bluuebunny/crossref_metadata_2025_split huggingface dataset:
Utilization and future of biomarkers in biofluid as outcome measures in clinical trials for Alzheimer’s disease: a systematic review
Authors: Oosthoek Marlies , Vermunt Lisa , de Wilde Arno , Bongers Bram , Antwi‐Berko Daniel , Scheltens Philip , Van Bokhoven Pieter , Vijverberg Everard G.B. , Teunissen Charlotte E. 
Published: December 2023

AbstractBackgroundIn recent years, the availability of biofluid markers in Alzheimer’s disease (AD) has increased substantially, but it is unclear to what extend these are applied to support drug development. Therefore, we provide an overview of biofluid biomarker use within trials.MethodTo identify how fluid biomarkers are used in clinical trials, we performed a search (8‐FEB‐2022) on www.clinicaltrials.gov, using the search term ‘Alzheimer’s disease’, and selected trials aimed at disease modification starting from 1‐JAN‐2017 to 1‐JAN‐2022. Biofluid markers and their purpose in each trial were described. Results are summarized by trial phase, target class, and endpoint information.ResultWe identified 186 trials of which 44% used biofluid markers. 15% of phase 1 trials, 15% of phase 2 trials, and 6% of phase 3 and 4 trials employ fluid biomarkers as primary outcome (Figure 1). Blood and CSF biomarkers were used equally frequent. CSF biomarkers for Aβ, Tau, and other biomarkers were employed in 21%, 25%, and 16% of the 186 trials, respectively. Blood biomarkers for Aβ, Tau, and other biomarkers were used in 14%, 13%, and 23% of the trials, respectively. Moving further in the drug development phases, contribution of classic AD biomarkers increased, especially in CSF. Overall, a combination of Aβ, Tau and other biomarkers was used most frequent. 25% of the trials use biofluid target engagement markers. Target engagement marker use is most prominent in amyloid and tau targeting drugs. Lack of target engagement markers is most prominent in synaptic plasticity/neuroprotection, neurotransmitter receptor, vasculature, epigenetic regulators, proteostasis, gut‐brain axis targeting drugs.ConclusionThere exists a need for new fluid biomarkers, to reflect pathology which can be used in certain target classes where there currently is a lack of fluid biomarkers. To support future use biofluid markers as surrogate outcomes, research into the specific pathological processes they reflect and their correlation with cognition is warranted. This can pave the way into implementation of surrogacy biomarkers in AD clinical trials.
Investigation of inflammation in Lewy body dementia: a scoping review
Authors: Loveland Paula M , Yu Jenny , Churilov Leonid , Yassi Nawaf , Watson Rosie 
Published: December 2023

AbstractBackgroundInflammatory mechanisms are increasingly recognized as part of the pathogenesis of neurodegenerative diseases, including Lewy body dementia (LBD). Advances in analytical techniques using in vivo and postmortem samples have been applied to address questions of key mechanisms and relevance to clinical manifestations. Our primary objective was to review methods used to investigate inflammation in LBD (dementia with Lewy bodies and Parkinson’s disease dementia), and how these are applied to conceptualise inflammation. Our secondary objective was to identify alterations in inflammatory signals in LBD compared to people without neurodegenerative disease, and compared to related neurodegenerative disease, in particular AD and PD.MethodA scoping review was performed by identifying relevant human studies that investigated inflammation in LBD. The major electronic databases MEDLINE, Embase, Web of Science, and PSYCHInfo were searched. Two authors performed abstract screening and full text review.ResultOf 1970 results screened, 65 studies were included. Twenty‐nine studies analysed postmortem brain tissue and 35 included living subjects. Largely cross‐sectional data were available, although 2 longitudinal clinical studies of prodromal Lewy body disease were noted. Analysis of biofluid (blood and cerebrospinal fluid) was the most common in vivo method used (n = 31) and 3 studies investigated LBD genetics. Investigations were focused on inflammatory immune cell activity (microglia, astrocytes, lymphocytes), and molecules linked to inflammation (e.g., cytokines). Results of included studies supported innate and adaptive immune system contribution to inflammation associated with Lewy body pathology and clinical features of the disease. Different signals in early and late‐stage disease, with possible late immune senescence including dystrophic microglia and altered adaptive immunity, were distinct from Alzheimer’s disease. The strength of these associations is limited by the varying methodologies, small study sizes and cross‐sectional nature of data.ConclusionCurrent investigation of inflammation in LBD utilises substrate collected from early to late‐stage disease. Strengths and limitations of the range of analytical techniques used must be considered when forming conclusions. Longitudinal data that informs associations with clinical and other biomarker outcomes is needed to improve understanding of inflammatory activity over the disease course of LBD. This could identify markers of disease activity and therapeutic targets.
Sex‐specific effects of Ceramides on White Matter Hyperintensities in the Rhineland Study
Authors: Landstra Elvire Nadieh , Lohner Valerie , Breteler Monique M.B. 
Published: December 2023

AbstractBackgroundThe frequency of white matter hyperintensities (WMH), which are considered to reflect cerebral small vessel disease, shows substantial sex differences. The biology underlying this remains unknown. Ceramides (CERs) are important sphingolipids, have been associated with WMH, and might play a key role in WMH pathogenesis. Of note, their plasma levels reportedly differ between men and women. Here, we examined sex‐specific effects of CER concentrations, CER ratios and the CER score on WMH load.MethodThe analysis is based on the first 3,284 participants aged 30‐95 years of the community‐based Rhineland Study with brain MRI and sphingolipid data available. Twelve CERs were measured in plasma on the Metabolon Complex Lipids Platform, while WMH were automatically segmented on T1, T2 and FLAIR images. Using multivariable linear regression, we examined the association of scaled absolute (nmol) and relative (mol%) CER concentrations, 6 CER ratios and a CER score with logit‐transformed WMH load. In model 1, we adjusted for age, sex and age‐squared, while model 2 was additionally adjusted for body mass index (BMI), smoking and use of lipid‐lowering medication. Additionally, we included a sex‐interaction term and performed a sex‐stratified analysis where it was significant. P‐values were FDR adjusted.ResultMean age of participants was 54±14 years, 57% were women. Multiple CERs (CER18:0, CER20:0, %CER18:0), CER ratios (CER18:0/16:0, CER18:0/24:0, CER20:0/24:0, CER22:0/24:0), and the CER score were associated with increased WMH load independent of sex and age. The absolute concentration of almost all CERs and some ratios were more strongly associated with WMH in women compared to men (Figure 1). Associations were largely independent of body‐mass index, use of lipid‐lowering medication and smoking.ConclusionWe showed novel associations of CERs, CER ratios and the CER score with WMH, and found a significant sex‐interaction for the majority of these associations. Thus, our results suggest that CERs could be important in understanding sex‐specific mechanisms of WMH and possibly explain the higher WMH burden in women.
Clinical Characteristics of a PSEN1 Variant in the Argentine Cohort of the Dominantly Inherited Alzheimer Network
Authors: Clarens Maria Florencia , Mendez Patricio Chrem , Tapajoz Fernanda , Martinez Carlos , Helou Belén , Surace Ezequiel , Crivelli Lucía , Romero Daniela , Vigo Gabriela , Allegri Ricardo Francisco 
Published: December 2023

AbstractBackgroundIn recent years, there has been an increase in the number of case reports of families with autosomal dominant Alzheimer’s disease (ADAD) in Latin America (LA). Nevertheless, little is known about the clinical phenotypes and demographic characteristics of mutations in each country. Past literature has proved that variants in LA have different and unique characteristics than those reported in Asia, North America, and Europe. Clinical heterogeneity in ADAD supports the need to study clinical phenotypes, especially in preclinical stages, to develop cognitive and clinical markers of the disease.We aimed to describe clinical and cognitive characteristics at baseline assessment of an Argentina PSEN1 p.M146L family enrolled at DIAN.MethodFifteen Dian Participants living in Buenos Aires and its suburbs and in Taco Pozo, a rural and isolated community from the Province of Salta, positive for the PSEN1 p.M146L mutation, were recruited. DNA was obtained from peripheral blood leukocytes according to standard protocols. In addition, exon 5 of the PSEN1 gene was PCR‐amplified, and Sanger sequencing was performed. NACC Uniform Data Set clinical assessment, including the 2.0 UDS Neuropsychological Battery, was administered. Two groups were used to compare cognitive data: Patients with CDR:0 (n:10) and patients with CDR>0 (n:5).ResultThe mean age at symptom onset reported in this cohort was 42,90 (SD: 4,62). Significant differences were found in several cognitive measures: Logical Memory Immediate, TMT B and Digit Backward (<0,001); MMSE, Category Fluency Animals, TMT A and Digit Symbol(<0,05). In neurological signs, paraplegia was reported in one of the patients.ConclusionAs expected, differences in neuropsychological tests showed a prevalence of memory deficits, however, dysexecutive symptoms were also present for this mutation. Paraplegia in PSEN1 p.M146L has not been reported in the literature so far. Ongoing longitudinal work will be important in tracking changes in this cohort. Other characteristics, proper of underrepresented groups, such as socioeconomic status, education, race, and ethnicity, deserve appropriate follow‐up. Future studies are planned, comparing urban and rural populations in this cohort with the same mutation.
Neurofilament Light Chain modifies the association of olfactory dysfunction with cognitive decline: a 12‐year follow‐up of the Shanghai Aging Study
Authors: Xiao Zhenxu , Wu Wanqing , Ma Xiaoxi , Wu Jie , Liang Xiaoniu , Zhao Qianhua , Ding Ding 
Published: December 2023

AbstractBackgroundOlfactory dysfunction has been reported for its association with cognitive impairment and incident dementia. However, the underlying role of neurodegeneration in this relationship is not fully understood.MethodThis prospective cohort study included participants from the Shanghai Aging Study (SAS) who were 60 years or older and diagnosed as dementia‐free at baseline and completed at least one follow‐up interview between 2010 and 2022. At baseline, olfactory identification function was assessed by the 12‐item Sniffin’ Sticks Smell test (SSST‐12). Olfactory dysfunction was defined as SSST‐12 < 7, 6, and 5 in three age groups of participants with (age < 70, 70 ≤ age < 80, and age ≥ 80), respectively, according to previously reported normative data of olfaction in the SAS. Baseline blood Neurofilament Light Chain (NfL) was quantified using the ultra‐sensitive Single Molecular Array technology (Quanterix), and dichotomized into low and high levels according to the median concentration. Multiple cognitive function assessments were administered by the Mini‐mental State Examination (MMSE) at baseline and follow‐ups. We used the linear mixed‐effect model to fit the MMSE trajectories in participants with and without olfactory dysfunction adjusting for baseline age, sex, education year, smoking, and APOE ε4, with person‐specific MMSE intercept and slope. Stratified analysis was conducted in participants with low and high NfL.ResultAmong 1125 participants included in this study, 296 were defined as having olfactory dysfunction at baseline. Less education, higher proportion of APOE ε4 allele, and lower baseline and follow‐up MMSE scores were observed in participants with olfactory dysfunction (Table 1). During the median 9.4 years follow‐up, participants with olfactory dysfunction at baseline evidenced a faster MMSE decline compared with those without olfactory dysfunction (b [95% CI]: ‐0.08 [‐0.15, ‐0.02], P = 0.02) (Figure 1). Such association remained statistically significant (‐0.18 [‐0.31, ‐0.06], P = 0.005) in the subgroup with high NfL, but not in the subgroup with low NfL (0.004 [‐0.07, 0.07], P = 0.92) (Figure 2).ConclusionBlood NfL may modify the association of olfactory dysfunction with long‐term cognitive decline in community‐dwelling older adults. In individuals with high potential neurodegeneration, olfactory dysfunction may be an independent indicator of future cognitive deterioration.
Comparison of brain volume estimation via cerebral computed tomography and magnetic resonance imaging
Authors: Schmieschek Maximilian H. T. , Richter Nils , Gramespacher Hannes , Dronse Julian , Onur Oezguer A. 
Published: December 2023

AbstractBackgroundIn clinical routine, cerebral computed tomography (cCT) is easily accessible and more commonly used than brain magnetic resonance imaging (cMRI). However, to the best of our knowledge a fully automated, validated regional specific volume estimation tool is lacking. Therefore, the aim of this study was to investigate the association between tissue classification for gray matter of both modalities.MethodBrain imaging segmentations of cCT and structural MRI of 37 healthy controls and 20 patients with mild cognitive impairment due to Alzheimer’s disease were performed. The intensity and voxel count of normalized gray matter maps (MNI) in regions of interest using the Automated Anatomical Labelling Atlas (AAL3) were computed and compared between cCT and cMRI in both cohorts.ResultBrain Volume, measured by intensity and voxel count of gray matter, is associated between cortical regions acquired by cCT and cMRI. Although correlation coefficients varied between different brain areas, cortical compared to subcortical regions showed a relatively strong correlation.ConclusionThe evaluation of brain atrophy using segmented brain images acquired by cCT may be a simple, cost‐effective, and valuable addition to the clinical workflow, particularly in the context of socioeconomic and health disparities.
Education as Risk Factor of Mild Cognitive Impairment ‐ the Role of the Gut Microbiome
Authors: Klee Matthias , Aho Velma T. E. , May Patrick , Krüger Rejko , Wilmes Paul , Leist Anja K. 
Published: December 2023

AbstractBackgroundResearch on social determinants of health has identified modifiable risk factors that contribute to an individual’s risk of developing dementia [1]. Individuals with mild cognitive impairment (MCI) present a group with highest potential of lifestyle interventions due to the risk of progressing to dementia [2]. The pathways from identified modifiable risk factors for dementia such as education have not been clarified, however understanding the relationships between risk factors and MCI could help identify mechanisms for intervention and reducing risk of progressing to dementia. Previous findings found taxonomic differences in dementia and MCI patients, and further education linked to indicators of gut dysbiosis [3–5]. We sought to test the possibly mediating role of gut dysbiosis and taxonomic differences in the relationship between modifiable risk factors and MCI, independent of genetic risk for developing dementia.MethodGut microbiome composition was ascertained with 16S rRNA gene amplicon sequencing. MCI classification was based on MoCA performance. Educational attainment in years was grouped. Mediation analysis [6] was conducted decomposing direct and indirect effects of educational attainment on MCI mediated by markers of dysbiosis (Chao1, Inverse Simpson, Shannon) while controlling for polygenic risk of Alzheimer’s Disease, Lewy Body Dementia and Parkinson’s Disease to account for different etiologic neurodegenerative pathways manifesting as MCI. Taxonomic differences across education groups were further tested (ANCOM‐BC, DESeq2) and PAM clustering based on relative abundance at Genus level was conducted to explore underlying signatures.ResultAfter exclusion of participants below age 50, or with missing data, n = 256 participants (n = 58 with MCI) of the Luxembourg Parkinson’s Study without Parkinson’s disease were eligible for analysis (M[SD] Age = 64.7[8.3] years). Higher vs lower educational attainment had a controlled direct effect (CDE) = 0.35 (P<.01) on MCI, Chao1 included as mediator. We did not find significant indirect effects via any indicator of dysbiosis. Clusters with lower abundance of Bacteroides relative to Prevotella and Ruminococcus were at higher risk of MCI.ConclusionOur findings indicate direct effects of education not mediated by markers of dysbiosis. Taxonomic analysis suggests a signature linked to lower risk of dementia in higher educated individuals.
Grey matter alterations associated with the phenomenology of visual hallucinations in Lewy Body Disease
Authors: D'Antonio Fabrizia , Teghil Alice , Boccia Maddalena , Suppa Antonio , Fabbrini Andrea , Canevelli Marco , Fiorelli Marco , Caramia Francesca , Bruno Giuseppe , Ferracuti Stefano , Guariglia Cecilia , Aarsland Dag , Ffytche Dominic H 
Published: December 2023

AbstractBackgroundVisual hallucinations (VH) phenomenology in Lewy Body Disease (LBD) is heterogenous, including minor phenomena (passage, presence, illusions) and complex hallucinations. Neural substrates and mechanisms involved are still unclear. Here we investigated grey matter (GM) alterations associated with minor (MVH) and complex VH (CVH).MethodLBD patients (n = 28) with VH and Healthy controls (HC‐n = 20) underwent MRI. We administered the North East Visual Hallucinations Interview (NEVHI), a semi‐structured interview assessing the phenomenology of VH, their duration and frequency. VH were clustered in MVH and CVH and treated as a patient’s trait. First we compared GM volume of LBD and HC. Then, multiple regressions were performed to disclose alterations associated with the duration, frequency and severity of MVH and CVH, including the opposite VH domain, total intracranial volume (TIV) and MMSE as nuisance regressors.ResultWe found a decreased GM volume in the bilateral fusiform gyrus (FG), in the left posterior cingulate and in the right inferior frontal gyrus in LBD compared to HC. We also found that CVH duration was negatively associated with GM volume in the left FG. We did not find any association with MVH phenomenology.ConclusionLBD patients showed GM alterations in ventral‐visual‐stream, default‐mode‐network and inhibitory regions compared to HC. Although the LBD versus HC comparison is not specific to VH, the regions identified have been implicated in VH in previous studies suggesting they may represent structural hallmarks of functional alterations in networks contributing to VH. When the association with VH phenomenology was tested, we did not find GM alterations associated with MVH. It is likely that these phenomena might be not associated with structural alterations but with functional alterations within visual networks. CVH were instead associated with decreased GM in FG. The atrophy in the FG may lead to a spontaneous activation of this region that sustain CVH duration, accounting for VH content (D’Antonio et al., 2022). These alterations may represent the predisposing condition to VH in LBD. According to the hodotopic model, VH phenomenology may help identify brain regions implicated and might reveal the substrates for cortical region/network dysfunctions occurring during VH state (ffytche et al., 2008).
Brain dynamics during mnemonic discrimination in preclinical and prodromal Alzheimer’s disease
Authors: Gellersen Helena M , Baumeister Hannah , Heneka Michael T. , Schneider Anja , Fliessbach Klaus , Spottke Annika , Teipel Stefan , Wiltfang Jens , Jessen Frank , Düzel Emrah , Berron David 
Published: December 2023

AbstractBackgroundMnemonic discrimination of similar lures and targets is emerging as a promising marker of subtle memory decline in early Alzheimer’s disease (AD) due to its reliance on regions most affected by AD pathology. Tau pathology initially targets medial temporal lobe (MTL) regions in an anterior‐temporal (AT) brain network, which is preferentially involved in object processing, before it can be found in the posterior‐medial (PM) network associated with scene processing. Tests of object and scene mnemonic discrimination may therefore serve as behavioural indicators of the functional integrity of AT and PM regions, respectively. We investigated behavioural and neural changes in mnemonic discrimination across the AD spectrum.Method201 DELCODE cohort participants underwent fMRI scanning during an object‐scene mnemonic discrimination task at four time points from baseline to three‐year follow‐up. At baseline, participants were split by diagnostic group (cognitively unimpaired = CU, subjective cognitive decline = SCD, mild cognitive impairment = MCI, dementia of the Alzheimer’s type = DAT; Table 1). We identified brain regions showing lower activity to repeated targets but not similar lures, indicative of successful pattern separation of overlapping memory representations.ResultThese findings present cross‐sectional baseline data. Behavioural data showed a main effect of group but no group by category (objects, scenes) interaction. CUs and SCDs outperformed patients across domains and CUs scored higher than SCDs only in scene discrimination. Amyloid positive and negative CUs and SCDs did not differ in performance. Successful mnemonic discrimination engaged hippocampus, parahippocampal cortex, precuneus, angular gyrus, and inferior frontal regions for both objects and scenes. Correct object discrimination was additionally associated with amygdala and transentorhinal cortical activity. Reduced brain activation in regions of the anterior‐temporal and posterior‐medial network during successful object and scene mnemonic discrimination, respectively, was found in patient groups (MCI+DAT) compared to cognitively normal (CU+SCD) older adults.ConclusionOur findings lend further support to the utility of mnemonic discrimination as indicator of memory impairment in early AD. Object and scene tasks engage partially dissociable brain networks and individuals with cognitive impairment show reduced neural pattern separation effects. These findings lay the groundwork for future longitudinal analyses to track these changes based on clinical and biomarker status.