Introduction
Neurodegeneration has many causes. However, there is increasing evidence that different causes of neurodegeneration share similar molecular mechanisms and converge on shared pathways to cause network dysfunction and cognitive decline. The Comprehensive Assessment of Neurodegeneration and Dementia (COMPASS-ND) study is a Canada-wide prospective cohort study to investigate multiple different causes of neurodegeneration, and their interactions, in a single study. with a comprehensive protocol. Reference Chertkow, Borrie and Whitehead1
One of the most common contributors to neurodegeneration and cognitive decline is cerebrovascular disease, which can lead to vascular brain lesions that cause cognitive impairment. In this paper, we describe the methods for investigating vascular brain lesions in the COMPASS-ND study, including magnetic resonance imaging (MRI) measurement. Although the overall protocol for COMPASS-ND has been published, it did not include the methods for MRI review and their reliability. Reference Chertkow, Borrie and Whitehead1 Initial findings from the first wave of study 200 participants are presented. We hypothesized that vascular brain injury would be common across all cognitive disorders even if not recognized at the time of enrollment.
Methods
Patient Population
COMPASS-ND is a Canada-wide multi-center prospective, longitudinal cohort study. The overall study design and methods have been published previously. Reference Chertkow, Borrie and Whitehead1 The study is registered on clinicaltrials.gov (NCT03402919). In brief, the objective is to create a platform for research on neurodegenerative and vascular causes of mild cognitive impairment (MCI) and dementia. Recruitment began in 2016 and is expected to complete in approximately 2023. The study is conducted with ethical approval by institutional review boards at each site, with written informed consent of the participants. In this manuscript we report the methods for assessing vascular contributions to neurodegeneration, with interim findings.
In total, 2310 participants will be recruited in these groups: cognitively intact elderly (n = 660), subjective cognitive impairment (SCI; 300), MCI (400), subcortical ischemic vascular MCI (V-MCI; 200), mild dementia due to clinically probable Alzheimer’s disease (AD; 150), mild dementia of mixed etiology (200), Parkinson’s disease (PD) and Lewy body dementias (LBDs; 200), and frontotemporal dementia (200). Full selection criteria have been published previously. Reference Chertkow, Borrie and Whitehead1 Participants are being recruited, generally from specialty cognitive clinics, at 31 sites across Canada.
Diagnoses are made by the site investigator based on all available clinical and research information available at the time of assessment. A screening diagnosis is made based on the information from the referral and screening along with referral information including clinical neuroimaging, and then a clinical diagnosis is made additionally incorporating information collected at the research clinical and physical assessment but prior to research MRI or other biomarker information. Group analyses in this paper are based on the clinical diagnosis groupings.
Based on a priori scientific interest, two groups of patients with vascular cognitive impairment were identified using specific selection criteria: subcortical ischemic V-MCI, and mixed etiology dementia with a vascular component. Criteria for V-MCI were derived from consensus criteria from the American Heart Association Reference Gorelick, Scuteri and Black2 and International Society for Vascular Cognitive and Behavioral Disorders (Vas-Cog). Reference Sachdev, Kalaria and O’Brien3 V-MCI participants were required to be age ≥60, have MCI according to National Institute on Aging-Alzheimer’s Association criteria (NIA-AA), Reference Albert, DeKosky and Dickson4 not have a prior history of clinical stroke, and to have evidence of cerebrovascular disease on brain computed tomography (CT) or MRI defined as two or more supratentorial infarcts (i.e., excluding brainstem or cerebellar infarcts) or beginning confluent or confluent white matter hyperintensity (WMH) according to the Age-Related White Matter Change (ARWMC) scale Reference Wahlund, Barkhof and Fazekas5 on any slice. For the V-MCI group, participants with history of symptomatic stroke were excluded so that the focus is on V-MCI caused by covert cerebrovascular disease, predominantly due to cerebral small vessel disease. Criteria for mixed dementia were adapted from NIA-AA criteria for dementia due to AD Reference McKhann, Knopman and Chertkow6 and required that a non-AD cause of dementia should additionally be present. Although the presence of vascular disease was not required for the mixed dementia group, in practice most cases of mixed dementia have a vascular component. Reference Rabinovici, Carrillo and Forman7 Persons with symptomatic stroke within the last year were excluded. Full details of the study inclusion and exclusion criteria are provided in the online-only supplement (online Table I).
Measurements and Outcomes
Data on age, sex, past medical and surgical history, medications, tobacco and alcohol intake, hearing, and vision are collected. Cognitive and neurobehavioral measurements include the Montreal Cognitive Assessment, Reference Nasreddine, Phillips and Bedirian8 Clinical Dementia Rating Scale, Reference Morris9 Mild Behavioral Impairment Checklist Reference Ismail, Aguera-Ortiz and Brodaty10 and Apathy questionnaire. The Hachinski Ischemic Score Reference Hachinski, Iliff and Zilhka11 is collected. A two-hour neuropsychological test battery is administered. Full details of these assessments have been published previously. Reference Chertkow, Borrie and Whitehead1 Participants will be followed for two years with a repeat of these assessments at two years. At this time, repeat brain imaging is not planned.
Physiological measurements include sitting and orthostatic blood pressure, height and weight (to calculate body mass index), and waist and hip circumference. Blood measurements include complete blood count, creatinine, hemoglobin A1c, insulin, homocysteine, C-reactive protein, high-density and low-density lipoprotein (HDL and LDL), and apolipoprotein B. Lumbar puncture is offered as a voluntary option and will be analyzed for beta-amyloid, total tau, and phosphorylated tau. Additional measurements potentially relevant to defining vascular contributions to neurodegeneration are shown in Table 1.
Table 1: COMPASS-ND assessments of interest for vascular cognitive impairment
Full details of the neuropsychological test battery have been published previously. Reference Chertkow, Borrie and Whitehead1
Brain MRI are acquired using the previously validated Canadian Dementia Imaging Protocol (www.cdip-pcid.ca). Reference Duchesne, Chouinard and Potvin12,Reference Potvin, Chouinard and Dieumegarde13 The protocol is summarized in Table 2. Compliant with the Standards for Reporting Vascular Changes on Imaging (STRIVE), Reference Wardlaw, Smith and Biessels14 it was harmonized on three major vendor platforms and includes a common procedure for qualification, quality control, and quality assurance.
Table 2: Canadian Dementia Imaging Protocol Reference Duchesne, Chouinard and Potvin12
FLAIR = fluid attenuated inversion recovery; GRE = gradient-recalled echo; BOLD = blood oxygen level dependent.
A Vascular Core Lab for visual review of brain MRI is distributed between the University of Calgary and Sunnybrook Hospital (University of Toronto). Each MRI is visually reviewed for evidence of vascular brain injury by one of two trained readers qualified by the Vascular Core Lab. Readers are required to be neurologists or radiologists with more than five years of clinical experience with cerebrovascular lesions on MRI, to complete a training module, and to exhibit good inter-rater reliability on a training set (kappa ≥ 0.60) for common vascular lesions (presence of brain infarcts, presence of microbleeds, and Fazekas WMH rating scale Reference Fazekas, Chawluk, Alavi, Hurtig and Zimmerman15 ). MRI scans are reviewed, blinded to clinical information, using a standardized case report form. Infarcts, microbleeds, and WMH are defined according to STRIVE. Reference Wardlaw, Smith and Biessels14 Infarcts are classified by size, number, location, and vascular territory, which allows their subdivision as lacunar versus non-lacunar type. Microbleeds are classified by number and location as in the Brain Observer Microbleeds (BOMBS) scale. Reference Cordonnier, Potter and Jackson16 If microbleeds or cortical superficial siderosis are present their pattern is classified as probably, possibly, or not consistent with cerebral amyloid angiopathy as defined by revised Boston criteria. Reference Linn, Halpin and Demaerel17 When lobar microbleeds or cortical superficial siderosis were accompanied by non-lobar microbleeds, the pattern is described as “mixed”. Reference Pasi, Charidimou and Boulouis18 WMH are visually rated using the Fazekas Scale. Reference Fazekas, Chawluk, Alavi, Hurtig and Zimmerman15 Each scan is visually reviewed for quality. Standard operating procedures have been developed and are stored in a study binder, following FDA guidance for imaging endpoints and guidelines for multi-center brain imaging studies. Reference Wiseman, Meijboom and Valdes Hernandez19
Neuroimaging evidence of a potential vascular cause or contribution to cognitive decline is defined, a priori, as either the presence of two or more infarcts or beginning confluent or confluent WMH according to the ARWMC scale on any MRI or CT slice. The ARWMC scale was chosen because it is simple for sites to apply and can be used with either CT or MRI, facilitating site identification of participants for the V-MCI group. Additionally, the MRI-based Fazekas scale will be recorded. The imaging criteria for V-MCI are based on Vas-Cog criteria for pure vascular cognitive impairment, Reference Sachdev, Kalaria and O’Brien3 but to increase sensitivity the criteria were revised to require only two infarcts instead of three and to include beginning confluent WMH instead of confluent WMH, and to increase specificity supratentorial infarcts are required. Post-hoc analyses will test the validity of these criteria for identifying patients at risk of continued cognitive decline. Strategic locations of infarcts were not part of the imaging criteria because the required locations and sizes are not precisely defined in the literature.
A visual assessment of medial temporal atrophy is made using the Scheltens scale, Reference Korf, Wahlund, Visser and Scheltens20 which is rated from 0 to 4 on each side and was averaged for this analysis. Quantitative segmentation of the hippocampus using high-resolution T1-weighted is planned.
Quantitative analyses of brain images will be batched and performed near the end of the study recruitment period according to the best available methods at that time. The Canadian Dementia Imaging Protocol acquires images suitable for analysis of global and regional brain volumes including cortical thickness; DTI for analysis of white matter connectivity, and multiple BOLD volumes suitable for analyzing resting state functional connectivity.
The data from COMPASS-ND used in this paper, including MRI Digital Communication in Medicine (DICOM) is stored and curated on the Longitudinal Online Research Information System (LORIS). Reference Mohaddes, Das and Abou-Haidar21,Reference Das, Zijdenbos, Harlap, Vins and Evans22
Statistical Analyses, Sample Size, and Data Access Policies
The study is designed to be an open access platform for secondary analyses of the risk factors, predictors, and cognitive outcomes of common neurodegenerative diseases. Therefore, there is no pre-defined primary outcome.
The V-MCI group sample size of 200 was based on having 80% power to detect factors that would double the risk of progression to dementia at two years (from 20% to 40%), assuming 20% loss to follow-up at two years, alpha of 0.05, and a two-tailed p value.
Access to COMPASS-ND data will be provided to the worldwide research community according to the policies of the Canadian Consortium on Neurodegeneration in Aging (CCNA; https://ccna-ccnv.ca/policies/). Project proposals should be submitted to the publications and Data Access Committee (PDAC). After study recruitment is completed, data will be provided to the Global Alzheimer’s Association Interactive Network (GAAIN) for access through their portal.
To explore the feasibility of recruitment and study measurements, we present descriptive statistics of the distribution of vascular risk factors and vascular MRI findings in the first 200 recruited participants according to clinical diagnosis. V-MCI and mixed dementia are grouped for analysis. To compare prevalence across groups the chi-square test is used, and to compare medial temporal atrophy scores analysis of variance (ANOVA) is used. The kappa statistic is used to test the reliability of the two readers on 50 COMPASS-ND cases (7 with infarcts and 10 with microbleeds), with values ≥0.60 indicating substantial agreement. Agreement was based on the presence or absence of any lesions of that type; there were too few participants with multiple lesions to test the reliability of lesion counts. Because these are interim, exploratory analyses without the full planned sample size, multivariable adjustments are not done and there is no adjustment for multiple comparisons. Analyses were done using SAS version 9.4 (Cary, NC). A p value of <0.05 is considered significant.
Results
The first wave of 200 consenting participants were recruited from 13 sites across Canada. MRI was performed in 197 participants. One participant could not complete the MRI because their head was too large for the coil, one had an MRI incompatible prosthesis that was not recognized at the time of consent, and one declined. MRI were judged adequate for determining infarcts and WMH in all participants. Two participants (1%) did not have measurement of microbleeds or cSS because of motion (one participant) or susceptibility artifact (one participant).
Characteristics of the 197 participants who completed MRI are shown in Table 3. As expected, distribution of vascular risk factors differed across groups and was highest in the participants with V-MCI or mixed dementia (n = 18). The pre-specified radiological criteria for potential vascular contributions to cognitive impairment was seen in 34% overall, including in 8/10 with V-MCI and 7/8 with mixed dementia. Additionally, many participants in the other disease groups (ranging from 12.9% to 40.0%) also met our radiological criteria for a vascular component (Table 3).
Table 3: Characteristics of the First 200 participants
V-MCI = vascular mild cognitive impairment; MCI = mild cognitive impairment; SCI = subjective cognitive impairment; PD/LBD = Parkinson’s disease/Lewy body dementias.
Values are displayed as percent or mean (standard deviation).
Infarcts were seen in 24.9% (Table 4), including many with dementia due to AD (11/24). Among the 49 with infarcts the median number was 1, the maximum was 5, and the interquartile range was 1–2. However, most patients with AD had only one infarct. Non-lacunar infarcts were not uncommon (13.7%). Infarcts were least common in participants with subjective cognitive impairment (SCI).
Table 4: MRI findings in first 200 participants
AD = Alzheimer’s disease; V-MCI = vascular mild cognitive impairment; MCI = mild cognitive impairment; SCI = subjective cognitive impairment; PD/LBD = Parkinson’s disease/Lewy body dementias; ARWMC = Age-Related White Matter Changes scale; CMB = cerebral microbleed; WMH = white matter hyperintensity.
Values are percentages or mean (standard deviation).
Microbleeds were seen in 25.6% including 20.0% with lobar microbleeds and 6.2% with deep microbleeds (Table 3). Among the 48 with microbleeds, the median was 2, the maximum was 14, and the interquartile range was 1–3. Only two participants had cortical superficial siderosis; one with V-MCI/mixed dementia and one with MCI.
Beginning confluent or confluent WMH was common (31.0%; Table 4). Mean Scheltens medial temporal atrophy scores were highest in patients with AD dementia (Table 4).
Reliability of the two readers is shown in Table 5. Reliability was good to excellent for the different lesion types.
Table 5: Inter-rater Reliability of COMPASS-ND Measurements
Agreement between the two study readers for presence or absence of that lesion type, based on 50 cases.
Twelve participants (6.1%) had incidental non-vascular findings: three suspected meningiomas, two pituitary masses, one presumed lipoma, one intraparenchymal brain tumor, one parotid tumor, one aneurysm, one developmental venous anomaly, one presumed dermoid cyst, and one traumatic encephalomalacia.
Discussion
The COMPASS-ND study will provide a platform for investigating vascular contributions to neurodegeneration across multiple neurological diseases and syndromes in a prospective cohort study with standardized methods. The preliminary findings demonstrate the feasibility of the study protocols, and that radiological evidence of vascular brain injury was common even in participants recruited without clinical knowledge of vascular comorbidity. These findings concord with neuropathological studies at autopsy showing that mixed pathology with a vascular component is the most common cause of dementia. Reference Schneider, Arvanitakis, Bang and Bennett23 Future analyses in the entire dataset will explore the relationship between vascular brain injury and its impact on neurodegeneration across multiple conditions, including when other neurodegenerative diseases are present. This will include analyses of the impact of vascular brain injury on cognition, behavior, activities of living, atrophy, and brain connectivity. Per COMPASS-ND data access policies, the entire de-identified dataset (n = 2310) including digital imaging compliant in medicine (DICOM) MRI images will be made available for access by the worldwide research community after study recruitment is completed.
The high prevalence of vascular brain injury in cognitively impaired persons is concordant with findings from autopsy studies in the general population. Even among persons with clinically diagnosed and neuropathologically confirmed AD, vascular pathology is common and is not a mere bystander. A large neuropathological study of the risk for AD dementia found that macroscopic infarcts accounted for 8.9%, cerebral amyloid angiopathy for 8.1%, atherosclerosis for 6.0%, and arteriolosclerosis for 5.2% of the risk. Reference Boyle, Yu and Leurgans24 Most prior studies of multiple etiology dementia have focused on the combination of AD pathology and cerebrovascular disease. The COMPASS-ND study will make an important contribution by enabling the study of vascular contributions to the expression of PD, Reference Ramirez, Dilliott and Binns25 LBD, and fronto-temporal lobar degeneration, which so far have attracted less attention.
Some (3/18) of the participants recruited with into the vascular/mixed category did not meet radiological criteria for a vascular contribution (defined as multiple supratentorial infarcts or beginning confluent WMH) according to the Vascular Core Lab review. Potential reasons for this could include a lower local threshold for the degree of vascular brain injury deemed clinically sufficient to impair cognition, the presence of strategic infarcts (which were not included in the Core Lab definition based on lack of research consensus), the presence of clinical non-radiological information known only to the local team (e.g., a history of stroke that was not detected on neuroimaging), or lack of reliability between the local radiology read and the Vascular Core Lab read. Higher local sensitivity for detecting vascular brain injury could also account for this, although we suspect that instead the Vascular Core Lab was more sensitive because the MRI data were acquired using a high quality research protocol and the assessments were done by experienced readers specifically tasked with identifying vascular brain injury using standardized criteria.
We commonly found that participants had radiological evidence of vascular brain injury that may have been sufficient to support a vascular contribution to their cognitive syndrome, including 25% of the participants recruited into the AD group and 39% of the participants in the MCI group. These participants could have been recruited into the vascular/mixed group had the vascular component been recognized at the time of clinical diagnosis. Similarly, another cohort study found that 6% of participants referred to a research study with AD-dementia or AD-MCI had to be reassigned to the VCI group based on infarcts or severe WMH that were not recognized based on their clinical neuroimaging. Reference Kapoor, Bartha and Black26 This suggests that vascular contributions to neurodegeneration are probably under-recognized in clinical practice.
Clinicians should be careful to assess whether a vascular contribution to neurodegeneration is present in any patient with cognitive symptoms or decline. Given the commonality of mixed disease, this is important even when another contributor such as AD or PD is already recognized. Our findings support recommendations for neuroimaging in cases of mild cognitive impairment or dementia. Reference Gorelick, Scuteri and Black2,Reference Ismail, Black and Camicioli27 However, the treatment of covert cerebrovascular disease is controversial with limited evidence from clinical trials. Reference Smith, Saposnik and Biessels28 At minimum, a history of vascular conditions and risk factors should be taken, blood pressure should be measured, and the pulse checked (to screen for atrial fibrillation). Reference Smith, Saposnik and Biessels28 The use of aspirin could be considered for patients with covert brain infarcts. Reference Smith, Barber and Field29 Even though definitive clinical trial evidence has not yet been amassed, it nonetheless is likely that vascular disease is the most modifiable contributor to dementia. Anything that prevents stroke will also prevent dementia. Reference Hachinski, Einhaupl and Ganten30
Strengths of this study include the use of a standardized research MRI protocol, a centralized Vascular Core Lab following good clinical practices and FDA guidance for imaging endpoints, and MRI assessments done by qualified, experienced radiologists according to STRIVE criteria. There are also some limitations to the methods. To share the workload the Vascular Core Lab was distributed between two sites; however, we show similar inter-rater reliability of measurements as those achieved by single sites. Quantitative analyses, for example of WMH volume, have not been completed yet but the data will be made available later to the research community at large. Sequences for measuring brain volume Reference Potvin, Chouinard and Dieumegarde13 resting state functional MRI, Reference Badhwar, Collin-Verreault and Orban31 and diffusion tensor imaging have also been collected and can be used in later analyses. However, given time and resource constraints some advanced sequences relevant for vascular disease, for example for vascular reactivity and blood brain barrier permeability, Reference Smith and Beaudin32 could not be included in the protocol.
The COMPASS-ND dataset will be an excellent resource for analyzing the vascular contributions to neurodegeneration, both within and across common neurodegenerative illnesses. Analyses are being undertaken currently by COMPASS-ND investigators, but the dataset is open to all investigators subject to COMPASS-ND data access and publication policies. This first look at our data shows that it is reliable and consistent with neuropathological evidence that vascular brain injury commonly accompanies age-related neurodegenerative diseases. These findings support the use of neuroimaging in clinical practice to identify potentially preventable covert cerebrovascular disease.
Acknowledgments
The study was funded by the Canadian Institutes of Health Research through the Canadian Consortium on Neurodegeneration in Aging.
Disclosures
Dr. Smith has received consulting fees from Biogen and Alnylam, and royalties from UpToDate. Dr. Duchesne is a shareholder and officer of True Positive Medical Devices Inc. Dr. Black has received consulting fees from Biogen and Roche, and receives research funding for clinical trials from Biogen, Genentech, Roche, Eli Lilly, Novartis, and Optina. The other authors report no conflicts.
Statement of Authorship
EES analyzed study data, performed statistical analysis, and drafted the manuscript. SD designed the MRI acquisition protocol, analyzed study data, and revised the manuscript critically for intellectual content. FG and FS made study measurements and revised the manuscript critically for intellectual content. VW coordinated the study and reviewed and revised the manuscript critically for intellectual content. CRM maintained study databases, reviewed study data for quality, revised the manuscript critically for intellectual content. RF, SG, RC and MB contributed to study protocols and revised the manuscript critically for intellectual content. SB co-developed the MRI acquisition protocol, analyzed study data and revised the manuscript critically for intellectual content.
Supplementary material
To view supplementary material for this article, please visit https://doi.org/10.1017/cjn.2021.19.
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