bluuebunny/crossref_metadata_2025 huggingface dataset:
The assessment of synaptic dysfunction in neurodegenerative disorders by a novel single molecular array for Neuronal pentraxin 2
Authors: Sauer Mathias , Gomes Bárbara Fernandes , Zetterberg Henrik , Blennow Kaj , Brinkmalm Ann , Belbin Olivia , Alcolea Daniel , Fortea Juan , Hansson Oskar , Nilsson Johanna , Ashton Nicholas J.
Published: January 2025

Background

Synaptic dysfunction is a prominent feature in neurodegenerative disorders, associating with cognition. In contrast to most synaptic proteins assessed in cerebrospinal fluid (CSF), Neuronal pentraxin 2 (NPTX2), essential for synaptic plasticity, exhibits downregulation neurodegenerative disorders through mass spectrometry (MS) methods. While MS‐based assays hold promise, their constraints hinder widespread clinical adoption. Thus, our study aimed to develop a novel single molecular array (Simoa) for quantifying NPTX2 levels in CSF.

Method

Homebrew NPTX2 was validated for the Simoa platform using commercial antibodies (EPR15618, ERP24020‐38; Abcam) in 2uL of CSF. After validation, we performed a study in Alzheimer’s disease (AD) and healthy controls (HC) from the BioFINDER pilot cohort (n = 99 participants; 48.5%AD; mean age 76.2 years [7.0 SD]). As a further validation, we quantified NPTX2 in the Sant Pau Initiative on Neurodegeneration (SPIN) cohort with 199 patients (58 AD, 51 HC, 60 Lewy body dementia (LBD) and 41 behavioral variant of frontotemporal dementia (bvFTD)). The mean age was 69.5 (11.4 SD) and both cohorts had an even distribution of sex. We examined group differences by the Wilcoxon rank sum test (corrected with Dunn‐test) and associations between the biomarkers and MRI, Tau PET, amyloid‐β (Aβ) PET and MMSE were determined by linear regression, adjusting for age and sex.

Result

In BioFINDER, Fold change (FC) in NPTX2 was significantly decreased in AD (median [95%CI], 0.85[0.65‐1.00]; p = 0.005) as compared to HC. NPTX2 showed a significant association in the full cohort with MMSE (β = 5.46, p<0.001), cortical thickness (β = 0.18, p<0.001) and Tau PET (β = ‐0.46, p = 0.002), but not with Aβ PET. In the SPIN cohort, the FC for neurodegenerative groups were significantly decreased as compared to HC (AD, 0.58[0.52‐0.79]; p<0.001; LBD, 0.66[0.56‐0.81]; p<0.001; and bvFTD, 0.50[0.33‐0.61]; p<0.001), with AUCs of 0.77(AD, 95%CI = 0.68‐0.86), 0.73(LBD, 0.63‐0.83) and 0.86(bvFTD, 0.78‐0.94). NPTX2 showed a significant association with MMSE (β = 2.10, p = 0.01) in the full cohort. Further results will explore NPTX2 in blood.

Conclusion

This novel ultra‐sensitive immunoassay confirms the decrease of CSF NPTX2 in neurodegenerative diseases and a significant relationship to cognitive decline. This approach could streamline and increase the assessment of synaptic dysfunction in neurodegenerative diseases, providing valuable insights for disease management and treatment strategies.
The impact of a smartphone‐assisted real‐world wayfinding training on spatial memory performance as measured in VR in older adults
Authors: Marquardt Jonas , Kuehn Esther , Schreiber Stefanie , Maass Anne , Diersch Nadine
Published: January 2025

Background

Non‐pharmacological interventions that improve cognitive functioning in patients with Alzheimer’s disease will play a crucial role in the coming years to support their independence in daily living. Here, we investigated the potential of a novel smartphone‐assisted real‐world wayfinding training, tailored for older adults, to improve their spatial memory as one of the first cognitive functions affected by the disease. Spatial memory performance was assessed using a VR‐based navigation task and the Gardony map drawing analyzer.

Method

To date, eight cognitively healthy older adults (65‐73 years) completed the wayfinding training on the medical campus area in Magdeburg, Germany, using our smartphone application “Explore” (Figure 1). In two egocentric sessions, participants had to walk repeatedly from a fixed start location to a target location and back. In four allocentric sessions, participants had to walk to several target locations consecutively by planning a route (four routes per session). All target locations were shown on a map in the app at the beginning of a track, which disappeared during walking but could be re‐opened. The app recorded GPS data and the number of map views. Potential changes in spatial memory were assessed by means of a pointing task in a virtual campus version before and after the training and by comparing the accuracy in the computerized map drawing after each session.

Result

A linear mixed‐effect model analysis confirmed a significant training effect on pointing errors, while controlling for pre‐training familiarity, p < .001 (Figure 2). Map drawing accuracy improved over the course of the training, p < .001 (Figure 3a), while the number of map views during walking in allocentric sessions decreased, p = .021 (Figure 3b).

Conclusion

We provide first evidence that a remotely administered real‐world wayfinding training might be able to improve spatial memory in older adults. As a next step, data will be collected in more participants with some of them assigned to a walking‐only control group. (f)MRI data, measured during the virtual pointing task, and biomarker status will be analyzed to investigate the mechanisms of the training effects and to determine the applicability as dementia intervention.
Associations between sleep apnea and tau in cognitively unimpaired older adults
Authors: Tennant Victoria R , Tsiknia Amaryllis A , Peltz Carrie B. , Lee Noelle , Hand Maxwell W , Leng Yue , Stone Katie L , Redline Susan , O'Bryant Sid E. , Braskie Meredith N , Yaffe Kristine
Published: January 2025

Background

Older age is associated with sleep disruptions and the aggregation of pathological tau in the medial temporal lobe (MTL). Associations between sleep disruptions and the progression of Alzheimer’s disease (AD) have been widely demonstrated. However, data addressing the association of objectively measured sleep apnea to tau deposition beyond the MTL in cognitively unimpaired older adults are limited.

Method

We included 357 cognitively unimpaired participants from the DORMIR sleep study, an ancillary study of HABS‐HD, with available information on the apnea‐hypopnea index (AHI; number of respiratory events with ≥3% desaturation divided by the estimated all‐night sleep time) derived from a home sleep apnea test (WatchPat, Itamar, Medical), Aβ (florbetaben), and tau (PI‐2620) PET scans. We calculated Aβ and tau standardized uptake value ratio (SUVR) using FreeSurfer (v5.3.0) derived regions, with whole cerebellum and posterior gray matter of the cerebellum as the reference regions, respectively. Between‐group differences for high AHI (AHI≥15) and low AHI (AHI<15) were assessed using t‐tests for continuous variables and χ2 tests for categorical variables. We evaluated the independent effect of log‐transformed AHI on continuous global Aβ and tau in separate linear regression models, adjusting for age, sex, education, ethnoracial group, and APOE4 carrier status. When predicting tau, we also included continuous global Aβ as a covariate.

Result

Median lateral parietal tau SUVR was significantly higher in the high AHI group (p = 0.04). Higher AHI was associated with higher median lateral parietal tau SUVR (p = 0.02, std.β = 0.11) and higher posterior cingulate tau SUVR (trend; p = 0.07, std.β = 0.10), but not with MTL tau SUVR (p = 0.71, std.β = ‐0.02) (Figure 1). AHI was not associated with global Aβ SUVR (p = 0.24, std.β = 0.06).

Conclusion

Past work has linked sleep apnea to impaired Aβ clearance. Intriguingly, our findings link higher AHI to more tau in the lateral parietal and posterior cingulate cortex, independent of Aβ burden, suggesting a separate pathway by which sleep apnea may exert effects on the aging brain. If replicated in longitudinal studies, this may have important implications for the development of sleep health guidelines and AD prevention strategies.
Word Young Leaders of Dementia Roadmap 2024‐2029: Approaches and Global Goals for Dementia Challenges
Authors: Clarens Maria Florencia , Arruabarrena Micaela Maria , Suemoto Claudia Kimie , Llibre‐Guerra Jorge J. , Crivelli Lucía , Sexton Claire , Ismail Ozama
Published: January 2025

Background

The 2021 WHO report highlights the importance of global planning for dementia. Initiatives that unite and support young leaders and stakeholders from diverse backgrounds in dementia care & research are crucial. The G8 Summit on Dementia in 2013 led to the creation of the World Dementia Council and the World Young Leaders in Dementia (WYLD) network, which connects professionals to work together on finding solutions to dementia challenges. With the emergence of new leadership and structure in January 2024 we aim to present our 2024‐2029 roadmap.

Method

We conducted a systematic review of the WYLD’s membership database to map out the geographical and sociodemographic landscape of our members and to further improve our recruitment of young leaders. Approaches and Goals for WYLD 2024‐2029 have been established with the advisory council and global partners, ensuring that the roadmap’s objectives are informed by a wide spectrum of insights and expert contributions.

Result

Our review of current membership has revealed a diverse member network in 21 countries‐Fig. 1‐ with a majority of female professionals (67.78%)‐Fig. 2‐.

Our mission, empowering emerging leaders through innovation, collaboration, and creative problem‐solving in dementia care strategies guided us in our roadmap, influencing our strategic proposal and aims.

WYLD Structure: We are creating an advisory council and global partnerships by fostering strategic partnerships with leading organizations in the field. Appointments of Regional Leads in Africa, Asia, Australia/New Zealand, Europe, North America, and South America demonstrate our commitment to diversity.

Leadership Development Activities: WYLD will offer leadership development through diverse mentorship training programs, curated webinars for young members in dementia care & research, and grant opportunities for rising Young Leaders

Outreach: Regular and extensive distribution of young dementia leader’s work to inspire and facilitate worldwide progress in the field.

Conclusion

The WYLD 2024‐2029 roadmap is a strategic blueprint that guides our mission to empower young leaders and innovate dementia care globally. Our growing, diverse membership, and collaborative initiatives set the stage for impactful change, ensuring that the vital work of these leaders is recognized and disseminated worldwide.
Funding Opportunity in Functional Target Validation for ADRD
Authors: Laeng Pascal , Cywin Charles
Published: January 2025

Background

Although the success rate of novel treatments for CNS diseases is low, this has not limited the enthusiasm of academic and industry neuroscientists to undertake novel drug discovery approaches for the treatment of Alzheimer’s Disease‐Related Dementias (ADRD) due to the significant unmet need. A first major obstacle in the development of promising treatments for ADRD and other CNS disorders is the need for well‐validated targets linked to the disease process. Partial and incomplete knowledge about the biology of the selected molecular target(s) often limit their chance to translate into successful drug discovery projects. Translating these discoveries to the clinic will depend on the quality of the target validation process and the confidence in a causative link between the modulation of a target(s) and its functional physiological consequence(s) associated with treating or preventing a disease state. Recent technological innovations provide new opportunities in developing new converging approaches to validate the molecular and physiological functions of novel target candidates and their causality in disease progression.

Method

NINDS, in partnership with NIA, is supporting new funding opportunity in functional target validation for ADRD to increase confidence in the efficacy and safety of novel emerging target(s) to trigger the development of customized therapeutic strategies. This will be implemented by a NOFO to fund the development of customized technologies, models, and protocols to modulate the expression (or activity) of ADRD target candidate(s) and monitor their functional biological consequences in in vitro and in vivo disease models. To inform future therapeutic efforts, positive as well as the negative functional impacts of the target modulation need to be tested in different modalities and across collaborating laboratories.

Result

NINDS invites applications to propose the comprehensive functional validation of newly identified therapeutic target candidates for ADRD. This poster will outline in more detail, the eligibility requirements for the target candidate, potential druggability and knowledge gaps as well as the budget and the research objectives and scope.

Conclusion

This funding opportunity will provide the translational research community with increased confidence in the efficacy and safety of the novel emerging target(s).
Exploring the Safety and Tolerability of IGC‐AD1 in Alzheimer’s Patients: Insights from CYP2C9 Polymorphism Assessment
Authors: Sulvaran Marian A , Arbelaez Maria Juanita , Gutiérrez Evelyn , Tangarife Maria Alejandra , Rao Jagadeesh S , Venegas Margarita , Sánchez Laura Tatiana , Shahnawaz Saadia , De Jesus William Julio , Pujals Karen Y , Grimaldi Claudia , Hong Elliot , Mukunda Ram
Published: January 2025

Background

Alzheimer’s disease (AD) affects millions of Americans, with potential future increases without breakthroughs in treatment. IGC‐AD1, a novel formulation comprising of delta‐9 tetrahydrocannabinol (“THC”) and melatonin, is being studied in AD‐associated agitation. THC is predominantly metabolized by cytochrome P450 and specifically by CYP2C9. We present the comparison of Adverse Events (“AE”) between two polymorphisms of CYP2C9, intermediate (“IM”) and normal metabolizers (“NM”).

Methods

Thirteen Puerto Rican AD patients participated in a three‐cohort MAD, Phase‐1 safety, and tolerability trial (IND146069, NCT04749563). In Cohorts‐1, 2, and 3, one mL of IGC‐AD1 was administered QD, BID, TID, respectively, for 14‐days, with a minimum washout period of 4‐days between cohorts. CYP2C9 genotyping was assessed. Active Participants were grouped by phenotypes, Intermediate, or Normal. The IM group was assessed by genotype (*1/*2, *1/*3). Frequency of Adverse Events (“AE”s) was evaluated by group. Chi‐squared was used to compare differences between groups (SPSSv.28).

Results

Seven patients were IM (allele *1/*2 = 4, allele*1/*3 = 3), while five were NM. Both groups IM and NM presented somnolence (IM: 57%; NM: 80%, p = 0.63), hypertension (IM: 43%; NM: 20%, p = 0.50), dizziness (IM: 43%; NM: 40% p = 0.94), and falls (IM: 29%; NM: 40% p = 0.74). No serious adverse events were reported.

Conclusion

In this limited sample size and trial, there were no significant differences in AE frequencies between the two CYP2C9 phenotypes IM and NM, suggesting that IGC‐AD1 has a safety profile that does not vary greatly, based on these two CYP2C9 polymorphisms. This analysis and initial results are important because the pharmacokinetics of THC are different for IM and NM. We continue to study these and other polymorphisms of CYP2C9 to understand their impact on AEs as it is crucial for personalized treatment strategies for the aged AD population.
Relationship between Anticholinergics and Cognitive Measures Important to the Diagnosis of Dementia
Authors: Keshk Noha , Khalil Hussein , Campbell Noll L
Published: January 2025

Background

Over half of ambulatory older adults are prescribed at least one anticholinergic medication to address a myriad of conditions, including incontinence, allergies, anxiety and insomnia. Longitudinal studies suggest an association between anticholinergic exposure and risk of dementia. Prior studies often rely on crude exposure measures (use vs. non‐use), lacking detailed analysis of anticholinergic effects across different cognitive domains indicative of dementia. This study adopts a more comprehensive exposure measure, considering dosage, duration, and strength, to explore its association with a spectrum of cognitive assessments commonly used in diagnosing dementia.

Method

A retrospective observational design was employed, analyzing one‐year electronic prescription data of 735 participants (age, 70.12±6.33; 75.2% Female; 88.3% White) recruited in two clinical trials (BrainSafe and R2D2 studies). Anticholinergic exposure was quantified using total standardized daily doses (TSDD). Outcomes were cognitive test scores of phonemic fluency, semantic fluency, symbol digit modalities, oral trail making (OTMT Part A and B), and hopkins verbal learning test (HVLT) collected at baseline. Generalized Linear models were applied to evaluate the impact of TSDD on cognitive performance, and Least Square means with Tukey’s adjustment were utilized to compare effects across anticholinergic subclasses. Subclasses compared were antimuscarinics, antihistamines, skeletal muscle relaxants and antidepressants. Covariates included in all the models are age, gender, ethnicity, educational level, and Charlson Co‐morbidity Index (CCI) Scores.

Result

Higher anticholinergic exposure was associated with poorer performance in semantic fluency test (p‐value = 0.0002) and OTMT‐A (p‐value = 0.0034). The comparison between anticholinergic subclasses showed that antimuscarinic only users performed significantly better in HVLT total recall test than those using a combination of antihistamines and antimuscarinics (p‐value = 0.0037), after adjusting for TSDD and other covariates. Both antihistamine users and antimuscarinic users exhibited worse outcomes than antidepressant users in semantic fluency (p‐value = 0.008 and p‐value = 0.005, respectively).

Conclusion

This study indicates an adverse dose‐duration effect of anticholinergic drugs on language, complex attention, executive functioning, and processing speed. Specifically, antimuscarinics users and antihistamine users demonstrated inferior performance in language, processing speed, and executive function compared to those on antidepressants. Additionally, combination use of antihistamines and antimuscarinics may lead to worse memory recall compared to the use of antimuscarinics alone.
Lingual Taste Neuroepithelium Precursor Hippocampal Implantation: A Novel Neurosurgical Intervention Hypothesis for Alzheimer’s Dementia
Authors: Ismail Youssef A. , Mohamed Hazim , El‐Satar Youssef M. Abd , Haitham Youssef , Walid Mohammad
Published: January 2025

Background

Lingual taste cells (LTCs) are taste buds' sensory cells that modulate gustation. This study’s aim is to assess whether it can be successfully implanted in hippocampus, modulating learning and memory deficits observed in Alzheimer’s Dementia (AD).

Methods

Retrospective trials on rodents i.e., rats and guinea pigs showed that LTCs have been detected to demonstrate similarities with neurons, releasing neurotransmitters, synapsing and even antagonizing pathologies associated with AD. We mapped how it possibly can enhance cognitive function and memory deficits. Previous literature will be demonstrated in this study supporting and/or opposing therapeutic perspective.

Results

LTCs are classified into type I (glial‐like), type II receptor, and type III presynaptic cells. Preliminary evaluation noted that only type III LTCs possess conventional synapses, and transmission of taste stimulus from type II to nerve fiber requires a non‐conventional pathway, by subsurface cisternae and specialized mitochondria and also suggesting neurotransmitters. Type II LTCs have been identified to secrete acetylcholine, and type III’s have also serotonin (5‐HT), γ‐aminobutyric acid (GABA), and noradrenalin. Type II LTCs have been also found to express taste receptor type 1 member 1 (T1R1) and 3 (T1R3), been involved in the detection of glutamate gustatory stimulus from afferent nerve fibers. In long‐withstanding AD patients, decreased intracellular and increased extracellular adenosine triphosphate (ATP), by ATP synthase deficiency and P2X7 respectively, have been evident. Purinergic signaling in LTCs is also evident, type II has been recognized to secrete ATP by Panx1 with taste stimulation, and hydrolyzed by nucleoside triphosphate diphosphohydrolase‐2 (NTPDase2), expressed on the membranes of type I LTCs, which constitute the majority of cells within each bud. ATP also activates sour‐sensitive type III LTCs via P2Y4, causing vesicular release of 5‐HT and GABA, which in turn induce negative feedback on ATP release from type II LTCs. Glutamate also activates ionotropic glutamate receptors, N‐methyl‐D‐aspartate receptor (NMDAR), in type III LTCs, secreting 5‐HT and inducing previous feedback.

Conclusion

LTCs possess set of characteristics that could possibly compensating learning and memory impairment in AD, even in neuroplasticity in autism spectrum disorder (ASD), multiple sclerosis (MS) and other neurodegenerative diseases.
Subtypes of Longitudinal Progression Trajectories Among Cognitively Impaired Older Adults with A+N+ Biomarkers: Trajectory Clustering Analysis
Authors: Park Sangyong , Byun Min Soo , Yi Dahyun , Ahn Hyejin , Chumin Evgeny J. , Jung Gijung , Kim Kyung Tae , Choi Hyeji , Kim Yoon Hee , Kim Yu Kyeong , Lee Yun‐Sang , Kang Koung Mi , Sohn Chul‐Ho , Lee Jun‐Young , Risacher Shannon L. , Sporns Olaf , Saykin Andrew J. , Nho Kwangsik , Lee Dong Young
Published: January 2025

Background

We investigated heterogeneities in clinical progression trajectories among cognitively impaired (CI) older adults who were positive for both beta‐amyloid (Aβ) and neurodegeneration biomarkers of Alzheimer’s disease (AD) using trajectory clustering analysis. We then compared clinical and neuroimaging variables across clusters with different clinical trajectories.

Method

CI older adults, consisting of individuals with mild cognitive impairment (MCI) or mild AD dementia were recruited from the Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer’s disease (KBASE). All participants underwent comprehensive clinical assessment, and multi‐modal neuroimaging including 11C‐PiB PET, 18F‐FDG PET, and MRI with resting‐state functional MRI (fMRI). Among them, participants who were both amyloid positive (A+) and neurodegeneration positive (N+), including those with hypometabolism and cortical thinning in AD‐vulnerable regions, as well as hippocampal atrophy, were included. A subset of participants underwent 18F‐AV1451 PET to measure brain tau deposition. Group‐based trajectory modeling (GBTM) using the Clinical Dementia Rating (CDR)‐Sum of boxes (SOB) measured at baseline and longitudinal follow‐up up to four years, was used to identify clusters among A+N+ CI participants.

Result

A total of 86 A+N+ CI individuals were included for the final analysis. A GBTM, based on longitudinal CDR‐SOB, identified two clusters with different trajectories: Cluster A (N = 54 [62.8%]) with slow progression and Cluster B (N = 32 [37.2%]) with rapid progression (Figure 1). No significant differences among age, sex, educational years, clinical diagnosis, global CDR, and APOE e4 carrier status were observed between the two clusters at baseline. These two clusters did not differ regarding global tau deposition and Braak Stages in a subset of participants (N = 34). However, at baseline, network segregation measure for the whole cortex and sensory‐motor network, and functional connectivity (FC) within the sensory‐motor network, differed between the two clusters after adjusting for age, sex, and education.

Conclusion

Our study identified two clusters with heterogeneous clinical progression trajectories even among CI older adults who exhibited both Aβ and neurodegeneration biomarkers. Further studies are necessary to elucidate the relationship between resting‐state FC measures and AD subtypes with different clinical trajectories.
Emotional valence in rapid automatized naming for early detection of Alzheimer disease
Authors: Lafenthaler Sandra , Höller Yvonne , Bergmann Jürgen , Kirschner Margarita , Frey Vanessa , Rossini Fabio , Trinka Eugen , Staffen Wolfgang
Published: January 2025

Background

Alzheimer disease (AD) worsens naming abilities as the disease progresses. It is argued that traditional naming tests, commonly used to aid in staging AD severity, may overestimate semantic abilities. This study explored whether a more challenging naming task can distinguish between healthy adults and those with amnestic mild cognitive impairment (aMCI) or mild AD.

Method

In a cross‐sectional study, 16 individuals with aMCI, 15 with mild AD, and 20 healthy controls (see Table 1 for demographic details) performed a rapid automatized naming (RAN) task with emotionally balanced object and action pictures. Naming performance was assessed by response times (RTs) and accuracy (error rates). Regression analyses examined the relationship between RTs/error rates and group, sex, age, education, anxiety, and depression. Receiver operating characteristic (ROC) curves evaluated the discriminative ability of the RAN task.

Result

Patients with aMCI and mild AD showed significantly slower RTs and higher error rates compared to healthy controls (all p‐values < .001). Naming performance was especially impaired for negative stimuli compared to positive and neutral ones in healthy controls (p < 0.001) and aMCI patients (p < 0.01). However, this effect was absent in the AD group. Regression analyses revealed significant associations between RTs/error rates and group (both p‐values < 0.001), but not for age, sex, education, anxiety, and depression (see Table 2). ROC analysis demonstrated moderate diagnostic accuracy in classifying mild AD versus healthy controls (AUC of 0.887 for RTs; AUC of 0.854 for error rates; see Figure 1), but not in classifying aMCI versus healthy controls.

Conclusion

The RAN task reliably detects variations in naming ability across different stages of cognitive decline associated with AD. We observed an inhibitory effect of negative valence on lexical retrieval processes, which appeared to be dependent on the degree of cognitive impairment, as it was no longer evident in our AD group. Further research with larger sample sizes is warranted. A significant limitation of our study is the lack of standardization of our visual stimuli. It is possible that the ratings for emotional valence derived from written words may not precisely reflect the emotional responses of our participants.
Kirrel3 is associated with disordered sleep in presymptomatic Alzheimer’s disease mice.
Authors: Singh Surjeet , Hadad Niran , Dunn Amy R , Kaur Harpreet , Kravchenko Julia A. , O'Connell Kristen , Hohman Timothy J. , Pack Allan I , Kaczorowski Catherine C.
Published: January 2025

Background

Sleep dysfunctions are highly comorbid with Alzheimer’s disease (AD), though often associated with later stages of AD, sleep disruptions have been noted to appear decades before the onset of cognitive symptoms. Here, we provide the first evidence that genetic factors interact with AD mutations to influence sleep behavior even before the onset of cognitive symptoms.

Method

To identify novel genetic factors underlying disordered sleep that precede cognitive decline in our AD‐BXD mouse genetic reference panel (n = 179 mice across 25 strains, 7‐months‐old), we first used sleep phenotypes measured in the PiezoSleep chambers and performed quantitative trait loci (QTL) mapping and discovered Kirrel3 as the novel gene candidate associated with disordered sleep. To further evaluate the causal role of Kirrel3 in susceptibility to sleep decline in the presence of Alzheimer’s disease pathology, we generated mice heterozygous for the Kirrel3 gene with and without the 5XFAD transgene, and then did sleep phenotyping in these mice (n = 153, 7‐months‐old).

Result

We found that in AD‐BXD mouse population sleep was highly heritable (h2RIx̄ = 22% – 71%) and varied by light/dark cycle, sex, and the presence of the 5XFAD transgene. This implies high heritability of sleep that lays within the heritability observed in humans. Using QTL mapping we then identified Kirrel3 as a novel genetic factor underlying disordered sleep that precedes AD‐related cognitive decline in mice. Further evaluation of sleep changes in Kirrel3 heterozygous mice revealed a significant reduction in total sleep and sleep during dark cycle, for both sexes but only in the presence of 5XFAD transgene.

Conclusion

Recent GWAS studies in humans nominated Kirrel3 (aka Neph2) as a potential AD risk gene and as a regulator of sleep behavior (independent of disease). In this study we identified Kirrel3 as a novel genetic factor contributing to disordered sleep that precedes cognitive decline in our AD‐BXD mouse genetic reference panel. Further, using Kirrel3 heterozygous mice, we provide, first evidence for the causal role of Kirrel3 in sleep regulation only in the presence of 5XFAD transgene.
Classifier algorithms to characterize various stages of Alzheimer’s disease based on analysis of circulating brain‐enriched and inflammation‐associated microRNAs
Authors: Kunwar Arzu , Ablordeppey Kenny K , Goldman Jacob , Mireskandari Alidad , Kumar Gyanendra , Kiefer Michael , Wolk David A , Sheinerman Kira S. , Umansky Samuil R.
Published: January 2025

Background

Minimally invasive diagnostic tools are crucial to characterize heterogeneous mild cognitive impairment (MCI), pre‐MCI, and Alzheimer’s disease (AD) cohorts. Our approach is based on targeted selection and quantitative analysis of microRNAs enriched in the brain and detectable in blood plasma. Here, we report the comparative analysis of 24 microRNAs comprising CogniMIR panel in 200 plasma samples with our Gen1 and Gen2 software algorithms towards distinguishing cognitively unimpaired (CU), MCI and AD cohorts.

Method

The expression of 24 brain‐enriched and inflammation‐associated microRNAs were analyzed in 200 plasma samples collected at the Univ. of Pennsylvania’s ADRC from 76 CU, 85 MCI, and 39 AD study participants. RNA from plasma samples was isolated using the MagMAX mirVana kit (ThermoFisher). microRNA concentrations were measured by qPCR using custom plates (Qiagen) pre‐plated with lyophilized miRCURY LNA‐based primers. Performance of classifier algorithms in differentiating clinically distinct groups was evaluated using Gen1 (self‐validation) and Gen2 (five‐fold cross validation) algorithms.

Result

AUC generated with Gen1 for differentiation of CU Aβ‐/APOE4‐ vs AD APOE4+ was 91%, while the mean of five‐fold cross validation AUC for the same cohort was 85%. Similarly, the self‐validation AUC for CU Aβ‐/APOE4‐ vs MCI Aβ+/APOE4+ was 82%, while the five‐fold cross validation AUC was 77%. Further, the self‐validation AUC for CU Aβ‐/APOE4‐ vs CU Aβ+/APOE4+ was 85%, whereas the AUC generated with the five‐fold cross validation for the same groups was 61%. These analyses demonstrate higher self‐validation performance metrics as compared to the five‐fold cross validation metrics. It is likely that self‐validation (Gen1), which utilizes the full sample set for the analysis, provides an overestimation of the classifier’s performance. Whereas, in the five‐fold validation (Gen2) 20% of samples are held back during the classifier training step and used for testing evaluation; this process is repeated five times with different withheld subsets, and the performance results are averaged out.

Conclusion

DiamiR’s Gen2 classifier algorithm offers a more reliable estimate of generalized performance compared to our Gen1 classifier. The data generated in this study further support the development of assays based on brain‐enriched and inflammation‐associated microRNAs detectable in the blood. A larger study is ongoing.
Liver‐specific changes in Ppp1r3b expression impact cognitive function and neuroinflammation in mice
Authors: Punnuru Varnitha , Wu Jacqueline , Rodrigues Amrith , Wilson Aisha , Mahmood Malaika , Lo Emily , Rader Daniel J. , Corder Gregory , Creasy Kate Townsend
Published: January 2025

Background

Cardiometabolic disorders represent a pressing public health challenge and confer heightened susceptibility to age‐related cognitive decline, including increased risk of developing Alzheimer’s disease (AD). There is a strong genetic component underlying risks for these conditions, and human Genome‐Wide Association Studies (GWAS) have associated the PPP1R3B genetic locus with both cardiometabolic dysfunction and AD. PPP1R3B protein is primarily expressed in liver hepatocytes, regulating liver glycogen metabolism. However, there is no clear understanding of its genetic association with AD or its role in the brain. We aim to investigate the molecular mechanisms underlying the association of PPP1R3B with AD and to clarify how liver metabolic dysfunction contributes to neurological symptoms.

Method

Hepatocyte‐specific Ppp1r3b deletion (KO), over‐expression (OE), and wild‐type (WT) control mice underwent baseline learning and memory assessments by Y‐maze and Novel Object Recognition, and blood samples were collected. Mice were aged to 1 year then underwent additional cognitive assessments and were subsequently euthanized. Brain, liver, and blood samples were collected for assessments of metabolic and neurological dysfunction.

Result

Hepatocyte‐specific Ppp1r3b KO mice displayed impaired spatial memory recall as early as four months. Mice with hepatocyte Ppp1r3b OE showed no differences in memory compared to WT mice. Brain section immunohistochemistry revealed KO mice exhibited increased activation of microglia in memory‐related brain regions compared to both OE and WT mice. WT mice had some activated microglia while OE mice had less, suggesting OE protection from age‐related microglia dysfunction. Lipidomics performed on brain, liver, and blood samples revealed significant changes in lipid species that suggest a connection between liver metabolic dysfunction and observed cognitive phenotypes.

Conclusion

Hepatocyte‐specific Ppp1r3b KO mice develop glucose intolerance and liver metabolic dysfunction that coincides with impaired memory and learning behaviors. After a year of aging, brains from KO mice have increased microglia activation, and altered circulating, brain, and liver lipid profiles that may contribute to the cognitive dysfunction. These data support the role of a liver‐brain axis connecting liver metabolic disease and cognitive impairment. Future studies aim to further clarify the role of specific lipids involved in cardiometabolic disease and AD.
Caregiver‐Driven Cognitive training (CDCT) – A feasible approach to dementia care in the Indian Population
Authors: Kanmani S Aparna , Kumar Keshav J , Sivakumar PT , Mathuranath PS
Published: January 2025

Background

Dementia care is incomplete without active caregiver involvement. Yet, existing cognitive interventions often overlook this crucial aspect. This study aims to develop and evaluate the feasibility of a Caregiver Driven Cognitive Training (CDCT) program in the Indian context, recognizing caregivers as essential partners in the care process.

Method

In Phase I, the CDCT Program was meticulously crafted through a comprehensive literature review and expert input, resulting in nine tailored cognitive tasks spanning attention, executive function, memory, and language domains. Caregivers, whether family members or professionals, were trained as co‐therapists with guidance from neuropsychologists. Phase II involved a pilot test (n = 5), using a quasi‐experimental research design (n = 5) by recruiting a dyad ‐ 1 patient with dementia (with a diagnosis of AD/FTD) + 1 caregiver. Eligible and consenting dyads were allocated (1:1) to the CDCT group or Treatment as usual (TAU) group and received intervention for five weeks. A thus modified CDCT was used in Phase III data collection (n = 32), utilizing the NIMHANS Neuropsychological Battery for Elderly (NNB‐E) and caregiver‐reported scales to assess outcomes assessed at three points: baseline, post‐intervention, and one month follow‐up

Result

The CDCT Program yielded encouraging results, with participants demonstrating improved cognitive function, particularly in attention, executive function, and memory, post‐intervention compared to a Treatment as Usual (TAU) group. Additionally, CDCT participants exhibited enhanced quality of life, increased independence in daily activities, and reduced symptom severity. Caregivers reported subjective improvements in confidence, error detection, self‐correction, communication, and insight. The program received high feasibility ratings from caregivers, indicating its suitability for the Indian population. The quantitative and qualitative evidence of the same shall be presented.

Conclusion

The CDCT program represents a paradigm shift in dementia care, emphasizing the active involvement of caregivers as co‐therapists. This approach not only enhances patient outcomes but also empowers caregivers, fostering a sustainable model of cognitive care tailored to the Indian socio‐cultural context.
Plasma Exchange reduces amyloid plaques and microglial activation in APP/PS1 mice at the advanced stage of pathology
Authors: Koerich Suelyn , Ramirez Santiago , Astudillo Natalia , Soto Claudio
Published: January 2025

Background

Amyloid plaques predominantly consist of extracellular aggregates of amyloid‐β (Aβ) peptide and represent a hallmark pathological feature of Alzheimer’s disease (AD). Evidence suggests that peripheral Aβ plays a crucial role in AD pathogenesis. Additionally, studies have indicated that Plasma Exchange (PE) with albumin replacement can slow the decline or stabilize AD symptoms. However, the factors that influence the mechanisms behind this are largely unknown. In this context, we have previously demonstrated the potential benefit of PE in reducing Aβ plaques in APP/PS1 mice at the early stage of AD pathology. Here, we tested the effectiveness of using PE monthly to decrease Aβ accumulation and alter brain inflammation in APP/PS1 mice at the advanced stage of pathology.

Methods

300µL of blood was obtained monthly from APP/PS1 mice from the jugular vein. Subsequently, the blood was centrifuged to remove the plasma, and the same volume was replaced with 5% albumin in saline and reinfused into the jugular vein (Figure 1). The procedure was performed four times between 11 and 14 months, and animals were humanely euthanized at 15 months. For histological analysis, brains were dissected after transcardiac brain perfusion. The right hemisphere was fixed for histology, and 10µm sections were stained with thioflavin‐S (Thio‐S) to analyze burden, number of plaques, and plaques size or incubated with anti‐Aβ antibody 4G8 plus Iba‐1 to analyze Aβ burden and microglia area. All images were analyzed using NIH Image J software.

Results

The data demonstrate that PE with a 5% mouse albumin solution effectively reduced thioflavin‐S‐positive amyloid burden and plaque size in the cortex and Aβ burden in the cortex and hippocampus. Additionally, the Iba‐1+ area in the hippocampus was significantly lower in PE‐treated animals than in controls.

Conclusions

These results suggest that PE reduced amyloid plaques applied at advanced stages of the disease and supports PE’s potential efficacy as an alternative non‐pharmacological intervention for attenuating the progression of AD pathology.
Emory Wisconsin Card Sorting Test and Trail Making Test B as Measures of Executive Dysfunction
Authors: Lincoln Gabrielle A , Pal Subhamoy , Reader Jonathan M , Rose Savannah G , Maher Amanda Cook , Giordani Bruno
Published: January 2025

Background

Wisconsin Card Sorting Test (WCST) and Trail Making Test‐Part B (Trails B) are commonly used neuropsychological measures of executive functioning. Previously, Trails B was found to be more sensitive than the WCST in predicting executive dysfunction. The Emory WCST (eWCST) was adapted to remove cards with multiple sort options and duplicate cards, creating a more direct measure of executive function. This study aimed to assess whether the eWCST was a better predictor of executive dysfunction compared to Trails B.

Method

Data from 864 participants enrolled in the longitudinal University of Michigan Memory and Aging Project within the Michigan Alzheimer’s Disease Center were analyzed (34.3% Male, 34.7% Black/African American). Participants completed baseline neuropsychological testing and other Unified Data Set activities and received a consensus diagnosis: Cognitively Normal, amnestic Mild Cognitive Impairment (aMCI), non‐amnestic MCI (naMCI), or dementia due to suspected Alzheimer’s disease (AD). eWCST total errors and Trails B completion time were standardized and converted to T‐scores. Mean test scores within each diagnostic group were compared via Welch 2 sample t‐tests. Analysis of variance (ANOVAs) were used to compare group differences in eWCST and Trails B performance. Multinomial logistic regression was used to predict cognitive diagnosis using eWCST and Trails B performance.

Result

Within the three impaired groups (aMCI, naMCI, AD), mean T‐scores were lower (e.g., less impaired) for eWCST compared to Trails B (p’s<0.01). There was no between‐test difference for the cognitively normal group. All four groups showed significant differences for Trails B scores while eWCST differences were seen between all groups except between aMCI and naMCI. Logistic regression results found Trails B performance distinguished AD from both MCI groups (aMCI OR = 0.97, p<0.001; naMCI OR = 0.98, p<0.01), whereas eWCST errors trended toward differentiating AD from aMCI (p = 0.06) but not naMCI.

Conclusion

Findings suggest Trails B completion time better differentiates AD from both amnestic and non‐amnestic MCI compared to the eWCST, similar to previous findings (Hammers et al., 2015). Determining the best predictors of cognitive diagnosis enables the selection of a concise testing battery to minimize participant burden and maximizing diagnostic utility, given the limited time and resources available at research centers.
Exploring cortical perivascular space as a biomarker in neurodegenerative diseases through optimized CSF‐only MRI at 7T
Authors: Demir Zeynep , Saib Gael , Talagala Lalith , Taylor Paul , Kwan Justin Y , Koretsky Alan
Published: January 2025

Background

Detecting changes in perivascular spaces (PVS) holds promise as a biomarker for neurodegenerative diseases. These spaces exhibit increased protein accumulation and dilatation in neurodegenerative diseases even preceding symptomatic stages. Advanced MRI techniques at high fields offer unparalleled clarity in visualizing these subtle structures. Notably, patients with Alzheimer’s disease (AD) show increased number of dilated PVS compared to healthy individuals in 7T MRI. While previous studies have primarily focused on white matter PVS due to their large size and visibility, cortical PVS remain relatively unexplored despite their potential diagnostic significance in diseases such as AD and motor neuron disease (MND). Recently, we optimized heavily T2‐weighted Turbo Spin Echo (TSE) at 7T, exclusively highlighting cerebrospinal fluid (CSF) signals, thus enabling the visualization of cortical PVS for the first time in healthy individuals. Leveraging this ability to detect cortical PVS, we aim to investigate cortical PVS in neurodegenerative diseases.

Method

Seven MND and 5 AD/ADRD patients enrolled in an NIH IRB approved protocol (NCT03225144), and 20 healthy controls were scanned using Seimens Terra 7T MRI with our optimized T2‐weighted TSE sequence (TR = 2430 ms, TE = 500 ms, ETL = 108, TA = 10 min) achieving an isotropic resolution of 0.5 mm (125 nl voxels).

Result

The optimized sequence achieved a CSF‐to‐tissue signal ratio of approximately 30:1. After thresholding above noise, it was possible to detect CSF volumes of 10 nanoliters per voxel. In controls, cortical perivascular spaces were detected with unique morphology and have a density of 1‐2% of grey matter with the highest density in insular region. In one control, the CSF images revealed extensive PVS‐like structures in a previously suspected cyst formation at the juxtacortical area (Figure 1). Furthermore, patients with MND exhibited multiple distinct cortical PVS, most pronounced in the motor cortex (Figure 2).

Conclusion

Our findings underscore the utility of CSF‐only MRI in uncovering intricate structural details of cortical PVS, which can be explored in neurodegenerative diseases. This non‐invasive imaging modality holds promise as a sensitive biomarker for neurodegenerative diseases, with ongoing efforts aimed at quantifying disease‐specific cortical PVS and elucidating clinical implications of changes on cortical PVS.
The integration of epigenomic and transcriptomic sequencing data reveals cell‐specific Bexarotene‐induced transcriptional activity in APP/PS1 mouse brain
Authors: Lu Yi , Saibro‐Girardi Carolina , Fitz Nicholas F , Lefterov Iliya , Koldamova Radosveta
Published: January 2025

Background

Treatment with the RXR‐specific agonist Bexarotene exerts neuroprotective effects in Alzheimer’s disease (AD) mouse models by improving cognition and increasing Aβ clearance. At the transcriptional level, ligand‐activated RXR receptors regulate gene networks linked to neural development, neuroinflammation, and metabolism. This study aimed to reveal the association between changes in chromatin architecture and transcriptional activity in the brain of Bexarotene‐treated APP/PS1 mice.

Methods

APP/PS1D9 mice were treated orally with bexarotene or vehicle (corn oil, DMSO 1%). Mouse brains were dissociated and used for cDNA library generation on a 10x Genomics platform for single‐cell resolution. Seurat pipeline was performed to resolve cell populations and for differential expression analysis, followed by GO analysis to reveal cell population‐specific transcriptional response to Bexarotene. Changes in chromatin architecture were evaluated by single‐cell ATAC‐seq. scATAC‐seq data were processed and integrated with scRNA‐seq using the ArchR pipeline.

Results

We present a single‐cell‐resolution map of transcriptomic and epigenomic changes in Bexarotene‐treated mice. We profiled transcriptional and epigenomic landscapes of 37,640 cells (scRNA‐seq) and 61,353 individual nuclei (snATAC‐seq) from 8 samples (4 Bexa and 4 vehicle controls). To predict candidate upstream regulators that may be shaping the chromatin accessibility landscape of brain cells following ligand activation of RXR and contributing to cell type identity and cell fate specification, we used chromVar. We discovered 67 high‐confidence candidate regulators that show strong correlations between TF enrichment and ATAC‐inferred expression and between ATAC‐inferred expression and RNA‐measured expression. Next, we used the integrated single cell RNA‐seq and ATAC‐seq data to identify cell type‐ and disease‐specific cis‐regulatory elements (CREs) and their target genes by correlating gene expression with chromatin accessibility across all nuclei in the dataset. We then asked if the differential gene expression we observed could be mediated by candidate CREs. The majority of the DEGs identified between Bexa and control nuclei had a linked peak in the same cell type where the gene was differentially expressed. An example is Apoe gene located in the Apoe/Apoc locus that was significantly upregulated by Bexa in microglia but not in astrocytes.

Conclusions

Results revealed that Bexarotene affected chromatin accessibility in microglia in correlation with Apoe expression.