Dementia Risk Assessed By Brain Artery Diameter
Overview
In this study, the association between brain artery diameters and the risk of dementia and stroke was investigated across three distinct population-based studies utilizing conventional T2-weighted brain magnetic resonance imaging (MRI) images. A total of 8,420 adults aged over 40 years from these longitudinal studies were included in the analysis. The findings revealed that individuals with dilated brain arteries have a higher risk of both dementia and stroke across diverse populations.
The results showed that overall and carotid artery diameters greater than the 95th percentile were associated with an increased risk of dementia, with hazard ratios (HRs) of 1.74 (95% confidence interval [CI], 1.13–2.68) and 1.48 (95% CI, 1.12–1.96) respectively. Similarly, for stroke, meta-analyses indicated HRs of 1.59 (95% CI, 1.04–2.42) for overall arteries and 2.11 (95% CI, 1.45–3.08) for basilar artery diameters greater than the 95th percentile.
These findings highlight the potential significance of T2-weighted brain MRI-based assessment of brain artery diameter in estimating the risk of dementia and stroke. The study underscores the importance of early detection and intervention strategies for individuals with dilated brain arteries to mitigate the risk of these debilitating neurological conditions.
Introduction
Dementia and stroke are prevalent neurological conditions associated with aging, posing substantial challenges to individuals, families, and healthcare systems worldwide. While their etiology is multifaceted, vascular changes play a crucial role in their development and progression. Traditionally, vascular alterations such as atherosclerosis and luminal stenosis leading to inward remodeling of blood vessels have been the focus of research into the pathogenesis of these conditions. However, recent studies have illuminated the importance of generalized vascular changes, including dilation and tortuosity, known as dolichoectasia, in contributing to neurological outcomes of presumed vascular origin.
One significant obstacle in studying dolichoectasia is the requirement for specialized arterial imaging techniques like magnetic resonance angiography or computerized tomography angiography, which are not routinely obtained in large population-based cohort studies due to logistical and cost constraints. To overcome this limitation, researchers have explored alternative methods, such as assessing the cross-sectional diameters of brain carotid and basilar arteries using routine magnetic resonance imaging (MRI) scans. This approach provides a feasible way to examine vascular morphology in large-scale epidemiological studies and clinical settings.
Building upon previous findings suggesting a potential link between dilated brain arteries and dementia risk in the elderly, researchers sought to investigate whether this association could be generalized to the broader population and extended to include the risk of stroke. By analyzing data from three large population-based cohort studies conducted in the United States, France, and the Netherlands, researchers aimed to elucidate the relationship between brain artery diameters and the incidence of dementia and stroke.
This multi-national approach allowed researchers to examine the association across diverse populations, providing valuable insights into the vascular mechanisms underlying these neurological conditions. Understanding the role of dilated brain arteries in dementia and stroke risk has significant implications for preventive strategies, early detection, and targeted interventions aimed at reducing the burden of these debilitating conditions.
By leveraging existing MRI data from large-scale cohort studies, this research contributes to our understanding of the vascular factors contributing to dementia and stroke, ultimately guiding future research directions and informing clinical practice in managing these complex neurological syndromes.
Methods
The study conducted a thorough analysis utilizing data from three distinct prospective observational population-based cohorts: the Northern Manhattan Study (NOMAS) from the United States, the Three-City Study (3C Study) from France, and the Rotterdam Study from the Netherlands. These cohorts collectively included a diverse range of participants aged 40 years and above (NOMAS), 65 years and above (3C Study), and 40 years and above (Rotterdam Study), thereby offering a broad representation of different age groups within the adult population.
Each cohort employed ethical approval procedures in accordance with the Declaration of Helsinki, with participants providing written informed consent. MRI scans were utilized as the primary modality for assessing brain artery diameters, and comprehensive protocols were established for the acquisition of imaging data using various MRI scanners and sequences. The meticulous measurement of arterial diameters from T2-weighted scans, facilitated by trained raters supervised by experts in vascular neurology and epidemiology, ensured accuracy and reliability in the assessment process.
The study’s follow-up procedures involved the systematic monitoring of fatal and non-fatal outcomes, including dementia and stroke, which were adjudicated by experienced physician scientists or neurologists. Adherence to standardized protocols and coding criteria, such as the International Classification of Diseases, ensured consistency in outcome ascertainment across cohorts. Additionally, vital status was continuously tracked through robust linkage mechanisms with practitioner files and municipal records, enhancing the completeness of outcome data.
Dementia adjudication involved multidisciplinary consensus panels that meticulously reviewed cognitive, functional, and medical data, with neuropsychological batteries employed to assess various cognitive domains. Similarly, stroke classification followed rigorous criteria, with expert panels or neurologists blinded to participants’ status in the study.
The collection of demographic and clinical variables, including hypertension, hypercholesterolemia, diabetes mellitus, and medication usage, allowed for comprehensive adjustment in the analyses to account for potential confounders. Standardized definitions for these variables were applied consistently across cohorts, ensuring comparability and reliability of the findings.
Overall, the study’s robust methodology, encompassing rigorous imaging protocols, standardized outcome adjudication procedures, and comprehensive data collection on relevant covariates, underscores the reliability and validity of its findings. By leveraging data from multiple population-based cohorts, the study offers valuable insights into the association between brain artery diameters and the risk of developing dementia and stroke across diverse populations, thereby informing strategies for the prevention and management of cerebrovascular diseases.
Statistical Analysis
The study reported baseline characteristics using means with standard deviations for normally distributed continuous variables and medians with interquartile ranges (IQRs) for non-normally distributed variables. Arterial diameters of carotid and basilar arteries were rank-normalized to standardize comparisons, and an overall brain arterial diameter was calculated by averaging the three arterial measures. This continuous variable was categorized into percentiles, defining dilated arterial diameters (>95th percentile), small arteries (<5th percentile), and a reference group (5th-95th percentiles) to avoid extreme phenotypes while maintaining statistical power.
The age-, sex-, and head size/brain volume-adjusted incidence of dementia and stroke was estimated according to brain artery diameter categories. Cox regression models assessed the risk association, expressing hazard ratios (HRs) and 95% confidence intervals (CIs) for small and dilated brain artery diameters compared to the reference group. Analyses were also performed using averaged carotid diameters and basilar artery measurements separately, with proportional hazard assumptions checked. Exploratory analyses included adjusting for total mortality as a competing risk, exploring higher cutoffs for large brain artery diameters, and assessing associations with dementia and stroke risk based on modifiable cardiovascular risk factors.
SAS software version 9.4 was used for database management and statistical analysis, with statistical significance set at a two-tailed α-level of 0.05 or less. Additionally, RevMan software (5.4) facilitated meta-analysis. The methodology aimed to comprehensively analyze the relationship between brain artery diameters and dementia/stroke risk while addressing potential confounders and exploring alternative cutoffs and subgroup associations.
Result
The study examined the baseline characteristics of three distinct cohorts, providing insights into the demographics and vascular parameters of the participants. Across these cohorts, the mean ages ranged from 64.7 to 72.9 years, highlighting the inclusion of older individuals in the study population. Notably, women accounted for a significant proportion, constituting over 57% of participants in each cohort, underscoring the importance of gender representation in the analysis.
Furthermore, the racial and ethnic compositions varied among the cohorts, with NOMAS comprising a diverse mix of non-Hispanic White, non-Hispanic Black, and Hispanic participants, while the Rotterdam Study predominantly included White individuals. The lack of documentation of race/ethnicity in the 3C Study reflects a potential limitation in understanding the demographic diversity of that cohort.
Regarding vascular parameters, the median carotid artery diameters ranged from 3.7 to 4.6 mm, with corresponding values for the basilar artery ranging from 2.0 to 2.9 mm. These measurements provide valuable information about the anatomical characteristics of the participants’ cerebral vasculature, which is essential for understanding their risk profiles for neurological conditions.
The study then delved into the incidence rates of dementia and stroke across the three cohorts, considering factors such as follow-up duration and adjustment for confounding variables like age, sex, and head size/brain volume. The analysis revealed a consistent association between dilated brain artery diameters and elevated risks of both dementia and stroke, as evidenced by adjusted Cox proportional models.
Moreover, meta-analyses corroborated these findings, providing further evidence of the heightened risk of dementia and stroke associated with dilated brain arterial diameters. The segregation of carotid and basilar artery measurements allowed for a more nuanced understanding of these associations, with carotid diameters demonstrating a particularly strong link to adverse neurological outcomes.
Exploratory analyses conducted as part of the study provided additional insights, including the impact of total mortality as a competing risk and subgroup analyses based on modifiable cardiovascular risk factors. These analyses underscored the robustness of the initial findings, further supporting the association between dilated brain artery diameters and increased risks of dementia and stroke.
Overall, the study contributes valuable knowledge about the relationship between cerebral vasculature and neurological outcomes, shedding light on potential risk factors and avenues for further research in the field of neurovascular health.
Conclusion
This study, involving 8310 adults from three prospective population-based cohorts with a median follow-up exceeding 7 years, aimed to explore the association between dementia, stroke, and brain artery diameters measured on T2-weighted MRI axial scans. The findings revealed that individuals with dilated brain arteries face an elevated risk of developing dementia and stroke across diverse populations. Meta-analysis results indicated hazard ratios ranging from 1.48 to 1.74 for dementia risk and 1.59 to 2.11 for stroke risk associated with dilated brain arteries.
These findings underscore the potential significance of conventional T2-weighted MRI-based diameter assessment in investigating dementia and stroke risk. The pathological mechanisms underlying small or dilated brain arteries may differ, with dilated arteries potentially contributing to poor vascular aging rather than arteriosclerosis-induced reductions in brain perfusion pressure.
Physiologically, brain outward remodeling, often associated with increased blood flow states, may lead to dilated brain arteries. Such outward remodeling, likely reflective of generalized brain dolichoectasia, could result in blood-brain barrier dysfunction, neurotoxic protein extravasation, inflammation, oxidative stress, and synaptic alterations, all of which correlate with Alzheimer’s disease pathology.
Moreover, the study suggests that dilated brain arteries may exacerbate mechanical brain tissue damage caused by high pulsatility waves, particularly in conjunction with arterial stiffness. The coexistence of dilated brain arteries and systemic arterial disease, such as aortic stiffening, may render the brain more susceptible to pulse-wave velocities, further increasing the risk of neurological events.
The study also highlights variations in average brain artery diameters among cohorts, potentially influenced by population characteristics like height. However, the association between brain arterial diameters and adverse neurological events may depend on absolute size thresholds, which could vary across populations.
While the study benefits from its multiethnic population-based cohorts and standardized protocols, limitations include reliance on axial T2-weighted MRI measurements, which may introduce error, and the need for more advanced imaging techniques for better characterization of arterial phenotypes.
In conclusion, contrary to clinical intuition, the study suggests that individuals with dilated brain arteries face an elevated risk of dementia and stroke. By leveraging ubiquitous MRI sequences, future research may delve deeper into the mechanisms linking dilated brain arteries to neurological outcomes, thereby advancing our understanding of vascular aging and its implications for brain health.
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