title: Diagnostic effectiveness of quantitative [¹⁸F]flutemetamol PET imaging for detection of fibrillar amyloid β using cortical biopsy histopathology as the standard of truth in subjects with idiopathic normal pressure hydrocephalus.
abstract: BACKGROUND
  PET imaging of amyloid-β (Aβ) in vivo holds promise for aiding in earlier diagnosis and intervention in Alzheimer's disease (AD) and mild cognitive impairment. AD-like Aβ pathology is a common comorbidity in patients with idiopathic normal pressure hydrocephalus (iNPH). Fifty patients with iNPH needing ventriculo-peritoneal shunting or intracranial pressure monitoring underwent [18F]flutemetamol PET before (N = 28) or after (N = 22) surgery. Cortical uptake of [18F]flutemetamol was assessed visually by blinded reviewers, and also quantitatively via standard uptake value ratio (SUVR) in specific neocortical regions in relation to either cerebellum or pons reference region: the cerebral cortex of (prospective studies) or surrounding (retrospective studies) the biopsy site, the contralateral homolog, and a calculated composite brain measure. Aβ pathology in the biopsy specimen (standard of truth [SoT]) was measured using Bielschowsky silver and thioflavin S plaque scores, percentage area of grey matter positive for monoclonal antibody to Aβ (4G8), and overall pathology impression. We set out to find (1) which pair(s) of PET SUVR and pathology SoT endpoints matched best, (2) whether quantitative measures of [18F]flutemetamol PET were better for predicting the pathology outcome than blinded image examination (BIE), and (3) whether there was a better match between PET image findings in retrospective vs. prospective studies.
  
  
  RESULTS
  Of the 24 possible endpoint/SoT combinations, the one with composite-cerebellum SUVR and SoT based on overall pathology had the highest Youden index (1.000), receiver operating characteristic area under the curve (1.000), sensitivity (1.000), specificity (1.000), and sum of sensitivity and specificity for the pooled data as well as for the retrospective and prospective studies separately (2.00, for all 3). The BIE sum of sensitivity and specificity, comparable to that for quantitation, was highest using Bielschowsky silver as SoT for all SUVRs (ipsilateral, contralateral, and composite, for both reference regions). The composite SUVR had a 100% positive predictive value (both reference regions) for the overall pathology diagnosis. All SUVRs had a 100% negative predictive value for the Bielschowsky silver result.
  
  
  CONCLUSIONS
  Bielschowsky silver stain and overall pathology judgment showed the strongest associations with imaging results.
authors.forename: Ville
authors.initials: V
authors.lastname: Leinonen
authors.forename: Juha O
authors.initials: JO
authors.lastname: Rinne
authors.forename: Dean F
authors.initials: DF
authors.lastname: Wong
authors.forename: David A
authors.initials: DA
authors.lastname: Wolk
authors.forename: John Q
authors.initials: JQ
authors.lastname: Trojanowski
authors.forename: Paul F
authors.initials: PF
authors.lastname: Sherwin
authors.forename: Adrian
authors.initials: A
authors.lastname: Smith
authors.forename: Kerstin
authors.initials: K
authors.lastname: Heurling
authors.forename: Mandy
authors.initials: M
authors.lastname: Su
authors.affiliation: Life Sciences, GE Healthcare, 101 Carnegie Center, Princeton, NJ 08540, USA. grachevi@hotmail.com.
authors.forename: Igor D
authors.initials: ID
authors.lastname: Grachev
mesh_terms: D000368:Aged; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000814:Aniline Compounds; D052160:Benzothiazoles; D001706:Biopsy; D002540:Cerebral Cortex / Q000000981:diagnostic imaging*; D005260:Female; D007839:Functional Laterality; D006801:Humans; D006850:Hydrocephalus, Normal Pressure / Q000000981:diagnostic imaging / Q000473:pathology*; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D049268:Positron-Emission Tomography; D011446:Prospective Studies; D012372:ROC Curve; D012189:Retrospective Studies; D015898:Tomography Scanners, X-Ray Computed
chemical_list: D016229:Amyloid beta-Peptides; D000814:Aniline Compounds; D052160:Benzothiazoles; C581552:flutemetamol
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