bluuebunny/crossref_metadata_2025 huggingface dataset:
Translational potential of JAX humanized‐APOE mice: sex differences in bioenergetic function in brain
Authors: Cortes‐Flores Helena , Altemus Jesse , Wiegand Jean‐Paul L. , Brinton Roberta Diaz
Published: December 2022

Background

The preclinical phase of late onset Alzheimer’s disease (LOAD), known as the preclinical phase, can start 10 to 20 years prior to onset of clinical symptoms. Hypometabolism and impaired mitochondrial bioenergetics can emerge during prodromal phase as early indicators of AD risk. APOEe4, the greatest genetic risk factor for LOAD, is well documented to induce lipid metabolic dysregulation. We therefore sought to determine the impact of APOEe4. The following study analyzed body composition and mitochondrial functions to elucidate how the presence of APOEe4 in a mouse model contributes to bioenergetic changes, and whether they affect females and males equally.

Method

18mo old transgenic mouse models (JAX #029018 and #027894) carrying humanized APOE alleles (hAPOE3/3, hAPOE3/4 or hAPOE4/4) were assessed for fat and lean mass content via EchoMRI. A week later, fasting blood glucose levels were assessed prior to sacrifice, and brain tissues were collected to determine mitochondria function by Complex I and IV activity.

Result

Body composition analyses indicated that hAPOEe4 males had significantly lower fat percentage than male APOEe3 mice. Females, irrespective of APOE genotype, exhibited significantly lower lean weight relative to males. No sex or APOE genotype difference was detected in fasting blood glucose plasma levels nor in mitochondrial Complex I activity. In contrast, mitochondrial Complex IV activity was significantly lower in females relative to males. Lastly, Complex IV activity was lower in mice exhibiting dominance aggressive behavior, specifically barbering, irrespective of sex or genotype.

Conclusion

APOE mice resembling a human population of approximately 60 years of age displayed a sex difference in body composition parameters, where total and lean weight was higher in males than females. Sex differences also emerged in bioenergetic function, with females exhibiting lower mitochondria Complex IV activity relative to males. Sex differences are consistent with human data, whereas no genotype differences were observed and thus may influence the translational potential of the humanized APOE mouse model in LOAD research. However, the translational potential might be greater when linked with phenotypic characteristics.

This work was supported by NIA grants R01AG057931, and RF1AG059093
Voxel to voxel validation of brainstem MRI novel sequences to postmortem tissue reconstruction
Authors: LaMore Tia , Chen Yuheng , Otaduy Maria , Li Song Hua , Lee Wing Hung , Heinsen Helmut , Shi Yonggang , Grinberg Lea Tenenholz
Published: December 2022

Background

Neuroimaging of brainstem structures has gained importance in ADRD as these regions degenerate early in AD. In recent years there has been an explosion of novel neuroimaging sequences to image the brainstem. However, most of these methods lack validation against the ground truth, i.e tissue visualization, making these methods less attractive for clinical use. Among the new proposed methods, high‐definition connectome promises to revolutionize BS imaging as it overcomes several limitations of standard structural MRI, including a high level of imaging deformation. In this project we have developed a pipeline to validate BS connectome sequences using a voxel to voxel comparison between 3D histological volumes and connectome signal. To this date we applied this pipeline to 6 human brains.

Method

We used 6 AD cases collected by the Neuroradiology Lab at the University of Sao Paulo. Patients underwent postmortem MRI prior to autopsy.We used a pipeline developed in‐house that allows for precise alignment of histology‐based cytoarchitectural 3D reconstructions of the brainstem to its T2 weighted 7T‐MRI counterpart. Upon procurement, the brains were fixed in formalin, embedded in celloidin, and cut in horizontal sections of 300um. Selected BS structures were delineated on these slides stained for Nissl(gallocyanin)(Fig.1). Delineated images underwent manual quality checks, a series of alignment and registration processes to recover original coordinates. The stained sections and corresponding ROI masks were registered to the blockface to correct for any deformation of tissue during the staining process. Freeview commands applied to reconstruct the brainstems and masks. We registered the resulting 3D reconstruction to the matching MRI coordinates(Fig. 2), enabling voxel‐to‐voxel comparisons.

Result

6 cases went through the pipeline with ROIs reconstructed on block reconstructions(Fig. 3). Currently, dice coefficient analysis between MRI signal and the manually outlined ROIs on histology are being finalized.

Conclusion

Our pipeline enables voxel‐to‐voxel correlation analysis between histology and MRI scans for validation of brainstem neuroimaging. Current finalization of a total 9 cases is ongoing. Validation of such correlation maps will inform interpretations of connectome results in living patients with the potential to act as an eventual diagnostic tool for ADRD.
Clinically relevant monitoring of long‐term night‐time behaviour and physiology from the homes of people living with dementia.
Authors: Kolanko Magdalena A , Soreq Eyal , Lai Helen , Barnaghi Payam , Dijk Derk‐Jan , Sharp David J
Published: December 2022

Background

Disturbances of sleep and night‐time behaviours are amongst the most disabling symptoms of dementia. They often increase carers’ burden and the risk of institutionalization. The causes are complex and are difficult to investigate because of a lack of acceptable methods for monitoring behaviours in the home. Here we show that a passive under‐mattress can be used to track changes in night‐time behaviour and physiology, and that a range of digital biomarkers produced are informative in understanding the effects of medication changes, disease progression and intercurrent illness in patients living with dementia (PLWD).

Method

We used contactless Withings Sleep Mattress (WSM) to monitor bed‐occupancy in 4 PLWD (age 74‐93, 3males) enrolled into the CR&T MINDER cohort study. Each participant was tracked over 1000 nights between 2019 and 2021. Minute‐to‐minute timeseries were extracted from WSM to calculate bed occupancy metrics and nocturnal physiology measures (heart and breathing rates (HR/BR)). Raw measures were standardized within subjects by comparing each time point to the mean of the time points that preceded it. We then investigated the relationship between these metrics and clinical events such as infections and medication.

Result

The 4 case studies illustrate the potential of this technology for passive health monitoring in PLWD. High levels of intraindividual variability in behavioural and physiological metrics were observed. Progressive changes in bed occupancy were observed in two patients with frontotemporal dementia and Alzheimer’s disease (Cases 1&2). Intercurrent illness and medications changes influenced the measures. For example, Patient 1 showed progressive night‐time wandering with increasing time spent out of bed, which improved following the initiation of risperidone. Case 2 showed recurrent episodes of heart failure accompanied by increased nocturnal HR. Cases 3 and 4 showed urinary tract infections, which were accompanied by transient changes in bed occupancy measures.

Conclusion

Passive monitoring of night‐time behaviour and physiology is a simple and cost‐effective way to monitor the effects of medication change and medical events in PLWD. Digital biomarkers derived from these simple measures hold great promise as measures of dementia progression, to enhance dementia care by identifying at risk individuals and as novel clinical outcome measures in clinical trials.
Psychotropic medication use is higher in early‐ than late‐onset Alzheimer’s disease
Authors: Polsinelli Angelina J , Salazaar Krystal , Lane Kathleen A. , Gao Sujuan , Apostolova Liana G.
Published: December 2022

Background

Psychotropic medication use in Alzheimer’s disease (AD) is important in symptom management as neuropsychiatric symptoms (NPS) often reduced quality of life for both patients and families. The extent to which these medications are prescribed at similar or discrepant rates between those with early symptom onset (EOAD) and late symptom onset (LOAD) is unknown but may have important implicants for clinical care

Method

Data were obtained from the National Alzheimer’s Coordinating Center database. Baseline data from those with primary Alzheimer’s disease (AD) diagnosis were used for this analysis. Baseline was defined as the first time the individual was diagnosed with impaired cognition. Participants who completed the Neuropsychiatric Inventory Questionnaire (NPI‐Q) at baseline and had psychotropic medication use data available were included. Participants were excluded if they had additional neurological, systemic, psychiatric, or medical disease that could have significantly contributed to cognitive impairment. The AD group was divided into EOAD (n = 2796) or LOAD (n = 8446) using onset age < 65 or ≥65, respectively.

Multiple logistic regression models (examining any medication use) and multiple poisson regression models (examining number of medications used) were run for each of the NPI‐Q categories to examine the association between age of symptom onset (i.e., EOAD, LOAD) and medication use, adjusting for sex, education and disease severity (CDR‐SB).

Result

Participant demographics are in Table 1. EOAD were more likely than LOAD participants to be taking at least one psychotropic medication for all NPS, except motor disturbance and nighttime behaviors (OR range: 1.16‐1.47; Table 2). Similarly, EOAD compared to LOAD participants were more likely to be taking a greater number of medications for each NPS, except motor disturbance (OR range: 1.10‐1.33; Table 3).

Conclusion

Compared to LOAD, EOAD is associated with increased psychotropic medication use at baseline – in terms of both presence and number of mediations prescribed – for almost all NPS. This fits well with previous findings showing greater NPS burden in EOAD. Future research will examine medication use longitudinally and explore potential group differences in efficacy.
Clinical validation of the Virtual Reality Functional Capacity Assessment Test – Short List (VRFCAT‐SLx) for assessment of iADL functioning in early symptomatic Dementia: Sensitivity to cognitive and functional change over time
Authors: Schoemaker Dorothee , Atkins Alexandra S , Abraham Chelsea , Flanagan Chloe , Evans Haley , Madsen Corrine , Sickel Nancy , Stevens Heather , Amaya Alexandra C , Plassman Brenda L , Loewenstein David , Welsh‐Bohmer Kathleen A. , Keefe Richard SE
Published: December 2022

Background

Assessment of functional capacity is critical to the diagnosis and monitoring of Alzheimer’s disease and related dementias. The VRFCAT (Keefe et al., 2016) is a performance‐based assessment of iADL functioning that is completed on a tablet. Previous work on the VRFCAT has demonstrated correlations with clinical endpoints and sensitivity to cognitive impairment in individuals with subjective cognitive decline (SCD) and schizophrenia. To facilitate use longitudinally and in more impaired patient groups, the VRFCAT “short list” (VRFCAT‐SLx) was recently developed to reduce task complexity and length (see Atkins et al. AAIC submission). The aim of the present work was to characterize the VRFCAT‐SLx’s sensitivity to longitudinal clinical changes in subjects with early symptomatic MCI/AD dementia

Method

At the time of submission, participants included 77 adults (32 male; mean baseline? age = 73.29, SD = 7.52) with clinical diagnoses of MCI/AD and CDR global scores of 0.5 or 1.0. Participants completed the VRFCAT‐SLx and other established measures (i.e., ADCS‐ADL‐MCI, MMSE, CDR, BAC cognitive tests) at Baseline and Follow‐up. At submission, 22 participants had completed both visits (mean follow‐up interval ± SD: 13 ± 4.8 months). We evaluated VRFCAT‐SLx performance as a predictor of cognitive and functional change over time, and examined relationships between longitudinal change on the VRFCAT‐SLx, MMSE, ADCS‐ADL‐MCI, and CDR‐SB.

Result

Baseline VRFCAT‐SLx performance predicted decline on both the CDR Sum of Boxes (β = 0.44, p<0.05) and MMSE Total score (β = ‐0.48, p = 0.01), even when controlling for baseline performance, age, and length of follow‐up interval. Additionally, increases in the VRFCAT‐SLx Total Adjusted Time (i.e., worsening performance) at follow‐up was significantly correlated with observed decline on the MMSE (r = ‐0.55, p<0.01), CDR‐SB (r = 0.59, p<0.01), and ADCS‐ADL‐MCI (r = 0.44, p<0.05). These associations remained significant after adjusting for age and length of follow‐up interval.

Conclusion

Longitudinal results indicate that performance on the VRFCAT‐SLx reliably predicts and tracks cognitive and functional change in early symptomatic dementia. These findings support the validity of the VRFCAT‐SLx as a sensitive assessment of iADL functioning in MCI/AD dementia.
Recruitment and enrolment feasibility of the Luci risk reduction study in Québec
Authors: Lussier Isabelle
Published: December 2022

Background

Evidence suggests that lifestyle interventions can reduce the incidence of cognitive decline in older adults. Multidomain lifestyle intervention thus generates major interest. Luci is a Web‐based multidomain coach‐assisted dementia risk reduction program. Although such a technology‐based delivery mode represents a scalability opportunity, reaching the target population may be a challenge. A main goal of the Luci pilot feasibility study was to evaluate recruitment and enrolment rates.

Method

This is an ongoing 24‐week, Luci vs waitlist randomized, single‐blind pilot feasibility study to enrol cognitively healthy individuals aged 50‐70 with ≥1 lifestyle risk factor (physical activity, diet, cognitive engagement). Exclusion criteria comprised severe health conditions (e.g., neurocognitive, psychiatric) and logistical reasons (e.g., no device or internet). We aimed to recruit 120 participants at a rate of ≥30 participants/month over 4 months, and to achieve a screening‐to‐enrolment ratio of ≥48%. Participants were recruited in weekly waves from a list of volunteers obtained through a media campaign on the Luci project, and a research centre database.

Result

Of the 178 people invited to complete screening, 157 (88.2%) did so, and 124 (78.9%) met inclusion/exclusion criteria. The recruitment of the 120 participants was achieved over 1 week, and screening‐to‐enrolment ratio was 76.4%. Reasons for exclusion were not having any lifestyle risk factor (18.9%), exceeding study capacity (10.8%), logistical (24.3%) and health (45.9%) reasons. Included participants had a mean age of 60.7 (SD = 5.6) and 16.7 (SD = 3.4) years of education; 85% were female. Within enrolled individuals, 71.7% were living with someone, 37.5% were retired, and 66.7% had a household income greater than the Quebec median. 75.0% had ≥2 lifestyle risk factors.

Conclusion

Our recruitment and enrolment goals were met. Eligibility slightly exceeded our enrolment aim, a situation not unexpected. Almost all individuals who completed the screening had dementia risk factors suitable for Luci preventive interventions. However, some subgroups are not well represented in our sample, and in particular, men, individuals who are older (≥65 years), less educated, with a low‐income, and living alone. Results highlight the need to develop recruitment strategies to reach a more diverse population, and that specifically target individuals facing social inequities.
What patients and caregivers do with knowledge of Alzheimer’s disease CSF test results: Findings from the IMPACT‐AD BC study
Authors: Patel Khushbu Jayeshkumar , Yang David , Chambers Colleen , Feldman Howard H. , Hsiung Ging‐Yuek Robin , Nygaard Haakon B. , Best John R. , Dwosh Emily , Robillard Julie M. , DeMarco Mari L.
Published: December 2022

Background

The growing clinical use of the analysis of CSF amyloid‐beta peptides and tau proteins to assist in the diagnosis Alzheimer’s disease (AD) highlights an urgent need to understand the impact of this testing on patients, as well as their care partners. We aimed to address this knowledge gap by examining the perspectives of patients who underwent CSF AD biomarker testing as part of routine care, and a family member (‘care partner’).

Method

Within the ‘Investigating the Impact of Alzheimer’s Disease Diagnostics in British Columbia’ (IMPACT‐AD BC) study (NCT05002699), we conducted semi‐structured telephone interviews with patients that meet the appropriate use criteria for AD CSF biomarker testing and separate interviews with their care partner. A subset of patients (n=33) and care partners (n=31) were interviewed post‐CSF biomarker disclosure and again ∼5 months (median: 4.9 [4.2‐5.3]) after the initial interview. Thematic content analysis was performed to understand the impact of AD biomarker testing on health behaviors, financial and care planning decisions, and resources and support needs.

Result

Most patients (94%) rated their decision to undergo testing as “easy”, with the remainder noting the decision was neither easy nor difficult. After result disclosure, a few patients (8%) reported feelings of concern, but the majority (80%) reported overall positive feelings from having more information about their brain health, certainty around their diagnosis, and the ability to plan ahead. Regarding actions patients planned to take after learning their test result, many expressed an intention to adopt or continue with healthy behaviors, such as exercise (42%). From the care partners’ perspective, many expressed relief at having more diagnostic certainty post‐disclosure, and that this information would help them plan for future care needs. Post‐disclosure, care partners also relayed an increased awareness of future caregiving responsibilities and the need or desire to connect with community resources to help navigate this new role. Additional analyses investigated responses based on patients’ amyloid status and disease severity.

Conclusion

In summary, individuals undergoing AD CSF biomarker testing and their care partners found that CSF testing provided the information needed to help them make wellbeing decisions and plan their future.
Differential impact of APOE genetic variants on autosomal dominant‐ and sporadic‐ Alzheimer disease
Authors: McKay Nicole S. , Hobbs Diana A. , Doering Stephanie , Campbell Connor C. , Kwak Iris , Mei Bochun , Keefe Sarah J. , Flores Shaney , Hornbeck Russ C. , Chen Gengsheng , Renton Alan E. , Cruchaga Carlos , Bateman Randall J. , McDade Eric , Hassenstab Jason J. , Morris John C. , Gordon Brian A. , Benzinger Tammie L.S. ,   the Dominantly Inherited Alzheimer Network
Published: December 2022

Background

Variants in the apolipoprotein E (APOE) gene represent the greatest genetic risk factor for Alzheimer disease (AD). Carriers of the ε4 allele have an increased risk of developing AD pathology and a lower age of symptom onset. While prior work has focused on the sporadic form of AD, little is known about how the ε4 allele impacts AD‐specific pathology in autosomal dominant AD (ADAD).

Method

430 participants from the Charles and Joanne F. Knight Alzheimer Disease Research Center and 276 ADAD mutation‐carriers from the Dominantly Inherited Alzheimer Network, were included in these analyses. Participants were classified as ε4‐positive or ‐negative, and further grouped using Clinical Dementia Rating® (CDR®) scores as cognitively impaired or –unimpaired (Table 1). All participants completed magnetic resonance imaging (MRI), beta‐amyloid positron emission tomography (Ab‐PET), and cognitive testing within a 12‐month period.

Result

Using regression models, we replicated prior work demonstrating that the ε4 allele is associated with an increase in AD pathology measured by Ab‐PET and MRI in a sporadic AD cohort. Furthermore, the ε4 allele was also associated with a decline in cognitive performance. Follow‐up pairwise comparisons revealed that within the sporadic‐AD cohort, the influence of the ε4 allele was most pronounced in individuals who were cognitively impaired. In contrast, in a cohort of individuals possessing autosomal dominant mutations, the ε4 allele was not associated with increases in pathology measured by Ab‐PET and MRI, nor was it associated with a decrease in cognition (Table 1; Figure 1).

Conclusion

We present quantitative evidence that the APOE‐ ε4 allele differentially impacts the pathology and cognitive outcomes of sporadic‐ and autosomal dominant AD. In those with sporadic AD, possession of at least one copy of the ε4 allele is associated with increased amyloid deposition and cortical thinning, as well as decreased cognition, particularly in individuals who are cognitively impaired. However, in ADAD mutation‐carriers, these same patterns are not evident. We propose that this is due to the overwhelming influence of the autosomal dominant genetic mutations that drive this unique and rare form of AD.
Childhood perceived financial status, current financial concerns, and late‐life cognition: Study of Healthy Aging in African Americans (STAR)
Authors: Gilsanz Paola , Soh Yenee , Malladi Pallavi , Barnes Lisa L. , Peterson Rachel L. , George Kristen M. , Mungas Dan M. , Whitmer Rachel A.
Published: December 2022

Background

Low socioeconomic status in childhood has been associated with worse late‐life cognition. However, few studies have examined the association between perceived childhood financial status on late‐life cognition in this population.

Method

764 participants of the Study of Healthy Aging in African Americans (STAR), a cohort of Black Americans aged 50+ (mean age 62) reported their childhood financial status (response options: pretty well off (henceforth above average), about average (henceforth average) varied, or poor) and frequency of current financial concerns (coded as always/often, sometimes, never). Baseline executive function, semantic memory, and verbal episodic memory were assessed through the Spanish and English Neuropsychological Assessment Scales. Linear regression models estimated the associations of childhood financial status and current financial concerns with domain‐specific scores adjusting for age, sex, and education. Sensitivity analyses concurrently included childhood financial status and current financial concerns.

Result

Among participants, 68% were female, 28% reported poor childhood financial status, and 12% reported “always” or “often” having current financial concerns (Table 1). Compared to individuals reporting above average childhood finances, sematic memory scores were lower among those reporting average (β = ‐0.16; 95% CI: ‐0.32, 0.001; Figure 2), varied (β = ‐0.34; 95% CI: ‐0.61, ‐0.07), or poor childhood financial status (β = ‐0.20; 95% CI: ‐0.37, ‐0.03). There were no differences in executive function scores or verbal episodic memory scores by childhood financial status (Figures 1 and 3). Frequency of current financial concern was not associated with executive function, semantic memory, nor verbal episodic memory scores (Figures 1‐3). The association between childhood financial status and semantic memory scores persisted when additionally adjusted for frequency of current financial concerns. There were no associations between childhood financial status and current financial concerns with executive function or verbal episodic memory scores.

Conclusion

Childhood financial status was associated with lower semantic memory test performance, even after accounting for current financial concerns. Future studies including direct measurement of brain health (e.g. brain imaging) are needed to better illuminate associations between childhood socioeconomic status with late‐life brain health.
Dementia Spousal Caregiving
Authors: Johnson Florence U , Robinson‐Lane Sheria G , Veliz Philip
Published: December 2022

Introduction

Dementia family caregiving has been linked to depression, anxiety, insomnia, and other negative mental health symptoms, particularly among spousal caregivers who are most likely to have higher levels of caregiving hours. Further, depressive symptoms often present differently based on caregiver race and ethnicity. This study aimed to examine the association between spousal caregiving hours and self‐reported depressive symptoms as well as identify any racial/ethnic disparities in depression self‐reporting.

Method

Data was drawn from Wave 9 (2008) of the Health and Retirement Study and included 10,120 participants. Linear regression was used to evaluate the relationships between caregiving hours and depression symptoms. Further, a negative binomial model was used to test whether race/ ethnicity moderated the relationship between caregiving hours and self‐reported depressive symptoms.

Results

As expected, self‐reported depressive symptoms increased as caregiving hours increased (1.65, SD = 2.02, p <0.01). Among the racial and ethnic groups evaluated, Latinx participants experienced the highest levels of depressive symptoms relative to caregiving hours.

Discussion

Dementia affects families. Care and consideration of the family are as important as the care of the individual affected by a dementia‐related diagnosis. Depression is a serious anticipated mental health outcome linked to dementia family caregiving responsibilities. As such, there is a need for increased culturally responsive professional screening and treatment for depression among family caregivers. Relatedly, primary care providers play an important role in identifying patients serving as family caregivers and offering necessary supports and referrals.
Altered Affect and Increased CLIP+ B cells in the Meningeal Lymphatics of 5xFAD mice are mitigated by antagonizing MHCII‐associated invariant chain (CLIP)
Authors: Iannucci Jaclyn , Beevers Samantha , Tobin Richard , Newell‐Rogers M. Karen , Shapiro Lee A.
Published: December 2022

Background

Depression often occurs prior to Alzheimer’s disease (AD) and both depression and AD have been linked to immune mechanisms. A key role for activated B cells in AD pathogenesis was recently identified. The study found that B cell depletion reduced Aβ plaque accumulation, neuroinflammation, and behavioral deficits in three AD transgenic mouse models. Our work has shown that treatment with a peptide antagonist for Major histocompatibility complex class II (MHCII) invariant peptide (CLIP), a key component in the transition between innate and adaptive immunity, results in selective depletion of pro‐inflammatory, CLIP+ve B cells and neuroprotection. We hypothesized that selective depletion of CLIP+ve B cells in the 5xFAD model of AD would reduce depression‐associated behavioral deficits.

Method

11‐week‐old male WT and 5xFAD mice underwent social interaction and burrowing pre‐testing. 12‐week‐old mice were treated once with a competitive antagonist peptide (CAP) or vehicle, followed by social interaction and burrowing testing once a month for 5 months. 6 months post‐treatment, meningeal lymphatics were collected, stained, and analyzed flow cytometrically for markers of B cells (CD19), T cells (CD3), and CLIP.

Result

Affective alterations were observed in 5xFAD mice as early as 11 weeks of age and persisted up to 9 months of age. CAP treatment in 5xFAD mice protected against an age‐associated decline in social interaction. At 9 months of age 5xFAD mice were found to have significantly more B cells and CLIP+ve B cells in the meningeal lymphatics when compared to age‐matched WT, and CLIP+ve B cells were significantly decreased by a single CAP injection at 3 months of age.

Conclusion

A key function of B cells is their role as antigen presenting cells (APCs). CLIP occupies the MHCII antigen binding groove until it is displaced by antigen to be presented to CD4+ T cells, marking the transition between an innate and an adaptive immune response. Our findings suggest that 5xFAD mice exhibit depression‐associated behavior by 11 weeks of age, that CLIP+ve cells are elevated in 5xFAD mice, and that antagonizing CLIP depletes these B cells and functionally protects mice genetically predisposed to AD.
Sexually‐dimorphic effects of C3aR1 disruption in a mouse model of Alzheimer’s disease
Authors: Quipildor Gabriela E. Farias , Audrain Mickael , Gandy Sam , Ehrlich Michelle E. , Salton Stephen
Published: December 2022

Background

The complement system can act as part of the innate immune system as well as the adaptive immune system. Complement activation in the brain has been shown to play a role in neurogenesis, synaptic pruning and plasticity. It has also been specifically involved in microglial function, since our group has previously shown that when the complement component 3a receptor 1 (C3aR1) is disrupted in mice, phagocytosis by primary microglia cells is impaired as compared to WT microglia. Therefore, it is hypothesized that complement might have neuroprotective effects early in life but neurotoxic effects later in life or within a disease context, such as during Alzheimer’s disease (AD) impeding to effectively clear hallmarks of the disease.

Method

We performed bulk RNA sequencing (RNAseq) analysis from cortex tissue of 8mo old male and female wild‐type, C3aR1 knock‐out (KO), 5xFAD and 5xFAD‐C3aR1 KO mice. We also performed Barnes Maze on these mice to assess spatial learning and memory, as well as biochemical assays to measure several AD markers.

Result

Data obtained from RNAseq analysis has shown a sexually‐dimorphic trend in various differentially‐expressed genes (DEGs). For instance, when comparing 5xFAD‐C3aR1 KO with 5xFAD mice, male mice show downregulated DEGs in axon guidance and calcium signaling pathways according to KEGG pathway terms, but this is not seen in females. Similarly, barnes maze has shown sexually‐dimorphic differences, with 5xFAD‐C3aR1 KO male mice showing improve memory and learning when compared to 5xFAD mice, and no differences are seen in female mice.

Conclusion

Interestingly, other studies in humans have shown increased complement proteins in the cerebrospinal fluid of men, compared to women, showing the importance of studying the complement system in both males and females. Assessing these sexually‐dimorphic differences in this AD mouse model is also important, given that generally not only female mice present more aggressive phenotypes of AD, but also AD in humans is more prevalent in women.
Characteristics and quantitative impact of off‐target skull binding in tau PET studies of Alzheimer disease
Authors: Flores Shaney , Chen Charles D. , Su Yi , Dincer Aylin , Keefe Sarah J. , Perez‐Carrillo Gloria Guzman , Hornbeck Russ C. , Goyal Manu S. , Vlassenko Andrei G. , Schwarz Sally , Nickels Michael L. , Wong Dean F , Tu Zhude , McConathy Jonathan , Morris John C. , Benzinger Tammie L.S. , Gordon Brian A.
Published: December 2022

Background

Binding of 18F‐Flortaucipir (FTP) has qualitatively been noted in the skull. We investigate the characteristics of this off‐target signal, as well as its impact on regional PET analyses.

Method

FTP tau PET, 18F‐Florbetapir (FBP) amyloid PET, head CT, and T1‐weighted MR images were acquired for 313 cognitively unimpaired and impaired older participants. A subset (n=152) also received a 11C‐PiB PET scan. Another subset (n=14) received longitudinal FTP scans. MR images were segmented into ROIs using FreeSurfer and a skull ROI for each participant was defined from the head CT after removing non‐skull bone and tissue. Standard uptake value ratios (SUVRs) were calculated for all ROIs. Skull binding was correlated across FTP, FBP, and PiB to determine if binding is radioisotope specific. Longitudinal persistence of FTP skull signal was tested in the subset with longitudinal data. Finally, participants were grouped by amyloid positivity based on FBP and linear models controlling for age and sex predicted regional non‐partial volume corrected (non‐PVC) and PVC SUVR from skull SUVR to assess the regional impact of skull signal.

Result

FTP skull binding was significantly correlated with both FBP (ρ=0.48, p<0.001, Figure 1A) and PiB (ρ=0.34, p<0.001, Figure 1B), suggesting the binding is not due to tracer defluorination. In the longitudinal subset, baseline SUVR was significantly correlated with follow‐up SUVR (Figure 2). Higher skull SUVR resulted in erroneously elevated regional SUVRs for areas in the frontal, parietal, and temporal lobes in amyloid negative individuals. After applying PVC, only medial temporal, inferior parietal, and lateral occipital continued to show significant positive relationships with skull SUVR (Figure 3). Decreased skull bone density was significantly related to higher skull SUVR in women but not men (see Figure 4).

Conclusion

Skull signal from FTP is a stable, subject‐specific phenomenon that can persist across longitudinal visits and tracers. This off‐target signal can potentially bias quantitative PET measurements in AD tauopathy regions in amyloid negative but not positive individuals even after PVC is applied. The bone binding was overwhelmingly driven by women, suggesting at least some proportion of previously observed sex effects may be driven by bone uptake.
Not sexy enough: the uphill battle faced by non‐traditional treatments in the U.S. despite having the most compelling AD results to date
Authors: Hendrix Suzanne B. , Nicodemus‐Johnson Jessie , Hogan Nathaniel J. , Knowlton Newman , Hennessey Sean , Dickson Samuel P.
Published: December 2022

Background

The most followed investigational treatments for Alzheimer’s disease are small molecules (80/140 in development, 57%) and immunotherapies (32/140, 23%). These treatments have a clear regulatory path and are based on innovative scientific approaches that are generally patentable and marketable. The remaining 20% (28/140) of therapeutic approaches involve procedures, devices, supplements, combination treatments and others.

Method

A literature review was performed for all interventions in phase 2 or later as listed on Alzforum.org for any stage of Alzheimer’s disease. Results were considered against the standard of the most progressive aspects of disease by either combining ADAS‐cog, ADCS‐ADL and a global outcome (CDR‐sb, CIBIC or CGIC) or assessing a progression composite such as ADCOMS. This was to ensure comparable results across studies and relevance to disease progression. The percent slowing versus placebo was compared.

Result

Of the studies investigated, Souvenaid (mild cognitive impairment (MCI)) and AMBAR (mild‐to‐moderate) demonstrated the most compelling AD results to date. The Souvenaid results demonstrated a 36% slowing of progression over 24 months in MCI due to AD (ADCOMS). The AMBAR results (active vs control) demonstrated 59% slowing of progression over 14 months in Mild‐to‐Moderate AD (ADAS‐cog, ADCS‐ADL, and CDR‐sb+CGIC). Neither of these treatments have major side effects.

Conclusion

Regulatory approval increases visibility and availability of effective treatment to those suffering from AD. Unfortunately, no clear approval path is available for either of these promising treatments. If Souvenaid becomes available in the U.S., it will be considered one of many general supplements for cognitive health, despite the strong clinical trial data collected to a regulatory standard. Plasmapheresis is a procedure that is not subject to FDA regulation. The AMBAR treatment is available for other indications, and most plasmapheresis treatments are approved by payors if they are recommended by a plasmapheresis board, leading to a challenging regulatory path. Unless the regulatory playing field is leveled for non‐traditional treatments, the safest and most promising treatments may be overlooked in favor of sexier treatments like immunotherapies and small molecules.
Factors Associated with Cognitive Resilience in Persons Aged 80 and Older
Authors: Trammell Antoine R , Goldstein Felicia C , Parker Monica W , Hajjar Ihab
Published: December 2022

Background

African Americans (AA) have increased Alzheimer’s disease (AD) risk. Despite a high prevalence of risk factors for cognitive decline like vascular disease, data indicates that AA have a high degree of cognitive resilience, the ability to maintain normal cognitive functioning with aging. Most knowledge about cognitive resilience and SuperAgers (SA) is based on results from predominantly white samples. In a biracial sample, we investigated factors related to cognitive resilience in persons aged 80 and older.

Method

Data from the National Alzheimer’s Coordinating Center (NACC) through November 2020 was analyzed. NC was defined per global CDR score = 0 and SA by cognitive performance for episodic memory, executive function, naming, and phonemic fluency within 1 standard deviation of the mean or better. Using ANOVA or chi‐square, we compared demographic, medical, and lifestyle factors by race and cognition [normal cognition (NC) vs. SA]. Logistic regression evaluated factors related to cognitive group by race. The significance level for all tests was p < 0.05.

Result

AA SA had more education years (15.3 vs. 13.9, p = .01), no alcohol abuse (11.7 vs. 1.4%, p<.01), and fewer lived alone (5.4 vs. 53.2%, p<.01) compared to NC. White SA had more education years (16.9 vs. 15.4, p<.01) and higher BMI (26.3 vs. 25.7, p = .03) compared to NC. In AA, regression showed that female sex (OR:3.12, 95% CI:1.19‐8.17) and no depression history (OR:7.46, 95% CI: 1.01‐55.1) were more likely to be SA. In whites, female sex (OR: 2.02, 95% CI: 1.56‐2.62) and no heart disease (OR:4.27, 95% CI:2.36‐7.72) were more likely to be SA.

Conclusion

In persons of advanced age, factors associated with SA can vary with race. Prospective investigation with a diverse study sample is needed to investigate whether the findings are replicated.
Predicting gene regulatory networks from multi‐omics to link genetic risk variants and neuroimmunology to Alzheimer’s disease phenotypes
Authors: Khullar Saniya , Wang Daifeng
Published: December 2022

Background

Genome‐wide association studies have found many genetic risk variants associated with Alzheimer’s disease (AD). However, how these risk variants affect deeper phenotypes such as disease progression and immune response remains elusive. Also, our understanding of cellular and molecular mechanisms from disease SNPs to various phenotypes is still limited. To address these problems, we performed an integrative multi‐omics analysis of genotype, transcriptomics, and epigenomics for revealing gene regulatory mechanisms from disease variants to AD phenotypes.

Method

First, given population gene expression data of a cohort, we construct and cluster its gene co‐expression network to identify modules for various AD phenotypes. Next, we predict transcription factors (TFs) regulating co‐expressed genes and SNPs interrupting TF binding sites on regulatory elements. Finally, we construct a gene regulatory network (GRN) linking SNPs, interrupted TFs, and regulatory elements to target genes and modules for AD phenotypes. This network provides systematic insights into gene regulatory mechanisms from SNPs to phenotypes. We looked at our GRNs relating to genes from shared AD‐Covid pathways (e.g. NFKB Pathway) and used machine learning to prioritize those genes for predicting Covid‐19 severity

Result

Our analysis predicted cross‐region‐conserved and region‐specific GRNs in 3 regions Hippocampus, Dorsolateral Prefrontal Cortex (DLPFC), Lateral Temporal Lobe (LTL). For instance, SNPs rs13404184 and rs61068452 disrupt SPI1 binding and regulation of INPP5D in Hippocampus and LTL. While rs4802200 disrupts E2F7 regulation of KCNN4 (belongs to AD LTL module), rs117863556 interrupts REST regulation of GAB2 in DLPFC. Further, we used Covid‐19 as a proxy for immune dysregulation to identify possible regulatory mechanisms for AD neuroimmunology. Decision Curve Analysis suggest our AD‐Covid genes along with linked SNPs (that outperform known genes) can be potential novel biomarkers for neuroimmunology. Finally, our results are open‐source available as a comprehensive AD functional genomic map, providing deeper mechanistic understanding of the interplay among multi‐omics, regions, gene functions, phenotypes.

Conclusion

Our pipeline predicts how non‐coding risk SNPs may be associated with changes in regulation and subsequent expression of genes associated with different phenotypes and pathways in AD. Moreover, we flagged 51 potential AD‐neuroinflammatory risk genes, which may be early biomarkers as neuroinflammation may begin decades before clinical onset.
Translational potential of JAX humanized APOE mice: Peripheral interferon gamma induces systemic immuno‐metabolic dysfunction
Authors: Van Rossum Hannah , Delatorre Nicole , Mishra Aarti , Bhattrai Avnish , Raikes Adam C. , Rodgers Kathleen E. , Brinton Roberta Diaz
Published: December 2022

Background

Inflammation is a well‐documented feature of Alzheimer’s disease (AD) in human brain. Previous findings from our group demonstrated upregulated immune transcripts in the AD brain as well as sex differences in immune transcript levels during pre‐clinical midlife aging. Using our humanized APOE mouse model, we identified elevated immune transcripts in the female brain including interferon signaling genes, CD3, CD4, and MHCII. We hypothesized that activation via increased interferon gamma (IFN‐γ) during endocrine aging may disrupt the immune‐metabolic balance in the brain and therefore advance changes in grey and white matter. With this study, we test the hypothesis that increased levels of peripheral IFN‐γ induces genotype dependent immuno‐metabolic changes in the JAX humanized APOE (hAPOE) mouse model.

Method

To determine the role of IFN‐γ in female midlife aging and AD risk, pre‐menopausal and peri‐menopausal hAPOE mice were intraperitoneally treated with recombinant IFN‐γ for 9 days. Immunophenotyping using multi‐color flow cytometry was conducted microglial reactivity, phagocytosis, neutral lipid content, oxidative stress, and the presence of lymphocytes were determined. Structural and diffusion weighted analysis using MRI was conducted to evaluate grey and white matter structural integrity in the brain. ELISA assays were conducted to assess the presence of beta amyloid 40 and 42 and levels of pro‐inflammatory cytokines.

Result

IFN‐γ treated animals exhibited upregulation of markers that perpetuate neuroinflammation and white matter catabolism including MHCII, CD8, pHrodo, and BODIPY. Peripheral immune effects were genotype dependent while immune signaling in brain largely exhibited treatment‐dependent effects. Fasting blood glucose levels were significantly increased by IFN‐γ consistent with an accelerated aging profile. Diffusion metrics including mean and radial kurtosis in addition to mean, axial, and radial diffusivity were greater in IFN‐treated animals.

Conclusion

Peripheral increase of interferon gamma signaling during female endocrine aging in hAPOE mice induced 1) dysfunction of metabolic systems and neuroinflammatory response and 2) decreases in white and grey matter microstructural integrity throughout the brain. These outcomes support the investigation of therapeutic strategies targeting interferon signaling pathways at the earliest stages of midlife aging to reduce risk of AD or delay AD onset.
Discovery and Characterization of Intracellularly Stable hnRNPA2B1 Specific Nanobodies for Live‐Cell Imaging and Targeted Protein Degradation
Authors: Pirhanov Azady
Published: December 2022

Background

Heterogeneous nuclear ribonuclear proteins, hnRNPs, play a variety of roles in regulating transcriptional, and post‐transcriptional gene expression. A core member of the hnRNP family, hnRNPA2/B1 proteins are involved in the formation of membraneless‐organelles such as stress granules (SGs) under certain conditions. Mutations in hnRNPA2/B1 proteins are known to cause multisystem proteinopathy (MSP), a pleiotropic group of inherited disorders that cause neurodegeneration, myopathy, and bone disease. Mutations in hnRNPA2/B1 are also risk factors for the development of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Despite growing evidence implicating hnRNPA2/B1 proteins in a multitude of diseases, our ability to study them in live cells is severely limited due to the lack of intracellularly stable hnRNPA2/B1 specific antibodies. Nanobodies (sdAbs) are antibody fragments derived from heavy‐chain‐only antibodies found in camelids and sharks. Owing to their small size (∼15 kDa) and unique biochemical properties, nanobodies emerged as promising alternatives to conventional‐antibody derived protein fragments. Nanobodies have superior stability that facilitate their intracellular expression. Full length antibodies and bulkier antibody‐derived fragments, such as single chain variable fragments (scFvs), are not amenable to intracellular expression, in part due to the reducing cytoplasmic environment that prevents the formation of disulfide bonds needed for their correct folding.

Method

We have developed a high‐throughput nanobody discovery platform from synthetic yeast surface display libraries by using antigen coated magnetics beads. Furthermore, we have developed generalizable and straightforward cellular assays to characterize nanobody specificity in live cells.

Result

Using above described platforms, we have identified novel hnRNPA2/B1 specific nanobodies and characterized their intracellular stability by expressing them in HEK293 cells. In addition to using nanobodies for studying hnRNPA2/B1 biology in live cells, we have also engineered a panel of modular E3 ubiquitin ligases targeting hnRNPA2/B1 for degradation. ∼30% reduction in hnRNPA2/B1 level was observed when targeted for degradation by using hnRNPA2B1 targeting E3 ubiquitin ligase.

Conclusion

In summary, we have optimized factors affecting successful high‐throughput antibody discovery using yeast‐surface display antibody libraries. We also developed generalizable methods to characterize nanobody specificity in live cells. Platforms we have developed will help build tools to study protein aggregation and protein stability in live cells.