bluuebunny/crossref_metadata_2025 huggingface dataset:
Cerebral blood flow dysregulation in dementia, Alzheimer’s disease and COVID19
Authors: Iadecola Costantino
Published: December 2023

Background

Cerebral blood vessels are essential for optimal brain health by maintaining the metabolic, thermal, biochemical and cellular homeostasis of the brain’s internal milieu. Alterations of the neurovasculature disrupt such vital homeostatic functions and are a frequent correlate of cognitive impairment in a wide variety of neurovascular, neurodegenerative, and neuroinflammatory pathologies.

Results

Neurovascular pathologies (e.g., vascular cognitive impairment), neurodegenerative conditions (e.g., Alzheimer’s disease), and systemic infections associated with immune hyperactivation (e.g., COVID19), result in neurovascular dysfunction which may contribute to short‐ and long‐term impairment of cognition. The mechanisms by which neurovascular dysfunction lead to cognitive impairment are diverse and include: (a) alterations in the factors regulating the delivery of blood to the brain (coupling between neural activity and blood flow, autoregulation, endothelial vasoactivity), (b) alterations of the blood‐brain barrier, (c) vascular trophic factor deficiency resulting in increased vulnerability of neurons and glia to injury, (d) dysregulation of the brain’s immune surveillance, (e) reduced waste disposal through perivascular, paravascular (glymphatics), and transvascular clearance pathways. In addition, in COVID19 hypoxia and endothelial inflammation caused by cytokines and hemostatic abnormalities lead to endothelial dysfunction, microvascular occlusions, and increased the risk of stroke and hypoxic brain injury. Longer term consequences (long COVID) are likely to be linked to non‐resolving inflammation driven by persistence of the virus spike protein in the skull bone marrow, meninges, and brain.

Conclusion

Neurovascular alterations play a central role in the mechanisms of neurovascular, neurodegenerative and neuroimmune diseases resulting in cognitive impairment. Neurovascular dysfunction impairs cognition by promoting white matter damage, accumulation of pathogenic proteins (Abeta, tau, etc.) and neuroinflammation, and by reducing the resilience of the brain to injury. Interventions to improve neurovascular function may be beneficial in the management of these devastating conditions and should be considered as an added preventative or therapeutic approach.
A novel 3D imaging method to establish baseline amyloid‐beta plaque load and analyze compound efficacy in pre‐clinical Alzheimer’s disease animal models
Authors: Ferron Gianna , Linehan Stefan T , Ragan Tim , Elk Kevin J , Garceau Dylan , Sasner Michael
Published: December 2023

Background

Amyloid‐beta (Aß) plaque deposition in the brain represents a significant hallmark of Alzheimer’s Disease (AD). Standard laboratory approaches assessing Aß lack the ability to pair high‐throughput whole‐organ imaging with region‐specific quantitation, and often require tissue homogenization. To analyze changes in Aß spatiotemporally, we developed a novel Serial Two‐Photon Plus (STP2) pipeline to quantify plaque progression and depression as a function of brain region, resulting in indexed brain sections for secondary analysis using MALDI HiPLEX‐IHC with imaging mass spectrometry (IMS).

Method

Plaques in the well characterized 5XFAD mouse model of AD were labeled with Methoxy‐X04, an Aß plaque‐specific compound, prior to transcardial perfusion and whole‐brain excision. The STP2 platform uses a TissueCyte system to produce high‐resolution multi‐channel datasets, yielding 3D models of each brain. The Allen Mouse Brain Common Coordinate Framework (CCFv3) was registered to each brain, and our automated pipeline quantified plaque load and density per brain region. Select resulting sections were analyzed using AmberGen MALDI HiPLEX‐IHC and Bruker Daltonics IMS for Aß42, pTau, GFAP, GLUT1, MBP, NeuN, NF‐L, PVALB, SNCA and SYN‐I.

Result

Quantifying baseload plaque distribution in the 5XFAD model at 2, 3, 4, and 6‐months revealed significant changes in density of Aß plaques both spatially and temporally. STP2 imaging, combined with CCFv3 mapping and secondary proteomic analysis allows for targeted evaluation of compound treatment on the Aß plaques.

Conclusion

The STP2 pipeline produces translational high‐throughput pre‐clinical AD data with enhanced sensitivity and precision, with resulting sections remaining in‐tact for further secondary analysis of spatial proteomics and pharmacodynamics in the brain.
BrainChart cortical thickness centile scores: a generalizable tool to detect age‐inappropriate cortical neurodegeneration in Alzheimer’s disease
Authors: Parker Thomas D , Bethlehem Richard A.I. , Seidlitz Jakob , White Simon R , Bernstock Joshua D , Bourke Niall , David Michael CB , de Taurines Anastasia Francoise L Gailly , Giovane Martina Del , Graham Neil SN , Kolanko Magdalena A , Zimmerman Karl A , Malhotra Paresh A , Patel Maneesh , Scott Gregory , Alexander‐Bloch Aaron , Bullmore Edward T , Sharp David J
Published: December 2023

Background

Identifying age‐inappropriate cortical neurodegeneration on structural MRI is a key component of Alzheimer’s disease (AD) assessment. However, widely available reference standards that enable objective interpretation are lacking. BrainChart (www.BrainChart.io; https://github.com/BrainChart/Lifespan) calculates age and sex adjusted centile scores for structural MRI metrics using normative data from 101,457 participants across the lifecourse and can be applied across different datasets. We applied this approach to regional cortical thickness estimates and explored its utility in identifying patients with AD associated neurodegeneration.

Method

Cross‐sectional BrainChart cortical thickness centile scores were calculated for 241 individuals with pathologically confirmed AD (median scan time prior to death 5.8 years), as well as 1432 cognitively normal participants (CN) from the NACC dataset. Area under the receiver operating characteristic curve (AUC) analyses were performed to identify the cortical regions that best identified patients with pathologically confirmed AD. This approach was then applied to 305 participants from the ADNI‐3 cohort, all of whom underwent clinical amyloid (florbetapir) PET and tau (flortaucipir) PET within 6 months of structural MRI (CN = 185; Mild Cognitive Impairment (MCI) = 95); AD = 26).

Result

The top ten performing regions for differentiating pathologically confirmed AD from CN in the NACC dataset were entorhinal, middle temporal, inferior parietal, isthmus cingulate, fusiform, supramarginal, inferior temporal, superior temporal, precuneus and temporal pole. AUCs ranged from 0.72 – 0.77 (figure 1 and table 1). Combining these ten regions into a single model significantly improved diagnostic separability (AUC = 0.81, figure 1). Optimal cut‐points for individual regions ranged from the 25th centile to the 35th centile, with sensitivities ranging from 57.7% to 68.9%, and specificities ranging from 72.6% to 80.9%. Using progressively lower centile scores increased specificity but decreased sensitivity (table 1). In ADNI‐3 participants, a combined model of the same ten regions derived from the NACC dataset was able to discriminate amyloid and tau pet positive AD patients from amyloid and tau negative CN (AUC = 0.98), as well as amyloid and tau positive MCI patients from amyloid and tau negative CN (AUC = 0.85) (figure 2).

Conclusion

BrainChart age and sex adjusted cortical thickness centile scores, derived from an extensive normative dataset, represent a generalizable method for objectively identifying cortical neurodegeneration in AD.
Lower thickness of inner retinal layers is associated with an increased risk of incident dementia and Alzheimer’s disease – an individual participant data analysis of four prospective cohort studies (69,955 participants)
Authors: van der Heide Frank , Khawaja Anthony , Berendschot Tos T.J.M. , Littlejohns Thomas J , Kuzma Elzbieta , Foster Paul J , Patel Praveen , Bertelsen Geir , von Hanno Therese , Johnsen Bente , Schirmer Henrik , Rebouças Sara Cristina Lima , Grasset Leslie , Delcourt Cécile , Helmer Catherine , Webers Carroll , Kroon Abraham A , van der Kallen Carla J.H. , Eussen Simone J.P.M. , van Dongen Martien , Schalkwijk Casper , Bosma Hans , Köhler Sebastian , Schram Miranda T. , Blokland Gabriella , Linden David , Wesselius Anke , Stehouwer Coen D.A.
Published: December 2023

Background

Retinal imaging tools may be biomarkers for the early identification of individuals at risk for dementia. Currently, it remains unclear whether retinal neurodegeneration precedes the onset of clinical dementia as few prospective data have been published. The objective To investigate whether retinal neurodegeneration, estimated from lower thickness of inner retinal layers, was associated with incident all‐cause dementia and Alzheimer’s disease.

Method

We performed an individual participant data meta‐analysis using data from four prospective cohort studies with a total of 69,955 participants (n = 1,087 cases of incident all‐cause dementia; n = 520 cases incident Alzheimer’s disease; follow‐up time median [interquartile range; IQR] 11.3 [8.8 ‐ 11.5] years). We investigated the associations of baseline macular retinal nerve fiber layer (mRNFL) thickness and ganglion cell‐inner plexiform layer (mGCIPL) thickness (expressed per standard deviation lower thickness) with incident dementia. We used Cox proportional hazards models adjusted for age, sex, educational level, and other key dementia risk factors. Missing data for covariables were imputed. We tested for interaction with age, sex, apolipoprotein E (APOE) genotype status, and educational level.

Result

After adjustment for age, sex, educational level, and key dementia risk factors, lower baseline mRNFL thickness was significantly associated with higher incidence of all‐cause dementia and Alzheimer’s disease (per SD lower mRNFL thickness, hazard risk [95% confidence interval], 1.10 [1.02; 1.17] and 1.11 [1.001; 1.23], respectively); and lower mGCIPL thickness was not significantly associated with these outcomes (per SD lower mGCIPL thickness, 1.04 [0.99; 1.10] and 1.01 [0.94; 1.09], respectively). Age, sex, apolipoprotein E (APOE) genotype status, and educational level did not (consistently) modify these associations.

Conclusion

This individual participant data meta‐analysis found that lower baseline thickness of inner retinal layers was associated with up to approximately 10% higher risk of incident all‐cause dementia and Alzheimer’s disease. These findings suggest that retinal neurodegeneration precedes the onset of clinical dementia and that retinal imaging tools may be biomarkers for the early identification of individuals at risk for dementia.
Novel genomic loci shape two neuroanatomical dimensions of AD in non‐demented populations
Authors: Wen Junhao , Yang Zhijian , Skampardoni Ioanna , De Pian Marilena , Erus Guray , Mamourian Elizabeth , Cui Yuhan , Zhao Bingxin , Nasrallah Ilya M. , Toga Arthur W. , Shou Haochang , Shen Li , Davatzikos Christos
Published: December 2023

Background

Artificial intelligence has been in burgeoning demand to be applied to magnetic imaging resonance (MRI) data to parse the neuroanatomical heterogeneity of Alzheimer’s disease (AD) and/or mild cognitive impairment (MCI) (Wen et al., 2021a, 2021b; Yang et al., 2021). However, the genetic heterogeneity leading to this neuroanatomical heterogeneity, especially at the early asymptomatic stages, is not fully elucidated.

Method

A deep semi‐supervised representation learning method, called Surreal‐GAN (Yang et al., 2022), was applied to T1‐weighted MRI from AD/MCI patients from ADNI to define the two neuroanatomical dimensions of AD at the symptomatic stages. The R1 dimension was characterized by widespread brain atrophy without an exclusive focus on the medial temporal lobe, whereas the R2 dimension showed focal medial temporal lobe atrophy (Wen et al., 2022). We then applied the trained model to 33,540 non‐demented individuals from UK Biobank. Imputed genotyping data were analyzed in genome‐wide association studies (GWAS). We performed multiple linear regressions controlling for confounding factors (e.g., age) via Plink (Purcell et al., 2007). We defined a genomic locus (represented by the top lead SNP) considering linkage disequilibrium. Finally, we manually queried all leading SNPs on GWAS Catalog (Buniello et al., 2019) to determine if the genomic loci were novel, provided they were not previously associated with any clinical traits.

Result

GWAS discovered 24 genomic loci, of which 7 were novel for R1 and R2, respectively (Fig. 1). For R1, 8 mapped genes, based on physical positions, eQTL, and chromatin interactions, were associated with AD‐related traits in the literature. For example, the KDM2B gene from the genomic locus (rs9795600, P‐value = 1.13e‐08) was previously associated with AD (Gouveia et al., 2022). For R2, 13 mapped genes were associated with AD‐related traits. For example, the TESC gene from the genomic locus (rs77956314, P‐value = 9.99e‐29) was associated with neurofibrillary tangles measurement, which is formed by hyperphosphorylation of a microtubule‐associated protein known as tau in AD (Wang et al., 2020).

Conclusion

Our results confirmed genetic variants previously associated with AD and identified novel genomic loci contributing to this neuroanatomical heterogeneity. Further research is needed to understand these novel loci’s biological pathways and functional consequences.
Investigating the association between white matter fiber density in the superior longitudinal fasciculus and inhibitory control in groups at‐risk of Alzheimer’s disease
Authors: Tahara‐Eckl Lenore T , Roberts Reece P , Morgan Catherine A , Dell'Acqua Flavio , Kirk Ian J , Melzer Tracy R , Dalrymple‐Alford John C , Anderson Tim J , Cutfield Nick J , Tippett Lynette J
Published: December 2023

Background

Alzheimer’s disease (AD) is associated with poorer memory and reduced grey matter volume. Non‐amnestic cognition and white matter (WM) changes are an alternative line of enquiry and may reveal earlier changes. We investigated how inhibitory control relates to the superior longitudinal fasciculus (SLF) in groups at‐risk of AD.

Method

Participants (n = 229; aged > 55 years) from the Dementia Prevention Research Clinic, New Zealand were classified as control (C; n = 35), subjective cognitive decline (SCD; n = 60), single‐domain amnestic MCI (aMCI; n = 55), multiple‐domain MCI (mMCI; n = 52), and AD (n = 27). Using diffusion MRI, we measured WM fiber density (FD), fiber cross‐section (FC), and fiber density cross‐section (FDC) in the SLF (SLF1, SLF2, SLF3 in each hemisphere, Figure 1). We also measured inhibition (Trail‐Making B, Stroop Inhibition, Switching, Hayling Incongruency), generativity (Letter Fluency, Category Fluency), and processing speed (Trail‐Making A, Stroop Color Naming, Word Reading).

Result

Multivariate analyses showed impaired cognition across groups, with stronger impairments in inhibition (F(4, 206) = 5.41, p < .001; Wilk’s Λ = 0.55, η2p = 0.12) than processing speed (F(4, 217) = 2.45, p = .001; Wilk’s Λ = 0.84, η2p = 0.04). Generativity was also impaired across groups (p < .01). Significant variation in FD was found across groups in all SLF tracts, except for left SLF1 (Figure 2a). Between‐group differences (Figure 2c) included greater FD in C in the right SLF2 than mMCI (p = .04, d = 0.58), in the right SLF3 than SCD (p = .04, d = 0.57) and mMCI (p = .003, d = 0.77), and in the left SLF3 than SCD (p = .04, d = 0.65), mMCI (p = .01, d = 0.69), and AD (p = .02, d = 0.67). Two separate partial least‐squares analyses showed that poorer inhibition, but not processing speed, was associated with lower FD in the SLF (Figure 3).

Conclusion

Overall, we found that reduced FD in the SLF was associated with poorer inhibitory control in risk groups of AD. Therefore, WM alterations in the SLF may provide an early marker in AD.
Vascular risk factors and fMRI activation in a prodromal dementia population
Authors: Kallevag Oystein
Published: December 2023

Background

Vascular risk factors (VRF) are associated with an increased risk of developing dementia (1). Functional magnetic resonance imaging (fMRI) demonstrates the ability to detect early changes in neuronal activation before cognitive changes are clinically measurable (2). We investigate whether the number of VRF in cognitively healthy persons with a minimum of two VRF present was associated with a change in neuronal activation in the brain measured with task‐based fMRI.

Method

56 cognitively healthy, defined by Mini‐Mental State Exam (MMSE) and clinical dementia rating (CDR), elderly persons completed an fMRI examination with task‐based fMRI and N‐Back paradigm to access Working Memory (WM). Vascular risk factors included in the study were stable coronary artery disease or cerebrovascular disease according to MRI criteria, hypercholesterolemia, hypertension, diabetes mellitus and overweight (3). We analyzed the fMRI data at a single time point using the FMRIB Software Library (FSL v6.0; Analysis Group, Oxford, UK).

Result

The mean age was 68.4 (± 5.4) years. The number of VRF present were VRF2 (n = 21), VRF3 (n = 25) and VRF4 (n = 10). The median MMSE were: VRF2: 29 (IQR 29 ‐ 30), VRF3: 30 (IQR 28.8 ‐ 30) and VRF4: 29.5 (IQR 28.3 ‐ 30). A low number of VRF (VRF2) revealed higher neuronal activation than the groups with a higher number of VRF (VRF3 and VRF4). The regional activated clusters in the VRF2 group showed activation in the superior parietal lobule, visual cortex, premotor cortex, Broca’s area and anterior intra‐parietal sulcus.

Conclusion

Our results show that a lower neuronal activation measured with fMRI is associated with a higher number of VRF. We suggest further studies to assess whether altered neuronal activation measured by fMRI in cognitively healthy elderly persons with VRFs can be associated with a higher risk of developing cognitive decline and dementia. • O'Brien JT, Thomas A. Vascular dementia. The Lancet. 2015;386(10004):1698‐706. • Chen J, Glover G. Functional Magnetic Resonance Imaging Methods. Neuropsychology Review. 2015;25(3):289‐313. • Khalifa K, Bergland AK, Soennesyn H, Oppedal K, Oesterhus R, Dalen I, et al. Effects of Purified Anthocyanins in People at Risk for Dementia: Study Protocol for a Phase II Randomized Controlled Trial. Front Neurol. 2020;11:916.
Sleep apnea‐related hypoxemia, not sleep fragmentation, is associated with white matter hyperintensities in older adults
Authors: Berisha Destiny E , Rizvi Batool , Chappel‐Farley Miranda G. , Taylor Lisa M. , Sattari Negin , Dave Abhishek , Chen Ivy Y. , Neikrug Ariel , Benca Ruth M , Yassa Michael A. , Mander Bryce A
Published: December 2023

Background

Sleep apnea is a type of sleep‐disordered breathing that increases risk for Alzheimer’s disease‐related pathology potentially through cerebrovascular pathology, likely exacerbated by two features of sleep apnea: intermittent hypoxia and sleep fragmentation. White matter hyperintensities (WMH), a marker of small vessel cerebrovascular disease, increase in aging and in AD. Here, we tested the hypothesis that apnea‐related hypoxemia severity, and not sleep fragmentation, are associated with WMH volume in older adults.

Method

Thirty‐two older adults (73.4±5.3 years, 19 female, AHI = 15.2±18.9) were evaluated with overnight polysomnography (PSG). Apnea severity was quantified using the Apnea‐Hypopnea Index (AHI), Respiratory Disturbance Index (RDI), and blood oxygen desaturation (Oxygen Desaturation Index (ODI), duration, frequency of = 4% desaturations, and desaturation nadir) stratified by sleep stages. T1‐MPRAGE and T2‐FLAIR scans were acquired using a 3T Siemens scanner. Total WMH volumes were derived using a semi‐automated algorithm. Overnight memory retention was assessed using the change in the lure discrimination index (LDI) for the emotional version of the Mnemonic Discrimination Task.

Result

Traditional measures of apnea severity and sleep fragmentation were not significantly associated with global WMH volume. However, both max duration of oxygen desaturation events (r = 0.44, p = 0.011) and max oxygen desaturation percentage (in rapid‐eye movement (REM) and in total sleep: r = 0.48, p = 0.005, and r = 0.44, p = 0.01), were significantly associated with total WMH volume. Similar relationships were found with time spent below 90% and 80% oxygen saturation (Kendall’s tau = 0.33, p = 0.02 and tau = 0.275, p = 0.03). These relationships survived adjustment for sex, age, and hyperlipidemia and/or hypertension medication at time of PSG. Global WMH volume was also negatively associated with overnight memory retention (r = ‐0.38, p = 0.03).

Conclusion

These findings suggest that hypoxemia severity, compared to sleep fragmentation, are more strongly associated with global WMH volume. As WMH volume was associated with overnight memory retention, this may suggest a pathway in which OSA increases WMH, which is subsequently associated with tau burden, worsening sleep‐dependent memory.
Predicting cognitive decline in a low‐dimensional representation of brain morphology
Authors: Lamontagne‐Caron Rémi , Desrosiers Patrick , Potvin Olivier , Duchesne Simon , Doyon Nicolas
Published: December 2023

Background

Identifying early signs of neurodegeneration due to Alzheimer’s disease (AD) is a necessary first step towards preventing cognitive decline. Individual cortical thickness measures, available after processing anatomical magnetic resonance imaging (MRI), are sensitive markers of neurodegeneration. However, cortical decline in aging and high inter‐individual variability complicates the determination of AD‐related neurodegeneration on trajectories. Further, the high‐dimensional nature of these trajectories necessitate the use of a transformation into lower‐dimensional spaces in order to perform comparative statistical analyses, model decline, and identify criteria differentiating pathological from normal trajectories.

Method

In this project, we computed trajectories in a 2D representation of a 62‐dimensional manifold of individual cortical thickness measures. To compute this representation, we used a nonlinear dimension reduction algorithm called Uniform Manifold Approximation and Projection (UMAP). We first created a UMAP embedding on measurements from 6,237 cognitively healthy participants (3,556 women) aged 18 to 100 years old from the NOMIS database. We then projected longitudinal data from 537 mild cognitively impaired (MCI) subjects and 340 AD subjects from ADNI into this embedding. Each participant had multiple visits (n = 2), one year apart. Finally, differences in trajectories were analysed by clustering the reduced data and comparing the positional variations through time between MCI and AD subjects. The validity of the approach was verified through cross‐validation.

Result

First, the embedding was shown to be positively associated (r = 0.65) with participants' age (see figure 1) in the NOMIS data. When projected in this space, differences between ADNI’s MCI and AD distributions were found (see figure 2). Average trajectories between clusters were shown to be significantly different between MCI and AD subjects (see figure 3). Moreover, we showed that some clusters and trajectories between clusters were more prone to host AD subjects. Finally, cross‐validation showed an accuracy of up to 72% at predicting cognitive decline in MCI participants over 2,000 bootstrap iterations.

Conclusion

A 2D low‐dimensional cortical thickness representation embeds sufficient discriminatory information as to predict decline to AD in MCI participants with strong accuracy.
Associations of plasma GFAP, NfL, and p‐tau231 with early‐onset Alzheimer’s Disease pathology
Authors: Logan Paige E. , Dage Jeff L. , Hammers Dustin B. , Manchella Mohit K. , Eloyan Ani , Mundada Nidhi S. , La Joie Renaud , Iaccarino Leonardo , Fagan Anne M. , Foroud Tatiana M. , Zetterberg Henrik , Blennow Kaj , Koeppe Robert A. , Aisen Paul S. S , Carrillo Maria C. , Rabinovici Gil D. , Dickerson Brad C. , Apostolova Liana G.
Published: December 2023

Background

Increased levels of glial fibrillary acidic protein (GFAP), neurofilament light (NfL), and phosphorylated tau 231 (p‐tau231) in plasma have been associated with late‐onset Alzheimer’s Disease (AD). The impact of these biomarkers in early‐onset AD (EOAD) is unclear and the novel plasma biomarker, p‐tau231, has not been studied in this population. We aimed to demonstrate the effect of each biomarker on EOAD pathology by investigating their associations with amyloid burden, tau burden, and gray matter density (GMD).

Method

183 EOAD participants from the Longitudinal EOAD study with available baseline plasma GFAP, NfL, p‐tau231, MRI, amyloid PET, and tau PET data were included (mean age = 58.7, 55.2% female, 54.1% APOE‐e4 carrier, mean MMSE = 21.9). Voxel‐wise multiple linear regression models of amyloid PET, tau PET, and T1‐weighted MRI images yielded statistical maps with GFAP, NfL, or p‐tau231 as predictors. Covariates were hierarchically added: Model 1: age, sex; Model 2: age, sex and APOE‐e4; Model 3: age, sex, APOE‐e4 and MMSE. All models are displayed at a family‐wise error adjustment of p<.05.

Result

Higher levels of GFAP, NfL, and p‐tau231 were significantly associated with greater amyloid burden and tau burden. Higher levels of GFAP and NfL were also significantly associated with lower GMD. No significant associations were found for p‐tau231 and GMD (Figures 1, 2 & 3). When controlling for APOE‐e4 carrier status, the effect of GFAP on amyloid burden was no longer significant (Figure 1). After additionally controlling for MMSE, the effects of NfL and p‐tau231 on amyloid burden were no longer significant, while the effects of all three biomarkers on tau burden were reduced but remained significant. In terms in of GMD, the effect of NfL survived correction for dementia severity, while the effect of GFAP did not.

Conclusion

These results suggest that all three plasma biomarkers show stronger associations with neurodegeneration (cortical atrophy and/or tau burden) than with amyloid burden. Furthermore, this study highlights the importance of plasma biomarkers for AD diagnosis and monitoring. Future work should investigate longitudinal associations and the mediational role of APOE‐e4 and dementia severity.
Association between brain amyloid deposition and longitudinal changes of white matter hyperintensities
Authors: Cha Woo‐Jin , Yi Dahyun , Ahn Hyejin , Byun Min Soo , Jung Joon Hyung , Kong Nayeong , Jung Gijung , Lee Jun‐Young , Lee Yun‐Sang , Kim Yu Kyeong , Kang Koung Mi , Sohn Chul‐Ho , Lee Dong Young
Published: December 2023

Background

White matter injury had been mostly considered a result of chronic ischemia caused by cerebral small vessel disease. However, recent studies reported that white matter degeneration could also be an important pathophysiological feature in Alzheimer’s disease (AD). This study aimed to identify the relationship between AD biomarkers, particularly amyloid‐beta (Aß) and tau deposition, with white matter hyperintensities (WMHs) representing cerebral white matter injury.

Method

A total 456 older adults aging from 55 to 90 years including cognitively normal and cognitively impaired individuals were recruited from the Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer’s Disease (KBASE) cohort. The participants underwent comprehensive clinical and neuropsychological assessment, [11C] Pittsburgh Compound B PET for measuring Aß deposition, [18F] AV‐1451 PET for measuring tau deposition, and MRI scans with fluid‐attenuated inversion recovery image for measuring WMH volume. For PET scans, standard uptake value ratio (SUVR) was used for the analyses; combined regions of hemispheric white matter, inferior cerebellum and pons were used as the reference region when obtaining SUVRs. The relationships between Aß or tau deposition and WMH volume were examined using multiple regression analysis. In this analysis, baseline Aß or tau were used as independent variables, and baseline as well as change of WMH volume over 2 years were used as dependent variables.

Result

Baseline Aß deposition levels had significant positive association with longitudinal change of WMH volume over 2 years (ß = 0.238, p = 0.009), but not with WMH volume at baseline. Baseline tau was not related with any of WMH volume at baseline and longitudinal change of WMH volume over 2 years. We also found significant interaction effect between baseline Aß deposition level and sex on longitudinal change of WMH volume. Subsequent subgroup analyses showed that high baseline Aß deposition was associated with increase of WMH volume over 2 years in female (ß = 0.427, p = 0.001), but not in male.

Conclusion

Our findings suggest that Aß deposition, but not tau, accelerates cerebral white matter injury, particularly in female.
Machine‐learning derived MRI‐based atrophy biomarker predicts long‐term cognitive decline in stroke or transient ischemic attack
Authors: Yuan CAI , Lam Bonnie Y.K. , Fan Xiang , Liu Wanting , Shi Lin , Au Lisa Wing Chi , Ko Ho , Mok Vincent Chung Tong
Published: December 2023

Background

Alzheimer’s disease‐resemblance atrophy index (AD‐RAI) is a machine‐learning derived MRI‐based brain atrophy biomarker that is valid in predicting cognitive decline in subjects with AD. We investigated the performance of AD‐RAI in predicting long‐term cognitive decline in subjects with stroke or transient ischemic attack (TIA).

Method

We recruited consecutive dementia‐free stroke/TIA subjects who had brain MRI at baseline (i.e., within 3‐6 months after the index event) and cognitive data at both baseline and 3 years. We defined cognitive decline as an increase in clinical dementia rating scale from 0 to 0.5 or above or from 0.5 to 1 or above at 3 years when compared with baseline. We investigated the association between AD‐RAI, traditional brain atrophy biomarkers (hippocampus volume [HV], hippocampal fraction [HF], total brain volume [TBV], TBV/intracranial volume [ICV] ratio, ventricular‐brain‐ratio, presence of medial temporal lobe atrophy [MTLA]), and cerebral small vessel disease biomarkers (white matter hyperintensity [WMH]) volume, WMHV/ICV ratio presence of confluent WMH, presence of >/ = 3 lacunes) with cognitive decline.

Result

Of 231 participants (mean age 66.0 ± 10.9, 124 [53.7] male), 55(23.8) had cognitive decline at 3 years. Among all the imaging biomarkers, AD‐RAI and HV were associated with cognitive decline in univariate regression. Such a relationship was still significant with AD‐RAI after adjusted for age, gender, and education (aOR [95%CI] 3.900 [1.221‐12.458]). Among all imaging biomarkers, only AD‐RAI was associated with slope of Montreal cognitive assessment (MoCA) after adjusted to age, gender, education (ß(SE) ‐0.742[0.242], p = 0.002).

Conclusion

AD‐RAI predicted long term cognitive decline in subjects with stroke/TIA.
Individuals from Memory Clinic were Associated with Severer Amyloid Deposition in the Chinese Population in Urban Cities
Authors: He Kun , Li Binyin , Huang Lin , Zhao Jun , Hua Fengchun , Wang Tao , Li Junpeng , Wang Jie , Wang Mengjie , Huang Qi , Xu Shasha , Chen Ke‐Liang , Ren Shuhua , Cai Huawei , Jiang Donglang , Hu Jingchao , Han Xinmin , Guan Yihui , Guo Qihao , Xie Fang
Published: December 2023

Background

Amyloid deposition is considered the initial pathology in Alzheimer’s disease (AD), investigation of amyloid pathology and the risk factor for amyloid pathology and cognitive declines in the Chinese population is critical for personalized management. However, the prevalence of amyloid deposition and the risk factors for amyloid pathology are unknown in the Chinese population.

Method

Participants were recruited from urban communities and memory clinics in Shanghai and Zhengzhou, China. A total of 246 AD individuals, 274 Mild cognitive impairment (MCI) individuals, and 506 Normal cognition (NC) individuals were identified: 106 AD, 156 MCI and 506 NC from the Community‐based cohort (COMC) as well as 140 AD and 118 MCI from the Clinic‐based cohort (CLIC). Amyloid positivity and deposition were analyzed based on amyloid positron emission tomography (PET) scans. We also performed a partial least squares (PLS) analysis to evaluate the associations of cohort, age, sex, education level, and ApoE genotype with amyloid qualification, quantification results and global cognition in all 1026 participants.

Result

Across the two cohorts, the AD group displayed the significantly highest rate of amyloid positivity (211/246, 85.8%), followed by the MCI (122/274, 44.5%) and NC groups (136/506, 26.9%, all P < 0.001). Participants from the CLIC displayed a higher rate of amyloid positivity than those from the COMC in the MCI (68/118, 57.6% vs. 54/156, 34.6%, P < 0.001) and AD groups (128/140, 91.4% vs. 83/106, 78.3%, P = 0.006). MCI (SUVr: 1.37 ± 0.25 vs. 1.25 ± 0.18, P < 0.001), Aß+ MCI (SUVr: 1.48 ± 0.27 vs. 1.37 ± 0.24, P = 0.03) and AD individuals (SUVr: 1.47 ± 0.23 vs. 1.39 ± 0.23, P = 0.01) in the CLIC displayed significantly greater amyloid deposition than those in the COMC. According to the PLS model, we found that the CLIC was significantly associated with positive amyloid deposition and severer amyloid deposition.

Conclusion

We found that individuals from CLIC displayed a higher amyloid positive rate and severer amyloid deposition. Specifically, in a PLS model, The CLIC, was strongly associated with amyloid pathology.
Higher systolic and diastolic blood pressures in recently postmenopausal women are associated with greater WMH more than a decade later in the KEEPS Continuation
Authors: Kara Firat , Tosakulwong Nirubol , Lesnick Timothy G. , Fought Angela J. , Schwarz Christopher G. , Senjem Matthew L. , Fields Julie A. , Min Paul H , Lowe Val J. , Jack Clifford R. , Bailey Kent R. , James Taryn T. , Lobo Rogerio A. , Manson JoAnn E. , Pal Lubna , Hammers Dustin B. , Malek‐Ahmadi Michael H. , Cedars Marcelle I. , Naftolin Frederick N. , Miller Virginia M. , Harman Sherman M. , Dowling Maritza N. , Gleason Carey E. , Kantarci Kejal
Published: December 2023

Background

Higher blood pressure (BP) is associated with greater white matter hyperintensity (WMH) volume, but research is limited in recently menopausal and postmenopausal women. Postmenopausal women have a greater burden of WMH than men and premenopausal women, but whether hormone therapy (HT) modifies the association between systolic and diastolic BP (SBP, DBP) and WMH is unknown. We investigated the association of SBP and DBP in recently postmenopausal women who participated in an HT trial with WMH volumes measured 14 years later and explored whether HT modified the results.

Method

Women with good cardiovascular (CV) health, who were previously enrolled in a randomized placebo‐controlled HT trial, the Kronos Early Estrogen Prevention Study (KEEPS), participated in the current observational KEEPS continuation (n = 212; median age = 67; range 58‐72). SBP and DBP were measured at KEEPS baseline (median age = 54 years; range 44‐59) and continuation. Antihypertensive users were excluded (baseline, n = 34; continuation, n = 61). Approximately 10 years after the end of KEEPS HT versus placebo 4‐year interventions, automated WMH volumes were measured from 3D‐FLAIR MRI. Associations of KEEPS baseline and continuation SBP and DBP with log WMH volume at KEEPS continuation were tested using linear regression analyses adjusting for covariates in model 1 (age, total intracranial volume, study site) and model 2 (model 1 plus cardiovascular risk factors (CVRF)).

Result

Higher KEEPS baseline SBP and DBP were associated with greater WMH volume measured 14 years later, and after adjusting for CVRF (p = 0.01). Similarly, in KEEPS continuation, higher SBP and DBP were associated with greater WMH volume measured concurrently and after adjusting for CVRF (p<0.001). We did not find statistically significant evidence that HT versus placebo modified these associations. Topographically, higher SBP and DBP were associated with greater periventricular WMH in the frontal and parietal lobes after adjusting for age (Figure).

Conclusion

Higher SBP and DBP in recently menopausal women with good CV health were associated with greater WMH volumes more than a decade later after adjusting for CVRF, independent of randomization to HT. Our results show the importance of blood pressure control in recently menopausal women, that may reduce the white matter injury later in life.
Effects of de‐facing T1 MRI, FLAIR MRI, Amyloid PET, and Tau PET scans on imaging‐clinical correlations analyses
Authors: Schwarz Christopher G. , Kremers Walter K. , Weigand Stephen D. , Prakaashana Carl M. , Senjem Matthew L. , Lowe Val J. , Gunter Jeffrey L. , Kantarci Kejal , Vemuri Prashanthi , Petersen Ronald C. , Knopman David S. , Jack Clifford R.
Published: December 2023

Background

Automated face recognition can potentially re‐identify de‐identified research brain MRI, PET, and CT, and direct differences of brain measurements from original and de‐faced images are statistically significant but very minor, i.e. below scan‐rescan differences. Their effects on analyses correlating brain imaging biomarkers with clinical variables remain unknown.

Method

We sampled 3 age‐and‐sex‐matched groups (CU, MCI, and clinical AD) from Mayo Clinic aging studies, each with 61 participants with same‐visit 3D T1‐weighted and 3D T2‐FLAIR MRI, PiB amyloid PET, and Flortaucipir tau PET (total n = 183). We automatically measured hippocampal volume, PIB global SUVR, and tau temporal meta‐ROI SUVR using a) our in‐house pipeline with SPM12, MCALT, and ANTs, and b) FreeSurfer 7.3.2 (PETSurfer), and we measured voxels associated with clinical group separation using SPM12. We also measured WMH from FLAIR using a) our in‐house pipeline, b) Lesion Segmentation Tool (LST), and c) FreeSurfer’s Samseg. For each measurement, we calculated pair‐wise group separation AUC values and Spearman’s rho with age and CDR‐SOB. We then de‐faced all PET and MRI using mri_reface, our top‐performing automated de‐facing software that replaces imaged faces with an average face (“re‐facing”), and we repeated all measurements and analyses with de‐faced images. We then compared the magnitudes of clinical correlations with original images and those of de‐faced images.

Result

Analyses of original and de‐faced images had very high agreement. Only 2/55 paired comparisons were significant (Tables 1‐2): FreeSurfer‐measured global PIB SUVR from de‐faced images was more correlated with age (rho 0.003 vs ‐0.227, p = 0.046), and Mayo‐measured WMH volume from original images was more correlated with CDR‐SOB (rho 0.321 vs 0.308, p = 0.020). Another comparison‐pair tested p = 0.041 for an AUC change +0.008, which we consider not practically meaningful. All others had p>0.05. In voxel‐based analyses of CU vs AD participants, all comparisons were qualitatively similar between original and de‐faced variants (Figure 1).

Conclusion

De‐facing PET and MRI using mri_reface did not significantly affect 53/55 correlations between imaging and clinical variables; of the two affected, one became stronger with re‐faced images. Stronger correlations with clinical variables may be explained by de‐facing’s standardizing face voxels and artifacts that irrelevantly affect brain segmentations.
Synaptic density is correlated with Aβ plaques and neurofibrillary tau tangles across the clinical and biologic Alzheimer’s disease continuum
Authors: DiFilippo Alexandra H , McLachlan Max , McVea Andrew K , Bettcher Brecca , Jonaitis Erin M. , Ennis Gilda E. , Pasquesi Mary‐Elizabeth , Davenport Nancy J , Thor Yer , Grover Ethan , Hudson Sarah , Barnhart Todd E , Engle Jonathan W , Betthauser Tobey J , Johnson Sterling C , Bendlin Barbara B , Christian Bradley T.
Published: December 2023

Background

The extent to which amyloid‐ß burden and neurofibrillary tau tangle burden are associated with synaptic degeneration in vivo is not well known. PET imaging was used to examine the cross‐sectional relationship between neurofibrillary tau tangle burden and amyloid‐ß plaque burden with synaptic density among individuals who spanned the clinical and biologic Alzheimer’s disease continuum.

Method

Participants were recruited from the Wisconsin Alzheimer’s Disease Research Center and the Wisconsin Registry for Alzheimer’s Prevention study. N = 64 participants were included in the analysis based on completed cognitive testing, structural MR and PET imaging using [11C]PiB DVR for amyloid burden, [18F]MK‐6240 SUVR for regional neurofibrillary tau burden, and [11C]UCB‐J DVR for regional synaptic density burden analysis. Amyloid burden was indexed as a global [11C]PiB DVR representing the mean of brain regions that typically accumulate amyloid. UCB‐J DVR and MK‐6240 SUVR regions of interest were selected based on the histopathological staging of tau pathology in Alzheimer’s disease with a focus on regions of tau pathology described by earlier and later Braak stages. The first composite region of interest (ROI1) comprised the hippocampus and entorhinal cortex, and the second (ROI2) comprised the amygdala, fusiform, lingual gyrus, and the inferior temporal gyrus. Linear correlations (Pearson’s r) tested the relationship between UCB‐J DVR and PiB DVR, as well as UCB‐J DVR and MK‐6240 SUVR.

Result

Global [11C]PiB DVR showed a moderate negative relationship with UCB‐J DVR in ROI1 (r = ‐0.42, p = 0.0006) and a weak relationship with UCB‐J DVR in ROI2 (r = ‐0.33, p = 009). [18F]MK‐6240 SUVR and UCB‐J DVR were negatively correlated in ROI1 (r = ‐0.44, p = 0.0003) and in ROI2 (r = ‐0.42, p = 0.005).

Conclusion

Both amyloid burden and tau pathology were associated with lower synaptic density. Tau and synaptic density appeared to show moderate correlations among brain regions involved in both earlier and more advanced tau pathology, whereas amyloid burden appeared to be more strongly related to synaptic density in brain regions where more advanced disease is typically observed.
Cerebral Blood Flow and Arterial Transit Time Variations in Elders with Long COVID
Authors: Patel Milan , Cohen Alexander D , Pommy Jessica , Umfleet Laura Glass , Franczak Malgorzata , Swanson Sara J , Obarski Shawn , Agarwal Mohit , Wang Yang
Published: December 2023

Background

Many COVID‐19 patients experience persistant neurological symptoms that often extend beyond the period of acute infection, referred to as “Long COVID”, where most patients reported brain fog and cognitive dysfunction. While elderly individuals are more vulnerable to possible enduring cognitive impairments after acute COVID‐19 requiring hospitalization, there is increasing concern that older patients with Long COVID will be at high risk for developing Alzheimer’s disease (AD) and dementia. Although there is emerging recognition of Long COVID, its underlying neuropathology remains unknown. This study aimed to investigate neurovascular function using advanced MRI perfusion in elder patients with Long COVID.

Method

Well‐matched elderly Long COVID patients (n = 14, mean age = 60.1±4.3 years, 12F, 2M) and control subjects (n = 25, mean age = 60.4±7.2 years, 19F, 6M) underwent neurocognitive testing as well as neuroimaging. Patients were seen 711.57 ± 165.02 days after the initial mild non‐hospitalized COVID‐19 infection. Clinical cognitive complaints of Long COVID patients included memory changes (n = 12, 85.7%), attention (n = 12, 85.7%), speech/writing (n = 9, 64.3%), and multitasking (n = 9, 64.3%). Brain perfusion was evaluated using an advanced 3D pseudo‐continuous arterial spin labeling (pCASL) sequence with Hadamard encoded multiple post‐labeling delays (PLDs), enabling estimation of Cerebral Blood Flow (CBF) and Arterial Transit Time (ATT) ATT and ATT corrected CBF.

Result

Conventional MRI scans (T1, T2, and FlAIR) appear normal in all subjects. Voxelwise comparisons between Long‐COVID and control subjects showed a significant global decrease in the ATT (p < 0.05, cluster corrected at a < 0.05), along default mode and other key networks, where there is a trend of decreased CBF (p<0.05, uncorrected) specifically in the frontal lobe in those with Long COVID.

Conclusion

These preliminary results in an aging group indicate that neurocognitive effects of Long COVID could be attributed to neurovascular dysfunction, even in those cases with initial non‐hospitalized mild COVID‐19 of more than 500 days. The novel finding of diffusely decreased ATT could be something attributable to the unique neurovascular mechanism of Long COVID. Future longitudinal research following the progression of those elderly Long COVID patients with known abnormal neurovascular function to fully evaluate their risk for developing AD and dementia.
Testing bidirectional relationships between functional brain networks and preclinical Alzheimer disease biomarkers
Authors: Millar Peter R , Singhe Nawang , Macharia Kiana Angela , Metcalf Nicholas V , Roman June , Morris John C , Benzinger Tammie L.S. , Ances Beau
Published: December 2023

Background

Resting‐state functional connectivity (RSFC) provides estimates of brain networks using fMRI. There are conflicting reports regarding the effects of amyloid‐ß (Aß) and tau on RSFC networks in cognitively normal participants. These inconsistencies might be explained by a recently‐proposed theoretical model that Aß and tau have an interactive effect on RSFC, marked first by hyper‐connectivity in association with Aß, then by hypo‐connectivity in association with tau. Although there is preliminary support for this model, independent validations and further characterizations of the effects of Aß and tau on RSFC are needed.

Method

We analyzed RSFC, Aß PET, and tau PET data from the Knight Alzheimer Disease Research Center (ADRC). All participants were cognitively normal (Clinical Dementia Rating®: 0). RSFC was collected on two scanners in partly‐overlapping samples (PETMR N: 190, TRIO N: 149). RSFC data were processed with framewise censoring and global signal regression. RSFC networks were defined using 298 regions of interest. Aß was measured with PET PiB and AV‐45 tracers, which were harmonized using a Centiloid conversion. Tau was measured with a PET AV‐1451 tracer and was summarized in pre‐defined regions. Main effect and interaction relationships between Aß, tau PET, and RSFC were tested with linear regression models, controlling for age, sex, education, and head motion as covariates, with a false discovery rate correction.

Result

We did not observe a bidirectional interaction effect in any of the hypothesized networks (default mode [DMN], salience [SAL], frontoparietal [FPN]). Aß was positively associated with RSFC, independent of tau, in the DMN and SAL, while tau was negatively associated with RSFC, independent of Aß, in the SAL only. Exploratory analyses of FC within and between all networks did not identify clear patterns of interactive biomarker effects, nor consistent patterns of main effect relationships within any of the other networks.

Conclusion

These results do not support an interactive model of RSFC in preclinical AD. Inconsistencies with previous interactions may be driven by sample‐specific or methodological differences, or the low reliability of FC and brain‐behavior relationships. Prominent biomarker relationships in the DMN and SAL are consistent with regional overlap with Aß deposition in early AD.