bluuebunny/crossref_metadata_2025 huggingface dataset:
Association between basal forebrain and medial temporal lobe tau, and gray matter volume
Authors: Shafer Andrea T , MacAlpine Maiya F. , Bañuelos Cristina , Moghekar Abhay , Resnick Susan M. , Bilgel Murat
Published: December 2023

Background

Tau pathology is a hallmark of Alzheimer’s disease (AD). The basal forebrain (BF) is a significant cholinergic projection site with cholinergic groups 1‐3 (Ch1‐3) projecting to the hippocampus, hypothalamus, and olfactory bulb, and group 4 (Ch4) projecting to the cortical mantle and amygdala. Braak stage 1 includes BF tau and recent literature suggests BF degeneration precedes medial temporal lobe (MTL) degeneration, thus implicating early involvement of the BF in AD. This study examines BF 18F‐flortaucipir (FTP) retention and gray matter (GM) volume, and their associations with MTL FTP retention and GM volume.

Method

Data were acquired for 111 older adults (Table 1) in the Baltimore Longitudinal Study of Aging. Binary masks for BF subregions Ch1‐3 and Ch4 were generated using a probabilistic atlas (Figure 1). We computed mean standardized uptake value ratio (SUVR) using an inferior cerebellar GM reference region and mean GM volume using average voxel‐based morphometry values for each BF subregion. Colocalized relationships between BF tau and volume were assessed using Pearson correlations. Proximal relationships between BF tau/GM and MTL tau/GM were assessed at the voxel level controlling for age, sex, and intracranial volume and corrected for multiple comparisons using non‐parametric permutations.

Results

Within the BF, FTP‐SUVR in Ch1‐3 was strongly related to FTP‐SUVR in Ch4, and FTP‐SUVR was associated with larger volume in Ch1‐3, but not Ch4 (Figure 2). Voxelwise analyses showed strong BF‐MTL associations with higher Ch1‐3 and Ch4 FTP‐SUVR associated with higher FTP‐SUVR throughout the MTL. The strongest associations were observed anteriorly (amygdala, peri/entorhinal cortices) and medially along the longitudinal axis of the hippocampus/parahippocampal gyrus. Moreover, for both BF Ch groups, larger volume was associated with larger MTL volume. This association was strongest in the amygdala and hippocampal head and body.

Conclusion

As expected, BF FTP‐SUVR was positively associated with MTL FTP‐SUVR, and BF volume was positively associated with MTL GM volume, supporting the use of these BF measures. Further analysis is necessary to better understand the positive associations between BF FTP‐SUVR and GM volume and to assess the temporal ordering of FTP‐SUVR accumulation in the BF and MTL.
Effects of Metformin Administration on Behavioral and Biochemical Parameters in a Familial Hypercholesterolemia Mouse Model
Authors: Nascimento Natália Baltazar , Farias Hemelin Resende , Schons Tainá , Rodrigues Matheus Scarpatto , Oliveira Jade
Published: December 2023

Background

Low‐density lipoprotein (LDL) is responsible for the transport of cholesterol to peripheric tissues (Cortes et al. 2014), and it enters the cells via LDL receptors (LDLr) (Luo, Yang, Song 2020). Cholesterol metabolism alterations, i.e., hypercholesterolemia are well‐known cardiovascular risk factors and have also been linked to cognitive and behavioral alterations (De Oliveira et al. 2011, Sparks et al. 1990, WHO 2008). Familial hypercholesterolemia (FH) is a prevalent disease caused by dysfunctions of cholesterol metabolism (Akioyamen et al. 2017), and several reports show its connection to neuroinflammation (Ariza et al. 2016, De Oliveira et al. 2020). Recent studies associate mTOR inhibition with conservation of blood‐brain barrier integrity, cognitive damage attenuation, and systemic and cerebral inflammation reduction in dementia and FH animal models (Jahrling et al. 2018, Van Skike et al. 2018). In this regard, Metformin presents critical therapeutic potential because it inhibits mTOR through AMPK.

Objective

Evaluation of Metformin treatment on cognitive disturbances and central and peripheric biochemical parameters in C57BL/6 LDLr deficient (LDLr‐/‐) mice.

Method

LDLr‐/‐ and wild‐type (WT) male mice (3‐month‐old, 20‐3 g) received a daily oral administration via gavage of Metformin (200 mg/kg) or Saline for 30 days. All animals were weighed weekly. Mice were submitted to behavioral tasks in the last week of treatment. Following the last day of treatment, animals fasted for 12 hours and were euthanized by cardiac exsanguination. Heparinized plasma was used to determine total cholesterol and triglyceride levels. Another cohort of animals was perfused with paraformaldehyde to collect fixed total brains, which were used in immunofluorescence assays for labeling glial fibrillary acidic protein (GFAP).

Result

LDLr‐/‐ mice showed higher total cholesterol levels compared to WT groups. Metformin treatment increased triglyceride levels and decreased total body weight in LDLr‐/‐ mice in comparison to Saline administration. LDLr‐/‐ mice showed hyperlocomotive activity, cognitive damage, and a depressed phenotype, which was in parts attenuated by Metformin treatment. Metformin treatment ameliorated astrogliosis in the hippocampus of LDLr‐/‐ mice.

Conclusion

Metformin treatment showed a promising effect on the memory impairment and astrocyte reactivity observed in LDLr‐/‐ mice, which was not via a cholesterol‐lowering outcome.
Comparison of LBD research priorities by caregiver characteristics
Authors: Patel Bhavana , Stacy Kelly E , Farley Morgan , Bedenfield Noheli , Taylor Angela , Bayram Ece , Wood Julia , Armstrong Melissa J , Holden Samantha K.
Published: December 2023

Background

Caregivers of individuals with Lewy body dementia (LBD) experience high levels of caregiver burden while having a pivotal role in clinical and research decision‐making. Despite the importance of the caregivers in LBD, little is known about their research priorities. Targeting these priorities may help research engagement and more meaningful study aims.

Method

A web‐based survey of current and former caregivers of people with LBD investigated research priorities through forced ranking and exploration of experiences in LBD. Importance of research topics were queried and further analyzed descriptively based on age, gender, relationship type (spouse, sibling, adult child), and location type (large city, suburb, small town, rural). Race and ethnicity were not included due to small sample size.

Result

Between 4/7/2021‐7/1/2021, 984 responses were recorded: 550 identified as current caregivers and 280 as former caregivers. Younger caregivers (<60 years) were more likely to express interest in research participation, as were those residing in large cities. No difference in research interest was seen between caregiver gender or relationship type. The top research priority for all caregivers was development of disease modifying therapy. More women were interested in LBD‐specific healthcare education. Both women and adult children caregivers prioritized identifying individuals at risk for LBD. Spouses prioritized understanding disease course and progression, whereas siblings prioritized pathophysiological changes and alternative medicine approaches. Individuals from large cities and suburbs prioritized medication development and those from rural areas and small cities valued improving methods to diagnose LBD.

Conclusion

This study emphasizes varying research priorities based on age, gender, relationship, and area of residence of LBD caregivers. Recognition of the heterogeneity of LBD caregivers allows for personalized outreach and support, as well as tailored research projects and goals. Identifying the unique priorities of those personally affected by LBD can guide research development towards maximally impactful outcomes.
Changes in cognitive functioning by a multifactorial intervention to prevent dementia‐The Japan‐Multimodal Intervention Trial for Prevention of Dementia PRIME Tamba‐
Authors: Oki Yutaro , Osaki Tohmi , Murata Shunsuke , Kumagai Ryoko , Encho Haruhi , Ono Rei , Yasuda Hisafumi , Kowa Hisatomo
Published: December 2023

Background

Many efforts for early detection and prevention of cognitive decline have been reported. In this study, we examined the changes in possible Nou‐KNOW (Cognigram by Cogstate; Japanese version Cognigram) after an 18‐month multifactorial intervention to prevent dementia in cognitively normal elderly subjects living in areas at risk for dementia.

Method

The Japan‐Multimodal Intervention Trial for Prevention of Dementia PRIME Tamba (J‐MINT), a randomized controlled trial to prevent cognitive decline in cognitively normal older people living in areas at risk of dementia, was conducted. PRIME Tamba), a randomized controlled trial to prevent cognitive decline. 203 participants (male: 57 participants, mean age: 73.86±4.84, mean MMSE score: 28.65±1.36) were randomly assigned to the intervention group (101 participants) or the control group (102 participants). The intervention group received 90 minutes of group‐based physical exercise once a week, cognitive training, nutritional counseling, and vascular risk factor management for 18 months (78 sessions in total). Reaction speed, attention, visual learning, and attentional scores were measured twice (Baseline and 18 months after intervention) by the Nou‐KNOW. Statistical analyses were conducted using a general linear mixed‐effects model with a significance level of less than 5%.

Result

There was a statistically significant difference in the Reaction time score (intervention group vs. control group; 101.62 ± 7.07 vs. 98.63 ± 9.75, p<0.01) and Attention score (100.19 ± 7.19 vs. 98.16 ± 7.56, p = 0.02) in the Cognigram at the 18‐month measurement in the intervention group. On the other hand, no statistically significant differences were found in the Visual memory score (100.26±13.26 vs. 98.63±13.71, p = 0.89) and Working memory score (98.99 ± 8.13 vs. 96.71 ± 7.39, p = 0.29).

Conclusion

An 18‐month multifactorial intervention to prevent dementia in cognitively normal older adults living in areas at risk for dementia was suggested to improve reaction time and attention.
Reduced density of serotonergic axons without prominent neuron loss or tau pathology in the dorsal raphe nucleus in App knock‐in mouse models of amyloid‐β pathology
Authors: Sakakibara Yasufumi , Hirota Yu , Ibaraki Kyoko , Takei Kimi , Nishijima Risa , Sekiya Michiko , Iijima Koichi M.
Published: December 2023

Background

Dorsal raphe nucleus (DRN) is a nucleus containing the cell bodies of serotonergic neurons in the brainstem and is one of the earliest regions affected by Alzheimer’s disease (AD). Defect in serotoninergic system is related to cognitive declines and behavioral and psychiatric problems and has been a drug target to improve clinical symptoms in AD. Why and how serotonergic system is severely damaged in AD remain elusive. In this study, we examined how serotonergic system is affected by amyloid‐β (Aβ) pathology using AppNL‐G‐F/NL‐G‐F mice, which harbor three familial AD mutations and exhibit massive Aβ pathology in cortical areas.

Method

We compared the density of serotonin (5‐HT)‐positive axons in the cortex and hippocampus and the number of serotonergic neurons in the DRN between AppNL‐G‐F/NL‐G‐F and wild‐type (WT) C57BL/6J mice at 24 months of age. We also asked whether tau pathology was formed in the serotonergic axons and in the DRN in AppNL‐G‐F/NL‐G‐F mice.

Result

Immunohistochemical analyses revealed that 24‐month‐old AppNL‐G‐F/NL‐G‐F mice exhibited significant decreases in the density of 5‐HT‐positive axons in the cortex and hippocampus compared to WT mice. In contrast, AppNL‐G‐F/NL‐G‐F mice did not display loss of 5‐HT‐positive neurons in the DRN even at 24 months of age. Moreover, phosphorylated tau was not accumulated in either the nerve terminals or the cell bodies of DRN neurons in the brains of AppNL‐G‐F/NL‐G‐F mice.

Conclusion

This study demonstrates that cortical Aβ pathology reduces the density of serotonergic axons independent of neuron loss and tau pathology in the DRN. These results also suggest that age‐dependent accumulation of Aβ in the cortex chronically damages serotonergic axons, which may lead to loss of DRN neurons accumulating tau during aging in AD pathogenesis.
Genetic and pharmacologic proteasome augmentation ameliorates Alzheimer’s‐like pathology in animal models of AD
Authors: Pickering Andrew
Published: December 2023

Background

The proteasome has key roles in neuronal proteostasis, including the removal of misfolded and oxidized proteins, presynaptic protein turnover, and synaptic efficacy and plasticity. Proteasome dysfunction is a prominent feature of Alzheimer’s disease (AD).

Method

We investigate proteasome augmentation through overexpression of a rate limiting proteasome subunit and treatment with proteasome activating peptidomimetics developed by our team in hAPP(J20) mice, MC65 cells overexpressing a C99 fragment of APP and elav‐GS‐GAL4>UAS‐APP;UAS‐BACE1 fly models of AD.

Result

We show that prevention of proteasome dysfunction by genetic manipulation delays mortality, cell death, and cognitive deficits in fly and cell culture AD models. We developed a transgenic mouse with neuronal‐specific proteasome overexpression that, when crossed with an AD mouse model, showed reduced mortality and cognitive deficits. To establish translational relevance, we developed a set of TAT‐based proteasome‐activating peptidomimetics that stably penetrated the blood‐brain barrier and enhanced 20S/26S proteasome activity. These agonists protected against cell death, cognitive decline, and mortality in cell culture, fly, and mouse AD models.

Conclusion

We demonstrate proteasome modulation as a viable target for prevention of AD‐like deficits and present a set of novel proteasome agonists as AD therapeutics
Does texture analysis classify semantic dementia from Alzheimer’s disease better than volumetric analysis?
Authors: Kwon Min Jeong
Published: December 2023

Background

Texture analysis may capture subtle changes in the gray matter more sensitively than volumetric analysis. We aimed to investigate the patterns of neurodegeneration in semantic dementia (SD) and Alzheimer’s disease (AD) by comparing the temporal gray matter texture and volume between cognitively normal controls and older adults with SD and AD.

Method

We enrolled all participants from three national university hospitals in Korea. We obtained T1‐weighted magnetic resonance images and compared the gray matter texture and volume of regions of interest (ROIs) between the groups using analysis of variance with Bonferroni posthoc comparisons. We also developed models for classifying SD, AD and control groups using logistic regression analyses, and validated the models using receiver operator characteristics analysis.

Result

Compared to the AD group, the SD group showed lower volumes in five ROIs (bilateral temporal poles, and the left inferior, middle, and superior temporal cortices) and higher texture in these five ROIs and two additional ROIs (right inferior temporal and left entorhinal cortices). The performances of both texture‐ and volume‐based models were good and comparable in classifying SD from NC (mean area under the curve [AUC] = 0.914 for texture; mean AUC = 0.894 for volume). However, only the texture‐based model achieved a good level of performance in classifying SD and AD (mean AUC = 0.775 for texture; mean AUC = 0.658 for volume).

Conclusion

Texture may be a useful neuroimaging marker for early detection of SD in older adults and its differentiation from AD.
Exploring green care approaches for healthy aging, healing from trauma and holistic environmental, social, spiritual, intellectual and emotional wellness among individuals with dementia: A scoping review
Authors: Hand Michelle D , Anderson Keith , Schleitwiler Tess D
Published: December 2023

Background

Green care approaches, or nature‐based treatment for greater health and healing, can offer a sense of place and community, empowerment, and various psychological, physical, social, spiritual and environmental benefits, as well as less isolation, depression and posttraumatic stress among older adults, including among people with dementia. This is particularly relevant since the onset of the COVID‐19 pandemic, which has given rise to further isolation, depression anxiety and trauma in this population. Still, while green care practices have been in place for more than 100 years, research on green care approaches, such as through care farms and gardens, for promoting healthy aging and holistic wellness among individuals with dementia is limited. Thus, a scoping review was conducted to explore what is currently known about the use of horticulture‐based green care approaches for promoting healthy aging, holistic wellness and potential psychological healing from past trauma.

Method

Included were peer‐reviewed articles that reported on primary qualitative, quantitative, mixed methods study findings relating to green care approaches for healthy aging and holistic wellness, including with regard to psychological healing. While no geographical parameter was set, all included articles were published in the English language.

Results

In total, 101 potentially relevant sources were identified in Academic Search Complete and Google Scholar using the search terms “care farm*” or “green care” or “horticulture” or “therapeutic garden” or “nature‐based” AND “dementia” or “Alzheimers.” Of these, 42 peer‐reviewed articles were screened in for full text reading, and a thematic analysis was conducted to offer an overview of current research on horticulture‐based strategies for promoting holistic wellness, healing and healthy aging among individuals with dementia as well as implications for future research, practice, and policy.

Conclusion

Key overarching themes surround the use of green care for psychological, social, spiritual, environmental and social wellness among individuals with dementia as well as the relevance of green care approaches to advancing trauma‐responsive and culturally appropriate care. Further implications for future research, practice and policy will also be discussed.
Plasma rejuvenation factor GDF11 associates with amyloid‐related cognitive decline in older adults across the Alzheimer’s Disease spectrum
Authors: Lee Shannon Y. , Paolillo Emily W. , Saloner Rowan , VandeBunte Anna M , Rabinovici Gil D. , La Joie Renaud , Kramer Joel H. , Villeda Saul , Casaletto Kaitlin B.
Published: December 2023

Background

Through studies of animal heterochronic parabiosis (fusion of juvenile and older adult animal circulatory systems), growth differentiation factor 11 (GDF11) has been identified as a blood rejuvenation factor that can promote neurogenesis, vascular remodeling, and memory improvement in the presence of age‐related declines. However, it is unknown whether GDF11’s associations with cognitive and neural outcomes translate to humans. We assessed the relationship between plasma GDF11, cerebral amyloid pathology, and cognitive performance in older adults across the Alzheimer’s disease (AD) spectrum.

Method

Participants were 71 older adults from the UCSF Memory and Aging Center who ranged in age from 63 to 93 (Meanage = 79.5; Meanedu = 17.5, 66 cognitively unimpaired, 56% women, 38% amyloid PET positive) and completed blood draws with plasma analyzed on Somascan (version 4.1), neuropsychological evaluations, and amyloid PET scans (18‐AV‐45). Cognition was operationalized as a of validated tests of memory and executive function. Pearson’s correlations examined interrelationships among plasma GDF11, cognition, and amyloid PET centiloids. To determine whether plasma GDF11 moderated the effects of amyloid on cognition, linear regression examined cognition as a function of GDF11, amyloid, and their interaction, controlling for age, sex, and education.

Result

Higher amyloid PET centiloids correlated with worse cognition (r = ‐0.20, p = 0.09) and lower levels of GDF11 (r = ‐0.15, p = 0.20), though relationships did not reach statistical significance. GDF11 also did not strongly univariately correlate with cognition (r = ‐0.07, p = 0.59). However, there was a significant interaction between GDF11 and amyloid PET centiloids on cognition (β = 0.55, 95% CI = 0.15, 0.95, p = 0.008) such that the negative relationship between amyloid PET centiloids and cognition was significantly in participants with higher levels of GDF11.

Conclusion

GDF11 is a blood‐based rejuvenation factor that supports neurogenesis and cognition in animal models and attenuates the association between higher amyloid burden and worse cognition in cognitively unimpaired older adults. These results coupled with prior findings provide translational evidence that GDF11 supports brain resilience and further examination of GDF11 as a therapeutic target for Alzheimer’s disease is warranted.
Alterations in the integrity of cortical and subcortical circuits in AD and MCI: Connectivity study in rs‐fMRI.
Authors: Rodriguez Keveen , Aponte Claudia , Quintero Carlos Andrés Andrés Tobón , Ochoa John F , Puche Aura C , Hidalgo Maria Jose
Published: December 2023

Background

rs‐FC has been altered in AD continuum with hyper‐hypoconnectivity patterns attributed not only to regional changes, but to disruption of functional integration or aberrant connectivity between cortical and subcortical brain regions . This study seeks to find connectivity patterns in MCI and AD with a different network extraction approach taking each network as a whole and not separated into ROIs.

Methods

rs‐fMRI data from ADNI3 and OASIS3 of 64/85 AD/Control subjects, 57/59 MCI/Control subjects from both repositories were preprocessed with the CONN toolbox. Resting state networks (RSN) were extracted by cGICA using GIFT toolbox (semi‐blind INFOMAX) with 300 ROI Set template with 14 RSN. A non parametric 2‐sample t‐test was applied using the SnPM tool, all analyses in SnPM were performed using 10000 random permutations and the anatomical association of each reported cluster is extracted from the AAL atlas using the xjView tool . Regions that had statistically significant clusters with p FWE<0.001 and with k> = 100 voxels were analyzed.

Results

There were alterations in regions of every network for each groups comparison (p < 0.001). Several ROI were repeatedly altered in analyzed RSN, temporal pole, MTG, STG, cerebellar crus, OFC, PCC, MCC, precuneus, AG, SMG, SPL, IPL, SFG, MFG, IFG, thalamus, FG and posterior cerebellar lobe. Decreased/increased activation area, changes in activation intensity and reorganization of activation areas, specially reduced activation areas in AD and greater activation areas in MCI. The RSN with more changes in connectivity patterns were DMN, DAN/VAN, MTL, SAL and FPN.

Conclusion

Changes in connectivity in MCI and AD show reorganization of RSN related to enlargement, reduction or displacement of activation areas, the greatest amount of change was observed in MCI with increases in activation areas and in AD a general decrease in activation areas was observed, these alterations are consistent with the inverted u‐pattern that has been described in other studies . The common ROI we found altered had been related with accumulation and aggregation of p‐Tau and βA and this could be an explanation of connectivity changes duet to the neurodegeneration and synaptic dysfunction caused by this proteins
Spatial Transcriptomics of Human Postmortem Brain Tissue Uncovers Molecular Pathways Associated with Amyloid‐Beta Plaques
Authors: Avey Denis , Ng Bernard , Iatrou Artemis , Vialle Ricardo A , Lopes Katia de Paiva , Tasaki Shinya , Xu Jishu , De Tissera Sashini L , Flood Daniel , Bennett David A. A , Wang Yanling
Published: December 2023

Background

Alzheimer’s disease (AD) pathologies include extracellular amyloid‐beta (A‐beta) plaques, intracellular neurofibrillary tangles, neuronal cell loss, and chronic glial inflammation. Recent studies profiling gene expression in human postmortem brain tissue have uncovered cell‐type‐specific changes in AD. However, these studies did not provide simultaneous, direct measurements of AD pathologies in the native microenvironment.

Method

To this end, we applied the 10X Genomics Visium platform to post‐mortem dorsolateral prefrontal cortex (DLPFC) from 20 ROSMAP participants with or without AD dementia. In total, we obtained spatial transcriptomic (ST) data for ∼260,000 tissue microdomains (“spots” comprised of ∼1‐10 cells).

Result

We clustered spots and annotated clusters according to expression of genes with known enrichment in anatomical layers (i.e. cortical layers 1‐6, meninges, and white matter). We deconvoluted the cell type(s) comprising each spot using cell2location, and found significant changes in the abundance of specific cell types in AD. Using a two‐stage pseudobulk regression approach, we identified hundreds of genes whose spatial expression is significantly associated with nearby A‐beta plaques and/or astrocyte reactivity (GFAP). A‐beta‐associated genes are enriched for diverse biological processes, including translation, metabolism, inflammation, gliosis, and immune cell infiltration. We also detected genes that distinguish A‐beta plaques surrounded by reactive glial nets. We validated the spatial expression pattern of a subset of plaque‐associated genes by RNAScope.

Conclusion

In summary, our study reveals genes and pathways that shape molecular states in the spatial context of AD pathology. Our data represent a comprehensive application of ST technology in AD brains, providing a valuable resource for the research community.
Care partner burden and emergency service use: what is the link?
Authors: Lindauer Allison , Gothard Sarah , Bernard Hannah , Steele Joel S.
Published: December 2023

Background

Persons with dementia (PWD) are significantly more likely to use emergency services (defined here as emergency department or urgent care visits) than age‐matched controls (1). The bi‐directional relationship between care partner (CP) burden and their PWD’s emergency service use is not well‐understood (2). A possible limiting factor is the infrequent assessment of emergency service use by the PWD and corresponding CP burden. Here, we used high frequency longitudinal data from the telehealth‐based Tele‐STELLA (Support via TEchnology: Living and Learning with Advancing ADRD) study (NIA R01AG067546) to examine the relationship between CP burden and PWD emergency service use.

Method

CPs (n = 80; age = 65.7±11.6 years) completed weekly online “Orbit” surveys (3). The survey measures burden (ZBI‐4 [9±3.48 points]), cost‐of‐care, medication use, and emergency service use (4). Using R software (5), descriptive statistics and generalized mixed effect models were developed to examine the effects of CP burden on PWD emergency service use.

Result

A median of 27 (min = 1;max = 61) weeks of CP responses were captured. Simple generalized mixed effects models showed a significant positive relationship between ZBI‐4 scores and emergency service use the week of event occurrence (β = 0.0853; p = 0.04). As ZBI‐4 scores increased, the greater the likelihood of an event. Additionally, a mixed effects model that examined the 5 weeks prior to emergency service use showed the absolute magnitude of change of ZBI‐4 scores had a negative relationship to the events (β = ‐0.393;p = 0.00;OR = 0.675). Taking the results of the two models together, as the range of burden narrowed towards higher ZBI‐4 scores, the chance of emergency service use increased.

Conclusion

High frequency electronic self‐reported data in this telehealth‐based study allowed for identification of emergent events closer to real time than the standard practice. As the range of CP burden scores decreased, trending toward higher burden, there was an increased likelihood of emergency service use occurring for the PWD. This information can be used to anticipate the likelihood of future events and create targeted interventions both for the CP and PWD prior to the need of emergency service use. Limitations in this analysis and gaps in research on this topic warrant further investigation.
Education, digital tools, and diagnostic support to increase PCP‐based cognitive testing in patients 65 years and older
Authors: Gitelman Darren R. , Mishos Jennifer , Canda Cristybelle‐Marie , Pagel Patti , Dimitris Lisa , Malone Michael
Published: December 2023

In the United States, primary care clinicians (PCPs) typically diagnose and treat most patients who have or who may be developing neurocognitive disorders (NCDs). However, as many as two‐thirds of patients remain underdiagnosed, misdiagnosed or experience a delay in the diagnosis. Many barriers to care have been cited for these failures in diagnosis, including PCP limitations in time and expertise, as well as inadequate technical, financial, and staffing resources. Diagnostic delays may particularly impact minority populations, exacerbating the disparate burden these communities bear from dementing disorders. In contrast, an early diagnosis is an impetus to advanced care planning, to strategizing for patient safety, and to initiating interventions that may preserve cognitive function and enhance quality of life.

The main objective for this proposal is to increase the rate of cognitive screening in patients 65 years and older. PCP practices that serve diverse communities are early implementation sites. This proposal focuses on addressing barriers to testing by providing PCPs with educational resources to enhance the efficiency and quality of care for patients with neurocognitive disorders. The goal is to educate PCPs on the importance of early cognitive screening and to provide tools to help manage their patients with cognitive disorders and dementia more efficiently. Primary care providers are offered multiple educational and practice supports for managing patients who have an abnormal cognitive screen. The BrainCheck digital cognitive testing tool allows clinical support staff to rapidly test patients for cognitive impairment. Educational tools include succinct didactic lectures; a SharePoint site that serves as a resource hub for and weekly Project ECHO® based Memory Care Case Conferences (CME provided). EHR tools include simple order sets and templates. The practice support tool is an implementation of eConsults to quickly link PCPs to dementia experts in order to answer questions about patient care.

The outcomes of this project measured in terms of PCP feedback, cognitive testing gains, educational participation, and tool usage will allow us to design more effective strategies for increasing cognitive testing and improving the management of patients with dementia at the health system level.
NEUROPROTECTIVE EFFECT OF PERILLYL ALCOHOL IN EXPERIMENTAL SPORADIC AD
Authors: Malik Shahid Mushtaq , Chauhan Dolly , Deshmukh Rahul Renukadas
Published: December 2023

Background

Alzheimer’s is most common neurodegenerative disorder characterized by memory loss due to accumulation of amyloid‐ β fibrils. There are different pathologies that count for AD like neuro inflammation. This study highlights the role of oxidative stress and inflammation in progression of AD where as Perillyl alcohol (POH) shows antioxidative & anti‐inflammatory properties.

Method

Sprague Dawley ICV‐STZ (3mg/kg) rats (250‐300g, 7‐8 weeks) were treated with Perillyl alcohol treated with three different doses of (25, 50 and 100mg/kg p.o.) for 13 days from 15th to 27th day. Weight measured on 1st and 28th day. Behavioral analysis done using Open Field Test and Morris Water Maze.

Result

Perillyl alcohol treatment significantly attenuates declined body weight in ICV‐STZ induced dementia in rats, showed significant increase in crossing number, and active time. Dementia induced rats were unable to discriminate familiar and novel objects, which is improved by POH. POH attenuates STZ induced acquisition deficits and retention time, increased MDA and nitrite levels. POH attenuated depleted levels of GSH, Catalase, SOD comparable to standard drug donepezil, POH decreased AChE levels in cortex and hippocampus.

Conclusion

Study outcomes demonstrate neuroprotective potential of Perillyl alcohol against ICV‐STZ administration of streptozotocin induced behavioural and biochemical abnormalities. Biventricular STZ infusion produced significant impairment in learning, memory, cholinergic hypofunction and elevation in hippocampal oxidative stress in rats. Rats showed poor learning, memory and unable to discriminate between familiar & novel objects in MWM and ORT. POH administration significantly attenuated STZ induced biochemical consequences. Observed beneficial effects of POH include restored cholinergic functions and antioxidant mechanism
Dementia diagnosis using Addenbrooke’s Cognitive Examination in low literates and illiterates in three Indian languages
Authors: Paplikar Avanthi , Varghese Feba , Battacharyya Bidisha , Shukla Vasundhara , Tripathi Manjari , Biswas Atanu , Alladi Suvarna
Published: December 2023

Background

With a rising burden of dementia globally, there is a need to harmonize dementia diagnosis and research across diverse populations. Majority of dementia patients reside in low‐middle income countries (LMICs) such as India. Major challenges in the diagnosis of dementia in LMICs include the lack of a proper diagnostic tool for low literates and illiterates besides the lack of awareness of society about the disease. Addenbrooke’s Cognitive Examination‐III (ACE‐III) is a screening instrument with good validity and reliability to diagnose patients with mild cognitive impairment (MCI) and dementia. Although ACE‐III has been adapted to many languages both in India and worldwide, it has not been adapted for the low literate and illiterate population. The objective of the study is to i) develop a culturally relevant illiterate ACE‐III for the Indian context and standardize the instrument across three commonly used Indian languages: Hindi, Bengali, and Kannada; and ii) to establish the sensitivity and specificity of the illiterate Indian versions of ACE‐III to detect dementia and MCI.

Method

The illiterate version of ACE‐III was adapted from the literate version of ACE‐III based on the suggestions from multidisciplinary expert panel comprising cognitive neurologists, stroke specialists, speech–language pathologists and psychologists from different centres (see Figure 1). In total, 84 controls, 50 dementia, and 46 MCI patients were recruited across three cities in India for the validation study. Psychometric properties of adapted versions were examined, and their sensitivity and specificity were established.

Result

The sensitivity and specificity of illiterate ACE‐III in identifying dementia ranged from 93.3% to 99.9%, sensitivity for MCI ranged from 93.3% to 99%, and specificity from 72.7% to 99.9%. Optimum cut‐off scores were established (see Table 1).

Conclusion

The adapted versions of illiterate ACE‐III have been standardized and validated for use across three Indian languages, with high diagnostic accuracy in identifying dementia and MCI in a linguistically diverse context. The study provides a cognitive screening tool that can be used to uniformly diagnose cognitive impairment in people speaking different languages from both rural and urban populations located across India.
Neuroprotective Potential of Limonene in LPS induced Parkinson’s Disease in Rats
Authors: Sharma Pratyancha , Deshmukh Rahul Renukadas
Published: December 2023

Background

Parkinson’s disease is a hypokinetic disorder characterized by selective loss of dopaminergic in the substantia nigra pars compacta (SNPc) region of the mid‐brain. Dopaminergic degeneration of neurons is considered to be due to oxidative stress, neuroinflammation, mitochondrial dysfunction, etc.

Method

Infusion of LPS induced motor deficit and increased oxidative–nitritive stress in rats. Chronic treatment with limonene (25, 50 and 100 mg/kg/p.o.) for 21 days. LPS induced motor deficit and increase in striatal oxidative burden.

Result

Chronic treatment with limonene (25, 50 and 100 mg/kg/p.o.) for 21 days, significantly attenuated motor deficit and increased in striatal oxidative burden. Biochemically limonene significantly reduced the oxidative–nitrative stress, as evidenced by the decrease in malondialdehyde (MDA) and nitrite levels, and restored the reduced catalase, glutathione (GSH), and Superoxide dismutase (SOD) levels.

Conclusion

The observed beneficial effects of limonene in motor defects may be due to its ability to reduce oxidative burden.
The Alzheimer Disease Sequencing Project: Enabling Discovery Through Diversity
Authors: Haines Jonathan L.
Published: December 2023

Background

In 2011, the U.S. congress passed the National Alzheimer’s Project Act to address the rapidly growing problem of Alzheimer disease and related disorders (ADRD). In response, the National Institute on Aging (NIA) initiated the Alzheimer’s Disease Sequencing Project (ADSP), a large‐scale effort to leverage genetics and genomics technology and expertise to unravel the underlying fundamental understanding of ADRD and accelerate the development of effective treatments for ADRD.

Method

The ADSP initially assembled existing datasets and now has invested heavily in developing new datasets (through the Follow‐Up Study (FUS) and Family‐Based Study (FBS) efforts) representing global diversity, now spanning nearly every continent. Necessary and critical infrastructure is in place, including the Genome Center for Alzheimer Disease (GCAD; DNA sequence processing), the NIA Genetics of Alzheimer Disease Data Storage Site (NIAGADS; data repository and access), and the National Centralized Repository for Alzheimer disease (NCRAD: sample repository). Data generation is performed through centralized laboratories for both whole genome sequencing (WGS) and plasma biomarkers. The resulting data are analyzed through multiple complementary consortia including those for data harmonization, genetic analysis, functional genomics, and computational analysis. This collaborative global initiative is coordinated through an oversight committee (the Executive Committee‐Cross Consortium Collaboration and Coordination; EC‐4C) with representation from all these important groups.

Results

Data is released to the research community on a regular basis with the most recent release containing ∼37,000 WGS.

Conclusion

Future releases will contain more detailed and harmonized clinical information, plasma biomarkers, WGS, and multi‐omics data, with the goal of having >100,000 samples with strong representation of global diversity.
Multi‐Ancestry Genetics for Alzheimer’s Disease: Alzheimer’s Disease Genetics Consortium
Authors: Jun Gyungah R
Published: December 2023

Background

Alzheimer’s disease (AD) affects individuals of all races and ethnicities, yet large‐scale genetic research to compare genetic makeups for risk or protection of AD between multi‐ancestry datasets is limited. The Alzheimer’s Disease Genetics Consortium (ADGC) assembled the largest multi‐ancestry dataset including 56,241 subjects from non‐Hispanic Whites (NHW), African Americans (AA), Hispanics (HI), and East Asians (EAS) to understand ancestral similarities and differences in genetic risk and protective variants for AD.

Method

We established a Steering Committee with 5 members, 4 main Workgroups including Primary Meta‐Analysis, Follow‐Up Analysis, Secondary Analysis, and Method Evaluation, and 3 affiliated Workgroups consisting of Phenotype Harmonization, Imputation Development, and genome‐wide association study (GWAS)/whole genome sequencing (WGS) Integration. A new computing infrastructure was developed for shared analytic space on Amazon Web Services (AWS), where all members from different institutes accessed to genetic and phenotypic data and conducted analysis under the master analysis plan with centrally developed pipelines and scripts. We conducted ancestry‐specific GWAS using single nucleotide polymorphisms (SNPs) for AD, cross‐ancestry meta‐analysis of 4 ancestry GWASs, fine‐mapping for allelic heterogeneity in known and novel loci for AD, and pathway analysis.

Result

We confirmed 12 known including APOE ɛ4 and ɛ2 variants and identified 2 novel loci for AD in cross‐ancestry meta‐analysis with P<5.4×10−8. African and Asian ancestry subjects displayed greater heterogeneity in effect sizes and significant levels with the previously known AD loci for AD. Ancestry‐specific fine‐mapping indicated presence of potential distinct causal variants across different ancestry groups from multiple known AD loci. Two APOE alleles had greatest effect sizes among East Asians compared to others (EAS>NHW>AA>HI), while we failed to observe significant association signals with AD in SHARPIN and TREM2 regions from African Americans. Of two novel loci, the association signal in the LRRC4C‐API5 region was contributed from all four ancestry groups; in contrast, the signal in the LHX5‐AS1‐RBM19 region was predominantly from Hispanics.

Conclusion

Genetic risk profiling in multi‐ancestry datasets provided unique opportunity to understand ancestry‐specific and cross‐ancestry genetic risk factors for AD. Further evaluation of these established and novel loci for AD by integrating GWAS and WGS data from ADSP is underway
Factors Associated With Dementia‐Related Behaviors Among Caregivers Experiencing Poor Sleep
Authors: Patel Mansi , Papazyan Anna , Min Andrea , Winn Isabel , Josephson Karen , Teng Edmond , Alessi Cathy A , Martin Jennifer L , Song Yeonsu
Published: December 2023

Background

Neuropsychiatric symptoms of dementia are common and have the potential to negatively impact the physical and mental health of family caregivers, hindering their ability to provide care. Such impact may be worse among caregivers experiencing poor sleep. This study aimed to explore factors associated with the frequency of and caregivers’ distress to dementia‐related problematic behaviors.

Method

This was a cross‐sectional study, using data from a clinical trial of dyadic sleep intervention for persons living with dementia (PLWD) and their family caregivers. Dementia‐related behaviors were measured using a 24‐item, Revised Memory and Behavioral Problems Checklist (RMBPC): total scores of frequencies and caregivers’ distress; scores for three subscales (memory‐related, depression, and disruptive behaviors). Caregiver‐related variables included demographic background, Zarit Burden Interview (ZBI), Positive Aspects of Caregiving (PAC), Pittsburgh Sleep Quality Index (PSQI), and Center for Epidemiological Studies of Depression (CESD). Patient‐related variables included activities of daily living (ADLs), instrumental ADLs (IADLs), and Mini‐Mental State Examination (MMSE) scores. A total of 47 dyads were included in the analysis (caregivers: n = 29 spouses, n = 17 non‐spouses; 40% Whites). Pearson correlation analyses were conducted.

Result

Higher ZBI and CESD scores were significantly associated with higher RMBPC frequency total (r = 0.41, r = 0.48, respectively; p<0.01) and caregiver distress total scores (r = 0.58, r = 0.43, respectively; p<0.01). Lower PAC (r = ‐0.31, p = 0.04) and higher MMSE scores (r = 0.37, p = 0.03) were also associated with higher caregiver distress total scores. ZBI and CESD scores were associated with RMBPC‐depression subscale scores (frequency/caregiver distress). There were positive associations between CESD and MMSE with RMBPC‐disruptive behaviors (frequency), and ZBI and PAC scores with RMBPC‐disruptive behaviors (caregiver distress). No patient or caregiver‐related factors were associated with RMBPC‐memory subscale scores. There was no significant association between PSQI scores and RMBPC total/subscale scores. Patient factors were not significantly associated with RMBPC frequency total or caregiver distress total scores.

Conclusion

Dementia‐related problems, particularly depressive symptoms and disruptive behaviors of PLWD are associated with both positive and negative aspects of caregiving. Future studies will need to further examine how each RMBPC subscale of behavior contributes to caregiver burden or perceived caregiving experiences among family caregivers.
Functional genomic studies in diverse populations to characterize risk loci for Alzheimer Disease
Authors: Nuytemans Karen ,   the Alzheimer’s Disease Sequencing Project Functional Genomics consortium
Published: December 2023

Background

As part of the ADSP Functional Genomics consortium, we aim to unravel ancestry specific effects of genomic regulation of AD loci. African Americans (AA) and Hispanics (HI) are at higher risk for Alzheimer’s disease (AD) compared to non‐Hispanic whites (NHW). Even though AA, HI and other diverse groups make up 40% of the US population, over 90% of participants in large‐scale genomic research studies have been NHW, representing European (EU) ancestry. Recent AD research including diverse groups has shown that genes and variants contributing to disease can have different risk effect dependent on the ancestral background they reside on (i.e. APOE). Together these clearly indicate a need to expand genome‐wide and gene‐specific analyses of genomic organization and regulation for other ancestries contributing to diverse, admixed populations, such as African (AF) or Amerindian (AI) ancestries.

Method

We analyzed interaction of variants in the APOE region with AD risk in WGS of diverse populations to identify modifiers of the APOEɛ4 risk effect. Additionally, to assess overall differences in chromatin regulation genome‐wide across ancestries, we performed bulk and single cell chromatin accessibility (ATAC‐seq) and bulk chromatin interaction (Hi‐C) assays in brains from admixed individuals with high EU, AF (>95%) or AI (>75%) ancestry contribution.

Result

We identified both close‐by and distant modifier variants (in the downstream PSG gene family region) inferring protection against the APOEɛ4 risk on the AF ancestry. Single cell ATAC‐seq data in brain showed higher accessibility of the APOE region and large regions of chr19 in astrocytes, but not microglia, of EU versus AF ancestry. Lastly, bulk Hi‐C analyses in brain strongly supported the hypothesis of ancestry dependent regulation by genome‐wide detection of differential chromatin interactions comparing EU to AF ancestry.

Conclusion

Our analyses using complementary functional genomic assay methods show clear differences of genome regulation between EU and AF ancestry. Overall, these data support genome regulation to be strongly influenced by ancestral origin. The generated data on samples with high single ancestral contributions will help elucidate risk effects seen for AD related genes in different population groups, as we describe for the APOE region.
NEUROPROTECTIVE POTENTIAL OF ALOGLIPTIN IN LIPOPOLYSACCHARIDE INDUCED EXPERIMENTAL MODEL OF PARKINSON’S DISEASE
Authors: Dhureja Maanvi , Deshmukh Rahul Renukadas
Published: December 2023

Background

Parkinson’s disease is a hypokinetic movement disorder characterized by selective loss of dopaminergic neurons in the substantia nigra. Dopaminergic degeneration of neurons is considered to be due to oxidative stress, neuroinflammation, mitochondrial dysfunction etc. Thus therapies that could alter all the pathologies linked with the disease and produces less or minimal side effects may work as better therapeutic target than the existing one.

Method

The intranigral LPS (5µg/μl) administration was used to induce PD like symptoms in rats. LPS‐infused rats were treated with alogliptin (10, 20 and 40 mg/kg/day/p.o.) for 21 days. Behavioral parameters and body weight analysis were performed on weekly basis to examine the movement disabilities in rats. On 21st day, animals were sacrificed; biochemical and histological assessment was done to evaluate role of alogliptin in LPS‐infused rats.

Result

It has been observed that Alogliptin at significant dose level attenuates movement disabilities in LPS induced in PD rats. Alogliptin significantly reduces malondialdehyde, nitrites levels and raises glutathione levels. These suggest that neuroprotective action of alogliptin is due to its anti‐oxidant activity. Moreover, histomorphological assessment confirms the neuroprotective activity of alogliptin.

Conclusion

Alogliptin has neuroprotective potential and observed increment in the motor activity of LPS‐infused rats following alogliptin treatment may be due to its antioxidant potential and ability to prevent the morphological alterations in brain cells.