bluuebunny/crossref_metadata_2025 huggingface dataset:
Activation of the muscle‐to‐brain‐axis reduces amyloid plaque accumulation and rescues behavioral deficits by enhancing synaptic integrity and neurotrophic signaling in a mouse model of Alzheimer’s disease
Authors: Taha Hash Brown , Birnbaum Allison , Matthews Ian , Aceituno Karel , Leon Jocelyne , Thorwald Max A , Godoy‐Lugo Jose A , Cortes Constanza J
Published: January 2025

Background

Alzheimer’s disease (AD) is associated with complex pathophysiology including synaptic dysregulation, compromised neurotrophic signaling, deficits in autophagic flux and neuroinflammation). Skeletal muscle regulates many brain functions relevant to aging, by activating the muscle‐to‐brain axis through the secretion of skeletal muscle originating factors (myokines) with cellular‐modifying, neuro and geroprotective properties. Our group developed transgenic mice that overexpress the skeletal muscle human Transcription Factor EB (TFEB), a master regulator of lysosomal‐to‐nucleus signaling, resulting in enhanced proteostasis and neuroprotection in a Tau mouse model. However, the precise mechanisms remain unknown. Therefore, we further validated these effects in an AD amyloid β (Aβ) mouse model and investigated the underlying mechanism.

Method

We crossbred female 5xFAD mice, carrying 5 AD familial mutations, with transgenic mice that overexpress human TFEB to create 5xFAD;cTFEB;HSA‐Cre (3FA) mice. At 4 and 8 months of age, we analyzed Aβ plaque accumulation through immunohistochemistry and conducted western blot analysis for multiple synaptic markers, growth factors, autophagic/lysosomal regulators, and myokines across the muscle‐to‐brain axis. We also performed a battery of neurocognitive tests (open field, the Barnes maze, and fear conditioning) at 8 months of age, when this model has previously been reported to demonstrate robust cognitive impairment.

Result

Skeletal muscle‐targeted TFEB expression reduced Aβ plaque accumulation in cortices of 4‐month‐old female mice. Furthermore, muscle‐TFEB expression altered synaptic‐associated gene transcriptional signatures in hippocampi, and rescued behavioral deficits in 8‐month‐old female 5xFAD mice. Western blots of cortex from 8‐month‐old female 3FA mice confirmed a rescue of several synaptic markers including SNAP25, synaptophysin I, synaptotagmin I and PSD95, neurotrophic factors such as BDNF and autophagic/lysosomal regulators such as Cathepsin D and B, prosaposin (PSAP) and saposin C. Levels of PSAP (a recently identified exercise‐responsive myokine) were also increased in skeletal muscle, plasma and cortices, suggesting that PSAP may act as a novel myokine involved in muscle‐to‐brain rescue mechanisms. scle, plasma and cortices of 8‐month‐old female mice, suggesting that PSAP may act as a novel myokine involved in muscle‐to‐brain rescue mechanisms.

Conclusion

Skeletal muscle directly regulates CNS function and health in the 5xFAD model regulating synaptic integrity, neurotrophic signaling and autophagic flux, potentially through release of CNS‐targeting myokines.
A harmonized, histology‐based protocol for selection of medial temporal lobe cortical subregion ranges on magnetic resonance imaging
Authors: Adams Jenna N. , Baumeister Hannah , Doan Thanh , Maass Anne , Mazloum‐Farzaghi Negar , Tran Tammy T , Wuestefeld Anika , Augustinack Jean , Ding Song‐Lin , Insausti Ricardo , Kedo Olga , Bakker Arnold , Berron David , Canada Kelsey L. , Carr Valerie A , Dalton Marshall Axel , Daugherty Ana M. , de Flores Robin , La Joie Renaud , Mueller Susanne G , Olsen Rosanna K , Stark Craig EL , Wang Lei , Wisse Laura E.M. , Yushkevich Paul A.
Published: January 2025

Background

The medial temporal lobe (MTL) has distinct cortical subregions that are differentially vulnerable to pathology and neurodegeneration in diseases such as Alzheimer’s disease. However, previous protocols for segmentation of MTL cortical subregions on magnetic resonance imaging (MRI) vary substantially across research groups, and have been informed by different cytoarchitectonic definitions, precluding consistent interpretations. The Hippocampal Subfields Group aims to create a harmonized, histology‐based protocol for segmentation of MTL cortical subregions that can reliably be applied to T2‐weighted MRI with high in‐plane resolution.

Method

Nissl‐stained sections from the temporal lobes of three human specimens (66‐90 years old; 2 female) were annotated by four expert neuroanatomists for the following MTL subregions: entorhinal cortex (ERC), Brodmann’s Area 35 (BA35; largely corresponding to “transentorhinal” cortex), Brodmann’s Area 36 (BA36), and parahippocampal cortex (PHC). On each histology section, the number of annotations and the spatial overlap of annotations were analyzed to determine the consensus of the anterior to posterior range of each structure. Gross anatomical landmarks, detectable on MRI and reliably corresponding with each range, were then selected to create an MRI ranging protocol. Feasibility of this MRI protocol was tested by two independent raters across four MRI scans (two healthy adults, two older adults), and agreement in range selection was assessed using Cohen’s kappa statistic.

Result

The proposed MTL ranging protocol is shown in Fig. 1, and corresponding histology data substantiating the protocol is shown in Fig. 2. MRI‐visible gross anatomical landmarks that reliably corresponded with the anterior or posterior range of each subregion on histology included the anterior‐most appearance of the collateral sulcus (Fig. 3A), hippocampal head (Fig. 3B), hippocampal body, and anterior calcarine fissure (Fig. 3C). This protocol demonstrated high feasibility when applied to MRI, with average kappa values of 0.75 ± 0.07, representing a “substantial” level of agreement of range selection.

Conclusion

Future directions include obtaining consensus on this protocol from the larger research community through a Delphi procedure, and expansion of the protocol to include slice‐by‐slice segmentation guidelines for full delineation. This harmonized, histology‐based protocol will facilitate critical research on MTL subregion vulnerability and their contributions to memory deficits in Alzheimer’s disease.
Studying protein interactions in human synapses using array tomography
Authors: Holt Kristjan , Taylor Lewis W. , McGeachan Robert I. , Simzer Elizabeth , Colom‐Cadena Martí , Sánchez‐Aced Érika , King Declan , Davies Caitlin , Hamby Mary E. , Horrocks Mathew H. , Lleo Alberto , Durrant Claire S. , Spires‐Jones Tara L.
Published: January 2025

Background

Synapse loss represents the closest correlate of cognitive decline in Alzheimer’s Disease (AD). Standard microscopy, due to increased diffraction of light with tissue depth, imposes a limit on axial resolution extending to ∼ 700nm. Array tomography (AT), developed by Micheva & Smith (2007), extends this axial limit via physical sectioning of resin‐embedded tissue into ribbons of 70nm contiguous sections that are serially imaged and reconstructed into 3D volumes; thus, allowing for nanometric synaptic puncta to be resolved at the mesoscale. Our group has, for the past decade, adapted AT to investigate synapse loss in human post‐mortem brain tissue from people who died with Alzheimer’s disease; other neurodegenerative diseases, and control subjects. We have published recent developments to AT that further improve X‐Y resolution, permitting in‐depth investigation of synapse‐protein interactions. Highlighted here are Förster Resonance Energy Transfer (FRET), Reconstruction Microscopy (dsSTORM) and DNA‐PAINT to assess interactions between Aβ, tau and protein binding partners, at the synapse. This work was funded by Cognition Therapeutics, Medical Research Council (MRC), UK Dementia Research Institute (UKDRI) and Race Against Dementia.

Method

Fixation, embedding, sectioning and immunostaining are detailed in work published previously by Kay et al. (2013). Advances to AT presented here include FRET, dsSTORM, DNA‐PAINT, and investigation of synaptic composition in organotypic human brain slices from surgical resections challenged with disease‐relevant proteins. Further, we report advances in our image analysis pipeline with scripts available to use on https://github.com/Spires‐Jones‐Lab.

Result

FRET‐AT has been used to profile over 1 million individual synaptic puncta in the temporal cortex and generates sufficient signal to indicate molecular interaction between Aβ and putative binding partners including TMEM97 in control (n = 9) and Alzheimer’s disease (n = 11) human brain tissue. FRET‐AT also suggests interaction between p‐tau Ser356 and synaptic terminals (n = 5/group). This, coupled with evidence of synaptic tau from dsSTORM/DNA‐PAINT, provides indirect evidence of disease progression via tau‐synapse interaction.

Conclusion

AT can be combined with other methodologies, allowing for in‐depth investigation of synapse‐protein interactions at a scale larger than afforded by electron microscopy (EM). This provides important insight into neurodegenerative disease and presents targets for potential therapeutics disrupting protein‐protein interactions.
Cryo‐EM structures of amyloid beta and tau filaments in down syndrome
Authors: Fernandez Anllely , Hoq Md Rejaul , Hallinan Grace , Li Daoyi , Bharath Sakshibeedu R. , Vago Frank S. , Ozcan Kadir A. , Newell Kathy L , Garringer Holly J. , Jiang Wen , Ghetti Bernardino , Vidal Ruben
Published: January 2025

Background

Down syndrome (DS) is the most common and best‐known chromosomal disorder in humans and the most frequent cause of intellectual disability of genetic origin, affecting about 6 million people worldwide. Individuals with DS may develop Alzheimer disease (AD) by age 55‐60 years, and sometimes as young as 40 years due to the triplication of the amyloid β precursor protein (AβPP) gene, which is located on chromosome 21. The AD neuropathological phenotype in DS includes amyloid‐β (Aβ) deposition (parenchymal and vascular) and neurofibrillary tangles comprised of tau protein. Aβ peptide species ending at 42 (Aβ42) are the main component of senile plaques and diffuse deposits in AD and AD in DS, while Aβ peptides ending at position 40 (Aβ40) are the predominant Aβ peptides found in both leptomeningeal and cortical vessels. Whether there is a difference in the structures of Aβ and tau filaments between AD and AD in DS, is unknown.

Method

We used cryo‐electron microscopy (cryo‐EM) to study the structure of Aβ and tau filaments extracted from the brains of two individuals with DS. Both individuals had been clinically diagnosed with AD, which was neuropathologically confirmed.

Result

We found two types of Aβ42 filaments (I and II) identical to those found in sporadic and familiar AD and two novel Aβ40 filaments (type IIIa and IIIb) that differ from those previously reported in AD. Tau filaments (paired helical filaments, PHFs, and straight filaments, SFs), were identical to those from AD and related diseases.

Conclusion

This cryo‐EM study emphasizes the similarities and differences between amyloid filaments in AD and AD in DS. The relevance of the structural differences between Aβ40 filaments in cerebral amyloid angiopathy in AD and DS is unknown. Further research is needed to determine whether type IIIa and IIIb Aβ40 filaments are unique to DS. Tau filaments (PHFs and SFs) were identical to those in AD, supporting the notion of a common mechanism through which amyloids trigger aggregation of tau. This knowledge is crucial for understanding AD in individuals with DS and assessing whether adults with DS could be included in AD clinical trials.
Validation that miRNAs altered in Alzheimer’s disease in human cerebrospinal fluid also function as miRNA biomarkers for Alzheimer’s disease in human plasma
Authors: Saugstad Julie A , Sandau Ursula S , Wiedrick Jack , McFarland Trevor J. , Galasko Douglas R. , Quinn Joseph F
Published: January 2025

Background

Alzheimer’s disease (AD) is the most common cause of dementia, and the fifth leading cause of death for those 65 and older. Brain changes in AD begin 10‐20 years before symptoms appear, yet markers for early brain changes are lacking. We discovered and validated miRNAs in human cerebrospinal fluid (CSF) that differentiate AD from Controls. However, as blood is a preferred biofluid for biomarker profiling, we evaluated 1) the intraindividual longitudinal stability of human miRNAs in plasma, then 2) expression of the CSF AD miRNAs in plasma.

Method

For the longitudinal stability study, blood was collected by venipuncture biweekly over 3 months from 22 donors who had fasted overnight. For the CSF‐plasma miRNA correlation, we obtained 320 donor‐ and date‐ matched CSF and plasma AD and Control samples from the AD Neuroimaging Initiative. We isolated total RNA from 1) 200 µL of platelet‐free plasma or 2) 250 µL of CSF and plasma. MiRNA expression was assessed by qPCR using custom TaqMan human arrays. All studies were approved by OHSU IRB00009707.

Result

1) For the longitudinal stability study, of 134 miRNAs amplified, 74 had high test‐retest reliability and low percentage level drift. Importantly, 13 candidate miRNA biomarkers for AD were stable in plasma over 3 months, and we found that hemolysis and tobacco use had the greatest impact on miRNA levels and variance. 2) For the CSF‐plasma study, the data revealed that individual plasma miRNAs are more predictive than CSF for AD, and a combination of plasma miRNAs are more predictive for AD than CSF. In addition, the highest‐probability plasma model for AD contains 2 complementary miRNAs, one positive (increased log fold change in expression), and one negative for fold change (decreased log fold change in expression).

Conclusion

These studies revealed plasma miRNAs that are stable over the 3‐month time, including candidate AD biomarkers. They also revealed miRNAs that are not stable over the 3‐month time, including miRNAs previously reported as biomarkers AD. In addition, the CSF‐plasma studies validated that AD CSF miRNAs differentiate AD from Controls in plasma, supporting the use of plasma for further development of AD miRNA biomarkers for clinical assays.
Investigating Alzheimer’s disease progression using a radiomics approach: The hippocampal‐amygdala border in FDG‐PET Scans
Authors: Rasi Ramin , Guvenis Albert
Published: January 2025

Background

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by memory loss and cognitive decline. Detecting AD early and tracking its development is essential for better management. This study delves into the potential of radiomics to identify the AD stages and monitor its progression using FDG PET images. The particular objective is to explore the potential of tracking progression using a reduced and meaningful set of imaging biomarkers at the borders of neighboring brain regions.

Method

Our study analyzed 18FDG‐PET scans from 931 participants across five stages of AD from the ADNI database. Focusing on 95 brain regions, we employed the PyRadiomics tool and eight feature selection techniques. The Hippocampus, Amygdala, and Entorhinal regions emerged as consistently important across these methods. We delineated the connecting regions between these regions using a sliding window approach and identified the best two features that help detect AD by the use of a random forest classifier. We then plotted the values of the two features to track progression.

Result

The connectivity area between the hippocampus and amygdala demonstrated superior efficacy for diagnosing AD progression. The two most important features for this region, namely “Shape Mesh Volume“ and SDLGLE ”GLDM Small Dependence Low Gray Level Emphasis" exhibited the highest classification capability for predicting AD versus control normal individuals (Accuracy = 0.77, sensitivity = 0.73, specificity = 0.81). We plotted these two features across deteriorating stages. The features mean values were able to demonstrate the incremental deterioration. The variance of the feature values increased for deteriorating cases.

Conclusion

We found that the small connection border between the hippocampus and the amygdala can serve as a biomarker to help us partially detect and interpret the presence and severity of AD. In particular, we found that changes in the volume and a measure called SDLGLE within this small border region were strongly linked to AD progression. The SDLGLE increase suggests a potential weakening of the tissue structure, possibly due to neurodegeneration. This preliminary finding highlights the power of a minimal set of radiomic features to not only detect and potentially explain the mechanisms behind AD progression but also to help track disease severity.
Revised Criteria for Diagnosis and Staging of Alzheimer’s Disease
Authors: Jack Clifford R.
Published: January 2025

The National Institute on Aging and the Alzheimer’s Association (NIA‐AA) convened three separate work groups in 2011 and a single work group in 2018 to create recommendations for the diagnosis and characterization of Alzheimer’s disease (AD). Several fundamental principles emerged from these efforts. These include, AD should be defined biologically, not by clinical syndromes. The disease is a continuum that is first evident with the appearance of brain pathologic changes in asymptomatic individuals and progresses through stages of increasing pathologic burden eventually leading to appearance/progression of clinical symptoms.

The Revised Criteria for Diagnosis and Staging of Alzheimer's Disease is the product of a work group sponsored by the Alzheimer’s Association. The revised Criteria update the 2018 Research Framework in response to major recent developments. First, since 2018, for the first time, treatments that target core disease pathology have received regulatory approval. Second, accepted biomarkers in 2018 were either CSF assays or imaging. Since then, plasma‐based biomarkers were developed, and some (but not all) demonstrate excellent diagnostic performance.

The objective of the work group was to propose objective criteria for diagnosis and staging AD to serve as a bridge between research and clinical care. These criteria are not intended to be specific clinical practise guidelines, but rather criteria for diagnosis and staging of AD that reflect current science.

Defining neurodegenerative diseases by their underlying biology rather than by non‐specific syndromic presentations has gained momentum in recent years. In addition, investigators increasingly recognize that across the spectrum of neurodegenerative disorders, the disease progresses along a continuum that begins with the appearance of the defining neuropathology while patients are asymptomatic. This symposium will examine the unifying theme of biologically based diagnosis and staging across neurodegenerative diseases.
Non‐clinical evidence for modulating synaptic CSF biomarkers by E2511, a novel small molecule TrkA biased positive allosteric modulator
Authors: Hiramatsu Naoki , Tomioka Takeyasu , Sasaki Kazunari , Saxena Satya , Wildsmith Kristin R , Sachdev Pallavi , Penner Natasha , Giorgi Luigi
Published: January 2025

Background

Cholinergic innervation is particularly vulnerable in many neurodegenerative diseases such as Alzheimer’s diseases. Nerve growth factor (NGF) plays a major role in the maintenance and function of cholinergic neurons, and a decrease in trophic signalling by NGF‐Tropomyosin receptor kinase A (TrkA) contributes to cholinergic and synaptic degeneration. E2511 is a novel small molecule TrkA biased positive allosteric modulator showing an increase in specific trophic signalling via direct binding to TrkA with a potential to recover and reinnervate damaged cholinergic neurons. We have shown that multi‐platform global proteomic approaches identified novel candidate PD biomarkers for E2511 using pre‐ and post‐treatment CSF samples from E2511‐A001‐005 (a multiple‐ascending dose study in healthy volunteers). Modulation of proteins related to cholinergic pathway, neurotrophin/Trk signalling and synaptic pathway was demonstrated for E2511 relative to placebo (CTAD2023, ADPD2024). Here we examined the mechanism of each biomarker changes by E2511 by non‐clinical study.

Method

The effect of E2511 on gene expression of candidate PD biomarkers identified using multi‐platform global proteomic approaches was assessed by qPCR in septum, one of the basal forebrain regions and where cholinergic nerves are localized, of normal SD rats treated with once‐daily oral E2511 for 14 days. The effect of cholinesterase inhibitor (ChEI) on gene expression was also investigated in rats treated with TID oral donepezil for 4 days.

Result

E2511 increased gene expression of several candidate biomarkers related to cholinergic pathway, neurotrophin/Trk signalling and synaptic pathway. In contrast, treatment with donepezil which resulted in an increase in ACh levels failed to elicit such effects on the candidate biomarkers. These results suggest that the increase in gene expression related to cholinergic pathway, neurotrophin/Trk signalling and synaptic pathway by E2511 is via NGF‐TrkA signal activation and E2511 has a mechanism of action distinct from ChEIs.

Conclusion

The mechanism of modulating novel candidate PD biomarkers in human CSF by E2511 was clarified by non‐clinical study using rats. The convergence of clinical global proteomics data and non‐clinical data have identified PD biomarkers for E2511 consistent with the proposed mechanism of action. Results are supportive of continued development of a E2511‐specific biomarker panel and suggestive of pathway activation in healthy volunteers.
Impact of Yoga in Transformation of Quality of Life of Alzheimer’s disease cases
Authors: Kaushik Meenakshi
Published: January 2025

Background

Alzheimer’s disease (AD) constitutes a formidable challenge, profoundly affecting the fabric of individuals' lives and intricately entwined with disturbances in their quality of life. This study embarks on a mission to unravel the transformative potential of a carefully crafted 12‐week yoga intervention, specifically tailored to address the multifaceted dimensions of quality of life. Our aim is to unravel the impact of a yoga intervention on their overall quality of life with AD and mild cognitively impairment subjects.

Method

A case control yoga interventional study was conducted on 30 subjects (male‐18 and female‐12) were enrolled from the department of neurology and neurocognitive assessments were done in department of Anatomy, AIIMS, New Delhi, India. All the participants, aged >60 years were recruited. The 12‐week yoga intervention entailed daily hour‐long sessions over 6 days. The multifaceted evaluation encompassed the Geriatric Depression Scale (GDS) including the evaluation of 15 questions and the Montreal Cognitive Assessment (MoCA) scale including for overall quality of life assessment with measuring language, memory, attention, visuospatial, naming, delayed recall, abstraction, and orientation for quality‐of‐life of the AD subjects.

Result

The AD subjects cohort exhibited statistically significant enhancements (P < 0.001) in quality‐of‐life scores (GDS & MoCA) pre and post Yoga intervention. GDS scores of 15 questions experienced a remarkable transition from pre‐yoga (8.36 ± 2.7) to post‐yoga (5.13 ± 3.0). While total MoCA scores ascended from pre yoga (18.65 ± 4.13) to post yoga (25.06 ± 6.3). MoCA scores of individual points pre yoga includes language (1.10 ± 0.2), memory (no points), attention (3.54 ± 1.8), visuospatial (4.0 ± 1.30), naming (2.16 ± 0.4), delayed recall (3.55 ± 0.25), abstraction (0.50 ± 0.0), and orientation (3.80 ± 0.18). MoCA scores of individual points post yoga includes language (2.16 ± 0.6), memory (no points), attention (4.60 ± 1.3), visuospatial (4.90 ± 2.50), naming (2.85 ± 0.75), delayed recall (4.85 ± 0.50), abstraction (1.40 ± 0.20), and orientation (4.30 ± 0.45).

Conclusion

This discerning study illuminates the transformative potential of a 12‐week yoga program, showcasing significant enhancements in the quality of life of individuals grappling with mild to moderate Alzheimer’s disease.
Assessing and illuminating the Impact of Ultra‐Processed Food Intake on Alzheimer’s Disease‐A Systematic Review and Meta‐Analysis:
Authors: Khalifa Mostafa A. , Elsead Jana Ahmed
Published: January 2025

Background

As there is currently no therapy available for Alzheimer’s disease, efforts are now focused on improving quality of life through various means, one of them is dietary intake. While several studies have demonstrated that consuming ultra‐processed food may contribute to the development of chronic diseases such as diabetes, there is insufficient evidence to directly link the consumption of ultra‐processed food to an increased risk of developing Alzheimer’s disease. However, it has been established that ultra‐processed foods have negative effects on biological mechanisms, such as oxidative stress and inflammation. Therefore, it is our role to clarify the impact of ultra‐processed food on Alzheimer’s disease

Method

Our systematic review will include all records in Medline and Web of Science up to 2024 that describe the relationship between ultra‐processed food and Alzheimer’s disease as determined by the NOVA classification system. There were no limitations placed on the earliest search date. Studies not classified by NOVA were excluded, and we adhered to the PRISMA guidelines. Our systematic review is currently in progress and is expected to be completed by the end of 2024.

Result

Our research yielded a total of 7560 observational studies. After removing 700 duplicate records, we screened the titles and abstracts of 6860 papers, excluding 6760. We then proceeded to review the full text of 100 papers, 10 of them met the inclusion criteria. A pilot study was conducted on 5 of these papers, revealing that all studies demonstrated a significant increase in the risk of developing Alzheimer’s disease among individuals with a high intake of ultra‐processed food.

Conclusion

Based on our preliminary findings, we suggest that a high intake of ultra‐processed food may contribute to the development of Alzheimer’s disease. Further clinical trials are needed to illustrate the association between ultra‐processed food and Alzheimer’s disease.
Association of insomnia with incident dementia – considering the competing risk of death
Authors: Sulkava Sonja , Haukka Jari , Paunio Tiina
Published: January 2025

Background

Sleep disturbances have been suggested as potential risk factors for neurodegenerative diseases. However, longitudinal studies on insomnia and dementia have mostly had too short follow‐up time to separate etiological risk factors from prodromal symptoms. Moreover, the impact of mortality as a competing risk has been overlooked. This study aims to clarify the relationship between insomnia symptoms and dementia incidence, considering the competing risk of death, within a large cohort from the Finnish population.

Method

The National FINRISK study, collected every five years from 1972 to 2012, included 63 013 Finns with baseline data. Approximately 12% (7638) developed dementia according to the health care registers. The follow‐up time varied from 7 to 47 years (mean = 25 years). We studied association of self‐reported insomnia (never, sometimes, often) at baseline with dementia incidence using in parallel Poisson model and Fine‐Gray model accounting for the competing risk of death. Additional analysis directly examined this competing risk. Study year, follow‐up time, sex, education, and cardiovascular risk factors were adjusted for. Sensitivity analyses included individuals with over 10 years of follow‐up.

Result

In the Poisson model, insomnia symptoms “sometimes” (IRR = 1.10[1.05‐1.16]) and “often” (IRR = 1.18[1.09‐1.28]) showed significant association with incident dementia and a dose‐response relationship. The results survived the sensitivity analyses. In the Fine‐Gray model, insomnia “sometimes” (HR = 1.07[1.02‐1.12) but not “often” (1.07[0.99‐1.16]) showed significant associations. Significant associations with the competing risk of death surpassing that of dementia were detected for both categories with IRRs of 1.12[1.09‐1.15]) and 1.32[1.27‐1.37]), respectively.

Conclusion

The findings from the Poisson model suggest that insomnia may serve as an etiological risk factor for dementia. However, the Fine‐Gray model, which focuses on the incidence of dementia in the presence of competing risk, did not show significant association with insomnia “often”. This suggests that individuals with insomnia face a higher risk of death before potentially developing dementia, implying that insomnia might not increase the true dementia incidence, despite being a risk factor. These results highlight the significance of including the competing risk of death in dementia epidemiological studies to fully understand the associations with risk factors.
Strategy Use on Digital Cognitive Assessment Differs Between Individuals with and without Elevated Phosphorylated Tau 217 in Cognitively Normal Older Adults: Results from the BioFINDER‐Brown Study
Authors: De Vito Alyssa N. , Joyce Hannah E , Lawrence Molly , Thompson Louisa I. , Caffery Phillip , Bernstein John P.K. , Salloway Steve
Published: January 2025

Background

New immunotherapies for Alzheimer’s Disease (AD) have shown promise in slowing disease progression and are most effective in the early stages of the disease. New, low‐cost methodologies are needed to detect early AD pathological change. Digital cognitive tools may represent a cost effective, efficient, and sensitive method to detect early AD‐related pathological change. The present analysis utilizes data from the BioFINDER‐Brown study to investigate whether individuals with and without elevated plasma phosphorylated tau‐ 217 (p‐tau217) demonstrate differential performance on digital cognitive assessments of spatial working memory (SWM) and paired associates learning (PAL).

Method

90 cognitively normal (CN; M
MMSE = 29.00) older adults (M
age = 63.36, 72.2% female, 95.6% white, 5.6% Latinx) completed a blood draw to evaluate plasma p‐tau217 and two brief tablet‐based digital cognitive assessments: SWM and PAL. as part of screening for the BioFINDER‐Brown study. Approximately 42% of the sample (n = 38) had elevated plasma p‐tau217. Independent samples t‐tests were used to determine whether performance on these measures differed between individuals with and without elevated p‐tau217. Lower scores on both measures are indicative of better performance.

Result

The total number of errors on the SWM was not found to differ between individuals with and without elevated plasma p‐tau217 (t(89) = ‐1.33, p = 0.093). However, differences in strategy use were found on the SWM task (t(89) = ‐2.11, p = 0.019); Individuals with elevated p‐tau217 had a less efficient strategy and required more trials to complete the task (M = 8.79 trials) than non‐elevated individuals (M = 7.65 trials). Group differences between those with and without elevated p‐tau217 on the PAL task approached significance (t(89) = 1.08, p = .075), with worse performance in those with elevated p‐tau217.

Conclusion

The preliminary findings suggest that group differences may exist for process scores (i.e., strategy use) but not overall performance on digital cognitive assessments between individuals with and without elevated plasma p‐tau217. Future research should evaluate 1) which digital assessments are most sensitive to AD‐related pathological change and 2) whether digital cognitive assessments can be used in conjunction with novel, affordable plasma biomarkers to improve early detection of AD.
Identifying diverse agitation profiles in dementia: Insights from longitudinal in‐home monitoring data
Authors: Bafaloukou Marirena , Schalkamp Ann‐Kathrin , Sandor Cynthia , Nilforooshan Ramin , Barnaghi Payam ,   CR&T Group
Published: January 2025

Background

Agitation, affecting 30% of people living with dementia (PLwD), presents with heterogeneity, diverse triggers, and variable responses to interventions. Subtype identification particularly in real‐world settings, thus, holds promise for more tailored care.

Method

We used longitudinal, in‐home monitoring data from 61 PLwD from the Minder study. 235 agitation episodes were reported, each describing the presence of agitation during an 8‐day window. Using sensor data, we derived 67 behavioural features related to activity, sleep, and physiology, normalised per PLwD to accommodate individual differences. Principal component analysis identified 14 components via Horn’s parallel analysis. We compared k‐means, Birch, Gaussian Mixture, and k‐Medoids clustering. Number of clusters was determined by Silhouette and Calinski Harabasz Score (chi). Two‐sided Welch’s t‐tests with Bonferroni correction (p<0.05) were used for feature comparison between subtypes. A logistic regression model was trained to predict subtypes based on 47 ambient parameters, with performance compared to a baseline model only incorporating age and sex.

Result

K‐means clustering achieved the highest scores with 2 identified subtypes (chi = 34.75, silhouette = 0.21) (Figure 1). 24 (63.16%) of the investigated sleep features were significantly different between the subtypes. No activity or physiological feature was significantly different. The first subtype (71 agitation episodes) was defined by more nocturnal awakenings (p−value = 2.60×10−5, t = 5.48), increased time spent out of bed (p−value = 5.85×10−11
, t = 8.34) and greater variability in bedtimes (p−value = 7.76×10−6
, t = 5.72). The second subtype (164 episodes) exhibited longer sleep durations (p‐value = 1.58×10−3, t = 4.44) and a higher ratio of deep sleep (p−value = 2.41×10−3, t = 4.28) (Figure 2). Ambient features could predict agitation subtype (F1‐score = 70.98%) better than baseline (p−value = 2.71×10−4
, t = 4.51) with lounge morning illuminance contributing most. Agitation subtypes were not stable within participants with 21 (34.43%) appearing in both clusters. The subtypes did not show differences in demographics.

Conclusion

Our analysis revealed two distinct behavioural agitation patterns, one associated with poor and one with good sleep, that can be predicted with ambient features. Tailoring agitation care to accommodate these subtypes could render treatment strategies more targeted and effective.
Examining domain‐specific cognitive associations with p‐tau217 in a cognitively normal sample: results from the BioFINDER‐Brown Study
Authors: Joyce Hannah E , De Vito Alyssa N. , Caffery Phillip , Salloway Steve , Thompson Louisa I.
Published: January 2025

Background

Emerging research on plasma Alzheimer’s disease (AD) biomarkers represents a new path towards earlier detection of AD pathology and potentially earlier intervention in cognitively normal individuals. Existing cognitive screening tools lack the sensitivity to distinguish between cognitively normal individuals with and without AD pathology. The present analysis investigated associations between performance on TabCAT digital assessment subtests and levels of plasma phosphorylated tau 217 (p‐tau217) in a cognitively healthy sample.

Methods

Participants were cognitively normal (tMoCA ≥ 16, MMSE ≥ 26) adults (ages 50‐80) screening for the Biofinder‐Brown Study (n = 172, 68.6% female, meanage = 64.3, meaneducation = 17.2). Participants underwent a blood draw for p‐tau217 analysis. A p‐tau level of .17pg/ml was considered elevated. The first 58 individuals screened completed the full TabCAT Brain Health Assessment battery consisting of four subtests: Favorites (episodic memory), Match (processing speed), Line Orientation (visuospatial ability), and Animal Fluency (semantic fluency). Our screening protocol was then abbreviated, and the remaining 114 participants completed only the Favorites subtest. We used Spearman correlations to test associations between p‐tau levels and cognitive performance and independent samples t‐tests to examine differences in cognitive performance by p‐tau status (Elevated vs. Not).

Results

Age‐, sex‐, and education‐adjusted TabCAT scores were not significantly associated with plasma p‐tau 217, except for animal fluency, which was negatively associated with p‐tau level (p = .029). TabCAT BHA Composite and MMSE also showed no associations with p‐tau level. None of the cognitive scores were able to distinguish between individuals with elevated and non‐ elevated plasma p‐tau. Individuals with higher education had significantly lower p‐tau (p = .05). There was no significant relationship between age and p‐tau level.

Conclusions

Semantic fluency (animals subtest) performance was significantly correlated with p‐tau217, such that higher fluency scores were associated with lower p‐tau levels. Performances in other cognitive domains, including episodic memory, showed no significant associations. These results suggest that semantic fluency may be more sensitive to elevated p‐tau217 compared other cognitive abilities in cognitively healthy samples. However, the restricted range of cognitive performance in this highly educated sample may have reduced our ability to detect subtle associations between cognition and p‐tau217 levels.
Comparative in‐vitro assessment of RV and KI loaded nanostructured lipid carriers (NLCs) individually and in combination on Neuro‐2a cell lines
Authors: Khan Saif Ahmad , Qamar Zufika , Singh Pirthi Pal , Pervez Suhel , Baboota Sanjula , Ali Javed
Published: January 2025

Background

Butyrylcholinesterase enzyme inhibitor (RV), and kinase inhibitor (KI), as combination therapy is considered more effective treatment approach for Alzheimer’s disease (AD). Hence, this combination has been chosen as a treatment strategy. So, this study emphasises the effectiveness of RV and KI in individuals and in combination on the viability of cell lines.

Method

The cytotoxicity of each drug namely RV and KI were screened on Neuro‐2a cell using MTT assay. The treatments of cells were done with different concentrations of individual drug ranging from 0.97 to 500 µg/ml. Afterwards, IC50 of RV and KI was established, and ratio of both drugs was optimized using combination index (CI), assessing their impact on cell line viability. So, optimised combination ratio (1:1) of RV and KI were loaded in the NLC which was formulated using modified emulsio‐sonication method and optimized using Central Composite Design. Simultaneously, individual drug was also loaded in the NLC using same method. Later the viability of cell line towards different formulations was studied and compared at different concentrations.

Results

On performing cell line studies, it was observed that there was dose‐dependent %cell viability of drug‐loaded formulation, individually and in combination. At concentration of 1.95 µg/ml, RV‐NLC and KI‐NLC showed there was significant increase (p<0.05) i.e., 25 to 30% in the viability of the cells when compared to RV suspension and KI suspension. On other hand, (RV‐KI)‐NLC showed the highest %cell viability at 500 µg/ml in comparison to the other NLC formulations.

Conclusion

RV‐NLC, KI‐NLC and RV‐KI NLC exhibited improved delivery of RV and KI into Neuro‐2a cell lines, resulting in higher viability efficacy in comparison to the suspensions of the drugs. However, (RV‐KI)‐loaded NLCs demonstrated even greater viability of the cell lines than the individual drug‐loaded NLCs. Therefore, dual drug‐loaded NLCs can be used as promising drug delivery system for achieving excellent therapeutic efficacy in the treatment of AD.
Exploring the Relationship Between Aβ and α‐Synuclein Pathologies: Longitudinal CSF Analysis and Cognitive Decline in the ADNI
Authors: Tosun Duygu , Hausle Zachary , Zobel‐Thropp Pamela , Shaw Leslie M. , Concha Luis , Singleton Andrew , Weiner Michael W. , Blauwendraat Cornelis
Published: January 2025

Background

AD and Lewy body (LB) disease are characterised by the pathological deposition of Aβ and α‐synuclein, respectively, and represent two of the most common forms of neurodegenerative diseases. Co‐pathologies are commonly identified at autopsy, suggesting crosstalk between Aβ and α‐synuclein during disease progression. CSF α‐synuclein seed amplification assay (SAA) has proven to be a sensitive and specific tool for detecting α‐synuclein seeds as evidence of LB‐pathology. We recently applied SAA cross‐sectionally to the ADNI cohort on the most recent CSF draw (Phase‐1) and looked at LB pathology prevalence (SAA positivity, SAA+) and its association with AD biomarkers and cognition. Here, we expand the ADNI CSF SAA analysis by incorporating longitudinal time‐points (Phase‐2), specifically focusing on SAA+ participants from Phase‐1. We examined the longitudinal dynamics of Aβ, α‐synuclein seeds, and p‐tau181, along with global and domain‐specific cognitive measures in stable SAA+, stable SAA‐, and those who converted to SAA+ from SAA‐.

Method

In longitudinal Phase‐2 study, 407 CSF samples from 222 participants across ADNI‐1‐3 phases were tested with SAA. Cox regression models were performed to assess factors increasing risk for biomarker positivity progression, separately for SAA, CSF Aβ42, and CSF p‐tau181. Additionally, factors contributing to clinical diagnosis progression (CU‐to‐MCI or MCI‐to‐Dementia) were assessed. Changes in cognitive decline rates accompanying SAA conversion were assessed.

Result

Among Phase‐2 participants, 34 individuals progressed from SAA− to SAA+ by their final CSF time‐point (“SAA Converters”; Figure‐1). Conversion to SAA+ was associated with APOE ε4 homozygosity, Aβ pathology (Figure‐2), and greater rates of cognitive decline after time of SAA conversion (Figure‐3). SAA status did not impact progression of either Aβ or tau phenotypes, or progression in clinical diagnosis (Figure‐2).

Conclusion

The findings of this longitudinal study demonstrated a significant association between Aβ pathology and onset of α‐synuclein pathology, as measured by SAA. Moreover, presence of SAA‐positivity was linked to accelerated cognitive decline, although greater risk for clinical diagnosis progression was associated with positivity in Aβ42 and p‐tau181 but not SAA‐positivity. These results highlight the interplay between Aβ and α‐synuclein and their impact on disease progression, emphasizing the importance of further investigation into their underlying mechanisms.
Target Engagement and Therapeutic Effects of AR1001, a Phosphodiesterase‐5 Inhibitor, in Alzheimer’s Disease Models
Authors: Xi Tianyang , Kim Fred , Kim Ju Won , Jung Jun‐Sub , Jeon Eunhae , Jo Hyunji , Nam Ju‐Suk , Song Dong‐Keun , Choung Jai Jun
Published: January 2025

Background

AR1001 is a specific inhibitor of phosphodiesterase‐5 (PDE5), which degrades cyclic guanosine monophosphate (cGMP). cGMP/cAMP response element‐binding protein (CREB)/brain‐derived neurotrophic factor (BDNF) signaling, which is critical for learning and memory processes, is disturbed in Alzheimer’s disease (AD). AR1001 at the oral dose of 30 mg QD is currently in a global Phase 3 clinical trial in early AD patients (NCT05531526). In this study we sought to determine if AR1001showed target engagement and therapeutic effects in mice at the equivalent dose to that being tested in humans.

Method

An AR1001 oral dose of 6 mg/kg QD in mice is equivalent to an oral dose of 30 mg QD in humans. For the target engagement study, AR1001 was orally administered at 3, 6, and 9 mg/kg QD to overnight‐fasted normal ICR mice for 1 week. Hippocampal levels of cGMP and BDNF 15 min after the last dose were measured by ELISA. To assess the therapeutic effects of AR1001, mice transgenic for familiar AD (3xfAD) were administered 3, 6, and 9 mg/kg QD for 3 weeks, followed by cognitive evaluation using passive avoidance and Morris water maze tests.

Result

In the target engagement study, AR1001 significantly increased hippocampal cGMP and BDNF at doses of 6 and 9 mg/kg QD. In the therapeutic effects study, all 3 doses of AR1001 significantly increased latency in the passive avoidance test compared to untreated controls, and recovered performance to levels of non‐transgenic comparator mice. In the Morris water maze test, AR1001 at 6 and 9 mg/kg significantly increased time spent in the target quadrant compared to untreated controls, and restored performance to levels of non‐transgenic mice.

Conclusion

We demonstrate target engagement of AR1001, a PDE5 inhibitor, by showing an increase in cGMP and BNDF levels in the hippocampus following daily treatment. AR1001 had pronounced effects in recovery of cognitive functions in a transgenic mouse model of AD at a dose equivalent to that being tested in the Phase 3 trial in early AD patients.
The Association between Brain Amyloid‐Beta Deposition and Postoperative Cognitive Dysfunction After Pelvic Organ Prolapse Surgery: A Pilot Study
Authors: Ackenbom Mary F , Royse Sarah K. , Davis Esa M. , Orris Steven R. , Vargas Laura G. , Butters Meryl A
Published: January 2025

Background

Research on the role of preclinical AD pathology (brain Aβ deposition) and postoperative cognitive dysfunction is limited. We aimed to explore the association between brain Aβ deposition measured via Pittsburgh Compound B (PiB) PET imaging and POCD. We hypothesized that brain Aβ deposition would be associated with POCD in older women at 2 weeks and 3 months after surgery.

Method

This is a prospective cohort study of women aged ≥60 years who underwent urogynecologic surgery. Exclusion criteria included cognitive impairment diagnosis, abnormal cognition screen (Modified Mini‐mental State Exam (3MS) score < 84), and history of stroke. Baseline clinical and sociodemographic data were ascertained by interview and chart review. Brain Aβ deposition (global PiB standardized uptake value ratio (SUVR)) was measured through PiB‐PET using a combined MR/PET scanner. Eight neuropsychological tests, assessing memory, executive function, attention, and language were administered preoperatively, 2 weeks post‐surgery and 3 months post‐surgery. POCD was defined as ≥1 standard deviation (SD) decline on ≥2 neuropsychological tests or ≥ 2 SD decline on ≥1 tests. The association between Aβ PiB SUVR and cognitive performance was tested with Spearman correlation coefficient. Linear regression models, adjusted for clinically relevant variables, were generated.

Result

There were 20 patients enrolled with mean±SD age of 71.3±5.4 years, 14.7±2.23 years of education, baseline 3MS score of 97.3±2.63, and 1.12±0.20 global PiB SUVR. There was 45% (n = 9) POCD incidence at 2 weeks postoperatively and at 24% (n = 4/17) POCD prevalence at 3 months postoperatively. Table 1 summarizes demographics and cognitive performance at each time point. There were no significant correlations between PiB and cognitive domain at each time point although there appears to be a trend towards association of Aβ deposition on Spearman correlations (Table 2; Figure 1). On exploratory linear mixed models, there were no significant associations between Aβ deposition and cognitive performance by domain, nor with POCD.

Conclusion

In this cohort of older women, 45% had POCD 2 weeks post‐surgery and 24% had POCD 3 months post‐surgery. Brain Aβ deposition was not associated with cognitive performance nor POCD. Studies with larger cohorts are needed to fully investigate this potential predisposing risk factor.