bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hypothalamic involvement and biomarker candidacy in Alzheimer’s disease in Down syndrome
Authors: Brown Stephanie S G , Zaman Shahid , O'Brien John T ,   ABC‐DS Consortium
Published: January 2025

AbstractBackgroundPoor sleep is emerging as an important and modifiable risk factor in the development of dementia. The hypothalamus is the only neuroanatomical site of orexin‐producing neurones in the brain and modulates sleep and wakefulness behaviour. Due its small size and lack of defined contrast in conventional neuroimaging acquisitions, relatively little evidence exists as to the role of the hypothalamus in humans in neurodegeneration and sleep quality, and whether it may have mechanistic importance and biomarker candidacy.MethodsA total of 353 participants with DS and 37 sibling controls underwent structural brain scanning at 3T as part of the ABC‐DS international consortium research project. Hypothalami were segmented in the T1‐weighted images (Figure 1) and assessed volumetrically as proportional to intracranial volume (ICV) and grey matter volume.ResultsWhole hypothalamic volumes, when normalised to ICV, are significantly reduced in people with DS who have mild cognitive impairment (MCI) and dementia compared to those who are healthy (p < 0.05) (Figure 2). Additionally, smaller hypothalamic volumes normalised to ICV were significantly associated with poorer cognitive performance (p < 0.05). When normalised to grey matter volume, which controls for the atrophic processes of dementia on a whole brain level, we find that healthy people with DS disproportionally smaller hypothalamic nuclei developmentally. Specifically, hypothalamic volume in the anterior‐inferior sub‐nucleus is significantly smaller in people with DS with an AD diagnosis (p < 0.05) when normalised to grey matter volume, and significantly associated with age (p < 0.05), indicating an accelerated or preferential atrophy in this location. Larger hypothalamic volumes were associated with being overweight or obese.ConclusionsThese findings suggest that the whole hypothalamic structure is sensitive to AD‐related atrophic processes (Figure 3), which are not present in sibling controls, and that hypothalamus volume is closely associated with cognitive performance in DS. The finding of an anterior‐inferior nucleus‐specific atrophy in AD which is disproportionate to whole brain grey matter loss is supportive of this region having an accelerated decline which may be linked to sleep as a risk factor or sleep‐related dementia symptomatology, as it is known to contain the suprachiasmatic nucleus.
The impact of BDNF on the interplay between sleep time and cognitive function
Authors: Zeynoun Joy , Wiedner Crystal , Baril Andree‐Ann , Young Vanessa M. , Bernal Rebecca , Beiser Alexa S , Pase Matthew P. , Seshadri Sudha , Himali Jayandra J. 
Published: January 2025

AbstractBackgroundDisrupted sleep patterns have been shown to exacerbate Alzheimer's disease (AD) risk, potentially because of sleep's role in memory consolidation and synaptic plasticity. Recent evidence highlights that high brain‐derived neurotrophic factor (BDNF) levels, a protein enabling neuroplasticity and memory functions, could play a protective role in age related cognitive impairment. We examined the association between total sleep time and cognition, and BDNF levels as a potential modifier.MethodThird Generation, Omni 2, and New Offspring cohorts from the Framingham Heart Study Exam 2 (2008‐2011) were included (n=2,344; age 48(9.1) y; 48%F; Table 1). Self‐reported total sleep duration was categorized as: short sleep duration (≤6h), average sleep (7‐8h, reference), and long sleep duration (≥9h). A composite measure of global cognition was calculated from neuropsychological tests, including Trails B, visual reproduction (VR), logical memory (LM), and similarities. A multivariable linear regression estimated the association between sleep duration and global cognition, and individual cognitive tasks. We further tested effect modification by BDNF level (median split).ResultsLong sleep duration was associated with worse global cognition (β±SE: ‐2.19 ±0.06; p<.001), compared to average sleep (Table 2). The association between sleep duration and individual cognitive tests are shown in Table 2. BDNF levels significantly modified the association of sleep duration with global cognition (p=0.03). Long sleep duration was associated with poorer global cognition (‐0.17±0.08; p=0.04) in persons with lower BDNF, but not in those with higher BDNF levels (Table 3). Finally, short sleep duration was associated with poorer global cognition (‐0.1±0.05; p=0.04) only among those with higher BDNF (Table 3).ConclusionLong sleep duration was associated with poorer global cognition, an effect most notable in those with lower BDNF levels. Short sleep duration was also associated with worse global cognition, but in those with higher BDNF. An appropriate sleep duration may promote neuronal integrity and prevent age‐related cognitive disorders. Further studies shall elucidate the role of BDNF in the interplay between sleep duration and cognition.
Brain Functional Connectivity During Stroop Task and CSF Amyloid/tau in Cognitively Healthy Individuals
Authors: Al‐Ezzi Abdulhakim , Astraea Natalie , Yu J , Wu Xiaomeng , Fonteh Alfred N. , Minazad Yafa , Kloner Robert A , Arakaki Xianghong 
Published: January 2025

AbstractBackgroundAt the pre‐clinical stages of Alzheimer’s disease (AD) development, the accumulation of amyloid‐β (Aβ) and tau induces neural toxicity, synaptic dysfunction, and excitation/inhibition instability of neural network activity, leading to cognitive decline. However, the effects of Aβ/tau accumulation on electroencephalography (EEG) functional connectivity (FC) in cognitively healthy (CH) individuals during a cognitive challenge have not been elucidated. Therefore, the main objective of this work is to evaluate the association between Aβ/tau level and brain FC during a cognitive challenge in CH individuals.MethodEstablished EEG data was recorded using a 21‐EEG sensor headset (Wearable Sensing, DSI‐24) during a cognitive challenge (Stroop interference test). Amyloid‐β and total‐tau proteins were measured from cerebrospinal fluid (CSF) using electrochemiluminescence. We assessed FC at sensor level using Partial Directed Coherence (PDC) from EEG data of CH participants including 22 normal CSF Aβ/tau ratio (CH‐NAT) and 24 pathological CSF Aβ/tau (CH‐PAT). For each trial type (congruent or incongruent) in the Stroop task and each of 19 sensors, linear regression was used to estimate the difference in mean FC between CH‐NAT and CH‐PAT, while controlling for age, gender, and years of education. The Benjamini–Hochberg procedure was used to control the false discovery rate below q = .1.ResultCompared with CH‐NATs, CH‐PATs exhibit higher causal connectivity at specific sensors which each had an estimated local effect size index Cohen’s f2 >0.15, and putatively represent brain regions including medial prefrontal cortex (Fz, Fp1, and F8), central cortex (Cz and C4), and posterior cingulate cortex (Pz). For each of the same sensors, the estimated difference between CH‐NAT and CH‐PAT had an adjusted P value below .1.ConclusionThese findings suggest a potential association between the CSF Aβ42/tau pathology and differences between individuals in brain connectivity during a cognitive challenge. These differences may involve compensatory mechanisms as the brain adapts to the amyloid/tau pathology. These results provide potential insights into the neurobiological implications of varying CSF amyloid/tau on brain networks. The areas with estimated medium‐to‐large effect sizes are favorable to doing a study with a lower significance level to confirm the findings.
Evaluating BDNF Levels in Plasma and its Relationship to Established Biomarkers of Alzheimer’s Disease
Authors: Kueck Paul J , Honea Robyn A , Kemna Riley E , Burns Jeffrey M , Morris Jill K 
Published: January 2025

AbstractBackgroundPlasma biomarkers show a promising future to improving the quality of diagnosing Alzheimer's Disease (AD). However, blood processing procedures should be considered when measuring plasma biomarkers. Here we investigate brain‐derived neurotrophic factor (BDNF) in platelet‐rich and platelet‐poor plasma. Furthermore, we examine the relationship between BDNF and pTau181, a known biomarker of AD, in comparison to healthy older adults (CH).Method98 participants (21 AD) completed a clinical and cognitive examination, a fasting blood draw and MRI scan. Participants with cognitive impairment other than dementia were excluded. Cognitive scores were standardized to yield a global z‐score. EDTA platelet‐rich plasma (PRP) was centrifuged 1500xg for 10min, while platelet‐poor plasma (PPP) was generated by immediately centrifuging a second time at 1700xg for 15min. Biomarker analyses were performed on Simoa HD‐X (Quanterix). T1‐weighted images were collected on a Siemens 3.0T scanner. Gray matter volume (GMV) was calculated using CAT12 toolbox and normalized to total intracranial volume. Log transform was used to normalize biomarker data. Diagnostic differences were assessed using ANOVA controlling for age and sex, and relationships between continuous variables were analyzed via linear regression.ResultThere were no differences in age and sex between groups. As expected, AD global cognitive z‐scores (p<0.001) and GMV (p<0.001) were lower compared to CH. BDNF measured from PRP was significantly greater than PPP (p<0.001). Group differences were not observed in PRP BDNF (p=0.765), and AD were trending to have lower PPP BDNF (p=0.075) compared to CH. AD were observed to have elevated pTau181 (p=0.015) compared to CH. pTau181 showed a negative association with GMV across both groups (β=‐0.252, p=0.012). PPP BDNF showed a positive association to pTau181 in the AD (β=0.645, p=0.008) but not in the CH.ConclusionPlatelets can release BDNF and thus it’s important to remove during processing to better reflect circulating BDNF levels. BDNF protects against tau‐related neurodegeneration in animal models. Here we see cross‐sectionally a relationship between BDNF and pTau181. The positive association may reflect a compensatory mechanism, given BDNF’s known role in neuroplasticity. Further research is needed to better understand the possible mechanism involved and the long‐term relationship between these biomarkers.
Using fixel‐based analysis to understand the role of crossing fibers in age‐related white matter decline
Authors: Sathe Aditi , Shashikumar Niranjana , Moore Elizabeth E. , Pechman Kimberly R. , Schilling Kurt , Landman Bennett A. , Gifford Katherine A. , Bender Andrew R. , Hohman Timothy J. , Jefferson Angela L. , Archer Derek B. 
Published: January 2025

AbstractBackgroundAging is linked to significant white matter abnormalities, which are often studied using traditional diffusion tensor imaging (DTI) metrics; however, these traditional metrics have limited sensitivity/specificity to neurobiological characteristics. Here, we use fixel‐based analysis (FBA) – an approach with more precision in areas of crossing fibers – to study age‐related white matter microstructural decline.MethodThis study uses cross‐sectional data from the Vanderbilt Memory & Aging Project cohort [n=325, age at baseline: 72.9 ± 7.3 years, 40% mild cognitive impairment (MCI)]. Diffusion MRI was preprocessed using the PreQual pipeline and MRtrix was used to calculate fiber density (FD), fiber‐bundle cross‐section (FC), their combined effect (FDC), and complexity (CX) of the multi‐fiber organization within a voxel. To account for heterogeneity in the number of crossing fibers, the TractSeg Bottleneck atlas was split into distinct low/medium/high regions‐of‐interest (ROIs) based on the number of white matter bundles converging within a single voxel. Fixel‐based metrics were then quantified in each ROI. We conducted a linear regression to determine the association between age and all FBA metrics, covarying for age, sex, education, race/ethnicity, apolipoprotein‐e4 status, and cognitive status.ResultFD, FC, and FDC all show significant decline with age, with the primary fiber bundle displaying the greatest reductions in FDC (p<0.0001). This decrease is predominantly driven by changes in FD, while FC remains relatively consistent over time. Alterations to the primary fiber bundle are the most prominent in the high and medium bottleneck ROIs as opposed to low (p<0.0001). FBA of the cingulum bundle (a tract vulnerable to abnormal aging) also showed differential decline in FD and FC over time. Figures 1‐3 provide illustrations of notable findings. The low/medium/high bottleneck ROIs correlate exceedingly well with global CX, supporting the use of the Bottleneck atlas to interpret structural white matter differences.ConclusionThis study provides novel insights into the micro‐ and macro‐structural differences underlying age‐related white matter alterations. The findings underscore the value of FBA in characterizing age‐related white matter degeneration, particularly in regions susceptible to bottleneck effects. This research also lays the foundation for future investigations into tract‐specific patterns of neurodegeneration in aging.
Retinal perivascular amyloid imaging in relationship to MRI neuroimaging abnormalities and cognitive impairment
Authors: Dumitrascu Oana M , Doustar Jonah , Fuchs Dieu‐Trang , Koronyo Yosef , Sherman Dale S. , Miller Michelle , Johnson Ken , Carare Roxana O. , Verdooner Steven R , Lyden Patrick , Schneider Julie A. , Black Keith L , Koronyo‐Hamaoui Maya 
Published: January 2025

AbstractBackgroundScanning laser ophthalmoscopy (SLO) visualizes two important markers of cognitive dysfunction in the retina: vascular changes and amyloid plaque (AP) deposition. The relationship between retinal arteriolar versus venular changes and perivascular amyloid deposition across the continuum of neurodegeneration is imperfectly understood. We investigate the retinal perivascular AP distribution in relationship to cognitive and neuroimaging measures in a cohort of cognitively normal and impaired individuals.Method34 subjects with normal or impaired cognition underwent retinal SLO, brain magnetic resonance imaging and standard neuropsychometric testing. Retinal peri‐arteriolar and peri‐venular curcumin positive AP were quantified in the supero‐temporal retinal quadrant, in the first, second and third‐order retinal vascular branches. The peri‐venular and peri‐arteriolar AP count were compared between patients with normal and impaired cognition, and their correlation with brain volumes, white matter hyperintensities and cognitive Z‐scores was determined.ResultWe analyzed retinal para‐venous and para‐arteriolar amyloid count in 28 subjects, mean (SD) age 65 (7.3), 50% female, 19 (52.6%) with impaired cognition. Para‐arteriolar plaque count was higher than peri‐venular plaque in the entire cohort (p<0.0001). Secondary branch peri‐venular amyloid plaque count was higher in patients with MOCA ≤26. Tertiary branch perivascular AP count significantly and negatively correlated with hippocampal volume and positively correlated white matter hyperintensity lesion count.ConclusionRetinal AP deposit peri‐arteriolarly overall and peri‐venularly in the secondary branches in cognitively impaired. Perivascular amyloid burden in small retinal branches correlates with hippocampal volume and white matter hyperintensities.
ApoE genotype and hippocampus have heterogenic influence on diagnosis and cognitive performance in the UCD ADRC longitudinal diversity cohort
Authors: Min Eva , Farias Sarah Tomaszewski , Johnson David K , Jin Lee‐Way , Maillard Pauline , Fletcher Evan , Whitmer Rachel A. , Decarli Charles 
Published: January 2025

AbstractBackgroundThe UCD ADRC longitudinal diversity cohort consists of individuals from diverse backgrounds including White, Black African or Hispanic/Latino Americans that vary in cognitive ability from normal to dementia. Prior studies show differences in the pathological substrate of dementia in this group1 as well as the relationship between MRI measures and cognition2. Prior work also indicates differential influence of ApoE genotype on dementia by race3. For this study, we analyzed the influence of ApoE genotype and hippocampal volume on episodic memory performance and clinical syndrome of normal (NL), mild cognitive impairment (MCI) or dementia as a group and stratified by race/ethnicity.MethodMethods of participant recruitment and assessment for the UCD ADRC have been previously described4 Clinical syndrome was determined by a multispecialty group and coded according the UDS5. Episodic memory was measured by the SENAS6. Hippocampus was quantified using published methods7. Multivariate linear and logistic regressions were used to assess the relationships between ApoE4 genotype, diagnosis, cognition, and hippocampal volume for the entire group in addition to stratified analyses for each ethnoracial group. All analyses were adjusted for age, sex, and education (and race/ethnicity as needed).ResultSubject characteristics are summarized in Table 1. In brief, this is a cohort diverse in race/ethnicity, cognitive ability, and educational achievement.For the entire group, odds ratios for ApoE4 prevalence were significantly higher comparing NL to MCI (1.7, p= 0.002), NL to Dementia (3.1, p <0.001) and MCI to dementia (1.7, p=0.004). ApoE4 (Table 2) was also significantly associated with smaller hippocampus (β=‐0.14, p<0.001)) and poorer memory (β=‐0.21, p<0.001). In models where hippocampus is included, both measures are associated with episodic memory and syndrome.Different results were found for the stratified analysis where ApoE4 was not associated with syndrome or episodic memory among Blacks (Table 3). Hippocampal volume was also not associated with ApoE among Hispanic/Latinos.ConclusionThe relationship between ApoE genotype, hippocampus, syndrome, and memory performance is variable by ethnoracial background with only White participants showing associations of ApoE with both hippocampal volume and cognition. Further evaluation is needed to understand possible causes for these differences.
Distinct Spatial Patterns for White Matter Microstructure Changes in an Aging and Alzheimer’s Disease Cohort
Authors: Tian Jianqiao , Raghavan Sheelakumari , Cogswell Petrice M , Reid Robert I. , Przybelski Scott A. , Schwarz Christopher G. , Graff‐Radford Jonathan , Lowe Val J. , Kantarci Kejal , Knopman David S. , Petersen Ronald C. , Jack Clifford R. , Vemuri Prashanthi 
Published: January 2025

AbstractBackgroundWhite matter (WM) damage is seen with neurodegenerative and cerebrovascular pathologies and contributes to cognitive dysfunction. We hypothesized that there are multiple disease progression patterns in WM microstructural changes related to aging and dementia, and these can be identified using SuStaIn (data‐driven clustering algorithm for disease subtype and stage discovery) on multishell diffusion MRI (NODDI) data. NODDI provides information on cellular tissue architecture – neurite density index (NDI) measures packing density of axons and dendrites, and free water fraction (FWF) measures unrestricted water, e.g., interstitial and cerebrospinal fluid.MethodWe identified 1136 participants (mean age=70 years, 51% male, 40% Aβ‐positive, 19% MCI/AD dementia) from the Mayo ADRC and Mayo Clinic Study of Aging. We analyzed NDI and FWF in 55 WM regions. We selected a subset of WM features that monotonically changed with clinical disease progression and then applied the Z‐score SuStaIn algorithm.ResultNDI in seven regions and FWF in six regions survived selection criteria (Figure 1). Noteworthy, the NDI regions were predominantly located in the temporal lobe, while FWF regions were primarily distributed in the frontal and subcortical regions. The SuStaIn algorithm discovered two stable clusters: the NDI‐First (Temporal) and FWF‐First (Frontal) groups (Figure 2). For the NDI‐First group, temporal lobe NDI changed early followed by frontal FWF. The FWF‐First group had the reverse order. There was clear phase separation based on which measure changed first. Stages of the NDI‐First group correlated better with meta‐ROI Tau‐PET SUVR and with MMSE than the FWF‐First group (p<0.01), suggesting that NDI‐First may be indicative of a primarily AD pathway.ConclusionGiven NDI changes are likely degenerative and FWF are suggested to be other processes such as neurodegeneration or inflammatory, the observed changes in the temporal and frontal regions may be due to distinct etiologies, i.e., neurodegenerative in the temporal lobes vs. vascular dysfunction often observed in the frontal lobes. The SuStaIn algorithm showed promise in discovering disease subtypes of WM microstructural changes. Further work is needed to understand the mechanistic basis of these observed changes and integrate WM changes for differential etiology identification and disease staging.
Understanding sex differences in neuroimaging biomarkers and clinical trials
Authors: Buckley Rachel F. 
Published: January 2025

AbstractThe most recent Alzheimer’s clinical trials, including those which reported successful outcomes, use neuroimaging biomarkers of both amyloid and tau for screening participants and demonstrating a treatment effect on pathology. Some of these trials, notably Lecanemab, hint at a potential sex bias in treatment outcome, alluding to major implications for clinical practice when recommending treatment options. Sex differences in treatment response are not surprising given that women are at greater risk of progression to AD dementia, particularly if they carry APOEe4. Clinical trials, however, do not tend to sex disaggregate their topline results. Over the past 5 years, many independent studies across the world have reported sex differences in neuroimaging biomarkers of tau through positron emission tomography (PET). Women, primarily those with higher levels of amyloid, show significantly higher tau signal in the medial temporal and lateral temporal regions of the brain than men, after adjusting for age. This sex difference is evident not only in clinically normal middle and older‐aged adults, but also in diverse populations, and those with clinical impairment. Sex differences in tau‐PET also translate to faster rates of cognitive decline in women than men. Most recently, our group conducted a meta‐analysis of 1,286 unimpaired adults from four longitudinal cohorts including Alzheimer’s Disease Neuroimaging Initiative, Harvard Aging Brain Study, Wisconsin Registry of Alzheimer’s Prevention and Mayo Clinic Study of Aging. Among individuals with elevated baseline amyloid, women exhibited significantly faster tau accumulation in the medial and lateral temporal gyrus. This is some of the strongest evidence to date to suggest that not only could screening for clinical trials be effected by sex differences, but that treatment response – impacted by lowering pathological burden – could be highly sex‐specific. In this talk, we will present simulated data to demonstrate the issue of sex‐biases in tau baseline and accumulation levels to influence treatment response outcomes. We sit at a junction in the field where knowledge from observational studies of sex differences in AD neuroimaging biomarkers has not yet filtered through to clinical trials. This will be critical to ensure that both sexes are well served by treatment outcomes.