bluuebunny/crossref_metadata_2025 huggingface dataset:
ALZpath pTau217: Alzheimer’s disease specificity in the context of multiple comorbidities and predictive capabilities for amyloid burden in combination with other blood‐based biomarkers
Authors: Chaby Lauren E , Borello Jacob , Vaughan Timothy , Portbury Stuart D , Frykman Hans , Mammel Anna , Encarnacion Mary , Serrano Geidy E , Beach Thomas G. , Masters Colin L , Rowe Christopher C. , Fowler Christopher J , Wilson Rachael E , Du Lianlian , Jonaitis Erin M. , Johnson Sterling C. , Jeromin Andreas
Published: January 2025

Background

Tau phosphorylated at position 217 (pTau217) is considered to have the highest accuracy in identifying Alzheimer’s disease (AD) pathology using blood. We describe a multi‐cohort evaluation of the Simoa ALZpath pTau217 assay for the prediction of amyloid status in combination with additional blood‐based AD biomarkers (GFAP, pTau181, etc.), as well as comparisons between histopathological and PET based amyloid measurements. We describe the contribution of a spectrum of neurodegenerative diseases and demographic features to circulating plasma pTau217 levels.

Method

The Simoa ALZpath pTau217 assay is an ultra‐sensitive blood‐based assay developed on the semi‐automated single‐molecule array Simoa platform. We evaluate Simoa ALZpath pTau217 in the Banner Brain and Body Donation Program (characterized by several clinically meaningful comorbidities and mid‐to‐late stage AD; pTau217 subset: mean Braak Score = 4.17, ADNC High Plaques = 28%, ADNC Intermediate Plaques = 33%), the Wisconsin Registry for Alzheimer’s Prevention (a longitudinal cohort focused on healthy cognition through MCI), and a cognitively normal amyloid negative subset of the Australian Imaging, Biomarker and Lifestyle (AIBL) study.

Result

We discuss ALZpath pTau217 predictive capabilities in the context of PET imaging and post‐mortem histopathology for total and region‐specific pathological burden and the relative contribution of other blood‐based biomarkers and demographic features. We also report AD and MCI specificity in driving plasma levels of ALZpath pTau217 in the context of multiple comorbidities including CAA, DLB, and VAD.

Conclusion

Findings support ALZpath pTau217 as a high performing biomarker of CNS amyloid and tau burden that is driven specifically by AD and MCI in the context of multiple comorbidities. The ALZpath pTau217 performance capabilities can support timely AD diagnosis and intervention.
Spatial heterogeneity in white matter hyperintensities revealed by postmortem MRI‐guided histopathological staining
Authors: Mojtabai Mariam , Li Karl , Rashid Tanweer , Li Jinqi , Honnorat Nicolas , Nirmala Anoop Benet , Martinez David M , Wang David H , Charisis Sokratis , Franklin Crystal , Keating Mallory , Boisselier Marco I , Katragadda Haritha V. , Maestre Gladys E. , Flanagan Margaret E , Richardson Tim , Walker Jamie M. , Fox Peter T , Seshadri Sudha , Bieniek Kevin F. , Habes Mohamad
Published: January 2025

Background

White matter (WM) hyperintensities are bright areas on T2 MRI that reflect increased interstitial fluid caused by demyelination and axonal loss; these tissue alterations have been associated with cognitive impairment. Previous in‐vivo studies have suggested that the underlying pathogenesis for WM changes differs between the anterior and posterior brain, with cerebrovascular disease contributing more to anterior WM lesions and neurodegenerative processes contributing more to posterior WM lesions.

Method

Periventricular (PV) and deep subcortical (DS) WM hyperintensities both in the anterior and posterior portions of the brain were identified using postmortem T2 MRI of cerebral hemispheres from the Biggs Institute Brain Bank (Figure 1) in 7 Alzheimer’s Disease patients (four male, three female, average age 75). Normal appearing (NA) WM at the base of the postcentral gyrus was selected as an internal control. Slide sections were obtained from these five regions across seven brains for 35 slides total using MRI landmarks to guide brain sectioning for histopathological analysis. The slides were stained using Luxol fast blue (LFB) and hematoxylin and eosin (H&E) and scanned digitally. Myelin was measured with the LFB, and vacuolation was measured with the H&E. Machine learning methods were used to segment and analyze the slides as the percent area stained in a selected region of interest (Figure 2).

Results

Compared to NA WM, areas of WM hyperintensities exhibited a lower average LFB‐stained area (p=0.001) and H&E‐stained area (p<0.001), indicating increased demyelination and vacuolation within the lesions. Anterior PV WM lesions demonstrated a higher extent of demyelination (p=0.055) and vacuolation (p=0.074) than posterior PV WM lesions (Table 1). Posterior DS WM lesions showed significantly more demyelination than posterior PV WM lesions (p=0.022).

Conclusion

The variations in demyelination within the WM lesions suggest differing underlying pathogenesis. This may be mediated by the differences in contribution from vascular and neurodegenerative causes as confirmed in previous studies. These preliminary results encourage the use of additional histopathological methods to better understand how different heterogeneous etiologies contribute to the development of white matter damage and how this can be translated into prevention strategies.
Adaptation and feasibility assessment of an intervention using mHealth and care navigation systems for people living with demencia and their caregivers in Peru
Authors: Flores Miriam Lucar , Cuba María Sofía , Canseco Francisco Diez , Moore Graham , Butler Christopher ,   Impact Dementia Study Group
Published: January 2025

Background

Dementia is a complex health condition that poses challenges not only to people living with dementia (PLWD) but to their families, the health system and society as a whole. Even though there is still no cure for dementia, different interventions are showing substantial contribution. mHealth‐based assistive technology has shown the potential to provide efficient healthcare for PLWD and their caregivers in cognitive training, health and safety monitoring, educational support, and socialization. Also, Care Navigation Systems offers person‐centered, strengths‐based, and continuous support to PLWD and their caregivers across the illness trajectory and different settings through collaborative problem‐solving and coaching. The IMPACT project will propose innovative solutions for dementia using a collaborative and multidisciplinary approach. For that reason, one of its components aims to adapt an existing intervention to improve the quality of life for PLWD and wellbeing of their caregivers to develop a context‐fit intervention in Peru.

Methods

To adapt an existing intervention from a High‐Income Country to the Peruvian context: The original intervention, The Care Ecosystem, is a supportive care navigation system delivered over the phone and the internet by care team navigators who respond to PLWD and caregivers’ immediate needs, provide personalized support and education using care plan protocols.

Phase 1: Will include the revision of the care protocols used by the original intervention to contrast their relevance and cultural fit with the experiences and needs of PLWD and ther caregivers from 4 regions of Peru (Lima, Tumbes, Iquitos, and Huancayo). This process will include a co‐design process with dementia experts, health providers and target population.

Phase 2: Conduct a feasibility trial of the adapted intervention on 120 PLWD/caregiver dyas (60 control group, 60 intervention group) during a period of 9 months.

Result

We expect to identify core change mechanisims of the Care Ecosystem program and develop an adapted intervention that can be cosidered feasible to implement within the Peruvian context.

Conclusion

The adaptation of the intervention will offer insights about the convenience of working with evidence‐ based interventions and the opportunities that can arise when they are carefully tailored to different context, norms and existing resources.
Characterization of plasma biomarkers of individuals with amyloid‐independent increased tau positron‐emission tomography uptake
Authors: Chan Tevy , Therriault Joseph , Wang Yi‐Ting , Aumont Etienne , Arias Jaime Fernandez , Macedo Arthur C. , Rahmouni Nesrine , Servaes Stijn , Trudel Lydia , Hosseini Seyyed Ali , Zheng Yansheng , Socualaya Kely Monica Quispialaya , Mathotaarachchi Sulantha , Stevenson Jenna , Jia Wan Lu , Matsudaira Takashi , Hall Brandon J , Lussier Firoza Z , Gauthier Serge , Triana‐Baltzer Gallen , Kolb Hartmuth C. , Karikari Thomas K , Ashton Nicholas J. , Benedet Andrea L. , Zetterberg Henrik , Blennow Kaj , Pascoal Tharick Ali , Rosa‐Neto Pedro
Published: January 2025

Background

Increased uptake on Tau positron‐emission tomography (PET) is sometimes observed in the absence of amyloid β accumulation. This A‐T+ PET profile might represent primary age‐related tauopathy (PART), an amyloid β‐independent 3R/4R tauopathy observed in aging brains. Although A‐T+ individuals have been shown to follow a different cognitive trajectory compared to A‐T‐ and A+T+ individuals, it remains unknown how they differ in terms of plasma biomarkers. Here, we aim to characterize the plasma biomarkers of A‐T+ individuals.

Method

This is a cross‐sectional study with data from the Translational Biomarkers in Aging and Dementia (TRIAD) cohort. Participants were classified into four categories based on their amyloid β ([18F]AZD4694) and Tau ([18F]MK6240) PET status (A‐T‐, A+T‐, A+T+ and A‐T+). Plasma biomarkers phosphorylated tau (p‐tau)181, p‐tau217, p‐tau231, total tau (t‐tau), neurofilament light (NfL) and GFAP were compared using the Kruskal‐Wallis test with post hoc Benjamini‐Hochberg (BH) correction. Discriminative performance was assessed using the area under the receiver operating characteristic curve (AUROC).

Result

Among the total 468 participants, 64 (13.7%) had A‐T+ PET status. The A‐T+ PET participants had a mean age 66.9 years (SD: 12.8), with 62.5% women and 39.1% showing cognitive impairment. Plasma p‐tau181, p‐tau217, p‐tau231 and GFAP were significantly higher in A+T+ individuals compared to A‐T+ (all p < 0.001). On the other hand, plasma p‐tau181 and 217 were significantly different between A‐T‐ vs A‐T+ (p<0.05), but not p‐tau231 and plasma GFAP. No significant differences were found in t‐tau or NfL regarding A‐T‐. Plasma p‐tau217 and plasma GFAP had the highest discriminative accuracies for A‐T+ vs A+T+ (AUROC: 0.860 and 0.836 respectively).

Conclusion

Our data suggest that individuals with an A‐T+ PET status exhibit a different plasma biomarker profile than those with A+T+ and A‐T‐ status. Further characterization of fluid biomarkers could help identify this group of individuals and facilitate the differential diagnosis of adults with cognitive impairment. Furthermore, our results lend support to the use of plasma biomarkers for identifying amyloid β PET positivity.
Identifying anatomical subtypes of sporadic EOAD in LEADS via unsupervised clustering of MRI‐based regional atrophy patterns
Authors: McGinnis Scott M , Katsumi Yuta , Eckbo Ryan , Brickhouse Michael , Eloyan Ani , Nudelman Kelly N. , Foroud Tatiana M. , Dage Jeffrey L. , Carrillo Maria C. , Rabinovici Gil D. , Apostolova Liana G. , Touroutoglou Alexandra , Dickerson Bradford C.
Published: January 2025

Background

Neurodegeneration in sporadic early‐onset Alzheimer disease (EOAD) is topographically heterogeneous, as suggested by variability in syndromic presentation. We performed an unsupervised clustering analysis of structural MRI data to identify anatomical subtypes of EOAD. We hypothesized that distinct clusters will be present but will: (1) share areas of overlap focused around posterior regions of our newly developed EOAD signature of cortical atrophy (Touroutoglou et al., 2023), including the posterior default mode (DMN) and frontoparietal control networks (FPN) of the cerebral cortex; and (2) show non‐overlapping topography inclusive of nodes of other networks including dorsal attention (DAN) and visual association (VIS) networks.

Methods

We analyzed structural MRI data from 183 individuals with EOAD and 88 cognitively unimpaired (CU) participants from the Longitudinal Early‐Onset Alzheimer's Disease Study (LEADS). MRI data were processed using FreeSurfer v6.0 to estimate vertex‐wise cortical thickness, which was converted to W‐scores (i.e., Z‐scores relative to CU participants adjusted for age and sex). We then performed an agglomerative hierarchical clustering analysis on a between‐patients similarity matrix computed from rank‐ordered whole‐cortex W‐scores.

Results

Analysis yielded 2 major clusters, with subordinate clustering failing to delineate additional unique topographies. One cluster (n=54) exhibited prominent atrophy in the anterior DMN (medial prefrontal cortex, anterior lateral temporal cortex) and rostral FPN (rostral middle and superior frontal gyri). The other cluster (n=129) showed prominent atrophy in the DAN (superior parietal lobule, caudal superior frontal gyrus, posterior temporal cortex) and VIS (posterior inferior temporal/occipital cortex, posterior parietal cortex). Both clusters showed atrophy in the posterior DMN (posterior cingulate cortex, precuneus, posterior inferior parietal lobule, mid lateral temporal cortex) and the FPN (middle and superior frontal gyri, anterior inferior parietal lobule, mid inferior temporal cortex). The clusters did not differ with respect to age, sex, education, APOE status, or clinical measures of disease severity.

Conclusions

Our sample of sporadic EOAD patients comprised 2 principal anatomical subtypes, commonly overlapping with the posterior DMN and FPN that constitute the EOAD signature, one subtype uniquely overlapped with the anterior DMN/rostral FPN and the other with the DAN/VIS network. Anatomical differences between the subtypes likely correspond to aspects of phenotypic heterogeneity.
Errors on Cognitive Testing in Asymptomatic and Prodromal Familial Frontotemporal Dementia and their Prognostic Utility
Authors: Palacios Brandon R. , Sanderson‐Cimino Mark E. , Paolillo Emily W. , Casaletto Kaitlin B. , Taylor Jack C. , Wise Amy B. , Dhanam Sreya , Bui Mai Anh , Heuer Hilary W. , Forsberg Leah K. , Boeve Brad F. , Rosen Howard J. , Boxer Adam L. , Miller Bruce L. , Seeley William W. , Tempini Maria Luisa Gorno , Kramer Joel H. , Staffaroni Adam M.
Published: January 2025

Background

The earliest cognitive manifestations of asymptomatic and prodromal familial frontotemporal dementia (f‐FTD) mutation carriers are still being characterized. Patients with symptomatic FTD are known to be error prone, particularly on tasks of executive function, but little is known about the frequency or predictive utility of these errors in the earliest stages of f‐FTD. The current study compared error rates on executive functioning tasks in controls and asymptomatic and prodromal mutation carriers and investigated whether errors predict worsening clinical status as follow up.

Method

This study included 90 participants (mean age = 48.57, SD = 13.30; 51.1% female; 86.67% white) with pathogenic FTD mutations (C9orf72, n = 45; GRN, n = 30; or MAPT, n = 15) who were asymptomatic or prodromal (Clinical Dementia Rating plus FTLD; CDR®+NACC‐FTLD ≤ 0.5). Propensity score matching identified (CDR®+NACC‐FTLD = 0) who did not carry pathogenic mutation but were matched on age, education, and sex. Regressions were used to compare controls and mutation carriers on error scores (rule violations and/or repetitions) from three executive functioning tasks: design fluency, lexical fluency, and Stroop inhibition. Mutation carriers with longitudinal data within 1.5 years were binarized as stable (n = 35) or progressors (n = 13) based on whether their CDR®+NACC‐FTLD sum of boxes score was worse at follow up (mean follow up = 1.07 years). Regressions were fit to evaluate the relationship between baseline error scores and group (i.e., stable vs. progressor).

Result

Mutation carriers committed significantly more errors than controls on the Stroop task (β = 0.67, p = 0.03) and lexical fluency (repetitions: β = 0.27, p = 0.02). The groups did not significantly differ in errors on the remaining tasks. A greater number of Stroop errors predicted mutation carriers who progressed at follow up (β = 1.04, p<0.001). When introducing the primary outcome from each task as a covariate (e.g., correct responses), the fluency task (repetitions: β = 0.10, p = 0.03) and Stroop task (errors: β = 0.82, p<0.001) were significantly associated with progression.

Conclusion

Errors on executive tasks may be early cognitive features in familial FTD. Importantly, errors were uniquely predictive above and beyond total scores. Research in larger samples will enable investigations of genetic differences in error rates.
Creating Universal Tau PET Scale (Uniτ) Parametric Images – The HEAD Study
Authors: Povala Guilherme , Bauer‐Negrini Guilherme , Bellaver Bruna , Lussier Firoza Z , Amaral Livia , Ferreira Pamela C.L. , Finn Quentin , Zatt Bruno , Tudorascu Dana , Jagust William J. , Klunk William E , Lowe Val J. , soleimani‐meigooni David N. , Oh Hwamee , Pascual Belen , Gordon Brian A. , Rosa‐Neto Pedro , Baker Suzanne L. , Pascoal Tharick Ali
Published: January 2025

Background

The HEAD study focuses on collecting an extensive dataset from various tau‐PET tracers, aiming to establish robust anchor values, which are essential for harmonizing tau‐PET measurements. Here, we aim to showcase the capability of converting 3D tau‐PET images into a common scale using the Universal Tau‐PET Scale, Uniτ (tau), and to use these 3D images to subsequently obtain ROIs as needed.

Methods

We assessed 185 individuals across the aging and AD spectrum from the HEAD study, with [18F]Flortaucipir and [18F]MK‐6240 tau‐PET tracers. Tau‐PET SUVR images were standardized to a common 8mm FWHM, using the inferior cerebellar gray matter as the reference region. We generated Uniτ Tau‐PET 3D images using a single formula based on Meta‐temporal parameters in two steps: first, within‐tracer anchoring based on young (<25 years) and cognitively impaired individuals; second, between‐tracer anchoring using a piecewise transformation from [18F]Flortaucipir to [18F]MK‐6240, with smoothing at the piecewise inflection point. Subsequently, we extracted mean Uniτ values from these 3D images for key ROIs, including meta‐temporal, mesial, temporo‐parietal, frontal, and Braak stages III‐VI. Finally, we correlated Uniτ values across ROIs between the two tracers to evaluate the accuracy of estimates from the voxel‐wise transformation.

Results

The original SUVR images present large differences between the two tau‐PET tracers (Figure 1). However, upon applying the Uniτ piecewise transformation with smoothing to all brain voxels, we were able to reasonably harmonize these images to the Uniτ scale, substantially reducing visual variability. Notably, the mean Uniτ values for the ROIs extracted from these harmonized 3D tau‐PET brain images demonstrated a high level of association between the two tracers (Figure 2). Furthermore, estimates generated from ROIs or extracted from our 3D parametric Uniτ model yielded identical estimates (Figure 3).

Conclusion

The strong associations between tracers after directly harmonizing 3D images to Uniτ scale using the piecewise transformation with smoothing, underscore the effectiveness of the proposed method. This approach provides a reliable and standardized way to compare tau‐PET data across different tracers. Our results indicate the feasibility of harmonizing 3D tau‐PET images without relying on pre‐established ROIs, overcoming the limitation of restricting the analysis to only few brain regions.
Can a picture description differentiate the nonfluent/agrammatic and logopenic variants of primary progressive aphasia?: Evidence from Catalan‐Spanish bilinguals
Authors: Pugalenthi Lokesha , Montagut Núria , Marques‐Kiderle Sonia Karin , Rodriguez Camille Wagner , Iyer Ami , Chaires Jan Christian Holst , Motta Whendy Avila , Filella‐Merce Júlia , Zhu Nuole , Rubio‐Guerra Sara , Illán‐Gala Ignacio , Borrego‐Écija Sergi , Lladó Albert , Fortea Juan , Lleo Alberto , Sanchez‐Valle Raquel , Santos‐Santos Miguel A , Grasso Stephanie M
Published: January 2025

Background

Primary progressive aphasia (PPA) is a language‐based dementia linked with underlying Alzheimer’s disease (AD) or frontotemporal dementia. Clinicians often report difficulty differentiating between the logopenic (lv) and nonfluent/agrammatic (nfv) subtypes, as both variants present with disruptions to “fluency” yet for different underlying reasons. In English, acoustic and linguistic markers from connected speech samples have shown promise in machine learning (ML)‐based differentiation of nfv from lv. To our knowledge, this approach has not been evaluated in other languages nor in the context of bilingualism.

Method

Twenty‐four Spanish‐Catalan bilingual patients (lv=15, nfv=9) were asked to describe a picture (WAB Picnic Scene) in both their dominant and non‐dominant language. From the participant’s recorded response, 10 acoustic features were derived with PRAAT and 15 linguistic features were derived with the Natural Language Processing (NLP) tools SpaCy and CLAN. A similarity score between the image and patient’s transcription was derived with the Vision‐Language model CLIP. The acoustic features, linguistic features, and CLIP scores, were separately fed into ML classification algorithms for differentiating nfv from lv in participants’ dominant and non‐dominant samples.

Result

The acoustic‐based classifiers achieved classification accuracy (F1 score) of 59% in the dominant and 86% in the non‐dominant language, respectively. The linguistic‐based classifiers achieved F1 scores of 73% in the dominant and 77% in the non‐dominant language, respectively. The CLIP‐based classifier achieved F1 scores of 82% in the dominant and 82% in the nondominant language, respectively. The acoustic and linguistic classifier performed 25% (p=0.077) and 4% (p=0.18) better given only non‐dominant samples compared to only dominant samples.

Conclusion

Taking advantage of recent advances in multilingual NLP, we achieved promising and effective differentiation of nfv from lv for Spanish‐Catalan bilingual patients using a nearly automated pipeline. Interestingly, our acoustic and linguistic‐based classifiers performed better given responses from a patient’s non‐dominant language, and the acoustic feature set was more accurate in discriminating between nfv and lv compared to the linguistic model. Future directions include examining patterns in a larger sample size and comparison of performance on different types of connected speech tasks.
Unraveling the earliest phases of vascular cognitive impairment and dementia by establishing a large USA CADASIL Consortium
Authors: Paulsen Jane S , Jayadev Suman , Geschwind Michael D , Biller Jose , Elliott Jamie L , Gutierrez Jose , Seshadri Sudha , Majersik Jennifer J , Orjuela Karen D , Liebeskind David S , Lutsep Helmi L , Hajjar Ihab , Bockholt Henry J , Salloway Stephen
Published: January 2025

Background

CADASIL, linked to NOTCH3 variants, is a primary monogenic cause of vascular dementia, leading to vascular cognitive impairment and dementia (VCID) observable in early stages. The NIH‐funded USA CADASIL Consortium aims to explore CADASIL's onset and progression in the USA, crucial due to varying phenotype‐genotype associations globally. The consortium will identify biological and clinical markers across the disease spectrum, contributing to clinical trial preparations. It will focus on clinical outcome assessments, biofluids and neuroimaging for biomarker identification, and disease modeling for subtypes, informing future clinical trial designs. The study will also examine genetic, health, and lifestyle factors impacting CADASIL outcomes.

Method

The methodology involves establishing a longitudinal cohort of 400 NOTCH3 carriers and 100 non‐carrier family members across 12 USA sites (www.cadasil‐consortium.org). Participants undergo annual clinical, cognitive assessments, advanced neuroimaging, and blood‐based phenotyping, targeting optimal biomarkers to determine minimal sample sizes for clinical trials.

Results

Despite COVID‐19 challenges, over 200 participants are enrolled, many already in longitudinal assessments. The Symptomatic (SYM) group, individuals with mild to moderate disability (Rankin Scale scores 1‐3), displays different cognitive and functional patterns from the Non‐Symptomatic (NSYM) group. The SYM group, mostly females (63) and Caucasians (101), has lower MOCA scores (average 25.2 vs. NSYM's 26.8) and SDMT averages (43.7 vs. NSYM's 51.4), indicating reduced cognitive function and processing speed. Functionally, SYM's average WHODAS score is 9.1, higher than NSYM's 3.1. The SYM group, averaging 53 years, is older than NSYM's 47.7 years, highlighting age's role in symptom severity.

Conclusion

The upcoming AAIC presentation will provide a comprehensive overview of the US CADASIL cohort, contrasting it with international data. Efforts are ongoing to establish a worldwide CADASIL Study Group to advance knowledge and treatment for vascular cognitive impairment and dementias.
Evaluating quality of routine vs. tape‐transfer histology sections for 3D reconstruction of paraffin embedded brain tissue and correlation with 7T MRI
Authors: Ho William Hai Dang , Wang Yixin , Taghavi Hossein Moein , DiGiacomo Phillip , Nirschl Jeffrey , Chu Pauline , Georgiadis Marios , Zeineh Michael
Published: January 2025

Background

Specimen analysis is crucial for identifying imaging and neuropathological signatures. Histology is the gold‐standard, but sample preparation and sectioning induce tissue deformations which hinder quantitative analysis or registration of histology to 3D MRI providing a challenge to the development of MRI biomarkers. Overall, we aim to develop a workflow to correlate histology with high‐resolution MRI at a microscopic level (Figure 1), Here, we evaluate a critical step in this process ‐ the section quality from tissue mounting techniques, comparing: A) traditional water bath (Figure 1F), and B) tape transfer (Figure 1G), for the purpose of image segmentation and correlation with high‐resolution MRI.

Methods

Fixed human brain specimens were MRI scanned, dehydrated with graded ethanol, xylene‐cleared, and paraffin‐embedded. Before sectioning, the specimen surface was captured by a brightfield microscope (Figure 2, top left, “Blockface image”). Embedded tissue was sectioned at 7 μm using a Leica 100 microtome and mounted on slides using either A) traditional water bath capture onto standard charged slides (Figure 1F), or B) tape‐transfer capture onto adhesive‐coated slides (Alphametrix) (Figure 1G). Slides were hematoxylin and eosin stained followed by imaging using the same microscope settings as the blockface image, and total stained tissue area was calculated. Area of expansion was determined by change from the blockface image (Figure 2, 3rd column). Internal tissue distortions were calculated by subtracting the tissue section mask from the original blockface mask (Figure 2, 2nd column).

Results

The tissue area measurements show that traditional capture resulted in average expansion of 16.7% relative to the blockface image, whereas tape transfer had 0.9% expansion (Figure 3). Both methods had similar amounts of average total tissue damage (approximately 3%), representing regions with tissue in the blockface image where no tissue was present on the slide. Subjectively, tissue distortion was concentrated at the periphery on traditional capture, whereas there were linear striations within internal structures on tape transfer (red arrows). Tissue yield for tape transfer was subjectively near 100% compared to traditional at approximately 60‐70%.

Conclusion

Tape transfer had a more consistent yield and better edge preservation with blockface image but had more internal microfractures
The use of FDG PET in the assessment of dementia syndromes: numbers from a reference center in Recife, Brazil
Authors: Pinheiro Mariana Gonçalves Maciel , da Silva Alberto Henrique Torres Trindade , Nunes Luiz Eduardo Duarte Borges , Arca Vitor Maia , Silva Milena Beatriz de Araújo , Barbosa Breno José Alencar Pires
Published: January 2025

Background

Positrons Emission Tomography associated with Computed Tomography – PET/CT using the 18F‐fluorodeoxyglucose is a well‐established exam for the context of dementia evaluation. However, FDG PET is a method still unavailable in most centers and diagnostic accuracy depends on the development of a flowchart that involves proper indication by clinicians and specialized evaluation by nuclear medicine specialists. Our study aims to investigate the indications of FDG PET in the differential diagnosis of dementia in a single center; secondarily, to evaluate how this method aided the diagnostic process.

Method

single‐center, descriptive analysis of patients with an initial diagnosis of neuropsychiatric syndromes that underwent FDG PET between 2018‐2023. We used an Excel chart to register clinical data and diagnostic hypothesis, followed by the FDG PET results. The final classification of each patient’s clinical diagnosis and image diagnosis findings was: concordant, discordant and undetermined concordation.

Result

56 patients were included. The mean age was 71 years‐old and 55.36% were female. The diagnostic impression of the PET‐CT report of these cases showed 13 non‐specific changes in the metabolic view, 16 changes compatible with Alzheimer’s Disease (AD), 7 Lewy Bodies Dementia (LBD), 11 Frontotemporal dementia (FTD), 1 was associated with Mild Cognitive Decline (CLD). Furthermore, 7 of the reports were described as “Negative for dementia” and 1 as progressive supranuclear palsy (PSP). The main indications for PET‐CT scans were suspicion between the diagnosis of AD versus FTD and AD versus LBD. Suspicions for pseudodementia and other diseases progressing to cognitive impairment were also evaluated. Of the 56 patients in the sample, 14 (25.00%) of the clinical impressions were discordant with the results of the imaging exam, 24 (42.86%) were concordant and in 18 (32.14%) comparisons the exam pointed to indeterminate result.

Conclusion

In this study, we observed that PET‐CT had the contributive potential to diagnostics of dementia in the majority of analyzed cases, in which it added value to initial clinical suspicions. In this sense, expanding data and carrying out new studies is still necessary.
Carotid stiffening with impaired damping is associated with cognitive impairment and reduced cerebral perfusion in elderly adults
Authors: Tang Jianing , Zhao Tianrui , Joe Elizabeth B , Pahlavian Soroush Heidari , Chui Helena C , Yan Lirong
Published: January 2025

Background

Emerging evidence indicates that arterial stiffening is associated with aging and cognitive impairment. Arterial stiffness is typically assessed by measuring pulse wave velocity (PWV) between carotid and femoral arteries. A recent study has introduced a fast oblique‐sagittal PC‐MRI (OS PC‐MRI) technique that allows for simultaneously quantifying carotid PWV (cPWV) and CCA‐ICA damping factor (cDF) within 2 minutes. This study aims to investigate the relationship between the pulsatile measures by OS PC‐MRI and cognitive impairment and cerebral perfusion in elderly adults.

Method

Forty elderly participants (22 female,73.3 ± 7.7 years) were enrolled in the study and underwent MRI scans at 3T including a vessel scout, retrospectively gated OS PC‐MRI (n=40), and pCASL (n=25). Neuropsychological tests were also conducted, including Clinical Dementia Rating (CDR, n=29), Mini‐Mental State Exam (MMSE, n=29), and Montreal Cognitive Assessment (MoCA, n=40). As shown in Figure 1, in OS PC‐MRI, Pearson correlation was performed to test the associations of the metrics pulsatile measures with cognitive functions and cerebral perfusion.

Result

Elevated cPWV was strongly associated with cognitive decline after controlling for age, gender, and years of education (cPWV vs. MoCA: r = ‐0.36, p = 0.03; cPWV vs. MMSE: r = ‐0.53, p = 0.005;) (Figure 2a). The participants with CDR>0 (n=19) showed higher cPWV values compared to those with CDR=0 (p=0.0045) (Figure 2b). cDF showed a significant correlation with MoCA (p = 0.036) (Figure 2c). Increased cPWV was also associated with downstream CBF in gray matter (p=0.034) and AD‐related regions (Figure 3).

Conclusion

Our results showed that both elevated CCA‐ICA PWV and DF were strongly associated with cognitive impairment and downstream cerebral perfusion deficits in elderly adults. These findings suggest that arterial stiffening with reduced damping leads to excessive transmission of pulse energy to downstream vasculature resulting in microvascular dysfunction and thus cognitive impairment.
The DICE Approach to Intervene the Behavioral and Psychological Symptoms of Dementia: a Study Protocol
Authors: Zheng Yaonan , Zhang Xingyu , Xia Mengmeng , Wang Huali
Published: January 2025

Background

The “Describe‐Investigate‐Create‐Evaluate” (DICE) approach has been considered as a guide for managing behavioral and psychological symptoms of dementia (BPSD). However, the implementation of DICE approach may be limited by few available resources. With the development of AI technology, the effectiveness of AI‐aided DICE algorithm for BPSD management has yet to be determined. Therefore, this study aims to examine the effectiveness of the AI‐aided DICE algorithm for managing BPSD in low‐resource setting.

Methods

The cluster randomized controlled trial will be conducted in 12 medical facilities where geriatric psychiatrists are not fully installed. One hundred and eighty‐four persons with mild and moderate BPSD will be enrolled and randomized to the AI‐aided DICE group (n = 92) and usual care group (n = 92). In the AI‐aided DICE group, all participants will receive comprehensive assessment on a digital triage platform to identify individualized needs and target symptoms, be prescribed with personalized management plan based on the AI‐aided decision process, be monitored about the implementation of management plan, and receive follow‐up assessment to evaluate the effectiveness. The neuropsychiatric inventory questionnaire and caregiver burden inventory will be used to measure primary and secondary outcomes. assess caregiver burden, records of care and adverse event. The study duration for each participant will be 12 weeks.

Discussion

We expect that the study will examine the effectiveness of the AI‐aided DICE algorithm for managing BPSD in low‐resource setting. The findings will support the implementation of AI‐aided algorithm and leverage the practice for quality care for dementia.
Temporal dynamics of brain connectivity across the dementia spectrum
Authors: King Jace B , Prigge Molly B.D. , Duff Kevin , Hoffman John M.
Published: January 2025

Background

Traditional functional connectivity is calculated as the correlation between resting‐state fMRI time series from pairs of brain regions or networks. Our innovative method extracts time series information from cross‐correlations curves between brain regions, thus deriving the relative duration of functional connections. These temporal analysis methods provide a means for examining how the timing of brain connections is affected across the dementia spectrum. This study extends previous research efforts into understanding the neural correlates of dementia by applying innovative resting‐state functional connectivity analysis methods to a sample of cognitively intact older adults (HC), individuals with mild cognitive impairment (MCI), and Alzheimer’s disease (AD).

Method

109 participants were included in this analysis (HC: n=47, 29 female, age=72.13±4.68; MCI: n=32, 18 female, age=73.84±5.14; AD: n=30, 19 female, age=77.37±6.45). All study participants were administered the Mini Mental Status Examination (MMSE), and completed MP2RAGE structural imaging and two 15‐minute resting fMRI scans. Cross‐correlation curves were constructed utilizing the Pearson correlation coefficient between pairs of times series for each of the 17 brain networks in the Yeo et al. parcellation. Correlation values were recorded at each of ±20 lags by shifting one of the time points by one volume. Sustained connectivity is derived from the full width at half maximum of the curve (Figure 1A) whereas lag‐based connectivity utilizes the correlation value at each lag. T statistics and p‐values are reported for across‐group connectivity values. Partial correlations were computed between connectivity measures and MMSE scores. All results include controlling for the effects of mean head motion, age, and sex.

Result

Sustained connectivity demonstrated distributed increases across groups (Figure 1B; HC<MCI<AD; pFDR<.05). At zero‐lag, we see decreased connectivity in MCI and AD compared to HC; however, as lag‐based connectivity is increased, we see increases in connectivity corresponding to diagnostic groups (Figure 2; HC<MCI<AD). Across study participants, both sustained and lag‐based connectivity were negatively correlated with MMSE scores (Figure 3; pFDR <.05).

Conclusion

Taken together, these findings suggest that functional connections between brain networks persist longer across disease states and that this longer duration of connectivity may reflect increased cognitive demand related to underlying cognitive processes.
The effect of traumatic brain injury and post‐traumatic stress disorders on AD pathologies, small vessel changes and ultimately cognitive function
Authors: Sibilia Francesca , Cen Steven , Choupan Jeiran , Hazany Saman , Ayala Rene , Cheng Jocelyn , Nejatpoor Tiana , Sheikh‐Bahaei Nasim
Published: January 2025

Background

Although many studies have shown that traumatic brain injury (TBI) and post‐traumatic stress disorder (PTSD) regardless of their severity, are associated with a significantly increased risk of all‐cause dementia, the specific pathophysiological mechanisms that underlie these associations remain poorly understood, resulting in discordance findings among different studies and contradictory claims in the current literature.

In this study we investigated the effect of TBI and PTSD on the level of amyloid, tau, as well as markers of small vessel health including white matter hyperintensity and perivascular spaces and consequently assessed their effect on the cognitive function in order to understand the pathways through which TBI and PTSD may result in dementia.

Method

The participants in this study were MCI cases drawn from the ADNI‐DOD (n=58). Cognitive performance was assessed using the Mini‐Mental State Exam (MMSE) and Clinical Dementia Rating (CDR). Inclusion criteria for TBI involved the history of moderate to severe nonpenetrating head trauma as well as combat history or presence in the battlefield. Inclusion in the PTSD group required a minimum Clinician Administered PTSD Scale (CAPS) score of 40 points. PET images with tracers AV1451 and AV45 were obtained. Perivascular spaces (PVS) volume fraction in the total white matter and basal ganglia was obtained using automated segmentation pipeline developed at our institute, as well as the grade of white matter hyperintensities.

Result

The volume of PVS in the white matter was found to be significantly higher in veterans with PTSD (p=0.01) or with TBI (p=0.02) after age adjustment. Elevated amyloid was also found in veterans with PTSD 1.3 (1.23‐1.39) vs. 1.23 (1.1‐1.53), p=0.05 and trend of increased amyloid with TBI 1.3 (1.18‐1.44) vs. 1.28 (1.23‐1.31), p=0.09. Our day also indicates a strong correlation between amyloid and CDR (adjusted ranking score correlation of 0.45 (p<0.01) among veteran sample.

Conclusion

Preliminary evidence showed the association from PTSD to amyloid as well as TBI to amyloid. Since amyloid strongly associated with cognitive function, it may suggest a biological pathway from PTSD and/or TBI through amyloid deposition to cognitive decline in veteran. Larger sample will be needed to confirm the causal pathway.
Association of plasma neurofilament light and white matter hyperintensity on memory: Differential findings across Apolipoprotein E risk groups in normal aging
Authors: So Mae Yue , Maillard Pauline , Jin Lee‐Way , Farias Sarah Tomaszewski , Decarli Charles , Sapkota Shraddha
Published: January 2025

Background

Neurocognitive trajectories in normal aging are a result of complex and synergistic associations of multiple risk domains. Blood‐based, neuroimaging, and genetic biomarkers all play fundamental roles that span decades leading to cognitive decline. We study all three risk domains on memory using an ethnoracially diverse cohort. Specifically, we examine (1) independent associations of plasma Neurofilament Light (pNfL) levels and white matter hyperintensity volume (WMHV) on episodic memory (EM), (2) pNfL levels on WMHV, and (3) synergistic model with pNfL and WMHV to predict EM, independently and as stratified by Apolipoprotein E (APOE) risk groups.

Method

We used an ethnically diverse cohort of cognitively normal (CN) older adults from the University of California, Davis‐Alzheimer’s Research Center (n=299, Table 1). EM was measured using the Spanish and English Neuropsychological Assessment Scales across eleven waves. WMHV and pNfL levels were obtained at baseline. Statistical analyses included a latent growth modeling to establish latent EM growth model, and regression analyses to test independent associations and stratification with APOE. APOE genotype risk was examined as ε4‐/ε4+. Age was centered at 75 years, and sex and education were included as covariates.

Result

First, higher pNfL level was associated with steeper EM decline (Table 2). Second, higher WMHV was associated with lower EM performance and steeper EM decline. Third, higher pNfL level was associated with higher baseline WMHV. Fourth, in the combined model, higher pNfL level was associated with steeper EM decline, higher WMHV was associated with lower EM performance, and higher pNfL level was associated with higher baseline WMHV. When stratified by APOE genotype risk, higher pNfL level and higher WMHV were associated with steeper EM decline only in the APOE ε4‐ group. However, higher pNfL level was associated with higher baseline WMHV across APOE ε4‐ and ε4+ groups (Figure 1).

Conclusion

We observed that the association between pNfL and EM, and WMHV and EM are both modified by APOE genotype (Figure 1). However, the relationship between pNfL and WMHV is present regardless of genetic risk. Examining biomarkers across multiple domains may lead to novel and effective clinical interventions in diverse CN populations.
Elevated IRS‐1 pS616 Pathology in Human Hippocampal Area CA1 as a Biomarker of Preclinical and Alzheimer's Disease Dementia
Authors: Gu Xuelin , Distel Tim , Talbot Konrad
Published: January 2025

Background

Alzheimer's disease (AD) is a progressive neurodegenerative disease whose risk can be assessed in the AT(N) framework based on brain levels of Aβ and pathological tau with or without neuronal injury. This helps determine if a cognitively normal or mildly cognitively impaired (MCI) person has clear signs of AD pathogenesis. The AT(N) framework might be enhanced by also considering brain insulin resistance (BIR), which is a common feature in AD dementia (ADd). However, a clear biomarker for brain insulin resistance has yet to be identified. Some studies have identified elevated insulin receptor substrate‐1 phosphorylated at S616 (IRS‐1pS616) in ADd, with conflicting results in other studies. Here, we observed IRS‐1pS616 is mostly limited to cell nuclei in hippocampal field CA1 of normal cases but becomes prominent in neuronal cytoplasm in ADd cases, quantifying this pathological feature using artificial intelligence‐based analysis.

Methods

We performed quantitative immunohistochemical studies on fixed hippocampal sections from 217 age‐ and sex‐matched cases: 68 non‐cognitively impaired (NCI), 13 preclinical (PrCl; i.e., NCI but A+T+), 24 non‐amnestic MCI (naMCI), 32 amnestic MCI (aMCI), and 80 ADd from 3 brain banks (University of Pennsylvania [UPenn], Rush University, and the Banner Research Institute) for β‐amyloid (NAB228), phospho‐tau (AT8), and IRS‐1pS616 (44‐550G). Immunoreactive cells and plaques were quantified using supervised deep‐learning U‐Net neural networks with additional morphology‐based criterions.

Results

Demographical characteristics of study participants are presented in Table 1. The density of CA1 neurons with IRS‐1pS616 pathology was significantly elevated in ADd cases across all cohorts, in PrCl cases from some cohorts, but not in MCI cases (Figure 1). Significant associations were found between IRS‐1pS616, β‐amyloid, and phospho‐tau pathologies in regression analyses, which were weak between IRS‐1pS616 cells and β‐amyloid plaques (Figure 2). No significant differences in IRS‐1pS616 pathology were found between APOE genotypes.

Conclusion

These results suggest that elevated IRS‐1pS616 pathology in hippocampal field CA1 is a potential biomarker for BIR in preclinical and ADd, which may be treatable with antidiabetics in the class of incretin receptor agonists shown to reduce BIR in ex vivo preparations of the hippocampus from MCI and ADd cases (see Abstract 89821).
Distinct associations between the neurite microstructure of white matter bundles, tau pathology and cognitive decline in preclinical Alzheimer's disease
Authors: Gozdas Elveda , Hosseini Hadi
Published: January 2025

Background

Recent advancements in molecular positron emission tomography (PET) enable precise tracking of tau pathology in Alzheimer's disease (AD). Tau pathology typically begins focally in the medial temporal lobe, rapidly expanding due to amyloid‐β (Aβ) influence. This expansion may lead to neurodegeneration along connected pathways to the tau epicenters, resulting in cognitive decline. Our study utilized PET scans, diffusion Orientation Dispersion and Density Imaging (NODDI), and longitudinal memory data to investigate the intricate connections between tau accumulation and neurite microstructures in white matter bundles connected to the tau epicenter and resulting cognitive decline.

Method

The study had 155 participants, including 90 cognitively normal (CN) and 65 mild cognitive impairment (MCI) from the Alzheimer's Disease Neuroimaging Initiative dataset (Table 1). The study included cortical tau accumulations in the entorhinal cortex (EC) to the hippocampus (H) and neurite microstructures of the cingulum hippocampal bundle (CHB). The study also included longitudinal episodic memory scores measured using the Rey Auditory Verbal Learning Test Immediate (RAVLT‐I).

Result

The association between tau accumulation in EC and H in the right and left hemispheres was found to be significantly related to the increased isotropic water (FISO) of HCB (p<0.01). In contrast, the fiber complexity (ODI) along the CHBshowed a correlation with tau accumulation in the right EC (p=0.03, t=2.31) and H (p=0.02, t=‐2.33) for the entire sample. It's worth noting that significant correlations between FISO and ODI and tau accumulations in the epicenters remained significant for the amyloid‐positive group (Aβ+ CN and MCI). Also, the tau aggregation in the retrosplenial cortex (RSC) was significantly correlated with the neurite layout of CHB (p<0.05). Finally, we explored the correlation between the microstructural changes in neurites along the CHB and cognitive decline. The linear mixed effect model showed a significant interaction effect of tau_EC (left)xCHB_ODI (left)xtime (p=0.03, f=4.58) and tau_RSC (left)xCHB_ODI (left)xtime (p=0.04, f=4.4) for predicting cognitive decline over three years.

Conclusion

Our research has revealed significant connections between the tau accumulation in tau epicenters and posterior regions and the microstructures of neurites along CHB, suggesting that CHB plays a crucial role in tau spreading and cognitive decline.