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Review

Vascular dementia: diagnosis, management and possible prevention

There has been a recent upsurge of interest in the clinical features of and risk factors for vascular dementia, and consensus is emerging on its diagnostic characteristics. We discuss these features and risk factors and the main intervention strategies, both for treatment and prevention.

Perminder S Sachdev, Henry Brodaty and Jeffrey C L Looi

MJA 1999; 170: 81-85

Introduction - Definition - Epidemiology - Clinical-pathological correlates and pathogenesis - Clinical features and diagnosis - Prognosis - Prevention and treatment - Acknowledgements - References - Authors' details
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Introduction Developments in the past three decades have led to a radical rethinking of the association between cerebrovascular disease (CVD) and dementia, and set the stage for a reconceptualisation of dementia from vascular causes. We will review recent developments in the concept of vascular dementia (VaD), and discuss its importance as a common, and potentially preventable, form of dementia.

Definition There are two obvious steps in the diagnosis of VaD -- diagnosis of dementia per se and establishment of its vascular aetiology. Dementia is defined as a multifaceted decline in cognitive functioning causing impaired functioning in daily life.1,2 Impairment of memory is generally regarded as a necessary aspect, but decline in one or more other cognitive domains (ie, language, praxis, gnosis, visuoconstructive function, frontal-executive functions) must also be demonstrated.1,2 VaD is diagnosed if significant CVD is present and is judged to be causally relevant to the cognitive impairment.1-4

What constitutes significant vascular aetiology is not always easy to establish. Minor cerebrovascular pathology is common in healthy elderly people5 and in association with other dementias, notably Alzheimer's disease (AD).6 Recent studies using magnetic resonance imaging (MRI) of the brain have reported periventricular hyperintensities on T2-weighted images, arguably vascular in origin, in up to 93% of healthy elderly individuals,5 so guidelines for determining the significance of cerebral vascular lesions are needed. An early approach was to base the diagnosis on the score obtained on an ischaemia scale,7 which comprises a list of historical and clinical examination items known to discriminate multi-infarct dementia (MID) from AD. On a 13-item scale (maximum score 18), a score of seven or more suggested MID and four or less suggested AD.7 This approach has limitations as it is based on a concept that VaD is caused by multiple strokes (hence, MID), now recognised to be only one vascular pathway to dementia. In addition, it uses only some of the relevant clinical information, and it excludes neuroimaging from consideration.

More recent efforts have attempted to address these deficiencies. According to the NINDS-AIREN criteria (developed at an international workshop involving 54 neurologists and neuroscientists),4 a diagnosis of probable VaD is made if dementia is associated with focal neurological signs and imaging evidence of CVD is present. On computed tomography (CT) or MRI this could comprise multiple or strategic single infarcts, multiple lacunae, extensive white matter lesions (WMLs), or combinations of these. Like other dementias, VaD requires histopathological confirmation and is a postmortem diagnosis.

Some investigators have argued that the emphasis on dementia in patients with CVD may be inappropriate for several reasons: (i) the diagnosis of dementia is contentious in many patients because a qualitative judgement is involved; (ii) it imposes a categorical distinction on the continuous construct of cognitive impairment; and (iii) it is important to recognise cognitive impairment before it has reached the stage of dementia, especially if prevention strategies are to be introduced. Thus, the term "vascular cognitive impairment" has been proposed, in which "vascular" refers to all causes of ischaemic CVD, and "cognitive impairment" encompasses all levels of cognitive decline, which may fall well short of dementia.8

Epidemiology Prevalences of VaD have varied across studies because of methodological differences, but point to VaD being the second most common dementia after AD in Western societies. A quantitative integration of studies published between 1945 and 1985 suggested an overall prevalence of dementia of 5.6% in people older than 60 years.9 AD was more prevalent than MID by a relative factor of 1.05 to 1.43 in Western societies. VaD had an increasing prevalence with age (a doubling every 5.3 years). It also found an excess of VaD in men, and a cross-national effect, with AD being more common in Western countries and VaD being much more common in Japan, China and Russia.9 A Swedish study estimated the lifetime risk of VaD as 34.5% for men and 19.4% for women.10 In community-based studies, the incidence of VaD has ranged from 0.17 to 0.71 per 100 person-years.10,11 In a sample of hospitalised ischaemic stroke patients, the incidence of VaD was estimated to be 8.4 per 100 person-years.12 Dementia was diagnosed in 26.3% and 31.8% of patients, respectively, in two studies at three months after an acute stroke.12,13

Risk factors for VaD (summarised in Box 1) are incompletely understood.14 As stroke is a major determinant of VaD, it is reasonable to expect that risk factors for stroke would also increase the risk of VaD.

While hypertension increases the risk of VaD, high systolic blood pressure may serve a protective role once dementia has set in.15 In one study, although subjects with VaD were more likely to have been hypertensive in the past, they currently had lower blood pressure values and more orthostatic hypotension than stroke patients without dementia.13

Genetic factors for CVD, and consequently VaD, are not well understood. Exceptions are rare disorders such as cerebral autosomal dominant arteriopathy with subcortical infarct and leukoencephalopathy (CADASIL) and autosomal dominant hereditary cerebral haemorrhage with amyloidosis -- Dutch type. The role of apolipoprotein E polymorphism in VaD is unclear; there is conflicting evidence for a link with the e4 allele.14

Not all stroke patients develop dementia, suggesting the nature and extent of strokes and their interaction with host factors are important. Left hemisphere strokes are more likely to produce severe cognitive impairment, and the infarction of certain strategic areas may be crucial (eg, deep frontal white matter, dominant thalamus and angular gyrus).12,13 VaD may occur in the absence of strokes, and this is usually associated with periventricular WMLs or lacunae and silent infarcts.4


Clinical-pathological correlates and pathogenesis
Brain parenchymal lesions of vascular origin may be produced through ischaemia, haemorrhage or oedema. VaD may therefore be caused by multiple mechanisms, individually or in combination (Box 2). The resulting neuropathology will vary according to the dominant mechanisms and will comprise combinations of multiple large infarcts, single strategic infarcts, lacunae and WMLs. Multiple large infarcts may result in summative damage to widespread regions causing a heterogeneous pattern of deficits, overwhelming compensatory mechanisms. Single infarcts, when strategically placed and large, may affect a critical cortical or subcortical region to disrupt multiple cognitive functions. Lacunae (or lacunar infarcts) are small cavities, up to 1.5 cm in diameter, that usually occur in the basal ganglia, thalamus, pons, internal capsule and deep white matter areas irrigated by the superficial and deep penetrating arteries and arterioles. WMLs are commonly seen on CT and especially on T2-weighted MRI. As they are present in otherwise healthy elderly individuals, their pathological significance has been greatly debated.5 When their severity was considered, periventricular WMLs were reported in VaD to be 11.6 times greater than in AD and 3.5 times greater than in healthy people, and subcortical WMLs were 2.6 and 13.5 times greater, respectively.16 A threshold effect has been suggested, with cognitive impairment resulting when WMLs reach a certain severity. WMLs must nevertheless be distinguished from Binswanger's disease,17 a rare clinicopathological entity characterised by slowly progressive dementia, usually beginning in the fifth or sixth decade, and associated with hypertension, psychiatric features, gait disturbance, parkinsonism, corticobulbar features and incontinence.

The vascular pathology in VaD is varied; atherosclerosis, arteriosclerosis, lipohyalinosis, amyloid angiopathy, senile arteriolar sclerosis and other angiopathies have been described.4 Systemic causes of thromboembolism are important in some cases: inflammatory diseases (eg, systemic lupus erythematosus, polyarteritis nodosa, sarcoidosis), hyperviscosity syndromes (eg, polycythaemia vera, sickle cell anaemia) and embolic disorders (eg, atrial fibrillation, myocardial infarction with mural thrombus, congenital heart disease, as well as septic, air or fat emboli). VaD and Alzheimer-type changes not uncommonly co-occur, and 10%-20% of patients with dementia are classified clinically and pathologically as having both AD and VaD. VaD is known to promote the clinical expression of AD;6 the relationship between these two dementias needs further study.


Clinical features and diagnosis
The onset of VaD is often sudden, with a transient ischaemic attack (TIA) or a stroke, after which the clinical course may be static, remitting or progressive, often with a fluctuating or stepwise deterioration. Predominantly subcortical lesions may produce cognitive impairment of gradual onset and slow progression. Other features that distinguish VaD from AD are nocturnal confusion and wandering, relative preservation of emotional responsiveness and personality until the later stages of the disease, and the presence of depression, emotional lability, incontinence and somatic symptoms.4 A history of risk factors for CVD should alert the clinician to the possibility of VaD, and the presence of focal neurological symptoms (such as visual disturbances, brainstem abnormalities, sensory or motor symptoms) and signs (hemiparesis, visual field defects, pseudobulbar palsy, extrapyramidal signs) will provide further support.

The cognitive deficits in VaD are multifocal and therefore more varied than generally seen in AD. Memory deficit may not be as marked; discrepancies between verbal and non-verbal memory performance are often notable. Other common elements are visuospatial dysfunction, dysphasia, cognitive slowing and impairment of executive function.4 Impairment in frontal lobe functioning is usually more severe for VaD than AD. Language impairment in patients with left hemispheric strokes may impede the assessment of abnormalities in other cognitive domains.

Assessment of a patient with possible VaD should include establishment of the diagnosis of dementia; documentation of evidence for CVD; determination of the aetiological role of CVD; evaluation of functional status of the individual and his or her disability, and the interpersonal and community supports available; and determination of risk and protective factors that could be modified (Box 3). Absence of vascular lesions on CT and, in particular, MRI is strong evidence against vascular aetiology. As CVD is commonly present in otherwise healthy individuals, guidelines are available for the topography and severity of lesions to be considered significant.4 At least a quarter of all white matter would need to be involved for the lesions to be clearly significant (Figure).

Prognosis While not totally consistent, longitudinal studies of VaD suggest mortality rates greater than for AD and rates of admission to nursing homes comparable in the two. One study reported a five-year mortality rate of 63.6% (compared with 31.8% for AD) and a nursing home admission rate of 31.8% (compared with 20.6% for AD).19 Cognitive impairment in patients with stroke has adverse functional consequences, independent of any physical impairments. The prognosis may be improved by better treatment and preventive strategies.


Prevention and treatment
The management of risk factors for VaD offers the opportunity to reduce its incidence significantly, or, if dementia has already been diagnosed, halt its progression and sometimes achieve partial improvement. Some strategies for primary prevention of VaD are listed in Box 4. One of the more established interventions is control of hypertension. Treatment of patients with diastolic blood pressure (BP) greater than 110 mmHg is universally accepted, and there is evidence that treatment of those with diastolic BP of 90-110 mmHg and systolic BP greater than 160 mmHg is beneficial.20 While antihypertensive drugs are often indicated, lifestyle changes which lower BP are advisable at all levels of BP. In controlling hypertension, avoidance of hypotension is strongly advocated, as poor autoregulation in VaD patients increases its deleterious effects on cerebral blood flow. The control of risk factors such as hyperlipidaemia and diabetes mellitus may also have a stabilising effect, although evidence is lacking.21 Other modifiable factors include cigarette smoking, excessive alcohol consumption, obesity, and lack of exercise.

Non-atherogenic risk factors that may be modifiable include atrial fibrillation and carotid artery stenosis. Warfarin is clearly beneficial in reducing the risk of stroke in patients with atrial fibrillation, with aspirin being less effective.22 In those with a past TIA or non-haemorrhagic stroke, antiplatelet therapy is helpful in reducing the risk of further such events. The optimal dose of aspirin to be used is not known, and doses between 75 mg and 325 mg are recommended.22 For those "failing" aspirin therapy, other antiplatelet agents, such as ticlopidine, may be indicated. Current evidence is insufficient to recommend aspirin for the primary prevention of stroke and VaD in low-risk individuals; there may be a slight increase in the risk of haemorrhagic stroke with such treatment.23 In stroke or TIA patients with a severe carotid artery stenosis (> 70% occlusion), carotid endarterectomy is an effective procedure. The role of such surgery in the presence of moderate stenosis or for asymptomatic individuals is uncertain.23

Many drugs have been investigated for treating VaD, but with limited success, and no drug can be positively recommended at present. Vasodilators (eg, hydergine [co-dergocrine mesylate; Sandoz], other alkaloids and cyclandelate) have some positive effects, and modest gains in cognition have been reported with an orally active haemorheological agent (pentoxifylline).22 A related drug, propentofylline, may exert an additional neuroprotective effect and has shown some promise in clinical trials.24 Other drugs that have been tried include the vinca alkaloids, calcium channel antagonists, nootropics, and extracts of Ginkgo biloba, with no convincing successes.25 Some of the drugs that improve memory in some AD patients (eg, cholinergic drugs such as tacrine and donepezil) may find a role in VaD. Other drugs may serve a neuroprotective role (eg, propentofylline, calcium channel antagonists and N-methyl-D-aspartate receptor antagonists).

The mainstay of treatment is preventive and supportive. Supportive measures should include rigorous treatment of psychiatric complications such as depression, measures to facilitate independence, community or institutional care, and support for the carer. Specific neuropsychological rehabilitative measures may have a role in particular cases. Self-help groups such as the Alzheimer's (and Related Disorders) Association and the Stroke Society play an important supportive and educational role.


Acknowledgements
The assistance of Barbara Brierley and Agata Wachala in literature search is gratefully acknowledged.

References
  1. World Health Organization. The ICD-10 classification of mental and behavioural disorders. Diagnostic criteria for research. Geneva: World Health Organization, 1993.
  2. American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 4th ed. Washington DC: American Psychiatric Association, 1994.
  3. Chui HC, Victoroff JI, Margolin MD, et al. Criteria for the diagnosis of ischemic vascular dementia proposed by the State of California Alzheimer's Disease Diagnostic and Treatment Centers. Neurology 1992; 42: 473-480.
  4. Roman GC, Tatemichi TK, Erkinjuntti T, et al. Vascular dementia: diagnostic criteria for research studies. Report of the NINDS-AIREN international workshop. Neurology 1993; 43: 250-260.
  5. Kertesz A, Black SE, Tokar G, et al. Periventricular and subcortical hyperintensities on magnetic resonance imaging. "Rims, caps and unidentified bright objects." Arch Neurol 1988; 45: 404-408.
  6. Snowdon DA, Greiner LH, Mortimer JA, et al. Brain infarction and the clinical expression of Alzheimer disease: the nun study. JAMA 1997; 277: 813-817.
  7. Hachinski VC, Iliff LD, Zilkha E, et al. Cerebral blood flow in dementia. Arch Neurol 1975; 32: 632-637.
  8. Hachinski VC, Bowler JV. Vascular dementia. Neurology 1993; 43: 2159-2160.
  9. Jorm AF, Korten AE, Henderson AS. The prevalence of dementia: a quantitative integration of the literature. Acta Psychiatr Scand 1987; 76: 465-479.
  10. Hagnell O, Franck A, Grasbeck A, et al. Vascular dementia in the Lundby study: 1. A prospective, epidemiological study of incidence and risk from 1957-1972. Neuropsychobiology 1992; 26: 43-49.
  11. Schoenberg BS, Kokmen E, Okazaki H. Alzheimer's disease and other dementing illnesses in a defined United States population: incidence rates and clinical features. Ann Neurol 1987; 22: 724-729.
  12. Tatemichi TK, Paik M, Bagiella E, et al. Risk of dementia in a hospitalized cohort: results of a longitudinal study. Neurology 1994; 44: 1885-1892.
  13. Pohjasvaara T, Erkinjuntti T, Ylikoski R, et al. Clinical determinants of poststroke dementia. Stroke 1998; 29: 75-81.
  14. Gorelick PB. Status of risk factors for dementia associated with stroke. Stroke 1997; 28: 459-463.
  15. Gorelick PB, Brody JA, Cohen DC, et al. Risk factors for dementia associated with multiple cerebral infarcts: a case-control analysis in predominantly African-American hospital-based patients. Arch Neurol 1993; 50: 714-720.
  16. Boone BK, Miller BL, Lesser IM, et al. Neuropathological correlates of white matter lesions in healthy elderly subjects: a threshold effect. Arch Neurol 1992; 49: 546-554.
  17. Binswanger O. Die abgrenzung der allgemeined progressiven paralyse, I-III. Berl Klin Wochenschr 1884; 48: 1103-1105, 1137-1139, 1180-1186.
  18. Folstein M, Folstein S, McHugh PR. Mini-Mental State: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975; 12: 189-198.
  19. Brodaty H, McGilchrist C, Harris L, Peters KE. Time until institutionalization and death in patients with dementia: role of caregiver training and risk factors. Arch Neurol 1993; 50: 643-650.
  20. Lawrence M, Cruickshank K. Hypertension. In: Lawrence M, Neil A, Mant D, Fowler G, editors. Prevention of cardiovascular disease. Oxford: Oxford University Press, 1996; 18-34.
  21. Atkins D, Psaty BM, Koepsell TD, et al. Cholesterol reduction and the risk for stroke in men: a meta-analysis of randomized controlled trials. Ann Intern Med 1993; 119: 136-145.
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  23. Mant J. Prevention of stroke. In: Lawrence M, Neil A, Mant D, Fowler G, editors. Prevention of cardiovascular disease. Oxford: Oxford University Press, 1996; 162-174.
  24. Marcusson J, and European Propentofylline Study Group. HWA 285 for the treatment of dementia: results of a 12 months clinical trial. J Cerebr Blood Flow Metab 1995; 15 Suppl 1: S107.
  25. Wong AHC, Smith M, Boon HS. Herbal remedies in psychiatric practice [review]. Arch Gen Psychiatry 1998; 55: 1033-1044.

(Received 21 Apr, accepted 30 Jul, 1998)

Authors' details School of Psychiatry, University of New South Wales, NSW.
Perminder S Sachdev, MD, PhD, Professor of Neuropsychiatry, and Neuropsychiatric Institute, The Prince Henry Hospital, NSW;
Henry Brodaty, MD, FRANZCP, Professor of Psychogeriatrics, and Academic Department of Psychogeriatrics, The Prince Henry Hospital, NSW.

Neuropsychiatric Institute, The Prince Henry Hospital, NSW.
Jeffrey C L Looi, MB BS, NSW Institute of Psychiatry Fellow.

Reprints will not be available from the authors.
Correspondence: Dr P S Sachdev, NPI, The Prince Henry Hospital, Little Bay, NSW 2036.
Email: P.SachdevATunsw.edu.au

©MJA 1999
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Two magnetic resonance imaging proton-density transaxial cuts from the brain of a hypertensive patient with vascular dementia. Note extensive involvement of white matter, which appears as hyperintense signals. The patient's computed tomography brain scan showed minor periventricular hypodensity.
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1: Risk factors for vascular dementia

Sociodemographic
AgeIncreasing incidence with age, especially after 60 years
Race/ethnicHigher rates in Asian and black populations15
SexHigher rates in men
EducationMay have a protective effect12-15
Atherogenic12-15
HypertensionMajor risk factor
Coronary artery disease Increases stroke risk
Diabetes mellitusRisk factor for stroke
Cigarette smokingRisk factor for stroke
HypercholesterolaemiaRisk factor for stroke
Fibrinogen, obesityEvidence lacking
Other cardiovascular
Atrial fibrillationRisk of cerebral embolism
Mitral valve prolapseCerebral embolism
Peripheral vascular disease Inconsistent evidence
Other factors
GeneticWeak; CADASIL an exception
Apolipoprotein E polymorphism Evidence inconsistent
Anticardiolipin antibodies Evidence inconsistent
AlcoholismEvidence inconsistent
Stroke-related
Number, volume, location of stroke12,13
Strategic silent infarcts
Pre-existent atrophy
Presence of abnormal periventricular signal on magnetic
  resonance imaging, or (especially) on computed
  tomography
CADASIL = cerebral autosomal dominant arteriopathy with subcortical infarct and leukoencephalopathy
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2: Pathogenetic mechanisms of vascular dementia

I.Infarct (single or multiple)
A. Arterial territory infarct
  • Multiple infarcts
  • Single strategic infarcts

B. Watershed infarction
C. Lacunar infarction

II.Non-infarction ischaemia
A. Subcortical leukoencephalopathy (Binswanger's)
B. Laminar necrosis
C. Granular atrophy
D. Gliosis or sclerosis

III.Haemorrhage
A. Subdural
B. Subarachnoid
C. Intracerebral
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3: Clinical assessment for vascular dementia

History should include onset, course and nature of cognitive deficits, and information from the carer or other person close to the patient on subtle personality and behavioural changes that may have been noticed.

Full neuropsychological evaluation is required at some stage, although the Mini-Mental State Examination,18 supplemented by clock-drawing and clinical assessment of frontal lobe functioning, may be useful for screening.

Assessment of functional losses. This may be aided by administration of scales for activities of daily living and instrumental activities of daily living, and assessment at home by an occupational therapist.

Psychiatric evaluation is important, as depressive disorder is common in patients with cerebrovascular disease and depression may produce a syndrome resembling dementia. Anxiety disorders and psychotic symptoms may also occur in people with vascular dementia.

General physical examination, including pulse irregularity, cardiovascular status, carotid bruits, fundus examination, peripheral vascular disease and hypertension (multiple blood pressure measurements).

Examination for focal neurological signs, in particular gait abnormality, visual field defects, pseudobulbar palsy (dysarthria, dysphagia, spastic tongue, brisk jaw jerk), brisk reflexes, extensor-plantar responses and spasticity in the limbs.

Routine investigations, including full blood count, erythrocyte sedimentation rate, blood glucose, serum cholesterol and triglyceride level, syphilis serology, electrocardiogram, and chest x-ray. Investigations are directed towards providing evidence for CVD and its risk factors.

Structural brain imaging (computed tomography or magnetic resonance imaging) is essential to provide information on the extent, type and distribution of vascular lesions and to exclude other potential causes of dementia, such as subdural haematoma or tumour.

Functional imaging, such as single photon emission tomography, positron emission tomography and functional magnetic resonance imaging, may provide further information on the functional significance of any observed lesions or detect abnormalities not apparent on structural imaging.

Other specialised investigations may include echocardiography, carotid doppler, antinuclear antibodies, antiphospholipid antibodies, lupus anticoagulant, serum protein electrophoresis and cerebrospinal fluid examination.

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4: Some strategies for primary prevention of vascular dementia

Target high risk groups. These include elderly people; people with hypertension, diabetes, atrial fibrillation, or past transient ischaemic attack or stroke; and smokers.

  1. Treat hypertension optimally.
  2. Treat diabetes.
  3. Control hyperlipidaemia.
  4. Persuade patients to cease smoking and decrease alcohol intake.
  5. Prescribe anticoagulants for atrial fibrillation.
  6. Provide antiplatelet therapy for high risk patients.
  7. Perform carotid endarterectomy for severe (> 70%) carotid stenosis.
  8. Use dietary control for diabetes, obesity and hyperlipidaemia.
  9. Recommend lifestyle changes (eg, weight loss, exercise, reduce stress, decrease salt intake).
  10. Intervene early for stroke and transient ischaemic attacks with neuroprotective agents (eg, propentofylline, calcium channel antagonists, N-methyl-D-aspartate receptor antagonists, antioxidants).
  11. Provide intensive rehabilitation after stroke.
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