bluuebunny/crossref_metadata_2025 huggingface dataset:
Voxel‐wise Florzolotau (APN‐1607) Tau PET Covariance Patterns in Alzheimer’s Disease and Progressive Supranuclear Palsy
Authors: Blazhenets Ganna , Brumberg Joachim , Endo Hironobu , Hsu Jung‐Lung , Frings Lars , Schroeter Nils , Hellwig Sabine , Chang Chiung‐Chih , Higuchi Makoto , Meyer Philipp Tobias
Published: January 2025

Background

Florzolotau (APN‐1607) tau‐PET has shown distinct patterns of binding in patients with AD and 4‐repeat tauopathies. We aimed to establish disease‐specific tau covariance patterns in AD and PSP/CBS and validate them as user‐independent quantitative biomarkers for reference‐region‐free evaluation of tau‐PET in an independent clinical cohort.

Method

We analyzed Florzolotau PET data from four different cohorts. The derivation dataset included 30 Aβ‐ healthy controls (HC) and 30 patients each with Aβ+ AD and PSP with Richardson’s syndrome (PSP‐RS). The validation dataset included 44, 51, 6, 15, and 17 patients with AD, PSP/CBS, MSA, LBD, and FTD, respectively. First, we applied scaled sub‐profile modelling principal components analysis to the derivation dataset to define the AD‐ and PSP‐RS‐related covariance patterns. Second, the topographic profile rating algorithm was applied to each scan to calculate AD‐ and PSP‐RS‐related pattern scores.

Result

The AD‐ and PSP‐RS‐related patterns are described in Figures 1 and 2. In the derivation dataset, the AD‐ and PSP‐RS‐scores showed strong increases compared to HC (both p<0.001, AUC‐ROC=0.994 and 0.898, respectively). AD‐scores showed a significant negative association with age (r=‐0.66, p<0.001) and MMSE (r=‐0.64, p<0.001) in AD, while PSP‐RS‐scores correlated with the PSP rating scale (r=0.43, p=0.018) in PSP‐RS. In the validation dataset (Figure 3), AD‐scores were highest in AD (p<0.001 vs. all other, AUC‐ROC[AD vs. all other]=0.946) and were negatively associated with age and MMSE in AD (r=‐0.62, p<0.001 and r=‐0.49, p=0.002, respectively). PSP‐RS‐scores were highest in the PSP/CBS (p<0.001 vs. all other [at least p<0.05 vs. each group], AUC‐ROC[PSP/CBS vs. all other]=0.734), though also relatively increased in FTD and MSA. UPDRS‐III scores (off‐state) were available in 23 PSP/CBS patients and significantly associated with PSP‐RS‐scores (r=0.60, p=0.002).

Conclusion

Modelling with principal components analysis allows for reference‐region‐free quantification of tau imaging data by constructing disease‐specific covariance patterns. When applied to Florzolotau, AD‐ and PSP‐RS‐related patterns showed high discrimination power in both the derivation and the clinically heterogeneous validation cohorts. PSP‐RS‐related pattern expression in FTD and MSA may be related to PSP pathology and known striatal off‐target binding, respectively. Strong association with respective disease severity scores further advocates for use of AD‐ and PSP‐RS‐related patterns as potential quantitative biomarkers of tau pathology.
Analysis of medical reports of guardianship proceedings of people with dementia a sample from Belo Horizonte, Minas Gerais, Brazil
Authors: Real Mariana S L C , Barbosa Izabela G , Carvalho Carla V , Romano‐Silva Marco Aurelio , Bicalho Maria Aparecida Camargos , de Moraes Edgar Nunes , Viana Bernardo M
Published: January 2025

Background

Dementia syndromes are chronic health conditions that lead to significant cognitive decline and functional impairment, including acts of civil life. Concerning the latter, a guardianship petition maybe needed when patients or family are at risk.

Methods

Retrospective cross‐sectional study of documentary research on 72 electronical guardianship proceedings involving adults with dementia. The study sample comprises reports from six out of twelve Family Courts within the Court of Justice of Minas Gerais, with twelve reports collected from each selected court. The results were analyzed using descriptive statistics, involving mean, standard deviation, median, minimum and maximum. For statistical analyzes the software SPSS Version 20.0 for Microsoft Windows was used. When comparing continuous variables, the non‐parametric Mann‐Whitney test and the Kruskal‐Wallis test were used. The study was approved by the ethics committee by Federal University of Minas Gerais.

Results

The sample had median age of 82.5 years with high level of education by Brazilian standards with a median of 8 years, and mainly composed by elderly women (68,1%) and widows (41,7%). Notably, 76.4% of guardianship proceedings were petitioned by sons, with predominance of daughters appointed as guardians. Geriatrics and Family Physicians (54.1%) stood out as the specialties that issued the majority of the initial medical reports. Alzheimer’s Disease Dementia (ADD) (61.1%) was the most prevalent diagnosis with a predominance of women (67.3%) and older people with a mean of 84.9 years (SD 8,6). In second place, vascular dementia (VD) (15.3%) followed by unspecified etiology of dementia (12.5%). In the non‐Alzheimer dementia group, the median age was 79.5 years (p = 0.016). In relation to education, there was no statistically significant difference between the group of patients with Alzheimer’s disease and non‐Alzheimer’s disease (p = 0.547).

Conclusions

The present work identified that the majority of medical reports were related to ADD and VD and were made by geriatricians and family physicians. This points to the importance of these specialties regarding the protection and promotion of rights of people with these dementias.
What does engagement mean to you? Exploring the experiences of the League older adult advisory group for social robot technology research
Authors: Martin Susanna E. , Zhang Cindy C. , Robillard Julie M.
Published: January 2025

Background

Co‐creation methods are increasingly being used in the research and development of technologies that support older adults living with dementia and their care partners to live well. Use of collaborative methods to engage with the dementia community helps to ensure that research processes and end solutions are sensitively designed, reflective of needs and values, and responsive to priorities. Engagement also has proximal benefits for older adults: Being involved in purposeful activity has been shown to positively impact health and wellbeing outcomes. However, despite these benefits, the value of co‐creation methods in dementia research remains under‐investigated from the perspectives of older adults themselves. Here we seek to address this gap in the context of social robot research exploring the impact and value that older adults derive from engaging in dementia technology research.

Method

We carry out semi‐structed interviews with older adults who are members of a lived experience advisory group, known as the League. League members provide ongoing consultation on research activities carried out at the Neuroscience, Engagement and Smart Tech Lab.

League members also complete surveys, including a subset of questions from the Patient Engagement In Research (PEIR) Framework, to capture quantitative responses on key components of engagement. We adopt a social‐technical perspective to generate a holistic appreciation for the impacts of engagement.

Result

Individual perspectives captured in this mixed methods study reveal that older adults have unique experiences with technology, and technology research, that modulate their level of engagement and the meanings that they derive from participation. Results demonstrate the impact that engagement has on biopsychosocial factors, roles, and identity, and underscore the ethical imperative of human‐centered research methods.

Conclusion

Insights will support the evidence base for person‐centred, co‐creation methodologies in dementia research, and showcase the potential for meaningful engagement to support the health and wellbeing of older adult collaborators.
A pilot pragmatic trial of Mindfulness Based Dementia Care for care partners
Authors: Hanson Leah R , Chrenka Ella A , Herrmann Amanda A , JaKa Meghan M , Barclay Michelle , Dioquino Ymkje WJ , O'Brien Meghan , Brombach Ann M , Rice‐Oeschger Laura
Published: January 2025

Background

Care partners (CPs) of people with dementia suffer from chronic stress impacting their mental and physical health. Mindfulness Based Stress Reduction (MBSR) has been shown to reduce depressive symptoms in CPs. Mindfulness‐Based Dementia Care (MBDC) is an adaptation of MBSR tailored to CPs. In addition to the core practices, stress related education, and attitudinal approaches to everyday stressors taught in MBSR, the mindfulness practices are linked with caregiving. In MBDC, care partnering becomes the practice. The primary aim of this study was to assess the feasibility, acceptability, and fidelity of implementing MBDC. The secondary aim was to determine the feasibility of obtaining pragmatic CP outcomes.

Method

Care partners were referred from 3 memory care clinics plus community support groups and registered for MBDC on a centralized website. Feasibility measures included recruitment metrics, attendance, and questionnaire response rates. Care partner outcomes were included in the administrative data collection at registration and follow‐up, which included symptoms of CP depression, burden, self‐compassion, and mindful attention. Follow‐up questionnaires were emailed immediately before and after MBDC, and again after 3 months.

Result

Eleven virtual MBDC courses were conducted January‐November 2023. A total of 124 CPs registered for MBDC with a mean age of 65 years (83% white, 79% female) and 62% were caring for a spouse. Eighteen CPs remained on a waiting list as no MBDC course times fit their schedule. Five CPs were found to be ineligible after registration, 8 withdrew and 9 were lost to follow‐up prior to starting MBDC. Of the 84 CPs that started MBDC, 77 completed. Attendance rates ranged from 89‐98%. Questionnaire response rates were 100% at registration, 98% pre‐MBDC and 88% post‐MBDC. Complete outcome data at all three time points was available for 53 CPs. A preliminary analysis demonstrated that over the course of MBDC, CPs had a 2.6 point larger decrease in CESD‐10 scores, measuring depressive symptoms, as compared to their own control period (p<0.01).

Conclusion

This study demonstrated that MBDC was successfully implemented with fidelity including high attendance rates. However, pragmatic collection of CP outcomes through administrative data may not be adequate for an effectiveness trial.
Senescence‐associated secretory phenotype (SASP) index in individuals across the Alzheimer’s disease continuum
Authors: Franco Alvaro de Oliveira , Schlickmann Thomas Hugentobler , Ferrari‐Souza João Pedro , de Bastiani Marco Antônio , Castilhos Raphael Machado , Zimmer Eduardo R.
Published: January 2025

Background

Cellular senescence (CS) is a hallmark of aging. Senescence‐associated secretory phenotype (SASP) index was recently developed based on the levels of blood SASP‐related proteins. Although aging is a primary risk factor for Alzheimer's disease (AD), the role of CS in this neurodegenerative condition is not well understood. Here, we investigated the association of the SASP index (SI) with classical markers of AD.

Methods

We assessed 593 participants (60 cognitively unimpaired [CU], 412 with mild cognitive impairment [MCI], and 121 with AD dementia), from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort (Table 1). SI was derived through a weighted sum of the standardized concentrations of 12 available SASP proteins, each weighted according to the eigenvectors from a Principal Component Analysis of these proteins (Table 2). Associations were tested using generalized linear models adjusted for age, sex, education, and APOEε4 status. Statistical analyses were performed in the R environment, significance set at p < 0.05, and multiple comparisons correction was performed using the false discovery rate.

Results

Regression analysis demonstrated that CU individuals showed lower SI values than MCI (p = 0.044) and AD dementia (p = 0.039) individuals. We found that the SI was positively associated with age (p < 0.001), cerebrospinal fluid (CSF) neurofilament light (NfL) (β = 94.838, p = 0.007), plasma NfL (β = 4.08, p‐value < 0.001) and Clinical Dementia Rating sum of the boxes (β = 0.12, p = 0.004). On the other hand, the SI was negatively associated with the middle temporal gyrus volume (β = ‐208.81, p = 0.013), with a negative trend with hippocampus volume (β = ‐56.15, p = 0.053). Additionally, the SI showed no significant correlation with CSF Aβ42, CSF t‐tau and p‐tau181, CSF GFAP, education level, and the whole brain, entorhinal gyrus, fusiform, and entorhinal cortices volumes.

Conclusions

Here, we showed that the SI closely associates with hallmark features of AD, such as age, cognition, fluid, and imaging biomarkers. Our results help to better understand the role of aging in AD and suggest that the SI can be used as a proxy for CS in AD.
The use of neural‐derived extracellular vesicles as a biomarker tool of neuropathology (with focus on Alzheimer’s disease and Lewy body dementia)
Authors: Sander Millie , Bozbas Esra , Ballard Clive G
Published: January 2025

Background

Establishing novel biomarkers to detect of Alzheimer’s disease (AD) and Lewy body dementia (LBD) neuropathology is integral to support early diagnosis and the differentiation between dementia subtypes. Neural‐derived extracellular vesicles (NDEVs) – released by neural cells into circulation – provide promise in this regard. NDEV cargo, such as p‐T181‐tau and Aβ‐42, have previously been shown to be associated with cognitive decline and disease progression among AD patients (Winston et al, 2016; Kapogiannis et al, 2019). Here, we assess various protocols for the isolation of NDEVs, with the aim of establishing both AD and LBD NDEV profiles.

Method

Plasma samples are being collected from individuals with AD, LBD, MCI and healthy controls. Three EV isolation techniques – differential ultracentrifugation, size exclusion chromatography, and ExoQuick – are being compared to assess the presence of NDEVs (via western blot and transmission electron microscopy), as well as their size and yield (via nanoparticle track analysis). The enrichment of EVs of neural origin using L1CAM and NCAM will be assessed, to address conflict and doubt in the field.

Result

The data for this study is currently being collected, and results will be available prior to the conference.

Conclusion

NDEVs present a promising tool for detecting and monitoring neuropathology during dementias such as AD and LBD. The optimal isolation technique for NDEVs is still controversial, and so this work will address said problem.
Cumulative Incidence Rate Score for Alzheimer’s Disease Risk is Associated with White Matter Hyperintensity Volume in Older Adults Without Dementia
Authors: Lippert Rafael V. , Edwards Natalie C. , Tosto Giuseppe , Pyne Jeffrey D. , Lao Patrick J. , Brickman Adam M.
Published: January 2025

Background

Small vessel cerebrovascular disease (CVD), visualized as white matter hyperintensities (WMH) on magnetic resonance imaging (MRI), is associated with risk and progression of Alzheimer’s disease (AD) in clinical, community, and genetic studies of AD. However, it is unclear whether these observations indicate a role of CVD in AD pathogenesis. One approach towards understanding whether there is a mechanistic or fundamental function of CVD in AD pathogenesis is by examining whether genetic risk factors for AD are also associated with WMH. Here, we examined whether polygenic hazard scores (PHS) and cumulative incidence rates (CIR) scores are associated with WMH volume in older adults without dementia.

Methods

We used data from the Alzheimer’s Disease Neuroimaging Initiative, including available WMH, PHS, and CIR scores from individuals without dementia. Polygenic hazard scores reflect the contribution of APOE and 31 other genetic variants to future risk for AD, calculated from over 54,000 AD cases and controls by Desikan and colleagues. The CIR scores combined the PHS and US population‐based incidence rates to reflect an age‐specific instantaneous risk for developing AD in each participant. Linear models were used to evaluate the relationship of PHS and CIR scores with log transformed WMH volumes. To confirm our findings among people with pathophysiological evidence of AD, we restricted the analysis to a subset of participants with amyloid positivity on amyloid PET scans.

Results

Six hundred two participants were included (mean±SD age=72.6±7.12, 46% women). Polygenic hazard scores for AD were not associated with WMH volume (R=‐0.04, 95% CI:[‐0.12‐0.04], p=0.33), but higher CIR scores were associated with greater WMH volume (R=0.29, 95% CI:[0.21‐0.36], p<0.0001). The association between WMH and CIR remained after restricting the analyses to the amyloid positive subgroup (n=271, age=73.8±6.83, 51% women; R=0.20, 95% CI:[0.09‐0.31], p=0.0007).

Conclusion

Higher cumulative incidence rate derived from polygenic risk scores for AD is related to WMH volume in individuals without dementia, suggesting that age‐anchored genetic risk for development of AD also increases small vessel CVD. The findings implicate WMH in the genetic pathway towards AD pathogenesis.
Associations Between Sex‐ and APOE‐Specific Transcriptomic Signatures in Alzheimer's Disease and Imaging‐Derived Phenotypes: An AZ‐ADRC‐Research Education Scholars Team Science Project
Authors: Raikes Adam C. , Vitali Francesca , Hernandez Gerson D , Yin Fei
Published: January 2025

Background

Age, female sex and the APOEε4 allele are among the top risk factors for developing late‐onset Alzheimer’s disease (LOAD). Precision medicine for AD drug development necessitates targeting specific biological pathways driving AD pathology. We previously identified LOAD‐associated transcriptomic signatures specific to both sex and APOE genotype. Here we extend these analyses to examine the association between these signatures and imaging‐derived phenotypes (IDPs).

Method

Brain RNA‐Seq datasets from ROSMAP (syn8456637) were obtained from the RNA‐Seq Harmonization Study on AMP‐AD, including 369 frontal cortex samples from APOEε3/ε3 and APOEε3/ε4 individuals. Differentially expressed genes (DEGs, p‐value<0.01) between LOAD and cognitively normal controls were identified for each sex‐genotype. IDPs were generated from 1155 individuals in ROSMAP, with 62 overlapping the RNA‐Seq Harmonization Study. T1‐weighted MRIs were processed using Fastsurfer (v.2.0.4), and cortical thickness (CT) and subcortical volumes (SV) were computed. After multi‐site harmonization and covariate adjustment, effect sizes (Cohen’s d) for controls vs. AD were computed for each sex‐genotype pairing. Correlations between these effect sizes and median regional DEG expression from the Allen Human Brain Atlas were examined.

Result

Controls showed anticipated CT and SV patterns, though male APOEε4s exhibited greater CT in more regions. Higher median expression of up (female APOEε3/ε3, male APOEε4) and down (female APOEε3/ε3, male APOEε3/ε3, male APOEε4) regulated DEGs correlated with less CT in AD patients (r=0.21‐0.41, p < 0.046). In APOEε4 carriers, higher median up (male, female) and down (female) DEG expression correlated with greater SV in AD patients (r=0.48‐0.57, p < 0.043). Greater median downregulated DEG expression in APOEε3/ε3s correlated with smaller SV (r=0.56, p=0.021). Higher median APOE expression was correlated with less CT in AD patients across sex‐genotype pairings (r=0.38‐0.86, p < 0.002), lower SV (females, all genotypes), and greater SV (male APOEε3/ε3). No associations between median DEG expression and CT were observed in female APOEε4 carriers.

Conclusion

Our analyses reveal novel sex and APOE genotype‐specific transcriptomic signatures associations with imaging‐derived features in LOAD. Our findings transcriptome signature specific CT and SV profiles that may inform therapeutic targets. The present analyses provide support the identification and use of risk‐factor specific biomarkers of target engagement for preventative and therapeutic interventions.
Impact of anchoring cutoff point of tau positivity on CU young or older adults using Flortaucipir and MK‐6240 – Head Study
Authors: Ruppert Emma Patrice , Povala Guilherme , Bauer‐Negrini Guilherme , Lussier Firoza Z , Ferreira Pamela C.L. , Bellaver Bruna , Amaral Livia , Zalzale Hussein , Oliveira Markley , Saha Pampa , Rodrigues Matheus Scarpatto , Abbas Sarah , Soares Carolina , Felix Cynthia , Madeiros Marina Scop , de Paula Elisa , Resende França , Caramelli Paulo , Klunk William E , Tudorascu Dana , Jagust William J. , Pascual Belen , Gordon Brian A. , Lowe Val J. , Oh Hwamee , soleimani‐meigooni David N. , Rosa‐Neto Pedro , Baker Suzanne L. , Pascoal Tharick Ali
Published: January 2025

Background

Tau PET provides continuous measurements of tau tangle pathology in the human brain. However, establishing cutoffs is crucial for selecting individuals for treatment in clinical trials or practice. In the absence of postmortem data, PET cutoffs must be established using statistical methods based on what is considered normal tracer uptake. In this study, we tested the impact of various methods to determine tau positivity using two different tau PET tracers in individuals scanned head‐to‐head.

Methods

We studied 147 individuals from Head‐to‐Head Harmonization of Tau Tracers in Alzheimer's Disease (HEAD) study with tau tangle PET scans with [18F]Flortaucipir and [18F]MK‐6240, and amyloid‐β (Aβ) PET. Tau deposition was measured with the standardized uptake value ratio (SUVR) of each agent in the Medial Temporal Lobe (MTL) and the Entorhinal Cortex (EC). To determine Tau positivity three different methods were used: >2.5 standard deviations (SD) than the mean of the young, >1.5 SD mean of the cognitively unimpaired (CU) and >1.5 SD mean of CUAβ‐.

Results

Demographic characteristics of the study population are reported in Table 1. Using the cutoff >2.5 SD mean of young, [18F]Flortaucipir was positive in 35 (23.8%) and 69 (46.9%) individuals in the EC and MTL, respectively. [18F]MK‐6240 was positive in 49 (33.3%) and 58 (39.5%) individuals in EC and in MTL. Using >1.5 SD mean of CUAβ‐, [18F]Flortaucipir was positive in 38 (25.9%) and 45 (30.6%) individuals in EC and MTL, while [18F]MK‐6240 was positive in 51 (34.7%) and 50 (34.0%) in EC and in MTL (Figure 1).

Conclusions

Our findings indicate variations in tau positivity when employing different methods based on either the young or CUAβ‐. [18F]Flortaucipir exhibited a higher rate of positive results when the method based on young individuals was applied in the MTL. Conversely, [18F]MK‐6240 showed more consistent and generally higher positivity when other methods were used for cutoff determination and/or in the EC region. Further research with a larger sample size is required to gain a better understanding of the optimal cutoff determination methods for these tracers.
Association between Tau and Cognition as a Function of Age
Authors: Ackley Sarah F , Wang Jingxuan , Decarli Charles , Fletcher Evan , Joie Renaud La , Corrada María M. M. , Glymour M. Maria
Published: January 2025

Background

The relationship between tau pathology and cognition as a function of age and whether these relationships are consistent across samples is unknown. A growing number of studies now perform positron emission tomography with tau ligands (tau‐PET), making it possible for an improved understanding of the dynamics of tau and cognition in relation to other biomarkers.

Method

We used data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort (ages 55‐90) and The 90+ Study (Table 1) to cover a broad age range. We examined the association between region‐specific tau uptake by composite Braak stage and cognitive outcomes at the visit at which tau‐PET was performed (ADNI) or the closest visit (90+). We examined two cognitive outcomes: the mini mental status exam (MMSE) and clinical dementia rating sum of box scores. Spearman‐rank correlation coefficients between tau‐PET standardized uptake value ratios (SUVRs) with cerebellar cortex normalization and cognitive outcome are calculated for four distinct age ranges in ADNI: <60, 60‐70, 70‐80, and 80+ and among the 90+ study participants. Associations adjusted for age and age‐squared, race/ethnicity, number of APOE‐ε4 alleles, educational attainment, and gender are determined using bootstrapped linear regression.

Result

The association between region‐specific tau uptake by composite Braak stage and cognition appears consistent for ages 60‐80 (Figures 1 and 2), with worse cognition with higher tau. Over age 80, tau does not appear to be associated with cognition. Based on point estimates, some associations appear to be reversed over age 80 in ADNI, which is not the case in the 90+ study, although these differences between cohorts are not statistically significant.

Conclusion

Tau‐PET association varies with age, becoming less reliably associated with cognition over age 80. This is likely due to increased incidence of co‐occurring pathologies and selective survival. Associations may further depend on features of the source population.
Consistent Explainable features for Alzheimer’s Disease Assessment through Handwriting
Authors: Thebaud Thomas , Oh Esther S , Moro‐Velazquez Laureano , Dehak Najim
Published: January 2025

Background

Motoric changes are one of the earlier changes in neurodegenerative diseases such as Alzheimer’s disease (AD), but they are often difficult to detect especially in the early stages. In the past, examination of handwriting has been used to investigate motoric changes as a proxy for cognitive impairment. In this study, we explore a wide array of explainable features from the handwriting of patients, obtained using signal processing, and their impact on assessment of AD and Mild cognitive impairment (MCI).

Method

We collected data from 69 participants, 25 with AD or MCI, and 44 for the control group (CTL) on a digital tablet. We analyzed 13 different tasks, categorized into 4 groups: Point tasks (maintaining the pen still, close to the tablet), Spiral tasks (drawing spirals), Writing tasks (paragraphs from different stimuli), and Drawing tasks (drawing various images). Note that not all the participants succeeded to finish all the tasks. From the drawings of each subject were computed multiple characteristics: derivates of the positions, pressions and angles, then we used multiple statistics to get 367 global explainable features.

Those features were compared to obtain the ones providing consistently the most significant differences between the two studied groups using Welch's t‐test, with false discovery rate (FDR) correction. We checked their consistency by comparing which ones were significant across all the tasks of a certain group.

Result

Our results showed that out of the 367 features extracted, 189 features were significantly different between AD/MCI and the control group after FDR‐correction (p‐value<0.05), and 52 were statistically significant for all the tasks of at least one group of tasks.

Most of the significant features were directly related to the velocity with which participants executed the various tasks (average speed, angular speed, variations of the speed on tablet, etc.), and related to the non‐effective movements, measured by the entropies.

Conclusion

The analysis of a large variety of handwriting segments employing machine learning techniques can provide an assessment of patients with AD and MCI that may be useful in their early diagnosis.
Differences between high‐precision Alzheimer's disease plasma and PET biomarkers among cognitively normal older Black and White adults
Authors: Bubu Omonigho M , Boutajangout Allal , Debure Ludovic , Vedvyas Alok , Briggs Anthony Q , Bernard Mark A , Gills Joshua L , Valkanova Elena , Mbah Alfred , Ghuman Mobeena , Jean‐Louis Girardin A , Betensky Rebecca A , Marsh Karyn , Rusinek Henry , Osorio Ricardo S. , Wisniewski Thomas , Masurkar Arjun V.
Published: January 2025

Background

We evaluated whether baseline differences existed in various plasma Alzheimer’s disease (AD) biomarkers in cognitively normal participants racialized as Black or White.

Method

This cross‐sectional study included 203 (n=83 non‐Hispanic Black [NHB] and n=120 non‐Hispanic White [NHW]) cognitively unimpaired older adults from the NYU Alzheimer's Disease Research Center. Of the 203, 115 (39NHB, 76 NHW) had tau‐PET (PI‐2620/MK‐6240) data; 195 (85 NHB, 110 NHW) had amyloid‐PET (florbetaben); 98 (39 NHB, 59 NHW) had plasma Aβ40 and Ab42 data, 93 (37 NHB, 56 NHW) had data for total tau, 135 (55 NHB, 80 NHW) had neurofilament light (NfL) and glial fibrillary protein (GFAP) data and 139 (57 NHB, 82 NHW) had pTau181 data. Plasma biomarkers assay Aβ 40, Aβ42, total tau [t‐tau], neurofilament light [NfL], glial fibrillary acid protein [GFAP], ubiquitin carboxyl‐terminal hydrolase L1 [UCH‐L1] and pTau181 were measured were measured using Quanterix SIMOA HD‐1.

Result

Overall, mean (SD) age was 75.6 (6.5) NHW vs. 68.9 NHB (p=.008), BMI was 27.4 (9.7) vs. 32.4 (11.2) (p=.161), and education 17.0 (2.1) vs. 16.4 (2.32) (p=.273) for NHW vs. NHB respectively. Overall, 135 (66.5%) were females, of which 61 (73.5%) were NHB, and 62 were APOE ε4 carriers [30.5%], of which 27 were NHB. Compared to NHW, NHB subjects had significantly lower plasma Aβ40 (One‐tailed t‐test p=.006), NfL levels (p=.0005), Tau (p=.0313), pTau181 (p=.0015), and GFAP (p=.0005). NHB subjects had lower amyloid‐PET SUVR levels compared to NHW subjects (p=.0014). Baseline plasma Aβ42/40 and pTau181/Aβ42 levels were higher in NHB versus NHW participants (p=.002), consistent lower levels of amyloid pathology in NHB participants. There were no significant differences in levels of plasma Aβ42, tau‐PET SUVR, and UCH‐L1.

Conclusion

In this sample of cognitively normal older adults, NHB participants had biomarker measures suggestive of lower levels of cerebral amyloid pathology. This warrants further correlation with brain imaging and cognitive outcomes, and examination of the potential impact of demographic, socio‐structural and genetic factors on observed differences. Additionally, this may imply that racial variability in amyloid threshold possibly exists before clinical AD onset, potentially lowering the proportion of NHB patients eligible for AD therapies and trials.
Evaluation of image processing methods on amyloid PET scanner effects for multisite cross‐sectional and longitudinal studies of Down syndrome
Authors: Luo Weiquan , Laymon Charles M , Tudorascu Dana , Cohen Ann D , Ances Beau , Zaman Shahid , Christian Bradley T. , Klunk William E , Handen Benjamin L , Minhas Davneet S
Published: January 2025

Background

Gaussian smoothing to a common image resolution is frequently employed to harmonize Aβ PET in multisite studies. However, spatial smoothing of PET can increase spill‐over contamination between neighboring regions. Geometric transfer matrix partial volume correction (PVC) has been applied, in turn, to correct for such contamination. Despite being common practices, the impact of smoothing and PVC on scanner effects remains unclear for cross‐sectional and longitudinal outcomes.

We applied four putative image processing and statistical harmonization methods to unharmonized, multisite 11C‐PiB PET data from the ABC‐DS (11C‐PiB only) Down syndrome dataset to evaluate their impact on amyloid status group separation in cross‐sectional and longitudinal analyses.

Method

11C‐PiB images (Raw) from 4 different PET scanners (Table 1) were included in the analyses. Putative image‐processing harmonization methods evaluated were: (1) smoothing of PET images to an effective resolution of 8mm (Smo); (2) application of PVC to raw PET (Raw+PVC); (3) application of PVC to smoothed PET (Smo+PVC); and (4) application of ComBat/LongComBat to cross‐sectional/longitudinal Raw regional values.

SUVR outcomes were extracted for all methods from 9 Aβ‐relevant regions. Mean normalized additive and multiplicative scanner effects were assessed for image‐processing method outcomes using ComBat/LongComBat frameworks. Hedge’s g effect sizes were evaluated for all image‐processing and ComBat/LongComBat methods between Aβ status groups cross‐sectionally on regional SUVR outcomes and longitudinally on change score outcomes between baseline and follow‐up SUVRs.

Result

Estimated scanner effects across image‐processing methods are presented in Figure 1. Smoothing did not decrease scanner effects for any analyses, while Raw+PVC and Smo+PVC tended to increase scanner effects.

Effect sizes across methods, including ComBat and LongComBat, are presented in Figure 2. Cross‐sectionally, ComBat outperformed all other methods in 5/9 regions, with the greatest increase in effect size observed in the anterior ventral striatum. Longitudinally, Raw+PVC or Smo+PVC resulted in the greatest effect sizes in 8/9 regions. Importantly, smoothing reduced longitudinal effect sizes in 9/9 regions relative to Raw and obscured group differences in the anterior and posterior cingulates.

Conclusion

Gaussian smoothing may not address 11C‐PiB PET scanner effects estimated using ComBat/LongComBat frameworks. Spatial smoothing, in fact, may confound the ability to differentiate longitudinal change between groups.
Regional brain metabolism across the Alzheimer's Disease continuum in Down Syndrome
Authors: Arriola‐Infante José Enrique , Morcillo‐Nieto Alejandra O. , Zsadanyi Sara E , Franquesa‐Mullerat María , Vaqué‐Alcázar Lídia , Aranha Mateus Rozalem , Arranz Javier , Rodríguez‐Baz Íñigo , Maure‐Blesa Lucía , Videla Laura , Barroeta Isabel , Hoyo Laura Del , Benejam Bessy , Fernandez Susana , Hernandez Aida Sanjuan , Giménez Sandra , Alcolea Daniel , Belbin Olivia , Flotats Albert , Camacho Valle , Lleo Alberto , Carmona‐Iragui Maria , Fortea Juan , Bejanin Alexandre
Published: January 2025

Background

To date, limited data exist concerning the utility of FDG‐PET in detecting Alzheimer's Disease (AD) in Down Syndrome (DS). Yet, sensitive biomarkers for neurodegeneration are essential in this population genetically predisposed for AD. Therefore, we aimed at characterizing the effect of age, disease stage and AD pathology on brain metabolism in a large cohort of adults with DS.

Method

Cross‐sectional study with 72 controls (HC) and 100 participants with DS (63 asymptomatic [aDS], 13 prodromal AD [pDS], 24 AD dementia [dDS]) from the Down‐Alzheimer Barcelona Neuroimaging Initiative, undergoing 3T‐MRI, 18F‐FDG‐PET, lumbar puncture, and clinical assessment. 18F‐FDG‐PET scans were normalized using MRI data and scaled using the pons. CSF biomarkers were assessed utilizing Lumipulse (Aβ42/Aβ40 ratio and phosphorylated tau [p‐tau]) and ELISA (neurofilament light chain [NfL]) methods. Voxelwise analyses in SPM12 examined i) the effect of age, ii) AD clinical stage and iii) relationships with CSF biomarkers on brain metabolism.

Result

In HCs, brain metabolism decreased with age mainly in the frontal lobe, while in DS we observed a more distributed pattern, predominating in temporoparietal regions (Figure 1A‐B). The interaction indicated greater metabolic loss with age in DS compared to HC in lateral temporoparietal regions (Figure 1C). Compared to aDS, symptomatic DS exhibited lower metabolism in most regions, with the strongest effect in medial parietal and lateral temporoparietal structures (Figure 2). Additional comparisons revealed a clear decreased metabolism in posterior cingulate and angular gyrus in pDS vs aDS, and a more subtle metabolic loss in posterior lateral parietal areas in dDS compared to pDS. Associations between metabolism and CSF biomarkers were found in brain regions showing hypometabolism in symptomatic AD, and were most significant for NfL (Figure 3).

Conclusion

The age‐related decrease in brain metabolism was more pronounced in DS compared to HCs and likely reflects AD processes. The pattern of hypometabolism at the symptomatic stage predominated in temporoparietal regions and strongly resembles the pattern observed in sporadic AD, further emphasizing similarities between genetic and sporadic AD forms. The hypometabolism in parietal structures at the prodromal stage demonstrated 18F‐FDG‐PET´s sensitivity as biomarker for early AD diagnosis in DS.
Feasibility of A Multi‐Pronged, Multi‐Sensor Cognitive Aging Protocol in a diversified Cohort: Results from the Einstein Aging Study
Authors: Roque Nelson A. , Sliwinski Martin J. , Derby Carol A. , Lipton Richard B. , Buxton Orfeu M. , Katz Mindy J.
Published: January 2025

Background

Older adults, especially from diverse populations, are often presumed to be unwilling or unable to participate in mobile health (mHealth) studies. Since 2017, the Einstein Aging Study (EAS) participants have been instructed on and actively supported in completing comprehensive and intensive longitudinal assessments, harnessing the capabilities of smartphones and wearable devices. Notably, since early 2023, the EAS has expanded its scope by incorporating the gathering of data from multiple wearable sensors.

Method

In addition to clinic‐based neuropsychological testing, neurological exams and blood draws, the main protocol of the Einstein Aging Study asks participants to complete 14‐days of app‐based surveys and ambulatory cognitive assessments five times per day (i.e., upon wake‐up, at bedtime, and three notified assessments in between). Participants are also wearing sensors to collect data on air quality (via Atmotube Pro) and monitoring sleep, physical activity, and sedentary behavior (via Actiwatch, Actipal). We present compliance data for our new Ecological Momentary Assessment protocol.

Result

There are 112 total EAS participants (mean age = 80.87, SD= 6.06; % Female = 71.2; % non‐Hispanic Whites = 38.74%, % non‐Hispanic Blacks = 49.55%, % Hispanics = 11.71%). Overall, across our new ambulatory data collection protocol (i.e., data collected after yearly clinic visit on study smartphones and wearables), the EAS has robust compliance, with median total minutes of daily surveys ∼47 minutes. Specifically, for the Ecological Momentary Assessment (EMA) protocol delivered on study smartphones, 85% of participants completed 11 or more days of wake‐up surveys (self‐initiated), 79% of the first notified survey, 80% of the second, 77% of the third, and 82% completed the bedtime surveys (self‐initiated). There were no significant differences by race or ethnicity in adherence (one‐way ANOVA, all p's > 0.05).

Conclusion

These preliminary data for our longitudinal protocol provide continuing evidence of feasibility that older adults from diverse populations are adherent to intensive longitudinal data collection procedures, including when involving numerous wearable sensors. Future research may explore the influence or perturbations of EMA adherence when adding additional participant burden to a protocol (e.g., adding a continuous glucose monitor (CGM) sensor).
Effects of Amyloid Pathology and Vascular Risk Factors on Regional Cerebral Blood Flow Patterns
Authors: Taghvaei Mohammad , Sadaghiani Shokufeh , Shakibajahromi Banafsheh , Khandelwal Pulkit , Das Sandhitsu R. , Nasrallah Ilya M. , Yushkevich Paul A. , Wolk David A , Detre John A. , Dolui Sudipto
Published: January 2025

Background

Regional cerebral blood flow (CBF) can be noninvasively quantified using arterial spin labeled (ASL) perfusion MRI. In Alzheimer’s disease (AD) and mild cognitive impairment (MCI), hypoperfusion typically occurs in precuneus, posterior cingulate cortex (PCC), and hippocampus. Small vessel disease (SVD), a systemic disorder that commonly underlies vascular cognitive impairment, also causes brain hypoperfusion. Many dementia patients demonstrate both neurodegenerative and vascular pathologies, which may interact to accelerate cognitive decline. Here we used advanced background‐suppressed 3D ASL to assess CBF variations across the AD spectrum and in relation to risk factors for AD and SVD.

Method

Data from 258 participants comprising 180 cognitively unimpaired (CU), 54 MCI, and 24 AD participants, diagnosed by clinical consensus, were obtained from the Penn Alzheimer Disease Research Center. ASL CBF was quantified in gray matter (GM), white matter (WM), AD‐associated cortical regions of PCC+precuneus and hippocampus. We also considered normal‐appearing WM (NA‐WM) and periventricular WM (NA‐PVWM) in which voxels containing T2 white matter hyperintensities were excluded. PVWM is supplied exclusively by microvessels and may be a sensitive region for CBF reductions in SVD despite its small size. Global and regional CBF was compared across diagnostic groups. Furthermore, the influence of PET‐derived amyloid status and vascular risk factors (VRF: presence of any of hypertension, diabetes, obesity, hypercholesteremia, and smoking) on CBF were also evaluated.

Result

Across the AD spectrum, CBF was lower in AD‐associated cortical regions. AD also exhibited reduced CBF in GM, WM, NA‐WM, and NA‐PVWM (Table 1). Voxel‐wise comparisons of CBF contrasting amyloid‐positive or VRF‐positive MCI with corresponding amyloid‐negative or VRF‐negative CU showed that VRF effects were more widely distributed in GM and WM than amyloid status effects (Figure 1). There was a trend of reduced regional CBF with VRF‐positivity in amyloid‐positive AD+MCI suggesting an additive effect of VRF with amyloid and diagnosis (Figure 2).

Conclusion

Putative SVD regions showed diagnosis‐related CBF changes comparable in magnitude to typical AD cortical regions that may reflect vascular effects. Vascular risk was associated with more spatially distributed CBF reductions than amyloid status and may reflect its additive effect with amyloid on cognitive decline.
Baseline Aβ and tau markers contribute to localized patterns of brain tissue atrophy across 1223 individuals from four harmonized longitudinal datasets
Authors: Somu Sunanda , Zhu Alyssa H , Narula Siddharth , Gari Iyad Ba , Gadewar Shruti , Nir Talia M , Jahanshad Neda
Published: January 2025

Background

Amyloid‐β (Aβ) plaques and tau pathogenesis in the brain precede cognitive decline in the progression of Alzheimer’s dementia, yet the extent to which these measures can predict localized brain tissue atrophy has not been studied in a large, diverse population. Multisite studies offer robust statistical power with larger sample sizes but are confounded by variations in biomarker quantification across studies, including variations in MRI scanners, PET tracers, and CSF assays. Longitudinal data from N=1223 individuals from four independent AD studies were harmonized to assess localized brain tissue atrophy over 2 to 5 years. We tested for associations between volumetric changes and baseline measures of Aβ, phosphorylated tau (p‐tau), and cognitive function. Associations between atrophy and ApoE4 and diagnostic conversion were also assessed.

Method

Baseline (BL) and follow‐up (FU; mean=2.3+/‐0.5 years) 3T T1‐weighted brain MRI (T1w) from ADNI3 (N=373), Prevent‐AD (N=213), HABS‐MGH (N=213), and OASIS3 (N=424) were used along with corresponding PET measures obtained from FBB, FBP or PiB tracers, and CSF measures (Figure 1A). Subject‐wise maps of volumetric brain changes were created and warped to a common template for statistical analyses (Figure 1B). Voxel‐wise mixed effects linear regressions were run to test for associations between change in brain volume and Aβ‐42 positivity (CSF / PET), CSF p‐tau‐181 positivity, ApoE4 genotype, Clinical Dementia Rating (CDR), and diagnostic conversion (i.e., cognitively normal vs decline). Fixed effects included BL age, sex, scan time interval, and PET imaging tracer type or CSF processing batch; scan site was a random effect. FDR was used for voxel‐wise multiple comparisons correction.

Result

Aβ and p‐tau positivity at baseline, and the ApoE4 genotype, were associated with accelerated atrophy in the temporal lobe, medial‐parietal lobe and amygdala (Figure 2). CDR and conversion were associated with ventricular expansion and atrophy in the insula, temporal lobe, hippocampus and amygdala (Figure 3).

Conclusion

Our multi‐study brain mapping and harmonization approaches showed how baseline PET and CSF based amyloid and tau metrics are predictive of common and localized brain atrophy across multiple studies with diverse data collection protocols and study designs.
The synaptic marker NPTX2 and longitudinal brain atrophy among cognitively unimpaired adults
Authors: Anderson Claire L , Vazquez Juan , Zhu Yuxin , Pettigrew Corinne , Moghekar Abhay , Erus Guray , Davatzikos Christos , Xiao Mei‐Fang , Worley Paul F , Albert Marilyn S. , Soldan Anja
Published: January 2025

Background

Previous studies have shown that higher levels of the synaptic protein NPTX2, measured in cerebrospinal fluid (CSF), are associated with lower risk of progression from normal cognition to Mild Cognitive Impairment (MCI) and dementia. Among those with MCI or dementia, higher NPTX2 levels have been associated with decreased atrophy in AD‐vulnerable brain regions. It is not known, however, whether NPTX2 levels influence brain atrophy among cognitively unimpaired participants. This study examined the association between baseline CSF NPTX2 and longitudinal MRI brain volumetric measures among participants who were cognitively unimpaired at baseline, and whether AD pathology levels modify this relationship.

Methods

CSF and MRI data were collected from 213 BIOCARD Study participants (M baseline age = 57.2y, mean MRI follow‐up=13.9y), including 41 who have since progressed to MCI/dementia (Table 1). The analysis focused on a z‐transformed composite measure of three NPTX2 peptides, measured using parallel reaction monitoring mass spectroscopy. CSF Ab1‐42/Ab1‐40 and p‐tau181 were measured using the Fujirebio Lumipulse G1200 assays, with levels of AD pathology summarized as the p‐tau181/(Ab1‐42/Ab1‐40) ratio. Atrophy on volumetric MRI scans was quantified with MUSE and assessed as three composites including: (1) AD vulnerable regions (SPARE‐AD), (2) medial temporal lobe (MTL) regions, and (3) regions indexing advanced non‐AD related brain aging (SPARE‐BA).

Results

In mixed‐effects models covarying age, sex, and AD pathology levels (i.e., p‐tau181/(Ab1‐42/Ab1‐40)), higher baseline NPTX2 levels were associated with less atrophy over time in AD vulnerable (β=‐.008, p=0.03) and in age‐related regions (β=‐.01 p=0.01), see Table 2. Higher AD‐biomarker levels were associated with greater longitudinal atrophy in all MRI composites (all p<=0.001) but did not moderate the association between NPTX2 and atrophy (all p>0.52 for interactions of NPTX2 x p‐tau181/(Ab1‐42/Ab1‐40) x time).

Conclusions

These findings suggest that among cognitively unimpaired individuals, higher levels of NPTX2 may slow longitudinal atrophy in AD‐vulnerable and age‐related regions, independently of AD pathology levels. As a non‐AD‐specific marker of synaptic and neuronal function, these findings support the view that NPTX2 may be a resilience factor against neurodegeneration and cognitive decline and suggest that developing novel therapeutics that target NPTX2 and related synaptic proteins may have broad applicability.