AusCADASIL: An Australian Cohort of CADASIL

Study Overview
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Brief Summary
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The aim of this project is to establish an Australian cohort of patients diagnosed with Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL). This study will examine the clinical features and longitudinal course of CADASIL. Outcome measures include neuropsychological profile, neuroimaging, genetics, blood biomarkers, and retinal imaging.

Detailed Description
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Using clinical examination, questionnaires, neuropsychological evaluation, brain MRI, blood sample evaluation and retinal imaging, we aim to characterise the clinical profile and progression of CADASIL in an Australian cohort. This is multi-centre observational cohort study currently based at six sites (clinics, hospitals and universities) across three states in Australia (New South Wales, Victoria and Queensland). The multidisciplinary team aims to be the first to develop an Australian cohort of CADASIL which will contribute to global efforts and understanding of the disease.

Official Title
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AusCADASIL: An Australian Cohort of CADASIL

Conditions
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Cadasil

Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Adults ≥18 years old Ability to provide written informed consent A large-print version is available for individuals with visual impairment An easy-to-read version is available for individuals with cognitive difficulties who may require extra support Ability to attend a testing site Ability to complete minimum dataset (medical examination and medical history questionnaire, blood test to determine genetic status and a short (20 minute) neuropsychology assessment). CADASIL participants according to one of the following categories: confirmed diagnosis via genetic testing (NOTCH3 pathogenic variant), OR suspected diagnosis based on medical history and brain MRI, OR first degree relative of participant who is positive for NOTCH3 pathogenic variant OR 6. Unrelated individual who is negative for the NOTCH3 pathogenic variant, and has no cognitive complaints (i.e. control participant) Exclusion criteria: 1. Significant cognitive impairment leading to an inability to provide informed consent.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| CADASIL cohort<br> | |
| Control Cohort<br> | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Online Medical Questionnaire | Includes questions on participant's medical history (CADASIL and other), family history, and medication use. Outcome will be used to inform clinical profile | Baseline, Year 1, Year 2, Year 3, Year 4 | 
| Weight and height will be combined to report BMI in kg/m^2 | Participants will undergo structured physical examination which will provide further details on their clinical profile. | Baseline, Year 1, Year 2, Year 3, Year 4 | 
| Blood Pressure | Participants will undergo structured physical examination which will provide further details on their clinical profile. Systolic/diastolic blood pressure will be recorded 3 times during the physical examination | Baseline, Year 1, Year 2, Year 3, Year 4 | 
| Modified Rankin Scale (mRS) | Participants will undergo structured physical examination which will provide further details on their clinical profile. Scale from 0-5 (0 no symptoms, 5 severe disability) | Baseline, Year 1, Year 2, Year 3, Year 4 | 
| National Institute of Health Stroke Scale (NIHSS) | Participants will undergo structured physical examination which will provide further details on their clinical profile. Individual items (11) relating to stroke symptoms and disability, for each item 0 indicates normal. | Baseline, Year 1, Year 2, Year 3, Year 4 | 
| Alphabet required for Trail Making A/B | As part of the neuropsychological battery, participants will need to complete the alphabet to inform ability to complete Trail Making tests A and B. These indicate executive function | Baseline, Year 1, Year 2, Year 3, Year 4 | 
| Montreal Cognitive Assessment (MoCA) | As part of the neuropsychological battery, participants will complete the MoCA to provide a measure of global cognitive function | Baseline, Year 1, Year 2, Year 3, Year 4 | 
| Category Fluency (animals) | As part of the neuropsychological battery, participants will complete Category Fluency to provide a measure of processing speed | Baseline, Year 1, Year 2, Year 3, Year 4 | 
| Digit Span Backwards (WAIS-IV) | As part of the neuropsychological battery, participants will complete digit span backwards to provide a measure of executive function | Baseline, Year 1, Year 2, Year 3, Year 4 | 
| National Institute of Health Computerised Toolbox (NIHCTB) | As part of the neuropsychological battery, participants will complete the NIHCTB to provide measures of global function | Baseline, Year 1, Year 2, Year 3, Year 4 | 
| Letter Fluency (FAS) | As part of the neuropsychological battery, participants will complete the FAS to provide measures of executive function | Baseline, Year 1, Year 2, Year 3, Year 4 | 
| Rey Auditory Verbal Learning Test (RAVLT) | As part of the neuropsychological battery, participants will complete the RAVLT to provide measures of learning and memory | Baseline, Year 1, Year 2, Year 3, Year 4 | 
| Brain MRI scan (total scan time 60 mins)- includes T1 weighted imaging | To assess brain morphology | Baseline, Year 3 | 
| Brain MRI scan (total scan time 60 mins)- includes T2-weighted fluid attenuated inversion recovery (FLAIR) imaging | Combined with T1 outcome to assess brain morphology | Baseline, Year 3 | 
| Brain MRI scan (total scan time 60 mins)- includes susceptibility-weighted MRI | Assesses cerebral microbleeds. Signal magnitude will be processed to estimate signal decay time (i.e., T2* maps), which reflect compartmentalisation of magnetised tissue constituents (iron, calcium) [22]. Signal phase will be processed for quantitative susceptibility mapping. | Baseline, Year 3 | 
| Brain MRI scan (total scan time 60 mins)- includes multi-shell diffusion weighted MRI | Measures of brain white matter microstructural integrity, such as fractional anisotropy and mean diffusivity, will be calculated using tensor models. Fixel-based analyses of fibre density and cross-section will also be performed. Markers of cerebrovascular diseases derived from diffusion data, such as Peak width of Skeletonised Mean Diffusivity (PSMD), will be calculated. Structural connectivity will also be examined. | Baseline, Year 3 | 
| Brain MRI scan (total scan time 60 mins)- includes pseudo-continuous arterial spin labelling (PCASL) perfusion imaging with multiple post-labelling delays. | Used to assess quantitative cerebral blood flow and arterial transit time. | Baseline, Year 3 | 
| Brain MRI scan (total scan time 60 mins)- includes resting-state blood oxygenation level dependent (BOLD) imaging. | Used to assess brain functional activity and amplitude of low-frequency fluctuations which embeds signal of cerebrovascular reactivity. For sites with available capnography monitors, participants' end-tidal carbon dioxide concentrations will be recorded during acquiring resting-state BOLD data for more accurate quantification of cerebrovascular reactivity | Baseline, Year 3 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Blood biochemistry | Analysed by local pathology lab to indicate clinical profile. Measures will include fasting glucose, HbA1c, lipids, C-reactive protein, creatinine, vit D and liver function tests. | Baseline, Year 3 | 
| Ocular Questionnaire | Includes questions regarding vision ability and ocular symptoms, and history | Baseline, Year 3 | 
| Genetic Profile | Genetic testing for NOTCH3 variants as well as potentially modifying genes | Baseline | 
| Instrumental Activities of Daily Living Scale (IADL) | Completed online, 8 items to assess daily living skills in older adults. Outcome will be used to inform clinical profile | Baseline | 
| Quality of Life Scale (EQ-5D-5L) | Completed online, 6 items to assess mobility, self-care, activities, pain/discomfort, anxiety/depression. Outcome will be used to inform clinical profile | Baseline | 
| STOP-BANG Sleep Questionnaire | Completed online, 8 items to assess Obstructive Sleep Apnoea risk. Outcome will be used to inform clinical profile | Baseline | 
| PROMIS Sleep Disturbance | Completed online, 8 items to assess sleep quality. Outcome will be used to inform clinical profile | Baseline | 
| Apathy Evaluation Scale (AES) | Completed online, 18 items to assess apathy by goal-directed behaviour, goal-related cognition, and goal-related emotional responses. Outcome will be used to inform clinical profile | Baseline | 
| Multidimensional Fatigue Inventory (MFI) | Completed online, 20 items to assess physical and mental fatigue and motivation. Outcome will be used to inform clinical profile | Baseline | 
| Patient Health Questionnaire-9 (PHQ-9) | Completed online, 9 items to assess depression symptoms and severity. Outcome will be used to inform clinical profile | Baseline | 
| Hospital Anxiety and Depression Scale (HADS) | Completed online, includes 14 items to assess non-physical symptoms of anxiety and depression. Outcome will be used to inform clinical profile | Baseline | 
| Study Partner Apathy Evaluation Scale (AES) | Completed online by nominated study partner (someone who knows the participant well e.g. spouse, carer, friend etc). Inform's participant's apathy by goal-directed behaviour, goal-related cognition, and goal-related emotional responses | Baseline | 
| Study Partner Instrumental Activities of Daily Living Scale (IADL) | Completed online by nominated study partner (someone who knows the participant well e.g. spouse, carer, friend etc). 8 items to assess daily living skills in older adults. Outcome will be used to inform participant's clinical profile | Baseline | 
| Neuropsychiatric Inventory (NPI-Q) | Completed online by nominated study partner (someone who knows the participant well e.g. spouse, carer, friend etc). 12 domains, approx. 100 questions. Used to inform psychopathology in participants | Baseline | 
| Blood Omic investigation | Blood tubes will be transported to the University of New South Wales for genomics, proteomics, lipidomics, and epigenomics analysis | Baseline and year 3 | 
| Ocular Assessment-Visual Acuity | a measure of the vision function using high contrast letters will be performed with standardised vision charts at distance and at near. | Baseline and year 3 | 
| Ocular Assessment- Contrast Sensitivity | A measure of vision function, relating to the ability to distinguish between an object and the background behind it. | Baseline and year 3 | 
| Ocular Assessment- Stereopsis | The perception of depth will be measured using a stereo acuity instrument by viewing a series of stereograms. | Baseline and year 3 | 
| Ocular Assessment- Slit-lamp examination | Involves viewing of the ocular structures using a slit-lamp illumination system and biomicroscope viewing system. The slit-lamp examination will be conducted by a trained observer and will allow identification of ocular media opacities, abnormalities of the eye lids, tear film and anterior structures. | Baseline and year 3 | 
| Ocular Assessment- Standard automated perimetry | A measure of the sensitivity of the visual field. | Baseline and year 3 | 
| Ocular Assessment- Intraocular pressure | A measure of the pressure within the eye. | Baseline and year 3 | 
| Ocular Assessment- Fundus imaging (requires pupil dilation using tropicamide 0.5 or 1.0% eye drops | Used to visualise the back of the eye | Baseline and year 3 | 
| Ocular Assessment- Optical Coherence Tomography (OCT) and OCT-Angiography | Used to visualise the back of the eye in retinal layers, and the retinal vessels | Baseline and year 3 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CADASIL, Clinical Research, Genetics, Cognition, Neuroimaging, Blood markers, Retinal imaging