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Article ; Online: Associating Alzheimer’s disease pathology with its cerebrospinal fluid biomarkers

Bridel, Claire / Somers, Charisse / Sieben, Anne / Rozemuller, Annemieke / Niemantsverdriet, Ellis / Struyfs, Hanne / Vermeiren, Yannick / Van Broeckhoven, Christine / De Deyn, Peter P. / Bjerke, Maria / Nagels, Guy / Teunissen, Charlotte E. / Engelborghs, Sebastiaan

Brain

2022 Volume 145, Issue 11

Abstract: Alzheimer’s disease cerebrospinal fluid (CSF) biomarkers 42 amino acid long amyloid-β peptide (Aβ1 ... considered surrogate biomarkers of Alzheimer’s disease pathology, and significantly improve diagnostic ... Alzheimer’s disease to reflect post mortem neuropathological changes. Individuals were selected from 2 autopsy cohorts ...

Abstract	Alzheimer’s disease cerebrospinal fluid (CSF) biomarkers 42 amino acid long amyloid-β peptide (Aβ1-42), total tau protein (T-tau), and tau protein phosphorylated at threonine 181 (P-tau181) are considered surrogate biomarkers of Alzheimer’s disease pathology, and significantly improve diagnostic accuracy. Their ability to reflect neuropathological changes later in the disease course is not well characterized. This study aimed to assess the potential of CSF biomarkers measured in mid- to late-stage Alzheimer’s disease to reflect post mortem neuropathological changes. Individuals were selected from 2 autopsy cohorts of Alzheimer’s disease patients in Antwerp and Amsterdam. Neuropathological diagnosis was performed according to the updated consensus National Institute on Aging-Alzheimer’s Association guidelines by Montine et al, which includes quantification of amyloid beta plaque, neurofibrillary tangle, and neuritic plaque load. CSF samples were analyzed for Aβ1-42, T-tau, and P-tau181 by ELISA. 114 cases of pure definite Alzheimer’s disease were included in the study (mean age 74 years, disease duration 6 years at CSF sampling, 50% females). Median interval between CSF sampling and death was one year. We found no association between Aβ1-42 and Alzheimer’s disease neuropathological change profile. In contrast, an association of P-tau181 and T-tau with Alzheimer’s disease neuropathological change profile was observed. P-tau181 was associated with all three individual Montine scores, and the associations became stronger and more significant as the interval between lumbar puncture and death increased. T-tau was also associated with all three Montine scores, but in individuals with longer intervals from lumbar puncture to death only. Stratification of the cohort according to APOE ε4 carrier status revealed that the associations applied mostly to APOE ε4 non-carriers. Our data suggest that similarly to what has been reported for Aβ1-42, plateau levels of P-tau181 and T-tau are reached during the disease course, albeit ...
Keywords	Life Science
Subject code	610
Language	English
Publishing country	nl
Document type	Article ; Online
ZDB-ID	80072-7
ISSN	0006-8950
ISSN	0006-8950
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Association between Low Vitamin D Status, Serotonin, and Clinico-Biobehavioral Parameters in Alzheimer’s Disease

Richter, Anna-Lena / Diepeveen-de Bruin, Marlies / Balvers, Michiel G.J. / de Groot, Lisette C.P.G.M. / de Deyn, Peter Paul / Engelborghs, Sebastiaan / Witkamp, Renger F. / Vermeiren, Yannick

Dementia and Geriatric Cognitive Disorders

2023 Volume 52, Issue 5

Abstract: ... of Alzheimer’s disease (AD), with few in vitro studies pointing to effects on serotonergic and amyloidogenic turnover ...

Abstract	Introduction: Studies suggest a role of vitamin D in the progression and symptomatology of Alzheimer’s disease (AD), with few in vitro studies pointing to effects on serotonergic and amyloidogenic turnover. However, limited data exist in AD patients on the potential association with cognition and behavioral and psychological signs and symptoms of dementia (BPSD). In this retrospective cross-sectional study, we, therefore, explored potential correlations of serum 25-hydroxyvitamin D3 (25(OH)D3) concentrations, indicative of vitamin D status, with serum serotonin (5-hydroxytryptamine, 5-HT) levels, cognitive/BPSD scorings, and cerebrospinal fluid (CSF) biomarker levels. Methods: Frozen serum samples of 25 well-characterized AD subjects as part of a previous BPSD cohort were analyzed, of which 15 had a neuropathologically confirmed diagnosis. Serum 25(OH)D3 levels were analyzed by means of LC-MS/MS, whereas 5-HT concentrations were quantified by competitive ELISA. Results: Among AD patients, vitamin D deficiency was highly prevalent, defined as levels below 50 nmol/L. Regression analyses, adjusted for age, gender, and psychotropic medications, revealed that serum 25(OH)D3 and 5-HT levels were positively associated (p = 0.012). Furthermore, serum 25(OH)D3 concentrations correlated inversely with CSF amyloid-beta (Aβ1-42) levels (p = 0.006), and serum 5-HT levels correlated positively with aggressiveness (p = 0.001), frontal behavior (p = 0.001), depression (p = 0.004), and partly with cognitive performance (p < 0.005). Lastly, AD patients on cholinesterase inhibitors had higher serum 25(OH)D3 (p = 0.030) and lower serum 5-HT (p = 0.012) levels. Conclusions: The molecular associations between low vitamin D status, serum 5-HT, and CSF Aβ1-42 levels are highly remarkable, warranting further mechanistic and intervention studies to disclose potential involvement in the clinico-biobehavioral pathophysiology of AD.
Keywords	Life Science
Subject code	610
Language	English
Publishing country	nl
Document type	Article ; Online
ZDB-ID	1360843-5
ISSN	1421-9824 ; 1420-8008
ISSN (online)	1421-9824
ISSN	1420-8008
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Article ; Online: Contribution of rare homozygous and compound heterozygous VPS13C missense mutations to dementia with Lewy bodies and Parkinson’s disease

Smolders, Stefanie / Philtjens, Stéphanie / Crosiers, David / Sieben, Anne / Hens, Elisabeth / Heeman, Bavo / Van Mossevelde, Sara / Pals, Philippe / Asselbergh, Bob / Dos Santos Dias, Roberto / Vermeiren, Yannick / Vandenberghe, Rik / Engelborghs, Sebastiaan / De Deyn, Peter Paul / Martin, Jean-Jacques / Cras, Patrick / Annaert, Wim / Van Broeckhoven, Christine

Acta Neuropathologica Communications

2021 Volume 9, Issue 1

Abstract: Dementia with Lewy bodies (DLB) and Parkinson’s disease (PD) are clinically, pathologically and ...

Abstract	Dementia with Lewy bodies (DLB) and Parkinson’s disease (PD) are clinically, pathologically and etiologically disorders embedded in the Lewy body disease (LBD) continuum, characterized by neuronal α-synuclein pathology. Rare homozygous and compound heterozygous premature termination codon (PTC) mutations in the Vacuolar Protein Sorting 13 homolog C gene (VPS13C) are associated with early-onset recessive PD. We observed in two siblings with early-onset age (< 45) and autopsy confirmed DLB, compound heterozygous missense mutations in VPS13C, p.Trp395Cys and p.Ala444Pro, inherited from their healthy parents in a recessive manner. In lymphoblast cells of the index patient, the missense mutations reduced VPS13C expression by 90% (p = 0.0002). Subsequent, we performed targeted resequencing of VPS13C in 844 LBD patients and 664 control persons. Using the optimized sequence kernel association test, we obtained a significant association (p = 0.0233) of rare VPS13C genetic variants (minor allele frequency ≤ 1%) with LBD. Among the LBD patients, we identified one patient with homozygous missense mutations and three with compound heterozygous missense mutations in trans position, indicative for recessive inheritance. In four patients with compound heterozygous mutations, we were unable to determine trans position. The frequency of LBD patient carriers of proven recessive compound heterozygous missense mutations is 0.59% (5/844). In autopsy brain tissue of two unrelated LBD patients, the recessive compound heterozygous missense mutations reduced VPS13C expression. Overexpressing of wild type or mutant VPS13C in HeLa or SH-SY5Y cells, demonstrated that the mutations p.Trp395Cys or p.Ala444Pro, abolish the endosomal/lysosomal localization of VPS13C. Overall, our data indicate that rare missense mutations in VPS13C are associated with LBD and recessive compound heterozygous missense mutations might have variable effects on the expression and functioning of VPS13C. We conclude that comparable to the recessive inherited PTC ...
Keywords	DLB ; Dementia with lewy bodies ; Lewy body disease ; Loss-of-function ; Missense mutations ; PD ; Parkinson’s disease ; Recessive inheritance ; VPS13C ; Vacuolar protein sorting 13 homolog C
Subject code	616
Language	English
Publishing country	nl
Document type	Article ; Online
ZDB-ID	2715589-4
ISSN	2051-5960
ISSN	2051-5960
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Article ; Conference proceedings ; Online: ABCA7 PTC mutation carriers present with Alzheimer’s disease pathology and cerebral amyloid angiopathy

Hens, Elisabeth / Bossaerts, Liene / Sieben, Anne / Bossche, Tobi Van Den / Engelborghs, Sebastiaan / Peeters, Karin / Vermeiren, Yannick / De Roeck, Naomi / Hanseeuw, Bernard J. / Vandenberghe, Rik / Deyn, Peter Paul De / Cras, Patrick / Martin, Jean-Jacques / Van Broeckhoven, Christine

Basic science and pathogenesis: Genetics and omics of AD

2020

Abstract: Genetic screening of our Belgian Alzheimer’s Disease (AD) cohort (n = 1478) observed in 69 patients ... with cerebral amyloid angiopathy (CAA) were described in 3 patients, and 2 other patients suffered from (a) lobar hemorrhage(s ...

Abstract	Genetic screening of our Belgian Alzheimer’s Disease (AD) cohort (n = 1478) observed in 69 patients, 15 different premature termination codon (PTC)mutations in the gene coding ATP-Binding Cassette Subfamily A Member 7 (ABCA7) leading to loss of ABCA7 protein. We aimed to delineate the clinicopathological AD phenotype of the ABCA7 mutation carriers. The ABCA7 gene was initially identified as a risk gene in genome wide association studies of large AD patient cohorts. Methods: Reviewing of available demographic and (n = 44) clinical data (n = 64), neuroimaging studies (n = 62), CSF analysis (n = 28) and neuropathological (n = 10) data. Result: The 69 ABCA7 carriers had a mean onset age of 69.5 ± 9.7 years. In 68 carriers, onset age ranged from 48 to 90 years and mean disease duration was 8.1 ± 4.3 years (range 1-18). APOE genotypes did not have a modifying effect. A positive familial disease history was noted in 75.0% of carriers. Most carriers displayed an amnestic phenotype (87.6%) without clear distinctive features in clinical examination or neuroimaging. Cerebrospinal fluid (CSF) biomarkers were available for 28 carriers, showing an AD profile in 82.1% of patients. Additional (re)analysis of CSF biomarkers is ongoing for 36 carriers, including Aβ1-42/Aβ1-40 ratio as an ancillary biomarker. Imaging features compatible with cerebral amyloid angiopathy (CAA) were described in 3 patients, and 2 other patients suffered from (a) lobar hemorrhage(s). Chronic microvascular damage was noticed in 78.2% of patients. Brain autopsy revealed typical AD pathology together with CAA in all 10 carriers. High levels of CAA were present in both the meningeal and capillary blood vessels, and moderate to high levels of CAA in the parenchymal blood vessels. Further, CAA was not limited to the occipital brain region, but extended to the other neocortices and even to the medial temporal region (n = 5). CAA did not correlate with the levels of AD pathology or APOE genotype.
Keywords	Life Science
Subject code	610
Language	English
Publishing country	nl
Document type	Article ; Conference proceedings ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Impact of hearing loss and vestibular decline on cognition in Alzheimer’s disease

Patrick Cras / Vincent Van Rompaey / Joyce Bosmans / Cathérine Jorissen / Angelique Van Ombergen / Sebastiaan Engelborghs / Annick Gilles / Eline Princen / Julie Moyaert / Griet Mertens

BMJ Open, Vol 10, Iss

a prospective longitudinal study protocol (Gehoor, Evenwicht en Cognitie, GECkO)

2020 Volume 9

Abstract: ... Alzheimer’s disease (AD) is the most common cause of dementia. Previous research investigated the link between ...

Abstract	Introduction Dementia is a prevalent disease affecting a growing number of the ageing population. Alzheimer’s disease (AD) is the most common cause of dementia. Previous research investigated the link between hearing loss and cognition, and the effect of vestibular dysfunction on cognition. Hearing loss and, to a lesser extent, vestibular decline both result in a decreasing cognitive function. However, their interaction should not be underestimated. The aim of this study is to assess the effect of hearing loss, vestibular decline and their interaction on cognition in people suffering from mild cognitive impairment (MCI) and dementia due to AD (ADD).Methods and analysis We designed a prospective longitudinal study to assess the effect of hearing loss and vestibular decline on cognition. A total of 100 cognitively impaired elderly (between 55 and 84 years of age), consisting of 60 patients with MCI due to AD and 40 patients with ADD will be included. The control group will consist of individuals with preserved cognition group-matched based on age, hearing level and vestibular function. A comprehensive assessment is performed at baseline, 12-month and 24-month follow-ups. The primary outcome measure is the change in the Repeatable Battery for the Assessment of Neuropsychological Status adjusted for Hearing-impaired individuals total score, a cognitive test battery assessing different cognitive domains. Secondary outcome measures include additional neuropsychological assessments, cortical auditory-evoked potentials, and evaluation of general and disease-specific health-related quality of life. Variables include cognitive, audiological and vestibular evaluation. Variance analyses will assess the effect of hearing loss and vestibular decline on cognition. More precisely, the link between hearing loss and non-spatial cognitive functioning, the effect of vestibular decline on spatial cognition and the impact of both factors on the rate of conversion from MCI due to AD to ADD will be investigated.Ethics and dissemination ...
Keywords	Medicine ; R
Subject code	150
Language	English
Publishing date	2020-09-01T00:00:00Z
Publisher	BMJ Publishing Group
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Adults with cerebral palsy and Alzheimer disease: a missing link?

Engelborghs, Sebastiaan

Developmental medicine and child neurology

2021 Volume 64, Issue 3, Page(s) 284

MeSH term(s)	Adult ; Alzheimer Disease/complications ; Cerebral Palsy/complications ; Humans
Language	English
Publishing date	2021-10-10
Publishing country	England
Document type	Journal Article ; Comment
ZDB-ID	80369-8
ISSN	1469-8749 ; 0012-1622
ISSN (online)	1469-8749
ISSN	0012-1622
DOI	10.1111/dmcn.15080
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Article ; Online: Sex-Specific Metabolic Pathways Were Associated with Alzheimer’s Disease (AD) Endophenotypes in the European Medical Information Framework for AD Multimodal Biomarker Discovery Cohort

Jin Xu / Rebecca Green / Min Kim / Jodie Lord / Amera Ebshiana / Sarah Westwood / Alison L. Baird / Alejo J. Nevado-Holgado / Liu Shi / Abdul Hye / Stuart G. Snowden / Isabelle Bos / Stephanie J. B. Vos / Rik Vandenberghe / Charlotte E. Teunissen / Mara Ten Kate / Philip Scheltens / Silvy Gabel / Karen Meersmans /

Olivier Blin / Jill Richardson / Ellen Elisa De Roeck / Sebastiaan Engelborghs / Kristel Sleegers / Régis Bordet / Lorena Rami / Petronella Kettunen / Magda Tsolaki / Frans R. J. Verhey / Daniel Alcolea / Alberto Lleó / Gwendoline Peyratout / Mikel Tainta / Peter Johannsen / Yvonne Freund-Levi / Lutz Frölich / Valerija Dobricic / Giovanni B. Frisoni / José Luis Molinuevo / Anders Wallin / Julius Popp / Pablo Martinez-Lage / Lars Bertram / Kaj Blennow / Henrik Zetterberg / Johannes Streffer / Pieter Jelle Visser / Simon Lovestone / Petroula Proitsi / Cristina Legido-Quigley

Biomedicines, Vol 9, Iss 1610, p

2021 Volume 1610

Abstract: ... of Alzheimer’s Disease (AD). Here, we examined metabolic pathways that may lead to precision medicine initiatives ...

Abstract	Background: physiological differences between males and females could contribute to the development of Alzheimer’s Disease (AD). Here, we examined metabolic pathways that may lead to precision medicine initiatives. Methods: We explored whether sex modifies the association of 540 plasma metabolites with AD endophenotypes including diagnosis, cerebrospinal fluid (CSF) biomarkers, brain imaging, and cognition using regression analyses for 695 participants (377 females), followed by sex-specific pathway overrepresentation analyses, APOE ε4 stratification and assessment of metabolites’ discriminatory performance in AD. Results: In females with AD, vanillylmandelate (tyrosine pathway) was increased and tryptophan betaine (tryptophan pathway) was decreased. The inclusion of these two metabolites (area under curve (AUC) = 0.83, standard error (SE) = 0.029) to a baseline model (covariates + CSF biomarkers, AUC = 0.92, SE = 0.019) resulted in a significantly higher AUC of 0.96 (SE = 0.012). Kynurenate was decreased in males with AD (AUC = 0.679, SE = 0.046). Conclusions: metabolic sex-specific differences were reported, covering neurotransmission and inflammation pathways with AD endophenotypes. Two metabolites, in pathways related to dopamine and serotonin, were associated to females, paving the way to personalised treatment.
Keywords	sex ; Alzheimer’s disease ; metabolomics ; metabolic pathway ; blood ; vanillylmandelate ; Biology (General) ; QH301-705.5
Language	English
Publishing date	2021-11-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: Mild Cognitive Impairment: What’s in a Name?

Dierckx, E. / Engelborghs, S. / De Raedt, R. / De Deyn, P.P. / Ponjaert-Kristoffersen, I.

Gerontology

2006 Volume 53, Issue 1, Page(s) 28–35

Abstract: Background: Nowadays the term mild cognitive impairment (MCI) is used to fill the gap between cognitive changes associated with normal ageing and those associated with dementia. Despite some agreement in general definitions, MCI is still a heterogeneous ... ...

Institution	Developmental and Lifespan Psychology, Vrije Universiteit Brussel, Brussels Department of Neurology and Memory Clinic, Middelheim General Hospital (ZNA Laboratory of Neurochemistry and Behaviour, Institute Born-Bunge, University of Antwerp, Antwerp, and Department of Psychology, Ghent University, Ghent, Belgium
Abstract	Background: Nowadays the term mild cognitive impairment (MCI) is used to fill the gap between cognitive changes associated with normal ageing and those associated with dementia. Despite some agreement in general definitions, MCI is still a heterogeneous clinical syndrome for which no DSM-IV criteria have yet been established. Criteria by Petersen et al. are presently the most applied in clinical practice. Moreover, little attention has been paid to the specific relation between MCI and depression. Objective: This review highlights some concerns about the concept of MCI and provides guidelines within the field of neuropsychology to solve them. In a second part, the paper focuses on the specific relationship between depression in the elderly and MCI. Results: We hypothesize that certain test instruments can be used to operationalize the criteria proposed by Petersen et al. Moreover, we suggest that cued recall might be of help to differentiate between progressive and non-progressive MCI. Concerning the specific relation between depression and MCI, we assume that elderly depression with concomitant cognitive problems can be seen as an MCI. Conclusion: The proposed adjustments and additions (neuropsychological instruments and the incorporation of depressive symptoms) in the diagnostic flowchart of Petersen may serve as useful tools for clinicians when making a diagnosis of MCI.
Keywords	Alzheimer’s disease ; Depression ; Mild cognitive impairment ; Neuropsychology ; Older persons
Language	English
Publishing date	2006-09-20
Publisher	S. Karger AG
Publishing place	Basel, Switzerland
Document type	Article
Note	Debate
ZDB-ID	193798-4
ISSN	1423-0003 ; 0304-324X
ISSN (online)	1423-0003
ISSN	0304-324X
DOI	10.1159/000095763
Database	Karger publisher's database

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Article ; Online: Anti-CASPR2 antibody-associated limbic encephalitis in a patient with a squamous cell carcinoma of the throat.

Goovaerts, Sarah / Gens, Robin / Seynaeve, Laura / Engelborghs, Sebastiaan / Vandervorst, Fenne

Acta neurologica Belgica

2023 Volume 123, Issue 3, Page(s) 1205–1207

MeSH term(s)	Humans ; Limbic Encephalitis/complications ; Pharynx ; Membrane Proteins ; Encephalitis/complications ; Carcinoma, Squamous Cell/complications ; Autoantibodies
Chemical Substances	Membrane Proteins ; Autoantibodies
Language	English
Publishing date	2023-04-29
Publishing country	Italy
Document type	Letter
ZDB-ID	127315-2
ISSN	2240-2993 ; 0300-9009
ISSN (online)	2240-2993
ISSN	0300-9009
DOI	10.1007/s13760-023-02272-4
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Article ; Online: Cerebrospinal fluid inflammatory biomarkers for disease progression in Alzheimer's disease and multiple sclerosis: a systematic review.

Temmerman, Joke / Engelborghs, Sebastiaan / Bjerke, Maria / D'haeseleer, Miguel

Frontiers in immunology

2023 Volume 14, Page(s) 1162340

Abstract: Inflammatory processes are involved in the pathophysiology of both Alzheimer's disease (AD) and multiple sclerosis (MS) but their exact contribution to disease progression remains to be deciphered. Biomarkers are needed to define pathophysiological ... ...

Abstract	Inflammatory processes are involved in the pathophysiology of both Alzheimer's disease (AD) and multiple sclerosis (MS) but their exact contribution to disease progression remains to be deciphered. Biomarkers are needed to define pathophysiological processes of these disorders, who may increasingly co-exist in the elderly generations of the future, due to the rising prevalence in both and ameliorated treatment options with improved life expectancy in MS. The purpose of this review was to provide a systematic overview of inflammatory biomarkers, as measured in the cerebrospinal fluid (CSF), that are associated with clinical disease progression. International peer-reviewed literature was screened using the PubMed and Web of Science databases. Disease progression had to be measured using clinically validated tests representing baseline functional and/or cognitive status, the evolution of such clinical scores over time and/or the transitioning from one disease stage to a more severe stage. The quality of included studies was systematically evaluated using a set of questions for clinical, neurochemical and statistical characteristics of the study. A total of 84 papers were included (twenty-five for AD and 59 for MS). Elevated CSF levels of chitinase-3-like protein 1 (YKL-40) were associated with disease progression in both AD and MS. Osteopontin and monocyte chemoattractant protein-1 were more specifically related to disease progression in AD, whereas the same was true for interleukin-1 beta, tumor necrosis factor alpha, C-X-C motif ligand 13, glial fibrillary acidic protein and IgG oligoclonal bands in MS. We observed a broad heterogeneity of studies with varying cohort characterization, non-disclosure of quality measures for neurochemical analyses and a lack of adequate longitudinal designs. Most of the retrieved biomarkers are related to innate immune system activity, which seems to be an important mediator of clinical disease progression in AD and MS. Overall study quality was limited and we have framed some recommendations for future biomarker research in this field. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42021264741.
MeSH term(s)	Humans ; Aged ; Alzheimer Disease ; Biomarkers/cerebrospinal fluid ; Disease Progression ; Multiple Sclerosis
Chemical Substances	Biomarkers
Language	English
Publishing date	2023-07-13
Publishing country	Switzerland
Document type	Systematic Review ; Journal Article ; Review
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2023.1162340
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