Publications by authors named "Peter De Deyn"

476 Publications

Lipocalin 2 as a link between ageing, risk factor conditions and age-related brain diseases.

Ageing Res Rev 2021 Jul 26:101414. Epub 2021 Jul 26.

Department of Neurology and Alzheimer Center Groningen, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; Department of Molecular Neurobiology, Groningen Institute for Evolutionary Life Sciences (GELIFES), University of Groningen, Groningen, the Netherlands; Department of Psychiatry and Mental Health and Neuroscience Institute, Brain Behaviour Unit, University of Cape Town, Cape Town, South Africa. Electronic address:

Chronic (neuro)inflammation plays an important role in many age-related central nervous system (CNS) diseases, including Alzheimer's disease, Parkinson's disease and vascular dementia. Inflammation also characterizes many conditions that form a risk factor for these CNS disorders, such as physical inactivity, obesity and cardiovascular disease. Lipocalin 2 (Lcn2) is an inflammatory protein shown to be involved in different age-related CNS diseases, as well as risk factor conditions thereof. Lcn2 expression is increased in the periphery and the brain in different age-related CNS diseases and also their risk factor conditions. Experimental studies indicate that Lcn2 contributes to various neuropathophysiological processes of age-related CNS diseases, including exacerbated neuroinflammation, cell death and iron dysregulation, which may negatively impact cognitive function. We hypothesize that increased Lcn2 levels as a result of age-related risk factor conditions may sensitize the brain and increase the risk to develop age-related CNS diseases. In this review we first provide a comprehensive overview of the known functions of Lcn2, and its effects in the CNS. Subsequently, this review explores Lcn2 as a potential (neuro)inflammatory link between different risk factor conditions and the development of age-related CNS disorders. Altogether, evidence convincingly indicates Lcn2 as a key constituent in ageing and age-related brain diseases.
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http://dx.doi.org/10.1016/j.arr.2021.101414DOI Listing
July 2021

Pain processing in older adults with dementia-related cognitive impairment is associated with frontal neurodegeneration.

Neurobiol Aging 2021 Jun 18;106:139-152. Epub 2021 Jun 18.

Department of General Practice and Elderly Care Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; Department of Medical Psychology and Sociology, University of Augsburg, Augsburg, Germany.

Experimental pain research has shown that pain processing seems to be heightened in dementia. It is unclear which neuropathological changes underlie these alterations. This study examined whether differences in pressure pain sensitivity and endogenous pain inhibition (conditioned pain modulation (CPM)) between individuals with a dementia-related cognitive impairment (N=23) and healthy controls (N=35) are linked to dementia-related neurodegeneration. Pain was assessed via self-report ratings and by analyzing the facial expression of pain using the Facial Action Coding System. We found that cognitively impaired individuals show decreased CPM inhibition as assessed by facial responses compared to healthy controls, which was mediated by decreased gray matter volume in the medial orbitofrontal and anterior cingulate cortex in the patient group. This study confirms previous findings of intensified pain processing in dementia when pain is assessed using non-verbal responses. Our findings suggest that a loss of pain inhibitory functioning caused by structural changes in prefrontal areas might be one of the underlying mechanisms responsible for amplified pain responses in individuals with a dementia-related cognitive impairment.
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http://dx.doi.org/10.1016/j.neurobiolaging.2021.06.009DOI Listing
June 2021

The neglected puzzle of dementia in people with severe/profound intellectual disabilities: A systematic literature review of observable symptoms.

J Appl Res Intellect Disabil 2021 Jul 4. Epub 2021 Jul 4.

Department of Neurology and Alzheimer Center, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

Background: Dementia is increasingly prevalent in people with severe/profound intellectual disabilities. However, early detection and diagnosis of dementia is complex in this population. This study aimed to identify observable dementia symptoms in adults with severe/profound intellectual disabilities in available literature.

Method: A systematic literature search was conducted in PubMed, PsycINFO and Web of Science with an exhaustive search string using a combination of search terms for severe/profound intellectual disabilities and dementia/ageing.

Results: Eleven studies met inclusion criteria. Cognitive decline, behavioural and psychological alterations, decline in activities of daily living as well as neurological and physical changes were found.

Conclusions: Only a very limited number of studies reported symptoms ascribed to dementia in adults with severe/profound intellectual disabilities. Given the complexity of signalling and diagnosing dementia, dedicated studies are required to unravel the natural history of dementia in this population.
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http://dx.doi.org/10.1111/jar.12920DOI Listing
July 2021

Dementia in people with severe or profound intellectual (and multiple) disabilities: Focus group research into relevance, symptoms and training needs.

J Appl Res Intellect Disabil 2021 Jul 2. Epub 2021 Jul 2.

Research Group Healthy Ageing, Allied Health Care and Nursing, Hanze University of Applied Sciences, Groningen, The Netherlands.

Background: Differentiating dementia from baseline level of functioning is difficult among people with severe/profound intellectual (and multiple) disabilities. Moreover, studies on observable dementia symptoms are scarce. This study examined (a) the relevance of dementia diagnosis, (b) observable symptoms and (c) training/information needs.

Methods: Four explorative focus groups were held with care professionals and family members who have experience with people with severe/profound intellectual (and multiple) disabilities (≥40 years) and decline/dementia.

Results: Thematic analysis showed that participants wanted to know about a dementia diagnosis for a better understanding and to be able to make informed choices (question 1). Using a categorisation matrix, cognitive and behavioural changes were shown to be most prominent (question 2). Participants indicated that they needed enhanced training, more knowledge development and translation, and supportive organisational choices/policies (question 3).

Conclusions: Timely identifying/diagnosing dementia allows for a timely response to changing needs. This requires a better understanding of symptoms.
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http://dx.doi.org/10.1111/jar.12912DOI Listing
July 2021

Serum Corticosterone and Insulin Resistance as Early Biomarkers in the hAPP23 Overexpressing Mouse Model of Alzheimer's Disease.

Int J Mol Sci 2021 Jun 22;22(13). Epub 2021 Jun 22.

Laboratory of Physiopharmacology, Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, Campus Drie Eiken, Universiteitsplein 1, University of Antwerp, 2610 Wilrijk, Antwerp, Belgium.

Increasing epidemiological evidence highlights the association between systemic insulin resistance and Alzheimer's disease (AD). As insulin resistance can be caused by high-stress hormone levels and since hypercortisolism appears to be an important risk factor of AD, we aimed to investigate the systemic insulin functionality and circulating stress hormone levels in a mutant humanized amyloid precursor protein (APP) overexpressing (hAPP23+/-) AD mouse model. Memory and spatial learning of male hAPP23+/- and C57BL/6 (wild type, WT) mice were assessed by a Morris Water Maze (MWM) test at the age of 4 and 12 months. The systemic metabolism was examined by intraperitoneal glucose and insulin tolerance tests (GTT, ITT). Insulin and corticosterone levels were determined in serum. In the hippocampus, parietal and occipital cortex of hAPP23+/- brains, amyloid-beta (Aβ) deposits were present at 12 months of age. MWM demonstrated a cognitive decline in hAPP23+/- mice at 12 but not at 4 months, evidenced by increasing total path lengths and deteriorating probe trials compared to WT mice. hAPP23+/- animals presented increased serum corticosterone levels compared to WT mice at both 4 and 12 months. hAPP23+/- mice exhibited peripheral insulin resistance compared to WT mice at 4 months, which stabilized at 12 months of age. Serum insulin levels were similar between genotypes at 4 months of age but were significantly higher in hAPP23+/- mice at 12 months of age. Peripheral glucose homeostasis remained unchanged. These results indicate that peripheral insulin resistance combined with elevated circulating stress hormone levels could be potential biomarkers of the pre-symptomatic phase of AD.
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http://dx.doi.org/10.3390/ijms22136656DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8269119PMC
June 2021

Cross-cohort generalizability of deep and conventional machine learning for MRI-based diagnosis and prediction of Alzheimer's disease.

Neuroimage Clin 2021 Jun 4;31:102712. Epub 2021 Jun 4.

Department of Radiology and Nuclear Medicine, Erasmus MC, Rotterdam, The Netherlands.

This work validates the generalizability of MRI-based classification of Alzheimer's disease (AD) patients and controls (CN) to an external data set and to the task of prediction of conversion to AD in individuals with mild cognitive impairment (MCI). We used a conventional support vector machine (SVM) and a deep convolutional neural network (CNN) approach based on structural MRI scans that underwent either minimal pre-processing or more extensive pre-processing into modulated gray matter (GM) maps. Classifiers were optimized and evaluated using cross-validation in the Alzheimer's Disease Neuroimaging Initiative (ADNI; 334 AD, 520 CN). Trained classifiers were subsequently applied to predict conversion to AD in ADNI MCI patients (231 converters, 628 non-converters) and in the independent Health-RI Parelsnoer Neurodegenerative Diseases Biobank data set. From this multi-center study representing a tertiary memory clinic population, we included 199 AD patients, 139 participants with subjective cognitive decline, 48 MCI patients converting to dementia, and 91 MCI patients who did not convert to dementia. AD-CN classification based on modulated GM maps resulted in a similar area-under-the-curve (AUC) for SVM (0.940; 95%CI: 0.924-0.955) and CNN (0.933; 95%CI: 0.918-0.948). Application to conversion prediction in MCI yielded significantly higher performance for SVM (AUC = 0.756; 95%CI: 0.720-0.788) than for CNN (AUC = 0.742; 95%CI: 0.709-0.776) (p<0.01 for McNemar's test). In external validation, performance was slightly decreased. For AD-CN, it again gave similar AUCs for SVM (0.896; 95%CI: 0.855-0.932) and CNN (0.876; 95%CI: 0.836-0.913). For prediction in MCI, performances decreased for both SVM (AUC = 0.665; 95%CI: 0.576-0.760) and CNN (AUC = 0.702; 95%CI: 0.624-0.786). Both with SVM and CNN, classification based on modulated GM maps significantly outperformed classification based on minimally processed images (p=0.01). Deep and conventional classifiers performed equally well for AD classification and their performance decreased only slightly when applied to the external cohort. We expect that this work on external validation contributes towards translation of machine learning to clinical practice.
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http://dx.doi.org/10.1016/j.nicl.2021.102712DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8203808PMC
June 2021

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

Neurobiol Dis 2021 Aug 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.
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http://dx.doi.org/10.1016/j.nbd.2021.105421DOI Listing
August 2021

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

Neurobiol Aging 2021 May 2. 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.
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http://dx.doi.org/10.1016/j.neurobiolaging.2021.04.023DOI Listing
May 2021

Evaluation of P-glycoprotein function at the blood-brain barrier using [F]MC225-PET.

Eur J Nucl Med Mol Imaging 2021 Jun 5. Epub 2021 Jun 5.

Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands.

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http://dx.doi.org/10.1007/s00259-021-05419-8DOI Listing
June 2021

How well do people living with neurodegenerative diseases manage their finances? A meta-analysis and systematic review on the capacity to make financial decisions in people living with neurodegenerative diseases.

Neurosci Biobehav Rev 2021 Aug 28;127:709-739. Epub 2021 May 28.

Department of Clinical and Developmental Neuropsychology, University of Groningen, Groningen, the Netherlands. Electronic address:

Self and proxy reported questionnaires indicate that people living with a neurodegenerative disease (NDD) have more difficulties with financial decision-making (FDM) than healthy controls. Self-reports, however, rely on adequate insight into everyday functioning and might, therefore, be less reliable. The present study provides a comprehensive overview and meta-analysis of studies evaluating FDM in people living with an NDD. For this, the reliability of performance-based tests to consistently identify FDM difficulties in people living with an NDD compared to healthy controls is evaluated. Furthermore, the associations between FDM and disease severity, performances on standard measures of cognition and demographics are evaluated. All 47 included articles, consistently reported lower performances on performance-based FDM tests of people living with an NDD (including Alzheimer's disease, mild cognitive impairment, frontotemporal dementia, Parkinson's disease, multiple sclerosis or Huntington's disease) compared to healthy controls. The majority of studies, however, focused on Alzheimer's disease and mild cognitive impairment (k = 38). FDM performance appears to be related to cognitive decline, specifically in working memory, processing speed and numeracy.
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http://dx.doi.org/10.1016/j.neubiorev.2021.05.021DOI Listing
August 2021

PapRIV, a BV-2 microglial cell activating quorum sensing peptide.

Sci Rep 2021 May 21;11(1):10723. Epub 2021 May 21.

Drug Quality and Registration (DruQuaR) Group, Faculty of Pharmaceutical Sciences, Ghent University, Ghent, Belgium.

Quorum sensing peptides (QSPs) are bacterial peptides produced by Gram-positive bacteria to communicate with their peers in a cell-density dependent manner. These peptides do not only act as interbacterial communication signals, but can also have effects on the host. Compelling evidence demonstrates the presence of a gut-brain axis and more specifically, the role of the gut microbiota in microglial functioning. The aim of this study is to investigate microglial activating properties of a selected QSP (PapRIV) which is produced by Bacillus cereus species. PapRIV showed in vitro activating properties of BV-2 microglia cells and was able to cross the in vitro Caco-2 cell model and reach the brain. In vivo peptide presence was also demonstrated in mouse plasma. The peptide caused induction of IL-6, TNFα and ROS expression and increased the fraction of ameboid BV-2 microglia cells in an NF-κB dependent manner. Different metabolites were identified in serum, of which the main metabolite still remained active. PapRIV is thus able to cross the gastro-intestinal tract and the blood-brain barrier and shows in vitro activating properties in BV-2 microglia cells, hereby indicating a potential role of this quorum sensing peptide in gut-brain interaction.
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http://dx.doi.org/10.1038/s41598-021-90030-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8140105PMC
May 2021

Kinetics and 28-day test-retest repeatability and reproducibility of [C]UCB-J PET brain imaging.

J Cereb Blood Flow Metab 2021 06 8;41(6):1338-1350. Epub 2020 Oct 8.

Department of Radiology & Nuclear Medicine, Amsterdam Neuroscience, Amsterdam UMC, Amsterdam, The Netherlands.

[C]UCB-J is a novel radioligand that binds to synaptic vesicle glycoprotein 2A (SV2A). The main objective of this study was to determine the 28-day test-retest repeatability (TRT) of quantitative [C]UCB-J brain positron emission tomography (PET) imaging in Alzheimer's disease (AD) patients and healthy controls (HCs). Nine HCs and eight AD patients underwent two 60 min dynamic [C]UCB-J PET scans with arterial sampling with an interval of 28 days. The optimal tracer kinetic model was assessed using the Akaike criteria (AIC). Micro-/macro-parameters such as tracer delivery (K) and volume of distribution (V) were estimated using the optimal model. Data were also analysed for simplified reference tissue model (SRTM) with centrum semi-ovale (white matter) as reference region. Based on AIC, both 1T2k_V and 2T4k_V described the [C]UCB-J kinetics equally well. Analysis showed that whole-brain grey matter TRT for V, DVR and SRTM BP were -2.2% ± 8.5, 0.4% ± 12.0 and -8.0% ± 10.2, averaged over all subjects. [C]UCB-J kinetics can be well described by a 1T2k_V model, and a 60 min scan duration was sufficient to obtain reliable estimates for both plasma input and reference tissue models. TRT for V, DVR and BP was <15% (1SD) averaged over all subjects and indicates adequate quantitative repeatability of [C]UCB-J PET.
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http://dx.doi.org/10.1177/0271678X20964248DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8138337PMC
June 2021

The Behavioral and Psychological Symptoms of Dementia in Down Syndrome Scale (BPSD-DS II): Optimization and Further Validation.

J Alzheimers Dis 2021 ;81(4):1505-1527

Department of Neurology and Alzheimer Center, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

Background: People with Down syndrome (DS) are at high risk to develop Alzheimer's disease dementia (AD). Behavioral and psychological symptoms of dementia (BPSD) are common and may also serve as early signals for dementia. However, comprehensive evaluation scales for BPSD, adapted to DS, are lacking. Therefore, we previously developed the BPSD-DS scale to identify behavioral changes between the last six months and pre-existing life-long characteristic behavior.

Objective: To optimize and further study the scale (discriminative ability and reliability) in a large representative DS study population.

Methods: Optimization was based on item irrelevance and clinical experiences obtained in the initial study. Using the shortened and refined BPSD-DS II, informant interviews were conducted to evaluate 524 individuals with DS grouped according to dementia status: no dementia (DS, N = 292), questionable dementia (DS + Q, N = 119), and clinically diagnosed dementia (DS + AD, N = 113).

Results: Comparing item change scores between groups revealed prominent changes in frequency and severity for anxious, sleep-related, irritable, restless/stereotypic, apathetic, depressive, and eating/drinking behavior. For most items, the proportion of individuals displaying an increased frequency was highest in DS + AD, intermediate in DS + Q, and lowest in DS. For various items within sections about anxious, sleep-related, irritable, apathetic, and depressive behaviors, the proportion of individuals showing an increased frequency was already substantial in DS + Q, suggesting that these changes may serve as early signals of AD in DS. Reliability data were promising.

Conclusion: The optimized scale yields largely similar results as obtained with the initial version. Systematically evaluating BPSD in DS may increase understanding of changes among caregivers and (timely) adaptation of care/treatment.
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http://dx.doi.org/10.3233/JAD-201427DOI Listing
January 2021

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

Neurobiol Aging 2021 Aug 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.
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http://dx.doi.org/10.1016/j.neurobiolaging.2021.03.011DOI Listing
August 2021

The Anaesthetic Biobank of Cerebrospinal fluid: a unique repository for neuroscientific biomarker research.

Ann Transl Med 2021 Mar;9(6):455

Department of Anesthesiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

Background: The pathophysiology of numerous central nervous system disorders remains poorly understood. Biomarker research using cerebrospinal fluid (CSF) is a promising way to illuminate the neurobiology of neuropsychiatric disorders. CSF biomarker studies performed so far generally included patients with neurodegenerative diseases without an adequate control group. The Anaesthetic Biobank of Cerebrospinal fluid (ABC) was established to address this. The aims are to (I) provide healthy-control reference values for CSF-based biomarkers, and (II) to investigate associations between CSF-based candidate biomarkers and neuropsychiatric symptoms.

Methods: In this cross-sectional study, we collect and store CSF and blood from adult patients undergoing spinal anaesthesia for elective surgery. Blood (20.5 mL) is collected during intravenous cannulation and CSF (10 mL) is aspirated prior to intrathecal local anaesthetic injection. A portion of the blood and CSF is sent for routine laboratory analyses, the remaining material is stored at -80 °C. Relevant clinical, surgical and anaesthetic data are registered. A neurological examination and Montreal Cognitive Assessment (MoCA) are performed pre-operatively and a subset of patients fill in questionnaires on somatic and mental health (depression, anxiety and stress).

Results: Four-hundred-fifty patients (58% male; median age: 56 years) have been enrolled in the ABC. The planned spinal anaesthetic procedure was not attempted for various reasons in eleven patients, in fourteen patients the spinal puncture failed and in twelve patients CSF aspiration was unsuccessful. A mean of 9.3 mL CSF was obtained in the remaining 413 of patients. Most patients had a minor medical history and 60% scored in the normal range on the MoCA (median score: 26).

Conclusions: The ABC is an ongoing biobanking project that can contribute to CSF-based biomarker research. The large sample size with constant sampling methods and extensive patient phenotyping provide excellent conditions for future neuroscientific research.
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http://dx.doi.org/10.21037/atm-20-4498DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8039635PMC
March 2021

Feasibility of pharmacokinetic parametric PET images in scaled subprofile modelling using principal component analysis.

Neuroimage Clin 2021 13;30:102625. Epub 2021 Mar 13.

University of Groningen, University Medical Center Groningen, Department of Nuclear Medicine and Molecular Imaging, The Netherlands.

Scaled subprofile model using principal component analysis (SSM/PCA) is a multivariate analysis technique used, mainly in [F]-2-fluoro-2-deoxy-d-glucose (FDG) PET studies, for the generation of disease-specific metabolic patterns (DP) that may aid with the classification of subjects with neurological disorders, like Alzheimer's disease (AD). The aim of this study was to explore the feasibility of using quantitative parametric images for this type of analysis, with dynamic [C]-labelled Pittsburgh Compound B (PIB) PET data as an example. Therefore, 15 AD patients and 15 healthy control subjects were included in an SSM/PCA analysis to generate four AD-DPs using relative cerebral blood flow (R), binding potential (BP) and SUVR images derived from dynamic PIB and static FDG-PET studies. Furthermore, 49 new subjects with a variety of neurodegenerative cognitive disorders were tested against these DPs. The AD-DP was characterized by a reduction in the frontal, parietal, and temporal lobes voxel values for R and SUVR-FDG DPs; and by a general increase of values in cortical areas for BP and SUVR-PIB DPs. In conclusion, the results suggest that the combination of parametric images derived from a single dynamic scan might be a good alternative for subject classification instead of using 2 independent PET studies.
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http://dx.doi.org/10.1016/j.nicl.2021.102625DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8020472PMC
July 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

Amyloid burden quantification depends on PET and MR image processing methodology.

PLoS One 2021 5;16(3):e0248122. Epub 2021 Mar 5.

Medical Imaging Center, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

Quantification of amyloid load with positron emission tomography can be useful to assess Alzheimer's Disease in-vivo. However, quantification can be affected by the image processing methodology applied. This study's goal was to address how amyloid quantification is influenced by different semi-automatic image processing pipelines. Images were analysed in their Native Space and Standard Space; non-rigid spatial transformation methods based on maximum a posteriori approaches and tissue probability maps (TPM) for regularisation were explored. Furthermore, grey matter tissue segmentations were defined before and after spatial normalisation, and also using a population-based template. Five quantification metrics were analysed: two intensity-based, two volumetric-based, and one multi-parametric feature. Intensity-related metrics were not substantially affected by spatial normalisation and did not significantly depend on the grey matter segmentation method, with an impact similar to that expected from test-retest studies (≤10%). Yet, volumetric and multi-parametric features were sensitive to the image processing methodology, with an overall variability up to 45%. Therefore, the analysis should be carried out in Native Space avoiding non-rigid spatial transformations. For analyses in Standard Space, spatial normalisation regularised by TPM is preferred. Volumetric-based measurements should be done in Native Space, while intensity-based metrics are more robust against differences in image processing pipelines.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0248122PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7935288PMC
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

Distinct amyloid-β and tau-associated microglia profiles in Alzheimer's disease.

Acta Neuropathol 2021 05 20;141(5):681-696. Epub 2021 Feb 20.

Department of Biomedical Sciences of Cells and Systems, Section Molecular Neurobiology, University of Groningen and University Medical Center Groningen (UMCG), Antonius Deusinglaan 1, 9713AV, Groningen, the Netherlands.

Alzheimer's disease (AD) is the most prevalent form of dementia and is characterized by abnormal extracellular aggregates of amyloid-β and intraneuronal hyperphosphorylated tau tangles and neuropil threads. Microglia, the tissue-resident macrophages of the central nervous system (CNS), are important for CNS homeostasis and implicated in AD pathology. In amyloid mouse models, a phagocytic/activated microglia phenotype has been identified. How increasing levels of amyloid-β and tau pathology affect human microglia transcriptional profiles is unknown. Here, we performed snRNAseq on 482,472 nuclei from non-demented control brains and AD brains containing only amyloid-β plaques or both amyloid-β plaques and tau pathology. Within the microglia population, distinct expression profiles were identified of which two were AD pathology-associated. The phagocytic/activated AD1-microglia population abundance strongly correlated with tissue amyloid-β load and localized to amyloid-β plaques. The AD2-microglia abundance strongly correlated with tissue phospho-tau load and these microglia were more abundant in samples with overt tau pathology. This full characterization of human disease-associated microglia phenotypes provides new insights in the pathophysiological role of microglia in AD and offers new targets for microglia-state-specific therapeutic strategies.
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http://dx.doi.org/10.1007/s00401-021-02263-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8043951PMC
May 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

Functional connectivity differences in Alzheimer's disease and amnestic mild cognitive impairment associated with AT(N) classification and anosognosia.

Neurobiol Aging 2021 05 8;101:22-39. Epub 2021 Jan 8.

University of Groningen, University Medical Center Groningen, Department of Neurology, Groningen, the Netherlands; University of Groningen, University Medical Center Groningen, Alzheimer Center Groningen, Groningen, the Netherlands; Laboratory of Neurochemistry and Behavior, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.

Alzheimer's continuum biological profiles (ATN, ATN, ATN, and ATN) were established in the 2018 National Institute on Aging and Alzheimer's Association research framework for Alzheimer's disease (AD). We aim to assess the relation between AT(N) biomarker profiles and brain functional connectivity (FC) and assess the neural correlates of anosognosia. We assessed local functional coupling and between-network connectivity through between-group intrinsic local correlation and independent component analyses. The neural correlates of anosognosia were assessed via voxel-wise linear regression analysis in prodromal AD. Statistical significance for the FC analysis was set at p ≤ 0.05 false discovery rate (FDR)-corrected for cluster size. One hundred and twenty-one and 73 participants were included in the FC and the anosognosia analysis, respectively. The FC in the default mode network is greater in prodromal AD than AD with dementia (i.e., local correlation: T = 8.26, p-FDR < 0.001, k = 1179; independent component analysis: cerebellar network, T = 4.01, p-FDR = 0.0012, k = 493). The default mode network is persistently affected in the early stages of Alzheimer's biological continuum. The anterior cingulate cortex (T = 2.52, p-FDR = 0.043, k = 704) is associated with anosognosia in prodromal AD.
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http://dx.doi.org/10.1016/j.neurobiolaging.2020.12.021DOI Listing
May 2021

Widespread white matter aberration is associated with the severity of apathy in amnestic Mild Cognitive Impairment: Tract-based spatial statistics analysis.

Neuroimage Clin 2021 19;29:102567. Epub 2021 Jan 19.

Cognitive Neuroscience Center, Department of Biomedical Sciences of Cells & Systems, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

Apathy is recognized as a prevalent behavioral symptom of amnestic Mild Cognitive Impairment (aMCI). In aMCI, apathy is associated with an increased risk and increases the risk of progression to Alzheimer's Disease (AD). Previous DTI study in aMCI showed that apathy has been associated with white matter alterations in the cingulum, middle and inferior longitudinal fasciculus, fornix, and uncinate fasciculus. However, the underlying white matter correlates associated with apathy in aMCI are still unclear. We investigated this relationship using whole-brain diffusion tensor imaging (DTI). Twenty-nine aMCI patients and 20 matched cognitively healthy controls were included. Apathy severity was assessed using the Apathy Evaluation Scale Clinician version. We applied the tract-based spatial statistics analyses to DTI parameters: fractional anisotropy (FA), mean diffusivity, axial diffusivity, and radial diffusivity to investigate changes in white matter pathways associated with the severity of apathy. No significant difference was found in any of the DTI parameters between aMCI and the control group. In aMCI, higher severity of apathy was associated with lower FA in various white matter pathways including the left anterior part of inferior fronto-occipital fasciculus/uncinate fasciculus, genu and body of the corpus callosum, superior and anterior corona radiata, anterior thalamic radiation of both hemispheres and in the right superior longitudinal fasciculus/anterior segment of arcuate fasciculus (p < .05, TFCE-corrected) after controlling for age, gender and GDS non-apathy. A trend association was observed in the right posterior corona radiata and corticospinal tract/internal capsule, and bilateral forceps minor (p < .065, TFCE-corrected). In conclusion, in aMCI, severity of apathy is associated with aberrant white matter integrity in widely distributed pathways, within and between hemispheres.
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http://dx.doi.org/10.1016/j.nicl.2021.102567DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7856325PMC
June 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

Author Correction: A complete pupillometry toolbox for real-time monitoring of locus coeruleus activity in rodents.

Nat Protoc 2021 Jan 14. Epub 2021 Jan 14.

Laboratory of Molecular and Behavioral Neuroscience, Institute for Neuroscience, Department of Health Sciences and Technology, ETH Zurich, Zurich, Switzerland.

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http://dx.doi.org/10.1038/s41596-021-00493-6DOI Listing
January 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

Comparison of size distribution and (Pro249-Ser258) epitope exposure in in vitro and in vivo derived Tau fibrils.

BMC Mol Cell Biol 2020 Nov 12;21(1):81. Epub 2020 Nov 12.

Neuroscience department, Janssen Pharmaceutical Companies of Johnson and Johnson, 2340, Beerse, Belgium.

Background: Although several studies demonstrate prion-like properties of Tau fibrils, the effect of size in the seeding capacity of these aggregates is not fully understood. The aim of this study is to characterize Tau seeds by their size and seeding capacity.

Methods: Tau aggregates were isolated from postmortem AD brain tissue and separated from low molecular weight species by sucrose gradient ultracentrifugation. Biochemical characterization of the different fractions was done by non-reducing Western blotting and aggregate-specific immuno-assays using in house developed anti-Tau monoclonal antibodies, including PT76 which binds to an epitope close to the microtubule-binding domain and, hence, also to K18. Seeding efficiency was then assessed in HEK293 cells expressing K18 FRET sensors.

Results: We observed that upon sonication of Tau aggregates different size-distributed tau aggregates are obtained. In biochemical assays, these forms show higher signals than the non-sonicated material in some aggregation-specific Tau assays. This could be explained by an increased epitope exposure of the smaller aggregates created by the sonication. By analyzing human brain derived and recombinant (K18) Tau aggregates in a cellular FRET assay, it was observed that, in the absence of transfection reagent, sonicated aggregates showed higher aggregation induction. Preparations also showed altered profiles on native PAGE upon sonication and we could further separate different aggregate species based on their molecular weight via sucrose gradients.

Conclusions: This study further elucidates the molecular properties regarding relative aggregate size and seeding efficiency of sonicated vs. non-sonicated high molecular weight Tau species. This information will provide a better knowledge on how sonication, a commonly used technique in the field of study of Tau aggregation, impacts the aggregates. In addition, the description of PT76-based aggregation specific assay is a valuable tool to quantify K18 and human AD Tau fibrils.
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http://dx.doi.org/10.1186/s12860-020-00320-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7661158PMC
November 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
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