bluuebunny/crossref_metadata_2025 huggingface dataset:
Targeting Substance P Pathway as an Emerging Novel Therapeutic Mechanism for Modulating Amyloid Beta in APP/PS1 Mouse Model
Authors: Yuede Carla M , Cirrito John R , Johns Stefanie , Knie Robb
Published: December 2022

Background

Neurodegeneration associated with Alzheimer’s disease (AD) is well established to be mediated by amyloid β (Aβ) plaques and neurofibrillary tangles (NFTs) of Tau protein in the brain. However, there are a multitude of underlying processes that individually contribute to the development of these aberrant Aβ aggregations and NFTs over time that are still being elucidated. The substance P/neurokinin‐1 receptor signaling pathways play an important role in regulating neuroinflammation and have recently been demonstrated to also influence mechanisms responsible for Aβ amyloidogenesis and toxicity1,2,3. Accordingly, HT‐ALZ is under development as a novel AD therapeutic to target the SP/NK1R pathway.

Method

Using microdialysis, Aβ levels in the interstitial fluid (ISF) of the hippocampus were measured in male and female APP/PS1 mice (3‐4 months old). ISF samples were collected every hour for 6 hours prior to treatment to establish a baseline, HT‐ALZ or vehicle was administered via oral gavage, and samples were collected continuously for 12‐15 hours following treatment. Aβ levels were measured using ELISA and changes from baseline were calculated for each mouse.

Result

We observed a significant change from baseline in mice treated with HT‐ALZ, but not in vehicle treated mice. Mice treated with HT‐ALZ show a decrease in average ISF Aβ following treatment.

Conclusion

Results of our microdialysis study indicate targeting the SP/NK1R pathway has a beneficial effect on circulating Aβ levels in the mouse brain, which may lead to lower plaque load with longer term treatment. We are currently investigating the impact of HT‐ALZ on the cognitive and behavioral impairments in APP/PS1 mice; the results of these studies will be provided at the time of presentation.

References:

1. Martinez AN, Philipp MT. Substance P and Antagonists of the Neurokinin‐1 Receptor in Neuroinflammation Associated with Infectious and Neurodegenerative Diseases of the Central Nervous System. J Neurol Neuromedicine. 2016;1(2):29‐36. doi:10.29245/2572.942x/2016/2.1020

2. Severini C, Petrella C, Calissano P. Substance P and Alzheimer’s Disease: Emerging Novel Roles. Curr Alzheimer Res. 2016;13(9):964‐72. https://doi.org/10.2174/1567205013666160401114039. PMID: 27033058.

3. Chen XY, Du YF, Chen L. Neuropeptides Exert Neuroprotective Effects in Alzheimer’s Disease. Front Mol Neurosci. 2019;11:493. Published 2019 Jan 11. https://doi.org/10.3389/fnmol.2018.00493
Pathological tau in cognitively normal older adults predicts prospective neurodegeneration and cognitive decline
Authors: Chen Xi , Toueg Tyler N , Harrison Theresa M. , Baker Suzanne L. , Jagust William J.
Published: December 2022

Background

Pathological tau burden has been linked to neurodegeneration in AD patients. Although previous studies have linked brain atrophy in people at the preclinical stage of AD to early tau deposition, most evidence is based on cross‐sectional findings or retrospective changes before the tau measurement. This study examines longitudinal atrophy and cognitive decline following the assessment of tau, and specifically the relationship between whole brain tau measures and prospective changes in brain structure and memory.

Methods

124 cognitively normal older adults (> 65 yrs old) underwent FTP PET to measure voxel‐wise tau pathology and PiB PET to measure amyloid positivity at baseline. Rates of change in hippocampal volume (N=74) and memory (N=108) following the PET scan were correlated with whole brain (voxel‐wise) FTP‐PET data.

Results

Prospective memory decline was related to tau deposition in the left temporal, parietal, and posterior regions, and the right parahippocampal gyrus (Figure 1), driven by Aß+ individuals (Figure 2). Prospective hippocampal atrophy was related to tau in the parahippocampal and entorhinal cortices (Figure 3), regardless of Aß status. The overlapping cluster in the right parahippocampal/entorhinal region suggested tau burden in this area was predictive of both hippocampal atrophy and memory decline (Figure 4). Finally, we explored how tau and hippocampal atrophy contributed to memory decline together. We found that memory decline in Aß‐ people was mediated by hippocampal atrophy (31.9%) and that there was very little direct effect of tau on memory decline. However, no mediation of hippocampal atrophy was found in Aß+ people, suggesting a strong effect of tau on memory decline in Aß+ people above and beyond hippocampal atrophy (Figure 5).

Conclusions

Our findings suggest that tau effects on cognitive decline and neurodegeneration are already present in cognitively normal people, and that memory decline may be driven by different factors in normal aging and preclinical AD. Entorhinal tau in Aß‐ adults may be linked to age‐related hippocampal atrophy, which was related to memory decline, whereas degeneration in other regions, or other brain changes (e.g., network integrity, functional activity, etc.), may explain the detrimental effect of tau on memory in Aß+ people.
Premature aging in co‐occurring Alcohol Use Disorder and Post‐Traumatic Stress Disorder from a functional connectome perspective
Authors: Joseph Jane E , Bustos Nicholas , Nowling Duncan , Warner Graham , Barlis Katie L , Mintzer Jacobo E , Dean Brian , Lawson Andrew , Jensen Jens H. , Benitez Andreana , Peterson Alan , Fox Peter T , Flanagan Julianne , Back Sudie
Published: December 2022

Background

Post‐Traumatic Stress Disorder (PTSD) and Alcohol Use Disorder (AUD) may be associated with premature brain aging which increases the risk for Alzheimer’s Disease and Related Dementias (ADRD). While each disorder alone has been studied as a risk factor for ADRD, few studies have examined premature brain aging in co‐occurring PTSD/AUD. It is important to know whether co‐occurring PTSD/AUD may amplify ADRD risk. Consequently, the present study tested the hypothesis that, relative to healthy controls (HC), PTSD/AUD would show more pronounced premature brain aging than AUD alone.

Method

A functional connectome approach was used to develop a model of healthy brain aging. The graph‐theory measure eigenvector centrality was calculated from resting state fMRI scans in 60 mid‐life HC (HC‐mid; mean age=56.9), 69 older adult HC (HC‐older; mean age = 74.1), 36 AUD (mean age=54.4), and 30 PTSD/AUD participants (mean age=55.7). AUD and PTSD/AUD diagnoses were determined by a structured clinical interview. Connectome node features that were most predictive of age in HC‐mid and HC‐older were used in predictive modeling with bootstrap aggregation. These features were from multiple cortical areas and resting state networks. The healthy aging model was transferred to the AUD and PTSD/AUD groups to estimate brain age. Estimated ages in AUD and PTSD/AUD were compared to the predicted age in HC‐mid and HC‐older using generalized linear mixed modeling (GLMM).

Result

Predictive modeling in HC yielded an aggregate model with 49.5% accuracy in predicting age (p < .0001), with some network features showing increases in eigenvector centrality with age and others showing decreases. After model transfer and correcting for age estimation bias, the GLMM yielded a main effect of diagnostic group (Wald c23=141.6, p < .0001). Predicted age for PTSD/AUD was significantly higher (M=61.0) than HC‐mid (M=57.2; p=.048) but predicted age for AUD (M=59.9) was not different from HC‐mid (p=.133). HC‐older predicted age (M=74.1) was different from all other groups (p < .0001).

Conclusion

In this preliminary analysis, premature brain aging in PTSD/AUD was more pronounced than in AUD alone which may suggest greater vulnerability to AD‐like neurodegenerative processes that are manifest at the level of large‐scale network connectivity.
Targeting mitochondria for healthy brain aging: a case study of non‐psychoactive cannabinoids to rescue mitochondrial dysfunction in Alzheimer’s disease
Authors: Liang Zhibin , Maher Pamela
Published: December 2022

Background

Alzheimer’s disease (AD) arises from complex and multifaceted pathogenic mechanisms. Although many alterations occur in the aging brain that are likely to contribute to AD, there is growing evidence that mitochondrial inefficiency and dysfunction are one of the pathophysiological changes contributing to neurodegeneration in AD. The oxytosis/ferroptosis regulated cell death pathway recapitulates many features of mitochondrial dysfunction associated with the aging brain and has emerged as a potential key mediator of neurodegeneration. It has thus been proposed that the oxytosis/ferroptosis pathway could be used to identify novel AD drug candidates that act by preserving mitochondrial function.

Methods

Aiming to identify AD drug candidates from natural products that preserve mitochondrial function, we have focused on phytochemical libraries with medicinal properties. We used a novel preclinical drug‐screening platform based on phenotypic assays that mimic different cellular toxicities and stresses associated with the AD brain that are characterized by mitochondrial dysfunction. To elucidate the molecular mechanisms for mitochondrial regulation, we harnessed an inducible, mitochondrially‐depleted neuronal cell line and employed the combined techniques of live‐cell imaging, super‐resolution microscopy, real‐time mitochondrial metabolic analysis, biochemical assays, immunoblotting, and qPCR.

Results

Using this combined approach, we discovered that cannabinol (CBN), a non‐psychoactive cannabinoid, is a novel and potent neuroprotector. We demonstrated that not only does CBN protect neurons from oxytosis/ferroptosis in a manner that is dependent on mitochondria, it does so independently of cannabinoid CB1/CB2 receptors. Specifically, CBN alleviates intraneuronal amyloid toxicity, directly targets mitochondria, and preserves key mitochondrial functions including redox regulation, calcium uptake, membrane potential, bioenergetics, biogenesis, and modulation of fusion/fission dynamics that are disrupted following induction of oxytosis/ferroptosis in neuronal cells. These neuroprotective effects of CBN are at least partly mediated by the promotion of endogenous antioxidant defenses and the activation of AMP‐activated protein kinase (AMPK) signaling which help to maintain mitochondrial homeostasis.

Conclusions

This study highlights the potential of mitochondrially‐targeted compounds such as CBN as novel oxytotic/ferroptotic inhibitors to rescue mitochondrial dysfunction for healthy brain aging, as well as opportunities for the discovery and development of future therapeutics for Alzheimer’s disease and other age‐associated neurological disorders.
Functional network modularity and efficiency supports episodic memory in older adults with amyloid‐beta pathology
Authors: Adams Jenna N. , Chappel‐Farley Miranda G. , Yaros Jessica L. , Taylor Lisa , Harris Alyssa L. , Mikhail Abanoub , McMillan Liv , Keator David B. , Yassa Michael A.
Published: December 2022

Background

Episodic memory is one of the first cognitive domains to decline in preclinical Alzheimer’s disease. We investigated whether graph metrics of functional networks, specifically modularity and local efficiency, are related to episodic memory and amyloid‐β (Aβ) positivity in cognitively normal older adults.

Method

Sixty‐five cognitively normal older adults (mean age 72.3 ± 6.2 years; 62% female) underwent high‐resolution resting state fMRI (1.8mm3, partial acquisition) to measure functional connectivity, 18F‐Florbetapir‐PET to measure Aβ pathology, and cognitive assessment. Resting state fMRI data was processed with CONN. ROIs (n=135) from the Brainnetome Atlas contained within rsfMRI coverage were used to generate ROI‐to‐ROI functional connectivity matrices. Graph measures of modularity (Q) and local efficiency were computed with the Brain Connectivity Toolbox using binary graphs at costs ranging from 5%‐50% of network sparsity (5% step size). Aβ status was determined using a >1.11 SUVR threshold of a composite region spanning the association cortex, resulting in 32% of the sample being classified as Aβ+. Episodic memory was measured using the immediate recall measure of the Rey Auditory Verbal Learning Test (RAVLT A5).

Result

Aβ+ participants had significantly increased modularity compared to Aβ‐ (Fig1A, p<0.05 for costs 25 and 50), but no differences in local efficiency (Fig1B). There was no significant effect of Aβ positivity on RAVLT A5 performance (t(63)=‐0.67, p = 0.51). However, there were significant interactions between Aβ status and RAVLT A5 with both modularity and local efficiency at most cost functions (Fig2). Better RAVLT A5 performance was associated with higher modularity (Fig2A; ex. cost 25: r = 0.54, p=0.01) and higher local efficiency (Fig2B; ex. cost 25: r = 0.63, p=0.002) within Aβ+ participants, but not Aβ‐ participants (ps>0.36).

Conclusion

Our findings suggest that increases in functional network modularity and local efficiency within Aβ+ cognitively normal older adults may act as a compensatory mechanism to maintain equivalent levels of episodic memory performance.
Early norming data for engagement and recruitment of diverse populations into ADRD research
Authors: Taikeff Nicole , Pham Tiffany , Bennett Erin E , Caruthers Rebekah , Eddings Fran , Resendez Jason , Jackson Jonathan D.
Published: December 2022

Background

Research studies and clinical trials in Alzheimer’s disease and related dementias (ADRD) attract smaller and increasingly less‐representative populations. Enrollment barriers are compounded for historically marginalized and minoritized populations (HMM), despite a higher risk of ADRD. Advancements in participant recruitment, retention, and engagement (RER), and clinical research design are urgently needed to address ADRD disparities and inequities. In light of these critical shortfalls in diverse and representative RER, we aimed to improve the understanding of research awareness and motivations of lay communities.

Method

Partnering with a community mobilization firm, we canvassed 15,000 residents of Harris County, TX, a diverse county that broadly generalizes to populations across the United States. Oversampling of multiple HMM communities was conducted to assess enrollment barriers and facilitators, as well as attitudes regarding ADRD and ADRD research. Individuals were contacted via a combination of in‐person and phone canvassing. These detailed canvassing data were paired with geospatial mapping tools to develop robust, dynamic catchment areas.

Result

An initial set of RER norms were developed across HMM and non‐HMM populations; this presentation focuses on stratified norms for Black, Latinx, and East Asian populations intersecting with gender identity and educational attainment to demonstrate the complexity of tailored best practices in RER, as well as identification of HMM subsamples that may be readily engaged in RER for ADRD studies. Using Houston as a case study, these norms were developed in contextualized catchment areas that ascertain the type, prevalence, and intersection of ADRD research barriers. Recommendations to improve diversity and representativeness in ADRD research are additionally summarized for HMM and non‐HMM populations.

Conclusion

The current study sought to develop a robust approach to RER centering sustainable and inclusive recruitment into ADRD studies. These data were used to develop detailed RER profiles of general and intersectional HMM populations that may function as initial RER norms, supplanting poorly‐defined catchment area estimates for ADRD study sites. These tools will allow researchers to define communities a priori to limit sampling and recruitment bias, and to determine RER barriers with validity. These data are foundational to advance equitable progress in dementia research.
Trem2R47H NSS; 5xFAD mice display age/disease progression‐dependent changes in plaques and plaque‐associated microglia, and increased plasma neurofilament light chain
Authors: Tran Kristine M , Kawauchi Shimako , Javonillo Dominic I , Da Cunha Celia , Phan Jimmy , Rezaie Narges , Liang Heidi Yahan , Milinkeviciute Giedre , Gomez‐Arboledas Angela , Forner Stefania , Mortazavi Ali , Tenner Andrea J , LaFerla Frank , MacGregor Grant R , Green Kim N
Published: December 2022

Background

Genome‐Wide Association Studies revealed Triggering receptor expressed on myeloid cells 2 (TREM2) R47H mutation as one of the strongest genetic risk factors for late‐onset Alzheimer’s Disease (AD). In the brain, TREM2 is a transmembrane receptor expressed exclusively by myeloid cells. Many current TREM2*R47H mouse models have observed evidence of cryptic splicing products of the mutant allele, resulting in artefactually reduced protein product. Model Organism Development & Evaluation for Late‐Onset Alzheimer’s Disease (MODEL‐AD) consortium at University of California ‐ Irvine has developed the Trem2
R47H NSS (Normal Splice Site) mouse model where the Trem2 allele is expressed at a level similar to the wild‐type Trem2 allele, with no evidence of cryptic splicing products from the mutant allele.

Method

We generated four groups – WT (C57BL6/J), Trem2
R47H homozygous (HO), 5xFAD, and 5xFAD/ Trem2
R47H HO. Coronal brain slices of 4 and 12‐month‐old mice (n=5/sex/genotype/age) were immunolabeled with Thioflavin‐S for dense‐core plaques, ionized calcium binding adaptor molecule 1 (IBA1) for microglia and lysosome‐associated membrane glycoprotein 1 (LAMP1) for neuritic dystrophy. We also measured plasma neurofilament light chain (NfL) as a surrogate measure of brain damage via Meso Scale Discovery (MSD) technology.

Result

Sex‐related differences in dense‐core Aß plaque burden and size are found in 4‐month 5xFAD/ Trem2
R47H, where female 5xFAD/ Trem2
R47H mice exhibit increased plaque load compared to 5xFAD mice. In males, stark reductions in plaque load are observed. This sex‐difference is not observed at 12‐month. Examination of IBA1+ microglia at 4‐month reveals significant reductions in microglia volume in both Trem2
R47H and 5xFAD/ Trem2
R47H mice compared to their controls. Notably, there is a significant impairment of plaque‐microglia interaction in 5xFAD/ Trem2
R47H at 4‐month that is rescued at 12‐month. Moreover, we find a significant increase in plaque‐associated neuritic damage in 5xFAD/ Trem2
R47H when immunolabeled with LAMP1 at 4‐month that was also absent at 12‐month. Similarly, plasma NfL levels revealed significant increases in brain damage of 5xFAD/ Trem2
R47H compared to 5xFAD at 4‐month and a trending increase at 12‐month.

Conclusion

Collectively, these results show the effects of the Trem2
R47H variant on plaque development and downstream pathology, highlighting sex differences as well as age/ disease progression‐dependent changes.
Developing the ‘Good Life’ Model: The Recruitment and Training of ‘Dementia Ambassadors’ to Provide a Novel Coaching Approach for Family Caregivers
Authors: Webster Melinda J , Bouranis Nicole G , Gitlin Laura N. , Gliebus Gediminas Peter
Published: December 2022

Background

The Good Life Model is an evidence‐informed service extension program that seeks to improve the quality of daily life for people living with dementia (PLWD) and their caregivers through an integrated, replicable health professional learning service approach. To provide this service, caregivers referred from a neurology clinic are matched to Dementia Ambassadors (DAs), nursing and health profession faculty and graduate students who are trained in family‐centric and nonpharmacological approaches. DAs serve as coaches to telephonically provide disease education, referrals and linkages, support and skills in managing caregiver‐identified care challenges. Good Life offers a service‐learning approach for developing a workforce that is prepared to care for families living with dementia, while improving the quality of daily life for both people living with dementia and their caregivers.

Methods

DAs involve various health professionals and students and receive training tailored to their level of expertise in dementia care. Regardless of dementia expertise, key competencies include 1) knowledge about dementia types and etiologies, 2) core clinical signs (e.g., behavioral and psychological symptoms, cognitive and functional decline), 3) knowledge of caregiver experiences, 4) ability to assess care challenges and serve as a coach, and 5) ability to rapidly develop rapport and engage in active listening. Caregivers receive support through bimonthly one hour telephone sessions for up to 12 sessions over 6 months. Biweekly case debriefings provide ongoing oversight and support for DAs.

Results

To date, 36 caregivers have been referred, with 19 enrolled having completed 123 sessions. Of the 8 caregivers who have completed the 6 month program, all have elected to continue optional post‐program sessions.

Conclusions

In providing access and support to underserved populations with a nonpharmacological phone intervention, Good Life demonstrates not only the need for service extension practices as part of standard dementia care to support PLWD and caregivers, but highlights the importance of preparing a workforce to help caregivers manage challenges. Furthermore, caregivers to date having unanimously elected to continue post‐program sessions attests to the rapid and powerful relationship developed between DAs trained in these practices and the caregivers who gain value from participating.
Validation of Mitochondria‐Targeted AD Therapeutics in Human Neuronal Cells
Authors: Hasan Md Fayad , Nguyen Thi Kim Oanh , Trushina Eugenia
Published: December 2022

Background

Neurons and astrocytes were differentiated separately from human induced pluripotent stem cells (HiPSC) derived from Late‐Onset Alzheimer Disease (LOAD) female patients carrying Apolipoprotein E4 (ApoE4) allele. Cells from age and sex matched healthy subject carrying Apolipoprotein E3 allele were used as control. These neuronal, astrocytic, and their co‐cultures were assessed to investigate cell‐specific AD phenotypes (Figure 1). We recently demonstrated that application of a small molecule partial mitochondrial complex I inhibitor CP2 blocked neurodegeneration and cognitive decline in multiple mouse models of AD. However, the demonstration that this novel therapeutic approach is efficacious in human brain cells has not been done. Here, we aimed to validate neuroprotective mechanisms induced by CP2 using patient‐derived neuronal cells form LOAD patient. Outcomes will further support the development of these compounds for clinical application.

Method

Axonal trafficking of MitoTracker Red stained mitochondria in neuron‐astrocyte co‐cultures was captured using live confocal imaging. The Seahorse XFe96 flux analyzer was used to evaluate mitochondrial bioenergetics in co‐cultures and pure neuronal or astrocytic cultures. Cell Viability Assays were used to perform H2O2 challenge. Quantitative polymerase chain reaction (qPCR), immunohistochemistry, and western blot were carried out to assess alterations in the expression of relevant genes and protein products.

Result

We have found that LOAD cells have a significant reduction in the percentage of motile mitochondria in axons, increased accumulation of neuronal phosphorylated Tau, and altered bioenergetics in neurons and astrocytes compared to the control cells. qPCR revealed elevated expression of inflammation related genes in LOAD co‐cultures. CP2 treatment at concentrations found therapeutically relevant in vivo in APP/PS1 and 3xTgAD mice improved cellular bioenergetics, rescued mitochondrial motility, and provided neuroprotection against H2O2 induced oxidative stress.

Conclusion

LOAD HiPSC‐derived neuronal co‐cultures and individual brain cells recapitulate mechanisms associated with LOAD allowing validation of a novel mitochondria‐targeted therapeutics. Our results support previous observation in AD mice and the hypothesis that partial inhibition of mitochondrial complex I activates neuroprotective compensatory mechanisms improving cellular energetics in LOAD human neurons even in the presence of mitochondria with abnormal dynamics and energetics. Further efforts are focused on the determination of a cell‐specific mechanisms of neuroprotection.
Using an entorhinal cortex‐based virtual reality navigation task to differentiate between individuals with and without subjective cognitive decline
Authors: Segen Vladislava , Wolbers Thomas
Published: December 2022

Background

Entorhinal cortex is vulnerable to neurodegenerative changes in the earliest stages of AD. However, this early AD stage cannot be detected by currently available neuropsychological tests. The entorhinal cortex contains spatial modulated cells, known as grid cells, that play a key role in supporting path integration (PI), a crucial component of spatial navigation that supports continuous integration of self‐motion information and in combination with environmental cues provides accurate internal representation of space. Previously, PI deficits were associaed with impaired grid cell function in healthy older adults and in young APOE‐E4 carriers. Importantly, PI performance has successfully discriminated between biomarker positive and negative mild cognitive impairment patients and between healthy older adults at higher and lower risk of AD. In this study, we tested whether performance on an immersive virtual reality PI task can differentiate between patients with and without subjective cognitive decline (SCD).

Method

A group of healthy older adults and SCD patients will perform an immersive virtual reality PI task. In this task, participants are immersed in an open‐field virtual environment and are guided along short, curved paths. At certain points they are asked to stop and indicate their initial heading orientation and the location of an object, providing information about distance and orientation coding. During the task participants have access to multisensory self‐motion cues (visual, vestibular and proprioceptive), all of which are pivotal for supporting grid cell function. Additionally, participants will be screened for presence of objective cognitive impairments and will undergo an assessment of their visuospatial working memory and balance.

Result

We will compare if SCD patients perform worse than healthy older controls in the general PI performance measures (e.g., PI error, response time). Furthermore, we will apply a recently developed computational model to identify multiple sources of PI error. This approach allows for a very nuanced characterization of PI deficits, and, as a result, provides additional, potentially even more sensitive markers of very early AD compared to typical PI performance measures.

Conclusion

The results will be discussed with reference to the utility of immersive virtual PI as a sensitive biomarker for early, preclinical, AD manifestation.
Cell‐specific responses to Tau pathology in the aging brain
Authors: Wu Timothy , Guo Caiwei , Deger Jennifer Marie , Dhindsa Justin , Al‐Ouran Rami , Shulman Joshua M
Published: December 2022

Background

Gene expression profiling has emerged as a promising unbiased approach to characterize putative mechanisms of Alzheimer’s disease (AD). We previously highlighted transcriptional signatures that are driven by Tau pathology or aging in a longitudinal Drosophila model of tauopathy and human RNA‐sequencing data. However, cellular heterogeneity confounds the interpretation of bulk‐tissue gene expression. Defining cell types and characterizing cell‐specific processes that precipitate neurodegeneration is crucial for elucidating AD pathogenesis.

Method

We use a highly tractable, longitudinal, Drosophila model of tauopathy and single cell transcriptomics (scRNA‐seq) to explore cell‐specific contributions to tau‐mediated gene expression while accounting for age‐related changes. Brains of adult Drosophila pan‐neuronally expressing a mutant variant of human Tau (R406W) and respective controls were dissociated for droplet‐based scRNA‐seq at 1‐, 10‐, and 20‐ days post‐eclosion. We computed differentially expressed genes (DEGs) for each cell subpopulation and profiled gene regulatory networks (regulons), highlighting cell‐specific Tau‐ and aging‐related changes. Tau‐induced changes were compared with previously published bulk RNA‐sequencing data and gene co‐expression networks. To address cross‐species conservation of single cell transcriptional signatures, we leverage published human single nuclei RNA‐sequencing (snRNA‐seq) data.

Result

We identified 96 cell subpopulations clustered by transcriptomic similarities in the adult Drosophila brain and annotated 59 with cell identities. We mapped half of all DEGs identified in our published bulk‐tissue RNA‐sequencing to cell subpopulations. We characterized 183 regulons in our dataset and demonstrated network‐level expression changes driven by Tau. Most Tau‐induced gene expression changes were observed in glutamatergic and cholinergic excitatory neurons while fewer changes were seen in GABAergic inhibitory neurons. Likewise, we observed Tau‐induced reductions in cholinergic and glutamatergic neuron numbers. Correlation of cluster‐specific transcriptional profiles between our data and mammalian snRNA‐seq demonstrate conservation of gene expression among inferred cell identities. Strikingly, we found abundant innate immune gene expression signatures among neuronal subpopulations, and pinpointed cell autonomous Nuclear Factor Kappa B (NFkB) signaling as a modifier in Tau‐induced neurodegeneration.

Conclusion

Our results comprise a powerful single cell transcriptomic resource for studying tau‐mediated disruption of gene expression and dynamic age‐dependent changes at cellular resolution in a tractable model system.
Cognitive Reserve Moderates the Association Between Cerebral Blood Flow and Language Performance in Older Adults with Mild Cognitive Impairment
Authors: Brenner Einat K , Edwards Lauren , Thomas Kelsey R. , Weigand Alexandra J. , Edmonds Emily C. , Bondi Mark W. , Bangen Katherine J.
Published: December 2022

Background

It has consistently been demonstrated that individuals with higher cognitive reserve (CR) exhibit decreased risk for dementia, and differences in cerebral blood flow (CBF) among those with higher CR may offer a protective mechanism against the cognitive changes associated with dementia. We sought to investigate CR as a moderator of the effect of CBF on memory and language performance in patients with mild cognitive impairment (MCI) and those who are cognitively unimpaired (CU).

Method

Older adults from the Alzheimer’s Disease Neuroimaging Initiative (ADNI; N = 46 MCI, 101 CU) underwent neuropsychological evaluation and arterial spin labeling MRI, which was used to quantify CBF in a priori regions. Estimated VIQ from the American National Adult Reading Test was used as a CR proxy. Multiple linear regressions assessed for (1) effect of CR on cognition, (2) effect of CR on CBF, and (3) interaction between CR and CBF on cognition. Cognitive outcomes included memory (word list) and language (category fluency, naming). All models adjusted for age, gender, APOE e4 allele frequency, and education, and interactions additionally adjusted for baseline FDG and pulse pressure.

Result

VIQ was not associated with memory but was positively associated with fluency and naming in both groups (ps<0.005). VIQ was not associated with CBF in either group. Individuals with MCI showed a significant interaction between VIQ and CBF on fluency across several regions, including the bilateral hippocampus (p = 0.003), bilateral inferior temporal gyrus (p = 0.008), superior frontal gyrus (p = 0.005), and inferior frontal gyrus (p<0.001). For all models, as CR increased, the magnitude of the association between CBF and performance increased. These interactions were not significant in the CU group. Models with naming or memory as the outcome variable were not significant in either group. Results remained similar when education was not adjusted for.

Conclusion

These results suggest that among individuals with MCI, the association between CBF and category fluency is dependent on CR, even after adjusting for several factors. Specifically, higher CR may serve as a protective factor against the negative effect of CBF reductions on fluency. Further research is needed to clarify the role that CR plays as a moderator of CBF and cognition.
Identification and characterization of novel anti‐tau antibodies that inhibit tau‐seed mediated pathology in a P301S tauopathy mouse model Alzheimer’s Disease and tauopathies
Authors: Liu Wencheng , Kurella Vinodh , Liu Li , Kavanagh Dillon , Paranjpe Maneesha , Holth Jerrah , Chung Charlotte , Powers Alex , Ren Xiao‐Qin , Shu Yanqun , Capili Allen , Hou Jay , Ghetti Bernardino Francesco , Bales Kelly R. , Paul Steven M. , Carter Todd
Published: December 2022

Background

The current hypothesis for the progression of tau pathology in Alzheimer’s disease (AD) and tauopathies (for example, Progressive supranuclear palsy (PSP)), is based on mechanisms involving seeding and propagation of pathologic tau via cell‐to‐cell transmission, including trans‐synaptic propagation, a mechanism which provides the opportunity for anti‐tau immunotherapy as a logical and promising therapy for these diseases.

Method

We have carried out parallel immunization campaigns with various immunogens and host animals aimed to isolate a diverse starting pool of anti‐tau antibodies. Immunization of mice with AD patient‐derived PHF‐tau (paired helical filamentous tau) as the immunogen yielded 113 hits demonstrating significant binding to PHF‐tau and an absence of binding to wild type recombinant tau.

Result

Here, we describe the characterization of these 113 anti‐tau antibodies based on their biochemical and biophysical properties, including affinity for PHF‐tau, immunohistochemical selectivity for AD/PSP in human brain sections, functional inhibition of PHF seeding in vitro, developability, as well as epitope mapping. 10 antibodies that met the target profile described above were selected for in vivo efficacy screening in the P301S seeding‐propagation tauopathy mouse model. Epitope mapping for these 10 antibodies demonstrates that these antibodies target phospho‐tau epitopes in diverse locations throughout the tau protein, with six antibodies targeting the mid‐domain region, three targeting the C‐terminal region, and one targeting the N‐terminal/mid‐domain region. We have evaluated five antibodies for their ability to block PHF seeding/propagation in a P301S mouse seeding model and demonstrated substantial reduction of induced tau pathology. Five additional antibodies are currently under evaluation

Conclusion

In summary, we have generated a set of potent and specific anti‐tau antibodies targeting a diverse set of phospho‐tau epitopes that are candidates for the treatment of Alzheimer’s disease and/or other tauopathies. Both the in vitro and in vivo data on this series of tau‐specific antibodies will be presented.
Association of Spousal Separation and Widowhood with Incident Dementia: The Atherosclerosis Risk in Communities (ARIC) Neurocognitive Study (NCS)
Authors: Xie Jiaxin , Pike James R. , Walker Keenan A , Sullivan Kevin J , Windham B Gwen , Gottesman Rebecca F
Published: December 2022

Background

Community‐based investigations suggest that being unmarried in mid‐ to late‐life increases dementia risk. However, these studies rarely distinguish the cause of unmarried status (i.e., whether divorced, widowed, or never married). We prospectively examined spousal separation/loss and dementia incidence in the ARIC study.

Method

14,922 participants reported marital status and were dementia‐free at baseline (Visit 3, 1993‐95; mean age 59.6, SD 5.8). They were followed through 2019 with annual follow‐up surveys of marital status (never married [n = 390], married [n = 7,314], divorced/separated [n = 1,512], widowed [n = 5,706]). Widowed or divorced/separated participants were asked when this event occurred. Dementia cases were adjudicated through in‐person evaluations, informant interviews, and phone assessments from Visit 5 onward, and pre‐ and post‐Visit 5 hospitalization codes and death certificates. We investigated the association between being widowed and being divorced/separated (both as time‐varying variables) with dementia (excluding dementia in the first year after widowhood event) using Cox proportional hazards models, adjusted for demographics, APOEε4, and vascular risk factors.

Results

2,931 dementia cases were identified. Demographic‐ and APOEε4‐adjusted hazard ratio (HR) (95% CI) for dementia was 1.11 (1.02‐1.21) in participants who were widowed compared to those who were not widowed, when time‐varying widowhood status was considered. (Table 1). This association was no longer significant when the model was further adjusted for time‐variant covariates (e.g., vascular risk factors, occupation, health insurance status). A similar pattern was seen for number of times widowed, where results were suggestive of elevated dementia risk in minimally adjusted but not more fully adjusted models. Compared to participants who were neither widowed nor separated, participants who were widowed had a higher unadjusted HR (95% CI) for dementia, HR = 1.78 (1.65‐1.93) vs HR = 0.94 for those who were separated or divorced (0.81‐1.09) (Table 2).

Conclusion

Widowhood is associated with dementia incidence in minimally adjusted models, with limited evidence that the association is stronger than that which is seen from divorce/separation alone. However, this association was not statistically significant in the adjusted model, indicating that other factors may contribute to the observed relationship.
The effects of outdoor versus indoor exercise on psychological health, physical health, and exercise behaviour: a systematic review of longitudinal trials
Authors: Noseworthy Matt W , Peddie Luke , Buckler Elizabeth Jean , Park Faith , Pham Margaret , Pratt Spencer , Singh Arpreet , Liu‐Ambrose Teresa , Puterman Eli
Published: December 2022

Background

A growing body of research is exploring the potential added health benefits of exercise when it is performed outdoors in nature, as compared with indoors. We systematically reviewed longitudinal trials comparing the effects of exercise in outdoor versus indoor environments on psychological and physical health, and exercise behaviour.

Methods

We searched the following nine databases from inception to March 2021 for English‐language, peer‐reviewed articles: MEDLINE, Embase, PubMed, Scopus, Web of Science, CINAHL, SportsDiscus, GreenFile, CENTRAL. We included randomized and non‐randomized trials that compared multiple bouts of exercise in outdoor versus indoor environments, and that assessed at least one of the following main outcomes of interest: physical health, psychological health, or exercise behaviour. We assessed risk of bias using the Revised Cochrane risk‐of‐bias tool for randomized trials. At least two authors screened articles for eligibility, extracted data, and evaluated risk of bias, with discrepancies resolved by discussion with at least one other author. Due to outcome heterogeneity and a paucity of studies, we performed a narrative synthesis.

Results

We identified 10 eligible trials from 12 papers, including seven randomized controlled trials. Participants’ (n = 496 total) demographics varied widely (mean age ranging from 11‐80 years). Most exercise protocols involved 30‐60 minutes of aerobic training (walking or running) at moderate to high intensity. Other forms of training included mixed aerobic and resistance training, agility, balance, and strength training, and dual‐task training. Exercise sessions took place one to 5 times per week for one to 18 weeks. Outcomes overlapped minimally between trials, with psychological outcomes assessed in seven trials, physical outcomes assessed in eight trials, and behavioural outcomes assessed in three trials. In total, 123 comparisons were made between outdoor and indoor exercise, including 33 significant comparisons, all of which favoured outdoor exercise. Interpretation of findings was hindered by an overall high risk of bias, unclear reporting, and high heterogeneity in reported outcomes.

Conclusion

There is limited evidence for added health or behaviour benefits of chronic exercise in outdoor environments, as compared with indoors, and a need for future, high‐quality longitudinal trials with adequate power and clear reporting.
Nurr1 and Foxa2 Delivered by Adeno‐Associated Virus 9 Ameliorate the Pathologies and Symptoms of Alzheimer’s Disease Models
Authors: Lee Sang‐Hun , Lee Seong Hoon , Kim Tae‐Gyun
Published: December 2022

Background

Since conventional chemical drugs or proteins have not shown sufficient clinical benefits for cognitive impairments in Alzheimer’s disease (AD), we could try to develop novel therapeutic interventions for AD such as gene therapy. In this study, we evaluated a novel therapeutic modality of AAV9 vectors expressing Nurr1 and Foxa2 genes to treat AD symptoms and pathologies in animal disease models.

Method

The AAV9 vectors expression Nurr1 and Foxa2 were injected together into the hippocampi and lateral ventricles of two different AD models, such as 3x Transgenic (15‐18 months) and 5x Familial Alzheimer Disease (3 months) mice. We tested memory and cognitive functions, accumulation of amyloid β and Tau protein, inflammation and immune activity in the brain of AD models.

Result

Combined transduction of AAV9‐Nurr1 and AAV9‐Foxa2 remarkably improved memory and cognitive functions of 3xTg mice in Y‐maze and water‐maze tests compared to vehicle‐treated group. In 5xFAD mice, Nurr1 and Foxa2 co‐expression effectively rescued memory deficits in the passive avoidance and novel object recognition tests, and made the impaired long‐term potentiation restore to wild‐type level.

We intensively investigated modes of action of therapeutic genes. Nurr1 and Foxa2 co‐expression significantly decreased Aβ deposits in the brain of 3xTg and 5xFAD mice. Subsequent transcriptome analyses revealed that two genes up‐regulated the expression of Aβ‐degrading enzymes.

Tau plaque formation was also reduced in therapeutic gene‐treated 3xTg group, accompanied by deceased phosphorylation of Tau through inflammasome suppression and GSK‐3β inactivation.

Nurr1 and Foxa2 ameliorated neuro‐toxic environment by correcting pathologic inflammatory glial phenotypes. They decreased the expression of inflammatory cytokines, chemokines, and complements through inactivation of NF‐κB pathway, while up‐regulated expression of neurotrophic factors.

Along with increased expression of pre‐ and post‐synaptic markers, synaptic density in the hippocampal CA1 was greater in the 3xTg mice treated with therapeutic genes than control.

Conclusion

A series of functional, histologic and transcriptome analyses revealed that the co‐expression of Nurr1 and Foxa2 attenuated AD‐associated Aβ and Tau proteinopathy, neuro‐inflammation, immune activation, and synaptic loss in multiple in vitro and in vivo AD models. These findings collectively indicate intra‐cranial delivery of Nurr1 and Foxa2 using AAV9 could be an efficient disease‐modifying therapy for AD.
Clinical significance of physical frailty in SCD subjects: A prospective study with amyloid PET data
Authors: Lim Eun Ye , Yang Dong Won , CHO Ahyun , Ho SeongHee
Published: December 2022

Background

Physical frailty is known to be closely associated with cognitive impairment and that it could be an early sign of Alzheimer disease (AD). We aimed to understand the characteristics of physical frailty and define factors associated with physical frailty in SCD subjects with amyloid data.

Method

We prospectively enrolled SCD subjects from of cohort study to identify predictors for the clinical progression to mild cognitive impairment or dementia from subjective cognitive decline (CoSCo) study. They all went through brain magnetic resonance imaging (MRI), and Florbetaben brain amyloid‐beta Positron Emission Tomography (PET). For physical frailty, self‐reported exhaustion, hand grip strength and gait speed were measured.

Result

Of total 120 SCD subjects, 26 (21.7%) subjects showed positivity in amyloid PET scan. Logistic regression analyses showed that women (OR 3.79, p = 0.002) and amyloid PET positive (OR 3.80, p = 0.008) SCD subjects showed significantly more self‐reported exhaustion. Weak hand grip strength was significantly associated with Amyloid PET positivity (OR 3.22, p = 0.047) and high burden of periventricular WMH (OR 3.34, p = 0.023). The SCD subjects with physical frailty showed lower cognitive performance in neuropsychological test, especially information‐processing speed and executive function.

Conclusion

The components of physical frailty are closely related to amyloid and cerebral vascular pathology in SCD subjects and the SCD subjects with physical frailty showed lower cognitive performance in neuro‐psychological test, especially information‐processing speed and executive function.
Prevalence, incidence and associations of dementia with cardiovascular risk factors in the Latin American and Caribbean population. A population‐based cohort study of 10/66 Dementia Research Group
Authors: Llibre‐Rodriguez Juan J. , Acosta Daisy M , Llibre‐Guerra Jorge J , Guerra Mariella , Velazquez Ivonne Z. Jimenez , Salas Aquiles , Ortiz Ana Luisa Sosa , Prince Martin J
Published: December 2022

Background

Latin America and the Caribbean (LAC) countries are experiencing unprecedentedly rapid demographic ageing. Growing evidence shows that cardiovascular health (CVH) is associated with brain health. Little is known about this topic among older adults in Latin America, where the number of people living with dementia is rising. The present study aimed to examine the prevalence, incidence and associations of socioeconomic determinants and cardiovascular risk factors with dementia across six LAC countries.

Methods

The 10/66 Dementia Research Group has carried out population‐based catchment area surveys, using a common protocol, in six Latin‐American countries Cuba, Dominican Republic, Mexico, Peru, Puerto Rico and Venezuela of all over 65 year old (n = 12 704). An incidence wave was conducted 4 ‐5 years after cohort inception, 8 502 participants were reinter viewed, contributing 34 000 person‐years of follow‐up. The outcomes were 10/66 dementia and DSM IV dementia. An index of modifiable CVH factors (ranging from 0 to 14) was calculated. Incident dementia was modeled using competing risks regression to adjust for risk of death.

Results

The prevalence of dementia varied widely across different countries, ranging from 4.8% in Peru and 11.7% in Puerto Rico and the Dominican Republic. Incidence of 10/66 dementia varied between 18.2 (95% CI 14.3‐23.0) per 1000 person‐years in Peru to 30.4 (25.5‐36.3) per 1000 person‐years in Mexico. Being male, having higher education and younger age were all protective of dementia. Specific cognitive tests including literacy, verbal fluency and motor sequencing had also similar protective associations with dementia, providing more supporting evidence for the cognitive reserve hypothesis. Compared to poor CVH, participants with moderate and ideal levels of CVH had a significantly lower risk of dementia both in the unadjusted (subhazard ratio for moderate: 0.77; ideal: 0.59) and adjusted models (moderate: 0.73; ideal: 0.66).

Conclusions

The prevalence of dementia in the older Latin American and Caribbean population is high. Moderate and ideal levels of CVH in old age may protect against dementia incidence. These findings may inform health promotion efforts within dementia national plans adopted recently in some Latin American countries