1,721,574 research outputs found
Biobanking of CSF : international standardization to optimize biomarker development
No full textAbstract: Cerebrospinal fluid (CSF) reflects pathophysiological aspects of neurological diseases, where neuroprotective strategies and biomarkers are urgently needed. Therefore, biobanking is very relevant for biomarker discovery and evaluation of neurological diseases. Important and unique features of CSF biobanking are intensive collaboration in international networks and the tight application of standardized protocols. The current adoption of standardized protocols for CSF and blood collection as presented in this review enables biomarker studies in large cohorts of patients and controls. Another topic of this review is the selection of control groups, which influences the outcome of biomarker investigations. Control groups in CSF biobanks mainly consist of different disease controls. This is in part due to the fact that lumbar punctures are mostly performed for clinical indications and rarely for research purposes only, as it is a relatively invasive procedure. Moreover, there is a lack of homogenous criteria and definition of control groups. We therefore propose uniform consensus definitions for such control groups in biomarker research, i.e. Healthy controls (HC), Spinal anesthesia subjects (SAS), Symptomatic controls (SC), Inflammatory Neurological Disease Controls (CINDC), Peripheral Inflammatory Neurological Disease Controls (PINDC) and Non-inflammatory Neurological Disease Controls (NINDC). Another important aspect of CSF biobanking is quality control. Systematic studies to address effects of pre-analytical and storage variation on a broad range of CSF proteins are needed. In conclusion, biomarker research in neurodegenerative diseases has entered a new era due to the collaborative and multicenter efforts of many groups. The streamlining of biobanking procedures, including quality control, and the selection of optimal control groups for investigating biomarkers are important improvements to perform high quality biomarker studies
Automated quantitative structural magnetic resonance imaging volumetrics towards clinical application in Alzheimer\u2019s disease
No full textAbstract: Alzheimer\u2019s disease (AD) is a global health challenge influenced by genetic, lifestyle, and environmental factors. Though its precise onset remains unclear, AD is characterized by amyloid-\u3b2 plaques, tau tangles, and neuronal loss, leading to cognitive impairments. The adoption of a clinical-biological biomarker framework enables earlier intervention and personalized treatment, driving research toward refining biomarkers for improved diagnosis and prognosis. Magnetic resonance imaging (MRI) biomarkers, including medial temporal lobe atrophy (MTA), hippocampal volume reduction, and ventricular enlargement, are valuable for detecting brain changes. Traditionally, manual segmentation has been the gold standard, but automated volumetric tools using machine learning are now enhancing accuracy and efficiency. This study evaluates icobrain dm, an automated brain volumetry tool for clinical MRI scans, assessing its feasibility for routine clinical integration. By addressing validation, standardization, and biomarker integration challenges, this research aims to enhance AD detection, staging, and management, supporting personalized treatment strategies. Our findings show that icobrain dm demonstrates robust intra- and inter-scanner reliability (mean DSC > 0.88) and high reproducibility (mean CV < 3%) across global, cortical, and subcortical structures. Icobrain\u2019s automated MTA assessment, expressed as the ratio between inferior lateral ventricle and hippocampal volumes, correlates strongly with visual MTA ratings across cognitive decline stages. However, automated hippocampal volumes alone exhibit moderate correlation, highlighting the inferior lateral ventricle's crucial role in MTA assessment. Comparing automated MTA scores with age-matched healthy controls could aid in clinical interpretation of medial temporal atrophy severity. Additional findings suggest icobrain dm enhances diagnostic certainty by assessing hippocampal and temporal cortex volumes in AD. Brain age and Brain-Predicted Age Difference (BPAD) correlate with accelerated brain aging beyond chronological age and classify cognitive states effectively. Notably, heavy alcohol consumption accelerates brain aging, as reflected in significant BPAD differences between heavy drinkers and non-drinkers. The development of event-based models (EBMs) for AD staging has shown promising generalizability and reliability across datasets. Notably, amnestic Mild Cognitive Impairment (MCI) subjects exhibit higher biomarker event scores than non-amnestic MCI, improving precision in clinical trial recruitment. Additionally, analysis of white matter hyperintensity (WMH), neuropsychological scores, and hippocampal volumes underscores the complex relationship between WMH and cognitive function. Despite progress, challenges remain in validating automated measurements across diverse populations. Tailored EBMs for AD subtypes are crucial for accurate staging, and further research is needed to interpret the interplay between WMH load and cognitive outcomes. Addressing these challenges will enhance the adoption of automated MRI analysis, improving AD diagnosis and patient care
Drug development in Alzheimer's disease supported by translational cerebrospinal fluid biomarkers
No full textTowards global Alzheimer diagnosis : standardization and harmonization of a biomarker-based work-up for Alzheimer's disease
No full textAlzheimer's disease cerebrospinal fluid biomarkers for differential dementia diagnosis : limitations and opportunities
No full textContribution of rare variants in ABCA7 to the genetic etiology of Alzheimer\u2019s disease
No full textAbstract: Despite decades of research, no treatment is available to halt or slow down Alzheimer\u2019s disease (AD), the leading cause of dementia. Unravelling the molecular mechanisms underlying the pathogenesis of AD is imperative to find novel therapeutic targets. Genome-wide association studies in large AD and control cohorts identified ABCA7 as a risk gene for AD. ABCA7, or the ATP-binding cassette subfamily A member 7 gene, encodes a transmembrane protein involved in lipid metabolism and phagocytosis, and was found to regulate the generation and clearance of amyloid \u3b2, an important neuropathological hallmark of AD. Post-GWAS studies identified an enrichment of rare heterozygous premature termination codon (PTC) mutations in AD patients versus healthy control individuals. In fact, our research group was one of the first to report this association in a Belgian cohort of 772 AD patients and 757 control individuals. The general aim of this PhD work was to explore the genetic contribution of rare ABCA7 variants to AD. To get more insights in the mutational spectrum and prevalence of PTC mutations, as well as to better understand the variability in onset age of PTC carriers, we first expanded the ABCA7 screening to a larger Belgian patient (n = 1376) and control (n = 976) cohort. This screening revealed 67 PTC mutations in the patient cohort and 18 in the control group. We also investigated the frequency and pathogenicity of missense, indel and splice variants in the Belgian AD and control cohort. We explored the effect of missense mutations, selected from the Belgian patient cohort, on the subcellular localization of ABCA7 in HeLa cells and show for the first time that these mutations can induce mislocalization and impaired trafficking to the plasma membrane, resulting in a loss-of-functional ABCA7. In addition, we describe co-segregation of a mislocalizing missense mutation with AD in a pedigree showing an autosomal dominant inheritance pattern. Neuropathological examination in ABCA7 PTC and missense mutation carriers revealed prominent levels of cerebral amyloid angiopathy (CAA) additional to AD pathological hallmarks. Therefore, we investigated the contribution of rare ABCA7 variants to CAA in a cohort of 83 Belgian CAA patients. This pilot study reveals a significant role for ABCA7 in the pathogenesis of CAA. In conclusion, this work contributes to the establishment of ABCA7 as a strong genetic risk factor for AD and CAA. In addition, we highlight new pathogenic mechanisms through which rare variants in ABCA7 contribute to AD and CAA
Biological markers to differentiate between Alzheimer\u2019s disease and dementia with Lewy bodies
No full textAbstract: abstract not availabl
Novel insights into genotype-phenotype correlations in frontotemporal lobar degeneration
No full textAbstract: Frontotemporal lobar degeneration (FTLD) represents a group of neurodegenerative disorders characterized by relatively localized degeneration of the frontal and temporal lobes. The most important clinical entity caused by FTLD is frontotemporal dementia (FTD), which is a rare disorder accounting for about 3% of all dementias. In patients under 65 years, however, FTD is the second most common dementia subtype, after Alzheimer\u2019s disease, accounting for approximately 10% of cases. FTD commonly presents with a behavioral variant (bvFTD) subtype, where changes in behavior such as disinhibition, apathy and hyperorality stand out, as well as cognitive impairment such as executive dysfunction. Language variants of the disease (primary progressive aphasia, PPA) may also occur and are characterized by word finding difficulties, impaired motor speech or impaired language understanding. Due to the progressive nature of FTD, with ever-increasing disability in often young patients, the burden of disease is considerable, even more so because an effective cure has yet to be found. FTD is a disorder characterized by tremendous heterogeneity, not only when it comes to the clinical picture. Neuropathologically, different types of protein inclusions are known to cause the neuronal degradation (FTLD-tau, FTLD-TDP, FTLD-UPS, \u2026). Genetically, multiple different pathogenic mutations have been shown to be associated with FTD. The most common FTD-related genes so far are MAPT, GRN and C9orf72. Though some correlations between underlying pathogenic mutations and associated clinical phenotypes have been reported in previous studies, these associations remain largely unexplained and pointed out an interesting knowledge gap. The aim of this PhD project was to elucidate genotype-phenotype correlations in Belgian FTD patients carrying pathogenic mutations in genes associated with FTD. We aimed to perform deep-phenotyping of these factors and analyze their role in the heterogenous spectrum of FTD. We also aimed to uncover genetic modifiers that could further explain this wide variability. Within the scope of this PhD, we were able to provide in-depth phenotypic data on a known pathogenic missense variant, p.R406W, in the MAPT gene encoding the tau protein. Previous reports had shown an unusual, Alzheimer\u2019s disease (AD)-like phenotype in carriers of this variant. In our cohort of 38 Belgian carriers, which is the largest so far, to our knowledge, we uncovered a remarkable clinical phenotype. Mutation carriers presented with an intriguing spectrum of disease, ranging from typical bvFTD on one side to pure clinical AD on the other. In between these extremes, overlap syndromes with characteristics of both diseases occurred. Our findings provide a novel presentation of this known pathogenic mutation and shed more light on the clinical variability with this familial FTLD-tau syndrome. In this PhD thesis, we also present an interesting new pedigree carrying a novel, highly likely pathogenic variant in GRN. Functional mRNA analysis, suggestive clinical features and inheritance pattern, and serum progranulin measurement all provided evidence that helped shed light on the role and pathomechanism of this novel mutation. We have also sought to reproduce findings that were reported by a different group, suggesting a modifying role for locus C6orf10/LOC101929163 in patients with C9orf72 repeat expansion mutations. In our Belgian carrier cohort, we were not able to confirm these previous results. More research will be required to determine the true effect of this potential modifier. More extensive knowledge on genotype-phenotype correlations is relevant in clinical practice, as it may provide the clinician with more tools to suspect a genetic cause of FTD. This will help guide the diagnostic workup in patients as well as in their family members. These findings may also guide research into new disease-modifying therapies and disease-specific biomarkers. Genotype-phenotype correlations linking a set of clinical characteristics to an underlying genetic mutation and pathology can help identify patients most likely to benefit from novel therapies, ensuring more reliable and accurate results in future clinical trials
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