Publications by authors named "Mathieu Vandenbulcke"

128 Publications

The efficacy of exergaming in people with major neurocognitive disorder residing in long-term care facilities: a pilot randomized controlled trial.

Alzheimers Res Ther 2021 03 30;13(1):70. Epub 2021 Mar 30.

KU Leuven Department of Rehabilitation Sciences, Leuven, Belgium.

Background: It is currently unknown whether exergaming is efficacious in people with major neurocognitive disorder (MNCD) residing in long-term care facilities. This pilot randomized controlled trial (RCT) explored the efficacy of a stepping exergame program on gait speed, balance, mobility, reaction time, cognitive and neuropsychiatric outcomes, quality of life, and daily life functioning in people with MNCD residing in long-term care facilities.

Methods: Participants were randomly assigned to 8 weeks, three times weekly, 15 min of exergaming versus watching preferred music videos. The exergame device consisted of a pressure-sensitive step training platform on which participants performed stepping movements to play the games. The device automatically adapted the training level to the participants' capabilities. The Short Physical Performance Battery (SPPB), step reaction time test (SRTT), Montréal Cognitive Assessment (MoCA), Neuropsychiatric Inventory (NPI), Cornell Scale for Depression in Dementia (CSDD), Dementia Quality of Life (DQoL), and Katz Activities of Daily Living (Katz ADL) were assessed at baseline and post-intervention. A Quade's non-parametric ANCOVA controlling for baseline values with post hoc Bonferroni correction (p < 0.00625) was used to analyze pre- and post-differences between the groups. Partial eta-squared (ηp) effect sizes were calculated.

Results: Forty-five of 55 randomized inpatients with mild to moderate MNCD (Mini-Mental State Examination score = 17.2 ± 4.5; aged 70-91; 35 women) completed the study. The exergame group (n = 23) demonstrated improvements in gait speed (p < 0.001, η = 0.41), total SPPB (p < 0.001, η = 0.64), SRTT (p<0.001, η = 0.51), MoCA (p<0.001, η = 0.38), and reductions in CSDD (p<0.001, η = 0.43) compared to the control group (n = 22). There were no differences in NPI (p = 0.165, η = 0.05), DQoL (p = 0.012, η = 0.16), and ADL (p = 0.008, η = 0.16) post-intervention scores between the experimental and control group, albeit DQol and ADL measures showed large effect sizes in the exergame group. The mean attendance rate was 82.9% in the exergame group and 73.7% in the music control group. There were no study-related adverse events reported by the participants, nor observed by the research team.

Conclusions: The findings of this pilot RCT suggest that an individually adapted exergame training improves lower extremity functioning, cognitive functioning and step reaction time and symptoms of depression in inpatients with MNCD residing in long-term care facilities.

Trial Registration: ClinicalTrials.gov, NCT04436302.
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http://dx.doi.org/10.1186/s13195-021-00806-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8008333PMC
March 2021

Synaptic density in healthy human aging is not influenced by age or sex: a C-UCB-J PET study.

Neuroimage 2021 05 24;232:117877. Epub 2021 Feb 24.

Nuclear Medicine and Molecular Imaging, Department of Imaging and Pathology, KU Leuven, Belgium; Division of Nuclear Medicine, University Hospitals Leuven, Belgium.

Rationale: C-UCB-J binds to synaptic vesicle glycoprotein 2A, a protein ubiquitously expressed in presynaptic nerve terminals, and can therefore serve as in vivo proxy of synaptic density. There are discrepancies in postmortem data on stability of synaptic density with healthy aging. In this study, healthy aging and sex as potential modifiers of C-UCB-J binding were investigated in healthy volunteers over 7 adult decades, assuming that the number of SV2A vesicles per synapse is not influenced by age or sex.

Methods: 80 healthy volunteers underwent C-UCB-J PET and structural T1 and T2 MR imaging. Grey matter changes with aging were firstly evaluated by voxel-based morphometry (VBM). Parametric C-UCB-J standardized uptake value ratio (SUVR) images were calculated using the centrum semiovale as reference tissue. To correct for atrophy-related partial volume effects, a region-based voxel-wise type partial volume correction (PVC) was applied in FreeSurfer. The correlations of C-UCB-J binding with age and with sex were investigated by a voxel-based and volume-of-interest (VOI)-based approach, and with and without PVC to assess the contribution of underlying morphology changes upon aging.

Results: Full results were available for 78 participants (19-85y; 33 M/45 F). VBM grey matter concentration changes with aging were most predominant in the perisylvian and frontal regions. After PVC, no significantly decreased C-UCB-J SUVR with aging was found in the voxel-based analysis, whereas the VOI-based analysis showed a slight decrease in the caudate nucleus (-1.7% decrease per decade, p= 0.0025) only. There was no association between sex and C-UCB-J SUVR, nor an interaction between aging and sex for this parameter.

Conclusion: In vivo, PET using C-UCB-J does not support a cortical decrease of synaptic density with aging, whereas subcortically a small effect with aging in the caudate nucleus was observed. In addition, no association between synaptic density and sex was detected, which allows pooling of datasets of both sexes.
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http://dx.doi.org/10.1016/j.neuroimage.2021.117877DOI Listing
May 2021

The Leuven late life depression (L3D) study: PET-MRI biomarkers of pathological brain ageing in late-life depression: study protocol.

BMC Psychiatry 2021 01 28;21(1):64. Epub 2021 Jan 28.

Geriatric Psychiatry, University Psychiatric Center KU Leuven, B-3000, Leuven, Belgium.

Background: Major depressive disorders rank in the top ten causes of ill health in all but four countries worldwide and are the leading cause of years lived with disability in Europe (WHO). Recent research suggests that neurodegenerative pathology may contribute to the development of late-life depression (LLD) in a sub-group of patients and represent a target for prevention and early diagnosis. In parallel, electroconvulsive therapy (ECT), which is the most effective treatment for severe LLD, has been associated with significant brain structural changes. In both LLD and ECT hippocampal volume change plays a central role; however, the neurobiological mechanism underlying it and its relevance for clinical outcomes remain unresolved.

Methods: This is a monocentric, clinical cohort study with a cross-sectional arm evaluating PET-MR imaging and behavioural measures in 64 patients with LLD compared to 64 healthy controls, and a longitudinal arm evaluating the same imaging and behavioural measures after 10 ECT sessions in 20 patients receiving ECT as part of their normal clinical management. Triple tracer PET-MRI data will be used to measure: hippocampal volume (high resolution MRI), synaptic density using [C]UCB-J, which targets the Synaptic Vesicle Glycoprotein 2A receptor, tau pathology using [F]MK-6240, and cerebral amyloid using [F]-Flutemetamol, which targets beta-amyloid neuritic plaques in the brain. Additional MRI measures and ultrasound will assess cerebral vascular structure and brain connectivity. Formal clinical and neuropsychological assessments will be conducted alongside experience sampling and physiological monitoring to assess mood, stress, cognition and psychomotor function.

Discussion: The main aim of the study is to identify the origin and consequences of hippocampal volume differences in LLD by investigating how biomarkers of pathological ageing contribute to medial temporal lobe pathology. Studying how synaptic density, tau, amyloid and vascular pathology relate to neuropsychological, psychomotor function, stress and ECT, will increase our pathophysiological understanding of the in vivo molecular, structural and functional alterations occurring in depression and what effect this has on clinical outcome. It may also lead to improvements in the differential diagnosis of depression and dementia yielding earlier, more optimal, cost-effective clinical management. Finally, it will improve our understanding of the neurobiological mechanism of ECT.

Trial Registration: ClinicalTrials.gov Identifier: NCT03849417 , 21/2/2019.
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http://dx.doi.org/10.1186/s12888-021-03063-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7845114PMC
January 2021

Maturation of neuronal AD-tau pathology involves site-specific phosphorylation of cytoplasmic and synaptic tau preceding conformational change and fibril formation.

Acta Neuropathol 2021 02 11;141(2):173-192. Epub 2021 Jan 11.

Laboratory for Neuropathology, Department of Imaging and Pathology, KU-Leuven, Herestraat 49, 3000, Leuven, Belgium.

In Alzheimer's disease (AD), tau-protein undergoes a multi-step process involving the transition from a natively unfolded monomer to large, aggregated structures such as neurofibrillary tangles (NFTs). However, it is not yet clear which events initiate the early preclinical phase of AD tauopathy and whether they have impact on the propagation of tau pathology in later disease stages. To address this question, we analyzed the distribution of tau species phosphorylated at T231, S396/S404 and S202/T205, conformationally modified at the MC1 epitope and fibrillary tau detected by the Gallyas method (Gallyas-tau), in the brains of 15 symptomatic and 20 asymptomatic cases with AD pathology as well as of 19 nonAD cases. As initial tau lesions, we identified phosphorylated-T231-tau diffusely distributed within the somatodendritic compartment (IC-tau) and phosphorylated-S396/pS404-tau in axonal lesions of the white matter and in the neuropil (IN-tau). The subcellular localization of pT231-tau in the cell body and pS396/pS404-tau in the presynapse was confirmed in hP301L mutant Drosophila larvae. Phosphorylated-S202/T205-tau, MC1-tau and Gallyas-tau were negative for these lesions. IC- and IN-tau were observed in all analyzed regions of the human brain, including early affected regions in nonAD cases (entorhinal cortex) and late affected regions in symptomatic AD cases (cerebellum), indicating that tau pathology initiation follows similar processes when propagating into previously unaffected regions. Furthermore, a sequence of AD-related maturation of tau-aggregates was observed, initiated by the appearance of IC- and IN-tau, followed by the formation of pretangles exhibiting pT231-tau, pS396/pS404-tau and pS202/pT205-tau, then by MC1-conformational tau, and, finally, by the formation of Gallyas-positive NFTs. Since cases classified as nonAD [Braak NFT stages < I (including a-1b)] already showed IC- and IN-tau, our findings suggest that these lesions are a prerequisite for the development of AD.
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http://dx.doi.org/10.1007/s00401-020-02251-6DOI Listing
February 2021

Continuing to participate in the dance of life as oneself: The lived experience of meaning in life for older adults with Alzheimer's disease.

Gerontologist 2020 Dec 15. Epub 2020 Dec 15.

Faculty of Psychology and Educational Sciences, KU Leuven, Leuven, Belgium.

Background And Objectives: Meaning in life is an important aspect of positive psychological functioning for older adults. Limited work suggests the relevance of the experience of meaning for people with dementia, but research into this experience from their personal perspective is lacking. The current study provides an in-depth investigation of the lived experience of meaning in life for older adults with Alzheimer's disease.

Research Design And Methods: The study was conducted following the phenomenological reflective lifeworld approach. In-depth interviews were conducted with sixteen older adults (+65) with Alzheimer's disease living either at home or in a nursing home in Belgium. Data-analysis was an iterative process aimed at illuminating the constituents and essence of the phenomenon.

Results: The essence of the experience of meaning in life for participants was understood as 'continuing to participate in the dance of life as oneself.' This experience was further clarified in four closely intertwined constituents: (1) feeling connected and involved, (2) continuing everyday life as oneself, (3) calmly surrendering and letting go, and (4) desiring freedom, growth, and invigoration.

Discussion And Implications: Our findings contribute to a deeper understanding of meaning in life as experienced by older adults with Alzheimer's disease themselves. They emphasize the relevance of the concept for psychological dementia research and offer original insight for the inclusion of meaning in life as an important aspect of holistic dementia care.
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http://dx.doi.org/10.1093/geront/gnaa206DOI Listing
December 2020

Combination of snapshot hyperspectral retinal imaging and optical coherence tomography to identify Alzheimer's disease patients.

Alzheimers Res Ther 2020 11 10;12(1):144. Epub 2020 Nov 10.

Department of Ophthalmology, University Hospitals UZ Leuven, Herestraat 49, 3000, Leuven, Belgium.

Introduction: The eye offers potential for the diagnosis of Alzheimer's disease (AD) with retinal imaging techniques being explored to quantify amyloid accumulation and aspects of neurodegeneration. To assess these changes, this proof-of-concept study combined hyperspectral imaging and optical coherence tomography to build a classification model to differentiate between AD patients and controls.

Methods: In a memory clinic setting, patients with a diagnosis of clinically probable AD (n = 10) or biomarker-proven AD (n = 7) and controls (n = 22) underwent non-invasive retinal imaging with an easy-to-use hyperspectral snapshot camera that collects information from 16 spectral bands (460-620 nm, 10-nm bandwidth) in one capture. The individuals were also imaged using optical coherence tomography for assessing retinal nerve fiber layer thickness (RNFL). Dedicated image preprocessing analysis was followed by machine learning to discriminate between both groups.

Results: Hyperspectral data and retinal nerve fiber layer thickness data were used in a linear discriminant classification model to discriminate between AD patients and controls. Nested leave-one-out cross-validation resulted in a fair accuracy, providing an area under the receiver operating characteristic curve of 0.74 (95% confidence interval [0.60-0.89]). Inner loop results showed that the inclusion of the RNFL features resulted in an improvement of the area under the receiver operating characteristic curve: for the most informative region assessed, the average area under the receiver operating characteristic curve was 0.70 (95% confidence interval [0.55, 0.86]) and 0.79 (95% confidence interval [0.65, 0.93]), respectively. The robust statistics used in this study reduces the risk of overfitting and partly compensates for the limited sample size.

Conclusions: This study in a memory-clinic-based cohort supports the potential of hyperspectral imaging and suggests an added value of combining retinal imaging modalities. Standardization and longitudinal data on fully amyloid-phenotyped cohorts are required to elucidate the relationship between retinal structure and cognitive function and to evaluate the robustness of the classification model.
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http://dx.doi.org/10.1186/s13195-020-00715-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7654576PMC
November 2020

Exergaming for people with major neurocognitive disorder: a qualitative study.

Disabil Rehabil 2020 Sep 23:1-9. Epub 2020 Sep 23.

Department of Rehabilitation Sciences, KU Leuven, Leuven, Belgium.

Purpose: This study investigated the experiences of participation in a standing balance exergame program amongst people with major neurocognitive disorder (MNCD) within residential care settings.

Materials And Methods: A qualitative descriptive study was conducted in participants with MNCD recruited from two residential settings. Participants exergamed for 15 min, three times per week for 8 weeks. Semi-structured interviews were conducted in all participants of the trial after 4 and 8 weeks. Audio files were transcribed and subsequently a thematic content analysis was performed using NVivo 12. Activity logs including adherence and attrition rates were kept.

Results: Thirty-one participants with MNCD participated (median age = 85 (67-93) years; 77.4% women; Mini-Mental State Examination score = 19 (10-25)). Four broad themes emerged: (1) cognitive effects; (2) physical effects; (3) psychosocial effects and (4) motivators. The tailored exergame program was perceived as enjoyable. It stimulated participants' attention, concentration, reaction time, and memory. Participants reported improvements in balance, flexibility, and gait. Exergaming made participants energetic and calm. The attrition rate was 0% and the mean attendance rate was 79.3%.

Conclusions: The results indicate that standing balance exergaming is feasible, beneficial, and engaging in people with MNCD.Implications for rehabilitationExergames present a personalised intervention for engaging people with major neurocognitive disorder in physical activity.An exergame intervention is feasible and highly appreciated in this population.Exergames should be adapted to the individuals' needs and possibilities in order to enhance motivation and learning.
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http://dx.doi.org/10.1080/09638288.2020.1822934DOI Listing
September 2020

Hippocampal volume as a vulnerability marker for late onset psychosis: Associations with memory function and childhood trauma.

Schizophr Res 2020 Oct 17;224:201-202. Epub 2020 Aug 17.

Geriatric Psychiatry, University Psychiatric Center KU Leuven, Leuven, Belgium; Laboratory for Translational Neuropsychiatry, Department of Neurosciences, KU Leuven, Leuven, Belgium.

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http://dx.doi.org/10.1016/j.schres.2020.08.004DOI Listing
October 2020

Exergames in people with major neurocognitive disorder: a systematic review.

Disabil Rehabil Assist Technol 2020 Jul 22:1-14. Epub 2020 Jul 22.

University Psychiatric Center, KU Leuven, Kortenberg, Belgium.

Purpose: To systematically evaluate the efficacy of exergames in individuals with major neurocognitive disorder.

Materials And Methods: PubMed, EMBASE and PEDro were systematically searched from inception until October 2019 for randomised and clinical controlled trials. Methodological quality of the trials was assessed with the PEDro rating scale or Risk of Bias in Nonrandomised Studies of Interventions-I (ROBINS-I), when appropriate. Grading of Recommendations Assessments, Development and Evaluation (GRADE) was used to assess the overall quality of the evidence.

Results: Eight trials, all of moderate to high methodological quality (i.e., PEDro score of 6 or higher or a Robins-I moderate quality score) were included. The overall quality of evidence was moderate to high according to the GRADE criteria. Improvements in gait, mobility and balance and beneficial effects on activities of daily living performance, cognitive function, fear of falls, quality of life and mood following exergaming were reported. Heterogeneity in outcome measures, intervention characteristics and included participants precluded a meta-analysis.

Conclusions: The current literature is of moderate to high quality and demonstrates that exergames have a wide range of physical and mental benefits in people with major neurocognitive disorder. More controlled trials are however needed to confirm the existing evidence before exergames can be recommended in treatment guidelines for people with major neurocognitive disorder.Implications for rehabilitationExergames have many physical and mental benefits in people with major neurocognitive disorderExergaming can enhance gait, mobility and balance in people with major neurocognitive disorderEvidence for beneficial cognitive effects of exergaming is emerging.
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http://dx.doi.org/10.1080/17483107.2020.1785566DOI Listing
July 2020

Effects of a mindfulness-based intervention on cancer-related cognitive impairment: Results of a randomized controlled functional magnetic resonance imaging pilot study.

Cancer 2020 09 8;126(18):4246-4255. Epub 2020 Jul 8.

Department of Imaging and Pathology, Catholic University of Leuven, Leuven, Belgium.

Background: Many breast cancer survivors suffer from cognitive complaints after cancer treatment, affecting their quality of life. The objective of this pilot study was to investigate the effect of a blended-care mindfulness-based intervention (MBI) on chemotherapy-related cognitive impairment and functional brain changes. Furthermore, correlations between changes in cognitive functioning and self-reported behavioral factors were investigated.

Methods: Breast cancer survivors (n = 33) who reported cognitive impairment were randomly allocated to a mindfulness condition (n = 18) or a waitlist control condition (n = 15). Patients completed questionnaires on cognitive impairment, emotional distress, and fatigue; neuropsychological tests; and resting-state functional magnetic resonance imaging before the start of MBI (time 1 [T1]), immediately after the completion of an 8-week MBI program (T2), and 3 months postintervention (T3). Resting-state functional connectivity was estimated in the default mode network, the dorsal and salience attention networks, and the frontoparietal network. Mixed model repeated-measures analysis was performed to test the intervention effect.

Results: Patients in the mindfulness condition exhibited significantly higher connectivity between the dorsal and salience attention networks after the mindfulness intervention compared with those in the control condition. MBI participants also had reduced subjective cognitive impairment, emotional distress, and fatigue. No intervention effect was observed on neurocognitive tests.

Conclusions: MBI may induce functional brain changes in networks related to attention and may have a positive effect on subjective measures of cognitive impairment in breast cancer survivors. Therefore, MBI could be a suitable intervention to improve quality of life in this population and deserves further study in this context.
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http://dx.doi.org/10.1002/cncr.33074DOI Listing
September 2020

Network level characteristics in the emotion recognition network after unilateral temporal lobe surgery.

Eur J Neurosci 2020 09 2;52(5):3470-3484. Epub 2020 Jul 2.

Department of Neurosciences, Neuropsychiatry, Leuven Brain Institute, KU Leuven, Leuven, Belgium.

The human amygdala is considered a key region for successful emotion recognition. We recently reported that temporal lobe surgery (TLS), including resection of the amygdala, does not affect emotion recognition performance (Journal of Neuroscience, 2018, 38, 9263). In the present study, we investigate the neural basis of this preserved function at the network level. We use generalized psychophysiological interaction and graph theory indices to investigate network level characteristics of the emotion recognition network in TLS patients and healthy controls. Based on conflicting emotion processing theories, we anticipated two possible outcomes: a substantial increase of the non-amygdalar connections of the emotion recognition network to compensate functionally for the loss of the amygdala, in line with basic emotion theory versus only minor changes in network level properties as predicted by psychological construction theory. We defined the emotion recognition network in the total sample and investigated group differences on five network level indices (i.e. characteristic path length, global efficiency, clustering coefficient, local efficiency and small-worldness). The results did not reveal a significant increase in the left or right temporal lobectomy group (compared to the control group) in any of the graph measures, indicating that preserved behavioural emotion recognition in TLS is not associated with a massive connectivity increase between non-amygdalar nodes at network level. We conclude that the emotion recognition network is robust and functionally able to compensate for structural damage without substantial global reorganization, in line with a psychological construction theory.
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http://dx.doi.org/10.1111/ejn.14849DOI Listing
September 2020

In vivo synaptic density loss is related to tau deposition in amnestic mild cognitive impairment.

Neurology 2020 08 3;95(5):e545-e553. Epub 2020 Jun 3.

From the Division of Nuclear Medicine (H.V., J.C., M.K., K.V.L.) and Department of Neurology (L.M., R.L.), University Hospitals Leuven; Nuclear Medicine and Molecular Imaging (H.V., J.C., M.K., S.S., L.E., K.V.L.) and Translational MRI (S.S., L.E.), Department of Imaging and Pathology, and Department of Geriatric Psychiatry (H.V., L.E., M.V.), University Psychiatric Centre, Laboratory for Neurobiology (L.M., R.L.), KU Leuven; and Center for Brain and Disease Research (L.M., R.L.), VIB-KU Leuven, Belgium. Dr. Triau is in private practice in Leuven, Belgium.

Objective: To investigate in vivo whether synaptic loss and neurofibrillary tangle load spatially overlap and correlate with clinical symptoms in patients with amnestic mild cognitive impairment (aMCI).

Methods: In this cross-sectional study, 10 patients with aMCI and 10 healthy controls underwent triple PET-MRI with C-UCB-J (synaptic vesicle protein 2A), F-MK-6240 (tau deposition), and C-Pittsburgh compound B (β-amyloid) and neuropsychological assessment. Gray matter atrophy was assessed by voxel-based morphometry with T1-weighted MRIs. Voxel-wise and volume-of-interest analyses were conducted on PET data. The interrelationship of synaptic density and tau deposition was investigated. We also investigated correlations of F-MK-6240 and C-UCB-J binding with cognitive performance.

Results: Compared to controls, patients with aMCI showed a decreased C-UCB-J binding mainly in substructures of the medial temporal lobe (MTL; 48%-51%, = 0.02). Increased F-MK6240 binding in the same region was observed (42%-44%, = 0.0003), spreading to association cortices. In the MTL, higher F-MK-6240 binding inversely related to lower C-UCB-J binding ( = 0.02, = -0.76). Decreased performance on cognitive tests was associated with both increased F-MK-6240 and decreased C-UCB-J binding in the hippocampus ( < 0.01, > 0.7), although in a multivariate analysis only F-MK-6240 binding was significantly related to cognitive performance.

Conclusions: Patients with aMCI have high tau deposition and synaptic density loss mainly in key regions known to be involved in early cognitive impairment, indicating that these are interrelated in the MTL, while tau binding had already spread toward association cortices. Longitudinal data are needed to provide further insight into the temporal aspects of this relationship.
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http://dx.doi.org/10.1212/WNL.0000000000009818DOI Listing
August 2020

Use of Multimodal Imaging and Clinical Biomarkers in Presymptomatic Carriers of C9orf72 Repeat Expansion.

JAMA Neurol 2020 08;77(8):1008-1017

KU Leuven, Department of Neurosciences, Experimental Neurology, B-3000 Leuven, Belgium.

Importance: During a time with the potential for novel treatment strategies, early detection of disease manifestations at an individual level in presymptomatic carriers of a hexanucleotide repeat expansion in the C9orf72 gene (preSxC9) is becoming increasingly relevant.

Objectives: To evaluate changes in glucose metabolism before symptom onset of amyotrophic lateral sclerosis or frontotemporal dementia in preSxC9 using simultaneous fluorine 18-labeled fluorodeoxyglucose ([18F]FDG positron emission tomographic (PET) and magnetic resonance imaging as well as the mutation's association with clinical and fluid biomarkers.

Design, Setting, And Participants: A prospective, case-control study enrolled 46 participants from November 30, 2015, until December 11, 2018. The study was conducted at the neuromuscular reference center of the University Hospitals Leuven, Leuven, Belgium.

Main Outcomes And Measures: Neuroimaging data were spatially normalized and analyzed at the voxel level at a height threshold of P < .001, cluster-level familywise error-corrected threshold of P < .05, and statistical significance was set at P < .05 for the volume-of-interest level analysis, using Benjamini-Hochberg correction for multiple correction. W-score maps were computed using the individuals serving as controls as a reference to quantify the degree of [18F]FDG PET abnormality. The threshold for abnormality on the W-score maps was designated as an absolute W-score greater than or equal to 1.96. Neurofilament levels and performance on cognitive and neurologic examinations were determined. All hypothesis tests were 1-sided.

Results: Of the 42 included participants, there were 17 with the preSxC9 mutation (12 women [71%]; mean [SD] age, 51 [9] years) and 25 healthy controls (12 women [48%]; mean [SD] age, 47 [10] years). Compared with control participants, significant clusters of relative hypometabolism were found in frontotemporal regions, basal ganglia, and thalami of preSxC9 participants and relative hypermetabolism in the peri-Rolandic region, superior frontal gyrus, and precuneus cortex. W-score frequency maps revealed reduced glucose metabolism with local maxima in the insular cortices, central opercular cortex, and thalami in up to 82% of preSxC9 participants and increased glucose metabolism in the precentral gyrus and precuneus cortex in up to 71% of preSxC9 participants. Other findings in the preSxC9 group were upper motor neuron involvement in 10 participants (59%), cognitive abnormalities in 5 participants (29%), and elevated neurofilament levels in 3 of 16 individuals (19%) who underwent lumbar puncture.

Conclusions And Relevance: The results suggest that [18F]FDG PET can identify glucose metabolic changes in preSxC9 at an individual level, preceding significantly elevated neurofilament levels and onset of symptoms.
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http://dx.doi.org/10.1001/jamaneurol.2020.1087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7417970PMC
August 2020

A mindfulness-based intervention for breast cancer patients with cognitive impairment after chemotherapy: study protocol of a three-group randomized controlled trial.

Trials 2020 Mar 23;21(1):290. Epub 2020 Mar 23.

Department of Imaging and Pathology, KU Leuven, Herestraat 49, 3000, Leuven, Belgium.

Background: Mindfulness has been applied to improve cancer care by enhancing psychological well-being. However, little is known about its impact on cognitive impairment experienced by cancer patients after chemotherapy. Mindfulness may be relevant in tackling cognitive impairment by decreasing emotional distress and fatigue, by decreasing inflammation, and by strengthening functional brain connectivity. The aim of the present study protocol is to evaluate the efficacy and mechanisms of a mindfulness-based intervention to reduce cognitive impairment in breast cancer patients after chemotherapy.

Methods/design: The present study is a three-arm, parallel-group, randomized controlled trial with assessments at baseline, 1 to 3 weeks after the intervention and at 3 months' follow-up. One hundred and twenty breast cancer patients who ended treatment a minimum of 6 months and a maximum of 5 years before, and who have cognitive complaints, will be enrolled. They will be randomized into one of the following three study arms: (1) a mindfulness-based intervention group (n = 40), (2) an active control condition based on physical training (n = 40), or (3) a treatment as usual (TAU) control group (n = 40). Both the mindfulness-based intervention and the active control condition consist of four group sessions (3 h for the mindfulness condition and 2 h for the physical training) spread over 8 weeks. The primary outcomes will be cognitive symptoms as measured by the Cognitive Failure Questionnaire and changes in functional brain connectivity in the attention network. Secondary outcomes will be (1) levels of emotional distress, fatigue, mindfulness, quality of life; (2) neurocognitive tests; (3) structural and functional brain changes using MR imaging and (4) measures of inflammation.

Discussion: The study will examine the impact of a mindfulness-based intervention on cognitive impairment in breast cancer patients. If the findings of this study confirm the effectiveness of a mindfulness-based program to reduce cognitive impairment, it will be possible to improve quality of life for ex-cancer patients. We will inform health care providers about the potential use of a mindfulness-based intervention as a non-pharmaceutical, low-threshold mental health intervention to improve cognitive impairment after cancer.

Trial Registration: ClinicalTrials.gov, ID: NCT03736460. Retrospectively registered on 8 November 2018.
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http://dx.doi.org/10.1186/s13063-020-4204-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7092531PMC
March 2020

Structural changes induced by electroconvulsive therapy are associated with clinical outcome.

Brain Stimul 2020 May - Jun;13(3):696-704. Epub 2020 Feb 21.

Department of Psychiatry, Radboud University Medical Center, Nijmegen, the Netherlands; Donders Institute for Brain, Cognition and Behavior, Centre for Cognitive Neuroimaging, Nijmegen, the Netherlands; Department of Psychiatry and Psychotherapy, University Hospital Essen, Essen, Germany.

Background: Electroconvulsive therapy (ECT) is the most effective treatment option for major depressive disorder, so understanding whether its clinical effect relates to structural brain changes is vital for current and future antidepressant research.

Objective: To determine whether clinical response to ECT is related to structural volumetric changes in the brain as measured by structural magnetic resonance imaging (MRI) and, if so, which regions are related to this clinical effect. We also determine whether a similar model can be used to identify regions associated with electrode placement (unilateral versus bilateral ECT).

Methods: Longitudinal MRI and clinical data (Hamilton Depression Rating Scale) was collected from 10 sites as part of the Global ECT-MRI research collaboration (GEMRIC). From 192 subjects, relative changes in 80 (sub)cortical areas were used as potential features for classifying treatment response. We used recursive feature elimination to extract relevant features, which were subsequently used to train a linear classifier. As a validation, the same was done for electrode placement. We report accuracy as well as the structural coefficients of regions included in the discriminative spatial patterns obtained.

Results: A pattern of structural changes in cortical midline, striatal and lateral prefrontal areas discriminates responders from non-responders (75% accuracy, p < 0.001) while left-sided mediotemporal changes discriminate unilateral from bilateral electrode placement (81% accuracy, p < 0.001).

Conclusions: The identification of a multivariate discriminative pattern shows that structural change is relevant for clinical response to ECT, but this pattern does not include mediotemporal regions that have been the focus of electroconvulsive therapy research so far.
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http://dx.doi.org/10.1016/j.brs.2020.02.020DOI Listing
November 2020

Recommendations to distinguish behavioural variant frontotemporal dementia from psychiatric disorders.

Brain 2020 06;143(6):1632-1650

Department of Neurology, UCLA Medical Centre, University of California Los Angeles, Los Angeles, USA.

The behavioural variant of frontotemporal dementia (bvFTD) is a frequent cause of early-onset dementia. The diagnosis of bvFTD remains challenging because of the limited accuracy of neuroimaging in the early disease stages and the absence of molecular biomarkers, and therefore relies predominantly on clinical assessment. BvFTD shows significant symptomatic overlap with non-degenerative primary psychiatric disorders including major depressive disorder, bipolar disorder, schizophrenia, obsessive-compulsive disorder, autism spectrum disorders and even personality disorders. To date, ∼50% of patients with bvFTD receive a prior psychiatric diagnosis, and average diagnostic delay is up to 5-6 years from symptom onset. It is also not uncommon for patients with primary psychiatric disorders to be wrongly diagnosed with bvFTD. The Neuropsychiatric International Consortium for Frontotemporal Dementia was recently established to determine the current best clinical practice and set up an international collaboration to share a common dataset for future research. The goal of the present paper was to review the existing literature on the diagnosis of bvFTD and its differential diagnosis with primary psychiatric disorders to provide consensus recommendations on the clinical assessment. A systematic literature search with a narrative review was performed to determine all bvFTD-related diagnostic evidence for the following topics: bvFTD history taking, psychiatric assessment, clinical scales, physical and neurological examination, bedside cognitive tests, neuropsychological assessment, social cognition, structural neuroimaging, functional neuroimaging, CSF and genetic testing. For each topic, responsible team members proposed a set of minimal requirements, optimal clinical recommendations, and tools requiring further research or those that should be developed. Recommendations were listed if they reached a ≥ 85% expert consensus based on an online survey among all consortium participants. New recommendations include performing at least one formal social cognition test in the standard neuropsychological battery for bvFTD. We emphasize the importance of 3D-T1 brain MRI with a standardized review protocol including validated visual atrophy rating scales, and to consider volumetric analyses if available. We clarify the role of 18F-fluorodeoxyglucose PET for the exclusion of bvFTD when normal, whereas non-specific regional metabolism abnormalities should not be over-interpreted in the case of a psychiatric differential diagnosis. We highlight the potential role of serum or CSF neurofilament light chain to differentiate bvFTD from primary psychiatric disorders. Finally, based on the increasing literature and clinical experience, the consortium determined that screening for C9orf72 mutation should be performed in all possible/probable bvFTD cases or suspected cases with strong psychiatric features.
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http://dx.doi.org/10.1093/brain/awaa018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7849953PMC
June 2020

The Impact of Pharmacologic and Nonpharmacologic Interventions to Improve Physical Health Outcomes in People With Dementia: A Meta-Review of Meta-Analyses of Randomized Controlled Trials.

J Am Med Dir Assoc 2020 10 19;21(10):1410-1414.e2. Epub 2020 Feb 19.

South London and Maudsley NHS Foundation Trust, Denmark Hill, London, United Kingdom; Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King's College London, London, United Kingdom.

Objectives: We summarized and compared meta-analyses of pharmacologic and nonpharmacologic interventions targeting physical health outcomes among people with dementia.

Design: This is a systematic review and meta-analysis.

Setting And Participants: People with dementia, confirmed through validated assessment measures.

Methods: Major databases were searched until October 21, 2019. Effect sizes [standardized mean difference (SMD)/Hedges g or risk ratio (RR)] were compared separately.

Results: Of 3773 search engine hits, 4 meta-analyses were included, representing 31 meta-analyzed trials and 10,054 study participants. Although meta-analyses were generally of adequate high quality, meta-analyzed studies were less so. Nutritional supplements were the only one to show a weight-increasing effect [SMD 0.53, 95% confidence interval (CI) 0.38-0.68, ie, medium effect; N = 12, n = 748]. Acetylcholinesterase inhibitors are associated with an increased risk for weight loss (RR 2.1, 95% CI 1.5‒3.0; N = 9, n = 7010). For the treatment of pain, sensory stimulation has a medium effect (SMD -0.58, 95% CI -0.99 to -0.17; N = 6, n = 199), whereas physical activity has a small effect (SMD -0.24, 95% CI -1.06 to 0.59; N = 2, n = 75). When exploring the characteristics of the psychosocial interventions, group-based interventions demonstrated a medium (SMD -0.55, 95% CI -1.02 to -0.09; N = 6, n = 157) and individual psychosocial interventions a small effect (SMD -0.27, 95% CI -1.06 to 0.53; N = 2, n = 55).

Conclusions And Implications: Despite frequent physical comorbidities, the current evidence for pharmacologic and nonpharmacologic interventions in people with dementia to prevent and treat these conditions is still in its infancy, and larger trials targeting a wide range of physical health outcomes are urgently needed. Based on the SMDs and RRs, nutritional supplements can be recommended as an intervention to treat malnutrition. Clinicians should be careful in treating patients with acetylcholinesterase inhibitors, as it shows medium weight reducing effects. For the treatment of comorbid pain, sensory stimulation and psychosocial interventions are recommended.
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http://dx.doi.org/10.1016/j.jamda.2020.01.010DOI Listing
October 2020

Are Apathy and Depressive Symptoms Related to Vascular White Matter Hyperintensities in Severe Late Life Depression?

J Geriatr Psychiatry Neurol 2021 Jan 10;34(1):21-28. Epub 2020 Feb 10.

159194GGZ inGeest Specialized Mental Health Care, Amsterdam, the Netherlands.

Objective: Apathy symptoms are defined as a lack of interest and motivation. Patients with late-life depression (LLD) also suffer from lack of interest and motivation and previous studies have linked apathy to vascular white matter hyperintensities (WMH) of the brain in depressed and nondepressed patients. The aim of this study was to investigate the relationship between apathy symptoms, depressive symptoms, and WMH in LLD. We hypothesize that late-onset depression (LOD; first episode of depression after 55 years of age) is associated with WMH and apathy symptoms.

Methods: Apathy scores were collected for 87 inpatients diagnosed with LLD. Eighty patients underwent brain magnetic resonance imaging. Associations between depressive and apathy symptoms and WMH were analyzed using linear regression.

Results: All 3 subdomains of the 10-item Montgomery-Åsberg Depression Rating Scale correlated significantly with the apathy scale score (all < .05). In the total sample, apathy nor depressive symptoms were related to specific WMH. In LOD only, periventricular WMH were associated with depression severity (β = 5.21, = .04), while WMH in the left infratentorial region were associated with apathy symptoms (β coefficient = 5.89, = .03).

Conclusion: Apathy and depressive symptoms are highly overlapping in the current cohort of older patients with severe LLD, leading to the hypothesis that apathy symptoms are part of depressive symptoms in the symptom profile of older patients with severe LLD. Neither apathy nor depressive symptoms were related to WMH, suggesting that radiological markers of cerebrovascular disease, such as WMH, may not be useful in predicting these symptoms in severe LLD.
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http://dx.doi.org/10.1177/0891988720901783DOI Listing
January 2021

Brain-behaviour associations and neural representations of emotions in frontotemporal dementia.

Brain 2020 03;143(3):e17

Laboratory for Translational Neuropsychiatry, Leuven Brain Institute, KU Leuven, Leuven, Belgium.

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http://dx.doi.org/10.1093/brain/awaa005DOI Listing
March 2020

Direct prospective comparison of F-FDG PET and arterial spin labelling MR using simultaneous PET/MR in patients referred for diagnosis of dementia.

Eur J Nucl Med Mol Imaging 2020 08 20;47(9):2142-2154. Epub 2020 Jan 20.

Department of Imaging and Pathology, University Hospitals Leuven and KU Leuven, Herestraat 49, 3000, Leuven, Belgium.

Purpose: F-FDG PET is routinely used as an imaging marker in the early and differential diagnosis of dementing disorders and has incremental value over the clinical neurological and neuropsychological evaluation. Perfusion MR imaging by means of arterial spin labelling (ASL) is an alternative modality to indirectly measure neuronal functioning and could be used as complement measurement in a single MR session in the workup of dementia. Using simultaneous PET-MR, we performed a direct head-to-head comparison between enhanced multiplane tagging ASL (eASL) and F-FDG PET in a true clinical context of subjects referred for suspicion of neurodegenerative dementia.

Methods: Twenty-seven patients underwent a 20-min F-FDG PET/MR and simultaneously acquired eASL on a GE Signa PET/MR. Data were compared with 30 screened age- and gender-matched healthy controls. Both integral eASL and F-FDG datasets were analysed visually by two readers unaware of the final clinical diagnosis, either in normal/abnormal classes, or full differential diagnosis (normal, Alzheimer type dementia [AD], dementia with Lewy Bodies [LBD], frontotemporal dementia [FTD] or other). Reader confidence was assessed with a rating scale (range 1-4). Data were also analysed semiquantitatively by VOI and voxel-based analyses.

Results: The ground truth diagnosis for the patient group resulted in 14 patients with a neurodegenerative cognitive disorder (AD, FTD, LBD) and 13 patients with no arguments for an underlying neurodegenerative cause. Visual analysis resulted in equal specificity (0.70) for differentiating normal and abnormal cases between the two modalities, but in a higher sensitivity (0.93), confidence rating (0.64) and interobserver agreement for F-FDG PET compared with eASL. The same was true for assigning a specific differential diagnosis (sensitivity: and 0.39 for F-FDG PET and eASL, respectively). Semiquantitative analyses revealed prototypical patterns for AD and FTD, with both higher volumes of abnormality and intensity differences on F-FDG PET.

Conclusion: In a direct head-to-head comparison on a simultaneous GE Signa PET/MR, F-FDG PET performed better compared with ASL in terms of sensitivity and reader confidence, as well as volume and intensity of abnormalities. However, using pure semiquantitative analysis, similar diagnostic accuracy between the two modalities was obtained. Therefore, ASL may still serve as complement to neuroreceptor or protein deposition PET studies when a single simultaneous investigation is warranted.
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http://dx.doi.org/10.1007/s00259-020-04694-1DOI Listing
August 2020

Multivariate analysis reveals anatomical correlates of naming errors in primary progressive aphasia.

Neurobiol Aging 2020 04 20;88:71-82. Epub 2019 Dec 20.

Laboratory for Cognitive Neurology, Department of Neurosciences, KU Leuven, Leuven, Belgium; Neurology Department, University Hospitals Leuven, Leuven, Belgium.

Primary progressive aphasia (PPA) is an overarching term for a heterogeneous group of neurodegenerative diseases which affect language processing. Impaired picture naming has been linked to atrophy of the anterior temporal lobe in the semantic variant of PPA. Although atrophy of the anterior temporal lobe proposedly impairs picture naming by undermining access to semantic knowledge, picture naming also entails object recognition and lexical retrieval. Using multivariate analysis, we investigated whether cortical atrophy relates to different types of naming errors generated during picture naming in 43 PPA patients (13 semantic, 9 logopenic, 11 nonfluent, and 10 mixed variant). Omissions were associated with atrophy of the anterior temporal lobes. Semantic errors, for example, mistaking a rhinoceros for a hippopotamus, were associated with atrophy of the left mid and posterior fusiform cortex and the posterior middle and inferior temporal gyrus. Semantic errors and atrophy in these regions occurred in each PPA subtype, without major between-subtype differences. We propose that pathological changes to neural mechanisms associated with semantic errors occur across the PPA spectrum.
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http://dx.doi.org/10.1016/j.neurobiolaging.2019.12.016DOI Listing
April 2020

Necrosome complex detected in granulovacuolar degeneration is associated with neuronal loss in Alzheimer's disease.

Acta Neuropathol 2020 03 4;139(3):463-484. Epub 2019 Dec 4.

Laboratory for Neuropathology, Department of Imaging and Pathology, Leuven Brain Institute (LBI), KU Leuven (University of Leuven), O&N IV, Herestraat 49, box 1032, 3000, Leuven, Belgium.

Alzheimer's disease (AD) is characterized by a specific pattern of neuropathological changes, including extracellular amyloid β (Aβ) deposits, intracellular neurofibrillary tangles (NFTs), granulovacuolar degeneration (GVD) representing cytoplasmic vacuolar lesions, synapse dysfunction and neuronal loss. Necroptosis, a programmed form of necrosis characterized by the assembly of the necrosome complex composed of phosphorylated proteins, i.e. receptor-interacting serine/threonine-protein kinase 1 and 3 (pRIPK1 and pRIPK3) and mixed lineage kinase domain-like protein (pMLKL), has recently been shown to be involved in AD. However, it is not yet clear whether necrosome assembly takes place in brain regions showing AD-related neuronal loss and whether it is associated with AD-related neuropathological changes. Here, we analyzed brains of AD, pathologically defined preclinical AD (p-preAD) and non-AD control cases to determine the neuropathological characteristics and distribution pattern of the necrosome components. We demonstrated that all three activated necrosome components can be detected in GVD lesions (GVDn+, i.e. GVD with activated necrosome) in neurons, that they colocalize with classical GVD markers, such as pTDP-43 and CK1δ, and similarly to these markers detect GVD lesions. GVDn + neurons inversely correlated with neuronal density in the early affected CA1 region of the hippocampus and in the late affected frontal cortex layer III. Additionally, AD-related GVD lesions were associated with AD-defining parameters, showing the strongest correlation and partial colocalization with NFT pathology. Therefore, we conclude that the presence of the necrosome in GVD plays a role in AD, possibly by representing an AD-specific form of necroptosis-related neuron death. Hence, necroptosis-related neuron loss could be an interesting therapeutic target for treating AD.
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http://dx.doi.org/10.1007/s00401-019-02103-yDOI Listing
March 2020

Sources of well-being for older adults with and without dementia in residential care: relations to presence of meaning and life satisfaction.

Aging Ment Health 2021 01 15;25(1):170-178. Epub 2019 Nov 15.

KU Leuven, Leuven, Belgium.

Objectives: To explore what sources of well-being are rated meaningful by older adults in residential care and how they are related to two important well-being outcomes.

Method: Two cross-sectional questionnaire studies were conducted in a sample of care residents without cognitive disability ( = 329) and with Alzheimer's disease ( = 104). Structural equation modelling was used to test a hypothesized and exploratory model of different sources as predictors of presence of meaning in life (POM) and satisfaction with life (SWL).

Results: Family and Health were rated most meaningful by residents with and without dementia. In both studies, the hypothesized model showed adequate fit with the data. For cognitively intact residents, Personal Growth, Spirituality/Religion, and Interpersonal Relationships predicted POM, while Family and Leisure predicted SWL. Exploratory testing identified Leisure as a possible additional predictor of POM. For residents with Alzheimer's disease, Personal Growth and Society/Community predicted POM, while Family predicted SWL.

Conclusion: For older adults in residential care, many sources of well-being remain highly meaningful and some are directly related to the experience of meaning and life satisfaction. Both for residents with and without dementia, continued or increased investment in moments that foster personal growth and family relationships might be especially valuable.
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http://dx.doi.org/10.1080/13607863.2019.1691144DOI Listing
January 2021

Different aspects of Alzheimer's disease-related amyloid β-peptide pathology and their relationship to amyloid positron emission tomography imaging and dementia.

Acta Neuropathol Commun 2019 11 14;7(1):178. Epub 2019 Nov 14.

Department of Neurology, University of Bonn, Bonn, Germany.

Alzheimer's disease (AD)-related amyloid β-peptide (Aβ) pathology in the form of amyloid plaques and cerebral amyloid angiopathy (CAA) spreads in its topographical distribution, increases in quantity, and undergoes qualitative changes in its composition of modified Aβ species throughout the pathogenesis of AD. It is not clear which of these aspects of Aβ pathology contribute to AD progression and to what extent amyloid positron emission tomography (PET) reflects each of these aspects. To address these questions three cohorts of human autopsy cases (in total n = 271) were neuropathologically and biochemically examined for the topographical distribution of Aβ pathology (plaques and CAA), its quantity and its composition. These parameters were compared with neurofibrillary tangle (NFT) and neuritic plaque pathology, the degree of dementia and the results from [F]flutemetamol amyloid PET imaging in cohort 3. All three aspects of Aβ pathology correlated with one another, the estimation of Aβ pathology by [F]flutemetamol PET, AD-related NFT pathology, neuritic plaques, and with the degree of dementia. These results show that one aspect of Aβ pathology can be used to predict the other two, and correlates well with the development of dementia, advancing NFT and neuritic plaque pathology. Moreover, amyloid PET estimates all three aspects of Aβ pathology in-vivo. Accordingly, amyloid PET-based estimates for staging of amyloid pathology indicate the progression status of amyloid pathology in general and, in doing so, also of AD pathology. Only 7.75% of our cases deviated from this general association.
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http://dx.doi.org/10.1186/s40478-019-0837-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6854805PMC
November 2019

Brain Changes Induced by Electroconvulsive Therapy Are Broadly Distributed.

Biol Psychiatry 2020 03 25;87(5):451-461. Epub 2019 Jul 25.

Center for Multimodal Imaging and Genetics, University of California, San Diego, La Jolla, California; Department of Radiology, University of California, San Diego, La Jolla, California.

Background: Electroconvulsive therapy (ECT) is associated with volumetric enlargements of corticolimbic brain regions. However, the pattern of whole-brain structural alterations following ECT remains unresolved. Here, we examined the longitudinal effects of ECT on global and local variations in gray matter, white matter, and ventricle volumes in patients with major depressive disorder as well as predictors of ECT-related clinical response.

Methods: Longitudinal magnetic resonance imaging and clinical data from the Global ECT-MRI Research Collaboration (GEMRIC) were used to investigate changes in white matter, gray matter, and ventricle volumes before and after ECT in 328 patients experiencing a major depressive episode. In addition, 95 nondepressed control subjects were scanned twice. We performed a mega-analysis of single subject data from 14 independent GEMRIC sites.

Results: Volumetric increases occurred in 79 of 84 gray matter regions of interest. In total, the cortical volume increased by mean ± SD of 1.04 ± 1.03% (Cohen's d = 1.01, p < .001) and the subcortical gray matter volume increased by 1.47 ± 1.05% (d = 1.40, p < .001) in patients. The subcortical gray matter increase was negatively associated with total ventricle volume (Spearman's rank correlation ρ = -.44, p < .001), while total white matter volume remained unchanged (d = -0.05, p = .41). The changes were modulated by number of ECTs and mode of electrode placements. However, the gray matter volumetric enlargements were not associated with clinical outcome.

Conclusions: The findings suggest that ECT induces gray matter volumetric increases that are broadly distributed. However, gross volumetric increases of specific anatomically defined regions may not serve as feasible biomarkers of clinical response.
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http://dx.doi.org/10.1016/j.biopsych.2019.07.010DOI Listing
March 2020

S100 calcium-binding protein B in older patients with depression treated with electroconvulsive therapy.

Psychoneuroendocrinology 2019 12 24;110:104414. Epub 2019 Aug 24.

GGZ inGeest Specialized Mental Health Care, Department of Old Age Psychiatry, Oldenaller 1, 1081 HJ, Amsterdam, the Netherlands; Amsterdam UMC, Vrije Universiteit Amsterdam, Psychiatry, Amsterdam Public Health Research Institute and Neuroscience Amsterdam, De Boelelaan 1117, 1081 HV, Amsterdam, the Netherlands.

Background: Increasing evidence suggests that glial mediated disruption of neuroplasticity contributes to depression. S100 calcium-binding protein B (S100B) promotes neuronal protection in nanomolar concentrations. Studies on its possible role as a treatment outcome marker in affective disorders are limited. Recent evidence suggests a putative role for S100B as a state marker of illness activity as it is found elevated in episodes of major depression.

Aim: To investigate whether higher S100B is associated with favourable treatment outcome following electroconvulsive therapy (ECT) and to further explore whether S100B reflects a state marker of depression activity.

Methods: Serum S100B samples, at baseline and post-ECT and clinical assessments including Montgomery Åsberg Rating scales were collected in 91 older depressed patients (mean age: 73.0 years), referred for ECT. Change in pre- and post-ECT S100B was compared between remitters and nonremitters. Logistic and Cox regression analyses were used to determine whether S100B was associated with remission of depression.

Results: Patients with S100B levels in the intermediate tertile, that is, between 33 ng/L and 53 ng/L, had higher odds on remission, odds ratio: 5.5 (95%Confidence Interval (CI): 1.55-19.20, p = <0.01), and were more likely to remit from depression over time, hazard ratio: 1.96 (95%CI: 1.04-3.72, p = 0.04), compared with patients in the lowest tertile. There was no significant decrease in levels of S100B after ECT in both remitters and nonremitters.

Conclusion: Our findings demonstrate that patients with higher S100B levels at baseline were more likely to remit from depression suggesting an association between higher S100B and responsiveness to ECT. Next, S100B levels do not decrease after remission, suggesting S100B is not a state marker of depression. S100B is not capable of predicting treatment outcome by itself, further research may combine outcome markers.
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http://dx.doi.org/10.1016/j.psyneuen.2019.104414DOI Listing
December 2019

Age-dependent brain volume and neuropsychological changes after chemotherapy in breast cancer patients.

Hum Brain Mapp 2019 12 21;40(17):4994-5010. Epub 2019 Aug 21.

Department of Imaging & Pathology, KU Leuven, Leuven, Belgium.

This study investigated volumetric brain changes and cognitive performance in premenopausal and postmenopausal patients treated for early-stage breast cancer. Participants underwent elaborate neurocognitive assessments (neuropsychological testing, cognitive failure questionnaire, and high-resolution T1-weighted structural MRI) before and after chemotherapy. Volumetric brain changes were estimated, using longitudinal deformation-based morphometry, and correlated with cognitive changes. In total, 180 women participated in this study, of whom 72 patients with breast cancer had received adjuvant chemotherapy (C+), 49 patients did not receive chemotherapy (C-), and 59 healthy controls (HC). The population was categorized into two age groups: A young group who were premenopausal and younger than 52 years at baseline (n = 55C+/32C-/41HC), and an older group who were postmenopausal and older than 60 years (n = 17C+/17C-/18HC). Cognitive impairment occurred after chemotherapy in both young and older patients, although older patients showed more decline in processing speed (Trail making test b). White matter volume expansion was observed after chemotherapy, only significantly present in the younger subgroup of patients. In patients not treated with chemotherapy, diffuse gray and white matter volume reduction was observed. Less white matter expansion concurred with more cognitive decline (r > .349, p < .05). In conclusion, we found age-dependent cognitive decline and white matter volume changes in patients with breast cancer after chemotherapy, which could possibly be linked to neuroinflammatory processes. White matter expansion after chemotherapy, more pronounced in premenopausal patients, correlated with less cognitive decline. This suggests such expansion to be age-dependent, possibly caused by a protective response in the younger brain to chemotherapy-induced neurotoxicity.
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http://dx.doi.org/10.1002/hbm.24753DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6865635PMC
December 2019

Hippocampal volume change following ECT is mediated by rs699947 in the promotor region of VEGF.

Transl Psychiatry 2019 08 20;9(1):191. Epub 2019 Aug 20.

Department of Geriatric Psychiatry, University Psychiatric Center KU Leuven, Leuven, Belgium.

Several studies have shown that electroconvulsive therapy (ECT) results in increased hippocampal volume. It is likely that a multitude of mechanisms including neurogenesis, gliogenesis, synaptogenesis, angiogenesis, and vasculogenesis contribute to this volume increase. Neurotrophins, like vascular endothelial growth factor (VEGF) and brain-derived neurotrophic factor (BDNF) seem to play a crucial mediating role in several of these mechanisms. We hypothesized that two regulatory SNPs in the VEGF and BDNF gene influence the changes in hippocampal volume following ECT. We combined genotyping and brain MRI assessment in a sample of older adults suffering from major depressive disorder to test this hypothesis. Our results show an effect of rs699947 (in the promotor region of VEGF) on hippocampal volume changes following ECT. However, we did not find a clear effect of rs6265 (in BDNF). To the best of our knowledge, this is the first study investigating possible genetic mechanisms involved in hippocampal volume change during ECT treatment.
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http://dx.doi.org/10.1038/s41398-019-0530-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6702208PMC
August 2019