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Browsing by Author "Greaves, Caroline V."

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  • CSF glial markers are elevated in a subset of patients with genetic frontotemporal dementia
    Publication . the Genetic FTD Initiative, GENFI; Woollacott, Ione O.C.; Swift, Imogen J.; Sogorb-Esteve, Aitana; Heller, Carolin; Knowles, Kathryn; Bouzigues, Arabella; Russell, Lucy L.; Peakman, Georgia; Greaves, Caroline V.; Convery, Rhian; Heslegrave, Amanda; Rowe, James B.; Borroni, Barbara; Galimberti, Daniela; Tiraboschi, Pietro; Masellis, Mario; Tartaglia, Maria Carmela; Finger, Elizabeth; van Swieten, John C.; Seelaar, Harro; Jiskoot, Lize; Sorbi, Sandro; Butler, Chris R.; Graff, Caroline; Gerhard, Alexander; Laforce, Robert; Sanchez-Valle, Raquel; de Mendonça, Alexandre; Moreno, Fermin; Synofzik, Matthis; Vandenberghe, Rik; Ducharme, Simon; Ber, Isabelle Le; Levin, Johannes; Otto, Markus; Pasquier, Florence; Santana, Isabel; Zetterberg, Henrik; Rohrer, Jonathan D.; Nelson, Annabel; Bocchetta, Martina; Cash, David; Thomas, David L.; Todd, Emily; Benotmane, Hanya; Nicholas, Jennifer; Samra, Kiran; Maruta, Carolina; do Couto, Frederico Simões; Almeida, Maria Rosário
    Background: 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 95th 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.
    2022-11Journal article Open access Show more
  • Extending the phenotypic spectrum assessed by the CDR plus NACC FTLD in genetic frontotemporal dementia
    Publication . Genetic FTD Initiative (GENFI); Samra, Kiran; Peakman, Georgia; MacDougall, Amy M.; Bouzigues, Arabella; Greaves, Caroline V.; Convery, Rhian S.; Swieten, John C. van; Jiskoot, Lize; Seelaar, Harro; Moreno, Fermin; Sanchez-Valle, Raquel; Laforce, Robert; Graff, Caroline; Masellis, Mario; Tartaglia, Maria Carmela; Rowe, James B.; Borroni, Barbara; Finger, Elizabeth; Synofzik, Matthis; Galimberti, Daniela; Vandenberghe, Rik; Mendonça, Alexandre de; Butler, Chris R.; Gerhard, Alexander; Ducharme, Simon; Ber, Isabelle Le; Tiraboschi, Pietro; Santana, Isabel; Pasquier, Florence; Levin, Johannes; Otto, Markus; Sorbi, Sandro; Rohrer, Jonathan D.; Russell, Lucy L.; Bocchetta, Martina; Cash, David; Thomas, David L.; Cope, Thomas; Rittman, Timothy; Benussi, Alberto; Premi, Enrico; Gasparotti, Roberto; Archetti, Silvana; Gazzina, Stefano; Cantoni, Valentina; Arighi, Andrea; Maruta, Carolina; do Couto, Frederico Simões; Alves, Patricia; Almeida, Maria Rosario
    INTRODUCTION: We aimed to expand the range of the frontotemporal dementia (FTD) phenotypes assessed by the Clinical Dementia Rating Dementia Staging Instrument plus National Alzheimer's Coordinating Center Behavior and Language Domains (CDR plus NACC FTLD). METHODS: Neuropsychiatric and motor domains were added to the standard CDR plus NACC FTLD generating a new CDR plus NACC FTLD-NM scale. This was assessed in 522 mutation carriers and 310 mutation-negative controls from the Genetic Frontotemporal dementia Initiative (GENFI). RESULTS: The new scale led to higher global severity scores than the CDR plus NACC FTLD: 1.4% of participants were now considered prodromal rather than asymptomatic, while 1.3% were now considered symptomatic rather than asymptomatic or prodromal. No participants with a clinical diagnosis of an FTD spectrum disorder were classified as asymptomatic using the new scales. DISCUSSION: Adding new domains to the CDR plus NACC FTLD leads to a scale that encompasses the wider phenotypic spectrum of FTD with further work needed to validate its use more widely. Highlights: The new Clinical Dementia Rating Dementia Staging Instrument plus National Alzheimer's Coordinating Center Behavior and Language Domains neuropsychiatric and motor (CDR plus NACC FTLD-NM) rating scale was significantly positively correlated with the original CDR plus NACC FTLD and negatively correlated with the FTD Rating Scale (FRS). No participants with a clinical diagnosis in the frontotemporal dementia spectrum were classified as asymptomatic with the new CDR plus NACC FTLD-NM rating scale. Individuals had higher global severity scores with the addition of the neuropsychiatric and motor domains. A receiver operating characteristic analysis of symptomatic diagnosis showed nominally higher areas under the curve for the new scales.
    2024-04-01Journal article Open access Show more
  • Language impairment in the genetic forms of behavioural variant frontotemporal dementia
    Publication . On Behalf of the Genetic FTD Initiative (GENFI); Samra, Kiran; MacDougall, Amy M.; Bouzigues, Arabella; Bocchetta, Martina; Cash, David M.; Greaves, Caroline V.; Convery, Rhian S.; van Swieten, John C.; Seelaar, Harro; Jiskoot, Lize; Moreno, Fermin; Sanchez-Valle, Raquel; Laforce, Robert; Graff, Caroline; Masellis, Mario; Tartaglia, Maria Carmela; Rowe, James B.; Borroni, Barbara; Finger, Elizabeth; Synofzik, Matthis; Galimberti, Daniela; Vandenberghe, Rik; de Mendonça, Alexandre; Butler, Christopher R.; Gerhard, Alexander; Ducharme, Simon; Le Ber, Isabelle; Tiraboschi, Pietro; Santana, Isabel; Pasquier, Florence; Levin, Johannes; Otto, Markus; Sorbi, Sandro; Rohrer, Jonathan D.; Russell, Lucy L.; Nelson, Annabel; Thomas, David L.; Todd, Emily; Benotmane, Hanya; Nicholas, Jennifer; Shafei, Rachelle; Timberlake, Carolyn; Cope, Thomas; Rittman, Timothy; Benussi, Alberto; Premi, Enrico; Gasparotti, Roberto; Archetti, Silvana; Maruta, Carolina; do Couto, Frederico Simões
    Background: Behavioural variant fronto-temporal dementia (bvFTD) is characterised by a progressive change in personality in association with atrophy of the frontal and temporal lobes. Whilst language impairment has been described in people with bvFTD, little is currently known about the extent or type of linguistic difficulties that occur, particularly in the genetic forms. Methods: Participants with genetic bvFTD along with healthy controls were recruited from the international multicentre Genetic FTD Initiative (GENFI). Linguistic symptoms were assessed using items from the Progressive Aphasia Severity Scale (PASS). Additionally, participants undertook the Boston Naming Test (BNT), modified Camel and Cactus Test (mCCT) and a category fluency test. Participants underwent a 3T volumetric T1-weighted MRI, with language network regional brain volumes measured and compared between the genetic groups and controls. Results: 76% of the genetic bvFTD cohort had impairment in at least one language symptom: 83% C9orf72, 80% MAPT and 56% GRN mutation carriers. All three genetic groups had significantly impaired functional communication, decreased fluency, and impaired sentence comprehension. C9orf72 mutation carriers also had significantly impaired articulation and word retrieval as well as dysgraphia whilst the MAPT mutation group also had impaired word retrieval and single word comprehension. All three groups had difficulties with naming, semantic knowledge and verbal fluency. Atrophy in key left perisylvian language regions differed between the groups, with generalised involvement in the C9orf72 group and more focal temporal and insula involvement in the other groups. Correlates of language symptoms and test scores also differed between the groups. Conclusions: Language deficits exist in a substantial proportion of people with familial bvFTD across all three genetic groups. Significant atrophy is seen in the dominant perisylvian language areas and correlates with language impairments within each of the genetic groups. Improved understanding of the language phenotype in the main genetic bvFTD subtypes will be helpful in future studies, particularly in clinical trials where accurate stratification and monitoring of disease progression is required.
    2023-04Journal article Open access Show more