bluuebunny/crossref_metadata_2025_split huggingface dataset:
Rapid review: How rare are rare dementias?
Authors: Hayes Oliver S , Baou Celine El , Brotherhood Emilie V , Crutch Sebastian J , Camic Paul 
Published: December 2023

AbstractBackgroundCompared to global prevalence data for common forms of dementia (Alzheimer’s disease, vascular dementia, and mixed Alzheimer’s and vascular dementia), our understanding of the prevalence of atypical, inherited, and young onset forms of dementia is poor. Furthermore, estimates are biased towards figures from a subset of countries and regions. Estimates of the relative prevalence of atypical, inherited and young onset forms of dementia (colloquially referred to as ‘rare dementias’) within overall dementia prevalence should improve awareness and diagnosis rates, and enhance the access of individuals with these conditions to tailored support and interventions.MethodRapid review methods will be applied to a systematic review of the relative prevalence of rare forms of dementia as a proportion of overall dementia prevalence. The English language databases of CENTRAL, MEDLINE, Embase and PsycINFO will be searched for systematic reviews and primary studies relating to relevant conditions, with dementia types and search terms being determined by a consensus process involving UK and international clinicians and academics. Major national and international formal epidemiological studies, regional epidemiological studies, multi‐service data, individual clinic and service data referencing the prevalence, incidence, and risk data of at least one rare form of dementia will be included. Key grey literature from organisations and charities such as Alzheimer’s Society, Alzheimer’s Association and the WHO will also be included if available data sources provide valuable insight, and their methodologies are transparent and verifiable.ResultWe will report estimates of relative prevalence of atypical, inherited, and young onset forms of dementia, both individually and collectively.ConclusionThe application of the present rapid review method allows for timely appraisal of evidence useful in understanding global prevalence of rare forms of dementia. Review findings will also be discussed in terms of a working definition of the convenience label ‘rare dementia’, and consideration of constraints including: (1) the paucity of information on rare forms of dementia, (2) publication bias and biases associated with organisational reports, (3) overlaps and confusions between syndrome‐ and disease‐level descriptions, and (4) the variable precision with which certain diagnostic labels can be applied at more advanced disease stages.
Histone deacetylase 4‐dependent regulation of cortical synaptic plasticity and the higher cognitive function during adulthood
Authors: Chung Seungsoo , Jeong Ji‐Hyun , Ahn Ji‐Woong , Sung Hansol , Shin Sunyoung , Jeong Minhee , Kim Young‐Hwan 
Published: December 2023

AbstractBackgroundIt is known that the primary sensory cortex contributes to the higher cognitive function, such as decision‐making. Still, a detailed synaptic mechanism explaining the relationship between sensory input and perceptual decision‐making remains elucidated. Previously, we demonstrated sensory deprivation restores critical‐period‐like synaptic plasticity to the barrel cortex in unilateral infraorbital injury (IO) mice.MethodTherefore, we explored the relationship between adult primary synaptic input and perceptual decision‐making in adult IO mice using the head‐fixed texture discrimination test and brain slice patch‐clamp technique. We also explored a molecular mechanism underlying IO‐induced reactivation of thalamocortical (TC) synaptic plasticity in the barrel cortex using immunoblotting of HDAC4 and BDNF as well as AAV/shRNA‐mediating knockdown of HDAC4.ResultIO mice learned the spared TC input‐mediated perceptual decision‐making task more effectively than sham‐controls. This improvement in perceptual learning was intimately correlated with spared TC synaptic efficacy. In terms of a possible molecular mechanism for the IO‐induced reactivation of TC synaptic plasticity, histone deacetylase 4 (HDAC4) and brain‐derived neurotrophic factor (BDNF) expression was significantly reduced in layers 4 and 5 of the barrel cortex from PO7 to PO9 in IO mice compared with Sham‐controls. The IO‐induced potentiation of spared TC synaptic efficacy was nearly prevented by blockage of BDNF/TrkB signaling with cyclotraxin B. In addition, HDAC4 knockdown by injecting AAV5‐U6‐mHDAC4‐shRNA‐CMV‐EGFP to the S1 barrel cortex significantly increased BDNF expression and TC synaptic efficacy in the layer4 barrel cortex. Similarly, the application of HDAC4 inhibitor to the S1 barrel cortex via an osmotic pump effectively potentiated TC synaptic efficacy without alteration of excitation/inhibition balance, similar to IO mice.ConclusionThese results suggest that the reactivation of synaptic plasticity of primary TC input may regulate the higher cognitive function by modulating HDAC4/BDNF/TrKB signaling during adulthood.
Abnormalities of reactivity of posterior resting‐state electroencephalographic alpha rhythms during eyes opening in patients with dementia due to Alzheimer’s disease and Parkinson’s disease
Authors: Percio Claudio Del , Lizio Roberta , Lopez Susanna , Tucci Federico , Noce Giuseppe , Jakhar Dharmendra , Güntekin Bahar , Yener Görsev , Taylor John‐Paul , Babiloni Claudio 
Published: December 2023

AbstractBackgroundPatients with dementia due to Alzheimer’s disease (ADD) and Parkinson’s disease (PDD) suffer from vigilance dysregulation. We hypothesized that such dysregulation may be reflected by altered reactivity of posterior resting‐state electroencephalographic (rsEEG) alpha rhythms during the vigilance transition from eyes‐closed to ‐open condition.MethodA Eurasian database provided clinical, demographic, and rsEEG datasets in 73 PDD patients, 35 ADD patients, and 25 matched cognitively unimpaired (Healthy) persons. The eLORETA freeware was used to estimate cortical rsEEG sources at delta, theta, alpha, beta, and gamma frequency bands during eyes‐closed and‐open conditions.ResultResults showed substantial (> ‐10%) reduction (reactivity) in the posterior alpha source activities from the eyes‐closed to the eyes‐open condition in 88% of the Healthy seniors, 57% of the ADD patients, and only 35% of the PDD patients (Figure 1). In these alpha‐reactive participants, there were lower reductions in the posterior alpha activities in the ADD and PDD groups than in the Healthy group. That reduction in the parietal region was lower in the PDD than in the ADD group (Figure 2).ConclusionThese results suggest that ADD and PDD is characterized by poor reactivity of mechanisms desynchronizing posterior rsEEG alpha rhythms in response to visual inputs. This finding could be an interesting biomarker of impaired vigilance regulation in the quiet wakefulness in ADD and PDD patients. Such biomarkers may provide endpoints targets for pharmacological intervention and brain electromagnetic stimulations to improve the ADD and PDD patients’ general ability to regulate vigilance and visual primary consciousness in the activities of daily living.
APP‐dependent cell adhesion is regulated by GWAS genes
Authors: Chapuis Julien , NAJDEK Chloé , Coulon Audrey , Eysert Fanny , Grenier‐Boley Benjamin , Bellenguez Céline , Demiautte Florie , Amouyel Philippe , Dumont Julie , Kilinc Devrim , Lambert Jean‐Charles 
Published: December 2023

AbstractBackgroundThanks to Genome‐Wide Association Studies (GWAS), 75 susceptibility loci for Alzheimer’s disease (AD) have been identified (Bellenguez et al, Nat genetics. 2022). However, one of the greatest challenges resides in the understanding of the functional consequences of these genetic determinants. One of the main hypothesis would be that some of these genetic factors could be involved in APP metabolism and Aβ production. Indeed, even if numerous players of the APP metabolism have been characterized over the last 20 years, a large part of the is still unknown. Moreover, with more than 200 genes localized in the AD susceptibility loci, the classical approach, i.e., studying genes one by one, cannot be done in a timely manner. Therefore, we took advantage of Genome‐Wide siRNA screening using a High Content Screening (HCS) approach allowing a systematic functional assessment of human genes on APP metabolism.MethodA HEK293 cell line stably over‐expressing a fluorescently‐tagged APP was transitory transfected in 384‐well plates with the human siGENOME siRNA library to silence every human gene. High content analysis was performed to automatically quantify (i) fluorescence intensities reflecting the intracellular accumulation of APP byproducts and (ii) cell‐cell interaction. Enrichment pathway analysis was performed to identify the pathways in which the modulators of APP are mainly involved.ResultExpected GWAS‐defined genes were identified among the genes showing the stronger effects on APP metabolism (APP, ADAM10, SORL1). Moreover, we observed that a large portion of the GWAS‐defined genes are modulators of APP metabolism and are involved in cell adhesion signaling, including the genetic risk factors FERMT2 and Cass4. In our model, silencing of these genes was also able to modulate cell‐cell interaction, suggesting that APP‐dependent cell adhesion is regulated by GWAS‐defined genes.ConclusionRemarkably, many genetic risk factors of AD are involved in cell adhesion pathway, such as APP which has been shown to be involved in synaptic formation and plasticity. Since synaptic dysfunction and loss is one of the very early hallmarks of AD, our data suggest that beyond Aβ production, APP could impact AD process through an impairment of cell adhesion at the synaptic level.
Single domain antibodies as promising tools for the selective detection and neutralization of neurotoxic Aβ42 oligomers in the cerebrospinal fluid of Alzheimer’s disease patients
Authors: Napolitano Liliana , Bigi Alessandra , Vadukul Devkee , Aprile Francesco , Chiti Fabrizio , Cecchi Cristina , Cascella Roberta 
Published: December 2023

AbstractBackgroundExtracellular amyloid β (Aβ) plaques and intracellular neurofibrillary tangles of the hyperphosphorylated tau protein are the main hallmarks of Alzheimer’s disease (AD). Small, soluble oligomers, rather than mature fibrils, are the major neurotoxic agents. The heterogeneous structures and the transient nature of these oligomers make their isolation and characterization very challenging. Single domain Abs (sdAbs), composed only of a variable domain of the heavy chain with high specificity and affinity, appear as promising tools for an early diagnosis and therapy for AD.MethodsPerforming an in vitro and in vivo screening of different sdAbs, we selected those targeting Aβ42 oligomers or fibrils with high specificity using dot‐blot, ELISA assay and the super resolution stimulated emission depletion (STED) microscopy. The potential of sdAbs was also investigated in preventing Aβ42 oligomer‐induced cytotoxicity in cultured neuronal cells. Then, the sdAbs were used to selectively detect Aβ42 species in the cerebrospinal fluid (CSF) of AD patients and control subjects and to neutralize their associated harmful effects following cell exposure to CSF samples.ResultssdAbs can selectively detect Aβ42 oligomers or fibrils both in vitro and in cultured cells, preventing the neurotoxicity induced by small oligomers. Moreover, sdAbs can significantly identify Aβ42 oligomers in the CSF of AD patients counteracting their induced toxicity in our cell models.ConclusionsAll these data provide a solid foundation for the development of sdAbs‐based immunodiagnostic tools that can selectively detect toxic aggregates in human body fluids for an early differential diagnosis of protein deposition diseases, such as AD. Furthermore, our results contribute to the improvement of the current therapeutic approaches against AD.The study was supported by Airalzh (AGYR 2020 to R.C.).
Speaker Identification in Dementia Households
Authors: Jouaiti Melanie , Vaidyanathan Ravi 
Published: December 2023

AbstractBackgroundSpeaker identification on datasets collected in the wild faces several challenges, including the scarcity of labelled data, noisy data and data where several people are talking. Previous works have focused on speaker identification using large amounts of labelled data or semi‐supervised approaches where a small amount of data is used a training set, but in this case, the datasets used only contain clean data and often the same sentences repeated several times by each participant.MethodIn this work, we propose a new approach to achieve fuzzy semi‐supervised clustering on Alexa data collected in households of people living with dementia (PLwD). In this context we wish to identify the carer and the PLwD, but also visitors. We extract x‐vectors from the audio data, apply PCA and use those as input features for our algorithm. The clusters are initialised with a small amount of data from each identified speaker (carer, PLwD). New data is added iteratively and membership scores are computed for each cluster. Membership is computed according to the Euclidian distance between the data point and each cluster. Centroids are updated every 30 iterations, only considering the points with high membership. Membership is also updated with the new centroids and considering the Mahalanolis distance.ResultOur method performs comparatively to unsupervised learning and supervised learning in a two‐class problem (carer and PLwD), with 100% accuracy and 96% recall in identifying the PLwD with a training set of 5 files. When considering visitors as an unknown class, unsupervised learning fails. Our method performs similarly to supervised learning in identifying the carer and PLwD (97% accuracy and 80% recall), but is better at identifying visitors as unknown speakers than supervised learning (around 40% accuracy, and 4% respectively).ConclusionIn this work, we propose a new method to perform speaker identification on data collected in the wild. We endeavour to address the shortcomings of supervised learning which tends to overfit and unsupervised learning which does not perform well with unknown classes.
Revealing hidden sensorimotor memories in mice with AD‐relevant pathology
Authors: Santi Andrea , Moore Sharlen , Lawlor Jennifer , Wang Aaron , Fogelson Kelly , Kuchibhotla Kishore 
Published: December 2023

AbstractBackgroundMemories must be accessible for them to be useful. Alzheimer’s disease (AD) is a progressive form of dementia in which cognitive capacities slowly deteriorate due to underlying neurodegeneration. Interestingly, anecdotal observations have demonstrated that Alzheimer’s patients can exhibit cognitive fluctuations during all stages of the disease. In particular, it is thought that contextual factors are critical for unlocking these hidden memories. To date, however, exploration of the neural basis of cognitive fluctuations has been hampered due to the lack of a behavioral approach in mouse models to dissociate memories from contextual performance.MethodOur previous work demonstrated that interleaving ‘reinforced’ trials with trials without reinforcement (‘probe’ trials) in an auditory go/no‐go discrimination task, allows us to distinguish between acquired sensorimotor memories and their contextual expression. Here, we used this approach, together with two‐photon calcium imaging on behaving AD‐relevant mice (APP/PS1+), to determine whether amyloid accumulation impacts underlying sensorimotor memories (measured using ‘probe’ trials) and/or contextual‐performance (measured using ‘reinforced’ trials) in an age dependent manner.ResultImportantly, peripheral auditory function, measured using the threshold for detecting an auditory brainstem response, was similar between WT and APP/PS1+ mice. We found that while contextual‐performance is significantly impaired in young adult APP/PS1+ mice compared to age‐matched controls, these animals show only minor impairments in the underlying sensorimotor memories. However, middle aged APP/PS1+ mice show deficits in both domains. The impairment found in the young adults was accompanied by a reduction in stimulus selectivity and behavioral encoding in the auditory cortex of APP/PS1+ mice that that can be partially restored in probe trials. Ongoing analyses aim to identify whether this impairment is cortex‐wide or is concentrated near Aβ plaques. Finally, these effects were recapitulated by using a reinforcement learning model that accounts for changes in contextual signals. The main network model parameters affected between the control and the APP/PS1+ mice were those governing contextual scaling and behavioral inhibition.ConclusionThese results suggest that Aβ deposition impacts circuits involved in contextual computations before those involved in acquiring knowledge and that neural circuit interventions, such as modulating inhibition, may hold promise to reveal hidden memories.
Functional Variants Identify Sex Specific Genes and Pathways in Alzheimer’s Disease
Authors: Lee Kwanghyuk Danny , Bourquard Thomas , Al‐Ramahi Ismael , Pham Minh , Shapiro Dillon , Lagiesetty Yashwanth , Soleimani Shirin , Mota Samantha , Wilhelm Kevin , Samieinasab Maryam , Kim Youngwon , Huh Eunna , Asmussen Jenn , Katsonis Panagiotis , Botas Juan , Lichtarge Olivier 
Published: December 2023

AbstractBackgroundAlzheimer’s Disease (AD) incidence is almost double in women, suggesting sex‐specific risk genes for AD remain to be uncovered.MethodTo identify AD risk genes in smaller cohorts of only male or only female subjects we designed a machine learning case‐control study of genome variant differences that included a functional importance score as a feature. The method robustly finds genes in smaller cohorts, enabling us to analyze men and women separately.ResultWe found AD‐associated risk genes men‐only, women‐only, or combined subjects. These genes were consistent with a) prior AD GWAS; b) expression in AD patients brain regions; c) transcriptome analyses; d) and in vivo experiments in fly models of Amyloid beta and Tau neurodegeneration. Notably, the sex‐specific genes implicate pathways that are differentially altered in each sex – a stress response pathway unique to AD affected men and cell‐cycle/DNA quality control pathways unique to AD affected women.ConclusionA machine learning combined with an evolution‐based training feature for variant impact identified common as well as sex‐specific AD‐associated genes and mechanisms of potential value for pre‐symptomatic risk assessment and drug targeting.
Alzheimer’s Dementia and Care: Legal aspects of the use of technology
Authors: Schmitz‐Luhn Björn , Chandler Jennifer 
Published: December 2023

AbstractBackgroundModern technology promises many improvements for the lives of persons suffering from Alzheimer’s dementia and their caregivers. For example, technology can help with the assessment and measurement of symptoms, monitoring of disease progression, supporting decision‐making to alleviate symptoms and foster well‐being, facilitating training, physical activity and remote care.For example, wearable, clothing, or ambient sensors can be used to closely monitor physiological functions and detect any falls or accidents, automatically alert physicians or caregivers, and warn about slightest changes in biological function. Wandering can be tracked, and assistive technology can help in case of disorientation. It can assist with cognitive training and physical activity. Above all, the algorithmic analysis of large sets of patient data can, e.g., point to potential indicators for disease risk or progress, allowing for the development or personalization of possible treatments, or for algorithmically assisted care decision‐making.MethodIn an international prospect of existing rules and regulations regarding the use of technology for AD care, challenges, divergencies and possible gaps have been identified, highlighting pitfalls and hindrances for medical care as technology evolves.ResultIn spite of major advantages brought about by technology, there are also challenges from legal and ethical perspectives. They include questions of liability for technology by developers and medical practitioners, of equity and access to assistive technology in statutory and private health care, of information and consent regarding the use of complex technology, as well as of privacy, autonomy and the internationally diverging levels of data protection regulation.ConclusionGiven challenges and hindrances must be considered in order to protect the interests of the affected persons and to ensure the responsible use of technology to benefit patients and caregivers. We will present some of these, and point to solutions for health policy makers in order to both foster emerging technology and ensure its safe use for patients as well as regulatory reliability for medical practitioners.
Disambiguating the macro‐scale anatomy of dysexecutive and behavioral degenerative diseases of the mind
Authors: Corriveau‐Lecavalier Nick , Barnard Leland R , Botha Hugo , Radford Jonathan Graff , Ramanan Vijay K , Lee Jeyeon , Dicks Ellen , Boeve Brad F. , Machulda Mary M. , Dickson Dennis W. , Graff‐Radford Neill R , Knopman David S. , Lowe Val J. , Petersen Ronald C. , Jack Clifford R. , Jones David T. 
Published: December 2023

AbstractBackgroundThere is a longstanding ambiguity regarding the clinical diagnosis of dementia syndromes predominantly targeting executive functions versus behavior/personality. This is due to a lack of knowledge about the macro‐scale anatomy underlying these symptomatologies, a partial overlap in clinical features, and the fact that a single underlying pathology can give rise to both phenotypes and vice‐versa.MethodWe included data from patients with genetic, biomarker, and/or autopsy evidence for fronto‐temporal lobar degeneration (FTLD) diagnosed with behavioral variant fronto‐temporal dementia (bvFTD, n = 30) and patients with biomarker and/or autopsy evidence for Alzheimer’s disease (AD) pathology diagnosed with either an initial and predominant dysexecutive (dAD, n = 52), behavioral (bvAD, n = 7), or amnestic (aAD, n = 28) syndrome. We assessed group‐wise differences in clinical/cognitive features and 18Fluorodeoxyglucose‐positron emission tomography (FDG‐PET) patterns. This was followed by a spectral covariance decomposition between FDG‐PET images to yield latent patterns of relative metabolism (“eigenbrains”). These eigenbrains were subsequently linked to clinical/cognitive data and meta‐analytic topics reflecting a wide range of mental abilities. We used a linear discriminant analysis (LDA) to perform eigenbrain‐based diagnostic predictions.ResultdAD and bvFTD patients were the youngest at symptom onset, followed by bvAD, then aAD. dAD patients had worse cognitive performance on nearly all cognitive domains compared to other groups. Hypometabolism was observed across associative cortices in dAD, temporo‐parietal areas in aAD, and fronto‐temporal areas in bvFTD and bvAD (Fig. 1). The spectral covariance decomposition yielded nine eigenbrains which explained 61% of the variance in patterns of FDG‐PET, and only the first three are presented (Fig. 2). These eigenbrains revealed that relative hypometabolism in association cortices, notably lateral parietal areas, associated with dysexecutive symptomatology and a lower likelihood of behavior/personality problems, whereas relative hypometabolism restricted to frontal and temporopolar areas showed opposite associations. The LDA yielded an accuracy of 82.1% in predicting diagnostic category (Fig. 3).ConclusionThis study suggests distinct macro‐scale underpinnings underlying predominant dysexecutive versus behavioral symptomatology in degenerative dementia phenotypes. This has implication for the implementation of clinical and research criteria for these dementia syndromes and highlights the importance of data‐driven techniques to inform the classification of degenerative diseases.