bluuebunny/crossref_metadata_2025_split huggingface dataset:
TAU EXACERBATES THE DEVELOPMENT OF DISTINCT NEUROPSYCHIATRIC SYMPTOMS IN LATE BRAAK STAGE – THE HEAD STUDY
Authors: Aguzzoli Cristiano Schaffer , Povala Guilherme , Ferreira Pamela C.L. , Lussier Firoza Z , Bauer‐Negrini Guilherme , Amaral Livia , Soares Carolina , Ferrari‐Souza João Pedro , Zalzale Hussein , Bellaver Bruna , Rohden Francieli , Abbas Sarah , Leffa Douglas Teixeira , Schilling Lucas Porcello , Zimmer Eduardo R. , Tudorascu Dana , Pascual Belen , Gordon Brian A. , Lowe Val J. , Oh Hwamee , Soleimani‐Meigooni David N. , Rosa‐Neto Pedro , Baker Suzanne L. , Pascoal Tharick Ali 
Published: January 2025

AbstractBackgroundRecent studies showed that neuroinflammation plays a key role in triggering specific neuropsychiatric symptoms (NPS), such as irritability and agitation, in individuals with Alzheimer’s disease (AD). While prior studies showed an association between tau pathology and all NPS domains, the extent to which tau influences each specific NPS domain remains unclear. Here, we aim to investigate the association of tau and NPS domains in the AD continuum. We hypothesize that tau plays a comparatively greater effect on the emergence of psychotic symptoms compared to other NPS domains.MethodWe assessed 56 individuals (21 cognitively unimpaired (CU), 23 MCI, and 12 AD dementia) from the HEAD study who underwent clinical assessments with the Neuropsychiatry Inventory Questionnaire (NPI‐Q) and had positron emission tomography (PET) for amyloid‐ß (Aß) ([18F]AZD4694 or [11C]PiB), and tau tangles ([18F]MK6240) at the same visit. We selected individuals with an NPI‐Q total score =1. Tau SUVR values were tailored with a mask from Braak stages I‐VI, using the inferior cerebellar gray matter as reference region. Leave‐one‐out voxel wise and linear regression tested the association between each NPI‐Q domain and biomarkers accounting for age, sex, cognitive status, and study site.ResultCI individuals had significantly higher NPI‐Q score and Braak VI PET SUVR than CU individuals (Table 1). NPI‐Q score was significantly associated with tau‐PET in the periRolandic and supplementary motor cortex (Figures 1A). Linear regression showed that NPI‐Q associates with tau‐PET in the Braak stage VI (Figure 1B). Leave‐one‐out regression analysis revealed that delusions, motor disturbances, and anxiety contributed most to the association between tau‐PET and NPS (Figure 2A, C). These domains presented a higher magnitude of association compared to each other NPI‐Q domain (Figure 2B). Notably, irritability, agitation, and disinhibition exerted a negative effect to the association, emphasizing that tau may not play a role in the development of these symptoms (Figure 2A, D)ConclusionOur study supports previous evidence suggesting that irritability and agitation may not be triggered by tau, but rather by other pathological process such as neuroinflammation. These findings provide additional rationale for the therapeutics aiming to mitigate irritability and agitation in AD patients.
Cortical tau aggregation drives axonal degeneration in white matter fiber tracts in Alzheimer's disease
Authors: Pescoller Julia , Dewenter Anna , Steward Anna , Dehsarvi Amir , Wagner Fabian , Gross Mattes , Zhu Zeyu , Ewers Michael , Roemer Sebastian Niclas , Brendel Matthias , Franzmeier Nicolai 
Published: January 2025

AbstractBackgroundIn Alzheimer’s disease (AD), cortical tau aggregation is a strong predictor of cortical brain atrophy as shown by MRI and PET studies, particularly driving the degeneration of neuronal somata in the grey matter. However, tau’s physiological role is to stabilize microtubules within axons in the brain’s white matter (WM) pathways. Therefore, tau’s white‐to‐grey‐matter translocation and aggregation in neurofibrillary tangles close to neuronal somata may induce WM degeneration through destabilization of axonal microtubule integrity. To address this, we determined whether cortical tau predicted faster atrophy of connected WM tracts in AD.MethodWe included from ADNI cohort 37 amyloid‐PET negative (Aß‐) cognitively normal (CN) participants and 88 amyloid‐PET positive (Aß+) participants across the AD‐spectrum (i.e. CN/MCI/Dementia = 50/28/10), with baseline amyloid‐PET, longitudinal tau‐PET and longitudinal structural MRI data. For replication, we included baseline amyloid‐PET, tau‐PET and MRI data of 321 CN‐Aß+ subjects from the A4 cohort. T1‐weighed MRIs were segmented into grey and white matter and non‐linearly normalized to MNI space using CAT12. The cortical Brainnetome Atlas and a diffusion imaging‐based tractography atlas were applied tau‐PET and MRI data to i) determine cortical tau‐PET accumulation rates within Brainnetome ROIs, and ii) assess WM volume changes within fiber tracts connected to each cortical ROI. Statistical regression‐models were adjusted for age, sex, WM hyperintensity volume, global amyloid, intracranial volume, and APOE4‐status.ResultIn ADNI, higher baseline temporo‐parietal tau‐PET predicted faster volume reductions in connected WM tracts (Figure 1A), especially pronounced in Aß+ subjects (Figure 1B). Similarly, faster tau accumulation was strongly linked to widespread WM volume reductions in connected fiber tracts (Figure 2A; Figure 2B), particularly exacerbated in Aß+ APOE4 carriers (Figure 3A) compared to non‐carriers (Figure 3B). These results suggest that tau accumulation and WM degeneration are parallel processes in AD, modulated by APOE4. In the A4 validation sample of preclinical AD patients, we detected congruent associations between inferio‐temporal tau‐PET increase and reduced WM volume in connected fiber tracts (Figure 4).ConclusionCortical tau aggregation is associated with progressive WM atrophy in connected fiber tracts throughout the brain, suggesting that tau accumulation triggers axonal degeneration, which may induce neuronal disconnection and dysfunction and thereby contributing to AD progression.
4D flow MRI of CSF dynamics: relations to CSF morphology and Aβ status
Authors: Vikner Tomas P. , Johnson Kevin M. , Hudson Sarah C. , Pompa Christian C. , Cadman Robert V. , Bevis William B. , Betthauser Tobey J. , Chin Nathaniel A. , Eisenmenger Laura B. , Johnson Sterling C. , Rivera‐Rivera Leonardo A. 
Published: January 2025

AbstractBackgroundCerebrospinal fluid (CSF) dynamics are increasingly studied to understand potential pathologic coupling with neurological disorders. In Alzheimer’s disease (AD), CSF dynamics may be altered secondary to AD‐related atrophy and enlarged CSF spaces. Additionally, animal studies suggest that altered CSF dynamics could impair clearance of metabolic waste, leading to accumulation of amyloid‐beta (Aß). However, assessment of human CSF dynamics has typically been limited to the cerebral aqueduct using 2D phase contrast MRI. In this work, we used 4D flow MRI to enable volumetric characterization of CSF flow dynamics in the human brain, to study its associations with CSF morphology and Aß burden from 11C‐PiB PET.MethodCardiac‐resolved 4D flow MRI was used to assess CSF motion in N=69 participants (age 69±8 years; 17 Aß+) from the Wisconsin Registry for Alzheimer’s Prevention, using a clinical 3T scanner (GE Premier) and a velocity encoding of 5 cm/s. Region‐averaged velocity waveforms were acquired in the spinal canal (SC), fourth ventricle (4V), cerebral aqueduct (CA), third ventricle (3V), the foramens of Monro (FMo), and the lateral ventricles (LV), segmented from T1‐weighted volumes. The waveforms were characterized by root‐mean‐square (RMS) velocity and were evaluated in relation to total CSF volume and Aß status from an established PiB global distribution volume ratio threshold >1.16.ResultVelocity waveforms demonstrated cardiac‐pulsatility in all regions of interest (ROIs) (Figure 1), with RMS velocities ranging from high in the SC (6.56±2.29 mm/s) to low in the lateral ventricles (right LV 0.31±0.15 mm/s). RMS velocities were related to total CSF volume for the SC (R=‐0.24; p=0.043), CA (R=0.27; p=0.034), 3V (R=‐0.28; p=0.018), left LV (R=‐0.39; p=0.002), and right LV (R=‐0.35; p=0.009) (Figure 2). In preliminary analysis, RMS velocities were higher in Aß+ compared to Aß‐ for the SC (p=0.048) and right LV (p=0.024) (Figure 3).Conclusion4D CSF flow MRI is feasible for the assessment of CSF dynamics throughout the ventricular system. Total CSF volume was related to RMS velocities in 5/8 ROIs, highlighting the influence of CSF morphology on CSF dynamics. Finally, Aß status was related to RMS velocity in 2/8 ROIs, indicating that altered CSF dynamics could play a role in incipient AD.
Altered Regional and Whole‐Brain Excitation/Inhibition Balance Correlates with Alzheimer’s Disease Risk Factors
Authors: Burns Andrew P , Fortel Igor , Bendlin Barbara B. , Zhan Liang , Leow Alex 
Published: January 2025

AbstractBackgroundResearch indicates that the brain operates near a critical excitation/inhibition (E/I) balance point, which, when disrupted, correlates with Alzheimer’s Disease (AD) risk factors such as APOE genotype and sex. Utilizing our established multimodal imaging method (Fortel, Igor, et al. Network Neuroscience 6.2 (2022): 420‐444.), we investigated the E/I balance in cognitively normal and impaired individuals, focusing on factors like APOE status, amyloid status, age, sex, and dementia ratings.MethodWe analyzed 593 participants, aged 43‐92 (m = 62), including 495 cognitively intact and 98 impaired individuals, through 871 E/I ratio assessments (207 had multiple assessments). Participants underwent T1‐weighted, resting‐state, and diffusion‐weighted MRI to construct hybrid resting state structural connectomes for 105 regions using a recent multimodal connectome technique to detect whole‐brain and region‐specific E/I ratios. We employed two linear mixed models to correlate E/I ratios with age, sex, e4+/e4‐ status (binary) or APOE‐npscore (continuous), whole‐brain amyloid status (binary), and clinical dementia rating, adjusting for multiple comparisons. Patient IDs were used as random effects in the models to account for repeated measurements, with no interaction effects included. All imaging and variables were obtained from OASIS‐3: Longitudinal Multimodal Neuroimaging: Principal Investigators: T. Benzinger, D. Marcus, J. Morris; NIH P30 AG066444, P50 AG00561, P30 NS09857781, P01 AG026276, P01 AG003991, R01 AG043434, UL1 TR000448, R01 EB009352. AV‐45 doses were provided by Avid Radiopharmaceuticals, a wholly owned subsidiary of Eli Lilly.ResultBoth linear mixed models identified 26, significant E/I variations across the brain related to age, clinical dementia rating, and sex. Specific AD‐relevant regions such as the hippocampus and amygdala (Figure 1) show notable E/I changes. Whole brain E/I was negatively correlated with the APOE‐e4 allele in the binary APOE status model but not in the continuous APOE‐npscore model.ConclusionWe demonstrated significant E/I ratio alterations in the whole brain and known AD relevant regions, such as the hippocampus and amygdala, against the largest risk factor of AD (age), clinical dementia rating, and binary APOE status. Our findings are consistent with past studies exhibiting correlations between altered E/I metrics and known AD risk factors.
Visual memory is primarily impacted by tau load in the right hemisphere
Authors: Arias Jaime Fernandez , Therriault Joseph , Servaes Stijn , Macedo Arthur C. , Wang Yi‐Ting , Rahmouni Nesrine , Socualaya Kely Monica Quispialaya , Aumont Etienne , Trudel Lydia , Hosseini Seyyed Ali , Hall Brandon J , Chan Tevy , Kunach Peter , Mathotaarachchi Sulantha , Vitali Paolo , Rosa‐Neto Pedro 
Published: January 2025

AbstractBackgroundClassical literature has pointed at lateralization of the relationship between memory scores and cerebral hemisphere injury. Epilepsy studies have suggested an association between left hippocampal damage and verbal memory deficits, and between right hippocampal damage and visual memory deficits. We aimed to explore this concept in the context of tauopathy due to Alzheimer’s disease.Methodwe assessed 132 cognitively unimpaired (CU) older adults, and 44 cognitively impaired (CI), amyloid‐ß positive individuals from the Translational Biomarkers in Aging and Dementia (TRIAD) cohort. All participants had amyloid‐PET with [18F]AZD4694 and tau‐PET with [18F]MK6240, verbal memory assessments with Rey Auditory Verbal Learning Test (RAVLT), and visual memory assessments with Aggie Figures Learning Test (AFLT). We conducted voxel‐wise analyses to explore the relationship between tau PET and memory modality. In addition, we run regression models with right or left tau temporal metaROI as predictor and memory scores as outcome variables. We entered global amyloid (PET), sex, age, years of education, ApoE status, grey matter volume and handedness as covariates. Finally, we used the laterality index (LI) to investigate correlations with memory modality. Right laterality is indicated by an LI below 0, while left laterality would be signaled by an LI above 0.Resultvoxel‐wise analyses suggested a lateralized relationship between tau and visual memory scores on the right hemisphere, whereas tau and verbal memory scores were bilaterally associated. Regression analyses showed a trend towards a stronger relationship between temporal tau on the right and visual memory scores. The LI was significantly associated with visual memory performance. Further analyses showed that this relationship seems to be driven by tau positive individuals.Conclusionvisual memory performance might be more prominently affected by tau load on the right hemisphere in Alzheimer’s disease. Furthermore, a hemispheric imbalance in the amount of tau is related to visual, but not verbal, memory scores.
Amyloid‐PET in patients with a clinical diagnosis of sporadic early‐ versus late‐onset AD: comparison of the LEADS and ADNI cohorts
Authors: Lagarde Julien , Maiti Piyush , Schonhaut Daniel R. , Zhang Jiaxiuxiu , soleimani‐meigooni David N. , Zeltzer Ehud , Windon Charles , Raya Maison Abu , Vrillon Agathe , Hammers Dustin B. , Dage Jeffrey L. , Nudelman Kelly N. , Eloyan Ani , Koeppe Robert A. , Landau Susan M. , Carrillo Maria C. , Touroutoglou Alexandra , Vemuri Prashanthi , Dickerson Bradford C. , Apostolova Liana G. , Rabinovici Gil D. , La Joie Renaud 
Published: January 2025

AbstractBackgroundLarge‐scale studies comparing sporadic early‐onset AD (EOAD, age<65) and late‐onset AD (LOAD, age = 65) are lacking. We compared amyloid‐PET outcomes (positivity rate and amyloid burden) between patients clinically diagnosed with sporadic EOAD vs LOAD, leveraging data from the Longitudinal Early‐Onset AD Study (LEADS) and the Alzheimer’s Disease Neuroimaging Initiative 3 (ADNI3).Method731 patients meeting the 2011 NIA‐AA criteria for AD dementia or MCI were included (505 early‐onset from LEADS, 226 late‐onset from ADNI3, Table 1). All participants underwent amyloid‐PET with [18F]Florbetaben or [18F]Florbetapir. Amyloid positivity was centrally determined by a process involving a visual read by a trained expert and PET‐only quantification; in case of a discrepancy, a read from an independent physician acted as a tiebreaker. Logistic regressions in each cohort examined relations between amyloid positivity and age, sex, MMSE and APOE4 genotype. Amyloid burden was independently quantified in Centiloids using an MRI‐based pipeline. Mean Centiloids in LEADS and ADNI were compared with two‐way ANOVA, for visually positive and visually negative scans.ResultAmyloid positivity rate was higher in LEADS (76%) than ADNI (64%, p<0.001, Figure 1A). Lower MMSE and APOE4 genotype increased odds of amyloid positivity in both cohorts, although the APOE4 effect was stronger in ADNI than LEADS (OR = 10.1 versus 2.4, p = 0.007, Table 2). Amyloid positivity was more common in females across cohorts, but this effect was only statistically significant in LEADS (Table 2). Centiloids were bimodally distributed in both cohorts, although the separation between positive and negative scans was more prominent in LEADS (Figure 1B). Visually positive scans had significantly higher Centiloids in LEADS than in ADNI, whereas no cohort difference was observed for visually negative scans (Figure 1C). Sensitivity analyses showed that this effect was driven by patients with MCI (CDR = 0.5; Figure 1D‐E).ConclusionThe lower amyloid positivity rate in ADNI might be due to AD‐mimicking pathologies being more common at an older age. The higher amyloid burden in early‐onset, amyloid‐positive patients could reflect younger patients being diagnosed later in the disease course compared to typical, late‐onset patients. Alternatively, younger patients might tolerate higher neuropathology burden due to higher brain reserve or fewer co‐pathologies.
Differences between high‐precision Alzheimer’s disease plasma and PET biomarkers among cognitively normal older Black and White adults
Authors: Bubu Omonigho M , Boutajangout Allal , Debure Ludovic , Vedvyas Alok , Briggs Anthony Q , Bernard Mark A , Gills Joshua L , Valkanova Elena , Mbah Alfred , Ghuman Mobeena , Jean‐Louis Girardin A , Betensky Rebecca A , Marsh Karyn , Rusinek Henry , Osorio Ricardo S. , Wisniewski Thomas , Masurkar Arjun V. 
Published: January 2025

AbstractBackgroundWe evaluated whether baseline differences existed in various plasma Alzheimer’s disease (AD) biomarkers in cognitively normal participants racialized as Black or White.MethodThis cross‐sectional study included 203 (n = 83 non‐Hispanic Black [NHB] and n = 120 non‐Hispanic White [NHW]) cognitively unimpaired older adults from the NYU Alzheimer’s Disease Research Center. Of the 203, 115 (39NHB, 76 NHW) had tau‐PET (PI‐2620/MK‐6240) data; 195 (85 NHB, 110 NHW) had amyloid‐PET (florbetaben); 98 (39 NHB, 59 NHW) had plasma Aß40 and Ab42 data, 93 (37 NHB, 56 NHW) had data for total tau, 135 (55 NHB, 80 NHW) had neurofilament light (NfL) and glial fibrillary protein (GFAP) data and 139 (57 NHB, 82 NHW) had pTau181 data. Plasma biomarkers assay Aß 40, Aß42, total tau [t‐tau], neurofilament light [NfL], glial fibrillary acid protein [GFAP], ubiquitin carboxyl‐terminal hydrolase L1 [UCH‐L1] and pTau181 were measured were measured using Quanterix SIMOA HD‐1.ResultOverall, mean (SD) age was 75.6 (6.5) NHW vs. 68.9 NHB (p = .008), BMI was 27.4 (9.7) vs. 32.4 (11.2) (p = .161), and education 17.0 (2.1) vs. 16.4 (2.32) (p = .273) for NHW vs. NHB respectively. Overall, 135 (66.5%) were females, of which 61 (73.5%) were NHB, and 62 were APOE e4 carriers [30.5%], of which 27 were NHB. Compared to NHW, NHB subjects had significantly lower plasma Aß40 (One‐tailed t‐test p = .006), NfL levels (p = .0005), Tau (p = .0313), pTau181 (p = .0015), and GFAP (p = .0005). NHB subjects had lower amyloid‐PET SUVR levels compared to NHW subjects (p = .0014). Baseline plasma Aß42/40 and pTau181/Aß42 levels were higher in NHB versus NHW participants (p = .002), consistent lower levels of amyloid pathology in NHB participants. There were no significant differences in levels of plasma Aß42, tau‐PET SUVR, and UCH‐L1.ConclusionIn this sample of cognitively normal older adults, NHB participants had biomarker measures suggestive of lower levels of cerebral amyloid pathology. This warrants further correlation with brain imaging and cognitive outcomes, and examination of the potential impact of demographic, socio‐structural and genetic factors on observed differences. Additionally, this may imply that racial variability in amyloid threshold possibly exists before clinical AD onset, potentially lowering the proportion of NHB patients eligible for AD therapies and trials.
Comparison of reference region stability for longitudinal amyloid PET in Down syndrome
Authors: McLachlan Max , Rouanet Jeremy P. , Garimella Arun , Price Julie C , Tudorascu Dana , Laymon Charles M , Keator David B. , Betthauser Tobey J. , Kreisl William Charles , Lao Patrick J. , Minhas Davneet S , Klunk William E , Cohen Annie , Handen Benjamin L , Fryer Tim D , Zaman Shahid , Koeppe Robert A. , Head Elizabeth , Mapstone Mark , Bettcher Brecca , LeMerise Lisette , McVea Andrew K , DiFilippo Alexandra H , Zammit Matthew D , Hartley Sigan L , Christian Bradley T. 
Published: January 2025

AbstractBackgroundThe cerebellum is frequently used as the reference region for amyloid PET analysis. However, this reference region has been shown to demonstrate longitudinal variability, particularly with [18F]florbetapir (FBP) PET (Landau, JNM 2015). For investigations in individuals with Down syndrome (DS), cerebellar atrophy and rapid disease progression may increase these longitudinal variabilities. Although white matter possesses different non‐displaceable uptake properties, the relative lack of specific binding makes white matter a suitable reference region for longitudinal studies. This work compares the observed longitudinal change when using whole cerebellum and white matter reference regions in [18F]FBP and [11C]PiB scans of adults with DS.MethodParticipants with DS, recruited through the ABC‐DS study, underwent longitudinal PiB or FBP PET imaging and T1w MRIs (Table 1 lists cohort differences). PET images were smoothed to 8mm resolution, summed 50‐70 min, co‐registered with the MRI, and normalized to a common DS MRI template (LeMerise, 2022). GAINN whole cerebellum (WC) VOI was applied to create SUVRWC. Whole brain white matter was segmented in native space using SPM, smoothed to PET resolution, and eroded to 90% tissue probability. The resulting eroded white matter (EWM) mask was used as reference to create SUVREWM. Average SUVR was calculated for GAINN global cortex (CTX). Longitudinal scans were assessed for correlations between reference region strategies and average rate of SUVR change: % Change/year = (SUVR2‐SUVR1)/(SUVR1*Δt).ResultFigure 1 displays the averaged EWM reference template. Figure 2 displays longitudinal PET data and regressions between SUVRs. Across participants, SUVRWC shows 78/90 (PiB) and 50/83 (FBP) between‐scan increases. SUVREWM shows 66/90 (PiB) and 71/83 (FBP) between‐scan increases. For A+ individuals (18CL cutoff), the average difference (% ChangeEWM ‐ % ChangeWC)/year is ‐0.5%/year [‐1.2,0.3] (PiB) and 1.9%/yr [0.5,3.3]** (FBP). FBP group SD in % Change/year decreases from 5.6% (WC) to 2.9% (EWM).ConclusionAs observed in LOAD, SUVREWM demonstrates lower group variability and greater longitudinal change in FBP. SUVREWM shows strong agreement with SUVRWC in PiB. These data suggest that an EWM reference region can reduce variability in longitudinal FBP studies in DS.