cerebral small vessel disease clinical, neuropsychological, and

Review ArticleCerebral Small Vessel Disease Clinical Neuropsychologicaland Radiological Phenotypes Histopathological Correlates andDescribed Genotypes A Review

Thomas Gregor Issac1 Sadandavalli Retnaswami Chandra2 Rita Christopher3

Jamuna Rajeswaran4 and Mariamma Philip5

1Clinical Neurosciences National Institute of Mental Health and Neurosciences Bangalore 560029 India2Department of Neurology National Institute of Mental Health and Neurosciences (NIMHANS) Bangalore 560029 India3Department of Neurochemistry National Institute of Mental Health and Neurosciences (NIMHANS) Bangalore 560029 India4Department of Clinical Psychology National Institute of Mental Health and Neurosciences (NIMHANS) Bangalore 560029 India5Department of Biostatistics National Institute of Mental Health and Neurosciences (NIMHANS) Bangalore 560029 India

Correspondence should be addressed to Sadandavalli Retnaswami Chandra drchandrasasiyahoocom

Received 12 August 2015 Revised 9 December 2015 Accepted 10 December 2015

Academic Editor Stephen D Ginsberg

Copyright copy 2015 Thomas Gregor Issac et al This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

Introduction Vascular cognitive impairment is a common yet preventable cause for dementia It needs high degree of suspicion andappropriate designing of investigatory tools to confirm diagnosis identify comorbidities and ascertain the areas of impairmentCommonly DSM-IV criterion is applied for diagnosis and detailed clinical and neuropsychological examination for identifying thespecific phenotype is used Early diagnosis using the mandatory criteria will help in early initiation of disease modifying treatmentstrategies which can result in partial reversal of vascular changes and arrest of progression Patients with young onset disease mightrequire genetic characterization for designing more aggressive treatment Discussion and Conclusion Dementias as such carrypoor course and prognosis resulting in severe Disability Adjusted Life Years (DALYs) for patients and caregivers Therefore it ismandatory to identify treatable and preventable causes so that man power loss can be reduced

1 Introduction

Cerebral small vessel disease (SVD) is characterized bydisease of the small perforating arteries which are defined asldquovessels with a diameter less than 50120583mrdquo and ldquoall the vesselswithin the brain parenchyma plus the vessels with a diameterless than 500 120583m in the leptomeningeal spacerdquo supplyingthe deep brain structures [1] It is the most important andcommon cause of vascular dementia accounting for morethan 40 of the total prevalenceThe term vascular cognitiveimpairmentwas proposed by Sachdev [2] as an umbrella termto denote cognitive disorders due to cerebrovascular causeranging fromMild Cognitive Impairment stage (MCI) to vas-cular dementia and cerebral SVD is an important and majorcontributor to the same [1 3] Since cerebral SVD is difficult to

detect in vivo we have to rely on radiological markers for thesame and predominantly the triad of Periventricular whitematter hyperintensities lacunes and microbleeds constitutethe continuum of SVD [3 4] The newer neuropathologicalcorrelates of the lesions ascribed to SVD also have immenselyhelped in understanding the pathophysiology of this hithertocommon but often missed disease [1 5] Unlike other degen-erative dementias of cortical and subcortical origin vasculardementia is partially reversible and preventable

Cerebral SVD is not a rare entity It was even describedby the ancient Indian Physician Charaka as Smritbhramshadue to the hardening of the Dhamani or the blood vesselultimately resulting in the hampering of the flow of Rasa andRakta to the brain tissue leading to cognitive impairment [67] Later the work of Otto Binswanger and Alois Alzheimer

Hindawi Publishing CorporationJournal of GeriatricsVolume 2015 Article ID 564870 11 pageshttpdxdoiorg1011552015564870

2 Journal of Geriatrics

Table 1 NINDS-AIREN and ADDTC criteria for vascular dementia

ADDTC NINDS-AIREN

Dementia definitionDeterioration from a known level of intellectualfunction sufficient to interfere with the patientscustomary affairs of life and which is not isolated to asingle category of intellectual performance

Impairment of memory plus at least two other areas ofcognitive domains which should be severe enough tointerfere with activities of daily living and not due tophysical effects of stroke alone

Probable VaD

Requiring all of the followingDementiaEvidence of two or more strokes by history neurologicalsigns andor imaging or a single stroke with a cleartemporal relationship to the onset of dementiaEvidence of at least one infarct outside the cerebellumby CT or T1 weighted MRI

Requiring all of the followingDementiaCVD focal signs on examination + evidence of relevantCVD by CTMRIA relationship between the above two disordersmanifested by one or more of the followingDementia onset within 3 months of a strokeAbrupt deterioration in cognitive function orfluctuating stepwise course

Possible VaD

Dementia and one of the followingHistory or evidence of a single stroke without a cleartemporal relationship to the dementia onsetBinswangerrsquos disease that includes all the followingearly onset of urinary incontinence or gait disturbancevascular risk factors extensive white matter changes onneuroimaging

May be made in the presence of dementia and focalneurological signs in patients either with no evidence ofCVD on neuroimaging with the absence of a cleartemporal relationship between stroke and dementia orwith subtle onset and variable course of cognitive deficitand evidence of CVD

ADDTC State of California Alzheimerrsquos Disease Diagnostic and Treatment Centers CT computed tomography CVD cerebrovascular diseaseMRI magneticresonance imaging NINDS-AIRENNational Institute ofNeurological Diseases and Stroke andAssociation Internationale pour la Recherche et lrsquoEnseignementen Neurosciences VaD vascular dementia

in late 1897 differentiated vascular causes of dementia fromneurosyphilis [8 9] In 1910 Kreaplin concluded that insan-ity due to arteriosclerosis was the most frequent form ofsenile dementia [10] By 1970s the focus had shifted overto Alzheimerrsquos disease but Tomlinson Blessed and Rothshowed that the loss of more than 50ndash100mm3 of brain tissueconsequent on strokes caused cognitive impairment and wasreferred to as multi-infarct dementia [11] Diagnostic criteriacommonly applied are DSM-IV and NINDS-AIREN criteriaand Hachinskirsquos ischemic score (Tables 1 and 2 and Box 1)

C M Fisher did the maximum work on the clinico-pathological studies on cerebral SVD and is credited forcoining the term lacune as well as describing the Fishersrule which implicates that for every single cerebral vesselwhich is affected two coronaries and three peripheral vesselsare already affected He was thus the pioneer in research invascular dementia especially with regard to cerebral SVDUnlike large vessel disease even though there is a progressivechronic course in SVD a subacute onset is often describedin SVD due to lacunar state A chronic progressive coursebehaving as a progressive frontotemporal syndrome waspreviously referred to as Binswangerrsquos disease

Cerebral SVD is often classified on the basis of etiologyinto 5 major groups which include the following

Type 1 Arteriolosclerosis (or age and vascular risk factors-related SVD)

Type 2 Cerebral amyloid angiopathy (sporadic and heredi-tary)

Table 2 Hachinskirsquos ischemic score Purpose the Hachinski ischae-mic score (HIS) represents a brief clinical tool helpful in the ldquobed-siderdquo differentiation of the commonest dementia types Dementiaof Alzheimerrsquos Type (DAT) and Vascular Dementia (VaD) A cut-off score le4 for DAT and ge7 for VaD has a sensitivity of 89 and aspecificity of 89 [23]

Item number Description Value1 Abrupt onset 22 Stepwise deterioration 13 Fluctuating course 24 Nocturnal confusion 15 Preservation of personality 16 Depression 17 Somatic complaints 18 Emotional incontinence 19 History of hypertension 110 History of stroke 211 Associated atherosclerosis 112 Focal neurological symptoms 213 Focal neurological signs 2Reference Moroney et al [23]

Type 3 Inherited or genetic SVD (distinct from cerebralamyloid angiopathy eg CADASIL CARASIL Fabryrsquos dis-ease and SVD due to COL4A1 mutations)

Type 4 Inflammatory and immunomediated SVD (systemicand cerebral vasculitis central nervous system vasculitissecondary to infections)

Journal of Geriatrics 3

(A)The development of multiple cognitive deficits manifested by both(1) Memory impairment (impaired ability to learn new information or to recall previously learned information)(2) One or more of the following cognitive disturbances

(a) Aphasia (language disturbance)(b) Apraxia (impaired ability to carry out motor activities despite intact motor function)(c) Agnosia (failure to recognize or identify objects despite intact sensory function)(d) Disturbance in executive functioning (ie planning organizing sequencing and abstracting)

(B) The cognitive deficits in criteria (A)mdash(1) and (2) each cause significant impairment in social or occupationalfunctioning and represent a significant decline from a previous level of functioning

(C) Focal neurological signs and symptoms (eg exaggeration of deep tendon reflexes extensor plantar responsepseudobulbar palsy gait abnormalities and weakness of an extremity) or laboratory evidence indicative ofcerebrovascular disease (eg multiple infarctions involving cortex and underlying white matter) that are judged to beetiologically related to the disturbance

(D) The deficits do not occur exclusively during the course of a delirium

Box 1 DSM-IV criteria for vascular dementia

Type 5 Venous collagenosis

Type 6 Other SVD (eg postradiation angiopathy and non-amyloid microvessel degeneration in Alzheimerrsquos disease)

Currently cerebral SVD is a neuroimaging defined con-cept and there has been a unified approach to the neu-roimaging standards for research in SVD under the acronymSTRIVE (STandards for ReportIng Vascular changes onnEuroimaging) which has resulted in the adaptation of majorfour conclusionswhich include the following (A) the numberof SVD lesion subtypes was broadened to include six typesof neuroimaging lesions (1) recent small subcortical infarcts(2) lacunes of presumed vascular origin (3) white matterhyperintensity of presumed vascular origin (4) perivascularspaces (5) cerebral microbleeds and (6) brain atrophy basedon the association between subcortical lesions and brainatrophy (B) the establishment of a common language aboutterms and definitions for SVD features visible on magneticresonance imaging (MRI) (C) maintenance of minimumstandards for image acquisition and analysis (D) agreementon standards for scientific reporting of changes related toSVD on neuroimaging along with review of the newerimaging techniques for the detection and quantification ofpreclinical manifestations of SVD [1 3]

Presence of long term hypertension was identified as themost important risk factor with regards to the same andthe role of renin-angiotensin-aldosterone both internal andexternal to the blood brain barrier is postulated to maintainan important homeostatic role determining the progressionof SVD [1 3 12ndash15]

This review article focusses mainly on the clinical mani-festations of sporadic SVD referring to a heterogeneous groupof phenotypes based on brain imaging their neuropsycholog-ical correlates the common radiological findings seen in bothCT scan and MR imaging and the scales used to quantifythe same and some described genetic mechanisms especiallyboth important monogenic causes of SVD as well as therole of certain specific pathways like the renin-angiotensin-aldosterone system in the genesis and evolution of the diseasecondition The word sporadic SVD is mentioned but in view

of the gross variation in clinical symptomatology in thepresence of similar grade of radiological features we believethat there is a probably genetic factor hitherto unidentifiedthat could be causally involved This review article dealswith pure vascular dementias and therefore other dementiasassociated with vascular changes and mixed dementias havenot been considered

2 Clinical Manifestations

Patients presenting with SVD usually present in their laterdecades with often features suggestive of cognitive slowingpsychomotor withdrawal due to severe executive dysfunctiondescribed as difficulty to pay attention retrieval defecttip of the tongue phenomena short term memory defectsand occasionally impaired judgement [16] Gait and balancedisturbances and falls are also major symptoms of patientswith cerebral small vessel disease (SVD) and an importantcause of morbidity and mortality in the elderly Motordeficits associated with SVD present in different ways suchas unsteadiness of gait impaired balance on walking andincreased risk of falls Furthermore gait abnormalities havebeen shown to predict non-Alzheimerrsquos dementia that ismainly vascular dementia A 22 greater risk for falls forthose with moderate white matter lesions (WMLs) was seenthan for those with minimal WMLs and a 26 greaterrisk for participants with at least one brain infarct thanfor those with no infarcts Interestingly participants withmoderate to severe brain abnormalities experienced fastergait speed decline and features suggestive of lower segmentparkinsonism Soumare et al postulated a threshold effectof WMH load a pathologic change in the white matter willbe compensated up to a certain degree without leading tofunctional decline WMH load stands for visual quantifi-cation of the white matter changes based on well-definedcriteria Once this threshold is surpassed subjects will showimpairment Periventricular and deep frontal WMHs werefound to be independently associatedwith falls [1 16]Thekeylink betweenWMLs and fall risk therefore is the impairmentof balance control compared with subjects without a history


of fall the mean single leg stance time was significantlyreduced in individuals with a history of a single or multiplefalls WMH also acts as an independent predictor of physicaldecline and cognitive impairment Vascular dementia is seenmore commonly in males than in females in view of theirmore proneness for comorbidities Elderly females are moreaffected by Alzheimerrsquos disease than males and relativelyyoungermales aremore affected by Frontotemporal dementiathan females [17]

The psychiatric symptoms include apathy and depressionThe relationship between SVD and depression does not nec-essarily have to be one-sidedWhile SVD could arguably leadto depression the reverse may also be true as depression hasbeen seen as a risk factor for vascular disease Radiologicalevidence for white matter pathology is seen in wide varietyof disorders as well as in normal people However ourarticle review consists of only those with phenotypically andradiologically confirmed small vessel disease patients onlyand other groups of disorders are not being considered in thisreview Obsessive Compulsive Disorder (OCD) is the subjectof a large number of neuroimaging and neuropsychologicalstudies WMHs have been described in early-onset OCDLate-onset OCD is however uncommon with only 15presenting after the age of 35 and neuroimaging data onthese are not available Late-onset OCD has been associatedwith more frequent brain lesions including silent strokeswith lesions largely being in the cerebral cortex or the basalganglia Neuroimaging findings in OCD have suggested anorbital-frontal-striatal circuit underlying the disorder andmicrostructural abnormalities of white matter demonstratedon DTI have added weight to the underlying disruptionof a circuit comprising of frontal striatal and thalamicconnectivity

Apathy is conceptualized as a diminution of motivationbut is variously described as a symptomaswell as a syndromecombining emotional behavioral and cognitive componentsLevy and Dubois emphasized the observable behavioralcomponents arising from disruptions in the basal ganglia andprefrontal cortex Apathy is often mistaken for depressionalthough the correlation between apathy and depressionratings is often low and the neuropsychological profiles differ[1 13 16]

They usually have associated comorbidities like hyper-tension diabetes mellitus hypercholesterolemia history ofischemic cardiac illness and renal diseases along with historyof substance abuse especially alcohol and tobacco Hyperten-sion is themost important risk factor for development of cere-bral SVD The neurological manifestations of SVD consistof a wide spectrum of clinical phenotypes which commonlyincludes the lacunar strokes like (1) pure motor hemiparesis(2) pure sensory hemiparesis (3) ataxic hemiparesis (4)dysarthria clumsy hand syndrome and (5) pseudobulbarsyndrome Apart from these there are features of executivedysfunction short term memory loss mood changes andautonomic dysfunction which has been described [1 5 6 18]

A small note has to be maintained regarding the pro-dromal phase of subclinical to clinical depression priorto the onset of the illness when the patient is detacheduninterested and often having poor attention span which

is often seen These features can be together described asldquovascular depressionrdquoWhether this depression is a cause or aconsequence of cerebral SVD is still not fully known althoughmany studies have implicated a positive correlation [5 6 19]

3 Neuropsychological Correlates of SVD

As described before executive dysfunction with retrievaldefect is the most common neuropsychological finding seenin patients with cerebral SVD Executive function refers tothose higher cognitive processes by which performance isoptimized in situations requiring the simultaneous operationof several cognitive processes Usually the patients with SVDhave difficulty in multitasking a common feature associatedwith normal ageing alongwith apathy disinterest poor atten-tion and often irritability Therefore executive skills whichare used to construct effective plans of action particularlyin the face of complex tasks are affected most in SVDand have to be distinguished from the benign forgetfulnessand executive dysfunction associated with normal ageingExecutive dysfunction mainly characterized by deficits in setshifting verbal fluency abstract problem solving attentionand decreased speed of information processing might bedetectable even in the initial stages of the disease Multiplelacunes located in the subcortical structures and confluentand extensiveWMCs can result in a disconnection of frontal-subcortical circuits (in particular the dorsolateral prefrontalcircuit) interrupting the central cholinergic pathway causingimpairment of the working memory and Judgement Patientsmay need repeated instructions to complete tasks and are eas-ily distractible Due to poor attention and impaired workingmemory new verbal and visual learning is usually affected[6 18 20] Mental and motor slowing can also be seen inpatients with cerebral SVD [19] The MMSE test is of notmuch value in assessment of SVD as per previous studies asthe items in MMSE are grossly insensitive to the executivefunctions [20] Hence the following neuropsychological testsare mandatory to assess SVD This includes digit forwardand backward test trail making tests to assess attention andworking memory The category fluency test is used for fundof knowledge or generativity the digit symbol substitutiontest to assess focused attention and performance IQ thestick test to assess visual recall and working memory thepassage or story telling test for verbal recall and learningand the Bender Gestalt test to determine organicity Digitforward and backward tests involve asking the patient torepeat random numbers told by the examiner in the sameorder as well as from the last to the first Digit forward testinvolves mostly attention and digit backward test involvesworking memory Trail making test involves type A wherepatient has to connect numbers in that order without criss-crossing Errors of commission and time taken are calculatedTrail making 2 test involves little more complex testing whereeach number has to be connected to a color in an alternatingfashion Category fluency test involves asking the patient totell the maximum number of words he can generate startingwith the letters F A and S in one minute Digit symbolsubstitution test involves patient rapidly putting the desig-nated numbers given in the test kit below each test symbol


Errors and timing are calculated Stick test involves showingthe nine standardized pictures formed using 5 straight lineseach shown for 30 seconds After that patient is asked toreproduce those figures from memory using 5 matchsticksThis test evaluates registration and delayed recall Passage testinvolves telling the patient a well validated story designatedas ldquoAsha Kumari storyrdquo which contains 21 parameters tobe registered and recalled by the patient Bender Gestalttest involves nine cards containing pictures of increasingcomplexity which the patient has to copy and is normally notaffected in patients with nonorganic problems [21] Executiveand activation functions are frequently assessed using timedtests with a variety of set shifting mental flexibility andresponse inhibition tasks Both executive functions and speedof processing are frequently impaired in patients with SVDLower scores on verbal fluency Stroop reading and colornaming tasks and trail making tests have been repeatedlyassociated with SVD On other nontimed instruments usedto assess mental flexibility and conceptualization such as theWisconsin Card Sorting Test changes on scores were alsoassociated with progression of white matter changes (WMC)in healthy community-dwelling elderly volunteers On abrief assessment battery used to differentiate patients withischemic leukoaraiosis from normal controls trail makingand digit symbol substitution tasks were the best individualtests identifying cognitive impairment Also on other studiesa decline in the digit symbol substitution test performancewas associated with worsening and progression of WMCsTests sensitive to reductions in psychomotor speed mentalflexibility working memory and attention such as the digitsymbol or trail making are useful instruments for detectingearly subtle changes in SVD patients

Memory deficits observed in SVD are distinctive fromthose observed in other pathologies such as MCI and ADStudies comparing patients with MCI with and withoutSVD tried to identify different cognitive profiles Zhou etal reported a nonspecific profile in MCI-SVD patients sincethey found extensive cognitive deficits in these patientsComparatively patients with MCI-AD had a more specificpattern characterized by a significantly worse performanceon verbal and visual delay recall and recognition measureswith a relatively preserved performance on processing speedtasks MCI patients with severe WMCs were compared withMCI patients with severe hippocampal atrophy using a com-prehensive neuropsychological battery The authors foundthat patients with hippocampal atrophy exhibited specificepisodic memory impairment while patients with WMCsexhibited deficits on episodic memory (assessed by a 36-itemobject color-association task) working memory (patientswere tested on two verbal working memory tasks and aspatial working memory task) and attention-control tasks(continuous performance test) suggesting that the episodicmemory deficit was secondary to a more general impairmentof executive control In fact working memory performancerequires an ability to hold manipulate and quickly accessinformation that is dependent on mental flexibility andspeed The mediation effect of executive functions on verbaland visual memory performance of SVD patients is alreadydescribed Distinctive patterns can be observed in relation

to memory impairment Ability to store information ismainly dependent on the limbic and hippocampal structureswhile retrieval and short term memory capacities are morerelated with the integrity of frontal-subcortical structuresand temporoparietal regions respectively In SVD patientsepisodic memory impairment is usually absent or mildin the initial phases but in later stages is described asbeing the most frequent deficit characterized by difficultyin recalling information that improves in the presence ofcues However these findings are frequently associated withother variables such as medial temporal lobe atrophy andcorpus callosum atrophy Poorer episodic memory has beenassociated with age related differences in central white matterregions Recent studies with SVD patients have explored therelationship of microstructural integrity of the hippocampusnot detected with conventional MRI and verbal memoryimpairmentThese authors found that deficits in verbalmem-ory (immediate delayed recall and delayed recognition)but not in psychomotor speed were related to changes inthe hippocampus microstructure and consequently in thecingulumThese results might lead us into a new perspectivein the understanding of memory impairment related to SVD[1 13 18 19]

Impairment in language functions is not frequent in SVDComparing patientswith initial dementia Kertesz et al foundthat patients with periventricular hyperintensities performedworse on comprehension and attention tasks compared tothose with no hyperintensities who showed worse perfor-mances on memory and conceptualization tasks Howeverother studies performed within the general population andwith high-risk nondemented patients with WMCs did notfind a relationship between the presence ofWMCs or lacunesand language deficits Nevertheless lexical and semanticfluency measures should be included in the assessment ofSVD patients Impairment in lexical tasks is more frequentand prominent than semantic difficulties and thus showinga different pattern of MCI As what occurs in other cogni-tive functional deficits observed in patients with SVD thetype of impairment found in verbal functions seems to berelated to the decrease in speed of processing and access toinformation that affect word-generation tasks The variousneuropsychological batteries utilized were designed to lookfor impairment in the executive function rather than anyother domain [6 20 21]

4 Radiological Correlates of SVD

White matter lesions were observed as diffuse areas of whitematter attenuation in CT scan and hence termed ldquoleukoaraio-sisrdquo derived from the Greek words ldquoleuko-rdquo for ldquowhiterdquo andldquoaraiosrdquo for ldquorarefiedrdquo SVD-related white matter changesappear as hypodensity in CT and are described as ldquowhitematter hypoattenuationrdquo or ldquowhite matter hypodensitiesrdquo butnever approach that of cerebrospinal fluid (CSF) as thiswould indicate complete tissue destruction Pathologicallysuch areas are characterized primarily by loss of myelinand axons [1] WMLs tend to be symmetrically distributedthroughout the brain with a preference for the periven-tricular and deep white matter These lesions are usually


(a) Deep and dense white matter hyperintensities inFLAIR

(b) Lacunar stroke Arrow indicates presence of lacunae in anteriorthalamic region

(c) SWI sequence showing diffuse microbleeds

Figure 1 (a) FLAIR sequence depicting dense white matter hyperintensities and (b) depicting lacunar strokes (c) SWI sequence depictingcerebral microbleeds

ill-defined and characteristically spare the subcortical U-fibers and therefore are easily distinguishable from infarctswhich are wedge shaped are sharply demarcated extendto the grey matter may involve the internal capsule basalganglia or thalamus and follow specific vascular territoryand enlargement of the ipsilateral ventricle or sulcus is seenPlain CT and conventional MR imaging are unable to pickup small acute infarcts in the territory of leukoaraiosis andspecific sequences like Diffusion Weighted Images (DWI)often need to be utilized

MR imaging on the other hand helps to correctly demar-cate these lesions and even smaller lesions in thalamus andposterior fossa can be picked up Fluid attenuation andinversion recovery (FLAIR) sequence is even more helpfuland commonly used as it helps in characterizing lacunarinfarcts and in distinguishing WMH from enlarged VirchowRobins (perivascular) spaces commonly seen in old age Aform of T2 weighted imaging using gradient echo sequencesknown as susceptibility weighted imaging is very sensitivein detection of microbleeds and is commonly utilized SVD-related WMLs occur preferentially in the deep white matterand close to the lateral ventricles but spare the subcorticalarcuate fibers as described above for leukoaraiosis seen onCT

A number of visual analogue scales to quantify and assessseverity of WMH are utilized and fairly good correlation totheWMH is found among the scales [1 3 5 6 21 22] (Table 3depicts the different visual scales used in SVD)

Many novel methods also include software to computethe volumes of lacunes and WMH as well as microbleedswhich can become a sensitive measure for further researchpurposes Magnetization transfer ratio derived susceptibilityweighted images are very useful in detection of microbleedsand their characterization [21] (Figures 1(a) 1(b) and 1(c))

5 Neuropathological Correlates in SVD

Fisher was the pioneer in describing the neuropathologicaldetails in SVD From autopsy studies he observed that major-ity of the lacunes were due to segmental arterial disorgani-zation which implicates patchy asymmetrical focal vascularchanges resulting in the loss of normal architecture andsmall vessel thickening along with extravasation of plasmaproteins into arteriolar wall and subsequent conversion tofibrin known as ldquolipohyalinosisrdquo and referred to by othersas fibrinoid necrosis These lesions particularly favor thedevelopment of spontaneous ICH in deep or infratentoriallocations (basal ganglia thalamus and pons) The recentwork by Pantoni [6] describes the common histopathologicallesions in SVD due to hypertensive vasculopathy whichincludes arteriosclerosis with loss of smooth muscle cellsfrom the tunica media deposits of fibrohyaline materialluminal stenosis and thickening of the vessel wall Thesefeatures are seen characteristically in aged hypertensive


Table 3 It depicts different visual scales for CT and MRI which are commonly used

(a)

Scales for CT whitematter changes (WMC) Assessment of severity Scores

Van Sweiten et al

Severity of WMCs on 3 subsequent CT slices is graded separately for the regions anteriorand posterior to the central sulcus 0 = no lesion 1 = partly involving the white matter and 2= extending up to the subcortical region The scores for the 2 regions have to be addedtogether

Minimum 0maximum 4

Blennow et al

Based on extent of WMC0 = no decrease in the attenuation of white matter 1 = decreased attenuation of white matterat the margins at the frontal and occipital horns of the lateral ventricles 2 = decreasedattenuation of white matter around the frontal and occipital horns of the lateral ventricleswith some extension toward the centrum semiovale and 3 = decreased attenuation of whitematter extending around the whole lateral ventricles and coalescing in the centrumsemiovaleBased on severity of WMC0 = none 1 = mild 2 = moderate and 3 = marked decrease in the attenuation of white matter

Minimum 0maximum 3(for extentand severityeach)

(b)

Scales for MRI whitematter hyperintensities(WMH)

Assessment of severity Scores

Fazekas et al

Periventricular and deep WMCs are rated separately A total score is obtainable by summingthe 2 partial scoresPeriventricular hyperintensitiesScores are as follows 0 = absence 1 = ldquocapsrdquo or pencil-thin lining 2 = smooth ldquohalordquo and 3 =irregular periventricular hyperintensities extending into the deep white matterDeep white matter hyperintense signalsScores are as follows 0 = absence 1 = punctuate foci 2 = beginning confluence of foci and 3 =large confluent areas

Total scoreminimum 0maximum 6

ModifiedScheltens et al [24]

Periventricular hyperintensities (minimum 0 maximum 6)Scoring is as follows caps occipital 012 and frontal 012 bands lateral ventricles 012 (0 =absent 1 = le5mm 2 = ge6mm and le10mm)White matter hyperintensities(minimum 0 maximum 24)Scoring is as follows frontal 0123456 parietal 0123456 occipital 0123456 andtemporal 0123456 (0 = no abnormalities 1 = le3mm 119899 le 5 2 = le3mm 119899 le 6 3 = 4 to10mm 119899 le 5 4 = 4 to 10mm 119899 ge 6 5 = ge11mm 119899 ge 1 6 = confluent)

Minimum 0maximum 30

Ylikoski et al

WMCs located at 4 locations (frontal horns body of the ventricles trigones and occipitalhorns) are rated separately on each hemispherePeriventricular leukoaraiosis (minimum 0 maximum 24)Scoring is as follows 0 = no hyperintensity 1 = punctuate small foci (mild) 2 = cappencil-thin lining (moderate) and 3 = nodular band extending hyperintensity (severe)Centrum semiovale leukoaraiosis including watershed areas (minimum 0 maximum 24)Scoring is as follows 0 = no hyperintensity 1 = punctuate small foci (mild) 2 = beginningconfluent (moderate) and 3 = large confluent areas (severe) Total leukoaraiosis score isperiventricular leukoaraiosis score plus centrum semiovale leukoaraiosis score equal to 0 to 48

Minimum 0maximum 48

Manolio et al

Periventricular and subcortical regions are not rated separately Including 9 grades 0 = nowhite matter signal abnormalities 1 = discontinuous periventricular rim or minimal ldquodotsrdquo ofsubcortical white matter 2 = thin continuous periventricular rim or few patches of subcorticalwhite matter lesions 3 = thicker continuous periventricular rim with scattered patches ofsubcortical white matter lesions 4 = thicker shaggier periventricular rim and mild subcorticalwhite matter lesions and may have minimal confluent periventricular lesions 5 = mildperiventricular confluence surrounding frontal and occipital horns 6 = moderateperiventricular confluence surrounding frontal and occipital horns 7 = periventricularconfluence with moderate involvement of centrum semiovale 8 = periventricular confluenceinvolving most of centrum semiovale and 9 = all white matter involved

Minimum 0maximum 9


individuals and hence called hypertensive small vessel dis-ease Other characteristic lesions also include formation ofmicroatheromas in early stage and microaneurysms due tothe weakened vessel wall along with poor pliability dueto fibrinoid necrosis in later stages Cerebral white matterdamage appears to be also promoted by cerebral amyloidangiopathy (CAA) which preferentially affects the occipitalregion CAA is characterized by inflammatory changes withposterior lobar and leptomeningeal vessel involvement withdilated perivascular spaces cortical siderosis beta amy-loid deposition in the vessel walls and occasional lobarhemorrhages with coexistence of fresh and old lesions inmultiple locations The word cerebral small vessel diseaseconventionally stands for the triad of microbleeds lacunesand white matter changes Therefore the other secondaryvascular disorders are not discussed in this review as this isnot the primary objective of this paper [24ndash27]

6 Treatment

Treatment options can be grouped into treatment of comor-bidities disease modifying treatment and symptomatictreatment Serious comorbidities like substance dependenceshould be completely stopped High blood pressure dys-lipidemia diabetes mellitus and heart disease should bemanaged based on a patient oriented way taking into accountthe severity of the various risk factors regular monitoringof treatment response and avoiding certain drugs based onthe target organ dysfunction like associated renal and cardiacdysfunction commonly existing in these patients Elaboratediscussion of the pharmacological agents involved is beyondthe scope of this paper Disease modifying treatment withreference to cerebral small vessel disease involves antiplateletlike Aspirin Clopidogrel and Dipyridamole based on toler-ability and response Anticoagulants are used when there isevidence for source of embolism like atrial fibrillation signif-icant heart disease or atherosclerotic plaques inmajor vesselslike arch of aorta Neuroprotective agents homocysteine andantioxidants are beneficial to some extent Symptom modi-fying treatment is chosen based on the symptoms prevalentin the given patient Patients with cognitive dysfunction aretreated with cholinergic drugs and NMDA receptor blockersin addition to cognitive enhancement therapies If thereare seizures they are treated with anticonvulsants lowersegment parkinsonism which is common in these patientsis treated with low dose of Levodopa with decarboxylaseinhibitors Spasticity aphasia and dysarthria are treatedwith antispasticity agents and speech therapy Occupationalrehabilitation is given to patients who have problems inactivities of daily living Dietary advice based on the numberand type of comorbidities present is chosen by the dieticianbased on the occupational demand of the individual [28 29]

61 Single Gene Disorders

611 Cerebral Autosomal Dominant Arteriopathy with Sub-cortical Infarcts and Leukoencephalopathy (CADASIL) It isa hereditary form of SVD causing stroke and WMH withinsignificant involvement of the large vessels It is the most

common monogenic condition resulting in SVD It hasnearly 100 penetrance and is due to mutations of theNOTCH3 gene on chromosome 19 which normally codesfor a cell signaling receptor in the vascular smooth musclecells resulting in uneven production of cysteine residues inthe signaling protein leading to abnormal signal transductionand impaired smooth muscle maturation and differentiationThe annual incidence is about 15ndash5100000 people andis usually characterized by repeated episodes of migrainewith aura visual field defects recurrent transient ischemicattacks (TIAs) or strokes and cognitive impairment usuallybeing detected by the sixth decade Cognitive impairmentis usually manifested as subcortical impairment in attentionand retrieval memory and in later stages language andvisuospatial disorientation are reported Epigenetic factorsgreatly influence the onset of manifestation of illness even intwin studies Detailed data on these parameters is very scarceand methylation defect is quoted in the study by Brucki et al[28ndash30]

MR imaging in CADASIL shows an increased predilec-tion ofWMH in the anterior temporal pole external capsuleand insular region which is not seen in normal ageingCerebral atrophy is also seen along with cerebral microb-leeds in one third of the patients but deep intracranialhemorrhages are rarely seen Histopathology is suggestiveof a severe small vessel arteriopathy on immunohistologicalstaining characterized by the finding of granular osmophilicinclusions affecting mainly the vascular smooth muscle cellsand relative sparing of the endothelium These pathologicalfindings are remarkably different from normal age relatedWMH and deep brain infarcts suggesting an alternativemolecular pathophysiology

Treatment consists of use of oral Aspirin but its efficacyis still not proved in this condition Cholinesterase inhibitorslike donepezil have been tried and proven to have limited rolein maintenance of cognition but large trials are still lackingand mainstay of treatment is still supportive measures [28]

612 Cerebral Autosomal Recessive Arteriopathy with Sub-cortical Infarcts and Leukoencephalopathy (CARASIL) It isan autosomal recessive disorder with 25 risk in eachpregnancy of heterozygous parents first described in Japanesepopulation Patients usually present with alopecia beginningin the second decade and spondylosis in the second or thirddecade Patient can have early dementia mood changes andgait disturbances with spasticity in the lower extremities It isdue to the mutation in the HTRA1 gene which is involved inTGF-120573 signaling MR imaging findings are similar to that inCADASIL In addition symmetrical WMH along with signalchanges in anterior temporal lobe cerebellum brainstemmiddle cerebellar peduncle and external capsulewith sparingof the U fibers is characteristic

Histopathological picture is suggestive of arteriosclerosiswith intimal thickening loss of smoothmuscle cells and hya-line degeneration resembling characteristic nonhereditarySVD as previously described Granular osmiophilic materialwithin vascular media adjacent to smooth muscles seen inCADASIL is never seen


Treatment is mainly symptomatic and supportive Use ofantiplatelet is recommended along with lifestyle modificationand early management of comorbidities especially hyperten-sion [28 29 31]

613 Hereditary Angiopathy with Nephropathy Aneurysmsand Muscle Cramps (HANAC) It is an autosomal dominantdisease with pathogenic mutation in the COL4A1 gene onchromosome 13 which codes for the alpha-1 subunit ofcollagen type IV Affected individuals have microscopichematuria muscle cramps with elevated creatine kinaselevels and bilateral retinal artery tortuosity causing repeatedretinal hemorrhages Raynaudrsquos phenomenon and supraven-tricular arrhythmia are also reported Diagnosis is madeby magnetic resonance brain imaging featuring frequentleukoaraiosis subcortical microbleeds lacunar infarctionand dilated perivascular spaces in conjunction with systemicfeatures or positive family history

Histopathological assessment reveals irregular abnormalthickening of the basement membrane of the tubules Bow-manrsquos capsule and interstitial capillaries Skin biopsy revealsduplication of the basement membrane at the dermoepi-dermal junction and dermal arterioles Vascular smoothmuscle cells are dissociated due to abnormal spreading ofthe basement membrane Treatment is mainly symptomaticbut surgical interventions may be required for aneurysmsmore than 10mm COL4A1 gene mutations have been alsoimplicated in autosomal dominant type 1 porencephaly brainsmall vessel disease with hemorrhage and brain small vesseldisease with Axenfeld-Rieger anomaly (congenital cataractmicrocornea retinal detachment increased intraocular pres-sure and optic nerve excavation) [26 27 32 33]

614 Autosomal Dominant Retinal Vasculopathy with Cere-bral Leukodystrophy (AD-RVCL) It is an autosomal domi-nant inherited condition resulting from a frameshift muta-tion to the TREX1 (three-prime repair exonuclease 1) geneinvolved in DNA repair on chromosome 3 whose symptomscommonly begin in the early mid-forties It is associatedwith progressive loss of vision migraines strokes motor andextrapyramidal features and cognitive decline A subset ofaffected individuals have systemic vascular involvement evi-denced by Raynaudrsquos phenomenon micronodular cirrhosisand glomerular dysfunction This disorder is redesignatedas CHARIOT (cerebral hereditary angiopathy with vascularretinopathy and impaired organ function caused by TREX1mutations) Specific treatment options other than antiplateletare not available [31ndash34]

615 Fabryrsquos Disease It is an X-linked disorder of glycosph-ingolipid metabolism due to deficient or absent lysosomalalpha galactosidase A activity due to gt300 types of mutationsin the GLA gene (galactosidase alpha) The GLA geneis located in the long arm of X-chromosome at position22 Glycosphingolipids (mainly globotriaosylceramide GL-3) accumulate in lysosomes due to120572-GalAdeficiency leadingto lysosomal and cell dysfunction this in turn triggers tissue

ischemia and fibrosis Annual incidence is 1 in 100000 pop-ulation Classically affected patients are males with angiok-eratomas acroparesthesias hypohidrosis corneal opacityand progressive vascular involvement of the brain heartand kidneys There can be recurrent ischemic strokes andpainful neuropathies requiring attention In female carriershigh incidence of strokes also has been reportedMicroscopicexamination of urine will show lipid laden epithelial cellsalong with serum electrolyte abnormalities Enzyme analysiswill show deficiency of the alpha-galactosidase A enzyme[35]

Treatment includes enzyme replacement therapy (ERT)and Pharmacological ChaperoneTherapy (PCT) [35 36]

616 The Role of Renin-Angiotensin-Aldosterone System Thegenes of the renin-angiotensin-aldosterone system (RAAS)system are important candidate genes for SVD as they are thegenes controlling hypertension which is the most importantrisk for SVD The RAAS is a homeostatic system that affectsblood pressure regulation vasoconstriction thrombosis andvessel wall damage The angiotensin-converting enzyme(ACE) which modulates the proliferation of smooth musclecells and the tone of vessel walls may be involved in vascularremodeling and atherosclerosis It has been proposed thatACE may be a potential determinant for the risk of SVDAn early study reported an association between an ACEinsertion-deletion (ID) polymorphism and lacunar strokeand less or no association with other types of ischemic stroke[1 17]This polymorphism is associated with elevated plasmaACE levels Similar findings have been shown in some but notall other studies in Caucasian populations [32 33] A numberof studies have also been performed in Asian predominantlyChinese populations In this ethnic group cerebral SVDappears more common [37]

Angiotensinogen is the precursor of angiotensin I Theplasma concentrations of angiotensinogen have been directlyrelated to arterial blood pressure and were found to be mod-ified by variations in the angiotensinogen gene [36] A mis-sense mutation in exon of the angiotensinogen gene (T704-C) encoding threonine instead of methionine at position235 (M235T) of the amino acid sequence commonly occursamong various ethnic groups The frequency of the T235allele ranges from 035 in whites to approximately 080 inblacks [38] A large meta-analysis has attributed an increasedrisk for arterial hypertension to the presence of the T-alleleIn comparison with the MM reference group the excess riskwas 31 in TT homozygotes and 11 in MT heterozygotes[39] Studies have found this genetic variant to be associatedwith coronary artery disease and myocardial infarction [26ndash28] In a study of SVD no differences were found in thethree promoter (minus18GgtA minus20AgtC and minus6GgtA) and twocoding exonic SNPs (174TgtM and 235MgtT) or haplotypedistribution between cases and control subjects Amongsthypertensives however only theminus20AgtCpolymorphismwasassociatedwith the leukoaraiosis subtype of SVD [35 36]Theangiotensin II receptors which mediate the vasoconstrictiveand salt-conserving actions of the RAAS also representinteresting candidate genes for SVD Two subtypes of cell


surface receptors have been identified (AT1 and AT2) usingligand binding studies [40]The AT1 receptor through whichare exerted most of the actions of angiotensin II is a Gprotein-coupled receptor spanning seven transmembranedomains [41 42] Several studies suggest that theAT1 receptormight be involved in hypertension A polymorphism locatedin the 31015840 untranslated region of the AT1 receptor gene(AT1) (corresponding to an adeninecytosine (AC) basesubstitution at the 1166 position) has been shown to modifythe association of the ID ACE polymorphism with theoccurrence of myocardial infarction [31]

Aldosterone synthase is a key enzyme in the biosynthesisof aldosterone a mineralocorticoid that regulates arterialfunction and stimulates arterial fibrosis [41ndash44] Studiesalso indicate that the endogenous aldosterone system mayhave a role in cerebral SVD [16 41] However there areno published reports from Indian population on the role ofthe aldosterone synthase CYP11B2 T-344C polymorphism invascular cognitive dysfunction associated with SVD [15 45]Thus gene polymorphisms involved in the RAAS pathwayalong with aldosterone and ACE levels are of prime interestin regulating the blood pressures and may have a directinfluence in the development of cerebral SVD Knowledge inthis area is likely to generate novel treatment options in themanagement of vascular cognitive impairment

7 Conclusions and Future Directions

Cerebral SVD is a common condition representing about25 of all strokes and is of profound importance in viewof its probable preventable and treatable nature The mostcommon risk factor is hypertension which has to be strin-gently managed Specific neurochemical pathways whichinfluence blood pressure changes like renin-angiotensin-aldosterone system homocysteine metabolism influencingepigenetic mechanisms in the RAAS genes causing endothe-lial injury and the sympathetic autonomic nervous systemhave a probable role in cognitive decline A deep insight intothese pathways can help in treatment and even prevent thisdisorder

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

References

[1] L Pantoni and P Gorelick Cerebral Small Vessel DiseaseCambridge University Press Cambridge UK 1st edition 2014

[2] P Sachdev Vascular Dementia The Ageing Brain 299 2005[3] C Moran T G Phan and V K Srikanth ldquoCerebral small vessel

disease a review of clinical radiological and histopathologicalphenotypesrdquo International Journal of Stroke vol 7 no 1 pp 36ndash46 2012

[4] K F De Laat A G W Van Norden R A R Gons et al ldquoGaitin elderly with cerebral small vessel diseaserdquo Stroke vol 41 no8 pp 1652ndash1658 2010

[5] B Patel and H S Markus ldquoMagnetic resonance imaging incerebral small vessel disease and its use as a surrogate diseasemarkerrdquo International Journal of Stroke vol 6 no 1 pp 47ndash592011

[6] L Pantoni ldquoCerebral small vessel disease from pathogene-sis and clinical characteristics to therapeutic challengesrdquo TheLancet Neurology vol 9 no 7 pp 689ndash701 2010

[7] S R Chandra R Yadav C S Puneeth J Saini and T G IssacldquolsquoThe spectrum of vascular dementiarsquomdasha retrospective studyfrom South Indiardquo Journal of Association of Physicians of Indiavol 62 no 6 pp 498ndash503 2014

[8] O Micke J Hubner and K Munstedt ldquoAyurvedardquo DerOnkologe vol 15 no 8 pp 792ndash798 2009

[9] L R Caplan and J A Gomes ldquoBinswanger diseasemdashan updaterdquoJournal of the Neurological Sciences vol 299 no 1-2 pp 9ndash102010

[10] A P Palha andM F Esteves ldquoThe origin of dementia praecoxrdquoSchizophrenia Research vol 28 no 2-3 pp 99ndash103 1997

[11] A D Korczyn ldquoThe complex nosological concept of vasculardementiardquo Journal of the Neurological Sciences vol 203-204 pp3ndash6 2002

[12] C Brayne C Gill F A Huppert et al ldquoVascular risks andincident dementia results from a cohort study of the very oldrdquoDementia and Geriatric Cognitive Disorders vol 9 no 3 pp175ndash180 1998

[13] G C Roman T Erkinjuntti A Wallin L Pantoni and H CChui ldquoSubcortical ischaemic vascular dementiardquo The LancetNeurology vol 1 no 7 pp 426ndash436 2002

[14] C Millikan and N Futrell ldquoThe fallacy of the lacune hypothe-sisrdquo Stroke vol 21 no 9 pp 1251ndash1257 1990

[15] J M Wardlaw C Smith and M Dichgans ldquoMechanisms ofsporadic cerebral small vessel disease insights fromneuroimag-ingrdquoThe Lancet Neurology vol 12 no 5 pp 483ndash497 2013

[16] D Brenner J Labreuche F Pico et al ldquoThe renin-angiotensin-aldosterone system in cerebral small vessel diseaserdquo Journal ofNeurology vol 255 no 7 pp 993ndash1000 2008

[17] K Andersen L J Launer M E Dewey et al ldquoGenderdifferences in the incidence of AD and vascular dementia theEURODEM Studiesrdquo Neurology vol 53 no 9 pp 1992ndash19971999 ADmore in females and no difference in vascular betweenmales and females

[18] N D Prins E J van Dijk T den Heijer et al ldquoCerebral small-vessel disease and decline in information processing speedexecutive function andmemoryrdquoBrain vol 128 no 9 pp 2034ndash2041 2005

[19] G S Alexopoulos B S Meyers R C Young S Campbell DSilbersweig and M Charlson ldquolsquoVascular depressionrsquo hypothe-sisrdquo Archives of General Psychiatry vol 54 no 10 pp 915ndash9221997

[20] W D Taylor H J Aizenstein and G S Alexopoulos ldquoThevascular depression hypothesis mechanisms linking vasculardisease with depressionrdquoMolecular Psychiatry vol 18 no 9 pp963ndash974 2013

[21] M Mazzoni L Ferroni L Lombardi E Del Torto M Vistaand P Moretti ldquoMini-Mental State Examination (MMSE)sensitivity in an Italian sample of patients with dementiardquo TheItalian Journal of Neurological Sciences vol 13 no 4 pp 323ndash329 1992

[22] T Erkinjuntti R Laaksonen R Sulkava R Syrjalainen andJ Palo ldquoNeuropsychological differentiation between normalaging Alzheimerrsquos disease and vascular dementiardquo Acta Neu-rologica Scandinavica vol 74 no 5 pp 393ndash403 1986


[23] J T Moroney E Bagiella D W Desmond et al ldquoMeta-analysisof the Hachinski Ischaemic Score in pathologically verifieddementiasrdquo Neurology vol 49 no 4 pp 1096ndash1105 1997

[24] P Scheltens T Erkinjunti D Leys et al ldquoWhite matter changeson CT and MRI an overview of visual rating scalesrdquo EuropeanNeurology vol 39 no 2 pp 80ndash89 1998

[25] K A Jellinger ldquoThe pathology of lsquovascular dementiarsquo a criticalupdaterdquo Journal of Alzheimerrsquos Disease vol 14 no 1 pp 107ndash1232008

[26] T Erkinjuntti G Roman and S Gauthier ldquoTreatment of vascu-lar dementiamdashevidence from clinical trials with cholinesteraseinhibitorsrdquo Journal of the Neurological Sciences vol 226 no 1-2pp 63ndash66 2004

[27] K Okamoto M Tanaka and S Kondo ldquoTreatment of vasculardementiardquoAnnals of the New York Academy of Sciences vol 977no 1 pp 507ndash512 2002

[28] S M D Brucki A C Ferraz G R de Freitas A R Massaro MRadanovic andR R Schultz ldquoTreatment of vascular dementiardquoDementia e Neuropsychologia vol 5 no 4 pp 275ndash287 2011

[29] A D Korczyn V Vakhapova and L T Grinberg ldquoVasculardementiardquo Journal of the Neurological Sciences vol 322 no 1-2 pp 2ndash10 2012

[30] S Lanfranconi and H S Markus ldquoCOL4A1 mutations as amonogenic cause of cerebral small vessel disease a systematicreviewrdquo Stroke vol 41 no 8 pp e513ndashe518 2010

[31] E Ballabio A Bersano N Bresolin and L Candelise ldquoMono-genic vessel diseases related to ischemic stroke a clinicalapproachrdquo Journal of Cerebral Blood Flow and Metabolism vol27 no 10 pp 1649ndash1662 2007

[32] S Alamowitch E Plaisier P Favrole et al ldquoCerebrovasculardisease related to COL4A1 mutations in HANAC syndromerdquoNeurology vol 73 no 22 pp 1873ndash1882 2009

[33] P Ronco and E Plaisier ldquoHereditary angiopathy withnephropathy aneurysms and muscle cramps (HANAC) anew basement membrane-disease associated with mutationsof the COL4A1 generdquo Bulletin de lrsquoAcademie Nationale deMedecine vol 192 pp 971ndash986 2008

[34] T Fukutake ldquoCerebral autosomal recessive arteriopathy withsubcortical infarcts and leukoencephalopathy (CARASIL)from discovery to gene identificationrdquo Journal of Stroke andCerebrovascular Diseases vol 20 no 2 pp 85ndash93 2011

[35] A M Gruver L Schoenfield J F Coleman R Hajj-Ali E RRodriguez and C D Tan ldquoNovel ophthalmic pathology in anautopsy case of autosomal dominant retinal vasculopathy withcerebral leukodystrophyrdquo Journal of Neuro-Ophthalmology vol31 no 1 pp 20ndash24 2011

[36] R P Grewal and N W Barton ldquoFabryrsquos disease presenting withstrokerdquo Clinical Neurology and Neurosurgery vol 94 no 2 pp177ndash179 1992

[37] M O Giwa J Williams K Elderfield et al ldquoNeuropathologicevidence of endothelial changes in cerebral small vessel diseaserdquoNeurology vol 78 no 3 pp 167ndash174 2012

[38] X Jeunemaitre F Soubrier Y V Kotelevtsev et al ldquoMolecularbasis of human hypertension role of angiotensinogenrdquoCell vol71 no 1 pp 169ndash180 1992

[39] S A Cooper A Whaley-Connell J Habibi et al ldquoRenin-angiotensin-aldosterone system and oxidative stress in cardio-vascular insulin resistancerdquo American Journal of PhysiologyHeart and Circulatory Physiology vol 293 no 4 pp H2009ndashH2023 2007

[40] J A Staessen T Kuznetsova J G Wang D EmelianovR Vlietinck and R Fagard ldquoM235T angiotensinogen genepolymorphism and cardiovascular renal riskrdquo Journal of Hyper-tension vol 17 no 1 pp 9ndash17 1999

[41] A T Chiu W F Herblin D E McCall et al ldquoIdentification ofangiotensin II receptor subtypesrdquo Biochemical and BiophysicalResearch Communications vol 165 no 1 pp 196ndash203 1989

[42] H Furuta D-F Guo and T Inagami ldquoMolecular cloning andsequencing of the gene encoding human angiotensin II typeI receptorrdquo Biochemical and Biophysical Research Communica-tions vol 183 no 1 pp 8ndash13 1992

[43] L Tiret A Bonnardeaux O Poirier et al ldquoSynergistic effectsof angiotensin-converting enzyme and angiotensin-II type 1receptor gene polymorphisms on risk of myocardial infarctionrdquoLancet vol 344 no 8927 pp 910ndash913 1994

[44] J M C Connell R Fraser S MacKenzie and E DaviesldquoIs altered adrenal steroid biosynthesis a key intermediatephenotype in hypertensionrdquo Hypertension vol 41 no 5 pp993ndash999 2003

[45] M J E Van Rijn M J Bos A Isaacs et al ldquoPolymorphismsof the renin-angiotensin system are associated with bloodpressure atherosclerosis and cerebral white matter pathologyrdquoJournal of Neurology Neurosurgery amp Psychiatry vol 78 no 10pp 1083ndash1087 2007

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


MEDIATORSINFLAMMATION

of


Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of



Computational and Mathematical Methods in Medicine

OphthalmologyJournal of


Diabetes ResearchJournal of



Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


Table 1 NINDS-AIREN and ADDTC criteria for vascular dementia

ADDTC NINDS-AIREN

Dementia definitionDeterioration from a known level of intellectualfunction sufficient to interfere with the patientscustomary affairs of life and which is not isolated to asingle category of intellectual performance

Impairment of memory plus at least two other areas ofcognitive domains which should be severe enough tointerfere with activities of daily living and not due tophysical effects of stroke alone

Probable VaD

Requiring all of the followingDementiaEvidence of two or more strokes by history neurologicalsigns andor imaging or a single stroke with a cleartemporal relationship to the onset of dementiaEvidence of at least one infarct outside the cerebellumby CT or T1 weighted MRI

Requiring all of the followingDementiaCVD focal signs on examination + evidence of relevantCVD by CTMRIA relationship between the above two disordersmanifested by one or more of the followingDementia onset within 3 months of a strokeAbrupt deterioration in cognitive function orfluctuating stepwise course

Possible VaD

Dementia and one of the followingHistory or evidence of a single stroke without a cleartemporal relationship to the dementia onsetBinswangerrsquos disease that includes all the followingearly onset of urinary incontinence or gait disturbancevascular risk factors extensive white matter changes onneuroimaging

May be made in the presence of dementia and focalneurological signs in patients either with no evidence ofCVD on neuroimaging with the absence of a cleartemporal relationship between stroke and dementia orwith subtle onset and variable course of cognitive deficitand evidence of CVD

ADDTC State of California Alzheimerrsquos Disease Diagnostic and Treatment Centers CT computed tomography CVD cerebrovascular diseaseMRI magneticresonance imaging NINDS-AIRENNational Institute ofNeurological Diseases and Stroke andAssociation Internationale pour la Recherche et lrsquoEnseignementen Neurosciences VaD vascular dementia

in late 1897 differentiated vascular causes of dementia fromneurosyphilis [8 9] In 1910 Kreaplin concluded that insan-ity due to arteriosclerosis was the most frequent form ofsenile dementia [10] By 1970s the focus had shifted overto Alzheimerrsquos disease but Tomlinson Blessed and Rothshowed that the loss of more than 50ndash100mm3 of brain tissueconsequent on strokes caused cognitive impairment and wasreferred to as multi-infarct dementia [11] Diagnostic criteriacommonly applied are DSM-IV and NINDS-AIREN criteriaand Hachinskirsquos ischemic score (Tables 1 and 2 and Box 1)

C M Fisher did the maximum work on the clinico-pathological studies on cerebral SVD and is credited forcoining the term lacune as well as describing the Fishersrule which implicates that for every single cerebral vesselwhich is affected two coronaries and three peripheral vesselsare already affected He was thus the pioneer in research invascular dementia especially with regard to cerebral SVDUnlike large vessel disease even though there is a progressivechronic course in SVD a subacute onset is often describedin SVD due to lacunar state A chronic progressive coursebehaving as a progressive frontotemporal syndrome waspreviously referred to as Binswangerrsquos disease

Cerebral SVD is often classified on the basis of etiologyinto 5 major groups which include the following

Type 1 Arteriolosclerosis (or age and vascular risk factors-related SVD)

Type 2 Cerebral amyloid angiopathy (sporadic and heredi-tary)

Table 2 Hachinskirsquos ischemic score Purpose the Hachinski ischae-mic score (HIS) represents a brief clinical tool helpful in the ldquobed-siderdquo differentiation of the commonest dementia types Dementiaof Alzheimerrsquos Type (DAT) and Vascular Dementia (VaD) A cut-off score le4 for DAT and ge7 for VaD has a sensitivity of 89 and aspecificity of 89 [23]

Item number Description Value1 Abrupt onset 22 Stepwise deterioration 13 Fluctuating course 24 Nocturnal confusion 15 Preservation of personality 16 Depression 17 Somatic complaints 18 Emotional incontinence 19 History of hypertension 110 History of stroke 211 Associated atherosclerosis 112 Focal neurological symptoms 213 Focal neurological signs 2Reference Moroney et al [23]

Type 3 Inherited or genetic SVD (distinct from cerebralamyloid angiopathy eg CADASIL CARASIL Fabryrsquos dis-ease and SVD due to COL4A1 mutations)

Type 4 Inflammatory and immunomediated SVD (systemicand cerebral vasculitis central nervous system vasculitissecondary to infections)













































(a)


Van Sweiten et al


Minimum 0maximum 4

Blennow et al



(b)



Fazekas et al





Minimum 0maximum 30

Ylikoski et al


Minimum 0maximum 48

Manolio et al


Minimum 0maximum 9



6 Treatment


























References




















































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of




























































(a)


Van Sweiten et al


Minimum 0maximum 4

Blennow et al



(b)



Fazekas et al





Minimum 0maximum 30

Ylikoski et al


Minimum 0maximum 48

Manolio et al


Minimum 0maximum 9



6 Treatment


























References




















































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


















6 Treatment


























References




















































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

































References




















































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of













































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















cerebral small vessel disease clinical, neuropsychological, and

Documents