bluuebunny/crossref_metadata_2025 huggingface dataset:
Height and intracranial volume as protective factors against Alzheimer’s disease: a Mendelian randomization analysis
Authors: Taylor Jack C , Brenowitz Willa D , Yaffe Kristine , Andrews Shea J
Published: December 2023

Background

Meta analyses have identified height as a risk factor inversely associated with Alzheimer’s disease. Height as a protective factor may be reflective of overlapping genetics with intracranial volume (ICV), which has also been shown to be inversely associated with AD, or height may reflect early life influences such as nutritional intake. Here we use Mendelian randomization (MR) analysis to further investigate these causal relationships.

Method

Two sample MR was used to obtain causal estimates of height and ICV on AD, using GWAS summary statistics from the GIANT consortium (n = 5,380,080), meta analyzed summary statistics from studies measuring ICV, brain volume, and head circumference, and the International Genomics of Alzheimer’s Project (n = 94,437). Independent (r2<0.001, 10mb window) genome‐wide significant single nucleotide polymorphisms (p<5×10−8) were included as genetic instruments (n = 960). MR methods included inverse variance weighted (IVW), weighted median, weighted mode, and MR Egger. Cochran’s Q test was used to test for heterogeneity; the MR‐Egger intercept for pleiotropy; and Radial MR to identify individual variants that were outliers.

Result

Genetically predicted height was associated with a reduced risk of AD (IVW logOR [95% CI]: ‐0.11 [‐0.16, ‐0.06], p = 7.3e−5). There was, however, evidence of heterogeneity and pleiotropy. After outlier removal (n = 1), height remained significantly associated with reduced risk of AD (IVW OR [95% CI]: ‐0.12 [‐0.18, ‐0.07], p = 1.49e−5), with sensitivity analyses showing the same direction of effect. Genetically predicted ICV was significantly associated with AD (IVW logOR [95% CI]: 0.16 [0.003, 0.31], p = 0.046), though tests of heterogeneity and pleiotropy were significant while sensitivity analyses were not. After outlier removal (n = 1), ICV was no longer significantly associated with reduced risk of AD (IVW logOR [95% CI]: 0.13 [‐0.03, 0.30], p = 0.11).

Conclusion

Genetically predicted height was protective against AD, while ICV had a suggestive protective causal effect. Together, these findings may imply a link between these phenotypes and AD. Further research using multivariate MR is needed to fully evaluate the potential mediating role of ICV in the protective effect of height on AD, as well as to explore other potential mediators such as nutritional intake.
Plasma biomarkers of Alzheimer’s Disease associate with gray matter volume and cerebral glucose metabolism in older adults with Mild Cognitive Impairment
Authors: Green Zachary D. , Morris Jill K , Lepping Rebecca , Vidoni Eric , Honea Robyn A
Published: December 2023

Background

Alzheimer’s Disease (AD) pathology in vivo has traditionally been measured in the cerebrospinal fluid or by positron emission tomography (PET). Developments in measuring plasma biomarkers present less invasive, cheaper ways to quantify AD pathology. However, the associations between these new plasma markers and neuroimaging markers of AD are not fully understood. We examined the relationship between plasma biomarkers of AD and measures of whole brain gray matter volume (GMV) and cerebral glucose metabolism in both cognitively unimpaired (n = 83) and impaired (n = 30) individuals.

Method

We collected data from individuals within the University of Kansas Alzheimer’s Disease Research Center’s (KU ADRC) Clinical Cohort who underwent MRI and FDG‐PET scans and had available plasma data. Participants included 64 females, and age of the neuroimaging cohort was 76.0 ± 6. Plasma biomarkers were measured in EDTA plasma using the Quanterix Simoa® HD‐X, and included NfL, Aβ42, Aβ40, GFAP, and p‐tau181. GMV was estimated using MPRAGE MRI processed in FreeSurfer. Cerebral glucose metabolism was estimated from FDG‐PET data using SUVR values calculated through SPM12, with standardization to pons. We used linear regression to examine the relationship between each biomarker to whole brain GMV and glucose metabolism. ANCOVA was used to evaluate differences in the plasma biomarkers between diagnosis groups. Analyses included sex and age as covariates.

Result

Whole brain GMV (F = 8.4, p = .004) and cerebral glucose metabolism (F = 10.9, p = .002) differed between diagnostic groups. In the linear regression, we observed an interaction effect between cognitive diagnosis and each biomarker, such that the slopes of regressions between each plasma biomarker and neuroimaging marker was significant in the impaired group, but not significant in the unimpaired. In the impaired group, the strongest association observed was between plasma NFL and whole brain GMV (β = ‐1.4, p = .020) and cerebral glucose metabolism (β = ‐1.7, p = .014). Additionally, all plasma biomarkers were found to differ between diagnostic groups.

Conclusion

We show that plasma markers of AD pathology associate with whole brain GMV and cerebral glucose metabolism in individuals with cognitive impairment. Further work will examine the relationship between biomarkers and regional neuroimaging measures
Early‐onset Lewy body dementia associated with PRKN gene mutation
Authors: Singh Neeraj
Published: December 2023

Background

A 42‐year‐old woman presented with a 1‐year history of head tremors, visual hallucinations, and concentration difficulty. On initial evaluation by a neurologist, she was told that her symptoms were due to anxiety, and no further workup was done. After seeking a second opinion, further workup was pursued.

Method

The patient underwent cognitive testing, with Montreal Cognitive Assessment revealing a normal score of 29/30. MRI Brain revealed a midline frontal meningioma without mass effect. Routine EEG revealed no evidence of seizure tendency. Due to persistent head tremors and visual hallucinations, further testing was considered.

Result

PET‐FDG CT Brain revealed bilateral parietotemporal and occipital hypometabolism with preserved cingulate gyrus metabolism, consistent with Lewy body dementia. Another PET‐FDG MRI Brain performed 13 months later revealed a similar hypometabolism pattern. Genetic testing revealed a heterozygous mutation for the PRKN gene.

Conclusion

In this case, a patient showing clinical signs of a potential neurodegenerative disorder was initially dismissed as having anxiety, but further workup with appropriate neurological studies revealed a genetic basis for early‐onset Lewy body dementia. This case demonstrates a unique association with the PRKN gene mutation with Lewy body dementia even though it is typically associated with Parkinson’s disease. This case also highlights the underrepresentation of young patients with neurodegenerative diseases, which is reinforced by biases against pursuing appropriate workup for young patients showing relevant clinical signs.
Integration of multiple single cell microglial datasets reveals radial differentiation into long‐lived substates associated with Alzheimer’s pathology
Authors: Baumgartner Andrew , Robinson Max , Huang Sui , Hadlock Jennifer , Funk Cory C
Published: December 2023

Background

Unsupervised classification of brain cell types can be readily achieved through analysis of gene expression patterns in multidimensional space. However, the small transcriptional differences between microglia subtypes require more principled, robust, and reproducible approaches to expose and distinguish biological differences from noise.

Method

Here we leverage Fokker‐Planck diffusion maps [1,2] to examine the dynamics of microglia subtypes by finding a low dimensional representation of the underlying stochastic dynamical system responsible for generating these transcriptional states. Clustering directly on this projection allows us to reduce noise, assign time scales to these substates, and generate a hierarchy of microglial cell states. Once these subtypes have been defined, we apply pseudobulk differential expression analysis to identify marker genes, and use those genes to build a boosted tree model to classify cells states. We then apply Shapley additive explanations (SHAP) to identify which genes are most important for distinguishing between cell states.

Result

We observe a radial transition pattern emanating, with a subtype that appears homeostatic, inactivated, and poised for transition. This is consistent with the observation that microglia dynamics are sensitive to their microenvironment. Deconvolution of an independent bulk microglia dataset (n = 130) showed depletion in subtypes linked to protein misfolding and myelin phagocytosis, as well as enrichment in immunoreactive microglia in Alzheimer’s patients. SHAP reveals DUSP1, CD83, PLCG2, OLR1,CCL2, and JUN among the most important genes for differentiating into these AD‐associated clusters.

Conclusion

Our approach enables us to reproducibly identify microglial subtypes across sets of single cell‐resolution high dimensional molecular profile data, identifying likely drivers of subtype differentiation. With several of our driver genes already associated with Alzheimer’s via GWAS and other analyses, our results will enable us to elucidate the role of these genes in determining microglial subtypes.

References:

[2] Nadler, B., Lafon, S., Coifman, R. R., & Kevrekidis, I. G. (2006). Diffusion maps, spectral clustering and reaction coordinates of dynamical systems. Applied and Computational Harmonic Analysis, 21(1), 113‐127.

[2] Coifman, R. R., Kevrekidis, I. G., Lafon, S., Maggioni, M., & Nadler, B. (2008). Diffusion maps, reduction coordinates, and low dimensional representation of stochastic systems. Multiscale Modeling & Simulation, 7(2), 842‐864.
The development of an explainable machine learning system for predicting brain atrophies from electronic health records
Authors: Ghosheh Mohammad , Ghosheh Ghadeer , Ghosheh Jamal
Published: December 2023

Background

The number of elderly living with dementia is projected to dramatically increase, especially in low‐income and middle‐income countries (LMICs). While obtaining brain scans to detect atrophies and significant radiology findings related to dementia might be costly, the use of electronic health record (EHR) for elderly patients could facilitate identifying patients at a high risk based on routinely collected data. This works, evaluates the use of an interpretable machine learning‐based system that predicts brain atrophies and small vessel disease based on EHR data.

Method

We develop a machine learning predictive system to predict atrophies or small vessel disease from retrospective anonymized EHR data recorded for patients above the age of 50 years from a multispecialty outpatient medical center from Ramallah, Palestine. The patient labelling involved using natural language processing to identify cases in unstructured radiology reports for structural brain Magnetic Resonance Imaging (MRI). For input features, we extracted and preprocessed 30 features for the most commonly collected clinical features such as demographics and laboratory results. The dataset was split into training and test sets, where data preprocessing and augmentation, and hyperparameter tuning were applied before training multiple models including Xgboost, Support Vector Machines, Random Forest, and Logistic Regression. To better understand the relative impact each feature had on the model’s prediction, shapely feature importance analysis was conducted for the top performing model.

Result

The top preforming model was Random Forest, with a performance of Area Under the Precision‐Recall Curve (AUPRC) of 0.989, and 0.842 for Area Under Receiving Operating Curve (AUROC). The feature importance analysis revealed that age, sex, Vitamin D, Vitamin B12 and red blood cell distribution width were the features with highest impact on the model’s prediction

Conclusion

Predicting atrophies from EHRs for elderly visiting outpatient clinics could assist in case‐finding for dementia patients and ultimately help identify patients that would benefit from an MRI. In future works, we aim to further investigate building low‐cost diagnostic tools based on a smaller feature set, which could be valuable for facilities from LMICs.
APOE‐targeted epigenome therapy for late onset Alzheimer’s disease
Authors: Kantor Boris , Rittiner Joseph , Odonovan Bernadette , Chiba‐Falek Ornit
Published: December 2023

Background

Carrying the APOEe4 variant significantly increases lifetime risk for LOAD. The accumulating evidence suggest that alteration of the expression of APOEe4 and APOE may hold promise as a potential therapeutics target for LOAD. In this study we developed an epigenome therapy platform to reduce APOE and APOEe4 specifically by targeted modification of the epigenome landscape within APOE locus.

Method

Our approach is based on CRISPR/dCas9‐editing strategy. The novel system based on the novel bipartite repressor platform, recently developed in the laboratory. We designed targeting of APOEe4 in the allele‐discriminatory fashion, as such the editing is allele specific and precise. Furthermore, we developed a similar approach to target the regulatory elements within APOE promoter. We evaluated our platform in vitro using human hiPSC‐derived neurons and organoids, as well as in vivo by stereotactic injection of the developed system into the hippocampus of the ApoE‐humanized mice, harboring human ApoE loci replaced the mouse ortholog.

Result

Using the system, we demonstrated an efficient and precise editing of APOeE4 and APOE expressions in the hiPSC‐derived neurons and the human isogenic APOEe4 organoids. We showed that the system can robustly reduce the levels of APOE‐mRNA and the protein in both models. Importantly, the allele‐discrimination approach has resulted in no detectable editing of the e3 allele in the isogeneic hiPSC‐derived neurons, and organoids homozygous for the e3 allele. Moving onto in vivo studies, the promoter‐targeted approach using adeno‐associated‐ dCas9‐KRAB‐MeCP2 vector injected into the hippocampus of APOEe4 and APOEe3 mice, showed 50‐70% decrease in the mRNA and the protein levels. Similar effect was observed using lentivirus‐ CRISPR/Cas system targeted ApoEe4 in allele‐specific manner. Collectively, our results provided in vitro and in vivo proof‐of‐concept for the utility and efficacy of the APOE‐targeted epigenome therapy.

Conclusion

Our epigenome therapy strategy for fine‐tuning of APOE expression based on dCas9 technology is translational toward the development of a therapeutics approach to prevent and/or delay LOAD onset. Furthermore, the technology offers the opportunity to refine the platform for the development of gene‐specific and even allele‐ and cell‐type‐ specific therapies, and by that enables the advancement of strategies for precision medicine in LOAD.
Evaluation of the neurocognitive and neuroprotective potentials of selected Nigerian medicinal plants in experimental models of dementia
Authors: Atunwa Soliu A.
Published: December 2023

Background

Recent studies have implicated oxidative stress, chronic neuroinflammation, functional cholinergic deficits, and glutamatergic pathway disruptions in the pathophysiology of dementia. However, certain medicinal plants are being used in the management of dementias by the inhabitants of Ibarapa Area of South‐Western Nigeria, hence this study.

Method

Ethno‐pharmacological survey of medicinal plants used in the management of dementias in Ibarapa Area of Oyo State, South‐Western Nigeria was conducted using semi‐structured questionnaires and open‐ended interviews. Phytochemical, antioxidant, anti‐inflammatory, anti‐nociceptive, and cholinesterase‐inhibiting screenings were conducted on selected medicinal plants (SMPs) using standard assays. Preliminary cytotoxicity screening of promising crude extracts were determined using brine shrimp lethality assay (BSLA). LD50, acute and sub‐chronic administrations of the SMPs into groups of mice were determined using Organization of Economic Cooperation and Development (OECD) 423 guideline. Haematological, biochemical, and histopathological examinations following single and repeated doses of crude extracts of SMPs into groups of mice were determined using standard assays. Behavioural studies using relevant mouse models were conducted. Mechanistic studies using cell lines are being carried out on the promising SMPs. Data are expressed as mean ± standard error of mean (SEM) and analyzed using one‐way analysis of variance (ANOVA) followed by post‐hoc test (Student‐Newman‐Keuls test).

Result

The ethnomedicinal survey revealed about 105 medicinal plants belonging to more than 50 families being used as memory enhancers in the management of dementias by the inhabitants of Ibarapa Area of Oyo State in south‐Western Nigeria. Phoenix dactylifera, Combretum mucranthum, Parquitena nigrescens, Crinum jagus, Blighia sapida, Entandrophragma utile, Ficus exasperate showed significant antioxidant, anti‐inflammatory, and anti‐cholinergic activities. Results of BSLA revealed LC50 values of 100 ‐ 1000 ppm for the screened plants. The oral LD50 values of crude methanol extracts of SMPs are 2000 ‐ 5000 mg/kg. Findings from haematological, biochemical, histological and behavioural assays following both single and repeated administrations of the tested SMPs in mice showed that they are safe and possess promising neurobehavioural potentials that warranted further exploration.

Conclusion

The SMPs are safe, highly rich in beneficial phytochemicals, exhibited significant antioxidant, anti‐inflammatory, anti‐cholinesterase, nootropic and neuroprotective potentials thereby suggesting the rationale for their ethnomedicinal use in the management of NNDs.
Efficient use of open label extension data to support additional evidence of efficacy and disease modification hypotheses
Authors: Hennessey Sean , Dickson Samuel P. , Mallinckrodt Craig , Nicodemus‐Johnson Jessie , Knowlton Newman , Wassom Mitchell , Hendrix Suzanne B.
Published: December 2023

Background

Many clinical trials have open label extension (OLE) phases in which all patients from the randomized controlled study go onto active treatment for some period of time. These OLEs provide the opportunity for placebo patients to have access to active treatment. Trial sponsors also want to get meaningful information from the OLE data.

Method

We evaluate the types of hypotheses that can be tested with OLE data in degenerative diseases and propose analyses aligned with these hypotheses. Challenges with OLE data are also enumerated and discussed. For these analyses, and for simplicity of examples, we are assuming that the randomized phase and the OLE phase are each 1 year in duration.

Result

6 key hypotheses can be addressed with OLE data. 1. Treatment effects differ during the randomized phase and the OLE, 2. Treatment groups differ at the end of the OLE, 3. The slope for placebo patients in the randomized phase differs from their slope during the OLE, 4. The slope over the entire duration of the randomized phase and the OLE phase differs between groups, 5. The slope of decline during the first 12 months of treatment combined across the original active patients and the placebo patients during the OLE phase differs from the placebo slope of decline during the original 12 month randomized phase. 6. The slope of the original placebo group differs from the original active group during the OLE phase. If a significant treatment effect is seen during the randomized phase, then hypotheses 2 and 6 can demonstrate disease modification in a pseudo staggered start analysis if they demonstrate that the treatment groups also differ at the end of the OLE phase, and are not converging during the OLE. Challenges with OLE analyses include high dropout rates, differential dropout between groups, ceiling and floor effects resulting in differing slopes (nonlinearity) during the randomized and OLE phases.

Conclusion

OLE phases can add to the weight of evidence for efficacy in clinical trials and can identify disease modifying effects as long as issues such as dropout and non‐linearity are accounted for.
Direct Reprogramming of the Marmoset Dermal Fibroblasts into Neural Stem Cells and Neurons
Authors: Park Jung Eun , Guimaraes Thais Rafael , Hachem Stephanie , Thathiah Amantha , Silva Afonso C
Published: December 2023

Background

The neuropathological hallmarks of Alzheimer’s Disease (AD) are characterized by the accumulation of beta‐amyloid (Ab) plaques and neurofibrillary tangles (NFTs) of a hyperphosphorylated form of the microtubule‐associated protein tau (MAPT) in the brain. However, Ab and tau accumulate in the brain decades before the clinical symptoms emerge and the biological basis for the relationship between abnormal aggregation of AD‐related proteins and neuronal deterioration remains unknown. Cell models play an imperative role in understanding the pathogenesis of the disorder. For this, the present studies aimed to establish a marmoset induced neurons directly converted from fibroblasts (induced neurons; iNs) as well as induced neural stem cells (iNSCs) that are further differentiated into neurons to quantify the spontaneous presence of AD‐related pathology in marmoset cell cultures in vitro.

Method

Marmoset fibroblasts were cultured from skin biopsies and reprogrammed into iNSCs by transfection with episomal reprogramming vectors carrying the Oct4, Sox2, Nanog, Lin28, Klf4, and L‐Myc and culture in the presence of small molecule inhibitors CHIR99021 and SB431542. The iNSCs were subsequently differentiated into neurons. Direct neuronal conversion from the marmoset fibroblast was performed by co‐overexpression of Ngn2 and Ascl1 under the control of the doxycycline‐inducible tetOn promoter and supplementation of medium containing doxycycline in combination with a defined cocktail of small molecule‐based pathway modulators.

Result

Highly proliferative marmoset iNSCs were established and expressed neural stem cell markers, including Sox2 and Pax6 when detected by immunofluorescence. iNSCs were differentiated into neurons and stained the neuron‐specific markers such as Tuj1, Map2, and NeuN. The Ngn2 and Ascl1 overexpressed marmoset fibroblasts underwent a morphological change into a neuron‐like structure within a few hours of neuronal induction and the resultant iNs were expressed the pan‐neuronal markers in the neurite‐like projection and cell bodies.

Conclusion

The directly reprogrammed iNSC and iNs have been shown to have neuronal characteristics and offer a cellular model system to quantify the natural incidence of AD‐related pathology in marmosets. The marmoset cellular system of AD will provide mechanistic insight into the etiology of the disease and may serve as a beneficial tool for drug discovery to treat the disorder.
Streamlining and standardizing logistical, administrative, and regulatory workflows for sharing data from AD trials
Authors: Brown Christopher T. ,   Banner Alzheimer’s Institute
Published: December 2023

Failure to share data successfully and quickly results in the waste of scientific resources as experiments are erroneously repeated or future resources are misallocated. Successful data sharing maximizes prior public and private investment of time, personal and cost in AD trials. To date, training resources regarding general regulatory requirements for managing data are widely available, however trainings addressing common logistical and administrative decision‐making and providing administrative strategies in the context of data sharing by AD trial teams and sponsoring partners are rare or too rigid to be broadly applicable. A widely available and well‐known training and education resource will provide a coherent systematic approach for multi‐stakeholder research projects that intend to share data publicly. Such projects are at increased risk of delay or mismanagement and a cohesive effort to generate flexible, streamlined modules offering repeatable solutions for multi‐stakeholder AD research data sharing would benefit the research team as well as the requesting investigators. AD research staff should rapidly develop familiarity and a common understanding of the practices and policies of data sharing so that this aspect of research similarly streamlined to other research practices such as informed consent, data privacy, etc. Attendees will participate in a discussion establish a priori principles for charting a course for establishing broad competence in data sharing by combining principles of scientific rigor with a synthesis of best practices for logistical, scientific, and regulatory workflows.
Phosphorylation differentially regulates tau isoforms
Authors: Naseri Nima N
Published: December 2023

Background

Six major tau isoforms are alternatively spliced in an age‐dependent manner: 3R tau (3‐repeat domain) is expressed in development, while both 3R and 4R (4‐repeat domain) tau isoforms are expressed in adult brain. While FTDP‐17‐causing point mutations in tau show isoform‐dependent effects on aggregation and microtubule stabilization, there are not tau mutations linked to Alzheimer’s disease. Meanwhile, effects of phosphorylation on different tau isoforms remain largely unexplored.

Method

We use a combination of recombinant proteins, mouse aging studies and iPSC‐derived neurons to test for isoform‐dependent effects of tau phosphorylation on its function and dysfunction.

Result

Phosphorylation at certain sites selectively diminishes microtubule polymerization activity by the fetal tau isoform while a comparable adult isoform was largely unaffected. Conversely, phosphorylation at these same sites accelerated in vitro aggregation of an adult isoform compared to the fetal isoform.

Conclusion

Phosphorylation to tau has isoform‐dependent effects on its function and dysfunction, thus emphasizing the importance of distinguishing pathological and regulatory phospho‐tau species in future therapeutic efforts.
Cognitive performance and normative data between Hispanic and non‐Hispanic cohorts: Results from the South Texas Alzheimer’s Disease Research Center (ADRC)
Authors: Patel Aishwarya N. , LaRoche Ashley , Young Vanessa M. , Alliey‐Rodriguez Ney , Sullivan A. Campbell , Satizabal Claudia L. , Savoia Sarah E. , Katragadda Haritha V. , Saklad Amy R. , Shipp Eric L. , Gilliam Frank , Mavarez Rosa P. , Patel Neela K. , Tanner Jeremy A. , Parker Alicia S. , Salardini Arash , de Erausquin Gabriel A. , Maestre Gladys E. , Seshadri Sudha , Gonzales Mitzi M.
Published: December 2023

Background

The prevalence of Alzheimer’s disease and related dementias (ADRD) in the United States was estimated as 6.5 million people in 2022, with a five‐fold increase for the Hispanic/Latinx population expected by 2060. The South Texas Alzheimer’s Disease Center (STAC) was designated as a new ADRC in 2021 by the National Institute on Aging (NIA) with a specific aim to serve the growing needs of the local underrepresented Hispanic population. As cultural and linguistic factors can impact performance on cognitive tests, the goal of the study was to compare UDS‐3 cognitive test raw scores and normative data in Hispanic and non‐Hispanic adults without cognitive impairment residing in South Texas.

Method

Participants from the STAC cohort completed the Uniform Data Set (UDS), V.3.0, which includes demographics and neuropsychological battery. All batteries were administered in the participants’ preferred language, English. Normative data was calculated using Weintraub et al. (2018)’s age, sex, and education adjusted regression models for UDSNB 3.0. Mean differences between baseline visit raw scores and normative data were compared using independent sample t‐tests among Hispanic and non‐Hispanic participants.

Result

Thirty‐four Hispanic (mean age = 70.4, 67.6% female) and thirty‐eight non‐Hispanic (mean age = 71.9, 57.9% female) participants were included. Hispanic participants had fewer years of education relative to non‐Hispanic participants [M(SD)] = [14.7(2.5)] to [16.5(2.5)], respectively; (t(70.1) = 3.0, p = 0.004); although, the groups did not differ in age or sex distribution (p>0.05). Hispanic and non‐Hispanic participants generally performed equivalently on the neuropsychological battery. However, Hispanics had lower mean raw scores on the Montreal Cognitive Assessment (MoCA) (t(70.8) = 3.6, p<0.001) and the Multilingual Naming Test (MINT) (t(71) = 4.0, p<0.001) relative to non‐Hispanic participants, which persisted when normative data was applied (MoCA: t(71) = 2.3, p = 0.024, MINT: t(71) = 2.8, p = 0.006).

Conclusion

Overall, Hispanic and non‐Hispanic participants performed similarly on the UDS‐3 neuropsychological battery. However, Hispanics had lower mean raw and normative scores on the MINT, as well as the MoCA which also includes language measures. Our findings highlight the importance of future research validating the sensitivity and specificity of normative data used in underrepresented populations, especially those at higher risk for ADRD.
Ultra‐high‐resolution quantitative MRI at the grey/white interface in Alzheimer’s disease and posterior cortical atrophy
Authors: Veale Thomas , Ocal Dilek , Edwards Luke J , Pine Kerrin J , Fox Nick C , Weiskopf Nikolaus , Cash David M
Published: December 2023

Background

Cortical grey matter (CGM) and superficial white matter (SWM) undergo pathological changes, but standard MRI spatial resolutions make interpreting disease‐related effects at their interface challenging. We present findings from a study investigating the grey/white interface in typical amnestic Alzheimer’s disease (tAD), posterior cortical atrophy (PCA) and healthy controls using ultra‐high‐resolution quantitative MRI measures sensitive to microstructural properties.

Method

Eleven participants (Table 1) were scanned at 7T using multi‐echo FLASH (0.5mm isotropic resolution with prospective motion correction) and diffusion MRI (dMRI) (1.25mm isotropic resolution). The hMRI toolbox produced multi‐parametric mapping (MPM) measures: R1, R2* and Proton Density (PD) (Vaculciakova et al., 2021https://doi.org/10.1002/mrm.29253). dMRI processing included denoising and correcting for Gibbs ringing, eddy currents, susceptibility artifacts and motion. Metrics from dMRI were fractional anisotropy (FA), and mean diffusivity (MD), as well as tissue fraction (TF), neurite density index (NDI) and orientation dispersion index (ODI) from Neurite Orientation Dispersion and Density Imaging (NODDI). A deep learning segmentation approach estimated the grey/white boundary (Billot et al., 2021, arXiv:2107.09559). MPM and dMRI measures were sampled from the CGM into the SWM at 0.5mm increments in regions of interest (Harvard‐Oxford cortical atlas). Tissue‐weighted (tw) averages were calculated for NDI and ODI. Metrics were visualized across the grey/white interface using boxplots.

Result

Figures 1‐2 show MPM and dMRI measures in the precuneus (dashed lines indicate group medians). Qualitatively, most tAD and PCA participants had lower R1 and R2* than controls, most prominently 0.5mm into the SWM (Figure 1). PD appeared higher in tAD and PCA patients across the grey/white interface. Qualitatively, most tAD and PCA participants had lower TF and higher MD in the CGM, where twNDI and FA appeared lower than controls across grey/white interface (Figure 2). Most tAD and PCA had qualitatively lower twODI in CGM and a flatter slope across the grey/white interface compared to controls.

Conclusion

Macromolecular (R1, R2* and twNDI) and iron content (R2*) MR measures at 7T appear reduced in tAD and PCA across the grey/white interface, whereas neurite organisational complexity (twODI) may become more homogeneous. Ongoing study will assess if these findings are consistent with further participants.
Altered BOLD Signal Fluctuations in precuneus relate to inflammatory markers and vascular risk in the AD spectrum
Authors: Maass Anne , Behrenbruch Niklas , Incesoy Enise I , Brosseron Frederic , Menze Inga , Bernal Jose , Hayek Dayana , Kleineidam Luca , Bürger Katharina , Fliessbach Klaus , Laske Christoph , Perneczky Robert , Peters Oliver , Priller Josef , Schneider Anja , Spottke Annika , Teipel Stefan , Wiltfang Jens , Wolfsgruber Steffen , Yakupov Renat , Wagner Michael , Jessen Frank , Duzel Emrah , Schreiber Stefanie , Heneka Michael T. , Ziegler Gabriel
Published: December 2023

Background

Inflammation, vascular disease and Alzheimer’s Disease (AD) appear to be closely linked. We recently showed that increased vascular risk relates to certain inflammatory profiles in CSF in the DELCODE cohort (Hayek et al, AAIC 2022). Moreover, we found cerebrovascular alterations in posterior‐midline regions including precuneus in subjects at risk for AD and with cognitive impairment relative to controls (Behrenbruch et al). Here, we examined the contributions of vascular risk and related inflammatory markers to alterations in resting‐state fMRI BOLD fluctuations that are sensitive to cerebrovascular reactivity (CVR)—a proposed marker of cerebrovascular dysfunction.

Method

Leveraging resting‐state fMRI BOLD signal, we mapped voxel‐wise relative CVR (rCVR), using mean global signal as regressor, and the relative coefficient of variation (rCV). See Figure 1 for methodological details. We derived average rCV/rCVR from the precuneus as region of interest. Inflammation‐related CSF markers and AD markers (ptau181 and Aß42/40) from CSF were available in 205 subjects with rCVR/rCV maps. A Principal component (PC) analysis on 16 inflammation‐related CSF markers previously revealed 4 PCs. PC2 and PC3 were related to higher vascular risk scores (covering hypertension, diabetes and abnormal fat metabolism based on medical reports). We used linear regression models to assess how inflammation PC scores and AD biomarkers related to precuneus rCVR or rCV (controlling for age, sex, site, education and mean framewise displacement). We also tested if rCVR/rCV was related to vascular risk or memory.

Result

Lower precuneus rCVR was predicted by higher values of the inflammatory component PC2 (mainly driven by markers CRP, C1q and FactorB), with no additional effect of other PCs or AD markers. Lower precuneus rCV was predicted by higher values of the inflammatory component PC3 (mainly driven by IP10, MCP1, MIF, CRP, C4) and by higher ptau. Lower precuneus rCVR was also related to higher vascular risk. Lower rCVR and rCV related to worse memory. Figure 2 shows supplementary correlations of individual inflammation markers.

Conclusion

Lower rCVR and rCV in the precuneus that are thought to reflect vascular dysfunction, relate to higher vascular‐risk related inflammatory markers beyond AD pathology. Their concurrent dynamics requires further investigation to understand their unique contributions to microvascular pathology.
Biological and methodological factors underlying a continuous amyloid CSF/PET imbalance model and its association with longitudinal cognition
Authors: Mastenbroek Sophie E , Sala Arianna , Gispert Juan Domingo , García David Vállez , Schmidt Mark E , Stephens Andrew W. , Gismondi Rossella , Farrar Gill , Frisoni Giovanni B , Boada Mercè , Ritchie Craig W , Visser Pieter Jelle , Bucci Marco , Hansson Oskar , Barkhof Frederik , Ossenkoppele Rik , Nordberg Agneta K , Rodriguez‐Vieitez Elena , Collij Lyduine E. ,   the AMYPAD consortium
Published: December 2023

Background

Discordance between cerebrospinal fluid (CSF) and positron emission tomography (PET) biomarkers of amyloid‐ß (Aß) occurs in up to 20% of individuals. Generally, Aß discordance is defined using binary cut‐offs. Given the methodological limitations of this approach, we propose a continuous Aß CSF/PET imbalance model. We investigated biological and methodological factors underlying discrepancy in these amyloid biomarkers and associations with longitudinal cognition.

Method

We included 383 non‐demented subjects (Nunimpaired = 326, Nmildly‐impaired = 57) from the AMYPAD‐PNHS cohort. Z‐scored CSF Aß42 and amyloid‐PET (Centiloids [CL]) units were fitted to a hyperbolic regression model by minimizing the Euclidian distance of the observed datapoints to the fitted line. Subject‐specific standardized residuals were derived as a measure of continuous imbalance (Zimbalance), with Zimbalance<0 reflecting greater Aß abnormality in CSF relative to PET and Zimbalance>0 greater Aß abnormality in PET relative to CSF (Figure‐1). Linear models adjusted for relevant covariates (Figure‐2) were run between Zimbalance and (1) methodological factors (CSF‐PET interval, CSF kit, PET tracer, and PET injected dose); (2) demographics (age, sex, education, APOE genotype) and CSF p‐tau biomarker; (3) vascular burden (white matter hyperintensities measured as Fazekas scores). Linear mixed models were used to investigate the predictive value of Zimbalance on longitudinal cognition in several domains.

Result

Sample characteristics are shown in Table‐1. Methodological factors were not significantly associated with Zimbalance. Increased CSF p‐tau levels were significantly associated with a higher Zimbalance (i.e. greater Aß abnormality in PET relative to CSF) (ß = 0.06±0.03, p = .033) (Figure‐2). In addition, a lower Zimbalance (i.e. greater Aß abnormality in CSF relative to PET) was associated with a higher Fazekas score (n = 189, ß = ‐0.55±0.26, p = .038) and predictive of faster cognitive decline on a language categorical fluency test (ß = ‐0.03±0.02, p = .038) (Figure‐2).

Conclusion

We found that methodological factors did not contribute to a continuous model of Aß CSF/PET imbalance, suggesting that this imbalance reflects distinct biological profiles. Indeed, continuous CSF/PET imbalance showed differential associations, with greater pathological levels of aggregated Aß relative to soluble Aß being related to increased CSF p‐tau levels and excess pathological levels of soluble Aß relative to aggregated Aß to increased white matter hyperintensities and steeper cognitive decline.
CSF Biomarkers and [18F]flutemetamol PET‐Derived Centiloids in Patients with SCD or MCI
Authors: Battle Mark R , Buckley Chris J , Farrar Gill , Janelidze Shorena , Palmqvist Sebastian , Ossenkoppele Rik , Smith Ruben , Hansson Oskar
Published: December 2023

Background

CSF biomarkers are well characterised as surrogate markers for amyloid deposition and neurofibrillary tau tangles reflecting pathological features of Alzheimer’s disease. Amyloid PET images provide a visual and quantitative assessment of brain amyloid burden. In diagnostic workup these biomarkers are considered interchangeable, however their relationship is not fully understood.

Method

Centiloid (CL) values for 387 [18F]flutemetamol images from the Swedish BioFINDER I study were derived following the methods of Klunk et.al. (Alzheimer’s & Dementia, 2015). Subjects, comprising Controls, SCD and MCI (Table 1), were ranked by Centiloid values (lowest to highest) and the average for each consecutive group of 30 subjects calculated. Corresponding CSF biomarker values (Aß42/40 and pTau181) were plotted for each group.

Result

Subjects in groups averaging ‐7.7 CL to 29.0 CL had a mean(±SD) Aß 42/40 ratio of 0.144 (±0.033, range 0.051 to 0.236, n = 240) with no statistically significant differences between groups (Fig. 1A). A statistically significant fall in CSF Aß42/40 ratio between the 29.0 CL and 47.3 CL groups (from 0.134 (+0.041, 0.066 to 0.236) to 0.088(+0.031, 0.045 to 0.183), p<0.0001) was observed. The average CSF Aß42/40 ratio value for all subjects ranging from 66.3 Cl to129.8 CL was 0.072 (±0.017, 0.030 to 0.127, n = 117) with no statistically significant difference in CSF levels across these CL bands. Subjects in the groups averaging ‐7.7 CL to 29.0 CL had a mean(±SD) pTau181 value of 48.9 pg/mL (±15.9, 22 to 138) with no statistically significant difference between groups (Fig. 1B). A statistically significant (p<0.05) increase between 29.0 CL (47.3±19.3, 24 to 116 pg/mL) and 47.3 CL groups (67.8±29.4, 24 to 175 pg/mL) was observed. For all Subjects from 66.3 CL to129.8 CL mean pTau181 levels were 79.6 (±30.3, 32 to 209 pg/mL) with no statistically significant difference across these CL bands.

Conclusion

Comparison of [18F]flutemetamol image quantitation and CSF biomarkers indicates CSF Aß42/40 and pTau181 starts to show amyloid positivity at approximately 30‐40 CL units. Recent comparisons between visual rating and Centiloids from PET imaging indicate visual positivity from approximately 20 CL units indicating sensitivity of amyloid PET imaging for the detection of early amyloid deposition.
Clinical and biomarker characteristics of amnestic MCI patients exhibiting a temporo‐limbic FDG‐PET pattern suggestive of LATE
Authors: Grothe Michel J. , Silva‐Rodríguez Jesús , Moscoso Alexis , Schöll Michael
Published: December 2023

Background

We have recently described a specific temporo‐limbic FDG‐PET signature that characterizes autopsy‐confirmed cases with limbic age‐related TDP‐43 encephalopathy (LATE), and have demonstrated its clinical utility for differential diagnosis of amnestic dementia patients. Here we assessed the utility of this pattern for patient stratification at a predementia disease stage, and further used tau‐PET data to study the degree to which this “LATE‐specific” FDG‐PET signature may correspond to a limbic‐predominant AD subtype.

Method

Individual FDG‐PET scans of 909 amnestic MCI (aMCI) patients from the ADNI cohort were screened for hypometabolic patterns being suggestive of LATE (sLATE) or typical AD (sAD) using automated pattern‐matching to autopsy‐confirmed pathology‐specific FDG‐PET signatures. sLATE and sAD patients were compared on clinical features, APOE4 genotype, and CSF biomarkers. Tau‐PET scans ([18F]Flortaucipir) were available in a smaller subsample (30%) and were analyzed for tau‐positivity using an FDA‐approved visual interpretation method as well as entorhinal SUVR (positivity‐threshold: SUVR = 2.1).

Result

734 aMCI patients showed evidence of significant regional hypometabolism, and of these 92 had a pronounced temporo‐limbic hypometabolic pattern classified as sLATE, whereas 68 had a classical temporo‐parietal pattern classified as sAD(Fig‐1). Compared to sAD, sLATE patients had similar MMSE and memory scores but more preserved executive function scores, and they showed generally slower cognitive decline over follow‐up (p<0.001)(Fig‐2). They were also significantly older (d = 0.83, p = 0.01), less often APOE4 carriers (39% vs 64%, p<0.001), and had less abnormal CSF Aß42 (d = 0.60, p = 0.001) and p‐tau181 levels (d = ‐0.40, p = 0.01). With regards to tau‐PET, 9/30 sLATE (30%) and 9/10 sAD (90%) patients were visually positive and similar proportions were seen for entorhinal SUVR (40% vs 90%).

Conclusion

The majority of amnestic MCI patients exhibiting a LATE‐typical temporo‐limbic FDG‐PET pattern show clinical and biomarker features that deviate from prodromal AD. A smaller subset of these patients shows elevated tau‐PET signal and could thus represent a limbic‐predominant AD subtype.
Association of FDG‐PET with co‐pathologies in autopsy‐proven AD
Authors: Chapleau Marianne , Mundada Nidhi , Spina Salvatore , Seeley William W. , Grinberg Lea T. , Schonhaut Daniel , Rosen Howard J. , Kramer Joel H. , Miller Bruce L , La Joie Renaud , Rabinovici Gil D.
Published: December 2023

Background

The presence of multiple pathologies is the rule and not the exception in Alzheimer’s disease (AD). The goal of this study was to assess whether 18F fluorodeoxyglucose (FDG) PET can provide information about the presence of non‐AD pathologies in autopsy‐proven AD patients.

Method

Our cohort included 55 patients with antemortem FDG‐PET and autopsy‐proven intermediate/high ADNC from the UCSF Neurodegenerative Diseases Brain Bank. All patients underwent FDG‐PET. Standardized uptake value ratio (SUVR) images were computed using the pons as reference region. W‐maps (adjusted Z‐score maps) were created, comparing each patient to a group of 187 controls (age range: 20‐96, 40% males). Voxel‐wise correlations were computed to verify the unique contribution of each neuropathology to cerebral hypometabolism, while controlling for age, sex, time between FDG‐PET scan and death, scanner type, Thal and Braak staging, and the presence of all other co‐pathologies. Associations between SUVR values in specific region of interests (ROIs) were also assessed. The ROIs included were the following: Landau AD ROI for AD pathology, Cingulate Island Sign (CIS) for Lewy body disease, Inferior/Medial Temporal Lobe (IMT) and IMT/Frontal Supraorbital (IMT/FSO) ratios for limbic‐predominant age‐related TDP43 encephalopathy neuropathologic change (LATE‐NC).

Result

Mean age was 63.8 ± 10.5, mean time between FDG and death was 6.2 ± 2.8, and mean MMSE was 21.1 ± 7.1 at the time of PET (Table 1). Group averaged W‐map showed the typical temporo‐parietal AD pattern; hypometabolism in these regions was associated with higher Thal phase and Braak stage (Figure 1). Lewy body disease (LBD), argyrophilic grain disease (AGD), aging‐related tau astrogliopathy (ARTAG), cerebral amyloid angiopathy (CAA) and vascular brain injury (VBI) were associated with hypometabolism in small discrete regional clusters (Figure 2). The Landau AD ROI was associated with both Thal (rs = ‐0.325, p = .015) and Braak stages (rs = ‐0.447, p<.001). The CIS sign was not associated with the presence of LBD (t(53) = 1.01, p = 0.319). Both the IMT (t(53) = ‐2.25, p = .028) and IMT/FSO (t(53) = ‐3.40, p = .001) ratios were associated with the presence of LATE‐NC.

Conclusion

Co‐pathologies make a relatively small contribution to hypometabolism in patients with intermediate‐high ADNC. Novel biomarkers are needed for precise detection of co‐pathologies.
Explainable AI and its instantiation in Computational Pathology for a better understanding of Alzheimer’s disease
Authors: Racoceanu Daniel
Published: December 2023

Background

EXplainable Artificial Intelligence (XAI) has an essential role to accelerate the AI adoption by empowering biomedical experts and catalyzing modern research through the emergence of a new generation of virtual actors, enabling traceable knowledge‐based quantification, as a guided qualification support. XAI instantiation is shown through our study, hypothesizing that rapid Alzheimer’s Disease (rAD) brains display subtle histological changes that would be undercovered by high‐throughput automated microscopic analysis. We study the topography and morphology of tau lesions’ aggregates to better understand the morphological substratum of Alzheimer’s Disease (AD) heterogeneity.

Method

To address this question at a large scale, we designed, tested and implemented a software for automatic segmentation, annotation and quantitation of brain lesions in histopathological whole slide images (WSI). A dataset of 15 whole slide images of postmortem human brain tissue is used in this study. These are fully annotated by neuropathologists yielding a set of more than 30,000 annotated plaques and tangle objects. A deep learning pipeline consisting of an attention‐UNet model with explainability features is trained for segmentation of tau aggregates in WSIs. The attention maps corresponding to segmentation predictions from the model are used by pathologists as a comparable reference to assist their decision making process.

Result

The DL‐based WSI analysis framework allows detecting a majority of the tau aggregates and refining tau aggregate boundaries with higher accuracy compared to manual annotations. Besides, with such a DL model based tau identification, the pathologist needs to annotate only a few samples for the DL model training. Overall, DL assisted analysis of tau aggregates could ease the effort of pathologists and facilitate analysis of hundreds of WSIs which are vital in AD research areas such as identifying different AD forms and AD patient stratification.

Conclusion

XAI is not only providing traceability by opening the way to an effective adoption, but also allows optimizing the ML/DL design, by keeping high performances. The green footprint is, therefore, considered, as well as the GDPR (European General Data Protection Regulation), towards Responsible Artificial Intelligence.