bluuebunny/crossref_metadata_2025 huggingface dataset:
Plasma glucose does not influence performance on standard cognitive screening tests in a mixed memory clinic cohort
Authors: Gramkow Mathias H. , Simonsen Anja Hviid , Hasselbalch Steen G. , Waldemar Gunhild , Frederiksen Kristian Steen
Published: December 2023

Background

It has been shown under experimental conditions that cognitive performance, especially working memory, is impaired in type I and type II diabetes during hyperglycemic and hypoglycemic conditions, perhaps due to altered cerebral glucose metabolism. It is not known if patients with neurodegenerative diseases, who also exhibit pathological cerebral glucose metabolism, are affected in a similar manner by their intrinsic plasma glucose levels. We aimed to test if performance on two standard cognitive screening tests is influenced by intrinsic plasma glucose levels in a memory clinic cohort.

Method

In this retrospective study, we included patients from the Copenhagen Memory Clinic Cohort (CMCC) with an available Mini Mental‐State Examination (MMSE) test score and a plasma glucose measurement performed in conjunction with cognitive testing. Patients were included from the inception of the cohort in 2008 till September 2021. We built linear regression models with MMSE and Addenbrooke’s Cognitive Examination (ACE) test scores as the outcome and plasma glucose as the explaining variable and adjusted models for age, sex and diabetes (plasma glucose measurement > 11.1 mmol/L). We explored non‐linear relationships by adding squared terms to the models and by fitting cubic spline regression models.

Result

In total, 2714 patients had an available MMSE score and a plasma glucose measurement. Patients had a mean age of 71.6 years [range 19‐99] and a baseline plasma glucose level of 5.8 mmol/L [range 2.7‐28.1]. A total of 581 of patients had a plasma glucose level outside normal range (<4.2 or >6.3 mmol/L). A total of 31.2% of the cohort studied had a diagnosis of Alzheimer’s disease (AD). MMSE and ACE total scores were not influenced by plasma glucose in a linear nor in a non‐linear fashion, when we adjusted for age, sex and diabetes. Sub‐group analyses in patients with AD and in patients with cerebrovascular disease showed similar results.

Conclusion

Plasma glucose levels inside normal range were not shown to influence performance on routinely applied cognitive tests and do not need be taken into consideration when interpreting test results from memory clinic patients.
Amyloid and tau fibrils induce different microglial phenotypes but converge to similar altered molecular processes
Authors: da Rocha Andreia Silva , Bastiani Marco Antônio De , Zimmer Eduardo R.
Published: December 2023

Background

Multiple studies in the past years have supported the idea that microglial cells play a crucial role in the pathophysiology of Alzheimer’s disease (AD) and that their response might be quite heterogeneous. However, whether these cells react differently to Amyloid‐β (Aβ) and Tau pathology, as well as, the molecular mechanisms and distinct pathways underlying these responses remains elusive. In this work, we aimed to investigate the response of microglia to Aβ and Tau fibrils, which are being recognized as one of their most toxic forms. We hypothesize that microglia will present a unique response for Aβ and Tau fibrils.

Method

Transcriptomic analysis of mice primary microglial cultures exposed to Aβ or Tau fibrils (5µM, 12‐24hs) was performed. Differentially expressed genes (DEGs) between control and Aβ or Tau fibrils were identified using the DESeq2 method. Functional enrichment (FEA), semantic similarities and protein‐protein interaction networks were conducted. Differences were statistically significant with FDR‐adjusted p‐value < 0.05 and logFC > 1.

Results

Compared to controls, microglia exposed to Aβ fibrils presented 917 DEGs, while the ones exposed to Tau fibrils presented 672 DEGs, of which, only 275 were shared. In contrast, the FEA indicated that more than 69% (736 BP, 50 MF and 32 CC) of the enriched terms were shared between Aβ and Tau. Among the not shared terms, the semantic similarities analysis identified 16 clusters specific for each treatment: Aβ clusters included “regulation of lipids, carbohydrate and ATP metabolic process”, “response to starvation” and “autophagy”, while Tau clusters included “regulation of transmembrane transport of ions”, “gliogenesis” and “neural cells proliferation”.

Conclusion

This work corroborates the idea that microglia react differently to Aβ or Tau pathology but reveals that this response might not be unique as we hypothesized. Although different at the gene level, a big portion of the microglial response to Aβ and Tau converged to the same mechanisms. Despite that, there is still a smaller quantity of adaptations that are specific, such as substrates handling for Aβ and ions transport for Tau. Further validation of these unique phenotypes is being conducted in additional Aβ and Tau pathology models.
Both clinically informed and brain region agnostic approaches identify neuroimaging derived phenotypes associated with genetically regulated gene expression of late‐onset Alzheimer’s disease genes
Authors: Wang Ting‐Chen , Bledsoe Xavier , Shaw Douglas , Chen Hung‐Hsin ,   International Genomics of Alzheimer’s Project (IGAP), Naj Adam C. , Bush William S. , Gamazon Eric J , Below Jennifer E.
Published: December 2023

Background

Genetically regulated gene expression (GReX) data leverages expression quantitative trait loci to investigate the genetic mechanism of Alzheimer’s disease (AD). This study utilized the GReX‐mediated neuro‐imaging derived phenotypes (NIDPs), summary features derived from brain imaging modalities, as an endophenotype to identify brain regions associated with late‐onset AD (LOAD) via gene expression.

Method

This study contained brain region‐agnostic and region‐informed approaches. Both approaches utilized a set of 25 genes causally associated with LOAD in our previous cross‐tissue transcriptome‐wide association studies (TWAS) (Chen et al., 2021) to identify LOAD‐associated GReX‐mediated NIDPs. We leveraged the UK Biobank (UKBB) neuroimaging TWAS resource to provide GReX‐mediated NIDP information.

Region‐agnostic: We assessed associations between GReX of LOAD genes and T1‐derived cortical and subcortical grey matter NIDPs from the UKBB neuroimaging TWAS.

Region‐informed: We identified a set of AD‐associated cortical grey matter NIDPs from diagnosed AD patients (Westman et al., 2013). Next, we subset the UKBB neuroimaging TWAS data to those describing associations between GReX of LOAD genes and the selected AD NIDPs.

A Benjamini‐Hochberg FDR p‐value threshold of 0.05 was used to establish statistical significance, and causal inference testing on associations between GReX of LOAD genes and NIDPs was conducted by implementing MR‐JTI in both approaches.

Result

Region‐agnostic: This approach found associations between GReX of 8 LOAD‐associated genes and 14 NIDPs (Figure 1). The most significant association is the GreX of ZNF296 and the right pars opercularis of the inferior frontal cortex, which replicated across 16 different tissues.

Region‐informed: A single highly significant causal association between the GReX of PSMC3 and the ventral diencephalon was identified and replicated in gene expression models of 3 different bansal ganglia‐derived tissue models.

Conclusion

Our study shows the highly significant causal association between the GReX of ZNF296 and the right pars opercularis on LOAD through the region‐agnostic approach and the strong causal association between the GReX of PSMC3 and the ventral diencephalon on LOAD in AD‐associated region‐informed analyses. Our methodologies provide opportunities to explore brain regions associated with LOAD that are mediated by GReX of AD‐associated genes illuminating the impact of LOAD‐associated genes on gene expression and brain physiology.
Investigating the role of ketogenic conditions on cholesterol metabolism and neuroinflammation in APOE4 carriers
Authors: Suhy Natalie , Mesentier‐Louro Louise A. , Goldman Camille , Forton‐Juarez Ana , Rooklin Rikki , Blanchard Joel
Published: December 2023

Background

The study of genetic risk factors in Alzheimer’s Disease (AD) in conjunction with lifestyle factors is critical in order to fully understand manifestations of disease phenotypes. APOE4, the primary genetic risk factor for AD, is a mutant implicated in dysfunctional lipid and cholesterol transport. We have demonstrated that APOE4‐expressing oligodendrocytes produce a multitude of dysfunctional cholesterol synthesis conditions including decreased cholesterol transport, increased cholesterol accumulation, and reduced levels of myelination (Blanchard et al. 2022). One avenue to study the intersection of genetic and lifestyle factors is to explore APOE mutants with particular dietary conditions that may implicate neuro‐inflammatory phenotypes. The role of cholesterol metabolic dysfunctionality in APOE4 carriers, taking into account the diverse diets that humans consume, has yet to be studied.

Method

In order to investigate this, we developed a 3D multi‐cellular integrated brain tissue (miBrain) technology that contains iPSC‐derived neurons, endothelial cells, astrocytes, pericytes, microglia, and oligodendrocytes. This model has the ability to recapitulate physiological conditions of disease with great accuracy. To study different dietary conditions with our miBrain technology, we employed ketogenic vs. glucose media conditions on APOE4‐carrying cell types within the miBrain model.

Result

We have found that ketogenic conditions promote a neuro‐inflammatory phenotype in APOE4 carriers. This is shown by our observed differences in cholesterol accumulation, levels of myelination, and transcriptomics, between APOE3 and APOE4 miBrain models treated with ketogenic energy sources. We are confirming these findings using in vivo models.

Conclusion

Ketogenic conditions may exacerbate the cholesterol abnormalities in APOE4 carriers, through promoting neuro‐inflammatory conditions that give rise to AD pathogenesis. Findings from these studies highlight therapeutic and diagnostic strategies to reduce the risk of developing AD in APOE4 carriers.

References: Blanchard, J.W., Akay, L.A., Davila‐Velderrain, J. et al. APOE4 impairs myelination via cholesterol dysregulation in oligodendrocytes. Nature
611, 769‐779 (2022). https://doi.org/10.1038/s41586-022-05439-w
Utility of Cortical Atrophy in Functional Networks as a Predictor of Progression in bvFTD
Authors: Krahn Erin , Katsumi Yuta , Brickhouse Michael , Rosen Howard J. , Touroutoglou Alexandra , Dickerson Brad C. , Eldaief Mark C.
Published: December 2023

Background

Behavioral variant frontotemporal dementia (bvFTD) is a clinically heterogeneous neurodegenerative disorder with variable rates of disease progression. Predictors of disease progression in bvFTD are significantly lacking, limiting the ability of clinical care planning. We recently showed that cortical atrophy in the frontoparietal control network (FPN) at baseline predicts the conversion to dementia in patients with Primary Progressive Aphasia (PPA). Leveraging this methodology, we hypothesized that FPN atrophy would predict progression of dementia in patients diagnosed with bvFTD.

Method

We analyzed data from 48 bvFTD patients (mean age 59.9 years, 20 Female) with very mild or mild dementia from our Frontotemporal Disorders Unit cohort and the Frontotemporal Lobar Degeneration Neuroimaging Initiative. Our primary outcome measure was change in the Clinical Dementia Rating‐FTLD Sum‐of‐Boxes (SoB) at baseline and at least one year later. Each participant underwent baseline MRI scanning for cortical thickness estimates. We ran a Pearson correlation analysis between the annualized change of CDR‐FTLD SoB from baseline to last observation, and baseline cortical network atrophy (quantified as network‐wise W scores). Vertex‐wise GLM analyses and network‐wise bivariate correlation analyses were also used to assess the relationship between network cortical atrophy and annualized CDR changes.

Result

Of the 7 networks investigated, only FPN atrophy predicted annualized change in CDR‐FTLD SoB scores (r = ‐0.31, p = 0.03). That is, in bvFTD patients at the very mild/mild dementia stage, the greater the baseline FPN atrophy, the more rapid the clinical decline. Vertex‐wise GLM maps did not show that atrophy across the entire FPN predicted clinical decline. Rather, baseline atrophy in the dorsal precuneus and supramarginal gyrus nodes of the FPN was most predictive of clinical disease progression.

Conclusion

Cortical atrophy in the FPN, and particularly in posterior regions of this network, is predictive of the rate of clinical decline in bvFTD patients, possibly due to the critical roles this network serves in executive function and affective regulation. This work could promote the use of structural imaging biomarkers to guide prognostication for bvFTD patients and their families, and to inform the design of clinical trials.
“It’s my life, it’s my choice and I want to say when” vs “A good death is to be on good terms with God”. Comparing the views of people with dementia in the UK and Brazil about a good death: Qualitative study
Authors: de Oliveira Vidal Edison Iglesias , Harrison‐Dening Karen , Vanelli Julia Maria , Neves Adriele Ferreira , Dekker Natashe Lemos , Oliveira Déborah , Roque Francelise Pivetta , Mikelyte Rasa
Published: December 2023

Background

Few studies have directly asked people living with dementia (PLwD) about their views regarding a good death taking into account their diagnosis or compared their perspectives cross‐culturally. We aimed to compare the meaning of a good death for PLwD in Brazil and the UK.

Method

In this qualitative study, a convenience sample of 32 PLwD (16 each in Brazil and the UK) took part in semi‐structured interviews between Jul 2019 and Aug 2021. A co‐developed topic guide was used in both countries. We assessed all participants for cognitive capacity to give informed consent. Two teams of interdisciplinary researchers independently analysed transcripts for their country using inductive thematic analysis, followed by jointly developing overarching themes on the contrasts and similarities across the two countries.

Result

We identified 3 main themes: Choice and Control; Spirituality and Religious Beliefs; and Fears and Wishes. Choice and Control permeated all aspects of what a good death meant to PLwD in the UK, but was largely absent from Brazillian narratives. The opposite was true for Spirituality, which was central to the meaning of a good death in Brazil, while far less prominent in the UK, even among religious participants. Fears and Wishes was the only theme showing substantial similarities between the two countries. Exploring relationships between the themes demonstrated that how participants experienced and assuaged Fears was predominantly related to Spirituality in Brazil, and Choice and Control in the UK.

Conclusion

Designing culturally‐sensitive approaches in palliative dementia care has to take into account how PLwD define both what a good death is and what helps to achieve it. Our findings also raise caution around replicating palliative care initiatives (e.g., on advance care planning) between countries without adapting its goals and means to achieve them so they are culturally meaningful.
Effects of comprehensive, individualized, person‐centered care on the relative risks of hospitalization and emergency department visits in community‐dwelling persons with advanced Alzheimer’s Disease in a 52‐week randomized controlled trial
Authors: Kenowsky Sunnie , Shao Yongzhao , Heller Sloane , Dafflisio Gianna , Vedvyas Alok , Marsh Karyn , Romero Arelis , Talbeh Mahmoud , Sadowski Martin J. , Masurkar Arjun V. , Reisberg Barry
Published: December 2023

Background

Rates of hospitalization are 3 times higher for community‐dwelling Alzheimer’s disease (AD) persons than non‐affected, age‐matched persons (Rudolph et al., J Am Geriatr Soc. 2010). These investigators reported that hospital outcomes were significantly worse for AD patients regarding delirium, prolonged length of stay, institutionalization and death. They concluded, “Given the frequency of hospitalization in …[AD]… patients, an intervention to prevent or shorten hospitalization would potentially save Medicare billions of dollars per year.” We conducted 28‐week, controlled, clinician‐blind, parallel group and 24‐week extension studies in which advanced AD persons were randomized to receive a comprehensive, individualized, person‐centered management program (CI‐PCM) developed by Sunnie Kenowsky and memantine or usual community care (UCC) and memantine (Reisberg…Kenowsky, Dement Geriatr Cogn Disord., 2017). Herein, we investigate the occurrence of hospitalization and emergency department visits (EDV) in the two groups at 52‐weeks.

Methods

Each occurrence of death, hospitalization and EDV was documented. Investigators blind to group assignment analyzed occurrences. Any fraction of a hospital stay or EDV occurring on or between the baseline and week 52 visit days was recorded as one incident. Relative Risk Reduction (RRR) was calculated for the incidence of hospitalization and EDV.

Results

40% of UCC subjects experienced EDV, 40% were hospitalized and 10% died. Comparatively, only 10% of CI‐PCM subjects experienced EDV and 10% were hospitalized. UCC subjects were hospitalized for C. difficile infection, a fall and subsequent pelvic fracture, syncope and gastrointestinal disease. One CI‐PCM subject was hospitalized for a fall and hip fracture secondary to osteoporosis. UCC subject falls were attributed to neuropsychiatric symptoms of dementia. A CI‐PCM subject had C. difficile successfully treated by their physician. The RRR for utilization of the CI‐PCM program was 0.75 for EDV and 0.75 for hospitalizations (Tables 1&2).

Conclusions

CI‐PCM subjects had a 75% decreased risk of EDV and a 75% decreased risk of hospitalization. Given the 5.8 million USA AD persons and the current high cost of hospitalization, the CI‐PCM program could potentially, significantly decrease the costs of care for AD persons, Medicare, and Medicaid while greatly increasing the AD person’s quality of life and alleviating their caregiver’s burden.
Patient and caregiver views on participating in clinical trials for behavior problems with Alzheimer’s disease
Authors: Velayudhan Latha , Dugonjic Marta , Pisani Sara , Seath Paige , Aarsland Dag , Sagnik Bhattacharyya
Published: December 2023

Background

Along with memory problems and functional impairment, people with Alzheimer’s dementia often suffer from behavioural and psychological symptoms of dementia (BPSD), such as hallucinations, delusions, anxiety and agitation. Current used medications have modest benefits and significant side effects. Promising evidence suggests that cannabidiol (CBD) a non‐psychoactive and non‐addictive substance present in the cannabis plant extract may be useful in treating these symptoms. We conducted a randomised, double‐blind, placebo‐controlled trial of CBD for AD patients with BPSD. However, it is also important to seek to explore the views of potential participants through qualitative research methods about their acceptance of such interventions and participating in such trials especially during the COVID‐19 pandemic period.

Methods

AD patients with BPSD were recruited within a single site, South London and Maudsley NHS trust, UK. We carried out semi structured quality interview for participants and their carers who were randomised and received treatment within the feasibility trial. The purpose of the qualitative interviews was to explore participants’ experiences of taking part in the trial including what encouraged them to take part, their views on the intervention and how they are finding the trial in general.

Results

Both AD participants (n = 15) and their carers (14) were interviewed. Only five AD participants could reasonably participate due to their symptoms. All the carers completed the interview. The key motivator for participating in the trial identified was to derive health benefits from the intervention (100% carers), and 43% also had altruistic motivation to help other people and research. Of the 5 AD patients, 4 had altruistic motivation and one said for health benefits. There were no concerns taking CBD orally in little capsule form. All the participants expressed positive experience with adequate information, thorough and flexible assessments (face to face and virtual), being visited at home or taxis arranged for hospital visits.

Conclusions

The findings demonstrate good acceptability and compliance for CBD among elderly with AD and BPSD. Health benefit was the key motivator for enrolling in the clinical trial facilitated by appropriate arrangements for participation. Learnings from this study would help plan further trials for this cohort.
Exploring the relationship between genetic patterns and brain properties using the Allen Human Brain Atlas
Authors: Hobbs Diana A. , McCullough Austin A. , Millar Peter R , Flores Shaney , Keefe Sarah J. , Benzinger Tammie L.S. , Gordon Brian A.
Published: December 2023

Background

Imaging transcriptomics is a rapidly developing field that combines neuroimaging with genomics to study mechanisms that influence the organization and activity of the nervous system. Using whole‐brain microarray mRNA expression data from the Allen Human Brain Atlas (AHBA), we examined spatial gradients of gene expression in the brain. We then related these gradients to known spatial patterns of brain function.

Method

We mapped regional mRNA expression data from more than 21,000 genes to the 200‐parcel Schaeffer atlas. Principle components analysis (PCA) was used to reduce the dimensionality of the data to ten principle components (PCs). This was done for all genes for the whole brain (WBExp) as well as those specific to Alzheimer Disease (ADExp). We additionally mapped eight other properties: functional connectivity gradients (Fig. 2A), myelin, cortical thickness, cerebral blood volume, cerebral blood flow, glucose consumption, and evolutionary expansion (Fig. 2B) to this atlas to explore their relationships with genetic patterns. Region weights from the PCs were predicted from these eight maps.

Result

The majority of variance for both WBExp (Fig. 1A & 1C) and ADExp (Fig. 1B & 1D) expression was explained by three PCs. Functional connectivity gradients one (β = ‐0.38, β = 0.14), two (β = 0.33, β = ‐0.45), and five (β = ‐0.44, β = 0.32) were moderately related to the first PC of WBExp (Fig. 3A) and ADExp (Fig. 3C) expression patterns (p < 0.05), respectively. Cortical thickness (β = ‐0.32, β = 0.19), cerebral brain volume (β = 0.10, β = ‐0.13), cerebral blood flow (β = 0.42, β = ‐0.52), and evolutionary expansion (β = 0.08, β = ‐0.20) were additionally moderately related to the the WBExp PC1 (Fig. 3B, p < 0.05) and the ADExp PC1 (Fig. 3D, p < 0.05), respectively.

Conclusion

Our results highlighted that gradients in genetic expressions are related to functional gradients seen using rs‐fMRI as well as biological properties such as cortical thickness, cerebral blood volume, cerebral blood flow, and evolutionary expansion. These findings shed light on mechanisms that influence the structure and function of the brain. Understanding the relationship between genetic patterns and these properties can give insight into healthy and diseased‐brain states such as Alzheimer disease.
Exploring Brain Functional Connectivity in Cognitively Healthy Individuals with Pathological CSF Amyloid/Tau
Authors: Al‐Ezzi Abdulhakim Abdullah A , Molloy Cathleen , Arakaki Xianghong , Fonteh Alfred N. , Buennagel David P , Aguda Shelly , Rising Shant , Spezzaferri Mitchell , Sin Caleb , Nolty Anne
Published: December 2023

Background

Disrupted brain connectivity precedes cognitive impairment in Alzheimer’s disease (AD), affects self‐regulation and executive functions, and can be revealed by quantitative electroencephalography (qEEG). Neuroimaging research on AD progression has demonstrated structural and functional abnormalities in specific brain regions and connections. However, little is known about the changes in directional functional connectivity in pre‐symptomatic AD. We aim to explore the information flow in pre‐symptomatic AD during cognitive flexibility challenge.

Method

During a task‐switching challenge, 21‐head channel EEG was recorded from 55 cognitively healthy individuals classified into two groups (9 were excluded from artifacts or suboptimal performance): with an abnormal (CH‐PAT, n = 27) versus normal (CH‐NAT or controls, n = 19) ratio of cerebrospinal fluid (CSF) amyloid/total‐tau. In the task‐switching paradigm, each trial included two stimuli, and participants were required to either name the ink color or read the word when color words were printed in different colors of ink. Only correctly responded trials were analyzed. Directed functional connectivity between brain regions was estimated with Partial Directed Coherence (PDC) in frontal, central, parietal, temporal, and occipital regions in alpha frequency band (8‐12 Hz) during word‐color trials. Two‐sided t‐tests were conducted, with p<0.05 considered the level for significance. No multiple comparison correction was used for this exploratory study.

Result

Pilot analysis shows significant differences between CH‐PATs and CH‐NATs: CH‐PATs has shown decreased information flow from the temporal and occipital regions compared to CH‐NATs with p‐values of 0.001 and 0.04, respectively. In addition, frontal brain regions have shown enhanced information flow in the CH‐PATs compared to CH‐NATs (p = 0.02) (Figs 1&2). Moreover, greater information flow between the medio‐frontal cortex and occipital regions was observed in CH‐PATS than CH‐NATS (Fig 1).

Conclusion

Compared to CH‐NATs, the enhanced connectivity in frontal regions in CH‐PATs suggests that their frontal brain regions are compensating for the damage caused by the amyloid/tau pathology. The decreased information flow from temporal and occipital regions in CH‐PATs may indicate a loss of relative functional importance of these regions. Our exploratory findings provide a novel and alternative approach for connectivity‐based analysis to identify the effects of amyloid/tau pathology in CH participants.
Lower locus coeruleus integrity in older COVID‐19 survivors: initial findings from an international 7T MRI consortium
Authors: Jacobs Heidi I.L. , Ibrahim Tamer , Vahidy Farhaan S , Girard Timothy D. , Hosseini Akram A. , Alkateeb Salem , Bowtell Richard , Penny Gowland , Habes Mohamad , Karmonik Christof , Mougin Olivier , Roman Gustavo C , Masdeu Joseph C. , Li Karl , Garbarino Valentina R. , Goss Monica , Nair Rejani R , Patel Vibhuti N , Snyder Heather M , Tannous Jonika D , de Erausquin Gabriel A. , Snitz Beth E. , Seshadri Sudha
Published: December 2023

Background

The SARS‐CoV‐2 coronavirus has been associated with structural brain changes, consistent with its neurological manifestations. Recent studies showed a specific predilection for brainstem glial activation and hypometabolism, possibly indicating involvement of the locus coeruleus. The locus coeruleus (LC) modulates many cognitive functions and behaviors and its norepinephrine projections regulate both immune responses and vascular reactivity. We aimed to examine differences in LC integrity between COVID‐19 survivors and controls.

Method

Participants are enrolled across 3 US and 1 UK sites using harmonized cognitive and 7T MR‐imaging protocols. Here, we analyzed data from 18 participants enrolled at Houston Methodist (12 COVID‐19 survivors, 6 controls; Figure 1). COVID‐19 survivors were required to have had a positive antigen test and an illness syndrome consistent with COVID‐19. Healthy controls were required to have no significant pre‐existing medical, neurologic, or psychiatric illness and no illness requiring hospitalization in the last 2 years. LC imaging was performed using a dedicated 7T MT‐TFL sequence (0.4×0.4×0.5mm). A site‐specific normalized template was constructed using ANTs/FSL. The entire average LC integrity as well as voxel‐wise integrity values were compared between COVID‐19 survivors and controls using a robust linear regression (age‐controlled and threshold free cluster enhancement corrected). LC integrity was correlated with age, sex, ethnicity and cognition using Spearman’s rank correlation.

Result

Average LC integrity was not correlated with age, sex, or Hispanic ethnicity (p>0.3). COVID‐19 survivors did not differ from Controls when examining the entire LC (p = 0.54). Voxel‐wise analyses revealed a small cluster (19 voxels) in the middle portion of the left LC where COVID‐19 survivors exhibited lower LC integrity than controls (p = 0.005; Figure 2). Integrity of this cluster was not related to age or Hispanic ethnicity (p = 0.9). LC integrity did not correlate with cognitive performance within the COVID‐19 survivors (Trail Making Test B: p = 0.43; Craft Story delayed recall p = 0.47; MoCA p = 0.84).

Conclusion

Consistent with previous animal and human studies, our initial findings provide evidence for neuroinvasive potential of SARS‐CoV‐2 localized in the middle LC. In the future, we aim to expand our sample and link these observations to the neurocognitive sequelae of COVID‐19.
Association of APOE with Alzheimer’s disease in Mexico, Caribbean‐Hispanics, Peruvian and Mexican Americans
Authors: Barral Sandra , Rentería Miguel Arce , Reyes‐Dumeyer Dolly , Arango Silvia Mejia , Obregon Alejandra Michaels , Samper‐Ternent Rafael , Wong Rebeca , Barber Robert , Phillips Nicole , O'Bryant Sid E. , Montesinos Rosa , Soto‐Añari Marcio F. , Custodio Nilton , Tosto Giuseppe
Published: December 2023

Background

The Apolipoprotein E (APOE) ε4 allele is the strongest genetic risk factor for Late Onset Alzheimer’s disease (LOAD). However, its genetic effect is heterogeneous across different ethnicities. We investigated the association of APOE with LOAD in five different Hispanic studies: Mexicans in the Mexican Health and Aging Study (MHAS), Caribbean Hispanics in the Washington Heights Inwood Aging project (WHICAP), Peruvians in the Genetics of Alzheimer’s disease In Peruvian Populations (GAPP) and Mexican Americans from The Health & Aging Brain among Latino Elders (HABLE) and the Texas Alzheimer’s Research and Care Consortium (TARCC).

Method

A total of 7,832 participants were included in the analysis. APOE genotypes were generated by direct genotyping or imputation. SNPs associations with LOAD were assessed using multivariate logistic regression models in PLINK. Analyses were adjusted for age (≥60 years old), sex, and education. Global ancestry proportions, Native Americans, European, African were estimated with ADMIXTURE software using the Human Genome Diversity Project as the reference panel. Genetic ancestry specific secondary analyses were conducted using the same models.

Result

The genetic ancestral composition was significantly different across cohorts. Peruvians and Mexicans showed a predominant native ancestry, Caribbean‐Hispanics appeared to have a major contribution of European ancestry, and Mexican Americans exhibited similar proportions of both European and Native ancestries. We observed a significant association with e4 allele dosage in all the cohorts, except for MHAS. The genetic effect of at least one copy of the e4 allele on LOAD risk was very similar in GAPP and HABLE (OR = 3.42, SE = 0.39 and OR = 3.33, SE = 0.33, respectively), while attenuated in TARCC (OR = 2.81, SE = 0.28) and WHICAP (OR = 1.82, SE = 0.16). Among MHAS participants with a predominant European ancestry, APOE association achieved statistical significance with an increased disease risk (OR = 3.42, SE = 0.55) for homozygous carriers. Within the native‐prevalent ancestry subsample, the increased LOAD risk among APOE_ e4 heterozygous carriers were similar in both GAPP and HABLE cohorts (OR = 3.61, SE = 0.44 and OR = 3.64, SE = 0.43, respectively).

Conclusion

Our results showed a differential risk for LOAD from the APOE_ e4 allele across populations with admixed genetic ancestry.
A genome‐wide association study in Puerto Ricans suggests new risk loci for Alzheimer disease
Authors: Rajabli Farid , Feliciano‐Astacio Briseida E. , Hamilton‐Nelson Kara L. , Rivero Joe , Akgun Bilcag , Adams Larry D. , Mena Pedro R. , Tejada Sergio J. , Celis Katrina , Sanchez Jose Javier , Feliciano Nereida I , Whitehead Patrice , Prough Michael B. , Gardner Olivia K. , Acosta Heriberto , Chinea Angel ,   The Alzheimer’s Disease Sequencing Project (ADSP), McInerney Katalina , Vance Jeffery M. , Cuccaro Michael L. , Beecham Gary W. , Pericak‐Vance Margaret A.
Published: December 2023

Background

Alzheimer disease (AD) is the fourth leading cause of death in Puerto Rico. The Puerto Rican (PR) population has a high proportion of older adults (18%, over > 65), with 12.5% of them suffering from ADThese statistics highlight the need to investigate the genetic risk factors underlying AD in the PR population, as it could lead to the development of targeted treatments and therapies. Moreover, the ancestrally admixed makeup of the PR population provides an opportunity to assess the role of the European (∼67%), African (∼20%) and Amerindian (∼13%) ancestry in AD risk. We performed genome wide association analysis (GWAS) using whole genome sequence data to identify genetic risk/protective factors associated with AD in the PR population.

Method

The PR dataset includes WGS and phenotype data from 640 individuals, comprising 335 AD and 305 cognitively unimpaired (CU) controls. To account for the population substructure, we calculated the global ancestry (principal components) using EIGENSTRAT. We performed GWAS analyses with a generalized linear mixed‐model using the SAIGE software. The model included genotype, sex, age, and principal components (population substructure) as fixed effects and genetic relationship matrix as a random effect. The genetic relationship matrix was calculated based on genomic data and accounted for the relatedness among the individuals in the dataset.

Result

We identified four suggestive significant loci (P<1×10−6) associated with the risk of AD in PRs: NACC2 (pv = 4.8×10−7) on chromosome 9, SCN8A (pv = 9.3×10−7) on chromosome 12, FOXK2 (pv = 9.9×10−7) on chromosome 17, and APOEe4 (pv = 6.8×10−8) on chromosome 19. Eight additional AD loci with the same lead marker from European GWAS study (Bellenquez et al.) showed nominal significance: FERMT2 (pv = 6.2×10−3), TREM2 (pv = 8.0×10−3), CLU (pv = 1.8×10−2), RASGEF1C (pv = 2.4×10−2), ADAM17 (pv = 3.5×10−2), DOC2A (pv = 4.3×10−2), GRN (pv = 4.4×10−2) and SORL1 (pv = 5.1×10−2).

Conclusion

This study identified three suggestive novel significant loci (NACC2, SCN8A, and FOXK2) associated with AD risk in PRs. In addition, GWAS study on PRs with a high proportion of European ancestry was able to replicate nine AD loci previously identified in European studies. These findings provide new insights into the genetic architecture of AD in the PR population.
Association between antipsychotics and all‐cause mortality in elderly patients diagnosed with dementia with different patterns of BPSD
Authors: Rogani Sara , Calsolaro Valeria , Coppini Giulia , Lemmi Bianca , Taverni Irene , Bianchi Elena , Pullia Rosanna , Carlo Ludovica Di , Okoye Chukwuma , Virdis Agostino , Monzani Fabio
Published: December 2023

Background

during the dementia time course Behavioral and Psychological Symptoms of Dementia (BPSD) may arise. Despite their use is still off‐label and they are associated with several side effects, antipsychotics represent the main pharmacological strategy to alleviate BPDS

Method

aim of this retrospective study was to evaluate the correlation between antipsychotics use and all‐cause mortality. BPSD were classified in three clusters: “mood/apathy”, “psychosis” and “hyperactivity”. ANOVA for repeated measures was used to evaluate the functional/cognitive changes over three time points (baseline, 6 months and 12 months follow‐up). Chi‐Square test was carried out to verify the correlation between antipsychotic drug use and mortality. Logistic regression and stepwise regression method were used to analyze the relationship between mortality and other potential influencing factors, including ADL, IADL, CFS, in addiction of antipsychotics drugs use.

Result

a total of 209 patients with a clinical diagnosis of dementia were enrolled (71.3% women; mean age = 83.24±4.98 years). The results of the ANOVA indicated a significant worsening of ADL and IADL over time [ADL Wilks’ Lambda = 0.744, F(2,80) = 13.75, p<0.001, η2 = 0.256, IADL Wilks’ Lambda = 0.71, F(2,80) = 16.3, p<0.001, η2 = 0.29, respectively], a significant progression of cognitive impairment as measured with MMSE and a significant worsening in frailty at CFS at 6 and 12 months follow up [MMSE Wilks’ Lambda = 0.751, F(2,73) = 12.11, p<0.001, η2 = 0.249, CFS Wilks’ Lambda = 0.749, F(2,79) = 13.224, p<0.001, η2 = 0.241]. Patients on antipsychotic therapy reported a higher mortality rate, although there is no statistically significant association between antipsychotic use and mortality. We found no significant correlation between mortality and antipsychotic drug use within the different BPSD cluster (“mood/apathy” p = 0.464, “psychosis” p = 0.569, “hyperactivity” 0.528), and no statistically significant association between mortality and other potential influencing factors. Using a stepwise regression, the loss of independence in IADL survived as factor associated to mortality (p = 0.002).

Conclusion

patients on antipsychotic therapy reported a higher mortality rate, although there is no statistically significant association between antipsychotic use and mortality. Further work is needed to establish the relationship between antipsychotics and mortality in elderly patients with dementia.
Region‐Specific Associations of Human Astrocytic Endfoot Genes with Alzheimer’s Disease Neuropathology and Cognitive Decline
Authors: Phillips Jared , Seto Mabel , Winfree Rebecca L , Wang Yanling , Schneider Julie A , Bennett David A. A , Dumitrescu Logan C , Hohman Timothy J.
Published: December 2023

Background

We completed a well‐powered bulk transcriptomic analysis of the astrocytic water channel aquaporin‐4 (AQP4) and related glymphatic molecules and discovered significant associations with Alzheimer’s disease (AD) neuropathological and cognitive outcomes. Genes included AQP4 and dystrophin‐associated complex components, namely DMD, DTNA, DAG1, and SNTA1, which encode proteins responsible for anchoring the AQP4 channel to the astrocytic endfoot membrane.

Method

Leveraging regional brain RNA sequencing from the ROS/MAP dataset (Table 1), we determined the effects of transcript‐level variation on neuropathological outcomes at autopsy and longitudinal cognition using multiple linear regression models and mixed effects models, respectively. Discrete brain regions included: the dorsolateral prefrontal cortex (DLPFC, N = 921), caudate nucleus (CN, N = 705), and posterior cingulate cortex (PCC, N = 516). Square‐root transformed neuropathological measures of amyloid and tau burden at autopsy were quantified using immunohistochemistry. Cognitive performance was assessed longitudinally with global cognition calculated as a composite score derived from 19 neuropsychological tests. All model covariates included age at death, sex, educational attainment, and post‐mortem interval. Longitudinal models also included latency to death and the fixed and random effect of interval between current and last visit.

Result

Higher AQP4 expression in the DLPFC related to higher amyloid pathology (β = 0.21, P.fdr = 0.04). Similarly, higher DTNA expression was associated with higher tau burden (βDLPFC = 0.36, P.fdrDLPFC = 0.008) and a faster rate of cognitive decline (βDLPFC = ‐0.036, P.fdrDLPFC = 0.0004; βPCC = ‐0.037, P.fdrPCC = 0.02). Higher SNTA1 in the CN related to a faster rate of cognitive decline (β = ‐0.038, P.fdr = 0.03). A summary of significant associations is presented in Table 2 and select plots are provided in Figure 2. AQP4, DTNA, and SNTA1 showed comparable associations with clinical AD in independent datasets within the AMP‐AD project (https://agora.adknowledgeportal.org/).

Conclusion

Our results indicate that gene expression at the AQP4‐dystrophin axis relates to both AD neuropathology and cognition, particularly in the prefrontal cortex. Future analyses will incorporate single‐nucleus measures of gene expression and cell‐type deconvolution to clarify cell‐type specific contributions in this pathway. Together, these results highlight a set of genes relevant to glymphatic function that should be prioritized for future mechanistic studies.
Plasma based assessment of extracellular vesicles biomarkers in Alzheimer’s Disease
Authors: Dayarathna Thamara , Roseborough Austyn D , Gomes Janice , Khazaee Reza , Whitehead Shawn N , Leong Hon , Pasternak Stephen H
Published: December 2023

Background

Currently there are no widely accepted diagnostic tests for Alzheimer’s disease (AD). Although there is much excitement in the field of biomarker development, most proposed tests for AD are expensive, require highly specialized sample handling, invasive approaches or radiation exposure. The goal of this project was to develop non‐invasive AD biomarker assessment using nanoflow cytometry to examine proteins on circulating brain‐derived extracellular vesicles in plasma.

Method

Plasma samples were collected from a population of individuals clinically diagnosed with MCI and mild, moderate or severe Alzheimer’s disease and cognitively intact control subjects. Plasma was incubated with fluorescently‐conjugated antibodies against candidate biomarkers including oligomeric amyloid, fibrillar amyloid, amyloidβ‐42, pTau‐T181, pTau‐T217, pTau‐S235, Ubiquitin, Neurofilament, α‐synuclein and synaptophysin. After incubation, labelled events were quantified using the Apogee Microplus nanoflow cytometer. Using Receiver‐Operator Curve (ROC) analysis, the ability of individual markers and various combinations to distinguish diagnostic groups was determined.

Result

Nanoflow cytometry quantification of pTau‐T181, pTau‐T217, pTau‐S235, pTau‐T231, Aβ‐42 (among others) successfully distinguished MCI and AD plasma from healthy controls. Using ROC analysis, our most sensitive antibodies (pTau‐ T231) separate controls from AD patients with an AUC of 0.96 (Sens: 0.95/Spec: 1.0). Other prominent antibodies include pTau 181 with an AUC of 0.93 (Sens: 0.92/Spec: 0.92). The most promising combination of antibodies combines beta‐amyloid42 and pTau‐181 to separate AD patients from controls with an AUC of 0.960 (Sens: 0.93, Spec: 0.92). Isolation of EVs from plasma and validation of marker labeling was performed with Western Blot, ELISA and transmission electron microscopy.

Conclusion

Here we demonstrate the use of nanoflow cytometry to directly quantitate proteins on circulating extracellular vesicles in plasma from MCI and AD patients. The assays are rapid, inexpensive, directly quantitative, and require mini sample volume and manipulation. Future studies are required involving a larger population of patients who have had ‘gold standard’ biomarkers (Amyloid and tau CSF measurements), longitudinal follow‐up and/or autopsy confirmed diagnosis of AD.
Associations of NREM Slow Wave Activity and Regional in‐vivo tau PET deposition in black and white community‐dwelling cognitively normal older‐adults with normal sleep
Authors: Bubu Omonigho Michael M , Umasabor‐Bubu Ogie Queen , Kovbasyuk Zanetta , Valkanova Elena M , Mbah Alfred , Cejudo Jaime Ramos , Turner Arlener , Hu Lu , Williams Natasha , Jean‐Louis Girardin A , de Leon Mony J. , Masurkar Arjun V. , Wisniewski Thomas , Varga Andrew , Osorio Ricardo S
Published: December 2023

Background

In this proof‐of‐concept study, we examined whether NREM slow wave activity (SWA) is associated with regional in‐vivo tau deposition; and whether race‐specific differences exist in this association, in clinically normal older adults with normal sleep, in the context of Aβ.

Method

This was a cross‐sectional analysis of baseline data from 21 community‐dwelling cognitively normal older‐adults with normal sleep. Participants were matched on age, sex, BMI, and APOE4 carrier status in a 1:3 ratio, blacks: whites. Normal sleep was defined as 6‐9 h of total sleep time and absence of AHI4%>15 and AHI4%>5 with sleepiness. SWA was defined as power between 0.5‐4.0 Hz during NREM with NREM cycles characterized as stages NREM 2‐3 of ≥15 min. terminated by rapid eye movement (REM) or wakefulness of ≥5 min. Tau burden was assessed using 18F‐PI2620. Linear mixed‐effects models with random intercept and slope were used to assess associations between NREM SWA, and regional in‐vivo tau PET deposition, respectively, controlling for Aβ, age, BMI, sex, APOE4‐status, education and other sleep variables.

Result

Of the 21 participants, 7 (33.3%) were black, 12 (57.1%) were women and 5 (24%) were APOE4 carriers. The mean (SD) age, and education were 69.1 (5.5), and 17.2 (3.8) years respectively. NREM SWA was associated with tau deposition in the entorhinal cortex, inferior and middle temporal ROIs, including gray matter neocortical ROIs i.e., anterior ventral striatum, orbitofrontal, precuneus, superior frontal, lateral temporal and posterior cingulate gyrus cortices (p <.01 for all). Racial differences existed in the entorhinal cortex, and inferior and middle temporal ROIs, including the lateral temporal, parietal, precuneus and posterior cingulate gyrus cortices (p <.02 for all), with black participants having lower tau levels relative to white participants. Divergent NREM SWA and tau associations were observed in the entorhinal cortex, precuneus, and inferior and middle temporal ROIs with NREM SWA negatively correlated with tau‐PET levels in whites and positively correlated in blacks.

Conclusion

Racial differences in physiological sleep features, uniquely associated with tau levels in the brain, may reflect one mechanism of how sociocultural factors, often through behavioral processes, become physiologically expressed as increased AD‐risk in blacks.