bluuebunny/crossref_metadata_2025 huggingface dataset:
MRI Assessment of Healthy Aging Trajectories in the Marmoset Brain
Authors: Szczupak Diego , Bhik‐Ghanie Rebecca , Zhang Bei , Papoti Daniel , Campos Vinicius , Dubberley Lauren R , Hitchens T Kevin , Yeh Fang‐Cheng , Schaeffer Lauren K Hayrynen , Carter Gregory W , Rizzo Stacey J Sukoff , Schaeffer David J , Silva Afonso C
Published: January 2025

Background

The common marmoset (Callithrix jacchus) is an important animal model in neuroscience and neurological diseases (e.g., Alzheimer’s disease ‐ AD), as they present primate‐specific evolutionary features such as an expanded frontal cortex. We established a new consortium with funding support from the National Institute on Aging to generate, characterize, and validate MArmosets as Research MOdels of AD (MARMO‐AD). This consortium develops and studies gene‐edited marmoset models carrying genetic risk for AD, comparing them against wild‐type aging marmosets from birth throughout their lifespan, using non‐invasive longitudinal assessments. Here, we aim to characterize healthy aging trajectories of regional brain volume in a population of marmosets.

Methods

We imaged a cohort of 59 marmosets ( 45 males, 14 females) across the lifespan (8 to 150 months) using a dedicated 9.4T 30cm bore MRI scanner (Bruker BioSpin Corp, Billerica). The animals were anesthetized under isoflurane and maintained under normal physiological conditions. High‐resolution (250 µm isotropic) T1‐, T2‐, and diffusion‐weighted structural MRI were acquired. The brain images were aligned and registered to the Marmoset Brain Mapping V3 template. The brain was segmented into cortical (CTX) and subcortical (SUB CTX) grey matter, white matter (WM), and cerebral spinal fluid (CSF), and voxel‐based‐morphometry was used to quantify regional brain volume in the left and right hemispheres.

Results

We discovered a decrease in grey matter volume in both males and females with age (Figure 1), reflected by the reduction in several cortical and subcortical brain regions in both sexes. Overall, we discovered that age affects female marmoset brains (38 CTX and 5 SUB CTX regions) more than males (15 CTX and 2 SUB CTX regions). We found no significant age‐dependent changes in WM and CSF.

Conclusions

Our work is the first to thoroughly describe the normal aging of the marmoset brain, a valuable model for age‐related neuropathologies (e.g., AD). This research will establish normative baselines for changes in regional marmoset brain volume with aging that will be used to evaluate our genetically engineered marmoset models of AD, which is the goal of the MARMO‐AD consortium.
Exploring Microtubule Dynamics in Alzheimer’s Disease: Longitudinal Assessment Using [11C]MPC‐6827 PET Imaging in APP/PS1 and PS301S Mouse Models
Authors: Damuka Naresh , Gollepalli Krishna Kumar , Krizan Ivan , Bhoopal Bhuvanachandra , Miller Mack , Deep Ojasvi , Bashetti Nagaraju , Kumar JV Shanmukha , Orr Miranda E. , Macauley Shannon L , Whitlow Christopher T , Mintz Akiva , Lockhart Samuel N. , Craft Suzanne , Sai Kiran K. Solingapuram
Published: January 2025

Background

Brains affected by Alzheimer’s disease (AD) exhibit senile plaques containing amyloid beta (Aß) peptides and neurofibrillary tangles, formed when tau becomes hyperphosphorylated and disengages from microtubules (MTs). Early instability in MTs is observed in the AD process, emphasizing its significance in connecting the hallmark pathologies of Aß/tau‐based degenerative events. While current Aß and tau PET approaches can characterize disease lesions, they fall short in capturing earlier molecular events. MT‐PET aims to address this gap by targeting these early events, providing crucial insights into AD pathophysiology. The PET radiotracer, [11C]MPC‐6827, capable of tracking and quantifying MT‐based changes in real‐time and in vivo, addresses an urgent unmet need and facilitates the monitoring of MT changes in the early stages of AD. Here we present for the first time a comprehensive longitudinal PET imaging study of [11C]MPC‐6827 in Aß‐overexpressing (APP/PS1) and tau‐overexpressing (P301S) mouse models of AD.

Methods

Longitudinal [11C]MPC‐6827 PET imaging, biodistribution studies, autoradiography, and behavioral assessments were conducted at multiple time points in APP/PS1 (3 to 22 mo old) and P301S (3 to 13‐mo‐old) transgenic (TG) and age‐matched wild‐type (WT) mice (n = 7/group). Whole‐brain standard uptake values for PET, %injected dose/gram for biodistribution, specific brain uptake for autoradiography, and nesting weight for cognitive assessments were determined and PET correlations for TG mice at different age‐points were calculated.

Results

Longitudinal PET imaging demonstrated a 1.3‐fold (***p<0.0001) and 0.9‐fold (**p<0.005) higher brain uptake in APP/PS1 TG mice from 3 to 22 mo and P301S TG mice from 3 to 13 mo respectively (Fig1) and uptake increased with increasing Aß and tau loads in AD brains. Longitudinal PET data positively correlated with biodistribution (Pearson r = 0.94), and autoradiography results (r = 0.55) and negatively correlated with cognitive data (r = ‐0.65) in APP/PS1 mice (Fig2).

Conclusion

Increased [11C]MPC‐6827 brain PET uptake with both increasing Aß and tau depositions longitudinally in AD brains (along with corroborating biodistribution and autoradiography results) clearly demonstrate the role of early MT dysregulations in Aß and tau‐based neurodegeneration processes. These findings highlight the potential of [11C]MPC‐6827 PET as a powerful tool for monitoring MT disintegration early‐on. Ongoing experiments are exploring translational potential in humans.
Multimodal phenotyping of successful cognitive aging
Authors: Behrenbruch Niklas , Molloy Eóin N. , Schwarck Svenja , Schumann‐Werner Beate , Garcia‐Garcia Berta , Vockert Niklas , Morgado Barbara , Rullmann Michael , Hochkeppler Anne , Fischer Larissa , Baldauf Kathrin , Schulze Peter , Müller Patrick , Stephens Andrew W. , Patt Marianne , Schildan Andreas , Behnisch Gusalija , Seidenbecher Constanze I. , Schott Björn H. , Esselmann Hermann , Wiltfang Jens , Barthel Henryk , Sabri Osama , Kreißl Michael C. , Düzel Emrah , Maass Anne
Published: January 2025

Background

While some memory decline in old age is “normal”, there are some older individuals with maintained high cognitive performance. Using a multimodal approach including neuroimaging, fitness, genetic and questionnaire data (Fig1A), we aimed to identify factors that are related to successful cognitive aging and whether these differ between sexes.

Method

We analyzed 165 cognitively normal older adults age = 60 years from an ongoing study (SFB1436) (age = 71±8years, 43% female). For all participants, we determined plasma Abeta1‐42/Abeta1‐40. Temporal lobe tau burden was estimated by [18F]PI‐2620 in a subsample (see Fig.1A for sample sizes). We assessed global white matter hyperintensity (WMH) volumes and gray matter thickness for medial temporal lobe (MTL), anterior cingulate cortex (ACC) and whole brain. We measured aerobic and muscular capacity (and blood pressure) by fitness assessment and trait/state anxiety by self‐reports. Genetic profiling included KLOTHO and KIBRA polymorphisms and APOE genotype. To phenotype successful cognitive aging, we i) grouped individuals age = 79.5 years into SuperAgers (N = 18) based on delayed verbal recall performance = normative values at age of 50‐60 years versus typical agers (N = 19). For the whole sample we ii) calculated cognitive age gap (CAG) as the difference between cognition‐predicted age and chronological age (Fig.3A). We assessed how markers of pathology, brain structure, fitness, mental health and genetics were related to CAG, covarying for chronological age, sex and education.

Result

SuperAgers and typical agers did not differ in age, sex, education, fitness, anxiety or Abeta42/40 (all p‐values>0.1). However, SuperAgers had less WMH volume, higher ACC thickness, lower blood pressure and less temporal lobe tau‐tracer binding (small subgroup;). In the whole sample, younger cognitive age related to higher MTL and global cortical thickness, less temporal tau‐tracer binding, less anxiety (all p<0.05; Figure 3B) and marginally to higher muscular capacity (p = .06). Only the association between anxiety measures and CAG was moderated by sex (Fig.3B). CAG was not related to genotype.

Conclusion

Our results suggest that successful cognitive aging is related to resistance against age‐related pathology and higher brain integrity. Younger cognitive age is linked to better mental health, especially in females.
Cavum Septum Pellucidum (CSP) as a Neuroimaging Signature of Head Impact Exposure compared to Non‐exposed Patients with Neurodegenerative Disease and Controls
Authors: Kamps Suzie , Hempel Hugo L. , van Amerongen Suzan , de Bruin Hannah , van der Linden Fleur H.C. , Barkhof Frederik , Scheltens Philip , Ossenkoppele Rik , Vijverberg Everard G.B.
Published: January 2025

Background

Cavum Septum Pellucidum [CSP] is commonly observed on neuroimaging in individuals exposed to repetitive head impacts [RHI] and in post‐mortem examination in Chronic Traumatic Encephalopathy [CTE]. A CSP is proposed as a potential biomarker for CTE, yet prevalence across neurodegenerative diseases and its clinical implications are largely unknown. We assessed CSP prevalence and clinical associations in RHI‐exposed individuals in comparison to veterans with a history of traumatic brain injury [TBI], individuals with a neurodegenerative disease (i.e. Alzheimer’s Disease [AD] or Frontotemporal dementia [FTD]) and Cognitively Unimpaired individuals [CU].

Method

The group‐of‐interest, i.e., individuals exposed to RHI in contact sports or military service (n = 66), was compared against age‐ and sex‐matched ADNI‐DOD participants with TBI (n = 62) and non‐exposed participants of the Amsterdam Dementia Cohort (AD, n = 30; FTD, n = 25; CU, n = 25). Structural 3D brain MRI scans were visually rated on CSP grade (ranging 0‐4, Figure 1) according to established criteria by two independent raters without access to clinical information. A CSP scored at least grade 2 was considered abnormal. If scores between raters differed, scans were discussed to reach consensus. Inter‐rater reliability was assessed with Cohens’ weighted Kappa (κ). We investigated group differences in CSP grade as well as associations between CSP grade and neuropsychiatric symptoms (using the Neuropsychiatric Inventory [NPI]) and CTE probability (using the Traumatic Encephalopathy Syndrome [TES] criteria).

Result

Inter‐rater reliability was substantial (κ = 0.712). Prevalence of an abnormal CSP differed between groups (χ2 = 11.72, p = .020). An abnormal CSP was observed most often in the RHI group (43%), followed by TBI (31%, OR = 0.589, p = .158), and significantly less in AD (16%, OR = 0.255, p = .014), FTD (17%, OR = 0.267, p = .029), and SCD (14%, OR = 0.222, p = .012) compared to RHI (Figure 2). Across groups, CSP grade was not associated with severity of neuropsychiatric symptoms (F = 1.7, p = 0.151). An abnormal CSP was observed more in RHI‐exposed individuals with probable (57%) or possible (55%) CTE compared to suggestive of CTE (36%) or no TES (36%).

Conclusion

A CSP was more prevalent in RHI‐exposed individuals and veterans with TBI compared to patients with a neurodegenerative disease or CU individuals. Presence of a CSP on MRI may be indicative of head impact exposure, especially repetitive impacts.
A Large Public Release of Clinical and Imaging Data from the Mayo Clinic Study of Aging
Authors: Schwarz Christopher G. , Kremers Walter K. , Prakaashana Carl M. , Przybelski Scott A. , Christenson Luke R. , Wiliams Josie M. , Gunter Jeffrey L. , Senjem Matthew L. , Arani Arvin , Reid Robert I. , Machulda Mary M. , Fields Julie A. , Lowe Val J. , Kantarci Kejal , Graff‐Radford Jonathan , Vemuri Prashanthi , Petersen Ronald C. , Knopman David S. , Jack Clifford R.
Published: January 2025

Background

The Mayo Clinic Study of Aging (MCSA) is a longitudinal, population‐based study of residents of Olmsted County, Minnesota, USA. MCSA is releasing de‐identified clinical and imaging data on GAAIN.org to benefit the research community.

Method

We included longitudinal clinical data from all participants of the Mayo Clinic Study of Aging 30‐90 years of age (average 70.0y) through the first 15 years of the study. Clinical data includes age, sex, self‐reported race/ethnicity, APoE4 allele status, cognitive impairment status (normal, MCI, dementia, or other), height, weight, blood pressure, multi‐domain neuropsychological scores, neuroimaging summary measurements, medications, cardiovascular risk factors, social activity, sleep, mood/anxiety, functional measures, and more. For our initial release of imaging data, we selected the first imaging timepoint acquired on 3T GE MRI scanners and amyloid (PiB) PET during the same visit, from all available imaging participants 50‐90 years of age (average 70.7y). Currently, we included 3D T1‐weighted (MPRAGE) MRI (1x1x1.2mm3), T2‐weighted FLAIR MRI (0.85x0.85x3.6mm3), diffusion MRI (2.7mm resolution with 41 directions at b=1000 and 5 b=0), and numeric cortical global SUVR and Centiloid values from PiB PET scans at 40‐60 minutes post‐injection. All images are released in DICOM format and thoroughly de‐identified using CTP while ensuring preservation of necessary fields for analyses. T1‐weighted and T2‐FLAIR MRI were also de‐faced (identifiable face imagery was removed and replaced with an average) using mri_reface version 0.3.3 to further protect participants’ privacy, and all de‐faced images were visually inspected by a trained data scientist for quality assurance.

Result

The first phase of our public data release includes clinical data from 5925 unique participants from the Mayo Clinic Study of Aging (MCSA), each ranging from 1‐12 visits at roughly 15‐month intervals, and three MRI sequences (T1‐w, T2‐w‐FLAIR, and diffusion) from 1802 unique participants. Demographic summaries are given in Table 1.

Conclusion

This large, richly characterized, de‐identified clinical and imaging dataset is available to the research community at https://www.gaaindata.org/partner/MCSA, and it is suitable for a wide range of research uses. Additional data will be released over time, including de‐faced amyloid PET images.
Measuring the Potential Risk of Re‐identification of Imaging Research Participants from Open‐Source Automated Face Recognition Software
Authors: Prakaashana Carl M. , Savvides Marios , Gunter Jeffrey L. , Senjem Matthew L. , Vemuri Prashanthi , Kantarci Kejal , Graff‐Radford Jonathan , Knopman David S. , Petersen Ronald C. , Jack Clifford R. , Schwarz Christopher G.
Published: January 2025

Background

Research subjects can potentially be re‐identified from de‐identified MRI, CT, and PET brain scans with up to 98% accuracy using Microsoft Azure’s cloud‐based commercial facial recognition software. This showed the need to “de‐face” publicly shared research brain scans. Subsequently, Microsoft has begun restricting its face recognition services, intending to prevent misuse. This study tests a variety of popular open‐source computer vision and facial recognition software packages to measure the re‐identification risk with only unrestricted free software.

Method

This study used brain MRI from Siemens 3T scanners and face photographs from 182 participants (ages 30‐90+) in the Mayo Clinic Study of Aging. Each participant had photos taken with an iPad, which were cropped loosely around the head and converted to black and white. A total of 81 renders (2D reconstruction images; Figure 1) were made from each 3D T2‐FLAIR MRI, simulating various camera and lighting positions. These face renders approximate black and white photos, allowing use with software packages developed for matching faces/features between photographs. Open‐source Python packages (OpenCV, DeepFace, face_recognition, scikit‐learn) and their included pre‐trained models (designed for photographs) were used to match participant photographs to the labelled library of MRI‐based face renders. A correct match was recorded when the top‐scoring render or set of renders automatically chosen by the algorithm was from the MRI of the correct participant.

Result

Feature matching with ORB and SWIFT (both from OpenCV) produced no correct matches, despite a prior publication reporting moderate success. The best match rates (Figure 2) were 58‐59% accuracy using face_recognition or DeepFace packages with support vector machines (SVMs). Without SVMs, these packages performed modestly worse (51%‐55%).

Conclusion

While the highest match rates obtained by widely available open‐source packages (roughly 60%) are much lower than those of a limited‐access commercial product (Microsoft Azure, with 98%), they show that actors with only access to no‐cost readily available software could still re‐identify a research subject from a brain scan most of the time. This further highlights the need for image refacing software, such as mri_reface, to protect the privacy and identifies of research volunteers.
Associations between tau accumulation and cognitive decline across the AD continuum differ by sex
Authors: Singleton Ellen Hanna , Mattsson‐Carlgren Niklas , Binette Alexa Pichet , Strandberg Olof , Stomrud Erik , Ossenkoppele Rik , Hansson Oskar
Published: January 2025

Background

female sex has been associated with faster tau accumulation over time and greater resilience in Alzheimer’s disease. However, relatively few studies have examined regional tau accumulation rates and cognitive resilience in a large amyloid‐positive cohort.

Method

We included n=761 amyloid‐positive (A+) participants from the Swedish BioFINDER‐2 study who had undergone (longitudinal) tau PET and cognitive testing, of whom n=253 were cognitively unimpaired (CU A+) and n=508 were cognitively impaired (CI A+). [18F]RO948‐tau‐PET SUVR within entorhinal, medial temporal, neocortical temporal, medial parietal, lateral parietal, occipital, frontal, anterior cingulate, insula and cortical composite regions was quantified. Cognition was assessed with the modified preclinical Alzheimer’s disease cognitive composite (mPACC5). Linear mixed models were fitted to assess the effect of the interaction between sex and baseline tau on cognition over time, adjusting for age, education and APOE e4 status.

Result

Demographic characteristics are shown in Table 1. Models assessing the effect of the interaction between baseline tau and sex on cognitive decline showed significant positive associations between multiple tau regions in CU A+ and longitudinal mPACC5 (medial parietal: 0.39±0.10, p=0.0005, lateral parietal: 0.31±0.08, p=0.0005, occipital: 0.26±0.07, p=0.0005, lateral temporal: 0.23±0.07, p=0.006, inferior middle temporal: 0.18±0.07, p=0.03, insula: 0.17±0.07, p=0.04, Figure 1), while models showed significant negative associations between some tau regions in CI A+ and longitudinal mPACC5 (lateral temporal: ‐0.38±0.11, p=0.007, inferior middle temporal: ‐0.35±0.11, p=0.01, anterior cingulate: ‐0.35±0.13, p=0.03, Figure 1). Assessing cognitive trajectories by sex per quartiles of baseline tau burden revealed that females show similar cognitive trajectories to males in the 1st‐3rd quartiles of tau burden, but seem to show less cognitive decline in the 4th quartile of tau burden in CU, while in CI, females show a steeper decline than males (Figure 2).

Conclusion

Our results suggest that cognitively unimpaired A+ females exhibit greater cognitive resilience, while cognitively impaired A+ females exhibit steeper cognitive decline than males in the face of tau pathology, and that these effects occur particularly at high levels of tau pathology.
Multisite Chronic Pain Accelerates Cognitive Decline Particularly in APOE e4 Allele Carriers
Authors: Bell Tyler R. , Franz Carol E. , Lerman Imanuel , Fennema‐Notestine Christine , Panizzon Matthew S. , Bennett David A. , Elman Jeremy A. , Kremen William S.
Published: January 2025

Background

Chronic pain is a predictor of cognitive decline and dementia, but whether risk is related to a specific site of pain versus multisite pain is unclear. Multisite chronic pain is theorized to involve hyper‐excitability in pain receptors and pain‐processing brain regions, possibly caused by neuroinflammation. These factors may increase vulnerability to cognitive decline, particularly in those at elevated risk for Alzheimer’s disease. We examined how multisite chronic pain relates to cognitive decline in older adults, the possible moderating role of APOE‐e4 allele status, and—in a postmortem subsample—associations with amyloid and tau.

Method

We examined 751 participants without dementia at baseline from the Religious Orders Study/Rush Memory and Aging Project (ROSMAP; Mean age = 79.47, SD = 6.93, Mean education = 6.42, SD = 3.63; 64% women) followed for up to 30 years with repeated cognitive testing measuring episodic memory, working memory, perceptual orientation, and processing speed (Mean years followed = 7.32, SD = 4.51). Individuals with multisite chronic pain, defined as joint pain in >2 body regions over the first 2 study waves, were compared to those without pain. Amyloid‐beta and tau were measured in a postmortem subsample assessed around 10 months after their last clinical evaluation using computer‐assisted immunoreactivity assays across 8 regions associated with Alzheimer’s disease (hippocampus; entorhinal cortex; midfrontal cortex; inferior temporal; angular gyrus; calcarine cortex; anterior cingulate cortex; superior frontal cortex

Result

Multisite chronic pain (n = 105) was associated with accelerated decline in episodic memory (b = ‐.03, p = .016) and processing speed (b = ‐.06, p<.001), particularly in APOE‐e4‐positive individuals (bs = ‐.05 and ‐.04, respectively, ps<.01). Only APOE‐e4‐positive individuals with multisite chronic pain showed significant decline in perceptual orientation (b = ‐.08, p = .015). Only APOE‐e4‐positive individuals with multisite chronic pain had higher levels of amyloid‐beta load compared to those without chronic pain (b = .51, p<.001). No differences in tau burden were detected. People with single‐site chronic pain showed no significant differences from people without chronic pain.

Conclusion

The results suggest that multisite chronic pain exacerbates cognitive decline, particularly in those at genetic risk for Alzheimer’s disease. In addition, the postmortem analyses suggest that early treatment of multisite chronic pain—a modifiable risk factor—might help to reduce amyloid accumulation.
Multi‐cohort temporal modeling of tau PET onset age and trajectories
Authors: Teague Jordan P , Heston Margo B. , Chavez Elena Ruiz De , Navaratna Ruvini , Cody Karly Alex , Morse Jacob , Deming Yuetiva , Christian Bradley T. , Johnson Sterling C. , Langhough Rebecca E. , Betthauser Tobey J.
Published: January 2025

Background

Sampled iterative local approximation (SILA) is a temporal modeling method previously validated in three cohorts to estimate person‐level amyloid PET onset age and predicted change. This study validates SILA to model longitudinal tau PET trajectories, generate person‐level estimated tau onset age (ETOA), and characterize forward and backward prediction accuracy in the Wisconsin Registry for Alzheimer’s Prevention (WRAP), Wisconsin Alzheimer’s Disease Research Center (WADRC), and the Alzheimer’s Disease Neuroimaging Initiative (ADNI).

Method

N=273 participants (mean(SD) baseline age=70.79(6.70)) from WRAP and WADRC underwent longitudinal 18 F‐MK‐6240 tau PET imaging. Data processing included Harvard‐Oxford ROI parcellation of T1‐weighted MRI and generation of regional MK‐6240 standard uptake volume ratios (SUVR; inferior cerebellar GM reference region; 70‐90 min). Volume‐weighted SUVR corresponding to the meta‐temporal composite (MTC) was averaged across amygdala, parahippocampal gyrus, temporal fusiform cortex, inferior‐temporal, and middle‐temporal bilateral ROIs. Gaussian mixture modeling was applied to baseline SUVR to establish tau positivity (T+) thresholds (MK‐6240 SUVR>1.39; FTP SUVR>1.36) 2SD above the mean of the lower distribution. Ten‐fold cross validation was used to characterize forward and backward SUVR prediction and T+/‐ stratification accuracy. Forward prediction was evaluated by predicting SUVR at each person’s last observation inputting each person’s first observation whereas backward prediction used the last observation to predict SUVR at the first observation. Results were compared with SILA validation using UC‐Berkeley processed ADNI Flortaucipir data with similar processing methods.

Result

SILA exhibited similar prediction accuracy and midpoint conversion error in Wisconsin and ADNI studies. Figure 1B/D depicts MTC‐tau onset‐age‐aligned trajectories in Wisconsin and ADNI cohorts, respectively. Backward SUVR prediction error was lower and T+/‐ stratification accuracy was higher than forward prediction (ADNI RMSEforward=0.12, ADNI RMSEbackward=0.08; WI RMSEforward=0.22, WI RMSEbackward=0.17; forward accuracy=0.90, 0.92; backward prediction accuracy=0.96, 0.98 for ADNI and WI, respectively; Table 1). In the T‐ to T+ converters subset, backwards ETOA confidence intervals were within ‐2.68 to 2.04 years of midpoint between the observed last negative and first positive scan (Figure 2).

Conclusion

SILA provides replicable estimates of T+ onset age and similar prediction accuracy with MK‐6240 and FTP. Future work will investigate how sources of tau PET variability influence temporal modeling outcomes.
Association of Chronic pain with Alzheimer’s‐related brain structure and plasma biomarkers in older men
Authors: Bell Tyler R. , Franz Carol E. , Fennema‐Notestine Christine , Panizzon Matthew S. , Lyons Michael J. , Elman Jeremy A. , Kremen William S.
Published: January 2025

Background

Chronic pain leads to tau accumulation and hippocampal atrophy in mice. Tau accumulation in the locus coeruleus (LC) precedes medial temporal accumulation in humans. Here we provide one of the first human studies examining the association of chronic pain with hippocampal volume, LC integrity, and Alzheimer’s Disease (AD)‐related plasma biomarkers. We predicted associations with rostral‐middle, but not caudal, LC because the former is more aging‐ and Alzheimer’s‐related.

Method

Data were from 3 waves of the Vietnam Era Twin Study of Aging (VETSA) at average ages 56, 62, and 68. Chronic pain was defined as moderate‐to‐severe pain occurring >2 waves. At wave 3, 424 participants (mean age = 67.06) underwent LC‐sensitive MRI scans from which we calculated an LC contrast‐to‐noise ratio (LCCNR), an index of LC integrity. We measured hippocampal volume with traditional structural MRI. At wave 3, biomarkers were obtained from fasting blood draws taken the morning of the medical interview and cognitive testing, typically a day prior to the MRI exam. Immunoassays calculated levels of plasma total tau, beta‐amyloid (Aß) 40, Aß42, Aß42/Aß40 ratio, and neurofilament light (NfL). All biomarkers were log‐transformed and adjusted for site and storage time. Analyses accounted age, major health conditions, depressive symptoms, and opioid use.

Result

Men with chronic pain had smaller hippocampal volume (ß = ‐0.24, p = .039) and lower rostral‐middle LCCNR (ß = ‐0.38, p = .004) but not caudal LCCNR (p = .750). Men with chronic pain also had higher levels of plasma total tau (ß = ‐0.32, p = .047), Aß42 (ß = .42, p = .033), and Aß40 (ß = .31, p = .032) compared to men without chronic pain. However, men with chronic pain did not differ from men without chronic pain on Aß42/Aß40 ratio (p = .979) or NfL (p = .313).

Conclusion

Extending the animal model, these findings suggest that chronic pain is associated with tau accumulation and reduced structural brain integrity in regions affected very early in the development of AD. Increases in individual Aß measures associated among those with chronic pain but lack of association with the Aß42/Aß40 ratio may reflect non‐AD‐specific health‐related factors rather than brain amyloid, or alternatively, might be due to the relatively young age of the sample or the sensitivity of the assay.
Relationships between PET and blood plasma biomarkers in corticobasal syndrome
Authors: Singh Neha Atulkumar , Alnobani Alla , Graff‐Radford Jonathan , Machulda Mary M. , Mielke Michelle M. , Schwarz Christopher G. , Senjem Matthew L. , Jack Clifford R. , Lowe Val J. , Kanekiyo Takahisa , Josephs Keith A. , Whitwell Jennifer L.
Published: January 2025

Background

Corticobasal syndrome (CBS) is a progressive neurodegenerative syndrome that can result from several underlying neuropathologies, including Alzheimer’s disease (AD). Little is known about the utility of blood plasma measures to predict PET biomarker confirmed AD in CBS.

Method

Eighteen CBS patients (8 PET Aß+; 10 PET Aß‐) and 8 cognitively unimpaired Aß‐ individuals (CU) were recruited by the Neurodegenerative Research group from the Department of Neurology, Mayo Clinic, Rochester, MN, underwent Aß (Pittsburgh Compound‐B) and tau (18F‐flortaucipir) PET and provided a blood sample. Blood plasma analysis was performed to assess p‐tau 181, total tau, Aß 42/40, neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) using the Quanterix Simoa platform. Plasma concentrations were compared between Aß‐, and Aß+ CBS and controls using Kruskal‐Wallis corrected for multiple comparisons using Dunn’s test, with effect size measured with area under the receiver operating characteristic curve (AUROC) analysis. Spearman correlations were calculated to assess relationships between plasma concentrations and Aß and tau PET uptake.

Result

The CBS Aß+ group showed reduced Aß42/40 ratio, with elevated p‐tau 181, GFAP and NfL plasma concentrations compared to CU, while the CBS Aß‐ group only showed elevated NfL concentration compared to CU (Figure 1). Both p‐tau 181 (AUROC=0.95) and GFAP (AUROC=0.91) plasma concentrations were able to differentiate CBS Aß‐ from CBS Aß+. Plasma p‐tau 181 and GFAP concentrations showed a positive correlation to both Aß and tau PET uptake, and the Aß42/40 ratio showed a negative correlation to Aß PET uptake (Figure 2). No correlations were observed between NfL and Aß and tau PET.

Conclusion

This study supports the use of plasma p‐tau 181 and GFAP to detect AD in CBS, while NfL shows potential as a nonspecific disease biomarker of CBS regardless of underlying pathology. Plasma concentrations of these biomarkers may potentially be incorporated into clinical trials targeting CBS patients with underlying AD pathology.
Asymmetrical Neuroimaging Insights in CSF‐Validated Early‐Onset Alzheimer's: Integrating PET, MRI, and Cognitive Assessment
Authors: Özçelik Sinem , Yiğit Pınar , Bozdemir Tolga Can , Kaya Gamze Çapa , Yildirim Zerrin , Tee Boon Lead , Gurvit Hakan , Yener Görsev , Tempini Maria Luisa Gorno , Öz Didem
Published: January 2025

Background

Early‐onset Alzheimer's disease (EOAD), manifesting before age 65, demands nuanced diagnostic approaches. FDG18‐PET unveils metabolic insights, the MRI scale captures structural changes, and ACE‐R assesses cognitive impairment details. A holistic evaluation enhances diagnostic precision and enriches our understanding of cognitive decline in early‐onset presentations.

Method

Early‐onset Alzheimer's disease (EOAD), manifesting before age 65, demands nuanced diagnostic approaches. FDG18‐PET unveils metabolic insights, the MRI scale captures structural changes, and ACE‐R assesses cognitive impairment details. A holistic evaluation enhances diagnostic precision and enriches our understanding of cognitive decline in early‐onset presentations.

Result

Twenty‐two patients (59.1% women) with a mean age at diagnosis of 55.3 (±6.52 StD) years participated. The mean disease duration was 5.06 (±2.95 StD) years. All of the patients were right‐handed. The mean Aß42 and phos‐tau were 392.49 (±200.13 StD) and 130.93 (±142.56 StD) pg/ml, respectively. No significant difference was found between the right and left insular cortex in PET, and no statistically significant asymmetry was found between VAS scores in MRI (p > 0.05). There was no correlation between PET index with CSF Aß42 and and phos‐tau values.

Conclusion

This study underscores notable asymmetries in PET atrophy scores between the corresponding right and left brain regions in Alzheimer's patients. Given that EOAD manifests with atypical clinical symptoms, and all participants in this study exhibited left‐hemispheric dominance, the observed metabolic asymmetry, in the absence of a corresponding structural asymmetry, holds clinical significance.
Association of amyloid and tau pathology in longitudinal cognitive reserve
Authors: Borelli Wyllians Vendramini , Schlickmann Thomas Hugentobler , Ferrari‐Souza João Pedro , de Bastiani Marco Antônio , Bieger Andrei , Schilling Lucas Porcello , Rosa‐Neto Pedro , Zimmer Eduardo R.
Published: January 2025

Background

Higher educational attainment is frequently associated with lower risk of cognitive decline. Many neuroprotective factors have been suggested as the biological underpinnings of cognitive reserve (CR), though the neural basis of CR is yet unclear. Herein, we aim at investigating the effect of CR using educational attainment in individuals stratified by amyloid and tau status.

Method

A total of 135 participants, classified as cognitively unimpaired (CU) or Mild Cognitively Impaired (MCI), were selected from the ADNI cohort. All individuals that presented longitudinal measures and available amyloid and tau PET at baseline were included in this study. Formal years of education were selected as a proxy of cognitive reserve in this study, and individuals were classified into high CR (>17 years of education), intermediate CR (between 17 and 16), and low CR (<16 years of education) based on interquartile range. This analysis was in accordance with the most recent research framework to identify the mechanisms of cognitive reserve. A linear mixed‐effect model was performed to evaluate the interaction of cognitive reserve in the relationship between cognitive decline and AT status. The model was adjusted for age, sex, baseline diagnosis. Data is presented in mean±SD.

Result

A total of 58 high CR (71.7±5, 57% males), 41 intermediate CR (70.4±6, 59% males) and 36 low CR (69.8±6.4% males) were included (Table). At baseline, these individuals were divided as A‐T‐ (n = 69), A‐T+ (n = 11), A+T‐ (n = 27) and A+T+ (n = 28). Mean follow‐up time of the sample was 3.15±0.9 years. Linear mixed‐effect model showed a significant interaction of cognitive reserve in the relationship between CDR‐SOB and A+T+ status (beta = 0.24, p‐val = 0.019), after adjusting for covariates. Sensitivity analysis adjusting for APOE status also demonstrated the same relationship.

Conclusion

The neuroprotective effect of cognitive reserve was prominent in individuals with both amyloid and tau pathology, but not in the Alzheimer’s pathological changes (A+T‐). Understanding the neural basis of cognitive reserve may greatly improve the advancements in therapeutic targets for secondary prevention of cognitive decline in individuals with identified Alzheimer’s disease pathology.
A polymorphism in RELN protects against amyloid‐driven tau pathology and cognitive decline in sporadic Alzheimer’s disease
Authors: Carello‐Collar Giovanna , Schlickmann Thomas Hugentobler , Ferrari‐Souza João Pedro , de Bastiani Marco Antônio , Cristino Alexandre Santos , Pascoal Tharick A. , Rosa‐Neto Pedro , Souza Diogo O. , Zimmer Eduardo R.
Published: January 2025

Background

A rare reelin gene variant (RELN‐COLBOS mutation) delayed dementia onset in almost 30 years in an autosomal dominant Alzheimer’s disease (ADAD) carrier. This patient presented with high amyloid‐ß (Aß) plaque load, but low tau accumulation, suggesting that this single‐nucleotide polymorphism (SNP) in RELN conferred a resilience not only to cognitive decline but also to tauopathy in ADAD. However, whether RELN SNPs are also protective in sporadic Alzheimer’s disease (AD) is yet to be determined. Thus, we sought to examine the impact of RELN SNPs on AD pathophysiology and cognitive deterioration in sporadic AD.

Method

We assessed 198 individuals [105 cognitively unimpaired (CU) and 85 cognitively impaired (CI)] from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) with available data on RELN SNPs and amyloid‐ and tau‐PET measures ([18F]‐florbetaben/florbetapir and [18F]‐flortaucipir, respectively), Aß1‐42 and ptau181 in the CSF, and neuropsychological testing (Clinical Dementia Rating Sum of Boxes). We analyzed the effect of RELN SNPs carriership in the association between amyloid and tau burden through linear regression analysis and on cognitive decline according to CSF AT status through linear mixed‐effect model correcting for age, sex, and ApoEe4 status (Bonferroni’s adjusted p‐value < 0.05).

Result

We performed linear regression analysis in all the 235 RELN SNPs available on ADNI (Fig.1). We found RELN rs802787 protected against amyloid‐driven tau pathology (adj. p‐value < 0.001, Fig.2). Dividing individuals according to the CSF AT status, we observed that RELN rs802787 did not impact the rate of decline in cognition in A‐T‐ and A‐T+ individuals (Fig.3A‐B). By contrast, RELN rs802787 CSF A+T‐ individuals presented a slower cognitive decline (Fig.3C), which was not observed in A+T+ individuals (Fig.3D).

Conclusion

Here, we show RELN rs802787 carriers presenting high amyloid load have lower tau accumulation than non‐carriers. In addition, CSF A+T‐ RELN carriers presented a slower cognitive decline compared to non‐carriers. Our results suggest that RELN rs802787 carriership protects against amyloid‐driven tau pathology and cognitive deterioration in sporadic AD individuals. To the best of our knowledge, this is the first RELN SNP found to be protective against non‐familial AD.
Longitudinal beta‐amyloid measured with [C‐11]PiB accumulates at an accelerated rate in Down syndrome compared to neurotypical populations
Authors: McVea Andrew K , DiFilippo Alexandra H , McLachlan Max , Bettcher Brecca , Zammit Matthew D , Betthauser Tobey J. , Converse Alexander K , Murali Dhanabalan , Stone Charles K , Hartley Sigan L , Johnson Sterling C. , Tudorascu Dana , Laymon Charles M , Cohen Annie , Minhas Davneet S , Mathis Chester , Ances Beau , Zaman Shahid , Mapstone Mark , Head Elizabeth , Klunk William E , Handen Benjamin L , Christian Bradley T.
Published: January 2025

Background

Trisomy 21 in Down syndrome (DS) is associated with an earlier accumulation of beta‐amyloid (Aß) plaques and a higher rate of Alzheimer’s Disease due to the triplication of the amyloid precursor protein gene. In this study we compare accumulation rates of Aß measured with [C‐11]PiB PET between large longitudinal cohorts of DS and neurotypical (NT) participants at a single site.

Methods

Participants imaged at the University of Wisconsin with =2 PiB scans and =2 years between scans were included in this study. DS participants were included from the Alzheimer’s Biomarker Consortium–DS (ABC‐DS) study (n = 57) and NT participants from studies enriched with familial risk for AD (n = 162) with several participants having 10+ years of PiB data. An identical imaging procedure was conducted for all subjects and reconstructed PET images were processed using a standardized pipeline and converted into SUVR images using the cerebellar grey matter reference region. Global PiB SUVR, defined by grey matter regions from the AAL atlas, was used as a metric for Aß deposition and input into a trajectory model (Betthauser, 2021) to estimate time from Aß(+) (SUVR = 1.40) for each scan (Fig. 1). Using this model the PiB data were normalized in time and then fit using the logistic growth curve () with t50 set to 0. Nonspecific binding (NS), found by taking the average SUVR of all Aß(‐) subject scans (n=491) at our site, and carrying capacity (K), represented by the highest total binding seen in any participant scanned, were set to 1.12 and 2.40 respectively. Aß accumulation rate (r) was calculated by fitting all normalized participant data across each population.

Results

Rate of Aß accumulation for DS was 0.25±0.02 and 0.17±0.01/yr for NT, corresponding to 0.065 and 0.038 SUVR/yr respectively when becoming Aß(+). No overlap in 95% CI between the DS (0.21‐0.29) and NT (0.15‐0.19) populations was observed.

Conclusions

There was a faster rate of Aß accumulation observed in our DS cohort compared to NT by 47%. However, the high variability in Aß rates requires further investigation towards understanding how genetic and lifestyle factors contribute to this process.
Plasma ADRD biomarkers predict longitudinal declines in intra‐network functional brain connectivity, and baseline functional connectivity predicts longitudinal cognition
Authors: Dark Heather E , Shafer Andrea T , Cordon Jenifer , An Yang , Lewis Alexandria , Moghekar Abhay , Landman Bennett A. , Resnick Susan M. , Walker Keenan A.
Published: January 2025

Background

AD is defined by cortical amyloid‐ß (Aß), tau neurofibrillary tangles, and neurodegeneration, pathological processes which may contribute to cognitive decline by altering large scale functional brain networks. To test this hypothesis, we examined whether plasma biomarkers of AD pathology (Aß42/40, phosphorylated tau [pTau‐181]), astrogliosis (glial fibrillary acidic protein [GFAP]), and neuronal injury (neurofilament light chain [NfL]) related to longitudinal changes in resting‐state functional connectivity (rsFC) in cognitively unimpaired participants from the Baltimore Longitudinal Study of Aging.

Method

Baseline plasma biomarkers were measured with Quanterix SIMOA assays. Functional connectivity (3T resting‐state fMRI) was derived using a predefined cortical parcellation mask from which intra‐network connectivity from seven functional networks was extracted for each participant. Amyloid status (positive/negative) was defined using plasma Aß42/40 (Figure 1). Linear mixed effects models adjusted for age, sex, race, education, gray matter volume, and time‐covariate interactions were used to determine whether 1) baseline plasma biomarkers predicted longitudinal changes in rsFC, 2) the magnitude of the biomarker‐related rsFC changes differed by amyloid status, and 3) rsFC predicted longitudinal changes in cognition.

Result

Longitudinal connectivity analyses (mean age±SD = 65.49±16.17) included 490 participants (1190 visits; mean follow‐up time = 4.31±1.68 years). Higher Aß42/40, GFAP, and NfL were associated with faster declines in rsFC within several networks (P‐range = 0.01‐0.04; Figure 2). Overall, plasma biomarker‐rsFC associations differed by amyloid status (P‐range = 0.01‐0.045). Among amyloid‐positive participants, lower levels of Aß42/40, and higher levels of GFAP, and NfL (Figure 2) were associated with faster declines in rsFC in the visual, dorsal and ventral attention, limbic, and frontoparietal networks (P range≤0.002‐0.04). There were no statistically significant associations between plasma biomarkers and rsFC change among amyloid‐negative participants. Among 760 participants with at least one rsFC scan (mean age±SD = 67.21±14.93; 1550 visits, follow‐up time = 3.94±1.60 years), we found that baseline rsFC in several networks predicted changes in cognition, e.g., working memory, verbal fluency, and visuospatial abilities (P range = 0.02‐0.049; Figure 3).

Conclusion

Among cognitively normal individuals, plasma biomarkers of Aß42/40, astrogliosis, and neuronal injury are associated with future intra‐network functional brain changes, particularly in the context of elevated amyloid. Hypo‐ and hyper‐ intra‐network connectivity may drive changes in cognitive performance.
Tau accumulation mediates β‐amyloid effects on hippocampal atrophy and memory in early Alzheimer’s disease
Authors: Fernandez‐Lozano Sofia , Fonov Vladimir S , Therriault Joseph , Rahmouni Nesrine , Servaes Stijn , Stevenson Jenna , Poltronetti Nina Marguerita , Rosa‐Neto Pedro , Collins D Louis
Published: January 2025

Background

While we know dementia in Alzheimer’s disease (AD) results from the accumulation of ß‐amyloid (Aß), tau pathology, and hippocampus atrophy (HC), it is still unclear how these factors impose cognitive decline.

Method

We used Structural Equation Models (SEM; lavaan R package) to explore the complex relationships between the neurobiological factors in the early stages preceding AD dementia in the TRIAD cohort. Our sample comprised 333 timepoints of neuropsychological evaluation (MoCA), structural MRI, Aß ([18F]AZD4694), and tau ([18F]MK6240) PET of cognitively healthy (NC) and mild cognitive impaired (MCI) participants. We measured neurodegeneration with an inverted HC‐to‐Ventricle ratio (HVR), i.e. 1‐HVR, an integrity measure composed of the ratio of the HC volume and the sum of the volumes of HC and the temporal horn of the lateral ventricle. We used a feature selection algorithm (Boruta R package) to select the most important Regions of Interest (ROIs) from the CerebrA atlas relating Aß & Tau to memory. We then used SEM to explore the mediation of Aß and Tau on HC‐atrophy and memory using 1) the average Aß & Tau SUVR of all ROIs and 2) separate models using the Aß & Tau SUVR for each of the ROIs. Age, sex and education were treated as covariates. For ease of comparison, we calculated the standardized coefficients in our models.

Result

The demographic data of our sample is presented in Table 1. The selected ROIs were: bilateral amygdala, hippocampus, and parahippocampal gyrus; right fusiform gyrus and orbitofrontal cortex (lateral and medial portions); and left middle temporal gyrus. The full SEM with all ROIs show full mediation between Aß, Tau and HC‐atrophy, and partial mediation between all biomarkers (Fig. 1). On the distinct models by ROI, Amyloid’s effect on MoCA is almost always indirect through Tau (Fig. 2).

Conclusion

We show that, even in the early stages of AD, Aß aggregation alone has no effect on HC atrophy, and only a weak effect on cognitive decline; interactions with tau pathology is required to modulate the effects of Aß aggregation on both HC atrophy and memory loss.