Access to DIAN Obs data is dependent on review and approval by the relevant DIAN Obs Core leaders and PI of the grant; Access to DIAN Obs tissue/cell samples are dependent on external review by experts in the field and the DIAN Obs Steering Committee approval.
Preparation of data
There will be one data freeze of the DIAN Obs data each year that includes all data that have passed relevant quality control processes at the time of the ‘freeze.’ Biostatistics Core personnel will prepare modules (ie., clinical, fluid biomarker, imaging, etc.) of the frozen dataset and provide statistical consultation if appropriate.
All precautions to ensure confidentiality must be taken by recipients of DIAN Obs data. The final dataset will be stripped of DIAN Obs identifiers and re-coded with dummy IDs prior to release and be transferred only with encryption and password protection by the Biostatistics Core. The code linking a subject’s identity to data will be maintained only at the DIAN Obs site where the participant is enrolled. This link will only be accessible to research staff on a need to know basis. All United States sites are required to have a Certificate of Confidentiality before they are approved to enroll subjects. The exact mutation will not be recorded in the National Institutes on Aging (NIA), National Cell Repository for Alzheimer’s Disease (NCRAD), DIAN Central Archive (DCA) databases nor will it be entered into DIAN Obs on-line electronic data capture system. Separation of this sensitive data is to prevent accidental disclosure of participant mutation status to a member of the research team. Any research data that goes outside of the study group will be coded with a second unique identifier (which is different from the study ID, another unique identifier) to limit the risk of loss of confidentiality. However, there is always the possibility of deductive disclosure of participant identity because participants are associated with specific institutions, and the dataset contains detailed demographic information, as well as detailed prospective information about their disease and mutation status, living situation, etc. Thus, we will make the data and associated documentation available to users only under the following prerequisites:
Recipient of data will:
- Provide documentation of IRB approval valid for the analysis of DIAN Obs data (or acknowledgment from their IRB that receiving coded data without access to other identifiers is not considered “research” requiring review).
- Provide assurance of ability to secure dataset in accordance with the most stringent protections possible compliant with local IRB and Health Insurance Portability and Accountability Act (HIPAA for US sites) standards for such sensitive data.
- Provide a signed Code Access Agreement (CAA) and Data Use Agreement (DUA) for data usage
- CAA: a simple statement that the recipient of the data signs, verifying they will use the data only for research purposes and will not attempt to identify any individual participant.
- DUA: a contractual document used for the transfer of non-public data that is subject to some restriction on its use. This contract outlines the terms and conditions of the transfer.
- Guarantee that individual mutation status data will be destroyed when analyses are complete.
If a DIAN Obs dataset is to be shared with a DIAN Obs Site, the site leader must identify a third party at the site who will conduct the analyses. This individual must not have contact with participants nor play any role in data processing that involves interpretation or judgment to avoid un-blinding of study personnel or biasing of the data.
Participant Characteristics at Enrollment
Asymptomatic 510 (75.78%) | Symptomatic 163 (24.22%) | |||
| N = 673* (Target 80% Asymptomatic, 20% Symptomatic) (*Table based on 657 participants. 16 Mutations in Process) | MUT: 457 (67.90%) | MUT: 144 (21.40%) | ||
| 243 (NC-) (48.80%) | 255 (MC+) (51.20%) | 17 (NC-) (10.69%) | 142(MC+) (89.31%) | |
| Age | 36.51 (SD 10.95) | 33.39 (SD 9.17) | 39.59 (SD 12.56) | 45.96 (SD 9.78) |
| Gender (% Female) | 142 (58.44%) | 146 (57.25%) | 9 (52.94%) | 77 (54.23%) |
| Parental Age of Onset | 47.56 (SD 6.46) | 48.20 (SD 7.21) | 46.00 (SD 6.26) | 45.47 (SD 8.72) |
| Education (years) | 14.89 (SD 2.82) | 14.75 (SD 2.85) | 11.88 (SD 3.69) | 13.60 (SD 3.40) |
| MMSE | 29.05 (SD 1.31) | 29.08 (SD 1.21) | 27.88 (SD 1.50) | 22.08 (SD 6.99) |
| ApoE4+ 1 E4 | 69 (28.40%) | 71 (27.84%) | 4 (23.53%) | 35 (24.65%) |
| ApoE4+ 2 E4 | 3 (1.23%) | 2 (0.78%) | 0 (0.0%) | 7 (4.93%) |
MC = Mutation Carrier; NC = Non-carrier *Table statistics based on 657 participants with confirmed mutation data available as of 30JUN2023 (inclusive). Of them 397 (60.43%) are mutation carriers, 260 (39.57%) are mutation non-carriers. | ||||
General Information about the clinical assessment
Participants are evaluated in a uniform manner at entry and longitudinally thereafter with instruments to include: the clinical and cognitive batteries that comprise the Uniform Data Set (UDS) (Morris et al., 2006) and additional DIAN Obs-specific testing listed below. Each site has designated a study coordinator who manages the day-to-day conduct of the study, ensures accurate administration of all instruments at the site, and supervises accurate data collection. Sites are responsible for identifying trained clinicians and raters to complete assessments such as the Clinical Dementia Rating (CDR), and the Neuropsychiatric Inventory Questionnaire (NPIQ), etc. It is the site’s responsibility to train interviewers and all other personnel who assess the participant and caregiver. Typically the CDR rater is a trained MD Clinician, but a RN or a PhD can also train and become certified for CDR rating. All clinicians must be blinded to the genetic status of DIAN Obs participants. Clinicians must successfully complete the training modules in order to administer the DIAN Obs assessments.
The clinical assessment, psychometric testing, MRI, PET PiB, FDG or tau PET, and blood and CSF collection may be completed over a few days or in several visits spread over no more than 12 weeks. The exact order of measures is not dictated by the protocol, but it is highly recommended that the clinical assessment be performed first. The rationale is that the clinical assessment could reveal that the participant is unable to complete all of the measures within the protocol prescribed 12-week window. The frequency of the in-person follow-up interval is every other year for asymptomatic participants and annually for those who are symptomatic.
Clinical data available for request
- Estimated Parental Age at Onset
- Participant Demographics
- Informant Demographics
- Exercise Questionnaire
- Hollingshead Index of Social Position (including participant level of education)
- Clinical Dementia Rating (CDR) including CDR Sum of Boxes
- Geriatric Depression Scale (GDS)
- Functional Assessment Questionnaire (FAQ) or Functional Assessment Scales (FAS)
- Neuropsychiatric Inventory-Q (NPI-Q)
- United Parkinson’s Disease Rating Scale (UPDRS)-Motor
- Hachinski Ischemic Score/Cerebrovascular Risk Factors
- Clinician Judgment of Symptoms (UDS Form B9)
- Form D1: Clinician Diagnosis – Cognitive Status and Dementia
- Vital Signs
- Neurologic Exam Findings
- Physical Exam Findings
- Clinician Judgment of Symptoms
Cognitive data include
- Mini Mental Stata Examination (MMSE)
- Category fluency for animals and vegetables (Goodglass 1983 a,b)
- Trailmaking A and B (Armitage, 1946)
- Wechsler Adult Intelligence Scale-Revised (Weschler, 1981)
- Word list recall (immediate and delayed) designed specifically for DIAN Obs
- Letter Fluency for F, A, S
- International Personality Item Pool (IPIP)
- DIAN Memory Complaint Questionnaire (MAC-Q)
- Buschke and Grober Free and Cued Selective Reminding Test (FCSRT) (Immediate and Delayed Recall)
- Wechsler Memory Scale-Revised (WMS-R) Logical Memory/Paragraph Memory (Immediate and Delayed Recall)
- Wechsler Adult Intelligence Scale-Revised (WMS-R) Digit-Symbol Substitution Test
- Wechsler Memory Scale-Revised (WMS-R) Digit Spatial Span Forward and Backward
Data
- Neuropathologic diagnosis: Khatchaturian, CERAD, NIA-Reagan, and NIA-AA neuropathologic diagnostic criteria
- Neuropathologic assessments: Thal beta-amyloid stage; Braak neurofibrillary tangle stage; CERAD neuritic plaque stage; Braak Lewy body stage
Tissue samples
- Formalin-fixed, paraffin wax-embedded (FFPE) histological sections of brain only (call for availability)
- Frozen brain tissue (call for available brain areas)
Data
- APOE Genotype
- Mutation Status (request must permit adequate de-identification, e.g. more than a few participants)
Tissue/cell lines
- DNA/Cell Lines – Upon approval from DIAN Obs Steering Committee, DNA/cell lines may be obtained from the National Cell Repository for Alzheimer’s Disease (NCRAD). Researchers requesting DNA samples will have two request options: A) pre-made plates that will have a reduced cost structure and are sent out rapidly; or B) customized set of samples that have a higher cost structure and will have a delay in shipment time due to preparation. The DNA for both options is cell line derived DNA and available in 25μg aliquots. There is a fee to obtain tissue from NCRAD.
- Dermal Fibroblasts – Dermal fibroblasts have been, and continue to be, collected from a subset of DIAN Obs participants (both mutation carriers and noncarriers). For an up-to-date list of the family mutations represented among banked fibroblast lines (not necessarily mutation carriers), please contact Dr. Alison Goate (alison.goate@mssm.edu). There is a fee to have fibroblast lines expanded for sharing.
- Induced Pluripotent Stem Cells (iPSCs) – Dr. Celeste Karch, with the DIAN Obs Genetics Core, has reprogrammed select fibroblast lines into iPSCs. These iPSC lines are available for sharing through the standard DIAN Obs resource request mechanism, with the stipulation that Dr. Karch be included as a collaborator on proposed research. For an up-to-date list of iPSC lines from DIAN Obs participants, please contact Dr. Goate (alison.goate@mssm.edu) or Dr. Karch (karchc@wustl.edu).
Procedures for Biological Fluids
Fasting Cerebrospinal Fluid and Blood To Be Collected
Polypropylene tubes are utilized for CSF and blood collection and storage since some key analytes, such as Aβ, are known to stick to glass and other plastics. All blood and CSF samples are collected in the morning (as close to 8:00AM as possible) before breakfast and after an overnight fast. Only water (and any medications that can be taken without food) is permitted until the blood draws and the LP procedure are completed. Blood (separated into plasma and serum) and CSF are collected so as to accommodate assaying the broadest range of the best antecedent biomarkers/analytes. CSF total tau, ptau181 and Aβ1-42, and plasma Aβ1-40, Aβx-40, Aβ1-42 and Aβx-42 are analyzed by xMAP bead-based ELISA or Lumipulse G1200. CSF Aβ 1-42 is also analyzed by INNOTEST plate-based ELISA.
Fasting Sample Collection
Blood for plasma is collected into two 10 mL EDTA vials, mixed thoroughly, then centrifuged for 15 minutes at 2000g. The plasma sample is transferred to one labeled polypropylene tube and flash frozen on dry ice. Serum is obtained by collecting two 10 mL vials of blood and allowing them to clot for 30 minutes at room temperature. The tubes are spun for 15 minutes at 2000g. Serum is then transferred to one labeled polypropylene tube and flash frozen on dry ice. LPs for CSF collection are performed using a small caliber atraumatic needle (e.g. 22 or 24 gauge Sprotte needle). CSF is typically obtained via gravity flow from participants in a sitting position unless otherwise stated. Use of 24 gauge needles requires collection by aspiration. The first 2 mL of clear CSF is sent to a local lab for cell counts, glucose, and total protein determination. The remaining 15-20 mL CSF for biomarker analysis is transferred to two labeled polypropylene tubes and flash frozen on dry ice.
Fasting Sample Aliquot, Storage, Inventory and Tracking
When frozen samples are received by the Biomarker Core they are assigned an encoded accession number and logged into a database. Consistent with ADNI protocols, the samples of frozen plasma, serum, and CSF are thawed on ice and then aliquoted (0.5 mL each) into sterile polypropylene vials. Sample vials are then flash frozen on dry ice prior to being placed in designated locations in -80ºC freezers (outfitted with both power and liquid CO2 back-up systems). As such, all DIAN Obs fluid samples will have undergone two freeze-thaw cycles prior to analyte measurement, consistent with the ADNI protocol.
Data (both cross-sectional and longitudinal available)
- CSF Aβ40 (INNOTEST ELISA)
- CSF Aβ1-42 (INNOTEST ELISA)
- CSF Aβ1-42, total tau, ptau181 (AlzBio3)
- Plasma Aβ1-40, Aβ1-42, Aβx-40, Aβx-42 AlzBio3 for plasma)
- Assay date
- Kit lot number
- Plate number
Samples (500ul aliquots)
- Fasted cerebrospinal fluid (CSF)
- Fasted plasma
- Fasted serum
- Future samples/data: CSF VILIP-1 and CSF YKL-40
Available on the DIAN Central Archive (DCA).
Data Formats
PiB: PET Technical Procedures Manual (pdf)
- Full or Partial Scan Download – DCA
- Regional Distribution Volume Ratios based on Manual Template and FreeSurfer derived Regions of Interest
FDG
- Full or Partial Scan Download – DCA
- Regional Averages of activity to assess relative metabolism based on Manual Template and FreeSurfer derived Regions of Interest
MRI: MRI Technical Procedures Manual (pdf)
- Full or Partial Scan Download for both anatomical and functional MRI – DCA
- Series Available
- MPRAGE (Volumetric)
- Rs-fcMRI (resting state)
- DTI (Diffusion tensor imaging)
- ASL (Blood flow)
- T2* or SWI (for assessment of microbleeds)
- FLAIR
- T2
- Field map
- Regional volumetric/subcortical volumetric and cortical thickness using FreeSurfer Version 5.2
Additional Image Analyses
Investigators can submit proposals for additional data analysis to the DIAN Obs Executive Imaging Committee and DIAN Obs Steering Committee. Once the proposal is approved, investigators may be given access to the DIAN Global Project in the DIAN Central Archive (DCA, primary data repository for DIAN). Requested modalities will be available in the DCA for specified approved analysis.