bluuebunny/crossref_metadata_2025_split huggingface dataset:
Systemic vascular risk, white matter injury, and relative cerebral blood flow independently contribute to cognitive decline beyond amyloid and tau burden
Authors: Shirzadi Zahra , Yau Wai‐Ying Wendy , Boyle Rory , Properzi Michael J , Buckley Rachel F. , Yang Hyun‐Sik , Scanlon Catherine E , Hsieh Stephanie , Amariglio Rebecca E. , Papp Kathryn V. , Rentz Dorene M. , Price Julie C , Johnson Keith A. , Sperling Reisa A. , Chhatwal Jasmeer P. , Schultz Aaron P. 
Published: December 2023

AbstractBackgroundAge, systemic vascular risk factors, white matter injury, cerebral blood flow, amyloid, and tau burden are well‐established contributors to late‐life cognitive decline. Given the strong relationship among these measures, we proposed a model to extract latent factors and isolate domain‐specific measures that underlie cognitive decline in preclinical AD.MethodData were available for 166 cognitively unimpaired older adults from Harvard Aging Brain Study (Table1). We used the following measures: 1) cortical amyloid burden from PiB‐PET; 2) inferior temporal cortex FTP‐PET; 3) relative cerebral blood flow (R1) from dynamically‐acquired PiB‐PET; 4) white matter hyperintensities (WMH) from FLAIR‐MRI; 5) Peak width of skeletonized mean diffusivity (PSMD) from DTI‐MRI; 6) gray matter volume (GMV) from MPRAGE‐MRI; 7) Framingham Heart Study cardiovascular disease risk (CVD); 8) Preclinical Alzheimer Cognitive Composite‐5 (PACC). We extracted slopes using linear mixed effect models for longitudinal PACC decline and GMV atrophy (follow‐up = 7.4±2.8 years). The remaining data were obtained from baseline. We used exploratory factor analysis (varimax rotations) to extract orthogonal factors. These factors were used in a regression model to explain PACC decline. We next examined whether GMV atrophy acts as a mediator of factors and PACC decline. Subsequently, we investigated whether factors interact to further explain PACC decline.ResultsOriginal variables were highly interrelated (Figure1A) and correlated with PACC decline (Figure1B). Scree test showed 6 factors were sufficient (cumulative variance:96%, Figure2A). All factors except Factor5 (age) independently explained PACC decline (Figure2B, r2 = 0.44). Including GMV atrophy removed effect of Factor1 (white matter injury, Figure2B, r2 = 0.51). Factor3 (amyloid) interacted with Factor1 and Factor4 (tau) in explaining PACC decline (Figure2C, r2 = 0.58).ConclusionLatent factors of systemic vascular risk, white matter injury, and relative cerebral blood flow (but not age) independently explain cognitive decline beyond amyloid and tau burden in this preclinical AD cohort. GMV atrophy mediates these associations with the strongest effect on white matter injury suggesting a strong link between white matter injury and neurodegeneration. These results suggest that current markers of cerebrovascular injury contribute to cognitive decline beyond systemic vascular risk (CVD), amyloid, and tau burden. The mechanism by which systemic vascular risk impacts cognition requires further explication.
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 Aβ‐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 Aβ(CL20‐40), rather than merely Aβ 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 Aβ 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 Aβ 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 Aβ 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 Aβ is more cost‐effective than trials using Aβ‐positive individuals in clinical.
Gut microbial families associate with brain volume in cognitively unimpaired aging adults
Authors: Ibrahim Muhaison H , Heston Margo B. , Kang Jea Woo , Ennis Gilda E. , Harding Sandra , González Antonio , Johnson Sterling C , Asthana Sanjay , Knight Rob , Kaddurah‐Daouk Rima F. , Rey Federico E. , Bendlin Barbara B 
Published: December 2023

AbstractBackgroundThe gut microbiome may be a potential modifiable risk factor for Alzheimer’s disease (AD). Studies have identified gut microbial associations with amyloid and tau pathology, however the microbiome’s preclinical relationship with neurodegeneration measures including brain gray matter (GM), white matter (WM), and total brain (TBV) volumes require further examination. For this study, we hypothesized that higher relative abundances of Ruminococcaceae, Prevotellaceae, Pasteurellaceae, Enterobacteriaceae, and Bifidobacteriacea would be associated with higher GM, WM, and TBV given prior differences in a smaller AD cohort.Method157 cognitively unimpaired participants from the Wisconsin Alzheimer’s Disease Research Center and Wisconsin Registry for Alzheimer’s Prevention provided fecal samples and underwent T1‐weighted neuroimaging. The sample was enriched for participants with preclinical AD and APOE e4 carriage. CAT12 (SPM12) was used to process images and quantify brain volumes. 16S rRNA V4 fecal bacteria sequencing was performed using published methods. Taxa were denoised, classified, and agglomerated at the family taxonomic rank. Multiple regressions tested the associations of each bacterial family with GM and WM individually, and with total volume (GM and WM volumes summed). Covariates included age and total intracranial volume.ResultAnalyses focused on relationships with the afore‐mentioned families even though several others were observed in the sample. Prevotellaceae showed significant positive associations with all three brain volume measures. Pasteurellaceae showed negative correlations with GM and TBV, and no significant association with WM. Enterobacteriaceae showed a significant negative association with TBV but no significant associations with other measures of brain volume. Ruminococcaceae and Bifidobacteriaceae had no significance with all measures of brain volume.ConclusionGreater abundance of Prevotellaceae was associated with larger volumes. Prevotellaceae are known to be diminished in Parkinson’s disease, and produce short chain fatty acids which maintain intestinal barrier integrity. Higher Enterobacteriaceae was associated with lower total volume, consistent with prior studies showing Enterobacteriaceaeare elevated in AD. Higher Pasteurellaceae was associated with smaller TBV; some bacteria in the family Pasteurellaceae are pathogenic and are associated with disease, possibly explaining this association. Ruminococcaceae and Bifidobacteriaceae were not liked with brain volume in this cognitively unimpaired cohort. Overall, these findings suggest specific microbial families associate with neurodegeneration.
Investigating associations of multiple common infections with brain structure and white matter lesions: findings from prospective neuroimaging studies
Authors: Green Rebecca E , Sudre Carole H , Warren‐Gash Charlotte , Waterboer Tim , Hughes Alun D , Richards Marcus , Schott Jonathan M , Chaturvedi Nishi , Williams Dylan M 
Published: December 2023

AbstractBackgroundEvidence for a role of common infections in neurodegenerative and cerebrovascular diseases is conflicting, and the extent to which pathogen exposure associates with subclinical imaging markers of these diseases is unclear. We aimed to investigate associations between a panel of serological measures characterising exposure to common pathogens – selected based on their relevance to public health – and brain volume, hippocampal volume, and white matter lesions in two population‐based cohorts in the UK.MethodSerology and imaging data were available for 1371 participants across two studies: the UK Biobank (N = 935, mean age(SD)[years] = 55.3(7.7) at serology; 63.8(7.7) at imaging) and the Medical Research Council National Survey of Health and Development [N = 436, mean age(SD) [years] = 63.3(1.1) years at serology; 70.7(0.7) years at imaging). Serology measures included a) serostatuses of 17 pathogens, b) total proportion of 17 pathogens exposed to, and c) total proportion of 11 neurotropic pathogens exposed to (Table 1). Associations between serology measures and outcomes (brain volume, hippocampal volume, and white matter lesion volume) were tested using linear regression. Regression models included adjustments for total intracranial volume and clinic information (basic models), and age, sex, ethnicity, education, socioeconomic position and lifestyle factors (Figure 1). Findings across cohorts were meta‐analysed using random‐effects models. The present study will be expanded to include an additional cohort (Southall and Brent Revisited,N≤1200) to add more precision for identifying associations.ResultSeropositivity to seven pathogens associated with an outcome in basic models, and four in fully‐adjusted models: seropositivity to JC virus was associated with smaller brain volumes, Epstein‐Barr virus with larger brain volumes, Merkel cell virus with larger hippocampal volumes and fewer white matter lesions, and C.trachomatis with fewer white matter lesions (Figure 2). Neurotropic pathogen burden scores associated with smaller hippocampal volumes in basic models, but no associations were seen for either pathogen burden score in fully‐adjusted models.ConclusionWe found some evidence of both positive and negative associations between common infections and imaging markers of subclinical cerebrovascular disease and neurodegeneration, with no evidence of relationships with pathogen burden. This work highlights key relationships for further investigation, which may reveal novel pathways associated with brain structure and cerebrovascular pathology.
Ascorbate insufficiency disrupts neuronal transmission by surface electroencephalogram in a mouse model of Alzheimer’s disease
Authors: Buchanan Rebecca A. , Wang Yuhan , Harrison Fiona E. 
Published: December 2023

AbstractBackgroundAscorbate, or vitamin C, is an important antioxidant obtained through diet. Alzheimer’s disease (AD) has a high oxidative stress burden due to both AD‐specific neuropathology and associated neuroinflammation. Multiple studies link lower antioxidant potential with poorer cognition and accelerated cognitive decline in both animal and human studies. Many AD patients also present with neuronal transmission abnormalities which are detectable using electroencephalogram (EEG) and correlate with earlier presentation, accelerated decline, and poorer cognition. Ascorbate may have a specific role as a neuromodulator in AD as it is released concomitantly with glutamate reuptake following excitatory neurotransmission. We hypothesize that ascorbate insufficiency alters neuronal transmission in AD including increased spike‐wave discharges and alterations in brainwave patterning consistent with glutamatergic dysfunction.MethodUsing a mouse model of AD that requires dietary ascorbate (Gulo−/−APPswe/PSEN1dE9), EEG was recorded at baseline, during 4 weeks of ascorbate depletion, and with repletion at week 5. We determined changes in global neuronal firing patterns in young (5 months) and aged (20 months) Gulo−/−APPswe/PSEN1dE9 and control male and female mice. Data were scored for changes in spike wave discharges, sleep‐wake rhythms, and brainwave power bands each week. Amyloid‐beta levels were quantified by ELISA. Protein expression levels of glutamate clearance transporters, GLT‐1 and GLAST, and ascorbate levels in cortex and liver were quantified in a separate cohort of mice.ResultPreliminary data suggest an early increase in neuronal spike discharges with age and following ascorbate depletion. A reduction in EEG amplitude is also observed with decreasing ascorbate. Our findings are consistent with epileptiform activity and an increase in wakeful periods compared to slow‐wave and paradoxical sleep in our aged mice which are observed in AD patient subpopulations. Amyloid‐beta levels were consistent with a genotype‐ and age‐dependent increase. Expression of GLAST in cortex was decreased in Gulo−/−APPswe/PSEN1dE9 mice, and no change in Gulo−/− mice, following 1‐week of ascorbate depletion.ConclusionOur data suggest that maintaining optimal brain ascorbate levels may support normal epileptiform activity and a sensitivity to changes in glutamate reuptake transporters, particularly in cases in which increased neuronal spike discharges, such as in AD subpopulations, are already observed.
Syntactic processing skills in elderly people with mild cognitive impairment and mild Alzheimer’s disease
Authors: Cruz Souza Wellington , Radanovic Marcia , Carvalho Claudia Lopes , Forlenza Orestes Vicente 
Published: December 2023

AbstractBackgroundCommunication and language impairments may be found in individuals with CCL. Thus, a better understanding language processing in this group and in healthy aging is necessary. Most studies in CCL and AD have focused on naming and semantic processes, and few studies have focused on syntactic processing skills, especially in the Brazilian population.MethodA total of 114 elderly people of both sexes, aged at least 60 years, living in the city of São Paulo, were evaluated. The subjects were divided into 32 healthy elderly, 22 with aminestic mild cognitive impairment, 43 with non‐aminestic mild cognitive impairment and 17 with mild Alzheimer’s disease. For language assessment, the Grammar Reception Test – TROG2 was used as the main instrument, as well as the tests Northwestern Anagram Test, Token Test and the Object and Verb Naming Battery. For cognitive evaluation using the tests and functionality, the following tests were used: MoCA, Rivermead Behavioral Memory Test, Tracks A and B Test, Rey‐Osterrieth Complex Figure Test, Stroop Test, Digit Extension Test, Learning Test Verbal de Rey FAS, Three Words Three Shapes Test. The functionality of the was assessed using the Lawton & Brody scale for Activities of Daily Living.ResultOur results showed differences in performance among the control, CCL, and AD groups in the total number and the profile of correct answers according to the type of sentence tested (p<0.05). Sentences with zero anaphora structure discriminated the control group from CCLa and AD, as well as CCLna from AD; pronoun gender/number sentences discriminated controls from CCLa (p<0.05). These sentence types bring to evidence the effect of increased demand on working memory and executive functions on syntactic processing.ConclusionThe use of the Grammar Reception Test ‐ TROG ‐ 2 instrument can be useful in the assessment of the elderly, serving as a reference to differentiate healthy aging from cognitive and language impairments. Patients with MCI already have difficulties in syntactic processing when syntactic complexity is increased, overloading working memory and executive functions. These difficulties are intensified in patients with AD.
Do we really need to normalize Hippocampal volume?
Authors: Fernandez‐Lozano Sofia , Fonov Vladimir S , Dadar Mahsa , Collins D Louis ,   for Alzheimer’s Disease Neuroimaging Initiative
Published: December 2023

AbstractBackgroundHippocampal volume (HCvol) is an important biomarker in the study of neurodegeneration (1‐3). A drawback of HCvol as a clinical biomarker is its high variability across the population (4). While the common approach to account for this variability is to normalize for head‐size variability using the intracranial volume (ICV) (5), other approaches use the idea of ex‐vacuo dilation, considering the expansion of the surrounding ventricle (6,7).MethodWith a library of 80 manually segmented hippocampi and surrounding temporal horns of the lateral ventricles from healthy subjects we trained three automatic segmentation methods: multi‐atlas label fusion (MALF) (8), non‐local patch‐based segmentation (NLPB, aka SNIPE) (9) and a Convolutional Neural Network (CNN) with a U‐Net architecture (10) and compared their performance (Cohen’s Kappa). We obtained the raw and normalized Hippocampal volumes (HCvol/ICV) as well as the Hippocampal‐to‐Ventricle Ratio (HVR = HCvol/(HCvol+CSFvol)) (7) on the baseline T1w MRI scans from the ADNI dataset for each segmentation method. We used these measures to calculate the robust effect sizes (Cohen’s d) and their confidence intervals (bootstrap: 5,000 resamples) between cognitively normal (CN), mild cognitive impaired (MCI) and subjects with dementia (AD) from ADNI‐1, 2, 3 and Go.ResultAfter acquisition QC (CN = 502, MCI = 815, AD = 324), Table 1 shows the number of successful HC and CSF segmentations for each method. The CNN U‐Net had the least number of failed segmentations. The CNN U‐Net also obtained the highest performance. While NLPB had similar Kappa values to MALF, it had less variability (Fig 1). On Fig 2, we show the calculated effect sizes between Diagnoses, HC measures and segmentation methods. HVR yields a greater effect size than HCvol and HCvol/ICV to separate AD from CN or MCI when using MALF. With NLPB, HVR and HCvol are better than HCvol/ICV. Finally, with the CNN U‐NET, the three metrics perform similarly.ConclusionThe CNN U‐Net provides improved segmentations over both MALF and NLPB. Such better‐quality segmentations reduce the need for normalization. However, HVR might be better suited than ICV normalized values when working with limited quality segmentations.
Functional Interactions of Low‐density Electroencephalography During Sleep Cycles to Detect Alzheimer’s Disease
Authors: Herzog Ruben A , Haghayegh Shahab , Hu Kun , Ibanez Agustin 
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD) causes disruption in the collective dynamics of the brain activities which can be captured by analyzing the functional interactions between electroencephalographic (EEG) signals in different regions of the brain. To better assess the AD‐related changes in the interactions, one possible approach is to increase the EEG electrode density for better spatial information. Alternatively, high order interactions within the fluctuations of low‐density EEG — a concept of the multivariate information theory — may better reveal complex EEG interactions and can be used to detect AD‐related changes in brain activities. This study is aimed to demonstrate this conceptual approach using machine learning.MethodWe analyzed overnight 4‐channel EEG recordings (left central, right central, left mastoid, and right mastoid) in the polysomnography (PSG) data collected from 28 older men in the Osteoporotic Fractures in Men Study (MrOS). 14 participants reported a history of clinical diagnosis of AD while the other 14 did not. Groups were matched in age and education. Each of 30‐second epochs of the PSG recording was scored as wake, N1, N2, N3, or rapid eye movement sleep according to the established guideline. Features based on low (2) and high order (3‐4) interactions between electrodes, i.e., total correlation (TC), dual total correlation (DTC), O‐information (O) and S‐information (S), were extracted from raw and band‐passed filtered data (δ: 0.5‐4 Hz, θ: 4‐8 Hz, α: 8‐12 Hz, β: 12‐30 Hz, γl: 30‐40 Hz, γh: 40‐100 Hz) within each wake/sleep stage. The optimal set of features was identified using a cross‐validated random forest classifier to maximize the group discrimination.ResultAD was discriminated from control with an average area under the receiver operating characteristic curve of 0.90±0.05 using just 3 features: O (triplet) measured in the γh band within wake stage, DTC (triplet) of raw EEG within N1 stage, and TC (pairwise) in the δ band within N1 stage.ConclusionThis proof‐of‐concept study shows the possibility of using low‐density sleep EEG to detect AD. This method might be useful for screening people with risk of AD in ambulatory setting.
Investigating the link between locus coeruleus activity during wakefulness and sleep electrophysiology using ultra‐high‐field MRI ‐ implications for AD
Authors: Gilles Vandewalle 
Published: December 2023

AbstractBackgroundA bidirectional link between sleep regulation and Alzheimer’s disease neuropathology emerges in the literature. The locus coeruleus (LC) is the main source of norepinephrine (NE) of the brain, it is the first brain site show signs of tau pathology and is central to the regulation of arousal and sleep. It may therefore contribute to the link between sleep and AD. However, the precise role of the LC in shaping healthy sleep variability is not established in humans.MethodHere, we used 7 Tesla functional Magnetic Resonance Imaging (7T fMRI) and sleep questionnaires and electroencephalography (EEG) in 53 younger (N = 34; 18‐30y) and older (N = 19; 50‐70y) healthy individuals to test whether the address this first question and assess whether activity of the LC during wakefulness was associated with sleep metrics in healthy younger and older individuals.ResultWe found that higher LC activity during wakefulness probed in an auditory attentional task is associated with worse subjective sleep quality (P = 0.007) and with lower EEG theta (4‐8 Hz) power during REM sleep in late midlife (50‐70 y) (P = 0.037), but not in young (18‐30 y) individuals. Further preliminary results suggest that LC activity probed with a visual perceptual rivalry task confirm the associations. These preliminary results may indicate, however, that higher LC activity during wakefulness may be association with better sleep quality.ConclusionThese results suggest that the inverted U‐shape between LC activity during wakefulness and brain functioning reported for cognition also pertains to some aspects of nighttime sleep. They contribute to the understanding of the role of the LC in sleep physiology and pave the to investigate its contribution to AD through sleep.