Paraskevas 2009.

Study characteristics
Patient Sampling	132 participants with dementia and 68 controls were recruited. Sampling procedure not reported. Separate data were available for the performance of the biomarkers in distinguishing AD from non‐AD dementia, and AD from VD. We did not include data on performance of the index test to discriminate AD participants from controls. Exclusion criteria: patients with one or more cardiovascular risk factors and patients with 1‐2 white matter lacunes were excluded from AD group; patients with causes of secondary dementia (including thyroid dysfunction, B12 deficiency and possible neurosyphilis) and those using anticoagulant medication (contra‐indication for lumbar puncture) were also excluded from the study.
Patient characteristics and setting	The sample considered in the review comprises of 115 participants: 92 AD, 23 VD. Seventeen participants with mixed dementia were not included in the analysis. 68 controls were also recruited, but not included in the analysis. All patients underwent clinical assessment. Both the VD and mixed groups had significant vascular disease on MRI or CT, either in the form of multiple infarctions, or multiple and/or confluent lacunar infarctions or 'leukoaraiosis of Binswanger type, together with multiple risk factors including hypertension, diabetes, obesity and/or carotid artery stenosis on ultrasound. None of the patients was under treatment for dementia at the time of lumbar puncture, but drugs for cardiovascular disease were allowed in patients with VD and mixed dementia. Sex: 36 males and 56 females for AD; 13 males and 10 females for VD; 9 males and 8 females for mixed dementia Age (SD) (y): 66 ± 10 for AD; 69 ± 10 for VD; 74 ± 7 for mixed dementia Disease duration (y): 3.4 ± 2.7 for AD; 2.9 ± 2.8 for VD; 3.1 ± 2.0 for mixed dementia Sources of recruitment: specialist care setting, Athens National University, Greece. Not reported whether inpatients or outpatients
Index tests	Patients gave CSF samples. The samples were stored at ‐80°C and analysed. Abeta42 was measured using enzyme‐linked immunosorbent assays, obtained from Innogenetics NV, Gent, Belgium. Threshold: 461 pg/ml; not prespecified; the cut‐off levels (for individual markers, or their ratios) were calculated, with the resulting percentages of correct classification. Were the index test results reported without knowledge of the reference standard? [Yes]
Target condition and reference standard(s)	Target condition: Alzheimer's disease dementia (1. differential diagnosis of AD from VD; 2. differential diagnosis of AD from mixed dementia) Reference standards: NINCDS‐ADRDA criteria Alzheimer's disease dementia Clinical diagnosis of VD and mixed dementia was based on NINDS‐AIREN criteria. Clinical diagnosis was established prior the results of the index test
Flow and timing	The interval between established clinical diagnosis and CSF sample collection was not reported. However, it appears that CSF samples were collected short after establishing the clinical diagnosis and following informed consent. Sample included in the analysis: 92 ADD; 23 VD AD vs VD (n=115) TP=72; FP=7; FN=20; TN=16 (Fig 1, p207) Sensitivity=78%; Specificity=70% (Calculated in RevMan5)
Comparative
Notes
Methodological quality
Item	Authors' judgement	Risk of bias	Applicability concerns
DOMAIN 1: Patient Selection
Was a consecutive or random sample of patients enrolled?	Unclear
Was a case‐control design avoided?	No
Did the study avoid inappropriate exclusions?	Yes
Could the selection of patients have introduced bias?		High risk
Are there concerns that the included patients and setting do not match the review question?			Low concern
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
Could the reference standard, its conduct, or its interpretation have introduced bias?		Low risk
Are there concerns that the target condition as defined by the reference standard does not match the question?			Low concern
DOMAIN 4: Flow and Timing
Was there an appropriate interval between index test and reference standard?	Yes
Were all patients included in the analysis?	Yes
Could the patient flow have introduced bias?		Low risk