bluuebunny/crossref_metadata_2025 huggingface dataset:
Empowering Youth Carers of a Parent with Younger‐Onset Dementia
Authors: Cose Diana Shulla , Dean William
Published: December 2023

Lorenzo’s House, an international nonprofit empowers families living with younger‐onset dementia through our holistic model. Younger‐onset does not just impact the person diagnosed: it impacts a whole family. Services for people impacted by dementia are geared towards older adults, but younger‐onset strikes people in their 30s, 40s, and 50s. There is an urgency as there has been a 200% increase between 2013‐2017, in this age range, according to BlueCross BlueShield. This gap in appropriate services and alarming uptick leaves families on an isolated path, searching for resources, support, and basic understanding.

Youth are often affected by a parent’s diagnosis at a neurobiologically vulnerable time in their lives. Youth whose parents have younger‐onset dementia frequently don’t know how to explain their experience as a carer with their peers, leaving them isolated and managing the ongoing change by themselves. By creating spaces specifically catered towards these young carers, Lorenzo’s House has radically shifted the journey of what younger‐onset dementia looks like for children and young adults.

Our three innovative Youth Initiatives empower young carers with strategies and a community that understands. Our Youth Summit, a virtual experience designed by young carers and trusted professionals builds an alliance by sharing stories, exchanging carer techniques and expanding brain health knowledge. Our Light Club, a virtual bi‐monthly youth carer hangout offers peer support, mindfulness practices, and laughter. Our Young Professionals Board magnifies our mission and works to break stigma through advocacy, education, and outreach.
Analysis of Alzheimer’s disease‐related synaptic alterations using microfluidic microglia/neuron co‐cultures
Authors: Siedlecki‐Wullich Dolores , Ayral Anne‐Marie , Buiche Valerie , Lambert Jean‐Charles , Kilinc Devrim
Published: December 2023

Background

Microglial cells are resident macrophages of the central nervous system. Genome‐wide association studies identified numerous Alzheimer’s disease (AD) risk genes highly or exclusively expressed in microglia, supporting their role as major players in AD pathogenesis. We aim to describe the effect of microglia activation on synaptic connectivity and its potential modulation by AD risk genes.

Method

We developed a microfluidic co‐culture device where fluidically isolated, mature neuronal synapses are brought in contact with microglia, enabling exclusive genetic and pharmacological interventions to neurons and microglia. We cultured cortical neurons from WT embryonic mice in pre‐ and postsynaptic chambers for 7 days, after which primary microglia from 10‐month‐old WT and APP (hAPPJ20, PDGFAPPSw,Ind) mice were added into the synapse chamber. Microglia morphology and synaptic connectivity near microglia were analyzed via immunocytochemistry and confocal microscopy.

Result

Exposure to lipopolysaccharide (LPS) activated microglia as evidenced by increased surface area and circularity. Morphological changes were correlated with Interleukin‐1 concentration in the medium, indicative of an inflammatory response. We observed a higher reactivity to LPS in microglia from APP mice compared to WT mice, suggesting that genotype‐related differences in microglia reactivity could also be applicable to pathologically relevant stimuli, such as exposure to amyloid‐β oligomers. On‐going work is focused on the synapse pruning process via live‐cell recordings of fluorescent microglia and neurons expressing fluorescently‐tagged synaptic proteins. This model will be used to characterize the dynamic response of microglia to amyloid‐β and include microglia harvested from mice carrying mutations for microglia‐related AD risk genes.

Conclusion

Our microfluidic co‐culture device enables specific modulation and high‐content analysis of microglial activity and synaptic connectivity in physiological and AD pathological conditions.
Biomarker collection from the Caribbean Hispanic families from Dominican Republic and New York.
Authors: Reyes‐Dumeyer Dolly , Piriz Angel , Soriano Belisa , Franco Yahaira , Coronado Zoraida Dominguez , Recio Patricia , Mejia Diones Rivera , Medrano Martin , Lantigua Rafael A. , Vardarajan Badri N , Honig Lawrence S. , Mayeux Richard
Published: December 2023

Background

Genetic Studies of Alzheimer’s Disease in Caribbean Hispanics (CH) has been ongoing for over 20 years. Our primary goal was to identify genes in large well‐phenotyped, multiplex families, and sporadic cases and controls. This longitudinal collection of data represents a unique resource for the scientific community. The project is led by collaborators in the United States (US) and the Dominican Republic (DR). For the past three years, our efforts have been centered on the collection of cerebrospinal fluid (CSF), plasma, serum and Paxgene tubes for RNA to study core biomarkers. Collection of blood samples for DNA to conduct genetic analyses is also ongoing.

Method

The cohort consisted of participants aged 50 and older from the DR, including those living in the New York City area, willing and able to provide a blood and CSF samples. Interviewers in the DR were trained to collect data, blood samples and CSF. DNA samples were sent overnight to Columbia university (CU) for processing. CSF, Paxgene tubes, serum and plasma samples were processed in the DR and stored at ‐80F for batch shipping to CU. APOE genotyping was conducted in the US. Biomarkers, metabolomics, and proteomics data was generated at Columbia University. Methylation assays from Paxgene was conducted at Uniformed Services University (USUHS).

Result

We have databased a total of 1899 individuals with plasma samples, 1707 with Paxgene, 1731 with serum and 203 with CSF. Blood samples from 1079 participants have genome wide arra, whole genome sequencing and APOE genotyping. 192 CSF samples have proteomics completed, 153 CSF samples have metabolomics data and 742 have plasma biomarkers (Ab40, Ab42, T‐tau, P‐tau181, NFL and GFAP)).

Conclusion

Sample collection for genetic studies in developing countries present important logistical challenges. Despite these challenges, sample quality is comparable to those collected in New York. Biomarkers from CSF, serum and plasma can give us a closer look into underrepresented populations such as Caribbean Hispanics. Results suggest that similar protocols can be successful in Latin America. Future work will augment the biosample collection of the cohort by collecting samples from additional subjects.
Applying Community Based Participatory Practices to Recruitment for the Asian Cohort for Alzheimer’s Disease
Authors: Yu W. Haung , McCallum Jake , Lam Eleanor , Deng Michelle , Li Xiang Helen , Chou Sephera , Wang Li‐San
Published: December 2023

Background

Alzheimer’s disease (AD) involves many risk and protective factors encompassing genetics and lived experiences. Despite disease heterogeneity, inclusion of Asian ancestry lags. In the National Alzheimer’s Coordinating Center (NACC) registry, only 2.5% of patients are of Asian ancestry. Lack of inclusion is even greater in the Alzheimer Disease Genetic Consortium, where Asian‐Americans represent only 0.7% of the population, 7‐fold less than the population (5%) of Asian‐Americans over 65. Cumulatively, disparity in research negatively impacts understanding of AD risk and protective factors and led to the formation of the Asian Cohort for Alzheimer’s Disease (ACAD) to address this lack of inclusion.

Method

Given the paucity of Asian American and Canadian older adults in AD research, ACAD applies a community‐based participatory research (CBPR) program to recruit participants, involving research‐community‐medicine partnerships to facilitate both better health outcomes and inclusion in research. A comprehensive program of brain health education, destigmatization, and bridging access to care are important aspects developed through ACAD Outreach and in Toronto. Extensive partnerships also help drive greater awareness about AD and related dementias to ensure a thriving dialog in the community.

Result

Since September 2021, the Toronto site has had interest from over 300 individuals of Chinese descent, successfully prescreened 2/3 of those and have thus far enrolled half in the study. Of completed participants, ∼50% are cognitively healthy, 20% with AD and 27% MCI, and 2/3 of participants have provided blood, despite societal reticence for blood donations. To achieve recruitment, we conducted multiple community events, including 15 virtual seminars, in addition to working with medical, long‐term care and community center partners, and using traditional print and social media. Tools to effectively community brain health education and ACAD were developed, including overcoming challenges to participation ensuring participant comfort. This has led to high referral rates (20%) indicating strong traction in the community.

Conclusion

ACAD has demonstrated feasibility in recruitment of voluntary participants to study the risk and protective factors of AD amongst Asian populations and will continue to recruit as well as analyze data, providing this information back to the community as part of the CBPR tenet.
Understanding Asian American, Native Hawaiian, and Pacific Islander participants' attitudes toward research: CARE research recruitment registry
Authors: Park Van Ta , Hoffmann Thomas J. , Tsoh Janice Y. , Meyer Oanh L. , Nam Bora , Tzuang Marian , Kanaya Alka , Hinton Ladson , Gallagher‐Thompson Dolores , Vuong Quyen , Kim David , Grill Joshua D
Published: December 2023

Background

Recruitment science includes the need for greater elucidation of barriers to participation as well as identification of factors, such as attitudes toward research, that can be addressed to improve recruitment outcomes. This is especially important in populations, such as Asian Americans, Native Hawaiians, and Pacific Islanders (AANHPI), who are significantly underrepresented in Alzheimer’s disease and related dementias (ADRD) research. We examined the Collaborative Approach for AANHPI Research and Education (CARE) research recruitment registry participants’ attitudes toward research.

Method

Upon enrollment, all CARE participants (n = 9,405 as of 10/2/22) were invited to complete a 7‐item Research Attitude Questionnaire (RAQ) with 5‐point Likert‐scale responses. RAQ scores range from 7‐35, with higher scores indicating more positive research attitudes. Cronbach’s α was 0.93 (and >0.91 in all language subgroups). Favorable scores were dichotomized at ³28.

Result

Of 6,793 participants (response rate: 68%) completing the RAQ, the median age of participants was 54y (interquartile range (IQR) = 38‐66y), including 2,028 middle‐aged (50‐64y) and 1,970 older (≥65y) who may be targeted groups for ADRD research. Overall, 14.2% (n = 968) reported having ADRD (median age = 66; IQR = 57‐73). Among the 1,766 caregivers (median age = 45, IQR = 36‐54), 6.5% were ADRD caregivers (n = 115). The major ethnic groups were Vietnamese (39.4%), Chinese (24.0%), Korean (15.8%), Asian Indian (5.3%), Japanese (2.9%), and Native Hawaiians and Pacific Islanders (4.6%). A total of 84.9% were foreign‐born, and 50.8% had limited English proficiency (LEP). Nearly two‐third of the respondents (63.9%) had less than favorable attitudes toward research. Preliminary findings indicate that women, Vietnamese Americans, immigrants to the US, and those with LEP had significantly less favorable attitudes toward research compared to their counterparts (Table 1).

Conclusion

Unfavorable attitudes toward research may be a frequent, but potentially modifiable, barrier to research participation among AANHPI populations. Certain subpopulations (e.g., those with LEP) may require more tailored and resource intensive engagement to increase their participation. Through enhanced understanding of community members’ attitudes toward research participation, investigators can better design studies to be inclusive and adapt outreach and recruitment strategies, in turn, ensuring the inclusivity, generalizability, and validity of their findings.
Community‐based recruitment in Nigeria and cell biobanking to understand the impact of the apolipoprotein E variants on Alzheimer’s disease
Authors: Maina Mahmoud Bukar , Goni Baba Waru , Marsh Jacob , Wray Selina , Serpell Louise , Karch Celeste M.
Published: December 2023

Background

Despite the human genetic diversity found in the African continent, there is a lack of understanding of dementia mechanisms in indigenous Africans, in part, due to a lack of access to African samples and models. Thus, we sought to develop a biobank of somatic and induced pluripotent stem cells (iPSC) from indigenous Africans to begin to bridge this gap.

Method

Community outreach was conducted in Nigeria with the help of the media, health workers and clinicians to recruit healthy biopsy donors from diverse ethnic groups. Interested donors were screened for inclusion/exclusion criteria, including health status, family history, ethnicity, and age.

Results

Forearm skin biopsies were performed for 11 donors, and fibroblasts were isolated and banked. Fibroblasts were then reprogrammed to generate iPSCs. Fibroblasts and iPSCs have been banked and will be made available to the global scientific community. The iPSCs are currently being screened for APOE genotypes, and selected lines will undergo CRISPR gene editing to generate isogenic APOE33 and APOE44 iPSCs for cellular and molecular studies of dementia mechanisms in comparison to iPSCs from European ancestral backgrounds.

Conclusion

Our work will facilitate the incorporation of genetically diverse iPSC brain models in neurodegenerative disease research towards an understanding of the contribution of ancestry to disease mechanisms.
Leveraging the full potential of Raman spectroscopy for the identification of amyloid aggregation states
Authors: Haessler Annika , Jung Nathalie , Windbergs Maike
Published: December 2023

Background

Raman spectroscopy is a label‐free method often used in the characterization of the beta‐amyloid (Aβ) aggregation process. This process involves peptide misfolding, which can be tracked with Raman microscopy in a non‐invasive manner, since the technique is sensitive for conformational changes in peptide structure. However, often only the spectral bands corresponding to β‐sheets and α‐helices are used for the evaluation of the aggregation state, leaving the remaining spectral information unused. The here presented evaluation aims to explore the full potential of Raman spectroscopy for the characterization of Aβ‐42 aggregates (monomers, oligomers, fibrils) in a comprehensive analysis approach, complemented by Thioflavin T (ThT) fluorescence measurements and atomic force microscopy (AFM).

Method

Aβ‐42 was reconstituted in diluted ammonia. were prepared by reconstituting peptide in diluted ammonia on ice and dilution with phosphate buffered saline (PBS). Oligomers and fibrils were obtained by incubation in MilliQ water or diluted hydrochloric acid for 24 hours at 4°C or 37°C, respectively. Samples were optionally further diluted for AFM, ThT fluorescence assays and . The Raman spectra were processed using Project 4 software (WITec GmbH, Ulm, Germany), and in‐house written Matlab scripts (The Mathworks, Inc., Natick, USA).

Result

Using Raman spectroscopy, as well as established methods such as AFM and ThT fluorescence, the size and aggregation state of monomeric, oligomeric and fibrillar Aβ‐42 could be confirmed and reproducibly obtained using standardized protocols. Corresponding Raman spectra of these Aβ‐42 aggregates display distinct differences not only in the β‐sheet and α‐helix spectral band, but in the whole spectrum, indicating especially changes in the orientation of tyrosine, phenylalanine, and aliphatic side chains.

Conclusion

Herein, the potential of Raman spectroscopy as a label‐free, conformation‐sensitive technique for the characterization of Aβ‐42 aggregates was explored by analyzing the full Raman spectrum. Clear differences between all aggregate types were identified in several spectral bands, unveiling detailed information in the Raman spectra that is often not included in the analysis of Aβ aggregates. Thus, this study provides a guideline for extracting comprehensive knowledge from spectroscopic data on peptide aggregation, potentially serving as a non‐destructive, quick addition or alternative to more established methods.
Does amyloid moderate practice effects in language measures in a cognitively unimpaired at‐risk sample?
Authors: Basche Kristin E , Jonaitis Erin M. , Betthauser Tobey J , Christian Bradley T. , Hermann Bruce P , Johnson Sterling C , Mueller Kimberly D , Langhough Rebecca E
Published: December 2023

Background

Lack of practice effects (PE) in common cognitive tests has been associated with increased risk of dementia. Previous studies have found connections between recall of proper names (PN) and amyloid positivity in cognitively unimpaired adults at risk for Alzheimer’s Disease (AD; Mueller et al., 2020). For several language‐related tests, including PN, we compared PE modeling options and then examined whether amyloid status moderated PE.

Method

Participants with language tasks and C‐Pittsburgh Compound‐B (PiB) amyloid positron emission tomography (PET) were selected from the Wisconsin Registry for Alzheimer’s Prevention (WRAP; n = 377). PE operationalizations included: number of language task exposures – 1 (“PEnvis‐1”), the square root of PEnvis‐1 (“PEsqrt”) and categorical PE (“PEcat”; reference = 0 (baseline) vs 1, 2, or 3+ follow‐up assessments). Language outcomes variables included letter fluency (CFL), animal naming, and logical memory (LM). From LM, we utilized item‐level data to create immediate and delayed PN recall. We used linear mixed effects models to identify the best fitting PE operationalization for each outcome and ran subsequent models examining amyloid*PE interactions (covariates: age at assessment, gender, and WRAT‐III reading score; random effects for intercept).

Result

Sample characteristics are shown in Table 1 overall and by amyloid status. AIC fit statistics were best overall for PEnvis‐1. In subsequent models, the PE*amyloid interaction was significant for LM Total Score (β = ‐0.08, 95% CI = (‐0.15, ‐0.01), p = 0.02) and PN immediate recall (β = ‐0.22, 95% CI = (‐0.38, ‐0.05), p = 0.01). For both outcomes, predicted Z‐scores increased with more practice for amyloid positive participants, but decreased for amyloid negative participants (Table 2; Figure 1). The main effect of PE was significant for CFL (β = 0.12, 95% CI = (0.08, 0.15 p<0.001) and Animal Naming (β = 0.07, 95% CI = (0.03‐0.11), p = 0.002).

Conclusion

PEnvis‐1 was generally the best‐fitting PE operationalization. In our relatively young sample (baseline mean age = 54.1; mean years between baseline and most recent LM = 9.12), improvements with practice for animal naming and CFL were not modified by amyloid status. In contrast, those with amyloid negative biomarkers showed practice‐related improvements on LM while those with positive amyloid showed decreased performance with more practice.
3D chromatin structure and massively parallel reporter assays in hiPSC‐derived microglia and human macrophages identifies novel putative Alzheimer’s Disease risk genes
Authors: Quiroga Ivana Yoseli , Bond Marielle L , D'Costa Susan , Bell Jessica L , McAfee Jessica C , Reed Kathleen S Metz , Sahasrabudhe Isha R , Patrucco Mary , Won Hyejung , Phanstiel Douglas H
Published: December 2023

Background

Alzheimer’s disease (AD) genome‐wide association studies (GWAS) identified 75 disease‐associated loci; however, interpretation of these results has proven difficult for two primary reasons. First, linkage disequilibrium between nearby variants makes it difficult to identify the causal variant(s) at each locus. Second, because the vast majority of OA risk variants are non‐coding and can regulate genes from distances of greater than one million base pairs, the genes impacted by AD risk variants are largely unknown. Recently developed genomic approaches can address these hurdles but must be applied to the correct cell types and biological contexts.

Method

We quantified the impact of 3,576 AD‐associated genetic variants on enhancer activity by performing massively parallel reporter assays (MPRAs) in resting and activated human macrophages. To map these variants to the genes they regulate we built regulatory networks by mapping 3D chromatin structure (Hi‐C), chromatin accessibility (ATAC), histone K27 acetylation (CUT&RUN), and gene expression (RNA‐seq) in both resting and activated iPSC‐derived microglia.

Result

In total we identified 20,992 chromatin loops across resting and activated iPSC‐derived microglia. Among these, 9,544 loops linked 14,576 enhancers to 11,487 genes. 58 loops connected 414 AD‐risk variants queried by our MPRA assays to 85 genes. 212, 19,256, and 2,790 of these loops, enhancers, and genes (respectively) changed in response to activation, providing further insight into their regulatory mechanisms and highlighting the need to study these events in the correct biological context.

Conclusion

Ongoing analyses and data integration should reveal further mechanistic details and provide novel AD risk genes for further research and therapeutic development. By intersecting our MPRA results and dynamic regulatory networks with AD GWAS, we were able to identify novel putative genes regulated by non‐coding AD risk variants in a cell‐type and condition‐specific manner.
The role of experiential avoidance and cognitive fusion in the development of anxiety symptoms among family carers of people with dementia
Authors: Van Hout Elien , Contreras Milena L , Mioshi Eneida , Kishita Naoko
Published: December 2023

Background

Despite the high prevalence of anxiety symptoms among family carers of people with dementia (Kaddour & Kishita, 2020), current carer interventions are considered to be not as effective for anxiety as they are for depression (Kishita et al., 2018). Therefore, understanding the mechanism by which a common stressor (i.e. carer subjective burden) and underlying psychological processes influence anxiety symptoms among this population is critical to inform future interventions. In this study, the roles of two psychological processes known to be associated with mental health problems were explored: experiential avoidance in caregiving (an attempt or desire to control or suppress distressing thoughts and feelings related to caregiving) and cognitive fusion (the tendency for one’s behaviour to be overly regulated and influenced by thoughts).

Method

With a sample of seventy‐seven family carers (mean age of 63.47 years (SD = 10.64) and 73% female), this study examined the indirect effect of carer subjective burden (ZBI‐12) on anxiety symptoms (GAD‐7) through experiential avoidance in caregiving (EACQ) and cognitive fusion (CFQ) using a path analysis approach.

Result

The whole sample model showed a good fit to the data. The indirect effect of carer subjective burden on anxiety symptoms through its effect on cognitive fusion (β = .17), and its combined effect on experiential avoidance in caregiving and cognitive fusion (β = .01) were significant. Examined variables accounted for 54% of the variance in anxiety symptoms.

Conclusion

Given the higher explanatory value demonstrated for the indirect effect of cognitive fusion alone, facilitating cognitive fusion through psychological interventions may be critical for preventing clinically significant levels of anxiety symptoms, particularly among those carers experiencing high levels of carer subjective burden. The results also demonstrated that family carers with higher experiential avoidance in caregiving may be prone to cognitive fusion, which in turn could lead to higher levels of anxiety symptoms. Therefore, an early intervention targeting experiential avoidance may be beneficial for preventing increased cognitive fusion and anxiety symptoms.
The role of Tau‐seed interactome in Alzheimer’s disease and other tauopathies
Authors: Martinez Pablo , Patel Henika , You Yanwen , Garfe Nur Jury , Zhang Jie , Troncoso Juan C , Reeves Cristian A Lasagna
Published: December 2023

Background

Pathological tau aggregation is a defining histopathological feature of Alzheimer’s disease (AD) and other neurodegenerative diseases collectively known as tauopathies. The propagation of pathological forms of tau in AD patient brains has been shown to follow neuronal networks. However, the cellular mechanisms involved in tau propagation and the nature of the tau species involved in spreading remain unclear.

Method

We performed an unbiased quantitative mass spectrometry‐based study to identify the proteins that specifically interact with this tau seed.

Result

Herein, we report the identification of bassoon (BSN), a scaffolding presynaptic protein, as an interactor of the tau seed isolated from a mouse model of tauopathy, and from AD and progressive supranuclear palsy (PSP) postmortem samples. We show that BSN exacerbates tau seeding and toxicity in vivo. Furthermore, BSN downregulation significantly decreases tau spreading and overall disease pathology in vivo, rescuing synaptic and behavioral impairment and reducing brain atrophy.

Conclusion

Our findings improve the understanding of tau seeds and highlight the importance of identifying interactors, such as BSN, that could stabilize these seeds. Inhibiting tau‐seed interactors is a potential new therapeutic approach for neurodegenerative tauopathies.
Neuroticism is associated with entorhinal cortex volume in cognitively unimpaired older adults
Authors: Akbarian Niki , Vandermorris Susan , Verhoeff Nicolaas Paul L.G. , Herrmann Nathan , Mah Linda
Published: December 2023

Background

Neuroticism, the tendency toward negative mood states, is associated with Alzheimer’s Disease (AD) and tau pathology within entorhinal cortex (EC) in mild cognitive impairment and healthy older adults. However, studies of the link between neuroticism and structural neurodegeneration of EC have been negative. This may result from failure to account for subsyndromal affective symptoms or previous psychiatric history, as neuroticism is closely related to mood conditions that in turn, affect similar brain regions vulnerable to AD. We examined the association between neuroticism and EC volume while accounting for cognition, affective symptoms, and other personality traits in cognitively unimpaired (CU) older adults without history of major psychiatric conditions.

Method

42 CU adults (age = 71.1 years, 27 females) with normal neuropsychological test performance and no known neurological conditions and current or past psychiatric disorders completed Geriatric Depression Scale, State‐Trait Anxiety Inventory, NEO Five‐Factor Inventory‐3 which assesses neuroticism, openness, conscientiousness, extraversion, and agreeableness, Montreal Cognitive Assessment (MoCA), and structural magnetic resonance imaging of whole brain at 3T. Regression analyses examined the unconditional ability of neuroticism to predict bilateral EC volume, and while considering the potential contribution of cognition (MoCA, California Verbal Learning Test Delayed Recall), affective state, other personality traits, and age, gender, and education. P<.10 was set as the significance threshold for β estimates.

Result

In univariable modelling, neuroticism was predictive of left EC volume (β = ‐17.4, p = .025), explaining 9.8% of its variability [F(1, 40) = 5.45, p = .025]. Neuroticism remained a significant predictor of left EC volume (β = ‐1.9, p = .045) after factoring in demographic, cognitive and affective/personality variables. Additional left EC predictors were extraversion and state anxiety (β = ‐2.61, p = .01; β = 1.71, p = .045 respectively). Neuroticism was not predictive of right EC in univariable or multivariable modelling, but agreeableness emerged as a significant predictor (β = ‐1.68, p = .091).

Conclusion

Neuroticism was predictive of left EC volume in CU adults without current or past history of psychiatric disorders, independent of cognition, affect, and other personality traits. These findings, which have not been previously reported, extend previous epidemiological evidence of increased AD risk due to neuroticism and suggest the importance of considering the impact of mood symptoms and psychiatric history in this context.
Glucocorticoid excess and insulin resistance in rat models of vascular contributions to cognitive impairment and dementia
Authors: Lansdell Theresa A , Ojeda‐Henaiz Angel , Lewis Ally , Dorrance Anne M
Published: December 2023

Background

Hypertension and insulin resistance are major risk factors for the development of dementia. While insulin resistance is considered an important risk factor for the development of hypertension and dementia, little consideration has been given to the idea that vascular disease could initiate insulin resistance and fuel a destructive cycle that hastens dementia. We previously showed that bilateral carotid artery stenosis results in HPA‐axis dysfunction and insulin resistance (Lansdell et al., 2022). We hypothesized that hypertension would also cause glucocorticoid excess and insulin resistance.

Method

To test this hypothesis, we measured fecal corticosterone and the expression of steroid biosynthetic genes in the adrenal glands of six‐month‐old spontaneously hypertensive rat/stroke‐prone (SHRSP) and normotensive Sprague Dawley (SD) rats. To assess glycemic control, rats were subjected to glucose and insulin tolerance tests.

Result

SHRSP were hypertensive and cognitively impaired. Corticosterone was elevated in hypertensive compared to normotensive rats (Male SD vs. SHRSP: 167±29 pg/g vs.1091±166 pg/g, P<0.0001; Female SD vs. SHRSP: 134±19 pg/g vs. 376±47 pg/g, P = 0.0017). Adrenal CYP11B1 mRNA expression was increased in SHRSP (Males 14.44±1.44, P = 0.0009; Females 710±59, P = 0.0016). STARD1 mRNA expression provided a marker of HPA negative feedback. Male SHRSPs had decreased STARD1 mRNA expression (0.56±0.09, P = 0.0217). However, female SHRSPs had increased STARD1 mRNA expression (12.5± 2.25, P = 0.0028). Female, but not male, hypertensive rats had increased fasting blood glucose, decreased fasting insulin, and reduced rates of glucose clearance (female SD vs. SHRSP: 73±6 vs. 92±4 mg/dL glucose, P = 0.0045; 33±2.0 vs. 12±5 pmol/L insulin, P = 0.0111; AUC 185±37 vs. 279±27 mg/dL/h, P = 0.0368). When fasting rats were challenged with insulin, both male and female hypertensive rats had decreased clearance of glucose compared to normotensive rats (Male SD vs. SHRSP AUC 87 ± 2 vs. 58 ± 4 mg/dL/h, P< 0.0001, Female SD vs. SHRSP AUC 82 ± 2 vs. 68 ± 3 mg/dL/h, P = 0.0007).

Conclusion

These results indicate that hypertension is associated with impaired HPA function and insulin resistance, with female hypertensive rats developing hyperglycemia at an earlier age than males.
A multicenter validation study on the diagnostic and prognostic value of CSF Neurogranin and BACE1
Authors: Wang Xiao , Freiesleben Silka Dawn , Schneider Luisa Sophie , Gabelin Tatjana , Preis Lukas , Priller Josef , Schneider Anja , Fließbach Klaus , Wiltfang Jens , Jessen Frank , Düzel Emrah , Buerger Katharina , Perneczky Robert , Teipel Stefan , Laske Christoph , Spottke Annika , Heneka Michael T. , Peters Oliver
Published: December 2023

Background

Cerebrospinal fluid (CSF) biomarkers have immense diagnostic and prognostic potential for Alzheimer disease (AD). Currently, AD is still mostly diagnosed relatively late in the disease process, sometimes even years after the initial manifestation of cognitive symptoms. Disease‐modifying treatments should be most effective in the earliest stages, before amyloid plaques and neurodegeneration become prevalent. Thus, further identification of biomarkers is required that can detect AD in the predementia stage. This study aimed to assess the clinical utility of synaptic proteins neurogranin and beta‐secretase 1 (BACE1) in the diagnosis and prognosis of AD.

Method

We enrolled 530 participants from DELCODE, a multicenter prospective cohort study, including healthy controls (HC), subjective cognitive decline (SCD) subjects, mild cognitive impairment (MCI) subjects, mild AD dementia and first‐degree relatives of AD patients. Based on amyloid and tau status, we divided the participants into four groups: A−T−; A−T+; A+T−; A+T+. Neurogranin and BACE1 levels across groups were assessed by ANCOVA after adjusted for age and sex. To test the correlation of the biomarkers to cognitive performance, we used linear mixed models to model baseline biomarker levels and 7 years longitudinal MMSE and PACC5 scores.

Result

Regardless of amyloid status, CSF neurogranin and BACE1 levels were significantly higher in T+ group compared with T‐ (all p < 0.0001). Furthermore, for participants with negative tau status, neurogranin and BACE1 levels were lower in A+ group compared with A‐ (both p < 0.0001). After adjusting for covariates (Age, Sex, Education, APOEε4), linear mixed‐effect models indicated that higher neurogranin predicts faster decline in MMSE (β = ‐0.14, p < 0.01) and PACC5 (β = ‐0.03, p < 0.05) over 7 years.

Conclusion

This study reveals that neurogranin and BACE1 could offer insight into identifying patients at early stages of AD and improve prediction of cognitive decline.
Late positive potential component and cognitive functioning in occipital area of Mild Cognitive Impairment
Authors: Zhang Zhenyu , Aleman André , Opmeer Esther , De Deyn Peter Paul , Reesink Fransje E , Spikman Jacoba M , Herrmann Christoph S , Wardana Nido Dipo , Enriquez‐Geppert Stefanie , Lejko Nena , Ćurčić‐Blake Branislava
Published: December 2023

Background

Mild Cognitive Impairment (MCI) is a prodromal stage of Alzheimer’s disease and other dementias (Langa & Levine, 2014). It has been suggested that a late event‐related potential (ERP) called the late positive potential (LPP) is related to cognitive functioning including sustained attention and reaction time in people with MCI (Waninger et al., 2018). The LPP in the occipital area was also suggested to be a biomarker of MCI (Liu et al., 2022). However, it remains unclear whether LPP in the occipital area is related to cognitive functioning.

Method

We collected EEG of 50 people with MCI (mean age 72.44±7.96; education: 5.52±1.07) by using a 20‐channel EEG recording system while participants performed the simple vigilance task (SVT). Their reaction time (ms) was taken as a measure of sustained attention. Vienna Reaction Time Task (VRTT) (Schuhfried GmbH, Moedling, Austria) was used to measure processing speed and inhibition while separating motor action (measured as a motor time) and cognitive processing (measured as a reaction time). Mini‐Mental State Examination (MMSE) was used to measure the severity of cognitive impairment (mean score: 26.20±2.44). Correlation analysis was used to analyze the liner relationship between the average LPP amplitude in the occipital areas (Oz, O1, and O2; time window: 400 to 800 ms after stimulus presentation), reaction time on the three versions of the VRTT, and reaction time on the SVT.

Result

We found significant correlations between reaction time on the SVT and motor time on VRTT (S1: p = 0.015; S2: p = 0.075; S3: p = 0.021;), but we found no significant correlations between reaction time on the SVT and VRTT (ps > 0.193), no significant correlations between LPP amplitude in the occipital areas and reaction time on any of the tasks (SVT: p > 0.056, VRTT: ps > 0.288) or between LPP amplitude and motor time on any version of the VRTT (ps > 0.500).

Conclusion

Our preliminary results indicate that LPP amplitude measured over the occipital area was not significantly associated with sustained attention or inhibition.
NIA Genetics of Alzheimer’s Disease Data Storage Site (NIAGADS): 2023 Update
Authors: Nicaretta Heather Issen , Kuzma Amanda B , Valladares Otto , Manuel Joseph , Greenfest‐Allen Emily , Gangadharan Prabhakaran , Katanic Zivadin , Kirsch Maureen , Armus Lauren , Saravanan Naveensri , Wilk Andrew , Zhao Yi , Qu Liming , Moon Michelle K , Rose Alexis Lerro , Keskinen Peter , Cifello Jeffrey , Chou Shin‐Yi , Lee Wan‐Ping , Leung Yuk Yee , Naj Adam C. , Schellenberg Gerald D. , Wang Li‐San
Published: December 2023

Background

NIAGADS is a national genomics data repository that facilitates access of genotypic and sequencing data to qualified investigators for the study of the genetics of Alzheimer’s disease (AD) and related neurological diseases. Collaborations with large consortia and centers such as the Alzheimer’s Disease Genetics Consortium (ADGC), Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium, the Alzheimer’s Disease Sequencing Project (ADSP), and the Genome Center for Alzheimer’s Disease (GCAD) allow NIAGADS to lead the effort in managing large AD datasets that can be easily accessed and fully utilized by the research community.

Method

NIAGADS is supported by National Institute on Aging (NIA) under a cooperative agreement. All data derived from NIA funded AD genetics studies are expected to be deposited in NIAGADS or another NIA approved site. NIAGADS manages a Data Sharing Service (DSS) that facilitates the deposition and sharing of genomic data and association results with approved users in the neurodegenerative research community. In addition, researchers are able to freely use the NIAGADS Alzheimer’s Genomics Database (www.niagads.org/genomics/) to search annotation resources that link published AD studies to AD‐relevant sequence features and genome‐wide annotations.

Result

As of January 2023, NIAGADS houses 93 datasets comprised of >149,000 samples including GWAS, sequencing, gene expression, annotations, deep phenotypes, and summary statistics. Qualified investigators can retrieve ADSP sequencing data with ease and flexibility through the NIAGADS DSS. To date, the ADSP and other contributing studies have completed whole exome sequencing (WES) of 20,503 samples and whole genome sequencing (WGS) of 36,361 samples. Raw WES and WGS files, quality controlled VCF files, and phenotype data files are available via qualified access. The next round of sequencing currently underway will generate around 30,000 additional genomes to be released in late 2023.

Conclusion

NIAGADS is a rich resource for AD researchers, with the goal of facilitating advances in Alzheimer’s genetics research. By housing datasets from many projects and institutions, NIAGADS enables AD researchers to meet their research goals more efficiently. Datasets, guidelines, and features are available on our website at https://www.niagads.org.
Informing policy development regarding the hospital management of people with dementia: A multi‐faceted approach
Authors: Batchelor Frances , Parker Amy , Garratt Stephanie , Williams Sue
Published: December 2023

Background

In Australia approximately 30% of older people are from culturally and linguistically diverse (CALD) backgrounds. Hospitals are difficult places for people with dementia and even more difficult for those from CALD backgrounds. 75‐90% of patients with dementia experience behavioural and psychological symptoms of dementia (BPSD) during a hospital stay, with agitation and aggression most common1,2. The factors associated with being acutely unwell, combined with unfamiliar environments, heightened by difficulties in communication, can exacerbate BPSD resulting in increased morbidity/mortality and distress. Our aim was to identify the current state regarding BPSD management, compare this with best practice, and inform policy development particularly in relation to those most vulnerable such as people from CALD backgrounds.

Method

Retrospective and prospective observational mixed‐methods design in Victorian hospitals. Six studies were conducted: 1) literature review regarding management of patients with dementia; 2) state‐wide population‐level analysis regarding patients with dementia; 3) inpatient‐ward point prevalence of BPSD; 4) hospital‐wide audit regarding the severity/impact of dementia; 5) gap analysis regarding models‐of‐care for patients with dementia; 6) interviews exploring the experiences of staff and family members of patients with dementia.

Result

The synthesised results will be presented. We will outline how these will contribute to a best practice model‐of‐care for people with dementia in hospital. The challenges in establishing and obtaining relevant data related to dementia, delirium and BPSD in hospitals impacting on evidence‐informed policy will also be highlighted.

Conclusion

Policy development for hospital management of people with dementia, particularly minority groups, is a challenge. This is due to the diversity of the population, the diversity in which the condition presents, the speed/severity of disease progression and the multi‐component interventions required. It is further complicated by the complexity of hospital systems and difficulties associated with obtaining meaningful and accurate qualitative and quantitative data. Comprehensive and collaborative approaches are urgently needed.

References:

1. Sampson EL, et al. Behavioural and psychiatric symptoms in people with dementia admitted to the acute hospital. British J Psych. 2014;205(3):189‐96.

2. White N, et al. The management of behavioural and psychological symptoms of dementia in the acute general medical hospital. Int J Geri Psych. 2017;32(3):297‐305.
Tele‐supervised home‐based transcranial alternating current stimulation (tACS) for Alzheimer’s disease
Authors: Fox Rachel , den Boer Tim , Yu Wanting , LaGanke Nicole , Cattaneo Gabriele , Perellón‐Alfonso Ruben , Bartrés‐Faz David , Manor Bradley , Pascual‐Leone Alvaro , Cappon Davide
Published: December 2023

Background

Over 55 million people worldwide are currently diagnosed with Alzheimer’s disease (AD) and live with debilitating episodic memory deficits (World Health Organization, 2022). Current pharmacological treatments have limited efficacy. Recently, transcranial alternating current stimulation (tACS) has shown memory improvement in AD by normalizing high‐frequency neuronal activity (Benussi et al., 2022). Our goal was to assess the safety, feasibility, and preliminary effects on episodic memory of a caregiver‐led home‐based tACS approach (HB‐tACS).

Method

8 participants diagnosed with AD (Table 1) underwent high‐definition HB‐tACS (40 Hz, 20‐minutes) targeting the left angular gyrus (AG), a key node of the memory network. The Acute Phase comprised 14‐weeks of HB‐tACS with at least five weekly sessions. Three participants underwent resting‐state electroencephalography (EEG) before and after. Subsequently, participants completed a 2–3‐month Hiatus Phase not receiving tACS. In the Taper Phase, participants received 2‐3 sessions per week over 3‐months. Primary outcomes were memory and global cognition, measured with the Memory Index Score (MIS) and Montreal Cognitive Assessment (MoCA), respectively, and EEG theta/gamma ratio. Results reported as mean±SD.

Result

All participants completed the study with, on average, 97 HB‐tACS sessions; reporting mild side effects during 25% of sessions, moderate during 5%, and severe during 1%. Acute Phase adherence was 98±6.8% and Taper Phase was 125±22.3% (from minimum of 2/week). After the Acute Phase, all participants showed memory improvement, MIS of 7.25±3.77, sustained during Hiatus 7.00±4.90 and Taper 4.63±2.39 Phases (Table 2), and decreased theta/gamma ratio in AG (Figure 1A). Conversely, participants did not show improvement in the MoCA, 1.13±3.80 after the Acute Phase, and there was modest decrease during the Hiatus ‐0.64± 3.28 and Taper ‐2.56±5.03 phases. These results suggest the specificity of the intervention for memory functioning (Figure 1B) and relate improvement to decreased theta/gamma ratio.

Conclusion

This pilot study shows the feasibility of a novel, remotely supervised, caregiver‐led HB‐tACS intervention for AD. Targeting the left AG, memory was noticeably improved while global cognition was relatively stable, indicating that future interventions might benefit from multifocal neuromodulation targeting multiple cognitive domains. These results are encouraging for the prospect of safe and feasible treatment within patients’ homes.
Pathological associations with parkinsonism in chronic traumatic encephalopathy
Authors: Adams Jason W , Kirsch Daniel A , Calderazzo Samantha M , Tuz‐Zahra Fatima , Aytan Nurgul , McKee Ann C. , Tripodis Yorghos , Mez Jesse B. , Alosco Michael L , Stein Thor D.
Published: December 2023

Background

Parkinsonism has been shown to be more frequent in those with a history of traumatic brain injury, repetitive head impacts (RHI), and chronic traumatic encephalopathy (CTE), a disease characterized by tau pathology. However, the underlying pathological associations with parkinsonism in this context are not well known.

Methods

Autopsy participants with a history of RHI exposure through contact sports participation and neuropathologically diagnosed with CTE (n = 481) were examined for pathology in the substantia nigra. Based on review of next‐of‐kin interviews and medical records, expert clinicians judged whether symptoms of parkinsonism, including bradykinesia, resting tremor, rigidity, micrographia, and shuffling gait, were present. The total number of consecutive years of contact sports play was used as a proxy for RHI exposure. Neuropathological diagnoses were made using established criteria. Pathology in the substantia nigra was quantified for alpha‐synuclein‐positive Lewy bodies, neurofibrillary tangles (NFTs), and neuronal loss.

Results

Of a total of 481 male CTE participants, 119 (24.7%) had symptoms of parkinsonism during life. Comparison of clinical characteristics of CTE participants with (n = 119) and without (n = 362) parkinsonism showed those with parkinsonism had an older age of death, and a larger proportion had symptoms of dementia, probable REM sleep behavior disorder, and visual hallucinations than participants without parkinsonism (p’s <0.00001). Of those with CTE and parkinsonism, the majority (70%) did not have Lewy bodies within the substantia nigra, suggesting other pathologies may also contribute to motor symptoms. In fact, those with parkinsonism were more likely to have nigral NFTs and neuronal loss (Figure), adjusting for age as well as when restricting to those age >65 (p’s<0.001). Years of contact sports play was associated with NFTs (p = 0.03) and neuronal loss (p = 0.016), but not Lewy bodies in the substantia nigra. Both nigral NFTs (p = 0.001) and Lewy bodies (p<0.001) were associated with nigral neuronal loss. Parkinsonism was associated with neuronal loss (p<0.001) and Lewy bodies (p = 0.027) in the substantia nigra.

Conclusion

Overall, these findings suggest that RHI contributes to tau pathology and neuronal loss in the substantia nigra. Those susceptible to Lewy body pathology may be further at risk for parkinsonism in CTE.