Publications by authors named "Peter Paul De Deyn"

223 Publications

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

Neurobiol Aging 2021 Mar 28. 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.
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http://dx.doi.org/10.1016/j.neurobiolaging.2021.03.011DOI Listing
March 2021

Temporal dynamics of depression, cognitive performance and sleep in older persons with depressive symptoms and cognitive impairments: a series of eight single-subject studies.

Int Psychogeriatr 2021 Mar 15:1-13. Epub 2021 Mar 15.

Department of Psychiatry, University of Groningen, University Medical Center Groningen, Interdisciplinary Center Psychopathology and Emotion regulation, Groningen, The Netherlands.

Objectives: To investigate the presence, nature and direction of the daily temporal association between depressive symptoms, cognitive performance and sleep in older individuals.

Design, Setting, Participants: Single-subject study design in eight older adults with cognitive impairments and depressive symptoms.

Measurements: For 63 consecutive days, depressive symptoms, working memory performance and night-time sleep duration were daily assessed with an electronic diary and actigraphy. The temporal associations of depressive symptoms, working memory and total sleep time were evaluated for each participant separately with time-series analysis (vector autoregressive modeling).

Results: For seven out of eight participants we found a temporal association between depressive symptoms and/or sleep and/or working memory performance. More depressive symptoms were preceded by longer sleep duration in one person (r = 0.39; p < .001), by longer or shorter sleep duration than usual in one other person (B = 0.49; p < .001), by worse working memory in one person (B = -0.45; p = .007), and by better working memory performance in one other person (B = 0.35; p = .009). Worse working memory performance was preceded by longer sleep duration (r = -.35; p = .005) in one person, by shorter or longer sleep duration in three other persons (B = -0.76; p = .005, B = -0.61; p < .001; B = -0.34; p = .002), and by more depressive symptoms in one person (B = -0.25; p = .009).

Conclusion: The presence, nature and direction of the temporal associations between depressive symptoms, cognitive performance and sleep differed between individuals. Knowledge of personal temporal associations may be valuable for the development of personalized intervention strategies in order to maintain their health, quality of life, functional outcomes and independence.
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http://dx.doi.org/10.1017/S1041610221000065DOI Listing
March 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.
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http://dx.doi.org/10.1093/jnen/nlab010DOI Listing
March 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.
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http://dx.doi.org/10.1186/s40478-021-01121-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7881566PMC
February 2021

Coronary Artery Calcium and Cognitive Function in Dutch Adults: Cross-Sectional Results of the Population-Based ImaLife Study.

J Am Heart Assoc 2021 Feb 2;10(4):e018172. Epub 2021 Feb 2.

Department of Radiology University of Groningen Groningen The Netherlands.

Background The aim of this study was to investigate whether increased severity of coronary artery calcium (CAC), an imaging biomarker of subclinical coronary atherosclerosis, is associated with worse cognitive function independent of cardiovascular risk factors in a large population-based Dutch cohort with broad age range. Methods and Results A cross-sectional analysis was performed in 4988 ImaLife participants (aged 45-91 years, 58.3% women) without history of cardiovascular disease. CAC scores were obtained using nonenhanced cardiac computed tomography scanning. The CogState Brief Battery was used to assess 4 cognitive domains: processing speed, attention, working memory, and visual learning based on detection task, identification task, 1-back task, and 1-card-learning task, respectively. Differences in mean scores of each cognitive domain were compared among 4 CAC categories (0, 1-99, 100-399, ≥400) using analysis of covariates to adjust for classical cardiovascular risk factors. Age-stratified analysis (45-54, 55-64, and ≥65 years) was performed to assess whether the association of CAC severity with cognitive function differed by age. Overall, higher CAC was associated with worse performance on 1-back task after adjusting for classical cardiovascular risk factors, but CAC was not associated with the other cognitive tasks. Age-stratified analyses revealed that the association of CAC severity with working memory persisted in participants aged 45 to 54 years, while in the elderly this association lost significance. Conclusions In this Dutch population of ≥45 years, increased CAC severity was associated with worse performance of working memory, independent of classical cardiovascular risk factors. The inverse relationship of CAC score categories with working memory was strongest in participants aged 45 to 54 years.
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http://dx.doi.org/10.1161/JAHA.120.018172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7955332PMC
February 2021

PET Agents in Dementia: An Overview.

Semin Nucl Med 2021 May 23;51(3):196-229. Epub 2021 Jan 23.

University of Groningen, University Medical Center Groningen, Department of Nuclear Medicine and Molecular Imaging, Groningen, the Netherlands; Ghent University, Ghent, Belgium.

This article presents an overview of imaging agents for PET that have been applied for research and diagnostic purposes in patients affected by dementia. Classified by the target which the agents visualize, seven groups of tracers can be distinguished, namely radiopharmaceuticals for: (1) Misfolded proteins (ß-amyloid, tau, α-synuclein), (2) Neuroinflammation (overexpression of translocator protein), (3) Elements of the cholinergic system, (4) Elements of monoamine neurotransmitter systems, (5) Synaptic density, (6) Cerebral energy metabolism (glucose transport/ hexokinase), and (7) Various other proteins. This last category contains proteins involved in mechanisms underlying neuroinflammation or cognitive impairment, which may also be potential therapeutic targets. Many receptors belong to this category: AMPA, cannabinoid, colony stimulating factor 1, metabotropic glutamate receptor 1 and 5 (mGluR1, mGluR5), opioid (kappa, mu), purinergic (P2X7, P2Y12), sigma-1, sigma-2, receptor for advanced glycation endproducts, and triggering receptor expressed on myeloid cells-1, besides several enzymes: cyclooxygenase-1 and 2 (COX-1, COX-2), phosphodiesterase-5 and 10 (PDE5, PDE10), and tropomyosin receptor kinase. Significant advances in neuroimaging have been made in the last 15 years. The use of 2-[F]-fluoro-2-deoxy-D-glucose (FDG) for quantification of regional cerebral glucose metabolism is well-established. Three tracers for ß-amyloid plaques have been approved by the Food and Drug Administration and European Medicines Agency. Several tracers for tau neurofibrillary tangles are already applied in clinical research. Since many novel agents are in the preclinical or experimental stage of development, further advances in nuclear medicine imaging can be expected in the near future. PET studies with established tracers and tracers for novel targets may result in early diagnosis and better classification of neurodegenerative disorders and in accurate monitoring of therapy trials which involve these targets. PET data have prognostic value and may be used to assess the response of the human brain to interventions, or to select the appropriate treatment strategy for an individual patient.
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http://dx.doi.org/10.1053/j.semnuclmed.2020.12.008DOI Listing
May 2021

Potential Involvement of the Ocular Glymphatic System in Optic Disc Edema in Astronauts.

Aerosp Med Hum Perform 2020 Dec;91(12):975-977

A significant proportion of the astronauts who spend extended periods in microgravity develop ophthalmic abnormalities, including optic disc edema, optic nerve sheath distention, globe flattening, chorioretinal folds, hyperopic refractive error shifts, and nerve fiber layer infarcts. A constellation of these neuro-ophthalmic findings has been termed spaceflight-associated neuro-ocular syndrome. An increased understanding of factors contributing to this syndrome is one of the top priorities for ESA and NASA because the length of missions is expected to increase substantially in the future. As discussed in the present article, the very recent discovery of an ocular glymphatic clearance system can potentially help to unlock mechanisms underlying microgravity-induced optic disc edema. Observations pertaining to the ocular glymphatic pathway provide supporting evidence for the hypothesis, originally proposed by our group, suggesting that the glymphatic outflow from the eye into the optic nerve may be impeded under prolonged microgravity conditions, leading to optic disc edema.
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http://dx.doi.org/10.3357/AMHP.5670.2020DOI Listing
December 2020

Uptake and effectiveness of a tailor-made online lifestyle programme targeting modifiable risk factors for dementia among middle-aged descendants of people with recently diagnosed dementia: study protocol of a cluster randomised controlled trial (Demin study).

BMJ Open 2020 10 16;10(10):e039439. Epub 2020 Oct 16.

Department of Epidemiology, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands.

Introduction: Descendants of patients with dementia have a higher risk to develop dementia. This study aims to investigate the uptake and effectiveness of an online tailor-made lifestyle programme for dementia risk reduction (DRR) among middle-aged descendants of people with recently diagnosed late-onset dementia.

Methods And Analysis: Demin is a cluster randomised controlled trial, aiming to include 21 memory clinics of which 13 will be randomly allocated to the passive (poster and flyer in a waiting room) and 8 to the active recruitment strategy (additional personal invitation by members of the team of the memory clinic). We aim to recruit 378 participants (40-60 years) with a parent who is recently diagnosed with Alzheimer's disease or vascular dementia at one of the participating memory clinics. All participants receive a dementia risk assessment (online questionnaire, physical examination and blood sample) and subsequently an online tailor-made lifestyle advice regarding protective (Mediterranean diet, low/moderate alcohol consumption and high cognitive activity) and risk factors (physical inactivity, smoking, loneliness, cardiovascular diseases (CVD), hypertension, high cholesterol, diabetes, obesity, renal dysfunction and depression) for dementia. The primary outcome is the difference in uptake between the two recruitment strategies. Secondary outcomes are change(s) in (1) the Lifestyle for Brain Health score, (2) individual health behaviours, (3) health beliefs and attitudes towards DRR and (4) compliance to the tailor-made lifestyle advice. Outcomes will be measured at 3, 6, 9 and 12 months after baseline. The effectiveness of this online tailor-made lifestyle programme will be evaluated by comparing Demin participants to a matched control group (lifelines cohort).

Ethics And Dissemination: This study has been approved by the Dutch Ministry of Health, Welfare and Sport according to the Population Screening Act. All participants have to give online informed consent using SMS-tan (transaction authentication number delivered via text message). Findings will be disseminated through peer-reviewed journals and (inter)national conferences.

Trial Registration Number: NTR7434.
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http://dx.doi.org/10.1136/bmjopen-2020-039439DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7569992PMC
October 2020

Progressive tau aggregation does not alter functional brain network connectivity in seeded hTau.P301L mice.

Neurobiol Dis 2020 09 10;143:105011. Epub 2020 Jul 10.

Laboratory of Cell Biology and Histology, University of Antwerp, Belgium. Electronic address:

Progressive accumulation of hyperphosphorylated tau is a hallmark of various neurodegenerative disorders including Alzheimer's disease. However, to date, the functional effects of tau pathology on brain network connectivity remain poorly understood. To directly interrogate the impact of tau pathology on functional brain connectivity, we conducted a longitudinal experiment in which we monitored a fibril-seeded hTau.P301L mouse model using correlative whole-brain microscopy and resting-state functional MRI. Despite a progressive aggravation of tau pathology across the brain, the major resting-state networks appeared unaffected up to 15 weeks after seeding. Targeted analyses also showed that the connectivity of regions with high levels of hyperphosphorylated tau was comparable to that observed in controls. In line with the ostensible retention of connectivity, no behavioural changes were detected between seeded and control hTau.P301L mice as determined by three different paradigms. Our data indicate that seeded tau pathology, with accumulation of tau aggregates throughout different regions of the brain, does not alter functional connectivity or behaviour in this mouse model. Additional correlative functional studies on different mouse models should help determine whether this is a generalizable trait of tauopathies.
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http://dx.doi.org/10.1016/j.nbd.2020.105011DOI Listing
September 2020

Mutated ATP10B increases Parkinson's disease risk by compromising lysosomal glucosylceramide export.

Acta Neuropathol 2020 06 14;139(6):1001-1024. Epub 2020 Mar 14.

Center for Molecular Neurology, VIB, University of Antwerp, Universiteitsplein 1, 2610, Antwerpen, Belgium.

Parkinson's disease (PD) is a progressive neurodegenerative brain disease presenting with a variety of motor and non-motor symptoms, loss of midbrain dopaminergic neurons in the substantia nigra pars compacta and the occurrence of α-synuclein-positive Lewy bodies in surviving neurons. Here, we performed whole exome sequencing in 52 early-onset PD patients and identified 3 carriers of compound heterozygous mutations in the ATP10B P4-type ATPase gene. Genetic screening of a Belgian PD and dementia with Lewy bodies (DLB) cohort identified 4 additional compound heterozygous mutation carriers (6/617 PD patients, 0.97%; 1/226 DLB patients, 0.44%). We established that ATP10B encodes a late endo-lysosomal lipid flippase that translocates the lipids glucosylceramide (GluCer) and phosphatidylcholine (PC) towards the cytosolic membrane leaflet. The PD associated ATP10B mutants are catalytically inactive and fail to provide cellular protection against the environmental PD risk factors rotenone and manganese. In isolated cortical neurons, loss of ATP10B leads to general lysosomal dysfunction and cell death. Impaired lysosomal functionality and integrity is well known to be implicated in PD pathology and linked to multiple causal PD genes and genetic risk factors. Our results indicate that recessive loss of function mutations in ATP10B increase risk for PD by disturbed lysosomal export of GluCer and PC. Both ATP10B and glucocerebrosidase 1, encoded by the PD risk gene GBA1, reduce lysosomal GluCer levels, emerging lysosomal GluCer accumulation as a potential PD driver.
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http://dx.doi.org/10.1007/s00401-020-02145-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7244618PMC
June 2020

The Association Between Biomarkers and Neuropsychiatric Symptoms Across the Alzheimer's Disease Spectrum.

Am J Geriatr Psychiatry 2020 07 20;28(7):735-744. Epub 2020 Feb 20.

Department of Psychiatry and Neuropsychology (LCPB, IHGBR, SK, FRJV, PA), Maastricht University, School for Mental Health and Neuroscience, Alzheimer Center Limburg, Maastricht, the Netherlands.

Objective: To investigate the relationship between Alzheimer's disease biomarkers and neuropsychiatric symptoms.

Methods: Data from two large cohort studies, the Dutch Parelsnoer Institute - Neurodegenerative Diseases and the Alzheimer's Disease Neuroimaging Initiative was used, including subjects with subjective cognitive decline (N = 650), mild cognitive impairment (N = 887), and Alzheimer's disease dementia (N = 626). Cerebrospinal fluid (CSF) levels of Aβ, t-tau, p-tau, and hippocampal volume were associated with neuropsychiatric symptoms (measured with the Neuropsychiatric Inventory) using multiple logistic regression analyses. The effect of the Mini-Mental State Examination (as proxy for cognitive functioning) on these relationships was assessed with mediation analyses.

Results: Alzheimer's disease biomarkers were not associated with depression, agitation, irritability, and sleep disturbances. Lower levels of CSF Aβ, higher levels of t- and p-tau were associated with presence of anxiety. Lower levels of CSF Aβ and smaller hippocampal volumes were associated with presence of apathy. All associations were mediated by cognitive functioning.

Conclusion: The association between Alzheimer's disease pathology and anxiety and apathy is partly due to impairment in cognitive functioning.
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http://dx.doi.org/10.1016/j.jagp.2020.01.012DOI Listing
July 2020

The Relationship of Coronary Artery Calcium and Clinical Coronary Artery Disease with Cognitive Function: A Systematic Review and Meta-Analysis.

J Atheroscler Thromb 2020 Sep 15;27(9):934-958. Epub 2020 Feb 15.

University of Groningen, University Medical Center Groningen, Department of Radiology.

Aim: Coronary artery disease (CAD) and cognitive impairment are common in the elderly, with evidence for shared risk factors and pathophysiological processes. The coronary artery calcium (CAC) score is a marker of subclinical CAD, which may allow early detection of individuals prone to cognitive decline. Prior studies on associations of CAC and clinical CAD with cognitive impairment had discrepant results. This systematic review aims to evaluate the association of (sub)clinical CAD with cognitive function, cognitive decline, and diagnosis of mild cognitive impairment (MCI) or dementia.

Methods: A systematic search was conducted in MEDLINE, Embase, and Web of Science until February 2019, supplemented with citations tracking. Two reviewers independently screened studies and extracted information including odds ratios (ORs) and hazard ratios (HRs).

Results: Forty-six studies, 10 on CAC and 36 on clinical CAD, comprising 1,248,908 participants were included in the systematic review. Studies about associations of (sub)clinical CAD with cognitive function and cognitive decline had heterogeneous methodology and inconsistent findings. Two population-based studies investigated the association between CAC and risk of dementia over 6-12.2 years using different CAC scoring methods. Both found a tendency toward higher risk of dementia as CAC severity increased. Meta-analysis in 15 studies (663,250 individuals) showed an association between CAD and MCI/dementia (pooled OR 1.32, 95%CI 1.17-1.48) with substantial heterogeneity (I=87.0%, p<0.001). Pooled HR of CAD for incident MCI/dementia over 3.2-25.5 years in six longitudinal studies (70,060 individuals) was 1.51 (95%CI 1.24-1.85), with low heterogeneity (I=14.1%, p=0.32). Sensitivity analysis did not detect any study that was of particular influence on the pooled OR or HR.

Conclusions: Limited evidence suggests the CAC score is associated with risk of dementia. In clinical CAD, risk of MCI and dementia is increased by 50%, as supported by stronger evidence.
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http://dx.doi.org/10.5551/jat.52928DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7508729PMC
September 2020

Functional network topology associated with apathy in Alzheimer's disease.

J Affect Disord 2020 04 30;266:473-481. Epub 2020 Jan 30.

NeuroImaging Center, University of Groningen, University Medical Center Groningen, the Netherlands; Department of Psychology, University of Groningen, the Netherlands.

Background: Apathy, a common neuropsychiatric (NPS) in patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD), is associated with structural and metabolic brain changes. However, functional connectivity changes across the brain in association with apathy remain unclear. In this study, graph theoretical measures of integration and segregation from resting state functional connectivity in MCI and AD patients with low depression scores, and healthy controls.

Methods: In MCI and AD patients with low depression scores, graph theoretical measures of integration and segregation were derived from resting state functional connectivity in patients, which were compared between those with apathy (NPS_A, n = 21) to those without NPS (NPS_None, n = 28) and those with NPS other than apathy (NPS_NA, n = 38). Additionally, the same measures were compared between AD patients and healthy controls (amyloid uptake below threshold levels).

Results: Altered whole brain global efficiency and reduced local efficiency were found in NPS_A compared to NPS_None and NPS_NA. In similar contrasts, apathy was associated with increased participation coefficient in the frontoparietal and cingulo-opercular template-based networks. A study-specific network definition also showed similar results. In comparison, AD patients showed higher modularity compared to controls at the whole brain level and higher participation coefficient in the ventral attention network.

Limitations: The severity and dimensions of apathy were not assessed.

Conclusions: Loss of segregation in the frontoparietal and cingulo-opercular network, which are involved in the control of goal-directed behavior, was associated with apathy in MCI/AD. The results also suggest that network-level changes in AD patients may underlie specific NPS.
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http://dx.doi.org/10.1016/j.jad.2020.01.158DOI Listing
April 2020

Pentylenetetrazole-induced Seizure Susceptibility in the Tau58/4 Transgenic Mouse Model of Tauopathy.

Neuroscience 2020 01 27;425:112-122. Epub 2019 Nov 27.

Laboratory of Neurochemistry and Behavior, Institute Born-Bunge, Department of Biomedical Sciences, University of Antwerp, Wilrijk (Antwerp), Belgium; Department of Neurology and Alzheimer Center, University of Groningen and University Medical Center Groningen (UMCG), Groningen, The Netherlands; Department of Neurology, Memory Clinic of Hospital Network Antwerp (ZNA) Middelheim and Hoge Beuken, Antwerp, Belgium. Electronic address:

In several tauopathies such as Alzheimer's disease (AD), an increased incidence of seizures is observed. Tau, one of the major proteins implicated in AD pathology, is an important regulator of neural network excitability and might participate in the underlying epileptic cascade. However, the mechanisms underlying this relationship are not fully elucidated. We aim to investigate this mechanism by analyzing seizure susceptibility to the convulsant pentylenetetrazole (PTZ) in a novel rodent tauopathy model. A single dose of PTZ was systemically injected in Tau58/4 transgenic mice. To investigate whether young and aged heterozygous (HET) mice exhibit a higher susceptibility to seizures in comparison with wild-type (WT) littermates, video electroencephalography (EEG) in combination with behavioral scoring according to a modified Racine scale was used. The employment of different dosage groups enabled us to characterize the dose range reliably inducing seizures. Here, we report an increased seizure susceptibility in young but not in old HET Tau58/4 mice. Young HET animals displayed more severe seizures and had a reduced latency to the first seizure compared to WTs. Also, age-related differences in susceptibility could be demonstrated for both genotypes. Identification and targeting of secondary diseases such as epilepsy, which aggravate dementia and lead to earlier institutionalization, is key. This study finds that tau pathology itself is sufficient to alter seizure susceptibility in a rodent model, indicating that the disease process is crucial in the emergence of epilepsy in patients with tauopathy.
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http://dx.doi.org/10.1016/j.neuroscience.2019.11.007DOI Listing
January 2020

The retinal nerve fiber layer as a window to the glymphatic system.

Clin Neurol Neurosurg 2020 01 10;188:105593. Epub 2019 Nov 10.

Department of Biomedical Sciences, Laboratory of Neurochemistry and Behavior, Institute Born-Bunge, University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium; Department of Neurology and Alzheimer Research Center, University of Groningen and University Medical Center Groningen, Hanzeplein 1, 9700 RB Groningen, the Netherlands; Department of Neurology and Memory Clinic, Middelheim General Hospital (ZNA), Lindendreef 1, 2020 Antwerp, Belgium.

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http://dx.doi.org/10.1016/j.clineuro.2019.105593DOI Listing
January 2020

How does a researcher choose the best rodent model for their Alzheimer's disease drug discovery study?

Expert Opin Drug Discov 2020 03 8;15(3):269-271. Epub 2019 Oct 8.

Laboratory of Neurochemistry and Behaviour, Institute Born-Bunge, Department of Biomedical Sciences, University of Antwerp, Wilrijk (Antwerp), Belgium.

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http://dx.doi.org/10.1080/17460441.2020.1676719DOI Listing
March 2020

Alzheimer's disease: Neurotransmitters of the sleep-wake cycle.

Neurosci Biobehav Rev 2019 10 1;105:72-80. Epub 2019 Aug 1.

Laboratory of Neurochemistry and Behavior, Institute Born-Bunge, Department of Biomedical Sciences, University of Antwerp, Wilrijk (Antwerp), Belgium; Department of Neurology and Alzheimer Center, University of Groningen and University Medical Center Groningen (UMCG), Groningen, The Netherlands; Department of Neurology, Memory Clinic of Hospital Network Antwerp (ZNA) Middelheim and Hoge Beuken, Antwerp, Belgium. Electronic address:

With aging, our sleeping pattern alters. Elderly often wake unrested because their sleep time and sleep efficacy is reduced. In Alzheimer's disease (AD) patients, these alterations are even more pronounced and may further aggravate cognitive decline. Therefore, sleep disturbances greatly impact self-care ability, caregiver exhaustion and institutionalization rate. Reestablishing an effective sleep-wake cycle in these patients still remains an unresolved challenge, partly because sleep physiology is quite complex and multiple neurotransmitter systems contribute to a single process. Gaining a better understanding of sleep physiology will be crucial for further research. Conjointly, animal models, along with a multidisciplinary approach, will be of great value to establish a common ground between AD and sleep disturbances and work towards a potential therapeutic application.
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http://dx.doi.org/10.1016/j.neubiorev.2019.07.019DOI Listing
October 2019

The buffering capacity of the brain and optic nerve against spaceflight-associated neuro-ocular syndrome.

Proc Natl Acad Sci U S A 2019 08 30;116(32):15770-15771. Epub 2019 Jul 30.

Department of Biomedical Sciences, Laboratory of Neurochemistry and Behavior, Institute Born-Bunge, University of Antwerp, 2610 Antwerp, Belgium.

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http://dx.doi.org/10.1073/pnas.1908865116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6689895PMC
August 2019

Sleep architecture changes in the APP23 mouse model manifest at onset of cognitive deficits.

Behav Brain Res 2019 11 17;373:112089. Epub 2019 Jul 17.

Laboratory of Neurochemistry and Behavior, Institute Born-Bunge, Department of Biomedical Sciences, University of Antwerp, Wilrijk (Antwerp), Belgium; Department of Neurology and Alzheimer Center, University of Groningen and University Medical Center Groningen (UMCG), Groningen, the Netherlands; Department of Neurology, Memory Clinic of Hospital Network Antwerp (ZNA) Middelheim and Hoge Beuken, Antwerp, Belgium. Electronic address:

Alzheimer's disease (AD), which accounts for most of the dementia cases, is, aside from cognitive deterioration, often characterized by the presence of non-cognitive symptoms such as activity and sleep disturbances. AD patients typically experience increased sleep fragmentation, excessive daytime sleepiness and night-time insomnia. Here, we sought to investigate the link between sleep architecture, cognition and amyloid pathology in the APP23 amyloidosis mouse model for AD. By means of polysomnographic recordings the sleep-wake cycle of freely-moving APP23 and wild-type (WT) littermates of 3, 6 and 12 months of age was examined. In addition, ambulatory cage activity was assessed by interruption of infrared beams surrounding the home cage. To assess visuo-spatial learning and memory a hidden-platform Morris-type Water Maze (MWM) experiment was performed. We found that sleep architecture is only slightly altered at early stages of pathology, but significantly deteriorates from 12 months of age, when amyloid plaques become diffusely present. APP23 mice of 12 months old had quantitative reductions of NREM and REM sleep and were more awake during the dark phase compared to WT littermates. These findings were confirmed by increased ambulatory cage activity during that phase of the light-dark cycle. No quantitative differences in sleep parameters were observed during the light phase. However, during this light phase, the sleep pattern of APP23 mice was more fragmented from 6 months of age, the point at which also cognitive abilities started to be affected in the MWM. Sleep time also positively correlated with MWM performance. We also found that spectral components in the EEG started to alter at the age of 6 months. To conclude, our results indicate that sleep architectural changes arise around the time the first amyloid plaques start to form and cognitive deterioration becomes apparent. These changes start subtle, but gradually worsen with age, adequately mimicking the clinical condition.
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http://dx.doi.org/10.1016/j.bbr.2019.112089DOI Listing
November 2019

Sleep architecture changes in the APP23 mouse model manifest at onset of cognitive deficits.

Behav Brain Res 2019 11 17;373:112089. Epub 2019 Jul 17.

Laboratory of Neurochemistry and Behavior, Institute Born-Bunge, Department of Biomedical Sciences, University of Antwerp, Wilrijk (Antwerp), Belgium; Department of Neurology and Alzheimer Center, University of Groningen and University Medical Center Groningen (UMCG), Groningen, the Netherlands; Department of Neurology, Memory Clinic of Hospital Network Antwerp (ZNA) Middelheim and Hoge Beuken, Antwerp, Belgium. Electronic address:

Alzheimer's disease (AD), which accounts for most of the dementia cases, is, aside from cognitive deterioration, often characterized by the presence of non-cognitive symptoms such as activity and sleep disturbances. AD patients typically experience increased sleep fragmentation, excessive daytime sleepiness and night-time insomnia. Here, we sought to investigate the link between sleep architecture, cognition and amyloid pathology in the APP23 amyloidosis mouse model for AD. By means of polysomnographic recordings the sleep-wake cycle of freely-moving APP23 and wild-type (WT) littermates of 3, 6 and 12 months of age was examined. In addition, ambulatory cage activity was assessed by interruption of infrared beams surrounding the home cage. To assess visuo-spatial learning and memory a hidden-platform Morris-type Water Maze (MWM) experiment was performed. We found that sleep architecture is only slightly altered at early stages of pathology, but significantly deteriorates from 12 months of age, when amyloid plaques become diffusely present. APP23 mice of 12 months old had quantitative reductions of NREM and REM sleep and were more awake during the dark phase compared to WT littermates. These findings were confirmed by increased ambulatory cage activity during that phase of the light-dark cycle. No quantitative differences in sleep parameters were observed during the light phase. However, during this light phase, the sleep pattern of APP23 mice was more fragmented from 6 months of age, the point at which also cognitive abilities started to be affected in the MWM. Sleep time also positively correlated with MWM performance. We also found that spectral components in the EEG started to alter at the age of 6 months. To conclude, our results indicate that sleep architectural changes arise around the time the first amyloid plaques start to form and cognitive deterioration becomes apparent. These changes start subtle, but gradually worsen with age, adequately mimicking the clinical condition.
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http://dx.doi.org/10.1016/j.bbr.2019.112089DOI Listing
November 2019

Rapid Reconfiguration of the Functional Connectome after Chemogenetic Locus Coeruleus Activation.

Neuron 2019 08 18;103(4):702-718.e5. Epub 2019 Jun 18.

Laboratory of Molecular and Behavioral Neuroscience, Institute for Neuroscience, Department of Health Sciences and Technology, ETH Zürich, Zürich, Switzerland; Neuroscience Center Zürich, ETH Zürich and University of Zürich, Zürich, Switzerland. Electronic address:

The locus coeruleus (LC) supplies norepinephrine (NE) to the entire forebrain and regulates many fundamental brain functions. Studies in humans have suggested that strong LC activation might shift network connectivity to favor salience processing. To causally test this hypothesis, we use a mouse model to study the effect of LC stimulation on large-scale functional connectivity by combining chemogenetic activation of the LC with resting-state fMRI, an approach we term "chemo-connectomics." We show that LC activation rapidly interrupts ongoing behavior and strongly increases brain-wide connectivity, with the most profound effects in the salience and amygdala networks. Functional connectivity changes strongly correlate with transcript levels of alpha-1 and beta-1 adrenergic receptors across the brain, and functional network connectivity correlates with NE turnover within select brain regions. We propose that these changes in large-scale network connectivity are critical for optimizing neural processing in the context of increased vigilance and threat detection.
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http://dx.doi.org/10.1016/j.neuron.2019.05.034DOI Listing
August 2019

Dementia, End of Life, and Euthanasia: A Survey Among Dementia Specialists Organized by the Belgian Dementia Council.

J Alzheimers Dis 2019 ;69(4):989-1001

Department of Neurology, Cliniques Universitaires St Luc, Université catholique de Louvain, Brussels, Belgium.

Background: Palliative care and Advance Care Planning (ACP) are increasingly recommended for an optimal management of late-stage dementia. In Belgium, euthanasia has been decriminalized in 2002 for patients who are "mentally competent" (interpreted as non-demented). It has been suggested that advance directives for euthanasia (ADE) should be made possible for dementia patients.

Objective: This study presents the results of an internet survey among Belgian dementia specialists.

Methods: In 2013, the Belgian Dementia Council (BeDeCo) organized a debate on end of life decisions in dementia. Participants were medical doctors who are specialists in the dementia field. After the debate, an anonymous internet survey was organized. The participation rate was 55%. The sample was representative of the BeDeCo members.

Results: The results showed consensus in favor of palliative care and ACP, although ACP is not systematically addressed in practice. Few patients with dementia have requested euthanasia, but for those who did the participants had agreed to implement it for some patients. A majority of participants (94%) believe that most patients and their families are poorly informed about euthanasia. Although most participants (77%) said they approved the Law on euthanasia, 65% said they were against an extension of the Law to allow ADE for dementia.

Conclusion: Palliative care and ACP are clearly accepted by professionals, although a gap between recommendation and practice remain. Euthanasia is a much more debated issue, even if a majority of professionals are, in principle, in favor of the current Law and seem to disapprove with a Law change allowing ADE for dementia. A better education for both health professionals and the lay public will be a key element in the future.
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http://dx.doi.org/10.3233/JAD-181277DOI Listing
September 2020

Driving Difficulties Among Patients with Alzheimer's Disease and Other Neurodegenerative Disorders.

J Alzheimers Dis 2019 ;69(4):1019-1030

Department of Clinical and Developmental Neuropsychology, University of Groningen, Groningen, The Netherlands.

Background/objective: Neurodegenerative disorders impact fitness to drive of older drivers, but on-road driving studies investigating patients with different neurodegenerative disorders are scarce. A variety of driving errors have been reported in patients with Alzheimer's disease (AD), but it is unclear which types of driving errors occur most frequently. Moreover, patients with other neurodegenerative disorders than AD typically present with different symptoms and impairments, therefore different driving errors may be expected.

Methods: Patients with AD (n = 80), patients with other neurodegenerative disorders with cognitive decline (i.e., vascular dementia, frontotemporal dementia, dementia with Lewy bodies/Parkinson's disease, n = 59), and healthy older drivers (n = 45) participated in a fitness-to-drive assessment study including on-road driving.

Results: Patients with AD performed significantly worse than healthy older drivers on operational, tactical, visual, and global aspects of on-road driving. In patients with AD, on-road measures were significantly associated with 'off-road' measures. Patients with neurodegenerative disorders other than AD showed large overlap in the types of driving errors. Several driving errors were identified that appear to be characteristic for patients with particular neurodegenerative disorders.

Conclusion: Patients from each group of neurodegenerative disorders commonly display tactical driving errors regarding lane positioning, slow driving, observation of the blind spot, and scanning behavior. Several other tactical and operational driving errors, including not communicating with cyclists and unsteady steering, were more frequently observed in patients with non-AD neurodegenerative disorders. These findings have implications for on-road and 'off-road' fitness-to-drive assessments for patients with neurodegenerative disorders with cognitive decline.
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http://dx.doi.org/10.3233/JAD-181095DOI Listing
September 2020

PTZ-induced seizures in mice require a revised Racine scale.

Epilepsy Behav 2019 06 24;95:51-55. Epub 2019 Apr 24.

Laboratory of Neurochemistry and Behavior, Institute Born-Bunge, Department of Biomedical Sciences, University of Antwerp, Wilrijk, Antwerp, Belgium; Department of Neurology and Alzheimer Center, University of Groningen and University Medical Center Groningen (UMCG), Groningen, the Netherlands; Department of Neurology, Memory Clinic of Hospital Network Antwerp (ZNA) Middelheim and Hoge Beuken, Antwerp, Belgium. Electronic address:

Seizure severity in experimental models of epilepsy is often evaluated by means of the Racine scale, in spite of the use of seizure induction methods that are different from those of the original paper by Racine in 1972. In such cases, the use of this scale is not always justified because some seizure behaviors are significantly different from those originally described or not present at all. Correspondingly, the pentylenetetrazole (PTZ) model, which is frequently used for antiepileptic drug research, lacked an adequate assessment tool to measure seizure severity. In 2009, an adapted intensity scale for PTZ-induced seizures was already designed for rats. Here, we evaluated electroencephalographic (EEG) and behavioral parameters after a single PTZ injection, to determine whether this scale is also suitable for use in mouse studies. We found that the scale designed for rats is quite robust and can thus be applied to score seizure severity in mice. Yet, certain convulsive behaviors and EEG characteristics were distinct between species. Therefore, a species-specific scale was designed, which included the concomitant EEG characteristic next to the behavioral expressions we observed, in order to establish a user-friendly scoring scale for PTZ-induced seizures in mice. To evaluate applicability, we utilized the scale in a seizure susceptibility study of a transgenic mouse model. We demonstrated that the maximum severity scores obtained with the newly revised Racine scale highly correlated with the administered dose. Hence, the revised scale differentiates well between different classes of seizure severity.
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http://dx.doi.org/10.1016/j.yebeh.2019.02.029DOI Listing
June 2019

Early imaging biomarkers of lung cancer, COPD and coronary artery disease in the general population: rationale and design of the ImaLife (Imaging in Lifelines) Study.

Eur J Epidemiol 2020 Jan 23;35(1):75-86. Epub 2019 Apr 23.

Department of Radiology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands.

Lung cancer, chronic obstructive pulmonary disease (COPD), and coronary artery disease (CAD) are expected to cause most deaths by 2050. State-of-the-art computed tomography (CT) allows early detection of lung cancer and simultaneous evaluation of imaging biomarkers for the early stages of COPD, based on pulmonary density and bronchial wall thickness, and of CAD, based on the coronary artery calcium score (CACS), at low radiation dose. To determine cut-off values for positive tests for elevated risk and presence of disease is one of the major tasks before considering implementation of CT screening in a general population. The ImaLife (Imaging in Lifelines) study, embedded in the Lifelines study, is designed to establish the reference values of the imaging biomarkers for the big three diseases in a well-defined general population aged 45 years and older. In total, 12,000 participants will undergo CACS and chest acquisitions with latest CT technology. The estimated percentage of individuals with lung nodules needing further workup is around 1-2%. Given the around 10% prevalence of COPD and CAD in the general population, the expected number of COPD and CAD is around 1000 each. So far, nearly 4000 participants have been included. The ImaLife study will allow differentiation between normal aging of the pulmonary and cardiovascular system and early stages of the big three diseases based on low-dose CT imaging. This information can be finally integrated into personalized precision health strategies in the general population.
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http://dx.doi.org/10.1007/s10654-019-00519-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7058676PMC
January 2020

Validation of the Erlangen Score Algorithm for Differential Dementia Diagnosis in Autopsy-Confirmed Subjects.

J Alzheimers Dis 2019 ;68(3):1151-1159

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

Background: Despite decades of research on the optimization of the diagnosis of Alzheimer's disease (AD), its biomarker-based 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 Aβ1-42, T-tau, and P-tau181 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.
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http://dx.doi.org/10.3233/JAD-180563DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6484252PMC
August 2020

Brief cognitive screening instruments for early detection of Alzheimer's disease: a systematic review.

Alzheimers Res Ther 2019 02 28;11(1):21. Epub 2019 Feb 28.

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

Objectives: The objective of this systematic review was (1) to give an overview of the available short screening instruments for the early detection of Alzheimer's disease (AD) and (2) to review the psychometric properties of these instruments.

Methods: First, a systematic search of titles and abstracts of PubMed and Web of Science was conducted between February and July 2015 and updated in April 2016 and May 2018. Only papers written in English or Dutch were considered. All full-text papers about cognitive screening instruments for the early detection of AD were included, resulting in the identification of 38 pencil and paper tests and 12 computer tests. In a second step, the psychometric quality of these instruments was evaluated. Therefore, the same databases were searched again to identify papers that described the psychometric properties of the instruments meanwhile applying diagnostic criteria for the diagnostic groups included.

Results: Out of 1454 papers, 96 clearly discussed the psychometric properties of the instruments. Eighty-nine papers discussed pencil and paper tests of which 80 were validated in a memory clinic setting. Based on the number of studies (31 articles) and the sensitivity (84%) and specificity (74%) values, the Montreal Cognitive Assessment (MoCA) seems to be a promising (pencil and paper) screening test for memory clinic testing as well as for population screening. Regarding computer tests, validation studies were only available for 7 out of 12 tests.

Conclusions: A large number of screening tests for AD are available. However, most tests are only validated in a memory clinic setting and description of the psychometric properties of the instruments is limited. Especially, computer tests require further research. The MoCA is a promising instrument, but the specificity to detect early AD is rather low.
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http://dx.doi.org/10.1186/s13195-019-0474-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6396539PMC
February 2019

Alzheimer's disease and glaucoma: Look-alike neurodegenerative diseases.

Alzheimers Dement 2019 04 31;15(4):600-601. Epub 2019 Jan 31.

Laboratory of Neurochemistry and Behavior, Institute Born-Bunge, University of Antwerp, Department of Biomedical Sciences, Antwerp, Belgium; Department of Neurology and Alzheimer Research Center, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands; Department of Neurology and Memory Clinic, Middelheim General Hospital (ZNA), Antwerp, Belgium.

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http://dx.doi.org/10.1016/j.jalz.2018.12.012DOI Listing
April 2019

Intrathecal cerebrospinal fluid infusion as a potential therapeutic strategy for Alzheimer's disease.

Med Hypotheses 2019 01 22;122:57. Epub 2018 Oct 22.

Department of Biomedical Sciences, Laboratory of Neurochemistry and Behavior, Institute Born-Bunge, University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium; Department of Neurology and Alzheimer Research Center, University of Groningen and University Medical Center Groningen, Hanzeplein 1, 9700 RB Groningen, The Netherlands; Department of Neurology and Memory Clinic, Middelheim General Hospital (ZNA), Lindendreef 1, 2020 Antwerp, Belgium.

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http://dx.doi.org/10.1016/j.mehy.2018.10.020DOI Listing
January 2019

Dilated Prelaminar Paravascular Spaces as a Possible Mechanism for Optic Disc Edema in Astronauts.

Aerosp Med Hum Perform 2018 12;89(12):1089-1091

A number of ophthalmic abnormalities, including optic disc edema, have been reported in several astronauts involved in long-duration spaceflights. An increased understanding of factors contributing to this syndrome, initially designated visual impairment and intracranial pressure syndrome and recently renamed spaceflight-associated neuro-ocular syndrome, has become a high priority for ESA and NASA, especially in view of future long-duration missions, including trips to Mars. The underlying pathophysiological mechanisms of this syndrome are still not well understood. In the present paper, we propose that optic disc edema in astronauts may occur, at least in part, as a result of retention of interstitial fluid in distended paravascular spaces at the prelaminar region of the optic nerve head. Preflight, in-flight, and postflight analysis of the optic nerve head and surrounding structures by optical coherence tomography in long-duration International Space Station crewmembers could provide important structural information in this respect.
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http://dx.doi.org/10.3357/AMHP.5095.2018DOI Listing
December 2018