Papers by Sebastiaan Engelborghs
Neuroradiology, Jan 18, 2024
Frontiers in Psychiatry, Aug 17, 2021
Background: The interaction between neuropsychiatric symptoms, mild cognitive impairment (MCI), a... more Background: The interaction between neuropsychiatric symptoms, mild cognitive impairment (MCI), and dementia is complex and remains to be elucidated. An additive or multiplicative effect of neuropsychiatric symptoms such as apathy or depression on cognitive decline has been suggested. Unraveling these interactions may allow the development of better prevention and treatment strategies. In the absence of available treatments for neurodegeneration, a timely and adequate identification of neuropsychiatric symptom changes in cognitive decline is highly relevant and can help identify treatment targets. Methods: An existing memory clinic-based research database of 476 individuals with MCI and 978 individuals with dementia due to Alzheimer's disease (AD) was reanalyzed. Neuropsychiatric symptoms were assessed in a prospective fashion using a battery of neuropsychiatric assessment scales: Middelheim Frontality Score, Behavioral Pathology in Alzheimer's Disease Rating Scale (Behave-AD), Cohen-Mansfield Agitation Inventory, Cornell Scale for Depression in Dementia (CSDD), and Geriatric Depression Scale (30 items). We subtyped subjects suffering from dementia as mild, moderate, or severe according to their Mini-Mental State Examination (MMSE) score and compared neuropsychiatric scores across these groups. A group of 126 subjects suffering from AD with a significant cerebrovascular component was examined separately as well. We compared the prevalence, nature, and severity of neuropsychiatric symptoms between subgroups of patients with MCI and dementia due to AD in a cross-sectional analysis. Results: Affective and sleep-related symptoms are common in MCI and remain constant in prevalence and severity across dementia groups. Depressive symptoms as assessed by the CSDD further increase in severe dementia. Most other neuropsychiatric symptoms (such as agitation and activity disturbances) progress in parallel with severity of cognitive decline. There are no significant differences in neuropsychiatric symptoms when comparing "pure" AD to AD with a significant vascular component. Neuropsychiatric symptoms such as frontal lobe symptoms, psychosis, agitation, aggression, and activity disturbances increase as dementia progresses. Affective symptoms such as anxiety and depressive symptoms, however, are more frequent in MCI than mild dementia but otherwise remain stable throughout the cognitive spectrum, except for an increase in CSDD score in severe dementia. There is no difference in neuropsychiatric symptoms when comparing mixed dementia (defined here as AD + significant cerebrovascular disease) to pure AD.
Management of Patients with Dementia, 2021
Diagnosing dementia requires a multiprofessional approach using an array of investigative methods... more Diagnosing dementia requires a multiprofessional approach using an array of investigative methods. A diagnosis of dementia and identification of the underlying cause, when possible, is essential for providing the necessary and appropriate treatment and care in a timely manner, including counseling. History taking from both patient and carer is a cornerstone of the diagnostic process. Within recent years, advances in biomarkers have pushed these to the forefront of the diagnostic work-up of patients with presumed dementia. These include advances within structural and functional imaging as well as cerebrospinal fluid (CSF)-based biomarkers. This has enabled biomarker-based diagnosis and more accurate identification of the underlying cause, especially with respect to neurodegenerative diseases. Besides a more accurate diagnosis, the present chapter will outline the diagnostic process and work-up of patients suspected of dementia and the utility of the tools available to the clinician.
Journal of Neurological Disorders, 2013
Alzheimer's research & therapy, Jun 14, 2024
Scientific Reports
Alzheimer’s disease (AD) is a neurodegenerative disease that eventually affects memory and behavi... more Alzheimer’s disease (AD) is a neurodegenerative disease that eventually affects memory and behavior. The identification of biomarkers based on risk factors for AD provides insight into the disease since the exact cause of AD remains unknown. Several studies have proposed microRNAs (miRNAs) in blood as potential biomarkers for AD. Exposure to heavy metals is a potential risk factor for onset and development of AD. Blood cells of subjects that are exposed to lead detected in the circulatory system, potentially reflect molecular responses to this exposure that are similar to the response of neurons. In this study we analyzed blood cell-derived miRNAs derived from a general population as proxies of potentially AD-related mechanisms triggered by lead exposure. Subsequently, we analyzed these mechanisms in the brain tissue of AD subjects and controls. A total of four miRNAs were identified as lead exposure-associated with hsa-miR-3651, hsa-miR-150-5p and hsa-miR-664b-3p being negatively a...
Acta Clinica Belgica, 2014
Background: Evidence suggests that the concordance between amyloid-PET and cerebrospinal fluid (C... more Background: Evidence suggests that the concordance between amyloid-PET and cerebrospinal fluid (CSF) amyloid- (A) increases when the CSF A 1-42 /A 1-40 ratio is used as compared to CSF A 1-42 levels alone. Objective: In order to test this hypothesis, we set up a prospective longitudinal study comparing the concordance between different amyloid biomarkers for Alzheimer's disease (AD) in a clinical setting. Methods: Seventy-eight subjects (AD dementia (n = 17), mild cognitive impairment (MCI, n = 48), and cognitively healthy controls (n = 13)) underwent a [ 18 F]Florbetapir ([ 18 F]AV45) PET scan, [ 18 F]FDG PET scan, MRI scan, and an extensive neuropsychological examination. In a large subset (n = 67), a lumbar puncture was performed and AD biomarkers were analyzed (A 1-42 , A 1-40 , T-tau, P-tau 181). Results: We detected an increased concordance in the visual and quantitative (standardized uptake value ratio (SUVR) and total volume of distribution (V T)) [ 18 F]AV45 PET measures when the CSF A 1-42 /A 1-40 was applied compared to A 1-42 alone. CSF biomarkers were stronger associated to [ 18 F]AV45 PET for SUVR values when considering the total brain white matter as reference region instead of cerebellar grey matter .
Brain, 2022
Alzheimer’s disease CSF biomarkers 42 amino acid long amyloid-β peptide (Aβ1–42), total tau prote... more Alzheimer’s disease 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 two 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, which includes quantification of amyloid-β plaque, neurofibrillary tangle, and neuritic plaque load. CSF samples were analysed for Aβ1–42, T-tau, and P-tau181 by ELISA. One hundred and fourteen cas...
Biomedicines, 2021
Background: physiological differences between males and females could contribute to the developme... more 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). K...
Journal of Alzheimer's Disease, 2019
Background: Despite decades of research on the optimization of the diagnosis of Alzheimer's disea... more Background: Despite decades of research on the optimization of the diagnosis of Alzheimer's disease (AD), its biomarkerbased diagnosis is being hampered by the lack of comparability of raw biomarker data. In order to overcome this limitation, the Erlangen Score (ES), among other approaches, was set up as a diagnostic-relevant interpretation algorithm. Objective: To validate the ES algorithm in a cohort of neuropathologically confirmed cases with AD (n = 106) and non-AD dementia (n = 57). Methods: Cerebrospinal fluid (CSF) biomarker concentrations of A 1-42 , T-tau, and P-tau 181 were measured with commercially available single analyte ELISA kits. Based on these biomarkers, ES was calculated as previously reported. Results: This algorithm proved to categorize AD in different degrees of likelihood, ranging from neurochemically "normal", "improbably having AD", "possibly having AD", to "probably having AD", with a diagnostic accuracy of 74% using the neuropathology as a reference. Conclusion: The ability of the ES to overcome the high variability of raw CSF biomarker data may provide a useful diagnostic tool for comparing neurochemical diagnoses between different labs or methods used.
Alzheimer's research & therapy, Jan 20, 2018
We explored the diagnostic performance of cerebrospinal fluid (CSF) biomarkers in allowing differ... more We explored the diagnostic performance of cerebrospinal fluid (CSF) biomarkers in allowing differentiation between frontotemporal lobar degeneration (FTLD) and Alzheimer's disease (AD), as well as between FTLD pathological subtypes. CSF levels of routine AD biomarkers (phosphorylated tau (p-tau), total tau (t-tau), and amyloid-beta (Aβ)) and neurofilament proteins, as well as progranulin levels in both CSF and serum were quantified in definite FTLD (n = 46), clinical AD (n = 45), and cognitively healthy controls (n = 20). FTLD subgroups were defined by genetic carrier status and/or postmortem neuropathological confirmation (FTLD-TDP: n = 34, including FTLD-C9orf72: n = 19 and FTLD-GRN: n = 9; FTLD-tau: n = 10). GRN mutation carriers had significantly lower progranulin levels compared to other FTLD patients, AD, and controls. Both t-tau and p-tau were normal in FTLD patients, even in FTLD-tau. Aβ levels were very variable in FTLD. Neurofilament light chain (Nf-L) was significantl...
Acta Neurologica Belgica, 2017
This review focusses on the validation and standardization of Alzheimer's disease (AD) cerebrospi... more This review focusses on the validation and standardization of Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers, as well as on the current clinical indications and rational use of CSF biomarkers in daily clinical practice. The validated AD CSF biomarkers, Ab 1-42 , T-tau, and P-tau 181 , have an added value in the (differential) diagnosis of AD and related disorders, including mixed pathologies, atypical presentations, and in case of ambiguous clinical dementia diagnosis. CSF biomarkers should not be routinely used in the diagnostic work-up of dementia and cannot be used to diagnose non-AD dementias. In cognitively healthy subjects, CSF biomarkers can only be applied for research purposes, e.g., to identify pre-clinical AD in the context of clinical trials with potentially disease-modifying drugs. Therefore, biomarkerbased early diagnosis of AD offers great opportunities for preventive treatment development in the near future.
Neurobiology of aging, Mar 21, 2016
Mutation screening and phenotypic profiling of 2 amyotrophic lateral sclerosis-(ALS) and frontote... more Mutation screening and phenotypic profiling of 2 amyotrophic lateral sclerosis-(ALS) and frontotemporal dementia-(FTD) associated genes, CHCHD10 and TUBA4A, were performed in a Belgian cohort of 459 FTD, 28 FTD-ALS, and 429 ALS patients. In CHCHD10, we identified a novel nonsense mutation (p.Gln108*) in a patient with atypical clinical FTD and pathology-confirmed Parkinson's disease (1/459, 0.22%) leading to loss of transcript. We further observed 3 previously described missense variants (p.Pro34Ser, p.Pro80Leu, and p.Pro96Thr) that were also present in the matched control series. In TUBA4A, we detected a novel frameshift mutation (p.Arg64Glyfs*90) leading to a truncated protein in 1 FTD patient (1/459 of 0.22%) with family history of Parkinson's disease and cognitive impairment, and a novel missense mutation (p.Thr381Met) in 2 sibs with familial ALS and memory problems (1 index patient/429, 0.23%) in whom we previously identified a pathogenic Chromosome 9 open reading frame...
Journal of Alzheimer's Disease, 2016
BACKGROUND: Tau protein, along with its phosphorylated forms (pTau), is one of the established ce... more BACKGROUND: Tau protein, along with its phosphorylated forms (pTau), is one of the established cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD), but virtually nothing is known about a potential diagnostic role of non-phosphorylated tau molecules (Non-P-Tau) in CSF. OBJECTIVE: To establish, and analytically and clinically validate the first assay capable to measure concentrations of Non-P-Tau in human CSF. METHODS: An antibody (1G2) was developed that selectively binds to the non-phosphorylated tau molecule at positions 175, 181, and 231, and was used for establishing an ELISA capable to measure Non-P-Tau in human CSF. In the analytical validation, linearity, repeatability of the standard curves, and intra-and interassay precision of the assay were tested, as well as inter-center variability with the QC samples sent either frozen or under ambient temperature. In the clinical part, concentrations of Non-P-Tau were measured in CSF samples from carefully selected AD or mild cognitive impairment (MCI) patients, whose diagnoses were supported by the results of the "classic" CSF biomarkers (n=58), and as well as in CSF samples from non-demented controls (n=42). RESULTS: The 1G2 antibody reacts with decreasing reactivity to tau peptides containing phosphorylation at positions T175, T181 and T231. The average OD of the blank sample was 0.067 ± 0.006; the CV's of the optical densities of the repeated standard curves were between 3.6-15.9%. Median intra-assay range-to-average imprecision of double measurements was 4.8%; inter-assay imprecision of was in the range of 11.2%-15.3%. Non-P-Tau concentrations are stabile in the CSF samples sent to distinct laboratories under ambient temperature; inter-laboratory variation was approximately 30%. The Non-P-Tau CSF concentrations were highly significantly increased in the AD/MCI group (109.2 ± 32.0 pg/mL) compared to the Controls (62.1 ± 9.3 pg/mL, p<0.001). At the cutoff of 78.3 mg/mL, the sensitivity and the specificity were 94.8% and 97.6%, respectively. CONCLUSIONS: For the first time, an assay is reported to reliably measure CSF concentrations of nonphosphorylated tau.
Translational stroke research, Apr 26, 2016
Dipeptidyl peptidase IV (DPPIV) inhibition may be a promising therapeutic strategy for acute stro... more Dipeptidyl peptidase IV (DPPIV) inhibition may be a promising therapeutic strategy for acute stroke treatment, given its potential to prolong the biological half-life of neuroprotective substrates. A related protease, fibroblast activation protein (FAP), was recently shown to inactivate the same substrates. Therefore, it should also be investigated as a potential target in stroke. The study aimed to investigate whether stroke severity and outcome correlate with DPPIV and FAP activities and their kinetics shortly after acute ischemic stroke. DPPIV and FAP activities were analyzed in the serum of 50 hyperacute stroke patients at admission, 1 day, 3 days, and 7 days after stroke onset and in 50 age-matched healthy controls. This was done as part of the Middelheim's Interdisciplinary Stroke Study. DPPIV activity tended to increase shortly after stroke compared to the control population. DPPIV and FAP activities steadily decreased in the first week after stroke onset. Higher infarct ...
Journal of the American Medical Directors Association, May 1, 2016
Journal of Alzheimer's Disease, 2016
Background: In diagnosing Alzheimer's disease (AD), ratios of cerebrospinal fluid (CSF) biomarker... more Background: In diagnosing Alzheimer's disease (AD), ratios of cerebrospinal fluid (CSF) biomarkers, such as CSF A 1-42 /tau, have an improved diagnostic performance compared to the single analytes, yet, still a limited value to predict cognitive decline. Since synaptic dysfunction/loss is closely linked to cognitive impairment, synaptic proteins are investigated as candidate CSF AD progression markers. Objective: We studied CSF levels of the postsynaptic protein neurogranin and protein BACE1, predominantly localized presynaptically, and their relation to CSF total-tau, A 1-42 , A 1-40 , and A 1-38. All six analytes were considered as single parameters as well as ratios. Methods: Every ELISA involved was based on monoclonal antibodies, including the BACE1 and neurogranin immunoassay. The latter specifically targets neurogranin C-terminally truncated at P75, a more abundant species of the protein in CSF. We studied patients with MCI due to AD (n = 38) and 50 dementia due to AD patients, as well as age-matched cognitively healthy elderly (n = 20). A significant subset of the patients was followed up by clinical and neuropsychologically (MMSE) examinations for at least one year. Results: The single analytes showed statistically significant differences between the clinical groups, but the ratios of analytes indeed had a higher diagnostic performance. Furthermore, only the ratio of CSF neurogranin trunc P75/BACE1 was significantly correlated with the yearly decline in MMSE scores in patients with MCI and dementia due to AD, pointing toward the prognostic value of the ratio.
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Papers by Sebastiaan Engelborghs