By John V. Bowler, MD and Vladimir Hachinski, MD

he term “vascular ” is often used as if it However, by the end of the 20th century, the increasingly rec- refers to only one condition, and research is often ognized Alzheimer’s disease overshadowed . done on the same assumption. However, there are Because Alzheimer’s disease was thought to be the major many etiologies responsible for cerebrovascular cause of dementia, its criteria became those applied to all lesions, producing an array of clinical manifesta- dementia. Alzheimer’s was separated from vascular dementia Ttions and psychological deficits. Lumping these conditions using clinical features thought to reflect vascular risk factors, together may not be appropriate under all circumstances, but vascular events and the manifestations of systemic and cerebral current practice does not recognize this. An integral part of a vascular disease. These elements are typically codified using the diagnosis of vascular dementia should be a statement concern- ischemic score (see Table 1). The basis of the definition has ing etiology, since this will inform treatment decisions. resulted in the criteria for vascular dementia emphasizing Despite the recognition of both Alzheimer’s disease and a memory loss and usually the progression and irreversibility of form of vascular dementia (Binswanger disease) at the end of the cognitive decline, none of which is necessarily the case. A the 19th century, for the greater part of the 20th century complete paradigm shift is required to develop new criteria and dementia was routinely attributed to arteriosclerosis and conse- alternative screening tools that focus on the cognitive domains quent chronic cerebral ischemia. This view changed with the most affected in vascular disease. increasing recognition of Alzheimer’s disease and the demon- In addition, dementia is defined as the level of cognitive im- stration that infarcts, rather than chronic ischemia, were the pairment at which normal daily functions are impaired; this basis of what came to be called “multi-infarct dementia.” The will identify only late cases, underestimating the prevalence of term “vascular dementia” subsequently replaced multi-infarct cognitive impairment due to vascular disease and depriving dementia since it was recognized that there were many etiolo- early cases the benefit of early preventative treatment. This crit- gies apart from multiple infarcts (e.g., single infarcts, hypoten- ical early stage has been termed “vascular cognitive impair- sion, , incomplete infarction, hemorrhage). ment.”1 Its importance lies in the fact that vascular disease is

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This multifaceted diagnosis is overdue for a reappraisal. Here’s a look at how its definition, and its role in clinical practice, is evolving.

the largest single identifiable risk factor for dementia apart ination and neuroimaging is required, as is evidence of a rela- from age and the only one that is currently treatable. tionship between the and cognitive decline. The latter Over the past decade, there has been another major change: can be provided by two of the following: (a) onset of dementia the increasing recognition of mixed dementia, where vascular within three months after a recognized stroke, (b) abrupt dete- dementia co-exists with other causes, particularly Alzheimer’s rioration in cognition and (c) stepwise deterioration. disease. These are now known to be common. Eighty percent Abnormalities on neuroimaging support the diagnosis of of the elderly have evidence of ,2 and vascular dementia only if they fulfill criteria regarding site and mixed VaD/AD may account for up to one-half of all demen- size. These criteria include large-vessel in the following tia cases.3-6 Furthermore, the interaction between the vascular sites: bilateral anterior cerebral, posterior cerebral, association component and other components more than doubles the rate areas or carotid watershed (superior frontal, parietal); small- of progression when compared to pure Alzheimer’s disease vessel disease in the basal ganglia and frontal ; alone.3,7 extensive periventricular white matter lesions; or bilateral thal- amic lesions. The criteria for severity specify that leukoen- Clinical Manifestations cephalopathy must involve at least 25 percent of the total white Two similar sets of vascular dementia identification criteria matter. have been proposed, but neither has met universal acceptance A diagnosis of possible vascular dementia is made (a) if there or been validated. Furthermore, they are difficult to apply con- is clinical evidence of cerebrovascular disease but no neu- sistently and produce different results. roimaging data; (b) in the absence of a clear temporal relation- The NINDS-AIREN criteria define probable vascular ship between dementia and stroke; or (c) in those cases with a dementia as decline in memory and two or more cognitive subtle onset and variable course. Hemorrhagic lesions are per- domains severe enough to interfere with activities of daily liv- mitted. Definite vascular dementia is diagnosed provided prob- ing. Evidence of cerebrovascular disease on both clinical exam- able dementia exists, accompanied by histopathological evi-

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Vascular Dementia

dence of cerebrovascular disease and no histopathological evi- development of a definition of vascular dementia than the cur- dence of other possible causes of the cognitive loss. Vascular rently proposed criteria that depend on memory loss. dementia is excluded in cases with disturbed consciousness, The presence of “patchy” or unequal cognitive deficits is a psychosis, severe aphasia, major sensorimotor deficits or other requirement for a diagnosis of vascular dementia in ICD-10, brain diseases such as Alzheimer’s disease that could themselves but this pattern of cognitive loss is to be expected only in true account for the deficit. Mixed dementia is not recognized, but multi-infarct dementia, where there are few (two or three) cor- the coexistence of Alzheimer’s is termed “Alzheimer’s disease tical infarcts. In vascular dementia in general, the extent to with cerebrovascular disease.” which the cognitive deficit is patchy is not different from The California criteria are not fundamentally different, but Alzheimer’s disease; however, the domains affected are differ- they do differ in details. Hemorrhagic and anoxic lesions are ent.10 not included. The number and type of cognitive defects are Atrophy on MRI has sometimes been taken to support deliberately not specified, but the loss should be sufficient to degenerative or mixed dementia rather than vascular dementia. interfere with the conduct of the patient’s customary affairs of Now, though, clear evidence shows that atrophy, particularly life and should not be confined to a single narrow category. central atrophy, is a common feature in vascular dementia and Two or more ischemic strokes (at least also in association with vascular risk 12 one of which is outside the cerebel- A T R O P H Y factors, transient ischemic attacks, lum) or one stroke with a clear tempo- and leukoaraiosis.13-17 The presence ral relationship to the onset of demen- N Clear evidence shows that of atrophy should, therefore, not tia are required. Risk factors and some weigh against a diagnosis of vascular clinical features are included as sup- S atrophy is a common dementia. portive features, but how these are to feature in vascular be operationalized is not stated. The W Pathogenesis and ischemic scale, while not intended to dementia and is associated Pathophysiology be the sole instrument used in the sep- E The processes that lead to vascular aration of Alzheimer’s disease from R with vascular risk factors, dementia may begin before infarc- vascular dementia, is accurate in this TIAs and leukoaraiosis. The tion has occurred. Risk factors, par- role. It cannot, however, separate vas- S ticularly hypertension, without clear cular dementia from mixed dementia. presence of atrophy should vascular events are associated with As there is no generally accepted not weigh against an both a relative increase in the vol- definition of vascular dementia, its ume of the lateral ventricles, suggest- manifestations are not agreed on and diagnosis of VaD ing central atrophy and cognitive data from studies using current criteria decline.18,19 In addition, there is the for vascular dementia cannot be used to describe it or to vali- aforementioned association between atrophy and vascular cog- date the criteria. For example, an analysis of case series meeting nitive impairment.13 Atrophy may, therefore, be associated with current criteria for vascular dementia should reveal memory both vascular disease and degenerative dementia, rather than loss in all cases. This may be taken as showing memory loss to just being a hallmark of degenerative dementia as previously be universal in vascular dementia. This is so only because it is supposed, and is similar in these various processes.20 defined that way. If the criteria are wrong, so is case identifica- Although early reports on the effects of leukoaraiosis on tion. A better source of information may be to look at the cog- cognition were mixed, there is now clear evidence that nitive changes seen in stroke in general without any selection leukoaraiosis is associated with both cognitive impairment and by artificial, and probably incorrect, criteria. Such series are focal signs in otherwise normal individuals.21-24 Even in early few but increasing in number. vascular cognitive impairment, there is a weak association The studies to date identify a variety of patterns of cogni- between leukoaraiosis and cognitive loss. Indeed, leukoaraiosis tive loss; the differing patterns often depending on case selec- may be the earliest correlate of cognitive symptoms.25 tion. The predominating theme, however, is of a primary sub- Functional imaging (diffusion tensor MRI) shows abnormali- cortical dementia with early impairment of frontal lobe func- ties of diffusivity in normal-appearing white matter in patients tion.8 Memory is involved but is often not pre-eminent.9-11 with leukoaraiosis, and diffusivity correlates better with cogni- Although the cases reported in these studies may not all meet tion than with simple lesion load.17 the currently proposed criteria for vascular dementia, the pat- Leukoaraiosis is etiologically associated with hypertension terns of cognitive loss reported may be more appropriate to the and a history of stroke, suggesting a vascular cause. It is not

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Vascular Dementia

associated with carotid disease. Episodic hypotension occurring through transient dysrhythmias, nocturnal hypotension or carotid sinus hypersensitivity superimposed on a background of diminished vascular reserve may be one group of etiological Table 1. The Ischemic Scale mechanisms for both leukoaraiosis and incomplete infarction. Scores that are higher than 7 suggest a vascular etiology for Data concerning hypotension as a risk factor for vascular dementia, whereas scores of 4 or less do not support a vascu- dementia remain contradictory.26-27 lar etiology. The term leukoaraiosis encompasses a range of . The term was originally used in the context of CT white mat- Feature Value ter changes, but it is also used to refer to white matter changes Abrupt onset ___ 2 on MRI. However, it encompasses a wide range of structural Stepwise deterioration ___ 1 changes ranging from increased water content without func- Fluctuating course ___ 2 tional loss through to axon or myelin loss and these all appear Nocturnal confusion ___ 1 similar or identical on MRI. This is a reason for the relatively Relative preservation of personality ___ 1 poor correlation between leukoaraiosis and cognition. Depression ___ 1 Infarct volume is also a factor, but because of the impor- Somatic complaints ___ 1 tance of location, it is not the sole determinant. There has been debate over the minimum volume of infarction needed to pro- Emotional incontinence ___ 1 duce dementia, but this is a matter of limited significance given History or presence of hypertension ___ 1 the importance of infarct location. It is unlikely that there History of strokes ___ 2 exists a precise volume of infarction that can reliably predict Evidence of associated ___ 1 vascular dementia other than at meaninglessly large volumes. Focal neurologic symptoms ___ 2 Within any one location, the correlation between infarct vol- Focal neurologic signs ___ 2 ume and cognition improves as would be expected as the effect TOTAL SCORE ___ of location is minimized. Infarcts located at sites such as the thalamus can be crucial. However, the most important locations outside these strategic lesions, but as the number of lesions increases, this scope locations are a matter of dispute, partly because of the applica- decreases, the consequences of each successive lesion thus in- tion of variable methods to differing populations. Evidence has creasing. variously favored bilateral, left-sided, thalamic, anterior cere- Neural nets also give clues to the probable order of cogni- bral artery territory and frontal lesions. Various patterns impor- tive decline produced by multiple lesions that would initially tant in producing dementia have also been suggested: thalamic affect the systems most dependent on complex neural nets. plus cortical, cortical and white matter, and dominant hemi- This partly explains why the frontal involvement is one of the sphere. Some work favors a special role for lacunar and other most prominent and why there may be frontal lobe deficits deep lesions over cortical lesions, but other work does not. even when there is no damage within recognized frontal lobe These contradictory findings will not be resolved until uniform connections. Memory, which also depends on an extensive criteria for patient selection and cognitive assessment have been neural net, may also be affected relatively early but not most developed. prominently. However, this would not hold true in cases where Lesions interact synergistically, and the study of neural nets the basis of the vascular dementia was not multiple small in cognition provides some clues as to why this may be. In a lesions, and the pattern of cognitive loss would be much more neural net, loss of one set of connections can initially be cir- closely linked to the precise site of the lesion. cumvented by the use of other circuits, which may be slower Even so, patients with right-sided lesions exhibit impair- and less efficient but may improve with use (learning). Thus, ment in verbal IQ and patients with left-sided lesions exhibit initial ischemic damage, particularly in the white matter, may impairment in performance IQ. This clearly shows the impor- not leave detectable deficits. However, the scope for recovery tance of generalized cognitive processing, presumably based on after further lesions decreases, and lesions late in the disease neural nets, as opposed to the more traditional localization of process may cause disproportionate damage because their loss function. Intuitively, sequential deficits closely spaced in time removes both their normal functions and the additional func- should leave a more severe deficit than the same lesions spaced tions acquired as part of the recovery process after earlier far enough apart for complete recovery between lesions, but events. Therefore, neural nets provide scope for recovery after this hypothesis remains untested.

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Vascular Dementia

Prevention There is little consistent information regarding risk factors. It is not clear whether the risk factors for vascular dementia are What Causes the same as those for stroke, as VaD may be more often due to small vessel disease than stroke in general. Although hyperten- Vascular Dementia? sion is certainly a powerful risk factor for vascular dementia, whether it is a disproportionate risk factor remains unproven. Subcortical vascular dementia is becoming increasingly recog- Recent data from the PROGRESS and Systolic Hypertension nized as the most common single variant of vascular demen- in Europe studies do, however, show that reduction of blood tia, accounting for perhaps 40 percent of cases. Infarcts con- pressure protects against dementia in general.28-29 tribute to most cases of vascular dementia, but multiple A number of large, long-term studies have reported that smaller infarcts and small vessel disease are more often a sub- modifying vascular risk factors reduces incident cognitive strate of vascular dementia than single major infarcts. impairment and dementia. In updated results from the Syst- In vascular dementia, cognitive decline may begin with 30 Eur study, a reduction of 7mm Hg in systolic and 3.2mm Hg the presence of risk factors alone, especially hypertension and in diastolic blood pressure over 3.9 years cut in half incident presumably the damage at this stage is at a microscopic level. dementia. The absolute figures are a little less impressive at Leukoaraiosis, hemorrhages, amyloid angiopathy, vasculi- three cases per 100 patient years. A variety of other risk factors tides, angioendotheliosis and incomplete infarction are less have been identified (with varying degrees of clinical impact) in various studies, including hypertension, heart disease, dia- common etiological factors. Incomplete infarction comprises betes, hyperlipidemia, smoking, carotid bruits, age, male sex, zones of partial neuronal or axonal loss with demyelination, education, race, prior stroke, ECG changes, hematocrit, histo- increased perivascular spaces, reactive astrocytosis, gliosis, and ry of myocardial infarction, carotid atherosclerosis, low-densi- sparse macrophages. Silent infarcts also contribute to cognitive ty lipoprotein cholesterol, isolated systolic hypertension and decline. Ischemic hippocampal sclerosis may account for a sig- proteinuria. There is clearly much overlap with stroke. Evi- nificant proportion of cases. Environmental factors, rather dence that modification of many of these risk factors protects than hereditary factors, seem to play a major role in vascular against vascular dementia is lacking, but it is reasonable to do dementia as distinct from Alzheimer’s disease. so on first principles. There is now clear evidence that atrial fibrillation is a risk factor.31-32 This association is curious given the usual association individuals aged 70 to 82 years was unable to demonstrate any of atrial fibrillation with large infarcts. The suggested mecha- benefit on stroke, cognition or activities of daily living, but the nism is by silent infarction; however, dysrhythmias producing study did show a benefit on myocardial infarction and TIA.35 hypotension and incomplete infarction cannot be ruled out. Given the established benefits of the statins in preventing The truth of the matter, as yet unknown, is important as it adverse vascular events, the discrepancy between these and would affect the most appropriate management. Orthostatic antihypertensive therapy requires some explanation. The dis- hypotension may also play a role, but nocturnal dipping of crepancy may lie in the fact that subcortical vascular dementia blood pressure may not. is the single most common form of vascular dementia and that Vascular risk factors in middle age, particularly hyperten- hypertension is, by a considerable margin, the most powerful sion, may predict cognitive loss in later life—even when the treatable risk factor. Cholesterol has little association with risk factors themselves have resolved—and may also accelerate small-vessel disease and the plaque-stabilizing antioxidant, and the appearance of Alzheimer’s disease in later life.33-34 Putative other properties attributed to the statins may not be relevant to nonvascular risk factors include high alcohol consumption, lipohyalinosis or to small-vessel disease. Taking these observa- psychological stress in early life, use of (presumably a tions together, it is readily possible to see why different treat- vascular marker), low education, blue collar occupation, occu- ments may have differing effects. pational exposure to a pesticides, herbicides, liquid plastic or Aspirin has been proposed on the basis of a pilot study done rubber, and premorbid personalities that make subjects more without placebo.36 Other nonsteroidal analgesics do not protect liable to stress or psychosomatic reactions. Most of these re- against vascular dementia.37 The PROGRESS study did not quire confirmation and quantification. confirm a “window” effect, but it did provide evidence for the There are now increasing data on drugs as preventive efficacy of treating hypertension in the secondary prevention of agents. Interestingly, evidence that the statins protect against dementia after stroke or transient ischemic attack.38 Primary cognitive loss is relatively weak. The PROSPER study of 6,000 prevention by control of blood pressure seems to make little

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difference,39 but importantly, the Honolulu-Asia aging study and to exclude structural causes. Although MRI will better show has reported that treatment of midlife hypertension can reduce leukoaraiosis and may be essential if certain conditions such as the risk of subsequent dementia.19,28 CADASIL are suspected, CT is sufficient in routine clinical Although a subject of much debate, the consumption of practice. The presence of white matter lesions on CT (but not on antioxidant vitamins in midlife may also protect against vascu- MRI) may help to distinguish vascular dementia from lar dementia.40 Alzheimer’s disease. Cortical sulcal atrophy and ventricular enlargement are more severe in patients with multiple infarcts Differential Diagnosis and dementia than in those with multiple infarcts without The principal differential diagnoses are Alzheimer’s disease and dementia, but there is no evidence to suggest that this is suffi- depression following stroke. In 90 percent of cases where mul- ciently discriminating to be a useful part of the evaluation. tiple infarcts are responsible, there is also a history of stroke or The vascular component of the investigations should be of transient ischemic attacks. directed by clinical suspicion. Not all However, in cases where subcortical Infarcts located at sites such as investigations are routinely required. ischemic change is the vascular mech- the thalamus can be crucial. However, a complete blood count, anism, a history of stroke may be erythrocyte sedimentation rate, glu- absent in up to 40 percent, and focal However, the most important cose, and ECG should be done. signs are also less common.41 The use Where appropriate, carotid duplex of the ischemic scale score (see Table locations outside these strategic Doppler, chest X-ray, echocardiogra- 1) has 89 percent sensitivity and speci- locations are a matter of dispute. phy, Holter monitoring, thrombophil- ficity. However, distinguishing mixed ia screen, lipid profile, lupus anticoag- dementia and either vascular dementia Evidence has variously favored ulant, anticardiolipin antibodies, and or Alzheimer’s disease remains diffi- 17 bilateral, left-sided, autoantibody screen are justifiable. A cult, with poor specificity. The use of I glycosylated hemoglobin may detect CT to identify infarcts increases diag- N thalamic, anterior unsuspected diabetes. Cerebral angio- nostic accuracy. cerebral artery graphy is indicated if carotid surgery is Compounding the difficulty of F considered or to demonstrate beading identifying vascular dementia is its territory and frontal of the smaller cerebral vessels if a cere- common coexistence with Alzheimer’s A bral vasculitis is suspected, but it is not disease and the important effect of lesions. a routine investigation and may in any cerebrovascular disease to hasten the R case miss an active vasculitis. CSF clinical manifestation of Alzheimer’s 22 examination may be required if an in what are, in effect, mixed cases even L O C A T I o N infectious or inflammatory etiology is though there may be no specific histo- suspected as, in rare cases, may be ry of stroke and the vascular disease T dural or brain biopsy. may amount to only microinfarcts. Furthermore, many previous studies concerning the diagnosis Prognosis and Complications of Alzheimer’s have dismissed small volumes of ischemic dam- The prognosis of vascular dementia varies considerably accord- age. In view of the interaction between cerebrovascular disease ing to the criteria used to make the diagnosis.42 Multi-infarct and Alzheimer’s disease, this now seems highly inappropriate, dementia shortens life expectancy to about 50 percent of nor- and about one-quarter of cases of clinically diagnosed “pure” mal at four years from initial evaluation.43-44 Females, people Alzheimer’s disease will have some vascular component.4 with higher education, and those who perform well on some Of at least equal importance to the identification of VaD neuropsychological tests do better. In the elderly, three-year itself is identification of the cause of the vascular events, since mortality may reach two-thirds, almost three times that of con- the treatment and prognosis depend on the cause. The remain- trols.45 In one study, the six-year survival was only 11.9 percent, der of the differential diagnosis is that of dementia. about one-quarter of that expected,46 although many of these patients were elderly and severely demented at entry. Diagnostic Workup About a third die from complications of the dementia itself, Dementia can be established by the clinical history and exami- one-third from cerebrovascular disease, eight percent from nation alone, including an assessment for depression. Imaging is other cardiovascular disease, and the rest from miscellaneous required to confirm the occurrence of cerebrovascular disease causes, including malignancy.46 Overall, the effect of vascular

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How Common is Vascular Dementia? The incidence of vascular dementia is about 3.8 per 1000 annually, with males more commonly affected than females. Dementia from all causes has a prevalence of about eight percent of the population over age 65. Between nine and 39 percent (typically 13 to 19 percent) of these cases are vascular.68,69 An additional 11 to 43 percent of cases may be mixed dementia.70 Although the propor- tion of cases due to vascular dementia falls with increasing age, the prevalence of all dementia rises so rapidly with age that the prevalence of vascular dementia also rises, from zero to two percent in the 60 to 69 year-old age group to up to 16 percent for males aged 80 to 89 years, although more typical figures are between three and six percent.68,71 Dementia after stroke is now increasingly recognized. Initial studies suggested that 30 percent of all stroke patients were dement- ed three months after stroke; however, in the Framingham study the 10-year risk of post-stroke dementia was rather lower at 19.3 percent of cases (compared to 11 percent of controls).72 However, the study methodology may have produced an underestimation.73 Even in those without prior dementia, post-stroke dementia correlates with pre-stroke cognitive status, suggesting pre-existing (most likely vascular) in at least some cases. Blacks may be at greater risk of post-stroke dementia than whites. The risk of dementia after stroke increases with age, from 14.8 percent in those aged 60 to 69 years to 52.3 percent for those over 80 years of age, but 36.4 percent of these had mixed dementia.74-79 The incidence of cognitive impairment after stroke suffi- cient to adversely affect outcome but not meeting current criteria for vascular dementia is as high as 35.2 percent, compared to just 3.8 percent with a similar degree of impairment in stroke-free controls.76 dementia on mortality is similar to, or mildly worse than, that competency, and advance directives. of Alzheimer’s disease. However, some allowance has to be A few drug trials have been completed. There is some evi- made for the criteria used to define vascular dementia in each dence for nimodipine in subcortical vascular dementia.49-50 case, and in the worst case, the mortality is almost twice that of Memantine may help in dementia in general (including mixed the best.42 disease), may reduce the burden on caregivers,51 and offers In one study, cognitive impairment short of dementia (i.e., some benefit in vascular dementia alone without major side vascular cognitive impairment) increased the likelihood of sub- effects.52-54 Propentofylline may improve cognitive function on sequent dementia from eight to 42 percent after nine years of formal testing but does not seem to affect activities of daily liv- follow-up.47 In the Canadian Study of Health and Aging, ap- ing.55-58 Some evidence exists for vincamine,59 vinpocetine,60 proximately half of subjects were dead and half institutional- pentoxifylline61-62 and posatirelin.63 As yet, though, there is no ized after five years. However, in 16 percent there was no cog- convincing evidence for any single drug, and none of these can nitive decline and even some cases of improvement, reflecting be recommended. the diversity of potential outcomes in this condition.48 The acetylcholinesterase inhibitors may be more helpful. Data from three trials have now been published, encompassing Management a variety of probable and possible vascular dementia cases as The treatment of vascular dementia is that of the underlying well as mixed dementia. These show statistically significant, cause. Care must be taken to identify and treat depression, but modest, benefits for galantamine and donepezil over place- which is common both in association with dementia and after bo in both cognition and activities of daily living.64-66 However, stroke. If there is any doubt, a course of treatment with antide- it is possible that these benefits are merely due to the drugs’ pressant medication is usually justifiable. effect on coexistent Alzheimer’s disease67 or the effect may be Begin treatment of hypertension cautiously. Chronically hy- non-specific. PN pertensive patients shift the autoregulatory range for cerebral blood flow to accommodate higher perfusion pressures. Even Adapted from Medlink Neurology™ (www.medlink.com) with per- with treatment, this will not fully return to normal. They are, mission. thus, susceptible to hypotension, which is a suspected mecha- John V. Bowler, MD is a Consultant Neurologist at Royal Free Hospital's nism for vascular dementia. Measures of general application to Department of Neurology in . dementia of all kinds are also appropriate, including referral to Vladimir Hachinski, MD Professor of Neurology at the University of community services and local support groups, consideration of Western Ontario. caregiver stress, and legal and ethical issues such as driving,

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