bluuebunny/crossref_metadata_2025 huggingface dataset:
Genomic atlas of human cerebrospinal fluid and brain metabolomics provides in‐depth understanding of cellular mechanism for neurodegeneration
Authors: Wang Ciyang , Western Daniel , Yang Chengran , Wang Lihua , Timsina Jigyasha , Ruiz Agustin , Pastor Pau , Fernandez Victoria , Sung Yun Ju , Cruchaga Carlos
Published: December 2023

Background

Brain metabolism is critical for the pathological mechanism of neurodegeneration. However, most metabolite quantitative trait loci (MQTL) studies have used tissues other than brain or cerebrospinal fluid (CSF) and are not ideal for neurodegeneration. We therefore pursued a large‐scale brain and CSF study to identify metabolites contributing to 27 brain‐related diseases.

Method

We obtained 440 metabolites in 2311 CSF samples and 962 metabolites in 1016 brain samples (WashU, ROSMAP, MAYO). We identified MQTL and performed metabolome‐wide association study (MWAS) to identify metabolites affecting diseases. Mendelian randomization (MR) and colocalization was performed for causality and shared genetic regulations.

Result

We identified 192 associations for 144 CSFmetabolites at 102 loci. Of those, 122 associations and 24 loci were novel, indicating tissue specificity. The brain study found 35 associations at 27 loci. Through MWAS, we identified 57 metabolites associated with 17 traits, in which 21 colocalized. Of the eight metabolites associated with AD, succinylcarnitine and adenine were causal. Succinylcarnitine was associated with AD risk gene LACTB, which product regulates lipid metabolism in mitochondrial, where succinylcarnitine generates energy. Both succinylcarnitine and LACTB have been implicated in obesity, a risk factor for AD. For Parkinson disease (PD), low galactosylglycerol level was causal, with signal colocalized at GALC with PD. The knockout of GALC gene prevented alpha‐synuclein accumulation in PD mice model, indicating that galactosylceramidase contributed to the development of PD. For cognitive performance, high levels of three metabolites (6‐oxopiperidine‐2‐carboxylate, 3‐hydroxyisobutyrate and argininosuccinate) were causal for low cognition, with additional support from colocalization and literature evidences. Pyridoxine‐dependent epilepsy patients, often with impaired cognition, had increased level of 6‐oxopiperidine‐2‐carboxylate. AD patients who underwent medium chain triglycerides treatment and improved cognition had changed level of beta‐hydroxybutyrate, related to 3‐hydroxyisobutyrate. Moreover, argininosuccinate lyase deficiency patients often develop severe cognitive impairment and seizures.

Conclusion

Our large‐scale CSF and brain MQTL study identified tissue‐specific MQTLs and multiple metabolites contributing to neurodegenerative disorders. Our results expand the knowledge on neurodegeneration, providing insights to neurodegeneration etiology, including AD, PD, and cognitive function.
Anticholinergic burden and cognitive impairment. Where do we stand?
Authors: García‐Lluch Gemma , Pardo Juan , García Hernán Ramos , Baquero Miguel , Peña‐Bautista Carmen , Cháfer‐Pericás Consuelo , Royo Lucrecia Moreno
Published: December 2023

Background

Polypharmacy is commonly observed among elderly patients and may increase the risk of anticholinergic burden, which is associated with frailty and cognitive impairment, among other side effects. As the long period association between anticholinergics and cognitive impairment remains under study, the present work aims to assess whether a significative anticholinergic burden is associated with cognitive impairment diagnosis.

Method

Patients between 50 and 80 years old were recruited at the Cognitive Disorders Unit from the Hospital Universitari I Politècnic La Fe of Valencia (Spain). Medical interviews, neurological examinations, neuropsychological tests, and CSF biomarkers were assessed to classify patients as Alzheimer’s Disease (AD) patients (based on the NIA‐AA criteria), other cognitive impairment (OCI) patients (when they had other cognitive impairments than AD), and controls (cognitively healthy patients without CSF biomarkers alteration). Pharmacological history was obtained throw medical history review and classified using the ATC/DDD classification (https://www.whocc.no/atc_ddd_index/). The CRIDECO Anticholinergic Burden Scale was applied to anticholinergic burden in all patients. A significant anticholinergic burden was considered when the overall punctuation was equal to or higher than 3 points. All the subjects signed the informed consent. This project was approved by an Ethics Committee (2020‐705‐1).

Result

An amount of 517 patients aged between 50 and 80 years participated in the present study. From them, 274 patients had AD, 192 were OCI, and 51 were control patients. Statistical differences were found between anticholinergic burden and diagnosis. The 24% of the cohort had a significant anticholinergic burden and were mainly AD and OCI patients. OCI patients had the highest rate of anticholinergic burden (29%), followed by AD patients (25%) and control patients (17%). Women showed a higher anticholinergic burden than men (p‐value <0.05). No differences were found between anticholinergic burden and CSF AD biomarkers.

Conclusion

Anticholinergic medication is more prescribed among patients with cognitive impairment, compared with control patients. As these drugs may promote the detrimental effects of anticholinergic burden on cognition, it is imperative to review the medications in patients at risk of dementia, especially women.
Modulation of cannabinoid receptor‐2 alters brain clearance of human tau
Authors: Joers Valerie L , Romero Julián , Hillard Cecilia , Tansey Malu Gámez
Published: December 2023

Background

Multiple studies have demonstrated a strong neuroinflammatory response in the presence of Tau pathology, which is strongly associated with the clinical symptoms and cognitive decline found in Alzheimer’s disease (AD). The correlation between AD progression and tau pathologies, rather than Ab accumulation, suggests that targeting pathological tau may be a more effective therapeutic approach. Microglia have been implicated in tauopathies as they may contribute to tau phosphorylation and aggregation and the uptake and spread of seed‐competent tau to healthy neurons due to dysfunctional degradation. Cannabinoid type 2 receptors (CB2) are highly expressed in immune cells and upregulated in activated microglia under conditions of neurologic disease, such as AD. The pharmacological modulation of CB2 have demonstrated a reduction in inflammation and plaque deposition, suggesting a role of CB2 on the immune system to influence AD‐related pathologies and phenotypes. However, there are limited findings on the CB2 regulation of tau accumulation.

Method

We have generated organotypic brain slice cultures from CB2‐EGFP/f/f mice and transduced with rAAV‐P301L/S320F‐human tau, which previously has shown to accumulate total tau and develop insoluble tau species. Slices were treated with CB2‐selective compounds and evaluated for tau pathology and microglial phenotypes using real‐time imaging and biochemical analyses.

Result

Previous investigation in our lab of a synucleinopathy animal model revealed the capacity of CB2 signaling to alter the function of immune cells and reduce accumulation of phosphorylated human alpha‐synuclein. Furthermore, we have determined that treatment with a CB2 inverse agonist will increase phagocytosis of pHrodo E. coli bioparticles in microglia BV2 cultures stimulated by LPS. Our preliminary work in brain slices over‐expressing mutant human tau show a trend toward reduced ratio of phosphorylated tau (Ser202/Thr205) to total tau in the soluble protein fraction (p = 0.0549) in slices treated with CB2 inverse agonist SR144528 compared to vehicle. We are repeating the experiment and performing further evaluations in organotypic brain slice cultures from CB2‐KO mice.

Conclusion

These studies will advance our understanding of the role of brain CB2 in pathologic tau removal and potentially highlight CB2 as a therapeutic target against tauopathies such as AD.
Sex differences in white matter bundle properties across menopausal transition states
Authors: Raikes Adam C. , Dyke Jonathan , Jett Steven , Williams Schantel , Pahlajani Silky , Brinton Roberta Diaz , Mosconi Lisa
Published: December 2023

Background

Women develop Alzheimer’s disease (AD) at a 2:1 rate compared to men. Changes associated with menopause exacerbate a midlife bioenergetic crisis that, when unsuccessfully resolved, leads to white matter degradation and ultimately brain atrophy. Understanding how white matter structural properties differ between sexes and evolve over midlife transitions may provide insight into the exacerbated AD risk for women. Here, we report differences in white matter bundle properties comparing pre‐ (n = 40, 44.1±3.34y), peri‐ (n = 60, 49.6±3.90y), and post‐menopausal women (n = 70, 56.0±4.12y) to age‐matched males.

Method

Diffusion weighted MRI was acquired for each participant. Data were preprocessed with QSIPrep and analyzed using a fixel‐based approach implemented in MRtrix (v. 3.0.3). Fiber density (FD), cross‐section (FC), and a combined density/cross‐section metric (FDC) were compared between sexes after controlling for age, education, APOE ε4 carrier status, and total brain volume (FC and FDC only). Continuous covariates were standardized to 2 standard deviations. Analyses were conducted using connectivity‐enhanced fixel‐based permutation analyses and thresholded at family‐wise error corrected p<0.05.

Result

Pre‐, peri‐, and post‐ menopausal women exhibited greater FD and FDC in the corpus callosum, inferior occipto‐frontal fasciculus, cortico‐spinal, and cingulum bundles. By contrast, males had greater fiber cross section in the splenium of the corpus callosum (compared to pre‐), (compared to peri‐), and in fibers near the left uncinate fasciculus and inferior longitudinal fasciculus (compared to both peri‐ and post‐menopausal women). After controlling for age, education, total brain volume, and APOE ε4 carrier status, a smaller cluster of fibers in the left splenium survived multiple comparisons correction demonstrating greater fiber cross‐section in post‐menopausal women compared to peri‐menopausal women.

Conclusion

Women across menopausal transition states exhibited greater fiber density than their age‐matched male counterparts in commissural and association tracts, which agrees with previous work demonstrating stronger inter‐hemispheric connections in women. However, peri‐ and post‐menopausal females exhibited 4‐8% decrease in fiber cross section in uncinate fasciculus fibers, which have been implicated in Alzheimer’s related cognitive decline. These findings suggest that reductions in white matter cross‐section, particularly in regions associated with Alzheimer’s disease, may begin for women in menopause and be an early indicator of neurodegenerative risk.
Longitudinal Trajectories of Normal versus Abnormal Cognitive Aging in the SIU Longitudinal Cognitive Aging Study as measured by the original Alzheimer’s disease Assessment Scale and a novel extended version
Authors: Trivedi Mehul Alkesh , Botchway Albert , Scaife Steven , McGinity Sean , Porter Nicholas , Zec Ronald F , Ala Thomas A , Hascup Erin R.
Published: December 2023

Background

The original Alzheimer’s disease Assessment Scale‐cognitive subscale (oADAS) is a common measure of cognition used in Alzheimer’s disease (AD) clinical trials. The oADAS may not be sensitive to pre‐dementia syndromes such as mild cognitive impairment (MCI), possibly due to ceiling effects for many of the subtests. However, little is known about the trajectories of cognitive aging on the oADAS in cognitively‐normal individuals who decline over time. We used Linear Mixed Effects Modeling to examine trajectories of cognitive aging on the oADAS, a novel extended version (eADAS), and the MMSE. We hypothesized that, compared to non‐decliners, individuals who declined from normal to MCI and/or AD (decliners) would demonstrate increased error scores on the ADAS and lower scores on the MMSE over time.

Methods

We included data from 608 older adults (72% female, mean age = 69.0 years) who were enrolled in SIU Longitudinal Cognitive Aging Study (LCAS). Total years of educational attainment ranged from 8‐26 years. The vast majority of the participants were White/Not‐Hispanic. There were 50 decliners and 558 non‐decliners included in the present analysis. The eADAS included short‐delay recall/recognition trials for the first word list, a short‐delay true‐false word recognition trial for the second word list, a letter‐digit d psychomotor test, supermarket fluency, spontaneous clock drawing, three additional items to the object naming subtest, three additional figure copies, and a similarities test. All analyses were completed after controlling for gender, education, age at first visit, time between visits, and number of visits.

Results

There was no significant difference between the groups for age at first visit. Greater age at first visit and lower education were associated with increased error scores for both ADAS versions and MMSE in the decliner group (p’s <0.001). There was no significant effect of the number of days between visits. The mean coefficients for the change in error score over time between visits for the oADAS, eADAS, and MMSE was 2.84, 10.30, and ‐1.09, respectively.

Conclusion

Our results indicate that the oADAS and eADAS are useful measures for examining trajectories of cognitive decline in cognitively‐normal individuals at increased risk for AD.
Morphometric Differences in Hippocampal Shape Across the Alzheimer’s Disease Spectrum
Authors: Madi Kedar V , Kawas Mohammad I , Lockhart Samuel N. , Barcus Richard A. , Hudson Jeremy Patton , Bateman James R. , Craft Suzanne , Wolfe Stacey Q , Whitlow Christopher T
Published: December 2023

Background

Prior studies have demonstrated that shape analysis of the hippocampus may provide a more accurate prognostic prediction of cognitive decline than simply volume. Here we deploy a novel automated pipeline for hippocampal morphometry to elucidate the surface regions sensitive to shape change along the AD spectrum.

Methods

Hippocampal volumes were segmented from 186 T1 images obtained from the Wake Forest Alzheimer’s Disease Research Center (ADRC) Clinical Core cohort including cognitively normal (CN, n = 62, mean age = 72.1, males = 29), mild cognitive impairment (MCI, n = 62, mean age = 73.2, males = 29), and dementia participants (DEM, n = 62, mean age = 73.4, males = 28). All chosen participants were matched for age, sex, and education. Correspondent surface meshes of each hippocampus were generated via spherical harmonics (SPHARM‐PDM) in SlicerSALT. Hippocampal mesh models were incorporated into a Multivariate Functional Shape Data Analysis (MFSDA), a linear model paradigm that builds associations between shape measurements, demographic information, and other clinical variables to determine if there exists a statistically significant morphological difference caused by variables of interest. Results were mapped onto a template hippocampus to visualize surface regions significantly associated with cognitive diagnosis. Adjudication of cognitive diagnosis by expert panel consensus occurred in accordance with NIA‐AA guidelines.

Results

Figure 1 displays surface regions of left hippocampus that significantly differed between DEM and CN participants. Figure 2 displays surface regions of left hippocampus that significantly differed between MCI and CN participants. Significant regions (p ≤ 0.05) are yellow‐red, while non‐significant regions (p > 0.05) are blue. Similar results were observed in right hippocampus (not shown).

Conclusion

Shape differences between DEM and CN subjects are significant across the majority of the hippocampal surface, while shape differences between MCI and CN subjects appear significant primarily at the posterior portions of CA1/CA3 and prosubiculum subregions, suggesting these particular regions may be vulnerable to atrophic shape change during the early stages of AD, consistent with previous findings.
High expression of Alzheimer’s disease‐related metabolic brain pattern is predictive of conversion to mild cognitive impairment or dementia and faster cognitive decline
Authors: Perovnik Matej , Jamšek Jan , Trošt Maja ,   Alzheimer’s Disease Neuroimaging Initiative
Published: December 2023

Background

Alzheimer’s disease‐related pattern (ADRP) is a metabolic brain biomarker of Alzheimer’s disease (AD), which was previously identified and validated. Its utility for differential diagnosis is known. Here, we aimed to explore its predictive value for conversion from cognitively normal (CN) to mild cognitive impairment (MCI), from MCI to dementia and for the rate of cognitive decline.

Methods

We analysed 609 participants followed for up to 15 years and their FDG PET scans from ADNI database (CN = 133, MCI = 352, dementia due to AD = 124) and 56 participants from University Medical centre Ljubljana (MCI = 22, AD = 34). ADRP expression was calculated from pre‐processed FDG PET scans. CN and MCI participants were stratified according to their conversion status and cerebrospinal fluid biomarkers. Amyloid positivity (A+) was defined as Aβ42 < 880 pg/mL and tau positivity (T+) as pTau > 21.8 pg/mL. AD patients were stratified into slow (< 2 points/per year decline on mini mental state examination (MMSE)) and fast (> 2 points/per year decline on MMSE) progressors.

Results

A+T+ cCN had higher baseline ADRP expression than A–T– (p<0.001), A+T– (p = 0.003) and A+T+ (p = 0.01) stable CN corrected for age, while the groups did not differ in gender, education or baseline MMSE scores. A+T+ cMCI had higher baseline ADRP expression than A–T– (p<0.001), A+T– (p = 0.001) and A+T+ (p<0.001) stable MCI, corrected for baseline age and MMSE. A+T– stable MCI had higher baseline ADRP expression than A–T– stable MCI (p = 0.02). ADRP was a predictor of conversion to dementia in survival analysis (HR = 4.5[2.4‐8.7]). Similarly, in the UMCL dataset A+T+ cMCI had higher baseline ADRP expression than A–T– stable MCI (p = 0.03). Fast progressing AD patients had higher baseline ADRP expression than slowly progressing AD patients (p<0.001). Similarly, in the UMCL dataset fast progressing AD patients had higher baseline ADRP expression than slowly progressing AD patients (p = 0.02). In neither dataset, AD groups differed in age, sex or baseline MMSE scores.

Conclusion

ADRP expression levels can be used to predict conversion from CN to MCI and from MCI to dementia in A+T+ individuals. AD patients with high ADRP expression are at an elevated risk for faster progression of cognitive decline.
Examining Complex Relationships among Cerebrovascular, β‐Amyloid, Tau and Cognitive Measures in a Cognitively Unimpaired Late‐Middle Aged Sample
Authors: Du Lianlian , Jonaitis Erin M. , Betthauser Tobey J , Cody Karly Alex , Burghy Cory , Rivera‐Rivera Leonardo A. , Mueller Kimberly D , Chin Nathaniel A. , Hermann Bruce P , Johnson Sterling C , Langhough Rebecca E
Published: December 2023

Background

Recent research linking vascular risk with promotion of tau pathology in the inferior temporal cortex (ITC) suggests a potential mechanism connecting cerebrovascular risk to AD pathology and cognitive decline among cognitively unimpaired (CU) individuals (Yau et al, 2022).We used MRI White Matter Hyperintensity (WMH), a neuroimaging marker of chronic cerebral small‐vessel disease/cerebrovascular disease, to further elucidate longitudinal relationships between cerebrovascular risk, PET AD pathological burden, and cognition.

Method

We examined baseline CU late middle‐aged adults from the University of Wisconsin’s Alzheimer’s disease research cohorts. β‐Amyloid burden was measured with 11C‐Pittsburgh compound B (“PiB”; DVR derived from a 0‐70 min dynamic PET scan; PET A+ threshold∼1.16 DVR/∼CL 17). Cerebrovascular risk was quantified using WMH volumes (T2‐FLAIR images; SPM Lesion Segmentation Tool). Tau burden was measured with florquinitau PET (MK6240 SUVR from 70‐90 min post‐injection). Tau outcomes included bilateral volume‐weighted averages for ITC, Medial temporal lobe (MTL) and Meta‐temporal (MTC) composites. Biomarker values were z‐transformed relative to CU/PET A‐ values. Random intercept models examined interactive effects of baseline WMH and Aβ levels on longitudinal tau (covarying baseline tau age, sex, APOE ε4 count). We modeled time two ways: years since baseline PiB (TimePiB1; replicating Yau, et al models); and, in parallel models, amyloid duration (years) at tau scans was substituted for years since PiB1 in the A+ subset (TimePiB1/PiB+). We also used LME to examine Aβ, WMH, and time interactions in longitudinal cognition (PACC3 and Digit Symbol Substitution).

Result

The mean(SD) tau baseline age was 67.9(6.8) years (sample details in Table1). The most parsimonious models using TimePiB1 included WMH*Aβ*Time for ITC and MTC and WMH*Aβ for MTL. Patterns showed a synergistic effect of WMH and Aβ on tau accumulation that was attenuated using TimePiB1/PiB+ where the most parsimonious models included Aβ_status*TimePiB1/PiB+ (ITC, MTC) or WMH*Aβ_status*TimePiB1/PiB+ (MTL; Figure1). AICc model fits were substantially better using TimePiB1/PiB+. Both Aβ and WMH contributed to cognitive trajectories (Figure2).

Conclusion

Although cerebrovascular risk’s apparent contribution to tau accumulation varied depending on how time was modeled, results suggest that cerebrovascular risk may complement imaging biomarkers in assessing risk of tau accumulation and cognitive decline in preclinical Alzheimer disease.
The Influence of White Matter Lesion Volume on Hippocampal Shape in Patients Along the Alzheimer’s Disease Continuum
Authors: Kawas Mohammad I , Madi Kedar V , Lockhart Samuel N. , Hudson Jeremy Patton , Barcus Richard A. , Bateman James R. , Craft Suzanne , Wolfe Stacey Q , Whitlow Christopher T.
Published: December 2023

Background

Alzheimer’s Disease (AD) is a progressive neurocognitive disorder with irreversible hippocampal atrophy and degradation of cognitive function. Hippocampal atrophy can be assessed by volume and shape changes on MRI, and hippocampal volume is a sensitive marker for AD diagnosis and progression; however, it does not reflect regional changes within the hippocampus. Interest in shape analysis of the hippocampus is growing, as it provides more detailed assessment of morphological changes that highlight regional atrophic differences. Cerebral small vessel disease (CSVD) burden quantified as white matter lesion volume from MRI is strongly associated with hippocampal volume loss in AD and mild cognitive impairment (MCI). Our goal was to examine relationships between hippocampal morphometric features and white matter hyperintensity (WMH) volume, a measure of CSVD burden, across the AD continuum.

Method

We analyzed baseline data from 186 participants from the Wake Forest Alzheimer’s Disease Research Center (ADRC) Clinical Core cohort whose cognitive diagnosis was adjudicated by an expert panel in accordance with NIA‐AA guidelines (without reference to AD biomarkers). Participants ranged from cognitively normal (CN) (n = 62, 72±8y), to MCI (n = 62, 73±7y), and dementia (n = 62, 73±9y). We focused on the left hippocampus and used T1‐weighted images from 3T brain MRI to generate left hippocampal segmentations and total intracranial volume estimates. Total WMH volume was estimated from FLAIR images using the lesion segmentation toolbox for SPM, it was then normalized to intracranial volume and log transformed to address skewness. Hippocampal shape analysis was performed using SlicerSALT, and a multivariate linear model was implemented to relate WMH volume to hippocampal shape features while adjusting for diagnosis, age, sex, and years of education.

Result

On the superior aspect of the hippocampus, greater WMH volume was associated with more surface contraction of the anterior portions of the CA1, CA2, CA3 and subiculum as shown in Figure 1A. Similar effects were seen on the inferior aspect as shown in Figure 1B.

Conclusion

These finding suggest that higher WMH volume is associated with selective hippocampal subfield degeneration in the anterior portions of the hippocampus which may be more vulnerable to CSVD buildup.
A Conceptual Framework of Data Readiness for the Health and Aging Brain Study‐Health Disparities
Authors: Zhang Fan , Petersen Melissa , Johnson Leigh , Hall James , O'Bryant Sid E.
Published: December 2023

Background

The Health and Aging Brain Study: Health Disparities (HABS‐HD) seeks to understand the biological, social and environmental factors that impact brain aging among diverse communities. HABS‐HD, like many other NIH funded data‐sharing projects, has important data assets for various uses, including social, environmental and behavioral data, and multiple data flow pathways. Machine learning (ML) develops algorithms and models to continuously improve itself over time, but the determination of data quality and its readiness are needed for these models to operate efficiently. Therefore, developing a data readiness reporting methodology has become a very urgent task for HABS‐HD.

Method

In this study, we developed a conceptual framework of data readiness. First, we analyzed the missing data percentage and used ML‐Based Multiple Imputation (MLMI) for missing data imputation. Then, we performed SVM based on Recursive Feature Elimination and Cross Validation (SVM‐RFE‐CV) for feature elimination and outlier removal. Lastly, we rated the data readiness based on the three metrics: missing data percentage, performance before feature engineering, and performance after feature engineering to rate data readiness. All the three scores were averaged to rate the overall readiness of data.

Result

A framework for calculating overall average score for readiness of data was presented (1 stands for completely accessible, 0 for not accessible at all, and 0.5 for neutral). Our results show that the framework of data readiness was straightforward and useful in assessing how ready the HABS‐HD data is for ML.

Conclusion

The systematic analysis of readiness of data before building ML models is of utmost importance. And it has a significant impact on biomarker discovery and disease prediction application for Alzheimer’s disease. The conceptual framework of data readiness works well for our Alzheimer’s disease models in HABS‐HD. It can also be applied to other disease data readiness reporting.
Genetic ancestry of human induced pluripotent stem cells banked for neurodegeneration research
Authors: Nudelman Kelly N. H. , Jackson Trever , Ohlemacher Sarah K , White Nicholas RM , O’Neil Olga , Sullen Katharina , Johnson Randal D. , Kirch Vera A. , Schwantes‐An Tae‐Hwi , Abreu Marco , Marshall Jeanine D. , Faber Kelley M. , Mitchell Colleen M. , Edler Michael C. , Meyer Jason S. , Foroud Tatiana M.
Published: December 2023

Background

The National Centralized Repository for Alzheimer’s Disease and Related Dementias (NCRAD) has established a centralized repository for human induced pluripotent stem cells (iPSCs) and fibroblasts in partnership with the National Institute on Aging (NIA). This is a critical resource for the research community, which can facilitate disease modeling, functional genetic studies, and drug development. However, the utility of this resource is still limited in terms of racial and ethnic diversity, which has the potential to bias neurodegenerative research and drug development unless steps are taken to create and share a more diverse array of cell lines.

Method

At NCRAD, banked iPSCs are subjected to quality control including short‐read whole genome sequencing (WGS). 78 samples have been submitted for sequencing; of these, data for 51 have been returned and analyzed, including multiple isogenic lines from three donors. WGS data was aligned, and quality control performed using Sentieon software, following GATK best practices. Data was combined with sequencing data from 2,548 1000 Genomes participants and pruned in PLINK. R package SNPRelate was used to generate a kinship matrix and perform principal component analysis (PCA). Clustering analysis was performed utilizing K‐means clustering to group samples into 5 clusters. PCs 1‐3 were graphed, color‐coded by cluster, and final ancestry calls reviewed for clustering with reference groups.

Result

The NCRAD 51 iPSC lines with analyzed WGS data were sourced from 28 neurodegenerative cases and 12 controls. In this data set, 83% of samples (89% of cases, 67% of controls) have European ancestry. The cohort also includes one case and one control line of East Asian ancestry, as well as 2 cases and 3 controls showing admixture of European/American ancestry. 17 individuals did not have reported race/ethnicity, while 2 controls showed genetic admixture though reported as White non‐Hispanic, and the remaining individuals’ genetic ancestry matched reported race/ethnicity.

Conclusion

Centralized banking of iPSCs from individuals with neurodegenerative diseases is creating a key resource to advance research; however, to date the diversity of these samples is limited. We urge researchers to develop and share more diverse cell lines, to promote diversity and equity in neurodegenerative research.
“Taxes, death, and trouble”: Role of structural socioeconomic racism on cognitive function for persons racialized as Black
Authors: Adkins‐Jackson Paris AJ , Kim Boeun , Avila Justina F , Higgins Cesar , Bailey Zinzi D , Ford Tiffany N , Hyun Jinshil , Belsky Daniel W , Seblova Dominika , Turney Indira C , Hill‐Jarrett Tanisha G , Okoye Safiyyah M. , Hardeman Rachel R , Matz Meies‐Amor Blagburn , Gee Gilbert , Szanton Sarah L , Manly Jennifer J.
Published: December 2023

Background

Structural racism has concentrated Americans racialized as Black in under‐resourced and disinvested neighborhoods. These same Americans experience higher rates of Alzheimer’s disease and related dementias (ADRD). Differences in socioeconomic opportunities structured by racism is a potential contributor to ADRD disparities. To investigate this hypothesis, we tested how life‐course exposure to area‐level measures of structural racism relate to late‐life cognitive test performance.

Method

We computed the Black‐White disparity in land ownership and value, residential and occupational segregation, and income, employment, and poverty at the county‐level using US Census data from 1930‐2010. We aggregated these data to the state‐level then created four unidimensional measures by life‐course period (Before‐Birth 1930‐50, Childhood 1960‐70, Adulthood 1980‐2000, Midlife 2010). We linked state‐ and life‐course‐period‐level data with individual‐level demographic and cognitive data from the US Health and Retirement Study. We included participants racialized as Black and born 1954‐59 (N = 1,172). We measured cognitive performance from repeated measures of the 27‐item global cognitive score from the modified Telephone Interview for Cognitive Status during 2010‐18 (average follow up of 4.1 years). Mixed effects models were used to test associations of life‐course‐period‐specific state‐level structural socioeconomic racism and cognitive change. Covariates were age, gender, education, Living arrangement, and year of death.

Result

Participants racialized as Black who lived in places with higher levels of area‐level structural socioeconomic racism experienced lower levels of cognition at baseline and at varying time points in the six‐year period—compared to those in places with lower structural socioeconomic racism. The effects of the life‐course‐period‐specific state‐level structural socioeconomic racism exposure on the slope were in the expected direction but not statistically different from zero (‐.02, SE 0.25, ‐.51, 4.7).

Conclusion

Among participants racialized as Black in the HRS born during 1954‐59, effects of exposure to state‐level structural racism varied according to life course period of exposure. These findings reveal the utility of examining the impact of racist U.S. policies enacted in the past and present that influence health over time. In addition to exploring the epigenetic and in utero exposures that may contribute to ADRD risk later in life.
Microglial Activation Contributes to Neuropsychiatric Dysfunction in Alzheimer’s Disease
Authors: Aguzzoli Cristiano Schaffer , Ferreira Pamela C.L. , Povala Guilherme , Soares Carolina , Ferrari‐Souza João Pedro , Bellaver Bruna , Zalzale Hussein , Lussier Firoza Z , Rohden Francieli , Abbas Sarah , Lemaire Peter Charles , Leffa Douglas Teixeira , Cabrera Arlec , Therriault Joseph , Benedet Andrea Lessa , Tissot Cécile , Servaes Stijn , Macedo Arthur C. , Vermeiren Marie , Bezgin Gleb , Kang Min Su , Stevenson Jenna , Rahmouni Nesrine , Pallen Vanessa , Cohen Annie , Lopez Oscar L. , Tudorascu Dana , Klunk William E , Villemagne Victor L , Poltronetti Nina Margherita , Soucy Jean‐Paul , Wang Yi‐Ting , Gauthier Serge , Souza Diogo O. , Ashton Nicholas J. , Schilling Lucas Porcello , Karikari Thomas K , Blennow Kaj , Zetterberg Henrik , Zimmer Eduardo R , Rosa‐Neto Pedro , Pascoal Tharick A.
Published: December 2023

Background

Previous studies have shown that microglial activation (MA) plays a key role in the pathophysiological and clinical progressions of Alzheimer’s disease (AD). However, little is known whether MA is also associated with the development of neuropsychiatric symptoms typically found in patients with AD. Thus, we aim to investigate here the association of MA with neuropsychiatric symptoms (NPS) of individuals across the AD continuum.

Method

We assessed 132 individuals (86 cognitively unimpaired (CU), 28 MCI, and 18 AD dementia) from the TRIAD cohort who underwent clinical assessments with the Neuropsychiatry Inventory Questionnaire (NPI‐Q), and had positron emission tomography (PET) for amyloid‐β (Aβ) ([18F]AZD4694), tau tangles ([18F]MK6240) and MA ([11C]PBR28) at the same visit. Regions were tailored using Desikan‐Killiany (DK) atlas. SUVRs were calculated using the cerebellum gray matter as a reference. Linear regression tested the association between biomarkers accounting for age, sex, and cognitive status.

Result

NPI‐Q total score was significantly associated with [11C]PBR28 in the cingulate, inferior temporal, and precuneus accounting for age, sex, and after false discovery rate (FDR) correction for multiple comparisons (Figures 1A, 1B, 1C). This association was independent of Aβ and tau levels (Table 1). Notably, MA predicted neuropsychiatric dysfunction with higher magnitude than Aß or tau using PET values from overlap region (regional SUVR) and if we use a global measure for all tracers (global SUVR) (Figure 2A). When we stratify NPI‐Q domains (agitation, irritability, motor disturbance, disinhibition, elation, delusion, hallucinations, nighttime disturbance, depression, anxiety, apathy, and appetite disturbance) severity score, we found that the hyperactivity subdomain (agitation, irritability, motor disturbance, disinhibition, and elation) showed the larger contribution to the results (Figure 2B).

Conclusion

Our results suggest MA as a key element associated with neuropsychiatric dysfunction in AD independent of Aβ and tau pathologies. These findings provide additional rationale for the therapeutics targeting glial cells activation in AD patients.
Multi‐ethnic genome‐wide, gene‐based study identifies genes that interact with vascular risk factors in Alzheimer’s Disease (AD)
Authors: Lee Annie J , Reyes‐Dumeyer Dolly , De Jager Philip L , Bennett David A. A , Schneider Julie A , Menon Vilas , Wang Yanling , Lantigua Rafael A. , Medrano Martin , Mejia Diones Rivera , Jiménez‐Velázquez Ivonne Z. , Kukull Walter A. , Brickman Adam M. , Manly Jennifer J. , Tosto Giuseppe , Kizil Caghan , Farrer Lindsay A. , Mez Jesse B. , Chung Jaeyoon , Vardarajan Badri N , Mayeux Richard
Published: December 2023

Background

Cardiovascular risk factors (CVRFs) increase the risk of cerebrovascular disease and AD, and over 30% of the patients with AD coincident cerebrovascular pathology. We previously found that FMNL2 interacts with CVRFs (p = 6.6e‐07) by altering the normal astroglial‐vascular mechanisms that underly amyloid clearance. The goal here was to identify additional genes that contribute to the interaction between CVRFs and AD.

Method

A collection of eight multi‐ethnic cohorts was explored to study genome‐wide gene‐CVRF score interaction analysis for AD, in 7,441 AD patients and 10,453 controls. The cardiovascular risk factors score (CVRF score) was created from a first principal component of the four vascular risk factors; self‐reported history of hypertension, diabetes, and heart disease, and measured body mass index. Gene‐based interaction test was performed using the adaptive gene‐environment interaction (aGE) test. Results were summarized using a meta‐analysis. We investigated the association of gene expression with pathological AD and AD phenotype (amyloid‐β, tau, or brain infarcts) in 1,092 samples from the frontal cortex in ROSMAP. The pathway enrichment analysis was performed on the differentially expressed genes. Age and sex were adjusted in the models.

Result

The previous interaction of CVRF score with FMNL2 (p = 3.64e‐07) was strengthened and additional genes were identified including BRINP1 (p = 2.45e‐06), CFAP99 (p = 3.3e‐06), and PRG3 (p = 3.71e‐06). FMNL2 encodes a formin‐related protein important in regulating actin and microtubules. FMNL2 and BRINP1 expressions were higher in the brains of patients with brain infarcts (p = 0.025 and p = 0.006, respectively). The expression level of BRINP1 interacted with brain infarcts on pathological AD (p = 0.02) and with amyloid‐β or tau on brain infarcts (p = 0.02 and p = 0.01, respectively). The pathways were relevant to cellular interactions between astrocytes and endothelia as well as the immune system reaction in the glio‐vascular niche.

Conclusion

The four novel genes are likely to be involved in the complex interaction between Alzheimer’s disease pathologies (amyloid and phosphorylated tau deposition) and cerebrovascular pathology, for example, at the glia‐vascular interface during AD progression. Understanding how these genes interfere with the mechanisms underlying the clearance of amyloid and tau increasing their deposition in brain will be essential.
MK‐6240 tau‐PET in an Aβ‐enriched sample from the 1946 British birth cohort
Authors: Coath William , Markiewicz Pawel J , Modat Marc , Scott Catherine J , Malone Ian B , Arstad Erik , Awais Ramla , Sander Kerstin , Weston Philip SJ , Thomas David L , Dickson John , Schöll Michael , Ourselin Sebastien , Richards Marcus , Fox Nick C , Cash David M , Schott Jonathan M
Published: December 2023

Background

We investigated imaging biomarkers of Aβ and neurodegeneration in relation to tau‐PET Braak stage in a preclinical birth cohort.

Method

Cognitively normal individuals enrolled in Insight 46, the neuroimaging sub‐study of the MRC National Survey of Health and Development (1946 British birth cohort), were scanned on combined PET/MR with [18F]florbetapir Aβ‐PET at age ∼70 years and again at ∼73 years. A sub‐sample enriched for Aβ (Aβ+; Centiloid> = 13, hole cerebellum reference) is currently being assessed with [18F]MK‐6240 tau‐PET at age ∼76 years. For this interim analysis, tau‐PET images (90‐110 minutes post‐injection) were co‐registered with T1‐weighted MRI. Anatomical areas were parcellated on the T1 to form Braak regions. Standard uptake value ratios (SUVRs) were calculated using an inferior cerebellar grey reference without partial volume correction. Tau‐PET positivity (Tau+) was defined using Gaussian mixture modelling in each region. Participants were assigned to Tau‐, Braak I‐II, III‐IV or V‐VI groups based on the most advanced Tau+ region. Group differences in baseline Aβ (Centiloids), Aβ accumulation (Centiloids/year) and hippocampal atrophy rate (%/year) were investigated with Mann‐Whitney U tests.

Result

Analysis included 80 individuals with tau‐PET data (Table 1), 45% of the sample were Aβ+ by age 73. Three individuals did not conform to the Braak stage hierarchy (orange triangles, Figure 1). No Aβ‐ individuals were Tau+ beyond Braak I. Figure 2 shows baseline Aβ, Aβ accumulation and hippocampal atrophy rates for Braak stage groups for participants who had data at all timepoints (N = 78). Tau+ individuals (in any Braak region) had significantly higher baseline Aβ than Tau‐ individuals. Rate of annual Aβ accumulation was higher for Braak III‐IV and Braak V‐VI compared to Tau‐ individuals. Hippocampal atrophy rate was elevated for Braak V‐VI compared to Tau‐, and Braak III‐IV was borderline significant.

Conclusion

In this preliminary analysis, tau‐PET positivity beyond Braak I was restricted to individuals who were Aβ+ three years prior. Participants with elevated tau aged 76 had increased Aβ at age 70. Increased rates of hippocampal atrophy were occurring at least three years prior to tau scanning in individuals with advanced tau pathology. These findings will be updated as more data is acquired.
Lower LC activity during high arousal conditions is related to greater plasma P‐Tau217 concentration in older individuals
Authors: Prokopiou Prokopis C. , Van Egroo Maxime , Riphagen Joost M. , Ashton Nicholas J. , Janelidze Shorena , Sperling Reisa A. , Johnson Keith A. , Blennow Kaj , Hansson Oskar , Zetterberg Henrik , Jacobs Heidi I.L.
Published: December 2023

Background

The noradrenergic locus coeruleus (LC) nucleus is critical in regulating many brain functions and processes, including arousal and emotion. Autopsy studies suggested that the LC is one of the earliest regions harboring hyperphosphorylated tau. Previous imaging work demonstrated that lower novelty‐related LC activity correlates with tau deposition in the entorhinal cortex. Here, we investigated the variability in activity across the rostro‐caudal LC under different arousal levels and its relationship with plasma markers of phosphorylated tau, including p‐tau231, p‐tau217, and p‐tau181.

Method

61 individuals (age range = [51,85], Male = 30) underwent a task‐based 7T BOLD‐fMRI scan and fasting blood draw. The task consisted of 100 high‐ or low‐arousing context images. The fMRI data were preprocessed using a brainstem‐specific denoising methodology to increase the LC signal‐to‐noise ratio. P‐tau181 and p‐tau231 were measured using in‐house Simoa methods, and p‐tau217 using MSD immunoassay. Voxel‐wise linear model analyses were performed to detect brainstem regions exhibiting significant high>low arousal (h>l) activation. Average h>l contrast values across activated voxels within an ex‐vivo validated LC region of interest (ROI) were extracted, and age‐ and sex‐adjusted associations between LC activity and p‐tau were evaluated using robust linear regression. Similar associations were also investigated for a control ROI defined ventral to the LC.

Result

We observed greater h>l activation of voxels in the bilateral LC (p<0.05 uncorrected–Fig.1A). We observed no regional differences in h>l activity along the LC rostral‐caudal axis (Fig.1B). Post‐hoc Mann‐Kendall trend analyses revealed a negative‐to‐positive trend in h>l LC activity across caudal‐to‐rostral LC. Lower h>l LC activity was associated with greater p‐tau217 (p = 0.042–Fig.2A). No significant associations were observed between h>l LC activity and either p‐tau231 or p‐tau181 (p>0.05–Fig.2B‐C), or between h>l activity in the control ROI and any plasma marker (p>0.05–Fig.2D‐F).

Conclusion

Our results show that lower h>l LC activation is associated with greater concentrations in p‐tau217. As p‐tau217 has been shown to correlate with LC neuronal loss, cortical tau‐ and amyloid‐β‐PET measures, our results suggest that LC dysfunction in higher states of arousal may signal LC degeneration. Future work includes investigating the mediating role of amyloid‐β on the observed relationship between h>l LC activation and p‐tau217.
Systematic Comparison of Reproducibility of Diffusion MRI‐Derived Free‐Water Measures Across Two Multi‐Shell Protocols
Authors: Mishra Virendra R , Sreenivasan Karthik , Cordes Dietmar
Published: December 2023

Background

Free‐water (FW) measures have been widely used to understand and predict the progression of various neurodegenerative disorders1,2. However, the estimation of FW in a brain voxel needs a multi‐shell acquisition to ensure reproducible fit3,4. With the availability of multi‐shell diffusion MRI (dMRI) protocol using simultaneous multislice technique from the Human Connectome Project (HCP) and Alzheimer’s Disease Neuroimaging Initiative (ADNI‐3), such protocols can now be harmonized across various centers and MRI vendors. However, limited knowledge exists on whether the results obtained for FW measures across HCP protocols are generalizable across ADNI‐3 protocols along with which protocol is more reproducible that will assist us in understanding the variability of FW measure in an individual participant longitudinally. Hence, in this study, we compared the reproducibility of FW across major white matter (WM) tracts across both HCP and ADNI‐3 protocols.

Methods

A 32‐year‐old healthy male participant was scanned over five weeks, both with Basic (2mm3, b‐value = 1000s/mm2) and Advanced ADNI‐3 protocol and 2 variants of the HCP sequence (1.5mm3 and 2mm3) both with 3 b‐values (500s/mm2, 1000s/mm2, and 2500s/mm2) and 213 directions on a clinical 3T Skyra scanner. FW dMRI measures were obtained using the original Matlab implementation (Matlab)5 and DiPY implementation6 of multi‐shell dMRI acquisition (DiPY). WM atlas from Johns Hopkins University (JHU) of 20 major WM tracts pre‐registered to MNI152 was then used as a mask to obtain FW at each WM tract, and the coefficient of variance (CoV) was computed across each protocol. The total acquisition scan time was 75 minutes.

Result

FW estimated using Matlab had a mean CoV = 2.78±1.09 across all the protocols with the least CoV for Basic ADNI‐3 (CoV = 1.31±0.54) and the maximum CoV for 2mm3 HCP sequence (CoV = 4.98±1.83) (Fig.1A) while FW estimated using DiPY had a mean CoV = 6.71±2.86 across all the protocols with the least CoV for Advanced ADNI‐3 (CoV = 4.31±1.85) and the maximum CoV for 2mm3 HCP sequence (CoV = 9.66±4.15) (Fig.1A).

Conclusion

Both acquisition parameters and processing techniques significantly affect the absolute quantification of FW measures. Furthermore, our data suggest that the pooling of dMRI data across various protocols should be performed with caution.