bluuebunny/crossref_metadata_2025 huggingface dataset:
Assessing inflammasome activity in mouse models of Down syndrome and organotypic brain slice cultures
Authors: Farrell Clíona , Mumford Paige , Salih Dervis , Toomey Christina E. , Fisher Elizabeth , Wiseman Frances K
Published: June 2023

Background

Down syndrome (DS) is caused by trisomy of chromosome 21 (Hsa21) and is a leading genetic cause of Alzheimer’s disease. Neuroinflammation occurs in the DS brain, with altered microglial morphology and transcriptional profiles, and upregulated proinflammatory cytokines, including IL‐1β. IL‐1β is produced by inflammasome activity. We hypothesize that IL‐1β levels are raised in the DS brain via upregulation of inflammasome activity or heightened sensitivity to inflammasome stimuli, which persists when people with DS develop AD.

Method

Levels of 10 cytokines, including IL‐1β, TNFα and IL‐6 were measured (MSD) in the 3‐month hippocampus of a panel of segmental duplication mouse models of DS; Dp1Tyb, Dp2Tyb, Dp3Tyb, Dp9Tyb, Dp10Yey and Dp17Yey. These models have a duplication on one chromosome of a number of orthologues for Hsa21 genes. Organotypic brain slice cultures (OBSCs) were prepared from Dp1Tyb mice and stimulated with LPS ± nigericin, to determine if they have an altered response to inflammasome stimuli, as measured by ELISA for cytokines and IHC for IBA1 and ASC.

Result

Raised IL‐1β abundance was identified in the hippocampus of the Dp1Tyb mouse, which has an additional copy of 148 mouse orthologues for Hsa21 genes. No difference in IL‐1β or other cytokines measured were identified in the Dp3Tyb, Dp9Tyb, Dp2Tyb, Dp10Yey or Dp17Yey hippocampus, which have 37, 76, 33, 31 and 19 genes in three copies respectively. LPS + nigericin treatment does not affect the secretion of IL‐1β from Dp1Tyb OHSCs compared to WT controls, nor the number of ASC specks formed.

Conclusion

Raised IL‐1β in the Dp1Tyb brain is a multigenic phenotype, with three‐copies of more than one gene/region of Hsa21 required to drive the phenotype. This is not due to increased sensitivity to inflammasome stimuli in Dp1Tyb OBSCs. Next, we will determine what products are raised in the Dp1Tyb brain that have the potential to increase IL‐1β production, and Dp1Tyb OBSCs will be treated with these products, E.g. Aβ. Here, we are further understanding the mechanisms of neuroinflammation in DS, which is critical in determining how AD‐DS differs from AD, and if people with DS can be included in AD research and clinical trials.
Computerized test‐retest of the Wisconsin Card Sorting Test in day‐to‐day consecutive performances in Mild Cognitive Impairment
Authors: Rosales‐Lagarde Alejandra , Rego Lourdes Cubero , Mendoza Enrique Vázquez , Martínez‐Alcalá Claudia
Published: June 2023

Background

We examined executive functions by testing cognitive flexibility, problem solving and response maintenance by means of the Wisconsin Card Sorting Test (WCST) on two consecutive days. This could render the performance gains obtained in the second assessment in Mild Cognitive Impaired (MCI) subjects, in contrast to a preserved cognitive function group (Control, CTRL group).

Method

17 older adults were evaluated with several tests (Fig. 1) and with the Neuropsi battery to classify them in two groups: those with three standard deviations below the mean in at least one of the cognitive functions (MCI group, n = 7) and those without this characteristic (n = 10) (Fig. 2). The WCST was delivered twice in a day‐to‐day assessment (1 subject did not repeat his session). A computerized version of the WCST was programmed using e‐prime software, v. 1, at the same time of day. The first three categories were randomly selected, and the categories were then repeated. A special keypad was designed, which included four keys for each card option. Written feedback on the screen was provided immediately.

Result

ANOVAs results did not show significant differences; nevertheless, the % of correct responses was almost significant within sessions in both groups (p < 0.07) and categories also showed a tendency towards significance between groups in the first session (p < 0.06) (Figs. 3, 4 & 5). Different subgroups emerged: from the first to the second session, one subgroup increased their frequency of categories (CTRL group: 50%; MCI group: 16.66%; chi2 = 16.6; df = 1, p < 0.0001); one subgroup lacked flexibility and remained the same (CTRL group: 30%; MCI group: 66.66%; chi2 = 13; df = 1, p < 0.0001), and one subgroup decreased the number of categories (CTRL group: 20%; MCI group: 16.66%; chi2 = 0.30; df = 1, p = 0.581).

Conclusion

In this study, the percentage of correct responses, and the number of categories achieved may provide a more flexible profile of the execution abilities in older adults, which could be more informative for the detection of groups and so, of transitional stages from normality to cognitive impairment.
Social isolation, lifestyle and cognitive functioning in midlife and early‐late life: Implications for risk reduction of cognitive decline and dementia
Authors: Röhr Susanne , Pabst Alexander , Witte A. Veronica , Schroeter Matthias L. , Loeffler Markus , Villringer Arno , Riedel‐Heller Steffi G.
Published: June 2023

Background

Social isolation (SI) is considered a modifiable risk factor for cognitive decline and dementia, is associated with unhealthy lifestyle. We investigated independent and combined associations of SI and lifestyle with cognitive functioning (CF) in a midlife to early‐late life population without dementia. This informs developing more targeted preventive strategies against cognitive decline and dementia.

Method

The “LIfestyle for BRAin health” (LIBRA) score was computed for 6,203 baseline participants of the LIFE‐Adult‐Study, a population‐based German cohort. LIBRA is validated for dementia prediction in midlife to early‐late life populations, consisting of 12 modifiable factors (heart disease, kidney disease, diabetes, obesity, hypertension, hypercholesterolemia, alcohol consumption, smoking, physical inactivity, diet, depression, cognitive activity). Higher scores (‐5.9,+12.7) indicate “worse” lifestyle. SI was assessed with the short Lubben Social Network Scale (score < 12). For CF, we calculated a z‐standardized composite score of the Verbal Fluency Test, the Trail Making Test A and B. Associations of SI and LIBRA with CF were investigated using generalized linear modelling. Bootstrapped structural equation modelling (SEM) tested whether LIBRA mediated the association between SI and CF. Sampling weights were applied, variables z‐standardized for SEM.

Results

Participants were M = 57.7 (SD = 12.0, range: 40‐79) years old; 50.7% were female; 15.8% were socially isolated. SI (β: ‐.17, 95%CI[‐.24,‐.10]; Wald = 21.45, p < .001) and a higher LIBRA score (β: ‐.03, 95%CI[‐.04,‐.02]; Wald = 31.49, p < .001) were independently associated with lower CF; there was no interaction (β: ‐.003, 95%CI[‐.03,.02]; Wald = 0.06, p = .814; Fig.1). Bootstrapped SEM (reps = 10,000; R² = .34) indicated that LIBRA partially mediated the association between SI and CF (IE = ‐.006, 95%CI[‐.008,‐.003], p < .001; proportion mediated = 8.5%; Fig.2).

Conclusion

CF is lower in socially isolated than socially integrated individuals without dementia. The CF difference can be partially attributed to modifiable health and lifestyle factors; however, only to a small extent. Therefore, public health initiatives aiming at preventing SI might be more effective in promoting good CF than lifestyle interventions in socially isolated individuals in midlife to early‐late life. This would likely benefit risk reduction of cognitive decline and dementia in later life.
Dual Role of Low Frequency Magnetic Field on Neuroinflammation Induced Dendritic Trimming And Memory Impairment on Rat Model of Sporadic Alzheimer’s Disease
Authors: Roy Avishek , Sharma Binney , Iyenger Soumya , Gupta Yogendra Kumar , Jain Suman , Banerjee Jyotirmoy
Published: June 2023

Background

Gliosis and dendritic loss is reported to be secondary to the amyloid beta (Aß) and hyperphosphorylated tau (hp‐tau) production in Alzheimer’s disease(AD) brain. STZ administration is reported to induce sporadic AD. Previous clinical or preclinical studies on effect of rTMS treatment in AD patients or APP23 mice showed cognitive improvement alone or as adjuvant therapy along‐with amelioration of the glial aggravation in the hippocampus. However, studies on the effect of magnetic field stimulation on the gliosis related dendritic trimming in animal models of sporadic AD is elusive. Therefore, in the present study we have looked in to the effect of extremely low frequency magnetic field stimulation (ELF‐MF; 17.96µT, 50Hz, 2hr/day) for one month post‐injection of STZ (bilateral, 3mg/kg).

Method

Total 45 animals were (ethical no. 937/IAEC/2016) randomly divided into five groups: Control, Sham, AD, Sham+MF and AD+MF. After assessing retention of spatial and avoidance memory using Morris water maze and passive avoidance step down test on 30th day, animals were sacrificed and tissues processed for oxidative stress and immunofluorescence, Golgi‐Cox staining.

Result

Behavioural analysis revealed spatial memory improvement with no effect on the avoidance memory loss in AD+MF group as compared to AD group. We also found significant decrease in superoxide dismutase, catalase, GSH and increase in malon‐di‐aldehyde (MDA) in AD group. ELF‐MF treatment only reduced MDA level in hippocampus and frontal cortex. GFAP, IBA‐1 and hp‐tau (ser356) positive cells were found to be reduced in AD+MF group, as compared to all groups except Control. Sholl analysis revealed partial improvement of reduction in the number of intersection, bifurcation and length in basal and apical dendrite in the AD group after ELF‐MF treatment in CA3 layer. Convex hull analysis revealed a contradictory result showing reduction in apical (p = 0.018) and increase in basal dendrite (p = 0.038) of AD group as compared to control.

Conclusion

These findings suggests dual role of ELF‐MF exposure on STZ model of AD showing improvement of spatial memory by reducing the gliosis induced dendritic loss but loss in avoidance memory.
Inhibition of Fli‐1 attenuates inflammation, pericyte loss and cognitive deficits in Alzheimer’s disease
Authors: Li Pengfei , Wu Yan , Hamlett Eric D , Goodwin Andrew , Halushka Perry , Carroll Steven , Liu Meng , Fan Hongkuan
Published: June 2023

Background

Brain pericytes maintain the integrity of the blood‐brain barrier (BBB) and facilitate the removal of amyloid β (Aβ) which is critical to healthy brain activity (Ethan et al., Brain Pathol., 24: 371‐386, 2014). Pericyte degeneration has been observed in brains from patients with Alzheimer’s disease (AD) and animal models (Jesse et al., Brain Pathol., 23: 303‐10, 2013; Wu et al., Aging (Albany NY), 11: 6120‐6133, 2019). Our previous data demonstrated that friend leukemia virus integration 1 (Fli‐1), an ETS transcription factor, regulates pericyte viability and vascular injury in murine sepsis (Li et al., J Infect Dis, 218: 1995‐2005, 2018); however, the role of Fli‐1 in AD remains unknown.

Methods

Fli‐1 levels and pericyte number were detected in postmortem brains from 21 patients with AD and 17 healthy controls, and in 5xFAD transgenic mice. Control or Fli‐1 antisense oligonucleotide Gapmers were injected into the hippocampus of 5xFAD mice at 3 and 4.5 months of age. Pericyte number, inflammatory mediators, Aβ deposition, BBB function and cognitive deficits were evaluated at 6 months of age. Human brain pericytes were transfected with control or Fli‐1 antisense Gapmers for 48 h and cultured with or without freshly aggregated Aβ40 for 7 consecutive days. Cell viability and apoptosis were detected.

Results

We demonstrated that Fli‐1 expression was increased in postmortem brains from a cohort of human AD donors and in 5xFAD mice, which corresponded with a decreased pericyte number, elevated inflammatory mediators, and increased Aβ accumulation as compared to cognitively normal individuals and WT mice, respectively. Antisense oligonucleotide Fli‐1 Gapmer administrated via intrahippocampal injection decelerated pericyte loss, reduced inflammatory responses, ameliorated cognitive deficits, improved BBB dysfunction, and decreased Aβ deposition in 5xFAD mice. Fli‐1 Gapmer‐mediated inhibition of Fli‐1 protected against Aβ accumulation induced human brain pericyte apoptosis in vitro.

Conclusion

These composite results indicate that Fli‐1 contributes to pericyte loss, inflammatory response, Aβ deposition, vascular dysfunction and cognitive decline, and suggest that suppression of Fli‐1 may represent a novel therapeutic strategy for AD.
Assessment of motivation, readiness to change, and general wellbeing among participants enrolled in a longitudinal study on brain health self‐management
Authors: Jose Roslin , Ross Sarah E
Published: June 2023

Background

Lifestyle choices are modifiable factors that contribute to the onset Alzheimer’s disease and related dementias. Health coaching can address risk factors related to lifestyle choices. This study aims to explore trends in motivation to change and the general health of participants enrolled in a brain health self‐management program.

Method

The program uses health coaching, education, and targeted assessments to provide a personalized approach for facilitating brain healthy lifestyle changes. After program enrollment, participants complete assessments specific to the 7 pillars of brain health (Diet, Exercise, Social Engagement, Cognitive Activity, Sleep, Mindfulness & Outlook, and General Health), demographics, and a motivation to change assessment. Participants then attend an intake visit and virtual health coaching sessions. Health coaching focuses on helping participants create specific lifestyle goal(s) in their pillar(s) of interest. We used the Motivation to Change Lifestyle and Health Behaviour for Dementia Risk Reduction (MCLHB‐DRR) Scale to assess for motivation to change, Readiness ruler from the Permanente Medical Group, and the SF‐20 questionnaire to assess General Health. We assessed for trends in participant demographics, motivation, readiness, and general wellbeing.

Result

As of January 2022, 40 participants enrolled for the study, 36 completed the pre‐survey, and 25 attended the intake and the virtual health coaching visits to set one or more brain healthy lifestyle goal. The participant demographics were predominantly female (80%), Caucasian (91.67%), and non‐Hispanic (97.22%), with an average participant age of 76.6. Among the components of the MCLHB‐DRR scale based on the Health Belief Model, the participants overall had a high average Self‐Efficacy 8.2±1.7 (4‐10) and General Health Motivation 17.5±2.7 (5‐20). The average readiness to work on the goal(s) set was 8.24±1.7 on a scale of 0‐10 (0‐Not Ready; 10‐Ready), with Exercise goals being the highest (9.2±0.8), and social engagement the lowest (5.7±2.8). 44.4% of participants rated their health as good (3 on scale 1‐5).

Conclusion

This program intends to promote life‐style changes aimed at dementia risk reduction and improving overall brain health. Those who elected to participate where highly motivated to implement lifestyle improvements and reported high ratings of their perception of their overall health.
Lipid rafts act as a common platform for Aβ oligomer‐induced Alzheimer’s pathology
Authors: Kawarabayashi Takeshi , Nakamura Takumi , Sato Kaoru , Seino Yusuke , Ichii Sadanobu , Nakahata Naoko , Takatama Masamitsu , Shoji Mikio
Published: June 2023

Background

Amyloid‐β (Aβ) oligomers induce the overproduction of phosphorylated tau and neurodegeneration. These cascades gradually cause cognitive impairment in Alzheimer’s disease (AD). While each pathological event in AD has been studied in detail separately, the spatial and temporal relationships between pathological events in AD remain unclear. We demonstrated that lipid rafts function as a common platform for the pathological cascades of AD.

Method

Cellular and synaptosomal lipid rafts were prepared from the brains of Aβ amyloid model mice (Tg2576 mice) and double transgenic mice (Tg2576 x TgTauP301L mice) and longitudinally analyzed.

Result

Aβ oligomers, the cellular prion protein (PrPc), and Aβ oligomer/PrPc complexes were detected in the lipid rafts. The levels of Fyn, the phosphorylated NR2B subunit of the N‐methyl‐D‐aspartate receptor, glycogen synthase kinase 3β, total tau, phosphorylated tau, and tau oligomers increased with Aβ oligomer accumulation in both the cellular and synaptosomal lipid rafts. Increases in the levels of these molecules were first seen at 6 months of age and corresponded with the early stages of Aβ accumulation in the amyloid model mice.

Conclusion

Lipid rafts act as a common platform for the progression of Alzheimer’s pathology. The findings of this study suggest a novel therapeutic approach to AD, involving the modification of lipid raft components and the inhibition of their roles in the sequential pathological events of AD.
The combined effect of β ‐amyloid and white matter hyperintensities on present and future executive function performance in cognitively normal older adults
Authors: Ali Doaa , Khouli Riham H El , Abner Erin L , Bahrani Ahmed A , Gold Brian T. , Jiang Yang , Wilcock Donna M. , Jicha Gregory A
Published: June 2023

Background

β‐amyloid (Aβ) and White matter hyperintensities (WMH) are key drivers of cognitive decline in healthy older adults and both are considered biomarkers of preclinical dementia. Deficit in executive function (EF) linked to WMHs and Aβ burden, have been shown to predict the development of dementia. The present study aimed to explore the interactions of regional and global Aβ with WMH on baseline and longitudinal performance in EF in cognitively normal (CN) older adults.

Method

Global and regional Standard Uptake Value ratios (SUVr) from Aβ‐PET, WMH volumes from MRI FLAIR images, and composite scores of EF at baseline and after approximately 2 years were analyzed across a sample of 714 clinically‐normal (Mini‐Mental State Examination (MMSE) ≥ 26), aged participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI2). We used multiple regression models including the interaction tem and main effects for Aβ and WMH to investigate the independent and combined associations of these pathologies with EF. Age, ApoE, education, baseline EF score, and time to follow up EF testing were entered as covariates in the regression models.

Result

The moderation regression analysis showed that additive effects on Aβ burden and WMH in relation to baseline EF with p value for the interaction term between the two pathologies 0.07, and significant interaction effects of global, frontal and cingulate Aβ burden, and WMH in relation to longitudinal EF performance with p values of 0.037, 0.03, and 0.032 respectively. The main effect from regression analysis demonstrated that baseline EF performance was predicted by the combination of Aβ burden and WMH, while Aβ burden was the only predictor for longitudinal EF performance.

Conclusion

These data demonstrated that baseline Aβ and WMHs have both independent effects on EF scores at baseline and synergistic effects on longitudinal EF performance. The biological relationships and interplay between Ab and WMH responsible for the synergistic effects seen on longitudinal EF performance warrants further study.
ELUCIDATING THE COMBINED EFFECTS OF AMYLOID AND TAU IN A NOVEL BIGENIC RAT MODEL WITH HUMAN ALZHEIMER’S DISEASE‐LIKE PATHOLOGY
Authors: Emmerson Joshua T , Carmo Sonia Do , Cuello Claudio A
Published: June 2023

Background

Both amyloid beta (Aβ) and tau pathologies co‐exist in Alzheimer’s disease. While studies have shown that Aβ and tau interaction results in elevated AD pathology, it is not clearly understood how they might affect one another during early pathology stages leading to Aβ plaque formation. This study aimed at determining how and to which extent a combination of gradually developing amyloid and tau pathologies exacerbate each other in the context of Alzheimer’s disease‐like pathology in a novel transgenic rat model.

Methods

Heterozygous McGill‐R‐Thy1‐APP and R955‐hTau single transgenic rats were crossed, producing a novel bigenic rat model with both human amyloid and tau pathologies, named McGill‐R‐APPxhTau955. Bigenic rats express human APP with the Swedish and Indiana mutations (KM670/671NL, V717F) as well as the longest isoform of human tau (2N4R) with the P301S mutation causative of frontotemporal dementia. Transgenic rats (n = 10‐12) were raised to cohorts at 12, 20 and 24 months of age and were subject to a battery of behavioural testing for cognition. Examination of amyloid and tau pathology, as well as inflammatory and neurodegenerative processes, was performed primarily using immunohistochemistry (IHC) and Western blot (WB). Levels of amyloid, tau and p‐tau were measured in CSF, brain and blood serum by electrochemiluminescence immunoassays. Bigenic animals were compared to single transgenics and wild‐type littermate controls.

Results

APPxR955‐hTau bigenic rats produced a gradual accumulation of human amyloid and tau, resulting in progressive cognitive deficits and Alzheimer‐like pathology. We discovered that tau accumulation produced a compensatory effect on cognition and long‐term potentiation at 20 months, rescuing amyloid‐induced cognitive effects. However, at 24 months of age, bigenic rats displayed worsened cognition compared to single transgenics in spatial learning and memory. Reflective of these findings, bigenic rats developed an increased phosphorylaton of tau at 24 months and increased Aβ plaque pathology. Status of biomarker levels, neuroinflammation and neurodegeneration are actively under investigation and are expected to trend similarly.

Conclusions

The McGill‐R‐APPxhTau novel bigenic rat, developing slow progressing amyloid and tau pathologies, is an attractive model for the further investigation of mechanisms by which both proteins effect one another, the observation of biomarker changes and elucidation of early disease stages.
Kinetic Modulation of Amyloid‐β (1‐42) Fibrillation and Alleviated Cytotoxicity with Rationally Designed Point Mutants
Authors: Im Dongjoon , Kim Hugh Inkon
Published: June 2023

Background

Most Alzheimer’s disease (AD) treatments focus on symptomatic relief by boosting the availability of neurotransmitters in the brain. Aside from symptomatic therapies, the amyloid‐β (Aβ) targeting approach has recently been established to reduce or postpone the production of Aβ plaques.1 Therefore, understanding the pathogenesis of AD requires regulation of Aβ fibrillation.

Method

We used the CamSol method and molecular dynamics simulations to find a group of residues that were significantly associated with Aβ fibrillation. To investigate the suppressed amyloid aggregation and reduced cytotoxicity of the designed mutants, we performed multiple in vitro experiments such as thioflavin T assay, circular dichroism spectroscopy measurement, transmission electron microscopy image analysis, liquid chromatography‐mass spectrometry based quantification, and cell viability test. We also characterized structural dynamics of the designed mutants using a multidisciplinary biophysical approach with small‐angle X‐ray scattering, ion mobility‐mass spectrometry, additional in silico experiments, and mass spectrometry.

Result

We rationally designed mutant constructs to suppress the fibrillation process using comprehensive molecular dynamics simulations and the atomic resolution structure of fibrils. Then, we used a multidisciplinary biophysical technique to investigate the physicochemical characteristics and unveil the structural basis associated with reduced self‐assembly. Lastly, cell‐based tests were performed to evaluate the alleviated cytotoxicity of designed mutant candidates.

Conclusion

More generally, our method for modulating the self‐assembly property of the pathologically disordered proteins offers a novel viewpoint to treating neurodegenerative diseases and other protein folding‐related issues.

Reference:

1. Sevigny, J., et al. “The antibody aducanumab reduces A beta plaques in Alzheimer’s disease.” Nature 2016, 537(7618), 50‐56.
Cell‐autonomous role of the AD susceptibility gene BIN1 in the regulation of hiPSC‐derived neurons network activity
Authors: Saha Orthis , De Farias Ana‐Raquel Melo , Pelletier Alexandre R , Kilinc Devrim , Delahaye Fabien R , Queiroz Claudio M , Lambert Jean‐Charles , Costa Marcos R
Published: June 2023

Background

Alzheimer’s disease (AD) is a multifactorial disease with a strong genetic background. Recent genomic wide association studies have identified several loci linked to an increased risk of AD. However, genes regulated by these variants and the pathophysiological mechanisms regulated by those genes remain largely elusive. In this work, we studied the role of Bridging Integrator 1 (BIN1), the second most important AD risk gene after APOE, in neurons generated from human induced pluripotent stem cells (hiPSCs) in bi‐dimensional cultures and cerebral organoids.

Method

We generated isogenic BIN1 wild‐type (WT), heterozygous (HET) and knockout (KO) hiPSC lines and used these cells to generate human‐induced neurons (hiNs) in bi‐dimensional (2D) and three‐dimensional (cerebral organoids) cell cultures. Next, we used calcium imaging and multi‐electrode array electrophysiology to study the functional properties of hiNs networks. Single‐nucleus RNA‐sequencing (snRNAseq) was used to identify gene expression alterations in individual cell types/subtypes. APP processing and TAU phosphorylation was assessed by western blotting and Alphalisa.

Result

We observed that deletion of BIN1 is sufficient to cause neuronal hyperactivation and network desynchronization in a cell‐autonomous fashion. These functional changes are observed both in 2D cultures and cerebral organoids, and are correlated with increased Tau phosphorylation and transcriptional changes similar to those observed in the brains of AD patients, particularly in glutamatergic neurons.

Conclusion

Our results reveal a role for BIN1 in the regulation of electrical activity in human neurons and suggest that its implication in AD pathogenesis could be related to the neuronal and network dysfunctions observed in the AD brain.
Human amyloid seeds induce a more profound pathology than seeds from old 3x‐Tg‐AD mice
Authors: Andreo‐Lopez Juana , Cantero‐Molina Francisco , Bettinetti‐Luque Miriam , Huynh Kelly Do , Nguyen Marie Minh Thu , Cheung Alwin , Tran Janine Pham , Da Cunha Celia , Trujillo‐Estrada Laura , Nuñez‐Diaz Cristina , Martini Alessandra Cadete , Forner Stefania , Gutierrez Antonia , LaFerla Frank , Baglietto‐Vargas David
Published: June 2023

Background

Most age‐associated neurodegenerative disorders involve the aggregation of specific proteins within the nervous system, as occurs in Alzheimer’s disease (AD). Recent evidence indicates that Aβ can misfold and aggregate into seeds that structurally corrupt native proteins, mimicking a prion‐like process of template protein corruption or seeding. In fact, studies in animal models show that the injection of brain homogenates from AD patients or from aged APP‐transgenic mice containing Aβ aggregates, can induce some of the neuropathological hallmarks of AD. However, it is still unknown which Aβ‐misfolded species are most efficient in triggering the aggregation process. Here, we seek to perform a comparative study to determine whether Aβ seeds from humans vs a familial AD line (the 3xTg‐AD model) is more efficient to generate amyloid aggregates.

Method

We employed histological and molecular approaches to determine amyloid level, species and aggregative capacity of brain homogenates from an AD patient (stage C for amyloid, from the Alzheimer’s Disease Research Center at UCI) vs old‐3xTg‐AD mice (25‐month‐old). Such brain homogenates were injected into the hippocampus of 7‐month‐old 3xTg‐AD mice and the mice were analyzed at 18 months of age.

Result

Our findings demonstrated that amyloid seeds from the human patient induce more aggressive amyloid pathology compared to seeds from aged 3xTg‐AD mice.

Conclusion

These results suggest that seeds from human patients seem to be more amyloidogenic than from aged 3xTg‐AD mice. Thus, more profound understanding these factors will provide key insight on how amyloid pathology progress in AD.
Adherence to a healthy lifestyle and brain structural imaging markers: A cross‐sectional study among middle‐aged and older adults
Authors: Pan Yuesong , Shen Jie , Cai Xueli , Zhu Wanlin , Jing Jing , Zhang Yanli , Jin Aoming , Yuan Changzheng , Wang Yongjun
Published: June 2023

Background

Previous research has linked specific modifiable lifestyle factors to age‐related cognitive decline in adults. Little is known about the potential role of an overall healthy lifestyle in brain structure. We investigated the association of adherence to a combination of healthy lifestyle factors with neurodegeneration‐related brain structural markers in middle‐aged and older adults.

Method

We conducted a cross‐sectional analysis in the PolyvasculaR Evaluation for Cognitive Impairment and vaScular Events (PRECISE) study among Chinese community‐dwelling elderly adults. Participants underwent lifestyle assessments and brain 3T MRI scanning between 2017‐2019. A healthy lifestyle score (0‐5) was constructed based on five modifiable lifestyle factors: diversified diet, physically active, non‐smoking, non‐alcohol‐drinking, and healthy body weight. Validated multimodal neuroimaging markers (across tissue volume, cortical thickness, and white matter micro‐structure, etc) were derived from MRI. Multivariable‐adjusted linear and logistic regression models were used to examine the associations.

Result

A total of 2370 participants (mean age 61.3 years; 53.9% female) was included in the final analysis. Compared to participants with lower healthy lifestyle score (0‐1), those with a higher lifestyle score had larger gray matter volume (GMV; β score 2‐3 = 0.34; β score 4‐5 = 0.31; p‐trend = 0.02) and lower odds of white matter hyperintensity (WMH; Odds Ratio [OR] score 2‐3 = 0.71, 95% Confidence Interval [CI]: 0.50, 1.02; OR score 4‐5 = 0.56, 95%CI: 0.35, 0.90; p‐trend = 0.003) and lacune (OR score 2‐3 = 0.62, 95%CI: 0.36, 1.06; OR score 4‐5 = 0.42, 95%CI: 0.18, 0.98; p‐trend = 0.02). In particular, diversified diet was associated with a significant lower risk of WMH and healthy body weight was associated with a variety of brain structure measures. Similar associations were observed across major subgroup variables.

Conclusion

Adherence to a healthier lifestyle was associated with a lower degree of neurodegeneration‐related brain structural markers in middle‐aged and older adults. Further large‐scale and longitudinal studies are warranted to confirm the study findings.
Association between social support and cognitive function
Authors: Kyaw Kay Thwe , Flagiello Thomas , Levine Alec , Salinas Joel
Published: June 2023

Background

Observational studies suggest social support is associated with vulnerability for cognitive decline in older adults. Because of racial/ethnic homogeneity in prior studies beings predominantly in White/European ancestry, less is known about the generalization of these putative psychosocial mechanisms. Thus, we evaluated whether better telecommunication social support systems were associated with better cognitive performance using a unique longitudinal cohort of rural South African older adults.

Method

We conducted a cross‐sectional study using 541 participants from the HAALSI (Health and Aging in Africa: A Longitudinal Study of an INDEPTH Community in South Africa) Dementia Cohort. Participants’ exposure to social support via telecommunication was measured using a standard assessment. Cognitive performance was measured using a neuropsychological battery validated in this population that assesses the domains consistent with the Alzheimer’s Disease Research Centers Uniform Data Set. Raw scores were converted into z scores and a composite global cognitive score was created as an additional indicator of global cognition. We examined cross‐sectional associations with multivariate robust regression analysis using robust S‐estimation. Telecommunication social support was modeled as the independent variable; cognitive measures were modeled as dependent variables.

Result

Higher telecommunication social support was associated with better global cognitive function after adjustment for age, gender, and education (β:0.01, 95% CI: 0.006, 0.022). This association persisted after additional adjustments for depressive symptoms and vascular risk factors. Higher telecommunication social support was also associated with cognitive function assessed by mini mental status examination and tests of executive function and memory.

Conclusion

Telecommunication‐based social support was associated with higher levels of cognitive performance in a rural South African cohort of Black older adults. Although these findings and the potential of reverse causality need to be further validated, our results suggest that intervention studies might be specifically merited to understand whether promoting social support through telecommunication in similar samples of older adult populations lessen vulnerability for cognitive decline.
CSF proteo‐genomic studies identify an interaction between LRRK2 genetic variants and GRN, GPNMB, CTSB, and ENTPD1
Authors: Wang Lihua , Yang Chengran , Mafimoghaddam Samira , Timsina Jigyasha , Gorijala Priyanka , Wang Fengxian , Alvarez Ignacio , Aguilar Miquel , Ruiz Agustin , Pastor Pau , Sung Yun Ju , Cruchaga Carlos
Published: June 2023

Background

Parkinson’s disease (PD) is a movement disorder characterized by dopaminergic neurodegeneration in the substantia nigra of the brain. Another neurodegenerative disorder, Alzheimer’s disease (AD), is a progressive memory loss disorder with pathological changes mainly at hippocampus and entorhinal cortex. As dementia is also present in late stage of PD, there might be common molecular mechanism between the pathogenesis of AD and PD. Evidence has nominated Leucine Rich Repeat Kinase 2 (LRRK2), Progranulin (GRN), Glycoprotein nonmetastatic melanoma protein B () since these proteins were linked to AD and PD. Identifying genetic variants of 5 proteins will be critical to shed lights on common disrupted pathways shared by AD and PD.

Method

To identify genetic variants associated with these 5 proteins, we performed protein quantitative trait loci (pQTL) analyses of log10 transformed CSF GRN, GPNMB, CTSB, ENTPD1 and LRRK2 assayed in SomaScan platform. We considered ∼11 million sequenced variants from 787 individuals recruited at PPMI in the discovery and ∼4.3 million imputed variants from 799 Knight ADRC samples in replication. Age, sex and 10 principal components were included as covariates. Genome‐wide threshold (5.0×10−8) was used in the meta‐analyses of discovery and replication for significance.

Result

On chromosome 12, exonic missense LRRK2 variant rs33939927 (MAF = 1.4%) was identified as shared pQTL for GRN (P = 7.87×10−10), CTSB (P = 8.99×10−9), GPNMB (P = 3.59×10−9), and ENTPD1 (P = 1.24×10−13). The second LRRK2 exonic missense variant rs34637584 (MAF = 11%) was pQTL consistent for 3 proteins (GRN: P = 2.34×10−8, GPNMB: P = 8.55×10−13, and ENTPD1: P = 1.75×10−13). The third LRRK2 exonic missense variant rs35303786 (MAF = 3.4%) was identified for GPNMB (P = 1.53×10−8) and ENTPD1 (P = 2.31×10−8). The risk allele of 3 SNPs were associated with higher amount of corresponding CSF proteins. No significant LRRK2 pQTL was identified. Additional analyses including colocalisation with AD and PD GWAS results are ongoing.

Conclusion

Two low frequency exonic missense LRRK2 variants (rs33939927 and rs35303786) and one common exonic missense LRRK2 variant (rs34637584) were pQTL shared by GRN, CTSB, GPNMB, and ENTPD1. Our findings indicate that the LRRK2 exonic variants are the key genetic regulators of LRRK2 activity and CSF level of GRN, CTSB, GPNMB, and ENTPD1.
The development and refinement of the enhancing active caregiver training (EnACT) intervention for caregivers of persons living with dementia
Authors: Eaton Jacqueline , Neller Sarah , Cajavilca Moroni Fernandez , Johnson Julene K. , Ellington Lee
Published: June 2023

Background

Behavioral symptoms affect up to 90% of persons living with dementia.1 While interventions have been developed to help caregivers manage symptoms,, these interventions show only weak to moderate effect size.2 The most successful psychoeducational interventions use active‐engagement techniques to facilitate the application of knowledge and skills.2‐5 Yet the optimization and systematic testing of active‐engagement techniques is lacking.2‐6 By optimizing active‐engagement techniques, we may strengthen caregiver preparation. Enhancing Active Caregiver Training (EnACT) is an arts‐based intervention aimed at engaging dementia caregivers by using techniques that allow them to better manage common behavioral symptoms associated with dementia. The purpose of this presentation is to describe the process of developing and refining EnACT in preparation for feasibility testing with dementia family caregivers.

Method

As part of a larger sequential qualitative‐to‐quantitative mixed‐method design to develop and test EnACT, we implemented an iterative three‐stage review process to prepare intervention materials for focus group feedback and future pilot testing. This included review from: 1) a caregiving expert/clinician, 2) two applied humanities researchers with expertise in arts‐based healthcare training, and 3) a three‐person research team completing a mock focus group.

Result

Intervention materials were revised following each stage of review. In stage 1, we identified caregiving scenarios for inclusion, clarified confusing process components, and emphasized questions to ask as part of discussion and reflection activities. During Stage 2, we reorganized activities to follow a narrative structure and allow participants to explore one caregiving scenario at a time. In addition, we added application questions that ask participants to explore how scenarios relate to their own experiences. In stage 3, we expanded focus group activities to the online platform to promote access and safety. Through testing the process in advance, we refined procedural steps to facilitate caregiver engagement and identified potential barriers to participation.

Conclusion

When preparing to conduct a feasibility and acceptability trial for a behavioral intervention, seeking feedback enhances protocols to improve intervention processes. Iterative review may reduce extraneous problems, enabling focus groups to target participant feedback specific to dementia caregivers and their needs.
Genome‐Wide Association Study of Dementia in a Community‐Based Sample of Older Subjects
Authors: Harper Jordan D. , Fan Kang‐Hsien , Aslam Muhammad Muaaz , Snitz Beth E , DeKosky Steven T , Lopez Oscar L. , Feingold Eleanor , Kamboh M. Ilyas
Published: June 2023

Background

Dementia broadly describes conditions that affect a person’s memory, cognition, and behavior with Alzheimer’s disease (AD) being the most common cause. AD affects millions of people in the U.S. and around the world causing a significant financial burden and placing significant stress on caretakers. AD is a complex disease influenced by both the environment and genetics, however, much of the genetic component remains unaccounted for. The purpose of this work was to use genome‐wide association analyses to detect genetic associations with incident AD in a sample of older adults age 75 and above.

Method

We performed a genome‐wide association study (GWAS) on the genome‐wide genotyped and imputed data (14,113,004 variants) on the Gingko Evaluation of Memory (GEM) study sample consisting of 424 incident dementia cases (mean age ± sd = 84.64±3.95) and 2,206 non‐demented subjects (mean age ± sd = 84.55±3.23).

Result

The established association of APOE*4 with AD was confirmed in this community‐based sample of older subjects (OR = 2.22; P = 9.36E‐14). In addition, a genome‐wide significant novel locus on chromosome 12 was observed near FAR2 and CCDC91 genes (OR = 3.31; P = 1.66E‐08). Sex‐stratified analyses showed a stronger association of APOE*4 with AD in females (P = 1.74E‐10) than in males (P = 2.43E‐05). In males, a novel SNP on chromosome 1 near LOC729987 and SNX7 genes reached genome‐wide significance (OR = 4.51; P = 3.72E‐08). Of the known AD genes, SNPs near or at TREM2, NME8/EPDR1, MS4A6A/MS4A4E, PICALM, APH1B, and PLCG2 showed nominal significance.

Conclusion

The use of community‐based samples of older individuals and incident dementia as a phenotype may be a helpful approach for the identification of novel genes for AD, which may not be detected in standard case‐control studies. Replication of these signals and further study of these regions and genes will help to provide a clearer picture for their role in AD.
Differential expression and differential coexpression analyses revealed altered gene expressions and pathways in atypical Alzheimer’s Disease sub‐cohort brains
Authors: Huang Xiaoqing , Garfe Nur Jury , Reeves Cristian A Lasagna , Zhang Jie
Published: June 2023

Background

In the Alzheimer’s disease (AD) brain, the hyperphosphorylated tau protein forms neurofibrillary tangles (NFTs), which extent usually matches the dementia severity. However, for some patients, this is not the case. which we name them as asymptomatic AD (AsymAD, heavy NFTs but relatively normal cognition) and Low‐NFT AD (light NFT but severe dementia). We aim to characterize these two subtypes’ transcriptome and proteome, to understand the role of tauopathy in the AD etiology and identify resilient/vulnerable factors contributing to the cognitive decline as well as the potential drug targets for the precision treatment of AD.

Method

We performed differential analyses on both RNA and protein expression data from the atypical groups of two separate datasets ROSMAP and MSBB, using typical AD sub‐cohort as reference. In addition, highly correlated gene/protein co‐expression network modules were mined for each of the four datasets. Enrichment analysis identified biological processes and functions associated with the differentially expressed genes (DEGs) and co‐expressed modules.

Result

Five DEG targets were tested in human AsymAD samples and compared with age‐matched controls and typical AD. Using western blot and qRT‐PCR, we confirmed the altered gene expressions in PSCK1 which is related to vesicle trafficking and neuron secretory pathway. Moreover, oppositely regulated pathways were identified for the two subtypes, such as oxidative phosphorylation pathway, neuron CREB signaling, necroptosis signaling pathway. Coexpression analysis also revealed that several coexpressed modules have significant altered expressions in the atypical AD subtypes as compared to typical AD group and are correlated with the disease severeness. For example, the protein modules from both ROSMAP and MSBB, which are enriched with mitochondrial functions and negatively correlated with disease severeness, are significantly elevated in Asym AD group than that of the typical AD or Low‐tau AD group.

Conclusion

We have identified several altered pathways and genes that potentially render neuron protection or vulnerability. Identifying key factors in such uncoupling between tauopathy and cognitive impairment will not only improve precision medicine in AD, but also provide insights to prevent or slow down cognitive decline during AD progression. Further validations in Drosophila will elucidate their roles in the pathology or disease progression.
Mechanisms linking hearing loss with risk for dementia depends on age
Authors: van ’t Hooft Jochum J. , Pelkmans Wiesje , Tomassen Jori , Smits Cas , Legdeur Nienke , den Braber Anouk , Barkhof Frederik , van Berckel Bart N.M. , Yaqub Maqsood , Scheltens Philip , Pijnenburg Yolande A.L. , Visser Pieter Jelle , Tijms Betty M.
Published: June 2023

Background

Age related hearing loss has been associated with increased prevalence and incidence of dementia. Underlying mechanisms that connect hearing loss with dementia remain largely unclear.

Methods

We studied the association of hearing loss and other risk markers for dementia in two cohorts with normal cognition and different age: 65 participants from the EMIF‐AD 90+ study (mean age 92.7 years, 56.9% female) and 60 participants from the EMIF‐AD PreclinAD study (mean age 74.4, 43.3% female). Individuals were selected when they had hearing function (‘digits‐in‐noise test’) and neuropsychological testing available. Amyloid binding potential (BPND) was derived from dynamic PET scans. We used linear regression analysis and generalized estimating equations to test the association of hearing loss and BPND. We used linear mixed models to test the association of hearing function and cognition over time. In the oldest‐to‐old individuals, magnetic resonance imaging was available at the time of hearing function testing, and we performed mediation analyses to study whether cognitive decline is mediated through regional brain regions. All models included age, sex, and amyloid status as covariates, and longitudinal analyses were corrected for education years.

Results

Oldest‐to‐old individuals showed worse hearing functioning than the younger cohort (p< .001). In oldest‐to‐old hearing loss was not associated with BPND (p = .70), whereas younger individuals showed an association of hearing loss with higher BPND (p = .003, figure 1). Oldest‐to‐old individuals showed associations of worse hearing with a steeper decline in memory (β ± SE = ‐0.018 ± 0.007), global cognition (β ± SE = ‐0.017 ± 0.007) and language (β ± SE = ‐0.014 ± 0.007), while in the younger cohort worse hearing was associated with steeper decline in language only (β ± SE = ‐0.086 ± 0.02, figure 2). Mediation analyses demonstrated that the hippocampus and nucleus accumbens fully mediate the effects of hearing loss on memory and global cognition in the older individuals (figure 3‐4).

Conclusions

Hearing loss was associated with amyloid burden in younger individuals only, and with cognitive decline in both age groups. These results suggest that mechanisms linking hearing loss with risk for dementia depends on age.
Aggregation and antibody‐based inhibition of TDP‐43
Authors: Arias Carlos Quintero , Esposto Josephine C , Martic Sanela
Published: June 2023

Background

TAR DNA‐binding protein 43 (TDP‐43) is a highly conserved nuclear protein, predominantly associated with RNA metabolism. Aberrant TDP‐43 inclusions are present in over 95% of post‐mortem brain tissue samples from Amyotrophic Lateral Sclerosis (ALS) patients. The highly disordered TDP‐43 C‐Terminal Domain (CTD) is associated with the greatest amount of disease‐related mutations and phosphorylation sites. The exact mechanism of TDP‐43 aggregation and formation into a pathological state has yet to be elucidated but is an important therapeutic target to consider.

Method

Full‐length phosphorylated TDP‐43 (pS410) protein was treated with 6 hours of daily agitation over 9 days in vitro. Agitation and aging took place with and without the presence of TDP‐43 RRM2‐CTD specific antibodies. Dot‐blot analysis was performed to confirm the binding of antibodies to TDP‐43. Aggregation was monitored and characterized using biophysical analysis; methods included Thioflavin T (ThT), turbidity, and transmission electron microscopy (TEM).

Result

Phospho‐TDP‐43 that had undergone agitation and extensive aging formed insoluble aggregates and ThT positive fibrils. The incubation with antibodies specific to the RRM2‐CTD inhibited aggregation and fibril formation in a concentration‐dependent manner.

Conclusion

Similar immunotherapies exist for other neurodegenerative disease‐related proteins; inhibition of TDP‐43 aggregation and fibril formation using antibodies demonstrates the potential for the epitope‐specific treatment of TDP‐43 proteinopathies.

1) Esposto, J., & Martic‐Milne, S. (2021). Biochimica et Biophysica Acta (BBA) ‐ Molecular Basis of Disease, 1867, https://doi.org/10.1016/j.bbadis.2021.166234.