Cohort Descriptives

Variable Response
Cohort name Cognitive Health in Ageing Register: Investigational, Observational, and Trial studies in dementia research (CHARIOT): Prospective Readiness cOhort Study (PRO)
Cohort acronym CHARIOT: PRO Sub Study
General Study Overview There is limited information on people with minimal cognitive changes who are likely to progress to both the earliest stage of cognitive impairment due to Alzheimer’s disease (AD) and then clinically evident dementia of the Alzheimer’s type. Characterizing change in cognition is essential to identify opportunity for intervention at the earliest stage of disease. Participants in both the Main Study and the Substudy will undergo a series of neuropsychological evaluations to characterize the patterns of cognitive change and their inter-relationship in the earliest stages of cognitive impairment. In addition, how such changes relate to the clinical presentation of cognitive impairment of the Alzheimer’s type may be evaluated over time. An opportunity is possible to identify and characterize individuals with different likelihoods of progressing along different clinical paths, which may form a framework for the evaluation of interventions.
Number of subjects at baseline 225
Institution name Imperial College London
Department name Neuroepidemiology and Ageing Research Unit
City London
Principal Investigator (PI): Name Professor Lefkos Middleton
PI: Address Neuroepidemiology and Ageing Research Unit, Imperial College London, Room 10L05, 10th Floor Laboratory Block, Charing Cross Hospital, St Dunstan's Road, London W6 8RP
PI: email

l.middleton@imperial.ac.uk

PI: phone 0203 311 0215
Administrative Contact (AC): Name Dr Chi Udeh-Momoh
AC: Address Neuroepidemiology and Ageing Research Unit, Imperial College London, Room 10L05, 10th Floor Laboratory Block, Charing Cross Hospital, St Dunstan's Road, London W6 8RP
AC: email C.udeh@imperial.ac.uk
AC: phone 0203 311 0320
Technical Contact/Data manager (TC): Name Dr Chi Udeh-Momoh
TC: Address Neuroepidemiology and Ageing Research Unit, Imperial College London, Room 10L05, 10th Floor Laboratory Block, Charing Cross Hospital, St Dunstan's Road, London W6 8RP
TC: email

c.udeh@imperial.ac.uk

TC: phone 0203 311 0320
Population based study? Yes
Family based study? No
Clinical based sample? No
Is there follow-up data available? Yes
Were participants included prior to development of dementia (may refer to controls only)? Yes
Were participants included prior to development of MCI (may refer to controls only)? Yes
How is data collected? In person: 90 day screening period with at least 4 study visits, followed by 3-monthly visits to ICL site post-baseline
Who carries out data collection? Clinicians
Clinical staff: Research nurses, Assistant Psychologists, Clinical Psychologists, Research Lab Technicians, Research Phlebotomists and Clinical Research Fellows
Does this take place in participants' homes or at a central location? Central: Charing Cross Hospital, Hammersmith, London
Do participants take part individually or are families/partners involved? Individually: Participants take part with a study partner
Dementia cases ascertained as part of study: No
Diagnosis based on review of existing clinical data No
How regular is follow-up? Every 3 months for a period of up to 3.5 years
Study start date 22/01/2015
Is study ongoing? Yes
Is study still recruiting? Yes
Inclusion criteria "1. Criterion modified per Amendment 7
1.1 Between 60 and 85 years of age, inclusive, and meets all Main Study inclusion/exclusion criteria
2. Criterion modified per Amendment 6
2.1. Completed RBANS and ADCS-PACC neurocognitive testing at least once during the SubStudy screening visits
3. Have a global CDR score of 0 at screening
4. Criterion modified per Amendment 8
4.1. Have had a history of educational and/or work experience to ensure that congenital learning disabilities are highly unlikely as determined by the Principal Investigator.
5. Be able to read and write and must have adequate hearing and visual acuity to complete the required psychometric tests
6. Have evidence of amyloid pathology by means of either criterion listed below (for amyloid positive cohort only) or have no evidence of amyloid pathology by these criteria (for amyloid negative cohort only):
a. Low CSF A42 concentrations at screeninga
b. Evidence of increased amyloid deposition on a PET scan at screeningb
aCut off value for CSF Aβ42 will be based on the value established by the central CSF screening laboratory and specified in a separate laboratory manual
bAmyloid status by PET scans will be assessed centrally by qualified readers for inclusion based on predefined criteria specified in the imaging manual
7. Criterion deleted per Amendment 8
8. Criterion modified per Amendment 9
8.1. Be otherwise healthy and medically stable on the basis of medical history, vital signs, and physical exam. Any abnormalities must not be the cause or be associated with cognitive impairment. The Sponsor's Medical Monitor may review selected screening data prior to participant enrollment in the SubStudy to confirm eligibility
9. Clinical and neurological examinations and laboratory tests performed during SubStudy screening to confirm participants are healthy and medically stable. If the results of the hematology, serum chemistry, C-reactive protein, coagulation panel, or urinalysis are outside the normal reference ranges, the participant may be included only if the investigator judges the abnormalities or deviations from normal to be not clinically significant, to be appropriate and reasonable for the population under study, and not to be a potential cause of cognitive impairment, with written concurrence from the Sponsor's Medical Monitor obtained prior to participant enrollment. The Sponsor's Medical Monitor will review all screening data prior to participant enrollment in the SubStudy to confirm eligibility
10. Have a reliable informant (relative, partner, or friend). The informant must be willing to participate as a source of information and have at least weekly contact with the participant (contact can be in-person, via telephone, or other audio/visual communication). The informant must have sufficient contact such that the investigator feels he/she can provide meaningful information about the participant’s daily function. If possible, an alternate informant who meets these criteria and can replace the primary informant should be identified prior to randomization considering this is a 3.5-year study
11. Be willing and able to adhere to the prohibitions and restrictions specified in this protocol
12. Women must have documentation of surgical sterility, be postmenopausal for at least 2 years, or have a negative urine pregnancy test at screening
13. Participants 60 to 64 years of age must also have a positive subject-reported family history of dementia suggestive of AD rather than other dementias (minimum of 1 first degree relative).
"
Exclusion criteria "1. Met clinical criteria for AD dementia or has any degenerative brain disorder that is associated with dementia
2. Criterion modified per Amendment 7
2.1 Criterion modified per Amendment 8
2.2 Criterion modified per Amendment 9
2.3 Screening age- and education-adjusted baseline cognitive performance is more than 1.5 SD below normal on any of the RBANS Index scores (note: when any screening RBANS Index scores are more than 1.5 SD below normal, the Sponsor’s Medical Monitor and/or designee(s) will adjudicate and approve enrollment, and if participants are enrolled, they will be assigned to the appropriate risk group)
3. Clinical evidence of any other brain disease
4. Criterion modified per Amendment 7
4.1 MRI evidence of abnormalities, as interpreted by the central radiologist, other than mild mediotemporal atrophy (eg, brain edema such as vasogenic edema including amyloid-related imaging abnormalities ARIA-E91, hydrocephalus, >25% age related white matter disease, frontal or temporal atrophy not typical of AD), history or evidence of a single prior hemorrhage >1 cm3, multiple lacunar infarcts (2 or more), or evidence of a single prior infarct >1 cm3, evidence of a cerebral contusion, encephalomalacia, aneurysms, vascular malformations, subdural hematoma, or space occupying lesions (eg, abscess or brain tumors such as meningioma >1cm), or MRI features atypical of AD dementia. Evidence of brain edema (eg, ARIA-E, vasogenic edema, hemosiderin deposits HD ≥10 mm in size or HD <10 mm in size but >10 in number will be reviewed by the Sponsor’s Medical Monitor to address plans for clinical evaluation and follow up as well as for potential inclusion/exclusion in the study.
5. Have ever received cholinesterase inhibitors (ChEI) and/or memantine
6. Receiving daily medications with the potential to affect cognition such as sedatives (eg, benzodiazepines), pain medications (eg, narcotic analgesics), or anticonvulsants (eg, barbiturates, valproic acid and congeners, phenytoin, carbamazepine) within the last 30 days prior to screening
7. Any known history of familial autosomal dominant Alzheimer’s disease or other familial dementing diseases
8. History of or current thyroid disease or thyroid dysfunction, which is currently uncontrolled or untreated, or clinically significant abnormal thyroid function tests. Participants treated for thyroid disease may be enrolled following review of their records of thyroid function, laboratory tests at screening, diagnosis and treatment history by the investigator, and with written concurrence by the Sponsor's Medical Monitor
9. Criterion modified per Amendment 9
9.1 Clinically significant vitamin B12 or folic acid deficiency. Abnormal B12 or folate levels performed at screening require assessment of homocysteine and methylmalonic acid to assess physiologic significance. Participants with abnormally low B12 or folate levels but normal methylmalonic acid or homocysteine levels may be eligible but must be reviewed and approved by the Sponsor’s Medical Monitor prior to enrollment. Participants treated with oral vitamin B12 or folic acid may be enrolled following review of their screening laboratory values and review of their records of diagnosis and treatment history by the investigator and with written concurrence by the Sponsor's Medical Monitor prior to randomization. Intramuscular B12 is not permitted.
10. Chromosome 21 trisomy (Down Syndrome)
11. History within the past 2 years or current diagnosis of significant psychiatric illness, as per the most current version of the Diagnostic & Statistical Manual of Mental Disorders (including but not limited to major depressive disorders and anxiety disorders), or the participant has a current diagnosis or history of schizophrenia or bipolar disorder at SubStudy entry
12. History within the last 5 years of a serious infectious disease affecting the brain (eg, neurosyphilis, meningitis, encephalitis) or head trauma resulting in protracted loss of consciousness
13. Any contraindications for MRI (eg, pacemaker, metal prostheses, implants, claustrophobia, pacemakers etc) unless MRI compatible
14. Major surgery, requiring general anesthesia within 8 weeks before screening for the SubStudy, and/or has not fully recovered from surgery. Participants are not permitted to enroll if they have preplanned major surgery requiring general anesthesia and with recovery periods of >2 weeks during the time the subject is expected to participate in the SubStudy. They may be enrolled after they have recovered fully
15. Any clinical condition for which, in the opinion of the investigator, participation would not be in the best interest of the subject or that could prevent, limit, or confound the results of protocol-specified assessments and cognitive testing
16. Unable to comply with the study-specific requirements
17. An employee of the investigator or study site with direct involvement in the proposed study or other studies under the direction of that investigator or study site, as well as family members of the employees or the investigator
18. Past or planned exposure to ionizing radiation that in combination with the planned administration with study amyloid PET ligand would result in a cumulative exposure that exceeds local recommended exposure limits.
"

Demographic and Clinical Information

Variable Response
Demographics
Age Yes
Age at time of diagnosis of dementia N/A
Age at last follow-up N/A
Age at time of death N/A
Sex Yes
Ethnicity Yes
Education Yes
Physical examinations
Any physical examination performed? Yes
Blood pressure Data available
Weight Data available
Height Data available
Neurological examination Data available
Medical conditions
Cardiovascular disease data Yes
Myocardial infarction Data available
Medication use for CVD Data available
Hypertension Data available
Systolic/diastolic BP Data available
Hypotension Data available
Hypercholesterolemia Yes
Medication use Yes
Cancer Data available
Diabetic Status Data available

Cognitive Outcomes

Variable Response
Any domain-specific cognitive test performed? Yes
Verbal Memory Data available
Data available
Language Data available
Data available
Vigilance Data available
Data available
Latent memory Data available
Data available
IQ data available? Yes
NART Yes
Cognitive background? Yes
Years of education Yes
Level of education Yes
Parental education No
Standard dementia global cognition scales? Yes
MMSE Yes
MoCA No
ADAS-Cog No
Addenbrooke's Cognitive Exam No
3MS No
GPCOG No
Other assessments of global cognition RBANS, DKEFS, Clinical Drug Research Assessment System, CogState, Neuropsychological Assessment Battery - Memory and Executive function modules, Clinical Dementia Rating Scale - Sum of boxes, ADCS-PACC

Non-Cognitive Clinical Outcomes

Variable Response
Dementia diagnosis
Subjective complaint Yes
Dementia diagnosis (Other comments) Study makes no dementia diagnosis of individual participants
Functional rating scales
Any information on dementia rating collected? Yes
ADCS-ADL Yes
Comments: Prevention Instrument used
ADCS-ADL-MCI No
Blessed Dementia Scale No
Clinical dementia rating scale (CDR) Yes
Complex Activities of Daily Living No
Dependence Scale No
Functional Assessment Questionniare (FAQ) No
FAST No
Global Deterioration Scale (GDS) No
Katz ADL No
Lawton IADL Yes
Comments: Incorporated into the CHARIOT:PRO Health and Lifestyle questionnaire
PDQ39 (PD specific) No
UPDRS (PD specific) No
Hoehn and Yahr (PD specific) No
Schwab and England (PD specific) No
UHDRS (HD specific) No
Any information on subjective complaints collected? Yes
Any neuropsychiatric rating scale administered? Yes
Aggression Scale No
Beck Depression Inventory No
Behave-AD No
Center for Epidemiologic Studies Depression scale (CES-D) No
Connor-Davidson Resilience Scale No
Cornell depression Scale No
Geriatric Depression Scale (GDS) Yes
Hamilton depression rating scale (HDRS) No
Montgomery-Asberg depression scale (MADRS) No
NPI No
NPI-Q No
Speilberger State Anxiety Scale Yes
Hospital anxiety depression scale/psychiatry (HADS) No
Any Quality of Life Data Colllected? Yes
Quality of Life-Alzheimers Disease (QOL-AD) No
Dementia Quality of Life Instrument (DEMQOL) No
Discomfort Scale for Dementia of Alzheimers Type (DS-DAT) No
Progressive Deterioration Scale (PDS) No
Quality of Life in Late-Stage Dementia Scale (QUALID) No
Bedfords Alzheimers Nursing Severity Scale(BANS-S) No
EQ-5DVAS No
Short Form (SF) 36 No
Health Utilities Index 1, 2 or 3 Yes
Specify any other quality of life scales CHARIOT:PRO Health and Lifestyle Questionnaire, State-Trait Anxiety Scale, Revised Perceived Deficits Questionnaire, Work Productivity and Activity Impairment, Scottish Collaborative Group Food Frequency Questionnaire, International Physical Activity Questionnaire, Berlin Questionnaire, Pittsburgh Sleep Quality Index, Cognitive Function Index, Technology Readiness Questionnaire
Any information on Caregivers and Caregiving Collected? No
Health service utilisation
Any Health Resource Utilisation Collected ? No
Other neurological or psychiatric measurements? No

Imaging

Variable Response
Structural T1 Acquired
Acquired
Fluid attenuation inversion recovery (FLAIR) Acquired
Acquired
Diffusion imaging (DTI/DWI) Acquired
Acquired
f-MRI (task) Not acquired
Not acquired
f-MRI (rest) Acquired
Acquired
PET Acquired
Acquired
SPECT Not acquired
Not acquired
MEG Not acquired
Not acquired
In vivo Spectroscopy Not acquired
Not acquired
Other (please specify) None
Primary contact for the technical aspects of the imaging data For enquiries, please contact Study Manager Dr Udeh-Momoh: c.udeh@imperial.ac.uk
Retinal imaging Data available
Comments: Yes - under Neurovision Ancillary Study

Genetics

Variable Response
Overview
Number Gwas subjects N/A
N APOE genotyped Blinded data until end of study
Gene screening
APOE Yes
TREM2 No
APP No
PSEN1 No
PSEN2 No
GRN No
MAPT No
C9ORF72 No
VCP No
CHMP2B No
TDP-43 No
PRNP No
SNCA No
LRRK2 No
PINK1 No
PARK2 No
PARK7 No
NOTCH3 No
CST3 No
TTR No
GSN No
ITM2B No
HTT No
NPC1 No
NPC2 No

Biological samples

Variable Response
Blood collected Yes
Plasma Yes
Serum Yes
RNA Yes
DNA Yes
Abeta 1-40 Yes
Comments: Data blinded until end of study
Abeta 1-42 Yes: Data blinded until end of study
Abeta x-40 No
Abeta x-42 No
Blood Metabolic Analytes
CRP (c-reactive protein) Yes
eGFR (estimated Glomular Filtration Rate) Yes
Glucose Yes
HbA1c Yes
Lipids Yes
Liver Function Tests Yes
Serum creatinine Yes
Homocysteine Yes
Folate Yes
Other blood samples No
Are laboratory protocols and storage information available for bloods Yes
Urine collection
Urine Yes
Autopsy data
Autopsy No
Measurements already performed No
Saliva
Saliva collected Yes: Data available in 2018
Cortisol Yes
Details: Data available in 2018
Are laboratory protocols and saliva storage information available? Yes
CSF
CSF collected Yes
Are CSF laboratory protocols and storage information available? Yes
Mitochondrial function Comments
mtDNA abnormalities No
Oxidative stress No

Brain donation

Variable Response
Is brain donation part of the existing protocol? No
Are information sheets made available to representative or consultees? No
Are retrospective interviews carried out after the participant's death? No
Is there a procedure for declining donation/failed recruitment/project termination? No
Has an actuarial analysis been completed? No

Lifestyle

Variable Response
Smoking Yes
Pack years Data available
Passive smoking Data available
Current smoking Data available
Former smoking Data available
Alcohol Data available
Specified beverage type (wine, spirits, beers) Data available
Drugs of abuse assessment
Obesity and associated risk factors
BMI Data available
Physical activity and exercise Yes
Exercise duration Data available
Objective measures of activity Data available
Diet Yes
Carbs, protein, fats, fish oil Data available
Anti-oxidants Data available
Vegetarian? Data available
Coffee and caffeine Data available
Vitamin A, B, E Data available
Food questionnaires Data available: SFFQ
Other dietary items Yes - listed in SFFQ
Employment status
Employment status Data available
Living situation
Living situation Data available
Socioeconomic status
Socioeconomic status measures Data available
Comments: Demographics, occupation & income
Sleep assessment
Questionnaires Data available
Actigraphy to measure sleep patterns Data available

Ethics and Engagement

Variable Response
Participant engagement
Is there participant representation in the governance of the cohort? No
Do existing mechanisms for consulting/involving participants exist? No
Ethics
Is there an ethics advisory or ELSI group within the cohort governance? No
Does the cohort include participants who lack capacity? No
Is there a process in place for participants who lose capacity? Yes
Do participants provide contact information for a person to act as a potential consultee? No
Disclosure
Do procedures exist for the disclosure of incidental findings? Yes
What kinds of finding do these relate to? (imaging, genotyping, etc) Cognitive, Psychiatric and Medical abnormalities
Who is responsible for disclosing incidental findings? Study Investigators - Principal Investigator, Co-investigators, Sub-investigators (Clinical Research Fellows) and Clinical Research Psychologists
Do procedures exist for the disclosure of clinically relevant information identified as a direct focus of the study? (e.g. a diagnosis of dementia) No
Recruitment
How was the cohort recruited (NHS or not, primary or secondary care)? Self-referrals, advertising and media, from the CHARIOT: Cognitive Health in Ageing Register: Investigational, Observational and Trial studies in dementia research
Does the study involve ongoing connections with participants' own doctors (e.g. GPs)? Yes
Consent and recontact
Is there consent for recontact? No

Data Management

Variable Response
Consent for linkage to routine data