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Cortical thickness in presymptomatic GRN and C9ORF72 mutation carriers Dowds, Emma Frances

Abstract

Objective: This thesis aimed to investigate cortical thickness in presymptomatic GRN and C9ORF72 mutation carriers prior to the onset of frontotemporal dementia (FTD). Methods: Subjects were recruited from 16 families with a family history of FTD caused by GRN or C9ORF72 mutations. The C9ORF72 group consisted of 8 mutation carriers (age 50.25 ± 6.90 years), 11 non-carrier family member controls (age 52.82 ± 17.15 years), and 3 affected carriers (age 55.00 ± 1.00 years). The GRN group consisted of 6 mutation carriers (age 53.33 ± 9.67 years) and 9 non-carrier family member controls (age 52.11 ± 8.82). Between group differences in cortical thickness were assessed using a surface based vertex-by-vertex model correcting for age, sex, MMSE and years to mean age of family onset. Significant clusters are reported at 10mm, 15mm and 20mm of smoothing and those identified at all three, two consecutive or one smoothing level are reported with strong, moderate and weak confidence, respectively. Results: Compared to non-carrier control family members, the C9ORF72 mutation carriers exhibited no difference in cognitive domain scores, but presented with strong to moderate asymmetrical patterns of thinning in the right temporoinsular and left mediofrontal and temporal regions. Compared to non-carrier controls, the GRN mutation carriers exhibited decreased performance on domains of working memory (p = 0.02) and executive function (p = 0.01), with a trend towards reduced language (p = 0.06) and visuospatial (p = 0.08) domains, but did not exhibit any difference in cortical thickness when compared to the non-carrier control family members. Conclusions: With the use of genetic screening and neuroimaging analyses this thesis demonstrated that grey matter atrophy occurs prior to cognitive decline in C9ORF72 mutation carriers, while GRN carriers exhibit subtle changes in cognitive domains prior to cortical grey matter atrophy. These findings could prove to be highly valuable as they suggest that the mechanism of disease progression between the two mutations may differ. As such, each mutation may require specific neuroimaging methods to track morphological changes prior to cognitive decline and clinical onset.

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Attribution-NonCommercial-NoDerivs 2.5 Canada