Publications by authors named "Sebastiaan Engelborghs"

290 Publications

Neuropsychiatric Symptoms in Mild Cognitive Impairment and Dementia Due to AD: Relation With Disease Stage and Cognitive Deficits.

Front Psychiatry 2021 17;12:707580. Epub 2021 Aug 17.

Center for Neurosciences (C4N), Vrije Universiteit Brussel (VUB), Brussels, Belgium.

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. 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. 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fpsyt.2021.707580DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8415837PMC
August 2021

CSF Proteomic Alzheimer's Disease-Predictive Subtypes in Cognitively Intact Amyloid Negative Individuals.

Proteomes 2021 Aug 2;9(3). Epub 2021 Aug 2.

Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Amsterdam UMC, 1007 MB Amsterdam, The Netherlands.

We recently discovered three distinct pathophysiological subtypes in Alzheimer's disease (AD) using cerebrospinal fluid (CSF) proteomics: one with neuronal hyperplasticity, a second with innate immune system activation, and a third subtype with blood-brain barrier dysfunction. It remains unclear whether AD proteomic subtype profiles are a consequence of amyloid aggregation, or might exist upstream from aggregated amyloid. We studied this question in 127 older individuals with intact cognition and normal AD biomarkers in two independent cohorts (EMIF-AD MBD and ADNI). We clustered 705 proteins measured in CSF that were previously related to AD. We identified in these cognitively intact individuals without AD pathology three subtypes: two subtypes were seen in both cohorts (n = 49 with neuronal hyperplasticity and n = 44 with blood-brain barrier dysfunction), and one only in ADNI (n = 12 with innate immune activation). The proteins specific for these subtypes strongly overlapped with AD subtype protein profiles (overlap coefficients 92%-71%). Longitudinal p-tau and amyloid β 1-42 (Aβ42) CSF analysis showed that in the hyperplasticity subtype p-tau increased (β = 2.6 pg/mL per year, = 0.01) and Aβ42 decreased over time (β = -4.4 pg/mL per year, = 0.03), in the innate immune activation subtype p-tau increased (β = 3.1 pg/mL per year, = 0.01) while in the blood-brain barrier dysfunction subtype Aβ42 decreased (β = -3.7 pg/mL per year, = 0.009). These findings suggest that AD proteomic subtypes might already manifest in cognitively normal individuals and may predispose for AD before amyloid has reached abnormal levels.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/proteomes9030036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8396164PMC
August 2021

Electrochemical Skin Conductance Alterations during Spinal Cord Stimulation: An Experimental Study.

J Clin Med 2021 Aug 13;10(16). Epub 2021 Aug 13.

Department of Neurosurgery, Universitair Ziekenhuis Brussel, Laarbeeklaan 101, 1090 Brussels, Belgium.

Despite the well-known clinical effects of spinal cord stimulation (SCS), the mechanisms of action have not yet been fully unraveled. The primary aim of this study was to measure whether electrochemical skin conductance, as a measure of peripheral sympathetic autonomic function, is altered by SCS. A second aim was to compare skin conductance levels of patients with failed back surgery syndrome (FBSS) with age- and sex-matched healthy controls. Twenty-three patients with FBSS treated with SCS participated in this study. Sudomotor function was measured with the Sudoscan instrument on the hands and feet during SCS on and off states. Difference scores in skin conductance between patients and age- and sex-matched healthy controls were calculated. Normal sudomotor function at the painful lower limb was revealed for 61% of the patients when SCS was activated. Skin conductance levels were not altered between on and off states of SCS. Differences in scores between patients and healthy controls were significantly different from zero. This study showed that SCS does not influencing the sympathetic nervous system in patients with FBSS, as measured by skin conductance levels. Moreover, it suggested that there is no normalization of the functioning of the sympathetic nervous system, despite the effectiveness of SCS to reduce pain intensity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/jcm10163565DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8397194PMC
August 2021

Plasma Proteomic Biomarkers Relating to Alzheimer's Disease: A Meta-Analysis Based on Our Own Studies.

Front Aging Neurosci 2021 21;13:712545. Epub 2021 Jul 21.

Department of Psychiatry, University of Oxford, Oxford, United Kingdom.

: Plasma biomarkers for the diagnosis and stratification of Alzheimer's disease (AD) are intensively sought. However, no plasma markers are well established so far for AD diagnosis. Our group has identified and validated various blood-based proteomic biomarkers relating to AD pathology in multiple cohorts. The study aims to conduct a meta-analysis based on our own studies to systematically assess the diagnostic performance of our previously identified blood biomarkers. : To do this, we included seven studies that our group has conducted during the last decade. These studies used either Luminex xMAP or ELISA to measure proteomic biomarkers. As proteins measured in these studies differed, we selected protein based on the criteria that it must be measured in at least four studies. We then examined biomarker performance using random-effect meta-analyses based on the mean difference between biomarker concentrations in AD and controls (CTL), AD and mild cognitive impairment (MCI), MCI, and CTL as well as MCI converted to dementia (MCIc) and non-converted (MCInc) individuals. : An overall of 2,879 subjects were retrieved for meta-analysis including 1,053 CTL, 895 MCI, 882 AD, and 49 frontotemporal dementia (FTD) patients. Six proteins were measured in at least four studies and were chosen for meta-analyses for AD diagnosis. Of them, three proteins had significant difference between AD and controls, among which alpha-2-macroglobulin (A2M) and ficolin-2 (FCN2) increased in AD while fibrinogen gamma chain (FGG) decreased in AD compared to CTL. Furthermore, FGG significantly increased in FTD compared to AD. None of the proteins passed the significance between AD and MCI, or MCI and CTL, or MCIc and MCInc, although complement component 4 (CC4) tended to increase in MCIc individuals compared to MCInc. : The results suggest that A2M, FCN2, and FGG are promising biomarkers to discriminate AD patients from controls, which are worthy of further validation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fnagi.2021.712545DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8335587PMC
July 2021

Serum Daytime Melatonin Levels Reflect Cerebrospinal Fluid Melatonin Levels in Alzheimer's Disease but Are Not Correlated with Cognitive Decline.

J Alzheimers Dis 2021 Aug 2. Epub 2021 Aug 2.

Department of Neurology, Universitair Ziekenhuis Brussel (UZ Brussel), Brussels, Belgium.

Background: Nocturnal cerebrospinal fluid (CSF) and blood melatonin levels are altered in Alzheimer's disease (AD). However, literature remains inconclusive on daytime blood melatonin levels. A positive correlation between melatonin levels and Mini-Mental State Examination (MMSE) scores in AD subjects has been evidenced following cross-sectional analyses. Whereas a correlation between serum and spinal CSF melatonin has been shown in healthy volunteers, an equal investigation in AD patients still has to be undertaken.

Objective: 1) To evaluate whether serum melatonin levels correlate with spinal CSF melatonin levels in AD. 2) To compare daytime CSF and serum melatonin levels between patients with AD dementia, mild cognitive impairment due to AD, and healthy controls, and to evaluate whether melatonin can affect cognitive decline in AD.

Methods: Subjects with AD and healthy controls included in two existing cohorts, of whom a CSF and serum sample was available at the neurobiobank and had at least 6 months of neuropsychological follow-up, were included in the present study. Melatonin concentrations were measured with liquid chromatography-mass spectrometry.

Results: Daytime serum melatonin levels correlated with spinal CSF melatonin levels in AD (r = 0.751, p <  0.001). No significant differences regarding daytime melatonin levels were found between patients and controls. No correlations were observed between daytime melatonin levels and MMSE score changes.

Conclusion: Daytime serum melatonin accurately reflects CSF melatonin levels in AD, raising the possibility to assess melatonin alterations by solely performing blood sampling if also confirmed for night-time values. However, daytime melatonin levels are not associated with changes of cognitive impairment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3233/JAD-210562DOI Listing
August 2021

Diagnostic Performance of Automated MRI Volumetry by icobrain dm for Alzheimer's Disease in a Clinical Setting: A REMEMBER Study.

J Alzheimers Dis 2021 Jul 27. Epub 2021 Jul 27.

Reference Center for Biological Markers of Dementia (BIODEM), Laboratory of Neurochemistry and Behavior, University of Antwerp, Antwerp, Belgium.

Background: Magnetic resonance imaging (MRI) has become important in the diagnostic work-up of neurodegenerative diseases. icobrain dm, a CE-labeled and FDA-cleared automated brain volumetry software, has shown potential in differentiating cognitively healthy controls (HC) from Alzheimer's disease (AD) dementia (ADD) patients in selected research cohorts.

Objective: This study examines the diagnostic value of icobrain dm for AD in routine clinical practice, including a comparison to the widely used FreeSurfer software, and investigates if combined brain volumes contribute to establish an AD diagnosis.

Methods: The study population included HC (n = 90), subjective cognitive decline (SCD, n = 93), mild cognitive impairment (MCI, n = 357), and ADD (n = 280) patients. Through automated volumetric analyses of global, cortical, and subcortical brain structures on clinical brain MRI T1w (n = 820) images from a retrospective, multi-center study (REMEMBER), icobrain dm's (v.4.4.0) ability to differentiate disease stages via ROC analysis was compared to FreeSurfer (v.6.0). Stepwise backward regression models were constructed to investigate if combined brain volumes can differentiate between AD stages.

Results: icobrain dm outperformed FreeSurfer in processing time (15-30 min versus 9-32 h), robustness (0 versus 67 failures), and diagnostic performance for whole brain, hippocampal volumes, and lateral ventricles between HC and ADD patients. Stepwise backward regression showed improved diagnostic accuracy for pairwise group differentiations, with highest performance obtained for distinguishing HC from ADD (AUC = 0.914; Specificity 83.0%; Sensitivity 86.3%).

Conclusion: Automated volumetry has a diagnostic value for ADD diagnosis in routine clinical practice. Our findings indicate that combined brain volumes improve diagnostic accuracy, using real-world imaging data from a clinical setting.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3233/JAD-210450DOI Listing
July 2021

Family-based exome sequencing identifies RBM45 as a possible candidate gene for frontotemporal dementia and amyotrophic lateral sclerosis.

Neurobiol Dis 2021 08 9;156:105421. Epub 2021 Jun 9.

Neurodegenerative Brain Diseases, VIB Center for Molecular Neurology, VIB, Antwerp, Belgium; Institute Born-Bunge, Antwerp, Belgium. Electronic address:

Neurodegenerative disorders like frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are pathologically characterized by toxic protein deposition in the cytoplasm or nucleus of affected neurons and glial cells. Many of these aggregated proteins belong to the class of RNA binding proteins (RBP), and, when mutated, account for a significant subset of familial ALS and FTD cases. Here, we present first genetic evidence for the RBP gene RBM45 in the FTD-ALS spectrum. RBM45 shows many parallels with other FTD-ALS associated genes and proteins. Multiple lines of evidence have demonstrated that RBM45 is an RBP that, upon mutation, redistributes to the cytoplasm where it co-aggregates with other RBPs into cytoplasmic stress granules (SG), evolving to persistent toxic TDP-43 immunoreactive inclusions. Exome sequencing in two affected first cousins of a heavily affected early-onset dementia family listed a number of candidate genes. The gene with the highest pathogenicity score was the RBP gene RBM45. In the family, the RBM45 Arg183* nonsense mutation co-segregated in both affected cousins. Validation in an unrelated patient (n = 548) / control (n = 734) cohort identified an additional RBM45 Arg183* carrier with bvFTD on a shared 4 Mb haplotype. Transcript and protein expression analysis demonstrated loss of nuclear RBM45, suggestive of a loss-of-function disease mechanism. Further, two more ultra-rare VUS, one in the nuclear localization signal (NLS, p.Lys456Arg) in an ALS patient and one in the intrinsically disordered homo-oligomer assembly (HOA) domain (p.Arg314Gln) in a patient with nfvPPA were detected. Our findings suggest that the pathomechanisms linking RBM45 with FTD and ALS may be related to its loss of nuclear function as a mediator of mRNA splicing, cytoplasmic retention or its inability to form homo-oligomers, leading to aggregate formation with trapping of other RBPs including TDP-43, which may accumulate into persisted TDP-43 inclusions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.nbd.2021.105421DOI Listing
August 2021

Common variants in Alzheimer's disease and risk stratification by polygenic risk scores.

Nat Commun 2021 06 7;12(1):3417. Epub 2021 Jun 7.

Servei de Neurologia, Hospital Universitari i Politècnic La Fe, Valencia, Spain.

Genetic discoveries of Alzheimer's disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer's disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer's disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer's disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-021-22491-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8184987PMC
June 2021

Premature termination codon mutations in ABCA7 contribute to Alzheimer's disease risk in Belgian patients.

Neurobiol Aging 2021 10 2;106:307.e1-307.e7. Epub 2021 May 2.

Neurodegenerative Brain Diseases Group, VIB Center for Molecular Neurology, Antwerp, Belgium; Institute Born-Bunge, Antwerp, Belgium; Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium. Electronic address:

The ATP-Binding Cassette Subfamily A Member 7 gene (ABCA7) was identified as a risk gene for Alzheimer's disease (AD) in genome-wide association studies of large cohorts of late-onset AD (LOAD) patients. Extended resequencing of the ABCA7 coding regions identified mutations that lead to premature termination codons (PTC) and loss of function of ABCA7. PTC mutations were enriched in LOAD patients and were frequently present in patients with early-onset AD (EOAD). We aimed at assessing the contribution of ABCA7 PTC mutations to AD in the Belgian population by screening the ABCA7 coding region in a Belgian AD cohort of 1376 patients, including LOAD and EOAD patients, and in a Belgian control cohort of 976 individuals. We identified a PTC mutation in 67 AD patients (4.9%) and in 18 control individuals (1.8%) confirming the enrichment of ABCA7 PTC mutations in Belgian AD patients. The patient carriers had a mean onset age of 69.7 ± 9.8 years with a wide onset age range of 42 years (48-90 years). In 77.3% of the families of ABCA7 carriers, there were AD patients present suggestive of a positive family history of disease, but a Mendelian co-segregation of ABCA7 PTC mutations with disease is not clear. Overall, our genetic data predict that PTC mutations in ABCA7 are common in the Belgian population and are present in LOAD and EOAD patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neurobiolaging.2021.04.023DOI Listing
October 2021

TMEM106B and CPOX are genetic determinants of cerebrospinal fluid Alzheimer's disease biomarker levels.

Alzheimers Dement 2021 May 14. Epub 2021 May 14.

Neurodegenerative Brain Diseases Group, Center for Molecular Neurology, VIB, Antwerp, Belgium.

Introduction: Neurofilament light (NfL), chitinase-3-like protein 1 (YKL-40), and neurogranin (Ng) are biomarkers for Alzheimer's disease (AD) to monitor axonal damage, astroglial activation, and synaptic degeneration, respectively.

Methods: We performed genome-wide association studies (GWAS) using DNA and cerebrospinal fluid (CSF) samples from the EMIF-AD Multimodal Biomarker Discovery study for discovery, and the Alzheimer's Disease Neuroimaging Initiative study for validation analyses. GWAS were performed for all three CSF biomarkers using linear regression models adjusting for relevant covariates.

Results: We identify novel genome-wide significant associations between DNA variants in TMEM106B and CSF levels of NfL, and between CPOX and YKL-40. We confirm previous work suggesting that YKL-40 levels are associated with DNA variants in CHI3L1.

Discussion: Our study provides important new insights into the genetic architecture underlying interindividual variation in three AD-related CSF biomarkers. In particular, our data shed light on the sequence of events regarding the initiation and progression of neuropathological processes relevant in AD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/alz.12330DOI Listing
May 2021

Vestibular Function in Older Adults With Cognitive Impairment: A Systematic Review.

Ear Hear 2021 Apr 22;42(5):1119-1126. Epub 2021 Apr 22.

Department of Translational Neurosciences, University of Antwerp, Antwerp, Belgium.

Importance: Given the rising prevalence of patients with dementia and those at risk for it, early identification is prioritized. As vestibular dysfunction is associated with Alzheimer's disease (AD) and may contribute to its onset, vestibular assessment may yield an opportunity in early dementia screening.

Objective: This systematic review structures and compares the different raw outcome measures used to assess vestibular function while comparing older adults with preserved cognition to individuals with cognitive impairment, either suffering from mild cognitive impairment (MCI) or AD.

Design: Two investigators independently and systematically searched publications performing objectively measured vestibular testing in a patient population consisting of either MCI or AD, compared with a control group of older adults with preserved cognition. No limitations regarding language or publication date were applied. References of the retrieved articles were hand searched for relevant articles.

Results: Seven articles were included for analysis. A total of 235 older adults with impaired cognition (150 AD, 85 MCI) were compared with a control group of 481 older adults with preserved cognition. Evaluation of the peripheral vestibular function included video head impulse test (vHIT), videonystagmography (VNG), electronystagmography (ENG) including bithermal caloric irrigation and vestibular evoked myogenic potentials (VEMP). The VEMP test, assessing otolith function and the elicited vestibulocollic reflex (VCR), was able to differentiate subjects with AD and its prodromal stage from healthy controls, with p13 latency (p < 0.05) and amplitude (p < 0.05) having the most discriminating power.No correlation between cognitive decline and vestibulo-ocular reflex measurements in different frequency ranges of the semicircular canals (using vHIT, rotatory chair testing, and caloric irrigation) was found. Because of the limited number of available studies and the large heterogeneity in outcome measures, these results have to be interpreted with caution.

Conclusions: Measurements of the VCR, as evoked by the VEMP test, discriminate between patients with cognitive impairment (MCI and AD) and older adults with preserved cognition, whereas measurements of the vestibulo-ocular reflex do not. More studies are needed to further elaborate on these findings.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/AUD.0000000000001040DOI Listing
April 2021

Investigation of the role of matrix metalloproteinases in the genetic etiology of Alzheimer's disease.

Neurobiol Aging 2021 08 28;104:105.e1-105.e6. Epub 2021 Mar 28.

Neurodegenerative Brain Diseases Group, VIB Center for Molecular Neurology, Antwerp, Belgium; Institute Born-Bunge, Antwerp, Belgium; Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium. Electronic address:

Matrix metalloproteinases (MMPs) are a multigene family of proteinases regulating the functions of a large number of signaling and scaffolding molecules that are involved in neuro-inflammation, synaptic dysfunction and neuronal death. MMPs have been associated with neurological conditions, such as Alzheimer's disease (AD), through a sudden and massive upregulation of particular members of the MMP family. Evidence for this hypothesis can be found in the clinical observation of increased MMP1 and MMP3 expression levels in plasma of AD patients compared to control individuals and in the pro-amyloidogenic effects that have been described for additional MMP family members like MMP13, MT1-MMP, and MT5-MMP. Consequently, we investigated the role of MMP1, 3, 13, MT1-MMP, and MT5-MMP in the genetic etiology of AD. We performed full exonic resequencing of these 5 MMPs in 1278 AD patients (mean age at onset [AAO]: 74.88 ± 9.10, range: 29-96) and 797 age-matched control individuals (mean age at inclusion [AAI]: 74.92 ± 6.48, range: 65-100) from Flanders-Belgium and identified MMP13 as most promising candidate gene. We identified 6 ultra-rare (≤0.01%) MMP13 missense mutations in 6 patients that were absent from the control cohort. We observed in one control individual a frameshift mutation (p.G269Qfs*2) leading to a premature termination codon. Based on previously described functional evidence, suggesting that MMP13 regulates BACE1 processing, and our genetic findings, we hypothesize a gain-of-function disease mechanism for the missense mutations found in patients. Functional experimental studies remain essential to assess the effect of these mutations on disease related processes and genetic replication studies are needed to corroborate our findings.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neurobiolaging.2021.03.011DOI Listing
August 2021

Replication study of plasma proteins relating to Alzheimer's pathology.

Alzheimers Dement 2021 Mar 31. Epub 2021 Mar 31.

Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.

Introduction: This study sought to discover and replicate plasma proteomic biomarkers relating to Alzheimer's disease (AD) including both the "ATN" (amyloid/tau/neurodegeneration) diagnostic framework and clinical diagnosis.

Methods: Plasma proteins from 972 subjects (372 controls, 409 mild cognitive impairment [MCI], and 191 AD) were measured using both SOMAscan and targeted assays, including 4001 and 25 proteins, respectively.

Results: Protein co-expression network analysis of SOMAscan data revealed the relation between proteins and "N" varied across different neurodegeneration markers, indicating that the ATN variants are not interchangeable. Using hub proteins, age, and apolipoprotein E ε4 genotype discriminated AD from controls with an area under the curve (AUC) of 0.81 and MCI convertors from non-convertors with an AUC of 0.74. Targeted assays replicated the relation of four proteins with the ATN framework and clinical diagnosis.

Discussion: Our study suggests that blood proteins can predict the presence of AD pathology as measured in the ATN framework as well as clinical diagnosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/alz.12322DOI Listing
March 2021

Time Trends of Cerebrospinal Fluid Biomarkers of Neurodegeneration in Idiopathic Normal Pressure Hydrocephalus.

J Alzheimers Dis 2021 ;80(4):1629-1642

Institute of Clinical Medicine -Neurosurgery, University of Eastern Finland and Department of Neurosurgery, Kuopio University Hospital, Kuopio, Finland.

Background: Longitudinal changes in cerebrospinal fluid (CSF) biomarkers are seldom studied. Furthermore, data on biomarker gradient between lumbar (L-) and ventricular (V-) compartments seems to be discordant.

Objective: To examine alteration of CSF biomarkers reflecting Alzheimer's disease (AD)-related amyloid-β (Aβ) aggregation, tau pathology, neurodegeneration, and early synaptic degeneration by CSF shunt surgery in idiopathic normal pressure hydrocephalus (iNPH) in relation to AD-related changes in brain biopsy. In addition, biomarker levels in L- and V-CSF were compared.

Methods: L-CSF was collected prior to shunt placement and, together with V-CSF, 3-73 months after surgery. Thereafter, additional CSF sampling took place at 3, 6, and 18 months after the baseline sample from 26 iNPH patients with confirmed Aβ plaques in frontal cortical brain biopsy and 13 iNPH patients without Aβ pathology. CSF Amyloid-β42 (Aβ42), total tau (T-tau), phosphorylated tau (P-tau181), neurofilament light (NFL), and neurogranin (NRGN) were analyzed with customized ELISAs.

Results: All biomarkers but Aβ42 increased notably by 140-810% in L-CSF after CSF diversion and then stabilized. Aβ42 instead showed divergent longitudinal decrease between Aβ-positive and -negative patients in L-CSF, and thereafter increase in Aβ-negative iNPH patients in both L- and V-CSF. All five biomarkers correlated highly between V-CSF and L-CSF (Aβ42 R = 0.87, T-tau R = 0.83, P-tau R = 0.92, NFL R = 0.94, NRGN R = 0.9; all p < 0.0001) but were systematically lower in V-CSF (Aβ42 14 %, T-tau 22%, P-tau 20%, NFL 32%, NRGN 19%). With APOE genotype-grouping, only Aβ42 showed higher concentration in non-carriers of allele ɛ4.

Conclusion: Longitudinal follow up shows that after an initial post-surgery increase, T-tau, P-tau, and NRGN are stable in iNPH patients regardless of brain biopsy Aβ pathology, while NFL normalized toward its pre-shunt levels. Aβ42 as biomarker seems to be the least affected by the surgical procedure or shunt and may be the best predictor of AD risk in iNPH patients. All biomarker concentrations were lower in V- than L-CSF yet showing strong correlations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3233/JAD-201361DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8150674PMC
September 2021

Hippocampal Sclerosis in Frontotemporal Dementia: When Vascular Pathology Meets Neurodegeneration.

J Neuropathol Exp Neurol 2021 Mar;80(4):313-324

Institute Born-Bunge, Neuropathology and Laboratory of Neurochemistry and Behavior, University of Antwerp, Antwerp, Belgium.

Hippocampal sclerosis (HS) is a common neuropathological finding and has been associated with advanced age, TDP-43 proteinopathy, and cerebrovascular pathology. We analyzed neuropathological data of an autopsy cohort of early-onset frontotemporal dementia patients. The study aimed to determine whether in this cohort HS was related to TDP-43 proteinopathy and whether additional factors could be identified. We examined the relationship between HS, proteinopathies in frontotemporal cortices and hippocampus, Alzheimer disease, cerebrovascular changes, and age. We confirmed a strong association between HS and hippocampal TDP-43, whereas there was a weaker association between HS and frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP). Nearly all of the FTLD-TDP cases had TDP-43 pathology in the hippocampus. HS was present in all FTLD-TDP type D cases, in 50% of the FTLD-TDP A cohort and in 6% of the FTLD-TDP B cohort. Our data also showed a significant association between HS and vascular changes. We reviewed the literature on HS and discuss possible pathophysiological mechanisms between TDP-43 pathology, cerebrovascular disease, and HS. Additionally, we introduced a quantitative neuronal cell count in CA1 to objectify the semiquantitative visual appreciation of HS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/jnen/nlab010DOI Listing
March 2021

CSF and Blood Neurofilament Levels in Athletes Participating in Physical Contact Sports: A Systematic Review.

Neurology 2021 04 26;96(15):705-715. Epub 2021 Feb 26.

From the Department of Physical Medicine and Rehabilitation (C.V., K.P.), Universitair Ziekenhuis Leuven; Katholieke Universiteit Leuven; Center for Neurosciences (M.B., J.D., S.E., J.V., M.D.), Vrije Universiteit Brussel; Reference Center for Biological Markers of Dementia (M.B., S.E.), Institute Born-Bunge, Universiteit Antwerpen; Neurochemistry Laboratory (M.B.), Department of Clinical Biology, Universitair Ziekenhuis Brussel; Department of Neurosurgery (J.D.), Universitair Ziekenhuis Brussel; Department of Neurology (S.E., J.V., M.D.), Universitair Ziekenhuis Brussel; and Nationaal Multiple Sclerose Centrum (M.D.); Melsbroek, Belgium.

Objective: To evaluate whether participating in physical contact sports is associated with a release of neurofilaments and whether such release is related to future clinical neurologic and/or psychiatric impairment.

Methods: We performed a systematic review of the PubMed, MEDLINE, and Cochrane Library databases using a combination of the search terms neurofilament(s)/intermediate filament and sport(s)/athletes. Original studies, written in English, reporting on neurofilaments in CSF and/or serum/plasma of contact sport athletes were included. This review was conducted following the Preferred Reporting Items for Systematic Review and Analyses guidelines.

Results: Eighteen studies in 8 different contact sports (i.e., boxing, American football, ice hockey, soccer, mixed martial arts, lacrosse, rugby, and wrestling) matched our criteria. Elevated light chain neurofilament (NfL) levels were described in 13/18 cohorts. Most compelling evidence was present in boxing and American football, where exposure-related increases were appreciable at the intraindividual level (up to 4.1- and 2.0-fold, respectively) in well-defined groups. Differences in exposure severity (including previous cumulative effects), sampling/measurement time points (with regard to expected peak values), and definitions of the baseline setting are considered as main contributors to the variability in findings. No studies were encountered that have investigated the relationship with the targeted clinical end points; therefore no NfL cutoffs exist that are associated with a poor outcome.

Conclusion: NfL release can be seen, as a potential marker of neuronal brain damage, in participants of physical contact sports, particularly boxing and American football. The exact significance regarding the risk for future clinical impairment remains to be elucidated.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/WNL.0000000000011750DOI Listing
April 2021

Melatonin levels in the Alzheimer's disease continuum: a systematic review.

Alzheimers Res Ther 2021 02 23;13(1):52. Epub 2021 Feb 23.

Research group Experimental Pharmacology (EFAR), Department of Pharmaceutical Chemistry, Drug Analysis and Drug Information (FASC), Center for Neurosciences (C4N), Vrije Universiteit Brussel, Laarbeeklaan 103, 1090, Brussels, Belgium.

Background: The search for new Alzheimer's disease (AD) cerebrospinal fluid (CSF) and blood biomarkers with potential pathophysiological and clinical relevance continues, as new biomarkers might lead to improved early and differential diagnosis, monitoring of disease progression and might even identify new druggable targets. Melatonin might be an interesting biomarker as an inverse correlation between CSF melatonin levels, and severity of the neuropathology as measured by Braak stages has been described. Melatonin can be measured in different body fluids, such as CSF, blood, saliva and urine.

Objectives: The aim of this systematic review was to review all available studies regarding melatonin levels in different body fluids in the AD continuum and give an extensive overview of reported outcomes.

Methods: We included papers comparing melatonin levels between healthy controls and human patients belonging to the AD continuum. A systematic search of PubMed and Web of Science led to inclusion of 20 full-length English papers following exclusion of duplicates.

Results: This systematic literature search showed that disruptions in melatonin levels occur with age, but also in AD when compared to age-matched controls. Night-time melatonin levels were found to be lower in CSF and blood of AD patients as compared to controls. Literature was not conclusive regarding alterations in blood daytime melatonin levels or regarding saliva melatonin in AD patients. Decreased total and night-time melatonin production has been described in urine of AD patients.

Conclusion: Our systematic review shows evidence for disruptions in (night-time) melatonin levels in AD as compared to age-matched controls. Although more studies are needed to understand the contribution of disruption of the melatonergic system to the pathophysiology of AD, the potential anti-AD effects that have been attributed to melatonin, renders research on this topic relevant for the discovery of potential future treatment effects of melatonin for AD. The use of melatonin as potential blood biomarker for disease progression should also be further investigated.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13195-021-00788-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7903801PMC
February 2021

Contribution of rare homozygous and compound heterozygous VPS13C missense mutations to dementia with Lewy bodies and Parkinson's disease.

Acta Neuropathol Commun 2021 02 12;9(1):25. Epub 2021 Feb 12.

Center for Molecular Neurology, VIB, Antwerp, Belgium.

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 mutations in VPS13C, combinations of rare recessive compound heterozygous missense mutations reduce VPS13C expression and contribute to increased risk of LBD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s40478-021-01121-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7881566PMC
February 2021

Pathophysiological subtypes of Alzheimer's disease based on cerebrospinal fluid proteomics.

Brain 2020 12;143(12):3776-3792

Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC - Location VUmc, The Netherlands.

Alzheimer's disease is biologically heterogeneous, and detailed understanding of the processes involved in patients is critical for development of treatments. CSF contains hundreds of proteins, with concentrations reflecting ongoing (patho)physiological processes. This provides the opportunity to study many biological processes at the same time in patients. We studied whether Alzheimer's disease biological subtypes can be detected in CSF proteomics using the dual clustering technique non-negative matrix factorization. In two independent cohorts (EMIF-AD MBD and ADNI) we found that 705 (77% of 911 tested) proteins differed between Alzheimer's disease (defined as having abnormal amyloid, n = 425) and controls (defined as having normal CSF amyloid and tau and normal cognition, n = 127). Using these proteins for data-driven clustering, we identified three robust pathophysiological Alzheimer's disease subtypes within each cohort showing (i) hyperplasticity and increased BACE1 levels; (ii) innate immune activation; and (iii) blood-brain barrier dysfunction with low BACE1 levels. In both cohorts, the majority of individuals were labelled as having subtype 1 (80, 36% in EMIF-AD MBD; 117, 59% in ADNI), 71 (32%) in EMIF-AD MBD and 41 (21%) in ADNI were labelled as subtype 2, and 72 (32%) in EMIF-AD MBD and 39 (20%) individuals in ADNI were labelled as subtype 3. Genetic analyses showed that all subtypes had an excess of genetic risk for Alzheimer's disease (all P > 0.01). Additional pathological comparisons that were available for a subset in ADNI suggested that subtypes showed similar severity of Alzheimer's disease pathology, and did not differ in the frequencies of co-pathologies, providing further support that found subtypes truly reflect Alzheimer's disease heterogeneity. Compared to controls, all non-demented Alzheimer's disease individuals had increased risk of showing clinical progression (all P < 0.01). Compared to subtype 1, subtype 2 showed faster clinical progression after correcting for age, sex, level of education and tau levels (hazard ratio = 2.5; 95% confidence interval = 1.2, 5.1; P = 0.01), and subtype 3 at trend level (hazard ratio = 2.1; 95% confidence interval = 1.0, 4.4; P = 0.06). Together, these results demonstrate the value of CSF proteomics in studying the biological heterogeneity in Alzheimer's disease patients, and suggest that subtypes may require tailored therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/brain/awaa325DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7805814PMC
December 2020

European Academy of Neurology/European Alzheimer's Disease Consortium position statement on diagnostic disclosure, biomarker counseling, and management of patients with mild cognitive impairment.

Eur J Neurol 2021 07 23;28(7):2147-2155. Epub 2020 Dec 23.

Department of Neurology, Danish Dementia Research Centre, Rigshospitalet, Copenhagen, Denmark.

Background And Purpose: Careful counseling through the diagnostic process and adequate postdiagnostic support in patients with mild cognitive impairment (MCI) is important. Previous studies have indicated heterogeneity in practice and the need for guidance for clinicians.

Methods: A joint European Academy of Neurology/European Alzheimer's Disease Consortium panel of dementia specialists was appointed. Through online meetings and emails, positions were developed regarding disclosing a syndrome diagnosis of MCI, pre- and postbiomarker sampling counseling, and postdiagnostic support.

Results: Prior to diagnostic evaluation, motives and wishes of the patient should be sought. Diagnostic disclosure should be carried out by a dementia specialist taking the ethical principles of "the right to know" versus "the wish not to know" into account. Disclosure should be accompanied by written information and a follow-up plan. It should be made clear that MCI is not dementia. Prebiomarker counseling should always be carried out if biomarker sampling is considered and postbiomarker counseling if sampling is carried out. A dementia specialist knowledgeable about biomarkers should inform about pros and cons, including alternatives, to enable an autonomous and informed decision. Postbiomarker counseling will depend in part on the results of biomarkers. Follow-up should be considered for all patients with MCI and include brain-healthy advice and possibly treatment for specific underlying causes. Advice on advance directives may be relevant.

Conclusions: Guidance to clinicians on various aspects of the diagnostic process in patients with MCI is presented here as position statements. Further studies are needed to enable more evidence-based and standardized recommendations in the future.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/ene.14668DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8246881PMC
July 2021

Genome-wide association study of Alzheimer's disease CSF biomarkers in the EMIF-AD Multimodal Biomarker Discovery dataset.

Transl Psychiatry 2020 11 22;10(1):403. Epub 2020 Nov 22.

Department of Psychiatry, University Hospital of Lausanne, Lausanne, Switzerland.

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder and the most common form of dementia in the elderly. Susceptibility to AD is considerably determined by genetic factors which hitherto were primarily identified using case-control designs. Elucidating the genetic architecture of additional AD-related phenotypic traits, ideally those linked to the underlying disease process, holds great promise in gaining deeper insights into the genetic basis of AD and in developing better clinical prediction models. To this end, we generated genome-wide single-nucleotide polymorphism (SNP) genotyping data in 931 participants of the European Medical Information Framework Alzheimer's Disease Multimodal Biomarker Discovery (EMIF-AD MBD) sample to search for novel genetic determinants of AD biomarker variability. Specifically, we performed genome-wide association study (GWAS) analyses on 16 traits, including 14 measures derived from quantifications of five separate amyloid-beta (Aβ) and tau-protein species in the cerebrospinal fluid (CSF). In addition to confirming the well-established effects of apolipoprotein E (APOE) on diagnostic outcome and phenotypes related to Aβ42, we detected novel potential signals in the zinc finger homeobox 3 (ZFHX3) for CSF-Aβ38 and CSF-Aβ40 levels, and confirmed the previously described sex-specific association between SNPs in geminin coiled-coil domain containing (GMNC) and CSF-tau. Utilizing the results from independent case-control AD GWAS to construct polygenic risk scores (PRS) revealed that AD risk variants only explain a small fraction of CSF biomarker variability. In conclusion, our study represents a detailed first account of GWAS analyses on CSF-Aβ and -tau-related traits in the EMIF-AD MBD dataset. In subsequent work, we will utilize the genomics data generated here in GWAS of other AD-relevant clinical outcomes ascertained in this unique dataset.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41398-020-01074-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7680793PMC
November 2020

Cerebrospinal fluid total tau levels indicate aberrant neuronal plasticity in Alzheimer's disease.

medRxiv 2020 Nov 3. Epub 2020 Nov 3.

Alzheimer's disease (AD) is characterised by abnormal amyloid beta and tau processing. Previous studies reported that cerebrospinal fluid (CSF) total tau (t-tau) levels vary between patients. Here we show that CSF t-tau variability is associated with distinct impairments in neuronal plasticity mediated by gene repression factors SUZ12 and REST. AD individuals with abnormal t-tau levels have increased CSF concentrations of plasticity proteins regulated by SUZ12 and REST. AD individuals with normal t-tau, on the contrary, have decreased concentrations of these plasticity proteins and increased concentrations in proteins associated with blood-brain and blood CSF-barrier dysfunction. Genomic analyses suggested that t-tau levels in part depend on genes involved in gene expression. The distinct plasticity abnormalities in AD as signaled by t-tau urge the need for personalised treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1101/2020.10.29.20211920DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7654872PMC
November 2020

Contribution of homozygous and compound heterozygous missense mutations in VWA2 to Alzheimer's disease.

Neurobiol Aging 2021 03 12;99:100.e17-100.e23. Epub 2020 Sep 12.

Neurodegenerative Brain Diseases Group, VIB Center for Molecular Neurology, Antwerp, Belgium; Institute Born-Bunge, Antwerp, Belgium; Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium. Electronic address:

Alzheimer's disease is the most frequent diagnosis of neurodegenerative dementia with early (≤65 years) and late (>65 years) onset ages in familial and sporadic patients. Causal mutations in 3 autosomal dominant Alzheimer genes, i.e. amyloid precursor protein (APP), presenilin 1 (PSEN1) and presenilin 2 (PSEN2), explain only 5%-10% of early-onset patients leaving the majority of patients genetically unresolved. To discover potential missing genetics, we used whole genome sequencing data of 17 early-onset patients with well-documented clinical diagnosis of Alzheimer's disease. In the discovery group, the mean onset age was 55.71 ± 6.83 years (range 37-65). Six patients had a brain autopsy and neuropathology confirmed Alzheimer's disease. Analysis of the genetic data identified in one patient a homozygous p.V366M missense mutation in the Von Willebrand factor A domain containing 2 gene (VWA2). Resequencing of the VWA2 coding region in an Alzheimer's disease patient cohort from Flanders-Belgium (n = 1148), including 152 early and 996 late onset patients, identified additional homozygous and compound heterozygous missense mutations in 1 early and 3 late-onset patients. Allele-sharing analysis identified common haplotypes among the compound heterozygous VWA2 mutation carriers, suggesting shared ancestors. Overall, we identified 5 patient carriers of homozygous or compound heterozygous missense mutations (5/1165; 0.43 %), 2 in early (2/169; 1.18 %) and 3 in late-onset (3/996; 0.30 %) patients. The frequencies of the homozygous and compound heterozygous missense mutations in patients are higher than expected from the frequencies calculated based on their combined single alleles. None of the homozygous/compound heterozygous missense mutation carriers had a family history of autosomal dominant Alzheimer's disease. Our findings suggest that homozygous and compound heterozygous missense mutations in VWA2 might contribute to the risk of Alzheimer's disease in sporadic patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neurobiolaging.2020.09.009DOI Listing
March 2021

Impact of hearing loss and vestibular decline on cognition in Alzheimer's disease: a prospective longitudinal study protocol (Gehoor, Evenwicht en Cognitie, GECkO).

BMJ Open 2020 09 17;10(9):e039601. Epub 2020 Sep 17.

Department of Translational Neurosciences, University of Antwerp, Faculty of Medicine and Health Sciences, Wilrijk, Belgium.

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: The study protocol was approved by the ethical committee of the Antwerp University Hospital on 4 February 2019 with protocol number B300201938949. The findings will be disseminated through peer-reviewed publications and conference presentations.

Trial Registration Number: ClinicalTrials.gov Registry (NCT04385225).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/bmjopen-2020-039601DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7500302PMC
September 2020

No association of CpG SNP rs9357140 with onset age in Belgian C9orf72 repeat expansion carriers.

Neurobiol Aging 2021 01 15;97:145.e1-145.e4. Epub 2020 Aug 15.

Neurodegenerative Brain Diseases Group, Center for Molecular Neurology, VIB, Antwerp, Belgium; Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium. Electronic address:

We investigated the impact of the recently described chromosome 6 open reading frame 10 (C6orf10)/LOC101929163 locus as age-at-onset modifier in an extended cohort of Belgian chromosome 9 open reading frame 72 (C9orf72) GC repeat expansion carriers. We genotyped the tagging CpG single-nucleotide polymorphism rs9357140 in 224 confirmed C9orf72 repeat expansion carriers, 102 index cases and 122 relatives, and tested association with onset age. The C9orf72 repeat expansion cohort consisted of 131 symptomatic carriers, that is, 78 with dementia only, 13 with frontotemporal dementia (FTD)-amyotrophic lateral sclerosis (ALS), and 40 ALS only, and 93 presymptomatic carriers. Cox proportional hazard regression analysis failed to identify significant association (adjusted hazard ratio = 1.15, p = 0.3). We further extended our analysis to a Belgian cohort of unrelated, mutation-negative FTD index patients (n = 230), but also found no association (adjusted hazard ratio = 0.96, p = 0.3). Overall, our findings suggest that in the Belgian cohort, the C6orf10/LOC101929163 locus cannot explain the marked variability in age at onset, and other genetic or environmental modifiers must drive the clinical heterogeneity observed among C9orf72 repeat expansion carriers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neurobiolaging.2020.07.021DOI Listing
January 2021

Amyloid-β cerebrospinal fluid levels and the interpretation of APP, PSEN1 and PSEN2 mutations.

Alzheimers Res Ther 2020 09 11;12(1):108. Epub 2020 Sep 11.

Neurodegenerative Brain Diseases Group, VIB Center for Molecular Neurology, Antwerp, Belgium.

Background: Alzheimer's disease (AD) mutations in amyloid precursor protein (APP) and presenilins (PSENs) could potentially lead to the production of longer amyloidogenic Aβ peptides. Amongst these, Aβ is more prone to aggregation and has higher toxic properties than the long-known Aβ. However, a direct effect on Aβ in biomaterials of individuals carrying genetic mutations in the known AD genes is yet to be determined.

Methods: N = 1431 AD patients (n = 280 early-onset (EO) and n = 1151 late-onset (LO) AD) and 809 control individuals were genetically screened for APP and PSENs. For the first time, Aβ levels were analysed in cerebrospinal fluid (CSF) of 38 individuals carrying pathogenic or unclear rare mutations or the common PSEN1 p.E318G variant and compared with Aβ and Aβ CSF levels. The soluble sAPPα and sAPPβ species were also measured for the first time in mutation carriers.

Results: A known pathogenic mutation was identified in 5.7% of EOAD patients (4.6% PSEN1, 1.07% APP) and in 0.3% of LOAD patients. Furthermore, 12 known variants with unclear pathogenicity and 11 novel were identified. Pathogenic and unclear mutation carriers showed a significant reduction in CSF Aβ levels compared to controls (p = 0.037; < 0.001). CSF Aβ levels positively correlated with CSF Aβ in both pathogenic and unclear carriers and controls (all p < 0.001). The p.E318G carriers showed reduced Aβ levels (p < 0.001), though genetic association with AD was not detected. sAPPα and sAPPβ CSF levels were significantly reduced in the group of unclear (p = 0.006; 0.005) and p.E318G carriers (p = 0.004; 0.039), suggesting their possible involvement in AD. Finally, using Aβ and Aβ levels, we could re-classify as "likely pathogenic" 3 of the unclear mutations.

Conclusion: This is the first time that Aβ levels were analysed in CSF of AD patients with genetic mutations in the AD causal genes. The observed reduction of Aβ in APP and PSENs carriers highlights the pathogenic role of longer Aβ peptides in AD pathogenesis. Alterations in Aβ could prove useful in understanding the pathogenicity of unclear APP and PSENs variants, a critical step towards a more efficient genetic counselling.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13195-020-00676-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7488767PMC
September 2020

Biomarker counseling, disclosure of diagnosis and follow-up in patients with mild cognitive impairment: A European Alzheimer's disease consortium survey.

Int J Geriatr Psychiatry 2021 02 16;36(2):324-333. Epub 2020 Sep 16.

Servicio de geriatria, Hospital Universitario Ramon y Cajal, Madrid, Spain.

Objectives: Mild cognitive impairment (MCI) is associated with an increased risk of further cognitive decline, partly depending on demographics and biomarker status. The aim of the present study was to survey the clinical practices of physicians in terms of biomarker counseling, management, and follow-up in European expert centers diagnosing patients with MCI.

Methods: An online email survey was distributed to physicians affiliated with European Alzheimer's disease Consortium centers (Northern Europe: 10 centers; Eastern and Central Europe: 9 centers; and Southern Europe: 15 centers) with questions on attitudes toward biomarkers and biomarker counseling in MCI and dementia. This included postbiomarker counseling and the process of diagnostic disclosure of MCI, as well as treatment and follow-up in MCI.

Results: The response rate for the survey was 80.9% (34 of 42 centers) across 20 countries. A large majority of physicians had access to biomarkers and found them useful. Pre- and postbiomarker counseling varied across centers, as did practices for referral to support groups and advice on preventive strategies. Less than half reported discussing driving and advance care planning with patients with MCI.

Conclusions: The variability in clinical practices across centers calls for better biomarker counseling and better training to improve communication skills. Future initiatives should address the importance of communicating preventive strategies and advance planning.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/gps.5427DOI Listing
February 2021

[Early diagnosis of Alzheimer's disease (with the announcement of the diagnosis)].

Rev Prat 2020 Feb;70(2):158-163

Département de neurologie, Cliniques universitaires Saint-Luc, Bruxelles, Belgique.

Early diagnosis of Alzheimer's disease (with the announcement of the diagnosis). The number of patients consulting to find out if they have Alzheimer's disease continues to grow. Reasons to consult most often include anxiety about being affected by this disease, confidence in medical and therapeutic advances relayed in the media and the desire to plan for the future, taking into account a possible deterioration. Advances in the knowledge of the natural history of the disease and the technical progress currently allow an early diagnosis, before the stage of dementia. Although the clinical use of biomarkers is justified in patients who have attended a Memory Clinic, ethical issues remain. The disclosure of the diagnosis of Alzheimer's disease to the person who is not yet suffering from dementia remains a sensitive subject. In this context, it seems appropriate at this stage to restrict the use of these methods to centers specializing in early diagnosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
February 2020

Encephalitis associated with the SARS-CoV-2 virus: A case report.

Interdiscip Neurosurg 2020 Dec 10;22:100821. Epub 2020 Jul 10.

Department of Neurology, UZ Brussel and Center for Neurosciences (C4N), Vrije Universiteit Brussel, Belgium.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) usually causes fever, respiratory symptoms, malaise and myalgia. Recent observations suggested possible neurological complications of COVID-19, including the first report of suspected viral encephalitis. We report a case of a 29-year-old male with -on nasopharyngeal testing- confirmed SARS-CoV-2 infection with severe respiratory symptoms, followed by clinical and radiological signs of encephalitis. Magnetic resonance imaging (MRI) of the brain showed an asymmetric FLAIR-hyperintensity of the left medial temporal cortex associated with mild gyral expansion. Lumbar puncture was normal and PCR's for SARS-CoV-2 virus on CSF were negative. Clinicians treating SARS-CoV-2 infected patients should be aware of possible neurological complications, like encephalitis. The diagnosis of SARS-CoV-2 encephalitis is difficult as CSF analysis may be normal.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.inat.2020.100821DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7347479PMC
December 2020
-->