China Cognition and Aging Study

China Cognition and Aging Study: a Multi-center, National-wide, Longitudinal Study in China

The aim of this study is to establish and perfect the China Cognition and Aging Study (China COAST) cohort, to clarify the epidemiology, influencing factors, genetic characteristics, pathogenesis, disease characteristics and diagnosis and treatment status of dementia and its subtypes in China. It is of great significance to establish a relatively comprehensive national database of cognitive disorders, improve the clinical diagnosis and treatment level of cognitive disorders, and formulate prevention and treatment strategies for dementia. The primary aims of China COAST are as follows:

1. To use the prospective cohort to establish a large database research platform, so as to provide comprehensive epidemiological data, clinical and neuropsychological evaluation data, biological samples, and laboratory tests and imaging data.
2. To update the prevalence and incidence rate of dementia and its subtypes every 2-3 years, and clarify the conversion pattern from normal elderly to MCI and from MCI to dementia.
3. To explore the known or unknown protective and risk factors of dementia and its major subtypes (AD, VaD, other dementia).
4. To discover new pathogenic genes and susceptible genes of dementia and its major subtypes (AD and VaD), as well as new mutation sites of known pathogenic genes. To study the genetic variation, mutation and polymorphism of PSEN1, PSEN2, APP and APOE genes in dementia patients, and to understand their distribution and roles in the pathogenesis.
5. To study the biomarkers (body fluid, genetics, imaging) with diagnostic value of MCI, AD (sporadic and familial) and VaD, to define their cut-off values, and to establish prediction models.
6. To study the diagnostic criteria of cognitive normal, MCI, dementia and their subtypes (clinical and molecular subtypes) in the cohort, and to make psychological assessment scales with high sensitivity and specificity, and in line with the characteristics of Chinese people.
7. To find potentially modifiable risk factors for dementia and to study the prevention and intervention effect of non-pharmacological treatment on APOE ε4 carriers, MCI and AD or other dementia patients，which included improvements in education, nutrition, health care, and lifestyle changes. This needs a long time follow-up.
8. To explore the relationship between dementia as well as its major subtype AD and cerebral and systemetic circulatory disorders (for example, mixed dmentia), as well as potential therapeutic strategies.
9. To carry out investigation and researches about dementia related education, improve the awareness of dementia, and strengthen the management of dementia.
10. To investigate the level of stigma and discrimination and its influencing factors in patients with Alzheimer's disease and their caregivers.

This study involved participants including Mild cognitive impairment (MCI) and its subtypes、Sporadic Alzheimer's disease (SAD)、 Familial Alzheimer's disease (FAD)、Vascular dementia (VaD)、Normal control in community population and hospital population. Research contents are as follow:

1. Through the collection of basic demographic information and clinical data from the multi-center cohort, we will calculate the prevalence and incidence rate of AD, VaD, other dementia (mixed dementia, FTD, DLB, PDD, alcohol dementia, hydrocephalus dementia, post-traumatic dementia, etc.), and update the numbers every 1-2 years.
2. To clarify the conversion pattern from normal elderly to MCI and from MCI to dementia. Through the collection and analysis of current medical history, past history, family history, living habits, drug use, physical examination and other information, we will explore the protective and risk factors of dementia and its main subtypes (AD, VaD, Other dementia), including age, gender, education level, rural/urban, marital status, parental dementia history, dietary habbit, blood pressure, drinking, smoking, diabetes, hyperlipidemia, cerebrovascular disease, heart disease, depression, hearing impairment, exercise habits (Tai chi, etc.), dementia specialist influence on patients, occupation, BMI, lifestyle changes, air pollution, head injury , social contact, low-income, and other unknown protective or risk factors. To investigate the role of ApoE gene, especially ApoEε4 in the disease onset and development, and to explore the non-pharmacological interventions For the study purpose we do follow-up every 2or 3 years.
3. By using exome sequencing, GWAS, WGS and other methods, we will search for new mutations of known pathogenic genes (APP, PSEN1, PSEN2) of AD in China, find new pathogenic genes and susceptible genes of dementia and its main subtypes (AD and VaD), and understand their distribution. We will explore the independent and combined effect of susceptibility gene variation on the risk of illness in Chinese AD population, and to obtain the key mutation sites that have a clear relationship with the incidence of AD. We will do regular follow up visits for the FAD members with new mutations of pathogenic genes, and clarify the important role of new mutations of pathogenic genes during the onset and progression of AD.
4. We will collect the biofluids (blood, cerebrospinal fluid, urine, etc.) and 18F-FDG / 11C-PIB PET/MR multimodal imaging data from people with normal cognition, MCI, AD (sporadic and familial) and VaD, and conduct regular follow up. Discover and verify the SAD related susceptible gene and FAD related pathogenic gene mutation. Through analyzing the imaging data (such as MRI brain regional volume, 18F-FDG PET and cortical Aβ load), cerebrospinal fluid and plasma markers (such as Aβ, T-tau and P-tau) and clinical features (such as psychiatric symptoms and age of onset), we will develop gene chip with high sensitivity and high specificity for early screening of dementia; develop diagnostic kits for biofluid markers (blood and cerebrospinal fluid); determine imaging cut-off values at all stages of dementia in Chinese people. We will do correlation analysis to establish early diagnosis and risk prediction model for dementia, and verify the newly developed instruments that can detect the peripheral markers of dementia patients and predict the disease progression in national large sample.
5. Through the unified and standardized neuropsychological scales, including MMSE, MoCA, CDR, NPI, ADL, etc, we will conduct investigation to subjects in baseline and follow-up period, and analyze the changes of cognitive function, ability of daily life and mental behavior symptoms in different cognitive disorders. According to the social, cultural and material changes in China in recent years, we will develop psychological assessment scales with high sensitivity and specificity, and in line with the characteristics of Chinese people. Meanwhile, on the basis of the international diagnostic standards of various subtypes of dementia, combined with the etiology, clinical manifestations, scale classification, imaging characteristics, biofluid examination, etc., we will study the novel typing method and diagnostic standards of cognitive normal, MCI, dementia and its subtypes (clinical and molecular subtypes) in Chinese population.
6. Through designing randomized controlled trials, we will study the systematic and effective NPT intervention program, including lifestyle (diet and sleep habits, smoking, drinking and social networking), health products, exercise habits, cognitive training, risk factor control, etc. We will explore the quantitative and objective evaluation criteria of NPT in AD and dementia, clarify its prevention and control efficacy on APOE ε4 carriers, MCI and dementia patients, and potential neurobiological mechanism. At the same time, we will carry out dementia related education in the community, improve the public knowledge, attention and awareness of dementia, so that patients can get early detection, early diagnosis and early intervention.
7. To explore the relationship between dementia as well as its major subtype AD and cerebral circulatory disorders (cerebral ischemic and hemorrhage diseases, cerebral arteriosclerosis and stenosis, cerebral venous diseases, etc.), especially clarify the relationship between chronic cerebral ischemia and AD, as well as its effect on AD onset, and whether or not it's risk factor for AD. Whether the therapeutic strategies for cerebral circulatory disorders should be included in the treatment of AD.

Community population: age ≥ 55 years, male or female, with consent to participant the study.

Hospital population: subjects are all over 18 years old. Through clinical evaluation, neuropsychological test, imaging examination, blood and cerebrospinal fluid examination, etc, we will comprehensively evaluate the cognitive function and various test measures.

(1) MCI and its subtypes

Inclusion criteria:

1. Diagnosis according to 2004 Peterson's MCI criteria.
2. CDR = 0.5.
3. Memory loss is prominent, and may also be with other cognitive domain dysfunction.
4. Insidious onset, slow progress.
5. Not reaching the level of dementia.

Exclusion criteria:

1. With history of stroke and a neurological focal sign, the imaging findings are consistent with cerebral small vessal disease (Fazekas score ≥ 2 points).
2. Other neurological diseases that can cause brain dysfunction (such as depression, brain tumor, Parkinson's disease, metabolic encephalopathy, encephalitis, multiple sclerosis, epilepsy, brain trauma, normal intracranial pressure hydrocephalus, etc.).
3. Other systemic diseases that can cause cognitive impairment (such as liver, renal and thyroid insufficiency, severe anemia, folic acid or vitamin B12 deficiency, syphilis, HIV infection, alcohol and drug abuse, etc.).
4. Mental and neurodevelopmental retardation.
5. Contraindications to MRI.
6. Suffering from a disease that cannot be combined with cognitive examination.
7. Refuse to draw blood.
8. Refuse to sign the informed consent at baseline

(2) Sporadic Alzheimer's disease (SAD)

Inclusion criteria:

1. Dementia is diagnosed according to the criteria described by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-R). The diagnosis of AD is made using the National Institute of Neurologic and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) or National Institute on Aging and the Alzheimer's Association (NIA-AA) criteria.
2. Subjects and their informed persons can complete relevant and follow- up examinations.
3. Subjects or their authorized legal guardians sign the informed consent.

Exclusion criteria:

1. With a family history of dementia.
2. Other neurological diseases that can cause brain dysfunction (such as depression, brain tumor, Parkinson's disease, metabolic encephalopathy, encephalitis, multiple sclerosis, epilepsy, brain trauma, normal intracranial pressure hydrocephalus, etc.).
3. Other systemic diseases that can cause cognitive impairment (such as liver, renal and thyroid insufficiency, severe anemia, folic acid or vitamin B12 deficiency, syphilis, HIV infection, alcohol and drug abuse, etc.).
4. Mental and neurodevelopmental retardation.
5. Contraindications to MRI.
6. Suffering from a disease that cannot be combined with cognitive examination.
7. Refuse to draw blood.
8. Refuse to sign the informed consent at baseline

(3) Familial Alzheimer's disease (FAD)

Inclusion criteria:

1. Written informed consent obtained from participant or legal guardian prior to any study-related procedures.
2. Members in FAD pedigree (FAD is defined as at least two first- degree relatives suffer from AD).
3. Aged 18 (inclusive) or older.
4. At least two persons who can provide reliable information for the study. Note: Dementia is diagnosed according to the criteria described by DSM-IV-R. The diagnosis of AD is made using NINCDS-ADRDA or NIA-AA criteria. A diagnosis of MCI is assigned according to Petersen criteria.

Exclusion criteria:

1. Dementia caused by other factors such as depression, other psychiatric illnesses, thyroid dysfunction, encephalitis, multiple sclerosis, brain trauma, brain tumor, syphilis, acquired immunodeficiency syndrome (AIDS), Creutzfeldt-Jakob disease and other types of dementias such as vascular dementia (VaD), frontotemporal dementia (FTD), dementia with Lewy bodies (DLB), and Parkinson's disease dementia (PDD).
2. MRI and laboratory tests do not support or rule out a diagnosis of AD.
3. Severe circulatory, respiratory, urinary, digestive, hematopoietic diseases (such as unstable angina, uncontrollable asthma, active gastric bleeding) and cancer.
4. Participant has severe psychiatric illness or severe dementia that would interfere in completing initial and follow-up clinical assessments.
5. With history of alcohol or drug abuse.
6. Pregnant or lactating women.
7. No reliable insiders.
8. Refuse to sign the informed consent at baseline.

(4) Vascular dementia (VaD)

Inclusion criteria:

Diagnosis for probable VaD according to NINDS-AIREN diagnostic criteria.

MRI inclusion criteria:

All patients who meet clinical inclusion criteria should accept MRI scans which include an assessment of hippocampal volume.

1. multiple (≥3) supratentorial subcortical small infarcts (3-20 mm in diameter) with or without any degree of white matter lesion (WML); or moderate to severe WML (Fazekas score ≥ 2), with or without small infarction; or ≥ 1 subcortical small infarct in key regions, such as caudate nucleus, globus pallidus, or thalamus.
2. no cortical and watershed infarction, hemorrhage, hydrocephalus, or WML with specific causes (such as multiple sclerosis).
3. no hippocampus or entorhinal cortex atrophy (MTA score = 0 point).

Exclusion criteria:

1. Other neurological diseases that can cause brain dysfunction (such as depression, brain tumor, Parkinson's disease, metabolic encephalopathy, encephalitis, multiple sclerosis, epilepsy, brain trauma, normal intracranial pressure hydrocephalus, etc.).
2. Other systemic diseases that can cause cognitive impairment (such as liver insufficiency, renal insufficiency, thyroid insufficiency, severe anemia, folic acid or vitamin B12 deficiency, syphilis, HIV infection, alcohol and drug abuse, etc.).
3. With a history of mental illness or those with congenital mental retardation.
4. Suffering from a disease that cannot be combined with a cognitive examination.
5. Contraindications to MRI.
6. Refuse to draw blood.
7. Refuse to sign informed consent.

(5) Normal control

Inclusion criteria:

1. Aged 18 (inclusive) or above.
2. Normal MMSE and MoCA evaluations. MMSE>19 points for illiteracy, >24 points for those educated less than 7 years, >27 points for those educated equal to or more than 7 years. MoCA>13 points for illiteracy, >19 points for those educated less than 7 years, >24 points for those educated equal to or more than 7 years.

Exclusion criteria:

1. Subjects with abnormal MMSE or MoCA scores.
2. Subjects with a history of cerebral infarction, traumatic brain injury or related manifestations in MRI.
3. Other neurological diseases that can cause brain dysfunction (such as depression, brain tumor, Parkinson's disease, metabolic encephalopathy, encephalitis, multiple sclerosis, epilepsy, brain trauma, normal intracranial pressure hydrocephalus, etc.).
4. Other systemic diseases that can cause cognitive impairment (such as liver, renal and thyroid insufficiency, severe anemia, folic acid or vitamin B12 deficiency, syphilis, HIV infection, alcohol and drug abuse, etc.).
5. Mental and neurodevelopmental retardation.
6. Suffering from a disease that cannot be combined with a cognitive examination.
7. Contraindications to MRI.
8. Refuse to draw blood.
9. Refuse to sign the informed consent at baseline.