure 1B). At the PD stage, cBF volumes were increased in LRRK2 compared to GBA mutation carriers (BF10=14.5) and idiopathic PD (BF10=3.6*107), with no difference between idiopathic PD and PD‐GBA (BF10=0.25). Whole‐brain voxelwise comparisons confirmed that increased volume in asymptomatic mutation carriers was mainly found in the region of the cBF (Figure 1C). There were no group differences in hippocampal volume (Figure 1B).

Over five years, idiopathic PD and PD‐GBA declined across all cognitive domains whereas the PD‐LRRK2 group only declined in processing speed. Linear mixed models revealed a significant interaction between cBF volume and time in predicting multiple cognitive domains in idiopathic PD and PD‐GBA, but not in PD‐LRRK2.

Conclusion

While LRRK2 and GBA mutations are both associated with increased cBF volume at the asymptomatic stage, at the PD stage this increase persists only in LRRK2 carriers and might be related to the slower rate of cognitive decline in these patients.
Preliminary Evaluation of the African American Alzheimer’s Caregiver Training and Support Project 2 (ACTS2) Facebook Live Workshop Series: A Mixed Methods Analysis
Authors: Lampe Nik M. , Nowakowski Alexandra C. H. , Norton‐Brown Tomeka , Paredes Joshua , Bastow Skyler , Savage‐Paik Marin , Bakshi Jayson , Patel Amar , Glueckauf Robert L.
Published: January 2025

Background

The African‐American Alzheimer’s Caregiver Training and Support Project 2 (ACTS2) is a faith‐integrated, skills‐training and support program for Black family caregivers of persons living with dementia in Florida. In response to the COVID‐19 pandemic, ACTS2 initiated a bi‐monthly Facebook Live Workshop series, offering practical information and resources for Black communities on dementia caregiving topics (e.g., caregiver self‐care and negotiating stressful caregiving situations). Using mixed assessment methods, we evaluated viewer reach, engagement, and satisfaction with the workshops.

Methods

We used quantitative (Facebook and YouTube usage statistics, online pre‐registrations, online evaluation surveys) and qualitative data (viewer engagement during workshops, online evaluation surveys) to evaluate viewer reach, engagement, and satisfaction with 22 workshops from bi‐monthly ACTS2 Facebook Live Workshops series, delivered from May 2020 to August 2023.

Results

The ACTS2 Facebook Live Workshop series reached a total of 1,193 individuals who pre‐registered (averaging 52 per workshop) and at least 1,032 individuals who attended the virtual workshops in live time (averaging 45 per workshop). To date, the series reached at least 9,697 Facebook user views and 274 YouTube user views. Thematic analysis of attendee engagement revealed three themes: (1) requesting additional information and community resources; (2) sharing personal information about caregiving experiences; and (3) gratitude towards workshop presenters and presentations. From the pool of 1,193 workshop pre‐registrants, 98 completed evaluation surveys. Nine out of ten survey completers reported the workshops were “extremely informative” or “very informative” (92.9%) and rated the overall quality of workshops as “excellent” or “good” (90.8%). Four themes emerged from the qualitative analysis of survey data: (1) gratitude for workshop presenters’ testimonies; (2) satisfaction with ACTS2 and other community resources; (3) centering Black dementia caregiver experiences; and (4) concerns with attendee/presenter communication format during workshops.

Conclusion

Initial findings of the mixed methods analysis suggested that the ACTS2 Facebook Live Workshop series was successful in reaching and engaging community members across Florida and the U.S., while serving as a useful tool in providing information and community resources for Black dementia caregivers. Further research is needed to enhance online communication between participants and presenters during live workshops and accrual of evaluation surveys.
Drug Trial Decision‐Making Among Patients with Mild Cognitive Impairment and their Study Partners
Authors: Cox Chelsea G , Salazar Christian R , Gillen Daniel L , Grill Joshua D
Published: January 2025

Background

Prodromal Alzheimer’s disease (AD) clinical trials of candidate treatments enroll individuals with mild cognitive impairment (MCI) and biomarker evidence of AD. These trials require co‐enrollment with a study partner and complex decision‐making, weighing potential risks and benefits of participation. Some patients with MCI lack capacity to provide trial informed consent.

Method

We performed structured interviews with patients with MCI and their study partners. We presented a description of a hypothetical prodromal AD drug trial, followed by questionnaires to assess (a) involvement of the study partner in trial decisions, (b) patient capacity to consent, and (c) patient performance in health numeracy. We assessed level of agreement among dyads using the weighted kappa statistic and examined the frequency with which patients demonstrated impaired health numeracy and lack of capacity to provide consent.

Result

Among 65 patients with MCI, most were male (66%) and non‐Hispanic White (88%) with a mean (SD) age of 74.9 (8.4) years. Among 57 study partners, most were spouses (83%), female (74%), and non‐Hispanic White (91%) with a mean (SD) age of 70.3 (13.6). Half of patients (51%) and 72% of study partners reported being very or extremely likely to participate in the trial. Most patients (66%) and study partners (72%) stated that they would make the decision to enroll in the trial in partnership, while 28% of patients said they would make the decision on their own with input from their partner. Half of dyads (50%) agreed the decision would be made in partnership, but we found limited dyadic agreement overall (kappa = 0.187, 95% CI: ‐0.057‐0.431). Thirty‐eight percent of patients lacked capacity to consent. Patient health numeracy scores ranged from 3‐12 with a mean (SD) of 8.6 (2.5); 38% demonstrated impaired health numeracy. Sixteen patients (25%) demonstrated both a lack of capacity and impaired health numeracy, among whom seven patients reported they would make trial decisions on their own with input from a partner.

Conclusion

Some patients with MCI may be at risk for decision errors in the informed consent process for a prodromal AD clinical trial.
Allostatic Load and its Impact on amyloid, tau, and hippocampus: a potential underlying mechanism explaining variability in Alzheimer's Disease pathology and progression
Authors: Souza‐Talarico Juliana Nery , Hein Maria , Perkhounkova Yelena , Lee Jihye
Published: January 2025

Background

Accumulation of β‐amyloid (Aβ) and tau proteins can predict the risk of Alzheimer's disease (AD) at asymptomatic stages and are promising measures for screening individuals at risk. However, not all individuals with Aβ and tau pathology progress to AD; some remain cognitively healthy. That variability challenges prediction accuracy and incorporation of AD pathology into clinical practice. Identifying underlying mechanisms that accelerate AD progression is critical to understanding disease trajectories, assessing risk, and promoting timely intervention. Allostatic load (AL), or the "wear and tear" of chronic stress, has been linked to AD risk. However, whether AL influences AD pathology requires further investigation. We aimed to determine the relationship between AL, Aβ, tau, and hippocampus volume (HV).

Methods

Using the Alzheimer's Disease Neuroimaging Initiative (ADNI) database, we analyzed longitudinal data from 385 older adults. Blood neuroendocrine (cortisol, LH, prolactin, testosterone) and immunologic (C‐reactive protein, fibrinogen, IL‐13, IL‐16, IL‐18, IL‐3, IL‐6, MCP‐3, MCP4, TNF‐alpha, insulin‐like growth factor) stress‐related biomarkers obtained at baseline and 12 months were combined into an AL index. Aβ42 measured in the blood (Aβ42blood) and cerebrospinal fluid (Aβ42CSF), CSF p‐tau proteins, and HV from brain MRI were analyzed over 24 months. Linear mixed models were adjusted for socioeconomic and APOE4 covariates.

Results

Higher AL increases over 12 months were associated with higher elevation on p‐tau (p=.007; 95%CI [‐.927,‐.147]), and Aβ42blood (p=.01; 95%CI [.282, 2.54]), and a trend to lower Aβ42CSF (p=.07;95%CI [‐.032, .001]) over 24 months. An interaction between AL increase and APOE4 was observed, indicating that higher increases in AL were associated with higher Aβ42blood but for APOE4 with two E4 copies only (p=.03;95%CI [‐2.568, ‐0.0908]). No association was observed with HV (p=.435).

Conclusion

Amyloid and tau deposition over time was higher among participants with increases in AL, suggesting that elevated AL profiles might signal a potential underlying mechanism explaining AD pathology trajectories. Further research is needed to examine whether incorporating AL in AD models improves the prediction of cognitive decline. A critical step for non‐pharmacological clinical trials testing interventions to reduce dementia risk.
Correlation between cerebral small vessel disease biomarkers and blood‐brain barrier permeability in participants of the encephalopathy and memory clinic cohort
Authors: Pongpitakmetha Thanakit , Thanapornsangsuth Poosanu , Pornteparak Nattanich , Ongphichetmetha Tatchaporn , Rianaree Juthamas , Luechaipanit Watayuth , Haethaisong Thanaporn , Chongsuksantikul Adipa , Thanprasertsuk Sekh , Likitjaroen Yuttachai , Hemachudha Thiravat
Published: January 2025

Background

The blood‐brain barrier (BBB) is considered the crucial part of neuroprotection from various neurological insults including infection, inflammation, and neurodegeneration including Alzheimer’s disease (AD). The cerebral small vessel disease (CSVD) pathologies especially cerebral microbleeds (CMBs) and gadolinium enhancement might reflect the disruption of BBB. The correlation between BBB permeability measured by cerebrospinal fluid (CSF)/plasma albumin quotient (Qalb) and CSVD biomarkers is poorly understood. Thus, we aim to further evaluate this correlation in our cohort.

Methods

Pooling participants from preceding studies on individuals with encephalopathy and from patients attending a memory clinic, where both plasma and CSF were recruited. The magnetic resonance imaging (MRI) closest to the Qalb date was independently rated by the trained investigator using STRIVE‐2 criteria (Duering M, et al. Lancet Neurol. 2023) blinded from the clinical information. The composite total CSVD score (Staals J, et al. Neurology. 2014) ranging from 0‐4 was calculated. The presence of gadolinium enhancement was evaluated. The non‐parametric correlations between neuroimaging biomarkers and Qalb were examined.

Results

110 participants were enrolled. Clinical, laboratory, and neuroimaging biomarkers were summarized in Table 1. A notable positive correlation exists between Qalb and total CSVD score in the whole cohort (Spearman rho = 0.45, p‐value = 7.837e‐07) and encephalopathy cohort (Spearman rho = 0.59, p‐value = 3.347e‐08). The Spearman’s correlation between Qalb and each neuroimaging biomarker was shown in Table 2. Wilcoxon rank sum test with continuity correction between Qalb and presence of gadolinium enhancement was significantly difference (W = 474, p‐value = 0.015). The visualized correlation plots were shown in Figure 1.

Conclusion

The total CSVD and Qalb showed a strong correlation in determining the BBB permeability only in encephalopathy population. The CSVD neuroimaging biomarkers and gadolinium enhancement, which reflect the BBB damage and risk of further neurological deterioration, should carefully be evaluated and considered in clinical practice. The strategies to slow the progression of CSVD including the optimized blood pressure control, avoiding the potential neurotoxic agents, etc. should be raised in this situation, resulting in slowing neuropathological progression. Further confirmatory validation studies, especially memory clinic settings, should be done.
Along‐Tract Analysis of White Matter Bundles in Alzheimer’s disease using Medial Tractography Analysis (MeTA)
Authors: Gari Iyad Ba , Narula Siddharth , Gadewar Shruti , Nir Talia M , Jahanshad Neda
Published: January 2025

Background

Along‐tract analysis of white matter (WM) bundles can help map detailed patterns of WM pathway degeneration in Alzheimer's disease. Here, we present Medial Tractography Analysis (MeTA), which aims to minimize partial voluming and microstructural heterogeneity in diffusion MRI (dMRI) metrics by extracting and parcellating the volume along the bundle length while preserving bundle shape and capturing variation within and along WM bundles. We evaluated along‐tract WM microstructure associations with clinical measures in ADNI using MeTA.

Method

We used dMRI and clinical data from 714 participants (aged 55‐96 years, 52% females) enrolled in ADNI3. The dMRI data were processed using: denoised using Local PCA, deGibbs, and corrected for eddy current and motion artifacts using FSL eddy. The fiber orientation distributions (iFOD2) were estimated using a multi‐tissue constrained spherical deconvolution approach. Whole brain probabilistic streamline tractography was generated. RecoBundles was used to identify and segment 12 WM bundles. We applied MeTA to the bundles and evaluated the diffusion tensor (DTI) fractional anisotropy (FA) and mean diffusivity (MD) associations with 1) clinical impairment (N=274) compared to cognitively normal (CN); 2) Clinical Dementia Rating Scale Sum of Boxes (CDR‐SB); 3) tau load indexed with AV‐1451; and 4) amyloid (Aβ) with FBB/FBP. Full details of the pipelines can be found in Figure 1. We used linear mixed models, with age and sex as fixed effects, and scan sites as nested random variables. We corrected for multiple comparisons across 315 tests (21 bundles x 15 regions) using the false discovery rate (FDR) procedure (q=0.05).

Result

Participants with cognitive impairment, higher CDR‐SB scores, tau and Aβ pathology showed negative associations with FA values and positive associations with MD measures across bundles such as IFOF_L, CPH_R, UF_R, AF_L, MdLF_L, EMC_L, CST, and CC as displayed in Figure 2. All the statistical tests were completed across 15 segments in one bundle in about 20 seconds.

Conclusion

MeTA is a fast and reliable approach for identifying regional WM brain abnormalities in neurodegenerative populations and can be used to map localized effects of disease progression. MeTA is a highly scalable approach that can be applied to large‐scale collaborative multisite AD efforts and consortia.
Performance of mutiple blood‐based biomarkers used in community Alzheimer’s disease screening via a new ultrasensitive micro‐array immunoassay platform
Authors: Cheng Peng , Zhang Minchao , Chen Hao , Li Hui
Published: January 2025

Background

AD is a neurodegenerative disease characterized by progressive cognitive dysfunction and behavioral impairment. The use of biomarkers for early detection of AD is crucial for developing potential treatments. The benefit of using blood‐based biomarkers in screening for AD is that the collection of blood is less invasive than the collection of cerebrospinal fluid, and less costly than neuroimaging. Numerous studies have reported that certain biomarkers are good candidates for AD diagnostics. However, most of the studies utilized clinical cohorts which are less heterogenous than the community‐based population. In China, the number of AD patients is growing rapidly, which poses a considerable burden on society and families. There is a need to establish predictive values of blood‐based biomarkers. This study evaluates the potential of an ultrasensitive micro‐array immunoassay to measure plasma biomarkers and further used in screening AD among the community‐based population in China.

Method

An ultrasensitive micro‐array immunoassay, with a limit of detection (LOD) under 100 fg/mL was developed to measure AD related biomarkers. Blood‐based biomarkers (pTau181, Aβ1‐42, Aβ1‐40 etc.) were measured using this method. Above 1500 plasma samples (age>55) were analyzed. Some of the samples had Aβ‐PET data. Results were adjusted for age, sex and year of education.

Result

The population that involved in this study are retired hospital employees. The levels of the blood‐based biomarkers were measured. The level of these biomarkers showed associations with age, sex, education level, BMI, as well as other medical conditions (hypertension, diabetes, etc.) The associations of these variables were used to construct adjusted models. Comparison of different models were performed to evaluate the predictive performance. Model PAV II was chosen as the best model for predicting AD.

Conclusion

By using an ultrasensitive micro‐array immunoassay, the levels of blood‐based biomarkers were evaluated. Models for predicting AD were constructed and evaluated. Model PAV II involve the levels of biomarkers, medical conditions and other variables showed the best result for predicting AD. The results from the community‐based population indicate that biomarkers in blood have high potential to be used as a screening tool for the detection of AD.
Utility of plasma GFAP as a biomarker for Alzheimer's Disease using chemiluminescent microparticle immunoassay
Authors: Pizarro Eduard Bargay , García Daniel Morell , Martin Ana García , Sanchez Susana Tarongi , Santos Lara Nuñez , Medina Lorena Garcia , Bertó María Santés , Ferrer Guillermo Amer
Published: January 2025

Background

Glial fibrillary acidic protein (GFAP) is a putative blood biomarker for Alzheimer's disease (AD). Most studies measure plasma GFAP (pGFAP) utilizing the Single Molecule Array (Simoa) platform or other high‐cost platforms. However, we aim to validate the value of GFAP as a blood biomarker for AD using chemiluminescent microparticle immunoassay (CMIA), an ubiquitous lower‐cost platform.

Method

A cohort of 56 subjects (from our memory clinic) with mild cognitive impairment (MCI) or dementia were analyzed retrospectively. Demographic and clinical data, neuroimaging, and neuropsychological test results were collected. AD cerebrospinal fluid biomarkers and pGFAP were simultaneously obtained from all patients between July 2022 and February 2023. pGFAP was measured using CMIA on the Alinity‐i‐series platform (Abbott, US), with a lower limit of quantification of 3.2pg/mL and an intra‐assay coefficient of variation <5%.

Result

38 patients were classified as part of the AD continuum: 21 dementia, 18 MCI. The remaining 18 were classified as non‐AD (FTLD, LBD and non‐neurodegenerative): 5 dementia, 13 MCI. The median age in the AD group was 75.7 (IQR: 71.3‐78.2), while in non‐AD it was 71.9 (IQR: 63.3‐73.8) in non‐AD, P=0.019. There were no differences between groups in other demographic factors. We found a significant correlation between age and pGFAP increase in all patients (P=0.035). In AD group median pGFAP was 54.4pg/ml (IQR: 41.8 ‐ 85.3), compared to 34.2pg/ml (IQR: 15.8 ‐ 40.7) in non‐AD, P<0.001. These results were consistent when adjusted for confounding variables (age and other clinical and demographic variables), P<0.001. There were several trends in pGFAP levels, although not significant: higher levels in AD dementia versus AD MCI (P=0.131) and in non‐AD dementia compared to non‐AD MCI (P=0.065), also an inverse correlation between pGFAP and MMSE score (P=0.104). Using a threshold of 46.3pg/ml, GFAP alone differentiated AD from non‐AD with an area under the curve (AUC) of 0.82 (CI: 0.71‐0.94), sensitivity of 89% and specificity of 68%.

Conclusion

Our findings obtained using a CMIA technique were similar to those found in the literature, in which other platforms have been used. This suggests that pGFAP measured using widely available low‐cost platform based on CMIA may have diagnostic utility for AD.
Patients’ perceptions and considerations regarding DNA testing in a memory clinic: DNA‐ABOARD
Authors: van der Schaar Jetske , van der Lee Sven J , Asscher Eva , van der Flier Wiesje M. , Pijnenburg Yolande A.L. , Bredenoord Annelien L. , van den Hoven Mariette A. , Smets Ellen M.A. , Visser Leonie N.C.
Published: January 2025

Background

Data‐driven criteria for DNA testing were implemented in routine care of Alzheimer Center Amsterdam. We aimed to explore patients’ perspectives and considerations regarding their decision to (not) be tested for a monogenic cause of their disease.

Methods

In this mixed method study, 150 of 519 new patients visiting Alzheimer Center Amsterdam who fulfilled the criteria were offered DNA‐diagnostics: 86(57%) accepted, 64(43%) did not. In 65/86(76%) cases results were negative, in 14/86(16%) a monogenic cause and in 7/86 (8%) variants of uncertain significance were found (Figure 1). Sex, age, education, family history of dementia, MMSE and diagnosis were retrieved. Before discussing DNA testing, patients completed a questionnaire assessing perceived risk of a genetic cause, susceptibility for, severity of, and experience with dementia, social support, coping strategies, anxiety, depression, and quality of life. Differences between those who did and did not consent to DNA testing were calculated using Pearson’s χ², Mann‐Whitney U or Independent Samples t‐tests; p‐values were FDR‐adjusted. A subset of 22 patients and/or relatives participated in semi‐structured interviews on motivations and considerations regarding their decision. Verbatim transcripts were analyzed inductively using MAXQDA‐software.

Results

Participants (n = 150) were 46% female and aged 61±8 (MMSE = 22±6, 5 Subjective Cognitive Decline, 9 MCI, 104 dementia [69 AD, 13 FTD, 22 other], 32 other/undetermined). Adjusted for multiple testing, no demographic, medical or psychosocial factors were associated with the decision on DNA testing (all p>0.05). Twenty‐one interviewees who agreed to DNA testing were generally motivated by obtaining information on heredity for their relatives, contributing to scientific research into a treatment, and gaining insight in the cause of their disease. One patient had blood stored, allowing their children to test it when opportune. The majority decided quickly, mostly on intuitions (e.g., responsibility towards relatives) rather than facts (e.g., information on risk and consequences). They expected to feel reassured or relieved by negative test results, and sad or worried if a genetic cause was found.

Conclusions

Over half of memory clinic patients eligible for DNA‐testing wanted to be tested. This decision was unrelated to demographic, medical or psychosocial characteristics, and mostly based on intuition and considerations regarding family.
A network approach to dementia care burden: exploring relationships between objective and subjective indicators of care burden in caregivers of community‐dwelling persons with dementia
Authors: Balvert Sanne C.E. , Butterbrod Elke , Sikkes Sietske A. M. , Dröes Rose‐Marie , Scherder Erik J. A. , Milders Maarten V.
Published: January 2025

Background

To support informal caregivers of persons with dementia (PwD), it is fundamental to understand how objective and subjective indicators of care burden are interrelated. This study used psychometric network analyses to explore care burden indicators and extend current models of care in informal caregivers of PwDs.

Methods

Baseline data from an intervention study of 170 informal caregivers of community‐dwelling PwDs was used. Variables included (subscales of) the following measures: a) time since diagnosis, b) objective indicators of care burden: hours of care provided, dependence of the PwD for (Instrumental) Activities of Daily Living (Interview for Deterioration in Daily Living Activities; IDDD), and c) subjective indicators of care burden: caregiver sense of competence (SCQ), positive experiences of caregiving (Positive experiences Scale; POS), shared activities (Pleasant Events Schedule; PES), caregiver depressive symptomatology (Center for Epidemiologic Studies–Depression; CES‐D) and caregiver self‐rated health (VAS‐score). A Gaussian graphical model was employed to explore unique relationships between the measures while accounting for all other relationships in the network. Node strength (strongest total associations of an indicator with other indicators), betweenness and closeness were interpreted if the central stability coefficient was sufficient (>0.25).

Results

Caregivers (71.8% female, 69.5±11.0 years) provided 4.80±5.57 hours of care daily (Table 1 and 2). Node strength and edges reached sufficient stability. The strongest unique relationships existed mostly within objective and subjective measures (e.g., between CES‐D somatic and depressed subscales (r = 0.51); and between total hours of care and ADL‐dependence (r = 0.29), see Figure 1). No significant cross‐connections existed between objective and subjective measures. Within subjective measures, several interrelations were found: PES was associated with SCQ ‐ satisfaction with the PwD (r = 0.20), POS was associated SCQ ‐ satisfaction as caregiver (r = 0.17), and both PES and POS were associated with CES‐D affect (r = ‐0.17, r = ‐0.24). Caregiver’s self‐rated health was only associated with CES‐D somatic (r = ‐0.22).

Conclusion

Our results suggest that objective care burden and disease duration may not be strongly related to caregivers’ experiences, and highlight the interconnectedness of subjective indicators. These insights can contribute to better understanding of care burden and ultimately to more effective support for caregivers of PwD.
Clinical consequences of the Alzheimer’s blood‐based biomarker panel: a prospective evaluation in memory clinics ‐ the CANTATE project
Authors: Vigneswaran Sinthujah , Verberk Inge M.W. , Boonkamp Lynn , Rousset Rebecca Z. , Claessen Thomas , Zwan Marissa D. , Ossenkoppele Rik , Muller Majon , Wilson David H , Lemstra Afina Willemina , Pijnenburg Yolande A.L. , van der Flier Wiesje M. , Teunissen Charlotte , van Harten Argonde C.
Published: January 2025

Background

Blood‐based biomarkers (BBM) are emerging as minimally invasive, scalable and relatively low‐cost options for discriminating different neurodegenerative diseases. Before implementation in clinical practice can take place, it is important to determine their real‐world clinical validity in patients presenting at a memory clinic. Therefore, we prospectively evaluated changes in diagnosis and diagnostic confidence resulting from the use of a BBM panel tailored to common differential diagnostic considerations (Verberk et al., Mastermind of the Alzheimer’s blood‐based biomarkers: development of cut‐offs and a visualization tool for use in clinical practice. https://doi.org/10.1002/alz.078748).

Methods

Consecutive patients who visited the Alzheimer Center Amsterdam or the Center Of Geriatrics Amsterdam (COGA) for a standardized diagnostic workup between September‐December 2023 and provided informed consent were included. Diagnoses were determined at a multidisciplinary meeting. BBM panel with pre‐specified cut‐off values (plasma pTau181, GFAP and NfL, Quanterix Corporation, USA) were disclosed after the clinical work‐up, neuropsychological tests and MRI results were presented on a weekly basis reflecting real world clinical practice. We evaluated syndrome diagnosis, suspected aetiology and confidence in the etiological diagnosis before and after disclosing BBM results.

Results

A total of 107 patients with a mean age of 68 ± 9 years and 42 females (39%) were included. The blood biomarker panel led to change in syndrome diagnoses in 10 patients (9%) and change in suspected aetiology in 9 patients (8%) (Table 1). Among those for whom both syndrome diagnosis and suspected aetiology remained unchanged (n=92, 86%), diagnostic certainty changed in 89 patients (83%) after showing the BBM panel. In these patients, the diagnostic confidence changed from 70% [IQR = 60 ‐ 80] to 90% [IQR = 80 ‐ 90]; P < .001) after showing the BBM panel results (Figure 1). The diagnostic confidence increased in 69 (64%) patients and decreased in 20 (19%) patients.

Conclusion

A BBM panel specific to individual differential diagnostic considerations generally led to an increase in diagnostic confidence and rarely resulted in a different diagnosis. These results suggest that BBM have added value in daily clinical practice. This is an ongoing study with inclusion rate of 15 persons per week, updated results will be presented at AAIC2024.
Data‐driven analysis of Aβ peptide ratios in iPSC models of familial Alzheimer's disease for diagnosis and prediction of symptom onset
Authors: Saguer Isaac Llorente , Gabriele Rebecca , Wray Selina , Oxtoby Neil P , Arber Charlie
Published: January 2025

Background

Familial Alzheimer's disease (fAD), arising from mutations in amyloid‐precursor‐protein (APP) and presenilin (PSEN1/2) genes, leads to the production of longer, aggregation‐prone amyloid‐beta (Aβ) peptides—a hallmark of Alzheimer's disease. Age‐at‐onset (AAO) varies among carriers of different mutations. Recent evidence challenges the Aβ42:40 ratio as the leading and predictor of AAO between different pathogenic variants, prompting exploration of peptide combinations as potential biomarkers for these tasks.

Method

Data consisted of patient‐derived in‐vitro iPSC models of fAD and Ab measurements via enzyme‐linked immunosorbent assay (ELISA). With novel data of our own (N=39) and published data from Liu et al. 2022 (N=134) (Table 1), we performed a data‐driven analysis of Aβ37/38/40/42/43 combinations, employing area under the curve (AUC) and coefficient of determination metrics for classification (WT vs AD) and AAO regression. A linear model optimized for these metrics was also explored.

Each peptide was divided by the average of the control group of the same assay. Then, we weighted each peptide in accordance with the average profile of the control population in Liu.

Result

Data transformation using controls proved necessary for to produce comparable ratios (Figure 1).

Table 2 presents diagnostic and predictive performance for each peptide‐ratio biomarker relative to biomarkers from the literature (top 3 rows). Our new data‐driven biomarkers improved upon the literature in both diagnostic AUC (not statistically significant: DeLong’s test p>0.47) and predicting AAO (Spearman’s R^2 significant differences in UCL data; Hittner’s p<0.005; p>0.5 in Liu’s).

Conclusion

Our results do not recapitulate Liu et al. findings, as Aβ37:42 did not outperform Aβ42:40 in our data; one explanation could be that our lines represent a physiological model of Ab production that is free from plaque deposition.

While no significant differences emerged in AD classification, specific peptide ratios demonstrated varying correlations with AAO: short‐to‐long ratio > Aβ42:40, and Aβ42:40 > Aβ37:42, but other ratios were found to perform better in each set, suggesting mutation‐specific profiles.

Data‐driven linear combination can improve the results, and notably, both optimizing for AUC or AAO found the same ratio of short/long, albeit with different weights. Standardization through control‐based data was essential for robust measures.
Using New Science to reduce bias of Old Science: AI‐driven Customization of Culturally Biased Tests
Authors: Devine Sherral A. , Lee Melissa , Gurnani Ashita S. , Sunderaraman Preeti , Kourtis Lampros , Pratap Abhishek , Low Spencer , Ho Kristi , Gifford Katherine A. , Au Rhoda
Published: January 2025

Background

Widely used neuropsychological test instruments are notoriously biased across the demographics of age, sex/gender, education, language and culture. This includes verbal memory tests that elicit speech such as the paragraph recall or list‐learning memory tests. Language tests are similarly biased, including the Boston Diagnostic Aphasia Examination Cookie Theft Test (CTT) that has been used to elicit both written and spoken responses for decades. Biased tests generate biased results, and this problem is exacerbated by the widespread practice of repurposing tests generated for those in largely high income, Westernized countries for use in other countries that are demographically and culturally distinct. We tested the use of large language model (LLM) tools to automatically generate verbal test stimuli that were more locally relevant.

Methods

Starting with the CTT, that involves describing a picture that contains 14 core content units, we used ChatGPT to aid in generating customized pictures with the same number of core content units that were more universally relevant, (e.g., open park area, beach, etc.) by suggesting parameters and integrating resulting features into new pictures. We also tested capabilities to generate pictorial scenes that are more representative of regional settings, such as the Asia Pacific or Middle East. We are testing LLM capacity to generate similarly regionally customized list learning stimuli that maintain the original list learning test word frequency and difficulty across languages.

Results

Using an iterative approach, we were able to use automated artificial intelligence (AI)‐driven tools to rapidly generate regionally relevant test stimuli that retained the original test characteristics to preserve generation of comparable results. Descriptive comparisons found that aided by automated AI tool, we could generate new neuropsychological test stimuli in a matter of minutes compared to months long manual methods.

Conclusion

The rapid emergence of AI has generated significant concerns about its appropriate use for health and health care applications. Given that AI is here to stay, we are testing the capacity of this technological advance to address long‐standing, persistent problems in AD research and usher in a new era of precision brain health that has global relevance in a rapidly aging world population.
Machine learning for privacy‐protected voice analysis in dementia assessment
Authors: Ahangaran Meysam , Dawalatabad Nauman , Karjadi Cody , Glass James , Au Rhoda , Kolachalama Vijaya B.
Published: January 2025

Background

The prevalence of cognitive impairments, such as mild cognitive impairment (MCI) and Alzheimer's disease (AD), has surged, necessitating rapid, cost‐effective, and non‐invasive diagnostic tools. Speech, as a rich source of cognitive indices, offers a promising avenue for distinguishing between healthy controls, MCI, and AD groups. However, the utilization of voice data poses privacy challenges, as speaker identities can be discerned through automatic speaker verification systems.

Method

We developed a machine learning framework for dementia assessment, utilizing acoustic features obtained through advanced speaker anonymization techniques. Our work leveraged a wealth of digital voice recordings from the Framingham Heart Study, which, since 2005, has captured extensive spoken responses to neuropsychological tests. These recordings were instrumental in refining our privacy‐conscious algorithmic approach to dementia assessment.

Result

The developed tool demonstrated efficacy in de‐identifying speakers while maintaining the integrity of cognitive features in speech. This retention allows for the continued development of vocal biomarkers that correlate with neuropsychological assessments and cognitive impairment diagnoses.

Conclusion

Our approach unites the need for privacy with the utility of voice data in dementia assessment. It offers a scalable, accessible solution that could revolutionize early cognitive decline detection, while also aligning with the increasing emphasis on patient privacy in medical research.
Differential Privacy Preserving Voice Conversion for Audio Health Data
Authors: Dawalatabad Nauman , Ahangaran Meysam , Karjadi Cody , Kourtis Lampros , Joung Philip , Kolachalama Vijaya B. , Au Rhoda , Glass James
Published: January 2025

Background

Speech is a predominant mode of human communication. Speech digital recordings are inexpensive to record and contain rich health related information. Deep learning, a key method, excels in detecting intricate patterns, however, it requires substantial training data. Laboratories have invested significantly to gather extensive digital voice datasets for health insights. The challenge lies in securely sharing this data while protecting the speaker's privacy.

Method

We applied a Generative Adversarial Network (GAN) approach. GANs can generate a voice that closely resembles a real voice and is composed of four key components: (i) Generator, (ii) Formant Extractor, (iii) Speaker Embedding Extractor, and (iv) Discriminator. Model training involves leveraging adversarial loss, wherein the generator strives to produce a voice that convincingly mimics reality to deceive the discriminator. Simultaneously, the discriminator endeavors to discern whether the generated voice is authentic or synthetic. Eventually the generator produces a voice that resembles closely to the real voice.

Result

We performed zero‐shot voice conversion using an emotion preserving GAN. The model preserves the fundamental frequency trajectories. This is one of the most important features in dementia classification.

Conclusion

By successfully altering voice prints while preserving sound quality, our initial findings suggest a way for sharing raw digital voice recordings. Future efforts will extend beyond preserving intonation patterns, focusing on preserving additional dementia related markers in the original signal.