bluuebunny/crossref_metadata_2025 huggingface dataset:
Topographical pattern of blood‐brain barrier impairment in preclinical and clinical Alzheimer’s disease
Authors: Yi Dahyun , Byun Min Soo , Park Joon Sik , Byeon Gihwan , Ahn Hyejin , Jung Gijung , Kang Koung Mi , Sohn Chul‐Ho , Park Jaeseok , Lee Dong Young
Published: December 2023

Background

While blood‐brain barrier (BBB) damage in some brain regions has been suggested in Alzheimer’s disease (AD) dementia and mild cognitive impairment (MCI), the topographical pattern of BBB impairment associated with AD process in whole brain level is still poorly understood. Using high‐resolution 3‐dimensional (3D) dynamic contrast‐enhanced (DCE) scans of BBB permeability (Ktrans) for the whole brain, we aimed to reveal topographical pattern of BBB impairment related to Alzheimer’s disease (AD) including preclinical as well as clinically impaired state.

Method

Ninety‐one participants were included in the study [45 cognitively normal (CN) older adults, 24 individuals with mild cognitive impairment (MCI), and 22 patients with AD dementia]. Comprehensive clinical and neuropsychological assessments were administered to all participants. High‐resolution DCE‐ as well as T1‐weighted‐MRI scans were obtained in addition to amyloid‐PET scans. Amyloid‐beta (Ab) positivity was obtained using previously established cut‐offs. Preprocessing of Ktrans maps incorporated FreeSurfer‐based (v6.0) segmentation to ensure exclusion of the voxels within cerebrospinal fluid (CSF) spaces. Voxel‐wise analyses were conducted using SPM12 implemented in MATLAB 2018b.

Result

Subtle BBB impairment, as measured by Ktrans map images based on high‐resolution 3D DCE‐MRI, was observed at multiple brain regions even in preclinical AD (i.e., Ab‐positive CN) as well as AD with cognitive impairment (i.e., Ab‐positive MCI and AD). The brain regions with impaired Ktrans closely corresponded to the AD‐signature regions (Figure). Compared to Ab‐negative CN, Ab‐positive CN showed increased breakdown of BBB in the precuneus, posterior‐cingulate cortex, and medial temporal lobe. Moreover, compared to Ab‐negative CN, Ab‐positive MCI and AD patients showed increased breakdown of BBB in more diffuse regions including bilateral frontal, parietal and inferior temporal areas. In contrast, when using low‐resolution BBB images for the same participants, BBB damage was not detected in preclinical AD and observed at only limited brain regions in AD with cognitive impairment.

Conclusion

We demonstrated topographical pattern of BBB impairment associated with preclinical AD as well as AD with cognitive impairment through technically advanced high‐resolution DCE‐MRI. The findings suggest that subtle BBB changes detectable from high‐resolution DCE‐MRI has potential as a biomarkers for detection and monitoring of BBB impairment in whole AD continuum.
Tau PET: utility as a biomarker for chronic traumatic encephalopathy
Authors: Krishnadas Natasha , Dore Vincent , Lamb Fiona , Guzman Rodney , Ponsford Jennie L , Hicks Amelia J , Williams Robert , Feizpour Azadeh , Villemagne Victor L , Rowe Christopher C
Published: December 2023

Background

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease characterized by tau deposition in the depths of the sulci associated with exposure to repetitive head impacts (RHI). It is a post‐mortem diagnosis. We previously reported a frontotemporal predominant tau 18F‐MK6240 PET pattern resembling the distribution of CTE in a retired Australian Rules Football player in the context of a moderate amyloid‐beta plaque burden.1 This study aimed to investigate the utility of 18F‐MK6240 PET as a potential biomarker for CTE in contact sports players with exposure to RHI (sRHI).

Method

sRHI (n = 33) and age‐matched healthy controls (HC) (n = 32) completed amyloid (18F‐NAV4694) and tau (18F‐MK6240) PET scans. Amyloid PET was quantified in Centiloids. 18F‐MK240 standardized uptake value ratios (SUVRs) were generated for the dorsolateral prefrontal cortex and composite regions of interest (ROI) (frontal; mesial temporal; temporoparietal).

Result

For sRHI, the primary contact sport was Australian Rules Football (n = 17), boxing/kickboxing/martial arts (n = 11), rugby (n = 4) and soccer (n = 1), with 36.4% participating at a professional level. sRHI had a mean age of 54.2 (±9.2) (vs HC 53.0±9.5, p = 0.61), and 94% were male (vs HC 78%, p = 0.08). sRHI did not differ from HC in years of education (p = 0.46) but had more impaired MMSE (28.1±1.9 vs 29.3±0.8, p = 0.006, d = ‐0.80) and Clinical Dementia Rating scores (0.21±0.3 vs 0±0, p<0.001, d = 1.25). sRHI and HC did not differ in mean Centiloid values (2.9±8.4 vs 3.0±8.2). sRHI and HC did not differ in 18F‐MK6240 SUVR in the regions examined, and no differences were observed between professional and amateur sRHI.

Conclusion

Contact sports players with exposure to repetitive head impacts did not differ from age‐matched healthy controls on 18F‐MK6240 SUVR in frontal, mesial temporal, and temporoparietal brain regions. Study limitations include the small sample size, heterogeneity in sports type and highest level of participation, and participants with relatively mild cognitive and functional impairments. Additionally, while 18F‐MK6240 has high affinity for 3R/4R tau in Alzheimer’s disease, its affinity in CTE, particularly important at early stages, remains unclear. References: 1 Krishnadas N et al. Case report: 18F‐MK6240 tau positron emission tomography pattern resembling chronic traumatic encephalopathy in a retired Australian Rules Football player. https://doi.org/10.3389/fneu.2020.598980.
Cluster analysis of the longitudinal progression of plasma biomarkers and amyloid imaging in the Wisconsin Registry for Alzheimer’s Prevention
Authors: Wells Michael , Bilgel Murat , Jonaitis Erin M. , Langhough Rebecca E , Du Lianlian , Betthauser Tobey J , Blennow Kaj , Ashton Nicholas J. , Zetterberg Henrik , Johnson Sterling C , Jedynak Bruno Michel
Published: December 2023

Background

The analysis of the longitudinal progression of plasma biomarkers and amyloid imaging might lead to new insights in the early pattern of biomarker changes.

Method

Plasma Aß42/Aß40, pTau231/Aß42, pTau181/Aß42, glial fibrillary acidic protein (GFAP), and neurofilament light chain (NFL) were measured for n = 223 subjects and 1673 total visits in the Wisconsin Registry for Alzheimer’s Prevention (WRAP) using Quanterix Simoa assays at the University of Gothenburg. Global distribution volume ratio (DVR) was computed from 11C‐Pittsburgh compound B PET scans. Inclusion criteria included Amyloid or CSF Amyloid positive status, and at least one plasma serial value. Trajectories spanning age 46.9 to 80.3 years old for the DVR and plasma biomarkers were estimated by fitting a vector field to the longitudinal data (https://arxiv.org/abs/2206.15215). A Louvain community clustering analysis was performed. The time from Amyloid positivity (DVR = 1.19; centiloid of 22) was also computed for all individual trajectories that crossed this threshold.

Result

The Louvain community clustering algorithm resulted in three distinct communities (Fig 1): no increase in DVR or plasma biomarkers (Green, n = 88(39.5%)); increase in DVR and all plasma biomarkers except NFL (Red, 41(18.4%)); and mixed DVR plus GFAP and NFL increase (Blue, 94(42.2%)). Time since Amyloid positivity (TSAP) was computed for the subset of subjects (n = 84) expected to cross the Amyloid positivity threshold. The Louvain communities as a function of TSAP are shown in Fig 2.

Conclusion

We identified three communities regarding the longitudinal progression of amyloid PET and plasma biomarker levels. Plasma biomarkers were dynamic up to 30 years before Amyloid positivity.
Sex‐associated differences in plasma and cerebrospinal fluid biomarkers in Early‐onset Alzheimer’s disease
Authors: Nemes Sára , Logan Paige E. , Dage Jeff L. , Hammers Dustin B. , Fagan Anne M. , Manchella Mohit K. , Eloyan Ani , Foroud Tatiana M. , Zetterberg Henrik , Koeppe Robert , Aisen Paul S. S , Carrillo Maria C. , Blennow Kaj , Schindler Suzanne E. , Gray Julia D , Dickerson Brad C. , Rabinovici Gil D. , Apostolova Liana G.
Published: December 2023

Background

Female sex is associated with greater atrophy, amyloid and tau burden in Early‐onset Alzheimer’s Disease (EOAD) in the Longitudinal EOAD Study (LEADS). APOE‐e4 non‐carrier‐status was found to be a further predictor of EOAD pathology. We expanded the analyses by examining the impact of sex and APOE‐e4 on plasma and cerebrospinal fluid (CSF) biomarkers of AD. Plasma markers included: neurofilament light chain (NfL), plasma glial fibrillary acidic protein (GFAP), Aß 42/40, and pTau231. CSF markers included: Aß 42/40, neurogranin, tTau, pTau181, synaptosomal‐associated protein‐25 (SNAP25), YKL‐40, and visinin‐like protein‐1 (VILIP1).

Method

We included 201 amyloid‐positive EOAD, 64 amyloid‐negative Early‐onset cognitively impaired (EOnonAD), and 86 Cognitively Normal (CN) LEADS participants with plasma biomarker data. Of these 100 EOAD, 35 EOnonAD, and 38 CN participants also had CSF data. Participants were stratified by sex and APOE‐e4 genotype. Demographics (age, education, APOE‐e4, MMSE) and biomarker differences were compared using ANOVA within each diagnostic group. ANCOVAs were run to control for the effects of age and education on biomarkers.

Result

Compared to men, EOAD women showed greater levels of plasma NfL (p = .03), and GFAP (p<.001) while Aß 42/40, and pTau231 were comparable. In CSF, EOAD women showed higher levels of neurogranin (p = .01), tTau (p = .01), pTau181 (p = .01) and VILIP1 (p = .02). EOnonAD women showed significantly greater plasma GFAP levels (p = .02). In the CN cohort, women had greater CSF SNAP25 levels (p = .03) while men showed a trend for higher plasma pTau231 levels (p = .05). APOE‐e4 carrier‐status was not associated with differences in levels of plasma or CSF biomarkers in either sex.

Conclusion

As highly selective and specific AD fluid biomarkers emerge, understanding sex‐based differences in CSF and plasma is imperative. Female sex is associated with higher levels of neurodegeneration (NfL, tTau, pTau181, neurogranin, VILIP1) in EOAD and astrogliosis (GFAP) in both EOAD and EOnonAD. This data supports our previous findings that greater pathology burden is associated with female sex. This paves the way for further examination of sex and APOE‐e4 genotype‐based differences in imaging and fluid biomarkers, their associations, and utility in early diagnosis.
Pseudo‐longitudinal trajectories of cerebrovascular disease biomarkers in adults with Down syndrome across the lifespan
Authors: Lao Patrick J. , Sedaghat Amirreza , Edwards Natalie C. , Lippert Rafael V. , Rizvi Batool , Smith Anna C. , Tudorascu Dana , Rosas H. Diana , Yassa Michael A. , Handen Benjamin L. , Christian Bradley T. , Gutierrez Jose , Wilcock Donna M. , Head Elizabeth , Brickman Adam M.
Published: December 2023

Background

Adults with Down syndrome (DS) overproduce amyloid precursor protein, develop amyloid plaques at an early age, and are diagnosed with Alzheimer’s disease (AD) dementia at a high frequency. There is emerging evidence that cerebrovascular disease is elevated across the AD continuum in older adults with DS, independent of age and vascular risk, but it is unknown when cerebrovascular disease emerges across the lifespan.

Method

Adults with DS from the multisite Alzheimer’s Biomarker Consortium‐Down Syndrome study (ABC‐DS; n = 241; age = 25‐72, 44±10; 45% women; 77/11/12% Cognitively‐Stable/MCI‐DS/AD dementia) underwent harmonized MRI and received a cognitive diagnosis at a consensus conference. Cross‐sectional white matter hyperintensity volume (WMH; ischemic small vessel disease), enlarged perivascular space score (PVS; impaired toxin clearance), chronic infarcts (large vessel disease), and microbleeds (hemorrhagic small vessel disease/cerebral amyloid angiopathy) were fit against piece‐wise, left null regression models with age to estimate the age inflection point at which these cerebrovascular markers emerged. The residuals for each biomarker (i.e., more than expected for their age) were then regressed on diagnosis.

Result

Total WMH volume (0.01‐31.7, 4±4.6 cm3), enlarged PVS score (0‐26, 8±5), infarcts (15% have at least one), and microbleeds (12% have at least one) were present in this lifespan sample of adults with DS. There was a significant inflection point in the fourth decade of life for total WMH (37±6, p = 7E‐3), enlarged PVS (31±6, p = 3E‐6), and infarcts (31±9, p = 2E‐3), but not microbleeds (36±21, p = 0.7). Regionally, there were significant inflection points for frontal (36±6, p = 3E‐3), parietal (36±7, p = 0.02), and occipital (42±6, p = 0.02), but not temporal WMH (33±14, p = 0.3). AD dementia was associated with higher residuals in parietal (0.5±0.2, p = 0.02) and occipital WMH (0.6±0.3, p = 0.02).

Conclusion

In adults with DS, there is cerebrovascular pathology on MRI that emerges around the same age as what has been reported for amyloid PET positivity and tau PET accumulation in this population. More posterior small vessel disease for a given age may arise with a diagnosis of AD, suggesting a cerebrovascular process in AD pathogenesis. Longitudinal assessment in relation to AD biomarkers, including amyloid and tau PET, will provide additional insight.
White matter hyperintensities associate with pathological stages of neurodegenerative disease
Authors: Jonkman Laura E. , Lin Chen‐Pei , Frigerio Irene , Noteboom Samantha , Bouwman Maud M.A. , Reijner Niels , Preziosa Paolo , Boon Baayla D.C. , Bouwman Femke H. , Rozemuller Annemieke J.M. , Steenwijk Martijn D. , Barkhof Frederik , van de Berg Wilma D.J.
Published: December 2023

Background

White matter hyper‐intensities (WMH) are observed on FLAIR MRI, increase with age and are more prominent in neurodegenerative diseases such as in Alzheimer’s disease (AD) and Parkinson’s disease (PD). The aim of this study was to assess the association between WMH and neuropathological staging of amyloid‐beta, neurofibrillary tangles (NFT) and a‐synuclein (a‐syn).

Method

In‐situ 3T‐MRI 3DT1‐weighted and 3D‐FLAIR data were collected for 77 clinically defined and pathologically‐confirmed brain donors; 31 AD, 21 PD and PD dementia (PDD), and 25 controls. WMH were segmented on FLAIR using an in‐house developed multiview convolutional neural network, followed by manual checking, and volume was obtained with FSL. Fifteen brain regions were dissected at autopsy, immunostained and evaluated for neuropathological diagnosis, including Thal amyloid phase, CAA type, and Braak stages for NFT and a‐syn. Group differences were assessed with linear models (corrected for age, gender, post‐mortem delay), and associations with Spearman and Pearson partial correlations.

Result

Compared to controls, WMH load was higher in AD (p<0.001), specifically amnestic AD (p = 0.003) rather than non‐amnestic AD (p = 0.053), and higher in PD (p = 0.016), specifically non‐demented PD (p = 0.015) rather than PDD (p = 1.0). No difference in gender was observed (p = 0.38). Without the influence of pathology (in controls), WMH was associated with age (r = 0.49,p = 0.016). In the whole cohort, WMH was associated with Fazekas score (r = 0.67; p<0.001), normalized brain volume (NBV; r = ‐0.31,p = 0.007), gray matter volume (NGMV; r = ‐0.36,p = 0.002), Thal phase (r = 0.24,p0.034), Braak NFT stage (r = 0.33,p = 0.004), and Braak a‐syn stage (r = 0.27, p0.018). Across controls and AD, WMH associated with NBV (r = ‐0.39,p = 0.004), NGMV (r = ‐0.42,p = 0.002), left and right hippocampal volume (r = ‐0.36,p = 0.008 and r = ‐0.32,p = 0.022), Braak NFT (r = 0.41,p<0.001), Thal phase (r = 0.41,p = 0.002), and CAA (r = 0.34,p = 0.01). Amnestic and non‐amnestic AD showed similar results, except for CAA, which was associated with WMH in non‐amnestic AD only (r = 0.33,p = 0.04). Across controls and PD(D), WMH associated with Braak NFT stage (r = 0.39,p = 0.008) and Braak a‐syn stage (r = 0.60,p<0.001), but not with MRI outcome measures. In this respect PD and PDD showed different results; in PD WMH associated with NGMV (r = ‐0.37,p = 0.031), in PDD with left and right hippocampal volume (r = ‐0.44,p = 0.014 and r = ‐0.44,p = 0.015).

Conclusion

WMH associate with pathological stages of AD and PD(D), and contributes to MRI atrophy.
Polyphenol intake beneficially associates with inflammation and cognitive performance, and is mediated by MRI‐derived features
Authors: Dryer‐Beers Elliot R , Matthews Paul M , Frost Gary S , Griffin Jennifer
Published: December 2023

Background

Early changes to cognitive performance and neurophysiological biomarkers offer insights into one’s future risk of developing Alzheimer’s disease or other dementias. Evidence suggests a link between polyphenol intake and reduced incidence of age‐associated cognitive decline and neurodegeneration. These relationships may be driven by the effect of dietary polyphenols on inflammation and degeneration of critical neurological structures and systems. These relationships are challenging to assess, as few cohorts allow cohesive assessment of polyphenol intake, systemic inflammation, neurophysiological measures and cognition.

Method

Polyphenol intake was assessed in two UK cohorts: The Airwave Health Monitoring Study and UK Biobank (UKB). Diet diary and questionnaire data were integrated with polyphenol composition data from Phenol‐Explorer to allow for testing of associations between polyphenol intake, blood biomarkers of inflammation, and cognitive performance. 9008 Airwave participants and 209,163 UKB participants were included in a cross‐sectional analysis. C‐reactive protein (CRP) and fibrinogen were used as blood biomarkers of inflammation, and cognitive assessments included reaction time (milliseconds) and fluid intelligence (score /13). Neuroimaging assessments included grey matter volumes and white matter integrity, and were considered individually and using PCA.

Result

Linear regressions showed inverse associations between total polyphenol intake and CRP: ß ‐0.00702 (Airwave) and ß = ‐0.00672 (UKB), both P <0.001, as well as fibrinogen: ß ‐0.00221; P = 0.038 (Airwave only), in addition to biomarker associations with polyphenols at the compound group level. Regarding cognition, linear regressions revealed beneficial associations between total intake and performance in fluid intelligence tests: ß 0.00657; P = 0.009 (Airwave) and ß 0.00715, P <0.001 (UKB), and reaction time ß ‐0.0000977; P = 0.020 (UKB). Mediations of the polyphenol‐fluid intelligence relationship were detected for IDPs including grey matter volumes of hippocampal‐associated regions, and white matter integrity measured using ISOVF.

Conclusion

We described polyphenol intake in two large, contemporary UK cohorts, and discovered associations between higher intake and improved inflammatory markers and cognitive performance, as well as mediations of the polyphenol‐cognition relationship by physical neurological markers. This contributes to evidence supporting the health benefits of dietary polyphenols, clarifies the physiological pathways through which they may act, and highlights their relevance when considering preventative interventions for neurodegeneration.
Diffusion MRI track cortical microstructural changes over time during the early stages of the Alzheimer’s disease continuum
Authors: Spotorno Nicola , Strandberg Olof , Stomrud Erik , van Westen Danielle , Hansson Oskar
Published: December 2023

Background

Markers of downstream events are a key component of clinical trials of disease‐modifying therapies for Alzheimer’s disease (AD). Previous cross‐sectional investigations suggested that diffusion MRI (dMRI) can provide metrics sensitive to cortical microstructural alteration linked to multiple aspects of the AD pathological cascade including Aß‐accumulation and astrocytic activity. However, currently little evidence is available regarding the ability of dMRI in tracking changes over time.

Method

Mean diffusivity (MD) was computed from dMRI data acquired from 363 cognitively unimpaired elderly and patients with mild cognitive impairment from the Swedish BioFINDER‐1 study. Each participant underwent multiple dMRI scan (range 2‐4 scans) and was classified as Aß‐negative/tau‐negative, Aß‐positive/tau‐negative, and Aß‐positive/tau‐positive based on CSF levels of Aß42/40 and ptau‐181. Rates of changes in MD, cortical thickness and plasma level of GFAP were computed in a linear mixed effect framework. Cortical regional values of MD were compared across biomarkers‐defined groups as well as to rates of change of GFAP.

Result

Analyses of MD revealed widespread differences in rates of change already between Aß‐negative/tau‐negative and Aß‐positive/tau‐negative participants with a spatial distribution that closely resembled the pattern of Aß accumulation (fig.1). Further, analyses focusing on two composite ROIs, one encompassing regions that accumulate Aß early in the disease process and a temporal meta‐ROI, confirmed that rates of change in MD significantly differed between groups even when cortical thickness was included in the model (Ps<0.05,fig.2). Regional MD rates of change in both neocortical temporal areas and key regions for Aß‐accumulation, were also positively correlated with rates of change in GFAP (fig.3). Such result was supported by the analysis based on the two meta‐ROIs which confirmed the positive association between rates of change GFAP and MD.

Conclusion

Mean diffusivity from dMRI is able to track cortical microstructural changes over time and to differentiate trajectories even during the early stages of the AD pathological cascade. The association between rates of change of MD and rates of change of GFAP suggested dMRI might reflect microstructural changes related to the astrocytic response to AD pathology. dMRI might help monitoring the effects of disease‐modifying therapies (e.g. Ab immunotherapies) in clinical trials.
Cerebral perfusion is not altered after 24 weeks of daily anthocyanin consumption in a population population of individuals at increased risk for dementia
Authors: Kallevag Oystein
Published: December 2023

Background

Preliminary research suggests that anthocyanin‐consumption may improve memory, with a positive influence on the blood vessels as a possible contributing factor to these effects (1). We investigate the potential of long‐term consumption of anthocyanins to improve regional cerebral perfusion in a population of individuals at increased risk for dementia.

Method

From 2018 to 2020 we performed a 24‐week randomised, doubleblind, placebo‐controlled study on 87 cognitively healthy, defined by Mini‐Mental State Exam (MMSE) and clinical dementia rating (CDR) (2. Anthocyanins were given in Medox® capsules that contained 80 mg natural purified anthocyanins, and the dosage was 4 capsules daily (i.e., 320mg/d of anthocyanins). Cerebral perfusion was measured non‐invasively with ASL‐MRI at baseline and after 24 weeks of daily anthocyanin‐consumption. The MRI‐scans analyzed using the FMRIB Software Library (FSL v 6.0.1; Analysis Group, Oxford, UK).

Result

The mean age in the anthocyanins group was 69.8 (± 5.5) years and the placebo group was 69.1 (± 6.0) years. When corrected for FWER, the anthocyanin > placebo analysis did not reveal any significant increased regional cerebral perfusion. There were no clusters found. When extracting maximum intensity, the lowest p‐value present was 0.839. When corrected for FWER, the placebo > anthocyanin analysis did not reveal any significant increased regional cerebral perfusion. The lowest p‐value present was 0.889 located in the right temporal pole.

Conclusion

Our results show no significant differences in cerebral perfusion found between the control and experimental group after 24 weeks. The data does not provide evidence for, in a population of older adults with risk of developing dementia, a daily dose of 320 mg anthocyanin ingested over a period of 24 weeks to affect cerebral perfusion to a level measureable by ASL‐MRI. • Kent K, Charlton K, Roodenrys S, Batterham M, Potter J, Traynor V, et al. Consumption of anthocyanin‐rich cherry juice for 12 weeks improves memory and cognition 23 in older adults with mild‐to‐moderate dementia. Eur J Nutr. 2017;56(1):333‐41. • 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.
Synapse dysfunction and astrocyte reactivity are associated independently of amyloid‐β and tau pathologies
Authors: Rohden Francieli , Bellaver Bruna , Ferreira Pamela C.L. , Aguzzoli Cristiano Schaffer , Lussier Firoza Z , Soares Carolina , Povala Guilherme , Ferrari‐Souza João Pedro , Zalzale Hussein , Leffa Douglas Teixeira , Abbas Sarah , Cabrera Arlec , Lemaire Peter Charles , Tissot Cécile , Therriault Joseph , Servaes Stijn , Stevenson Jenna , Rahmouni Nesrine , Benedet Andrea Lessa , Cohen Annie , Lopez Oscar L. , Karikari Thomas K , Ashton Nicholas J. , Zetterberg Henrik , Blennow Kaj , Souza Diogo O. , Zimmer Eduardo R , Rosa‐Neto Pedro , Pascoal Tharick A.
Published: December 2023

Background

Biomarkers of astrocyte reactivity have the potential to improve diagnostic precision, disease monitoring, and treatment efficacy. Glial fibrillary acidic protein (GFAP) protein is expressed in astrocytes, which is important to synaptic plasticity, cell communication, and reactive gliosis.

Method

Cerebrospinal fluid (CSF) biomarkers were measured in participants of the McGill TRIAD cohort. 75 individuals (>50 years old, 44 cognitively unimpaired (CU), and 31 with cognitive impairment (CI)), had available Aß and tau‐PET. We measured CSF GFAP and synaptic markers (growth‐associated protein 43 (GAP‐43), neurogranin (Ng), synaptotagmin 1 (SYT1), presynaptic protein synaptosomal‐associated protein 25 (SNAP‐25)). Linear regressions adjusted for age, sex, clinical diagnosis, and Aß/tau‐PET were used to test the associations between astrocyte reactivity and synaptic function.

Result

Demographic information is shown in Table 1. We found an association between CSF GFAP and presynaptic markers (GAP‐43: p<0.0001, ß = 0.1076; SYT1: p<0.0001, ß = 0.0024; SNAP‐25 long: p<0.0001, ß = 0.0008) as well as postsynaptic markers (Ng: p<0.05, ß = 0.0066) independently of Aß and tau burden (Figure 1).

Conclusion

Our biomarker results support experimental literature suggesting that astrocyte reactivity plays a role in downstream synaptic dysfunction independent of the brain levels of Aß and tau tangles pathologies. This supports in vitro literature suggesting that therapeutic interventions targeting astrocyte reactivity can contribute to halting AD progression.
CSF total tau is more closely associated with synaptic dysfunction than overt neurodegeneration
Authors: Soares Carolina , Bellaver Bruna , Ferreira Pamela C.L. , Povala Guilherme , Aguzzoli Cristiano Schaffer , Ferrari‐Souza João Pedro , Zalzale Hussein , Lussier Firoza Z , Rohden Francieli , Abbas Sarah , Lemaire Peter Charles , Leffa Douglas Teixeira , Cabrera Arlec , Therriault Joseph , Benedet Andrea Lessa , Tissot Cécile , Servaes Stijn , Macedo Arthur C. , Vermeiren Marie , Bezgin Gleb , Kang Min Su , Stevenson Jenna , Rahmouni Nesrine , Pallen Vanessa , Cohen Annie , Lopez Oscar L. , Tudorascu Dana , Klunk William E , Villemagne Victor L , Soucy Jean‐Paul , Gauthier Serge , Souza Diogo O. , Karikari Thomas K , Ashton Nicholas J. , Zetterberg Henrik , Blennow Kaj , Rosa‐Neto Pedro , Zimmer Eduardo R , Pascoal Tharick A.
Published: December 2023

Background

CSF total tau (t‐tau) is postulated as a marker of neuronal degeneration in the ATN criteria. Here, we hypothesize that CSF t‐tau is more closely related to synaptic loss than over neurodegeneration.

Method

We evaluated 128 older individuals (75 CU,33 MCI,20 AD) in the TRIAD cohort (McGill, Canada) with CSF t‐tau, SNAP25long and Neurofilament Light (NfL), Amyloid‐beta (Aß) positron emission tomography and magnetic resonance imaging, and clinical assessments. We used increased SNAP25long as an index of synaptic dysfunction (S+) and reduced hippocampal volume as neurodegeneration (N+). S and N positivity were determined using a cutoff anchored in young CU individuals. Linear regression models were used to test the association between CSF t‐tau, SNAP25long and NfL levels and hippocampal volume, adjusted for age, sex, and cognitive status. ANCOVA was employed to inspect CSF t‐tau levels across the groups 1) S‐N‐; 2) S+N‐; 3) S‐N+; 4) S+N+, adjusted for age, sex, cognitive status, and Aß burden.

Result

We found that a model with the addition of SNAP25long to the covariates explained 65% of the variance (p‐value<0.0001) of CSF t‐tau. Alternatively, hippocampal volume (R2 = 0.2187; p‐value<0.0001) and NfL (R2 = 0.3671; p‐value<0.0001) alone or in combination explained less than 40% of the variance of CSF t‐tau (R2 = 0.3597; p‐value<0.0001) (Figure 1). Interestingly, we observed an increase of CSF t‐tau in the S+N‐ group but not in the S‐N+, further supporting that CSF t‐tau is abnormal in the presence of synaptic dysfunction rather than neurodegeneration. Additionally, Loess regression lines confirm a larger magnitude of change of synaptic dysfunction as a function of t‐tau, compared with neurodegeneration (Figure 3).

Conclusion

Our results suggest that CSF t‐tau may reflect synaptic loss rather than neuronal degeneration. This has implications for the interpretability of results obtained with CSF t‐tau in biomarker studies.
Distinct Neural Correlates of Anxiety and Depression in Subjective Cognitive Decline versus Healthy Aging, a Microstructural Diffusion MRI Study
Authors: Flaherty Ryn , Sui Yu Veronica , Masurkar Arjun V. , Rusinek Henry , Lazar Mariana
Published: December 2023

Background

A common criticism of considering Subjective Cognitive Decline (SCD) as a preclinical stage of Alzheimer’s Disease is that it may be explained by depression or anxiety1. We used NODDI, a diffusion microstructural model2, to explore the pathophysiology of depression and anxiety in SCD versus controls.

Method

325 participants in the Cam‐CAN study 3 (127 SCD) older than 55 were included in the analysis. Diffusion imaging data was collected on a 3T Siemens TIM Trio scanner with a 32‐channel head coil for 0, 1000 and 2000 s/mm2 b‐values and 30 gradient directions. Preprocessing and calculation of the NODDI metric Intracellular Volume Fraction (ICVF) were completed using MRTrix3, AMICO and MATLAB. The hippocampal cingulum bundle and fornix regions of interest (ROIs)4 were extracted from the ICBM‐DTI‐81 atlas. Depression and anxiety were assessed using the Hamilton Anxiety and Depression Scale (HADS). Linear regression models were completed in R. Gender and age were included as nuisance variables.

Result

There were no differences in gender or age distribution between cohorts, however participants with SCD were more depressed and anxious on average (Table 1). There was a significant interaction effect between depression and cohort in the fornix (Figure 1), as well as between anxiety and cohort in the hippocampal cingulum (Figure 2). In post‐hoc analyses, only the SCD group showed a correlation between depression and ICVF in the fornix (Figure 1) while only controls showed a correlation between anxiety and ICVF in the hippocampal cingulum (Figure 2), indicating different pathophysiology underlying psychiatric symptoms in the two groups.

Conclusion

Anxiety and depression appear to be associated with different microstructural features in SCD versus controls, suggesting anxiety and depression in SCD is a phenomenon distinct from anxiety and depression in healthy aging. Future work will explore the relationship between anxiety and depression and risk of conversion to mild cognitive impairment. • Mitchell AJ, Beaumont H, Ferguson D, et al. Acta Psychiatrica Scandinavica. 2014;130(6):439‐51. • Daducci A, Canales‐Rodriguez EJ, Zhang H, et al. Neuroimage. 2015;105:32‐44. • Shafto MA, Tyler LK, Dixon M, et al. BMC neurology. 2014;14(1):1‐25. • Kantarci K. Frontiers in Aging Neuroscience. 2014;6.
Neurophysiological activity linked to Alzheimer’s disease pathology relates to longitudinal cognition and progression to mild cognitive impairment
Authors: Rudolf Jonathan E Gallego , Wiesman Alex I , Baillet Sylvain , Villeneuve Sylvia
Published: December 2023

Background

Alzheimer’s Disease (AD) is defined by the pathological accumulation of amyloid‐beta (Aß) and tau in the brain. Regional deposition of these proteins is associated with changes in frequency‐defined neurophysiological activity that can be detected using non‐invasive magnetoencephalography (MEG). Here we examined whether these neurophysiological alterations were associated with participants’ demographics and longitudinal changes in cognition. Additionally, we addressed the clinical utility of MEG to predict progression to mild cognitive impairment (MCI), as compared to other established AD imaging biomarkers.

Method

We used Positron Emission Tomography (PET) to measure the deposition of whole‐brain Aß ([18F]NAV4694) and tau ([18F] Flortaucipir), Magnetic Resonance Imaging (MRI) to measure hippocampal volume and resting‐state MEG to capture neurophysiological activity in a group of clinically unimpaired older adults with family history of AD (PREVENT‐AD cohort; n = 103). We implemented a multivariate partial least squares (PLS) analysis to test the association between imaging markers (i.e., neurophysiological activity and AD proteinopathy) and participants’ clinical profiles (i.e., demographic‐clinical variables and longitudinal cognition data). For the second analysis we used logistic regression models to assess the added value of neurophysiological activity to predict MCI progression compared to established MRI/PET imaging markers (n = 100; 14 MCI progressors).

Result

The PLS analysis identified significant latent variables that linked proteinopathy‐related neurophysiological activity slowing to older age, lower education, positive APOE e4 status and longitudinal deficits in cognition across multiple domains (Figure 1). The initial logistic regression model included demographic and clinical variables and had an AUC = 0.772, which increased to 0.794 after adding the MRI hippocampal volume. Incorporating MEG spectral power from temporal regions where tau accumulates resulted in a considerable increase in accuracy with an AUC = 0.873. The model including Aß and tau PET on top of MRI and MEG markers reached an AUC = 0.905 (Figure 2).

Conclusion

Our results show that the neurophysiological changes linked to AD pathology are associated with longitudinal cognitive impairment across multiple domains. MEG spectral power from early tau accumulating regions improved the accuracy for predicting MCI progression, contributing information beyond traditional demographic/clinical variables and structural MRI and representing a more accessible and less invasive alternative compared to PET imaging.
Association between glial and synaptic fluid biomarkers and brain [18F]FDG‐PET signal
Authors: Machado Luiza Santos , da Rocha Andreia Silva , De Bastiani Marco Antônio , Bellaver Bruna , Soares Carolina , Lazzarotto Gabriela , Vidor Pedro , Schlickmann Thomas , Rahmouni Nesrine , Siebert Marina , Ferreira Pamela C.L. , Pascoal Tharick A. , Souza Diogo O. , Rosa‐Neto Pedro , Benedet Andrea Lessa , Blennow Kaj , Zetterberg Henrik , Ashton Nicholas J. , Zimmer Eduardo R.
Published: December 2023

Background

Beyond the hypometabolic signature, indexed by [18F]FDG‐PET imaging, seen in the brain of Alzheimer’s disease (AD) patients, a transient brain glucose hypermetabolism has been recently identified in the early stages of AD. The cellular source of this dual metabolic response remains controversial, with glial cells gaining a lot of attention. In light of this, whether glial and synaptic fluid biomarkers are associated with [18F]FDG‐PET signal in the early stages of AD remains debatable. Thus, we evaluated the association of astrocyte, microglial and synaptic fluid biomarkers with [18F]FDG‐PET signal in an AD rat model.

Method

[18F]FDG‐PET imaging was conducted in ten‐month‐old (early amyloid stage) APP/PS1 (TgF344‐AD, n = 8‐17) and wild‐type (WT, n = 8‐15) rats. Glial (GFAP and sTREM2), synaptic (neurogranin), and amyloid biomarkers (Aß1‐40 and Aß1‐42) were quantified in the cerebrospinal fluid (CSF) and plasma through a multiplex immunoassay. T‐statistical maps of brain [18F]FDG‐PET and those fluid biomarkers were conducted at the voxel level using RMINC. Differences were considered statistically significant at p<0.05 (t>2).

Result

A large hypermetabolic cluster was identified in ten‐month‐old TgF344‐AD (Fig. 1AB, local maxima, t(13) = 4.28). We found positive correlations between CSF TREM2 and brain [18F]FDG‐PET signal (Fig. 2AC, local maxima, t(13) = 4.12). In addition, we identified a positive correlation between plasma GFAP and brain [18F]FDG‐PET signal (Fig. 2BC, local maxima, t(13) = 10.62). Plasma TREM2, CSF GFAP, and plasma neurogranin did not associate with brain glucose metabolism.

Conclusion

Our findings suggest that CSF TREM2 and plasma GFAP are associated with brain metabolism before amyloid load reaches a plateau. Stronger association of plasma GFAP, rather than CSF GFAP, with brain pathology corroborates cross‐sectional human studies. One could argue that [18F]FDG‐PET hypermetabolism identified is likely a response to astrocyte and microglial changes.
Aβ in the Lens of the Eye: A Noninvasively Detectable Early Biomarker of Alzheimer’s Disease β‐Amyloidopathy in Humans and Transgenic Mouse Model
Authors: Goldstein Lee E , Moncaster Juliet A , Moir Robert D , Minaeva Olga , Alvarez Victor E. , Clark John I , McKee Ann C. , Tanzi Rudolph E.
Published: December 2023

Background

Amyloid‐ß (Aß) accumulation in brain is an early hallmark of Alzheimer’s disease (AD). We discovered Aß deposition, ß‐amyloidopathy, and colocalizing supranuclear cataracts (SNC) in lenses from people with AD (Goldstein LE et al., Lancet, 2003) and Down syndrome (DS; Moncaster JA et al., PLoS One, 2010), but not other neurodegenerative diseases or normal aging. These findings spurred development of an investigational drug‐device lens Aß eye scanner (Sapphire II, Cognoptix) that combines an Aß‐binding fluorescent ligand (Aftobetin) and specialized laser scanning ophthalmoscope for noninvasive measurement of lens Aß (FDA Breakthrough Device, 2021). Early clinical results indicate that lens Aß is an ideal biomarker for early AD detection. Here, we investigated Aß accumulation and amyloidopathy in lens and brain.

Method

Tg2576 transgenic (Tg+) mice express Swedish mutant human amyloid precursor protein (hAPP‐Swe), human Aß (hAß), ß‐amyloidopathy, and cognitive deficits (Hsiao et al., Science, 1996). Non‐transgenic (Tg–) littermates were used as controls. Lenses were examined by ex vivo lens stereomicroscopy. Brains and lenses were analyzed by Aß immunohistochemistry, amyloid histopathology, anti‐Aß immunogold electron microscopy, tryptic digest mass spectrometry, anti‐hAß ELISA/immunoblotting. Quasi‐elastic light scattering hAß‐lens protein aggregation analysis.

Result

Tg2576 Tg+ mice, but not Tg– controls, age‐dependently express hAPP, accumulate hAß, and develop hAß molecular pathology in the lens and exhibit age‐dependent Aß supranuclear opacification that recapitulates lens pathology and SNC phenotype expression in human AD and DS. We detected hAß in conditioned medium from Tg+ but not Tg– lens explant cultures. hAß potently promotes mouse lens protein aggregation in vitro.

Conclusion

These results support mechanistic (genotype‐phenotype) linkage between age‐dependent Aß pathology and AD‐related phenotypes in lens and brain. Collectively, our findings identify Aß pathology as the shared molecular etiology of age‐dependent supranuclear cataracts associated with two human diseases (AD, DS) and homologous murine cataracts in the Tg2576 transgenic mouse model of AD. These results represent the first evidence of AD‐related Aß pathology outside the brain and support lens Aß as an optically‐accessible biomarker for early detection and longitudinal monitoring of AD.
Assessing amyloid plaque burden in aging marmosets and genetically engineered PSEN1 mutation carriers using 11C‐PiB PET
Authors: Schaeffer David J , Dubberley Lauren R , Schaeffer Lauren K Hayryren , Park Jung Eun , Homanics Gregg E , Strick Peter L , Carter Gregory W , Rizzo Stacey J Sukoff , Silva Afonso C
Published: December 2023

Background

There is an urgent need to develop novel animal models to investigate the underlying cellular and molecular root causes of the pathogenesis and progression of AD. Our group has worked to establish the common marmoset as the first primate‐specific model of AD to reveal the earliest cellular and molecular events of AD processes and allow charting of AD progression from its inception. For this, we established a colony of outbred marmosets and used genetic engineering techniques to generate marmosets carrying the PSEN1‐C410Y and PSEN1‐A426P mutations that cause early‐onset, familial AD. The present study aims to use PET imaging to access and track the progression of Ab plaque burden non‐invasively and longitudinally in our marmoset models of AD.

Method

Marmosets anesthetized with isoflurane delivered via a facemask were placed in a preclinical PET/CT scanner customized with marmoset‐specific beds. Respiratory rate, heart rate, arterial O2 saturation, and rectal temperature were monitored and maintained at normal physiological values. Our PET imaging protocol follows the Alzheimer’s Disease Neuroimaging Initiative (ADNI). The amyloid‐binding 11C‐Pittsburgh Compound B (11C‐PiB) was delivered intravenously in doses varying from 18.5 – 185 MBq (0.5 – 5 mCi). A 90‐min dynamic acquisition was performed immediately following the radiotracer injection, followed by a 3D CT scan acquired at 200 µm isotropic resolution. After the PET/CT neuroimaging scan, the marmosets were recovered from anesthesia and returned to their home cages.

Result

We observed positive 11C‐PiB binding and retention in the brains of aging outbred marmosets and in marmosets harboring PSEN1 mutations. Significant 11C‐PiB retention was observed in the cortex and white matter tracts. The areas with the highest 11C‐PiB retention were the lateral frontal cortex, anterior cingulate cortex, and temporal lobe regions.

Conclusion

This study demonstrates using 11C‐PiB to track Ab plaque burden in the brains of aging marmosets and marmosets harboring PSEN1 mutations. As observed in human patients of AD, the amount of 11C‐PiB bound (measured in SUV and SUVR units) varied from animal to animal, and we are currently performing group analysis to investigate the dependence of 11C‐PiB retention on age and sex. This research was funded by NIH/NIA grants R24AG073190 and U19AG074866.
Abnormal functional activation during response inhibition in mild cognitive impairment: an fMRI study
Authors: Pommy Jessica , Umfleet Laura Glass , Cohen Alexander D , Ristow Kelly , Mason Lilly , Obarski Shawn , Franczak Malgorzata , Wang Yang
Published: December 2023

Background

Declines in response inhibition are observed both typical and atypical aging, i.e., mild cognitive impairment (MCI). Increased functional activation in frontoparietal regions during response inhibition has been interpreted to represent the emergence of a compensatory mechanism in older adulthood. While electrophysiology studies suggest the decline in response inhibition in MCI reflects a similar but amplified process as seen in normal aging this has not been examined thoroughly using functional MRI (fMRI).

Method

31 cognitively normal older adults (M age = 73.6, 9 male) and 22 adult patients with MCI (M age = 67.2, 14 male) performed a Go/NoGo task during an fMRI scan. Group differences in accuracy and reaction time were examined for Go and NoGo trials. Individual BOLD signal change during task fMRI was examined, then voxel‐wise group comparison was conducted for MCI vs. HC groups, using age, gender, education, and gray matter density as covariates. Permutation‐estimated cluster size at alpha <.05 was defined to correct for errors of multiple comparisons.

Result

Behaviorally, the MCI group made significantly more errors during NoGo and Go trials (p<.001, p = .032, respectively), however, average reaction time did not differ significantly between groups. During NoGo trials, greater activation in the anterior default mode network (DMN), right dorsolateral prefrontal cortex (DLPFC), and motor areas was observed for MCI vs. HC, while during go trials, there was greater activation in DMN and right insula (corrected p<0.05). However, when Go vs. NoGo trials were examined, MCI showed more activation in right insula and DLPFC, but less activation in the motor area at trend level (p<0.05, uncorrected). While, there were no significant task performance differences between MCI subtypes (amnestic vs. non‐amnestic), amnestic MCI (aMCI) showed more activation in posterior DMN and dorsal attention area during NoGo trials (corrected p<0.05).

Conclusion

MCI demonstrated significantly greater activation during both Go and NoGo trials and made significantly more errors in performance during both trial types as well. While the MCI subtypes did not exhibit differences in performance on the task, the aMCI exhibited significantly greater activation in multiple regions. Our findings suggested inefficient DMN suppression during task performance in the MCI cohort, especially in the aMCI subgroup.