bluuebunny/crossref_metadata_2025 huggingface dataset:
Three‐dimensional study on morphological changes of arterioles in Cerebral Amyloid Angiopathy
Authors: Antunes Lissa Ventura , Bosworth Allison M , Nackenoff Alex , Shostak Alena , Snider John C , Sturgeon Sarah M , Merryman David W , Solopova Elena , Fernandez Wilber Romero , Lippmann Ethan S , Schrag Matthew
Published: December 2022

Background

The accumulation of β‐amyloid plaques in the brain is a hallmark of Alzheimer’s disease. Vascular involvement is also common in the form of cerebral amyloid angiopathy (CAA), a vasculopathy that is produced when the β‐amyloid forms toxic deposits on vessels wall. The accumulation of β‐amyloid makes blood vessels stiff and increases the thickness of the vessel wall, reducing the blood flow and energy supply for the tissue. This predisposes to hemorrhage and contribute to cognitive decline and stroke.

Method

We used the CLARITY method to analyze tissue samples from patients with CAA to characterize changes to vessel morphology associated with vascular degeneration. The blood vessels were stained with isolectin, β‐amyloid with thiazine red, and proteins with primary antibodies associated with the vascular structure. We conducted 3D microscopy using a light sheet microscope and performed surface volume reconstruction to assess the morphology of rupturing vessel. We also measured arteriolar stiffness of vessels damaged using atomic force microscopy (AFM). Finally, we assessed cerebral blood flow and autoregulation in vivo in a novel mouse model of CAA using laser speckle flowetry.

Result

Vessels with CAA demonstrate an organized ring‐shaped deposits β‐amyloid. At sites, these rings are shattered and the vessel diameter increase. Degenerating vessels also demonstrate depletion of vascular smooth muscle, circumferential luminal dilation, and thickening of the vessel wall. Lysyl oxidase levels and markers of fibrosis are increased in vessels with degenerating features. We found that the arteriolar wall was more than 400% stiffer in CAA than in arterioles without CAA in the mice model. Finally, in a novel mouse model of CAA we are terming the VASC‐FAD model, resting cerebral blood flow and vasoreactivity are both reduced.

Conclusion

Combining the CLARITY technique associated with surface volume rendering and AFM we have a better overview of microhemorrhages to understand the vascular fragility and morphological changes, and accumulation of myofibroblast markers caused by the β‐amyloid deposition and stiffness. These features combine to alter the physiology of cerebral blood flow. Defining mechanism of microvascular degeneration in AD and CAA may lead to novel treatment targets to restore the ECM and vascular network integrity.
Developing an oligogenic risk score for Alzheimer’s disease (adORS)
Authors: Lee Garam , Suh Erica H , Jung Sang‐Hyuk , Wen Zixuan , Shen Li , Kim Dokyoon , Initiative Disease Neuroimaging
Published: December 2022

Background

Polygenic risk score (PRS) has become a popular approach for estimating an individual’s genetic risk for disease, recently including Alzheimer’s disease. However, its limitations reveal the need to improve genetic modeling of the disease, i.e. pinpointing relevant genetic drivers for score calculation and improving interpretability and clinical utility. We propose a novel genetic risk score for Alzheimer’s disease (adORS), which—compared to PRS—combines a smaller set of more informative risk variants using known biomarkers to better predict those with high or low risk of disease, as well as mild cognitive impairment (MCI) conversion to AD.

Method

Genetic variants of 1,704 patients (364 controls, 550 AD cases, 273 MCI converters [MCIc], and 517 MCI non‐converters [MCInc]) were collected from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Participants were classified based on diagnosis at their last visit. Variants were transformed into a gene‐based burden to amplify the variance held by each variable, enabling smooth model estimation and gene‐level interpretation. The risk score was estimated based on genes exhibiting high correlations with well‐known biomarkers, FDG and AV45. PRS were generated with clumping and thresholding using the PLINK data analysis toolset. We compared the performances between adORS and PRS on two tasks: controls vs AD classification and MCI conversion prediction.

Result

Top 20 highly correlated genes including known AD‐relevant genes such as TOMM40 and APOC1 were used to calculate the AD risk score. Overall, adORS demonstrated better prediction performance than PRS (Table 1). adORS also showed better distinguishability between cases and controls and predicted lower risk scores in controls and MCInc patients versus higher risk scores in AD cases and MCIc. Additionally, adORS is well‐calibrated compared to PRS (Figure 1). The number of AD and MICc patients increases smoothly as the risk score increases.

Conclusion

We proposed a new method to calculate an AD‐specific genetic risk score. The main advantage of adORS is to use only significant AD‐relevant genes for calculation, yielding a score that is a better predictor of AD status and progression. Experiments demonstrated that adORS has enhanced performance of prediction accuracy, calibration, and interpretability over PRS.
Adult learning enrichment for people living with dementia and their caregivers: Early observations of introducing andragogic principles in adapting an existing museum‐based program.
Authors: Hoffmann Edye
Published: December 2022

Face‐to‐face community engagement for individuals living with dementia and their caregivers was drastically reduced by the pandemic. In response to these restrictions, the Portals to the World program (based in Cambridge, England) was adapted from museum‐based to a virtual setting.

This environmental change reduced the existing anchors of museum access, art enrichment, and one‐to‐one engagement with staff and volunteers. Our adaptations to this new environment stressed a more andragogic (adult learning) model of enrichment that built on our existing program. We moved away from art‐making and in‐person gallery engagement with subject specialists but kept our multi‐week course design.

We prioritized purposeful learning, ownership, layers of experience, and immediate value (usually with emerging research topics or contemporary exhibitions). These added layers of learning replaced the environmental anchors we had used in the past. We also addressed challenges linked to the virtual environment and other impairments present for the participants, such as vision and hearing. Throughout, we aimed to continue the sense of non‐traditional respite, improving the connection between care partners, peer‐to‐peer engagement, as well as access to high‐value museum objects and learning from subject specialists.

Our early observations and continued developments reveal advantages and disadvantages in delivery and expectations. These observations highlight contradictions in caregiver expectations between their understanding of dementia and learning. There were also challenges in where value should be placed: social capital, identity capital or economic capital, all while holding high value in access to the program and the course itself.
ULTRASENSITIVE NEUROFILAMENT LIGHT CHAIN (NfL) IMMUNOASSAY FOR THE SMCxPRO™ ASSAY PLATFORM
Authors: Wiese Rick , Ko Alex , Sweetwater Rose , Fiske Jared
Published: December 2022

Background

The recent advent of ultrasensitive assay technologies has enabled the measurement of low‐abundance blood‐based biomarkers of neurodegenerative conditions, thereby addressing the need for invasive nature of cerebrospinal fluid (CSF) collection, allowing for large scale sample acquisition and screening in research, and empowering studies into the transition between health and disease. Utilizing the SMCxPRO™ ultrasensitive immunoassay platform, we have developed an assay for the detection of neurofilament light chain (NfL) in human serum, plasma and CSF samples across healthy and diseased states. NfL is a valuable neurodegenerative biomarker for accessing progression and treatment of Alzheimer’s Disease (AD), Multiple Sclerosis (MS) and Huntington’s Disease, and is under investigation as a potential biomarker for several other neurological disorders.

Method

Rigorous assay development procedures were undertaken in an effort to produce an NfL immunoassay capable of accurately and reproducibly detecting NfL in human serum, plasma, and CSF samples.

Result

A robust kit for consistent and reliable NfL measurement at sub‐pg/mL concentrations has been developed and characterized using Single Molecule Counting (SMC™) ultrasensitive immunoassay technology. The developed assay demonstrates excellent performance characteristics for spike/recovery values and dilutional linearity (90‐110% for all three matrices). NfL was detected in all sample types tested. Increased NfL sample levels in AD and MS samples as compared to normal serum, plasma and CSF samples was also observed.

Conclusion

Our SMC™ NfL immunoassay kit provides a valuable tool for research in the areas of neurodegenerative disease and neurological injury.
Whole Blood Expression of the Vascular Endothelial Growth Factor Family Relates to Cognitive Performance
Authors: Libby Julia B. , Seto Mabel , Khan Omair A. , Liu Dandan , Petyuk Vladislav A , Gifford Katherine A. , Dumitrescu Logan , Jefferson Angela L. , Hohman Timothy J.
Published: December 2022

Background

The vascular endothelial growth factor (VEGF) family is involved in angiogenic signaling and has been implicated in Alzheimer’s Disease (AD). Previous work from our team has found that higher transcript levels of VEGFB, PGF, FLT1, and FLT4 in the brain relate to worse cognitive performance and higher levels of AD neuropathology. This study explored whether comparable associations are observed when measuring mRNA in whole blood.

Method

Transcriptomic, cognitive, and biomarker data were acquired from the Vanderbilt Memory & Aging Project. Participants (n=335) included older adults (age=72+/‐7.32) with normal cognition (n=203) or mild cognitive impairment (n=132). Expression of the ten genes in the VEGF family were quantified using RNA sequencing of blood. Outcomes included a composite measure of memory and cerebrospinal fluid (CSF) levels of β‐amyloid, total tau, and phosphorylated tau (ptau181). Linear regression models related VEGF family member expression to baseline cognitive performance and AD biomarkers. Linear mixed effects regression models assessed longitudinal change in cognition. All models covaried for age at baseline and sex. To aid in interpretation, Pearson correlations between blood and brain expression were calculated leveraging data from 137 participants from the Genotype Tissue Expression Project (GTexportal.org).

Result

At baseline, higher levels of VEGFB mRNA were associated with better memory performance (Figure 1, β=0.47, p=0.008). In longitudinal analyses, higher baseline expression of PGF was associated with more rapid decline in memory (β= 0.02, p=0.04). No other significant associations were observed (p‐values>0.09). Among GTEx participants, higher expression of VEGFB in blood was correlated with lower expression in the brain (Figure 2, r=‐0.19, p=0.02). PGF correlations did not reach statistical significance (r=0.09, p=0.27).

Conclusion

Higher PGF expression in blood relates to worse cognitive outcomes, consistent with previous findings in the brain. In contrast, higher levels of VEGFB in blood relates to better performance, opposite of the previously observed association in the brain. Notably, in GTEx we observed opposing correlations between blood levels of VEGFB and brain levels of VEGFB, suggesting that higher levels of VEGFB in the blood may indeed reflect lower levels in the brain. Our results highlight the potential of VEGFB and PGF as blood biomarkers in aging and AD.
An Old Pathway Learns Two New Tricks: Role of Complement in Postoperative Cognitive Dysfunction, and in Synaptic Damage in APOE4 carriers
Authors: Berger Miles ,   MADCO‐PC and INTUIT Study Groups
Published: December 2022

Background

Genetic studies in both mice and humans suggest a role for complement in Alzheimer's disease, but exactly how complement contributes to preclinical AD progression is unclear. It is also unclear to what extent complement may play a role in AD risk within APOE4 carriers, or in the pathophysiology of perioperative neurocognitive disorders in older adults.

Method

We developed a hybrid proteomics platform, which uses both LC‐MS/MS for unbiased discovery across the entire human proteome, as well as stable isotope labelled (SIL) peptides for complement proteins to precisely quantify complement protein‐derived peptides (as would normally be possible only in a targeted proteomics assay). This platform was then used to study proteins and pathways altered in the CSF of APOE4 carriers vs non‐carriers, in which the vast majority of both groups were amyloid negative. We also used this platform to study pre‐operative samples from patients who did and those who did not develop postoperative delirium. Generally Applicable Gene Set Enrichment (GAGE) analysis was used to study alterations within specific protein pathways in both APOE4 carriers, and in patients with postoperative cognitive dysfunction.

Result

In our unbiased data, we detected >9,000 different peptides from 884 different proteins in over 100 CSF samples from older adults with normal cognition, including over 200 different complement protein‐derived peptides. In the complement proteins for which we had SIL peptides, we found an average reduction of ∼8.4% ± 0.5% in the levels of more than 50 peptides from each protein in the classical, alternative and mannose binding lectin complement cascades in APOE4 homozygotes versus APOE4 non‐carriers; the odds of this happening by chance would be 1 out of 2 x10^15. We also found reductions in complement proteins (and a significant change in the complement pathway as a whole) at multiple time points before and after surgery in patients who developed postoperative cognitive dysfunction.

Conclusion

These results suggest that CNS complement pathway activation may play a role in both postoperative cognitive dysfunction, and in APOE4‐induced brain damage even in the absence of amyloid pathology.
Structural Modularity is a Feature of C9orf72 Intrinsic Network Degeneration
Authors: Sihag Saurabh , Massimo Lauren , Burke Sarah E , Phillips Jeffrey S , Cook Philip , Duda Jeffrey T , Gee James C. , Satterthwaite Theodore , Grossman Murray , Benatar Michael , McMillan Corey T
Published: December 2022

Background

Genetic forms of frontotemporal degeneration (FTD) and amyotrophic lateral sclerosis (ALS) provide an important target for early therapeutic interventions. However, pre‐symptomatic biomarkers to monitor disease progression are lacking. Prior neuroimaging studies suggest disruption of functional and structural networks are an early feature of neurodegenerative disease. Network modularity quantifies the degree of segregation between sub‐networks. We hypothesize that structural network modularity is a marker of neurodegeneration in C9orf72 carriers.

Method

We evaluated diffusion magnetic resonance imaging (dMRI) in two independent cohorts of C9orf72 carriers and controls: University of Pennsylvania Prodromal Study (Penn‐C9) including symptomatic C9orf72 carriers (SC9; N=27; FTD=20; ALS=7), asymptomatic C9orf72 carriers (AC9; N=24), and healthy controls (HC; N=29); and Human Connectome Project‐FTD (HCP‐FTD) also including SC9 (N=12), AC9 (N=12), and HC (N=20) individuals. We quantified modularity in 7 intrinsic networks of 400 nodes from the Schaefer Atlas using participation coefficient (PC), where lower PC corresponds to higher modularity, and also investigated its constituent measures: within‐network connectivity for each network and pairwise between‐network connectivity. Modularity metrics were residualized in the Penn‐C9 dataset using linear regression to adjust for age. Statistical analyses on residualized scores were first performed in Penn‐C9 and cross‐validated in the HCP‐FTD dataset.

Result

ANCOVAs on residualized scores in Penn‐C9 revealed group differences in PC for limbic network with SC9 lower than HC (partial‐η2=0.12, p=0.011). We also observed group differences in within‐module connectivity for limbic (partial‐η2=0.16, p=0.0016) and dorsal‐attention (partial‐η2=0.1, p=0.019) networks with SC9 lower than HC. Cross‐validation in HCP‐FTD revealed group differences in modularity metrics for limbic network (PC: partial‐η2=0.29, p=0.0012 and within module connectivity:partial‐η2=0.28, p=0.0016) with both metrics lower in SC9 relative to HC. The group differences were significant between AC9 and HC in Penn‐C9 and the means of aforementioned metrics for AC9 were between HC and SC9 in both datasets, suggesting an intermediate state towards modularity.

Conclusion

We observed cross‐validated evidence of greater network modularity, in limbic network, for SC9 relative to HC and intermediate evidence of modularity in AC9. Limbic network is plausible as earliest loci of TDP‐43 pathology in FTD. We suggest that structural network modularity may be an early feature of C9orf72 disease progression.
Hippocampal metabolism in preclinical Alzheimer’s disease
Authors: Rahmani Maryam , McAvoy Mark , Chang Ryan , Raichle Marcus E. , Benzinger Tammie L.S. , Morris John C. , Vlassenko Andrei G. , Goyal Manu S.
Published: December 2022

Background

Hippocampal metabolism has been variably reported to be decreased in Alzheimer’s disease (AD), and is less well studied during preclinical stages of AD. Since AD is associated with significant hippocampal atrophy, careful segmentation and partial volume correction methods are necessary. Here we performed manual segmentation of the hippocampus coupled with regional partial volume correction to estimate hippocampal glucose (rCMRGlc) and oxygen (rCMRO2) metabolism from positron emission tomography (PET) studies in cognitively normal adults with and without brain amyloid deposition.

Method

Multi‐tracer PET including [18F]fluoro‐deoxyglucose (FDG), 15O‐O2, 15O‐CO, and 15O‐H2O was performed in cognitively normal older adults with high brain amyloid‐β burden (n=17) and age and sex‐matched individuals with no brain amyloid burden (n=14). Hippocampi were manually segmented, including careful exclusion of intruding and surrounding CSF‐filled spaces. Partial volume correction was performed using the symmetric geometric transfer matrix approach. Mean standardized uptake value ratio (SUVR) for rCMRGlc and rCMRO2 were calculated, normalized to the whole brain and pons for confirmation.

Results

We found no significant decrease in hippocampal rCMRGlc in amyloid positive adults, despite their lower hippocampal volume compared to amyloid negative adults. We also saw no significant decrease in hippocampal rCMRO2 in the amyloid positive adults. These results were unaffected by choice of whole brain or pons as the reference region.

Conclusion

Hippocampal metabolism appears to be relatively preserved in cognitively normal amyloid positive adults. Reported alterations in hippocampal metabolism might therefore be more closely linked to the onset and progression of cognitive impairment.
Regional tau PET patterns predict prospective domain‐specific cognitive decline in Alzheimer’s Disease
Authors: Malpetti Maura , Iaccarino Leonardo , Tanner Jeremy A , Mundada Nidhi S. , Cobigo Yann , Arora Anupa , Pontecorvo Michael J. , La Joie Renaud , Rabinovici Gil D.
Published: December 2022

Background

Tau‐PET binding patterns are heterogenous, with regional binding showing strong cross‐sectional correlations with domain‐specific cognitive performance and longitudinal correlations with prospective neurodegeneration. The goal of this study was to evaluate whether regional patterns of baseline tau‐PET predict prospective longitudinal decline in specific cognitive domains in early symptomatic AD.

Methods

Seventy‐nine amyloid‐positive participants with a clinical diagnosis of mild cognitive impairment (MCI, n=47) or AD dementia (n=32) underwent a 18Flortaucipir PET (80‐100 minutes after injection), structural MRI, and neuropsychological testing as part of the AVID A05 study (Table 1). Cognitive assessment was repeated after 9 and 18 months. Single‐test annualized w‐scores (age‐corrected z‐scores) at each time point were calculated against 52 controls (age=67.5±10.3) and combined in composite scores for episodic memory, semantic memory, executive function, language, and visuospatial domains. Latent growth curve models were applied to longitudinal composite scores to estimate the rate of annual decline (slope) in each participant. Standardized uptake value ratio (SUVR) images were created using inferior cerebellar gray matter as the reference region. Voxelwise regression analyses were used to identify patterns of baseline tau‐PET associated with longitudinal changes in each cognitive domain. Regression analyses were repeated using cortical regional baseline SUVR values, extracted using FreeSurfer, as predictors of subsequent cognitive decline.

Results

Patients significantly declined in all domains (Figure 1). Differential FTP‐PET patterns showed significant negative associations with domain‐specific annual rates of decline (r≤‐0.3, p<0.001; r≤‐0.5, pFWE<0.05 at voxel level, Figure 2). Specifically, higher tau‐PET SUVR in temporo‐parietal regions was predictive of faster decline in episodic memory, tracer retention in the left anterior temporal lobe related to worse semantic memory, while a more extensive and asymmetric tau‐PET pattern in (L>R) fronto‐temporal regions and (R>L) fronto‐parietal regions related to a faster decline in language and visuospatial domains, respectively. Executive decline showed small inter‐individual variability. Region‐based analyses highlighted similar tau‐PET patterns as predictive of domain‐specific decline (pFDR<0.05, Figure 3).

Conclusion

At a group level, differential regional patterns of tau are associated with domain‐specific cognitive decline in MCI and early AD dementia. Tau PET may be a useful precision medicine tool for predicting patient‐specific trajectories in early symptomatic AD.
Impact of meningeal and age‐related off‐target binding on longitudinal [18F]MK6240 quantification
Authors: Tissot Cécile , Lussier Firoza Z , Ferrari‐Souza João Pedro , Servaes Stijn , Bezgin Gleb , Ferreira Pamela C.L. , Bellaver Bruna , Leffa Douglas Teixeira , Therriault Joseph , Vermeiren Marie , Kunach Peter , Stevenson Jenna , Rahmouni Nesrine , Chamoun Mira , Benedet Andréa Lessa , Wang Yi‐Ting , Arias Jaime Fernandez , Kang Min Su , Villemagne Victor L , Tudorascu Dana L , Cohen Ann D , Klunk William E , Baker Suzanne L. , Gauthier Serge , Rosa‐Neto Pedro , Pascoal Tharick A
Published: December 2022

Background

[18F]MK6240 tau‐PET can detect changes in the early and late stages of tau tangles accumulation. However, off‐target binding, often observed in the meninges and neuromelanin‐containing cells, can interfere with longitudinal tracer quantification. Here, we investigated the association of longitudinal changes in off‐target and target signals using [18F]MK6240.

Method

We assessed individuals from the TRIAD cohort with [18F]MK6240 tau‐PET and clinical evaluation. Longitudinal analyses included 83 cognitively unimpaired (CU) and 37 cognitively impaired (CI) individuals. Age‐related off‐target binding was estimated comparing 36 CU young individuals (<25 y.o) and 28 CU elderly amyloid/tau negative (40‐65 y.o). A t‐test was used to compare both groups. The ratio between baseline and follow‐up SUVR measured changes in off‐target and target regions. Pearson correlations tested the associations between regions, and Bonferroni analysis corrected for multiple comparisons.

Result

Although averaged images did not present a striking visual difference in [18F]MK6240 uptake between CU young and elderlies, t‐test revealed significant differences between groups in the cerebellar white matter and subcortical regions (Figure 1). Table 1 depicts the percentage of area of selected regions overlapping with the age‐related off‐target binding. Notably, we did not observe a significant association between longitudinal changes in age‐related or meningeal off‐target binding with longitudinal change in target regions (Braak‐II, BraakIII‐IV, BraakV‐VI), whereas changes in target regions were highly correlated (Figure 2).

Conclusion

Despite not being visually perceptible, [18F]MK6240 presents age‐related off‐target binding in subcortical regions, similar to regions reported using [18F]Flortaupicir. The overlap between age‐related off‐target and Braak IV region (∼3%) may lead to the confounding results in quantifying this region. The lack of correlation between off‐target and target [18F]MK6240 changes suggests little influence of the off‐target binding on longitudinal tracer quantification. Our results suggest that although off‐target uptake appears to have a modest influence on longitudinal quantification, it is necessary to consider both age‐related and meningeal off‐target signals for an accurate tracer assessment.
The induction of the mitochondrial morphofunctional pathways improves bioenergetics in Alzheimer Disease
Authors: Nguyen Thi Kim Oanh
Published: December 2022

Background

Alzheimer Disease (AD) currently has no effective treatments. A consistent failure of recent clinical trials focused on Aβ or pTau protein accumulation necessitates the identification of novel therapeutic targets and strategies. The loss of cellular energetics is considered as an underlying dysfunction in AD. We have identified small molecule compounds that partially inhibit mitochondrial complex I (MCI), blocking neurodegeneration via the induction of multiple neuroprotective mechanisms, including the improvement of cellular energy homeostasis in vitro and in vivo in multiple AD models. Mitochondria are highly motile organelles that respond to physiologic cues through the dynamic properties of mitochondrial networks, which are balanced by the flux of fusion and fission events. This study aims to demonstrate that treatment with partial MCI inhibitors improves cellular energetics and function via modulation of mitochondrial dynamics using multiple models, including neuronal cells generated from human iPSCs derived from ApoE4+ late‐onset AD (LOAD) patients and ApoE3+ controls.

Method

Changes in protein expression in response to treatment were assessed using the Western Blot analysis. The investigation of mitochondrial morphology was done using electron microscopy. Flow cytometry was used to measure the translocation of glucose transporters to the cell surface. Cellular energetics was assessed using a Seahorse Extracellular Flux Analyzer. Results were validated in 3xTgAD mice.

Result

We found that the 2D culture of LOAD cultures had accumulation of pTau and a significant reduction in the expression of proteins involved in mitochondrial dynamics and function, including mitochondrial preprotein translocase TIM23, mitochondrial transcription factor A, transcription factor FoxO3, and mitochondrial fusion proteins MFN2 and OPA1. Treatment with partial MCI inhibitors improved mitochondrial dynamics, rescuing the expression of MFN2 and OPA1, neuronal bioenergetics, and mitochondrial morphology. MCI inhibitors increased surface translocation of GLUTs enhancing glucose uptake and utilization, which could be measured in 3xTgAD mice in vivo using translational biomarker FDG‐PET.

Conclusion

Mild stress caused by the application of MCI inhibitors induced mitochondrial fusion, improved energy homeostasis, and enhanced glucose uptake and utilization in vitro and in vivo. These findings could be instrumental for the validation of a novel medicinal approach and the development of biomarkers for therapeutic efficacy.
Differential vulnerability of hippocampal microstructure in 5xFAD mouse model of Alzheimer’s Disease: A dMRI study
Authors: Shahid Syed Salman , Lamb Bruce T , Oblak Adrian L , Wu Yu‐Chien
Published: December 2022

Background

Hippocampal subfields exhibit differential vulnerabilities to Alzheimer’s disease (AD) associated pathologies. These pathological processes extensively attenuate the structural and functional interconnectivities of the subfields. Abnormal accumulation of beta‐amyloid (Aβ) is considered a primary hallmark of AD. Histopathological studies suggest region‐specific accumulation of Aβ in hippocampal subfields. The aim of the current study is to understand the subfield‐specific in‐vivo microstructural changes in hippocampus due to Aβ load in 2.5 months old 5xFAD mouse model of AD.

Method

Two and a half month old male 5xFAD and age‐matched littermate controls were used in this study. DWI and anatomical images were acquired on a horizontal bore 9.4T Biospec micro‐MRI system equipped with a H1 cryogenic surface coil. 2D T2‐weighted anatomical images were acquired using the following parameters: TE/TR=43.67/7500 ms, voxel size=117x117x250 µm3 and number of slices=20. DWIs were acquired using multi‐shot dual‐spin‐echo EPI sequence using following parameters: TE/TR=34.78/3000 ms, voxel size=117x117x250 µm3, number of slices=20, 3 b‐values (650, 1200 and 2500) s/mm2, 5 b0 per shell, 12 diffusion encoding direction for b=650, 60 for b=1200 and 80 for b=2500 s/mm2. T2‐W images were nonlinearly registered to Badhwar hippocampal atlas. Hippocampal subfields (CA1, CA2, CA3, DG and Subiculum) in atlas space were transformed to individual T2W space and then linearly transformed to DWI space. Multi‐compartment microstructural imaging was performed using Cortical‐NODDI. Volume fraction of isotropic water diffusivity (VFISO) and intracellular volume fraction (VFIC) maps were calculated. The regional mean values (VFIC and VFISO) of individual subfields were extracted and used in general linear model for group‐comparisons.

Result

The results of the study suggest group‐level differences between control and 5xFAD mice in cornu ammonis regions. Compared to 5xFAD, VFIC in littermate control mice was significantly higher in CA1 (p<0.05; d=1.47), CA2 (p<0.05; d=1.11) and CA3 (p<0.05; d=1.54). VFISO in DG was significantly lower in littermate control compared to 5xFAD mice (p<0.05; d=1.31).

Conclusion

The study demonstrates the importance of utilizing tissue‐specific microstructural imaging in detecting Aβ associated microstructural alterations in multiple hippocampal subfields. This study demonstrates that Aβ alters the hippocampal microstructure. study also suggests on the differential effect of Aβ pathology on hippocampal microstructure.
Functional connectivity of basal nucleus of Meynert, locus coeruleus and ventral tegmental area in MCI and mild dementia in Alzheimer’s disease
Authors: Burle Fernanda , Guimaraes Santos , Balthazar Marcio Luiz Figueredo , de Campos Brunno
Published: December 2022

Background

Cholinergic, noradrenergic and dopaminergic dysfunction plays an important role in Alzheimer’s disease (AD). Basal nucleus of Meynert (BNM), locus coeruleus (LC) and ventral tegmental area (VTA) are its main producer nuclei, respectively. Neuropathological studies have shown that structural changes are present in these areas from the beginning of the disease. As such, we aim to identify changes in the functional connectivity (FC) from these nuclei in patients with mild cognitive impairment (MCI) and dementia (DA) in AD, compared with healthy controls (HCs).

Method

We analyzed data from 43 subjects with altered beta‐amyloide in the cerebrospinal fluid (23 MCI; 20 mild to moderate dementia) and 16 controls. Participants underwent rs‐fMRI and neuropsychological evaluation. FC maps to the whole brain were generated (UF²C‐toolbox) using the BNM, LC and the VTA as seeds separately. The second level analysis was performed with an ANCOVA test including the individual FC maps, transformed to z‐score (Fischer R‐Z transformation) generated with each seed and group and regressing for age and years of education using SPM12‐toolbox. The significance level was defined as p<0.001 at the voxel level and p<0.05 FDR corrected at the cluster‐level. In addition, only anatomical regions with more than 60 voxels were described.

Result

Regarding BNM, compared to HCs, patients with MCI showed significantly decreased FC in the left precentral gyrus and left anterior insula (volume 62.05 and 61.59 voxels, respectively, Figure 1). Similarly, DA patients, when compared to HCs, showed significantly decreased FC in the left and right medial precentral gyrus (volume 104.06 and 82.75 voxels, respectively) and in the right supramarginal gyrus (volume 64.68 voxels, Figure 2). Regarding VTA, unexpectedly, we found that, compared with MCIs, DA patients showed increased FC in the left central operculum (volume 92.29 voxels, Figure 3). There were no other between‐group changes that reached statistical significance for right and LC and VTA.

Conclusion

AD patients present changes in the NBM‐FC to the precentral gyrus, insula and supramarginal gyrus. These findings may embase new research for cholinergic dysfunction and possible biomarkers.
Predicting neurodegenerative disease using the unique gut microbiota composition of transgenic mice modeling amyloid‐β plaques and neurofibrillary tangles
Authors: Borsom Emily M , Conn Kathryn A , Keefe Christopher R , Hirsch Allyson H , Orsini Gabrielle M , Jaramillo Sierra A , Testo George , Avila Melanie Palma , Bolyen Evan K , Dillon Matthew R , Lee Keehoon , Caporaso J. Gregory , Cope Emily K
Published: December 2022

Background

The gut microbiota, the aggregates of microbial cells that inhabit the gastrointestinal tract, communicates bidirectionally with the brain via immune, neural, metabolic, and endocrine pathways, known as the gut‐brain axis. The gut‐brain axis is suspected to contribute to the development of Alzheimer’s disease (AD). We hypothesize that altered gut microbiota composition contributes to the development of AD pathologies and neuroinflammation via the gut‐brain axis.

Method

To characterize the gut microbiota of 3xTg‐AD mice modeling plaque deposition and hyperphosphorylated tau, fecal samples were collected fortnightly from 4 to 52 weeks of age (n=57 3xTg‐AD mice, n=31 wild‐type). The V4 region of the 16S rRNA gene was amplified and sequenced on the Illumina MiSeq. Data were analyzed using QIIME 2. Targeted reverse transcription qPCR assays were used to assess inflammation in the hippocampus and colon at 8, 24, and 52 weeks of age. Fold change was calculated using ΔΔCt.

Result

Our results show altered microbial communities in 3xTg‐AD mice when compared to wild‐type [(PERMANOVA (8 weeks, p=0.001), (24 weeks, p=0.039), (52 weeks, p=0.058)]. Using q2‐longitudinal, we identified a temporal increase in Bacteroides acidifaciens and Turicibacter spp. in 3xTg‐AD mice (r‐squared = 0.658615). Using Random Forest, we successfully predicted strain in 3xTg‐AD mice 100% of the time, and in WT mice 92.85% of the time, improving accuracy over baseline assignment by 1.3 fold. Colonic expression of GFAP was increased at 24 week 3xTg‐AD mice compared to 52 week 3xTg‐AD mice (p=0.009, Mann‐Whitney). Colonic gene expression of IL‐6 was increased in 52 week 3xTg‐AD mice compared to 52 week WT mice (p=0.015, Mann‐Whitney). Hippocampal expression of GFAP was increased at 52 week 3xTg‐AD mice compared to 52 week WT (p=0.049, Mann‐Whitney). Finally, hippocampal expression of Mrc1 was elevated at 24 weeks in 3xTg‐AD mice compared to 52 weeks (p= 0.004, Mann‐Whitney).

Conclusion

We have identified changes in the gut microbiota and immune response that may be predictive of the development of AD pathologies. Future shallow shotgun metagenomics sequencing will assess strain‐level features and functions of the gut microbiota in AD.
Effects of Dementia and MCI on Diffusion Tensor Metrics Using the Updated ADNI3 DTI Preprocessing Pipeline
Authors: Thomopoulos Sophia I , Nir Talia M , Reina Julio E Villalon , Zavaliangos‐Petropulu Artemis , Maiti Piyush , Nourollahimoghadam Elnaz , Zheng Hong , Jahanshad Neda , Thompson Paul M
Published: December 2022

Background

Diffusion magnetic resonance imaging (dMRI) provides insight into white matter (WM) microstructural changes in Alzheimer’s disease and mild cognitive impairment (MCI). The Alzheimer’s Disease Neuroimaging Initiative’s (ADNI) has currently extended its ADNI3 imaging protocol to include dMRI from Siemens, Philips and General Electric (GE) scanners, resulting in seven vendor‐specific dMRI acquisition protocols (Table1). Here we present the updated ADNI3 preprocessing pipeline1 (Figure1) for diffusion tensor imaging (DTI) metrics made available via ADNI’s database, and evaluate their utility for detecting WM differences associated with clinical impairment.

Method

Raw dMRI downloaded from ADNI are first denoised using DiPy’s principal component analysis (PCA) denoising algorithms: local PCA for zero‐padded k‐space data (GE), or Marchenko‐Pastur PCA for data with the original acquisition matrix (Siemens/Philips). dMRI are then corrected for Gibbs ringing, eddy currents using FSL’s eddy_cuda with repol outlier estimation and slice‐to‐volume correction, intensity inhomogeneity with ANTS N4, and echo‐planar imaging distortions with a three‐channel non‐linear registration of the subject‐level preprocessed average B0 image to the subject’s skull‐stripped T1‐weighted MRI. Bias field correction is applied again to dMRI with FSL‐FAST. DTI fractional anisotropy (FA), axial, mean and radial diffusivity (AxD, MD, RD) are estimated with FSL’s dtifit, using weighted least squares. The JHU ICBM‐DTI‐81 atlas FA is warped to subject‐level FA maps using ANTS, and the transformations are applied to atlas labels. Subject‐level mean and robust mean (using M‐estimator from R’s ‘WRS2’ package) of DTI metrics within 73 WM regions of interest (ROIs; Table2) are extracted. Here, we fit linear mixed effects models of diagnosis (N=733) and clinical dementia rating (CDR‐sob; N=682; Table3) in 28 of the 73 available ROIs, covarying for age, sex, age*sex, and including nested protocol|site variables as random effects; multiple comparisons were corrected for using false discovery rate (q=0.05).

Result

Lower anisotropy and greater diffusivity were associated with greater impairment, particularly in the hippocampal cingulum (Figure2). Results from mean and robust mean metrics were comparable. Overall, our results follow previous work2,3 using publicly available ADNI dMRI.

Conclusion

Subject‐level ADNI3 dMRI measures, sensitive to clinical indices of impairment as presented here, are available at https://ida.loni.usc.edu/.

References: [1 ]Thomopoulos (2021), https://doi.org/10.1117/12.2606337; [2] Nir (2013), https://doi.org/10.1016/j.nicl.2013.07.006; [3] Zavaliangos‐Petropulu (2019), https://doi.org/10.3389/fninf.2019.00002.
Design, test, validate: development of a novel & robust analytic framework and econometric model using administrative claims data
Authors: Soenksen Dirk , Kleinman Nathan
Published: December 2022

Background

As health care expenditures continue to rise, policy makers and payers are assessing whether the cost of virtual care programs are justified by their outcomes.

Ceresti has developed a novel, robust analytic approach and econometric model to assess the efficacy and overall value of virtual care programs. The methodology uses an administrative claims‐based, analytic and statistical framework that accurately identifies and measures reduction in costs and services (including potential savings from avoiding other costly downstream events) attributable to deployed virtual care programs.

Method

The analytic framework and econometric model were developed for and validated in a pragmatic trial in a Medicare‐aged population.

A total of 164 subjects were enrolled in the trial sponsored by a leading Medicare Advantage plan and Ceresti Health. The pragmatic trial compared changes in patient outcomes between program enrollees (DCEP “Care Recipients”) and a matched comparison group using a “difference‐in‐differences” approach.

General Matching criteria included:

Age

Gender

Geographic region

Aligned index dates between Care Recipients and the comparison group

During the 6 month pre‐index period matching criteria included:

Charlson Comorbidity Index

number of condition‐specific medical claims

presence of a skilled nursing facility claim

emergency department (ED) visits and costs

inpatient hospital admissions and costs

costs for nursing or assisted living, office visits and other outpatient services

Costs and service utilization of Care Recipients and the matched comparator group were extracted from an administrative claims database.

Total medical and inpatient costs were captured during the pre‐ and post‐index periods for the active and comparator arms. The frequency of ED visits, inpatient admissions, and 30‐day readmissions were calculated per patient per month. The change in costs and visit frequency that Care Recipients incurred > 30 days post‐index to the end of the study was compared to the change experienced by the matched comparator controls.

Results

The analytic model detected statistically significant pre‐, post‐efficacy across health‐related and economic outcomes.

Conclusion

The analytic and statistical framework validated in this trial overcomes the challenge of attributing claims‐based outcomes to virtual care interventions, and contribute to the methods available to accurately measure the value of virtual care programs in Medicare‐aged populations.
Examining the Use and Value of Applied Skills Assessment for the Training of Cognitive Measures in Alzheimer’s Disease (AD) Trials
Authors: Carbo Melissa A , Scalzo Nola , Avrumson Rolana , Komorowsky Andrew , Ogden Kristine
Published: December 2022

Background

There are many potential variables that may confound trial results; Sadler, et al. (2017) supported use of Rater Training as an effective method to improve the reliability and accuracy of endpoint measures. Consistent administration and scoring of cognitive assessments are critical to the success of AD trials.

Method

This analysis examines the benefits of implementing an Applied Skills Assessment (ASA) component to standardized Rater Training programs across multiple AD trials. Data was collected from four trials, Phase II and POC, with raters of varying education and experience levels. A detailed review of conceptual knowledge was followed by an Applied Skills Assessment. The ASA required each rater to demonstrate their proficiency with administering a critical cognitive measure for each respective study (such as the Alzheimer’s Disease Assessment Scale‐Cognitive Subscale (ADAS‐Cog), Mini Mental State Examination (MMSE), Hopkins Verbal Learning Test‐Revised (HVLT‐R) and the Severe Impairment Battery (SIB)). Each ASA was evaluated by highly experienced and trained members of a clinical assessment team with immediate feedback delivered.

Result

Data was acquired from 314 raters of various education and experience levels across eight different countries. Following the detailed conceptual knowledge review, 62% of raters demonstrated errors during the Applied Skills Assessment. There was no notable difference identified across educational degree however there was a dispersion across experience level. It was found that 50% of errors demonstrated were made by raters who reported 0–5 years of Alzheimer’s research experience. Improved performance was observed among raters in the categories of 6–10 years and >10 years of Alzheimer’s Research Experience with a lower rate of error of 22% and 28%, respectively.

Conclusion

Results support the value in implementing an applied skills exercise to enhance the Rater Training programs for cognitive assessments. Khan (2016) suggests that rater performance tends to significantly improve with re‐training and feedback which applies across various experience levels. A training involving the evaluation of a rater’s applied performance, that includes feedback by a skilled assessor, may prove to be instrumental in contributing to the enrollment of appropriate study participants and achievement of high‐quality reliable endpoint data in Alzheimer’s Disease research.
Hippocampal CA1 volume is associated with higher p‐tau and diminished memory performance in normal older adults
Authors: Tran Tammy T , Trelle Alexandra N , Hunt Madison , Guo Wanjia , Nadiadwala Ayesha , Wilson Edward N. , Deutsch Gayle , Sha Sharon , Andreasson Katrin I. , Carr Valerie A , Kerchner Geoffrey A. , Mormino Elizabeth C. , Wagner Anthony D
Published: December 2022

Background

Prior work has demonstrated that elevated CSF biomarkers in older adults are associated with diminished performance across several hippocampally‐dependent memory tasks. It is unknown whether early structural changes in medial temporal lobe subfields (1) may be impacted by elevated p‐tau181, and (2) mediate the effect of p‐tau181 on memory performance in older adults.

Method

The current study draws on a cohort of 147 cognitively unimpaired older adults (Stanford Aging and Memory Study) that completed both 3T MRI and lumbar punctures. To examine memory performance, participants completed two hippocampally dependent tasks: a paired associate cued recall task and a mnemonic discrimination task (MST) that examined discrimination between previously studied “old” objects, novel “foil” objects and perceptually similar “lure” objects. Lure trials were binned in five difficulty levels, ranging from low to high similarity compared to previously presented stimuli. Hippocampal subregions (CA1, CA3/DG, subiculum) were manually delineated on T2*weighted images following Carr et al., (2017). CSF was processed with Lumipulse to measure Ab42:Ab40 ratio and p‐tau181. Multiple regression was used to assess the associative memory d’ from the paired associate task. Given the repeated measures design of the MST task, linear mixed models were conducted to understand the association between hippocampal subfields and p‐tau181 on performance as a function of similarity strength (Trelle et al., 2021). Age, sex, and education were controlled in all models.

Result

P‐tau181 was correlated with reduced left CA1 volume (partial r2=0.043, p = 0.01), but not with volume in other hippocampal subfields. Increased CA1 volume was positively associated with better memory performance, including higher associative memory recall and old‐lure discrimination. After controlling for p‐tau181, CA1 volume was no longer associated with performance on the associative memory task but remained significantly correlated with old/lure discrimination. Notably, increased CA1 volume improved overall discrimination for old/lure trials, independent of the difficulty level, while the association between p‐tau181 and performance was strongest at the lower similarity level.

Conclusion

Reduced CA1 volume and p‐tau explain unique variance in memory performance in older adults. This combination of biofluid biomarkers and high‐resolution MRI has the potential to understand mechanisms underlying age‐related memory decline.