Consensus statement for diagnosis of subcortical small vessel disease

Abstract

Vascular cognitive impairment (VCI) is the diagnostic term used to describe a heterogeneous group of sporadic and hereditary diseases of the large and small blood vessels. Subcortical small vessel disease (SVD) leads to lacunar infarcts and progressive damage to the white matter. Patients with progressive damage to the white matter, referred to as Binswanger's disease (BD), constitute a spectrum from pure vascular disease to a mixture with neurodegenerative changes. Binswanger's disease patients are a relatively homogeneous subgroup with hypoxic hypoperfusion, lacunar infarcts, and inflammation that act synergistically to disrupt the blood-brain barrier (BBB) and break down myelin. Identification of this subgroup can be facilitated by multimodal disease markers obtained from clinical, cerebrospinal fluid, neuropsychological, and imaging studies. This consensus statement identifies a potential set of biomarkers based on underlying pathologic changes that could facilitate diagnosis and aid patient selection for future collaborative treatment trials.

Figure 1.

Venn diagram of the various categories of small vessel vascular cognitive impairment (VCI). White-matter changes of aging or leukoaraiosis indicate that the etiology is uncertain. White-matter changes of aging can overlap with small vessel disease (SVD) in patients with Binswanger’s disease. When Alzheimer’s disease overlaps with SVD, mixed dementia is the appropriate term. Inherited forms of SVD (ISVD), such as CADASIL, are a separate category of SVD. CADASIL, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.

Figure 2.

Hypothetical pathophysiologic mechanisms for white-matter damage secondary to vascular risk factors (hypertension, diabetes etc.). Damage to the blood vessels leads to fibrosis with narrowing of the vessel lumen and thickening of the walls. There is reduction of cerebral blood flow with hypoxia/ischemia that triggers a molecular injury cascade, beginning with hypoxia inducible factor-1α (HIF-1α). The fur gene forms Furin, which is the activator of pro-membrane type metalloproteinase-1 (MT-MMP), the activator of proMMP-2. Proteolytic disruption of the blood–brain barrier (BBB), vasoconstriction due to activation of endothelin-1, ad demyelination, edema, and white-matter damage. HIF also activates a repair cascade that leads to angiogenesis and neurogenesis. (From Rosenberg Lancet Neurology, permission granted).

Figure 3.

Representative permeability maps in the white matter obtained with dynamic contrast-enhanced magnetic resonance imaging (DCEMRI). White-matter hyperintensities (WMHs) are colored in green and are derived from fluid attenuated inversion recovery (FLAIR) MRI. The color scale in the right indicates the amount of permeability change with yellow being the highest values and red being the lowest. (a) Upper row shows representative permeability maps for normal subjects. Scattered areas of red show that mild increases in permeability can be seen in normal some of whom have WMHs (white arrows). (b) Lower row shows white-matter permeability maps from several Binswanger’s disease (BD) patients. The large amount of green indicates that they have extensive WMHs. Areas of high permeability, which were not seen in the normal are seen as yellow areas at the edges of the WMHs (white arrows). Normal appearing white matter shows increased permeability. (Figure courtesy of Arvind Caprihan, PhD, MIND Research Network, Albuquerque, NM).

Figure 4.

Relationship of matrix metalloproteinase (MMP)-2 index to MMP-3 activity for the SVD and control groups. (a) Scatter plot of MMP-2 index and MMP-3 activity shows that the controls clustered in the high MMP-2 index and low MMP-3 activity quadrant (black dots). The SVD group clustered in the low MMP-2 index and high MMP-3 activity (red dots). (b) A density plot of the ratio of MMP-2 index to MMP-3 activity shows that the two groups could be separated based on their means with a P-value of 0.0005.

Figure 5.

Scatter plots showing univariate analyses of cerebrospinal fluid (CSF) biomarkers for controls, SVD, and AD. The SVD patient group consists of MD (filled diamonds) and VaD (open diamonds). Error bars are represented by median and interquartile range. (a) neurofilament light (NF-L), note the broken axis; (b) myelin basic protein (MBP); (c) heart fatty acid binding protein (H-FABP); (d) total tau (T-tau), one missing value (mv) in controls; (e) tau phosphorylated at threonine 181 (P-tau181), two mv in controls and one in MD; (f) amyloid beta 1–42 (Aβ 1–42); (g) matrix metalloproteinase 9 (MMP-9), lowest detection limit set to 40 ng/L; (h) matrix metalloproteinase 10 (MMP-10); (i) tissue inhibitor of metalloproteinase 1 (TIMP-1); (j) matrix metalloproteinase 2 (MMP-2); (k) matrix metalloproteinase 3 (MMP-3), one mv in MD and one in VaD; (l) tissue inhibitor of metalloproteinase 2 (TIMP-2). AD, Alzheimer’s disease; SVD, subcortical vascular disease; MD, mixed dementia; VaD, vascular dementia. (From M Bjerke et al., J Alzheimer’s Dis permission granted).

Figure 6.

The spectrum nature of Binswanger’s disease (BD) is illustrated. At one end of the spectrum on the left side is Alzheimer’s disease with high levels of amyloid and tau proteins. At the other end (right) is BD with vascular risk factors and without amyloid and tau. In the middle are the mixed dementia patients, which represent the majority of the patients with relative levels of pathology of both diseases.