bluuebunny/crossref_metadata_2025_split huggingface dataset:
Healthcare 3.0: How to Transform Machine Learning Prototypes into Functional Healthcare Applications for Diagnostic Assistance?
Authors: Dyrba Martin , Singh Devesh , Weber Marc‐André , Teipel Stefan 
Published: December 2023

AbstractBackgroundAs the number of elderly people is rapidly increasing, we are faced with the challenge that diagnostic services are demanded more frequently. At the same time, the number of medical centers and available experts remains almost constant. Tools for diagnostic assistance are urgently needed to improve the effectiveness of healthcare. In four externally funded projects, we will investigate aspects and strategies of how machine learning prototype systems can be translated into functional healthcare applications.MethodIn the ongoing project “ExplAInation” funded by the German research foundation (DFG), we are developing an artificial neural network framework to generate visual and textual explanations to improve the comprehensibility and interpretability of deep learning models. This effort includes participatory research with clinical users. In the complementary project “TESIComp” funded by the Federal Ministry of Education and Research (BMBF), we will investigate ethical and social aspects of the emerging field of computational psychiatry. Patients, caregivers, and medical doctors will be interviewed, which will be qualitatively analyzed. Within the German Medical Informatics Initiative, we will contribute to the project “Open Medical Inference” (OMI), which will develop a network of distributed machine learning evaluation services. We also participate in the international “Clinical AI‐based Diagnostics” (CAIDX) consortium, which receives funding from the European Interreg Baltic Sea Region program.ResultWe developed a deep learning application for the detection of dementia atrophy patterns in brain MRI scans. Derived relevance maps highlight diagnostically important brain areas for further evaluation by the radiologists. Interviews with clinicians will provide information on expectations, key requirements and the functional utility of machine learning‐based assistance. Interviews with patients and caregivers will elucidate future changes and challenges in the doctor’s role and responsibilities. The OMI network will allow hospitals to use distributed machine learning evaluation services remotely, without the need of operating all the tools locally. In CAIDX, we will develop best‐practice guidelines for the overarching process of integrating machine learning prototypes and commercial tools into the hospital.ConclusionIn “Healthcare 3.0”, the digital transformation will change current diagnostic procedures and roles. Our activities focus on the involved stakeholders, regulatory aspects and implementation strategies to better steer this process.
The limbic‐predominant hypometabolic subtype of AD is not enriched for comorbid TDP‐43 pathology or hippocampal sclerosis
Authors: Levin Fedor , Grothe Michel J. , Dyrba Martin , Teipel Stefan 
Published: December 2023

AbstractBackgroundPrevious research has identified distinct subtypes of AD that differed with respect to the distribution of neurofibrillary tangles (NFT). One of them, a limbic‐predominant subtype, was enriched for comorbid TDP‐43 pathology. Our previous data‐driven analysis used FDG‐PET to identify a limbic‐predominant subtype of AD that may correspond to the limbic‐predominant NFT subtype. In the current study, we tested the expected associations between measures of neuropathology such as TDP‐43 pathology, hippocampal sclerosis, and Braak stages of NFT accumulation, and the limbic‐predominant hypometabolic subtype.MethodWe analyzed ante‐mortem FDG‐PET and neuropathological data of 74 individuals from the autopsy cohort of the Alzheimer’s Disease Neuroimaging Initiative (ADNI), including 7 cognitively normal participants, 12 participants with MCI, and 55 with dementia (as assessed at the last available clinical evaluation). Severity of TDP‐43 pathology was operationalized as the number of brain areas with TDP‐43 immunoreactive inclusions (including amygdala, hippocampus, entorhinal/inferior temporal cortex and neocortex). Hippocampal sclerosis was operationalized as a binary variable. We measured similarity of individual FDG‐PET profiles to the limbic‐predominant subtype. For that, we used Euclidean distances from each individual profile to the mean profile of the limbic‐predominant AD subtype identified previously in a larger ADNI sample using a data‐driven hierarchical clustering approach (Fig.1). Lower Euclidean distances indicated higher similarity to the subtype. Bayesian linear regressions in JASP were used to assess associations between neuropathological markers and similarity to the limbic‐predominant FDG‐PET pattern, controlling for Thal phase of amyloid accumulation, age, sex, and time delay between the FDG‐PET scan and death in the null model. We assessed Bayes factors representing evidence for a given model in comparison to the null model (BF10).ResultOur results suggest that similarity of individual FDG‐PET profiles to the limbic‐predominant FDG‐PET pattern was not related to severity of TDP‐43 pathology (BF10 = 0.449), presence of hippocampal sclerosis (BF10 = 0.544), or Braak NFT stages (BF10 = 0.525).ConclusionContrary to the expected effects, our current analysis indicates a lack of reliable associations between neuropathological markers such as TDP‐43 pathology, hippocampal sclerosis, or global NFT accumulation and the limbic‐predominant hypometabolic subtype. Future analyses will assess potential alternative contributors, such as region‐specific patterns of NFT distribution.
The association between early diagnosis of dementia and health care utilization in psychiatric hospitalization for behavioral and psychological symptoms
Authors: Liu Chien‐Liang , Chueh Chen‐Han , Tsai Yi‐Wen , Yang Szu‐Nian 
Published: December 2023

AbstractBackgroundEarly diagnosis of dementia has been considered an effective strategy to reduce the healthcare cost for dementia but not conclusive. Our aim is to examine the association between early diagnosis of dementia and healthcare utilization in the first psychiatric hospitalization for behavioral and psychological symptoms.MethodsThis retrospective cohort study examined whether the diagnosis of dementia before index hospitalization affected healthcare management after the index hospitalization for 1972 elderly individuals between 2005 and 2015, using National Health Insurance claims data in Taiwan. Propensity scores, inverse probability of treatment weighting (IPTW), and regression analyses were used to adjust for confounding and examine the effect of early dementia diagnosis. The outcomes were chemical restraints, physical restraints, and healthcare utilization.ResultsAmong the 1,972 patients, 89.6% had an early diagnosis, and 10.4% had a delayed dementia diagnosis. The delayed dementia diagnosis group was younger and had less comorbidity. IPTW showed that the delayed diagnosis group received more chemical and physical restraints. The length of stay of index hospitalization in the delayed diagnosis group was 8 days longer than the early diagnosis group. Additionally, the delayed diagnosis group had significantly higher total medical expenses by NT$27,344 and higher total drug expenses by NT$1,912 than the early diagnosis group.ConclusionAn early diagnosis of dementia was associated with decreased use of physical and chemical restraints, shortened length of stay of acute hospitalization, and decreased overall healthcare costs in psychiatric hospital admissions compared with a delayed diagnosis.
RNAi knockdown of microtubule‐associated protein Tau prevents axonal damage and clears pre‐existing Tau aggregates in P301S transgenic tauopathy model mice
Authors: Haines Jeffery D , Farley Jonathan , Gannon Sean , Schlegel Mark , Castoreno Adam , Bisbe Anna , Zlatev Ivan , Rollins Jeff , Bostwick Bret , Avbersek Andreja , Brown Kirk , Macdonald Lynn , Gao Min , Anderson Matthew 
Published: December 2023

AbstractBackgroundThe hyperphosphorylation and subsequent aggregation of the microtubule‐associated protein Tau (encoded by the MAPT gene) is one of the major histopathological hallmarks of numerous tauopathies, including Alzheimer’s disease and progressive supranuclear palsy. The intracellular accumulation of aggregated Tau is associated with neuronal loss and disease progression in tauopathies. There is a high‐unmet need to identify strategies to target the intracellular accumulation of Tau aggregates with the aim of slowing tauopathy progression.MethodTo model this, we used mice carrying multiple copies of a transgene with a prion promoter driving human MAPT with human tauopathy‐inducing mutation P301S. P301S‐Tau transgenic mice progressively accumulate neuroglial Tau aggregates associated with axonal damage, gliosis, body weight loss, and ambulatory dysfunction.ResultP301S mice treated with a single intracerebroventricular injection of Tau siRNA at eight months of age, had a sustainable decrease in MAPT mRNA and soluble Tau protein for three months following siRNA treatment (reduced ∼83% and ∼59%, respectively). siRNA treatment also prevented the progressive decrease in body weight and abrogated axonal damage, evidenced by decreased neurofilament light (NFL) chain in plasma and cerebrospinal fluid of eleven‐month‐old mice. Importantly, immunohistochemical analysis of misfolded Tau in vivo and HEK293‐4RD‐CFP/YFP Tau aggregate biosensor assay testing in vitro revealed a ∼97% decrease of Tau aggregates in the eleven‐month‐old mice, suggesting there exists a yet‐to‐be identified mechanism of Tau fibril clearance.ConclusionTogether, these results suggest an RNAi therapeutics approach targeting of MAPT mRNA may be sufficient to improve multiple parameters of tauopathy disease progression and a provide a compelling rationale for further development of Tau‐lowering strategies.
Examining the validity of sleep diaries using a patient‐caregiver dyadic model of dementia
Authors: Youngkin Anna E , Manning Carol A , Quigg Mark S 
Published: December 2023

AbstractBackgroundDeveloping successful sleep interventions for both people with dementia (PWD) and their caregivers (CGS) is critical to alleviate a strong difficulty associated with dementia. In the majority of current studies, sleep diaries are used to quantify the sleep quality of participants. However, whether or not sleep diaries can accurately describe sleep statistics is unclear and the completion of daily diaries can be tedious for caregivers, leading to gaps and inaccuracies in data. The current study aimed to compare sleep diaries of both patients and caregivers with gold standard diagnostic polysomnography to determine the validity of sleep diaries for future research methodology.MethodParticipants: Six caregiver‐patient dyads. Polysomnography (PSG): recorded and scored for 1 night for each dyad member separately. Sleep Diaries (SDs): logged over the course of 14 days by the primary caregiver on behalf of themselves and their care recipient. Variables: Total sleep time (TST), Sleep onset latency (SOL) and number of awakenings.ResultOf the three variables assessed, TST was the only measure with meaningful correlations between SDs and PSG (CG r = 0.4315, PWD r = 0.7645). While those who reported greater sleep time in SDs also tended to have higher TST on PSG reports, SDs consistently overestimated the amount of sleep both PWD and CGS received compared to their sleep studies. SOL was inconsistent across SDs, with no clear pattern correlating SDs to PSG reports. However, data from both methods indicate significantly increased SOL in CGS compared to PWD (PSG p = 0.015, SDs p = 0.044). SDs additionally grossly underestimate the number of awakenings in both CGS and PWD.ConclusionSleep diaries can be helpful tools for identifying broad trends or differences between groups, however, our data suggest that they should not be used as surrogate markers for quantitative sleep statistics. Studies aiming to study sleep or sleep interventions should not rely on subjective sleep measurements provided by SDs alone, but should consider the addition of PSG in order to best understand the sleep architecture of their participants.
Pathophysiological mechanisms of grey matter morphometry changes in preclinical Alzheimer’s disease
Authors: Pelkmans Wiesje , Cacciaglia Raffaele , Salvadó Gemma , Falcon Carles , Minguillón Carolina , Fauria Karine , Kollmorgen Gwendlyn , Carboni Margherita , Molinuevo Jose Luis , Grau‐Rivera Oriol , Zetterberg Henrik , Blennow Kaj , Suarez‐Calvet Marc , Gispert Juan Domingo ,   ALFA study
Published: December 2023

AbstractBackgroundThe biological mechanisms underlying structural brain changes in early Alzheimer’s disease (AD) are not well understood. Combining a wide selection of biomarkers of AD pathology, synaptic dysfunction, neuroaxonal injury, and neuroinflammation, and examining their effects on grey matter (GM) changes may provide a deeper understanding of the multifactorial nature of AD. We aimed to identify biological components of key fluid biomarkers predictive of longitudinal GM changes in cognitively unimpaired adults.MethodWe studied 322 cognitively unimpaired individuals from the ALFA+ cohort (Table1) with available longitudinal MRI and cerebrospinal fluid (CSF) biomarkers of β‐amyloid (Aβ42/40), phospho‐tau (p‐tau181), neurogranin, neurofilament light chain (NfL), total‐tau, α‐synuclein, glial fibrillary acidic protein (GFAP), chitinase‐3‐like protein‐1 (YKL‐40), soluble triggering receptor expressed on myeloid cells‐2 (sTREM2), S100 calcium‐binding protein B (S100B), and interleukin‐6 measured using the Roche NeuroToolKit immunoassays. Pairwise longitudinal registration analysis was performed using SPM12 to calculate Jacobian determinant maps. Next, we performed partial least‐squares analysis to determine the optimal number of CSF biomarker components and tested their association with GM volume changes by AT (Amyloid‐Tau) stage.ResultFour distinct biomarker components (C1‐4) were identified (Figure1). C1 was driven by moderate contributions from several biomarkers, particularly markers of core AD pathology and neurodegeneration, which were strongly associated with temporal lobe atrophy in A+T‐ individuals. C2 represented mainly Aβ pathology and, to a lesser extent, axonal damage and astrogliosis that contributed to a decrease in GM volume, especially in the hippocampus in A‐T‐ participants, while showing strong correlations with volume increases in medial frontal regions in A+T+ participants. C3 loading was associated with greater frontoparietal atrophy, especially in A+T+ individuals, and consisted of microglial activation together with Aβ pathology but in the absence of reactive astrogliosis. Lastly, C4, reflecting mostly microglial activation alone, was also strongly associated with frontoparietal atrophy, particularly in A+T+ participants.ConclusionOur results suggest important contributions of Aβ pathology, neuroaxonal damage, and microglial activation to GM morphometry changes in the earliest stages of the AD continuum. Atrophy patterns differed depending on the underlying pathological drivers and on A and T positivity, showing stronger correlations with increasing disease severity; however, volumetric increases were also observed.
Diagnostic Paradigms and Prevalence Estimates
Authors: Hogervorst Eef 
Published: December 2023

AbstractBackgroundMost consensus based international clinical criteria for dementia or neuro‐cognitive disorders require valid and reliable cognitive tests to assess objective impairment. However, cognitive assessments can be affected by educational attainment, cultural background, test exposure and literacy of those tested. These cognitive tests may not always transfer to low and middle‐income countries (LMIC) or to participants with different cultural‐ethnic and/or socioeconomic backgrounds.MethodWe compared data from Indonesian and UK surveys which had included different cognitive assessments and objective dementia diagnoses as a gold standard. Previous work had shown that the Hopkins Verbal Learning Test (HVLT, Brandt, 1991) was cross‐culturally applicable for dementia diagnostics, in different cohorts in Indonesia (Hogervorst et al., 2011), as well as in the UK (Hogervorst, 2002) independent of age, gender and education. Similar results were found for diagnoses of early dementia in Singapore, China,and other LMIC (Xin, 2014). We also included a visual sensitivity test previously found to be sensitive to early dementia (Bandelow, 2008) and various other gold standard assessments (e.g. MMSE, CERAD word list etc) commonly used for dementia diagnostics, as well as confounds such as age, gender and education in regression analyses using the ROC established optimal cut‐off scores.ResultIn the two cohort studies in Indonesia and the UK, lower sensitivity and specificity for dementia was shown for the HVLT and visual sensitivity using ROC analyses than expected. However, the HVLT and in particular our in house developed visual sensitivity test were still able to identify important risk and protective factors for dementia in these cohorts. We also reviewed several other Indonesian cohorts using different cognitive screening methods which had very high dementia prevalence (e.g. 29‐32% > 60 years of age).ConclusionDifferent cognitive assessments can provide varying data on dementia prevalence. Attention should be given to potential overestimates of dementia prevalence and this can possibly be prevented by using culturally and educationally sensitive test. Training of testers should be consistently reviewed and supervised to reduce inter‐tester variability. Cheap, easy to use by non medical but trained staff and good culturally appropriate cognitive tests need to be developed for cross culturally dementia screening studies.
High‐throughput CRISPRi screening to investigate mechanisms underlying Alzheimer’s risk loci
Authors: Gallagher Michael D , Hazel Katheryn EA , Du Wenjuan , Aydin Zeynep , Cheng Yiran , Bell George W , Jaenisch Rudolf , Corradin Olivia 
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD) is a highly (60‐80%) heritable disease with 75 known genetic risk loci. Interestingly, preliminary data from human tissues suggests that these risk loci predominantly act through myeloid cells, implicating microglia, the brain’s resident immune cell, as playing a critical role in AD risk. However, whether the mechanisms underlying these risk loci can be studied in induced pluripotent stem cell (iPSC)‐derived systems, which are currently the only physiologically relevant human model system, remains unknown.MethodWe generated neural progenitors, excitatory neurons, astrocytes and microglia from two human iPSC lines, and performed RNA‐seq to identify all expressed genes and ChIP‐seq for H3K27ac to identify all active gene promoters and enhancers. We compared these data to ChIP‐seq data from primary uncultured (ex vivo) adult human microglia to compare the enrichment of AD risk loci polymorphisms in active promoters and enhancers, as well as a larger panel of neuropsychiatric and neurodegenerative conditions.ResultiPSC‐derived microglia‐like cells (iMGLs) recapitulated an enrichment of AD risk loci polymorphisms in microglial promoters and enhancers previously seen in ex vivo primary human microglia. Furthermore, the enrichments of polymorphisms conferring risk for other neurological and neurodegenerative conditions were similar in iMGLs and ex vivo microglia, suggesting that the epigenome of iMGLs is similar to that of in vivo human microglia.ConclusioniMGLs will serve as a useful cell‐based model for studying AD risk loci, and we are currently developing high‐throughput CRISPR‐based genome and epigenome editing systems to dissect the molecular and cellular mechanisms at these loci, which will nominate novel genes and pathways for therapeutic development.
Closing the sex/gender gap in dementia: honing in on the vasculature (clinical/epidemiology)
Authors: Liu‐Ambrose Teresa 
Published: December 2023

AbstractVascular cognitive impairment is the second most frequent form of dementia after Alzheimer’s Disease (AD). Cerebral small vessel disease accounts for the majority of covert cerebrovascular damage and development of the most common form of VCI. Individuals with cerebral small vessel disease predominantly exhibit white matter hyperintensities (WMHs) and lacunes of presumed vascular origin. These pathologies exacerbate other dementias, including AD.There are sex differences in the incidence and severity of cerebral small vessel disease. Females have greater WMH burden and progression, as well as incident lacunes vs. males. Preliminary evidence also suggest biological sex moderates the effect of aerobic exercise on WMH progression and cognitive function in adults with cerebral small vessel disease. Whether there is a sex difference in the effect of other types of exercise, such as resistance training, on WMH progression is currently unknown. Futures cohort and intervention studies need to include both sexes to examine sex differences in risk factors for cerebral small vessel disease as well as intervention effects. Understanding sex differences will allow precise recommendations that are sex specific for reducing the burden of VCI as well as AD.