bluuebunny/crossref_metadata_2025 huggingface dataset:
Explainable Artificial Intelligence using Model Agnostic Methods in detecting Alzheimer’s disease
Authors: Varghese Abraham , George Ben , Sherimon Vinu , Ahmed Saad Salman
Published: December 2023

Background

Alzheimer’s disease (AD) results in cognitive dysfunction among older people, making their lives nearly impossible. Early intervention is likely to be the most effective way to slow its progression. Machine learning models are critical to determine whether a patient is demented or not at an early stage. But the most highly accurate models are non‐linear and less transparent, so the logic behind the predictions are not revealed. In this study, a neural network model was created, and two model‐agnostic methods were applied on it to understand the important features the model used to make predictions.

Method

A total of 25 features were selected from Oasis‐2 dataset of 150 participants. A feature selection is performed using KRUSKAL algorithm and 10 potential features were selected. A feed forward neural network model with sigmoid hidden neurons and softmax output neurons was created for classification of demented and non‐demented cases. Then, two model agnostic methods, LIME (Local Interpretable Model‐Agnostic Explanations) and SHAP (SHapley Additive exPlanations) were applied on the model to identify the features contributing to the prediction. LIME was used to generate a human‐readable explanation for a single prediction by approximating the behavior of the model locally around the instance being predicted. SHAP is a method based on the concept of Shapley values from cooperative game theory. It assigns a contribution value to each feature of the model, indicating how much that feature contributes to the final prediction

Result

Neural network resulted in an accuracy of 91.4%. It is found that Clinical Dementia Rating (CDR) is the most significant feature, followed by the normalized brain volume (nWBV). CDR is also observed to positively influence the detection of dementia cases, whereas the nWBV has a negative impact, which is also true clinically. Additionally, the contribution of each feature to the prediction is shown, which may assist in the evaluation of the model’s trustworthiness.

Conclusion

The goal of this research is to create a neural network model that is highly accurate and highly interpretable so that any non‐technical stakeholder can understand the reasoning behind the predictions. So, accuracy combined with interpretability increases the reliability of AD prediction systems.
Development and validation of a natural language processing system that extracts cognitive test results from clinical notes
Authors: Chen Jinying , Li Xuyang , Aguilar Byron J. , Shishova Ekaterina , Morin Peter J , Berlowitz Dan , Miller Donald R , O'Connor Maureen K. , Nguyen Andrew H. , Zhang Raymond , Monfared Amir Abbas Tahami , Zhang Quanwu , Xia Weiming
Published: December 2023

Background

Cognitive test results from electronic health records (EHRs) are key information for assessing the severity and progression of patients with mild cognitive impairment (MCI) and Alzheimer’s’ disease (AD). However, such information is often recorded in unstructured clinical notes rather than in an administrative database. We developed and validated a natural language processing (NLP) system to extract cognitive test results from clinical notes in the Veterans Affair (VA) Healthcare System.

Method

An NLP system was developed using regular expression‐based rules and Python to extract results for six tests that have been used most frequently in VA: Mini‐Mental State Exam (MMSE), Montreal Cognitive Assessment (MoCA), Saint Louis University Mental Status Examination (SLUMS), Mini‐cog, Boston Naming Test (BNT), and Benton Visual Retention Test (BVRT). The system extracted test results from each note in two steps: (1) searched a test name, or variations and abbreviation of the test name and, if successful, (2) searched the quantitative results (e.g., 12/30 for MMSE, 74th percentile for BNT) and/or descriptive results (e.g., “borderline impairment” for BVRT) within 5 words or one sentence before or after the test name. To balance the system performance and speed, we developed 3‐8 extraction rules per test based on a manual review of 30‐50 notes for each test. We further validated NLP performance on 6 held‐out datasets (50‐200 notes/test). We automatically sampled the development and held‐out notes by searching the test name and its variations/abbreviation to increase positive cases, i.e., notes that contained the above test results.

Result

The NLP system achieved 0.72‐0.92 predictive positive values (PPV), 0.96‐1.00 recall, and 0.83‐0.95 F1 scores on the validation test sets (Table 1). In addition, it demonstrated a scalable performance (processed 200,000 notes in 7 min), allowing an extraction of millions of notes from ∼1 million patients within hours.

Conclusion

Rule‐based NLP can extract cognitive test results with adequate performance and scalable capability for clinical notes from patients with MCI or AD within the VA Healthcare System.
AI‐based Digital Biomarkers for Mild Dementia Decision Support using Mobile Playful Exercises with High Adherence
Authors: Paletta Lucas , Pszeida Martin , Russegger Silvia , Orgel Thomas , Draxler Sandra , Berger Martin , Koini Marisa , Fellner Maria , Spat Stephan , Schüssler Sandra , Zuschnegg Julia , Strobl Bernhard , Ploder Karin , Hofmarcher‐Holzhacker Maria
Published: December 2023

Background

Early detection of cognitive decline and monitoring of cognitive functioning in mild dementia are fundamental for timely adaptation of lifestyle and intervention strategies. The development of digital dementia biomarkers through playful exercises with high adherence rate was a key objective of the national project multimodAAL (no. FFG 875345). The results of a study on computer‐based cognitive and physical training (CCPT) in persons diagnosed with mild Alzheimer’s disease (PwAD) are presented.

Method

Tablet‐PC‐based intervention was applied within 6 months in Austria, engaging PwADs living at home by means of playful multimodal training and activation (n = 11; female N = 8, male N = 3; age M = 76.6 / SD = 9.2 years, MMSE score M = 21.50 / SD = 4.41). PwADs interacted with a prototypical version of the BRAINMEE app that included a suite of cognitive exercises (puzzle, pairs, text gap filling) based on audiovisual information. The playful training app was introduced and assisted by mobile care professionals with weekly visits, however, PwDs played alone between these visits.

Result

PwADs applied training with high adherence, finalizing M = 72 (M = 32) digital exercises per day within the first (last) month of the study. Duration of using exercise type ‘outsider’(p = .028*) and ‘quiz’ (p = .001**), averaged about 2 week figures, each provided statistically significant correlations (Spearman) with MMSE test scores, as well as ‘spot‐the‐difference’ (p = .003**) with Trail Making Test A, ‘outsider’ (p = .005**) with Auditory Verbal Learning Test (AVLT), respectively. A neural network (Support Vector Machine, linear kernel, 11‐fold cross validation) using duration of use of ‘quiz’, ’outsider’ and ‘hearing’ (guessing animal sounds) as input data resulted in M = 2.16 absolute error in MMSE score estimation on test data.

Conclusion

The work outlined within the Austrian study on digital biomarker development indicates successful steps towards daily use of cognitive assessment using highly adherent playful training. The playful training app is applied in the European project MARA (no. FFG 886427) to enable continuous estimates of MCI’s mental state over time. The app was very well accepted by both PwADs and persons with MCI. It offers with its pervasive mental assessment tool a large potential for future long‐term monitoring in dementia prevention, early detection as well as in numerous dementia care services.
Transcriptomic and proteomic characterization of the locus coeruleus in a rat model of Alzheimer’s disease
Authors: Kelberman Michael , McCann Katharine , Hurst Cheyenne D , Duong Duc M. , Marriott Alexia , Seyfried Nicholas T , Weinshenker David
Published: December 2023

Background

The noradrenergic locus coeruleus (LC) is the first region to accumulate hyperphosphorylated tau pathology (p‐tau) in Alzheimer’s disease (AD). Using TgF344‐AD transgenic rats, which develop endogenous p‐tau in the LC prior to pathology in forebrain regions, we have recently demonstrated age‐dependent effects of p‐tau on LC firing rates. Specifically, LC neurons exhibit early hyperactivity followed by late hypoactivity. These changes in LC firing rates are coincident with the emergence of behavioral phenotypes that characterize different stages of AD (neuropsychiatric symptoms followed by cognitive deficits). Here, we sought to identify molecular mechanisms that could contribute to these changes using RNAscope and proteomics in TgF344‐AD rats.

Methods

32 male and female TgF344‐AD rats and wild‐type (WT) littermates aged 6 and 15 months were used for this study. Brains were flash‐frozen in isopentane on dry ice and stored at ‐80°C until being sectioned. At the level of the LC, the left hemisphere LC was collected with a 1 mm tissue punch. Punches of the cerebellum were taken as a control to verify LC enrichment in the brainstem punches. The right LC hemisphere was sectioned at 16 µm for processing with fluorescent in situ hybridization using the RNAscope Multiplex Fluorescent V2 Assay according to the manufacturer’s protocol. Probes included noradrenergic markers (tyrosine hydroxylase, norepinephrine transporter) and those that influence LC activity (α2‐adrenergic receptors, GRIA2, GRIN, ADCYAP1R1). Separately, tissue punches were submitted to the Emory Integrated Proteomics Core for label‐free quantification of proteins.

Results

RNAscope revealed no differences in transcript levels of noradrenergic markers at either age. Similarly, there were no differences in transcript levels of α2‐adrenergic receptors, GRIA, or ADCYAP1R1 at either age, or GRIN in 6‐month animals. We observed an increase of GRIN mRNA in 15‐month TgF344‐AD animals, suggesting an upregulation of excitatory neurotransmission.

Conclusions

Noradrenergic neuronal identity remains in‐tact up to 15 months of age, a timepoint when there is no LC cell death in these rats. We have also uncovered a potential compensatory mechanism to maintain LC activity in late stages of disease. Proteomics and RNAscope analysis of other markers that may affect LC activity are ongoing.
Spatial navigation performance differentiates Alzheimer´s disease biomarker positive and biomarker negative cognitively impaired older adults
Authors: Laczó Martina , Svacova Zuzana , Sedlakova Veronika , Svatkova Radka , Kalinova Jana , Vyhnalek Martin , Hort Jakub , Hornberger Michael , Laczó Jan
Published: December 2023

Background

Spatial navigation deficits including egocentric (body‐centered) and allocentric (world‐centered) navigation impairment are present early in Alzheimer´s disease (AD). We evaluated a potential of a realistic‐looking spatial navigation task to differentiate older adults with amnestic mild cognitive impairment (aMCI) who have positive AD biomarkers (AD aMCI) from those with negative AD biomarkers (non‐AD aMCI).

Method

Participants with AD aMCI (n = 24), non‐AD aMCI (n = 25), mild AD dementia (n = 14) and cognitively normal (CN) older adults (n = 35) underwent spatial navigation assessment in the virtual Supermarket task. Participants passively travelled through the supermarket and followed different routes to reach specific locations. In the final location, the participants had to indicate their starting location (egocentric heading) and their current location and final heading orientation on an aerial spatial map of the supermarket (distance from the correct location and allocentric heading, respectively, both measures of allocentric navigation).

Result

In the egocentric heading, the AD aMCI and mild AD dementia groups indicated their original starting location less accurately than the CN group (p<0.001) and with similar accuracy as the non‐AD aMCI group (p> = 0.219). The non‐AD aMCI group did not significantly differ from the CN group (p = 0.055). In the first allocentric task (distance from the correct location), the AD aMCI group and mild AD dementia groups indicated their positions on a paper aerial map of the supermarket with greater distance errors compared to the non‐AD aMCI group (p< = 0.013) and CN (p<0.001) groups. The non‐AD aMCI group had comparable performance to the CN group (p = 0.172). In the second allocentric task (allocentric heading), both the AD aMCI and mild AD dementia groups made more errors indicating final heading orientation than the non‐AD aMCI (p< = 0.040) and the CN (p<0.001) groups. The non‐AD aMCI group had worse performance than the CN group (p = 0.004). The sensitivity and specificity for discriminating AD aMCI and non‐AD aMCI was 72% and 71%, respectively.

Conclusion

Both, egocentric and allocentric spatial navigation tasks detected spatial navigation impairment in older adults with AD aMCI. However, only the allocentric tasks differentiated AD aMCI from non‐AD aMCI. The virtual Supermarket task has a potential to become a screening tool for early AD‐related spatial navigation deficits.
Tracking the intracellular itinerary of APP and de novo Aβ generation using click chemistry
Authors: Xu Isabella , Czerniewski Leah R , Xiao Qingli , Yan Ping , Benz Ann , Cashikar Anil G , Mawuenyega Kwasi G. , Crick Scott L , Mennerick Steven , Bateman Randall J. , Hanson Phyllis I , Lee Jin‐Moo
Published: December 2023

Background

Amyloid‐beta (Aβ), is generated by sequential cleavage of the amyloid precursor protein (APP) by beta‐ and gamma‐secretase. The intracellular sites of cleavage are unknown due to the lack of tools that can detect de novo Aβ production.

Method

Using unnatural amino acid (UAA) mutagenesis and click chemistry, a single fluorophore (magenta) site‐specifically binds to Aβ within the APP construct. The C‐terminus of APP is fused with the green fluorescent protein mClover, allowing for a distinction between full‐length APP and Aβ, as the uncleaved APP will appear white (magenta+green) from the bifluorescence, contrasting with the magenta of Aβ alone when separated from the green mClover C‐terminus. Live cells expressing the APP‐mClover construct (green) were incubated with cell‐impermeable tetrazine‐AlexaFluor 594 (magenta) at 4°C, which click‐labeled the UAA on Aβ on cell surface APP. The cells were then incubated at 37°C, resuming endocytosis of bifluorescent APP.

Result

After click‐labeling, the APP construct resides exclusively at the cell surface. Once warmed to 37°C, the intracellular bifluorescence increases with time, suggesting APP endocytosis (Fig 1). Using object‐based analyses, the magenta click‐label:green mClover ratio was determined from super‐resolution z‐stack images (Fig 2). The magenta:green ratio was lower in cells treated with gamma‐secretase inhibitor (GSI).

Conclusion

A qualitative and semi‐quantitative picture can be created of Aβ’s localization by following the separation of the bifluorescent signal into intraluminal magenta click‐label and membrane‐bound green mClover. This technology will be coupled with immunocytochemistry of subcellular markers, which will allow for further specificity on the location of Aβ travel within a cell, with regards to the endolysosomal pathway. Furthermore, this technology can be applied to examine Aβ within the unique cytoarchitecture of primary neurons which may help inform the design of new therapeutics in this cell type central to AD pathogenesis.
Genetic associations with neuropathological outcomes revealed a novel role in neuritic plaque formation
Authors: Lin Eugene , Lerch Melissa , Chan Kwun C , Biber Sarah , Kukull Walter A.
Published: December 2023

Background

Numerous genome‐wide association studies (GWASs) have been performed for the determination of genes and variants contributing to Alzheimer’s disease (AD). We hypothesized that it is important to explore whether the previously‐reported AD‐associated genes in GWASs can have neuropathological effects in the brain and can be employed as potential biomarkers for neuropathological outcomes such as neuritic plaque development. Neuritic plaques (also known as amyloid plaques) are extracellular deposits of the amyloid beta protein primarily found in the grey matter of the brain and are the most discernible neuropathological alterations observed in individuals with dementia.

Method

Here, we report the genetic association study of neuropathology data such as neuritic plaque measurements in an AD cohort at the National Alzheimer’s Coordinating Center (NACC) using a sample of 1,283 individuals. We acquired the genetic data from the Alzheimer’s Disease Sequencing Project (ADSP) which generated whole genome sequencing data through the ADSP Quality Control pipeline. We employed 18 loci where the associations of these loci with AD risk were validated by the recent GWASs. Analysis was obtained using a linear mixed model after adjustment for covariates including age at death, gender, the number of the APOE e4 allele (i.e., 0, 1, and 2), ancestry representative principle components (i.e., population structure), and a genetic relatedness matrix (i.e., a polygenic effect due to genetic relatedness among individuals).

Result

From our analysis, we generalized to the NACC cohort significant associations after Bonferroni correction with neuritic plaque measurements and one previously identified locus such as BIN1 on chromosome 2 (p = 4.65×10−5). Furthermore, we detected, at the significance level after Bonferroni correction, a novel locus for neuritic plaque formation that has not previously been reported: PICALM (or nearby LINC02695 or nearby RNU6‐560P) on chromosome 11 (p = 1.02×10−3). PICALM is a strong candidate for playing a role in neuritic plaque formation because deficiency in PICALM results in diminished amyloid‐β clearance.

Conclusion

The results from our genetic association study of neuritic plaque formation in the AD cohort underline the potential of utilizing neuropathology data to discover additional support for relevant loci being associated with AD across diverse populations.
Phonetic‐phonological disturbances of spontaneous speech in autosomal dominant Alzheimer disease due to A431E PSEN1 mutation
Authors: Preciado‐Baron Ana Karen , Figuera‐Villanueva Luis Eduardo , Gallegos Alfonso , Orozco Maribel , Berumen‐Ocegueda Isaac Enrique , González Victor J. Sánchez , Ringman John M , Matute Esmeralda
Published: December 2023

Background

Considerable cognitive research in Alzheimer Disease (AD) has focused on memory as it is often the primary symptom; nevertheless, in A431E PSEN1 mutation carriers in Jalisco, a rapidly language impairment and verbal fluency decrease during the disease is reported (Petersen‐Dumois, et al., 2020) though this deficit is not well‐characterized. The aim of this study was to identify and characterize phonetic‐phonological abnormalities in the spontaneous speech through different stages of A431E PSEN1 mutation‐related AD.

Method

Eleven symptomatic A431E PSEN1 mutation carriers, with a mean age of 42.54 years (DE = 4.17) participated in the study: five with Mild Cognitive Impairment (MCI), three with Mild Dementia (MiD) and five with Moderate Dementia (MoD). We used three language tasks: trip planning, picture description, and narrative discourse of a risky and happy moment of their lives which were recorded and transcribed. For each participant, we computed the frequency of phonetic‐phonological features: stuttering, unintelligible productions, phonological paraphasias, fillers and pauses (≥2 seconds) and then converted into percentages dividing the number of occurrences of each feature by the number of words used on the speech sample (for pauses, time in seconds). Then, we obtained the percentage mean of each feature per group.

Result

We analyzed a total of 134.65 minutes of speech sample. Regarding verbal fluency, words per minute (means) varied across the groups MCI: 85.55 (SD = 39.34); MiD: 128.56 (SD = 34.14) MoD: 67.80. (SD = 32.71). All phonological features were present, stuttering: MCI: 1.38%; MiD: 3.2%; MoD: 4.05%; unintelligible productions: MCI: .22%; MiD: .64%; MoD: .76%; phonological paraphasias; MCI: 0.002%; MiD: .01% MoD: .01%; fillers: MCI: 2.05%; MiD: .29%; MoD: 2.88%; number of pauses: MCI: .04%; MiD: .05%; MoD: .03%. and pauses average: MCI: 3.42 (SD = .62); MiD: 2.55 (SD = .03) MoD = 3.43. (SD: 1.61).

Conclusion

We found that A431E PSEN1 mutation carriers present phonetic‐phonological traits even in the earliest stage (MCI) and for three of them (stuttering, unintelligible productions, and phonological paraphasias) their frequency is greater the more severe the impairment (MoD). Stuttering is their most prominent feature. These disturbances in the spontaneous speech could be a phenotype trait of this ADAD mutation.
Developing a DNAm Surrogate to Predict Cognitive Functioning among Older Adults
Authors: Farina Mateo , Klopack Eric , Crimmins Eileen M.
Published: December 2023

Background

Blood‐based epigenetic measures are being developed and used to predict aging‐related health outcomes. Specifically, researchers have developed “epigenetic clocks” based on predictions of chronological age and age‐related health declines by DNA methylation. However, these markers are meant to predict aging per se and are not disease specific. Recently, scholars have developed “DNAm surrogates” to predict specific outcomes. This methodological technique has yet to be applied to cognitive functioning despite its potential to improve prediction of cognitive health in later life and provide insight into the role of biological aging.

Method

This study developed a novel DNAm surrogate measure for cognitive functioning (DNAmCogScore) based on an elastic net approach linking using 833,865 CpG sites predicting the Telephone Interview Cognitive Status score (TICS) available in the Health and Retirement Study (HRS), a nationally representative sample of older adults in the United States. Additionally, we evaluate the association of this DNAm surrogate and other neuropathology biomarkers. We used used ridge regression to create DNAmCogScore with 50% of the sample for training and 50% for testing (N = 2009 for each subsample). The Irish Longitudinal Study of Aging (TILDA) will be used for validation (results forthcoming).

Result

We find a positive association and modest predictive value between DNAmCogScore and TICS (see Figure 1, r = .4). Table 1 shows the strong associations with the DNAmCogScore and demographic characteristics. Overall, we find a strong positive coefficient between DNAmCogScore with attenuation after controlling for demographic characteristics, from 1.12 in Model 1 to .20 in Model 3, but remaining statistically significant throughout. Table 3 shows modest negative correlations between DNAmCogScore and NfL, pTau181, and GFAP (ranging from ‐.24 to ‐.36) and no correlation with AB42:40.

Conclusion

This study is among the first to create a DNA methylation surrogate measure of cognitive functioning. Our measure is associated with cognitive functioning, even after adjusting for key demographic characteristics. And it has the expected association with other more neuropathology biomarkers. Overall, it suggests that changes in DNA methylation may be a molecular‐level mechanisms by which biological aging impacts cognitive health, and this measure may provide useful prediction of cognitive impairment before the onset of symptoms.
PROTAC tau degrader for the treatment of Alzheimer’s disease and primary tauopathies
Authors: Zhang Lili , Lai Yen‐Ting , Lin Yih‐Shyan , Lee Mi , Lin Shih‐Han , Hsu Mia , Chai Yuan , Wang Xiaojuan , Gu Xiang , Zhang Chenhua , Ma Haou‐Tzong , Jang Ming‐Kuei , Tempest Paul
Published: December 2023

Background

Alzheimer’s disease (AD) is characterized by progressive decline of memory and cognitive functions. Accumulation of hyperphosphorylated tau is a pathological hallmark of AD and also plays a pathogenic role in disease progression. Proteolysis Targeting Chimera (PROTAC) technology enables the selective removal of a target protein by cellular ubiquitin‐proteasome system. Here we describe the characterization of tau PROTAC degrader developed at APRINOIA as a novel disease modifying treatment.

Methods

Tau degrader was synthesized by linking a proprietary tau binder from Aprinoia tau PET tracer program with a ligand of E3 ligase. The PROTAC mediated tau degradation was first evaluated in HEK293 cells expressing P301L tau, which develops tau oligomer and aggregates upon incubation with “tau seeds” from brain lysates of rTg4510 mice. The reduction of tau aggregates was measured using a HTRF based immunoassay. A similar seeding induced tau aggregation assay was established in primary neurons to confirm the degrader activity. Efficacy was further evaluated in rTg4510 mice following treatment with IV injection.

Results

PROTAC tau degrader reduced tau oligomer/aggregates in cellular models as well as in therTg4510 mice. Preliminary data suggests degrader is more effective in degradation of soluble tau oligomers in early stage of pathological tau development.

Conclusion

Tau PROTAC degrader generated from proprietary tau warhead can selectively decrease the oligomer/aggregated tau in both in vitro and in vivo models. Current effort is focused on optimization of ADME properties of tau degrader as a promising therapy for AD primary tauopathies.
Improving Early Recognition of Potentially Treatable Causes of Rapidly Progressive Dementia
Authors: Satyadev Nihal , Tipton Philip W , Dunham S Richard , Brier Matthew R , Geschwind Michael D , Morris John C , Graff‐Radford Neill R , Day Gregory S.
Published: December 2023

Background

Rapidly progressive dementia (RPD) includes patients with less than two years from the onset of cognitive impairment to incapacitation due to dementia. Although RPD is often associated with fatal neurodegenerative diseases, including early‐onset Alzheimer disease or Creutzfeldt‐Jakob disease, treatable forms of RPD are increasingly recognized. Early recognition of patients with potentially treatable causes of RPD is key to the timely provision of therapies required to achieve the best possible long‐term outcomes.

Method

155 patients with RPD were prospectively enrolled from February 2016 to August 2022 via two tertiary care centers. Etiologic diagnoses were independently assigned by two neurologists with good agreement (>90%). Causes of RPD were further classified as treatment‐responsive or nonresponsive, referencing the extant literature. Demographic, clinical, and paraclinical features associated with treatable causes of RPD were identified using stepwise multivariate logistic regression and validated with 5‐fold cross validation.

Result

87/155 patients (56.1%) had a potentially treatable cause of RPD, including autoimmune/inflammatory disease (n = 52, 59.8%), vasculitis (n = 13, 14.9%), primary psychiatric disease (n = 4, 4.6%), or nutritional deficiency (n = 4, 4.6%). Multivariable analyses identified seven features that were independently associated with treatment‐responsiveness: age‐at‐symptom onset (OR: 0.62 per decade, 95%CI: 0.42‐0.93), seizures (OR: 9.81, 95%CI: 2.84‐33.89), MRI suggestive of autoimmune encephalitis (OR: 23.08, 95%CI: 2.28‐233.40), CSF white blood cell count ≥10 cells/mm3 (OR: 32.24, 95%CI:5.80‐179.21), movement abnormalities (OR: 4.99, 95%CI: 1.76‐14.10), presence of disease‐associated tumor (OR: 13.82, 95%CI: 2.25‐85.11), and mania (OR: 18.47, 95%CI: 1.76‐193.61). Model performance was excellent (c‐statistic = 0.88, 95%CI: 0.82‐0.94; p<0.001): 71 patients (81.6%) with potentially treatable causes of RPD and 56 patients (82.4%) with non‐treatable causes of RPD were correctly classified (PPV = 85.5%; NPV = 77.8%).

Conclusion

Treatment‐responsive causes of RPD were common in our series. Younger age, seizures, movement abnormalities, or mania at presentation, and paraclinical tests suggesting inflammation (MRI or CSF) or tumor in patients with RPD should prompt consideration of treatable causes of RPD and initiation of treatment when indicated.
Abnormalities of hippocampal shape in idiopathic normal‐pressure hydrocephalus patients
Authors: Kang Kyunghun , Kim Jaeil , Yoon Uicheul , Park Ki‐Su , Jeong Shin Young , Lee Sang‐Woo
Published: December 2023

Background

We utilized 3‐dimensional, surface‐based, morphometric analysis to investigate hippocampus shape between 2 groups: (1) idiopathic normal‐pressure hydrocephalus (INPH) patients who had a positive response to the cerebrospinal fluid tap test and (2) healthy controls. The aims were (1) to evaluate INPH‐related structural abnormalities of the hippocampi and (2) to investigate relationships between hippocampal shape changes and gait disturbance in INPH patients.

Method

Forty‐eight INPH patients and 25 healthy controls were imaged with MRI, including 3‐dimensional volumetric images, for vertex‐based 3‐dimensional hippocampal shape analysis.

Result

Vertex‐wise shape analysis revealed significant bilateral deformation in patients with INPH compared with healthy controls after FDR correction. Both the left and right hippocampi were more elongated and narrowed in INPH patients than in the healthy controls. In both hemispheres, INPH patients demonstrated an upward bending of the middle and posterior hippocampus reflecting a bilateral vertical displacement from body to tail. Significant correlations were found between local shape deformity and the timed up and go and 10 meter walking tests (to a greater degree on the right than on the left). Bilateral inward deformations at the superomedial hippocampal tail and inferior hippocampal body were consistently associated with inferior performance across tests. Inward deformations at the right medial and lateral hippocampal head and right superior hippocampal body were also consistently associated with worse performance across tests.

Conclusion

These results suggest that patients with INPH have unique patterns of hippocampal shape changes. Our findings encourage future studies to elucidate the underlying mechanism of hippocampal morphometric abnormalities in INPH patients. Changes in overall shape may contribute to the distinctive gait abnormalities associated with INPH.
The Multidimensional Autonomy Scale: a new integrative tool for clinicians and preliminary results
Authors: Dethoor Anais , Hainselin Mathieu , Vaugeois Arthur , Duclos Harmony
Published: December 2023

Background

Autonomy is the ability to perform daily living actions within the environment where we live in (Dos Santos & Makdessi, 2010). It is a multidimensional concept, including 5 dimensions: psychological, functional, professional, digital and social autonomy (Dethoor et al., 2021). However, most studies mainly focused on functional autonomy. In this study we focused on social autonomy (SA) within an integrative approach.

Methods

We built an integrative tool, the Multidimensional Autonomy Scale (MAS), to assess the 5 dimensions of autonomy. The MAS includes 26 questions, divided in 5 sub‐scales for each autonomy dimension, for which we ask frequency and impact on daily life.

In this study, we focused on SA and its relation with empathy and theory of mind among young (18‐40 years), intermediate (40‐60 years), and elderly participants (60‐80 years). We assessed empathy and theory of mind with the Social‐SMAF and the Movie for the Assessment of Social Cognition (MASC).

Results

We found a decrease of theory of mind through aging, but no social autonomy change nor correlation between theory of mind and social autonomy.

Conclusion

The decrease of theory of mind might be correlated with other dimensions of social cognition or autonomy. Older participants seem to have less relationships, but not worse, even better sometimes. We encourage clinicians and researcher to assess autonomy within a multidimensional framework and go beyond functional autonomy only.
Transferable individual brain regional atrophy progression prediction model using structural connectome
Authors: Xiao Yu , Chong Joanna Su Xian , Kok Bing Cai , Ng Kwun Kei , Chen Christopher Li‐Hsian , Zhou Juan Helen
Published: December 2023

Background

Brain microstructure, as measured by diffusion MR imaging (dMRI), is an early biomarker of Alzheimer’s disease (AD) and has been previously demonstrated to predict whole brain atrophy and cognition. The network‐based neurodegeneration hypothesis posits that the onset of AD occurs within key vulnerable regions, whose network connectivity guides the spread of atrophy into new regions. Graph convolutional network (GCN) models can mimic this spread through its convolution process. Here we present a GCN‐based model to predict future individual nodal atrophy and disease progression across the AD spectrum using structural connectome.

Method

We analyzed 371 participants with baseline dMRI scans (154 cognitively normal (CN), 161 mild cognitive impairment (MCI), 56 AD) and longitudinal T1 scans (2.7±1.2 years) from the ADNI study. To predict annual nodal atrophy rates (126 nodes) from baseline structural connectivity (SC), we constructed a two‐layer GCN followed by multilayer perceptron (GCN‐MLP). Five‐fold nested cross‐validation and Optuna were used for hyperparameter tuning. We applied the trained GCN‐MLP model to predict future disease progression via transfer learning. GNNExplainer was used to identify the predictive SC features for atrophy or cognition. The GCN‐MLP model was validated in another independent dataset from Singapore (MACC) with 226 participants (61 CN, 112 MCI, 53 AD, follow‐up period of T1 scans (3.1±1.3 years)) using transfer learning.

Result

The proposed GCN‐MLP model predicted the annual rate of regional atrophy at the individual level in the main (R = 0.5407±0.0480; MAE = 0.0013±0.0001; EV = 0.2930±0.0516) and validation (R = 0.5323±0.0564; MAE = 0.0009±0.0001; EV = 0.2808±0.0559) datasets (Table 1; Figure 1). Graph edge SC of the target network contributed most to the atrophy prediction of its own network (Figure 2A&C). Nodal feature SC in hippocampus, striatum, and temporal network were major predictors of atrophy progression across all 10 networks (Figure 2B&D).

Moreover, the trained atrophy prediction model predicted changes of CDR‐Sum‐of‐Boxes (main: R = 0.8035±0.0492; validation: R = 0.5555±0.0404), ADAS13 (main: R = 0.7475±0.0725), MMSE (main: R = 0.7124±0.0509; validation: R = 0.6377±0.0616), and MOCA (validation: R = 0.6764±0.0314).

Conclusion

We developed an accurate and interpretable individualized longitudinal nodal atrophy and disease progression prediction model in the AD spectrum by leveraging the comprehensive properties of whole‐brain structural connectome. The approach was validated in both Caucasian and Asian datasets, highlighting its generalizability and interpretability.
Alzheimer’s disease risk gene BIN1 modulates neural network activity through the regulation of L‐type calcium channel expression in human induced neurons
Authors: Costa Marcos R
Published: December 2023

Background

Bridging Integrator 1 (BIN1) is the second most important Alzheimer’s disease (AD) risk gene after APOE, but its physiological roles and contribution to brain pathology are largely elusive. In this work, we tackled the short‐ and long‐term effects of BIN1 deletion in human induced neurons (hiNs).

Method

We generated isogenic BIN1 WT, KO and HET human induced pluripotent stem cells (hiPSCs), which were differentiated into hiNs grown in 2D and 3D (cerebral organoids) cultures. We also developed a novel protocol for the generation of highly pure glutamatergic neuron cultures, allowing the study of cell‐autonomous roles of BIN1. Using these three different systems, we probed neuronal electrical activity using MEA electrophysiology and gene expression alterations in individual cell types using snRNA‐seq.

Result

We show that BIN1 depletion leads to specific transcriptional alterations in glutamatergic neurons involving mainly genes associated with calcium homeostasis, ion transport and synapse function. We also show that BIN1 regulates calcium transients and neuronal electrical activity through interaction with the L‐type voltage‐gated calcium channel Cav1.2 and regulation of activity‐dependent internalization of this channel. Treatment with the Cav1.2 antagonist nifedipine partly rescues neuronal electrical and gene expression alterations in BIN1 knockout hiNs.

Conclusion

Our results indicate that BIN1 loss‐of‐function impairs calcium homeostasis at least in glutamatergic neurons, potentially contributing to the transcriptional changes and neural network dysfunctions observed in AD.
Amyloid β‐specific T cell response is enhanced in individuals with mild cognitive impairment
Authors: Chiu Yen‐Ling , Hung Ruo‐Wei , Fang Chuang Yi‐
Published: December 2023

Background

Neuroinflammation is a key process in initiating and propagating Alzheimer’s disease (AD). Even though it is widely known that the deposit of amyloid plaques and CSF levels of amyloid distinguishes patients with AD or mild cognitive impairment (MCI) from cognitively normal (CN) individuals, little is known about the role of amyloid‐specific immune response in cognitive decline.

Method

Using a polyfunctionality assay typically used for detecting virus‐specific T cell responses, we tested participants from the Epidemiology of Mild Cognitive Impairment in Taiwan study (EMCIT) and the Taiwan Precision Medicine Initiative of Cognitive impairment and dementia (TPMIC) study to compare the amyloid‐specific T cell responses between CN and MCI individuals. The abilities of T cell response parameters and plasma p‐Tau181 to distinguish MCI from CN were tested.

Result

Results from both cohorts showed an enhanced amyloid‐specific T‐cell response in individuals with MCI. In the EMCIT cohort, the individual’s amyloid‐specific CD4+ response frequency of total CD4+ cells was significantly larger in MCI (n = 69, 0.93%) than in CN (n = 69, 0.51%, p < 0.001). CD4+ T cell response discriminated MCI versus CN (area under curve [AUC], 0.72 [0.64‐0.81]) with significantly higher accuracy than p‐Tau181 (AUC: 0.59 [0.5‐0.69], p < 0.01). In the TPMIC cohort, both CD4+ and CD8+ response frequencies were higher in MCI individuals (n = 21, CD4: 1.2%, CD8: 2.02%) than in CN (n = 30, CD4: 0.14%, CD8:0.27%; both p < 0.001). CD4+ T cell response frequency and CD8+ response frequency also outperform p‐Tau181 in their discriminative accuracy of MCI versus NC (CD4+ AUC, 0.97, [0.94‐1.01]; CD8+ AUC, 0.96, [0.92‐1.01]; p‐Tau181 AUC, 0.83, [0.69‐0.96]; both p < 0.05).

Conclusion

Our study validates the amyloid hypothesis by showing that amyloid‐associated neuroinflammation is involved in the process of neurodegeneration and demonstrated the accuracy of using amyloid‐specific T cell response to discriminate MCI from CN individuals. The TPMIC cohort is an ongoing longitudinal study that includes amyloid PET results and thus we will investigate the prognostic value of amyloid‐T cell response in the future.
Immunohistochemical study of synaptophysin expression in rat hippocampus during aging
Authors: Ekova Maria , Smirnov Alexey Vladimirovich , Tyurenkov Ivan Nikolaevich , Grigoryeva Natalya Vladimirovna
Published: December 2023

Background

In the process of aging, there is a general decrease in the physiological functions of the body, including cognitive ones. Cognitive abilities are a decisive factor in determining the quality of life of older people.

Method

2 groups were formed: group 1 ‐ rats at the age of 12 months (n = 10), group 2 ‐ rats at the age of 24 months (n = 10). The degree of expression of synaptophysin and the relative area of the immunoreactive material in the dorsal and ventral hippocampus were determined.

Result

Immunohistochemical study using antibodies against synaptophysin in 12‐ and 24‐month‐old animals revealed a crescent‐shaped distribution of immunoreactive material in the neuropil of the pyramidal layer CA1‐CA4 of the dorsal hippocampus, most pronounced in old animals. In 24‐month‐old animals, an increase in the degree of expression of the immunoreactive material in the neuropil of the pyramidal, radial and molecular layers CA1 and CA3 of the dorsal hippocampus was revealed. In 12‐month‐old animals, in the neuropil of the pyramidal layer in CA1 and CA3 of the ventral hippocampus, a high degree of orderliness was found in the arrangement of dendrites in the radial layer and the distribution of immunoreactive material over the surface of the dendrites in the pyramidal and radial layers of the hippocampus, the most pronounced in CA1. At the same time, no age‐dependent increase in the degree of expression of the immunoreactive material was found in the ventral hippocampus. We also did not reveal a significant increase or decrease in the relative area of the immunoreactive material in either the dorsal or ventral hippocampus.

Conclusion

During aging in rats at the age of 24 months, an increase in the degree of expression of synaptophysin‐immunoreactive material in the neuropil of the pyramidal, radial and molecular layers CA1 and CA3 of the dorsal hippocampus was revealed, which may be associated with the redistribution of synaptic vesicles in the presynaptic part of the synapses with their predominant localization in the presynaptic membranes, which determines the increase in the degree of expression of synaptophysin.
Female Brain and Endocrinological Research Veteran Study: Identifying endocrinological, lifestyle and psychosocial determinants of female brain health outcomes for future intervention success
Authors: Watermeyer Tamlyn J , Ansdell Paul , Atkinson Elliott J , McGill Gill , Dodds Christina , Howatson Glyn , Udeh‐Momoh Chi T.
Published: December 2023

Background

Recent studies have demonstrated a greater risk for dementia in female veterans compared to civilians; with highest prevalence noted for female veterans with a diagnosis of psychiatric (trauma, alcoholism, depression), and/or a physical health condition (brain injury, insomnia, diabetes). Such findings highlight the need for increased and early screening of medical and psychiatric conditions, and indeed dementia, in the female veteran population. Further, they call for better understanding of the underlying psychobiological mechanisms that might confer heightened risk for female veterans to prepare tailored preventative and interventional strategies that support brain health across the lifespan.

Method

Our feasibility study will create an innovative highly‐phenotyped readiness cohort of female veterans to assess the impacts of, and risks associated with, military service on brain health, using state‐of‐the‐art non‐invasive cognitive, physiological and biomarker capture techniques.

Result

FEMBER‐Vet will include 90 participants across study groups (30 female veterans, 30 male veterans, 30 female civilians) to delineate the precise biological, socio‐demographic, health, lifestyle, military‐related, and lifetime determinants of brain health outcomes (psychosocial, cognitive, neurophysiological, and other biomarkers).

Conclusion

This work addresses the poorly understood biopsychosocial outcomes that female veterans suffer compared to male counterparts and the general female population. Ultimately, it will promote tailored interventions for an emerging health priority that currently lacks sufficient evidence for screening and therapeutic intervention.
Neuroprotective Effect of Perillyl Alcohol in Experimental Sporadic Alzheimer’s Disease
Authors: Kapoor Satyan
Published: December 2023

Background

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

Method

‐Sprague Dawley ICV‐STZ (3mg/kg) rats (250‐300g, 7‐8 weeks) were treated with Perillyl alcohol treated with three different doses of (25, 50 and 100mg/kg p.o.) for 13 days from 15th to 27th day.

Result

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

Conclusion

In summary, present study has shown that Perillyl Alcohol is effective in amelorating i.c.v. STZ induced behavioral alterations, cholinergic dysfunctions and oxidative‐ nitrative stress.
iNOS expression in the pyramid layer of the rat hippocampus in the modeling of chronic cerebral discirculatory disorder
Authors: Smirnov Alexey Vladimirovich , Mednikov Dmitry , Tyurenkov Ivan Nikolaevich
Published: December 2023

Background

Studying of various forms of NO‐synthases is of great interest, since they are involved in many of the mechanisms of neuronal injury, aggravating the ischemic cascade and negatively affect the clinical status of cerebrovascular diseases. Impaired functioning of NO synthase plays an important role in the progressing of neurodegenerative diseases, since nitric oxide is a modulator of neuroplasticity.

Method

Chronic cerebrovascular disorder was modeled on rats by the method of overloading in the caudo‐cranial vector with a force 9 G for 5 minutes with an interval of 12 hours for 28 days. The level of iNOS expression was assessed by calculating the relative area of the immunoreactive material.

Result

The heterogeneity of the distribution of the immunoreactive material was expressed both in dust‐like cytoplasmic accumulation and in the presence of small‐lumpy deposits of iNOS‐positive material in the neurons of the pyramidal layer and in the neuropil, and in glial cells the intensity of expression was more pronounced, reaching a pronounced one. The relative area of iNOS‐positive material increased most significantly in CA3, by 8.3% (p<0.001), amounting to 12.1% [9.8;14.3]%. In CA1, the increase in the same indicator relative to the control was 3.9% (p<0.001), reaching 5.7 [4.5;6.1]%. In CA2 and CA4, respectively, the increase in the relative area of the IRM was 4.5% (p<0.05).

Conclusion

We presume that the pronounced neuronal injury that is observed in the chronic cerebrovascular disorder modeling is a factor in the disruption of the hematoencephalic barrier, leading to edema, the subsequent acquisition of a pro‐inflammatory phenotype by astrocytic and microglia and the switch from the constitutive type of NO‐synthesis to the predominantly inducible type associated with activation of iNOS.