Table 1

Postmortem studies on characterisation of white matter hyperintensities using postmortem MRI–pathology correlation

ReferenceSubjectsHistochemistryImmunohistochemistryMRIMain findings
Awad 1986187 neur (−) controlsHE, LFBGFAP1.5T
  • WMH correspond to a spectrum of histological alterations.

  • Mild tissue changes=enlarged perivascular spaces, vascular ectasia.

  • Severe tissue changes=degeneration axons, gliosis.

Englund 198716
  • 21 AD

  • 19 neur (+) controls

HE, LFB0.25TT1 and T2 relaxation times increased with severity of tissue changes in WMH.
Marshall 19881916 neur (−) controlsHE, Congo Red, Alcian Blue, LFBGFAP, IgG, albumin0.35T
  • WMH correspond to intermediate and old infarctions:

    • intermediate infarctions=necrosis, minimal cavitation, gliosis.

    • old infarction=cavitation, surrounded by demyelination, fibrohyalinosis and isomorphic gliosis (swollen reactive astrocytes, positive for IgG and albumin). Findings imply blood–brain barrier leakage.

  • No correlation with CAA.

Braffmann 19882023 neur (+/−) controlsHE, Weil, LFB, Bodian1.5TWMH vary from subtle gliosis and demyelination to frank infarction.
Mascalchi 1989211 VaDHE, Woelke, Congo Red0.5TCase report: WMH reflect demyelination, axonal loss, moderate astrogliosis, oligodendroglial swelling, a few macrophages and slight oedema. Arterial/arteriolar wall changes: severe thickening with stenosis, hyperplasia and hyalinosis. Scarce vascular amyloid deposition.
Revesz 1989224 VaDHE, KB, Nissl, Holzer axons, cresyl violet, EvG, Heidenhain's myelin, Bielschowsky, PTAH0.5T
  • Good correlation of extent of WMH on MRI and pathological changes.

  • Vascular wall changes=arteriosclerotic changes with thickening, fibrosis and splitting of the internal elastic lamina, dilated perivascular spaces.

Van Swieten 199123
  • 11 neur (−) controls

  • 8 demented pts

HE, LFB, Weil, EvG, PTAH, PAS, Congo Red, Bodian1.5T
  • WMH=demyelination, gliosis and arteriolosclerotic changes.

  • Arteriolar wall thickening in moderate/severe WMH.

Fazekas 199124
  • 2 controls - neur

  • 4 neur (+) controls

HE, Masson's trichrome, KB1.5TPunctate WMH=spectrum of perivascular damage with fibrohyalinosis, atrophic neuropil and rarefaction myelinated fibres.
Grafton 199125
  • 3 AD

  • 4 neur (+/−) controls

LFB-PAS, Holzer astrocytes, Holmes, gallocyaninGFAP
  • PVL=myelin pallor, gliosis and widened perivascular spaces.

  • DWMH did not correlate with any neuropathological measure.

Chimowitz 1992267 neur (−) controlsKB, Congo red, desminGFAP1.5T
  • Each type of WMH correlated with distinct PA:

  • Periventricular rims=ependymal loss and subependymal gliosis.

  • Periventricular caps/patches=myelin pallor.

  • Punctate DWMH=widened perivascular spaces.

Fazekas 19932711 neur (+) controlsHE, Masson's trichrome, KB1.5T
  • PVL: Smooth PVL=myelin pallor, loose fibres, tortuous venules, no arteriolosclerosis, discontinuity ependym, mild-moderate gliosis. Irregular PVL=varying fibre loss, gliosis and cavitation, fibrohyalinosis.

  • DWMH: Punctate DWMH=no ischaemic changes; demyelination, atrophic neuropil around fibrohyalinotic arterioles and perivenous damage. Early confluent DWMH=perivascular rarefaction of myelin, mild–moderate fibre loss, varying gliosis. Confluent DWMH=irregular areas of incomplete parenchymal destruction with focal transitions to true infarcts.

Munoz 199328
  • 2 AD

  • 13 neur (−) controls

HE, chromoxane cyanin, Bielschowsky, Congo red1.5TExtensive DWMH=broad areas of loss of myelin, axons and glial cells (oligodendrocytes) and spongiosis. No infarction or vascular wall changes. Punctate WMH=dilated perivascular spaces.
Scarpelli 199429
  • 16 neur (−) controls

  • 5 neur (+) controls

  • HE

  • LFB

GFAP1.0T
  • PVL=atherosclerotic changes, vacuolisation of the myelin, neuropil and fibrous gliosis with proliferation of ependymal cells.

  • DWMH=vacuolated myelin around atherosclerotic arteries/arterioles, widened perivascular spaces with degenerated myelin and recent infarction

  • PVL/focal DWMH no clinical consequences, whereas confluent DWMH are potentially pathological.

Scheltens 199512
  • 6 AD

  • 9 neur (−) controls

HE, PTAH, KB, Bodian, EvG, Congo Red0.6T
  • AD versus controls: some AD pts show more extensive WMH than controls. WMH=loss of myelinated axons, gliosis, no atherosclerosis.

  • In AD, the nature of pathological changes is comparable with but more severe than in controls.

Smith 20003012 pts not specifiedLFB-
  • Extent of WMH on MRI correlates well with extent of WM pathology.

  • No ischaemic changes (microinfarcts or lacunes) in a sample with few cardiovascular risk factors.

Bronge 2002316 ADHE, KB1.5T
  • More extensive WMH on PA than on MRI.

  • +PA/−MRI lesions: mild changes=lower myelin density, loose but intact fibre network, normal glial density.

  • +PA/+MRI lesions=variable myelin/ axonal loss, irregular and fragmented axons, vacuolation, decreased cell density, dilated perivascular spaces, smooth muscle degeneration. no gliosis/infarction.

Moody 20043221 neur (−) controlsAlkaline phosphatase, Congo red, Masson trichrome, Kultchitsky haematoxylin/LFB, Cresyl violet acetate plus light green and Gill haematoxylin.1.5T
  • WMH correlates with decreased vascular density (arteries/arterioles/capillaries).

  • Subjects with WMH have a decreased vascular density in WMH, NAWM and cortex, but especially apparent in youngest subjects.

Fernando 200433
  • 16 neur (−) controls

  • 17 AD + VaD

HE, LFB/Loyez methodCD68, collagen-IV, ICAM-11.0T
  • PVL-MRI: sensitivity=95% (87–99%), specificity=71% (44–90%), DWMH-MRI: sensitivity=86% (79–93%), specificity=80% (72–88%).

  • Weighted kappa MRI-PA: PVL=0.4, DWMH=0.3; underestimation small lesions.

  • MRI+ versus MRI− lesions: difference in myelin loss and endothelial upregulation. No difference in microglial activation.

Fernando 200634
  • 99 demented

  • 108 neur (+/−) controls

CD68, Col IV, ICAM1, HIF1α/ 2α, MMP7, Ngb, NMBR, VEFGR2, βA41.0T
  • Vascular changes in WMH: wall thickening, dilated perivascular spaces.

  • In PVL: ependym denudation.

  • In DWMH specifically: higher capillary network density, microglial activation (CD68), upregulation hypoxia factors (HIF1/2alpha, VEGFR2, Ngb) and correlation CAA∼ HIF1α. Both DWMH and PVL: upregulation MMP7.

  • C/hypoxia plays a role in a part of WMH. differences DWMH versus PVL. No differences demented and non-demented subjects.

Simpson 200735
  • Unselected tissue blocks:

  • 12 PVL, 12 DWMH,

  • 15 NAWM

HE, LFBMBP, GFAP, CD68, PDGFαR, MAP-2(+13), fibrinogen1.0T
  • DWMH and PVL differ with regard to pathological profiles and biological responses:

  • More microglial activation (CD68) in DWMH > PVL.

  • Clasmatodendritic astrocytosis, positive for serum proteins (42% DWMH, 67% PVL), suggesting blood–brain barrier dysfunction.

  • Attempts at regeneration/ remyelination in PVL (MAP-2+13, PDGFαR/OPC).

Simpson 200736
  • Unselected tissue blocks:

  • 12 PVL, 12 DWMH, 15 NAWM

HLA-DR, B7-2, CD40, Mcm2, PCNA, Ki671.0T
  • Microglial responses:

  • PVL: more MHCII positive microglia and costimulatory B7-2 and CD40, suggesting a more proliferative/ immune reactive environment.

  • In DWMH: amoeboid microglia for phagocytosis of myelin breakdown products.

Young 200837
  • 17 demented (various)

  • 3 neur (+/-) controls.

HE, PAS, WeildMBP, CD31, GFAP, hGLUT-5, APP, HLA-DR, P-gp, IgG3.0T
  • WMH extent scored using Scheltens Scale.38 PVL extent ∼ reactive microglia, DWMH extent ∼ vascular integrity. WMH not associated with myelin pallor.

  • Model for prediction of WMH extent (correctly classifies WMH/NAWM in 80%): only independent predictor=decreased vascular integrity (CD31). P-gp: WMH > NAWM, but no difference with IgG → Blood–brain barrier dysfunction.

QMRI
Englund 2003392 ADKB3.0T
  • Postmortem DTI is feasible in fixated brain specimens.

  • DTI measures in WMH correlates with severity of myelin loss.

Larsson 2004401 FTDHE, LFB3.0T
  • The area of DTI changes was more extensive than WMH areas on conventional MRI.

  • WMH correlates with gliosis and demyelination.

Gouw 20084111 AD 7 neur (−) controlsHE, LFB-CV, BodianGFAP, HLA-DR1.5T
  • Quantitative MRI distinguishes WMH from AD and controls. More microglial activation in WMH than NAWM in AD patients specifically. QMRI ∼ severity of pathological changes.

  • Independent predictor of fractional anisotropy in DTI=axonal loss

  • Independent predictors of T1 relaxation time=axonal loss, myelin loss, microglial activation.

  • AD, Alzheimer's disease; APP, amyloid precursor protein; CAA, cerebral amyloid angiopathy; CD31, vascular integrity; CD40 and CD40 ligand, immune costimulatory molecules; DTI, diffusion tensor imaging; (D)WMH, (deep) white matter hyperintensities; EvG, Elastic van Gieson; FTD, frontotemporal dementia; GFAP, glial fibrilary acidic protein; HE, haematoxylin–eosin; hGLUT-5, human glucose transporter-5; HIF, hypoxia inducible factor; HLA-DR, human leucocyte antigen-DR; ICAM1, intercellular adhesion molecule; IgG, immunoglobulin; KB, Klüver–Barrera; LFB, Luxol Fast Blue; LFB–PAS, Luxol Fast Blue/periodic acid-Schiff; MAP-2 +13, microtubule associated protein 2 expressing exon 13; MBP, myelin basic protein, Mcm2; MMP7, matrix metalloproteinase 7; NAWM, normal appearing white matter; neur (−) controls, non-demented subjects without neurological disease; neur (+) controls, non-demented patients with neurological disease; Ngb, neuroglobin; NMBR, neuromedin B receptor; OPC, oligodendrocyte precursor cells; PA, pathology; PCNA and Ki67, cell proliferation related molecules; PDGFaR, platelet derived growth factor a receptor; P-gp, P-glycoprotein; PTAH, phosphotungstic acid haematoxylin; PVL, periventricular white matter hyperintensities; (Q)MRI, (quantitative) MRI; VaD, vascular dementia. VEGFR2, vascular endothelial growth factor receptor 2.