bluuebunny/crossref_metadata_2025_split huggingface dataset:
Plasma p‐tau181 and nfl as surrogates biomarkers in clinical trials targeting preclinical stage of Alzheimer’s disease
Authors: Ferreira Pamela C.L. , Ferrari‐Souza João Pedro , Tissot Cécile , Bellaver Bruna , Leffa Douglas Teixeira , Povala Guilherme , Lussier Firoza Z , Therriault Joseph , Benedet Andrea Lessa , Ashton Nicholas J. , Cohen Ann D. , Lopez Oscar L. , Tudorascu Dana , Klunk William E , Soucy Jean‐Paul , Gauthier Serge , Villemagne Victor L , Zetterberg Henrik , Blennow Kaj , Rosa‐Neto Pedro , Zimmer Eduardo R. , Karikari Thomas K , Pascoal Tharick A. 
Published: December 2023

AbstractBackgroundThe preclinical stage of Alzheimer’s disease (AD) is one of the main focuses of clinical trials. Plasma and positron emission tomography (PET) biomarkers have already been proposed to monitor participants’ disease progression in clinical trials targeting cognitively unimpaired (CU) individuals. Although longitudinal changes in plasma phosphorylated tau 181 (p‐tau181) and neurofilament light chain(NfL) correlate with AD progression, it is unknown whether these changes can be used to monitor drug effects in preventive clinical trials. Here, we aimed to evaluate the utility of using changes in plasma p‐tau181 and NfL as surrogate biomarkers for clinical trials targeting preclinical AD.MethodWe access 257 CU older individuals that had available Aß‐PET at baseline, as well as the baseline, up to 24‐month plasma p‐tau181 and NfL measures from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). We calculate the estimated sample size needed to test a 25% drug effect with 80% of power at a 0.05 level on reducing changes in plasma markers.ResultWe demonstrated that therapeutical clinical trials of 24‐month follow‐up using p‐tau181 and NfL would require 78% and 63% smaller sample sizes compared with a 12‐month follow‐up(Figure 1). The use of intermediate levels of Aß(CL20‐40), rather than merely Aß positivity, as an enrichment strategy reduced the sample size by 73% for p‐tau181 and 59% for NfL over 24 months. As demonstrated in Figure 2A the estimated cost of a clinical trial using only plasma biomarkers is lower than using neuroimaging biomarkers for surrogacy(Figure 2A). However, as showed by Figure 2B a trial including all Aß positive individuals, the total estimated cost when considering surrogate biomarkers plus other related assessments are numerically higher using plasma than neuroimaging biomarkers; while trials including only individuals with intermediate Aß levels, the cost was similar using plasma and neuroimaging biomarkers for surrogacy.ConclusionOur results suggest that to monitor large scale large‐scale population interventions in CU Aß positive individuals’ plasma p‐tau181/ NfL could potentially be used. Furthermore, using a strategy that has been proposed in recent clinical trials, we demonstrated that the use of intermediate levels of Aß is more cost‐effective than trials using Aß‐positive individuals in clinical.
Moderate alcohol use, total brain volume, and white matter hyperintensities among racially and ethnically diverse middle‐aged adults
Authors: Guzmán Diana S. , Renteria Miguel Arce , Avila Justina F , Turney Indira C , Rossano Samantha , Johnson Aubrey S. , Smith Anna C. , Okafor Amarachukwu , Morales Clarissa , Gu Yian , Manly Jennifer J. , Brickman Adam M. , Lao Patrick J. 
Published: December 2023

AbstractBackgroundModerate alcohol use may provide later life cognitive benefits compared to heavy alcohol use. However, results have been mixed, with reports of both increased and decreased gray and white matter volumes with moderate drinking. Additionally, alcohol use on brain health may differ by sex and race/ethnicity. Understanding the association between brain health and moderate drinking in a representative, community‐based study will provide insight into the reported cognitive benefits. We investigated the relationship between alcohol use and total brain volume (TBV) and white matter hyperintensities (WMH) in a diverse sample of middle‐aged non‐alcohol dependent community‐dwelling adults.MethodParticipants (N = 350; Mage = 54±10 years; 33 Black Men, 38 Black Women, 66 Latinx Men, 166 Latinx Women, 7 White Men, 20 White Women) from the Offspring study of Racial and Ethnic Disparities in Alzheimer’s Disease, a community‐based study in Northern Manhattan, underwent structural (TBV = 1051±106cm3) and vascular (WMH = 3±4cm3) MRI. Alcohol use was assessed by the Alcohol Use Disorder Identification Test–Concise (AUDIT‐C). Individuals likely to be alcohol dependent (AUDIT‐C = 9) were excluded (n = 16). We assessed alcohol use and TBV or WMH, adjusting for age, in the overall group, and stratified by sex/gender groups, racial/ethnic groups, and sex/gender by race/ethnicity groups.ResultOverall, greater TBV was associated with younger age (‐3.5cm3 [‐4.7, ‐2.3], p = 9E‐10) and greater alcohol use (5.1cm3 [‐6.8, 10.8], p = 0.085). No associations were found within men and women separately. Within race/ethnic groups, greater alcohol use was associated with greater TBV only among Latinx (7.6cm3 [0.1, 15.3], p = 0.055). Within sex/gender by race/ethnicity groups, greater alcohol use was associated with lower TBV among White men (‐36.8cm3 [‐45.0, ‐28.5], p = 1E‐3). There were no associations with WMH.ConclusionModerate alcohol use was not reliably associated with brain health, but the effect was on the order of 1‐2 years of aging, in a diverse sample of middle‐aged non‐alcohol dependent community‐dwelling adults. However, moderate alcohol use may have effects on brain volume within specific sex/gender and race/ethnicity groups with implications for later life cognitive impairment. Future work should explore region specific associations, alcohol use factors (i.e., context of use, alcohol type, duration of use), and its relationship to change over time.
The Influence of Prior Head Injury on Late‐Life Cognition and White Matter Microstructure in Older Adults At‐Risk of Alzheimer’s disease
Authors: Chiu Larissa Kristi , Ai Meishan , Tremblay‐Mercier Jennifer , Villeneuve Sylvia , Geddes Maiya R. 
Published: December 2023

AbstractBackgroundThe long‐term combined effects of mild traumatic brain injury (mTBI) and APOE e4‐allele carrier status (APOE+/‐), a genetic risk factor of Alzheimer’s disease (AD), on cognition and white matter structural integrity in older adults at‐risk of AD is not fully understood.MethodTo investigate mTBI effects on late‐life neurobehavioural outcomes, a subsample of the PREVENT‐AD cohort was analyzed. Participants were cognitively normal adults over age 55 with a parental or multiple‐sibling history of AD. The mTBI group included individuals who self‐reported at least one prior mTBI with loss of consciousness and/or memory gap (n = 48, 33.3% APOE4+). Rey Auditory Verbal Learning Test measured immediate and delayed memory, Color‐Word Interference Test measured cognitive flexibility and inhibitory control, and Trail Making Test measured processing speed and attention. The control group included demographically‐matched (age, sex, years of education) participants from the same cohort without self‐reported mTBI (n = 62, 29.0% APOE4+). Data were analyzed using 2‐way ANOVAs with weighted means on years of education, corrected for multiple comparisons. To evaluate underlying structural differences in white matter tracts between mTBI and control groups, diffusion tensor imaging (DTI) metrics, including fractional anisotropy, axial and radial diffusivity, using the JHU‐atlas parcellation.ResultmTBI/APOE4+ individuals performed significantly worse on cognitive outcomes of delayed recall, cognitive flexibility, and inhibitory control compared to controls; however, they performed significantly better on tests of processing speed and visual attention compared to mTBI/APOE4‐ individuals. DTI results showed that the mTBI group, compared to the control group, had significantly decreased axial diffusivity in the left internal capsule, right superior longitudinal fasciculus, and superior frontooccipital fasciculus (SFOF) (p<0.05 uncorrected). Within the mTBI group, significant positive correlation between lower processing speed and decreased axial diffusivity of SFOF, accounting for age and sex.ConclusionOur findings suggest that prior mTBI impacts cognitive aging in older adults at‐risk of AD differentially depend on APOE4 status, where APOE4+ individuals with prior mTBI had worse working memory, cognitive flexibility, and inhibitory control but better processing speed outcomes. Lower cognitive outcomes in mTBI individuals may be supported by decreased diffusivity in specific white matter tracts. These results can inform dementia prevention in these individuals.
Sex modulates the role of astrocyte reactivity in preclinical Alzheimer’s disease
Authors: Bellaver Bruna , Povala Guilherme , Ferreira Pamela C.L. , Leffa Douglas Teixeira , Ferrari‐Souza João Pedro , Lussier Firoza Z , Zalzale Hussein , Soares Carolina , Aguzzoli Cristiano Schaffer , Rohden Francieli , Abbas Sarah , Benedet Andrea Lessa , Ashton Nicholas J. , Tissot Cécile , Therriault Joseph , Servaes Stijn , Stevenson Jenna , Rahmouni Nesrine , Lopez Oscar L. , Tudorascu Dana , Villemagne Victor L , Klunk William E , Cohen Ann D. , Gauthier Serge , Zimmer Eduardo R , Zetterberg Henrik , Blennow Kaj , Karikari Thomas K , Rosa‐Neto Pedro , Pascoal Tharick Ali 
Published: December 2023

AbstractBackgroundAstrocyte reactivity is a common finding in individuals across the Alzheimer’s disease (AD) continuum. Recently, we demonstrated that individuals with higher levels of plasma glial fibrillary acidic protein (GFAP), a marker of astrocyte reactivity, present a stronger association between amyloid‐ß (Aß) and tau pathologies in preclinical AD. Because cohort studies and clinical trials show sex differences in AD biomarkers, we investigated whether the effects of astrocyte reactivity on the association between Aß and tau differs in men and womenMethodWe assessed 1,016 CU individuals from three cohorts with available Aß (plasma/PET), plasma p‐tau181 and GFAP measures. A subset of individuals also has plasma p‐tau217 available (n = 136).Individuals were classified as positive (Ast+) or negative (Ast‐) for astrocyte reactivity using a cutoff based on plasma GFAP of younger Aß‐ individuals.Linear regressions accounting for age and sex were used to evaluate the association between plasma p‐tau epitopes and Aß burden.An interaction between term between Aß*sex was also added to the models.Voxel‐wise associations between biomarkers were tested using linear regressions accounting for age, sex, and adjusting for multiple comparisons.ResultWe found that Aß burden was associated with plasma p‐tau in Ast+ but not in Ast‐ . Men in the Ast+ group presented a much increased association between Aß with plasma p‐tau181 (ß = 0.71,p<0.0001,Fig.1a) or p‐tau217 (ß = 1.23,p = 0.00086,Fig.1b) compared to women. Similarly, a significant interaction between Aß and sex on plasma p‐tau181 (ß = 0.47,p = 0.005,Fig1a) and p‐tau217 (ß = 1.01,p = 0.002,Fig.1b) was observed only in the Ast+ individuals. Voxel‐wise analysis showed the differences in the topographical association between Aß and plasma p‐tau epitopes between men and women. In men but not women, Aß‐PET associates with plasma p‐tau181 (Fig.2) and plasma p‐tau217 (Fig.3) in important AD regions such as precuneus, posterior cingulate and orbitofrontal cortex.ConclusionA sex effect was observed in the association between Aß burden and plasma p‐tau epitopes in individuals with increased astrocyte reactivity, with the association being stronger in men than women. The greater effect of Aß on tau phosphorylation in the presence of Ast+ in men than in women may have implications for interpretation of biomarkers in clinical trials testing as anti‐Aß therapies already showed different effects between men and women.
In‐vivo Braak Stage Distribution of Screened and Randomized Participants from Auτonomy, a Phase 2 Anti‐p‐tau Monoclonal Antibody Trial in Early Symptomatic Alzheimer’s Disease
Authors: Saad Ziad S. , Cohen Julie S , Fedgchin Maggie M , Quiceno Mary Ellen , Henley David , Kolb Hartmuth C. 
Published: December 2023

AbstractBackgroundTau PET is the gold standard for in‐vivo quantification of tau neurofibrillary tangles (NFT) which, along with amyloid plaques and neurodegeneration, constitute the pathological hallmarks of Alzheimer’s Disease (AD). The ongoing Autonomy trial (NCT04619420) enrolls participants presenting with mild cognitive impairment (MCI) or mild AD dementia who are tau PET positive. The Janssen plasma p217+tau assay is being used as a pre‐screen for eligibility to proceed to tau PET to reduce participant burden and improve screening efficiency. Using preliminary screening data available to date, we report on the in‐vivo PET‐based Braak stage distribution and compare the outcomes to published, histology‐based Braak staging.MethodNFT levels were quantified using 18F‐MK‐6240 SUVR in Braak Regions Of Interest (ROI)[1] using cerebellar gray as the reference region. In‐vivo Braak staging (Braakiv) was implemented following the approach by Biel et al.[2], with 18F‐flortaucipir to 18F‐MK‐6240 SUVR threshold conversion from Gogola et al.[3]. Participants with atypical[2] stages were reassigned to the Braak stage corresponding to the highest Braak ROI with average SUVR > 1.4. The screening results reported herein are from the first 355 participants with available biomarker screening data.ResultOf 355 screened participants, 90% were assigned to typical Braakiv stages. Of the 10% atypical stages, 94% were lacking elevated uptake in Braak 2 ROI. When using the coerced stage assignment, the average Braakiv stage was 3.7 across all screened participants and 3.6 in randomized participants (Figure 1). For the 221 randomized participants, 59% were Braakiv stage 4 or less, and 40% were Braakiv stage 3 or less.ConclusionIn early Alzheimer’s disease participants who were screened with tau PET in the ongoing Autonomy trial, the average Braakiv stage was consistent with the average histology‐based Braak stage in MCI patients of 3.57 [4]. These results further support the use of tau PET‐based in‐vivo staging[5] as a proxy for histology‐based Braak staging. [1] Schöll et al. Neuron 2016. [2] Biel, D., et al. Alz Res Therapy 2021. [3] Gogola A. et al. J Nucl Med. 2022. [4] Markesbery WR. J Alzheimers Dis. 2010. [5] Therriault, J. et al. Nat Aging 2022
Relationship between white matter lesion coalescence and plasma cystatin C in an ethnically diverse population
Authors: Sudre Carole H , James Sarah‐Naomi , Barnes Jo , Huang Felicia , Direk Kenan , Barkhof Frederik , Jäger H. Rolf , Chaturvedi Nishi , Hughes Alun D 
Published: December 2023

AbstractBackgroundBrain and kidney share anatomical similarities in terms of the small vessels serving their irrigation. Previous work have shown associations between markers of cerebral small vessel disease (CSVD) e.g. white matter hyperintensities (WMH) and markers of renal function e.g. cystatin C. Few studies have however investigated the relationship between renal function and more detailed descriptions of lesion shape and distributionMethod768 individuals from the tri‐ethnic SABRE cohort underwent brain MRI including T1w and FLAIR sequences. WMH were automatically segmented and an overall measure of coalescence was derived from the lesion map ranging from 0 (only punctuate lesions) to 4 (high level of coalescence). Regional coalescence measures according to distance from the ventricles were further derived in 4 equidistant layers. Clinic blood samples were available for 731 individuals (45% female, mean age 71.3 (SD 6.4) years) including from 311 European; 172 African Caribbean; and 248 South Asian ethnicity. Blood measures include plasma cystatin C, a marker of glomerular filtration rate, white blood cell count (WBC) and HbA1c. Associations between cystatin C and coalescence score or lesion volume expressed as percentage of total intracranial volume were investigated using robust linear regression adjusting for age, ethnicity, sex, HbA1c and WBC; all factors known to be associated with cystatin C levels and WMH.ResultCystatin C was positively associated with male sex, WBC and HbA1c, and differed across ethnicities being highest in South Asians and lowest in African Caribbeans. After adjusting for potential confounders, cystatin C was positively associated with overall coalescence score (b = 0.026 [0.004;0.047], p = 0.018) despite unconvincing evidence of an association with overall lesion volume (b = 0.003 [‐0.0003; 0.007], p = 0.066). Associations between cystatin C and coalescence score were stronger in the South Asian group (b = 0.066 [0.027;0.105], p interaction = 0.001). Associations between cystatin C and coalescence score were similar across different layers.ConclusionShape patterns of WMH, rather than overall WMH volume, may provide a more sensitive measure to assess the relationship with markers of small vessel disease in the kidneys.
Brain‐age mediates the association between modifiable risk factors and cognitive decline early in the AD continuum
Authors: Cumplido‐Mayoral Irene , Brugulat‐Serrat Anna , Sánchez‐Benavides Gonzalo , Escalante Armand González , Anastasi Federica , Milà‐Alomà Marta , Falcon Carles , Shekari Mahnaz , Cacciaglia Raffaele , Minguillon Carolina , Fauria Karine , Molinuevo Jose Luis , Suarez‐Calvet Marc , Vilaplana Verónica , Gispert Juan Domingo ,   for the ALFA study
Published: December 2023

AbstractBackgroundNeuroimaging‐derived brain‐age is a useful biomarker to study the brain’s biological aging process. Brain‐age has shown cross‐sectional associations with cognitive function and modifiable risk factors for dementia. We aimed to study, in cognitively unimpaired (CU) individuals, the mediating role of brain‐age in the association between modifiable risk factors and cognitive changes, and the impact of AD pathology on this role.MethodWe included 416 CU individuals from the ALFA+ study with available structural MRI, measurements of the global cognitive Preclinical Alzheimer’s Cognitive Composite (PACC) (370 individuals had a follow‐up PACC assessment 3.28±0.27 years later), and lifestyle and cardiovascular risk factors assessments. We computed brain‐age delta as the difference between chronological and predicted brain‐age using a previously pre‐trained machine learning algorithm on structural MRI data. Partial Least Squares Path Modeling (PLS‐PM) was employed to investigate the mediation effect of brain‐age delta between a computed latent variable from modifiable risk factors (cardiovascular, mental health and mood, metabolic/endocrine disease history, and alcohol consumption factors; Table 1) and a latent variable from longitudinal PACC. Statistical bias adjustment was performed to control for the confounding effects of age and sex by using multiple linear regression. The analysis was performed on the whole sample (ALL) and after stratification by amyloid‐ß (Aß) status. Participants were classified as amyloid‐ß positive (Aß+) if CSF Aß42/40<0.071 (Milà‐Alomà et al, 2020). Significance of mediation was examined by 95% confidence interval bootstrap.ResultThe effect of risk factors (latent risk) on longitudinal cognition (latent cognition) was partially mediated by brain‐age delta only in Aß+ individuals (57.286%) (Figure 1C). Higher latent risk was associated with older brain‐age delta (p = 0.003) and older brain‐age delta was associated with worse latent cognition (p = 0.007). Conversely, the indirect effect was not significant in ALL nor in Aß‐ individuals, where brain‐age delta was not significantly associated with latent cognition (Figure 1A‐B). Still, higher latent risk was associated with older brain‐age delta (ALL: p<0.001; Aß‐: p = 0.004) and associated with worse latent cognition (ALL: p = 0.012, Aß‐: p = 0.001).ConclusionIn CU individuals in the AD continuum, biological brain aging mediates the association between modifiable risk factors and cognitive decline.
Assessing reactive astrogliosis in Parkinson’s brain with astroglial tracers BU99008 and deprenyl
Authors: Rocha Filipa Monteiro , Nordberg Agneta K , Kumar Amit 
Published: December 2023

AbstractBackgroundThe knowledge regarding the role of reactive astrogliosis in Parkinson’s disease (PD) is still at the surface level, however, a few in vivo PET studies have speculated that reactive astrogliosis could be an early event in PD pathology. Moreover, a direct link between a‐synuclein pathology and astrocytes in PD has been also shown, where astrocytes play a key role in a‐synuclein propagation by shuttling a‐synuclein between neurons and astrocytes. The PET imaging field is advancing very fast and different astrocytic‐tracers are now available, such as 11C‐Deprenyl (DED) (targeting MAO‐B) and 11C‐BU99008 (detect imidazoline‐2‐binding sites (I2Bs)), which we believe is crucial to explore the role of reactive astrogliosis, including astrocytic heterogeneity in PD. Hence, we used a multi‐tracer approach to understand the role of reactive astrogliosis and to validate its reliability as a potential biomarker in PD and related synucleinopathies.MethodWe used specialized postmortem saturation radioligand binding assay and small frozen human brain section autoradiography in PD and controls (CN) brains.ResultThe 3H‐BU99008 and 3H‐DED saturation binding studies in the frontal cortex (FC) brain homogenate (BH) of PD (n = 2‐3) and CN (n = 2) cases demonstrated relatively higher 3H‐DED binding as compared to 3H‐BU99008 with following Bmax (binding‐density) and Kd values: 3H‐BU99008 CNBmax – 59.1fmol/mg, Kd‐ 2.9nM vs. PDBmax – 51.6fmol/mg, 2.3nM; 3H‐DED CNBmax – 190.6fmol/mg, Kd‐ 2.7nM and PDBmax –244.2fmol/mg, Kd‐ 6.7nM. 3H‐BU99008 binding in the Cau in PD was ∼3‐fold higher than in CN. In contrast, the 3H‐DED binding between CN and PD brains in the Cau BH was almost comparable. Interestingly, qualitative, and semi‐quantitative assessment of small frozen brain section autoradiographies showed increased specific binding of 3H‐BU99008 and 3H‐DED in PD (n = 4) frontal & temporal cortices as compared to CN (n = 2‐3). In Cau, 3H‐BU99008 again showed higher binding than CN whereas 3H‐DED binding was comparable to CN, further complementing our saturation data.ConclusionThe first study to assess reactive astrogliosis signature in postmortem PD brains with astroglial tracers BU99008 and DED. The findings clearly highlight regional differences in BU99008 and DED binding in PD brains and suggest increased reactive astrogliosis at the end stages of the disease warrants further investigation.