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  • 1
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    A panel of CSF proteins separates genetic frontotemporal dementia from presymptomatic mutation carriers: a GENFI study
    Springer Science and Business Media LLC ; 2021
    In:  Molecular Neurodegeneration Vol. 16, No. 1 ( 2021-12)
    Details
    In: Molecular Neurodegeneration, Springer Science and Business Media LLC, Vol. 16, No. 1 ( 2021-12)
    Abstract: A detailed understanding of the pathological processes involved in genetic frontotemporal dementia is critical in order to provide the patients with an optimal future treatment. Protein levels in CSF have the potential to reflect different pathophysiological processes in the brain. We aimed to identify and evaluate panels of CSF proteins with potential to separate symptomatic individuals from individuals without clinical symptoms (unaffected), as well as presymptomatic individuals from mutation non-carriers. Methods A multiplexed antibody-based suspension bead array was used to analyse levels of 111 proteins in CSF samples from 221 individuals from families with genetic frontotemporal dementia. The data was explored using LASSO and Random forest. Results When comparing affected individuals with unaffected individuals, 14 proteins were identified as potentially important for the separation. Among these, four were identified as most important, namely neurofilament medium polypeptide (NEFM), neuronal pentraxin 2 (NPTX2), neurosecretory protein VGF (VGF) and aquaporin 4 (AQP4). The combined profile of these four proteins successfully separated the two groups, with higher levels of NEFM and AQP4 and lower levels of NPTX2 in affected compared to unaffected individuals. VGF contributed to the models, but the levels were not significantly lower in affected individuals. Next, when comparing presymptomatic GRN and C9orf72 mutation carriers in proximity to symptom onset with mutation non-carriers, six proteins were identified with a potential to contribute to a separation, including progranulin (GRN). Conclusion In conclusion, we have identified several proteins with the combined potential to separate affected individuals from unaffected individuals, as well as proteins with potential to contribute to the separation between presymptomatic individuals and mutation non-carriers. Further studies are needed to continue the investigation of these proteins and their potential association to the pathophysiological mechanisms in genetic FTD.
    Type of Medium: Online Resource
    ISSN: 1750-1326
    URL: Article
    DOI: 10.1186/s13024-021-00499-4
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
    detail.hit.zdb_id: 2244557-2
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  • 2
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    Faster Cortical Thinning and Surface Area Loss in Presymptomatic and Symptomatic C9orf72 Repeat Expansion Adult Carriers
    Wiley ; 2020
    In:  Annals of Neurology Vol. 88, No. 1 ( 2020-07), p. 113-122
    Details
    In: Annals of Neurology, Wiley, Vol. 88, No. 1 ( 2020-07), p. 113-122
    Abstract: C9orf72 expansion is the most common genetic cause of frontotemporal dementia (FTD). We examined aging trajectories of cortical thickness (CTh) and surface area in C9orf72 expansion adult carriers compared to healthy controls to characterize preclinical cerebral changes leading to symptoms. Methods Data were obtained from the Genetic Frontotemporal Dementia Initiative. T1‐weighted magnetic resonance imaging scans were processed with CIVET 2.1 to extract vertex‐wide CTh and cortical surface area (CSA). Symptomatic and presymptomatic subjects were compared to age‐matched controls using mixed‐effects models, controlling for demographic variables. Aging trajectories were compared between carriers and noncarriers by testing the “age by genetic status” interaction. False discovery rate corrections were applied to all vertex‐wide analyses. Results The sample included 640 scans from 386 subjects, including 54 symptomatic C9orf72 carriers (72.2% behavioral variant FTD), 83 asymptomatic carriers, and 249 controls (age range = 18–86 years). Symptomatic carriers showed fairly symmetric reduction in CTh/CSA in most of the frontal lobes, in addition to large temporoparietal areas. Presymptomatic subjects had reduced CTh/CSA in more restricted areas of the medial frontoparietal lobes, in addition to scattered lateral frontal, parietal, and temporal areas. These differences were explained by faster cortical thinning linearly throughout adulthood in a similar anatomical distribution, with differences emerging in the early 30s. CSA reduction was also faster in mutation carriers predominantly in the ventrofrontal regions. Interpretation C9orf72 mutation carriers have faster cortical thinning and surface loss throughout adulthood in regions that show atrophy in symptomatic subjects. This suggests that the pathogenic effects of the mutation lead to structural cerebral changes decades prior to symptoms. ANN NEUROL 2020 ANN NEUROL 2020;88:113–122
    Type of Medium: Online Resource
    ISSN: 0364-5134 , 1531-8249
    URL: Issue
    URL: Article
    DOI: 10.1002/ana.v88.1
    DOI: 10.1002/ana.25748
    Language: English
    Publisher: Wiley
    Publication Date: 2020
    detail.hit.zdb_id: 2037912-2
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  • 3
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    Data‐driven staging of genetic frontotemporal dementia using multi‐modal MRI
    Wiley ; 2022
    In:  Human Brain Mapping Vol. 43, No. 6 ( 2022-04-15), p. 1821-1835
    Details
    In: Human Brain Mapping, Wiley, Vol. 43, No. 6 ( 2022-04-15), p. 1821-1835
    Abstract: Frontotemporal dementia in genetic forms is highly heterogeneous and begins many years to prior symptom onset, complicating disease understanding and treatment development. Unifying methods to stage the disease during both the presymptomatic and symptomatic phases are needed for the development of clinical trials outcomes. Here we used the contrastive trajectory inference (cTI), an unsupervised machine learning algorithm that analyzes temporal patterns in high‐dimensional large‐scale population datasets to obtain individual scores of disease stage. We used cross‐sectional MRI data (gray matter density, T1/T2 ratio as a proxy for myelin content, resting‐state functional amplitude, gray matter fractional anisotropy, and mean diffusivity) from 383 gene carriers (269 presymptomatic and 115 symptomatic) and a control group of 253 noncarriers in the Genetic Frontotemporal Dementia Initiative. We compared the cTI‐obtained disease scores to the estimated years to onset (age—mean age of onset in relatives), clinical, and neuropsychological test scores. The cTI based disease scores were correlated with all clinical and neuropsychological tests (measuring behavioral symptoms, attention, memory, language, and executive functions), with the highest contribution coming from mean diffusivity. Mean cTI scores were higher in the presymptomatic carriers than controls, indicating that the method may capture subtle pre‐dementia cerebral changes, although this change was not replicated in a subset of subjects with complete data. This study provides a proof of concept that cTI can identify data‐driven disease stages in a heterogeneous sample combining different mutations and disease stages of genetic FTD using only MRI metrics.
    Type of Medium: Online Resource
    ISSN: 1065-9471 , 1097-0193
    URL: Issue
    URL: Article
    DOI: 10.1002/hbm.v43.6
    DOI: 10.1002/hbm.25727
    Language: English
    Publisher: Wiley
    Publication Date: 2022
    detail.hit.zdb_id: 1492703-2
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  • 4
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    Neuronal pentraxin 2: a synapse-derived CSF biomarker in genetic frontotemporal dementia
    BMJ ; 2020
    In:  Journal of Neurology, Neurosurgery & Psychiatry Vol. 91, No. 6 ( 2020-06), p. 612-621
    Details
    In: Journal of Neurology, Neurosurgery & Psychiatry, BMJ, Vol. 91, No. 6 ( 2020-06), p. 612-621
    Abstract: Synapse dysfunction is emerging as an early pathological event in frontotemporal dementia (FTD), however biomarkers are lacking. We aimed to investigate the value of cerebrospinal fluid (CSF) neuronal pentraxins (NPTXs), a family of proteins involved in homeostatic synapse plasticity, as novel biomarkers in genetic FTD. Methods We included 106 presymptomatic and 54 symptomatic carriers of a pathogenic mutation in GRN , C9orf72 or MAPT , and 70 healthy non-carriers participating in the Genetic Frontotemporal dementia Initiative (GENFI), all of whom had at least one CSF sample. We measured CSF concentrations of NPTX2 using an in-house ELISA, and NPTX1 and NPTX receptor (NPTXR) by Western blot. We correlated NPTX2 with corresponding clinical and neuroimaging datasets as well as with CSF neurofilament light chain (NfL) using linear regression analyses. Results Symptomatic mutation carriers had lower NPTX2 concentrations (median 643 pg/mL, IQR (301–872)) than presymptomatic carriers (1003 pg/mL (624–1358), p 〈 0.001) and non-carriers (990 pg/mL (597–1373), p 〈 0.001) (corrected for age). Similar results were found for NPTX1 and NPTXR. Among mutation carriers, NPTX2 concentration correlated with several clinical disease severity measures, NfL and grey matter volume of the frontal, temporal and parietal lobes, insula and whole brain. NPTX2 predicted subsequent decline in phonemic verbal fluency and Clinical Dementia Rating scale plus FTD modules. In longitudinal CSF samples, available in 13 subjects, NPTX2 decreased around symptom onset and in the symptomatic stage. Discussion We conclude that NPTX2 is a promising synapse-derived disease progression biomarker in genetic FTD.
    Type of Medium: Online Resource
    ISSN: 0022-3050 , 1468-330X
    URL: Article
    DOI: 10.1136/jnnp-2019-322493
    RVK:
    XA 10000
    Language: English
    Publisher: BMJ
    Publication Date: 2020
    detail.hit.zdb_id: 1480429-3
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  • 5
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    Plasma glial fibrillary acidic protein is raised in progranulin-associated frontotemporal dementia
    BMJ ; 2020
    In:  Journal of Neurology, Neurosurgery & Psychiatry Vol. 91, No. 3 ( 2020-03), p. 263-270
    Details
    In: Journal of Neurology, Neurosurgery & Psychiatry, BMJ, Vol. 91, No. 3 ( 2020-03), p. 263-270
    Abstract: There are few validated fluid biomarkers in frontotemporal dementia (FTD). Glial fibrillary acidic protein (GFAP) is a measure of astrogliosis, a known pathological process of FTD, but has yet to be explored as potential biomarker. Methods Plasma GFAP and neurofilament light chain (NfL) concentration were measured in 469 individuals enrolled in the Genetic FTD Initiative: 114 C9orf72 expansion carriers (74 presymptomatic, 40 symptomatic), 119 GRN mutation carriers (88 presymptomatic, 31 symptomatic), 53 MAPT mutation carriers (34 presymptomatic, 19 symptomatic) and 183 non-carrier controls. Biomarker measures were compared between groups using linear regression models adjusted for age and sex with family membership included as random effect. Participants underwent standardised clinical assessments including the Mini-Mental State Examination (MMSE), Frontotemporal Lobar Degeneration-Clinical Dementia Rating scale and MRI. Spearman’s correlation coefficient was used to investigate the relationship of plasma GFAP to clinical and imaging measures. Results Plasma GFAP concentration was significantly increased in symptomatic GRN mutation carriers (adjusted mean difference from controls 192.3 pg/mL, 95% CI 126.5 to 445.6), but not in those with C9orf72 expansions (9.0, –61.3 to 54.6), MAPT mutations (12.7, –33.3 to 90.4) or the presymptomatic groups. GFAP concentration was significantly positively correlated with age in both controls and the majority of the disease groups, as well as with NfL concentration. In the presymptomatic period, higher GFAP concentrations were correlated with a lower cognitive score (MMSE) and lower brain volume, while in the symptomatic period, higher concentrations were associated with faster rates of atrophy in the temporal lobe. Conclusions Raised GFAP concentrations appear to be unique to GRN -related FTD, with levels potentially increasing just prior to symptom onset, suggesting that GFAP may be an important marker of proximity to onset, and helpful for forthcoming therapeutic prevention trials.
    Type of Medium: Online Resource
    ISSN: 0022-3050 , 1468-330X
    URL: Article
    DOI: 10.1136/jnnp-2019-321954
    RVK:
    XA 10000
    Language: English
    Publisher: BMJ
    Publication Date: 2020
    detail.hit.zdb_id: 1480429-3
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  • 6
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    Education modulates brain maintenance in presymptomatic frontotemporal dementia
    BMJ ; 2019
    In:  Journal of Neurology, Neurosurgery & Psychiatry Vol. 90, No. 10 ( 2019-10), p. 1124-1130
    Details
    In: Journal of Neurology, Neurosurgery & Psychiatry, BMJ, Vol. 90, No. 10 ( 2019-10), p. 1124-1130
    Abstract: Cognitively engaging lifestyles have been associated with reduced risk of conversion to dementia. Multiple mechanisms have been advocated, including increased brain volumes (ie, brain reserve) and reduced disease progression (ie, brain maintenance). In cross-sectional studies of presymptomatic frontotemporal dementia (FTD), higher education has been related to increased grey matter volume. Here, we examine the effect of education on grey matter loss over time. Methods Two-hundred twenty-nine subjects at-risk of carrying a pathogenic mutation leading to FTD underwent longitudinal cognitive assessment and T1-weighted MRI at baseline and at 1 year follow-up. The first principal component score of the graph-Laplacian Principal Component Analysis on 112 grey matter region-of-interest volumes was used to summarise the grey matter volume (GMV). The effects of education on cognitive performances and GMV at baseline and on the change between 1 year follow-up and baseline (slope) were tested by Structural Equation Modelling. Results Highly educated at-risk subjects had better cognition and higher grey matter volume at baseline; moreover, higher educational attainment was associated with slower loss of grey matter over time in mutation carriers. Conclusions This longitudinal study demonstrates that even in presence of ongoing pathological processes, education may facilitate both brain reserve and brain maintenance in the presymptomatic phase of genetic FTD.
    Type of Medium: Online Resource
    ISSN: 0022-3050 , 1468-330X
    URL: Article
    DOI: 10.1136/jnnp-2019-320439
    RVK:
    XA 10000
    Language: English
    Publisher: BMJ
    Publication Date: 2019
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  • 7
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    Neuropsychiatric symptoms in genetic frontotemporal dementia: developing a new module for Clinical Rating Scales
    BMJ ; 2023
    In:  Journal of Neurology, Neurosurgery & Psychiatry Vol. 94, No. 5 ( 2023-05), p. 357-368
    Details
    In: Journal of Neurology, Neurosurgery & Psychiatry, BMJ, Vol. 94, No. 5 ( 2023-05), p. 357-368
    Abstract: Current clinical rating scales in frontotemporal dementia (FTD) often do not incorporate neuropsychiatric features and may therefore inadequately measure disease stage. Methods 832 participants from the Genetic FTD Initiative (GENFI) were recruited: 522 mutation carriers and 310 mutation-negative controls. The standardised GENFI clinical questionnaire assessed the frequency and severity of 14 neuropsychiatric symptoms: visual, auditory, and tactile hallucinations, delusions, depression, anxiety, irritability/lability, agitation/aggression, euphoria/elation, aberrant motor behaviour, hypersexuality, hyperreligiosity, impaired sleep, and altered sense of humour. A principal component analysis (PCA) was performed to identify key groupings of neuropsychiatric and behavioural items in order to create a new neuropsychiatric module that could be used as an addition to the Clinical Dementia Rating (CDR) plus National Alzheimer’s Coordinating Center Behaviour and Language Domains (NACC FTLD) rating scale. Results Overall, 46.4% of mutation carriers had neuropsychiatric symptoms (51.6% C9orf72 , 40.8% GRN , 46.6% MAPT ) compared with 24.5% of controls. Anxiety and depression were the most common in all genetic groups but fluctuated longitudinally and loaded separately in the PCA. Hallucinations and delusions loaded together, with the remaining neuropsychiatric symptoms loading with the core behavioural features of FTD. These results suggest using a single ‘psychosis’ neuropsychiatric module consisting of hallucinations and delusions. Adding this to the CDR plus NACC FTLD, called the CDR plus NACC FTLD-N, leads to a number of participants being scored more severely, including those who were previously considered asymptomatic now being scored as prodromal. Conclusions Neuropsychiatric symptoms occur in mutation carriers at all disease stages across all three genetic groups. However, only psychosis features provided additional staging benefit to the CDR plus NACC FTLD. Inclusion of these features brings us closer to optimising the rating scale for use in trials.
    Type of Medium: Online Resource
    ISSN: 0022-3050 , 1468-330X
    URL: Article
    DOI: 10.1136/jnnp-2022-330152
    RVK:
    XA 10000
    Language: English
    Publisher: BMJ
    Publication Date: 2023
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  • 8
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    CSF glial markers are elevated in a subset of patients with genetic frontotemporal dementia
    Wiley ; 2022
    In:  Annals of Clinical and Translational Neurology Vol. 9, No. 11 ( 2022-11), p. 1764-1777
    Details
    In: Annals of Clinical and Translational Neurology, Wiley, Vol. 9, No. 11 ( 2022-11), p. 1764-1777
    Abstract: Neuroinflammation has been shown to be an important pathophysiological disease mechanism in frontotemporal dementia (FTD). This includes activation of microglia, a process that can be measured in life through assaying different glia‐derived biomarkers in cerebrospinal fluid. However, only a few studies so far have taken place in FTD, and even fewer focusing on the genetic forms of FTD. Methods We investigated the cerebrospinal fluid concentrations of TREM2, YKL‐40 and chitotriosidase using immunoassays in 183 participants from the Genetic FTD Initiative (GENFI) study: 49 C9orf72 (36 presymptomatic, 13 symptomatic), 49 GRN (37 presymptomatic, 12 symptomatic) and 23 MAPT (16 presymptomatic, 7 symptomatic) mutation carriers and 62 mutation‐negative controls. Concentrations were compared between groups using a linear regression model adjusting for age and sex, with 95% bias‐corrected bootstrapped confidence intervals. Concentrations in each group were correlated with the Mini‐Mental State Examination (MMSE) score using non‐parametric partial correlations adjusting for age. Age‐adjusted z ‐scores were also created for the concentration of markers in each participant, investigating how many had a value above the 95th percentile of controls. Results Only chitotriosidase in symptomatic GRN mutation carriers had a concentration significantly higher than controls. No group had higher TREM2 or YKL‐40 concentrations than controls after adjusting for age and sex. There was a significant negative correlation of chitotriosidase concentration with MMSE in presymptomatic GRN mutation carriers. In the symptomatic groups, for TREM2 31% of C9orf72 , 25% of GRN , and 14% of MAPT mutation carriers had a concentration above the 95 th percentile of controls. For YKL‐40 this was 8% C9orf72 , 8% GRN and 0% MAPT mutation carriers, whilst for chitotriosidase it was 23% C9orf72 , 50% GRN , and 29% MAPT mutation carriers. Conclusions Although chitotriosidase concentrations in GRN mutation carriers were the only significantly raised glia‐derived biomarker as a group, a subset of mutation carriers in all three groups, particularly for chitotriosidase and TREM2, had elevated concentrations. Further work is required to understand the variability in concentrations and the extent of neuroinflammation across the genetic forms of FTD. However, the current findings suggest limited utility of these measures in forthcoming trials.
    Type of Medium: Online Resource
    ISSN: 2328-9503 , 2328-9503
    URL: Issue
    URL: Article
    DOI: 10.1002/acn3.v9.11
    DOI: 10.1002/acn3.51672
    Language: English
    Publisher: Wiley
    Publication Date: 2022
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  • 9
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    A modified Camel and Cactus Test detects presymptomatic semantic impairment in genetic frontotemporal dementia within the GENFI cohort
    Informa UK Limited ; 2022
    In:  Applied Neuropsychology: Adult Vol. 29, No. 1 ( 2022-01-02), p. 112-119
    Details
    In: Applied Neuropsychology: Adult, Informa UK Limited, Vol. 29, No. 1 ( 2022-01-02), p. 112-119
    Type of Medium: Online Resource
    ISSN: 2327-9095 , 2327-9109
    URL: Article
    DOI: 10.1080/23279095.2020.1716357
    Language: English
    Publisher: Informa UK Limited
    Publication Date: 2022
    detail.hit.zdb_id: 2673748-6
    SSG: 5,2
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  • 10
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    Analysis of brain atrophy and local gene expression in genetic frontotemporal dementia
    Oxford University Press (OUP) ; 2020
    In:  Brain Communications Vol. 2, No. 2 ( 2020-07-01)
    Details
    In: Brain Communications, Oxford University Press (OUP), Vol. 2, No. 2 ( 2020-07-01)
    Abstract: Frontotemporal dementia is a heterogeneous neurodegenerative disorder characterized by neuronal loss in the frontal and temporal lobes. Despite progress in understanding which genes are associated with the aetiology of frontotemporal dementia, the biological basis of how mutations in these genes lead to cell loss in specific cortical regions remains unclear. In this work, we combined gene expression data for 16 772 genes from the Allen Institute for Brain Science atlas with brain maps of grey matter atrophy in symptomatic C9orf72, GRN and MAPT mutation carriers obtained from the Genetic Frontotemporal dementia Initiative study. No significant association was seen between C9orf72, GRN and MAPT expression and the atrophy patterns in the respective genetic groups. After adjusting for spatial autocorrelation, between 1000 and 5000 genes showed a negative or positive association with the atrophy pattern within each individual genetic group, with the most significantly associated genes being TREM2, SSBP3 and GPR158 (negative association in C9Orf72, GRN and MAPT respectively) and RELN, MXRA8 and LPA (positive association in C9Orf72, GRN and MAPT respectively). An overrepresentation analysis identified a negative association with genes involved in mitochondrial function, and a positive association with genes involved in vascular and glial cell function in each of the genetic groups. A set of 423 and 700 genes showed significant positive and negative association, respectively, with atrophy patterns in all three maps. The gene set with increased expression in spared cortical regions was enriched for neuronal and microglial genes, while the gene set with increased expression in atrophied regions was enriched for astrocyte and endothelial cell genes. Our analysis suggests that these cell types may play a more active role in the onset of neurodegeneration in frontotemporal dementia than previously assumed, and in the case of the positively associated cell marker genes, potentially through emergence of neurotoxic astrocytes and alteration in the blood–brain barrier, respectively.
    Type of Medium: Online Resource
    ISSN: 2632-1297
    URL: Article
    DOI: 10.1093/braincomms/fcaa122
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2020
    detail.hit.zdb_id: 3020013-1
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