bluuebunny/crossref_metadata_2025 huggingface dataset:
Design, Synthesis and Evaluation of substituted Chromones as Acetylcholinesterase Inhibitors for the Treatment of Alzheimer’s Disease.
Authors: Kumar Naveen , Kumar Vijay , Kumar Vinay , Kailash  , Kumar Vinod
Published: December 2023

Background

Acetylcholinesterase (AChE) is one of the frontline targets involved in the progression of Alzheimer’s disease. AChE inhibitors are prescribed as the few drug therapies that have been proven clinically useful in the treatment of Alzheimer’s disease[1, 2]. AChE is involved in the termination of impulse transmission by rapid hydrolysis of the neurotransmitter acetylcholine in numerous cholinergic pathways[3]. The enzyme inactivation induced by various inhibitors, leads to acetylcholine accumulation, hyperstimulation of nicotine and muscarinic receptor and disrupted neurotransmission.

Method

A series of chromone derivatives were virtually screened, synthesised and biologically evaluated as acetylcholinesterase inhibitors. All the compounds were characterised by 1H‐NMR, 13C‐NMR and mass spectrometry.

Result

The in‐vitro evaluation of the compounds against hAChE enzyme showed promising inhibition varying in lower micromolar range. In the synthesized series, NSS‐17 is found to be the most potent AChE inhibitors (IC50 = 1.59± 0.02 μM). In molecular docking studies, compound NSS‐17 showed similar interaction to AChE (1EVE) as shown by reference compound donepezil.

Conclusion

Thus, NSS‐17 can be used as promising lead for the development of more potent AChE inhibitors by further biological assays and in‐vivo studies.

References

[1] B. Kumar, A.R. Dwivedi, B. Sarkar, S.K. Gupta, S. Krishnamurthy, A.K. Mantha, J. Parkash, V. Kumar, 4,6‐Diphenylpyrimidine Derivatives as Dual Inhibitors of Monoamine Oxidase and Acetylcholinesterase for the Treatment of Alzheimer’s Disease, ACS Chemical Neuroscience 10(1) (2019) 252‐265.

[2] B. Kumar, V. Kumar, V. Prashar, S. Saini, A.R. Dwivedi, B. Bajaj, D. Mehta, J. Parkash, V. Kumar, Dipropargyl substituted diphenylpyrimidines as dual inhibitors of monoamine oxidase and acetylcholinesterase, European Journal of Medicinal Chemistry 177 (2019) 221‐234.

[3] B. Kumar, Sheetal, A.K. Mantha, V. Kumar, Recent developments on the structure–activity relationship studies of MAO inhibitors and their role in different neurological disorders, RSC Advances 6(48) (2016) 42660‐42683.
Amyloid‐β Pathology Exacerbates Aging‐Induced Dysregulation of C1q Expression in Cortical Neurons
Authors: Semmedi Cemaliye , Moore Maxwell B , Mostany Ricardo
Published: December 2023

Background

Aging, even in the absence of age‐related pathologies such as Alzheimer’s disease (AD), is associated with a loss of neuronal function and structure, and cognitive decline. An initiator of the classical complement cascade, C1q, which enhances the immune response in the periphery, has been shown to mediate synaptic pruning in the developing brain (Stevens et al., 2007). It has been hypothesized that this cascade may be implicated in the cognitive decline associated with aging, as well as neurodegenerative diseases, such as AD.

Method

In this study, magnetic‐activated cell sorting (MACS), a cell separation technology based on the use of antibody‐conjugated beads, was utilized to isolate neurons from the whole cortex tissue dissociations of wild‐type (Thy1‐GFP) and AD model (APPNL‐G‐F‐GFP) mice at different life stages: 3 months (young adult), 6 months (adult), 12 months (middle‐aged adult), and > 21 months of age (aged). Droplet‐digital polymerase chain reaction (ddPCR), an advanced PCR technology with higher accuracy and consistency than traditional PCR methods, and Simple Western, an automated western blot system, were utilized to quantify the expression of C1QA and C1q, respectively, in isolated cortical neurons.

Result

There is a significant aging‐induced increase in C1q levels in cortical neurons of both wild‐type and AD model aged mice. Interestingly, in middle‐aged AD mice, in which the deposition of amyloid‐β plaques is already severe, the levels of C1q are significantly elevated compared with wild‐type mice, and the expression levels are comparable to that of aged mice of both genotypes.

Conclusion

These findings support the notion that the initiation of the classical complement cascade by cortical neurons is upregulated with healthy aging, and this aging‐induced upregulation is accelerated by amyloid‐β pathology.
The clinical usefulness of plasma biomarkers of neuronal dysfunction in Alzheimer’s disease
Authors: Mroczko Barbara , Kulczynska‐Przybik Agnieszka , Blennow Kaj , Dulewicz Maciej , Ashton Nicholas J. , Karikari Thomas K , Mroczko Jan , Borawska Renata , Slowik Agnieszka , Zetterberg Henrik
Published: December 2023

Background

Alzheimer’s disease (AD) is one of the most common neurodegenerative disorders, and one of the most significant medical and social problems worldwide. Neurodegeneration, which is a pivotal mechanism underlying the disease, begins a few decades before the first symptoms appear. Therefore, establishing biomarkers that allow for the detection of this process as early as possible is vital. Mounting evidence indicates the crucial role of GFAP and NFL in the pathology of neurodegeneration in AD. The aim of the present study was to assess plasma concentrations of GFAP and NFL, and to test their potential utility in AD diagnosis.

Method

Plasma concentrations of GFAP and NFL were measured using a Single molecule array (Simoa), while the classical biomarkers (Aβ‐42, Aβ‐42/Aβ‐40, tau, and pTau181) were assessed in the cerebrospinal fluid (CSF) of 20 AD patients and 18 elderly subjects without cognitive deficits using ELISA technique.

Result

Plasma concentrations of GFAP and NFL were significantly higher in AD patients as compared to non‐demented controls. The levels of plasma GFAP correlated negatively with MMSE, and CSF Aβ‐42, and positively with plasma concentrations of NFL, and CSF tau proteins in the whole study group. Furthermore, in the AD group, the association between GFAP and NFL was revealed.

Conclusion

Presented findings indicate that plasma GFAP and NFL could be applied as a non‐invasive and accessible tool for detection of early neuronal dysfunction in patients with AD.
Modifiable dementia risk factors associated with distinct subjective and objective cognitive outcomes
Authors: Rosická Anna M , Teckentrup Vanessa , Pringle Andrew , Gallagher Eoghan , Hanlon Anna K , Lawlor Brian , Naci Lorina , Gillan Claire M
Published: December 2023

Background

A range of potentially modifiable environmental, social, and lifestyle factors are estimated to contribute to over a third of dementia cases worldwide. Leading theories propose that these risk factors have different risk‐conferring mechanisms. For example, social isolation, hypertension, and exercise may respectively impact most on cognitive reserve, neurodegeneration, and inflammation. If true, this may support the development of more personalised preventative strategies, depending on risk profiles. Here, we aimed to address this by gathering multiple forms of cognitive assessment in a large sample, across lifespan.

Method

N = 2831 users of a free smartphone app, Neureka (aged 18‐82, M(SD) = 46.84(14.7)), completed questionnaires about their background, health, and lifestyle. Additionally, they completed subjective and objective assessments of their cognitive status, via questionnaires (subjective memory problems, attitude to own ageing, and cognitive fluctuations) and cognitive tests (working memory, processing speed, cognitive flexibility, and model‐based planning), respectively. We tested the differential cognitive correlates of previously established risk factors using univariate regressions, controlling for age and gender.

Result

Lower education and socio‐economic status (SES) were associated with worse cognitive status across all domains (all p<.05). However, the association between SES and subjective cognition (β = 0.38–0.51) was more than twice that of objective cognition (β = 0.05–0.09), while this was not the case for education (β = 0.15–0.32 for subjective and β = 0.10–0.16 for objective cognition). Subjective measures were also more sensitive to depression, loneliness, hearing handicap, age‐related hearing loss, and tinnitus (all p<.01 for subjective and .001<p<.75 for objective cognition). In contrast, cardiovascular factors like diabetes, hypertension, stroke, and smoking were associated with comparable impacts on objective and subjective cognition. Overall, there was little evidence for risk factor correlates of different aspects of objective cognition (e.g., working memory vs. processing speed).

Conclusion

Objective and subjective cognition have dissociable associations with certain potentially modifiable risk factors for dementia. This may aid in our understanding of the distinct mechanisms through which they confer risk for dementia. The objective cognitive assessments gathered, model‐based planning, memory, processing speed and flexibility, yielded remarkably similar associations with risk factors, suggesting a common mechanism through which they are linked to risk factors for dementia.
Genome‐wide identification of modifiers of age‐at‐onset for Alzheimer’s disease in African American populations
Authors: Nuytemans Karen , Guo Shengru , La Jong Ok , Naj Adam C. , Gao Xiaoyi Raymond , Li Yi‐Ju , Martin Eden R. ,   the Alzheimer Disease Genetics Consortium
Published: December 2023

Background

Several studies have attempted to identify genes for age‐at‐onset (AAO) of Alzheimer’s disease (AD) through genome‐wide linkage and genome‐wide association studies (GWAS). While these efforts have thus far focused predominantly on non‐Hispanic white (NHW) populations, we present here the first GWAS to identify genetic contributors to AAO in African Americans (AA) using AA genotype and phenotype data from the Alzheimer’s Disease Genetics Consortium (ADGC).

Method

We combined data from 13 AA prospective and case‐control ADGC datasets, excluding family‐based datasets. Genotype data underwent standard quality control and were imputed to the TOPMed R5 reference panel using the Michigan Imputation Server. Data were merged across cohorts using QCTOOL and GTOOL, filtering out variants with MAF≤0.005). We performed two analyses: case‐only linear mixed‐model regression with AAO as outcome (LMM); and survival analysis using Cox proportional‐hazards frailty modeling (COXPHF) with time‐to‐AD‐onset (AAO in cases and censoring of controls at age‐at‐last‐exam). Both models were adjusted for sex, principal components capturing population substructure, and APOE‐ε4 dosage with a random cohort effect.

Result

We examined 2,262 AA AD cases, including 1,561 females (69%) with mean (SD) AAO of 77.7 (8.1) years. The APOE‐adjusted COXPHF analyses identified twelve genome‐wide significant regions (P<5×10−8), the most significant in ABCA7 (P = 3.57×10−10), known to be associated with AD risk in AAs. In the LMM analysis, we observed strong novel associations with variants in CCDC141 on chr2q31.2 (Pmin = 2.93×10−9). In silico analyses of LD structure and functional potential suggest SESTD1, a gene involved in synaptic regulation, as driving the CCDC141 locus signal. Nine of 12 COXPHF loci were driven by African‐specific variants (MAF<0.0002 in gnomAD Non‐Finish Europeans). These significant loci identified in the AA COXPHF or LMM analyses were not significant (P>0.05) in equivalent analyses in NHW ADGC cohorts (9,220 AD cases/10,350 controls; Li et al. Alz Dement 2023), except for the ABCA7 locus (NHW P<0.0002).

Conclusion

In a large ADGC African American dataset, we confirmed AAO associations in the APOE region and ABCA7 and observed evidence for potential novel AD AAO loci including SESTD1; many of which might be African‐ancestry specific.
Evaluation of the cognitive enhancing properties of diosmin in lipopolysaccharide‐induced memory impairment in mice
Authors: Adeniyi Funmilayo Racheal , Adeoluwa Olusegun Adebayo , Adeoluwa Gladys Onyinye , Adeoye Rachel , Ibifiri Precious Jack
Published: December 2023

Background

Cognitive impairment is a major feature of many neurodegenerative disorders such as Alzheimer’s disease, dementia etc. The progressive cognitive decline in Alzheimer’s disease (AD) can be attributed to the fact that current anti‐Alzheimer’s drug only treat AD symptoms without completely reversing cognitive impairment in AD patients. Therefore, it is imperative to develop new therapeutic remedies that can improve memory and ameliorate cognitive impairment in AD patients. Disomin is a flavone with antioxidant, anti‐inflammatory and anti‐apoptotic properties. This study evaluated the neuroprotective effects of diosmin on LPS‐induced cognitive impairment in mice.

Method

Thirty‐six Swiss mice were randomly divided into six groups (n = 6). Group 1 received vehicle, group 2 received vehicle, groups 3 to 5 received diosmin (50, 100 and 200 mg/kg, p.o.) respectively group 6 received donepezil (50 mg/kg, p.o.). Sixty minutes after the treatment with the vehicle/Diosmin/Donepezil, lipopolysaccharide (LPS) (250ug/kg, i.p.) was administered daily to groups 2 to 6 for seven days. Twenty‐four hours after treatment on day 7, mice were subjected to Y‐maze test and the Novelty object recognition test (NORT) to assess their spatial and non‐spatial working memory. Subsequently, the mice were sacrificed and their brain samples were harvested for biochemical analysis (TNF‐alpha, Interferon gamma and interleukin‐12), immunohistochemical examinations (Amyloid beta, BDNF, IBA‐1, NLRP3 expression) and Golgi staining procedure for morphological alterations.

Result

Our data shows that diosmin increased percentage alternation in Y‐maze test and discrimination ratio in NORT compared with the control group. Diosmin significantly (p<0.05) decreased TNF‐alpha, Interferon gamma and interleukin‐12 and reduced neurodegeneration in the CA1 region of the hippocampus & dendate gyrus when compared with the control group.

Conclusion

Diosmin reversed LPS‐induced cognitive impairment, which can be attributed to its neuroprotective and anti‐inflammatory properties.
Shared and disparate transcriptomic signatures associated with cortical atrophy change in genetic behavioral variant frontotemporal degeneration
Authors: Shen Ting , Vogel Jacob W , Van Deerlin Vivianna M , Dratch Laynie , Lee Eddie B , Phillips Jeffrey S , Grossman Murray , Massimo Lauren , Irwin David J. , McMillan Corey T
Published: December 2023

Background

Cortical atrophy is a common manifestation in behavioral variant frontotemporal degeneration (bvFTD). Distinct atrophy patterns across different form of genetic bvFTD may be shaped by their different underlying biology. This study aimed to use an integrative imaging transcriptomics approach to identify shared and disparate transcriptomic signatures associated with cortical thickness changes in bvFTD with mutations in C9orf72, GRN, and MAPT.

Method

We extracted cortical thickness for 124 sporadic bvFTD patients, 32 C9orf72‐bvFTD, 11 GRN‐bvFTD, and 13 MAPT‐bvFTD mutation cases. Cortical thickness differences were computed between genetic and sporadic bvFTD patients, adjusted for age, sex and disease duration. Normative gene expression profiles were extracted from the Allen Human Brain Atlas. Partial least squares regression model was used to rank all genes by their correlation between gene expression and cortical thickness differences in each genetic form of bvFTD. Functional and cell‐type enrichment analyses were then conducted to explore underlying biological processes of top‐ranked genes.

Result

Relative to sporadic bvFTD, cortical thickness was decreased in temporal regions in C9orf72‐bvFTD, frontotemporal regions in MAPT‐bvFTD, and cortical atrophy was more extensively distributed in GRN‐bvFTD. We identified sets of genes that were positively or negatively associated with cortical thickness differences for each genetic form of bvFTD. Enrichment analyses indicated that genes negatively associated with GRN‐bvFTD atrophy were mainly involved in synaptic pathways and neuron projection development. These GRN‐bvFTD negatively associated genes were enriched in neurons, while the positively associated genes were mainly enriched in glial cells (Figure 1). The genes positively associated with MAPT‐bvFTD atrophy were involved in synaptic pathways and cognition‐related terms, and were preferentially expressed in neurons (Figure 2). Furthermore, an oligodendrocyte precursor cell enriched gene, Protocadherin‐15 (PCDH15), was found to be negatively associated with cortical thickness change in both C9orf72‐bvFTD and GRN‐bvFTD.

Conclusion

Spatial distribution of cortical structural change in each genetic form of bvFTD might be modulated by the expression of genes that were involved in common and different functional pathways, coupled with different cellular signatures. Identification of shared and disparate transcriptomic signatures will contribute to further understanding of potential genetic basis of heterogeneity for different genetic forms of bvFTD.
Associations of antihypertensive medication (AHM) consumption and drug‐drug interaction with Statin and Metformin with reduced Alzheimer’s disease and related dementias (ADRD) risk among hypertensive patients with mild cognitive impairment (MCI) using high volume claims data
Authors: Lundin Sori Kim , Hu Xinyue , Feng Jingna , Lundin Karl Kristian , Chen Yong , Tao Cui
Published: December 2023

Background

While hypertension is a modifiable risk factor of Alzheimer’s disease and related dementias (ADRD), limited studies have been conducted on drug effectiveness of antihypertensive medications (AHMs) on ADRD progression from mild cognitive impairment (MCI) or on drug‐drug interactions of AHMs with drugs for other risk factors such as type 2 diabetes and hypercholesterolemia.

Method

128,683 unique hypertensive patients with MCI on US‐based Optum claims data were identified. Diuretics, beta blockers (BBs), calcium channel blockers (CCBs), angiotensin‐converting enzyme inhibitors (ACE inhibitors), and angiotensin II receptor antagonists (ARBs) were identified as five major AHM classes. Baseline characteristics were compared. Cox proportional hazards (PH) models were used to study the association between specific AHM exposure and the progression from MCI to ADRD while controlling for demographic variables, comorbidities, and use of Statin and Metformin. To examine the association of AHM‐Statin or AHM‐Metformin interaction with ADRD progression, we also investigated models controlling for aforementioned confounders, as well as drug‐drug interaction terms.

Result

The study included 100,678 patients who were taking at least one class of AHM and 28,005 who were not taking any AHMs. AHM users had higher ratios for the comorbidities (all P≤0.039) and consumption of Metformin and Statin (both P<0.001) compared to non‐users. Users of each major AHM class showed significantly lower risk of developing ADRD compared to non‐users of that specific drug class (adjusted hazard ratio (aHR): 0.96‐0.98; all P≤0.048). Within patients on monotherapy (using only one AHM drug), no specific AHM class had significantly lower risk of ADRD diagnosis compared to other AHM drug classes (aHR: 0.97‐1.11; all P≥0.053). Use of Diuretics or CCBs in combination with Metformin consumption (aHR: 0.89, 0.91, respectively) showed lower risk of MCI to ADRD progression than that under Metformin non‐consumption (aHR: 0.97, 0.98), whereas use of any of the five major AHMs under Statin consumption (aHR: 0.91‐0.94) all showed lower risk than that under Statin non‐consumption (aHR: 0.98‐1.04).

Conclusion

All five major AHM classes show a protective effect against ADRD progression among hypertensive patients with MCI. Also, AHMs combined with consumption of Metformin or Statin showed a stronger protective effect compared to non‐consumption.
Alzheimer’s disease biomarkers of amyloid and tau influence white matter neurite alterations in dementia with Lewy bodies: a NODDI study
Authors: Mak Elijah , Reid Robert I. , Przybelski Scott A. , Lesnick Timothy G. , Schwarz Christopher G. , Senjem Matthew L. , Raghavan Sheelakumari , Vemuri Prashanthi , Jack Clifford R. , Min Hoon‐Ki , Jain Manoj K. , Miyagawa Toji , Forsberg Leah K. , Fields Julie A. , Savica Rodolfo , Graff‐Radford Jonathan , Jones David T. , Botha Hugo , St. Louis Erik K , Knopman David S. , Ramanan Vijay K , Graff‐Radford Neill R , Ferman Tanis J , Petersen Ronald C. , Lowe Val J. , Boeve Brad F. , O'Brien John T , Kantarci Kejal
Published: December 2023

Background

Co‐morbid Alzheimer’s disease (AD) pathology in the form of amyloid‐β plaques and tau neurofibrillary tangles are frequently observed in people with probable dementia with Lewy bodies (DLB). Neurite Orientation Dispersion and Density Imaging (NODDI) is an emerging technique to characterize white matter (WM) tissue microstructure, although NODDI alterations and associations with AD biomarkers remain undefined in DLB. The objectives of this study are to compare NODDI and DTI parameters between DLB and controls and (ii) evaluate the pattern of DTI and NODDI changes associated with amyloid and tau deposition.

Method

Consecutive patients within the DLB spectrum (n = 45), including probable DLB (n = 32) and probable Mild Cognitive Impairment with Lewy bodies (MCI‐LB) (n = 13) from the Mayo Clinic ADRC underwent multi‐shell diffusion MRI, [18F]‐Flortaucipir and [11C]‐PiB PET. A comparison group of 45 age‐ and gender‐matched clinically unimpaired controls (CU) was included. Voxelwise non‐parametric permutation models were used to determine pair‐wise group differences and assess the associations of AD biomarkers with fractional anisotropy (FA), mean diffusivity (MD), tissue‐weighted neurite density index (tNDI; NDI x (1 – Free water fraction)) and orientation dispersion index (ODI), controlling for age. Complementary analyses were performed using regions‐of‐interest (ROI) obtained from the JHU atlas.

Result

Compared to CU, the DLB spectrum group exhibited widespread decreases in FA and tNDI and increases in MD and ODI, with the most pronounced effects in the cingulum bundles, uncinate, inferior and superior longitudinal fasciculi (Fig. 1). Greater [18F]‐Flortaucipir uptake was also associated with lower FA and tNDI, and higher MD and ODI in the DLB spectrum compared to CU, independently of age and [11C]‐PiB uptake (Fig. 2). In contrast, no associations were found between [11C]‐PiB uptake and any of the DTI or NODDI parameters. Complementary ROI analyses corroborated these findings.

Conclusion

Widespread loss of WM integrity was observed on DTI and NODDI in probable DLB and prodromal DLB. These findings were associated with greater cortical tau, but not with amyloid‐β deposition. Although alpha‐synuclein pathology underlies the loss of WM integrity in DLB, amyloid‐independent tau pathology may also be an important influence on white matter integrity within the DLB spectrum.
Genome‐wide mapping implicates 5‐hydroxymethylcytosines in diabetes and Alzheimer’s disease
Authors: Zhang Zhou , Beadell Alana , Capuano Ana W. , Bennett David A. A , He Chuan , Zhang Wei , Arvanitakis Zoe
Published: December 2023

Background

Diabetes mellitus (DM) is a recognized risk factor for dementia including Alzheimer’s disease (AD). Because DM is a potentially modifiable risk factor, a greater understanding of the mechanisms linking DM to the clinical expression of AD may provide insights into the much‐needed dementia therapeutics or intervention approaches. Epigenetic analysis offers a powerful approach, and previous studies including our team’s exploration in circulating cell‐free DNA (cfDNA) suggested that the under‐investigated 5‐hydroxymethylcytosines (5hmC) is now emerging as a promising measure to investigate in DM‐related conditions.

Method

We used samples and data from the Rush Memory and Aging Project. Using the 5hmC‐Seal technique, we performed genome‐wide profiling of 5hmC in cfDNA samples (n = 74) from antemortem blood samples and brain tissue (n = 75) genomic DNA from postmortem prefrontal cortex tissue from 80 deceased individuals across four groups: AD (neuropathologically defined), DM (clinically defined Type 2 DM), DM with AD (AD+DM), and non‐AD/non‐DM controls. Differential analysis and machine learning approaches were used to investigate 5hmC signatures associated with different conditions and summarize epigenetic scores to evaluate diagnostic potential for AD in cfDNA. Pathway enrichment analysis was performed on differential 5hmC signatures to explore biological mechanisms underlying DM‐associated AD.

Result

We identified distinct 5hmC signatures and biological pathways, including Wnt signaling and inflammatory mediator regulation of TRP channels, as well as amino sugar and nucleotide sugar metabolism, that are associated with AD or AD+DM compared to non‐AD/non‐DM controls or DM alone. We further demonstrated the potential diagnostic value of 5hmC profiling in circulating cfDNA. Specifically, a 4‐gene model showed capacity for distinguishing AD+DM from DM (AUC [area under the curve] = 82.7%; 95% CI [confidence interval], 67.6‐97.9%), while an 11‐gene model distinguished AD from non‐AD/non‐DM controls (AUC = 90.0%; 95% CI, 80.4‐99.6%).

Conclusion

Genome‐wide 5hmC profiling uncovered epigenetic features and biological pathways related to nucleotide sugar metabolism that link DM to DM‐associated AD. Our findings also demonstrated the potential of utilizing 5hmC in circulating cfDNA as diagnostic biomarkers or disease monitoring tools, with the ultimate goal of preventing or ameliorating DM‐associated AD dementia and improving clinical outcomes. This study was supported partially by the NIH (RF1AG074549, R01AG17917).
Perceived needs for mobile interventions among Spanish language Latino family caregivers of persons living with dementia
Authors: Melero‐Dominguez Maria , Jain Felipe A , Madarasmi Saira , Gutierrez‐Ramirez Paulina , Ramirez‐Gomez Liliana A.
Published: December 2023

Background

Supportive and caregiver skills programs for Spanish language Latino caregivers of persons living with Alzheimer’s disease and related dementias (SLDCs) have been developed and researched primarily using in‐person delivery. However, in‐person interventions are limited by scalability constraints due to barriers such as time, cost of travel to intervention sites, and COVID‐19 containment measures. There is a tremendous need for caregiver interventions for SLDCs that can be delivered remotely by smartphone, the most accessible means for SLDCs to connect to the internet. A mobile application combining caregiver skills literacy, stress reduction tools, and chat‐based support groups might help fill this gap. However, whether SLDCs perceive a need for such an application is unclear. This research aimed to assess perceived needs and preferences for mobile intervention among SLDCs

Method

We conducted two virtual focus groups with 12 SLDCs (aged 37 to 87, 83% female) from the Greater Boston area to determine preferences for smartphone‐based intervention. Participants answered semi‐structured questions during the group and completed questionnaires individually regarding smartphone application usage. Topics included needs for caregiver skills, relaxation tools, and chat‐based social support. Data analysis was conducted with an inductive and deductive mixed‐methods approach.

Result

Opinions regarding the potential utility of a smartphone application that would combine caregiver skills, relaxation tools, and a smartphone chat for SLDCs were positive and demonstrated that such an application would serve unmet needs. Although only one participant had previously used a caregiver literacy app, all SLDCs expressed a desire to receive caregiver skills resources via mobile application. While just two (16.7%) had utilized a relaxation app, six (50%) felt that having access to relaxation instructions would be beneficial. Finally, an unmet social support need was identified, which caregivers felt would be possible to meet through chatroom‐based functionalities. Several participants felt the chat room would require facilitation by someone with expertise in dementia caregiving.

Conclusion

A mobile intervention could help meet the needs of SLDCs for caregiver skills, relaxation training, and social support. Further studies using participatory research should focus on the development and feasibility of a mobile application that provides these features.
“I think they killed him”: Long‐term trauma associated with perceived cause of death in bereaved dementia caregivers whose loved ones were in a nursing home at time of death
Authors: Baker Zachary G , Nelson‐Kaigama Cindy , Klosterman Kate , Millenbah Ashley , Segundo Joahana , Nkimbeng Manka , Gaugler Joseph
Published: December 2023

Background

One in three Medicare beneficiaries dies with dementia. COVID‐19 has disproportionately increased death rates among: persons living with dementia (PLWD), those in nursing homes, and members racially/ethnically minoritized groups. Simultaneously, COVID‐19 led to a mass exodus of nursing home staff, creating a perfect storm for abuse and neglect, especially of those most often historically and systematically disadvantaged. Reports of abuse and neglect in nursing homes, especially among PLWD are not new. But, the primary focus has been residents being abused or neglected. In the present paper we present the implications of abuse and neglect for the family and friends who provide care for PLWD in nursing homes.

Method

Together with community partners we explored experiences of dementia‐related bereavement with a 15‐member community advisory board over two years. Our authorship team includes experts in long‐term care, healthcare system administrators, nurses who have worked within healthcare systems, and those with lived experience. Lived experience perspectives come from caregivers who cared for parents and grandparents with dementia, identify with different racial/ethnic groups, are of different ages, and have had between 2 and 12 years since the death of the PLWD they cared for.

Result

As one community member stated, “there’s all kinds of ways that a facility could potentially kill someone, whether it be through like a willful act or just neglect.” We present the experiences of community partners who attribute the deaths of PLWD they cared for to such abuse and neglect and explore the ways that abuse and neglect manifested, potential precipitating events, and how those deaths continue to affect family members years or even decades after a PLWD’s death.

Conclusion

We explore and share these experiences to amplify the voices of these bereaved dementia caregivers and raise a call for the research and clinical communities to seek ways to aid former caregivers and nursing home staff. Community partners also made clear that interactions between each person with dementia and nursing home staff were exceedingly challenging and that those staff deserve additional support to help them prepare for and cope with those events.
EEG correlates in the three variants of Primary Progressive Aphasia
Authors: Cecchetti Giordano , Agosta Federica , Basaia Silvia , Cividini Camilla , Cursi Marco , Canu Elisa , Leocadi Michela , Santangelo Roberto , Caso Francesca , Fanelli Giovanna Franca , Minicucci Fabio , Magnani Giuseppe , Filippi Massimo
Published: December 2023

Background

The analysis of EEG cortical sources is promising for the investigation of neurodegenerative disorders. The aim of this study is to explore its value in the characterization of the three clinical presentations of primary progressive aphasia (PPA).

Method

A resting‐state 19‐channel EEG was obtained in 48 patients diagnosed with PPA (21 nonfluent/agrammatic variant PPA [nfv‐PPA], 18 logopenic variant PPA [lv‐PPA], 9 semantic variant PPA [sv‐PPA]) and in 21 matched healthy controls. Using eLORETA, EEG current source density (CSD) values were estimated at voxel‐level and compared among groups of patients and controls.

Result

Patients showed a low‐to‐moderate cognitive impairment. Lv‐PPA cases showed a higher delta density over the left frontal and temporal regions when compared to sv‐PPA subjects, and in left precuneus and posterior cingulate when compared to nfv‐PPA patients. They also displayed a higher delta density in left frontal, parietal and temporal regions than healthy subjects, and lower alpha1 density in left occipital regions compared with other patient groups. Lv‐PPA patients also showed reduced alpha2, beta1 and beta2 density over the left occipital regions when compared to healthy subjects. No significant differences were found in terms of CSD among sv‐PPA, nfv‐PPA and healthy subjects.

Conclusion

Consistently with our previous studies, findings in PPA patients suggest that Alzheimer’s disease (AD), but not fronto‐temporal degeneration (FTD), might induce a characteristic disruption of the cortical electrical activity, detectable by EEG. EEG might thus help in the differential diagnosis between AD‐related and FTD‐related PPA variants.
Sex differences in baseline sleep and dark phase rebound sleep after chronic sleep fragmentation in the APPXPS1 and 5XFAD mouse models
Authors: Duncan Marilyn J. , Johnson Carrie E , Guo Landys , Barth Sarah , Buzinova Valeria , Padgett Samantha , Turton Savannah , Jessup Michael Tyler , McCarty Leanna M , Beechem Lindsay E , Briones William , Subramoniam Anjana , Whitlock Haleigh R , Sucharski Michael , Bosh Kimberly , Kohler Katharina , Macheda Teresa , Bachstetter Adam D , Sunderam Sridhar , O'Hara Bruce F. , Murphy Michael Paul
Published: December 2023

Background

Fragmentation of the daily sleep‐wake rhythm is a risk factor for Alzheimer’s disease (AD) (Li et al, Lancet Healthy Longev 1:e96‐e105 [2020]). While women have a higher AD incidence than men, whether women are more sensitive to sleep fragmentation (SF) is not known. Studies in female 3xTg‐AD mice (8‐11 months old) show that chronic SF for four weeks alters the daily sleep‐wake rhythm and stimulates AD‐like neuropathology (Duncan et al, Neuroscience 481:111‐122 [2022]).

Method

To investigate possible sex differences in the effects of sleep fragmentation, we studied two AD mouse models and matching wild‐type controls, APPxPS1‐knock‐in mice (6.2‐11 months old; N = 127) and 5XFAD mice (2.3‐3.3 months old; N = 52). All mice were exposed to 3‐4 weeks of SF or undisturbed sleep while individually housed in cages interfaced for piezo electric sleep recording for monitoring of daily sleep‐wake rhythms. SF consisted of four daily sessions (1 hour each) of enforced wakefulness (induced with toys and paintbrush stimulation) that were evenly distributed during the light phase, for 5 days/week. Immediately after the last SF session, mice in both groups were euthanized and cortical and hippocampal tissue was dissected and frozen. Amyloid‐beta levels were determined in soluble fractions using ELISA.

Results

SF redistributed sleep from the light phase (loss) to the dark phase (gain) in APPxPS1‐ki (p<0.0001) and 5XFAD (p<0.05) mice and WT controls. Overall, females slept less than males (p<0.001) and were more affected by SF. Dark phase “rebound” sleep after SF was greater in APPxPS1‐ki females (∼70% of undisturbed controls) than in APPxPS1 males or WT mice of either sex (∼20% of undisturbed controls) (p<0.001). Cortical amyloid‐beta levels were higher in female than male AD mice, but surprisingly, neither cortical nor hippocampal amyloid‐beta levels were affected by SF in either strain.

Conclusion

These findings suggest an interaction between sex, AD mutations, and neuropathology on dark phase rebound sleep after chronic SF. To elucidate this interaction, on‐going studies are investigating the role of amyloid‐beta in sex‐differences in SF‐induced rebound sleep and potential sex differences in SF effects on gene expression in brain regions regulating sleep or circadian rhythms.
Association of neuropathological lesions with body mass index by the time of death
Authors: Reis Ururahy Raul , Val Marina Scott , Ciciliati Aline Maria Macagnan , Leite Renata Elaine Paraizo , Paes Vitor Ribeiro , Rodriguez Roberta Diehl , Grinberg Lea T. , Pasquallucci Carlos Augusto , Jacob‐Filho Wilson , Suemoto Claudia Kimie
Published: December 2023

Background

The association between moderate/severe dementia and lower Body Mass Index (BMI) is well described, but the weight decline seems to also occur in cognitively normal individuals with preclinical dementia. Considering that up to one‐fifth of individuals with normal cognition might meet the criteria for a neuropathological diagnosis, autopsy studies are key detecting neurodegenerative and cerebrovascular diseases that could be underlining weight changes during the life course. Therefore, we investigated the association between dementia‐related brain lesions and BMI and evaluated whether cognitive function was a mediator of this association.

Method

Neuropathological study in a population‐based sample of 1,170 Brazilians. Clinical variables and cognition evaluation were obtained through a post mortem interview with a proxy. Linear regression adjusted models were used to investigate the association between each neuropathologic lesion (independent variable) and the BMI (dependent variable). The direct and indirect (considering a mediation by cognitive abilities) effects of each neuropathologic lesion on BMI were evaluated through a mediation model.

Result

Individuals with lower body weight were more likely to have a higher burden of neuropathological lesions and worse cognitive abilities. Neurofibrillary tangles (NFT) and neuropathological comorbidity were associated with low BMI. Mediation analyses showed these lesions were directly associated with BMI and indirectly through cognitive abilities. Despite having normal cognitive abilities, 25% of the sample had at least one neuropathologic diagnosis. High NFT burden was associated with lower BMI even in these participants.

Conclusion

Neurofibrillary tangles were associated with lower BMI independent of cognitive abilities.
Prediction of longitudinal cortical amyloid deposition based on cerebrospinal fluid biomarkers for Alzheimer’s disease in cognitively unimpaired individuals: the role of APOE‐ε4
Authors: Rizzo Marianna , Oomens Julie Elisabeth , Jansen Willemijn J. , Gispert Juan Domingo , Ritchie Craig W , Jessen Frank , Rovira Mercè Boada , Marquié Marta , Hanseeuw Bernard J , Schmidt Mark E , Stephens Andrew W. , Gismondi Rossella , Frisoni Giovanni B , Farrar Gill , Barkhof Frederik , García David Vállez , Collij Lyduine E. , Alves Isadora Lopes , Visser Pieter Jelle , Vos Stephanie J. B. ,   the AMYPAD Consortium
Published: December 2023

Background

The relationship between cerebrospinal fluid (CSF) biomarkers for Alzheimer’s disease (AD), APOE‐ε4 and longitudinal cortical amyloid deposition in preclinical AD is relevant for AD trial design but remains unclear. Thus, we aimed to investigate longitudinal cortical amyloid accumulation on PET as predicted by baseline CSF AD biomarker profiles and APOE‐ε4 carriership in cognitively unimpaired individuals.

Method

We selected 330 cognitively unimpaired individuals from 6 cohorts of the AMYPAD study. All had available baseline data on CSF aß1‐42 (A), p‐tau181 (T), APOE‐ε4 carriership (yes/no), and baseline and follow‐up amyloid PET data. To evaluate different AD stages, individuals were classified as A‐T‐, A‐T+, A+T‐, or A+T+ based on CSF biomarker abnormality using center‐specific cut‐offs. We used a continuous outcome measure of global cortical amyloid deposition on PET expressed in centiloids. Analyses were performed in the total sample and stratified for APOE‐ε4, using generalized linear mixed models with random intercepts and slopes, adjusted for age and sex.

Result

58% were female, 49% APOE‐ε4 carriers, and mean age was 64+‐6.1 years, with an average follow‐up of 3 years. 170 individuals were A‐T‐, 70 A‐T+, 59 A+T‐, and 31 A+T+. Baseline cortical amyloid deposition was different between all groups, with A+T+ having the highest deposition, followed by A+T‐, A‐T+ and A‐T‐ (Figure 1, Table 1). Longitudinally, all groups showed increased amyloid deposition, except A‐T‐. Moreover, A+ groups showed greater increases in longitudinal amyloid deposition than A‐ groups. In APOE‐ε4 carriers, all AT groups showed increased longitudinal amyloid deposition, while in non‐carriers, A‐T+ and A‐T‐ did not (Figure 2, Table 1). Only in APOE‐ε4 carriers, A+T+ showed greater increases in longitudinal amyloid deposition than A+T‐, with A+T‐ showing a similar longitudinal deposition as A‐T+.

Conclusion

APOE‐ε4 impacts the association between CSF AD biomarkers and longitudinal amyloid PET deposition in cognitively unimpaired persons. Amyloid‐negative APOE‐ε4 carriers could be at an early AD stage, as they showed increased cortical amyloid longitudinally, independent of baseline p‐tau status. In amyloid‐positive persons, p‐tau abnormality related to higher baseline cortical amyloid, but only in APOE‐ε4 carriers to steeper increases in cortical amyloid longitudinally. This has important implications for AD trial design.
Role of a cellular thermal shift assay on evaluation of drug‐target engagement for compound selection
Authors: Mason Emily R , Chu Shaoyou
Published: December 2023

Background

Identification of small molecule‐target engagement is important for target‐based drug discovery. To support drug discovery efforts for Alzheimer’s Disease, we developed and implemented cellular thermal shift assays (CETSA) based on HiBiT/LgBiT reconstituted NanoLuc method (Promega). Advantages of the CETSA are testing target engagement in an intact cellular context, simple mix‐and‐read procedures, and high capacity to meet drug discovery project needs.

Method

Stable cell lines (HEK293t or HMC3) expressing HiBit (11 amino acids; Promega) tagged target were established. The CETSA uses Nano‐Glo HiBiT Lytic Detection kit (Promega) to detect abundance of undenatured HiBit‐tagged target protein in cells, while heat caused protein aggregates to be mostly undetectable. The CETSA procedures are 1) plating cells into 96‐well PCR plates; 2) treating cells with compounds for 60 min in 37 oC incubator; 3) heating cell plates for 3 min in a PCR machine; 4) processing with Nano‐Glo HiBiT Lytic Detection kit (10 min) and reading plates for luminescence. Before testing compounds, an Tagg (temperature at 50% maximal signal during aggregation) for each target was determined and used as baseline. When a compound engages the target, it caused Tagg shifts that can be quantified by the assay.

Result

1) Tagg is target specific, with INPP5D Tagg = 44.2 °C and PLCG2 Tagg = 45.9 °C. 2) Screening compounds at 100 µM on cells and heated at Tagg, the luminescent signal changes (compared to untreated control) suggesting compound‐target engagement. 3) The CETSA with compound dosing and heating at Tagg was used to confirm the compound engagement. 4) The HiBit tag control CETSA with compound dosing and Tagg heating was used to find non‐specific binders. The assay platform has been implemented for drug discovery efforts targeting INPP5D and PLCG2 respectively; example data will be shown.

Conclusion

The CETSA platform is efficient, reproducible and has high capacity, making it well‐suited to target based drug discovery research. Application of the CETSA on projects targeting INPP5D, PLCG2 of microglia has facilitated compound selection based on confirming molecule target engagement, which allowed our project team to quickly focus on selected compounds for further studies.
Isolated REM sleep behaviour disorder in the Tasmanian ISLAND Sleep Study: prevalence and profiles of prodromal dementia
Authors: Bramich Samantha , King Anna E , Noyce Alastair J , Bindoff Aidan D , Kuruvilla Maneesh , Naismith Sharon L , Bartlett Larissa , Vickers James C , Alty Jane E
Published: December 2023

Background

Identifying people with isolated REM sleep behaviour disorder (iRBD) provides important opportunities for targeted dementia prevention as iRBD is a prodrome of Lewy Body dementia (LBD) and other neurodegenerative diseases (NDD). There have been no prevalence studies of iRBD in Australia and little is known about whether associated motor, cognitive, olfactory and circadian features influence the progression to different NDD. The Island Study Linking Ageing and Neurodegenerative Disease (ISLAND) Sleep Study aims to identify the iRBD prevalence in Tasmania and determine how different iRBD profiles predict progression to dementia and other NDD.

Method

Adults aged 50+ years in Tasmania completed online questionnaires including the REM Sleep Behaviour Disorder Screening Questionnaire (RBDSQ), RBD single question screen (RBD1Q), Pittsburgh Sleep Quality Index (PSQI), and questions regarding dreaming, autonomic, motor s, and pain symptoms.

Result

2,905 participants have been recruited (mean (SD) age 64 (7.7) years; 26% male). 273 (9.4%) have ‘probable’ iRBD (pRBD) based on the RBDQ1. Compared to those without pRBD, the pRBD group have poorer sleep quality (66% vs 57%), greater autonomic dysfunction (median score 18 vs 13), more pain (particularly stabbing and itching pain), higher risk for sleep apnoea (30% vs 13%), more intense dreams (21% vs 8%), and more motor symptoms, including shaky limbs (16% vs 6%) and slurred speech (12% vs 6%).

Conclusion

2905 participants have been recruited (mean (SD) age 64 (7.7) years; 26% male). 273 (9.4%) have ‘probable’ iRBD (pRBD) based on the RBDQ1. Compared to those without pRBD, the pRBD group have poorer sleep quality (66% vs 57%), greater autonomic dysfunction (median score 18 vs 13), more pain (particularly stabbing and itching pain), higher risk for sleep apnoea (30% vs 13%), more intense dreams (21% vs 8%), and more motor symptoms, including shaky limbs (16% vs 6%) and slurred speech (12% vs 6%).