Publications by authors named "Peter P De Deyn"

250 Publications

Neurogranin as biomarker in CSF is non-specific to Alzheimer's disease dementia.

Neurobiol Aging 2021 Aug 8;108:99-109. Epub 2021 Aug 8.

Reference Center for Biological Markers of Dementia (BIODEM) and Laboratory of Neurochemistry and Behavior, Laboratory of Neurobiology, Laboratory of Neurogenetics, and Biobank, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium; Neurochemistry laboratory, Department of Clinical Biology and Center for Neurosciences (C4N), Universitair Ziekenhuis Brussel (UZ Brussel) and Vrije Universiteit Brussel (VUB), Brussels, Belgium. Electronic address:

We aimed to evaluate the specificity of neurogranin (Ng) for Alzheimer's disease (AD) in a dementia cohort. Cerebrospinal fluid (CSF) Ng was measured (ELISA) in two independent cohorts: (1) clinical (n = 116; age 72±11 years): AD, non-AD (+high T-tau), and controls; and (2) autopsy-confirmed (n = 97; age 71±11 years): AD and non-AD, and 50 controls (age 60±6 years). In 16 autopsy-confirmed AD and 8 control subjects, Ng was measured in tissue (BA6+BA22). Ng was compared across diagnostic groups or neuropathological staging using multilinear regression models. Median[IQR] Ng concentrations were elevated in AD (414[315-499]pg/mL) and non-AD (464[319-699]pg/mL) compared to controls (260[193-306]pg/mL), but highest in AD-high-T-tau (874[716, 1148] pg/mL) and Creutzfeldt-Jakob disease (CJD; 828[703-1373]pg/mL) in cohort 1 (p < 0.01), but not in cohort 2: AD: 358[249-470]pg/mL; non-AD:245[137-416]pg/mL; controls: 259[193-370]pg/mL. Ng and tau biomarkers strongly correlated (r = 0.4-0.9, p < 0.05), except in CJD. CSF Ng concentrations were not associated with neuropathological AD hallmarks, nor with tissue Ng concentrations. CSF Ng is a general biomarker for synaptic degeneration, strongly correlating with CSF tau, but without added value for AD differential diagnosis.
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http://dx.doi.org/10.1016/j.neurobiolaging.2021.08.002DOI Listing
August 2021

Serum and cerebrospinal fluid Neutrophil gelatinase-associated lipocalin (NGAL) levels as biomarkers for the conversion from mild cognitive impairment to Alzheimer's disease dementia.

Neurobiol Aging 2021 Jul 10;107:1-10. Epub 2021 Jul 10.

Department of Neurology and Alzheimer Research Centre, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands; Laboratory of Neurochemistry and Behavior, Biobank, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.

Neutrophil gelatinase-associated lipocalin (NGAL) is an acute phase protein that has been reported as a potential marker for pre-dementia stages of Alzheimer's disease (AD). Longitudinal studies for its association with the conversion of mild cognitive impairment to AD is still lacking. This study included n = 268 study participants with subjective cognitive decline (SCD) (n=82), mild cognitive impairment (MCI) (n=98) and AD dementia (n=88) at baseline and two-year follow-up clinical assessments. Serum and cerebrospinal fluid (CSF)NGAL, CSF amyloid beta, total-Tau, and phospho-Tau levels were measured with ELISA analysis. CSF NGAL levels were significantly lower in MCI participants compared to people with SCD at baseline. Lower baseline CSF NGAL levels predicted MCI converters to AD dementia vs. non-converters after 2-years follow-up. A positive correlation between CSF NGAL and amyloid beta was found particularly in MCI participants at baseline. NGAL in CSF holds potential to be used as a predictive marker for the conversion of MCI to AD dementia and may reflect pathophysiological processes of prodromal AD neuropathology.
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http://dx.doi.org/10.1016/j.neurobiolaging.2021.07.001DOI Listing
July 2021

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

Ageing Res Rev 2021 09 26;70:101414. 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
September 2021

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

Neurobiol Aging 2021 10 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
October 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

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

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

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

The ATP-Binding Cassette Subfamily A Member 7 gene (ABCA7) was identified as a risk gene for Alzheimer's disease (AD) in genome-wide association studies of large cohorts of late-onset AD (LOAD) patients. Extended resequencing of the ABCA7 coding regions identified mutations that lead to premature termination codons (PTC) and loss of function of ABCA7. PTC mutations were enriched in LOAD patients and were frequently present in patients with early-onset AD (EOAD). We aimed at assessing the contribution of ABCA7 PTC mutations to AD in the Belgian population by screening the ABCA7 coding region in a Belgian AD cohort of 1376 patients, including LOAD and EOAD patients, and in a Belgian control cohort of 976 individuals. We identified a PTC mutation in 67 AD patients (4.9%) and in 18 control individuals (1.8%) confirming the enrichment of ABCA7 PTC mutations in Belgian AD patients. The patient carriers had a mean onset age of 69.7 ± 9.8 years with a wide onset age range of 42 years (48-90 years). In 77.3% of the families of ABCA7 carriers, there were AD patients present suggestive of a positive family history of disease, but a Mendelian co-segregation of ABCA7 PTC mutations with disease is not clear. Overall, our genetic data predict that PTC mutations in ABCA7 are common in the Belgian population and are present in LOAD and EOAD patients.
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http://dx.doi.org/10.1016/j.neurobiolaging.2021.04.023DOI Listing
October 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 08 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

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
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8293661PMC
September 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

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

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

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

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

Nat Protoc 2021 Aug;16(8):4108

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
August 2021

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

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

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

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

Alzheimer's disease is the most frequent diagnosis of neurodegenerative dementia with early (≤65 years) and late (>65 years) onset ages in familial and sporadic patients. Causal mutations in 3 autosomal dominant Alzheimer genes, i.e. amyloid precursor protein (APP), presenilin 1 (PSEN1) and presenilin 2 (PSEN2), explain only 5%-10% of early-onset patients leaving the majority of patients genetically unresolved. To discover potential missing genetics, we used whole genome sequencing data of 17 early-onset patients with well-documented clinical diagnosis of Alzheimer's disease. In the discovery group, the mean onset age was 55.71 ± 6.83 years (range 37-65). Six patients had a brain autopsy and neuropathology confirmed Alzheimer's disease. Analysis of the genetic data identified in one patient a homozygous p.V366M missense mutation in the Von Willebrand factor A domain containing 2 gene (VWA2). Resequencing of the VWA2 coding region in an Alzheimer's disease patient cohort from Flanders-Belgium (n = 1148), including 152 early and 996 late onset patients, identified additional homozygous and compound heterozygous missense mutations in 1 early and 3 late-onset patients. Allele-sharing analysis identified common haplotypes among the compound heterozygous VWA2 mutation carriers, suggesting shared ancestors. Overall, we identified 5 patient carriers of homozygous or compound heterozygous missense mutations (5/1165; 0.43 %), 2 in early (2/169; 1.18 %) and 3 in late-onset (3/996; 0.30 %) patients. The frequencies of the homozygous and compound heterozygous missense mutations in patients are higher than expected from the frequencies calculated based on their combined single alleles. None of the homozygous/compound heterozygous missense mutation carriers had a family history of autosomal dominant Alzheimer's disease. Our findings suggest that homozygous and compound heterozygous missense mutations in VWA2 might contribute to the risk of Alzheimer's disease in sporadic patients.
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http://dx.doi.org/10.1016/j.neurobiolaging.2020.09.009DOI Listing
March 2021

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

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

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

We investigated the impact of the recently described chromosome 6 open reading frame 10 (C6orf10)/LOC101929163 locus as age-at-onset modifier in an extended cohort of Belgian chromosome 9 open reading frame 72 (C9orf72) GC repeat expansion carriers. We genotyped the tagging CpG single-nucleotide polymorphism rs9357140 in 224 confirmed C9orf72 repeat expansion carriers, 102 index cases and 122 relatives, and tested association with onset age. The C9orf72 repeat expansion cohort consisted of 131 symptomatic carriers, that is, 78 with dementia only, 13 with frontotemporal dementia (FTD)-amyotrophic lateral sclerosis (ALS), and 40 ALS only, and 93 presymptomatic carriers. Cox proportional hazard regression analysis failed to identify significant association (adjusted hazard ratio = 1.15, p = 0.3). We further extended our analysis to a Belgian cohort of unrelated, mutation-negative FTD index patients (n = 230), but also found no association (adjusted hazard ratio = 0.96, p = 0.3). Overall, our findings suggest that in the Belgian cohort, the C6orf10/LOC101929163 locus cannot explain the marked variability in age at onset, and other genetic or environmental modifiers must drive the clinical heterogeneity observed among C9orf72 repeat expansion carriers.
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http://dx.doi.org/10.1016/j.neurobiolaging.2020.07.021DOI Listing
January 2021

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

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

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

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

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

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

Conclusion: This is the first time that Aβ levels were analysed in CSF of AD patients with genetic mutations in the AD causal genes. The observed reduction of Aβ in APP and PSENs carriers highlights the pathogenic role of longer Aβ peptides in AD pathogenesis. Alterations in Aβ could prove useful in understanding the pathogenicity of unclear APP and PSENs variants, a critical step towards a more efficient genetic counselling.
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http://dx.doi.org/10.1186/s13195-020-00676-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7488767PMC
September 2020

Biofluid Markers for Prodromal Parkinson's Disease: Evidence From a Catecholaminergic Perspective.

Front Neurol 2020 15;11:595. Epub 2020 Jul 15.

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

Parkinson's disease (PD) is the most frequent of all Lewy body diseases, a family of progressive neurodegenerative disorders characterized by intra-neuronal cytoplasmic inclusions of α-synuclein. Its most defining features are bradykinesia, tremor, rigidity and postural instability. By the time PD manifests with motor signs, 70% of dopaminergic midbrain neurons are lost, and the disease is already in the middle or late stage. However, there are various non-motor symptoms occurring up to 20 years before the actual parkinsonism that are closely associated with profound deficiency of myocardial noradrenaline content and peripheral sympathetic denervation, as evidenced by neuroimaging experiments in recent years. Additionally, there is an inherent autotoxicity of catecholamines in the neuronal cells in which they are produced, forming toxic catecholaldehyde intermediates that make α-synuclein prone to aggregation, initiating a cascade of events that ultimately leads to neuronal death. The etiopathogenesis of PD and related synucleinopathies thus may well be a prototypical example of a catecholamine-regulated neurodegeneration, given that the synucleinopathy in PD spreads in synergy with central and peripheral catecholaminergic dysfunction from the earliest phases onward. That is why catecholamines and their metabolites, precursors, or derivatives in cerebrospinal fluid or plasma could be of particular interest as biomarkers for prodromal and PD. Because there is great demand for such markers, this mini-review summarizes all catecholamine-related studies to date, in addition to providing profound neurochemical evidence on a systemic and cellular level to further emphasize this hypothesis and with emphasis on extracellular vesicles as a novel diagnostic and therapeutic incentive.
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http://dx.doi.org/10.3389/fneur.2020.00595DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7373724PMC
July 2020

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

Nat Protoc 2020 08 6;15(8):2301-2320. Epub 2020 Jul 6.

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

The locus coeruleus (LC) is a region in the brainstem that produces noradrenaline and is involved in both normal and pathological brain function. Pupillometry, the measurement of pupil diameter, provides a powerful readout of LC activity in rodents, primates and humans. The protocol detailed here describes a miniaturized setup that can screen LC activity in rodents in real-time and can be established within 1-2 d. Using low-cost Raspberry Pi computers and cameras, the complete custom-built system costs only ~300 euros, is compatible with stereotaxic surgery frames and seamlessly integrates into complex experimental setups. Tools for pupil tracking and a user-friendly Pupillometry App allow quantification, analysis and visualization of pupil size. Pupillometry can discriminate between different, physiologically relevant firing patterns of the LC and can accurately report LC activation as measured by noradrenaline turnover. Pupillometry provides a rapid, non-invasive readout that can be used to verify accurate placement of electrodes/fibers in vivo, thus allowing decisions about the inclusion/exclusion of individual animals before experiments begin.
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http://dx.doi.org/10.1038/s41596-020-0324-6DOI Listing
August 2020

Bioethical implications of end-of-life decision-making in patients with dementia: a tale of two societies.

Monash Bioeth Rev 2020 May;38(1):49-67

Department of Neurology, University of Groningen, University Medical Center Groningen, PO Box 30001, 9700 RB, Groningen, The Netherlands.

End-of-life decision-making in patients with dementia is a complex topic. Belgium and the Netherlands have been at the forefront of legislative advancement and progressive societal changes concerning the perspectives toward physician-assisted death (PAD). Careful consideration of clinical and social aspects is essential during the end-of-life decision-making process in patients with dementia. Geriatric assent provides the physician, the patient and his family the opportunity to end life with dignity. Unbearable suffering, decisional competence, and awareness of memory deficits are among the clinical considerations that physicians should incorporate during the end-of-life decision-making process. However, as other societies introduce legislature granting the right of PAD, new social determinants should be considered; Mexico City is an example. Current perspectives regarding advance euthanasia directives (AED) and PAD in patients with dementia are evolving. A new perspective that hinges on the role of the family and geriatric assent should help culturally heterogeneous societies in the transition of their public health care policies regarding end-of-life choices.
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http://dx.doi.org/10.1007/s40592-020-00112-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7205770PMC
May 2020

Monoaminergic and Kynurenergic Characterization of Frontotemporal Dementia and Amyotrophic Lateral Sclerosis in Cerebrospinal Fluid and Serum.

Neurochem Res 2020 May 4;45(5):1191-1201. Epub 2020 Mar 4.

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

Exploring the neurochemical continuum between frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) with respect to monoamines and kynurenines in cerebrospinal fluid (CSF) and serum, may be useful to identify possible new research/therapeutic targets. Hence, we analysed monoamines and kynurenines in CSF and serum derived from patients with FTD (n = 39), ALS (n = 23), FTD-ALS (n = 4) and age-matched control subjects (n = 26), using reversed-phase ultra-high performance liquid chromatography (RP-UHPLC) with electrochemical detection (ECD) and liquid chromatography tandem mass spectrometry, respectively. We noted a shared dopaminergic disturbance in FTD and ALS when compared to CONTR, with significantly increased serum DA levels and decreased DOPAC concentrations, as well as decreased DOPAC/DA ratios in both disease groups. In CSF, significantly reduced DOPAC concentrations in FTD and ALS were observed as well. Here, a significant increase in DA levels and decrease in DOPAC/DA ratios was only found in FTD relative to CONTR. With respect to the kynurenine pathway (KP), we only found decreased HK/XA ratios, indicative for vitamin B6 status, in serum of ALS subjects compared to FTD. The dopaminergic commonalities observed in FTD and ALS might relate to a disturbance of dopaminergic nerve terminals in projection areas of the substantia nigra and/or ventral tegmental area, although these findings should first be confirmed in brain tissue. Lastly, based on the results of this work, the KP does not hold promise as a research/therapeutic target in FTD and ALS.
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http://dx.doi.org/10.1007/s11064-020-03002-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7162843PMC
May 2020

Iron chelators inhibit amyloid-β-induced production of lipocalin 2 in cultured astrocytes.

Neurochem Int 2020 01 21;132:104607. Epub 2019 Nov 21.

Department of Neurology and Alzheimer Center Groningen, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ, Groningen, the Netherlands; Department of Molecular Neurobiology, Groningen Institute for Evolutionary Life Sciences (GELIFES), University of Groningen, Nijenborgh 7, 9747 AG, Groningen, the Netherlands. Electronic address:

Lipocalin 2 (Lcn2) has been implicated to play a role in various neurodegenerative diseases, and normalizing its overexpression may be of therapeutic potential. Iron chelators were found to reduce Lcn2 levels in certain animal models of CNS injury. Focusing on Alzheimer's disease (AD), we found that the iron chelators deferoxamine and deferiprone inhibited amyloid-β (Aβ)-induced Lcn2 production in cultured primary astrocytes. Accordingly, Aβ-exposure increased astrocytic ferritin production, indicating the possibility that Aβ induces iron accumulation in astrocytes. This effect was not significantly modulated by Lcn2. Known neuroprotective effects of iron chelators may rely in part on normalization of Lcn2 levels.
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http://dx.doi.org/10.1016/j.neuint.2019.104607DOI Listing
January 2020

Tryptophan Metabolism in Inflammaging: From Biomarker to Therapeutic Target.

Front Immunol 2019 30;10:2565. Epub 2019 Oct 30.

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

Inflammation aims to restore tissue homeostasis after injury or infection. Age-related decline of tissue homeostasis causes a physiological low-grade chronic inflammatory phenotype known as inflammaging that is involved in many age-related diseases. Activation of tryptophan (Trp) metabolism along the kynurenine (Kyn) pathway prevents hyperinflammation and induces long-term immune tolerance. Systemic Trp and Kyn levels change upon aging and in age-related diseases. Moreover, modulation of Trp metabolism can either aggravate or prevent inflammaging-related diseases. In this review, we discuss how age-related Kyn/Trp activation is necessary to control inflammaging and alters the functioning of other metabolic faiths of Trp including Kyn metabolites, microbiota-derived indoles and nicotinamide adenine dinucleotide (NAD). We explore the potential of the Kyn/Trp ratio as a biomarker of inflammaging and discuss how intervening in Trp metabolism might extend health- and lifespan.
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http://dx.doi.org/10.3389/fimmu.2019.02565DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6833926PMC
October 2020

Inducing Physical Inactivity in Mice: Preventing Climbing and Reducing Cage Size Negatively Affect Physical Fitness and Body Composition.

Front Behav Neurosci 2019 4;13:221. Epub 2019 Oct 4.

Molecular Neurobiology, Groningen Institute for Evolutionary Life Sciences (GELIFES), University of Groningen, Groningen, Netherlands.

Physical inactivity has emerged as an important and risk factor for cardiovascular and metabolic diseases, independent of levels of exercise engagement. Moreover, inactivity is associated with poor brain functioning. However, little data on the effects of physical inactivity on the brain is available and few methods are suitable to investigate this matter. We tested whether preventing lid climbing and reducing cage size could be used to model physical inactivity in mice. Sixty young adult C57Bl6 mice (10 weeks old) were divided over six groups with different housing conditions: in cages of three different sizes with lids that either allowed or prevented lid climbing. Housing under these conditions was maintained for a period of 19 weeks before the mice were killed for body composition analysis. Physical fitness tests performed around 5 and 10 weeks into the intervention revealed that motor coordination in the balance beam test was reduced by 30.65%, grip strength by 8.91% and muscle stamina in the inverted screen test by 70.37% in non-climbing mice as compared to climbing controls. Preventing climbing increased visceral fat mass by 17.31%, but did not reduce muscle mass. Neither preventing climbing nor reducing cage size affected anxiety assessed in the Open Field test and the Elevated Plus Maze. We did not find any negative effect of inactivity on spatial learning and memory in the novel object location test or working memory measured with the Y-maze Alternation test. The reduced physical fitness and increase in visceral fat mass show that our inactivity method models most effects of physical inactivity that are observed in experimental and observational studies in humans. Whereas established methods such as hindlimb unloading mimic many of the effects of bed rest, our novel method can be applied to study the effects of less extreme forms of physical inactivity (i.e., sedentary behavior) in various disease models including rodent models for brain diseases (i.e., stroke, Alzheimer's disease).
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http://dx.doi.org/10.3389/fnbeh.2019.00221DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6797814PMC
October 2019
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