Prestia 2013.

Study characteristics
Patient sampling	Primary objectives: provide clinical evidence that brain amyloidosis biomarkers turn abnormal earlier than other biomarkers in patients with MCI converting to AD Study population: participants with MCI coming to observation at 3 independent memory clinics: Translational Outpatient Memory Clinic (TOMC), VU University Medical Center (VUMC), Karolinska University Hospital Huddinge (KUHH) Selection criteria: all patients with diagnosis of MCI at baseline, with available baseline MRI, FDG‐PET, CSF sampling and clinically followed to ascertain incident AD dementia. Patients included in the study were MCI at baseline and remained stable or developed AD during follow‐up. Exclusion criteria: not reported Study design: prospective longitudinal study (participants coming from 3 cohorts)
Patient characteristics and setting	Clinical presentations: in all 3 memory clinics diagnosis of MCI at baseline was made according to Petersen 1999 criteria. Age mean (SD): MCI who progressed to AD: 68 ± 9; stable MCI: 65 ± 9 Gender (% men): MCI who progressed to AD: 38%; stable MCI: 48% Education years mean (SD): not reported ApoE4 carriers (%): MCI who progressed to AD: 58%; stable MCI: 51% Neuropsychological tests: employed; MMSE mean (SD): MCI who progressed to AD: 26.7 ± 1.6; stable MCI 27.5 ± 1.8 Clinical stroke excluded: yes for the TOMC cohort; not specified for VUMC and KUHH cohorts Co‐morbidities: not reported Number enrolled: 73 (31 from TOMC, 25 VUMC, 17 KUHH) Number available for analysis: 73 (31 from TOMC, 25 VUMC, 17 KUHH) Setting: 3 independent memory clinics: TOMC in Brescia, VUMC in Amsterdam, KUHH in Stockholm Country: Italy, the Netherlands, Sweden Period: not reported Language: English
Index tests	Index test: MRI automated method for estimation of hippocampal volume Manufacturer: Philips for TOMC cohort (Caroli 2007); Siemens for VUMC and KUHH cohorts Tesla strength: 1.0 for TOMC; 1.5 for VUMC; 3 for KUHH Assessment methods: left and right hippocampal volumes were automatically computed using Freesurfer. The smallest between left and right volumes was retained for analyses. As the processing procedures do not account for age, pertinent age‐corrected scores, hereafter called W‐scores, were computed and retained for statistical analyses. Description of positive cases definition by index test as reported: hippocampal volume abnormality (W < −2.90) was defined as W‐score below the 5th percentile of its distribution in a group of 143 cognitively healthy elderly people taken from the ADNI dataset Examiners: no details Interobserver variability: not provided
Target condition and reference standard(s)	Target condition: AD Prevalence of AD in the sample: 29/73 (40% of enrolled participants); 18 from TOMC, 6 VUMC, 5 KUHH) Stable MCI or converted to other dementia: 44 (60%) stable MCI (13 from TOMC, 19 VUMC, 12 KUHH) Reference standards: NINCDS‐ADRDA criteria (McKhann 1984) Mean clinical follow‐up: 1.9 ± 1.3 years for MCI who progressed to AD; 2.7 ± 1.4 years for stable MCI
Flow and timing	Withdrawals explained and losses to follow‐up: none Uninterpretable MRI results have not been reported
Comparative
Key conclusions by the authors	The core biomarker pattern is in line with the current pathophysiologic model of AD. Fully normal and fully abnormal pattern is associated with exceptional and universal development of dementia. Cases not in line might be due to atypical neurobiology or inaccurate thresholds for biomarker (ab)normality
Conflict of interests	The study authors report no disclosures relevant to the manuscript. Invitation to go to Neurology.org for full disclosures
Notes	Source of funding: Swedish Research Council (project 05817), Strategic Research Program in Neuroscience at Karolinska Institutet, Swedish Brain Power, Sottoprogetto finalizzato strategico 2006, Programma Strategico 2006, Convenzione 71; Programma Strategico 2007, Convenzione PS39, Ricerca Corrente Italian Ministry of Health 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?	Unclear
Did the study provide a clear pre‐specified definition of what was considered to be a "positive" result of the index test?	Yes
Was the index test performed by a single operator or interpreted by consensus in a joint session?	Unclear
		Unclear	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