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Alzheimer Disease: HELP
Articles by John C. Van Swieten
Based on 41 articles published since 2010
(Why 41 articles?)
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Between 2010 and 2020, J. van Swieten wrote the following 41 articles about Alzheimer Disease.
 
+ Citations + Abstracts
Pages: 1 · 2
1 Editorial The role of the subgenual cingulate cortex in self-appraisal. 2013

van Swieten, John C / Pijnenburg, Yolande. · ·J Neurol Neurosurg Psychiatry · Pubmed #23033354.

ABSTRACT: -- No abstract --

2 Review Meta-analytic Review of Memory Impairment in Behavioral Variant Frontotemporal Dementia. 2018

Poos, Jackie M / Jiskoot, Lize C / Papma, Janne M / van Swieten, John C / van den Berg, Esther. ·Alzheimer Center and Department of Neurology, Erasmus University Medical Center, Rotterdam, the Netherlands. · Department of Radiology, Leiden University Medical Center, Leiden, the Netherlands. · Department of Clinical Genetics, VU Medical Center, Amsterdam, the Netherlands. ·J Int Neuropsychol Soc · Pubmed #29552997.

ABSTRACT: OBJECTIVES: A meta-analysis of the extent, nature and pattern of memory performance in behavioral variant frontotemporal dementia (bvFTD). Multiple observational studies have challenged the relative sparing of memory in bvFTD as stated in the current diagnostic criteria. METHODS: We performed a meta-analytic review covering the period 1967 to February 2017 of case-control studies on episodic memory in bvFTD versus control participants (16 studies, 383 patients, 603 control participants), and patients with bvFTD versus those with Alzheimer's disease (AD) (20 studies, 452 bvFTD, 874 AD). Differences between both verbal and non-verbal working memory, episodic memory learning and recall, and recognition memory were examined. Data were extracted from the papers and combined into a common metric measure of effect, Hedges' d. RESULTS: Patients with bvFTD show large deficits in memory performance compared to controls (Hedges' d -1.10; 95% confidence interval [CI] [-1.23, -0.95]), but perform significantly better than patients with AD (Hedges' d 0.85; 95% CI [0.69, 1.03]). Learning and recall tests differentiate best between patients with bvFTD and AD (p<.01). There is 37-62% overlap in test scores between the two groups. CONCLUSIONS: This study points to memory disorders in patients with bvFTD, with performance at an intermediate level between controls and patients with AD. This indicates that, instead of being an exclusion criterion for bvFTD diagnosis, memory deficits should be regarded as a potential integral part of the clinical spectrum. (JINS, 2018, 24, 593-605).

3 Article Genetic screening in early-onset Alzheimer's disease identified three novel presenilin mutations. 2020

Wong, Tsz Hang / Seelaar, Harro / Melhem, Shamiram / Rozemuller, Annemieke J M / van Swieten, John C. ·Alzheimer Center and Department of Neurology, Erasmus Medical Center, Rotterdam, the Netherlands. · Department of Pathology, VU University Medical Center, Amsterdam, the Netherlands. · Alzheimer Center and Department of Neurology, Erasmus Medical Center, Rotterdam, the Netherlands; Alzheimer Center and Department of Neurology, VU University Medical Center, Amsterdam, the Netherlands. Electronic address: j.c.vanswieten@erasmusmc.nl. ·Neurobiol Aging · Pubmed #30797548.

ABSTRACT: Mutations in presenilin 1 (PSEN1), presenilin 2 (PSEN2), and amyloid precursor protein (APP) are major genetic causes of early-onset Alzheimer's disease (EOAD). Clinical heterogeneity is frequently observed in patients with PSEN1 and PSEN2 mutations. Using whole exome sequencing, we screened a Dutch cohort of 68 patients with EOAD for rare variants in Mendelian Alzheimer's disease, frontotemporal dementia, and prion disease genes. We identified 3 PSEN1 and 2 PSEN2 variants. Three variants, 1 in PSEN1 (p.H21Profs*2) and both PSEN2 (p.A415S and p.M174I), were novel and absent in control exomes. These novel variants can be classified as probable pathogenic, except for PSEN1 (p.H21Profs*2) in which the pathogenicity is uncertain. The initial clinical symptoms between mutation carriers varied from behavioral problems to memory impairment. Our findings extend the mutation spectrum of EOAD and underline the clinical heterogeneity among PSEN1 and PSEN2 mutation carriers. Screening for Alzheimer's disease-causing genes is indicated in presenile dementia with an overlapping clinical diagnosis.

4 Article Multimodal MRI of grey matter, white matter, and functional connectivity in cognitively healthy mutation carriers at risk for frontotemporal dementia and Alzheimer's disease. 2019

Feis, Rogier A / Bouts, Mark J R J / Dopper, Elise G P / Filippini, Nicola / Heise, Verena / Trachtenberg, Aaron J / van Swieten, John C / van Buchem, Mark A / van der Grond, Jeroen / Mackay, Clare E / Rombouts, Serge A R B. ·Department of Radiology, Leiden University Medical Centre, Leiden, The Netherlands. r.a.feis@lumc.nl. · FMRIB, Oxford Centre for Functional Magnetic Resonance Imaging of the Brain, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK. r.a.feis@lumc.nl. · LIBC, Leiden Institute for Brain and Cognition, Leiden, The Netherlands. r.a.feis@lumc.nl. · Department of Radiology, Leiden University Medical Centre, Leiden, The Netherlands. · LIBC, Leiden Institute for Brain and Cognition, Leiden, The Netherlands. · Institute of Psychology, Leiden University, Leiden, The Netherlands. · Department of Neurology, Erasmus Medical Centre, Rotterdam, The Netherlands. · FMRIB, Oxford Centre for Functional Magnetic Resonance Imaging of the Brain, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK. · Department of Psychiatry, University of Oxford, Oxford, UK. ·BMC Neurol · Pubmed #31881858.

ABSTRACT: BACKGROUND: Frontotemporal dementia (FTD) and Alzheimer's disease (AD) are associated with divergent differences in grey matter volume, white matter diffusion, and functional connectivity. However, it is unknown at what disease stage these differences emerge. Here, we investigate whether divergent differences in grey matter volume, white matter diffusion, and functional connectivity are already apparent between cognitively healthy carriers of pathogenic FTD mutations, and cognitively healthy carriers at increased AD risk. METHODS: We acquired multimodal magnetic resonance imaging (MRI) brain scans in cognitively healthy subjects with (n=39) and without (n=36) microtubule-associated protein Tau (MAPT) or progranulin (GRN) mutations, and with (n=37) and without (n=38) apolipoprotein E ε4 (APOE4) allele. We evaluated grey matter volume using voxel-based morphometry, white matter diffusion using tract-based spatial statistics (TBSS), and region-to-network functional connectivity using dual regression in the default mode network and salience network. We tested for differences between the respective carriers and controls, as well as for divergence of those differences. For the divergence contrast, we additionally performed region-of-interest TBSS analyses in known areas of white matter diffusion differences between FTD and AD (i.e., uncinate fasciculus, forceps minor, and anterior thalamic radiation). RESULTS: MAPT/GRN carriers did not differ from controls in any modality. APOE4 carriers had lower fractional anisotropy than controls in the callosal splenium and right inferior fronto-occipital fasciculus, but did not show grey matter volume or functional connectivity differences. We found no divergent differences between both carrier-control contrasts in any modality, even in region-of-interest analyses. CONCLUSIONS: Concluding, we could not find differences suggestive of divergent pathways of underlying FTD and AD pathology in asymptomatic risk mutation carriers. Future studies should focus on asymptomatic mutation carriers that are closer to symptom onset to capture the first specific signs that may differentiate between FTD and AD.

5 Article CSF placental growth factor - a novel candidate biomarker of frontotemporal dementia. 2019

Hansson, Oskar / Santillo, Alexander F / Meeter, Lieke H / Nilsson, Karin / Landqvist Waldö, Maria / Nilsson, Christer / Blennow, Kaj / van Swieten, John C / Janelidze, Shorena. ·Clinical Memory Research Unit Department of Clinical Sciences Malmö Lund University Malmö Sweden. · Memory Clinic Skåne University Hospital Malmö Sweden. · Department of Neurology Erasmus Medical Center Rotterdam The Netherlands. · Clinical Sciences Helsingborg Department of Clinical Sciences Lund University Lund Sweden. · Department of Neurology Skåne University Hospital Lund Sweden. · Department of Psychiatry and Neurochemistry The Sahlgrenska Academy at the University of Gothenburg Mölndal Sweden. · Clinical Neurochemistry Laboratory Sahlgrenska University Hospital Mölndal Sweden. · Department of Clinical Genetics VU University Medical Center Amsterdam The Netherlands. ·Ann Clin Transl Neurol · Pubmed #31139684.

ABSTRACT: Objective: Diagnosis of frontotemporal dementia (FTD) is complicated by the overlap of clinical symptoms with other dementia disorders. Development of robust fluid biomarkers is critical to improve the diagnostic work-up of FTD. Methods: CSF concentrations of placental growth factor (PlGF) were measured in the discovery cohort including patients with FTD ( Results: In the discovery cohort, MCI, MCI-AD, AD dementia, DLB-PDD, VaD, and FTD patients all showed increased CSF levels of PlGF compared with controls (sMCI Interpretation: CSF PlGF is increased in FTD compared with other dementia disorders, MCI, and healthy controls and might be useful as a diagnostic biomarker of FTD.

6 Article Early recognition and treatment of neuropsychiatric symptoms to improve quality of life in early Alzheimer's disease: protocol of the BEAT-IT study. 2019

Eikelboom, Willem S / Singleton, Ellen / van den Berg, Esther / Coesmans, Michiel / Mattace Raso, Francesco / van Bruchem, Rozemarijn L / Goudzwaard, Jeannette A / de Jong, Frank Jan / Koopmanschap, Marc / den Heijer, Tom / Driesen, Jan J M / Vroegindeweij, Lilian J H M / Thomeer, Elsbeth C / Hoogers, Susanne E / Dijkstra, Anke A / Zuidema, Sytse U / Pijnenburg, Yolande A L / Scheltens, Philip / van Swieten, John C / Ossenkoppele, Rik / Papma, Janne M. ·Department of Neurology, Erasmus MC University Medical Center, PO Box 2040, 3000 CA, Rotterdam, the Netherlands. · Department of Neurology, Alzheimer Center Amsterdam, Amsterdam University Medical Center, PO Box 7057, 1007 MB, Amsterdam, the Netherlands. · Department of Psychiatry, Erasmus MC University Medical Center, PO Box 2040, 3000 CA, Rotterdam, the Netherlands. · Department of Internal Medicine, Erasmus MC University Medical Center, PO Box 2040, 3000 CA, Rotterdam, the Netherlands. · Erasmus School of Health Policy & Management, Erasmus University, PO Box 1738, 3000 DR, Rotterdam, the Netherlands. · Department of Neurology, Franciscus Gasthuis, PO Box 10900, 3004 BA, Rotterdam, the Netherlands. · Department of Neurology, Franciscus Vlietland, PO Box 215, 3100 AE, Schiedam, the Netherlands. · Department of Neurology, Het Van Weel-Bethesda Ziekenhuis, PO Box 153, 3240 AD, Dirksland, the Netherlands. · Department of Neurology, Maasstad Hospital, PO Box 9100, 3007 AC, Rotterdam, the Netherlands. · Department of Neurology, Spijkenisse Medical Center, PO Box 777, 3200 GA, Spijkenisse, the Netherlands. · Department of Anatomy and Neurosciences, Amsterdam University Medical Center, PO Box 7057, 1007 MB, Amsterdam, the Netherlands. · Department of General Practice and Elderly Care Medicine, University of Groningen, University Medical Center Groningen, PO Box 30,001, 9700 RB, Groningen, the Netherlands. · Clinical Memory Research Unit, Lund University, Simrisbanvägen 14, 212 24, Malmö, Sweden. · Department of Neurology, Erasmus MC University Medical Center, PO Box 2040, 3000 CA, Rotterdam, the Netherlands. j.papma@erasmusmc.nl. ·Alzheimers Res Ther · Pubmed #31122267.

ABSTRACT: BACKGROUND: Neuropsychiatric symptoms (NPS) are very common in patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD) dementia and are associated with various disadvantageous clinical outcomes including a negative impact on quality of life, caregiver burden, and accelerated disease progression. Despite growing evidence of the efficacy of (non)pharmacological interventions to reduce these symptoms, NPS remain underrecognized and undertreated in memory clinics. The BEhavioural symptoms in Alzheimer's disease Towards early Identification and Treatment (BEAT-IT) study is developed to (1) investigate the neurobiological etiology of NPS in AD and (2) study the effectiveness of the Describe, Investigate, Create, Evaluate (DICE) approach to structure and standardize the current care of NPS in AD. By means of the DICE method, we aim to improve the quality of life of AD patients with NPS and their caregivers who visit the memory clinic. This paper describes the protocol for the intervention study that incorporates the latter aim. METHODS: We aim to enroll a total of 150 community-dwelling patients with MCI or AD and their caregivers in two waves. First, we will recruit a control group who will receive care as usual. Next, the second wave of participants will undergo the DICE method. This approach consists of the following steps: (1) describe the context in which NPS occur, (2) investigate the possible causes, (3) create and implement a treatment plan, and (4) evaluate whether these interventions are effective. Primary outcomes are the quality of life of patients and their caregivers. Secondary outcomes include NPS change, caregiver burden, caregivers' confidence managing NPS, psychotropic medication use, the experiences of patients and caregivers who underwent the DICE method, and the cost-effectiveness of the intervention. CONCLUSIONS: This paper describes the protocol of an intervention study that is part of the BEAT-IT study and aims to improve current recognition and treatment of NPS in AD by structuring and standardizing the detection and treatment of NPS in AD using the DICE approach. TRIAL REGISTRATION: The trial was registered on the Netherlands Trial Registry ( NTR7459 ); registered 6 September 2018.

7 Article Exploring quantitative group-wise differentiation of Alzheimer's disease and behavioural variant frontotemporal dementia using tract-specific microstructural white matter and functional connectivity measures at multiple time points. 2019

Meijboom, R / Steketee, R M E / Ham, L S / Mantini, D / Bron, E E / van der Lugt, A / van Swieten, J C / Smits, M. ·Department of Radiology and Nuclear Medicine, Erasmus MC - University Medical Centre Rotterdam, Rotterdam, The Netherlands. · Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom. · Research Center for Motor Control and Neuroplasticity, KU Leuven, Leuven, Belgium. · Functional Neuroimaging Laboratory, IRCCS San Camillo Hospital Foundation, Lido, Italy. · Biomedical Imaging Group Rotterdam - Departments of Medical Informatics and Radiology, Erasmus MC - University Medical Centre Rotterdam, Rotterdam, The Netherlands. · Department of Neurology, Erasmus MC - University Medical Centre Rotterdam, Rotterdam, The Netherlands. · Department of Radiology and Nuclear Medicine, Erasmus MC - University Medical Centre Rotterdam, Rotterdam, The Netherlands. marion.smits@erasmusmc.nl. ·Eur Radiol · Pubmed #30859283.

ABSTRACT: OBJECTIVES: This study explored group-wise quantitative measures of tract-specific white matter (WM) microstructure and functional default mode network (DMN) connectivity to establish an initial indication of their clinical applicability for early-stage and follow-up differential diagnosis of Alzheimer's disease (AD) and behavioural variant frontotemporal dementia (bvFTD). METHODS: Eleven AD and 12 bvFTD early-stage patients and 18 controls underwent diffusion tensor imaging and resting state functional magnetic resonance imaging at 3 T. All AD and 6 bvFTD patients underwent the same protocol at 1-year follow-up. Functional connectivity measures of DMN and WM tract-specific diffusivity measures were determined for all groups. Exploratory analyses were performed to compare all measures between the three groups at baseline and between patients at follow-up. Additionally, the difference between baseline and follow-up diffusivity measures in AD and bvFTD patients was compared. RESULTS: Functional connectivity of the DMN was not different between groups at baseline and at follow-up. Diffusion abnormalities were observed widely in bvFTD and regionally in the hippocampal cingulum in AD. The extent of the differences between bvFTD and AD was diminished at follow-up, yet abnormalities were still more pronounced in bvFTD. The rate of change was similar in bvFTD and AD. CONCLUSIONS: This study provides a tentative indication that quantitative tract-specific microstructural WM abnormalities, but not quantitative functional connectivity of the DMN, may aid early-stage and follow-up differential diagnosis of bvFTD and AD. Specifically, pronounced microstructural changes in anterior WM tracts may characterise bvFTD, whereas microstructural abnormalities of the hippocampal cingulum may characterise AD. KEY POINTS: • The clinical applicability of quantitative brain imaging measures for early-stage and follow-up differential diagnosis of dementia subtypes was explored using a group-wise approach. • Quantitative tract-specific microstructural white matter abnormalities, but not quantitative functional connectivity of the default mode network, may aid early-stage and follow-up differential diagnosis of behavioural variant frontotemporal dementia and Alzheimer's disease. • Pronounced microstructural white matter (WM) changes in anterior WM tracts characterise behavioural variant frontotemporal dementia, whereas microstructural WM abnormalities of the hippocampal cingulum in the absence of other WM changes characterise Alzheimer's disease.

8 Article Hippocampal transcriptome profiling combined with protein-protein interaction analysis elucidates Alzheimer's disease pathways and genes. 2019

van Rooij, Jeroen G J / Meeter, Lieke H H / Melhem, Shami / Nijholt, Diana A T / Wong, Tsz Hang / Anonymous250971 / Rozemuller, Annemieke / Uitterlinden, Andre G / van Meurs, Joyce G / van Swieten, John C. ·Department of Neurology, Erasmus Medical Center, Rotterdam, the Netherlands; Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands. Electronic address: j.vanrooij@erasmusmc.nl. · Department of Neurology, Erasmus Medical Center, Rotterdam, the Netherlands. · Netherlands Institute for Neuroscience, Amsterdam, the Netherlands. · Department of Pathology, VU University Medical Center, Amsterdam, the Netherlands. · Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands. ·Neurobiol Aging · Pubmed #30497016.

ABSTRACT: Knowledge about the molecular mechanisms driving Alzheimer's disease (AD) is still limited. To learn more about AD biology, we performed whole transcriptome sequencing on the hippocampus of 20 AD cases and 10 age- and sex-matched cognitively healthy controls. We observed 2716 differentially expressed genes, of which 48% replicated in a second data set of 84 AD cases and 33 controls. We used an integrative network-based approach for combining transcriptomic and protein-protein interaction data to find differentially expressed gene modules that may reflect key processes in AD biology. A total of 735 differentially expressed genes were clustered into 33 modules, of which 82% replicated in a second data set, highlighting the robustness of this approach. These 27 modules were enriched for signal transduction, transport, response to stimulus, and several organic and cellular metabolic pathways. Ten modules interacted with previously described AD genes. Our study indicates that analyzing RNA-expression data based on annotated gene modules is more robust than on individual genes. We provide a comprehensive overview of the biological processes involved in AD, and the detected differentially expressed gene modules may provide a molecular basis for future research into mechanisms underlying AD.

9 Article EIF2AK3 variants in Dutch patients with Alzheimer's disease. 2019

Wong, Tsz Hang / van der Lee, Sven J / van Rooij, Jeroen G J / Meeter, Lieke H H / Frick, Petra / Melhem, Shamiram / Seelaar, Harro / Ikram, M Arfan / Rozemuller, Annemieke J / Holstege, Henne / Hulsman, Marc / Uitterlinden, Andre / Neumann, Manuela / Hoozemans, Jeroen J M / van Duijn, Cornelia M / Rademakers, Rosa / van Swieten, John C. ·Alzheimer Center and Department of Neurology, Erasmus Medical Center, Rotterdam, The Netherlands. · Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands. · Alzheimer Center and Department of Neurology, Erasmus Medical Center, Rotterdam, The Netherlands; Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands. · DZNE, German Centre for Neurodegenerative Disease, Tübingen, Germany. · Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands. · Alzheimer Center, Department of Neurology, VU University Medical Center, Amsterdam, The Netherlands; Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands. · Alzheimer Center, Department of Neurology, VU University Medical Center, Amsterdam, The Netherlands; Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands; Delft Bioinformatics Lab, Delft University of Technology, Delft, The Netherlands. · Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands. · DZNE, German Centre for Neurodegenerative Disease, Tübingen, Germany; Department of Neuropathology, University of Tübingen, Tübingen, Germany. · Department of Neuroscience, Mayo Clinic Florida, Jacksonville, FL, USA. · Alzheimer Center and Department of Neurology, Erasmus Medical Center, Rotterdam, The Netherlands; Alzheimer Center, Department of Neurology, VU University Medical Center, Amsterdam, The Netherlands. Electronic address: j.c.vanswieten@erasmusmc.nl. ·Neurobiol Aging · Pubmed #30314817.

ABSTRACT: Next-generation sequencing has contributed to our understanding of the genetics of Alzheimer's disease (AD) and has explained a substantial part of the missing heritability of familial AD. We sequenced 19 exomes from 8 Dutch families with a high AD burden and identified EIF2AK3, encoding for protein kinase RNA-like endoplasmic reticulum kinase (PERK), as a candidate gene. Gene-based burden analysis in a Dutch AD exome cohort containing 547 cases and 1070 controls showed a significant association of EIF2AK3 with AD (OR 1.84 [95% CI 1.07-3.17], p-value 0.03), mainly driven by the variant p.R240H. Genotyping of this variant in an additional cohort from the Rotterdam Study showed a trend toward association with AD (p-value 0.1). Immunohistochemical staining with pPERK and peIF2α of 3 EIF2AK3 AD carriers showed an increase in hippocampal neuronal cells expressing these proteins compared with nondemented controls, but no difference was observed in AD noncarriers. This study suggests that rare variants in EIF2AK3 may be associated with disease risk in AD.

10 Article Neuropsychiatric Symptoms Complicating the Diagnosis of Alzheimer's Disease: A Case Report. 2018

Eikelboom, Willem S / van Rooij, Jeroen G J / van den Berg, Esther / Coesmans, Michiel / Jiskoot, Lize C / Singleton, Ellen / Ossenkoppele, Rik / van Swieten, John C / Seelaar, Harro / Papma, Janne M. ·Department of Neurology, Erasmus MC, University Medical Center, Rotterdam, the Netherlands. · Department of Psychiatry, Erasmus MC, University Medical Center, Rotterdam, the Netherlands. · Department of Neurology, VUmc Alzheimer Center, Amsterdam, the Netherlands. · Clinical Memory Research Unit, Lund University, Malmö, Sweden. ·J Alzheimers Dis · Pubmed #30412494.

ABSTRACT: Neuropsychiatric symptoms (NPS) are increasingly recognized as a core element of Alzheimer's disease (AD); however, clinicians still consider AD primarily as a cognitive disorder. We describe a case in which the underrecognition of NPS as part of AD resulted in substantial delay of an AD diagnosis, a wrong psychiatric diagnosis, and the organization of inappropriate care. The aim of this paper is to acknowledge NPS as an (early) manifestation of AD and to suggest features that may point toward underlying AD in older adults with late-life behavioral changes.

11 Article Uncovering the heterogeneity and temporal complexity of neurodegenerative diseases with Subtype and Stage Inference. 2018

Young, Alexandra L / Marinescu, Razvan V / Oxtoby, Neil P / Bocchetta, Martina / Yong, Keir / Firth, Nicholas C / Cash, David M / Thomas, David L / Dick, Katrina M / Cardoso, Jorge / van Swieten, John / Borroni, Barbara / Galimberti, Daniela / Masellis, Mario / Tartaglia, Maria Carmela / Rowe, James B / Graff, Caroline / Tagliavini, Fabrizio / Frisoni, Giovanni B / Laforce, Robert / Finger, Elizabeth / de Mendonça, Alexandre / Sorbi, Sandro / Warren, Jason D / Crutch, Sebastian / Fox, Nick C / Ourselin, Sebastien / Schott, Jonathan M / Rohrer, Jonathan D / Alexander, Daniel C / Anonymous14351124 / Anonymous14361124. ·Centre for Medical Image Computing, University College London, London, WC1E 6BT, UK. alexandra.young@ucl.ac.uk. · Department of Computer Science, University College London, London, WC1E 6BT, UK. alexandra.young@ucl.ac.uk. · Centre for Medical Image Computing, University College London, London, WC1E 6BT, UK. · Department of Computer Science, University College London, London, WC1E 6BT, UK. · Dementia Research Centre, Institute of Neurology, University College London, London, WC1N 3BG, UK. · Leonard Wolfson Experimental Neurology Centre, UCL Institute of Neurology, University College London, London, WC1N 3BG, UK. · Neuroradiological Academic Unit, Department of Brain Repair and Rehabilitation, UCL Institute of Neurology, University College London, London, WC1N 3BG, UK. · School of Biomedical Engineering and Imaging Sciences, King's College London, London, WC2R 2LS, UK. · Erasmus Medical Center, 3000 CA, Rotterdam, The Netherlands. · Neurology Unit, Department of Clinical and Experimental Sciences, University of Brescia, 25121, Brescia, Italy. · Dept. of Physiopathology and Transplantation, University of Milan, Centro Dino Ferrari, 20122, Milan, Italy. · Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, via F. Sforza, 35, 20122, Milan, Italy. · Sunnybrook Health Sciences Centre, University of Toronto, ON, M4N 3M5, Canada. · Centre for Research in Neurodegenerative Diseases, University of Toronto, ON, Toronto, M5T 0S8, Canada. · University of Cambridge, Department of Clinical Neurosciences, Cambridge, CB2 0SZ, UK. · Karolinska Institutet, 171 77, Solna, Sweden. · Istituto Neurologico Carlo Besta, 20133, Milan, Italy. · University Hospitals and University of Geneva, Geneva, Switzerland. · Université Laval, Quebec, QC, G1V 0A6, Canada. · University of Western Ontario, London, ON, N6A 3K7, Canada. · Faculdade de Medicina, Universidade de Lisboa, 1649-028, Lisboa, Portugal. · Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, 50121, Florence, Italy. · IRCCS Fondazione Don Carlo Gnocchi, Florence, Italy. ·Nat Commun · Pubmed #30323170.

ABSTRACT: The heterogeneity of neurodegenerative diseases is a key confound to disease understanding and treatment development, as study cohorts typically include multiple phenotypes on distinct disease trajectories. Here we introduce a machine-learning technique-Subtype and Stage Inference (SuStaIn)-able to uncover data-driven disease phenotypes with distinct temporal progression patterns, from widely available cross-sectional patient studies. Results from imaging studies in two neurodegenerative diseases reveal subgroups and their distinct trajectories of regional neurodegeneration. In genetic frontotemporal dementia, SuStaIn identifies genotypes from imaging alone, validating its ability to identify subtypes; further the technique reveals within-genotype heterogeneity. In Alzheimer's disease, SuStaIn uncovers three subtypes, uniquely characterising their temporal complexity. SuStaIn provides fine-grained patient stratification, which substantially enhances the ability to predict conversion between diagnostic categories over standard models that ignore subtype (p = 7.18 × 10

12 Article Single Subject Classification of Alzheimer's Disease and Behavioral Variant Frontotemporal Dementia Using Anatomical, Diffusion Tensor, and Resting-State Functional Magnetic Resonance Imaging. 2018

Bouts, Mark J R J / Möller, Christiane / Hafkemeijer, Anne / van Swieten, John C / Dopper, Elise / van der Flier, Wiesje M / Vrenken, Hugo / Wink, Alle Meije / Pijnenburg, Yolande A L / Scheltens, Philip / Barkhof, Frederik / Schouten, Tijn M / de Vos, Frank / Feis, Rogier A / van der Grond, Jeroen / de Rooij, Mark / Rombouts, Serge A R B. ·Institute of Psychology, Leiden University, Leiden, The Netherlands. · Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands. · Leiden Institute for Brain and Cognition, Leiden University, Leiden, The Netherlands. · Department of Clinical Genetics, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands. · Department of Neurology, Erasmus Medical Center, Rotterdam, The Netherlands. · Alzheimer Center and Department of Neurology, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands. · Department of Epidemiology and Biostatistics, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands. · Department of Radiology and Nuclear Medicine, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands. · Department of Physics and Medical Technology, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands. · Institute of Neurology and Healthcare Engineering, University College London, London, UK. ·J Alzheimers Dis · Pubmed #29614652.

ABSTRACT: BACKGROUND/OBJECTIVE: Overlapping clinical symptoms often complicate differential diagnosis between patients with Alzheimer's disease (AD) and behavioral variant frontotemporal dementia (bvFTD). Magnetic resonance imaging (MRI) reveals disease specific structural and functional differences that aid in differentiating AD from bvFTD patients. However, the benefit of combining structural and functional connectivity measures to-on a subject-basis-differentiate these dementia-types is not yet known. METHODS: Anatomical, diffusion tensor (DTI), and resting-state functional MRI (rs-fMRI) of 30 patients with early stage AD, 23 with bvFTD, and 35 control subjects were collected and used to calculate measures of structural and functional tissue status. All measures were used separately or selectively combined as predictors for training an elastic net regression classifier. Each classifier's ability to accurately distinguish dementia-types was quantified by calculating the area under the receiver operating characteristic curves (AUC). RESULTS: Highest AUC values for AD and bvFTD discrimination were obtained when mean diffusivity, full correlations between rs-fMRI-derived independent components, and fractional anisotropy (FA) were combined (0.811). Similarly, combining gray matter density (GMD), FA, and rs-fMRI correlations resulted in highest AUC of 0.922 for control and bvFTD classifications. This, however, was not observed for control and AD differentiations. Classifications with GMD (0.940) and a GMD and DTI combination (0.941) resulted in similar AUC values (p = 0.41). CONCLUSION: Combining functional and structural connectivity measures improve dementia-type differentiations and may contribute to more accurate and substantiated differential diagnosis of AD and bvFTD patients. Imaging protocols for differential diagnosis may benefit from also including DTI and rs-fMRI.

13 Article The Effect of Predictive Testing in Adult-Onset Neurodegenerative Diseases on Social and Personal Life. 2018

Cohn-Hokke, Petra E / van Swieten, John C / Pijnenburg, Yolande A L / Tibben, Aad / Meijers-Heijboer, Hanne / Kievit, Anneke. ·Department of Clinical Genetics, VU University Medical Center, Amsterdam, 1081 HV, The Netherlands. · Alzheimer Center, Department of Neurology, VU University Medical Center, Neuroscience Campus Amsterdam, Amsterdam, 1081 HV, The Netherlands. · Department of Neurology, Erasmus Medical Center, Rotterdam, 3015 CE, The Netherlands. · Department of Clinical Genetics, Leiden University Medical Center, Leiden, 2333 ZA, The Netherlands. · Department of Clinical Genetics, Erasmus Medical Center, Wytemaweg 80, 3015 CE, Rotterdam, The Netherlands. j.a.kievit@erasmusmc.nl. ·J Genet Couns · Pubmed #29270849.

ABSTRACT: Follow-up studies on predictive testing for hereditary neurodegenerative diseases mainly focussed on psychological outcomes. We investigated whether the social and personal life of mutation carriers differ negatively from non-carriers and untested at-risk individuals. Asymptomatic individuals (≥ 35 years) who received a genetic test result for Huntington's disease, frontotemporal dementia or Alzheimer's disease more than 2 years before the onset of the study and untested subjects at 50% risk were invited to complete a questionnaire and an additional questionnaire with extra or adjusted items. Of the 283 selected individuals, 115 returned a positive informed consent (response rate 39.6%). Of these, 17 carriers, 30 non-carriers and 27 untested persons (n = 74) fulfilled the criteria and completed both questionnaires. We found no significant differences in employment, financial situation and lifestyle or anxiety and depression between carriers and non-carriers or untested individuals at risk. Carriers were more often single and childless, though these differences were not significant. The findings of this study suggest that the result of predictive testing on adult-onset neurodegenerative diseases does not have a large negative effect on social and personal life, although these observations should be interpreted with caution because of the small number of participants and low response rate.

14 Article Characterization of pathogenic SORL1 genetic variants for association with Alzheimer's disease: a clinical interpretation strategy. 2017

Holstege, Henne / van der Lee, Sven J / Hulsman, Marc / Wong, Tsz Hang / van Rooij, Jeroen Gj / Weiss, Marjan / Louwersheimer, Eva / Wolters, Frank J / Amin, Najaf / Uitterlinden, André G / Hofman, Albert / Ikram, M Arfan / van Swieten, John C / Meijers-Heijboer, Hanne / van der Flier, Wiesje M / Reinders, Marcel Jt / van Duijn, Cornelia M / Scheltens, Philip. ·Alzheimer Center, Department of Neurology, VU University Medical Center, Neuroscience Campus Amsterdam, Amsterdam, The Netherlands. · Department of Clinical Genetics, VU University Medical Center, Neuroscience Campus Amsterdam, Amsterdam, The Netherlands. · Delft Bioinformatics Lab, Delft University of Technology, Delft, The Netherlands. · Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands. · Department of Neurology, Erasmus Medical Center, Rotterdam, The Netherlands. · Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands. · Netherlands Consortium on Health Aging and National Genomics Initiative, Leiden, The Netherlands. · Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA. · Department of Radiology, Erasmus MC University Medical Center, Rotterdam, The Netherlands. · Department of Epidemiology &Biostatistics, VU University Medical Center, Neuroscience Campus Amsterdam, Amsterdam, The Netherlands. · Netherlands Metabolomics Centre, Leiden University, Leiden, The Netherlands. ·Eur J Hum Genet · Pubmed #28537274.

ABSTRACT: Accumulating evidence suggests that genetic variants in the SORL1 gene are associated with Alzheimer disease (AD), but a strategy to identify which variants are pathogenic is lacking. In a discovery sample of 115 SORL1 variants detected in 1908 Dutch AD cases and controls, we identified the variant characteristics associated with SORL1 variant pathogenicity. Findings were replicated in an independent sample of 103 SORL1 variants detected in 3193 AD cases and controls. In a combined sample of the discovery and replication samples, comprising 181 unique SORL1 variants, we developed a strategy to classify SORL1 variants into five subtypes ranging from pathogenic to benign. We tested this pathogenicity screen in SORL1 variants reported in two independent published studies. SORL1 variant pathogenicity is defined by the Combined Annotation Dependent Depletion (CADD) score and the minor allele frequency (MAF) reported by the Exome Aggregation Consortium (ExAC) database. Variants predicted strongly damaging (CADD score >30), which are extremely rare (ExAC-MAF <1 × 10

15 Article Distinct binding of PET ligands PBB3 and AV-1451 to tau fibril strains in neurodegenerative tauopathies. 2017

Ono, Maiko / Sahara, Naruhiko / Kumata, Katsushi / Ji, Bin / Ni, Ruiqing / Koga, Shunsuke / Dickson, Dennis W / Trojanowski, John Q / Lee, Virginia M-Y / Yoshida, Mari / Hozumi, Isao / Yoshiyama, Yasumasa / van Swieten, John C / Nordberg, Agneta / Suhara, Tetsuya / Zhang, Ming-Rong / Higuchi, Makoto. ·National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan. · Department of Molecular Neuroimaging, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan. · Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm 14157, Sweden. · Department of Neuroscience, Mayo Clinic, Jacksonville, Florida 32224, USA. · Center for Neurodegenerative Disease Research and Institute on Aging, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. · Department of Neuropathology, Institute for Medical Science of Aging, Aichi Medical University, Nagakute 480-1195, Japan. · Laboratory of Medical Therapeutics and Molecular Therapeutics, Gifu Pharmaceutical University, Gifu 501-1196, Japan. · Department of Neurology, Chiba-East National Hospital, Chiba 260-8712, Japan. · Department of Neurology, Erasmus Medical Center, Rotterdam 3015 CE, The Netherlands. ·Brain · Pubmed #28087578.

ABSTRACT: Diverse neurodegenerative disorders are characterized by deposition of tau fibrils composed of conformers (i.e. strains) unique to each illness. The development of tau imaging agents has enabled visualization of tau lesions in tauopathy patients, but the modes of their binding to different tau strains remain elusive. Here we compared binding of tau positron emission tomography ligands, PBB3 and AV-1451, by fluorescence, autoradiography and homogenate binding assays with homologous and heterologous blockades using tauopathy brain samples. Fluorescence microscopy demonstrated intense labelling of non-ghost and ghost tangles with PBB3 and AV-1451, while dystrophic neurites were more clearly detected by PBB3 in brains of Alzheimer's disease and diffuse neurofibrillary tangles with calcification, characterized by accumulation of all six tau isoforms. Correspondingly, partially distinct distributions of autoradiographic labelling of Alzheimer's disease slices with 11C-PBB3 and 18F-AV-1451 were noted. Neuronal and glial tau lesions comprised of 4-repeat isoforms in brains of progressive supranuclear palsy, corticobasal degeneration and familial tauopathy due to N279K tau mutation and 3-repeat isoforms in brains of Pick's disease and familial tauopathy due to G272V tau mutation were sensitively detected by PBB3 fluorescence in contrast to very weak AV-1451 signals. This was in line with moderate 11C-PBB3 versus faint 18F-AV-1451 autoradiographic labelling of these tissues. Radioligand binding to brain homogenates revealed multiple binding components with differential affinities for 11C-PBB3 and 18F-AV-1451, and higher availability of binding sites on progressive supranuclear palsy tau deposits for 11C-PBB3 than 18F-AV-1451. Our data indicate distinct selectivity of PBB3 compared to AV-1451 for diverse tau fibril strains. This highlights the more robust ability of PBB3 to capture wide-range tau pathologies.

16 Article Multiparametric computer-aided differential diagnosis of Alzheimer's disease and frontotemporal dementia using structural and advanced MRI. 2017

Bron, Esther E / Smits, Marion / Papma, Janne M / Steketee, Rebecca M E / Meijboom, Rozanna / de Groot, Marius / van Swieten, John C / Niessen, Wiro J / Klein, Stefan. ·Biomedical Imaging Group Rotterdam, Departments of Medical Informatics and Radiology & Nuclear Medicine, Erasmus MC, Office Na2502, P.O. Box 2040, 3000 CA, Rotterdam, The Netherlands. e.bron@erasmusmc.nl. · Department of Radiology & Nuclear Medicine, Erasmus MC, Rotterdam, The Netherlands. · Department of Neurology, Erasmus MC, Rotterdam, The Netherlands. · Biomedical Imaging Group Rotterdam, Departments of Medical Informatics and Radiology & Nuclear Medicine, Erasmus MC, Office Na2502, P.O. Box 2040, 3000 CA, Rotterdam, The Netherlands. · Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands. · Imaging Physics, Applied Sciences, Delft University of Technology, Delft, The Netherlands. ·Eur Radiol · Pubmed #27986990.

ABSTRACT: OBJECTIVES: To investigate the added diagnostic value of arterial spin labelling (ASL) and diffusion tensor imaging (DTI) to structural MRI for computer-aided classification of Alzheimer's disease (AD), frontotemporal dementia (FTD), and controls. METHODS: This retrospective study used MRI data from 24 early-onset AD and 33 early-onset FTD patients and 34 controls (CN). Classification was based on voxel-wise feature maps derived from structural MRI, ASL, and DTI. Support vector machines (SVMs) were trained to classify AD versus CN (AD-CN), FTD-CN, AD-FTD, and AD-FTD-CN (multi-class). Classification performance was assessed by the area under the receiver-operating-characteristic curve (AUC) and accuracy. Using SVM significance maps, we analysed contributions of brain regions. RESULTS: Combining ASL and DTI with structural MRI resulted in higher classification performance for differential diagnosis of AD and FTD (AUC = 84%; p = 0.05) than using structural MRI by itself (AUC = 72%). The performance of ASL and DTI themselves did not improve over structural MRI. The classifications were driven by different brain regions for ASL and DTI than for structural MRI, suggesting complementary information. CONCLUSIONS: ASL and DTI are promising additions to structural MRI for classification of early-onset AD, early-onset FTD, and controls, and may improve the computer-aided differential diagnosis on a single-subject level. KEY POINTS: • Multiparametric MRI is promising for computer-aided diagnosis of early-onset AD and FTD. • Diagnosis is driven by different brain regions when using different MRI methods. • Combining structural MRI, ASL, and DTI may improve differential diagnosis of dementia.

17 Article Rare Genetic Variant in SORL1 May Increase Penetrance of Alzheimer's Disease in a Family with Several Generations of APOE-ɛ4 Homozygosity. 2017

Louwersheimer, Eva / Cohn-Hokke, Petra E / Pijnenburg, Yolande A L / Weiss, Marjan M / Sistermans, Erik A / Rozemuller, Annemieke J / Hulsman, Marc / van Swieten, John C / van Duijn, Cock M / Barkhof, Frederik / Koene, Teddy / Scheltens, Philip / Van der Flier, Wiesje M / Holstege, Henne. ·Alzheimer Center and Department of Neurology, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands. · Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands. · Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands. · Delft Bioinformatics Laboratory, Delft University of Technology, Delft, The Netherlands. · Department of Neurology, Erasmus Medical Center, Rotterdam, The Netherlands. · Genetic Epidemiology Unit, Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands. · Department of Radiology and Nuclear Medicine, VU University Medical Center, Amsterdam, The Netherlands. · Institutes of Neurology and Healthcare Engineering, UCL, London, UK. · Alzheimer Center & Department of Medical Psychology, VU University Medical Center, Amsterdam, The Netherlands. · Department of Epidemiology & Biostatistics, VU University Medical Center, Amsterdam, The Netherlands. ·J Alzheimers Dis · Pubmed #27911290.

ABSTRACT: BACKGROUND: The major genetic risk factor for late onset Alzheimer's disease (AD) is the APOE-ɛ4 allele. However, APOE-ɛ4 homozygosity is not fully penetrant, suggesting co-occurrence of additional genetic variants. OBJECTIVE: To identify genetic factors that, next to APOE-ɛ4 homozygosity, contribute to the development of AD. METHODS: We identified a family with nine AD patients spanning four generations, with an inheritance pattern suggestive of autosomal dominant AD, with no variants in PSEN1, PSEN2, or APP. We collected DNA from four affected and seven unaffected family members and performed exome sequencing on DNA from three affected and one unaffected family members. RESULTS: All affected family members were homozygous for the APOE-ɛ4 allele. Statistical analysis revealed that AD onset in this family was significantly earlier than could be expected based on APOE genotype and gender. Next to APOE-ɛ4 homozygosity, we found that all four affected family members carried a rare variant in the VPS10 domain of the SORL1 gene, associated with AβPP processing and AD risk. Furthermore, three of four affected family members carried a rare variant in the TSHZ3 gene, also associated with AβPP processing. Affected family members presented between 61 and 74 years, with variable presence of microbleeds/cerebral amyloid angiopathy and electroencephalographic abnormalities. CONCLUSION: We hypothesize that next to APOE-ɛ4 homozygosity, impaired SORL1 protein function, and possibly impaired TSHZ3 function, further disturbed Aβ processing. The convergence of these genetic factors over several generations might clarify the increased AD penetrance and the autosomal dominant-like inheritance pattern of AD as observed in this family.

18 Article A Longitudinal Study on Resting State Functional Connectivity in Behavioral Variant Frontotemporal Dementia and Alzheimer's Disease. 2017

Hafkemeijer, Anne / Möller, Christiane / Dopper, Elise G P / Jiskoot, Lize C / van den Berg-Huysmans, Annette A / van Swieten, John C / van der Flier, Wiesje M / Vrenken, Hugo / Pijnenburg, Yolande A L / Barkhof, Frederik / Scheltens, Philip / van der Grond, Jeroen / Rombouts, Serge A R B. ·Department of Methodology and Statistics, Institute of Psychology, Leiden University, Leiden, The Netherlands. · Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands. · Leiden Institute for Brain and Cognition, Leiden University, Leiden, The Netherlands. · Alzheimer Center & Department of Neurology, VU University Medical Center, Amsterdam, The Netherlands. · Alzheimer Center & Department of Neurology, Erasmus Medical Center, Rotterdam, The Netherlands. · Department of Neuropsychology, Erasmus Medical Center, Rotterdam, The Netherlands. · Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands. · Department of Epidemiology and Biostatistics, VU University Medical Center, Amsterdam, The Netherlands. · Department of Radiology and Nuclear Medicine, VU University Medical Center, Amsterdam, The Netherlands. · Department of Physics and Medical Technology, VU University Medical Center, Amsterdam, The Netherlands. · Institutes of Neurology and Healthcare Engineering, University College London, London, UK. ·J Alzheimers Dis · Pubmed #27662284.

ABSTRACT: BACKGROUND/OBJECTIVE: Alzheimer's disease (AD) and behavioral variant frontotemporal dementia (bvFTD) are the most common types of early-onset dementia. We applied longitudinal resting state functional magnetic resonance imaging (fMRI) to delineate functional brain connections relevant for disease progression and diagnostic accuracy. METHODS: We used two-center resting state fMRI data of 20 AD patients (65.1±8.0 years), 12 bvFTD patients (64.7±5.4 years), and 22 control subjects (63.8±5.0 years) at baseline and 1.8-year follow-up. We used whole-network and voxel-based network-to-region analyses to study group differences in functional connectivity at baseline and follow-up, and longitudinal changes in connectivity within and between groups. RESULTS: At baseline, connectivity between paracingulate gyrus and executive control network, between cuneal cortex and medial visual network, and between paracingulate gyrus and salience network was higher in AD compared with controls. These differences were also present after 1.8 years. At follow-up, connectivity between angular gyrus and right frontoparietal network, and between paracingulate gyrus and default mode network was lower in bvFTD compared with controls, and lower compared with AD between anterior cingulate gyrus and executive control network, and between lateral occipital cortex and medial visual network. Over time, connectivity decreased in AD between precuneus and right frontoparietal network and in bvFTD between inferior frontal gyrus and left frontoparietal network. Longitudinal changes in connectivity between supramarginal gyrus and right frontoparietal network differ between both patient groups and controls. CONCLUSION: We found disease-specific brain regions with longitudinal connectivity changes. This suggests the potential of longitudinal resting state fMRI to delineate regions relevant for disease progression and for diagnostic accuracy, although no group differences in longitudinal changes in the direct comparison of AD and bvFTD were found.

19 Article A novel CCM2 variant in a family with non-progressive cognitive complaints and cerebral microbleeds. 2017

Cohn-Hokke, Petra E / Holstege, Henne / Weiss, Marjan M / van der Flier, Wiesje M / Barkhof, Frederik / Sistermans, Erik A / Pijnenburg, Yolande A L / van Swieten, John C / Meijers-Heijboer, Hanne / Scheltens, Philip. ·Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands. · Alzheimer Center, Department of Neurology, VU University Medical Center, Neuroscience Campus Amsterdam, Amsterdam, The Netherlands. · Department of Epidemiology and Biostatistics, VU University Medical Center, Amsterdam, The Netherlands. · Department of Radiology & Nuclear Medicine, VU University Medical Center, Neuroscience Campus Amsterdam, Amsterdam, The Netherlands. · Department of Neurology, Erasmus Medical Center, Rotterdam, The Netherlands. ·Am J Med Genet B Neuropsychiatr Genet · Pubmed #27277535.

ABSTRACT: Lobar cerebral microbleeds are most often sporadic and associated with Alzheimer's disease. The aim of our study was to identify the underlying genetic defect in a family with cognitive complaints and multiple lobar microbleeds and a positive family history for early onset Alzheimer's disease. We performed exome sequencing followed by Sanger sequencing for validation purposes on genomic DNA of three siblings with cognitive complaints, reduced amyloid-beta-42 in CSF and multiple cerebral lobar microbleeds. We checked for the occurrence of the variant in a cohort of 363 patients with early onset dementia and/or microbleeds. A novel frameshift variant (c.236_237delAC) generating a premature stop codon in the CCM2 gene shared by all three siblings was identified. Pathogenicity of the variant was supported by the presence of cerebral cavernous malformations in two of the siblings and by the absence of the variant exome variant databases. Two siblings were homozygous for APOE-ϵ4; one heterozygous. The cognitive complaints, reduced amyloid-beta-42 in CSF and microbleeds suggest preclinical Alzheimer's disease, but the stability of the cognitive complaints does not. We hypothesize that the phenotype in this family may be due to a combination of the CCM2 variant and the APOE status. © 2016 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics Published by Wiley Periodicals, Inc.

20 Article Cerebral blood flow in presymptomatic MAPT and GRN mutation carriers: A longitudinal arterial spin labeling study. 2016

Dopper, Elise G P / Chalos, Vicky / Ghariq, Eidrees / den Heijer, Tom / Hafkemeijer, Anne / Jiskoot, Lize C / de Koning, Inge / Seelaar, Harro / van Minkelen, Rick / van Osch, Matthias J P / Rombouts, Serge A R B / van Swieten, John C. ·Department of Neurology, Erasmus Medical Center, Rotterdam, The Netherlands; Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands; Department of Neurology, VU Medical Center, Amsterdam, The Netherlands. · Department of Neurology, Erasmus Medical Center, Rotterdam, The Netherlands. · C.J. Gorter Center for High Field MRI, Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands. · Department of Neurology, Erasmus Medical Center, Rotterdam, The Netherlands; Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands; Department of Neurology, Sint Franciscus Gasthuis, Rotterdam, The Netherlands. · Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands; Department of Methodology and Statistics, Institute of Psychology, Leiden University, Leiden, The Netherlands; Leiden Institute for Brain and Cognition, Leiden University, Leiden, The Netherlands. · Department of Neurology, Erasmus Medical Center, Rotterdam, The Netherlands; Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands; Department of Neuropsychology, Erasmus Medical Center, Rotterdam, The Netherlands. · Department of Neuropsychology, Erasmus Medical Center, Rotterdam, The Netherlands. · Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands. · Department of Neurology, Erasmus Medical Center, Rotterdam, The Netherlands; Department of Clinical Genetics, VU Medical Center, Amsterdam, The Netherlands. ·Neuroimage Clin · Pubmed #27625986.

ABSTRACT: OBJECTIVE: Frontotemporal dementia (FTD) is characterized by behavioral disturbances and language problems. Familial forms can be caused by genetic defects in microtubule-associated protein tau (MAPT), progranulin (GRN), and C9orf72. In light of upcoming clinical trials with potential disease-modifying agents, the development of sensitive biomarkers to evaluate such agents in the earliest stage of FTD is crucial. In the current longitudinal study we used arterial spin labeling MRI (ASL) in presymptomatic carriers of MAPT and GRN mutations to investigate early changes in cerebral blood flow (CBF). METHODS: Healthy first-degree relatives of patients with a MAPT or GRN mutation underwent ASL at baseline and follow-up after two years. We investigated cross-sectional and longitudinal differences in CBF between mutation carriers (n = 34) and controls without a mutation (n = 31). RESULTS: GRN mutation carriers showed significant frontoparietal hypoperfusion compared with controls at follow-up, whereas we found no cross-sectional group differences in the total study group or the MAPT subgroup. Longitudinal analyses revealed a significantly stronger decrease in CBF in frontal, temporal, parietal, and subcortical areas in the total group of mutation carriers and the GRN subgroup, with the strongest decrease in two mutation carriers who converted to clinical FTD during follow-up. INTERPRETATION: We demonstrated longitudinal alterations in CBF in presymptomatic FTD independent of grey matter atrophy, with the strongest decrease in individuals that developed symptoms during follow-up. Therefore, ASL could have the potential to serve as a sensitive biomarker of disease progression in the presymptomatic stage of FTD in future clinical trials.

21 Article 18F-AV-1451 tau PET imaging correlates strongly with tau neuropathology in MAPT mutation carriers. 2016

Smith, Ruben / Puschmann, Andreas / Schöll, Michael / Ohlsson, Tomas / van Swieten, John / Honer, Michael / Englund, Elisabet / Hansson, Oskar. ·1 Department of Clinical Sciences Lund, Department of Neurology, Lund University, Sweden 2 Department of Neurology and Rehabilitation Medicine, Skåne University Hospital, Lund, Sweden Ruben.Smith@med.lu.se oskar.hansson@med.lu.se. · 1 Department of Clinical Sciences Lund, Department of Neurology, Lund University, Sweden 2 Department of Neurology and Rehabilitation Medicine, Skåne University Hospital, Lund, Sweden. · 3 Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, Sweden 4 MedTech West and the Division of Clinical Neuroscience, Gothenburg University, Gothenburg, Sweden. · 5 Department of Radiation physics, Skåne University Hospital, Lund, Sweden. · 6 Department of Neurology, Erasmus Medical Centre, Rotterdam, The Netherlands. · 7 Roche Pharmaceutical Research and Early Development, Neuroscience Discovery and Biomarkers, Roche Innovation Center, Basel, Switzerland. · 8 Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Sweden. · 3 Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, Sweden 9 Memory Clinic, Skåne University Hospital, Malmö, Sweden Ruben.Smith@med.lu.se oskar.hansson@med.lu.se. ·Brain · Pubmed #27357347.

ABSTRACT: Tau positron emission tomography ligands provide the novel possibility to image tau pathology in vivo However, little is known about how in vivo brain uptake of tau positron emission tomography ligands relates to tau aggregates observed post-mortem. We performed tau positron emission tomography imaging with (18)F-AV-1451 in three patients harbouring a p.R406W mutation in the MAPT gene, encoding tau. This mutation results in 3- and 4-repeat tau aggregates similar to those in Alzheimer's disease, and many of the mutation carriers initially suffer from memory impairment and temporal lobe atrophy. Two patients with short disease duration and isolated memory impairment exhibited (18)F-AV-1451 uptake mainly in the hippocampus and adjacent temporal lobe regions, correlating with glucose hypometabolism in corresponding regions. One patient died after 26 years of disease duration with dementia and behavioural deficits. Pre-mortem, there was (18)F-AV-1451 uptake in the temporal and frontal lobes, as well as in the basal ganglia, which strongly correlated with the regional extent and amount of tau pathology in post-mortem brain sections. Amyloid-β ((18)F-flutemetamol) positron emission tomography scans were negative in all cases, as were stainings of brain sections for amyloid. This provides strong evidence that (18)F-AV-1451 positron emission tomography can be used to accurately quantify in vivo the regional distribution of hyperphosphorylated tau protein.

22 Article ABCA7 p.G215S as potential protective factor for Alzheimer's disease. 2016

Sassi, Celeste / Nalls, Michael A / Ridge, Perry G / Gibbs, Jesse R / Ding, Jinhui / Lupton, Michelle K / Troakes, Claire / Lunnon, Katie / Al-Sarraj, Safa / Brown, Kristelle S / Medway, Christopher / Clement, Naomi / Lord, Jenny / Turton, James / Bras, Jose / Almeida, Maria R / Anonymous5881022 / Holstege, Henne / Louwersheimer, Eva / van der Flier, Wiesje M / Scheltens, Philip / Van Swieten, John C / Santana, Isabel / Oliveira, Catarina / Morgan, Kevin / Powell, John F / Kauwe, John S / Cruchaga, Carlos / Goate, Alison M / Singleton, Andrew B / Guerreiro, Rita / Hardy, John. ·Reta Lila, Weston Research Laboratories, Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK; Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA; Department of Experimental Neurology, Center for Stroke Research Berlin (CSB), Charite' Universitätmedizin, Berlin, Germany; German Center for Neurodegenerative Diseases (DZNE), Berlin site, Germany. · Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA. · Department of Biology, Brigham Young University, Provo, UT, USA. · King's College London, Institute of Psychiatry, Psychology and Neuroscience, London, UK; QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia. · King's College London, Institute of Psychiatry, Psychology and Neuroscience, London, UK. · King's College London, Institute of Psychiatry, Psychology and Neuroscience, London, UK; Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, Devon, UK. · Translation Cell Sciences-Human Genetics, School of Life Sciences, Queens Medical Centre, University of Nottingham, Nottingham, UK. · Reta Lila, Weston Research Laboratories, Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK. · Neurogenetics Laboratory, Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal. · Department of Neurology, Alzheimer Center, VU University Medical Center, Neuroscience Campus Amsterdam, Amsterdam, the Netherlands. · Department of Neurology, Alzheimer Center, VU University Medical Center, Neuroscience Campus Amsterdam, Amsterdam, the Netherlands; Department of Neurology, Erasmus Medical Centre, Rotterdam, the Netherlands. · Neurology Department, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal; Faculty of Medicine, Coimbra University, Coimbra, Portugal. · CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal; Laboratory of Biochemistry, Faculty of Medicine, University of Coimbra, Coimbra, Portugal. · Department of Biology, Brigham Young University, Provo, UT, USA; Department of Neuroscience, Brigham Young University, Provo, UT, USA. · Division of Biology and Biomedical Sciences, Washington University, St. Louis, MO, USA. · Icahn School of Medicine at Mount Sinai, Icahn Medical Institute, New York, NY, USA. · Reta Lila, Weston Research Laboratories, Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK. Electronic address: j.hardy@ucl.ac.uk. ·Neurobiol Aging · Pubmed #27289440.

ABSTRACT: Genome-wide association studies (GWASs) have been effective approaches to dissect common genetic variability underlying complex diseases in a systematic and unbiased way. Recently, GWASs have led to the discovery of over 20 susceptibility loci for Alzheimer's disease (AD). Despite the evidence showing the contribution of these loci to AD pathogenesis, their genetic architecture has not been extensively investigated, leaving the possibility that low frequency and rare coding variants may also occur and contribute to the risk of disease. We have used exome and genome sequencing data to analyze the single independent and joint effect of rare and low-frequency protein coding variants in 9 AD GWAS loci with the strongest effect sizes after APOE (BIN1, CLU, CR1, PICALM, MS4A6A, ABCA7, EPHA1, CD33, and CD2AP) in a cohort of 332 sporadic AD cases and 676 elderly controls of British and North-American ancestry. We identified coding variability in ABCA7 as contributing to AD risk. This locus harbors a low-frequency coding variant (p.G215S, rs72973581, minor allele frequency = 4.3%) conferring a modest but statistically significant protection against AD (p-value = 0.024, odds ratio = 0.57, 95% confidence interval = 0.41-0.80). Notably, our results are not driven by an enrichment of loss of function variants in ABCA7, recently reported as main pathogenic factor underlying AD risk at this locus. In summary, our study confirms the role of ABCA7 in AD and provides new insights that should address functional studies.

23 Article Concurrent white and gray matter degeneration of disease-specific networks in early-stage Alzheimer's disease and behavioral variant frontotemporal dementia. 2016

Steketee, Rebecca M E / Meijboom, Rozanna / de Groot, Marius / Bron, Esther E / Niessen, Wiro J / van der Lugt, Aad / van Swieten, John C / Smits, Marion. ·Department of Radiology, Erasmus MC-University Medical Centre Rotterdam, Rotterdam, the Netherlands. · Department of Epidemiology, Erasmus MC-University Medical Centre Rotterdam, Rotterdam, the Netherlands; Biomedical Imaging Group Rotterdam, Department of Medical Informatics, Erasmus MC-University Medical Centre Rotterdam, Rotterdam, the Netherlands; Biomedical Imaging Group Rotterdam, Department of Radiology, Erasmus MC-University Medical Centre Rotterdam, Rotterdam, the Netherlands. · Biomedical Imaging Group Rotterdam, Department of Medical Informatics, Erasmus MC-University Medical Centre Rotterdam, Rotterdam, the Netherlands; Biomedical Imaging Group Rotterdam, Department of Radiology, Erasmus MC-University Medical Centre Rotterdam, Rotterdam, the Netherlands. · Biomedical Imaging Group Rotterdam, Department of Medical Informatics, Erasmus MC-University Medical Centre Rotterdam, Rotterdam, the Netherlands; Biomedical Imaging Group Rotterdam, Department of Radiology, Erasmus MC-University Medical Centre Rotterdam, Rotterdam, the Netherlands; Imaging Physics, Faculty of Applied Sciences, Delft University of Technology, Delft, the Netherlands. · Department of Neurology, Erasmus MC-University Medical Centre Rotterdam, Rotterdam, the Netherlands. · Department of Radiology, Erasmus MC-University Medical Centre Rotterdam, Rotterdam, the Netherlands. Electronic address: marion.smits@erasmusmc.nl. ·Neurobiol Aging · Pubmed #27255821.

ABSTRACT: This study investigates regional coherence between white matter (WM) microstructure and gray matter (GM) volume and perfusion measures in Alzheimer's disease (AD) and behavioral variant frontotemporal dementia (bvFTD) using a correlational approach. WM-GM coherence, compared with controls, was stronger between cingulum WM and frontotemporal GM in AD, and temporoparietal GM in bvFTD. In addition, in AD compared with controls, coherence was stronger between inferior fronto-occipital fasciculus WM microstructure and occipital GM perfusion. In this first study assessing regional WM-GM coherence in AD and bvFTD, we show that WM microstructure and GM volume and perfusion measures are coherent, particularly in regions implicated in AD and bvFTD pathology. This indicates concurrent degeneration in disease-specific networks. Our methodology allows for the detection of incipient abnormalities that go undetected in conventional between-group analyses.

24 Article Combining multiple anatomical MRI measures improves Alzheimer's disease classification. 2016

de Vos, Frank / Schouten, Tijn M / Hafkemeijer, Anne / Dopper, Elise G P / van Swieten, John C / de Rooij, Mark / van der Grond, Jeroen / Rombouts, Serge A R B. ·Leiden University, Institute of Psychology, The Netherlands. · Department of Radiology, Leiden University Medical Center, The Netherlands. · Leiden Institute for Brain and Cognition, The Netherlands. · Department of Neurology, Erasmus Medical Center, The Netherlands. · Department of Neurology, VU Medical Center, The Netherlands. · Department of Clinical Genetics, VU Medical Center, The Netherlands. ·Hum Brain Mapp · Pubmed #26915458.

ABSTRACT: Several anatomical MRI markers for Alzheimer's disease (AD) have been identified. Hippocampal volume, cortical thickness, and grey matter density have been used successfully to discriminate AD patients from controls. These anatomical MRI measures have so far mainly been used separately. The full potential of anatomical MRI scans for AD diagnosis might thus not yet have been used optimally. In this study, we therefore combined multiple anatomical MRI measures to improve diagnostic classification of AD. For 21 clinically diagnosed AD patients and 21 cognitively normal controls, we calculated (i) cortical thickness, (ii) cortical area, (iii) cortical curvature, (iv) grey matter density, (v) subcortical volumes, and (vi) hippocampal shape. These six measures were used separately and combined as predictors in an elastic net logistic regression. We made receiver operating curve plots and calculated the area under the curve (AUC) to determine classification performance. AUC values for the single measures ranged from 0.67 (cortical thickness) to 0.94 (grey matter density). The combination of all six measures resulted in an AUC of 0.98. Our results demonstrate that the different anatomical MRI measures contain complementary information. A combination of these measures may therefore improve accuracy of AD diagnosis in clinical practice. Hum Brain Mapp 37:1920-1929, 2016. © 2016 Wiley Periodicals, Inc.

25 Article Heterogeneous Language Profiles in Patients with Primary Progressive Aphasia due to Alzheimer's Disease. 2016

Louwersheimer, Eva / Keulen, M Antoinette / Steenwijk, Martijn D / Wattjes, Mike P / Jiskoot, Lize C / Vrenken, Hugo / Teunissen, Charlotte E / van Berckel, Bart N M / van der Flier, Wiesje M / Scheltens, Philip / van Swieten, John C / Pijnenburg, Yolande A L. ·Alzheimer Center and Department of Neurology, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands. · MS Center Amsterdam and Department of Radiology and Nuclear Medicine, Neuroscience campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands. · Department of Neurology, Erasmus University Medical Center, Rotterdam, The Netherlands. · Neurochemistry Laboratory and Biobank, Department of Clinical Chemistry, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands. · Department of Epidemiology & Biostatistics, VU University Medical Center, Amsterdam, The Netherlands. · Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands. ·J Alzheimers Dis · Pubmed #26890751.

ABSTRACT: BACKGROUND: The logopenic variant of Primary Progressive Aphasia (lvPPA) is associated with underlying Alzheimer's disease (AD) pathology and characterized by impaired single word retrieval and repetition of phrases and sentences. OBJECTIVE: We set out to study whether logopenic aphasia is indeed the prototypic language profile in PPA patients with biomarker evidence of underlying AD pathology and to correlate language profiles with cortical atrophy patterns on MRI. METHODS: Inclusion criteria: (I) clinical diagnosis of PPA; (II) CSF profile and/or PiB-PET scan indicative for amyloid pathology; (III) availability of expert language evaluation. Based on language evaluation, patients were classified as lvPPA (fulfilling lvPPA core criteria), lvPPA extended (fulfilling core criteria plus other language disturbances), or PPA unclassifiable (not fulfilling lvPPA core criteria). Cortical atrophy patterns on MRI were visually rated and quantitative measurements of cortical thickness were performed using FreeSurfer. RESULTS: We included 22 patients (age 67±7 years, 50% female, MMSE 21±6). 41% were classified as lvPPA, 36% as lvPPA extended with additional deficits in language comprehension and/or confrontation naming, and 23% as PPA unclassifiable. By both qualitative and quantitative measurements, patients with lvPPA showed mild global cortical atrophy on MRI, whereas patients with lvPPA extended showed more focal cortical atrophy, predominantly at the left tempo-parietal side. For PPA unclassifiable, qualitative measurements revealed a heterogeneous atrophy pattern. CONCLUSION: Although most patients fulfilled the lvPPA criteria, we found that their language profiles were heterogeneous. The clinical and radiological spectrum of PPA due to underlying AD pathology is broader than pure lvPPA.

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