Vascular Dementia: Changing the Paradigm

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Purpose of the Review: Recent progress in the field of vascular dementia is summarized, including a conceptual redefinition, and advances in the understanding of its pathogenesis, diagnosis, treatment and prevention.

Recent Findings: Vascular dementia is second only to Alzheimer's disease in frequency, according to population-based epidemiological studies, including neuropathological data. Projections based on growth of the elderly population and a rising incidence of ischemic heart disease and stroke suggest that vascular dementia may become the commonest form of dementia. Vascular factors in Alzheimer's disease continue to be an area of major research effort. Lacunes carry a poor long-term prognosis; silent lesions found on magnetic resonance imaging more than double the risk of dementia. Common manifestations of vascular dementia include executive dysfunction, abnormal gait, apathy and depression ('vascular depression'). A new therapeutic indication of cholinesterase inhibitors may result from positive results of phase III trials in vascular dementia. Diagnosis of vascular cognitive impairment should lead to prevention of dementia by appropriate control of risk factors and vascular brain burden.

Summary: Vascular dementia is an important and often overlooked form of dementia in the elderly. Cholinergic treatment may improve prognosis. Primary prevention of vascular dementia and Alzheimer's disease appears to depend on early identification and appropriate control of vascular risk factors. Secondary prevention, after clinical stroke or silent lacunes, must include energetic therapy to prevent stroke recurrence.

Roman GC. Vascular Dementia: Changing the Paradigm. Curr Opin Psychiatry. 2003;16(6)

Introduction

Vascular dementia is the commonest form of dementia in the elderly after Alzheimer's disease.[1] The term vascular dementia identifies patients with severe cognitive loss from cerebrovascular disease (CVD), mainly large ischemic or hemorrhagic strokes, lacunes, and microscopic cortical infarcts, as well as from cardiac and circulatory disorders causing incomplete white matter infarction.[2] Vascular risk factors, lacunes, and white matter lesions are also important in Alzheimer's disease. I review here some of the clinically relevant recent advances in this field.


Conceptual Redefinition: Vascular Dementia and Vascular Cognitive Impairment

Mild cognitive impairment is considered the earliest clinical manifestation of Alzheimer's disease.[3] A similar concept was proposed for vascular dementia under the name vascular cognitive impairment (VCI).[4,5] The concept of VCI includes patients with classic vascular risk factors and some degree of cognitive loss short of dementia (also known as VCI-no dementia or vascular CIND). Intrinsic to the VCI concept is the hope that appropriate prevention and treatment of the vascular brain burden could prevent the development of vascular dementia.[6-8] However appealing, it has been difficult to provide a strict definition and diagnostic criteria for VCI. This concept suffers from the same problems once criticized in vascular dementia: the notion is too wide and too vague for a precise operative definition;[9] moreover, as recently demonstrated in the Canadian Study on Health and Aging,[10-11] some patients with VCI improved spontaneously after a 5-year follow-up, indicating that VCI not always progresses to vascular dementia.

Mild cognitive impairment is considered the earliest clinical manifestation of Alzheimer's disease.[3] A similar concept was proposed for vascular dementia under the name vascular cognitive impairment (VCI).[4,5] The concept of VCI includes patients with classic vascular risk factors and some degree of cognitive loss short of dementia (also known as VCI-no dementia or vascular CIND). Intrinsic to the VCI concept is the hope that appropriate prevention and treatment of the vascular brain burden could prevent the development of vascular dementia.[6-8] However appealing, it has been difficult to provide a strict definition and diagnostic criteria for VCI. This concept suffers from the same problems once criticized in vascular dementia: the notion is too wide and too vague for a precise operative definition;[9] moreover, as recently demonstrated in the Canadian Study on Health and Aging,[10,11] some patients with VCI improved spontaneously after a 5-year follow-up, indicating that VCI not always progresses to vascular dementia.

The importance of stroke and vascular risk factors in Alzheimer's disease remains an area of intensive research.[12-16] Decreased incidence of Alzheimer's disease and vascular dementia has been observed with control of hypertension,[17] and with the use of statins,[18] suggesting that these measures could have public health importance.


Epidemiology and Risk Factors

Recent population-based epidemiological studies, including neuropathology data, have confirmed that vascular dementia is responsible for about 20% of cases of dementia in the elderly, second only to Alzheimer's disease; also, vascular lesions are commonly found in the very old with Alzheimer's disease pathology. Vascular dementia occurs more often than dementia with Lewy bodies.[19-24] Based on projected figures for the growing magnitude of the worldwide problem of ischemic heart disease and stroke, it has been postulated that vascular dementia may become the most common cause of dementia.[2,25] Currently, post-stroke dementia (multi-infarct dementia) often remains completely unrecognized.[26] Moreover, it is rare to see appropriate diagnosis and treatment of vascular dementia after congestive heart failure requiring hospital admission, after major surgery in the elderly, or after coronary artery bypass graft. This particular form of subcortical ischemic vascular dementia results from small-vessel disease, and produces lacunar strokes and incomplete white matter infarction.[27] The relatively poor prognosis of lacunes in terms of cognitive outcome and 5-year survival was recently reviewed.[28] Furthermore, silent lacunar strokes appear to double the risk of dementia.[29] It has been postulated that chronic brain edema from damage of the blood-brain barrier could explain their poor outcome.[30] Lacunes are markers of small-vessel disease and should prompt a search for diagnosis and treatment of relevant risk factors.


Diagnosis of Vascular Dementia

The diagnosis of vascular dementia can be defined by three elements: (1) presence of clinical dementia, (2) evidence of cerebrovascular disease (by brain imaging or findings on examination), and (3) exclusion of other conditions capable of producing dementia. For cases of post-stroke dementia, a 3-month temporal requirement is included between the clinical stroke and the onset of dementia.[31] Since the memory deficits may be mild in vascular dementia, the National Institute for Neurological Disorders and Stroke-Association Internationale pour la Recherche et l'Enseignement en Neurosciences (NINDS-AIREN) criteria[32,33] for dementia require the presence of involvement of memory plus two or more cognitive areas (instead of memory plus one, as required by the Diagnostic and statistical manual of mental disorders-IV).[34] A history of transient ischemic attacks, stroke, and vascular risk factors is more common in vascular dementia than in Alzheimer's disease; hence, a high ischemic score[35] is useful in separating patients with vascular dementia from those with pure Alzheimer's disease. A score over seven is consistent with multi-infarct dementia, and with Alzheimer's disease if under four. A score of five to six may suggest Alzheimer's disease plus CVD.

In contrast with the prominent and early involvement of memory in Alzheimer's disease, patients with vascular dementia have relatively mild memory loss but usually have early executive dysfunction.[36-39] Loss of executive control function is characterized by lack of planning, disorganized thought, behavior, or emotion.[39] Executive function is mediated by series of parallel cortico-subcortical circuits connecting the prefrontal cortex, the striatum-pallidum and the thalamus, with thalamo-cortical projections closing the loop. Vascular lesions may interrupt these pathways at any point of the loop, but the end-result is similar and leads to a subcortical form of dementia with loss of goal-directed activities, including planning, direction, execution, and supervision of behavior. Complex activities such as cooking, dressing, and housekeeping are predominantly affected in patients with dysexecutive cognitive impairment.[39,40] Most of the current tests for bedside assessment of dementia are relatively insensitive to executive function and universal acceptance of an appropriate test of dysexecutive function has been slow. However, impairment of activities of daily living (ADLs), including instrumental ADLs, has been correlated with abnormal results in a number of tests of executive cognitive function. Executive dysfunction is relatively common among elderly people living in the community, affecting one in six non-demented individuals.[40,41] Loss of executive function is an important cause of disability and predicts 43-49% of the variance of the instrumental ADLs scores in non-demented community-dwelling individuals,[41-44] as well as in patients with vascular dementia,[45-49] and Alzheimer's disease.[50] Moreover, other cognitive domains such as memory, language, visuospatial skills and motor speed, or demographic features such as age, education and health status, have minimal contribution to ADLs. Royall and colleagues[51,52] reached similar conclusions using two tests of executive function, the EXIT25 and a simple clock-drawing task, the CLOX test. Among elderly 'normal' retirees living in a comprehensive care retirement community, only these two tests, and age, explained impairment in each domain of the instrumental ADLs, including telephone use, transportation, shopping, meals, housework, medications and finances. Mini-mental state examination and sex made no contribution to the regression model, while depression and physical illness contributed little additional variance to the model.

Apathy and depression frequently occur in patients with stroke and these symptoms are an important component in the development of vascular dementia. Vascular depression is currently recognized as an independent condition in its own right.[53,54] A study of post-stroke patients in Finland[55] confirmed that executive dysfunction was the main determinant of abnormalities in both basic and instrumental ADLs; the authors suggested that executive function including instrumental ADLs may be more sensitive for the diagnosis of vascular dementia and could accurately measure the effects of potential therapies. In brief, instrumental ADLs appear to be an appropriate proxy examination for executive function in patients with post-stroke cognitive decline.[56-59] Apathy and depression appear to be related to disruption of prefrontal circuits, although there is no total agreement with this concept.[60]

In addition to the above, other typical clinical features of vascular dementia include cases with sudden onset and slow or stepwise progression, often increasing in severity with each ischemic event; fluctuations are commonplace and memory is mildly affected or intact. In fact, the easily identifiable amnestic form of mild cognitive impairment, characterized by isolated short-term memory impairment in the elderly, usually precedes the onset of dementia in patients with the so-called mixed dementia (Alzheimer's disease plus CVD). Finally, in vascular dementia patients, gait is typically disturbed, shuffling and with short steps, and often resembles that of patients with Parkinson's disease. In contrast, gait is usually normal in patients with Alzheimer's disease until very late.[61,62]


Emerging Treatments for Vascular Dementia

A number of medications have been used for the symptomatic treatment of vascular dementia, including vasodilators such as niacin, calcium channel blockers, pentoxifylline, antiplatelet agents, and nootropic agents such as memantine. More recently, the cholinesterase inhibitors donepezil hydrochloride, galantamine hydrobromide, and rivastigmine tartrate have been studied in controlled clinical trials in vascular dementia. Cholinergic deficits in the condition may result from ischemia of the nucleus basalis of Meynert or from interruption of cholinergic pathways by vascular lesions.
Donepezil

Donepezil was studied in one of the largest clinical trials of vascular dementia to date. A total of 1219 patients were recruited for a 24-week, randomized, placebo-controlled, multicenter, multinational study of donepezil in the condition.[63-65] Patients with either possible or probable vascular dementia according to the NINDS-AIREN criteria were eligible. All patients had brain imaging prior to the study (computed tomography or magnetic resonance) with demonstration of relevant cerebrovascular lesions. Patients with preexisting Alzheimer's disease were excluded, as were patients with Alzheimer's disease plus CVD. The patients were randomized to one of three groups: placebo, or donepezil at a dosage of 5 mg/day or 10 mg/day. The group receiving 10 mg/day initially received 5 mg/day for 4 weeks; the dosage was then titrated up to 10 mg/day.

Compared with placebo, both donepezil treatment groups showed statistically significant improvement in cognition, global function, and both basic and instrumental ADLs. Of interest, cognitive decline in untreated patients with vascular dementia in this trial was less severe than in placebo-treated patients with Alzheimer's disease during 24 weeks of study, using similar instruments.[66,67] Also, in contrast with Alzheimer's disease trials, these vascular dementia studies enrolled older patients, more men than women (58% versus 38%), and patients with higher ischemic scores (6.6±0.2 versus <4), hypertension, cardiovascular disease, diabetes, smoking, hypercholesterolemia, previous stroke and transient ischemic attacks.

Donepezil was generally well tolerated, although more adverse effects were reported in the 10 mg group than in the 5 mg or placebo groups. The adverse effects were assessed as mild to moderate and transient, and were typically diarrhea, nausea, arthralgia, leg cramps, anorexia, and headache. The incidence of bradycardia and syncope was not significantly different from the placebo group. There was no significant interaction with the numerous cardiovascular medications and antithrombotic agents used by this population. Donepezil demonstrated effectiveness and was well tolerated in the treatment of patients with vascular dementia.

Galantamine

A recent study[68] of galantamine in vascular dementia included patients who had either Alzheimer's disease plus CVD or vascular dementia. At baseline, 49% of patients had a diagnosis of Alzheimer's disease plus CVD; 42% had vascular dementia according to NINDS-AIREN criteria, and 9% had a nonspecific 'mixed dementia' diagnosis. All patients had neuroimaging evidence of CVD. Patients were randomized to treatment or placebo in a multicenter, international study of 24 weeks duration. The study involved 592 patients, 396 on galantamine and 196 on placebo. The patients with vascular dementia were randomly treated as follows: 81 on placebo (41%) and 171 (43%) on galantamine. The treatment group received 4 mg of galantamine daily for one week, titrated upward to 24 mg daily by week six and showed a statistically significant overall cognitive improvement over the placebo group, which had had overall deterioration. The study was not powered to evaluate the effect of galantamine on pure vascular dementia cases, but a trend was observed for improvement in the Alzheimer's disease assessment scale-cognitive subscale (ADAS-cog) over placebo in these cases (31% versus 23%, P=0.238). There was also significant improvement in the behavioral symptoms in the treated group versus placebo. Among these patients 20% of the galantamine group discontinued due to adverse effects, as did 8% of the placebo group. Adverse effects were primarily nausea and vomiting.

Rivastigmine

Two recent open-label studies of rivastigmine[69,70] involved patients with subcortical vascular dementia treated for up to 22 months. Patients were randomized to either 3-6 mg/day of rivastigmine or aspirin (100 mg/day). The change from baseline on the neuropsychiatric inventory score at 22 months showed that the rivastigmine group improved while the aspirin group deteriorated (P<0.001). Also, the rivastigmine group showed significant improvements in executive function, behavioral symptoms, and caregivers' relative stress score relative to the aspirin group. Baseline scores of global response, cognition, word fluency and ADLs were maintained in patients receiving rivastigmine, and there was no increase in benzodiazepine or neuroleptic intake. Side effects in both groups were tolerable and there were no study withdrawals.
Memantine

Memantine is an N-methyl-D-aspartate receptor antagonist that appears to protect neurons from the damaging effects of excitotoxicity induced in the ischemic brain. Memantine is also neuroprotective in several animal models of excitotoxicity and neurodegeneration. In two recent randomized, placebo-controlled clinical trials of memantine in patients with mild to moderate vascular dementia,[71,72] the mean ADAS-cog and the mini-mental state examination scores improved significantly with memantine compared with deterioration with placebo (P=0.003). Global function measured by the Clinician's Interview-based Impression of Change-plus remained stable. The nurses' observation scale for geriatric patients' disturbed behavior also showed differences in favor of memantine (P=0.07). Memantine was well tolerated and safe.


Primary and Secondary Prevention

There is a dearth of data on dementia prevention by implementation of measures to control stroke and cardiovascular risk factors at the population level. Interventions to prevent stroke should lower the risk of Alzheimer's disease and vascular dementia. The classic modifiable risk factors for vascular dementia include hypertension, cardiac abnormalities such as atrial fibrillation, smoking, lipid abnormalities, diabetes, and elevated homocysteine levels.

As mentioned at the outset, in an extension of the Systolic Hypertension in Europe Study (SYST-EUR),[17] more than 2800 patients were followed for 3.9 years and in comparison with the control subjects, long-term antihypertensive therapy reduced the risk of dementia by 55%, from 7.4 to 3.3 cases per 1000 patient-years. In SYST-EUR both Alzheimer's disease and post-stroke vascular dementia were prevented by the treatment with the calcium-channel blocker nitrendipine, suggesting that calcium-channel blockers may have neuroprotective effects in both vascular dementia and Alzheimer's disease, by improving calcium dysregulation, beyond blood pressure control. Antihypertensive treatment reduced the odds of incident cognitive impairment by 38% in a 946-participant cohort of African Americans.[73] This was a random sample of 2212 community-dwelling African Americans over 65 years with blood pressure documentation for 5 years. Antihypertensive therapy was associated with a 28% reduction in the risk of recurrent stroke and a 38-55% reduction in the risk of dementia.

Regarding secondary prevention, in the Perindopril Protection Against Recurrent Stroke Study (PROGRESS),[74] blood pressure lowering in patients with previous stroke or transient ischemic attack reduced the incidence of secondary stroke by 28%, of major vascular events by 26% and of major coronary events by 26%. These reductions were all magnified by approximately 50% in a subgroup of patients in whom the angiotensin-converting enzyme inhibitor perindopril was routinely combined with the diuretic indapamide. Significant reduction of cognitive decline and dementia was documented in the active treatment group, compared with the placebo.[75]

Use of oral folate and dietary modifications to include foods that are sources of folic acid, vitamins B6 and B12, and antioxidants such as lycopene and vitamins C and E may counteract the damaging effect of high homocysteine.[76-78] The Mediterranean diet, with its high content of fish, seafood, grains, vegetables, citrus fruits and olive oil, appears to be protective against vascular disease.[79,80] Finally, effortful mental activities appear to be protective against dementia.[81,82]


Conclusion

Vascular dementia is an important and often overlooked form of dementia in the elderly. Projections indicate that it may become the most common form of dementia in the elderly affected by ischemic heart disease and stroke. Most cases of vascular dementia present with a subcortical form of dementia with prominent executive dysfunction that is usually not recognized as dementia by relatives or caregivers. Cholinergic treatment may improve the prognosis of the condition. Primary prevention of vascular dementia and Alzheimer's disease appears to depend on early identification and appropriate control of vascular risk factors. Secondary prevention, after clinical stroke or silent lacunes, must include energetic therapy to prevent stroke recurrence.


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79. Hu FB. The Mediterranean diet and mortality: olive oil and beyond. N Engl J Med 2003; 348:2595-2596.
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