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.
Medial temporal lobe subregional atrophy patterns in presymptomatic and symptomatic genetic frontotemporal lobar degeneration
Authors: Gaynor Leslie S , Yballa Claire , Cobigo Yann , Mejía‐Perez Jhony Alejandro , Wuestefeld Anika , Wisse Laura E.M. , Forsberg Leah K. , Heuer Hilary W. , Rosen Howard J. , Boxer Adam L. , Boeve Brad F. , Kantarci Kejal , Staffaroni Adam M. , Joie Renaud La
Published: January 2025

Background

Medial temporal lobe (MTL) atrophy is an early feature of multiple neurodegenerative diseases. In genetic frontotemporal lobar degeneration (FTLD, i.e. individuals carrying GRN, MAPT, or C9orf72 mutations), MTL atrophy can occur 10‐15 years before symptom onset. We aimed to better characterize MTL atrophy patterns in presymptomatic and symptomatic genetic FTLD using a multi‐atlas segmentation pipeline that allows precise measurement of MTL subregions.

Method

Participants included a diagnostically mixed sample of familial FTLD mutation carriers (MAPT: N=87; C9orf72: N=117; GRN: N=65) and 142 non‐carrier family member controls from the ALLFTD study cohort (Table 1). T1‐weighted MRIs were preprocessed using a multi‐atlas automated pipeline (Automatic Segmentation of Hippocampal Subfields [ASHS]) to segment the amygdala, anterior and posterior hippocampus, and MTL cortices: entorhinal cortex (ERC), perirhinal cortex or Brodmann areas (BA) 35 and 36, and parahippocampal cortex (PHC). Following rigorous quality control and manual correction (Figure 1), we assessed bilateral volume differences in mutation carriers compared to controls, adjusted for age, sex, and total intracranial volume. Analyses were conducted separately for symptomatic (FTLD‐Clinical Dementia Rating Global Score≥0.5) and presymptomatic (Global Score=0) mutation carriers.

Result

Out of 413 scans, 317 (76.8%) segmentations passed quality control while 94 (22.8%) needed some manual edits—this was more common in symptomatic than presymptomatic carriers (32% versus 15%, p=0.001). Three scans were excluded (<1%; 2 complete scans, 1 for selected subregions) due to insufficient landmark visibility in symptomatic GRN and MAPT carriers. In symptomatic carriers, all MTL subregions demonstrated reduced volume compared to controls, although MAPT carriers exhibited particularly marked atrophy, especially in anterior MTL subregions (Table 2; amygdala, ERC, BA35, hippocampus). Presymptomatic MAPT and C9orf72 carriers also exhibited significant atrophy of primarily anterior MTL cortices, while presymptomatic GRN carriers only exhibited significantly smaller ERC volume compared to controls.

Conclusion

MTL atrophy is present in genetic FTLD across mutation carriers, even at the presymptomatic stage. Anterior MTL subregions, which are also susceptible to neuropathologic accumulation in early Alzheimer’s disease and Limbic‐predominant age‐related TDP‐43 encephalopathy neuropathologic change (LATE‐NC), tend to be more vulnerable than posterior subregions. Unsurprisingly, MAPT carriers show the greatest MTL atrophy compared to controls across groups.
Predictive accuracy of plasma markers for Alzheimer’s disease, cerebrovascular disease, and cognition in a population‐based study
Authors: Neitzel Julia , Streiber Anna M , Ma Yuan , Ho Phuong Thuy Nguyen , Wolters Frank J. , Hofman Albert , Bos Daniel , Vernooij Meike W.
Published: January 2025

Background

Validating the predictive value of plasma markers for Alzheimer’s disease, cerebrovascular disease and cognitive dysfunction in older adults representative of primary care settings, is needed to guide prevention and treatment decisions.

Method

At baseline, single molecule array plasma measures of Aβ42/40, pTau217, pTau181, GFAP and NfL were collected from 625 dementia‐free participants from the population‐based Rotterdam Study (mean age 63 years [range 54‐84], 51% women). After a mean follow‐up time of seven years [range 5‐9], participants underwent amyloid 18F‐florbetaben PET, brain MRI, and cognitive assessment. We investigated cross‐sectional associations between basic sample characteristics and plasma markers using linear/logistic regression. We estimated how accurately single plasma markers at baseline predicted amyloid‐PET positivity, high white matter hyperintensity burden (i.e. volume in 4th quartile) and low cognitive performance at follow‐up (i.e. composite score in 1st quartile) using receiver operating characteristic curve analysis. Predictive performance between different models was compared with DeLong test. We further identified the most parsimonious multi‐plasma marker model based on the lowest Akaike information criterion.

Result

Older participants had more abnormal plasma markers. Women showed higher GFAP, but lower pTau217 and 181 levels than men. APOE4 carriership was associated with more abnormal Ab42/40 and pTau217 levels. Education was not related to plasma markers. At follow‐up, 102 participants (16%) were amyloid‐PET positive. The area under the curve (AUC) for amyloid‐PET positivity using a base model containing age, sex, APOE4, and follow‐up time was 0.83 (Figure 1). Predictive accuracy significantly improved upon adding to the base model either GFAP (AUC=0.85), Aβ42/40 (AUC=0.87), or pTau217 (AUC=0.89; all p[DeLong]<0.05; Figure 1). AUC improved further to 0.92 for the most parsimonious model including all plasma markers (p[DeLong]<0.001). Using cutoffs based on Youden’s index, we estimated that 6.2 PET scans were needed to obtain one amyloid‐PET positive individual after screening with the base model. This number decreased to 4.7 or 2.8 when pTau217 or all plasma markers were considered. No plasma marker model seemed to outperform the base model for predicting high white matter hyperintensities or low cognitive performance.

Conclusion

Plasma pTau217, Aβ42/40 and GFAP levels markedly improved the prediction of amyloid‐PET positivity in the general population
Linking the estimated time of onset of low locus coeruleus integrity to the estimated time of onset of elevated entorhinal tau
Authors: Jacobs Heidi I.L. , Betthauser Tobey J. , Becker Alex , Riphagen Joost M. , Papp Kathryn V , Price Julie C , Rentz Dorene M , Sperling Reisa A , Johnson Keith A
Published: January 2025

Background

Estimating the time course of locus coeruleus integrity changes is important for a better understanding of the pathophysiological cascade and for identifying the optimal window of opportunity for prevention trials. We used samples iterative local approximation (SILA) to determine the individual estimated time of onset of low LC integrity and related this to early cortical tau deposition and cognitive decline.

Methods

101 individuals from the Harvard Aging Brain Study+ with longitudinal 3T MRI‐LC imaging, 18F‐Flortaucipir (FTP)‐PET imaging (n=92 with longitudinal data), longitudinal cognitive assessments and baseline PiB‐PET imaging were included (mean age: 69.97 years (SD: 12.46); 62 females; Table 1). LC intensity was derived by normalizing the LC to the pontine reference and averaging 5‐voxel‐clusters with the highest intensities (GMM‐based cut‐off: <1.34 = LC+). FTP‐burden was quantified in the entorhinal cortex (cerebellar grey reference region, partial volume corrected, GMM‐based cut‐off: >1.41 SUVr = EC+). SILA was used to model trajectories of LC intensity and EC FTP separately. Time to onset of LC+ was correlated with baseline entorhinal tau and neocortical amyloid. Repeated measures correlations related the time to onset to LC+ to longitudinal entorhinal FTP and longitudinal PACC scores. Time to onset to LC+ and elevated EC+ were correlated to each other.

Results

75.25% (n=76) of the individuals were considered LC+ (Figure 1A) and 40.22% (n=37) was EC+ (Figure 2A). Being closer to the LC+ time to onset was correlated with higher entorhinal FTP (r=0.34, p<0.001), but not with neocortical PiB (r=0.09, p=0.42; Figure 1B‐C). Moving closer to the time to onset to LC+ was associated with faster accumulation of entorhinal FTP (r=0.40, p<0.001), and faster cognitive decline (r=‐0.39, p<0.001; Figure 1D‐E). The LC+/EC+ onset trajectories were positively correlated (r=0.23, p=0.025; Figure 2B), and 36% of the individuals was LC‐EC‐, 3% LC‐EC+, 50% LC+EC‐ and 36% LC+EC+, and the time between LC+EC‐ to LC+EC+ was 6.06 years (SD:3.15; Figure 2C).

Conclusions

LC integrity imaging allows for temporal modeling and our data suggests that LC integrity precedes accumulation of entorhinal tau by on average 6 years. Future work will evaluate the impact of risk and protective factors on these trajectories.
Aging, beta‐amyloid deposition, and brain functional connectivity decline
Authors: Yi Dahyun , Chumin Evgeny J. , Byun Min Soo , Cha Woo‐Jin , Ahn Hyejin , Kim Yu Kyeong , Kang Koung Mi , Sohn Chul‐Ho , Risacher Shannon L. , Sporns Olaf , Nho Kwangsik , Saykin Andrew J. , Lee Dong Young ,   KBASE
Published: January 2025

Background

Changes in brain network organization are influenced by aging. Accumulation of amyloid‐beta (Aβ) and neurodegeneration in the neocortex are also expected to alter neuronal networks. Therefore, we examined the relationship between aging and brain functional connectivity (FC), as well as the effect of brain Aβ on this relationship.

Method

Resting state functional MRI (rsfMRI) from 594 participants spanning age and diagnostic severity of AD from the Korean Brain Aging Study for the Early Diagnosis and Prediction of AD (KBASE) was preprocessed as previously described in studies conducted at the Indiana AD Research Center (Chumin 2021, 2023). Cortical FC data from 200 regions (Schaefer 2018) grouped into 7 canonical resting state networks (RSN; Yeo 2011) was used to compute a network segregation measure (ratio of within‐ to between‐network connectivity (Chan 2014); here used as an index of FC) across all RSNs. Additionally, a subsample of older participants was classified as Aβ positive or negative based on global amyloid in Centiloid units (Klunk 2015).

Result

Intrinsic network connectivity was reduced with increasing age beginning in young adulthood (Fig, left), resulting in a dedifferentiated, or less segregated, network architecture (t = ‐4.79, p = 0.000002). The relationship between age and network segregation was significant in the Aβ negative group (t = ‐4.09, p = 0.00005); however, such relationship was not found in the Aβ positive group (Fig, right). Fitted Aβ values were significantly different (Welch Two Sample t‐test: p < 2.2e‐16).

Conclusion

This preliminary study elucidates age‐related decline of brain FC, quantified as network segregation, from young adulthood to late‐life, wherein RSN communication become less coherent, manifesting as a degeneration of FC structure. Such age‐related reduction pattern of brain connectivity appears disappear under the presence of pathological Aβ deposition in brain.
Evaluation of Plasma Glial Fibrillary Acidic Protein in Real‐life Memory Clinics in Thailand
Authors: Taweephol Thanapoom , Pongpitakmetha Thanakit , Thanapornsangsuth Poosanu , Booncharoen Kittithatch , Khieukhajee Jedsada , Luechaipanit Watayuth , Haethaisong Thanaporn , Chongsuksantikul Adipa , Likitjaroen Yuttachai , Hemachudha Thiravat
Published: January 2025

Background

The roles of reactive astrogliosis in response to the accumulation of amyloid‐β (Aβ) and early tau phosphorylation in Alzheimer’s disease (AD) have been more elucidated. Plasma glial fibrillary acidic protein (GFAP) has taken the spotlight, following phosphorylated tau (p‐tau), in evaluating patients with AD. In this study, we aimed to assess the performance of plasma GFAP compared to other biomarkers.

Method

We consecutively evaluated patients with cognitive complaints from two memory clinics in Bangkok, Thailand: Memory Clinic, King Chulalongkorn Memorial Hospital and the Neurology Clinic at the Prasat Neurological Institute. Individuals who underwent CSF analysis for core AD biomarkers or Amyloid PET to predict AD status were classified as Aβ positive (Aβ+) or negative (Aβ‐). The plasma biomarkers were measured, and their diagnostic performances were assessed using receiver operating characteristic curve. Cohen’s d was utilized to estimate the effect size of each plasma biomarkers between the Aβ+ and Aβ‐ groups. Loess regression models were employed to illustrate the trends between plasma biomarker levels and amyloid PET centiloid.

Result

Among 127 participants, 87 were female. The median age was 68 years (interquartile range: 61, 75). (Table 1) There were 72 patients with Aβ+. Plasma GFAP demonstrated an area under the curve (AUC) of 0.74 (95% confidence interval [CI] 0.65‐0.84) for detecting Aβ+ in patients with cognitive complaints. Comparatively, plasma p‐tau217, p‐tau181, neurofilament light chain, and the base model (BM, comprising age and APOE status) had AUC of 0.94 (95%CI 0.90‐0.98), 0.86 (95%CI 0.80‐0.92), 0.49 (95%CI 0.39‐0.60), and 0.70 (95%CI 0.61‐0.80), respectively. Unlike plasma p‐tau, the AUC of plasma GFAP showed no significant difference from the BM (p=0.555). (Figure 1) Plasma levels of GFAP, p‐tau217, and p‐tau181 have large effects on determining Aβ status, with Cohen’s d = 0.81 (95%CI 0.44‐1.18), 2.23 (95%CI 1.78‐2.68), and 1.54 (95%CI 1.14‐1.95), respectively. Furthermore, the loess regression showed an early increase in plasma GFAP, together with p‐tau in memory clinic patients (n=63). (Figure 2)

Conclusion

Plasma GFAP increases alongside p‐tau from early stages of AD, as indicated by amyloid PET centiloid. Nevertheless, the diagnostic performance does not differ from that of the BM.
Tau‐PET imaging in Progressive Supranuclear Palsy and relationship with biomarkers and clinical markers
Authors: Dilcher Roxane , Malpas Charles B , O'Brien Terence J , Vivash Lucy
Published: January 2025

Background

Identifying biomarkers for primary tau pathologies like Progressive Supranuclear Palsy (PSP) is crucial for diagnosis and treatment development. The novel positron emission tomography (PET) radiotracer 18F‐PI‐2620 shows promise in detecting tau protein in PSP and this study investigates its correlation with clinical markers.

Methods

We conducted a cross‐sectional analysis on 20 patients with clinically diagnosed probable PSP (Richardson’s Syndrome), who underwent T1‐weighted MRI, lumbar puncture, blood testing, and 0‐60 min dynamic 18F‐PI‐2620 PET scanning. Binding potential (BD) and Standardized uptake value ratios (SUVr) were generated for regions of interest. Clinical assessments included the Digit Span Memory task, Hayling, Stroop, Trail Making Test, NIH toolbox subtasks, the BRIEF‐A, and the PSP‐RS. Voxel‐wise and region‐based multiple regression analyses were employed to examine relationship between PET metrics and clinical markers using FSL, SPM, and R software.

Results

Preliminary results revealed a significant negative correlation between basal ganglia tau uptake and the Digit Span Reverse task or the BRIEF‐A (voxel‐wise, SUVr: p<0.01; BD: p<0.05). Region‐based analyses (SUVr) showed basal ganglia tau uptake significantly correlated with impairments in the Digit Span Forward and Reverse task (p<0.01), working memory subtask of the NIH (p<0.05), and the BRIEF‐A (‘Never’‐scores, p<0.05). Significant interaction effects (p<0.05) showed that these associations were predominantly localized in the basal ganglia as compared to frontal or occipital regions. Additionally, basal ganglia atrophy was negatively associated with tau uptake (SUVr) in the basal ganglia and brainstem. Ongoing analysis explores associations with CSF/blood biomarkers (GFAP/NfL/tau).

Conclusions

Our findings highlight the potential of 18F‐PI‐2620 as an in‐vivo tau biomarker in PSP diagnosis, demonstrating significant links between tau uptake in the basal ganglia, brain atrophy, executive dysfunction, and disease severity. These insights could drive the development of new biomarkers, advancing future clinical trial prospects.
Plasma Biomarkers Predict Cognitive Decline in Alzheimer's Disease
Authors: Guillén Núria , Sarto Jordi , Esteller Diana , Perales Iria , Ríos‐Guillermo Jose , Augé Josep Maria , Naranjo Laura , Ruiz‐García Raquel , Juncà‐Parella Jordi , Tort‐Merino Adrià , Fernandez‐Villullas Guadalupe , Alberique Ainoa , González Yolanda , Antonell Anna , Borrego‐Écija Sergi , Castellví Magdalena , Bosch Bea , Val‐Guardiola Andrea , Balasa Mircea , Sánchez‐Valle Raquel , Martínez Neus Falgàs , Lladó Albert
Published: January 2025

Background

Alzheimer's disease (AD) features a complex interplay of factors influencing cognitive decline. While CSF and plasma biomarkers have widely demonstrated their diagnostic utility, whether they may add prognostic value remains unrevealed. With this longitudinal study we aim to address this knowledge gap by evaluating the predictive value of several fluid biomarkers over cognitive decline in a cohort of biomarker‐confirmed AD individuals.

Method

We included 139 participants with biologically‐confirmed AD (A+T+N+). Four cerebrospinal fluid (CSF) biomarkers (Amyloid‐Beta1‐42 [Aβ1‐42], tau phosphorylated at threonine 181 [p‐tau181], total tau [t‐tau], and neurofilament light chain [NfL]) were determined with enzyme immunoassay, and three plasma biomarkers (p‐tau181, NfL and glial fibrillary acidic protein [GFAP]) were determined with single‐molecule array. Biomarkers were stratified into tertiles. Comprehensive neuropsychological assessments were administered at baseline (n=139) and annually (Year 1 n=108, Year 2 n=78, Year 3 n=25, Year 4 n=3 and Year 5 n=3; mean follow‐up time 1.7 years [SD 0.3]). Mixed Models for Repeated Measures explored the effectof CSF and blood biomarkers on Mini‐Mental State Examination (MMSE) score progression.

Result

Participants had a mean age at onset of 65.7 (SD 6.4) years, 17% were non‐amnestic, 58% were APOEε4 carriers. Higher baseline plasma p‐tau181 and GFAP concentrations correlated with MMSE score decline (p=0.009 and p=0.002, respectively) (Table 1, Table 2, Figure 1). Conversely, no significant associations were observed between plasma NfL or CSF biomarkers concentrations and MMSE decline.

Conclusion

This longitudinal study highlights the potential prognostic value of baseline plasma p‐tau181 and GFAP concentrations for cognitive decline progression in AD.
Accrual of Alzheimer’s Disease pathology as a function of proximity to parental dementia onset
Authors: Ziukelis Elina T , Mak Elijah , Ritchie Craig W , O'Brien John T , Aarsland Dag
Published: January 2025

Background

There is emerging evidence to substantiate temporal proximity to parental onset (PPO) of dementia as a proxy stage marker in studies of late onset Alzheimer’s Disease (AD). PPO predicts accrual of amyloid pathology cross‐sectionally and longitudinally. However interactions with gender, age, and APOE‐𝜀4 carriage have been inconsistent across datasets and amyloid measures.

Method

We investigated cross‐sectionally a subset of the European Prevention of Alzheimer's Dementia (EPAD) study cohort (n=688) (Table 1). PPO was calculated by substracting a subject’s age from the youngest age of diagnosis of an affected parent. Regressions were used to determine whether PPO predicts CSF fluid Aβ1‐42 in the whole sample or p‐tau in an amyloid‐positive subgroup (n=226). Possible interactions with age, gender, education, APOE‐𝜀 status, family history load, gender of affected parent and CDR score were explored.

Result

Nearer PPO predicted lower CSF Aβ1‐42 level (p<0.001), interacting significantly with APOE‐𝜀4 carriage only (β=12.683; T=3.295; p=0.001) accounting for effects of age, gender and education level. In APOE‐𝜀4+ subjects, APOE‐𝜀2 provided a protective effect (Figure 1). At least half of APOE‐𝜀4+/APOE‐𝜀2‐ subjects (n=255) within ten years of age of parental onset were amyloid positive (Figure 2). PPO did not predict p‐tau levels in amyloid positive subjects (n=226) (p=0.414).

Conclusion

In APOE‐𝜀4+/APOE‐𝜀2‐ individuals, PPO predicts accrual of amyloid but not tau pathology, independently of age. Selectively examining this population as they approach age of parental onset may better elucidate the natural history of preclinical late onset AD.
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 (Figure 1A), 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 Figure 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 (Figure 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 (Figure 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.
The impact of tau‐PET in a selected memory clinic cohort: design and rationale of the TAP‐TAU study
Authors: Vermeiren Marie R. , Somsen Joost , Luurtsema Gert , Reesink Fransje E. , Verwey Nicolaas A. , Hempenius Liesbeth , Tolboom Nelleke , Biessels Geert Jan , Biesbroek J. Matthijs , Vernooij Meike W. , van Zanten Sophie E.M. Veldhuijzen , Seelaar Harro , Coomans Emma M. , Teunissen Charlotte , Lemstra Afina Willemina , van Harten Argonde C. , Visser Leonie N.C. , van der Flier Wiesje M. , van de Giessen Elsmarieke , Ossenkoppele Rik
Published: January 2025

Background

Tau‐PET is a diagnostic tool with high sensitivity and high specificity for discriminating Alzheimer Disease (AD) dementia from other neurodegenerative disorders in well‐controlled research environments. The role of tau‐PET in “real‐world” clinical practice, however, remains to be established. We hypothesize that tau‐PET will lead to some changes of the pre‐PET clinical diagnosis and will improve diagnostic certainty and patient management in patients with considerable diagnostic uncertainty. The aim of the TAP‐TAU study is therefore to investigate the impact of tau‐PET in clinical practice.

Method

The TAP‐TAU study, is a prospective, longitudinal multi‐center study in 300 patients (≥50 years old) with prodromal or mild dementia recruited in six Dutch memory clinics. Patients are eligible if diagnostic certainty is <85% after routine dementia screening and if the differential diagnosis includes AD. For example, patients i) are suspected of having mixed pathology (e.g., AD and vascular pathology), and/or ii) have an atypical clinical presentation, and/or iii) show conflicting or inconclusive outcomes on other biomarkers (e.g., magnetic resonance imaging or cerebrospinal fluid). Participants will undergo a [18F]flortaucipir tau‐PET scan, blood‐based biomarker sampling, and fill out patient wellbeing surveys (Figure 1). The primary outcome measures are change (pre‐ versus post‐ tau‐PET) in diagnosis, diagnostic certainty, patient management and patient wellbeing. Secondary outcome measures are head‐to‐head comparisons between tau‐PET and less‐invasive, lower cost and more scalable diagnostic tools such as novel blood‐based biomarkers and artificial intelligence based classifiers. A control group will be formed by patients who do not wish to undergo any study intervention (n=60). All participants will be followed for a year in the memory clinic.

Result

The first participants will be enrolled in March 2024.

Conclusion

In TAP‐TAU, we will investigate the added clinical value of tau‐PET in a real‐world clinical setting, including memory clinic patients with limited diagnostic certainty after routine work‐up. Findings of our study may contribute to recommendations regarding which patients may benefit most from assessment with tau‐PET. This study is timely in the dawning era of disease‐modifying treatments as vigilance concerning mixed pathologies and atypical presentations in the memory clinic population grows.
Neurobiological correlates of grey matter morphometry changes in preclinical Alzheimer’s disease
Authors: Pelkmans Wiesje , Cacciaglia Raffaele , Salvadó Gemma , Fauria Karine , Minguillón Carolina , Kollmorgen Gwendlyn , Quijano‐Rubio Clara , Molinuevo Jose Luis , Grau‐Rivera Oriol , Wilson Rachael E , Jonaitis Erin M. , Langhough Rebecca E. , Blennow Kaj , Zetterberg Henrik , Johnson Sterling C. , Suárez‐Calvet Marc , Gispert Juan Domingo
Published: January 2025

Background

The driving mechanisms of structural brain alterations in the earliest stages of Alzheimer's disease (AD) are not well understood. Previous heterogeneous findings in preclinical AD, including subtle atrophy and also increased grey matter (GM) volume, underscore the need for further exploration. This study uses an extensive fluid biomarkers panel to identify pathological drivers behind longitudinal GM changes in cognitively unimpaired (CU) adults.

Method

We investigated 632 CU individuals (age 61.8±6.3, mean±SD) from the ALFA+, Wisconsin ADRC, and WRAP cohorts (Table 1), with available longitudinal MRI and cerebrospinal fluid biomarkers of Aβ42/40, p‐tau181, neurogranin, NfL, total‐tau, α‐synuclein, GFAP, YKL‐40, sTREM2, s100B, and IL‐6 measured using the NeuroToolKit panel of robust prototype assays (Roche Diagnostics International Ltd). We used non‐negative matrix factorization to decompose biomarkers into latent components. The per‐subject component weights were associated with voxel‐wise GM volume changes (years 3.5±0.9, mean±SD) and longitudinal performance on the preclinical Alzheimer's cognitive composite (PACC) using mixed model analysis.

Result

Six biomarker components (C1‐C6) were identified (Figure 1). High expression of astrocyte biomarkers (C1) was related to GM volume increases in frontotemporal and subcortical regions, and faster cognitive decline in A+ individuals, while axonal damage with glial reactivity (C2) was associated with temporal atrophy. Microglial reactivity (C3) showed subtle associations with both increases and decreases in GM volume in different regions. A component primarily based on Aβ pathology (C4) was strongly associated with widespread GM volume loss and faster cognitive decline. IL‐6 (C5) reflected non‐AD related inflammation. Finally, the co‐expression of tau pathology, neuronal injury, and synaptic damage (C6) showed robust associations with frontotemporal atrophy and cognitive decline in A+ individuals.

Conclusion

In a large longitudinal sample, we provide in vivo evidence that in the earliest stages of AD, Aβ pathology is also a strong contributor to future neuronal loss and cognitive decline besides neurofibrillary tangles and neuroaxonal damage. Astroglial reactivity (i.e. GFAP, s100B) in preclinical AD was associated with an increase in GM volume, which may suggest a neuroinflammatory response, and was associated with worse cognitive performance. These findings underscore the dynamic nature of structural brain changes within preclinical AD, shaped by the contributions from diverse pathophysiological processes.
Plasma phospho‐tau 217 rises with and not before early tau aggregation measured by MK6240 PET
Authors: Feizpour Azadeh , Dore Vincent , Doecke James D. , Masters Colin L , Rowe Christopher C.
Published: January 2025

Background

Rise in plasma phospho‐tau (pTau) is hypothesized to reflect a physiological response to brain Aβ plaques, preceding the formation of neurofibrillary tangles (NFT). An alternate explanation is poor sensitivity of tau PET for detection of early NFT formation. The tau tracer MK6240 has very low background “off‐target” binding and may better detect early tau aggregation. Choice of tau PET regions for analysis may also influence early detection of tau.

Method

Participants included 105 cognitively unimpaired (CU) and 178 cognitively impaired (CI), with plasma pTau217 Lumipulse® assay, 18F‐NAV4694 Aβ PET and 18F‐MK6240 tau PET data. The entorhinal, amygdala and meta temporal (MT) ROI 18F‐MK6240 SUVR and pTau217 levels were modelled as a function of Centiloid (CL).

Result

Rise in plasma pTau217 slightly lagged the rise in amygdala MK6240 binding and paralleled the rise in the meta temporal ROI (Figure 1), consistent with our previous report using Janssen p217+Tau measured by Simoa®1. Our findings also suggest that amygdala and meta temporal ROI were more robust for early detection of aggregated tau than the entorhinal cortex possibly related to PART and small ROI volume producing wide variance in the entorhinal normal range in Ab‐ CU.

Conclusion

This data suggests that the amygdala is a robust region for detecting early tau aggregation by MK6240 PET and that a rise in plasma pTau217 is associated with early formation of NFT rather than a direct physiological response to brain Aβ plaques prior to NFT formation.

Figure 1 legend: Modeling of 18F‐MK6240 quantification and pTau217 as a function of Centiloid. Biomarker values Z‐scored using the results from Aβ‐ cognitively unimpaired to define the normal range for p217+tau level and each tau PET ROI SUVR. The horizontal line is +2 standard deviations (SD).

1Doré V, Doecke JD, …, Rowe CC. Plasma p217+tau versus NAV4694 amyloid and MK6240 tau PET across the Alzheimer's continuum. Alzheimers Dement (Amst). 2022 Apr 5;14(1):e12307. doi: 10.1002/dad2.12307. PMID: 35415202; PMCID: PMC8984092.
Experts envision a valuable role for tau‐PET in clinical practice and drug trials
Authors: Vermeiren Marie R. , Calandri Ismael Luis , van der Flier Wiesje M. , van de Giessen Elsmarieke , Ossenkoppele Rik
Published: January 2025

Background

Recent advancements in Alzheimer’s disease (AD) biomarker research and AD drug trials prompt reflection on the value and appropriate use of tau‐PET in future clinical practice and trials. We therefore conducted a survey among dementia and PET experts worldwide to investigate how they envision the future role of tau‐PET in clinical practice and trials.

Method

An online survey was distributed to dementia clinicians and researchers who were invited to participate through personalized emails, social media channels and/or presentations at relevant conferences. With this approach we intended to recruit participants from different countries with diverse backgrounds and expertise. The survey questions explored experts’ opinions on the value of tau‐PET in clinical practice and in drug development and trials. We used a mix of multiple choice questions, statements with a 5‐point Likert scale (“strongly disagree” to “strongly agree”) and a few open questions.

Result

In total 269 dementia experts, comprising 144 clinicians and 121 researchers, covering six continents completed the survey (Figure 1). The vast majority (90%) fosters a positive attitude on the added value of tau‐PET in clinical practice, particularly for staging, diagnosing, monitoring and prognostication in a cognitively impaired memory clinic population (Figure 2). When confronted with clinical case vignettes, our findings suggest that a tau‐PET scan is perceived particularly useful in patients with an atypical presentation (78%) or suspicion of mixed pathology (66%) and less useful in a typical AD case (25%). Experts are confident that a tau‐PET scan could influence patient management in current practice (median 4 “agree” [IQR 4‐5]) and this would increase when effective disease‐modifying treatments are available (median 4 “agree” [IQR 3‐4]) (Figure 2). Experts anticipate an important role for tau‐PET for participant selection (76‐100%) and measuring endpoints (75‐97%), in both anti‐amyloid and anti‐tau drug trials (Figure 3).

Conclusion

Our global survey shows that dementia experts envision an important role for tau‐PET in the future, both in clinical practice and in drug trials.
Alpha Synuclein co‐pathology is associated with faster Ab‐related tau accumulation in Alzheimer’s disease
Authors: Roemer Sebastian Niclas , Dehsarvi Amir , Steward Anna , Dewenter Anna , Pescoller Julia , Wagner Fabian , Levin Johannes , Brendel Matthias , Höglinger Günter , Franzmeier Nicolai
Published: January 2025

Background

Lewy body pathology consisting of aggregated alpha‐Synuclein (a‐Syn) is the hallmark pathology in Parkinson’s disease, yet a‐Syn aggregates are also commonly observed post‐mortem as a co‐pathology in Alzheimer’s disease (AD) patients. Preclinical research has shown that a‐Syn can amplify Ab‐associated tau seeding and aggregation, hence a‐Syn co‐pathology may contribute to the Ab‐induced progression of tau pathology in AD. To address this, we combined a novel CSF‐based RT‐QuIC seed‐amplification assay to determine a‐Syn positivity, with PET‐neuroimaging in a large patient cohort ranging from cognitively normal to dementia, to determine whether a‐Syn co‐pathology accelerates Ab‐driven tau accumulation.

Method

In 261 Ab‐positive vs. 272 Ab‐negative subjects ranging from cognitively normal to dementia we employed amyloid‐PET, Flortaucipir tau‐PET and a CSF‐based a‐Syn RT‐QuIC assay for in vivo detection of abnormal a‐Syn aggregation. A subset of 136 Ab‐positive vs. 102 Ab‐negative subjects had longitudinal tau‐PET across ∼2.5years. Using linear regression, we tested whether a‐Syn positivity was linked to stronger Ab‐related tau aggregation (i.e. interaction a‐Syn x amyloid‐PET on tau‐PET).

Result

Prevalence of a‐Syn positivity rose across increasing clinical severity and was particularly pronounced in Ab+ (i.e. CN/MCI/Dementia=20/23/47%) vs. Ab‐ subjects (i.e. CN/MCI/Dementia=15/10/29%), suggesting that a‐Syn co‐pathology is more common in clinically advanced AD (chi‐squared‐test, p<0.001). When testing the interaction between a‐Syn and global amyloid‐PET, we found that a‐Syn positivity was associated with stronger Ab‐related tau deposition (Figure 1A, p<0.001), and faster Ab‐related tau accumulation rates (Figure 1B, p=0.010) in typical tau vulnerable brain regions (i.e. temporal meta ROI), adjusting for age and sex. Regional analyses confirmed that higher regional amyloid‐PET was associated with stronger temporal‐lobe tau deposition (Figure 2A) and faster tau accumulation in downstream regions (Figure 2B) in a‐Syn positive individuals. In addition, there was an independent effect of a‐Syn positivity on faster temporal lobe tau accumulation rates controlling for age, sex and global amyloid, suggesting that a‐Syn may also independently contribute to tau aggregation (Figure 3).

Conclusion

a‐Syn co‐pathology as detected by CSF seed‐amplification assays is more common at clinically advanced AD and related to faster Ab‐related tau aggregation. This suggests that a‐Syn co‐pathology may actively contribute to AD‐related tau accumulation and therefore contribute to dementia development.
Cerebellar white matter in musicians: Less is more?
Authors: Ghosh Aishwarya , Malo Palash K , Singh Sadhana , Issac Thomas Gregor
Published: January 2025

Background

Musical activity is known to act as a cognitive reserve and protect the brain against age‐related cognitive decline. The neural correlates of music perception and processing has been linked to the cerebellum, which is also known to be implicated in musical‐training related plasticity. These insights led us to explore the differences in cerebellar volumes between musicians and non‐musicians.

Method

We selected 29 cognitively healthy older adults, from the Tata Longitudinal Study of Aging (TLSA) cohort, who were identified and divided into two groups: musicians (vocalists), who were formally trained for more than five years (n=13) and non‐musicians, who had no or less than five years of training (n=16). Brain imaging was performed using a 3 Tesla MRI system and cerebellar volumes were obtained by voxel‐based morphometry. The volumetric differences between male and female musicians were analysed using Mann‐Whitney U test. Generalized Linear Regression Model (GLM) was used to compare musicians to non‐musicians.

Result

There was no significant difference between musicians and non‐musicians with respect to age (58.97±9, 57.83±5.31) and years of education (16.08±1.89, 16.06±4.20). Mann‐Whitney U test revealed a significant difference in the right cerebellar cortex (p=0.011), left cerebellar cortex (p=0.030) and left cerebellar White Matter (WM) (p=0.030) between male and female musicians with males having greater volume in each case. After adjusting for the Total Intracranial Volumes, GLM revealed musicians to have significantly less WM volumes in both left [β= ─777.86 (C.I. 95%); p=0.039] as well as right [β= ─1105.45 (C.I. 95%); p=0.011) cerebellum. Further, increase in years of involvement with music was positively correlated with right WM volume (0.197) and negative correlated with volumes of the right cerebellar cortex (─0.228), left cerebellar cortex (─0.257) and left cerebellar WM (─0.057), although not statistically significant.

Conclusion

It is surprising to note lower cerebellar volumes in musicians. The concept of meta‐plasticity might be used to explain the current findings which are in line with previous studies where musicians with extensive training since an early age were found to have smaller cerebellar volumes.
Understanding Cognition of Indian Superagers Through Handgrip Strength Examination
Authors: Roy Dwaiti , S Monisha , Issac Thomas Gregor
Published: January 2025

Background

Physiological and mental functions decline as the person ages. However, studies have found that a group of people who are more than 80 years have better cognitive functioning than their peers and also similar to 2‐3 decades younger counterpart group. These people are termed as “Superagers”. Earlier research has revealed that handgrip strength can predict frailty and eventually decline in cognition in healthy individuals. It is important to determine the patterns of functioning and risk factors of these superagers to ensure a greater quality of life for them in the future. Therefore, this study aims to look for the patterns of handgrip strength among the superagers in comparison to the typical agers.

Method

The analysis was done using baseline data from Tata Longitudinal Study of Aging (CBR‐TLSA) cohort. From this cohort, 65 octogenarians were identified. The cognition was assessed through Addenbrooke’s Cognitive Examination (ACE III) and Trail Making Test‐B(TMT‐B) The superagers were classified from these octogenarians based on Northwestern Criteria: having equal to or greater score in memory test than the 50‐65 gender and education matched age group and scores of tests of other cognitive domains not less than 1 SD compared to the same age group. Handgrip strength was measured by Camry EH101 hand dynamometer.

Results

Among 65 octogenarians 14 were identified as superagers from the TLSA cohort based on the Northwestern Criteria. The educational level was higher in superager group (p=0.022). They also exhibited higher handgrip strength in both right and left hand in trial 1 (p=0.001, p=0.003 respectively) as well as in trial 2 (p=0.001, p=0.001 respectively).

Conclusion

The results indicate a higher level of handgrip strength in superagers in both right and left hand. This indicates that there is less chance of frailty in superagers which in turn points to a lower risk of developing cognitive deficit.
Global Research Integration Platform (GRIP): Open‐source Digital Voice Processing Toolkit
Authors: Karjadi Cody , Ding Huitong , Searls Edward , Peterson Julia , Gifford Katherine A. , Pratap Abhishek , Ang Ting Fang Alvin , Au Rhoda
Published: January 2025

Background

Producing speech is a cognitively complex task and can be collected through devices such as handheld recorders, tablets, and smartphones. Digital voice data can also capture information at a granular millisecond‐level precision and serve as a widespread tool to collect cognitively relevant data in almost any diverse real‐world environments.

Digital voice recordings of spoken responses to neuropsychological test questions have been collected through the Framingham Heart Study (FHS) since 2005. The methods to analyze voice recordings were initially labor and time‐intensive approaches that were significant barriers to fully realizing the scientific objective of using speech and language as an alternative approach to cognitive assessment.

Methods

Through a collaboration with the Global Research Integration Platform (GRIP) and FHS, we leveraged existing open–source tools to create a digital voice processing toolkit that can be used by the general scientific community. GRIP is modularizing this toolkit to allow for seamless integration into various sites worldwide with low‐to‐high levels of technical experience.

Table 1 lists the initial open‐source tools we tested on 9,253 audio recordings collected on 5,399 FHS participants. Each open‐source tool has a Python Github repository that we leveraged.

Results

With minimal manual intervention, we generated prosodic, spectral, cepstral, and sound quality features from the ComParE‐2016 feature set via openSMILE. We produced 65 LLDs (low‐level descriptors) every 10 milliseconds over a 60‐millisecond window and 6373 features generated by applying several statistical functionals to the LLDs.

We segmented speakers via pyannote.audio and analyzed 9 acoustic and linguistic PRAAT features and 6373 openSMILE features in the context of a cognitive status classification task. Via Whisper, we generated timestamped transcriptions from both FHS and additional U.S. and international cohorts. We have noted difficulties in language detection and decreased transcription performance for non‐English speakers and English speakers with accents.

We have used these data in numerous studies relating digital voice to AD related outcomes.

Conclusion

Digital voice is a prime candidate for scalable collection of cognitively relevant information. The modularized toolkit being developed will provide scaled non‐proprietary post‐processing of digital voice data that can be seamlessly integrated by users worldwide with low‐to‐high levels of technical experience.