Hugo Vanderstichele - Academia.edu (original) (raw)

Papers by Hugo Vanderstichele

The American Journal of Pathology, 2000

Deposition of amyloid ␤-peptide (A␤) in cerebral vessel walls (cerebral amyloid angiopathy, CAA) ... more Deposition of amyloid ␤-peptide (A␤) in cerebral vessel walls (cerebral amyloid angiopathy, CAA) is very frequent in Alzheimer's disease and occurs also as a sporadic disorder. Here, we describe significant CAA in addition to amyloid plaques, in aging APP/Ld transgenic mice overexpressing the London mutant of human amyloid precursor protein (APP) exclusively in neurons. The number of amyloid-bearing vessels increased with age, from ϳ10 to >50 per coronal brain section in APP/Ld transgenic mice, aged 13 to 24 months. Vascular amyloid was preferentially deposited in arterioles and ranged from small focal to large circumferential depositions. Ultrastructural analysis allowed us to identify specific features contributing to weakening of the vessel wall and aneurysm formation, ie, disruption of the external elastic lamina, thinning of the internal elastic lamina, interruption of the smooth muscle layer, and loss of smooth muscle cells. Biochemically, the much lower A␤42:A␤40 ratio evident in vascular relative to plaque amyloid, demonstrated that in blood vessel walls A␤40 was the more abundant amyloid peptide. The exclusive neuronal origin of transgenic APP, the high levels of A␤ in cerebrospinal fluid compared to plasma, and the specific neuroanatomical localization of vascular amyloid strongly suggest specific drainage pathways, rather than local production or blood uptake of A␤ as the primary mechanism underlying CAA. The demonstration in APP/Ld mice of rare vascular amyloid deposits that immunostained only for A␤42, suggests that, similar to senile plaque formation, A␤42 may be the first amyloid to be deposited in the vessel walls and that it entraps the more soluble A␤40. Its ability to diffuse for larger distances along perivascular drainage pathways would also explain the abundance of A␤40 in vascular amyloid. Consistent with this hypothesis, incorporation of mutant presenilin-1 in APP/Ld mice, which resulted in selectively higher levels of A␤42, caused an increase in CAA and senile plaques. This mouse model will be useful in further elucidating the pathogenesis of CAA and Alzheimer's disease, and will allow testing of diagnostic and therapeutic strategies.

Archives of Neurology, 2010

Objective: To identify biomarker patterns typical for Alzheimer disease (AD) in an independent, u... more Objective: To identify biomarker patterns typical for Alzheimer disease (AD) in an independent, unsupervised way, without using information on the clinical diagnosis.

Methods: We compared the new multianalyte assay format with established ELISA techniques for the ... more Methods: We compared the new multianalyte assay format with established ELISA techniques for the same proteins. We then performed a clinical study using CSF samples from patients with AD or mild cognitive impairment with progression to AD, healthy controls, and patients with other neurologic disorders. Results: The INNO-BIA AlzBio3 selectively and specifically measured A␤ (1-42) , T-TAU, P-TAU (181P) in the CSF. The new assay format had intra-and interassay CVs <10% for all analytes, even at low concentrations. The measurement range of the new assay was 3 to 4 logs compared with 1 to 2 logs for ELISAs. By plotting the mean of the values obtained in ELISA and the xMAP technology against the difference, we found that a correction factor could be used to convert xMAP results to ELISA values. The clinical study demonstrated that the new multiparametric assay could accurately distinguish patients with AD from patients with other neurologic disorders or control patients, with the diagnostic accuracy reaching recommended consensus criteria for specificity and sensitivity.

Alzheimer's & Dementia, 2012

In Alzheimer's disease (AD), the cerebral pathological changes begin many years before the clinic... more In Alzheimer's disease (AD), the cerebral pathological changes begin many years before the clinical manifestation of the disease. Biomarkers for AD, such as the cerebrospinal fluid (CSF) concentrations of amyloid-,81-42 (A,Bl-42) and tau phosphorylated at threonine 181 (pTau181), may reflect these cerebral changes relatively early. Accordingly, cognitively healthy subjects at risk for AD often have altered CSF concentrations of A,Bl-42 and pTau181. In this study, we assessed the effects and interaction of two strong risk factors for AD, aging and the presence of the APOEc4 allele, on the CSF A,Bl-42 and pTau181 concentrations in 280 adults with normal cognition across the lifespan. For comparison, we further included 152 patients with probable AD. We found significant effects of age on the CSF A,Bl-42 and pTau181, and of the APOEc4 genotype on the A,Bl-42 levels in the cognitively normal participants. Carrying the APOEc4 allele was associated with a significant decrease of the A,Bl-42 concentrations in middle-aged and older participants. In the group of participants with AD, the A,Bl-42 levels were significantly lower in the APOEc4 carriers compared to the non-carriers. These findings demonstrate significant age effects on the CSF A,B 1 _ 42 and pTau181 across lifespan. They also suggest that the decrease of A,Bl-42, but not the increase ofpTaul81 CSF levels is accelerated by the APOEc4 genotype in middle-aged and older adults with normal cognition. of cerebrospinal fluid (CSF) A.B 1 -4 2 and pTau concentrations can already be detected in asymptomatic older subjects at risk for AD [1 ,2], and predict cognitive decline in cognitively healthy older adults and in subjects with mild cognitive impairment . The presence of the apolipoprotein c4 (APOEc4) allele is a well-established genetic risk factor for AD. Carrying the APOEc4 allele may accelerate the pathophysiological process [7) and lower the age of clinical onset of the disease . Some postmortem studies [I 0,11 ], but not all , have found associations of the APOEc4 genotype with higher levels of amyloid plaque deposition and neurofibrillary pathology. Studies on the associations of CSF biomarker levels with

Neurobiology of Aging, 2008

To establish diagnostic performance of the cerebrospinal fluid (CSF) biomarkers beta-amyloid pept... more To establish diagnostic performance of the cerebrospinal fluid (CSF) biomarkers beta-amyloid peptide (Abeta(1-42)), total tau-protein (T-tau) and tau phosphorylated at threonine 181 (P-tau(181P)) compared to clinical diagnosis, biomarker levels were determined in CSF samples from 100 autopsy-confirmed dementia and 100 control subjects. As the control and dementia groups were not age-matched and given the significant associations of biomarker concentrations with age in controls, age-corrected biomarker concentrations were calculated. New models were constructed by means of logistic regression. Using all biomarkers, dementia could be discriminated from controls (sensitivity (S)=86%, specificity (Sp)=89%). T-tau and Abeta(1-42) optimally discriminated Alzheimer&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease (AD) from other dementias (NONAD) and controls (S=90%, Sp=89%). AD was optimally discriminated from NONAD using P-tau(181P) and Abeta(1-42) (S=80%, Sp=93%). Diagnostic accuracy of the latter model (82.7%) was comparable to clinical diagnostic accuracy (81.6%) that was based on a whole clinical work-up (including imaging). Using this model, in cases with clinically doubtful diagnoses, a correct diagnosis would have been established in 4/6 autopsy-confirmed AD and 3/3 autopsy-confirmed NONAD cases. The value of biomarkers in differential dementia diagnosis was shown, using pathological diagnosis as a reference. New models have been developed, achieving sensitivity, specificity and diagnostic accuracy levels, consistently exceeding 80%.

Dementia and geriatric cognitive disorders, 2003

Accumulation of beta-amyloid (Abeta) in the brain is one of the central lesions in Alzheimer'... more Accumulation of beta-amyloid (Abeta) in the brain is one of the central lesions in Alzheimer's disease (AD). Alternative cleavage of the amyloid precursor protein (APP), occurring in both normal and AD subjects, results in the generation and secretion of soluble APP, Abeta(40) and Abeta(42). Platelets have been regarded as the primary source of circulating APP and Abeta. Plasma levels of Abeta may therefore be dependent on platelet activation. We analysed Abeta(40/42) in plasma in the presence of physiological agonists of platelet activation such as adenosine diphosphate, collagen, thrombin, and a synthetic agonist, thrombin receptor activator peptide 6. We found that the levels of Abeta(40/42) in plasma were not related to platelet activation, suggesting that sampling techniques affecting platelet activation do not confound measurement of Abeta(40/42 )in plasma.

Alzheimer's & Dementia, 2014

Background: Amyloid-b (A b 42) is a well-established biomarker for Alzheimer's disease (AD) in ce... more Background: Amyloid-b (A b 42) is a well-established biomarker for Alzheimer's disease (AD) in cerebrospinal fluid (CSF). For clinical diagnosis of AD several immunoassays for A b 42 are available, but differ in absolute values and may also suffer from matrix interference, thereby hampering inter-laboratory comparisons and the use of general cut-off levels. Hence we developed and validated a candidate reference measurement procedure (RMP) for A b 42 t ogether with the International Federation of Clinical Chemistry Working Group on CSF Proteins. Methods: The candidate RMP is based on solid phase extraction and isotope dilution liquid chromatography coupled to tandem mass spectrometry. It is antibody independent. The calibration procedure employed two differently stable isotope-labeled A b 42 peptides for calibration in human CSF, which is an important aspect since there is no analyte-free matrix available. To date no CSF certified reference material (CRM) exists. Therefore we used a non-labeled A b 42 standard, for which concentration was determined using amino acid analysis. The measurements were performed on a high-resolution quadrupole-Orbitrap hybrid instrument. Additionally the method was transferred to a routine laboratory using widely-spread triple quadrupole instrumentation. Results: Validation of the candidate RMP showed intra-assay and interassay imprecision of 5.0% and 6.4% respectively, and an expanded uncertainty of 15.7%.The recovery was 100615%. Additionally, no analytical interferences or carry over were detected. The method allowed quantification of CSF A b 42 between 150-4000 pg/mL. Method comparison between validated candidate RMP and the routine laboratory using de-identified CSF patient samples showed that bias and imprecision are within the acceptance limits. Thus the method is not restricted to the use of high resolution MS and clinical studies could be performed with standard triple quadrupole mass spectrometric instruments. Conclusions: Reliable diagnostic tools and exact cut-offs are highly important to make an accurate early diagnosis of AD, and of utmost importance when new types of disease-modifying drugs for treatment of the disease will reach the clinic. This candidate RMP will also help to set the value of CSF A b 42 in a CRM, which could be used to harmonize A b 42 assays, and facilitate the introduction of general cutoff concentrations for CSF A b 42 in clinical trials and practice.

NeuroToxicology, 2004

In children treated for hematological malignancies, a transient elevation of the neurodegenerativ... more In children treated for hematological malignancies, a transient elevation of the neurodegenerative marker Tau was found in the cerebrospinal fluid (CSF). In the first part of this study, CSF-Tau, CSF-Phospho-Tau, and CSF-Neuromodulin (CSF-NM) were measured in a heterogeneous group of patients presenting in the pediatric oncology department. In the second part, the neurodegenerative markers were analyzed in a group of children with non-B-cell acute lymphoblastic leukemia (nB-ALL) treated according to EORTC protocols 58881 and 58951. CSF was collected from lumbar punctures at diagnosis only in the first group, and at diagnosis and during treatment in the second group. CSF-proteins were measured with ELISA. There was no age variation in any of the markers at diagnosis in the first group of children. After prephase induction therapy with one intrathecal (IT) injection of methotrexate (MTX) and 7 days systemic corticosteroids, an increase in CSF-Tau was observed, and accompanied with increase of both CSF-P-Tau and CSF-NM. While CSF-Tau remained high during induction treatment, CSF-P-Tau, and CSF-NM decreased. Neurodegenerative markers do not vary with age. The different protein profiles suggest that the neurotoxicity from the prephase, which results in an increase of CSF-Tau, CSF-P-Tau, and CSF-NM, may have a different mechanism to the neurotoxicity induced later during induction treatment, when only CSF-Tau remains high.

Molecular Psychiatry, 2003

Early clinical symptoms of sporadic Creutzfeldt-Jakob disease (CJD) may overlap with other neurod... more Early clinical symptoms of sporadic Creutzfeldt-Jakob disease (CJD) may overlap with other neurodegenerative diseases like Alzheimer's disease (AD) and frontotemporal degeneration (FTD). On entering an era in which pharmaceutical treatment of CJD occurs, reliable diagnostic markers like immunodetection of 14-3-3 proteins in the cerebrospinal fluid (CSF) are required. However, false negative results in autopsy-proven, sporadic CJD cases, as well as false positive results in several other disorders including AD and FTD showing high CSF tau protein levels, limit the potential of this marker. Due to neuronal lysis the cytosolic fraction of total tau containing phosphorylated and non-phosphorylated isoforms is partially liberated into the CSF. Since hyperphosphorylation of tau may specifically occur in neurodegenerative diseases associated with neurofibrillary changes, we hypothesized that the phospho-tau (P-tau)/total tau ratio in CSF may be a useful marker to discriminate CJD from other neurodegenerative disorders. The P-tau/total tau ratio discriminated patients with CJD from all other neurodegenerative disorders including patients with AD and FTD without any overlap. Although the results have to be confirmed in a larger sample, the preliminary data suggest that simultaneous measurement of total tau and P-tau in CSF may be useful to identify patients with CJD.

Acta Neurologica Scandinavica, 2003

Alzheimer's disease (AD) is characterized at autopsy by the presence of plaques, tangles, and syn... more Alzheimer's disease (AD) is characterized at autopsy by the presence of plaques, tangles, and synapse loss ( ). Several proteins have been described as biomarkers for 'early diagnosis', 'differential diagnosis', or for the follow-up of treatments. The ultimate goal is to use such 'neurotheranostic' markers to further improve patient management in the field of neurodegeneration. The tau protein is an intracellular component of neurons, and ß-amyloid (Aß42) is the extracellular hallmark present in the plaques. Tau phosphorylation (phospho-tau) is an early event, restricted to brain cells/regions that are affected. Tau, phospho-tau, or both, are closely associated with the pathology of several age-related neurodegenerative conditions, such as AD, frontotemporal lobe dementia (FTD) and other so-called tauopathies. Tau, phospho-tau and Aß42 are quantifiable in the cerebrospinal fluid (CSF) by sensitive immunoassays (ELISA) using specific monoclonal antibodies.

Brain : a journal of neurology, Jan 27, 2015

In a large multicentre sample of cognitively normal subjects, as a function of age, gender and AP... more In a large multicentre sample of cognitively normal subjects, as a function of age, gender and APOE genotype, we studied the frequency of abnormal cerebrospinal fluid levels of Alzheimer's disease biomarkers including: total tau, phosphorylated tau and amyloid-β1-42. Fifteen cohorts from 12 different centres with either enzyme-linked immunosorbent assays or Luminex® measurements were selected for this study. Each centre sent nine new cerebrospinal fluid aliquots that were used to measure total tau, phosphorylated tau and amyloid-β1-42 in the Gothenburg laboratory. Seven centres showed a high correlation with the new Gothenburg measurements; therefore, 10 cohorts from these centres are included in the analyses here (1233 healthy control subjects, 40-84 years old). Amyloid-β amyloid status (negative or positive) and neurodegeneration status (negative or positive) was established based on the pathological cerebrospinal fluid Alzheimer's disease cut-off values for cerebrospinal ...

Alzheimer's & Dementia, 2015

Introduction: We describe Alzheimer's Disease Neuroimaging Initiative (ADNI) Biomarker Core progr... more Introduction: We describe Alzheimer's Disease Neuroimaging Initiative (ADNI) Biomarker Core progress including: the Biobank; cerebrospinal fluid (CSF) amyloid beta (Ab 1-42 ), t-tau, and ptau 181 analytical performance, definition of Alzheimer's disease (AD) profile for plaque, and tangle burden detection and increased risk for progression to AD; AD disease heterogeneity; progress in standardization; and new studies using ADNI biofluids. Methods: Review publications authored or coauthored by ADNI Biomarker core faculty and selected non-ADNI studies to deepen the understanding and interpretation of CSFAb 1-42 , t-tau, and p-tau 181 data. Results: CSF AD biomarker measurements with the qualified AlzBio3 immunoassay detects neuropathologic AD hallmarks in preclinical and prodromal disease stages, based on CSF studies in non-ADNI living subjects followed by the autopsy confirmation of AD. Collaboration across ADNI cores generated the temporal ordering model of AD biomarkers varying across individuals because of genetic/environmental factors that increase/decrease resilience to AD pathologies.

JAMA Neurology, 2015

Individuals in the presymptomatic stage of Alzheimer disease (AD) are increasingly being targeted... more Individuals in the presymptomatic stage of Alzheimer disease (AD) are increasingly being targeted for AD secondary prevention trials. How early during the normal life span underlying AD pathologies begin to develop, their patterns of change over time, and their relationship with future cognitive decline remain to be determined. To characterize the within-person trajectories of cerebrospinal fluid (CSF) biomarkers of AD over time and their association with changes in brain amyloid deposition and cognitive decline in cognitively normal middle-aged individuals. As part of a cohort study, cognitively normal (Clinical Dementia Rating [CDR] of 0) middle-aged research volunteers (n = 169) enrolled in the Adult Children Study at Washington University, St Louis, Missouri, had undergone serial CSF collection and longitudinal clinical assessment (mean, 6 years; range, 0.91-11.3 years) at 3-year intervals at the time of analysis, between January 2003 and November 2013. A subset (n = 74) had also undergone longitudinal amyloid positron emission tomographic imaging with Pittsburgh compound B (PiB) in the same period. Serial CSF samples were analyzed for β-amyloid 40 (Aβ40), Aβ42, total tau, tau phosphorylated at threonine 181 (P-tau181), visinin-like protein 1 (VILIP-1), and chitinase-3-like protein 1 (YKL-40). Within-person measures were plotted according to age and AD risk defined by APOE genotype (ε4 carriers vs noncarriers). Linear mixed models were used to compare estimated biomarker slopes among middle-age bins at baseline (early, 45-54 years; mid, 55-64 years; late, 65-74 years) and between risk groups. Within-person changes in CSF biomarkers were also compared with changes in cortical PiB binding and progression to a CDR higher than 0 at follow-up. Changes in Aβ40, Aβ42, total tau, P-tau181, VILIP-1, and YKL-40 and, in a subset of participants, changes in cortical PiB binding. While there were no consistent longitudinal patterns in Aβ40 (P = .001-.97), longitudinal reductions in Aβ42 were observed in some individuals as early as early middle age (P ≤ .05) and low Aβ42 levels were associated with the development of cortical PiB-positive amyloid plaques (area under receiver operating characteristic curve = 0.9352; 95% CI, 0.8895-0.9808), especially in mid middle age (P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; .001). Markers of neuronal injury (total tau, P-tau181, and VILIP-1) dramatically increased in some individuals in mid and late middle age (P ≤ .02), whereas the neuroinflammation marker YKL-40 increased consistently throughout middle age (P ≤ .003). These patterns were more apparent in at-risk ε4 carriers (Aβ42 in an allele dose-dependent manner) and appeared to be associated with future cognitive deficits as determined by CDR. Longitudinal CSF biomarker patterns consistent with AD are first detectable during early middle age and are associated with later amyloid positivity and cognitive decline. Such measures may be useful for targeting middle-aged, asymptomatic individuals for therapeutic trials designed to prevent cognitive decline.