Morphological, distributional, volumetric and intensity characterisation of periventricular white matter hyperintensities Rory J. Piper, Maria C. Valdés Hernández, Zoe Morris, Natalie A. Royle, Catherine Murray, Susana Muñoz Maniega, Benjamin S. Aribisala, Mark E. Bastin, Ian J. Deary and Joanna M. Wardlaw

Periventricular white matter hyperintensities (PVWMH) in FLAIR MRI Male 20 yrs old healthy Male 48 yrs old diagnosed MS Female 57 yrs old diagnosed MS Female 88 yrs old diagnosed stroke 3T 1.5T Images courtesy of RJ Piper, JM Wardlaw, TH Bak, M Sittampalam and S Chandran

Background Debate whether the innermost segment of PVWMH on axial MRI is indeed white matter pathology or is merely manifestation of artefact from CSF signal [Kim et al, 2002] Distinction between PVWMH and deep WMH is artificial [DeCarli et al, 2005] often decided by user-defined criteria and distance from the lateral ventricles (7 mm [van der Lijn F et al, 2012], 13 mm [Sachdev P et al, 2008]) Results from assessment of white matter lesion volumes in 43 regions defined by orientation and distance to the ventricles [van der Lijn F et al, 2012 Neuroimage 59(4): 3901-8]

Research questions (Q1) Is the hyperintense thin white line detected along the edge of the lateral ventricle a manifestation of a partial volume effect, or an evidence of PVWMH ?

Research questions (Q1) Is the hyperintense thin white line detected along the rim of the lateral ventricle a manifestation of a partial volume effect, or an evidence of PVWMH ?   (Q2) Given that PV- and DWMH share common vascular risk factors and increased burden of total WMH volume (PV- + DWMH) is highly associated with all of: hypertension [de Leeuw, 2002; Godin, 2011] cardiovascular disease [de Leeuw, 2000] cerebrovascular disease [Conijn, 2011] Is this dichotomy of WMH arbitrary? [Appelman, 2010] Opposed by pathological evidence of common vascular mechanisms? [DeCarli, 2005]

Research questions (Q1) Is the hyperintense thin white line detected along the rim of the lateral ventricle a manifestation of a partial volume effect, or an evidence of PVWMH ?   (Q2) Given that PV- and DWMH share common vascular risk factors and increased burden of total WMH volume (PV- + DWMH) is highly associated with all of: hypertension [de Leeuw, 2002; Godin, 2011] cardiovascular disease [de Leeuw, 2000] cerebrovascular disease [Conijn, 2011] Is this dichotomy of WMH arbitrary? [Appelman, 2010] Opposed by pathological evidence of common vascular mechanisms? [DeCarli, 2005] (Q3) Is PV- and DWMH dichotomisation both possible and appropriate by a rule of continuity from the ventricular surface, unique distribution patterns and morphological characteristics ?

Subjects: The Lothian Birth Cohort 1936 A longitudinal study of ageing http://www.lothianbirthcohort.ed.ac.uk/ non-demented living independently males and females 700 subjects had multimodality brain MRI scan at age 72-73 years old Underwent psychometric, cognitive, physical tests and completed dietary, lifestyle and health questionnaires at ages 70, 73 and 76 years old

Data from 665 subjects Hypertension (Y/N) Diabetes (Y/N) Hypercholesterolaemia (Y/N) Cardiov. disease (Y/N) Cerebrov. disease (Y/N) Clinical Imaging WMH binary masks FLAIR

thin white line penetrating big caps confluent with Deep WM diffuse PVWMH (i.e. dirty WM)

Software: ‘Intensity Analyser’ module (at www. sourceforge Software: ‘Intensity Analyser’ module (at www.sourceforge.net/projects/bric1936) % intensity increase width (mm)

Representativeness of the slice selected Intensity analysis with reference to healthy white matter

Results 2D, 3D and quantitative analyses (3D on a random subsample of 10%) thin white line (273) penetrating (233) big caps confluent with Deep WMH (90) diffuse WMH (69) % intensity increase width (mm)

Exploring width % intensity increase width (mm)

Exploring width % intensity increase m = 6.5mm width (mm)

Exploring intensity * (p < 0.05) % intensity increase width (mm)

Exploring relationship with WMH load (diffuse) (diffuse)

* hypercholesterolaemia Exploring relationship with vascular risk factors * hypertension * hypercholesterolaemia * evidence of stroke

Conclusions (Q1) Is the hyperintense thin white line detected along the rim of the lateral ventricle a manifestation of a partial volume effect, or an evidence of PVWMH ? (A1) Our analyses do not suggest that artefact at the ventricle wall does not occur, but rather that this artefact cannot be identified by measurements of PVWMH width or signal intensity

Conclusions (Q2) Is the dichotomy of PV- DWMH arbitrary? Or opposed by pathological evidence of common vascular mechanisms? (A2) The 3D analysis showed a clear separation between DWMH and PVWMH. However, the extent of WMH and the vascular risk factors associated appeared to be related to characteristics of PVWMH (increasing from categories thin line -> penetrating -> big caps confluent with DWMH)

Conclusions (Q3) Is PV- and DWMH dichotomisation both possible and appropriate by a rule of continuity from the ventricular surface, unique distribution patterns and morphological characteristics ? (A3) The results from these analyses conform to popular hypotheses that the boundary for the distinction of PV- and DWMH may lie in a 3 -13mm watershed zone

Row Fogo Charitable Trust Thanks Row Fogo Charitable Trust The Study participants All radiographers and support staff at BRIC (www.bric.ed.ac.uk ) … and you for your attention!

Software: BRIC1936 ‘MCMxxxVI_ALE’ for Segmentation of WMH MATLAB GUI and Windows standalone application www.sourceforge.net/projects/bric1936

Software: BRIC1936 ‘Intensity Analyser’ MATLAB GUI www.sourceforge.net/projects/bric1936

What may infringe the validity of this study?

Limitations of 1.5T Zwanenburg JJ et al. Eur Radiol. 2010; 20(4): 915-22.

Borderline cases: Kim KW et al. 2008. Biol Psychiatry. 64(4): 273-80.