INDEX                                                             INTRODUCTION                                           ...
their reliability has been questioned and nonstandard alternatives have arisen (14).Furthermore, "vascular dementia" (VaD)...
Abrupt onset                                 2 An "ischemic score" (IS) was proposed by                                   ...
Table 2. Criteria for the diagnosis of ischemic vascular dementia (IVD)I. Dementia          Dementia is a deterioration fr...
1. Transcortical sensory aphasia in the absence of corresponding focal lesions on neuroimaging studies          2. Absence...
such as the Tinker Toy test, may be able to distinguish between AD and MID, because ofprominent aspontaneity in the latter...
Figure 1. A, lipohyalinosis, B, lacunar infarctionFigure 2. Lacunes. Small cavitary infarcts, resulting from hypertension,...
more inclusive concept of ischemic vascular dementia. Pathologically multi-infactdementia, in ischemic microvascular brain...
Figure 4. Postmortem specimen.                                                        Note     the      topographically   ...
Figure 5. A case of multi-infarct dementia. There are multiple cystic spaces consistent withsmall remote infarcts. These a...
Rogers et al. argued (51) that a state of insufficient blood flow to the brain precedes theonset of dementia in MID patien...
Table 3. Pathological /clinical associates of multi-infarct dementiaVascular risk factors      Hypertension, NIDDM, type I...
Figure 6. Periventricular                                                               lacunar infarctions. Notice       ...
for O2 (CMRO2). Such studies demonstrated diminished cerebral metabolism in dementedsubjects, both with and without known ...
Figure 9. leukoaraiosis, MRI T2 image. The MRI T2 periventricular hyperintensities aremainly due to astrogliosis and inter...
Table 4. Pathological / radiological findings in multi -infarct dementiaPathology               descriptionCentral and cor...
overreduction in blood pressure can actually worsen cognition. That risk factormodification can affect the course of MID a...
4.Benson DF, Kuhl DE, Hawkins RA, Phelps ME, Cummings JL, Tsai SY. Thefluorodeoxyglucose 18F scan in Alzheimers disease an...
19.Gainotti G, Parlato V, Monteleone D, Carlomagno S. Neuropsychological markers ofdementia on visuospatial tasks: a compa...
34.Kase CS. The epidemiology of multi-infarct dementia. Alzheimers Dis Assoc Disord1991;5:71-76.35.Katzman R, Lasker B, Be...
48.Munoz DG. The pathological basis of multi-infarct dementia. Alzheimers Dis AssocDisord 1991;5:77-90.49.OBrien M. Vascul...
62.Yamaguchi F, Meyer JS, Yamamoto M, Sakai F, Shaw T. Noninvasive regional bloodflow measurements in dementia. Arch Neuro...
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Topic of the month: Radiological pathology of multi-infarct dementia


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Topic of the month: Radiological pathology of multi-infarct dementia

  1. 1. INDEX  INTRODUCTION  CLINICAL FEATURES  PATHOLOGY  IMAGINGINTRODUCTIONCerebrovascular disease is a leading contributor to dementia worldwide. In mostpopulations which have been studied, only Alzheimers disease (AD) is a more commoncause of dementia (8). In 1974, Hachinski et al. (24) popularized the phrase "multi-infarctdementia" (MID) to represent the syndrome of dementia accompanied by focal neurologicsigns or symptoms, characterized by stepwise deterioration, and frequently associated withhypertension. In some populations with a high prevalence of hypertension (such as AfricanAmerican men and the Japanese), MID is more common than AD (26, 56). Thenomenclature of MID is complicated by several overlapping terms. Though criteria for thediagnosis of MID were published in DSM-III-R in 1987 (2) and have been widely adopted,
  2. 2. their reliability has been questioned and nonstandard alternatives have arisen (14).Furthermore, "vascular dementia" (VaD) has emerged as a diagnostic category thatincludes not only the multiple discrete infarcts of MID, but other dementing syndromesattributed to cerebrovascular origins. Among these is a dementia associated with diffusesubcortical white-matter disease putatively attributed to chronic subcortical ischemia. Thisstate is commonly, but controversially, known as "Binswangers disease" or "subcorticalarteriosclerotic encephalopathy." In contrast, "Leuko-araiosis" was proposed byHachinski et al. (25) as a description of radiologic and pathologic subcortical white-matterabnormalities such as those encountered in Binswangers disease, but these changes are notobligately associated with dementia. Other less common causes of dementia, such asvasculitides, are also considered under the rubric of vascular dementia.MID has been considered a "subcortical dementia" (10). The term "subcortical dementia"provides a clinical shorthand for dementia with prominent motor effects and relative rarityof the "cortical syndromes" of aphasia, agnosia, and apraxia. Erkinjuntti (13) reported,however, that 65 of 79 MID patients in his series had sustained a cortical stroke and that56% of the subjects had evidence of cortical strokes alone. Mahler and Cummings (41)have subsequently considered large-vessel and small-vessel behavioral subtypes of vasculardementia. This distinction further clouds the concept of MID as a subcortical syndromebecause the behavioral neurology of large-vessel infarctions typically involves "cortical"signs. The theoretical problems inherent in a cortical-subcortical dichotomy for thedescription of dementia have also been previously addressed (61). The interpretation ofwhat constitutes MID is further complicated by a lack of specificity and uniformapplication of proposed criteria for diagnosis. Given the high prevalence ofcerebrovascular disease, strokes frequently contribute to the cognitive morbidity ofindividuals with dementia of all types, including AD. Although antemortem clinicalevaluations and imaging may confirm the presence of multiple strokes, those techniquescannot exclude the presence of AD pathology contributing to the overall condition. Forinstance, the presence of cerebral infarctions may allow the clinical expression ofAlzheimer-type dementia even though the pathologic criteria for AD are not met.Consequently, the frequency of pure MID in autopsy studies is 10-23%, comparable to thatof "mixed dementia" with changes of both MID and AD (35).CLINICAL FEATURESRecurrent cerebral infarctions are, by definition, the pathophysiologic basis of MID. Therisk factors for MID are, not surprisingly, those for cerebrovascular disease, especially ageand hypertension. There appear to be no risks specific for the development of MID withinthe context of cerebrovascular disease. In about 90% of pathologically verified cases ofMID there is a history of acute unilateral motor or sensory dysfunction consistent withstroke (14). There may also be a history of acute impairment of "cortical" functionsmanifest as aphasia, apraxia, or agnosia. Urinary dysfunction and gait disturbance havebeen suggested as early markers for the development of MID (38). With accumulation ofischemic brain lesions there is typically incremental impairment of memory and behavioralinitiation, along with extrapyramidal features such as facial masking and rigidity.
  3. 3. Abrupt onset 2 An "ischemic score" (IS) was proposed by Hachinski et al. (23) as a means ofStepwise progression 1 distinguishing MID from primaryFluctuating course 2 degenerative dementia. A number of variantsNocturnal confusion 1 have been employed since the introduction of the original IS; a typical example is shown inRelative preservation of personality 1 Table 1. These scales share the commonDepression 1 weaknesses that they are sensitive but notSomatic complaints 1 specific indicators of MID and do not address the presence or absence of ADEmotional incontinence 1 pathology (8). In the clinical setting, an IS isHistory of hypertension 1 most useful as an instrument for suggestingHistory of strokes 2 the presence of cerebrovascular contributors to a dementia syndrome.History of associated atherosclerosis 1Focal neurologic symptoms 2 Table 1. Hachinski ischemia scoreFocal neurologic signs 2The diagnosis of MID depends on the establishment of dementia — that is, a sustaineddecrement from previously attained levels of cognitive ability, sufficient to interfere witheveryday activities, without an associated impairment of consciousness. Dementia may bestable or progressive. If strokes are the cause of a dementia, it is conceivable that theremight be an improvement in cognitive status as the deficits from an acute stroke resolvewithout returning to baseline. When dementia is accompanied by a history of strokestemporally linked to stepwise deterioration in intellectual abilities, the clinical diagnosis ofMID is obvious, though mixed dementia is also a possibility. A more difficult diagnosticsituation is the patient with a history of strokes not temporally associated with onset ofworsening of cognitive impairment. Recently, Chui et al. (9) proposed criteria for thediagnosis of "ischemic vascular dementia," based on the model for diagnosis of AD (44).These criteria are summarized in Table 2. An even more broadly defined set ofinternational diagnostic criteria for research studies of vascular dementia has beenproposed (52), but these have been criticized for being overly inclusive and failing toaddress the importance of temporal association of vascular events with onset of intellectualimpairment (12). Of particular note is the inability of any criteria, short of autopsyexamination, to differentiate mixed dementia from MID. These factors have led toconsiderable controversy over the clinical usefulness of the "vascular dementia" concept (7,49). Hachinski (22) has further argued that diagnostic criteria for vascular dementia fail toaccount for the fact that it is a syndromic diagnosis of multiple origins and outcomes.
  4. 4. Table 2. Criteria for the diagnosis of ischemic vascular dementia (IVD)I. Dementia Dementia is a deterioration from a known or estimated prior level of intellectual function sufficient to interfere broadly with the conduct of the patients customary affairs of life, which is not isolated to a single narrow category of intellectual performance and which is independent of level of consciousness. This deterioration should be supported by historical evidence and documented either by bedside mental status testing or, ideally, by more detailed neuropsychological examination, using tests that are quantifiable and reproducible and for which normative data are available.II. Probable IVD A. The criteria for the clinical diagnosis of probable ivd include all of the following: 1. Dementia 2. Evidence of two or more ischemic strokes by history, neurologic signs, and/or neuroimaging studies (CT of T1- weighted MRI B. The diagnosis of probable ivd is supported by: 1. Evidence of multiple infrared in brain regions known to affect cognition 2. A history of multiple transient ischemic attacks 3. History of vascular risk factors (e.g., hypertension, heart disease, diabetes mellitus) 4. Elevated Hachinski Ischemia Scale (original or modified version) C. Clinical features that are thought to be associated with IVD but await further research include: 1. Relatively early appearance of gait disturbance 2. Periventricular and deep white-matter changes on T2-weighted MRI that are excessive for age3. Focal changes in electrophysiologic studies (e.g., EEG, evoked potentials) or physiologic neuroimaging studies (e.g., SPECT-ET-NMRspectroscopy) D. Other clinical features that do not constitute strong evidence either for or against a diagnosis of probable ivd include: 1. Periods of slowly progressive symptoms 2. Illusions, psychosis, hallucinations, delusions 3. Seizures E. Clinical features that cast doubt on a diagnosis of probable ivd include:
  5. 5. 1. Transcortical sensory aphasia in the absence of corresponding focal lesions on neuroimaging studies 2. Absence of central neurologic symptoms/signs, other than cognitive disturbanceIII. Possible IVDA clinical diagnosis of possible ivd may be made when there is: 1. Dementia and one or more of the following: 2a. A history or evidence of a single stroke (but not multiple strokes) without a clearly documented temporal relationship to the onset of dementia or 2b. Binswangers syndrome (without multiple strokes) which includes all of the following: i. Early-onset urinary incontinence not explained by urologic disease, or gait disturbance (e.g., parkinsonian, magnetic, apraxic, or "senile" gait) not explained by peripheral cause ii. Vascular risk factors iii Extensive white-matter changes on neuroimagingIV. Definite IVDDiagnosis of definite ivd requires histopathologic examination of the brain, as well as:A. Chemical evidence of dementiaB. Pathologic confirmation of multiple infarcts, some outside of the cerebellumV. Mixed dementia A diagnosis of mixed dementia should be made in the presence of one or more other systemic or brain disorders that are thought to be causally related to the dementia.The degree of confidence in the diagnosis of IVD should be specified as possible, probably, or definite, and the other disorder(s)contributing to the dementia should be listed. For example: mixed dementia due to probable IVD and possible Alzheimers disease, ormixed dementia due to definite IVD and hypothyroidism.Note: If there is evidence of Alzheimers disease or some other pathologic disorder that is thought to have contributed to the dementia, adiagnosis of mixed dementia should be made.NEUROPSYCHOLOGICAL FEATURESBecause they are sensitive to site of dysfunction as opposed to the mechanism causing it,neuropsychological tests have been incapable of consistently distinguishing between MID,AD, and mixed dementias (41). Gainotti et al. (19) reported that AD patients were morelikely than those with MID to make "globalistic" or "odd" type errors on Ravens ColoredProgressive Matrices task, and on a design copy task were more likely to demonstrate the"closing-in" phenomenon — that is, copying figures such that they overlap the model.Mendez and Ashla-Mendez (45) suggested that unstructured neuropsychological tasks,
  6. 6. such as the Tinker Toy test, may be able to distinguish between AD and MID, because ofprominent aspontaneity in the latter. As with other neuropsychological measures, theranges of performance of AD and MID patients overlap, which limits the diagnosticspecificity in any individual patient. Furthermore, how well these results generalize to apopulations not selected for the "classic" clinical courses of the syndromes is unknown.Rothlind and Brandt (53) have proposed the use of a Frontal/Subcortical AssessmentBattery as a supplement to common bedside cognitive examinations for differentiatingdementia types characterized by prominent subcortical pathology from AD.EPIDEMIOLOGYThe reported frequency of MID in demented populations ranges from 4.5% to 39% (34).Karasawa and Homma (33) have suggested that the prevalence of MID, at least in Japan,has decreased since 1980 as the result of fewer strokes affecting the elderly.Jorm et al.s (29) extensive review of previous studies provides the basis for much of thecurrent understanding of the demographics of MID. They calculated the prevalence ofMID as doubling with every 5.3 years of age, which is in contrast to a popular perceptionthat the prevalence of MID declines after age 75 because of mortality associated withrecurrent strokes (43). Men are affected with MID more frequently — as opposed to AD,which is more common among women (29). In Europe, there is also a trend toward higherrates of MID in rural populations than in urban ones (34).Meta-studies of the epidemiology of MID have been complicated by the lack of clear-cutand uniform diagnostic criteria. Another problem in the interpretation of MIDepidemiology is that the illness is often defined on the basis of its risk factors regardless oftemporal course. As pointed out by Kase (34), in the presence of dementia, the IS items of(a) history of hypertension, (b) history of stroke, (c) evidence of associated atherosclerosis,and (d) focal findings on neurologic exam are considered sufficient to diagnose MID.Prospective studies, using uniform diagnostic criteria and paying careful attention to thetiming and character of stroke and dementia, will be required to more fully understand theepidemiology and natural history of MID.PATHOLOGYTomlinson, Blessed, and Roths landmark article (59) on the neuropathology of dementedolder individuals clarified the importance of AD pathology in senile dementia. It alsoreported a 20% frequency of multiple, discrete infarcts. These findings, along withHachinski et al.s (24) popularization of the term MID, defined the role of focal infarctionsas a cause of dementia. Lacunar infarctions, also known as lacunes, are commonlyimplicated as a major contributor to MID because of the "subcortical" features oftenprominent in the clinical presentation of the illness. Lacunes are small cavitary lesionsattributed to the occlusion of deep penetrating arteries. There is no uniform definitionbased on size, but most lacunes are less than 2 cm in diameter. Lacunar infarctions arealmost invariably associated with lipohyalinosis of the brain microvasculature.
  7. 7. Figure 1. A, lipohyalinosis, B, lacunar infarctionFigure 2. Lacunes. Small cavitary infarcts, resulting from hypertension, most frequentlyinvolving the basal ganglia (caudate nucleus, globus pallidus, putamen, and amygdala) andbasis pontis. Compare right with left.Lacunar infarctions are strongly associated with a history of hypertension. In Fishers (16)report, 97% of 114 autopsy cases of lacunar infarction had a diagnosis of hypertension,though more recent studies with stricter criteria for hypertension suggest rates rangingfrom 60% to 75% (47). The importance of lacunes per se as contributors to the dementiahas been questioned. Both Tomlinson et al. (59) and Fisher (17) minimized the role of theselesions in cognitive deficits. Cases of MID with lacunes also typically show myelin-stainevidence for extensive white-matter degeneration (leukoaraiosis) (27, 48). Whether anaccumulation of lacunes themselves is able to produce dementia in the absence ofassociated noncavitary white-matter damage is unknown. Though frequently referred to asdemyelination, electron microscopy (EM) indicates that axons within the myelin-stainlesions are lost as well (63). Because the diffuse white-matter changes and the cavitarylesions almost always co-occur and share a common pathophysiology, it is unlikely thattheir differential effects will be elucidated from human clinical material. The problem indifferentiating "pure" MID pathologically is one factor contributing to the evolution of the
  8. 8. more inclusive concept of ischemic vascular dementia. Pathologically multi-infactdementia, in ischemic microvascular brain disease, often contains a mix of lacunarinfarctions, leukoaraiosis, central and cortical atrophy, granular atrophy and basalganglionic calcification in various combinations. History and or radiological / pathologicalstudies often show evidence of hypertensive hemorrhagic changes in MID patients. Figure 3. Lacunar infarctionsTwo other types of discrete infarctions contribute to many cases of MID. Large-vesselinfarctions are usually identifiable by history with features of hemiparesis, hemianopia,aphasia, and so on. These are also unequivocally evident on CT or MRI. The volume oftissue loss from such lesions is an important factor in the development of dementia.Tomlinson et al. (59) reported that all their autopsy subjects with greater than 100 ml oftissue loss were demented. However, it is clear that dementia can follow much smallerlosses of brain tissue if these are strategically located (11). The second type of cortical lesioncontributing to MID is the micro-infarct. These have been reported as the sole basis ofdementia (32, 59) and consist of 0.5-to 2-mm-diameter lesions within the cortical ribbon.They are associated with a history of transient ischemic attacks (48).
  9. 9. Figure 4. Postmortem specimen. Note the topographically extensive periventricular white matter changes in a hypertensive case with evidence of leukoaraiosis on MRI studyOther factors which predispose to the development of multiple cerebral infarctions areassociated with MID or vascular dementia. Conditions leading to thromboembolic showers,such as endocarditis or atrial myxoma, can lead to the rapid development of a dementedstate often after a period of acute encephalopathy or coma. Autoimmune vasculitides, suchas in systemic lupus erythematosus or granulomatous angiitis of the central nervoussystem, contribute to areas of cerebral ischemia and infarction. They can be associatedwith long-term cognitive impairments. Tertiary Lyme disease and syphilis can also causedementia on the basis of vasculitic thromboses. Cerebral amyloid angiopathy, though oftenlinked to AD, may lead to multiple intracerebral hemorrhages and play a significant role inthe development of vascular dementia (28). One other lesion of vascular origin which canpresent as dementia is chronic subdural hematoma. These intracranial fluid collections canmimic the fluctuating, stepwise cognitive deterioration and prominent motor symptomscharacteristic of MID, and they are largely reversible with surgical drainage of fluid andrelief of mass effect.
  10. 10. Figure 5. A case of multi-infarct dementia. There are multiple cystic spaces consistent withsmall remote infarcts. These are predominantly in the subcortical white matter (blackarrows) and basal ganglia (red arrow). In other sections more could be seen in thethalamus too. Note how small the basal ganglia are on the right vs. the left. There is also adilatation of the lateral ventricles. In this case it is probably due to loss of tissue rather thanincrease in CSF, hence it is called hydrocephalus ex vacuo. Finally there is moderateatherosclerosis of the middle cerebral artery on the right (yellow arrows).PATHOGENESISTo date, there remains no concise explanation for the pathogenesis of MID except forinfarctions causing loss of brain volume or loss of strategic, localized, areas integral tonormal cognition, or a combination of these two factors.Although CBF is diminished in MID, this is a feature common to most dementia andprobably represents a response to reduced cerebral metabolism, rather than the cause ofthe cognitive impairment. Some MID patients show foci of elevated regional oxygenextraction fraction (rOEF) suggestive of areas of chronic compensated ischemia (21).
  11. 11. Rogers et al. argued (51) that a state of insufficient blood flow to the brain precedes theonset of dementia in MID patients by up to 2 years. Brown and Frackowiak (6) havecautioned, however, that such rOEF changes are not common among MID patients andtherefore cannot be the major factor in the development of most MID. Two conditionsassociated with global diminution in CBF — cardiac disease (58) and hypertension (3) —have nonetheless been long recognized as contributors to impairment onneuropsychological testing. Meyer et al. (46), for example, reported that careful control ofblood pressure improved cognition in some in MID patients, but overcontrol (withpresumed diminution of CBF) worsened cognitive performance. Increased whole bloodviscosity often contributes to diminished brain perfusion in MID patients. Increased wholeblood viscosity is very common in essential hypertension.MID and, more inclusively, vascular dementia are associated with changes in the blood-brain barrier (BBB). Elevated cerebrospinal fluid (CSF) concentrations of albumin andimmunoglobulin G (IgG) have been reported for MID patients (40), though other studieshave found no difference for albumin (1) or IgG (5). Interestingly, Blennow et al. (5) alsoreported increased CSF/serum ratios for albumin in AD patients with white-matter lesionsor vascular risk factors. This indicates that BBB dysfunction in vascular dementia mayresult from risk factors for cerebrovascular disease rather than represent a uniquecontributor to MID. Wallin and Blennow (60) have argued that, because myelin lipids aresignificantly reduced in vascular dementia, the myelin sheath is a primary lesion site. Theyfurther hypothesize that the high metabolic demands of the oligodendrocytes render themprone to ischemic damage. These views are at odds with (a) the PET data, which suggestthat chronic ischemia is not a contributor to MID (6), and (b) the EM studies, which showaxonal loss in areas of noncavitary demyelination (63). Although myelin loss and BBBdysfunction may contribute to some vascular dementia syndromes, their causative role inMID is questionable. One of the difficulties in assessing the pathophysiology of vasculardementia is the considerable frequency of dementia with findings of both vascular diseaseand AD. Although this may simply represent the co-occurrence of two common illnesses,there is evidence that links cerebrovascular disease and AD pathology. Kalaria et al. (31),for instance, found that cerebral ischemia promotes deposition of potentially neurotoxicamyloid in the brain. Sofroniew et al. (57) reported that focal cerebral damage causesneuronal loss in the nucleus basalis of Meynert similar to that observed in AD.Furthermore, such changes in the basal forebrain, when associated with AD, have beenlinked to alterations of cerebral vascular regulation and diminution of CBF (54). Thesynthetic sites for the biogenic amines are also affected in AD (42, 50). Degeneration inthese sites, the locus coeruleus and dorsal raphe nuclei, may adversely affectcerebrovascular function, because norepinephrine and serotonin also influence vascularautoregulation (53). The distinction between causes of vascular and "primarydegenerative" dementias may therefore be more difficult than is commonly accepted.
  12. 12. Table 3. Pathological /clinical associates of multi-infarct dementiaVascular risk factors Hypertension, NIDDM, type IV hyperglycaemia, old age, and LVH are common in MID patients.Hypertensive vascular Lipohyalinosis and arteriolar wall fibrosis are common in MIDpathology patientsPathological findings Neuronal degeneration, ischaemic demyelination, diffuse lacunar state, and leukoaraiosis are common in MID patientsHaemorheological profile Increased whole blood viscosity and increased thrombotic tendency are common in MID patientsANIMAL MODELSAlthough a number of animal models for the development of MID have been employed,none have been satisfactory. Rodents tend not to have profound long-lasting behavioraleffects from cerebral infarctions, and the multiple or diffuse, gradually acquired lesionscharacteristic of MID in humans have not been reproduced. The promising technique ofinducing embolic ischemia in rats by injecting 35-m-diameter microspheres into ratcarotid arteries produced effects on memory, but these were not sustained (37).IMAGINGAs with most central nervous system diseases, imaging studies have an important role inthe diagnosis of MID. In contrast to the diagnosis of AD, in which cerebral images are usedto "rule out" structural changes contributing to the dementia, the images in MID canclearly identify significant pathology. In the neuropathologically verified series ofErkinjunttis group (14), 74% of MID patients had cortical infarcts and 13% had deepinfarcts on x-ray computed tomography (CT). Magnetic resonance imaging (MRI) is moresensitive to lesions in the brain than CT, but this is not necessarily an advantage in thediagnosis of MID. Cavities present on T1-weighted images are consistent with cerebralinfarction, but many of the changes observed on MRI may represent the effects of healthyaging, such as dilated perivascular spaces. The typical changes include small, focal areas ofincreased signal as well as patchy or confluent periventricular white-matter hyperintensityon T2-weighted images. These nonspecific changes are the basis of the term"leukoaraiosis" (LA). It is important to recognize that a large volume of diffuse signalchange may be present on CT or MRI without meaningful impairment of cognition.Nonetheless, LA is a frequent correlate of MID. In Erkinjuntti et al.s (15) clinical series,72% of MID patients had LA, as opposed to 19% of AD patients.
  13. 13. Figure 6. Periventricular lacunar infarctions. Notice central and /or cortical atrophy. Figure 7. Periventricular lacunar infarctions and calcificationsFor many years, "cerebral arteriosclerosis" was considered an important component ofmost senile dementia — hence the popular use of the phrase "hardening of the arteries" asa synonym for dementia. This perception understandably led to extensive study of cerebralblood flow and metabolism, but with little concern over clinical differentiation of dementiatypes. The earliest studies employed inert gas measures of global cerebral metabolic rate
  14. 14. for O2 (CMRO2). Such studies demonstrated diminished cerebral metabolism in dementedsubjects, both with and without known cerebrovascular disease (39).Figure 8. leukoaraiosis, CT scan images showing periventricular diffuse hypodensity,which is mainly due to astrogliosis and interstitial edema. Notice central and /or corticalatrophy.Developing technology subsequently allowed regional cerebral blood flow (CBF)measurements using the gamma-emitter 133Xe and multiple extracranial radiationdetectors for planar or tomographic imaging. Simultaneously, a greater understanding ofdementia subtypes improved the discriminative abilities of the techniques. Patients withvascular dementia, including MID, demonstrate patchy, irregular areas of decreased CBFconsistent with areas of infarction or ischemia, whereas AD patients have more uniformfrontal, parietal, and temporal decreases in CBF (36, 62). There is no general agreementthat diminished CBF by 133Xe methods correlates with dementia severity. Some studieshave found good correlation in MID only (23), and others have reported it in AD only (62);however most studies have found it in both (6).
  15. 15. Figure 9. leukoaraiosis, MRI T2 image. The MRI T2 periventricular hyperintensities aremainly due to astrogliosis and interstitial edema. Notice central and /or cortical atrophy.Positron emission tomography (PET) using 15O allows detailed mapping of O2metabolism. Neither AD nor MID patients typically demonstrate chronic ischemia by thismethod (18). Despite early enthusiasm for [18F]fluorodeoxyglucose (FDG) PET as a usefultechnique for the differentiation of MID and AD (4), subsequent investigations have notbeen as conclusive (6).Single photon emission computed tomography (SPECT) is more widely available than PETand has been used clinically to differentiate MID from AD, though the validity of SPECTfor this purpose is not known. Neither of the two isotopes in general use, 123I-labeledamphetamine (IMP) and 99mTc-labeled hexamethylpropylene amine oxime (HMPAO), hasbeen shown to be superior in the differential diagnosis of dementia (20). As with otherimaging modalities, MID patients tend to show patchy or multifocal hypoperfusionwhereas AD patients show more diffuse changes, but there is sufficient overlap to preventdiagnostic surety in any individual patient (55).
  16. 16. Table 4. Pathological / radiological findings in multi -infarct dementiaPathology descriptionCentral and cortical This is secondary to chronic global reduction of brain perfusion.atrophyLeukoaraiosis Leukoaraiosis is an ischaemic demyelination of the immediate periventricular white matter with axonal loss, astrogliosis and interstitial edema. It is secondary to chronic global reduction of brain perfusion.Lacunar infarctions lacunar infarctions are secondary to the micro vascular thrombo- occlusive episodes. They are most numerous in the periventricular gray matter (thalamus and basal ganglia) and the immediate periventricular white matter. Spasm of the fine penetrating arterioles (secondary to increased VSMCs sensitivity) -can also result in Lacunar infarctions. It is commonly associated with lipohyalinosis of the microvascular brain bed.Granular atrophy Granular atrophy is defined pathologically as infarctions localized to the cerebral cortex and not extending to the subcortical white matter.Basal ganglionic These are calcification of the the arteriolar wall of thecalcifications microcirculation within the basal ganglia .TREATMENTDrugs of many classes and presumed mechanisms of action have been tried in thetreatment of the cognitive symptoms in MID, but none have consistently beendemonstrated to be effective. No agent has been approved for such use in the United States.There are, however, potential means of symptomatic treatment. Improvement amongselected MID patients on a screening instrument for cognition, the Cognitive CapacityScreening Exam (CCSE), was reported with treatment of vascular risk factors such ashypertension and smoking. Similar treatments did not affect the cognition of AD patientsin the same paradigm (46). In systemic conditions that decrease CBF, such as valvularheart disease and hypertension, neuropsychological test performance can improve withtreatment of the causative factor(s) (30).Alteration of the course of the illness may also be accomplished. Reduction of bloodpressure is a primary goal of treatment in order to diminish the risk for recurrent stroke(43). Other risk factors, such as smoking and diabetes mellitus, can be addressed to reverseor slow the progression of vascular pathology. Any treatment approach that reduces thelikelihood of stroke, such as carotid endarterectomy in moderate stenoses or the use ofaspirin or ticlopidine in primary and secondary prevention, is likely to alter the course ofMID, but no definitive analyses have been reported. It is important, however, to emphasizethat many of the vascular changes contributing to strokes are the result of long-termpathologic processes which are not reversed with treatment. As Meyer et al. (46) found,
  17. 17. overreduction in blood pressure can actually worsen cognition. That risk factormodification can affect the course of MID after diagnosis has not been conclusivelydemonstrated, but a reduction in vascular dementia prevalence has been attributed toattention to risk factors (26).CONCLUSIONSMulti-infarct dementia is a syndrome which varies according to the site, size, nature,number, and timing of the lesions. Although criteria for the diagnosis of vascular dementiaas a whole have been proposed, the long-term utility of such criteria has been questioned(22). No specific risk factors beyond those for cerebral ischemia have been identified, but itis likely that with control of the risk factors, progression of the illness, and perhaps currentfunction, can be affected. The challenge lies in the early identification of those at risk forsubsequent development of cognitive impairments and intervention. Prevention of vasculardementia through risk factor management may have further impact because of potentialinteractions between cerebral ischemia and the expression of AD.FUTURE DIRECTIONSHachinski (22) has claimed that "Few areas in medicine are as ripe for action as thevascular dementias." The success of further efforts to understand vascular dementiadepends on several factors. Included among them are (a) a commonly accepted definition ofwhat constitutes vascular dementia and (b) the recognition that multiple, potentiallytreatable causes contribute to a final common clinical state of dementia. Early recognitionof risk, and subsequent intervention, are then possible before the evolution of the dementia.The development of more useful animal models and new techniques of functional imagingto understand the pathogenesis of dementia in the face of vascular compromise will be vitalin settling many of the controversies surrounding the field today. Despite thosecontroversies, and the impediments to progress engendered by them, it is apparent thatprevention and treatment of vascular dementia is an achievable goalREFERENCES1.Alafuzoff I, Adolfsson R, Bucht G, Winblad B. Albumin and immunoglobulin in plasmaand cerebrospinal fluid, and blood-cerebrospinal fluid barrier in patients with dementia ofAlzheimer type and multi-infarct dementia. J Neurol Sci 1983;60:465-472.2.American Psychiatric Association Committee on Nomenclature and Statistics. Diagnosticand statistical manual of mental disorders (DSM-III-R), 3rd ed. (revised). Washington, DC:American Psychiatric Association, 1987.3.Apter NS, Halstead WC, Heimburger RF. Impaired cerebral functions in essentialhypertension. Am J Psychiatry 1951;107:808-813.
  18. 18. 4.Benson DF, Kuhl DE, Hawkins RA, Phelps ME, Cummings JL, Tsai SY. Thefluorodeoxyglucose 18F scan in Alzheimers disease and multi-infarct dementia. ArchNeurol 1983;40:711-714.5.Blennow K, Wallin A, Fredman P, Karlsson I, Gottfries CG, Sverrholm L. Blood-brainbarrier disturbance in Alzheimers disease is related to vascular factors. Acta Neurol Scand1990;81:323-326.6.Brown WD, Frackowiak RSJ. Cerebral blood flow and metabolism studies in multi-infarct dementia. Alzheimers Dis Assoc Disord 1991;5:131-143.7.Brust JCM. Vascular dementia is overdiagnosed. Arch Neurol 1988;45:799.8.Chui HC. Dementia: a review emphasizing clinicopathologic correlation and brain-behavior relationships. Arch Neurol 1989;46:806-814.9.Chui HC, Victoroff JI, Margolin D, Jagust W, Shankle R, Katzman R. Criteria for thediagnosis of ischemic vascular dementia proposed by the State of California AlzheimersDisease Diagnostic and Treatment Centers. Neurology 1992;42:473-480.10.Cummings JL, Benson DF. Dementia: a clinical approach. Boston: Butterworth, 1983.11.del Ser T, Bermejo F, Portera A, Arredondo JM Bouras C, Constantinidis J. Vasculardementia: a clinicopathological study. J Neurol Sci 1990;96:1-17.12.Drachman DA. New criteria for the diagnosis of vascular dementia: do we know enoughyet? Neurology 1993;43:243-245.13.Erkinjuntti T. Types of multi-infarct dementia. Acta Neurol Scand 1987;75:391-399.14.Erkinjuntti T, Haltia M, Palo J, Sulkava R, Paetau A. Accuracy of the clinical diagnosisof vascular dementia: a prospective clinical and post-mortem pathological study. J NeurolNeurosurg Psychiatry 1988;51:1037-1044.15.Erkinjuntti T, Ketonen L, Sulkava R, Vuorialho M, Palo J. CT in the differentialdiagnosis between Alzheimers disease and vascular dementia. Acta Neurol Scand1987;75:262-270.16.Fisher CM. Lacunes: small, deep, cerebral infarcts. Neurology 1965;15:774-784.17.Fisher CM. Lacunar strokes and infarcts: a review. Neurology 1982;32:871-876.18.Frackowiak RSJ, Pozzilli C, Legg NJ, et al. Regional cerebral oxygen supply andutilization in dementia: a clinical and physiological study with oxygen-15 and positrontomography. Brain 1981;104: 753-778.
  19. 19. 19.Gainotti G, Parlato V, Monteleone D, Carlomagno S. Neuropsychological markers ofdementia on visuospatial tasks: a comparison between Alzheimers type and vascular formsof dementia. J Clin Exp Neuropsychol 1992;14:239-252.20.Gemmell HG, Sharp PF, Besson JAO, Ebmeier KP, Smith FW. A comparison of Tc-99m HM-PAO and I-123 IMP cerebral SPECT images in Alzheimers disease and multi-infarct dementia. Eur J Nucl Med 1988;14:463-466.21.Gibbs JM, Frackowiak RSJ, Legg NJ. Regional cerebral blood flow and oxygenmetabolism in dementia due to vascular disease. Gerontology 1986;32(Suppl):84-88.22.Hachinski V. Preventable senility: a call for action against the vascular dementias.Lancet 1992;340:645-648.23.Hachinski VC, Iliff LD, Zilhka E, et al. Cerebral blood flow in dementia. Arch Neurol1975;32:632-637.24.Hachinski VC, Lassen NA, Marshall J. Multi-infarct dementia: a cause of mentaldeterioration in the elderly. Lancet 1974;2:207-210.25.Hachinski VC, Potter P, Merskey H. Leuko-araiosis. Arch Neurol 1987;44:21-23.26.Homma A, Hasegawa K. Recent developments in gerontopsychiatric research on ageassociated dementia in Japan. Int Psychogeriatr 1989;1:31-49.27.Ishii N, Nichihara Y, Imamura T. Why do frontal lobe symptoms predominate invascular dementia with lacunes. Neurology 1986;36: 340-345.28.Jellinger K. Cerebrovascular amyloidosis with cerebral hemorrhage. J Neurol1977;214:195-206.29.Jorm AF, Korten AE, Henderson AS. The prevalence of dementia: a quantitativeintegration of the literature. Acta Psychiatr Scand 1987;76:465-479.30.Juolasmaa A, Outakoski J, Hirvenoja R, Tienari P, Sotaniemi K, Takunen J. Effect ofopen heart surgery on intellectual performance. J Clin Neuropsychol 1981;3:181-197.31.Kalaria RN, Bhatti SU, Palatinsky EA, et al. Accumulation of the beta amyloidprecursor protein at sites of ischemic injury in rat brain. Neuroreport 1993;4:211-214.32.Kaplan JG, Katzman R, Horoupin DS, Field PA, Mayeux R, Mays AP. Progressivedementia, visual deficits, amyotrophy and microinfarcts. Neurology 1985;35:789-796.33.Karasawa A, Homma A. Recent changes in the prevalence of dementia in the Tokyometropolis. In: Hasegawa K, Homma A, eds. Psychogeriatrics: biomedical and socialadvances. Tokyo: Excerpta Medica, 1990;24-29.
  20. 20. 34.Kase CS. The epidemiology of multi-infarct dementia. Alzheimers Dis Assoc Disord1991;5:71-76.35.Katzman R, Lasker B, Bernstein N. Advances in the diagnosis of dementia: accuracy ofdiagnosis and consequence of misdiagnosis of disorders causing dementia. In: Terry RD,ed. Aging and the brain. New York: Raven Press, 1988;17-62.36.Kitigawa Y, Meyer JS, Tachibana H, Mortel KF, Rogers RL. CT-CBF correlations ofcognitive deficits in multi-infarct dementia. Stroke 1984;15:1000--1009.37.Kiyoto Y, Miyamoto M, Nagayoka A, Nagawa Y. Cerebral embolization leads tomemory impairment of several learning tasks in rats. Pharmacol Biochem Behav1986;24:687-692.38.Kotsoris H, Barclay LL, Kheyfets S, Hulyalkar A, Dougherty J. Urinary and gaitdisturbances as markers for early multi-infarct dementia. Stroke 1987;18:138-141.39.Lassen NA, Munck O, Tottey ER. Mental function and cerebral oxygen consumption inorganic dementia. Arch Neurol Psychiatry 1957;77:126-133.40.Leonardi A, Gandolfo C, Caponetto C, Arata L, Vecchia R. The integrity of the blood-brain barrier in Alzheimers type and multi-infarct dementia evaluated by the study ofalbumin and IgG in serum and cerebrospinal fluid. J Neurol Sci 1985;67:253-261.41.Mahler ME, Cummings JL. The behavioral neurology of multi-infarct dementia.Alzheimers Dis Assoc Disord 1991;5:122-130.42.Mann DMA, Yates PO, Hawkes J. The noradrenergic system in Alzheimer and multi-infarct dementias. J Neurol Neurosurg Psychiatry 1982;45:113-119.43.Marshall J. Vascular dementias. In: Whitehouse PJ, ed. Dementia. Philadelphia: FADavis, 1993;215-236.44.McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinicaliagnosis of Alzheimers disease: report of the NINCDS-ADRDA work group under theauspices of the Department of Health and Human Services Task Force on AlzheimersDisease. Neurology 1984;34:939-944.45.Mendez MF, Ashla-Mendez M. Differences between multi-infarct dementia andAlzheimers disease on unstructured neuropsychological tasks. J Clin Exp Neuropsychol1991;13:923-932.46.Meyer JS, Judd BW, Tawaklna T, Rogers RL, Mortel KF. Improved cognition aftercontrol of risk factors for multi-infarct dementia. JAMA 1986;256:2203-2209.47.Miller VT. Lacunar stroke: a reassessment. Arch Neurol 1983; 40:129-134.
  21. 21. 48.Munoz DG. The pathological basis of multi-infarct dementia. Alzheimers Dis AssocDisord 1991;5:77-90.49.OBrien M. Vascular dementia is underdiagnosed. Arch Neurol 1988;45:799.50.Reinikainen KJ, Paljarvi L, Huuskonen M, et al. A post mortem study of noradrergic,serotonergic and GABAergic neurons in Alzheimers disease. J Neurol Sci 1988;84:101-116.51.Rogers RL, Meyer JS, Mortel KF, Mahurin RK, Judd BW. Decreased cerebral bloodflow precedes multi-infarct dementia, but follows senile dementia of the Alzheimer type.Neurology 1986;36:1-6.52.Roman GC, Tatemichi TK, Erkinjuntti T, et al. Vascular dementia: diagnostic criteriafor research studies; report of the NINDS-AIREN International Workshop. Neurology1993;43:250-260.53.Rothlind JC, Brandt J. A brief assessment of frontal and subcortical functions indementia. J Neuropsychiatry Clin Neurosci 1993;5:73-77.54.Sato A, Sato Y. Regulation of regional cerebral blood flow by cholinergic fibersoriginating in the basal forebrain. Neurosci Res 1992:242-274.55.Sharp PF, Gemmell HG, Besson JAO, Smith FW. Perfusion patterns in dementia. JNucl Med 1986;27:1939-1940.Smyth K, Whitehouse PJ, Rust M, Kahana J. Epidemiology, diagnosis, and management ofAlzheimers disease and related disorders: implications for minority populations. HealthMatrix 1988;4:28-32.57.Sofroniew MV, Pearson RCA, Eckenstein F, Cuello AC, Powell TPS. Retrogradechanges in cholinergic neurons in the basal forebrain of the rat following cortical damage.Brain Res 1983; 289:370-374.58.Spieth W. Cardiovascular health status, age and psychological performance. J Gerontol1964;19:277-284.59.Tomlinson BE, Blessed G, Roth M. Observations on the brains of demented old people.J Neurol Sci 1970;11:205-242.60.Wallin A, Blennow K. Pathogenetic basis of vascular dementia. Alzheimers Dis AssocDisord 1991;5:91-102.61.Whitehouse PJ. The concept of subcortical and cortical dementia: another look. AnnNeurol 1986;19:1-6.
  22. 22. 62.Yamaguchi F, Meyer JS, Yamamoto M, Sakai F, Shaw T. Noninvasive regional bloodflow measurements in dementia. Arch Neurol 1980;37:410-418.63.Yamanoucki H, Suguira S, Tomonage M. Decrease in nerve fibers in cerebral whitematter in progressive vascular encephalopathy of Binswanger type: an electron microscopystudy. J Neurol 1989;236:382-387.The author: Professor Yasser MetwallyProfessor Yasser Metwally, Ain Shams university, Cairo, February 26, 2012