O Connor 1. Appendix e-1

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1 O Connor 1 Appendix e-1 Neuropsychiatric assessment The Cambridge Behavioural Inventory Revised (CBI-R) 1, 2 is a proxy behavioural questionnaire that has been extensively used in studies involving FTD patients 3, 4. It comprises 45 items assessing the patient across ten domains (subscales: memory and orientation, everyday skills, self-care, abnormal behaviour, mood, beliefs, eating habits, sleep, stereotypic and motor behaviours, motivation). For each question the behaviour is rated on a five-point scale (0 = never, 1 = a few times per month, 2 = a few times per week, 3 = daily, and 4 = constantly), with higher scores indicating higher frequency of behavioural symptoms. Given the aims of the present study, focus was given to the disinhibition and apathy subscales from the CBI-R (data collected on the first visit to the research centre). To allow comparison between domains, these two subsection scores were converted to percentages, where higher scores represent greater behavioural change. Functional disability assessment The Disability Assessment for Dementia (DAD) 5 is a proxy assessment consisting of 40 items to assess ADLs widely used in dementia studies and drug trials 6, 7. Basic ADLs are measured over 17 items and include: hygiene, dressing, continence, and eating. Complex instrumental ADLs such as meal preparation, telephoning, going on an outing, finance and correspondence, medications, and leisure and housework are measured over 23 items. Non-applicable questions are omitted from the final score, which is reported as a percentage to avoid bias towards certain activities (e.g., meal preparation or housework). Greater impairment is indicated by lower DAD scores. In order to further distinguish baseline clinical differences between the groups in addition to overall DAD scores, basic ADL and instrumental ADL sub scores as well as performance components of initiation, planning and execution were included in the analyses. All caregivers were interviewed by experienced research occupational therapists (EM, COC or CK).

2 O Connor 2 General cognitive assessment To evaluate general cognition at baseline, the Addenbrooke s Cognitive Examination Revised (ACE-R) 8 was used with patients until February 2014, and the ACE-III 9, 10 was used with patients thereafter. These two ACE versions differ minimally and are significantly correlated (rp = 0.99, p<.01). The ACE assesses five cognitive domains: attention and orientation, memory, verbal fluency, language, and visuospatial abilities. The total score is 100, where higher scores indicate better cognitive functioning. The tool is sensitive to the early stages of dementia, where a cut-off of 88/100 for diagnosing dementia yields 89% specificity and 94% sensitivity for the ACE-R and 100% sensitivity and 96% specificity for the ACE-III. Validation of cluster analysis To validate the four cluster solution, two consecutive two-step clustering procedures using Euclidean distance were conducted - each with a different information criterion. The first analysis using Bayes information criterion (BIC) generated a 3-cluster solution, with an average silhouette width of 0.6; silhouette scores range from <0.25 (probably nil significant clusters) to >0.7 (excellent cluster separation) 11. For this analysis using BIC, apathy contributed 100% to the cluster separation, with disinhibition scores only contributing 58%. Finally the two-step cluster analysis was repeated using Akaike s information criterion (AIC), this time generating a 4-cluster solution. For this solution using AIC, the average silhouette width remained at 0.6 indicating this was also a good cluster solution, however in this 4-cluster solution, the variables contributed more equally to cluster formation; apathy (100%) and disinhibition (85%). Imaging acquisition and pre-processing For imaging analyses, 72 available scans for bvftd and 30 healthy controls were included. A total of 16 bvftd participants did not have scans available for analysis and were not included in the imaging analyses. Therefore, participants excluded across clusters were: PSA, n=5; SA+D, n=4; MA+D, n=5; and PSD, n=2. The mean time difference between CBI-R and imaging acquisition in patients was 3 months (Std dev 11 months). All participants underwent whole brain structural MRI with a 3 T Phillips scanner using a standard 8-channel head coil. 3D high-resolution

3 O Connor 3 turbo field echo T1-weighted sequences were acquired with the following parameters: coronal orientation, matrix , 200 slices, 1 mm2 in-plane resolution, slice thickness 1 mm, echo time/repetition time 2.6/5.8 ms, flip angle α=8. FreeSurfer software, version ( was used for surfacebased cortical processing 12 using standard methods 13. Cortical thickness was smoothed with a 20 mm full-width at half-height Gaussian kernel. All images were visually inspected and manually corrected in the event of tissue segmentation errors. Two bvftd patients had to be excluded due to excessive surface or subcortical segmentation errors. Thus, a total of 100 scans (70 bvftd and 30 healthy controls) were included in the final analyses. e-appendix References 1. Nagahama Y, Okina T, Suzuki N, Matsuda M. The Cambridge Behavioral Inventory: validation and application in a memory clinic. J Geriatr Psychiatry Neurol 2006;19: Wedderburn C, Wear H, Brown J, et al. The utility of the Cambridge Behavioural Inventory in neurodegenerative disease. J Neurol Neurosurg Psychiatry 2008;79: Kumfor F, Landin-Romero R, Devenney E, et al. On the right side? A longitudinal study of left- versus right-lateralized semantic dementia. Brain 2016;139: Piguet O, Petersen A, Lam BYK, et al. Eating and hypothalamus changes in behavioral-variant frontotemporal dementia. Ann Neurol 2011;69: Gelinas I, Gauthier L, McIntyre M, Gauthier S. Development of a functional measure for persons with Alzheimer s disease: The Disability Assessment for Dementia. Am J Occup Ther 1999;53: Rockwood K, Fay S, Song X, MacKnight C, Gorman M. Attainment of treatment goals by people with Alzheimer's disease receiving galantamine: a randomized controlled trial. CMAJ 2006;174: Vercelletto M, Boutoleau-Bretonniere C, Volteau C, et al. Memantine in behavioral variant frontotemporal dementia: negative results. J Alzheimers Dis 2011;23:

4 O Connor 4 8. Mioshi E, Dawson K, Mitchell J, Arnold R, Hodges JR. The Addenbrooke s Cognitive Examination Revised (ACE-R): A brief cognitive test battery for dementia screening. Int J Geriatr Psychiatry 2006;21: Hsieh S, McGrory S, Leslie F, et al. The Mini-Addenbrooke's Cognitive Examination: a new assessment tool for dementia. Dement Geriatr Cogn Disord 2014;39: Hsieh S, Schubert S, Hoon C, Mioshi E, Hodges JR. Validation of the Addenbrooke's Cognitive Examination III in frontotemporal dementia and Alzheimer's disease. Dement Geriatr Cogn Disord 2013;36: Mooi E, Sarstedt M. Cluster analysis. A Concise Guide to Market Research. Berlin: Springer, 2011: Dale AM, Fischl B, Sereno MI. Cortical surface-based analysis. I. Segmentation and surface reconstruction. Neuroimage 1999;9: Fischl B, Dale AM. Measuring the thickness of the human cerebral cortex from magnetic resonance images. Proc Natl Acad Sci U S A 2000;97:

5 O Connor 5 Table e-1 Component sub-regions for region of interest analyses. Component sub-regions of lobe Cortical lobes Frontal Temporal Parietal Occipital Cortical thickness of caudal middle frontal, rostral middle frontal, medial orbitofrontal, lateral orbitofrontal, pars opercularis, pars orbitalis, pars triangularis, superior frontal, precentral, and paracentral regions Cortical thickness of banks superior temporal sulcus, inferior temporal, middle temporal, superior temporal, fusiform, entorhinal, parahippocampal, transverse temporal, temporal pole, and insula regions Cortical thickness of inferior parietal, superior parietal, supramarginal, precuneus, and postcentral regions Cortical thickness of cuneus, lingual, pericalcarine, and lateral occipital regions Component sub-regions were identical in both hemispheres

6 O Connor 6 Figure e-1: Dendrogram generated in the hierarchical agglomerative cluster analysis

7 O Connor 7 Each of the 88 bvftd participants began in their own cluster before being progressively clustered together with each step of the analysis. PSA = primary severe apathy, SA+D = severe apathy and disinhibition, MA+D = mild apathy and disinhibition, PSD = primary severe disinhibition.

8 O Connor 8 Figure e-2: Patterns of brain atrophy in bvftd clusters vs healthy controls PSA = Primary severe apathy, SA+D = Severe apathy and disinhibition, MA+D = Mild apathy and disinhibition, PSD = Primary Severe Disinhibition, HC = Healthy controls. Statistical significance was set at p = uncorrected for multiple comparisons.

9 O Connor 9 Figure e-3: Kaplan-Meier survival plot from diagnosis to residential care admission for bvftd patient subgroups PSA = primary severe apathy, SA+D = severe apathy and disinhibition, MA+D = mild apathy and disinhibition, PSD = primary severe disinhibition.