Jack 2000.

Study characteristics
Patient sampling	Primary objectives: to test the hypothesis that the annualised rates of hippocampal atrophy differ as a function of both baseline and change in clinical group membership (control, MCI, or AD) Study population: amnestic MCI, community and referral patients Selection criteria: criteria for the diagnosis of MCI were: memory complaint documented by the patient and collateral source normal general cognition normal ADL not demented (DSM‐III‐R) American Psychiatric Association 1987 CDR score of 0.5. Participants must have had 2 Mayo ADPR/ADRC clinical assessments separated by a minimum of 2 and a maximum of 4 years. Participants who had symptoms which were clinically felt to be unrelated to AD were excluded. For example, participants who suffered a stroke or who developed depression before or during the follow‐up period were excluded Study design: prospective longitudinal study
Patient characteristics and setting	Clinical presentations: amnestic MCI (single domain) Age mean (SD): MCI who progressed to AD: 77 ± 8; stable MCI:78 ± 8 Gender (% men): MCI who progressed to AD: 50%; stable MCI: 44% Education years mean (SD): MCI who progressed to AD: 13.1 ± 3.1; stable MCI: 14.0 ± 3.1 ApoE4 carriers (%): MCI who progressed to AD: 39%; stable MCI: 28% Neuropsychological tests: fixed cut‐off scores on specific psychometric test of general cognitive performance and memory were not employed; MMSE mean (SD): MCI who progressed to AD: 24 ± 3.2; stable MCI: 27 ± 1.9 Clinical stroke excluded: yes Co‐morbidities: cases with depression were excluded Number enrolled: 43 Number available for analysis: 43 Setting: Mayo ADPR (population‐based) and ADRC (referral) Country: USA Period: not reported Language: English
Index tests	Index test: MRI manual method for estimation of the hippocampal volume Manufacturer: GE Tesla strength: 1.5 Assessment methods: manual segmentation according to (Jack 1992). The boundaries of the hippocampi were delineated on each anatomic slice, the number of voxel was calculated automatically with a summing ROI function. The borders of the hippocampi were manually traced with a mouse‐driven cursor for each slice sequentially from posterior to anterior. Inplane hippocampal anatomic boundaries were defined to include the CA1 through CA4 sectors of the hippocampus proper, the dentate gyrus, and subiculum Description of positive cases definition by index test as reported: deviation from normal value assessed with a W score, i.e. the value from a standard normal distribution corresponding to the observed percentile in controls. A cut‐off value was not clearly specified. Examiners: all image processing steps in every participant were performed by the same research associate who was blinded to all clinical information Interobserver variability: not provided (single rater)
Target condition and reference standard(s)	Target condition: AD Prevalence of AD in the sample: 18/43 (42% of enrolled participants) Stable MCI or converted to other dementia: 25 (58%) stable Reference standards: NINCDS/ADRDA criteria (McKhann 1984). The hippocampal volume data derived from the MRI examination and ApoE genotypes were not known to the ADPR/ADRC consensus committee throughout the study Mean clinical follow‐up (SD): 3 ± 1 years
Flow and timing	Withdrawals explained and losses to follow‐up: none reported Uninterpretable MRI results has not been reported
Comparative
Key conclusions by the authors	The data demonstrate a correlation between the rate of change in hippocampal volume and change in cognitive status; data also indicate that the distinction between stable vs a declining members of a group should be detectable both in early symptomatic patient groups (i.e., MCI) and in presymptomatic participants (i.e., controls)
Conflict of interests	Not reported
Notes	Source of funding: grant support: NIH, NIA, AG11378, AG08031, AG06786, AG16574, NS 29059, The DANA Foundation, The Alzheimer's Association 2 x 2 table: data to complete 2 x 2 table provided by the study authors
Methodological quality
Item	Authors' judgement	Risk of bias	Applicability concerns
DOMAIN 1: Patient Selection
Was a consecutive or random sample of patients enrolled?	No
Was a case‐control design avoided?	Yes
Did the study avoid inappropriate exclusions?	No
		High	Low
DOMAIN 2: Index Test All tests
Were the index test results interpreted without knowledge of the results of the reference standard?	Yes
Did the study provide a clear pre‐specified definition of what was considered to be a "positive" result of the index test?	No
Was the index test performed by a single operator or interpreted by consensus in a joint session?	Yes
		High	Low
DOMAIN 3: Reference Standard
Is the reference standards likely to correctly classify the target condition?	Yes
Were the reference standard results interpreted without knowledge of the results of the index tests?	Yes
		Low	Low
DOMAIN 4: Flow and Timing
Was there an appropriate interval between index test and reference standard?	Yes
Did all patients receive the same reference standard?	Yes
Were all patients included in the analysis?	Yes
		Low