title: Cerebrovascular function in presymptomatic and symptomatic individuals with hereditary cerebral amyloid angiopathy: a case-control study.
abstract: BACKGROUND
  Previous work suggests that impairments of cerebrovascular flow or reactivity might be early markers of cerebral amyloid angiopathy (CAA). Hereditary cerebral haemorrhage with amyloidosis-Dutch type (HCHWA-D) is a genetic form of CAA that can be diagnosed before the onset of clinical symptoms by DNA testing. We aimed to investigate whether haemodynamic measures are decreased in presymptomatic and symptomatic HCHWA-D mutation carriers compared with healthy controls.
  
  
  METHODS
  In this case-control study, we included presymptomatic and symptomatic HCHWA-D mutation carriers diagnosed through genetic testing and recruited through the HCHWA-D patient association (Katwijk, Netherlands) and the outpatient clinic of the Department of Neurology of the Leiden University Medical Center (Leiden, Netherlands), and healthy controls. We measured regional cerebral blood flow (rCBF) using pseudo-continuous arterial spin labelling. Quantitative flow was measured by phase-contrast magnetic resonance angiography of the cerebropetal vessels. Vascular reactivity was established by measuring changes in blood-oxygen-level-dependent (BOLD) signal after visual stimulation. Data from presymptomatic and symptomatic individuals were compared with healthy controls using mixed-model regression analysis.
  
  
  RESULTS
  Between May 15, 2012, and December 22, 2015, we investigated cross-sectional imaging data from 27 HCHWA-D mutation carriers (12 presymptomatic and 15 symptomatic) and 33 healthy controls. Compared with controls, symptomatic HCHWA-D carriers had significantly decreased cortical grey matter rCBF in the occipital lobe (mean difference -11·1 mL/100 g per min, 95% CI -2·8 to -19·3; uncorrected p=0·010) and decreased flux in the basilar artery (mean difference -0·9 mL/s, 95% CI -1·5 to -0·2; uncorrected p=0·019). However, we noted no changes in rCBF and flux in presymptomatic carriers compared with controls. Vascular reactivity was significantly decreased in the occipital lobe in both presymptomatic (mean BOLD change 1·1% [SD 0·5], mean difference -0·4% change, 95% CI -0·7 to -0·2; p=0·001; mean time to baseline 10·1 s [SD 7·6], mean difference 4·6 s, 95% CI 0·4 to 8·8; p=0·032) and symptomatic carriers (mean BOLD change 0·4% [SD 0·1], mean difference -0·9%, 95% CI -1·1 to -0·6; p<0·0001; mean time to baseline 20·3 s [SD 8·4], mean difference 13·1 s, 95% CI 9·4 to 16·9; p<0·0001) compared with controls; however, the difference in mean time to peak was only significant for symptomatic carriers (mean difference 12·2 s, 95% CI 8·6 to 15·9; p<0·0001).
  
  
  CONCLUSIONS
  Our findings suggest that determination of vascular reactivity might be a useful biomarker for early detection of vascular amyloid pathology in sporadic CAA, and a biomarker of efficacy in future intervention trials. Our data indicate that vascular reactivity measurements might be useful for differential diagnosis in dementia to determine the vascular component.
  
  
  BACKGROUND
  USA National Institutes of Health.
authors.affiliation: Department of Radiology, Leiden University Medical Center, Leiden, Netherlands. Electronic address: a.m.van_opstal@lumc.nl.
authors.forename: Anna M
authors.initials: AM
authors.lastname: van Opstal
authors.affiliation: Department of Radiology, Leiden University Medical Center, Leiden, Netherlands.
authors.forename: Sanneke
authors.initials: S
authors.lastname: van Rooden
authors.affiliation: Department of Radiology, Leiden University Medical Center, Leiden, Netherlands.
authors.forename: Thijs
authors.initials: T
authors.lastname: van Harten
authors.affiliation: Department of Radiology, Leiden University Medical Center, Leiden, Netherlands.
authors.forename: Eidrees
authors.initials: E
authors.lastname: Ghariq
authors.affiliation: Department of Radiology, Leiden University Medical Center, Leiden, Netherlands.
authors.forename: Gerda
authors.initials: G
authors.lastname: Labadie
authors.affiliation: Department of Neurology, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Fotiadis
authors.affiliation: Department of Neurology, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: M Edip
authors.initials: ME
authors.lastname: Gurol
authors.affiliation: Department of Neurology, Leiden University Medical Center, Leiden, Netherlands.
authors.forename: Gisela M
authors.initials: GM
authors.lastname: Terwindt
authors.affiliation: Department of Neurology, Leiden University Medical Center, Leiden, Netherlands.
authors.forename: Marieke J H
authors.initials: MJH
authors.lastname: Wermer
authors.affiliation: Department of Radiology, Leiden University Medical Center, Leiden, Netherlands.
authors.forename: Mark A
authors.initials: MA
authors.lastname: van Buchem
authors.affiliation: Department of Neurology, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Greenberg
authors.affiliation: Department of Radiology, Leiden University Medical Center, Leiden, Netherlands.
authors.forename: Jeroen
authors.initials: J
authors.lastname: van der Grond
mesh_terms: D000328:Adult; D015415:Biomarkers; D016022:Case-Control Studies; D028243:Cerebral Amyloid Angiopathy, Familial / Q000000981:diagnostic imaging* / Q000503:physiopathology*; D003430:Cross-Sectional Studies; D005260:Female; D006579:Heterozygote; D006801:Humans; D018810:Magnetic Resonance Angiography / Q000379:methods; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008297:Male; D008875:Middle Aged; D062706:Prodromal Symptoms; D013113:Spin Labels
chemical_list: D015415:Biomarkers; D013113:Spin Labels