bluuebunny/crossref_metadata_2025 huggingface dataset:
Donepezil‐indolyl hybrids as multipotent cholinesterase/monoamine oxidase inhibitors for the potential treatment of Alzheimer’s disease
Authors: Krastev Kaloyan Yuliyanov
Published: December 2023

Background

Numerous laboratory and clinical studies have evidenced that MAO‐B inhibitors are a potential therapeutic approach for the treatment of AD. Thus, drugs used to inhibit activated MAO, including rasagiline, ladostigil and selegiline, may provide neuroprotection against AD by improving cognitive impairment, modulating the proteolytic cleavage of APP and decreasing levels of Aβ protein fragments that accumulate in the brain. Future clinical studies on MAO inhibitors for the treatment of AD may provide further insights into the mechanism of action of antioxidants as therapeutic agents for AD.

Method

Series of donepezil‐indolyl hybrids were prepared and characterized via highresolution mass spectrometry, 1H nuclear magnetic resonance and 13C nuclear magnetic resonance techniques. In vitro fluorometric assay (by Amplex® UltraRed reagent to detect hydrogen peroxide or peroxidase activity in biological samples or enzymes.) was used to investigate the activity of the synthesized compounds on both MAO‐A and MAO‐B isozymes as well as acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) by Ellman method with modifications.

Result

The biological evaluation of molecules 1‐30 showed that most of these compounds are potent, in the nanomolar range, and selective AChEI, with moderate and equipotent selectivity for MAO‐A and MAO‐B inhibition. In overall, compound 11, as a potent and selective dual AChEI, showing a moderate MAO inhibitory profile, can be considered as an attractive multipotent drug for further development on two key pharmacological targets playing key roles in the therapy of Alzheimer’s disease.

Conclusion

The pharmacological profile of compound 11, as well as the fact that it is a readily available compound in a short synthetic sequence, in good chemical yields, prompts us to select it as a lead‐compound for further optimization in our current research programme targeted to the preparation of new molecules for the potential treatment of AD.
The role of Ataxin‐2 in Drosophila models of C9orf72‐related FTD expressing dipeptide‐repeats of a physiologically relevant length
Authors: Harper Nikki S. , Prokop Andreas , West Ryan J. H.
Published: December 2023

Background

Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are two devastating, incurable, early‐onset neurodegenerative diseases, which share a clinicopathological spectrum of disease; linked by a hexanucleotide (GGGGCC) repeat expansion within the C9orf72 gene. Bidirectional sense and antisense translation of C9orf72 repeat RNA produces five dipeptide repeat proteins (DPRs) which aggregate within neurons, disrupting a range of cellular processes, including stress granule dynamics. It is hypothesised that under conditions of chronic cellular stress, stress granule dysregulation could augment the concentration of aggregation‐prone proteins, such as TDP‐ 43, leading to the formation of pathological inclusions, characteristic of FTD/ALS. Furthermore, inhibition of stress granule assembly through ataxin‐2 knockdown has been shown to be protective in in vivo TDP‐43 models.

Method

Previously, using Drosophila, we have established the first, and currently only, in vivo models expressing DPRs of a pathologically and physiologically relevant repeat length. Combining primary neuronal cultures and in vivo analysis of these models we investigate the effect of DPRs on stress granule dynamics and the integrated stress response (ISR), and establish whether inhibition of stress granule assembly, through ataxin‐2 knockdown, is protective against DPR toxicity.

Result

In select Drosophila DPR models we identify a role for ataxin‐2 in DPR‐dependent toxicity, observe stress granule accumulation, and identify potential therapeutic targets upstream in the ISR pathway, to mitigate DPR toxicity.

Conclusion

Comprehensive characterisation of the mechanism by which DPR toxicity affects the ISR and stress granule dynamics, is essential to establish therapeutic targets, such as ataxin‐2, for C9orf72‐mediated FTD/ALS.
Dynamic change of hierarchical core voxels of functional brain network in aging
Authors: Kim Hyun Joo , Kang Hyejin , Lee Dong Soo
Published: December 2023

Background

Many methods were developed to assess the functional intervoxel connectivity to better understand the brain function in individuals. In this study, k‐core percolation method was assessed to reveal the dynamic hierarchical structure on resting‐state fMRI (rsfMRI) on voxel‐level and the feasibility of the method was evaluated by applying it in the aging process.

Method

Total 150 individuals were included in this study; 38 young healthy individuals from Seoul National University (SNU), and 32 aged healthy, 22 mild cognitive impairment‐converter (MCI‐C), 26 mild cognitive impairment non‐converter (MCI‐NC), and 32 Alzheimer’s disease (AD) subjects from Alzheimer’s Disease Neuroimaging Initiative (ADNI) database. K‐core percolation method, a voxel‐based approach was applied to reveal the hierarchical structure of voxels in the brain. k
max‐core and coreness k values derived from k‐core percolation characterizing the time‐varying core voxels were visualized on various plots to display the dynamic hierarchical structure more intuitively. Analysis was done in both static, dynamic studies, and in positive, negative correlations. Coreness k value map on brain T1 MRI was generated for further evaluation of the distribution of coreness k values.

Result

Dynamic hierarchical structure of voxels on various plots revealed time‐varying change of k
max‐core voxels and coreness k values, reflecting the dynamic change of brain function in an individual, which was not fully reflected on static study. Dynamic flow pattern was different in positive and negative correlations, portraying the dynamic brain function in different neuronal networks. Asymmetric, unsynchronized distribution was deteriorated in the aging process on corneas k map and the asymmetry indexes of coreness k values revealed distinctive difference between young and aged healthy groups. The difference was more evident on dynamic study than static study. Also, as the age increased, coreness k values decreased, representing decreased connectivity in aging. However, asymmetry and decrease of coreness k values were not deteriorated by the severity of cognitive impairment.

Conclusion

Investigation of dynamic functional connectivity with k‐core percolation on voxel‐level revealed time‐varying change of hierarchical structure of voxels in the aging process. With this method, characteristics of dynamic hierarchical structure of an individual can be discovered and have shown possibility of further clinical application.
A Pilot Study Assessing Central Cholinergic Integrity in Individuals with Down Syndrome Using [18F]‐FEOBV PET and Basal Forebrain Cholinergic Anatomy
Authors: Russell Jason K , Conley Alexander C , Boyd Brian , Schlossberg Rachel , Rosenberg Adam J , Acosta Lealani Mae Y. , Shokouhi Sepideh , Newhouse Paul A
Published: December 2023

Background

Down Syndrome (DS) individuals express an extra copy of chromosome 21, which contains the gene for APP, producing a higher risk of developing Alzheimer’s Disease (AD). By 40 years old, amyloid plaques and tau neurofibrillary tangles are present in most individuals with DS, with AD progression risk being greater than 90%. In AD, the cholinergic basal forebrain projections degenerate and are known to play a significant role in cognitive deficits. We assess the integrity of the cholinergic system directly in individuals with DS utilizing [18F]‐FEOBV PET imaging.

Method

Seven individuals (19‐50 years old) with DS, not exhibiting AD symptoms on neuropsychiatric assessment, completed a FEOBV PET scan (6.5mCi dose) and MRI. Participants over 25 years old were recruited from the TRC‐DS study, where individuals undergo multimodal imaging assessment, including brain amyloid and tau PET imaging. A Brodmann area (BA) atlas from MRIcron and Freesurfer cortical and subcortical parcellations were registered to participants’ MRI scans and transformed to native PET space. Regional FEOBV uptake was normalized to supraventricular white matter generating standard uptake value ratios (SUVRs). Initial analysis assessed uncorrected associations between FEOBV SUVR, cholinergic basal forebrain volumes, Ch1‐3 (medial septum, vertical and horizontal limbs of the diagonal band of Broca and Ch4 (basal nucleus of Meynert), and age.

Result

Individuals with DS displayed region‐specific uptake comparable to FEOBV data in normal non‐DS individuals published by other groups. FEOBV SUVRs in the posterior cingulate cortex positively correlated with left and right Ch1‐3 and right Ch4 volumes (r>0.79, p<0.05), with a trend observed with left Ch4 volumes (r = 0.73, p = 0.064), while FEOBV SUVR in the posterior cingulate cortex displayed a trend towards a negative association with age (r = ‐0.73, p = 0.063). Additionally, trends to positive correlations were observed between basal forebrain cholinergic nuclei volume and BA5, 24, and 44. (r>0.67 and p<0.1).

Conclusion

Given comparable results to previously published data in normal non‐DS individuals, FEOBV PET imaging appears a valid modality for assessing cholinergic integrity in individuals with DS. Initial analysis suggests associations between specific cortical regions, cholinergic basal forebrain volumes, and age. Ongoing assessments will investigate associations between FEOBV uptake, cognition, and amyloid deposition.
Identification of new electrophysiological biomarkers of Alzheimer’s disease with fast periodic visual stimulation and electroencephalography
Authors: David Justine , Quenon Lisa , Hanseeuw Bernard J , Ivanoiu Adrian , Oziat Julie , Koessler Laurent , Rossion Bruno
Published: December 2023

Background

Despite Alzheimer’s disease (AD)’s prevalence in the population, its current biological and neuropsychological markers have many inconveniences (e.g., variability, invasiveness, cost …). The identification of new biomarkers is therefore essential to monitor and predict patients’ cognitive reserve and its evolution.

Methods

For this purpose, electroencephalographic recording (EEG) and fast periodic visual stimulation (FPVS) were coupled to obtain objective, sensitive, reliable, and easy‐to‐use evoked cognitive electrophysiological biomarkers (Rossion et al., 2020). FPVS consists in the presentation of visual stimuli at a defined frequency that produces EEG responses at the exact same stimulated frequency. 15 diagnosed AD patients (CSF‐positive for AD biomarkers) and 14 healthy controls matched in sex and age (Fig.1) were tested with a recently validated FPVS paradigm (Volfart et al., 2021) consisting in the presentation of different written words belonging to the same semantic category (cities) at a frequency of 4 words per second (base frequency: 4Hz). Words from a different semantic category (animal) appeared every 4 stimuli (i.e, oddball frequency: 1Hz). EEG responses at 1Hz reflect subject’s implicit semantic categorization ability. EEG signals were analysed in the frequency domain to compare the response amplitudes between the two groups.

Results

While healthy controls had a clear significant 1Hz EEG amplitude response over the left occipito‐temporal cortex (0.22 ± 0.26 µV, Z = 7.3, p<.001), this response wasn’t significant for AD patients (0.04 ± 0.11 µV, Z = 0.6, p>.05) (CTR vs. AD: F(1,17.3) = 4.88, p = .04) (Fig.2). There was also a significant difference between the two groups for the EEG response at the base frequency (AD: 1.13 ± 0.73 µV; CTR: 1.86 ± 0.92 µV; F(1,25.2) = 5.34, p = .03), reflecting impairment at more general visual word processing, independently of the semantic categorization. Patient’s base frequency response amplitude was significantly correlated with the score obtained at verbal fluency neuropsychological test (r = 0.73, p <.01). AD patients can be discriminated from healthy elderly participants with better accuracy using base frequency amplitude response (AUC = 0.74, p<.05) than oddball frequency amplitude response (AUC = 0.72, p = .05) (Fig.3).

Conclusion

These preliminary observations suggest that combined FPVS‐EEG of written words offers promising cognitive EEG biomarkers for AD patients.
Living with a person with young onset dementia ‐ spousal experience
Authors: Håkansson Tania , Karlsson Staffan , Svensson Hilda
Published: December 2023

Background

Being of working age, and simultaneously needing to help a person with young onset dementia has specific consequences for spouses. Research to date has been sparse concerning this specific group of spouses.

Method

Nine spouses were included and interviewed in the study. The interviews were analyzed using content analysis.

Result

The results showed that the spouses experienced an emotional impact that varied from feelings of loneliness, frustration, and worry, to peace of mind. They expressed that they used coping strategies, which included adopting a positive mindset, adapting to inabilities, adopting an avoidant approach, and finding ways to recharge. Spouses also experienced a call for support from informal as well as formal support.

Conclusion

The spouse of a person with young onset dementia goes through a range of emotional experiences and has resourceful ways of handling everyday life. The degree of support is varied which leaves more to be desired from healthcare providers.
Omega‐3 fatty acid derivatives associated with reduced risk of cognitive impairment in older adults
Authors: Nelson Kendra L , Mass Baba , Bateman Trey , Craft Suzanne , Voruganti Saroja
Published: December 2023

Background

Cognitive decline etiology is not fully understood, and many pathways undoubtedly play a role. Oxidative stress, inflammation, and other factors likely modify one’s risk. To understand metabolic underpinnings of cognitive impairment, untargeted metabolomics were performed, and the data analyzed.

Method

Untargeted metabolomics were conducted, using UPLC‐mass spectrometry, in 167 fasted plasma samples obtained from the Wake Forest Alzheimer’s Disease Research Center. Subjects without diagnosis of mild cognitive impairment or any form of dementia per the National Alzheimer’s Coordinating Center’s criteria were deemed cognitively normal (n = 102), and comparisons were made between these subjects and subjects diagnosed with cognitive impairment (n = 65). For each of the 1,627 biochemicals assessed, Mann‐Whitney U tests were performed to determine if differences existed between cognition groups. Further investigation was performed via multinomial regression stratified by APOE genotype and by BMI category (<18.5, 18.5‐24.9, 25‐29.9, 30+ kg/m2), adjusted for sex, age, race, and educational attainment.

Result

Mann‐Whitney U testing identified 101 metabolites significantly different among those with cognitive impairment versus those without. Adjusted, stratified regression abrogated most associations, though several metabolites continued to show notable differences between groups. Elevation of eicosenedioate was associated with increased odds of cognitive impairment for both normal weight (OR 1.62, 95% CI [0.93,2.82], p = 0.08) and overweight/obesity groups (OR 1.79, CI [0.88,10.51], p = 0.07), nearing statistical significance. In those with overweight or obesity, elevation of three omega‐3‐derived fatty acids were significantly associated with decreased odds of being cognitively impaired (OR 0.08‐0.13, CI[0.006,0.99), p = 0.009‐0.049). Five omega‐3 derived fatty acids were also significantly associated with decreased risk of cognitive impairment among those APOE genotype E3/E3 (OR 0.09‐0.21, CI [0.01,0.82], p = 0.01‐0.02). Several additional metabolites of interest, including alpha‐tocopherol (OR 0.06, CI [0.06,1.45]), ergothioneine (OR 0.27, CI [0.06,1.18]), and carotene diols (OR 0.08, CI [0.006,1.24]) approached significance in association with reduced cognitive impairment risk.

Conclusion

In untargeted metabolomics, metabolites across a range of pathways were found to be associated with cognitive impairment. Upon adjustment for key, many omega‐3 fatty acid‐ derived metabolites continued to be associated with reduced risk of cognitive impairment.
Modulation of hippocampal protein expression by a brain penetrant biologic TNF‐α inhibitor in the 3xTg Alzheimer’s disease mice
Authors: Jagadeesan Nataraj , Roules Grace Anne Chuli , Chandrashekar Devaraj V , Yang Joshua , Kolluru Sanjana , Sumbria Rachita K
Published: December 2023

Background

Alzheimer’s disease (AD) is a chronic neuroinflammatory condition and the proinflammatory cytokine, tumor necrosis factor alpha (TNF‐α), is a key mediator of neuroinflammation in AD. Biologic TNF‐α inhibitors (bTNFIs) can block cerebral TNF‐α if these large molecules cross the blood‐brain barrier (BBB). Thus, a model bTNFI, the extracellular domain of type II TNF‐α receptor (TNFR) which can bind to and sequester TNF‐α, has been reengineered to enable brain delivery by fusion with a mouse transferrin receptor antibody (TfRMAb). TfRMAb binds to the BBB TfR to deliver the TNFR into the brain via receptor‐mediated transcytosis. Previously, we found the TfRMAb‐TNFR to be protective in a mouse model of amyloidosis (APP/PS1) and tauopathy (PS19), and the aim of the current study was to investigate its effects in a mouse model that combines both amyloidosis and tauopathy (3xTg‐AD mice).

Method

Eight‐month‐old female triple transgenic 3xTg‐AD mice were injected intraperitoneally with saline (n = 11) or TfRMAb‐TNFR (3 mg/kg; n = 11) three days per week for 12 weeks. At the end of treatment, brains were processed for hippocampal immunohistochemistry and high‐resolution multiplex NanoString spatial proteomics using the GeoMx protein assays for neuroscience.

Result

TfRMAb‐TNFR treatment significantly reduced mature β‐sheet rich Aβ plaques and increased plaque‐associated microglial localization around larger plaques in the 3xTg mice. Further, TfRMAb‐TNFR increased plaque‐associated microglial TREM2 compared with saline‐treated 3xTg mice. From a total of 64 target proteins studied using spatial proteomics (comparing protein expression in the Aβ‐plaque bearing vs. plaque‐free regions), 39 (61%) differentially expressed proteins (DEP) were identified in the 11‐month‐old 3xTg mice, comprising of proteins related to neurodegeneration (10% of DEP), neuroinflammation (41% of DEP), amyloid (21% of DEP) and tau (10% of DEP) pathology, autophagy (10% of DEP) and other pathways (8% of DEP). TfRMAb‐TNFR treatment modulated proteins involved in Aβ clearance and processing, microglial function, RNA processing, and neurodegeneration. Majority of these proteins were relevant to microglial function (∼ 40%).

Conclusion

The study highlights that TfRMAb‐TNFR modulates several proteins involved in AD pathology and progression and largely suggests a microglia‐centric mechanism of action of this treatment in the 3xTg mice.
A 2.5D residual U‐Net for improved amyloid PET harmonization preserving spatial information
Authors: Shah Jay , Sohankar Javad , Luo Ji , Chen Yinghua , Li Shan , Protas Hillary D. , Chen Kewei , Reiman Eric M. , Li Baoxin , Wu Teresa , Su Yi
Published: December 2023

Background

Multiple amyloid tracers with varying characteristics pose a significant challenge to standardized interpretation and quantification of amyloid PET measurements. We previously demonstrated that a deep learning based 2D residual inception encoder‐decoder network (RIED‐Net) architecture improved harmonization of florbetapir (FBP) and PiB PET. However, 2D networks fail to capture spatial information among image slices and 3D networks with more parameters require larger datasets and powerful computation for training. Here, we investigate the performance of a 2.5D approach to further improve harmonization preserving spatial information.

Method

92 PiB‐FBP image pairs from Open Access Series of Imaging Studies (OASIS) were processed using established pipelines to extract regional standard uptake value ratios (SUVRs), mean cortical SUVRs (mcSUVRs), and SUVR images. A 2.5D U‐Net model with residual connections was implemented to learn the nonlinear mappings from the image pairs. Input to the network is a stack of 3 adjacent FBP slices along a particular view, providing extra spatial information about volumetric data. The output of network is a stack of corresponding 3 PiB slices. Multi‐slice output avoids averaging/blurry effects common in traditional 2.5D approaches. 10‐fold cross‐validation was implemented on axial, coronal and sagittal views separately to generate synthetic PiB SUVR imaging from FBP data. The average synthetic PiB image from axial, coronal and sagittal views was used for performance evaluation. Correlation was evaluated between the virtual PiB mcSUVR derived from imputed PiB vs. the real PiB mcSUVR and voxel‐wise between the imputed vs. real PiB SUVR images.

Result

The agreement of mcSUVR improved from r = 0.90 between PiB and FBP to r = 0.95 between synthetic and real PiB SUVR images (p<0.0001) in cross‐validation dataset. Additionally, imputed PiB SUVR images were visually more similar to real PiB SUVR images than FBP. Voxel‐wise correlation improved from 0.88 to 0.93 (p<0.0001).

Conclusion

Our proposed 2.5D Residual U‐Net for synthetic imaging was able to learn voxel‐wise nonlinear associations between FBP and PiB images. The model trained in 2.5D approach with additional spatial information, was able to significantly improve agreements of amyloid burden measurement from two tracers and generate PiB SUVR images that are visually more similar to real PiB SUVR images than FBP.
The role of group motivation in post COVID‐19 cognitive rehabilitation treatment
Authors: Alves Larissa Scoralich , Dutra Letícia Silva , Shigaeff Nadia
Published: December 2023

Background

Cognitive rehabilitation is an effective treatment for remission of cognitive symptoms resulting from various pathologies. In Long Covid, it is known that the occurrence of cognitive symptoms is a result of the action of the virus in the brain, but the effectiveness of this technique for such patients has not yet been described. Furthermore, there is evidence that rehabilitation has its effect enhanced when individuals are engaged in treatment. Thus, the present report aims to describe the experience of a group of patients with cognitive symptoms from Long Covid undergoing cognitive rehabilitation treatment and discuss the effect of their motivation.

Method

We performed a cognitive rehabilitation intervention for individuals with cognitive symptoms after COVID‐19 infection. Six patients were followed up in 20 sessions and motivation and engagement were observed based on attendance at sessions and from patients ́ speeches during the therapeutic process.

Result

The participants had an average of 80% attendance at cognitive rehabilitation sessions. They also reported on the important role that the group played in the treatment, such as understanding that they were not the only individuals who had difficulties, which motivated them to continue the treatment and not give up, despite the fact that it was long (20 sessions). It was also noticed that the encouragement between them, based on the supportive relationships that were formed in the groups, was important to keep them focused on recovery.

Conclusion

Participants in a group can identify with each other and realize that their difficulties are also present in others, which can help to face the difficulties of the treatment process and favor additional motivation. Thus, it is recommended that rehabilitation treatment be carried out in groups of patients. Lastly, interpersonal relationships among group members represent support and increased social support networks.
Cardiovascular and Metabolic Disorders in Mild Cognitive Impairment among Older African‐American Adults
Authors: Turaani Mohammad , Hanna Sophie , Adams Hannah , DiCerbo Loraine M. , Martens Nancy , Kero Katherine , Giordani Bruno , Kavcic Voyko
Published: December 2023

Background

Mild Cognitive Impairment (MCI) is one of the early predictors of Alzheimer’s disease (AD) and dementia. Assessing comorbidities associated with an MCI diagnosis is crucial not only for diagnostic accuracy but also for understanding the role of comorbidities for evident cognitive impairment. In this study we investigated the association between MCI (amnestic and/or non‐amnestic) and primary comorbidities of hypertension (HTN), hyperlipidaemia (HLD), and Diabetes Mellitus (DM).

Methods

We recruited 116 community‐dwelling older African American adults with subjective complaints (103 females, 13 males, mean age = 73.93, range = 65‐91) through the Wayne State Institute of Gerontology and Michigan Alzheimer’s Disease Research Center. Participants were consensus diagnosed as 57 healthy controls (HC), 32 amnestic MCI (aMCI), and 27 nonamnestic MCI (naMCI) based on NAAC Unified Data Set3 protocol. NIH Toolbox‐Cognition battery (NIHTB‐C) also was administered, but not used for consensus.

Results

Across all the participants, UDS3 forms noted 69% with hypertension (HTN), 56% hyperlipidaemia (HLD), and 28% Type II Diabetes. Among the normal group: 65% had HTN, 51% had HLD, and 28% had DM. Among those diagnosed with aMCI: 66% had HTN, 53% had HLD, and 34% had DM. Among naMCI: 81% had HTN, 63% had HLD, and 22% had DM. Comorbidities did not differ significantly across diagnostic groups. Regarding NIHTB‐C, significant ANOVA interactions did show that aMCI and naMCI with DM were lower in Fluid Intelligence than scores for controls with DM (p = .017). Also, as compared to controls with HTN, naMCI with HTN were lower on Fluid Intelligence (p = .024).

Conclusion

Our findings did not demonstrate differences in cardiovascular‐ or diabetes‐related comorbidities across MCI groups and controls in this group of community‐dwelling African Americans. However, DM and HTN, but not HLD, did affect the relationship among the diagnostic groups for fluid intelligence, a summary measure of higher cognitive functioning. This suggests that comorbid medical factors can affect cognitive performance, particularly for MCI groups. Further research is needed to fully understand the scope of risk factors influencing cognitive decline in African Americans. Further analyses will assess relationships between cognitive diagnoses, race, health conditions, and demographic risk factors.
Multiomics Blood Biomarkers Predict Alzheimer from predementia with High Specificity
Authors: Souchet Benoit , Michaïl Alkéos , Heuillet Maud , Dupuy‐Gayral Aude , Haudebourg Eloi , Pech Catherine , Berthemy Antoine , Billoir Baptiste , Autelitano François , Fortea Juan , Fowler Christopher J , Jayadev Suman , Lleo Alberto , Masters Colin L , Mouton‐Liger Francois , Paquet Claire , Braudeau Jerome
Published: December 2023

Background

The core criteria for mild cognitive impairment (MCI) or dementia due to Alzheimer’s disease (AD) is based in part on cognitive criteria and biological evidence of at least moderately frequent amyloid plaques (Albert et al., 2011; McKhann et al., 2011). They predict AD among cognitively impaired patients with high sensitivity but low specificity (Kokkinou et al. 2021; Martinez et al. 2017; Ritchie et al. 2014): up to 25% of amyloid‐positive patients would be misdiagnosed as AD while suffering from another brain disorder. Therefore, there is a need to develop new biomarkers with high specificity to facilitate earlier diagnosis, rapid therapeutic intervention and monitoring of clinical trials.

Method

Targeted mass spectrometry assays were developed for 81 blood biomarkers (45 proteins and 36 metabolites) pre‐identified in AAV‐AD rats (Audrain et al. 2018). 345 cognitively impaired participants (193 MCI and 152 demented) were collected in plasma at baseline and followed clinically from 1 to 13 years. Participants’ diagnosis (AD, or non‐AD) was established at the last clinical visit based on cognitive diagnosis standard for each brain disorder subtype. 82.9% of participants had available amyloid status at baseline, 61.9% were determined as amyloid positive. Each clinical group contained amyloid positive and negative participants. Predictive machine learning models for AD participants (n = 123 Prodromal AD, n = 126 AD dementia) among individuals with Non‐AD brain disorder (Non‐AD, n = 96) was developed. The training dataset (70%) aimed to select the biomarkers subset, train the algorithm, and define the cut‐off. External test dataset (30%) aimed to validate in blind the locked predictive model.

Result

With 19 blood biomarkers and age, the model predicted AD participants (n = 41 Prodromal AD, n = 43 AD dementia) from non‐AD participants (n = 25) with 92.0% specificity and 52.4% sensitivity during external validation (AUROC = 71.8%, p = 0.001). When amyloid status (CSF or PET) and this predictive ML model were applied in series, and participants positive for both were predicted as AD, 100% specificity and 39.7% sensitivity were achieved.

Conclusion

Multiomics blood peripheral biomarkers predicted AD patients among cognitively impaired population with low FPR. In combination with amyloid screening, these biomarkers could identify a nearly pure AD population.
Associations between NIH‐Toolbox Flanker test and the Picture Sequence Memory Test and multimodal Alzheimer’s disease biomarkers in cognitively unimpaired individuals
Authors: Samaniego‐Reinoso Melissa , Sánchez‐Benavides Gonzalo , López‐Martos David , Suárez‐Calvet Marc , Gispert Juan Domingo , Garcia Marina , Carboni Margherita , Kollmorgen Gwendlyn , Minguillon Carolina , Zetterberg Henrik , Blennow Kaj , Grau‐Rivera Oriol
Published: December 2023

Background

Alzheimer’s disease (AD) pathologic changes start years before cognitive symptoms appear; however, some early cognitive changes can be detected. We aimed to investigate the association between performance changes in two NIH‐Toolbox tests, Flanker test and Picture Sequence Memory Test (PSMT), and baseline AD biomarkers in cognitively unimpaired (CU) individuals.

Method

We studied 356 ALFA+ participants (mean [SD] age = 60.8 [4.72] years). The rate of cognitive change after 3 years was measured through delta scores (Follow‐up ‐ Baseline). Biomarker data included cerebrospinal fluid (CSF) β‐amyloid (Aβ) 42/40 ratio, phosphorylated‐tau‐181 (p‐tau), neurofilament light (NfL), and neuroimaging (MRI‐based cortical thickness AD signature, hippocampal volumes, and FDG‐PET‐SUVR (fluorodeoxyglucose ‐ positron emission tomography ‐ standardized uptake value ratio) metaROI) measures (Table 1). CSF Aβ40, Aβ42 and NfL were measured with the exploratory NTK robust immunoassays, while CSF p‐tau181 was measured using the electrochemiluminescence Elecsys® Phospho‐Tau (181P) CSF immunoassays (Roche Diagnostics International Ltd). AT groups were defined according to published cut‐offs (A+ Aβ 42/40 <0.071; T+: p‐tau > 24 pg/ml) (Milà‐Alomà et al., 2020). Baseline biomarker levels were used as predictors of cognitive change in linear models. Interactions and stratified analyses were also explored.

Result

AT groups significantly differed in the change in the Flanker Test (p = 0.002), driven by poorer performance in A+T+ vs A‐T‐ groups (p = 0.001) (Figure1). Higher cortical thickness predicted better longitudinal cognitive performance in the Flanker Test in the whole group (p = 0.020; β = 0.983). We found a significant interaction between AT group and FDG‐PET‐SUVR (p = 0.042), and the right hippocampal volume (p = 0.001), but no significant associations were observed in analyses stratified by AT (Figure2A). A negative association between right hippocampal volume and Flanker test change was observed in A+T‐ (p = 0.026) and A+T+ (p = 0.029) (Figure2B). No associations were observed between the PSMT and AD biomarkers (Figure 1).

Conclusion

Our findings support the hypothesis that executive function show a steeper decline than episodic memory in CU individuals with evidence of pathologic AD biomarkers levels. We observed a negative association between executive change and neuroimaging neurodegeneration markers in A+T‐ and A+T+ groups. This is in accordance with previous studies that found non‐linear associations in incipient AD pathology.
Associations between gait velocity parameters and brain amyloid‐β levels in cognitive normal older adults: a cross‐sectional analysis from the AGUEDA trial
Authors: Martín‐Fuentes Isabel , Solis‐Urra Patricio , Shekari Mahnaz , Ruiz‐Malagón Emilio J. , Rivas‐Navas Daniel , Sclafani Alessandro , Sánchez‐Aranda Lucía , García‐Rivero Yolanda , Gispert Juan Domingo , Erickson Kirk I. , Esteban‐Cornejo Irene
Published: December 2023

Background

Amyloid beta (Aβ) is a protein associated with dementia‐related pathologies such Alzheimer’s Disease (AD). The accumulation of Aβ in the brain leads to neurodegeneration, cognitive decline, and motor impairment. Those factors might appear years before the onset of apparent symptoms. There is evidence for an association between gait performance and Aβ levels. Previous studies showed that gait variability has been associated with amyloid in older adults with mild dementia. Moreover, reduced gait velocity, has been associated with greater brain Aβ accumulation in adults with spontaneous memory complaints. However, the nature of this relationship needs further investigation. Thus, the aim of this study was to examine the associations between gait velocity and gait velocity variability, and brain amyloid burden in cognitively normal older adults. Our hypothesis was that gait parameters might differently predict amyloid‐β levels.

Method

Eighty‐six cognitively normal older adults participated in this study. The Optogait system (Microgate,Italy) was used to assess gait parameters. Participants walked back and forth across a 5‐m long track made up of two bars set 1‐meter apart at their maximum walking pace for 5 minutes. The mean and coefficient of variation (CV) of gait velocity (m/s) were calculated as gait parameters. All participants underwent T1‐weighted MRI scans and [18F] Florbetaben amyloid‐PET (positron emission tomography) scans. PET images were quantified using the Centiloid (CL) method with a 12 CL cutoff for amyloid positivity. The associations between gait parameters and amyloid burden were assessed by individual linear regressions unadjusted and adjusted by age, sex, and education as covariates.

Result

Table 1 shows descriptive characteristics of the participants (22% Aβ+; 19 participants). Results showed a positive trend for an association between gait variability and amyloid burden (unadjusted: β = 0.21, p = 0.05; adjusted: β = 0.20, p = 0.08). There was no association between gait velocity and amyloid burden (unadjusted: β = ‐0.08, p = 0.42; adjusted: β = ‐0.08, p = 0.54).

Conclusion

Greater gait velocity variability, but not gait velocity, was marginally associated with higher amyloid burden. This result suggests that gait velocity variability might be an important marker of amyloid burden in cognitively normal older adults.
Levels of nicastrin species are increased in Alzheimer’s disease cerebrospinal fluid
Authors: Hernández‐Villamizar Luis Felipe , García‐Ayllón María‐Salud , Pérez‐González Rocío , Zetterberg Henrik , Blennow Kaj , Sáez‐Valero Javier
Published: December 2023

Background

Previous studies demonstrated that presenilin‐1 (PS1), the active component of the intramembrane γ‐secretase complex, can be detected as soluble heteromeric aggregates in cerebrospinal fluid (CSF). The γ‐secretase components, APH‐1 (anterior pharynx‐defective 1) and PEN‐2 (presenilin enhancer 2), co‐exist within these CSF complexes, while nicastrin is not detected. Nicastrin plays a role in the complex regulation, and substrate recognition, being the unique γ‐secretase component that is a Type I, single‐pass transmembrane protein. Here, we aim to characterize and compare the levels of CSF nicastrin in Alzheimer’s disease (AD) and non‐AD control patients.

Method

Nicastrin levels were analyzed in the CSF by western blotting using antibodies against the ectodomain and the intracellular domain to identify the different species of the protein that are present in human CSF. Core AD CSF biomarkers (Aβ1‐42, T‐tau, and p‐Tau) were determined. We also assessed whether CSF nicastrin and PS1 are present in extracellular vesicles (EVs).

Result

We show that nicastrin is present in CSF as full‐length species of 130, 110, and 105 kDa. We demonstrated that nicastrin full‐length species are increased in AD patients (n = 21) in comparison with non‐AD controls (n = 21), and that the levels of the three species positively correlated with T‐tau and p‐Tau levels in AD patients. Nicastrin was also found to be present in EVs, different from PS1.

Conclusion

The increased levels of nicastrin in the CSF of AD patients confirmed the potential alteration of γ‐secretase subunits during pathology progression. Further studies are required to evaluate whether these proteins could act as biomarkers to facilitate AD diagnosis and/or prognosis.
Risk Reduction: A Novel Brain Health‐focused Pathway for Patients with Mild Cognitive Impairment in Greater Manchester
Authors: Bradley Rosie , Fox Sarah , Dunne Ross , Leroi Iracema
Published: December 2023

Background

Studies have indicated that addressing lifestyle risk factors in people with mild cognitive impairment (MCI), may slow symptom progression or even reduce their risk of progressing to dementia. However, this important window for dementia risk reduction and brain health promotion is often missed in existing UK clinical pathways. This work aims to develop and pilot a brain health navigation pathway for individuals receiving an MCI diagnosis from a UK memory assessment service in Greater Manchester.

Methods

To date we have worked closely with people living with MCI to develop this pathway and all associated resources and materials. In January 2023 we developed and embedded a new role, which we refer to as a brain health navigator, within an existing memory assessment service team in one commissioning region of Greater Manchester. Starting in April 2023, patients identified in memory assessments as having MCI, will receive a referral to the brain health navigation service. With support from our navigator, all those who accept the referral will receive:

• A personalised brain health plan.

• Brain health and prevention information and signposting to local community and professional resources.

• A follow‐up appointment to assess the impact of this intervention on their wellbeing, skills, knowledge, and confidence in managing their own health.

Results

We will use a mixed methods approach to evaluate this work. We will collect Quantitative data describing the number of patients between April and June 2023 accepting a referral into the program, the number accessing community services; and wellbeing scores (using the Warwick‐Edinburgh Mental Wellbeing scale) pre‐and post‐intervention. Qualitative feedback will also be discussed including patient and clinical reflections of the service.

Conclusions

Our poster will discuss the feasibility and effectiveness of this model of patient support and how this approach may be expanded across the UK and beyond.
Preliminary evaluation of the digital maze test in relation to neuropsychological tests and AD biomarkers
Authors: Robinson Talia L , Fu Jessie Fanglu , Montenegro Grace A Del Carmen , Properzi Michael J , Klinger Hannah M , Penney Dana , Davis Randall , Sperling Reisa A. , Johnson Keith A. , Amariglio Rebecca E. , Rentz Dorene M.
Published: December 2023

Background

Digital cognitive tools may provide unique opportunities to detect subtle changes in preclinical Alzheimer’s disease (AD). Here, a maze test using a digital pen was evaluated in relation to AD pathological changes measured by amyloid‐β and tau burden.

Method

172 participants (CN = 161, MCI = 6, dementia = 5) completed the digital maze test, which included multiple “no‐choice” (NC; i.e., no decisions required to complete maze) or “choice” (CH) conditions (i.e., problem‐solving required to complete maze). Maze composite scores were calculated using the total test duration, total number of strokes, and total pen‐off‐page time for the NC and CH conditions separately. Global amyloid‐β PET was quantified with [11C]Pittsburgh‐Compound‐B (PiB) in available participants (n = 171). Entorhinal and inferior temporal tau were quantified with [18F]Flortaucipir (FTP) in available participants (n = 135). Participants completed a battery of traditional neuropsychological tests, with domain factor scores calculated for Executive Functioning (EF), Processing Speed (PS), and Memory (Mem). The associations between maze composite scores, global amyloid‐β, entorhinal tau, and inferior temporal tau were evaluated in separate linear regression models for both the total sample and CN only, correcting for age and education.

Result

In the total sample, CH‐ and NC‐composites were moderately correlated with PS and EF factor scores (r’s = .41‐.46) and less so with Mem factor scores (r’s = 0.2‐0.35). In the total sample, higher PiB was significantly associated with worse performance in NC‐composite (β = 0.543, SE = 0.249, p <.05), but not for CH‐composite (β = 0.467, SE = 0.259, p = .07). Similar results were observed in the CN only sample (NC‐composite: β = 0.468, SE = 0.237, p <.05; CH‐composite: β = 0.469, SE = 0.278, p = .09). PiB was not associated with EF or PS factor scores in the total sample or CN only. Entorhinal and inferior temporal tau were not significantly associated with any maze composites.

Conclusion

In a largely cognitively normal sample, performance on the digital maze test was associated with global amyloid‐β burden, particularly in the no‐choice condition, but not with tau. Digitally captured, nuanced performance in EF and PS may be related to early amyloid‐β pathology, but less so with downstream effects of tau.
Comparing the effectiveness of a brief observational study protocol versus a telephone call for Alzheimer’s disease prevention trial prescreening
Authors: Christiano Caitlyn , Moreno Stephanie , Anzai Juliana A. U. , Viera Andrea M Román , Palou Mariana Margarita , Kirn Dylan , Muniz Martha C. , Ramirez Jennifer , Papp Kathryn V. , Amariglio Rebecca E. , Chhatwal Jasmeer P. , Johnson Keith A. , Rentz Dorene M. , Selkoe Dennis J , McGinnis Scott M. , Marshall Gad A , Gale Seth A , Sperling Reisa A. , Yang Hyun‐Sik
Published: December 2023

Background

Many Alzheimer’s disease (AD) clinical trials suffer from a high screen‐fail rate despite telephone pre‐screening, leading to a significant drain of time and resources. Thus, more efficient prescreening methods are required. Here, we examined whether prescreening through a brief on‐site observational study protocol could reduce clinical trial screen failure rate compared to telephone prescreening.

Method

De‐identified screening data from the AHEAD study (AD prevention trial) at the Brigham and Women’s Hospital (BWH) Center for Alzheimer Research and Treatment were used. Participants were referred for the AHEAD study screen either from a brief observational study protocol (Davis Memory and Aging Cohort [MAC]) or a telephone screen. MAC collects medical history, Mini‐Mental State Exam, Quick Dementia Rating System, and blood samples through a 60‐minute on‐site visit. Telephone screen uses medical history survey and Telephone Interview for Cognitive Status. We compared AHEAD screen failure rate due to (1) clinical exclusion criteria and (2) (for those with no clinical exclusion) amyloid‐β biomarker criteria (plasma, PET) between MAC and telephone screen referrals, using Fisher’s exact test.

Result

There was no significant difference in age, sex, race, or ethnicity between the MAC and Telephone prescreen groups (Table 1, MAC n = 61, telephone n = 55). The odds ratio (OR) for clinical screen‐fail for MAC (n = 9 out of 61, 15%) compared to telephone (n = 20 out of 55, 36%) was 0.31 (95% CI 0.12 to 0.80, p = 9.7×10−3). The OR for biomarker screen‐fail for MAC (n = 49 out of remaining 52, 94%) compared to telephone (n = 27 out of remaining 35, 77%) was 4.7 (95% CI 1.0 to 30.1, p = 0.024). The OR for randomization from MAC (n = 3 out of 61, 5%) compared to telephone (n = 8 out of 55, 15%) was not significantly different from 1 (p = 0.11).

Conclusion

Our findings show that, compared to a telephone screen, an on‐site prescreen assessing cognition, medical history, and venous access may prevent clinical trial screen fails attributable to clinical exclusion criteria and save participant/staff time and resources. However, an unexplained higher biomarker screen fail rate for the on‐site group offset this benefit, requiring further investigation.
Reduced slow‐wave sleep is associated with greater tau accumulation and reduced cortical thickness in the temporal lobe
Authors: Stankeviciute Laura , Chhatwal Jasmeer P. , Levin Raina , Pinilla Valentina , Schultz Aaron P. , Redline Susan , Johnson Keith A. , Sperling Reisa A. , Kozhemiako Nataliia , Purcell Shaun , Djonlagic Ina
Published: December 2023

Background

Slow wave sleep (SWS) plays an important role in overnight memory consolidation and promotes overnight clearance of amyloid‐β and tau proteins. Reduced SWS has been associated with higher amyloid burden in CSF in preclinical stages of Alzheimer’s disease (AD). However, little is known about the relationship between SWS, tau burden and neurodegeneration in cognitively unimpaired (CU) adults. Thus, we investigated the relationships between slow‐wave sleep, regional tau PET (18F‐flortaucipir; FTP‐PET) and temporal lobe cortical thickness in cognitively unimpaired adults at risk of AD.

Methods

This study included 39 CU adults from the Harvard Aging Brain Study (mean age 74.6 years, 61.5% females) who underwent at‐home polysomnography (PSG; Compumedics Somte), tau PET (FTP‐PET, amyloid PET (PIB‐PET) and MRI (Table 1). We used separate multivariate linear regressions to assess associations between the percentage of slow‐wave sleep (SWS) and tau PET signal in the following ROIs: entorhinal cortex, inferior temporal cortex, and a temporal composite comprised of entorhinal, inferior temporal, middle temporal and fusiform cortices. Primary analyses were adjusted for age and sex. Secondary analyses also adjusted for global amyloid (PiB‐PET) burden. Lastly, we investigated the relationship between SWS and cortical thickness in the same ROIs, assessed using FreeSurfer v6.0.

Results

Lower percentage of SWS was associated with greater tau burden in entorhinal (p = 0.036), inferior temporal (p = 0.011), and temporal composite ROIs (p = 0.005). Associations between reduced SWS and greater FTP‐PET signal in the inferior temporal cortex and temporal composite ROI remained after controlling for PiB‐PET (p = 0.028; p = 0.017, respectively; Table 2). Additionally, lower SWS was associated with reduced cortical thickness in the entorhinal (p = 0.031), inferior temporal (p = 0.023) and temporal composite ROIs (p = 0.002) (Table 3).

Conclusions

Lower SWS in CU adults was associated with higher tau burden in regions of the temporal lobe that are commonly sites of early tau accumulation. These effects were independent of amyloid burden, suggesting disrupted sleep may lead to increased tau accumulation via an amyloid‐independent pathway. Importantly, lower SWS was also associated with reduced cortical thickness in temporal regions, suggesting that disrupted sleep may be tied to early AD‐related neuronal loss in the temporal lobe.