bluuebunny/crossref_metadata_2025_split huggingface dataset:
Proteins involved in synapse organization are associated with longitudinal loss in gray matter network connectivity in prodromal AD
Authors: de Leeuw Diederick Martijn , Duits Flora H. , Vromen Eleonora M. , Dicks Ellen , Barkhof Frederik , Visser Pieter Jelle , Tijms Betty M. 
Published: December 2023

AbstractBackgroundLower gray matter connectivity measures are related to faster cognitive decline in prodromal Alzheimer’s Disease (AD). We investigated the biological underpinnings responsible for this loss of brain connections using cerebrospinal fluid (CSF) proteomics.MethodData from ADNI was used to select 82 individuals with MCI and abnormal CSF amyloid (mean age±SD 74±7) and 37 controls with normal amyloid levels (mean age±SD 75±5), for whom repeated MRI‐scans (median of 6 scans over 1.5 follow‐up years) and baseline CSF proteomic data (in total 306 proteins) were available. We used an automated pipeline (Tijms, Series et al. 2012) to construct gray matter networks from 3D‐T1 sequences and calculate connectivity density and gamma – measures previously found to be most strongly related to cognitive decline (Dicks, Vermunt et al. 2020). Linear mixed models were applied to test associations between baseline CSF protein levels and repeated connectivity metrics, controlling for intracranial volume, age and sex. Proteins that demonstrated significant associations (p<0.05) were identified and examined for their biological relevance according to Gene Ontology.ResultConnectivity density declined over time with ‐0.8% per year (pMCI = 0.001; figure 1), which did not differ from controls (pdif = 0.15). Gamma declined faster in MCI than in controls (bMCI = ‐0.016 vs. bCN = ‐0.007, pdif <0.001; figure 1). Higher levels of 99/108 proteins were associated with faster decline in connectivity density (a.o. tau and neuroprentaxins). These proteins were involved in regulation of synapse organization (GO:0050807; pFDR = 7.00E‐07; figure 2). Higher levels of 9/108 proteins associated with less decline and were involved in chemotaxis (GO:0048247; pFDR = 1.40E‐02). Similarly, 25 out 30 proteins (83%) associated with alterations in gamma over time, showed associations of higher levels with less gamma decline and were also involved in chemotaxis (GO:0050926; pFDR = 9.42E‐05; figure 3). There were no protein‐connectivity relationships in controls.ConclusionProteins involved in synapse organization were associated with faster decline in connectivity density over time in patients, while chemotaxis was associated with less decline. This suggests that synaptic degeneration may predict disease progression while immune responses may serve as a resilience mechanism in AD.
Neurological manifestation of post‐COVID‐19 conditions
Authors: Jung Young Hee H 
Published: December 2023

AbstractBackgroundWe aimed to investigate the factors associated with neurological manifestations of post‐ coronavirus disease 2019 (COVID‐19) conditions.MethodWe retrospectively collected data from 440 patients who visited our post‐COVID‐19 clinic more than 4 weeks after severe acute respiratory syndrome coronavirus 2 infection. We analyzed the prevalence of different neurological symptoms (brain fog, memory impairment, headache, and dizziness) and assessed the associated factors.ResultBrain fog was the most common symptom, observed in 170 patients (38.6%), followed by headaches (137, 31.1%), dizziness (128, 29%), and memory impairment (104, 23.6%). Brain fog was associated with hyposmia or hypogeusia (OR = 2.67, P < 0.001), fatigue (OR = 1.79, P < 0.001), sleep problems (OR = 1.72, P = 0.043), and anxiety (OR = 1.13, P < 0.001). Memory impairment was associated with sleep problems (OR = 2.89, P < 0.001), fatigue (OR = 1.47, P<0.001), depression (OR = 1.07, P = 0.032), and age (OR = 1.02, P = 0.010). Headache and dizziness were associated with sleep problems (OR = 1.5, P < 0.001 vs. OR = 2.79, P < 0.001) and fatigue (OR = 2.38, P < 0.001 vs. OR = 1.43, P < 0.001), respectively. The incidence of brain fog (P < 0.001), memory impairment (P < 0.001), dizziness (P = 0.007), and headache (P = 0.045) accompanied by hyposmia and hypogeusia was higher in patients with the aforementioned symptoms than in those without.ConclusionThis study suggests that there is a relationship between neurological symptoms and other clinical factors, such as fatigue, depression, anxiety, hyposmia, and hypogeusia.
Targeted proteomic search reveals new actors in the synaptic and lysosomal dysfunction in genetic FTD, a GENFI study.
Authors: Weiner Sophia , Malichova Frederika , Simrén Joel , Sauer Mathias , Swift Imogen J , Heller Carolin , Knowles Kathryn , van Swieten John C. , Jiskoot Lize C. , Seelaar Harro , Moreno Fermin , Sanchez‐Valle Raquel , Laforce Robert , Graff Caroline , Masellis Mario , Tartaglia Carmela , Rowe James B. , Borroni Barbara , Finger Elizabeth , Synofzik Matthis , Galimberti Daniela , Vandenberghe Rik , de Mendonça Alexandre , Butler Christopher , Gerhard Alexander , Ducharme Simon , Ber Isabelle Le , Tiraboschi Pietro , Santana Isabel , Pasquier Florence , Levin Johannes , Otto Markus , Sorbi Sandro , Blennow Kaj , Zetterberg Henrik , Rohrer Jonathan D. , Gobom Johan , Esteve Aitana Sogorb 
Published: December 2023

AbstractBackgroundAt present, there are limited fluid biomarkers which measure the underlying pathophysiology of frontotemporal dementia (FTD). Approximately a third of people with FTD have a genetic cause where the pathological basis is well understood. Studying fluid biomarkers in these genetic forms therefore allows greater insight into the relationship between the measure and the underlying disease mechanism. Based on prior work identifying synaptic and lysosomal dysfunction as common mechanisms across the different forms of FTD, we performed a targeted search of proteins related with synapses and the lysosomal pathway on an unbiased proteomic dataset generated from the GENetic FTD Initiative (GENFI) study.MethodThe dataset was obtained from a total of 248 cerebrospinal fluid samples (CSF) from the GENFI cohort including 109 presymptomatic (44 C9orf72, 39 GRN, 26 MAPT) and 63 symptomatic (34 C9orf72, 17 GRN, 12 MAPT) mutation carriers as well as 76 mutation‐negative controls where Tandem Mass Tag (TMT) proteomics had been performed. We selected the clusters obtained from a Gene Ontology analysis that corresponded to the terms “synapse” and “lysosome” and generated a list of proteins related to each category. We then analysed the differences in each specific protein between genetic groups.ResultA total of 42 of the synaptic proteins preselected were significantly changed in symptomatic MAPT mutation carriers, 70 in symptomatic GRN mutation carriers, and 92 in the symptomatic C9orf72 group. Among all of these, there were only 9 proteins that overlapped in the three genetic forms. This list included reelin, which was significantly decreased in each symptomatic group when compared to controls (MAPT p‐value = 0.0016, GRN = 0.0008, C9orf72 = 0.0064), and calretinin, which was significantly increased in symptomatic groups compared to controls (MAPT = 0.0260, GRN = 0.0000, C9orf72 = 0.0100). We then used the same approach to study lysosomal proteins, and found that 38 proteins were significantly changed in symptomatic MAPT, 31 in the symptomatic GRN group and 41 in symptomatic C9orf72 expansion carriers.ConclusionThis study provides new insights into candidate markers to assess synaptic and lysosomal dysfunction in FTD.
Investigation of the choroid plexus implication in Alzheimer’s disease pathophysiology using human proteomics and mouse transcriptomics
Authors: Delvenne Aurore , Vandendriessche Charysse , Gobom Johan , Fagan Anne M. , Verhey Frans R.J. , Zetterberg Henrik , Visser Pieter Jelle , Vandenbroucke Roosmarijn E , Vos Stephanie J. B. ,   EMIF‐AD MBD study group
Published: December 2023

AbstractBackgroundThe choroid plexus (CP) is responsible for the production of cerebrospinal fluid (CSF), transport of proteins to the CSF and clearance of proteins from the CSF. The CP becomes compromised during aging, which is exacerbated in AD. Nonetheless, the relation between CP and AD pathophysiology remains unclear. We aim to investigate the pathophysiology underlying the CP involvement in AD, utilizing human CSF proteomics and mouse CP transcriptomics.MethodWe included 526 individuals from EMIF‐AD MBD, St Louis Knight ADRC and Maastricht BB‐ACL studies. Based on CSF Aβ1‐42 (A, data‐driven cut‐offs), individuals were classified as controls (cognitively normal (CN) A‐, n = 171) or as amyloid‐positive (CN A+, n = 120; mild cognitive impairment (MCI) A+, n = 154; AD A+, n = 81). CSF proteomic data were generated using TMT spectrometry and protein concentrations were compared using ANOVA adjusted for age and sex. Transcriptomic was performed in CP tissue of APPNL‐G‐F (n = 17) and wild‐type C57BL/6J (n = 17) mice using Illumina RNA‐Seq and differential expression analysis was conducted. Next, Gene Ontology and Ingenuity Pathway analyses were performed. For proteomics, high expression of proteins in the CP was identified based on Allen Brain Atlas and the R package ABAEnrichment.ResultIn CN A+, 51 proteins were increased and 21 decreased relative to controls. Out of those increased proteins, 57% were enriched for expression in the CP (ABAEnrichment P<0.001, Figure 1) and were associated with lysosomes and the CLEAR pathway, extracellular matrix and coagulation. A similar pattern was observed for both MCI A+ and AD A+ compared to controls, with a significant percentage of increased proteins enriched for expression in the CP (22 to 30%), which are related to lysosomes and the CLEAR pathway, extracellular matrix and coagulation. In APPNL‐G‐F compared to wild‐type mice, CP transcriptomics revealed 313 upregulated and 198 downregulated genes (Figure 2). The upregulated genes were also associated with the lysosomes and the CLEAR pathway, as well as energy metabolism and lipids.ConclusionHuman proteomics and mice transcriptomics studies suggest an association between amyloid pathology, CP functioning and lysosomes. Dysfunction of lysosomes in AD could relate to compromised clearing events. This is important for future research and AD treatment development.
Longitudinal decrements in the sensitivity of cueing in the Free and Cued Selective Reminding Test predict A+T+ status in cognitively unimpaired individuals
Authors: Sánchez‐Benavides Gonzalo , López‐Martos David , Suarez‐Calvet Marc , Milà‐Alomà Marta , Gispert Juan Domingo , Minguillon Carolina , Zetterberg Henrik , Blennow Kaj , Grau‐Rivera Oriol 
Published: December 2023

AbstractBackgroundThe Index of Sensitivity of Cueing (ISC) from the Free and Cued Selective Reminding Test (FCSRT) memory test evaluates the efficacy of the semantic cues to facilitate retrieval from stored information. Although the ISC has been extensively studied in individuals with prodromal Alzheimer’s disease (AD), its association with AD core pathology, amyloid‐β (A) and p‐tau (T), in cognitively unimpaired (CU) individuals remains unknown. The aim of the present study was to explore the cross‐sectional and longitudinal differences in ISC scores among cerebrospinal fluid (CSF)‐defined AT groups in CU individuals.MethodsWe studied 341 CU participants from the ALFA+ study with available baseline CSF and longitudinal data for the word‐FCSRT‐without‐immediate‐recall version after 3 years. The ISC was computed as: (“total recall”‐“free recall”)/(48‐“free recall”). We defined AT groups (A‐T‐, A+T‐, and A+T+) using baseline CSF levels (Table1) using the cut‐offs defined in Milà‐Alomà et al., 2020. We set independent ANCOVAs to explore the associations between AT status and cross‐sectional and longitudinal (delta) ISC and main FCSRT variables (Table 1). All models were adjusted for age, education and sex, and longitudinal analyses were further adjusted for inter‐visit time and baseline scores. Nominal and FDR‐adjusted p‐values are reported.ResultsNo differences among AT groups were found for baseline FCSRT variables (Table 2). At nominal p‐value levels We observed differences in total recall (TR) and ISC both at visit2 and delta in association with AT status at nominal p‐value levels (Table2), but only the ISC change survived FDR corrections (pFDR = 0.03). Associations were driven by the A+T+ group (Figure1). No differences between A‐T‐ and A+T‐ were found (p>0.05). TR delta was still significant after adjusting for free recall (nominal p = 0.011), suggesting ISC as the main driver of TR decrements.ConclusionDecrements in sensitivity of cueing after 3 years, that in turn diminish FCSRT total recall, were related to concurrent CSF Aβ and p‐tau abnormal levels in CU individuals. No differences between AT groups were observed in free recall, in contrast with other studies using other FCSRT versions that include immediate recall during learning. Further research on secondary memory variables may elucidate the subtle changes related to early AD pathology.
White matter hyperintensities associate with pathological stages of neurodegenerative disease.
Authors: Jonkman Laura E. , Lin Chen‐Pei , Frigerio Irene , Noteboom Samantha , Bouwman Maud M.A. , Reijner Niels , Preziosa Paolo , Boon Baayla D.C. , Bouwman Femke H. , Rozemuller Annemieke J.M. , Steenwijk Martijn D. , Barkhof Frederik , Berg Wilma D.J. 
Published: December 2023

AbstractBackgroundWhite matter hyper‐intensities (WMH) are observed on FLAIR MRI, increase with age and are more prominent in neurodegenerative diseases such as in Alzheimer’s disease (AD) and Parkinson’s disease (PD). The aim of this study was to assess the association between WMH and neuropathological staging of amyloid‐beta, neurofibrillary tangles (NFT) and α‐synuclein (α‐syn).MethodIn‐situ 3T‐MRI 3DT1‐weighted and 3D‐FLAIR data were collected for 77 clinically defined and pathologically‐confirmed brain donors; 31 AD, 21 PD and PD dementia (PDD), and 25 controls. WMH were segmented on FLAIR using an in‐house developed multiview convolutional neural network, followed by manual checking, and volume was obtained with FSL. Fifteen brain regions were dissected at autopsy, immunostained and evaluated for neuropathological diagnosis, including Thal amyloid phase, CAA type, and Braak stages for NFT and α‐syn. Group differences were assessed with linear models (corrected for age, gender, post‐mortem delay), and associations with Spearman and Pearson partial correlations.ResultCompared to controls, WMH load was higher in AD (p<0.001), specifically amnestic AD (p = 0.003) rather than non‐amnestic AD (p = 0.053), and higher in PD (p = 0.016), specifically non‐demented PD (p = 0.015) rather than PDD (p = 1.0). No difference in gender was observed (p = 0.38). Without the influence of pathology (in controls), WMH was associated with age (r = 0.49,p = 0.016).In the whole cohort, WMH was associated with Fazekas score (r = 0.67; p<0.001), normalized brain volume (NBV; r = ‐0.31,p = 0.007), gray matter volume (NGMV; r = ‐0.36,p = 0.002), Thal phase (r = 0.24,p0.034), Braak NFT stage (r = 0.33,p = 0.004), and Braak α‐syn stage (r = 0.27, p0.018).Across controls and AD, WMH associated with NBV (r = ‐0.39,p = 0.004), NGMV (r = ‐0.42,p = 0.002), left and right hippocampal volume (r = ‐0.36,p = 0.008 and r = ‐0.32,p = 0.022), Braak NFT (r = 0.41,p<0.001), Thal phase (r = 0.41,p = 0.002), and CAA (r = 0.34,p = 0.01). Amnestic and non‐amnestic AD showed similar results, except for CAA, which was associated with WMH in non‐amnestic AD only (r = 0.33,p = 0.04).Across controls and PD(D), WMH associated with Braak NFT stage (r = 0.39,p = 0.008) and Braak α‐syn stage (r = 0.60,p<0.001), but not with MRI outcome measures. In this respect PD and PDD showed different results; in PD WMH associated with NGMV (r = ‐0.37,p = 0.031), in PDD with left and right hippocampal volume (r = ‐0.44,p = 0.014 and r = ‐0.44,p = 0.015).ConclusionWMH associate with pathological stages of AD and PD(D), and contributes to MRI atrophy.
Knowledge, Attitude, and Compliance with management of Patients with Selected Risk; Diabetes Mellitus & Hypertension On Dementia in Selected Primary Health Care Centres in Nigeria: An Impetus for Primary Prevention of Vascular Dementia
Authors: Nwinee Victor Boma , Ucheoma Allessandra Chinazo 
Published: December 2023

AbstractBackgroundDementia is clinical syndrome, characterized by a progressive and irreversible loss of cognitive function, has seen a rapid increase in Nigeria over the past 20 years1. As access to healthcare improves, more people are living into old age and becoming at risk of developing the condition. In Nigeria, 55% of the population primarily rely on primary care centers for their health needs2. Studies have shown that the prevalence of hypertension and diabetes in Nigeria is increasing, and these are listed as risk factors for dementia by the World Health Organization3. Despite this, there has been limited research on the knowledge and compliance to treatment among those at high risk for dementia, who are crucial for reducing its prevalence. This study focuses on two common risk factors in Nigeria, hypertension and Type 2 diabetes mellitus.ETHICAL COMMITTEE APPROVAL: Obtained from the Human Research Ethical Committee of Lagos University Teaching Hospital, Nigeria.
STUDY POPULATION: People with vascular risk factors (Hypertension & Type 2 Diabetes Mellitus) attending primary care facilities in selected centers in Nigeria.
Inclusion criteria:1.	Patients 35 to < 65 years.2.	Patients with correct diagnosis of Hypertension3.	Patients with correct diagnosis of Diabetes Mellitus4.	Patients with at least basic primary school education
Exclusion criteria:1.	Patients who don’t pass the cognitive test.2.	Patients with neuropsychiatric conditions3.	Hypertension in pregnancy
Study design: A clinic‐based descriptive cross‐sectional study.MaterialsMini mental State Exam tool prior to commencement of the questionnaire‐based interview. SPSS, structured interviewer‐based questionnaires.RESEARCH ASSISTANTS: Medical graduates of the College of Medicine, University of Lagos, Nigeria, are the field‐enumerators for this study.Results, Discussion & ConclusionOngoing study
FUNDING: Self‐funded
References
1. Adeloye D, Auta A, Ezejimofor M, Oyedokun A, Harhay MO, Rudan I, Chan KY. Prevalence of dementia in Nigeria: a systematic review of the evidence. J Glob Health Rep. 2019;3:e2019014. doi: 10.29392/joghr.3.e2019014. Epub 2019 Mar 27. PMID: 31528708; PMCID: PMC6746335.2. Akinlua JT, Meakin R, Umar AM, Freemantle N. Current Prevalence Pattern of Hypertension in Nigeria: A Systematic Review. PLoS One. 2015 Oct 13;10(10):e0140021. https://doi.org/10.1371/journal.pone.0140021. PMID: 26461923; PMCID: PMC4603956.3. World Health Organization. Dementia. September 2022 https://www.who.int/news‐room/fact‐sheets/detail/dementia. Accessed 15/12/2022
Differential Expression of Synaptic Biomarkers in the Cerebrospinal Fluid Differentiates Behavioural Variant of Frontotemporal Dementia from Primary Psychiatric Disorders and Alzheimer’s Disease
Authors: Das Shreyasee , van Engelen Marie‐Paule E. , Goossens Julie , Jacobs Dirk , Bongers Bram , Fieldhouse Jay L.P. , Pijnenburg Yolande A.L. , Teunissen Charlotte E. , Vanmechelen Eugeen , Verberk Inge M.W. 
Published: December 2023

AbstractBackgroundThe lack of early molecular biomarkers in sporadic behavioural variant of frontotemporal dementia (bvFTD) and its clinical overlap with primary psychiatric disorders (PPD) and Alzheimer’s Disease (AD) hampers its diagnostic distinction. Synaptic dysfunction is an early feature in bvFTD and identification of specific biomarkers might improve its diagnostic accuracy. We aimed to assess the diagnostic performance of synaptic biomarkers in bvFTD compared to PPD, AD and controls, and its association with social cognition, cognitive performance and disease severity.MethodParticipants with probable bvFTD (n = 60), PPD (n = 60), biomarker confirmed AD (n = 60), and cognitively normal AD biomarker negative controls (n = 58) with available CSF, (social) cognitive tests, FTLD‐CDR, and Ekman Faces Test score were included (Table 1). CSF synaptosomal associated protein 25 (SNAP25), neurogranin (Ng), neuronal pentraxin 2 (NPTX2) were measured, along with neurofilament light (NfL), and compared between groups using regression models adjusted for age and sex. Diagnostic accuracy was assessed using ROC analysis and Spearman’s correlation analysis for correlation with cognitive measures was performed.ResultNPTX2 was significantly lower in bvFTD patients compared to PPD and controls (P<0.001). NfL was higher in bvFTD patients compared to PPD, AD and controls (P<0.001) and showed the highest diagnostic accuracy between bvFTD and PPD (AUC: 0.95, CI: 0.91,0.99, sensitivity: 97% specificity: 82%). Between bvFTD versus AD, SNAP25 showed the highest diagnostic accuracy (AUC: 0.78 CI: 0.70, 0.86, sensitivity: 63% specificity: 83%). The selected biomarker panel to differentiate bvFTD from PPD consisted of NfL and NPTX2 and had the highest AUC among the measured biomarkers (AUC: 0.96, CI: 0.93, 0.99, sensitivity: 95%, specificity: 85%), while that for bvFTD and AD consisted of NfL and Ng (AUC: 0.82, CI: 0.75, 0.90, sensitivity: 63% specificity: 92%). Among cognitive scores of bvFTD patients, SNAP25 correlated significantly with visuospatial ability (r = 0.37, P<0.05). There was no correlation between synaptic markers and the Ekman 60 faces test or FTLD‐CDR scores of disease severity.ConclusionTogether with NfL, synaptic biomarkers NPTX2 and Ng have added value for the differential diagnosis of bvFTD versus PPD and AD respectively. However, there was almost no association of the CSF biomarkers with cognitive performance of bvFTD and PPD patients.