Cerebral Small Vessel Disease Reference Guide

eBRAIN GroupJournal Club

Fall 2017

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3138 Stroke November 2012

vegetables, fish, whole grains, nuts, and monounsaturated oils, and is low in high- fat dairy and meat.

Several prospective studies found that adherence to a Mediterranean diet is associated with a lower risk of cognitive decline10,11 and AD, although there are few data for VCI and VaD. Studies of E vitamins and B vitamins suggest that low basal vitamin status is critical, whereas persons with adequate status probably do not benefit from supplementary intake of vitamins.12

In general, RCT have failed to demonstrate a benefit from dietary supplementation. However, this may relate to method-ological limitations such as the inclusion of subjects with nor-mal vitamin status,12 supplementation through other sources, and short follow- up (Table 2). Against this background, a Mediterranean- type diet may be reasonable (Table 1).2

Homocysteine and HyperhomocysteinemiaElevated concentrations of plasma total homocysteine may cause vascular damage.13 They are associated with lower cog-nitive performance14 and an increased risk of AD and demen-tia, although it is still debated whether this link is causal.15 The levels of total homocysteine can be lowered by ≈20%

with oral supplementation of specific B vitamins, marking it a potentially modifiable risk factor. However, several RCT have failed to show any obvious benefits of homocysteine- lowering therapy on cognitive performance. This might relate to limi-tations in study design such as the inclusion of subjects with normal homocysteine levels12 and too short follow- up (Table 2). Also, there are no trials with AD or VaD as an end point. However, it currently is not recommended to administer B vitamins for the prevention of VCI (Table 1).

Physical ActivityPhysical activity has multiple biological effects, including beneficial actions on synaptogenesis and neurogenesis,16 and, in fact, observational studies demonstrate a beneficial role of physical activity on the risk of VaD,17 AD, dementia, and cog-nitive decline. However, there are few data from RCT. The largest trial so far compared a 24-week home- based program of physical activity with education and usual care in 170 non-demented volunteers with subjective memory impairment. Physical activity provided a modest improvement in cogni-tion over an 18-month follow- up period as assessed by the Alzheimer Disease Assessment Scale–Cognitive Subscale.18

Non-modifyable Risk Factorsage

genetic factors (APOE)

Lifestyle Factors

education

smoking

diet

homocysteine

physical activity

obesity, BMI

Physiological Risk Factors

hypertension

hyperglycemia, diabetes

lipids, dyslipidemia

infl ammation

Concomitant Clinical Vascular Disease

stroke

coronary artery disease

atrial fi brillation

peripheral arterial disease

chronic kidney disease

low cardiac output

depression

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Established Evidence

Inconsistent Results

Insuffi cient Evidence

Figure 1. Risk factors for vascular dementia (VaD), Alzheimer disease (AD), unspecified dementia, and cognitive impairment. Findings are derived from epidemiological studies. Relevant references are detailed in Supplementary Table I. VaD and AD share many risk factors, although the level of evi-dence varies for individual risk factors and demen-tia subtypes.

by guest on March 19, 2017

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Dichgans & Zietemann, 2012

Overlap of risk factors for vascular dementia, Alzheimer’s disease, dementia, and cognitive impairment in general

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TABLE 1 Summary of Referenced Neuroimaging Acronyms

Imaging Acronym Acronym Expansion Imaging Modality Explanation of Imaging Outcome

[O15]H2O PET Positron emission tomographyusing oxygen 15–labeled water

PET A form of PET using a freely diffusible tissue tracer [O15]H2Oto calculate regional cerebral blood flow

AD Axial diffusivity MRI (DTI) The measure of restriction along the axis of the axons(perpendicular to the direction of radial diffusivity). AD is amore specific index of axonal degeneration.

BOLD Blood oxygen level dependent MRI The principal mechanism of signal contrast in fMRI producedby a combination of brain neuronal oxygen consumption(oxygenation state of hemoglobin is measured) and bloodflow. The BOLD signal is associated with brain neuronalactivation, more activation ¼ increased BOLD.

Cho Choline MRS A metabolite quantified in the brain by MRS. Cho is a markerof cellular membrane turnover reflecting cellularproliferation. Increased Cho can be seen in malignancy,infarction, and inflammation.

Cr Creatine MRS A metabolite quantified in the brain by MRS. Cr is considered amarker of intracellular metabolism. It is considered a stablebrain metabolite.

DA D2 receptorbinding potential

Dopamine D2 receptorsubtype occupancy

PET ([11C]raclopride PET) [11C]Raclopride ligand PET scanning is used to determinechanges in brain DA D2 receptor binding potential, whichindexes changes in DA release in the brain.

DMN Default mode network MRI (fMRI) A brain functional network, the activity of which is measuredduring resting state fMRI. This network of brain regions isnormally engaged when patients are left to think tothemselves undisturbed; composed of medial temporal lobe,prefrontal cortex, posterior cingulate, and parietal cortex.

DTI Diffusion tensor imaging MRI DTI produces MRI indexes of white matter integrity and axonalbundle formation and geometries.

FA Fractional anisotropy MRI (DTI) An index of myelination or white matter integrity and/ororganization. FA is expressed as a number on a scalebetween 0 and 1, without any unit of measure. The greaterthe FA, the greater the integrity/organization of the whitematter tract.

FC Functional connectivity MRI or PET Time synchronous activation between multiple distantbrain regions.

FDG-PET Fluorodeoxyglucose positronemission tomography

PET Scanning technique measuring glucose metabolism in the brainusing a radiolabeled glucose analogue.

fMRI Functional magneticresonance imaging

MRI Stimulus-driven brain activation measured from the changes inoxygenation states of hemoglobin.

GM volume Gray matter volume MRI The volume of the brain GM can be expressed as a global orregion-specific measure. GM in the brain contains the cellbodies, dendrites, and axon terminals of neurons.

MAO-A Monoamine oxidase A PET ([11C]clorgyline PET) MAO-A metabolizes serotonin, norepinephrine, and dopamine.PET using [11C]clorgyline measures brain MAO-A.

MAO-B Monoamine oxidase B PET (deuterium substituted[11C]-L-deprenyl PET)

MAO-B primarily metabolizes dopamine. PET using deuteriumsubstituted [11C]-L-deprenyl measures brain MAO-B.

MD Mean diffusivity MRI (DTI) Also referred to as the apparent diffusion coefficient (ADC).It is a measure of diffusion (Brownian motion) of watermolecules in tissue measured in mm2/s. MD is affected byrestricted spaces, barriers such as cell membranes, tubules,and macromolecules. ADC maps of the brain can begenerated, and good diffusion is bright on these maps.

MRS Magnetic resonance spectroscopy MRS An imaging technique based on MRI that allows one tovisualize certain metabolite concentrations in brain tissue;either single-voxel spectra or metabolite images can beproduced (MRS imaging). The major peaks of the 1H-MRSspectrum (each peak represent a metabolite) reported inthis review include N-acetylaspartate (NAA), creatine (Cr),and choline (Cho) containing phospholipids.

NAA N-Acetylaspartate MRS A metabolite quantified in the brain by MRS. NAA is considereda metabolic marker reflecting the functional status ofneurons and axons in the brain, with a decrease indicatingneuronal or axonal loss or dysfunction.

NAA/Cr, NAA/Cho N-Acetylaspartate ratioswith Cr/Cho

MRS The concentration of Cr is relatively constant and is considered astable brain metabolite; therefore, it is used as an internalreference for calculating metabolite ratios such as NAA. Cho isalso used as an internal reference for calculating NAA ratios.

[O15]H2O PET Positron emission tomography usingoxygen 15–labeled water

PET A form of PET using a freely diffusible tissue tracer, [O15]H2O,to calculate regional cerebral blood flow.

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Neuroimaging reference

TABLE 1 Summary of Referenced Neuroimaging Acronyms

Imaging Acronym Acronym Expansion Imaging Modality Explanation of Imaging Outcome

[O15]H2O PET Positron emission tomographyusing oxygen 15–labeled water

PET A form of PET using a freely diffusible tissue tracer [O15]H2Oto calculate regional cerebral blood flow

AD Axial diffusivity MRI (DTI) The measure of restriction along the axis of the axons(perpendicular to the direction of radial diffusivity). AD is amore specific index of axonal degeneration.

BOLD Blood oxygen level dependent MRI The principal mechanism of signal contrast in fMRI producedby a combination of brain neuronal oxygen consumption(oxygenation state of hemoglobin is measured) and bloodflow. The BOLD signal is associated with brain neuronalactivation, more activation ¼ increased BOLD.

Cho Choline MRS A metabolite quantified in the brain by MRS. Cho is a markerof cellular membrane turnover reflecting cellularproliferation. Increased Cho can be seen in malignancy,infarction, and inflammation.

Cr Creatine MRS A metabolite quantified in the brain by MRS. Cr is considered amarker of intracellular metabolism. It is considered a stablebrain metabolite.

DA D2 receptorbinding potential

Dopamine D2 receptorsubtype occupancy

PET ([11C]raclopride PET) [11C]Raclopride ligand PET scanning is used to determinechanges in brain DA D2 receptor binding potential, whichindexes changes in DA release in the brain.

DMN Default mode network MRI (fMRI) A brain functional network, the activity of which is measuredduring resting state fMRI. This network of brain regions isnormally engaged when patients are left to think tothemselves undisturbed; composed of medial temporal lobe,prefrontal cortex, posterior cingulate, and parietal cortex.

DTI Diffusion tensor imaging MRI DTI produces MRI indexes of white matter integrity and axonalbundle formation and geometries.

FA Fractional anisotropy MRI (DTI) An index of myelination or white matter integrity and/ororganization. FA is expressed as a number on a scalebetween 0 and 1, without any unit of measure. The greaterthe FA, the greater the integrity/organization of the whitematter tract.

FC Functional connectivity MRI or PET Time synchronous activation between multiple distantbrain regions.

FDG-PET Fluorodeoxyglucose positronemission tomography

PET Scanning technique measuring glucose metabolism in the brainusing a radiolabeled glucose analogue.

fMRI Functional magneticresonance imaging

MRI Stimulus-driven brain activation measured from the changes inoxygenation states of hemoglobin.

GM volume Gray matter volume MRI The volume of the brain GM can be expressed as a global orregion-specific measure. GM in the brain contains the cellbodies, dendrites, and axon terminals of neurons.

MAO-A Monoamine oxidase A PET ([11C]clorgyline PET) MAO-A metabolizes serotonin, norepinephrine, and dopamine.PET using [11C]clorgyline measures brain MAO-A.

MAO-B Monoamine oxidase B PET (deuterium substituted[11C]-L-deprenyl PET)

MAO-B primarily metabolizes dopamine. PET using deuteriumsubstituted [11C]-L-deprenyl measures brain MAO-B.

MD Mean diffusivity MRI (DTI) Also referred to as the apparent diffusion coefficient (ADC).It is a measure of diffusion (Brownian motion) of watermolecules in tissue measured in mm2/s. MD is affected byrestricted spaces, barriers such as cell membranes, tubules,and macromolecules. ADC maps of the brain can begenerated, and good diffusion is bright on these maps.

MRS Magnetic resonance spectroscopy MRS An imaging technique based on MRI that allows one tovisualize certain metabolite concentrations in brain tissue;either single-voxel spectra or metabolite images can beproduced (MRS imaging). The major peaks of the 1H-MRSspectrum (each peak represent a metabolite) reported inthis review include N-acetylaspartate (NAA), creatine (Cr),and choline (Cho) containing phospholipids.

NAA N-Acetylaspartate MRS A metabolite quantified in the brain by MRS. NAA is considereda metabolic marker reflecting the functional status ofneurons and axons in the brain, with a decrease indicatingneuronal or axonal loss or dysfunction.

NAA/Cr, NAA/Cho N-Acetylaspartate ratioswith Cr/Cho

MRS The concentration of Cr is relatively constant and is considered astable brain metabolite; therefore, it is used as an internalreference for calculating metabolite ratios such as NAA. Cho isalso used as an internal reference for calculating NAA ratios.

[O15]H2O PET Positron emission tomography usingoxygen 15–labeled water

PET A form of PET using a freely diffusible tissue tracer, [O15]H2O,to calculate regional cerebral blood flow.

Continued on the next page

Friedman et al. J A C C : C A R D I O V A S C U L A R I M A G I N G , V O L . 7 , N O . 1 0 , 2 0 1 4

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report no volume loss (17,18). In addition, somestudies report higher DBP associated with greaterbrain GM volume loss over time (15), whereas othersreport higher SBP associated with greater volume loss(19).

When considering the effects of pharmacologicaltreatment of HTN on brain GM volumetric changes, 2outcomes emerge: 1) pharmacological treatment ofHTN fails to prevent increased brain GM loss overtime (14,16,19); and 2) pharmacological treatment ofHTN results in either a reduction or accelerationof brain GM volume loss over time, the directiondependent on the timing of treatment initiation andthe magnitude of BP reduction. For example, in-vestigators have shown that higher DBP in midlifepredicts more brain GM volume loss late in life whenantihypertensive medication is not used, whereasthis relationship is lost when antihypertensivemedication is used (15). However, when antihyper-tensive use is initiated late in life instead of midlife, itis associated with more pronounced brain GM loss,

particularly when there is a steeper decrease in DBP(15).White matter changes. Cross-sectional investigationshave shown a diagnosis of HTN to be associated withloss of prefrontal brain white matter (WM) volume(14) and a variable pattern of MRI-identified WMhyperintensity (WMH) increases with respect tooverall burden and location in the brain (11,13,14,19).WMHs are localized pathological changes in the WMof the brain caused by chronic hypoperfusion of theWM by arteriolosclerotic changes to the brain micro-vasculature, and thus WMHs can be considered anMRI index of brain microvascular pathology. Indeed,the relationship between HTN and the MRI indexof brain microvascular disease assumes a J-shapedfunction when nocturnal BP changes are considered,wherein hypertensive patients with extreme noc-turnal BP dips (>20% decrease from awake systolicblood pressure [SBP]) and those with no significantnocturnal dips (<10% decrease from awake SBP) showan increased MRI index of brain microvascular

TABLE 1 Continued

Imaging Acronym Acronym Expansion Imaging Modality Explanation of Imaging Outcome

rCBF Regional cerebral blood flow 99Tc-HMPAO SPECT133Xe SPECT[O15] water PETdynamic

susceptibility contrastMRI

The volume of blood traversing a brain region per unit of time(ml/100 g/min). rCBF is measured using SPECT (single-photon emission tomography) with 99Tc-HMPAO, 133XeSPECT, [O15]H2O PET, or dynamic susceptibility contrastMRI.

rCBV Regional cerebral blood volume MRI Total volume of blood traversing a brain region measured inml/100 g of brain tissue, commonly obtained usingcontrast-enhanced MRI.

rCMRglu Regional cerebral glucosemetabolic rate

PET (fluorodeoxyglucose-PET)

Metabolic rate of glucose in the brain.

RD Radial diffusivity MRI (DTI) Measures the degree of restriction due to the presence of themyelin sheath (i.e., perpendicular to the axonal fibers).Radial diffusivity is modulated by myelin in white matterand therefore is a more specific index of myelin pathology.

rsFDG-PET Resting state fluorodeoxyglucosepositron emission tomography

PET Glucose metabolic activity measured during resting state.

rsfMRI Resting state functional MRI MRI Functional connectivity measured using MRI with a subject atwakeful rest and not performing any goal-oriented task.

VT/fP Total volume of the radioligand 2FAcorrected for fraction in free plasma

PET (2FA-PET) The 2FA radioligand PET imaging procedure is used to quantifythe a-4b-2 nicotinic acetylcholine receptor in the brain.

WM volume White matter volume MRI Volume of the brain white matter can be expressed as a globalor region-specific measure. White matter is composed ofaxons connecting different regions of gray matter in thebrain to each other.

WMHNote: The commonly accepted

categorization of WMH is asfollows:1. PVWMH2. DWMH

White matter hyperintensity1. Periventricular white

matter hyperintensity2. Deep white matter hyperintensity

MRI These are hyperintense areas seen on T2-fluid attenuatedinversion recovery magnetic resonance images. WMHs areseen in normal aging and are also correlated with enlargedperivascular spaces, demyelination, or gliosis; localizedpathological changes in the white matter of the brain dueto chronic hypoperfusion by arteriolosclerotic changes tothe brain microvasculature.

1. WMH lining the lateral ventricles.2. WMH located in the remaining WM, not adjacent to the

lateral ventricles.

99Tc-HMPAO ¼ technetium 99 hexamethyl-propyl creatinine oxime.

J A C C : C A R D I O V A S C U L A R I M A G I N G , V O L . 7 , N O . 1 0 , 2 0 1 4 Friedman et al.O C T O B E R 2 0 1 4 : 1 0 3 9 – 5 3 Brain Imaging Changes With CV Risk Factors

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(20% to 30%)52–54; lacunes may form at the edge55 or (in ourexperience) in the middle of a WMH; WMH can “grow” at theedges of small subcortical infarcts56; incident lacunes57 andWMH58 are associated with cortical thinning and cerebralatrophy59; all of which indicate progressive and accumulatingbrain damage. Furthermore, WMH increase risk of braindamage in the presence of other pathologies, for example,they associate with infarct growth and worse outcome afterlarge artery stroke,60,61 and they predict poor functionalstroke outcome.62–64

The effects of all these SVD features on cognition arecumulative,65 (in submission) providing further indication thattogether these SVD features are closely related pathologi-cally,52 and represent cumulative brain damage,32 theprevention of which should help ameliorate brain tissuedamage, reduce loss of normal brain cognitive and physicalfunction and preserve independent survival in old age.43

What Do Pathology Studies Suggest ThatWMH Are Due To?Pathology studies are, unfortunately, infrequent12,66,67 com-pared with the number of WMH captured in imaging studies.There are particularly few pathology studies that have linkedindividual lesions seen on MRI with their pathologicalexamination.12,68,69 Pathology studies have been hamperedby difficulty in matching up individual small lesions on imagingwith their pathological counterpart,11,68 with limitations ofsampling,13 of fixation,70 of definitions,71–73 they provide“snapshots” of disease evolution, and because end-stagedamage may obliterate the earliest stages of disease.

As described above, the earlier pathology reports focusedon demyelination and axonal loss in WMH7 and described thechanges as “ischemic”.74,75 Demyelination and axonaldestruction imply that the changes are permanent. Indeed,

Figure 2. STRIVE examples of different features of small vessel disease, including white matter hyperintensities. Reproduced with permissionfrom Wardlaw et al.6 DWI indicates diffusion-weighted imaging; FLAIR, fluid attenuated inversion recovery; GRE, gradient recalled echo; STRIVE,standards for reporting vascular changes on neuroimaging; SWI, susceptibility-weighted imaging.

DOI: 10.1161/JAHA.114.001140 Journal of the American Heart Association 4

WMH and VCI Wardlaw et al

BASIC

SCIE

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Wardlaw, et al., 2013

Neuroimaging Markers of cSVD

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