The Journal of Quality Research in Dementia, Issue 6
Small vessel disease
Dr Ayesha Khan
Scientific Liaison Officer, Alzheimer's Society, Devon House, 58 St Katharine's Way, London E1W 1JX. Telephone 020 7423 3500, email firstname.lastname@example.org
Dementia is a term that describes the symptoms resulting from damage to the brain by specific diseases including Alzheimer's disease (AD) and vascular dementia (VaD). Symptoms of dementia include memory deficits, problem solving or general concentration issues. The brain requires oxygen supplied by blood via the vascular network to function normally. Vascular dementia, the second most common cause of dementia, results from problems with blood supply to the brain. If the vessels are damaged, blood may not be able to reach the brain cells and consequently the cells may die of oxygen starvation triggering the onset of vascular dementia. Increasingly, it seems that one particular type of vascular disease, small vessel disease, may be the major form of vascular dementia. This review will examine small vessel disease as a cause of vascular dementia in terms of disease progression, diagnosis and potential treatment methods.
Causes of vascular dementia
Damage to blood vessels in the brain may come about as a result of a number of conditions including high blood pressure, heart problems, high cholesterol and diabetes. Early recognition and treatment of any of these conditions is very important as they can lead to the onset of vascular dementia, but adequate management of these conditions can prevent the onset of VaD. Vascular dementia can be caused by two events that can occur in blood vessels. The first is stroke and the second is small vessel disease, although many people may have a mixture of causes. Stroke refers to brain damage that is permanent and results from interrupted blood supply to a specific part of the brain. Symptoms vary depending on which brain region has been affected. For example if a motor region of the brain were damaged then the symptom would be paralysis. If a speech centre is affected then communication will be impeded. Damage to other areas of the brain can result in the onset of dementia. Vascular dementia resulting from stroke is categorised in two ways, single-infarct or multi-infarct, depending on whether it was caused by one or several incidences of stroke.
Small vessel disease results from damage to blood vessels that sit deep in the brain matter and is the most frequent subtype of vascular cognitive impairment (VCI). SVD causes psychological symptoms as well as neurological symptoms concomitant with cognitive deficits. SVD can however be present in the absence of any cognitive impairment as well as varying levels of cognitive impairment ranging from mild cognitive impairment (MCI) to dementia.
Pathophysiology of small vessel disease
Events that occur in small vessel disease include thickening of vessel walls, blood-brain barrier disturbance, demyelination and axon loss amongst other problems. The mechanism of SVD development is not clear, although there are two main pathological features. These are lesions of the subcortical, deep and periventricular white matter, generally referred to as white matter lesions (WML) and lacunes of the central grey matter, including the thalamus and basal ganglia.
The thickening of the blood vessel walls, atherosclerosis, is accompanied by hardening of the vessel walls. Risk factors contributing to this phenomenon are hypertension and diabetes mellitus.. The small arterioles are more susceptible to atherosclerosis as they are less elastic than the larger blood vessels. The thickening and hardening of vessel walls result in narrowing of the lumen of the vessel, twisting the vessel itself and thereby creating two conditions.  The first is hypoperfusion whereby the supply of oxygen and nutrients to the brain tissue is slowly cut. The second condition is occlusion where blood supply to a particular part of the brain ceases. These conditions result in ischemic brain tissue.
Arterioles are found mostly in the subcortical region of the brain, close to the frontal lobe, these areas are where vascular damage is likeliest to occur [1, 2] .Extensive damage can lead to dementia which is signified by changes in behaviour that coincides with damage to ischemic regions of the brain. The changes may be either gradual or sudden followed by predictive progression of disease. Changes that are observed affect speech patterns, problem solving ability and a sense of social judgement. Damage to the circuit between the basal ganglia and frontal cortex results in slowness of motor skills, emotional numbness and lack of initiation giving the impression of depression.  SVD is mostly identified in groups where hypertension and diabetes mellitus are most prevalent.
Identifying small vessel disease as a cause of vascular dementia
There is no consensus about the level of SVD that is required for it to be deemed the cause of dementia. Multiple lacunes or extensive periventricular WML are required by the NINDS-AIREN criteria, providing high specificifty but low sensitivity for all types of vascular dementia [4, 5].
Research criteria have been proposed for clinical and image-based diagnosis of SVD, but a minimal number and size of lacunes and WML along with scoring methodology has not been defined . One group has set up imaging criteria to discriminate between dementia due to SVD and large vessel pathology, requiring that at least 4 lacunes WML covering 25% of white matter were necessary for a diagnosis of dementia due to SVD .
A second problem with diagnosis is that with the lack of biological markers it is difficult to distinguish between dementia that may be due to SVD or AD, although efforts have been made to identify differences in neuropsychological deficits. The patterns of lesions are in fact opposite between SVD and AD, cortical and sub-cortical. Although SVD was not considered separately in earlier neuropsychological studies of AD and vascular dementia.
One study found a high degree of overlap between AD and VaD with motor deficiency being a minor diffentiating factor between AD and VaD. Another compared AD patients and subcortical stroke patients, either with or without WML and found AD patients to have lower delayed rentention scores in a memory task.. A further study comparing probable AD patients with probable SVD patients, some of whom had a mixed type of damage, found that clock reading and recognition memory were the best tests to discriminate between AD and SVD. The same group also compared SVD with probable mixed dementia where clock reading and word fluency were found to be good predictors . Both of these studies gave an 81% correct diagnosis, where people with small vessel disease did much better at both tasks than people with mixed dementia.
Although these and other studies have identified that neuropsychological tests can aid in differential diagnosis, confirmation of these tests is required as well as post-mortem validation.
Pathological criteria for mixed AD/SVD do not exist. It is acceptable to assume the existence of mixed dementia if in the presence of SVD there is marked hippocampal/mediobasal atrophy, there is lexical-semantic and visio-spatial deficits at early stages, and if recognition memory is out of sync with executive deficits. The level of SVD identified through imaging should not be marked. Mixed dementia could also be considered to exist when AD is accompanied by SVD even though the level of SVD may be less than that set out by the NINDS-AIREN criteria.
There is a variety of experimental data illustrating that the progression of vascular dementia caused by SVD is continuous rather than stepwise. In a study of patients with probable or possible VaD showed a decline of 4.5 MMSE points per year, a significant drop in cognitive ability, although the cases of SVD were not recorded and the decline cannot be directly attributed directly to SVD . Another study found an increase in mortality, especially in the presence of WML, of patients with lacunar strokes. The presence of WML in patients with lacunar strokes is also a predictor of functional disability.  A further study of patients with SVD associated dementia and MCI resulted in 70% survival after 2.6 years and 50% survival after 4.3 years . Patients with dementia dropped 3.9 points on a shortened MMSE scale.
The natural progression of patients with MCI in relations to vascular lesions is not very well researched. There is minimal data on the conversion of SVD-MCI to SVD-dementia. One study of 73 patients with MCI resulted in development of SVD-dementia in 10 of them after a mean time of 3.9 years although the number of cases that has SVD at the start of the study is not known.  The Frisoni study showed that patients with SVD-MCI lost 2.5 of 22 MMSE points a year, although the control group of amnestic MCI exhibited less than half of this level of decline with 100% survival over the duration of the study .
Age and high blood pressure appear to be good predictors of WML. The occurrence of SVD is frequent with age, although elderly individuals with hypertension develop clinically relevant SVD. There is however a great deal of variability, which remains unexplained, among patients with WML. The twin study  suggests that unknown genetic factors are important in the expression of WML. Association between the level of WML and cognitive impairment has been shown to be minimal or absent by several MRI studies   , supporting the experience of clinicians that many patients with noticeable WML have no significant level of cognitive impairment. This makes it questionable as to whether WML are in fact a reliable indicator of the severity of SVD.
Evidence suggests that the progression of white matter hyperintensities (WMH) is dependent upon on the blood pressure and degree of WMH at the start of any given study. This was shown in an Austrian study over 3 years where blood pressure and initial level of WMH were strong predictors of disease progression. The same was evident after 6 years in the same group  . Repeat MRI scans in patients with high levels of WML over 2 years showed significant increase in WML from a mean of 6 to 7 on a 16 point scale with the increase being associated with high blood pressure at baseline. Another study looked at patients with SVD measuring parameters such as WML, atrophy, cognitive ability and cerebral metabolism. Following one year there was no significant change observed using imaging and cognitive measurements  .
Only a few studies have looked at the link between SVD progression and cognitive decline, and in most cases in people who had no cognitive impairment at the start of the studies. One study examined cognitive decline in people between ages 50-80 without dementia or known strokes. MRI scans at age 80 showed correlation of WML with cognitive decline. A longitudinal study in 563 people with dementia exhibited no relation between WML and cognitive decline  until further variables such as depression, atrophy and infarcts were taken into consideration, resulting in a more significant decline in people with WML, a drop of 0.28 MMSE vs. 0.1 MMSE points per year.
One previously mentioned study showed no correlation of occurrence of WML with cognitive change  , although the power to detect these changes was low, while a further study shows that the degree of WMH at baseline did not predict cognitive decline after 4years .
Evidence of disease progression from drug trials
Most drug trials of VaD were not designed to examine different types of vascular dementia. Analysis of subgroups in a trial of galantamine in probable VaD or AD with VaD showed that VaD patients treated with placebo showed no cognitive decline but AD patients treated with placebo did decline  . 46% of the VaD patients had SVD only. Further to this, VaD patients given medication were stable for 3 years . A double blind trial of donepezil, patients with mix VaD treated with placebo were also stable with respect to cognitive ability [21, 22]. A further study of the effects of memantine on VaD showed that placebo groups of SVD patients declined in cognitive ability while stroke patients were stable .
Another study of rivastigmine vs. cardiospirine, a drug with no known effects in VaD, showed no change after 22 months in the cardiospirine and improvement in 30% of the rivastigmine group . In further work after 12 months a 4-point decrease in MMSE score was observed in the cardispirine group and 2.2 point decline in the rivastigmine group.
Management of hypertension has been observed to improve cognitive functioning and prevents dementia [21, 25, 26]. Primary prevention through education and checks on factors such as blood pressure and diabetes is invaluable. Use of MRI screening for dementia could be used as a routine method for identification of SVD. Although AD is progressive and at present not controllable, SVD can be slowed and stabilised by management of risk factors.
SVD is an important disease that causes disability and disorientation in ageing people. It is important to elucidate the course of disease progression especially in individuals that have SVD-MCI or SVD-AD. Identification of predictors of SVD is of high priority and consideration of other factors such as cognition, behavioural effects, quality of life and somatic symptoms with an understanding of the changes observed using imaging techniques.
The occurrence of SVD is far lower than that of AD; the higher comorbidity and mortality rate due to coincidental cardiovascular diseases make it more difficult to study. It is necessary to understand the normal course of SVD to help design useful drug trials. The presence of undetected AD would bias the results of study looking at the disease progression or drug response in SVD patients. The lack of methods to differentiate between SVD and mixed SVD means that the bulk of data to date is assumed to be based on mixed SVD-AD . Studies using PET and CSF analysis could increase accuracy of diagnosis although not practical for large studies. A more accurate diagnosis of AD would also aid the identification of real cases of SVD for study.
WML are detectable by MRI from very early stages, giving the impression of a relatively long pre-clinical stage and slower SVD disease progression. The WML at pre-clinical stage progress slowly and do not correlate with cognitive decline. Imaging and clinical data seem to be in agreement with the idea that functional decline accelerates once there is a lot of accumulated damage. This would imply that it would be beneficial to have further studies of cognitively impaired SVD patients and not pre-clinical SVD.
 Chui H, (2001) Dementia due to subcortical ischemic vascular disease. Clin Cornerstone. 3 40-51.
 Cummings J L , (1994) Vascular subcortical dementias: clinical aspects. Dementia . 5 , 177-180.
 L. Bracco, D. Campani, E. Baratti, A. Lippi, D. Inzitari and G. Pracucci et al., (1993) Relation between MRI features and dementia in cerebrovascular disease patients with leukoaraiosis: a longitudinal study. J. Neurol. Sci. 120, 131-136.
 Roman G C, Tatemichi T K et al. (1993) Vascular dementia: diagnostic criteria for research studies: report of the NINDS-AIREN International Workshop,. Neurology 43, 250-260.
 Wetterling T , Kanitz R D and Borgis K J, (1996), Comparison of different diagnostic criteria for vascular dementia (ADDTC, DSM-IV, ICD-10, NINDS-AIREN). Stroke 27, 30-36
 Erkinjuntti T Inzitari D et al. (2000) Research criteria for subcortical vascular dementia in clinical trials. J. Neural Transm. 59 23-30 [Suppl.]
 Almkvist O , Backman, L et al (1993) Patterns of neuropsychological performance in Alzheimer's disease and vascular dementia. Cortex 29, 661-673.
 Cannatà A P , Alberoni M et al (2001) Frontal impairment in subcortical ischemic vascular dementia in comparison to Alzheimer's disease. Dementia 13 101-111.
 Schmidtke K and Hüll M (2002), Neuropsychological differentiation of small vessel disease, Alzheimer's disease and mixed dementia. J. Neurol. Sci. 9 419-429.
 Ballard C, O'Brien J et al. (2001) The progression of cognitive impairment in dementia with Lewy bodies, vascular dementia and Alzheimer's disease. Int. J. Geriatr. Psychiatry 16 , 499-503.
 Bennett H P , Corbett A J (2002) Subcortical vascular disease and functional decline: a 6-year predictor study. J. Am. Geriatr. Soc. 50 1969-1977.
 Frisoni G B , Galluzzi S et al, (2002) Mild cognitive impairment with subcortical vascular features: clinical characteristics and outcome. 249 ,1423-1432.
 Meyer J S , Xu G et al (2002) Is mild cognitive impairment prodromal for vascular dementia like Alzheimer's disease? Stroke. 33 ,1981-1985.
 Carmelli D , DeCarli C et al (1998) Evidence for genetic variance in white matter hyperintensity volume in normal elderly male twins, Stroke, 29, 1177-1181.
 Garde E, Mortensen E L et al (2000) Relation between age-related decline in intelligence and cerebral white-matter hyperintensities in healthy octogenarians: a longitudinal study, Lancet 356, 628-634.
 Sabri O , Ringelstein E B et al,. (1999) Neuropsychological impairment correlates with hypoperfusion and hypometabolism but not with severity of white matter lesions on MRI in patients with cerebral microangiopathy. Stroke 30 556-566.
 Schmidt R Schmidt H et al, (2002) The natural course of MRI white matter hyperintensities, J. Neurol. Sci. 203-204, 253-257.
 Sabri O , Hellwig D , et al (2000) One-year follow-up of neuropsychology, MRI, rCBF and glucose metabolism (rMRGlu) in cerebral microangiopathy, Nuklearmedizin 39 43-49.
 De Groot J C , De Leeuw F E et al/, Periventricular cerebral white matter lesions predict rate of cognitive decline. Ann. Neurol. 52, 335-341.
 Erkinjuntti T, Kurz A et al, (2002) Efficacy of Galantamine in probable vascular dementia and Alzheimer's disease combined with cerebrovascular disease: a randomised trial. Lancet. 359, 1283-1290.
 Kurz A, Brashear H R, (2003) Galantamine is safe and effective for 36 months in patients with probable vascular dementia or Alzheimer's disease and cerebrovascular disease. Poster presented at the 3rd International Congress on Vascular Dementia, Prague, October 23-26.
 Black S , Roman G C et al., (2003) Efficacy and tolerability of Donepezil in vascular dementia. Stroke. 34, 2322-2332.
 Wilkinson D, Doody R et al., (2003) Donepezil in vascular dementia: a randomized, placebo-controlled study. Neurology. 61, 479-486.
 Möbius H J and Stöffler A, (2002) New approaches to clinical trials in vascular dementia: memantine in small vessel disease. Cerebrovasc. Dis. 13 (Suppl. 2), 61-66.
 Williams P S , Rands G et al., (2000) Aspirin for vascular dementia, Cochrane Database Syst. Rev. 4, CD001296.
 De Leeuw F E , de Groot J C et al. (2002) Hypertension and cerebral white matter lesions in a prospective cohort study. Brain 125, 765-772.
 Fazekas F , Ropele S et al., (2002) Can small-vessel disease-related cerebral anormalities be used as a surrogate marker for vascular dementia trials?, J. Neuronal Transm. 62 61-67 [Suppl.].
 van Straaten E C , Scheltens P et al., (2003) Operational definitions for the NINDS-AIREN criteria for vascular dementia. An interobserver study. Stroke 34, 1907-1912.
In this section
- What's involved in pulling together a synthesis of evidence about risk and vascular dementia?
- The neurochemistry of vascular dementia
- Prevention of Vascular Dementia after Stroke
- Treatments for existing vascular dementia
- You are here: Small vessel disease
- Treatment of vascular dementia
Visit Talking Point and take part in the discussions