Development of Cohort Studies on Brain Health

Brain health as an emerging research hotspot in recent years commonly refers to a state in which people can preserve optimal brain integrity and mental and cognitive function at a given age without overt brain diseases affecting normal brain function. [1] This definition explains the basic frame of brain health and shares goals for disparate parties to reduce brain health impairment and achieve global brain health. Conversely, impaired brain health involves a wide range of clinical outcomes, including stroke, dementia, cognitive impairment, cognitive aging, and vascular functional impairment, among others. [2] The impaired brain health burden is heavy and increasing. Neurological conditions have been the leading cause of mortality and disability accounting for 9 million deaths per year. [3] The

corresponding disability-adjusted life years are estimated to increase by 50% by 2040. [3] Notably, cerebrovascular diseases and dementia, which are reciprocally correlated, are the leading contributors to impaired brain health among older people. [1, 4] The increasing burden requires more attention and resources to be devoted to brain health research. Cohort studies have been accepted as the primary designs to observe the longitudinal development of brain health and risk factors of impaired brain health. This article summarizes existing cohort studies on brain health and introduces an ongoing PolyvasculaR Evaluation for Cognitive Impairment and vaScular Events (PRECISE) study in China.

Several cohort studies focusing on cognitive function deterioration and dementia have been established. Among them, the Alzheimer's Disease Neuroimaging Initiative (ADNI) study and the Multimodal Interventions to Delay Dementia and Disability in Rural China (MIND-China) study are two well-known longitudinal studies. Specifically, the ADNI study is a naturalistic longitudinal study that started in 2005, to develop and validate biomarkers as surrogate outcome measures in clinical trials of Alzheimer's disease (AD)-modifying therapies. [5] ADNI4 is the latest phase of the ADNI study that will enroll up to 1500 participants including elderly controls and people with mild cognitive impairment (MCI) or AD/dementia from the USA and Canada from 2022-2027. [6] The ADNI study found that cognitive impairment is associated with AD biomarkers. [5] Neuropsychiatric symptoms, sleep breathing abnormalities, and cancer history are risk factors for cognition preservation, whereas fish oil supplements and higher educational attainment are protective factors. [5] The MIND-China study is a cluster-randomized, controlled multimodal intervention study conducted from March 2018 to December 2023 to evaluate the effects of multimodal interventions on cognitive function and dementia. [7-8] In 2018, 5765 residents aged >60 years were recruited from 52 villages of Yanlou, Shandong. [9] Among them, 2280 were randomly divided into three groups: the control group, the vascular intervention group, and the multimodal intervention group. All interventions were completed by the end of 2023 according to the protocol, and participants are undergoing continuous follow-up visits. [7-8] Currently, the baseline data of the MIND-China study are available and have revealed that the prevalence of MCI was 26.48% among rural older adults in 2018. [9]

Furthermore, several other cohort studies focus on the use of advanced brain imaging techniques in data collection for the in-depth evaluation of the development and risk factors of brain health impairment. For example, to analyze the risk of dementia and cognitive impairment attributable to vascular factors, the Three City (3C)-Dijon study recruited 9693 non-institutionalized individuals aged >65 years from the electoral rolls of Dijon, Bordeaux, and Montpellier, France, between March 1999 and March 2001. [10] Investigators used magnetic resonance imaging (MRI) to detect, measure, and localize white matter hyperintensity (WMH) signals and cerebral volumes (white matter, gray matter, ventricles) in 3442 participants at baseline. [10] Similarly, to investigate the risk factors and cognitive and motor consequences of brain changes, the Radboud University Nijmegen Diffusion Tensor and Magnetic Resonance Cohort (RUN DMC) study used a 1.5-T scanner to perform the cerebral MRI of 503 non-demented adults aged 50 to 85 years and diagnosed with cerebral small vessel disease (CSVD) to detect white matter lesions, brain volume, lacunar and territorial infarcts, and microbleeds. [11] The RUN DMC study describes the role of CSVD on the microstructural integrity of the white matter when people experience from "normal" aging to cognitive and motor decline and ultimately incident dementia and parkinsonism. [11] Different from the above studies, the Rotterdam study primarily focuses on various diseases, including but not exclusive to cardiovascular diseases (CVD), dermatological, endocrine, liver, and neurological diseases. [12] It started in 1990 in Rotterdam City, the Netherlands, and included 17931 participants aged >40 years at the beginning of 2021. [12] For neurological diseases, the Rotterdam study used a dedicated 1.5-T MRI scanner to detect brain imaging markers of neurovascular diseases, neurodegenerative diseases, and pre-symptomatic cerebral and peripheral nerve pathologies since August 2005. [12] To identify the risk factors of subclinical atherosclerosis and the progression of subclinical atherosclerosis to clinical CVD, the Atherosclerosis Risk In Communities (ARIC) study recruited 15792 middle-aged Black and White adults from four communities in the USA between 1987 and 2014.[13] The ARIC study performed brain MRI examinations in 1067 participants from 2004 to 2006 and in 1963 participants with cognitive decline from 2011 to 2013 to better understand the vascular basis of dementia. [13] The ARIC study revealed that hypertension, orthostatic hypotension, pre-diabetes, diabetes, smoking, and physical inactivity are midlife predictors of cognitive decline, dementia, and imaging-defined brain damage.[13] In China, the Shunyi cohort is the first community-based cohort study to investigate the determinants and consequences of CVD and age-related brain disorders in rural adults. [14] It enrolled 1586 residents aged >35 years from five villages in the Shunyi district, Beijing, between June 2013 and September 2014. [14] Notably, the Shunyi cohort study used a single 3.0-T Skyra scanner for brain MRI of all participants at baseline.[14] The Shunyi cohort study revealed that the prevalence of CSVD was 37% and higher than that of the same age group from developed countries. [14]

The PRECISE study is another population-based prospective cohort study on brain health in China, aiming to evaluate the association between polyvascular lesions and the future risk of cognitive impairment, cardiovascular/ cerebrovascular events, and death. [15] From May 2017 to September 2019, 3067 community-dwelling adults aged 50 to 75 years were enrolled from six villages and four communities in Lishui City through the cluster sampling method. [15] The participants represented a nationwide sample regarding demographics and medical histories. At baseline, information including demographics, vascular risk factors, medical examinations, blood and urine samples, and cognitive function was collected based on the standard protocol. All participants underwent brain MRI for the brain structure and function, vascular MRI for intracranial and carotidal arteries on a 3.0-T scanner, and thoracoabdominal computed tomography angiography for coronary, aortic, renal, hepatic, pancreatic, and iliofemoral arteries. [15] Subsequently, they were followed up at 2 and 4 years to record vascular events, progression rate of atherosclerotic plaque, and cognitive impairment. [15] At present, the PRECISE study has completed 2- and 4-year follow-up visits and is ongoing a 6-year visit. Data from the PRECISE study have shown that the prevalence of polyvascular atherosclerotic plaque was up to 82.8% and polyvascular stenosis was 13.4%. [16] Approximately 17.7% and 4.7% of participants had intracranial atherosclerotic plaques and intracranial atherosclerotic stenosis, respectively. [16] Apolipoprotein B, triglyceride glucose index, and insulin resistance are positively associated with the presence and burden of arterial atherosclerosis. [17-19] Furthermore, the overall prevalence of CSVD was 30.5%. [20] The most prevalent CSVD marker was confluent WMH (16.7%), followed by cerebral microbleed (10.2%), moderate-severe enlarged perivascular spaces in the basal ganglia (9.8%), and lacune (5.6%). [20]

Intracranial atherosclerosis and increased serum cystatin C level and neutrophil count are risk factors for CSVD burden.[21-23] Moreover, people with a healthy lifestyle had a larger total brain volume and gray matter volume, smaller WMH volume, and lower odds of lacune as compared to those with a poor lifestyle, supporting that association between adherence to a healthy lifestyle and a lower degree of the neurodegeneration-related brain structure.[24] The aforementioned findings provide valuable insights into the burden of polyvascular atherosclerotic plaque and the prevention of abnormal brain structure and function.

In summary, several ongoing cohort studies have been conducted on brain health. Most studies are from developed countries and are well known for their well-designed study, long follow-up time, and remarkable accomplishments in publications. China is catching up in the field of brain health and has established several Chinese cohorts after 2013. Although obvious gaps exist when China's emerging cohorts are compared with those in developed countries, the evidence from developing countries remains indispensable in understanding the dynamic changes in brain structure and function because developing countries cover a large part of the global population. With the long follow-up time and application of new imaging technologies, China will contribute more high-quality evidence for global brain health preservation.