AusCADASIL: An Australian Cohort of CADASIL

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.

Study Overview

• Status: Recruiting
• Conditions: Cadasil

Detailed Description

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.

• Study Type: Observational
• Enrollment (Estimated): 300

Contacts and Locations

• Study Contact: Name: Danit Saks, MBMSc, MRes, PhD; Phone Number: +612 9348 1658; Email: d.saks@unsw.edu.au

Study Locations

• Australia
  • New South Wales
    • Newcastle, New South Wales, Australia, 2305
      • Recruiting
      • John Hunter Hospital
      • Contact: Beata Bajorek, BPharm DipHospPharm PhD; Phone Number: +612 4055 0650; Email: Beata.Bajorek@newcastle.edu.au
    • Sydney, New South Wales, Australia, 2031
      • Recruiting
      • Prince of Wales Hospital
      • Contact: Danit Saks, PhD; Phone Number: +61 2 93481658; Email: d.saks@unsw.edu.au
    • Sydney, New South Wales, Australia, 2031
      • Recruiting
      • University of New South Wales
      • Contact: Danit Saks, PhD; Phone Number: +61 2 93481658; Email: d.saks@unsw.edu.au
  • Queensland
    • Brisbane, Queensland, Australia, 4006
      • Not yet recruiting
      • Royal Brisbane and Women's Hospital
      • Contact: Michael O'Sullivan, MD; Phone Number: +617 3646 8111; Email: m.osullivan1@uq.edu.au
  • Victoria
    • Melbourne, Victoria, Australia, 3052
      • Recruiting
      • Royal Melbourne Hospital
      • Contact: Ashley Park, MD; Phone Number: +613 9342 7000; Email: ashley.park@mh.org.au

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

• Sampling Method: Non-Probability Sample

Study Population

Individuals with CADASIL confirmed by genetic testing, suspected due to clinical symptoms, or family history of CADASIL.

Control cohort will be negative for the NOTCH3 pathogenic variant and have no cognitive complaints

Description

Inclusion criteria:

1. Adults ≥18 years old

2. 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
3. Ability to attend a testing site
4. Ability to complete minimum dataset (medical examination and medical history questionnaire, blood test to determine genetic status and a short (20 minute) neuropsychology assessment).

5. CADASIL participants according to one of the following categories:

   1. confirmed diagnosis via genetic testing (NOTCH3 pathogenic variant), OR
   2. suspected diagnosis based on medical history and brain MRI, OR
   3. 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.

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
CADASIL cohort
Control Cohort

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Perminder Sachdev
• Collaborators: Melbourne Health; Royal Brisbane and Women's Hospital; The University of Queensland; Prince of Wales Hospital, Sydney; John Hunter Hospital; St Vincent's Hospital - Sydney, Australia
• Investigators: Principal Investigator: Perminder S Sachdev, MBBS, MD, PhD, FRANZCP, FAAHMS, University of New South Wales

Study record dates

Study Major Dates

• Study Start (Actual): November 25, 2023
• Primary Completion (Estimated): March 31, 2027
• Study Completion (Estimated): March 31, 2027

Study Registration Dates

• First Submitted: November 7, 2023
• First Submitted That Met QC Criteria: November 18, 2023
• First Posted (Actual): November 28, 2023

Study Record Updates

• Last Update Posted (Actual): May 8, 2024
• Last Update Submitted That Met QC Criteria: May 7, 2024
• Last Verified: May 1, 2024

More Information

Terms related to this study

• Keywords: Genetics; Cognition; Neuroimaging; Clinical Research; CADASIL; Retinal imaging; Blood markers
• Additional Relevant MeSH Terms: Mental Disorders; Ischemia; Pathologic Processes; Necrosis; Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocognitive Disorders; Genetic Diseases, Inborn; Brain Ischemia; Dementia; Infarction; Stroke; Brain Infarction; Cerebral Arterial Diseases; Intracranial Arterial Diseases; Cerebral Small Vessel Diseases; Cerebral Infarction; Dementia, Vascular; CADASIL; Dementia, Multi-Infarct
• Other Study ID Numbers: AusCADASIL

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No