Vascular dementia. (Featured CME Topic: Stroke).

The relationship between vascular disease of the brain and cognitive impairment is unclear. It is known that extensive vascular lesions in the brain, large or small, can cause dementia. What is not known is how often this occurs and by what mechanism. Also unclear is the extent of overlap between vascular factors and underlying degenerative dementia, particularly Alzheimer's disease. We know that so-called mixed dementia (i.e., combined degenerative and vascular) commonly occurs. Some investigators believe that a common pathophysiology may be present in some cases. We are a long way from fully understanding vascular cognitive impairment; however, insight into this critical issue has changed dramatically in the past several decades. (1)

Historical Perspective

By the latter decades of the 19th century, pathologists had described diffuse small blood vessel narrowing in many organs; including the brain. They surmised that any organ so afflicted, kidney, heart, or brain, would show signs of progressive failure over time due to the resultant hypoperfusion. This thinking resulted in the concept of arteriosclerotic dementia in the brain, or hardening of the arteries. (2) In 1907, when Alzheimer described the pathologic changes that we now associate with Alzheimer's disease, he also posited that circulation problems could be the triggering factor in these changes. However, most neurologists and pathologists have considered Alzheimer's disease to be a degenerative disease of uncertain etiology.

It was not until the late 20th century that the dichotomy between arteriosclerotic dementia and degenerative dementia, primarily Alzheimer's disease, was challenged. Our concept of both dementia and cerebrovascular disease expanded and changed. Neurologists looked more critically at the entire issue of dementia and its varied etiologies and made several important observations: 1) aging alone did not inevitably lead to dementia (senility) and 2) Alzheimer presenile dementia and senile dementia (now called senile dementia of Alzheimer type) appeared to be basically the same disorder. These observations established senility as a disease (and not a normal event of aging) and expanded the scope of Alzheimer' s disease, establishing it as the most common type of dementia.

Arteriosclerotic dementia as a concept had lacked clinical definition until 1974 when Hachinski et a1 (3) redescribed the dementia of multiple small-vessel infarcts and coined the term multiinfarct dementia. Although constituting a small percentage of the total dementia population, this gave clinicians a new clinical perspective on the whole concept of cerebrovascular disease and its ability to cause dementia.

The final major development in the vascular dementia story to date has been the widespread use of magnetic resonance imaging (MRI) of the brain. This tool is so sensitive in its ability to demonstrate ischemic changes in the brain that it has revealed abnormalities in many normal elderly patients, even more changes in patients diagnosed with Alzheimer's disease, and still more extensive lesions in patients thought to have vascular dementia. (4) This has actually confused rather than clarified the dichotomy between vascular and degenerative disease; but in time, with additional clinical pathologic studies, the picture should become clearer.

Risk Factors

The risk factors for vascular dementia are the same as those for stroke in general, especially diseases that lead to small vessel infarcts such as hypertension, diabetes, lupus, and other immune vasculidities. It is the small vessel disease that is more likely to cause diffuse white (and gray) matter abnormalities; this process eventually interferes with cognition and can produce cognitive impairment and dementia. (5)

Definitions and Clinical Syndromes

Dementia. Dementia, most simply defined, is a progressive deterioration in cognitive and social adaptive functions that can eventually interfere with the patient's ability to live independently. There is, however, a continuum of cognitive change from mild cognitive impairment to dementia. (6) Patients may complain of mild, yet not disabling, cognitive problems in the early stages of their disease long before they actually obtain a diagnosis of dementia. (7) The clinical diagnosis of this early stage of mild cognitive impairment is made more difficult by the fact that there are some cognitive changes that naturally accompany advanced age. Particularly after age 70 but most marked in the population over 85 is a tendency to have increasing difficulty accessing names of people and objects, difficulty processing information rapidly, and the need for additional time to learn things and to think through problems. Because of these changes with aging, the clinician must be very cautious not to overdiagnose early deme ntia in the elderly.

A diagnosis of vascular cognitive impairment or dementia is made by demonstrating the presence of cognitive change from medical history and examination and showing that the patient has had vascular events that are believed to be sufficient to produce the cognitive change. (8) It is this last requirement that is difficult. Factors that increase the likelihood of vascular dementia are history of hypertension, history of transient ischemic attach and/or cerebrovascular accident, stepwise change in mental status, the presence of abnormal neurologic signs, and extensive changes on MRI that are compatible with ischemia.

Types of Vascular Dementia

Strategically Placed Multiple Embolic Infarcts or Hemorrhages. In embolic disease of the heart or the major cerebral vessels, multiple cortical infarcts can occur. With each event, the patient suffers a neurologic event that often produces a specific cognitive loss (eg, mild aphasia with left parietal infarct). With repeated events, the patient slowly becomes more demented and incapacitated. A similar clinical picture can occur with repeated lobar hemorrhages; these are occasionally seen in hypertension but are more common in cerebral amyloid angiopathy, a condition that is common in Alzheimer's disease. When the hemorrhages are seen with Alzheimer's disease, the dementia is usually of mixed etiology.

Multiinfarct Dementia. In classic multiinfarct dementia, the patient's cognitive deterioration is stepwise rather than smoothly progressive. (3) The cognitive changes vary but memory loss is usually much less prominent than in Alzheimer's disease. With each event (stroke), the patient suddenly worsens but then improves either completely or partially. As the disease progresses, the patient develops an accretion of abnormal neurologic signs such as asymmetric reflexes, pseudobulbar changes (ie, swallowing and speech difficulties along with emotional lability), pathologic reflexes (eg, Babinski signs), and sensory abnormalities. This condition is usually seen in hypertensive individuals and is caused by multiple small infarcts in the white matter of the brain as well as the basal ganglia and cortex. A variant of multiinfarct dementia is Binswanger subcortical arteriosclerotic encephalopathy in which the disease is confined to the white matter of the hemispheres and is usually reported as a fairly rapidly progre ssing dementia with significant neurologic and cognitive changes.

Dementia with Extensive MRI abnormalities without History of Stroke. With the widespread use of MRI, it has become apparent that many individuals can have a significant amount of white matter change without having had a clinically recognized TIA or completed stroke. Pathologically, the white matter lesions are a combination of lacunar infarcts, demyelination, and gliosis; all are due to small vessel disease and decreased blood flow and tissue perfusion. (8) These lesions occur in normal elderly individuals without dementia, in patients with Alzheimer's disease and, of course, most prominently in patients with mixed and vascular dementia. These changes are most commonly seen in patients with hypertension and/or diabetes but are not restricted to that patient population. (5)

We know that cognitive impairment will occur as this process progresses. (6,9) Initially patients may have complaints that are not serious enough to produce changes on mental status examination but, as the pathology progresses, the cognitive changes begin to show abnormalities on cognitive testing, from mild cognitive impairment to eventual dementia. (7) A combination of the extent of the lesions and the strategic location of these lesions seems to be involved in producing the mental changes. White matter of the brain is composed of the axons of the cortical brain cells that connect one cell to another. It is not difficult to understand why disruption of the connections within the brain will disconnect the various parts of the brain and produce cognitive problems. (10)

The mental status changes exhibited by this population of vascular dementia patients is characterized by solwness in mental processes, problems with decision making, poor organizational ability, difficulty adjusting to change (impaired executive functions of the frontal lobe), difficulty sustaining attention, and the appearance of apathy. These clinical features are due to the disconnection of pathways from the basal ganglia and ascending brainstem pathways to the frontal lobes. (11,12,3,14) Clinically this syndrome has been called subcortical dementia. (15) Memory function, while impaired, is not the principal and devastating feature that it is with Alzheimer's disease. There are some cases of extensive vascular disease where there is secondary atrophy of the hippocampus (the temporal lobe structure that is critical to recent memory and the area most commonly affected is Alzheimer's disease) but without Alzheimer changes. These patients have significant memory problems accompanying their other cognitive cha nges. (16)

Mixed Dementia. Many patients have aspects of both degenerative brain disease (eg, Alzheimer's disease) and evidence of either clinical strokes or significant changes on MRJ scan. Approximately 35% of Alzheimer patients have autopsy-proven vascular infarcts. Sixty percent have white matter lesions on MM. A very high percentage (70-90%) of Alzheimer patients have amyloid changes in their vessels that narrow the vessels and produce hypoperfusion. The overlap, therefore, between vascular and degenerative disease is significant; yet the exact interaction of the pathophysiology of the vascular lesions and the degenerative changes is not known. Can hypoperfusion trigger Alzheimer degeneration? Does the amyloid angiopathy produce white matter vascular changes? These and many other questions remain to be answered.

Diagnostic Tests

Imaging. The increased sophistication of cerebral imaging has heightened our awareness of cerebrovascular changes. Initially CT scanning demonstrated lacunar infarcts as well as patches of white matter disease (leukoariosis). Then the MRI scan, particularly with the newer fluid-attenuated inversion recovery (FLAIR) sequences dramatically demonstrated not only the extent of the white matter disease, the hallmark of small vessel disease, but also the small cortical lesions that were not identified on the old T1 and T2 sequences. In addition to localizing lesions in the brain, it is now possible to quantitate the extent of the white matter change using an automated magnetic resonance tissue class segmentation technique. (18) This data, in concert with localization analysis, may eventually be extremely useful in determining whether the vascular lesions are causal (vascular dementia) or merely contributory (mixed dementia) to the patient's cognitive decline.

In addition to the morphologic imaging techniques, functional scans; positron emission tomography and single photon emission computed tomography are able to image perfusion and, in the case of positron emission tomography, oxygen or glucose use of the cortical gray and subcortical white matter tissue. This is useful in differentiating Alzheimer's disease, where there is a temporal and parietal decrease in uptake, from the scattered perfusion defects seen in vascular dementia.

Transcranial Doppler. Transcranial Doppler sonography studies are now able to provide valuable information on cerebrovascular resistance, cerebrovascular reserve, and cerebral perfusion. Vascular resistance is calculated from the pulsative index (systolic-diastolic ratio); increased pulsative index indicates increased cerebrovascular resistance. Cerebrovascular reserve is calculated from the response of the cerebral vessels to a vasodilatory challenge either with carbon dioxide elevation as tested by breath holding or with acetazolamide injection. (19) Cerebral perfusion is assessed as a velocity measure of the individual vessels.

Patients with vascular dementia due to small vessel disease have a significant increase in vascular resistance and a decrease in vascular reserve. In Alzheimer's disease, vascular resistance and reserve are normal and there is a decrease in perfusion through the middle cerebral artery due to the atrophic brain tissue that it supplies. Therefore Doppler studies can be very helpful in sorting Out the vascular factors and establishing the diagnosis in dementia patients with abnormal MRI and a history compatible with cerebrovascular disease.

Treatment

The primary treatment for vascular dementia is control of the vascular risk factors. It is hoped that with early risk factor identification and treatment, vascular cognitive impairment and dementia can be decreased. (9) Once cognitive problems are present, studies have shown that the cholinesterase inhibitor drugs that were developed to treat Alzheimer's disease are also effective in treating vascular dementia. (20) As in Alzheimer's disease, the results are modest and only seen in some patients, but they are useful and should be considered in treatment.

Conclusions

Vascular disease of the brain, particularly hypertensive small vessel disease, is a more important factor in producing cognitive impairment and dementia than was previously thought. We do not know the true incidence of vascular and mixed dementia nor do we know all the risk factors. We do know that treatment of the dementia with anticholinesterase drugs helps but we do not know if risk factor control will decrease the incidence and severity of vascular cognitive change. We know a lot about Alzheimer's disease and vascular dementia but we do not know if there is any common pathogenesis. Our understanding of the interaction between cerebrovascular disease and cognition is just beginning; there are many pieces of the puzzle still in the box.

Accepted November 7, 2002.

References

(1.) Chui H. Vascular dementia, a new beginning: Shifting focus from clinical phenotype to ischemic brain injury. Neural Clin 2000;18:951-978.

(2.) Marshall J. Vascular dementias, in Whitehouse PJ (ed): Dementia. Philadelphia, F.A. Davis, 1992, pp 215-236.

(3.) Hachinski VC, Lassen NA, Marshall J. Multiinfarct dementia: A cause of mental deterioration in the elderly. Lancet 1974;2:207-210.

(4.) Pantoni L, Garcia JH. Pathogenesis of leukoariosis: A review. Stroke 1997;28:652-659.

(5.) Knopman D, Boland LL, Mosley T, Howard G, Liao D, Szklo M, et al. Cardiovascular risk factors and cognitive decline in middle-aged adults. Neurology 2001;56:42-48.

(6.) Wentzel C, Rockwood K, MacKnight C, Hachinski V, Hogan DB, Feldman H, et al. Progression of impairment in patients with vascular cognitive impairment without dementia. Neurology 2001;57:714-716.

(7.) deGroot JC, deLeeuw FE, Oudkerk M, Hofman A, Jolles J, Breteler MM. Cerebral white matter lesions and subjective cognitive dysfunction: The Rotterdam scan study. Neurology 2001;56:1539-1545.

(8.) Pohjasraara T, Mantyla R, Ylikoski MA, Kaste M, Erkinjuntti T. Comparison of different clinical criteria (DSM-III, ADDTC, ICD-10, NINDSAIREN, DSM-IV) for the diagnosis of vascular dementia. Stroke 2000;31:2952-2957.

(9.) Kivipelto M, Helkala EL, Hanninen T, Laakso MP, Hallikainen M, Alhainen K, et al. Midlife vascular risk factors and late-life mild cognitive impairment: A population-based study. Neurology 2001;56:1683-1689.

(10.) O'Sullivan M, Jones DK, Summers PE, Morris RG, Williams SC, Markus HS. Evidence for cortical "disconnection" as a mechanism of age-related cognitive decline. Neurology 2001;57:632-638.

(11.) Moser DJ, Cohen RA, Paul RH, Paulsen JS, Ott BR, Gordon NM, et al. Executive function and magnetic resonance imaging subcortical hyperintensities in vascular dementia. Neuropsychiatry Neuropsychol Behav Neurol 2001;14:89-92.

(12.) Almkvist O, Backman L, Basun H, Wahlund LO. Patterns of neuropsychological performance in Alzheimer's disease and vascular dementia. Cortex 1993;29:661-673.

(13.) Wolfe N, Linn R, Babikian VL, Knoefel JE, Albert ML. Frontal systems impairment following multiple lacunar infarcts. Arch Neurol 1990;47: 129-132.

(14.) Looi JCL, Sachdev PS. Differentiation of vascular dementia from AD on neuropsychological tests. Neurology 1999;53:670-678.

(15.) Albert ML. Subcortical dementia, in Katzman R, Terry RD, Bick KL (eds): Alzheimer 's Disease, Senile Dementia and Related Disorders. New York, Raven Press, 1978, pp 173-180.

(16.) Mungas D, Jagust WS, Reed BR, Kramer JH, Weiner MW, Schuff N, et al. MRI predictors of cognition in subcortical ischemic vascular disease and Alzheimer's disease. Neurology 2001;57:2229-2235.

(17.) Roman G. Diagnosis of vascular dementia and Alzheimer's disease. Int J Clin Pract Suppl 2001;120:9-13.

(18.) Wei X, Warfield S, Zou K, Wu Y, Li X, Guimond A, et al. Quantitative analysis of MRI white matter signal abnormalities with high reproducibility and accuracy. J Magn Reson Imaging 2002;15:203-209.

(19.) Sattel H, Forstl H, Biedert S. Senile dementia of Alzheimer type and multiinfarct dementia investigated by transcranial Doppler sonography. Dementia 1996;7:41-46.

(20.) Erkinjuntti T, Kurz A, Gauthier S, Bullock R, Lilienfeld S, Damaraju CV. Efficacy of galanthamine in probable vascular dementia and Alzheimer's disease combined with cerebrovascular disease: A randomized trial. Lancet 2002;359:1283-1290.

From the Department of Neurology, Ochsner Clinic, New Orleans, LA.

Reprint requests to Richard Strub, MD, Department of Neurology, Ochsner Clinic, 1514 Jefferson Highway, New Orleans, LA 7012 1-2429. Email: [e-mail]

Copyright [c] 2003 by The Southern Medical Association

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