Publications by authors named "Rik Vandenberghe"

252 Publications

A data-driven disease progression model of fluid biomarkers in genetic frontotemporal dementia.

Brain 2021 Oct 11. Epub 2021 Oct 11.

Nuffield Department of Clinical Neurosciences, Medical Sciences Division, University of Oxford, OX3 9DU Oxford, UK.

Several CSF and blood biomarkers for genetic frontotemporal dementia (FTD) have been proposed, including those reflecting neuroaxonal loss (neurofilament light chain (NfL) and phosphorylated neurofilament heavy chain (pNfH)), synapse dysfunction (neuronal pentraxin 2 (NPTX2)), astrogliosis (glial fibrillary acidic protein (GFAP)), and complement activation (C1q, C3b). Determining the sequence in which biomarkers become abnormal over the course of disease could facilitate disease staging and help identify mutation carriers with prodromal or early-stage FTD, which is especially important as pharmaceutical trials emerge. We aimed to model the sequence of biomarker abnormalities in presymptomatic and symptomatic genetic FTD using cross-sectional data from the Genetic Frontotemporal dementia Initiative (GENFI), a longitudinal cohort study. 275 presymptomatic and 127 symptomatic carriers of mutations in GRN, C9orf72 or MAPT, as well as 247 non-carriers, were selected from the GENFI cohort based on availability of one or more of the aforementioned biomarkers. Nine presymptomatic carriers developed symptoms within 18 months of sample collection ('converters'). Sequences of biomarker abnormalities were modelled for the entire group using discriminative event-based modelling (DEBM) and for each genetic subgroup using co-initialised DEBM. These models estimate probabilistic biomarker abnormalities in a data-driven way and do not rely on prior diagnostic information or biomarker cut-off points. Using cross-validation, subjects were subsequently assigned a disease stage based on their position along the disease progression timeline. CSF NPTX2 was the first biomarker to become abnormal, followed by blood and CSF NfL, blood pNfH, blood GFAP, and finally CSF C3b and C1q. Biomarker orderings did not differ significantly between genetic subgroups, but more uncertainty was noted in the C9orf72 and MAPT groups than for GRN. Estimated disease stages could distinguish symptomatic from presymptomatic carriers and non-carriers with areas under the curve (AUC) of 0.84 (95% confidence interval 0.80-0.89) and 0.90 (0.86-0.94) respectively. The AUC to distinguish converters from non-converting presymptomatic carriers was 0.85 (0.75-0.95). Our data-driven model of genetic FTD revealed that NPTX2 and NfL are the earliest to change among the selected biomarkers. Further research should investigate their utility as candidate selection tools for pharmaceutical trials. The model's ability to accurately estimate individual disease stages could improve patient stratification and track the efficacy of therapeutic interventions.
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http://dx.doi.org/10.1093/brain/awab382DOI Listing
October 2021

Dissemination in time and space in presymptomatic granulin mutation carriers: a GENFI spatial chronnectome study.

Neurobiol Aging 2021 Sep 8;108:155-167. Epub 2021 Sep 8.

Nueld Department of Clinical Neurosciences, Medical Sciences Division, University of Oxford, Oxford, UK.

The presymptomatic brain changes of granulin (GRN) disease, preceding by years frontotemporal dementia, has not been fully characterized. New approaches focus on the spatial chronnectome can capture both spatial network configurations and their dynamic changes over time. To investigate the spatial dynamics in 141 presymptomatic GRN mutation carriers and 282 noncarriers from the Genetic Frontotemporal dementia research Initiative cohort. We considered time-varying patterns of the default mode network, the language network, and the salience network, each summarized into 4 distinct recurring spatial configurations. Dwell time (DT) (the time each individual spends in each spatial state of each network), fractional occupacy (FO) (the total percentage of time spent by each individual in a state of a specific network) and total transition number (the total number of transitions performed by each individual in a specifict state) were considered. Correlations between DT, FO, and transition number and estimated years from expected symptom onset (EYO) and clinical performances were assessed. Presymptomatic GRN mutation carriers spent significantly more time in those spatial states characterised by greater activation of the insula and the parietal cortices, as compared to noncarriers (p < 0.05, FDR-corrected). A significant correlation between DT and FO of these spatial states and EYO was found, the longer the time spent in the spatial states, the closer the EYO. DT and FO significantly correlated with performances at tests tapping processing speed, with worse scores associated with increased spatial states' DT. Our results demonstrated that presymptomatic GRN disease presents a complex dynamic reorganization of brain connectivity. Change in both the spatial and temporal aspects of brain network connectivity could provide a unique glimpse into brain function and potentially allowing a more sophisticated evaluation of the earliest disease changes and the understanding of possible mechanisms in GRN disease.
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http://dx.doi.org/10.1016/j.neurobiolaging.2021.09.001DOI Listing
September 2021

Effect of the Histone Deacetylase Inhibitor FRM-0334 on Progranulin Levels in Patients With Progranulin Gene Haploinsufficiency: A Randomized Clinical Trial.

JAMA Netw Open 2021 Sep 1;4(9):e2125584. Epub 2021 Sep 1.

FORUM Pharmaceuticals Incorporated, Waltham, Massachusetts.

Importance: Histone deacetylase inhibitors have been repeatedly shown to elevate progranulin levels in preclinical models. This report describes the first randomized clinical trial of a histone deacetylase inhibitor in frontotemporal dementia (FTD) resulting from progranulin (GRN) gene variations.

Objective: To characterize the safety, tolerability, plasma pharmacokinetics, and pharmacodynamic effects of oral FRM-0334 on plasma progranulin and other exploratory biomarkers, including fluorodeoxyglucose (FDG)-positron emission tomography (PET), in individuals with GRN haploinsufficiency.

Design, Setting, And Participants: In this randomized, double-blind, placebo-controlled, dose-escalating, phase 2a safety, tolerability, and pharmacodynamic clinical study, 2 doses of a histone deacetylase inhibitor (FRM-0334) were administered to participants with prodromal to moderate FTD with granulin variations. Participants were recruited from January 13, 2015, to April 13, 2016. The study included 27 participants with prodromal (n = 8) or mild-to-moderate symptoms of FTD (n = 19) and heterozygous pathogenic variations in GRN and was conducted at multiple centers in North America, the UK, and the European Union. Data were analyzed from June 9, 2019, to May 13, 2021.

Interventions: Daily oral placebo (n = 5), 300 mg of FRM-0334 (n = 11), or 500 mg of FRM-0334 (n = 11) was administered for 28 days.

Main Outcomes And Measures: Primary outcomes were safety and tolerability of FRM-0334 and its peripheral pharmacodynamic effect on plasma progranulin. Secondary outcomes were the plasma pharmacokinetic profile of FRM-0334 and its pharmacodynamic effect on cerebrospinal fluid progranulin. Exploratory outcomes were FDG-PET, FTD clinical severity, and cerebrospinal fluid biomarkers (neurofilament light chain [NfL], amyloid β 1-42, phosphorylated tau 181, and total tau [t-tau]).

Results: A total of 27 participants (mean [SD] age, 56.6 [10.5] years; 16 women [59.3%]; 26 White participants [96.3%]) with GRN variations were randomized and completed treatment. FRM-0334 was safe and well tolerated but did not affect plasma progranulin (4.3 pg/mL per day change after treatment; 95% CI, -10.1 to 18.8 pg/mL; P = .56), cerebrospinal fluid progranulin (0.42 pg/mL per day; 95% CI, -0.12 to 0.95 pg/mL; P = .13), or exploratory pharmacodynamic measures. Plasma FRM-0334 exposure did not increase proportionally with dose. Brain FDG-PET data were available in 26 of 27 randomized participants. In a cross-sectional analysis of 26 individuals, bifrontal cortical FDG hypometabolism was associated with worse Clinical Dementia Rating (CDR) plus National Alzheimer's Coordinating Center frontotemporal lobar degeneration sum of boxes score (b = -3.6 × 10-2 standardized uptake value ratio [SUVR] units/CDR units; 95% CI, -4.9 × 10-2 to -2.2 × 10-2; P < .001), high cerebrospinal fluid NfL (b = -9.2 × 10-5 SUVR units/pg NfL/mL; 95% CI, -1.3 × 10-4 to -5.6 × 10-5; P < .001), and high CSF t-tau (-7.2 × 10-4 SUVR units/pg t-tau/mL; 95% CI, -1.4 × 10-3 to -9.5 × 10-5; P = .03).

Conclusions And Relevance: In this randomized clinical trial, the current formulation of FRM-0334 did not elevate PRGN levels, which could reflect a lack of efficacy at attained exposures, low bioavailability, or some combination of the 2 factors. Bifrontal FDG-PET is a sensitive measure of symptomatic GRN haploinsufficiency. International multicenter clinical trials of FTD-GRN are feasible.

Trial Registration: ClinicalTrials.gov Identifier: NCT02149160.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.25584DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8463943PMC
September 2021

Changes in the language system as amyloid-β accumulates.

Brain 2021 Sep 17. Epub 2021 Sep 17.

Laboratory for Cognitive Neurology, Department of Neurosciences, Leuven Brain Institute, KU Leuven, 3000 Leuven, Belgium.

Language dysfunction is common in Alzheimer's disease. There is increasing interest in the preclinical or asymptomatic phase of Alzheimer's disease. Here we examined in 35 cognitively intact older adults (age range 52-78 years at baseline, 17 male) in a longitudinal study design the association between accumulation of amyloid over a five to six year period, measured using PET, and functional changes in the language network measured over the same time period using task-related functional MRI. In the same participants, we also determined the association between the longitudinal functional MRI changes and a cross-sectional measure of tau load as measured with 18F-AV1451 PET. As predicted, the principal change occurred in posterior temporal cortex: In the cortex surrounding the right superior temporal sulcus, the response amplitude during the associative-semantic versus visuoperceptual task increased over time as amyloid load accumulated (Pcorrected = 0.008). In a whole-brain voxelwise analysis, amyloid accumulation was also associated with a decrease in response amplitude in the left inferior frontal sulcus (Pcorrected = 0.009) and the right dorsomedial prefrontal cortex (Pcorrected = 0.005). In cognitively intact older adults, cross-sectional tau load was not associated with longitudinal changes in fMRI response amplitude. Our findings confirm the central role of the neocortex surrounding the posterior superior temporal sulcus as the area of predilection within the language network in the earliest stages of Alzheimer's disease. Amyloid accumulation has an impact on cognitive brain circuitry in the asymptomatic phase of Alzheimer's disease.
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http://dx.doi.org/10.1093/brain/awab335DOI Listing
September 2021

Posterior Intraparietal Sulcus Mediates Detection of Salient Stimuli Outside the Endogenous Focus of Attention.

Cereb Cortex 2021 Aug 31. Epub 2021 Aug 31.

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

Visual consciousness is shaped by the interplay between endogenous selection and exogenous capture. If stimulus saliency is aligned with a subject's attentional priorities, endogenous selection will be facilitated. In case of a misalignment, endogenous selection may be compromised as attentional capture is a strong and automatic process. We manipulated task-congruent versus -incongruent saliency in a functional magnetic resonance imaging change-detection task and analyzed brain activity patterns in the cortex surrounding the intraparietal sulcus (IPS) within the Julich-Brain probabilistic cytoarchitectonic mapping reference frame. We predicted that exogenous effects would be seen mainly in the posterior regions of the IPS (hIP4-hIP7-hIP8), whereas a conflict between endogenous and exogenous orienting would elicit activity from more anterior cytoarchitectonic areas (hIP1-hIP2-hIP3). Contrary to our hypothesis, a conflict between endogenous and exogenous orienting had an effect early in the IPS (mainly in hIP7 and hIP8). This is strong evidence for an endogenous component in hIP7/8 responses to salient stimuli beyond effects of attentional bottom-up sweep. Our results suggest that hIP7 and hIP8 are implicated in the individuation of attended locations based on saliency as well as endogenous instructions.
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http://dx.doi.org/10.1093/cercor/bhab299DOI Listing
August 2021

CSF Proteomic Alzheimer's Disease-Predictive Subtypes in Cognitively Intact Amyloid Negative Individuals.

Proteomes 2021 Aug 2;9(3). Epub 2021 Aug 2.

Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Amsterdam UMC, 1007 MB Amsterdam, The Netherlands.

We recently discovered three distinct pathophysiological subtypes in Alzheimer's disease (AD) using cerebrospinal fluid (CSF) proteomics: one with neuronal hyperplasticity, a second with innate immune system activation, and a third subtype with blood-brain barrier dysfunction. It remains unclear whether AD proteomic subtype profiles are a consequence of amyloid aggregation, or might exist upstream from aggregated amyloid. We studied this question in 127 older individuals with intact cognition and normal AD biomarkers in two independent cohorts (EMIF-AD MBD and ADNI). We clustered 705 proteins measured in CSF that were previously related to AD. We identified in these cognitively intact individuals without AD pathology three subtypes: two subtypes were seen in both cohorts (n = 49 with neuronal hyperplasticity and n = 44 with blood-brain barrier dysfunction), and one only in ADNI (n = 12 with innate immune activation). The proteins specific for these subtypes strongly overlapped with AD subtype protein profiles (overlap coefficients 92%-71%). Longitudinal p-tau and amyloid β 1-42 (Aβ42) CSF analysis showed that in the hyperplasticity subtype p-tau increased (β = 2.6 pg/mL per year, = 0.01) and Aβ42 decreased over time (β = -4.4 pg/mL per year, = 0.03), in the innate immune activation subtype p-tau increased (β = 3.1 pg/mL per year, = 0.01) while in the blood-brain barrier dysfunction subtype Aβ42 decreased (β = -3.7 pg/mL per year, = 0.009). These findings suggest that AD proteomic subtypes might already manifest in cognitively normal individuals and may predispose for AD before amyloid has reached abnormal levels.
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http://dx.doi.org/10.3390/proteomes9030036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8396164PMC
August 2021

Lower regional gray matter volume in the absence of higher cortical amyloid burden in late-life depression.

Sci Rep 2021 08 5;11(1):15981. Epub 2021 Aug 5.

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

Late-life depression (LLD) is associated with a risk of developing Alzheimer's disease (AD). However, the role of AD-pathophysiology in LLD, and its association with clinical symptoms and cognitive function are elusive. In this study, one hundred subjects underwent amyloid positron emission tomography (PET) imaging with [F]-flutemetamol and structural MRI: 48 severely depressed elderly subjects (age 74.1 ± 7.5 years, 33 female) and 52 age-/gender-matched healthy controls (72.4 ± 6.4 years, 37 female). The Geriatric Depression Scale (GDS) and Rey Auditory Verbal Learning Test (RAVLT) were used to assess the severity of depressive symptoms and episodic memory function respectively. Amyloid deposition was quantified using the standardized uptake value ratio. Whole-brain voxel-wise comparisons of amyloid deposition and gray matter volume (GMV) between LLD and controls were performed. Multivariate analysis of covariance was conducted to investigate the association of regional differences in amyloid deposition and GMV with clinical factors, including GDS and RAVLT. As a result, there were no significant group differences in amyloid deposition. In contrast, LLD showed significant lower GMV in the left temporal and parietal region. GMV reduction in the left temporal region was associated with episodic memory dysfunction, but not with depression severity. Regional GMV reduction was not associated with amyloid deposition. LLD is associated with lower GMV in regions that overlap with AD-pathophysiology, and which are associated with episodic memory function. The lack of corresponding associations with amyloid suggests that lower GMV driven by non-amyloid pathology may play a central role in the neurobiology of LLD presenting as a psychiatric disorder.Trial registration: European Union Drug Regulating Authorities Clinical Trials identifier: EudraCT 2009-018064-95.
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http://dx.doi.org/10.1038/s41598-021-95206-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8342521PMC
August 2021

Comparison of clinical rating scales in genetic frontotemporal dementia within the GENFI cohort.

J Neurol Neurosurg Psychiatry 2021 Aug 5. Epub 2021 Aug 5.

Department of Neurofarba, University of Florence, Firenze, Italy.

Background: Therapeutic trials are now underway in genetic forms of frontotemporal dementia (FTD) but clinical outcome measures are limited. The two most commonly used measures, the Clinical Dementia Rating (CDR)+National Alzheimer's Disease Coordinating Center (NACC) Frontotemporal Lobar Degeneration (FTLD) and the FTD Rating Scale (FRS), have yet to be compared in detail in the genetic forms of FTD.

Methods: The CDR+NACC FTLD and FRS were assessed cross-sectionally in 725 consecutively recruited participants from the Genetic FTD Initiative: 457 mutation carriers (77 microtubule-associated protein tau (, 187 , 193 ) and 268 family members without mutations (non-carrier control group). 231 mutation carriers (51 92 88 ) and 145 non-carriers had available longitudinal data at a follow-up time point.

Results: Cross-sectionally, the mean FRS score was lower in all genetic groups compared with controls: mutation carriers mean 83.4 (SD 27.0), mutation carriers 78.2 (28.8), mutation carriers 71.0 (34.0), controls 96.2 (7.7), p<0.001 for all comparisons, while the mean CDR+NACC FTLD Sum of Boxes was significantly higher in all genetic groups: mutation carriers mean 2.6 (5.2), mutation carriers 3.2 (5.6), mutation carriers 4.2 (6.2), controls 0.2 (0.6), p<0.001 for all comparisons. Mean FRS score decreased and CDR+NACC FTLD Sum of Boxes increased with increasing disease severity within each individual genetic group. FRS and CDR+NACC FTLD Sum of Boxes scores were strongly negatively correlated across all mutation carriers (r=-0.77, p<0.001) and within each genetic group (r=-0.67 to -0.81, p<0.001 in each group). Nonetheless, discrepancies in disease staging were seen between the scales, and with each scale and clinician-judged symptomatic status. Longitudinally, annualised change in both FRS and CDR+NACC FTLD Sum of Boxes scores initially increased with disease severity level before decreasing in those with the most severe disease: controls -0.1 (6.0) for FRS, -0.1 (0.4) for CDR+NACC FTLD Sum of Boxes, asymptomatic mutation carriers -0.5 (8.2), 0.2 (0.9), prodromal disease -2.3 (9.9), 0.6 (2.7), mild disease -10.2 (18.6), 3.0 (4.1), moderate disease -9.6 (16.6), 4.4 (4.0), severe disease -2.7 (8.3), 1.7 (3.3). Sample sizes were calculated for a trial of prodromal mutation carriers: over 180 participants per arm would be needed to detect a moderate sized effect (30%) for both outcome measures, with sample sizes lower for the FRS.

Conclusions: Both the FRS and CDR+NACC FTLD measure disease severity in genetic FTD mutation carriers throughout the timeline of their disease, although the FRS may be preferable as an outcome measure. However, neither address a number of key symptoms in the FTD spectrum, for example, motor and neuropsychiatric deficits, which future scales will need to incorporate.
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http://dx.doi.org/10.1136/jnnp-2021-326868DOI Listing
August 2021

A 3D deep learning model to predict the diagnosis of dementia with Lewy bodies, Alzheimer's disease, and mild cognitive impairment using brain 18F-FDG PET.

Eur J Nucl Med Mol Imaging 2021 Jul 30. Epub 2021 Jul 30.

Department of Clinical Physiology, Department of Health, Medicine and Caring Sciences, Linköping University, Linköping, Sweden.

Purpose: The purpose of this study is to develop and validate a 3D deep learning model that predicts the final clinical diagnosis of Alzheimer's disease (AD), dementia with Lewy bodies (DLB), mild cognitive impairment due to Alzheimer's disease (MCI-AD), and cognitively normal (CN) using fluorine 18 fluorodeoxyglucose PET (18F-FDG PET) and compare model's performance to that of multiple expert nuclear medicine physicians' readers.

Materials And Methods: Retrospective 18F-FDG PET scans for AD, MCI-AD, and CN were collected from Alzheimer's disease neuroimaging initiative (556 patients from 2005 to 2020), and CN and DLB cases were from European DLB Consortium (201 patients from 2005 to 2018). The introduced 3D convolutional neural network was trained using 90% of the data and externally tested using 10% as well as comparison to human readers on the same independent test set. The model's performance was analyzed with sensitivity, specificity, precision, F1 score, receiver operating characteristic (ROC). The regional metabolic changes driving classification were visualized using uniform manifold approximation and projection (UMAP) and network attention.

Results: The proposed model achieved area under the ROC curve of 96.2% (95% confidence interval: 90.6-100) on predicting the final diagnosis of DLB in the independent test set, 96.4% (92.7-100) in AD, 71.4% (51.6-91.2) in MCI-AD, and 94.7% (90-99.5) in CN, which in ROC space outperformed human readers performance. The network attention depicted the posterior cingulate cortex is important for each neurodegenerative disease, and the UMAP visualization of the extracted features by the proposed model demonstrates the reality of development of the given disorders.

Conclusion: Using only 18F-FDG PET of the brain, a 3D deep learning model could predict the final diagnosis of the most common neurodegenerative disorders which achieved a competitive performance compared to the human readers as well as their consensus.
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http://dx.doi.org/10.1007/s00259-021-05483-0DOI Listing
July 2021

The Revised Self-Monitoring Scale detects early impairment of social cognition in genetic frontotemporal dementia within the GENFI cohort.

Alzheimers Res Ther 2021 07 12;13(1):127. Epub 2021 Jul 12.

Department of Neurology, Ludwig-Maximilians Universität München, Munich, Germany.

Background: Although social cognitive dysfunction is a major feature of frontotemporal dementia (FTD), it has been poorly studied in familial forms. A key goal of studies is to detect early cognitive impairment using validated measures in large patient cohorts.

Methods: We used the Revised Self-Monitoring Scale (RSMS) as a measure of socioemotional sensitivity in 730 participants from the genetic FTD initiative (GENFI) observational study: 269 mutation-negative healthy controls, 193 C9orf72 expansion carriers, 193 GRN mutation carriers and 75 MAPT mutation carriers. All participants underwent the standardised GENFI clinical assessment including the 'CDR® plus NACC FTLD' scale and RSMS. The RSMS total score and its two subscores, socioemotional expressiveness (EX score) and modification of self-presentation (SP score) were measured. Volumetric T1-weighted magnetic resonance imaging was available from 377 mutation carriers for voxel-based morphometry (VBM) analysis.

Results: The RSMS was decreased in symptomatic mutation carriers in all genetic groups but at a prodromal stage only in the C9orf72 (for the total score and both subscores) and GRN (for the modification of self-presentation subscore) groups. RSMS score correlated with disease severity in all groups. The VBM analysis implicated an overlapping network of regions including the orbitofrontal cortex, insula, temporal pole, medial temporal lobe and striatum.

Conclusions: The RSMS indexes socioemotional impairment at an early stage of genetic FTD and may be a suitable outcome measure in forthcoming trials.
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http://dx.doi.org/10.1186/s13195-021-00865-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8276486PMC
July 2021

Characterizing the Clinical Features and Atrophy Patterns of -Related Frontotemporal Dementia With Disease Progression Modeling.

Neurology 2021 08 22;97(9):e941-e952. Epub 2021 Jun 22.

From the Department of Neuroimaging (A.L.Y., S.C.R.W.), Institute of Psychiatry, Psychology and Neuroscience, King's College London; Departments of Computer Science (A.L.Y., D.C.A.) and Medical Physics and Biomedical Engineering (D.M.C.), Centre for Medical Image Computing, University College London; Dementia Research Centre (M.B., L.L.R., R.S.C., G.P., E.T., D.M.C., C.V.G., L.J., J.D.R.), Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK; Department of Neurology (J.v.S., L.J., H.S.), Erasmus Medical Centre, Rotterdam, the Netherlands; Cognitive Disorders Unit (F.M.), Department of Neurology, Donostia University Hospital; Neuroscience Area (F.M.), Biodonostia Health Research Institute, San Sebastian, Gipuzkoa, Spain; Alzheimer's Disease and Other Cognitive Disorders Unit (R.S.-V.), Neurology Service, Hospital Clínic, Institut d'Investigacións Biomèdiques August Pi I Sunyer, University of Barcelona, Spain; Neurology Unit (B.B.), Department of Clinical and Experimental Sciences, University of Brescia, Italy; Clinique Interdisciplinaire de Mémoire, Département des Sciences Neurologiques, CHU de Québec, and Faculté de Médecine (R.L.), Université Laval, Québec; Sunnybrook Health Sciences Centre, Sunnybrook Research Institute (M.M.), and Tanz Centre for Research in Neurodegenerative Diseases (M.C.T.), University of Toronto, Canada; Center for Alzheimer Research (C.G.), Division of Neurogeriatrics, Department of Neurobiology, Care Sciences and Society, Bioclinicum, Karolinska Institutet; Unit for Hereditary Dementias (C.G.), Theme Aging, Karolinska University Hospital, Solna, Sweden; Fondazione Ca'Granda (D.G.), IRCCS Ospedale Policlinico; University of Milan (D.G.), Centro Dino Ferrari, Italy; Department of Clinical Neurosciences and Cambridge University Hospitals NHS Trust (J.B.R.), University of Cambridge, UK; Department of Clinical Neurological Sciences (E.F.), University of Western Ontario, London, Canada; Department of Neurodegenerative Diseases (M.S.), Hertie-Institute for Clinical Brain Research and Center of Neurology, University of Tübingen; Center for Neurodegenerative Diseases (DZNE) (M.S.), Tübingen, Germany; Laboratory for Cognitive Neurology, Department of Neurosciences (R.V.), and Leuven Brain Institute (R.V.), KU Leuven; Neurology Service (R.V.), University Hospitals Leuven, Belgium; Faculty of Medicine (A.d.M.), University of Lisbon, Portugal; Fondazione IRCCS Istituto Neurologico Carlo Besta (F.T.), Milan, Italy; University Hospital of Coimbra (HUC), Neurology Service (I.S.), and Center for Neuroscience and Cell Biology (I.S.), Faculty of Medicine, University of Coimbra, Portugal; Department of Psychiatry, McGill University Health Centre (S.D.), and McConnell Brain Imaging Centre, Montreal Neurological Institute (S.D.), McGill University, Montreal, Canada; Nuffield Department of Clinical Neurosciences (C.B.), Medical Sciences Division, University of Oxford; Division of Neuroscience and Experimental Psychology (A.G.), Wolfson Molecular Imaging Centre, University of Manchester, UK; Departments of Geriatric Medicine and Nuclear Medicine (A.G.), University of Duisburg-Essen; Department of Neurology (J.L., A.D.), Ludwig-Maximilians Universität München; German Center for Neurodegenerative Diseases (DZNE) (J.L.); Munich Cluster of Systems Neurology (SyNergy) (J.L.), Munich; Department of Neurology (M.O.), University of Ulm, Germany; Departments of Neuroscience, Psychology, Drug Research, and Child Health (S.S.), University of Florence; and IRCCS Don Gnocchi (S.S.), Florence, Italy.

Background And Objective: Mutations in the gene cause frontotemporal dementia (FTD). Most previous studies investigating the neuroanatomical signature of mutations have grouped all different mutations together and shown an association with focal atrophy of the temporal lobe. The variability in atrophy patterns between each particular mutation is less well-characterized. We aimed to investigate whether there were distinct groups of mutation carriers based on their neuroanatomical signature.

Methods: We applied Subtype and Stage Inference (SuStaIn), an unsupervised machine learning technique that identifies groups of individuals with distinct progression patterns, to characterize patterns of regional atrophy in associated FTD within the Genetic FTD Initiative (GENFI) cohort study.

Results: Eighty-two mutation carriers were analyzed, the majority of whom had P301L, IVS10+16, or R406W mutations, along with 48 healthy noncarriers. SuStaIn identified 2 groups of mutation carriers with distinct atrophy patterns: a temporal subtype, in which atrophy was most prominent in the hippocampus, amygdala, temporal cortex, and insula; and a frontotemporal subtype, in which atrophy was more localized to the lateral temporal lobe and anterior insula, as well as the orbitofrontal and ventromedial prefrontal cortex and anterior cingulate. There was one-to-one mapping between IVS10+16 and R406W mutations and the temporal subtype and near one-to-one mapping between P301L mutations and the frontotemporal subtype. There were differences in clinical symptoms and neuropsychological test scores between subtypes: the temporal subtype was associated with amnestic symptoms, whereas the frontotemporal subtype was associated with executive dysfunction.

Conclusion: Our results demonstrate that different mutations give rise to distinct atrophy patterns and clinical phenotype, providing insights into the underlying disease biology and potential utility for patient stratification in therapeutic trials.
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http://dx.doi.org/10.1212/WNL.0000000000012410DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8408507PMC
August 2021

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

Neurobiol Dis 2021 08 9;156:105421. Epub 2021 Jun 9.

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

Neurodegenerative disorders like frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are pathologically characterized by toxic protein deposition in the cytoplasm or nucleus of affected neurons and glial cells. Many of these aggregated proteins belong to the class of RNA binding proteins (RBP), and, when mutated, account for a significant subset of familial ALS and FTD cases. Here, we present first genetic evidence for the RBP gene RBM45 in the FTD-ALS spectrum. RBM45 shows many parallels with other FTD-ALS associated genes and proteins. Multiple lines of evidence have demonstrated that RBM45 is an RBP that, upon mutation, redistributes to the cytoplasm where it co-aggregates with other RBPs into cytoplasmic stress granules (SG), evolving to persistent toxic TDP-43 immunoreactive inclusions. Exome sequencing in two affected first cousins of a heavily affected early-onset dementia family listed a number of candidate genes. The gene with the highest pathogenicity score was the RBP gene RBM45. In the family, the RBM45 Arg183* nonsense mutation co-segregated in both affected cousins. Validation in an unrelated patient (n = 548) / control (n = 734) cohort identified an additional RBM45 Arg183* carrier with bvFTD on a shared 4 Mb haplotype. Transcript and protein expression analysis demonstrated loss of nuclear RBM45, suggestive of a loss-of-function disease mechanism. Further, two more ultra-rare VUS, one in the nuclear localization signal (NLS, p.Lys456Arg) in an ALS patient and one in the intrinsically disordered homo-oligomer assembly (HOA) domain (p.Arg314Gln) in a patient with nfvPPA were detected. Our findings suggest that the pathomechanisms linking RBM45 with FTD and ALS may be related to its loss of nuclear function as a mediator of mRNA splicing, cytoplasmic retention or its inability to form homo-oligomers, leading to aggregate formation with trapping of other RBPs including TDP-43, which may accumulate into persisted TDP-43 inclusions.
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http://dx.doi.org/10.1016/j.nbd.2021.105421DOI Listing
August 2021

Common variants in Alzheimer's disease and risk stratification by polygenic risk scores.

Nat Commun 2021 06 7;12(1):3417. Epub 2021 Jun 7.

Servei de Neurologia, Hospital Universitari i Politècnic La Fe, Valencia, Spain.

Genetic discoveries of Alzheimer's disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer's disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer's disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer's disease.
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http://dx.doi.org/10.1038/s41467-021-22491-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8184987PMC
June 2021

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

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

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

The ATP-Binding Cassette Subfamily A Member 7 gene (ABCA7) was identified as a risk gene for Alzheimer's disease (AD) in genome-wide association studies of large cohorts of late-onset AD (LOAD) patients. Extended resequencing of the ABCA7 coding regions identified mutations that lead to premature termination codons (PTC) and loss of function of ABCA7. PTC mutations were enriched in LOAD patients and were frequently present in patients with early-onset AD (EOAD). We aimed at assessing the contribution of ABCA7 PTC mutations to AD in the Belgian population by screening the ABCA7 coding region in a Belgian AD cohort of 1376 patients, including LOAD and EOAD patients, and in a Belgian control cohort of 976 individuals. We identified a PTC mutation in 67 AD patients (4.9%) and in 18 control individuals (1.8%) confirming the enrichment of ABCA7 PTC mutations in Belgian AD patients. The patient carriers had a mean onset age of 69.7 ± 9.8 years with a wide onset age range of 42 years (48-90 years). In 77.3% of the families of ABCA7 carriers, there were AD patients present suggestive of a positive family history of disease, but a Mendelian co-segregation of ABCA7 PTC mutations with disease is not clear. Overall, our genetic data predict that PTC mutations in ABCA7 are common in the Belgian population and are present in LOAD and EOAD patients.
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http://dx.doi.org/10.1016/j.neurobiolaging.2021.04.023DOI Listing
October 2021

Impairment of episodic memory in genetic frontotemporal dementia: A GENFI study.

Alzheimers Dement (Amst) 2021 13;13(1):e12185. Epub 2021 May 13.

Douglas Mental Health University Institute Department of Psychiatry McGill University Montreal Canada.

Introduction: We aimed to assess episodic memory in genetic frontotemporal dementia (FTD) with the Free and Cued Selective Reminding Test (FCSRT).

Methods: The FCSRT was administered in 417 presymptomatic and symptomatic mutation carriers (181 chromosome 9 open reading frame 72 [], 163 progranulin [], and 73 microtubule-associated protein tau []) and 290 controls. Group differences and correlations with other neuropsychological tests were examined. We performed voxel-based morphometry to investigate the underlying neural substrates of the FCSRT.

Results: All symptomatic mutation carrier groups and presymptomatic mutation carriers performed significantly worse on all FCSRT scores compared to controls. In the presymptomatic group, deficits were found on all scores except for the delayed total recall task, while no deficits were found in presymptomatic mutation carriers. Performance on the FCSRT correlated with executive function, particularly in mutation carriers, but also with memory and naming tasks in the group. FCSRT performance also correlated with gray matter volumes of frontal, temporal, and subcortical regions in and , but mainly temporal areas in mutation carriers.

Discussion: The FCSRT detects presymptomatic deficits in - and -associated FTD and provides important insight into the underlying cause of memory impairment in different forms of FTD.
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http://dx.doi.org/10.1002/dad2.12185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8116844PMC
May 2021

TMEM106B and CPOX are genetic determinants of cerebrospinal fluid Alzheimer's disease biomarker levels.

Alzheimers Dement 2021 May 14. Epub 2021 May 14.

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

Introduction: Neurofilament light (NfL), chitinase-3-like protein 1 (YKL-40), and neurogranin (Ng) are biomarkers for Alzheimer's disease (AD) to monitor axonal damage, astroglial activation, and synaptic degeneration, respectively.

Methods: We performed genome-wide association studies (GWAS) using DNA and cerebrospinal fluid (CSF) samples from the EMIF-AD Multimodal Biomarker Discovery study for discovery, and the Alzheimer's Disease Neuroimaging Initiative study for validation analyses. GWAS were performed for all three CSF biomarkers using linear regression models adjusting for relevant covariates.

Results: We identify novel genome-wide significant associations between DNA variants in TMEM106B and CSF levels of NfL, and between CPOX and YKL-40. We confirm previous work suggesting that YKL-40 levels are associated with DNA variants in CHI3L1.

Discussion: Our study provides important new insights into the genetic architecture underlying interindividual variation in three AD-related CSF biomarkers. In particular, our data shed light on the sequence of events regarding the initiation and progression of neuropathological processes relevant in AD.
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http://dx.doi.org/10.1002/alz.12330DOI Listing
May 2021

CSF sTREM2 is elevated in a subset in GRN-related frontotemporal dementia.

Neurobiol Aging 2021 07 4;103:158.e1-158.e5. Epub 2021 Mar 4.

Alzheimer Center Rotterdam and Dept. of Neurology, Erasmus University Medical Center, Rotterdam, the Netherlands. Electronic address:

Excessive microglial activation might be a central pathological process in GRN-related frontotemporal dementia (FTD-GRN). We measured soluble triggering receptor expressed on myeloid cells 2 (sTREM2), which is shed from disease-associated microglia following cleavage of TREM2, in cerebrospinal fluid of 34 presymptomatic and 35 symptomatic GRN mutation carriers, 6 presymptomatic and 32 symptomatic C9orf72 mutation carriers and 67 healthy noncarriers by ELISA. Although no group differences in sTREM2 levels were observed (GRN: symptomatic (median 5.2 ng/mL, interquartile range [3.9-9.2]) vs. presymptomatic (4.3 ng/mL [2.6-6.1]) vs. noncarriers (4.2 ng/mL [2.6-5.5]): p = 0.059; C9orf72: symptomatic (4.3 [2.9-7.0]) vs. presymptomatic (3.2 [2.2-4.2]) vs. noncarriers: p = 0.294), high levels were seen in a subset of GRN, but not C9orf72, mutation carriers, which might reflect differential TREM2-related microglial activation. Interestingly, 2 presymptomatic carriers with low sTREM2 levels developed symptoms after 1 year, whereas 2 with high levels became symptomatic after >5 years. While sTREM2 is not a promising diagnostic biomarker for FTD-GRN or FTD-C9orf72, further research might elucidate its potential to monitor microglial activity and predict disease progression.
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http://dx.doi.org/10.1016/j.neurobiolaging.2021.02.024DOI Listing
July 2021

Differential early subcortical involvement in genetic FTD within the GENFI cohort.

Neuroimage Clin 2021 29;30:102646. Epub 2021 Mar 29.

Neurologische Klinik und Poliklinik, Ludwig-Maximilians-Universität, Munich German Center for Neurodegenerative Diseases (DZNE), Munich Munich Cluster of Systems Neurology, Munich, Germany.

Background: Studies have previously shown evidence for presymptomatic cortical atrophy in genetic FTD. Whilst initial investigations have also identified early deep grey matter volume loss, little is known about the extent of subcortical involvement, particularly within subregions, and how this differs between genetic groups.

Methods: 480 mutation carriers from the Genetic FTD Initiative (GENFI) were included (198 GRN, 202 C9orf72, 80 MAPT), together with 298 non-carrier cognitively normal controls. Cortical and subcortical volumes of interest were generated using automated parcellation methods on volumetric 3 T T1-weighted MRI scans. Mutation carriers were divided into three disease stages based on their global CDR® plus NACC FTLD score: asymptomatic (0), possibly or mildly symptomatic (0.5) and fully symptomatic (1 or more).

Results: In all three groups, subcortical involvement was seen at the CDR 0.5 stage prior to phenoconversion, whereas in the C9orf72 and MAPT mutation carriers there was also involvement at the CDR 0 stage. In the C9orf72 expansion carriers the earliest volume changes were in thalamic subnuclei (particularly pulvinar and lateral geniculate, 9-10%) cerebellum (lobules VIIa-Crus II and VIIIb, 2-3%), hippocampus (particularly presubiculum and CA1, 2-3%), amygdala (all subregions, 2-6%) and hypothalamus (superior tuberal region, 1%). In MAPT mutation carriers changes were seen at CDR 0 in the hippocampus (subiculum, presubiculum and tail, 3-4%) and amygdala (accessory basal and superficial nuclei, 2-4%). GRN mutation carriers showed subcortical differences at CDR 0.5 in the presubiculum of the hippocampus (8%).

Conclusions: C9orf72 expansion carriers show the earliest and most widespread changes including the thalamus, basal ganglia and medial temporal lobe. By investigating individual subregions, changes can also be seen at CDR 0 in MAPT mutation carriers within the limbic system. Our results suggest that subcortical brain volumes may be used as markers of neurodegeneration even prior to the onset of prodromal symptoms.
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http://dx.doi.org/10.1016/j.nicl.2021.102646DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099608PMC
July 2021

Prognostic value of amyloid/tau/neurodegeneration (ATN) classification based on diagnostic cerebrospinal fluid samples for Alzheimer's disease.

Alzheimers Res Ther 2021 04 20;13(1):84. Epub 2021 Apr 20.

Department of Neurology, University Hospitals Leuven, Herestraat 49, B-3000, Leuven, Belgium.

Objective: The primary study objective of this retrospective academic memory clinic-based observational longitudinal study was to investigate the prognostic value of a cerebrospinal fluid (CSF)-based ATN classification for subsequent cognitive decline during the 3 years following lumbar puncture in a clinical, real-life setting. The secondary objective was to investigate the prognostic value of CSF biomarkers as continuous variables.

Methods: Data from 228 patients (median age 67 (47-85) years), who presented at the Neurology Memory Clinic UZ/KU Leuven between September 2011 and December 2016, were included with a follow-up period of up to 36 months. Patients underwent a CSF AD biomarker test for amyloid-beta 1-42 (Aβ) hyperphosphorylated tau (p-tau) and total tau (t-tau) in the clinical work-up for diagnostic reasons. Patients were divided into ATN classes based on CSF biomarkers: Aβ for amyloid (A), p-tau for tau (T), and t-tau as a measure for neurodegeneration (N). Based on retrospective data analysis, cognitive performance was evaluated by Mini Mental State Examination (MMSE) scores every 6 months over a period up to 36 months following the lumbar puncture. The statistical analysis was based on linear mixed-effects modeling (LME).

Results: The distribution in the current clinical sample was as follows: A-/T-/N- 32.02%, A+/T-/N- 33.33%, A+/T+/N+ 17.11%, A+/T-/N+ 11.84%, A-/T-/N+ 4.39%, A-/T+/N+ 1.32% (3 cases), with no cases in the A-/T+/N- and A+/T+/N- class. Hence, the latter 3 classes were excluded from further analyses. The change of MMSE relative to A-/T-/N- over a 36-month period was significant in all four ATN classes: A+/T+/N+ = - 4.78 points on the MMSE; A-/T-/N+ = - 4.76; A+/T-/N+ = - 2.83; A+/T-/N- = - 1.96. The earliest significant difference was seen in the A+/T+/N+ class at 12 months after baseline. The effect of ATN class on future cognitive decline was confirmed for a different set of CSF thresholds. All individual baseline CSF biomarkers including the Aβ/t-tau ratio showed a significant correlation with subsequent cognitive decline, with the highest correlation seen for Aβ/t-tau.

Conclusion: ATN classification based on CSF biomarkers has a statistically significant and clinically relevant prognostic value for the course of cognitive decline in a 3-year period in a clinical practice setting.
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http://dx.doi.org/10.1186/s13195-021-00817-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8059197PMC
April 2021

Sequence of proteome profiles in preclinical and symptomatic Alzheimer's disease.

Alzheimers Dement 2021 06 19;17(6):946-958. Epub 2021 Apr 19.

Laboratory for Neuropathology, Department of Imaging and Pathology, KU Leuven (University of Leuven), Leuven, Belgium.

Proteome profile changes in Alzheimer's disease (AD) brains have been reported. However, it is unclear whether they represent a continuous process, or whether there is a sequential involvement of distinct proteins. To address this question, we used mass spectrometry. We analyzed soluble, dispersible, sodium dodecyl sulfate, and formic acid fractions of neocortex homogenates (mainly Brodmann area 17-19) from 18 pathologically diagnosed preclinical AD, 17 symptomatic AD, and 18 cases without signs of neurodegeneration. By doing so, we identified four groups of AD-related proteins being changed in levels in preclinical and symptomatic AD cases: early-responding, late-responding, gradually-changing, and fraction-shifting proteins. Gene ontology analysis of these proteins and all known AD-risk/causative genes identified vesicle endocytosis and the secretory pathway-related processes as an early-involved AD component. In conclusion, our findings suggest that subtle changes involving the secretory pathway and endocytosis precede severe proteome changes in symptomatic AD as part of the preclinical phase of AD. The respective early-responding proteins may also contribute to synaptic vesicle cycle alterations in symptomatic AD.
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http://dx.doi.org/10.1002/alz.12345DOI Listing
June 2021

Plasma Neurofilament Light for Prediction of Disease Progression in Familial Frontotemporal Lobar Degeneration.

Neurology 2021 05 7;96(18):e2296-e2312. Epub 2021 Apr 7.

From the University of California, San Francisco (J.C.R., P.W., A.M.S., Y.C., A.W., S.-Y.M.G., P.A.L., H.W.H., J.C.F., J.B.T., A.M.K., L.L.M., J.K., J.H.K., B.L.M., H.J.S., A.L.B.); UK Dementia Research Centre (C.H., D.M.C., R.S.C., M.B., M.F., C.V.G., G.P., L.R., I.S., E.T., J.D.R.), UCL Institute of Neurology, Queen Square, London; Quanterix Corp (E.V., L.S., A.J., D.H.), Lexington; Novartis Institutes for Biomedical Research Inc (L.Y., A. Khinikar, R.S.), Cambridge, MA; Novartis Pharma AG (A. Kieloch, M.-A.V.), Basel, Switzerland; Bluefield Project to Cure Frontotemporal Dementia (L.L.M., R.P.), San Francisco, CA; Mayo Clinic (K.K., D.S.K., B.F.B.), Rochester, MN; Mayo Clinic (N.G.-R., L.P., R.R.), Jacksonville, FL; University of Pennsylvania (D.J.I., M.G.), Philadelphia; University of California, Los Angeles (E.M.R., G.C., M.F.M., Y.B.); Harvard University/Massachusetts General Hospital (B.D.C.), Boston, MA; Washington University (N.G.), St. Louis, MO; Columbia University (E.D.H.), New York, NY; University of British Columbia (I.R.M., G.-Y.R.H.), Vancouver, Canada; Case Western Reserve University (B.S.A.), Cleveland, OH; University of Washington (K.D.-R.), Seattle; Laboratory of Neuroimaging (A.W.T.), University of Southern California, Los Angeles; Northwestern University (S.W.), Chicago, IL; University of North Carolina (D.I.K.), Chapel Hill; Texas Health Presbyterian Hospital Dallas (D.K.); University of California, San Diego (I.L.); Johns Hopkins Hospital (C.U.O., A.P.), Baltimore, MD; University of Alabama at Birmingham (E.D.R.); University of Toronto (M.C.T., M.M.), Ontario, Canada; Indiana University School of Medicine (T.F.), Indianapolis; Biogen Inc (W.C., J.C., D.L.G.), Cambridge, MA; Erasmus Medical Centre (J.C.v.S.), Rotterdam, the Netherlands; University of Brescia (B.B.), Italy; University of Barcelona (R.S.-V.); Donostia University Hospital (F.M.), San Sebastian, Gipuzkoa, Spain; Clinique Interdisciplinaire de Mémoire (R.L.), Département des Sciences Neurologiques, CHU de Québec; Faculté de Médecine (R.L.), Université Laval, Quebec, Canada; Center for Alzheimer Research (C.G.), Division of Neurogeriatrics, Department of Neurobiology, Care Sciences and Society, Bioclinicum, Karolinska Institutet; Unit for Hereditary Dementias (C.G.), Theme Aging, Karolinska University Hospital, Solna, Sweden; University of Tübingen (M.S.); Center for Neurodegenerative Diseases (DZNE) (M.S.), Tübingen, Germany; Fondazione IRCCS Ospedale Policlinico (D.G.); University of Milan (D.G.), Centro Dino Ferrari, Italy; Department of Clinical Neurosciences and Cambridge University Hospital (J.B.R.), University of Cambridge, UK; University of Western Ontario (E.F.), London, Canada; KU Leuven (R.V.), Belgium; Neurology Service (R.V.), University Hospitals Leuven, Belgium; University of Lisbon (A.d.M.), Portugal; Fondazione IRCCS Istituto Neurologico Carlo Besta (F.T.), Milan, Italy; University of Coimbra (I.S.), Portugal; McGill University (S.D.), Montreal, Québec, Canada; University of Oxford (C.R.B.); Wolfson Molecular Imaging Centre (A.G.), University of Manchester, UK; University of Duisburg-Essen (A.G.), Duisberg; Ludwig-Maximilians-Universität München (J.L., A.D.); German Center for Neurodegenerative Diseases (J.L.), Munich Cluster for Systems Neurology (SyNergy); University of Ulm (M.O.), Germany; and Department of Neuroscience, Psychology, Drug Research and Child Health (S.S.), University of Florence, and IRCCS Fondazione Don Carlo Gnocchi, Florence, Italy.

Objective: We tested the hypothesis that plasma neurofilament light chain (NfL) identifies asymptomatic carriers of familial frontotemporal lobar degeneration (FTLD)-causing mutations at risk of disease progression.

Methods: Baseline plasma NfL concentrations were measured with single-molecule array in original (n = 277) and validation (n = 297) cohorts. , , and mutation carriers and noncarriers from the same families were classified by disease severity (asymptomatic, prodromal, and full phenotype) using the CDR Dementia Staging Instrument plus behavior and language domains from the National Alzheimer's Disease Coordinating Center FTLD module (CDR+NACC-FTLD). Linear mixed-effect models related NfL to clinical variables.

Results: In both cohorts, baseline NfL was higher in asymptomatic mutation carriers who showed phenoconversion or disease progression compared to nonprogressors (original: 11.4 ± 7 pg/mL vs 6.7 ± 5 pg/mL, = 0.002; validation: 14.1 ± 12 pg/mL vs 8.7 ± 6 pg/mL, = 0.035). Plasma NfL discriminated symptomatic from asymptomatic mutation carriers or those with prodromal disease (original cutoff: 13.6 pg/mL, 87.5% sensitivity, 82.7% specificity; validation cutoff: 19.8 pg/mL, 87.4% sensitivity, 84.3% specificity). Higher baseline NfL correlated with worse longitudinal CDR+NACC-FTLD sum of boxes scores, neuropsychological function, and atrophy, regardless of genotype or disease severity, including asymptomatic mutation carriers.

Conclusions: Plasma NfL identifies asymptomatic carriers of FTLD-causing mutations at short-term risk of disease progression and is a potential tool to select participants for prevention clinical trials.

Trial Registration Information: ClinicalTrials.gov Identifier: NCT02372773 and NCT02365922.

Classification Of Evidence: This study provides Class I evidence that in carriers of FTLD-causing mutations, elevation of plasma NfL predicts short-term risk of clinical progression.
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http://dx.doi.org/10.1212/WNL.0000000000011848DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8166434PMC
May 2021

Baseline cognition is the best predictor of 4-year cognitive change in cognitively intact older adults.

Alzheimers Res Ther 2021 04 7;13(1):75. Epub 2021 Apr 7.

Laboratory for Cognitive Neurology, Department of Neurosciences, Leuven Brain Institute, KU Leuven, Leuven, Belgium.

Background: We examined in cognitively intact older adults the relative weight of cognitive, genetic, structural and amyloid brain imaging variables for predicting cognitive change over a 4-year time course.

Methods: One hundred-eighty community-recruited cognitively intact older adults (mean age 68 years, range 52-80 years, 81 women) belonging to the Flemish Prevent Alzheimer's Disease Cohort KU Leuven (F-PACK) longitudinal observational cohort underwent a baseline evaluation consisting of detailed cognitive assessment, structural MRI and F-flutemetamol PET. At inclusion, subjects were stratified based on Apolipoprotein E (APOE) ε4 and Brain-Derived Neurotrophic Factor (BDNF) val66met polymorphism according to a factorial design. At inclusion, 15% were amyloid-PET positive (Centiloid >23.4). All subjects underwent 2-yearly follow-up of cognitive performance for a 4-year time period. Baseline cognitive scores were analysed using factor analysis. The slope of cognitive change over time was modelled using latent growth curve analysis. Using correlation analysis, hierarchical regression and mediation analysis, we examined the effect of demographic (age, sex, education) and genetic variables, baseline cognition, MRI volumetric (both voxelwise and region-based) as well as amyloid imaging measures on the longitudinal slope of cognitive change.

Results: A base model of age and sex explained 18.5% of variance in episodic memory decline. This increased to 41.6% by adding baseline episodic memory scores. Adding amyloid load or volumetric measures explained only a negligible additional amount of variance (increase to 42.2%). A mediation analysis indicated that the effect of age on episodic memory scores was partly direct and partly mediated via hippocampal volume. Amyloid load did not play a significant role as mediator between age, hippocampal volume and episodic memory decline.

Conclusion: In cognitively intact older adults, the strongest baseline predictor of subsequent episodic memory decline was the baseline episodic memory score. When this score was included, only very limited explanatory power was added by brain volume or amyloid load measures. The data warn against classifications that are purely biomarker-based and highlight the value of baseline cognitive performance levels in predictive models.
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http://dx.doi.org/10.1186/s13195-021-00798-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8028179PMC
April 2021

Cognitive and Behavioral Manifestations in ALS: Beyond Motor System Involvement.

Diagnostics (Basel) 2021 Mar 30;11(4). Epub 2021 Mar 30.

Laboratory for Cognitive Neurology, Department of Neurosciences, Leuven Brain Institute (LBI), KU, 3000 Leuven, Belgium.

Amyotrophic lateral sclerosis (ALS) has long been considered to be a purely motor disorder. However, it has become apparent that many ALS patients develop cognitive and behavioral manifestations similar to frontotemporal dementia and the term amyotrophic lateral sclerosis-frontotemporal spectrum disorder (ALS-FTSD) is now used in these circumstances. This review is intended to be an overview of the cognitive and behavioral manifestations commonly encountered in ALS patients with the goal of improving case-oriented management in clinical practice. We introduce the principal ALS-FTSD subtypes and comment on their principal clinical manifestations, neuroimaging findings, neuropathological and genetic background, and summarize available therapeutic options. Diagnostic criteria for ALS-FTSD create distinct categories based on the type of neuropsychological manifestations, i.e., changes in behavior, impaired social cognition, executive dysfunction, and language or memory impairment. Cognitive impairment is found in up to 65%, while frank dementia affects about 15% of ALS patients. ALS motor and cognitive manifestations can worsen in parallel, becoming more pronounced when bulbar functions (affecting speech, swallowing, and salivation) are involved. Dementia can precede or develop after the appearance of motor symptoms. ALS-FTSD patients have a worse prognosis and shorter survival rates than patients with ALS or frontotemporal dementia alone. Important negative prognostic factors are behavioral and personality changes. From the clinician's perspective, there are five major distinguishable ALS-FTSD subtypes: ALS with cognitive impairment, ALS with behavioral impairment, ALS with combined cognitive and behavioral impairment, fully developed frontotemporal dementia in combination with ALS, and comorbid ALS and Alzheimer's disease. Although the most consistent ALS and ALS-FTSD pathology is a disturbance in transactive response DNA binding protein 43 kDa (TDP-43) metabolism, alterations in microtubule-associated tau protein metabolism have also been observed in ALS-FTSD. Early detection and careful monitoring of cognitive deficits in ALS are crucial for patient and caregiver support and enable personalized management of individual patient needs.
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http://dx.doi.org/10.3390/diagnostics11040624DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8065866PMC
March 2021

TDP-43 interacts with pathological τ protein in Alzheimer's disease.

Acta Neuropathol 2021 05 2;141(5):795-799. Epub 2021 Apr 2.

Department of Imaging and Pathology, Laboratory of Neuropathology, Leuven Brain Institute, KU-Leuven, O&N IV, Herestraat 49, box 1032, 3000, Leuven, Belgium.

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http://dx.doi.org/10.1007/s00401-021-02295-2DOI Listing
May 2021

Replication study of plasma proteins relating to Alzheimer's pathology.

Alzheimers Dement 2021 09 31;17(9):1452-1464. Epub 2021 Mar 31.

Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.

Introduction: This study sought to discover and replicate plasma proteomic biomarkers relating to Alzheimer's disease (AD) including both the "ATN" (amyloid/tau/neurodegeneration) diagnostic framework and clinical diagnosis.

Methods: Plasma proteins from 972 subjects (372 controls, 409 mild cognitive impairment [MCI], and 191 AD) were measured using both SOMAscan and targeted assays, including 4001 and 25 proteins, respectively.

Results: Protein co-expression network analysis of SOMAscan data revealed the relation between proteins and "N" varied across different neurodegeneration markers, indicating that the ATN variants are not interchangeable. Using hub proteins, age, and apolipoprotein E ε4 genotype discriminated AD from controls with an area under the curve (AUC) of 0.81 and MCI convertors from non-convertors with an AUC of 0.74. Targeted assays replicated the relation of four proteins with the ATN framework and clinical diagnosis.

Discussion: Our study suggests that blood proteins can predict the presence of AD pathology as measured in the ATN framework as well as clinical diagnosis.
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http://dx.doi.org/10.1002/alz.12322DOI Listing
September 2021

The Role of Amyloid PET in Diagnosing Possible Transmissible Cerebral Amyloid Angiopathy in Young Adults with a History of Neurosurgery: A Case Series.

Cerebrovasc Dis 2021 19;50(3):356-360. Epub 2021 Mar 19.

Department of Neurosciences, Experimental Neurology, KU Leuven, Leuven, Belgium.

Background: Cerebral amyloid angiopathy (CAA) is a common cause of cerebrovascular disease in the elderly. There is accumulating evidence suggestive of transmissibility of β-amyloid resulting in amyloid pathology at younger age. According to the Boston criteria, defining CAA in patients <55 years requires histological evidence which may hamper diagnosis. We explored the role of amyloid PET in the diagnosis of possible transmissible CAA in young adults.

Cases: We report 4 young adults (<55 years) presenting with clinical and neuroimaging features suggestive of CAA but without genetic evidence of hereditary CAA explaining the young onset. A common factor in all cases was a medical history of neurosurgery during childhood. All patients underwent amyloid PET to support the diagnosis of an amyloid-related pathology and the result was positive in all 4.

Conclusion: Combining the clinical presentation and imaging findings of the 4 cases, we postulate transmissible CAA as the possible diagnosis. Further epidemiological studies are required to gain more insight in the prevalence of this novel entity. Amyloid PET may be a useful, non-invasive tool in these analyses especially since pathological evidence will be lacking in most of these studies.
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http://dx.doi.org/10.1159/000514139DOI Listing
August 2021

MRI data-driven algorithm for the diagnosis of behavioural variant frontotemporal dementia.

J Neurol Neurosurg Psychiatry 2021 Mar 15. Epub 2021 Mar 15.

McConnell Brain Imaging Center, Montreal Neurological Institute and Hospital, McGill University, Montreal, Quebec, Canada.

Introduction: Structural brain imaging is paramount for the diagnosis of behavioural variant of frontotemporal dementia (bvFTD), but it has low sensitivity leading to erroneous or late diagnosis.

Methods: A total of 515 subjects from two different bvFTD cohorts (training and independent validation cohorts) were used to perform voxel-wise morphometric analysis to identify regions with significant differences between bvFTD and controls. A random forest classifier was used to individually predict bvFTD from deformation-based morphometry differences in isolation and together with semantic fluency. Tenfold cross validation was used to assess the performance of the classifier within the training cohort. A second held-out cohort of genetically confirmed bvFTD cases was used for additional validation.

Results: Average 10-fold cross-validation accuracy was 89% (82% sensitivity, 93% specificity) using only MRI and 94% (89% sensitivity, 98% specificity) with the addition of semantic fluency. In the separate validation cohort of definite bvFTD, accuracy was 88% (81% sensitivity, 92% specificity) with MRI and 91% (79% sensitivity, 96% specificity) with added semantic fluency scores.

Conclusion: Our results show that structural MRI and semantic fluency can accurately predict bvFTD at the individual subject level within a completely independent validation cohort coming from a different and independent database.
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http://dx.doi.org/10.1136/jnnp-2020-324106DOI Listing
March 2021

Toward a Universal Readout for F-Labeled Amyloid Tracers: The CAPTAINs Study.

J Nucl Med 2021 Jul 12;62(7):999-1005. Epub 2021 Mar 12.

University Hospital Cologne, Multimodal Neuroimaging Group, Department of Nuclear Medicine, Cologne, Germany.

To date, 3 F-labeled PET tracers have been approved for assessing cerebral amyloid plaque pathology in the diagnostic workup of suspected Alzheimer disease (AD). Although scanning protocols are relatively similar across tracers, U.S. Food and Drug Administration- and the European Medicines Agency-approved visual rating protocols differ among the 3 tracers. This proof-of-concept study assessed the comparability of the 3 approved visual rating protocols to classify a scan as amyloid-positive or -negative, when applied by groups of experts and nonexperts to all 3 amyloid tracers. In an international multicenter approach, both expert ( = 4) and nonexpert raters ( = 3) rated scans acquired with F-florbetaben, F-florbetapir and F-flutemetamol. Scans obtained with each tracer were presented for reading according to all 3 approved visual rating protocols. In a randomized order, every single scan was rated by each reader according to all 3 protocols. Raters were blinded for the amyloid tracer used and asked to rate each scan as positive or negative, giving a confidence judgment after each response. Percentage of visual reader agreement, interrater reliability, and agreement of each visual read with binary quantitative measures (fixed SUV ratio threshold for positive or negative scans) were computed. These metrics were analyzed separately for expert and nonexpert groups. No significant differences in using the different approved visual rating protocols were observed across the different metrics of agreement in the group of experts. Nominal differences suggested that the F-florbetaben visual rating protocol achieved the highest interrater reliability and accuracy especially under low confidence conditions. For the group of nonexpert raters, significant differences between the different visual rating protocols were observed with overall moderate-to-fair accuracy and with the highest reliability for the F-florbetapir visual rating protocol. We observed high interrater agreement despite applying different visual rating protocols for all F-labeled amyloid tracers. This implies that the results of the visual interpretation of amyloid imaging can be well standardized and do not depend on the rating protocol in experts. Consequently, the creation of a universal visual assessment protocol for all amyloid imaging tracers appears feasible, which could benefit especially the less-experienced readers.
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http://dx.doi.org/10.2967/jnumed.120.250290DOI Listing
July 2021

Contribution of rare homozygous and compound heterozygous VPS13C missense mutations to dementia with Lewy bodies and Parkinson's disease.

Acta Neuropathol Commun 2021 02 12;9(1):25. Epub 2021 Feb 12.

Center for Molecular Neurology, VIB, Antwerp, Belgium.

Dementia with Lewy bodies (DLB) and Parkinson's disease (PD) are clinically, pathologically and etiologically disorders embedded in the Lewy body disease (LBD) continuum, characterized by neuronal α-synuclein pathology. Rare homozygous and compound heterozygous premature termination codon (PTC) mutations in the Vacuolar Protein Sorting 13 homolog C gene (VPS13C) are associated with early-onset recessive PD. We observed in two siblings with early-onset age (< 45) and autopsy confirmed DLB, compound heterozygous missense mutations in VPS13C, p.Trp395Cys and p.Ala444Pro, inherited from their healthy parents in a recessive manner. In lymphoblast cells of the index patient, the missense mutations reduced VPS13C expression by 90% (p = 0.0002). Subsequent, we performed targeted resequencing of VPS13C in 844 LBD patients and 664 control persons. Using the optimized sequence kernel association test, we obtained a significant association (p = 0.0233) of rare VPS13C genetic variants (minor allele frequency ≤ 1%) with LBD. Among the LBD patients, we identified one patient with homozygous missense mutations and three with compound heterozygous missense mutations in trans position, indicative for recessive inheritance. In four patients with compound heterozygous mutations, we were unable to determine trans position. The frequency of LBD patient carriers of proven recessive compound heterozygous missense mutations is 0.59% (5/844). In autopsy brain tissue of two unrelated LBD patients, the recessive compound heterozygous missense mutations reduced VPS13C expression. Overexpressing of wild type or mutant VPS13C in HeLa or SH-SY5Y cells, demonstrated that the mutations p.Trp395Cys or p.Ala444Pro, abolish the endosomal/lysosomal localization of VPS13C. Overall, our data indicate that rare missense mutations in VPS13C are associated with LBD and recessive compound heterozygous missense mutations might have variable effects on the expression and functioning of VPS13C. We conclude that comparable to the recessive inherited PTC mutations in VPS13C, combinations of rare recessive compound heterozygous missense mutations reduce VPS13C expression and contribute to increased risk of LBD.
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http://dx.doi.org/10.1186/s40478-021-01121-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7881566PMC
February 2021
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