Clinical manifestations

Presentation and course

Early manifestations. Subcortical vascular cognitive impairment can present with slowing of mental processing, executive dysfunction, or impairment in working memory (32; 42; 38). These cognitive signs may be evident before functional problems appear, so the early subcortical vascular cognitive impairment patient technically qualifies as having “vascular cognitive impairment” instead of vascular dementia (35). These early manifestations may be found in a quarter of hypertensive individuals with white matter hyperintensities on MRI as early as the fifth decade.

Vascular risk factors. A history of hypertension and increased age were present as risk factors in those with periventricular white matter hyperintensities in the Whitehall II Study of older adults (32). In that study, higher body mass index (BMI) was associated with an increased amount of deep white matter hyperintensities. Other risk factors for vascular disease, especially diabetes, are often present. A history of stroke at some stage is common in advanced cases but is commonly absent in the early stages.

Vascular dementia. Dementia is variable in subcortical vascular cognitive impairment and is not usually the presenting symptom. It evolves over 3 to 10 years and is gradual or intermittently progressive initially, but it often becomes gradually progressive without further clear-cut vascular events. Aphasia, amnestic intervals, and neglect are seen in some cases. Memory loss is less prominent in subcortical vascular cognitive impairment than in Alzheimer disease, the neuropsychological picture being that of executive dysfunction and slow processing speed (24; 42). Learning is also impaired (29). At one year after stroke in those with small vessel disease, white matter hyperintensity volume more closely correlates with cognitive impairment than at the time of the stroke (13).

Other neurologic signs. Dysarthria, focal motor signs, incontinence, and gait disturbance evolve during the illness and may occur relatively early, although gait disturbance normally requires fairly prominent white matter hyperintensities on MRI and is more likely when this is frontal or periventricular or in the presence of silent infarcts or lacunar infarcts. When more severe, the gait disturbance has parkinsonian features.

Difficulty in leg use is out of proportion to other leg movements when lying or seated and also out of proportion to movements of the upper limbs and face, which are relatively preserved. Patients in the early stages of subcortical vascular cognitive impairment stand wide-based with the legs, arms, and trunk held straight (contrast this with Parkinson disease, where the base is narrow). The gait consists of short steps with a tendency to shuffle, especially when turning corners. The arm swing may be slightly reduced. Postural reflexes are preserved (in contrast with Parkinson disease, where the postural reflexes are often lost). In more severe cases, standing may be difficult, but even so, such patients can typically move their legs easily in a bicycling or walking action when seated (in contrast with Parkinson disease, where foot-tapping is slow). The gait is wide-based and the legs are held stiffly extended. The feet may appear stuck to the ground. Attempts to step forward are accompanied by forward flexing of the trunk and reaching out with the arms for support. These patients do not festinate; they would fall before increasing gait speed.

Psychiatric symptoms. Behavioral changes are early and prominent and may be the presenting feature in patients with subcortical vascular cognitive impairment. Some patients exhibit an early manic phase but in most there is progressively increasing abulia. Depression is common and may be particularly related to frontal deep white matter lesions (63), as is apathy (33; 89). Depression is common and may be particularly related to frontal deep white matter lesions and reduction in gray matter volume (63; 55). Apathy is also related to frontal white matter hyperintensities (33; 89). Some subcortical vascular dementia patients may exhibit signs of pseudobulbar affect, where there are frequent episodes of laughter or crying in response to minimal nonemotional stimuli (83). Psychosis (with delusions or hallucinations) may be a feature in as many as 15% of those who have vascular cognitive impairment with dementia (15).

Prognosis and complications

In the Cardiovascular Health Study, white matter disease increased in 28% of subjects over 65 years of age over the course of 5 years; the increase was usually modest, but nonetheless, it correlated with cognitive decline (57). More advanced disease progresses more rapidly, typically over 3 to 10 years.

Data are available on the progression of white matter hyperintensities on MRI and its cognitive correlates (Table 1). Cognitive correlates of white matter hyperintensities were universally found, and cognitive decline was 4 times faster in patients with the greatest progression of white matter hyperintensities. The changes reported in these studies were modest but may underestimate rates of change in those at greatest risk, as there was a pronounced tendency for patients with greater cognitive impairment to decline assessment (and they were excluded from PROSPER). In studies where factors predicting rate of decline were measured, greater disease (white matter hyperintensities or cognitive) at entry predicted more rapid increases in white matter hyperintensities and cognitive decline (92; 98). Lesion expansion, rather than new lesion formation, may account for a large proportion of the increase in volume of white matter hyperintensities, and lacunar infarcts tend to develop in regions of white matter hyperintensities as well. Other studies have confirmed that rate of progression increases with increased severity. In the Austrian Stroke Prevention Study, extensive white matter hyperintensities at entry doubled the rate of atrophy, but in addition, atrophy interacts with white matter hyperintensities to accelerate cognitive decline and psychomotor slowing (45). White matter hyperintensities also increase the risk of mild cognitive impairment progressing to vascular or mixed dementia (92). In the PROGRESS study, the incidence of severe cognitive deterioration over 4 years increased from 1.1 per 100 person-years in those with no white matter hyperintensities at entry to 9.1 in those with severe white matter hyperintensities at entry (23). Microvascular retinopathy, presumably sharing the same etiology, also correlates with evolving cognitive impairment.

Table 1. Studies on the Progression of Subcortical White Matter Hyperintensities and Its Cognitive Correlates

Biological basis

Etiology and pathogenesis

Elevated blood pressure and other risk factors acting on putatively abnormal cerebral arterioles, put at risk in part by genetic predisposition to produce lipohyalinosis and, subsequently, areas of lacunar infarction and other ischemic changes such as incomplete infarction and multiple microinfarcts within the deep white and gray matter represent the nearest approximation to the etiology (of periventricular white matter hyperintensities and subcortical vascular cognitive impairment (43; 32; 104). In cerebral amyloid angiopathy, the mechanistic basis for cognitive impairment is thought to be the associated presence of not only Alzheimer changes, but also white matter hyperintensities, microinfarcts, and microbleeds (09; 03).

Traditional risk factors. Of the traditional vascular risk factors, hypertension is particularly important, whereas other risk factors are more closely associated with large vessel disease, although diabetes and atrial fibrillation are very important in the elderly (25; 42). Blood pressure fluctuation is particularly important as a risk factor for vascular dementia (56; 75). Cholesterol may have little or no role in the etiology of white matter hyperintensities (79; 81).

Histopathology and imaging changes. The histopathology in Binswanger disease is characteristic. The only typical gross external abnormality is slight gyral atrophy. Hydrocephalus ex vacuo is seen on sectioning. Discrete lacunae are seen in 93% of cases, typically in the centrum semiovale, internal capsule, and basal ganglia. The corpus callosum may be thinned but it is not ischemic. Confluent areas of white matter discoloration occur separately from the infarcts and are commonly occipital, periventricular, and sometimes frontal, but the changes are primarily in the centrum semiovale and around the ventricles. In these areas, the pathology is variable. The earliest changes are of swollen myelin sheaths and oligodendrocytes. Subsequently, incomplete demyelination and loss of oligodendrocytes develop followed by fragmentation of axis cylinders (02). Axons may be relatively preserved. Rarefaction and cavitation with scattered microcystic areas of infarction follow. Gliosis and myelin loss are associated with periventricular white matter hyperintensities whereas axonal loss, vacuolization, and arteriosclerosis are more commonly associated with deep white matter hyperintensities (32). Subcortical association fibers are characteristically spared from direct lesions, but axons in the white matter remote from the lesions are reduced in number, presumably by Wallerian degeneration. Carotid disease may also coexist. Cortical infarcts occur in up to one third of cases and simply represent other manifestations of vascular disease. Enlargement of the lateral ventricles is typical. The arterioles supplying the deep white matter exhibit lipohyalinosis with perivascular lymphocytes. Some vessels show hypertrophy of smooth muscle cells, and others, where fibrosis has occurred, show a decrease (43). A longitudinal MRI study followed the fate of small diffusion-weighted imaging positive (DWI+) infarcts in 54 patients with small vessel disease (90). Of the 39 DWI+ lesions originally reported on 21 scans in 9 participants, 2 lesions evolved into areas of white matter hyperintensity, 4 changed to the appearance of lacunar infarcts, 3 evolved into microbleeds, and 27 of the DWI+ lesions were no longer detectable after follow-up at 10 months.

Cerebral perfusion changes. Within the deep white matter, stable xenon-enhanced CT shows that cerebral blood flow is decreased to a similar degree in both Alzheimer disease and multi-infarct dementia. This has been used to suggest chronic ischemia as an etiologic mechanism for the subcortical white matter hyperintensities of subcortical vascular cognitive impairment, but PET does not support this. More recent studies have shown that hypoperfusion is the consequence of white matter hyperintensities rather than the cause (85). An interesting study of patients with internal carotid occlusion demonstrated that cortical microinfarcts were more common on the ipsilateral side of carotid occlusion than on the contralateral side, arguing for hypoperfusion as a contributing cause for this type of small infarcts (96). Another study found that cerebrovascular reactivity was lower in patients with cerebral amyloid angiopathy (n=26), compared to age-matched controls (n=39) (04). Lower cerebrovascular reactivity in grey matter in these patients was associated with poorer global cognitive abilities, memory, and executive function. Even in older adults with normal cognition or mild cognitive impairment, lower cerebrovascular reactivity correlates with poorer global cognitive scores (88).

Axonal function. There is evidence for impairment of axonal transport, perhaps also on an ischemic basis, and diffusion tensor imaging shows changes outside regions that are abnormal on standard MRI, which may reflect functional and structural changes within fibre tracts (49; 59). Mean diffusivity and tractography correlate better with cognition and gait than does the simple volume of white matter hyperintensities (19; 53; 67; 114). Changes in diffusivity both predict and correlate with developing lesions and atrophy, suggesting that they are pathological and not just part of normal aging (17). Loss of axons leads to remote localized cortical thinning, which may lead to further cognitive and gait impairment and similarly, cortical atrophy correlates with extent of white matter hyperintensities (51; 95; 50).

Genetic risk. The primary pathology in subcortical vascular cognitive impairment includes arteriolar changes but the genetic factors that lead to extensive small vessel disease in these patients are not fully understood. There is increasing evidence for genetic susceptibility. This might be suspected as it is a common clinical experience that subcortical white matter hyperintensities are not directly related in severity to hypertension and may progress over time in those with low-normal blood pressures. There is now direct evidence that genetic factors may play an important part in lacunar infarction and in the development of white matter hyperintensities, for which heritable factors account for 70% of variability (52; 93; 78).

Apolipoprotein epsilon4 homozygotes have more white matter hyperintensities, and these patients progress more quickly than in heterozygotes or noncarriers (30). The APOE-e2 allele increases the risk of beta-amyloid deposition in brains of subcortical vascular cognitive impairment patients, compared to those who are e3/e3 carriers, but the e4 allele increases the risk even more (54). The APOE-e4 allele is seen in more cerebral amyloid angiopathy cases, compared to age-matched controls (74; 09). In the Dutch-type of hereditary cerebral amyloid angiopathy, an autosomal dominant disorder, MRI changes of white matter hyperintensities and microinfarcts precede cognitive changes and intracerebral hemorrhages (100; 84). Those with cerebral microbleeds, independent of cerebral amyloid angiopathy, are more likely to carry an APOE-e4 allele (31; 58).

Those with hyperhomocysteinemia in association with MTHFR mutations are at increased risk of subcortical white matter hyperintensities and lacunar stroke, but not other stroke types (77). COL4A1 mutations have been recognized as producing subcortical white matter hyperintensities, usually in conjunction with intracerebral hemorrhage and retinal changes (73). Data from the UK Biobank found a locus in the VCAN gene (76) and the PLEKHG1 gene (94). A useful review has been provided by Marcus and Schmidt (60).

Monogenic inherited conditions are well recognized. One condition is autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), which is caused by a mutation on the NOTCH3 gene (14). Early symptoms of patients with CADASIL include migraine and stroke whereas later symptoms include dementia and pseudobulbar affect. Another condition, confined mostly to Japan, is known as autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), where patients can also have stroke before the age of 40 but they also have unique features of premature loss of hair (alopecia) and attacks of low back pain (111). Another condition, CARASAL (cathepsin A-related arteriopathy with strokes and leukoencephalopathy), has been described (08).

Breakdown of the blood-brain barrier. Breakdown of the blood-brain barrier is demonstrable in subcortical vascular dementia (41; 37; 104), and plasma proteins can be found in glial cells in close relation to white matter hyperintensities. Matrix metalloproteinases can open the blood-brain barrier, and MMP-3 is increased in subcortical vascular cognitive impairment. Whether these changes are causal or merely consequences of ischemia remains to be established, although extravasated plasma proteins are known to be neurotoxic. Decreased local blood flow and increased blood-brain barrier permeability correlate with each other and are associated with white matter hyperintensities (110).

Enlarged perivascular spaces. Enlarged perivascular spaces, thought to reflect impaired drainage of interstitial fluid, correlate with subcortical infarcts, microbleeds, progression of white matter hyperintensities, and the development of incident all-cause and vascular dementia (21; 70; 65; 06). Specific correlation has been demonstrated between enlarged spaces in the hippocampus and verbal reasoning (44), although the correlation between enlarged perivascular spaces and cognition measured crudely using the MMSE in the general population did not reach significance (40). Nevertheless, enlarged perivascular spaces are markers for dysfunctional perivascular flow, a sign of poor interstitial clearance of beta-amyloid and other proteins (104; 06).

Interaction with Alzheimer pathology. Small vessel disease and Alzheimer pathology commonly coexist. Where this occurs, much of the progression of cognitive impairment by domain is related to the pathology; for example, higher white matter hyperintensities correlate with more rapid progression of executive dysfunction, whereas a greater burden of amyloid correlates with more rapid progression of episodic memory, a domain predominantly affected in Alzheimer disease (112; 38). In general, it is the total burden of comorbid pathologies rather than either vascular or Alzheimer pathology that determines cognitive impairment, the presence of only one type offering some protection (106). Among older nondemented individuals, those with abnormal beta-amyloid biomarkers are at increased risk for accelerated disease progression along the Alzheimer continuum if they also have signs on MRI of small vessel disease (white matter hyperintensities, lacunar infarcts, or cerebral microbleeds) (27). This synergistic effect was not seen among those who had already reached the dementia stage of Alzheimer disease. Others have examined the interaction of small vessel disease with beta-amyloid in predementia patients and found that there were synergistic effects of beta-amyloid with white matter hyperintensities but not with lacunes or microbleeds (80; 64). One study showed that greater baseline white matter hyperintensity volumes were associated with shorter times to the onset of mild cognitive impairment symptoms in participants with low CSF total tau levels and that there was no interaction between WMH volume and CSF p-tau or CSF A-beta levels (87).

Epidemiology

The limited number of cases reported makes estimating the incidence and prevalence of subcortical vascular dementia nearly impossible. Some limited data are, however, available. In 1 study of 1000 autopsies of elderly patients, 3.8% had pathological evidence of subcortical vascular dementia. This figure increased to 6.7% when restricted to patients with cerebrovascular disease (91). Vascular cognitive impairment has been shown to be more prevalent among genetically proven CADASIL patients (39.8%) than among age-matched controls (10.2%) (46). In this study, the lacune count was the only MRI parameter associated with vascular cognitive impairment; therefore, it is assumed that these patients qualified as having subcortical vascular cognitive impairment.

Prevention

There are few data on prevention of subcortical vascular cognitive impairment. Risk factor modification, especially hypertension, is appropriate. There is now evidence from the SPRINT-MIND study that intensive treatment of hypertension (vs. standard blood pressure control) in those 50 years of age and older reduces risk of developing mild cognitive impairment (HR=0.81) (108). A meta-analysis demonstrated the efficacy of antihypertensive medication in reducing white matter hyperintensities but not atrophy (99). This may be especially true where hypertension coexists with diabetes (18). Regular physical activity can halve silent infarcts, but does not affect white matter hyperintensities (107). Anticoagulation in those with atrial fibrillation may have a role through prevention of subclinical infarcts (11; 103); anticoagulation reduces vascular dementia by as much as 29% in those with atrial fibrillation (42). Extensive observational data suggest that greater physical activity in later life may protect against cognitive decline, an effect that could be mediated through modification of vascular risk factors. However, observational data could not eliminate the possibility that those of the elderly who were more active were already better cognitively; a randomized trial of physical activity in the sedentary elderly supports this possibility, as it showed no benefit for physical activity in preventing cognitive decline (86). Conversely, good cardiovascular health appeared to be protective (66). Smoking cessation is also recommended for those with vascular cognitive impairment (42).

Differential diagnosis

A variety of other conditions may cause similar white matter changes on imaging but should be readily distinguishable from subcortical vascular dementia on other criteria. These conditions include multiple sclerosis, acute disseminated encephalomyelitis, carbon monoxide poisoning, progressive multifocal leukoencephalopathy, HIV-associated dementia, Creutzfeldt-Jakob disease, Pick disease, Alzheimer disease, leukodystrophies, gangliosidoses and mucopolysaccharidoses, metabolic disease (hepatic and renal failure), hypertensive encephalopathy, methotrexate leukoencephalopathy, and radiation encephalopathy.

Confusing conditions

Conditions that may be confused with subcortical vascular dementia on both clinical and neuroimaging grounds are relatively few. Normal-pressure hydrocephalus is the most important of these, as its classical presenting triad of gait disorder, urinary incontinence, and cognitive impairment may resemble subcortical vascular dementia. It may occur in the same age group and periventricular white matter changes will be seen in both conditions. Nevertheless, the pattern of white matter changes may differ, with deep white matter changes in the subcortical vascular dementia group being more prominent.

Progressive supranuclear palsy, especially when associated with cognitive decline, shares several clinical similarities (gait apraxia, dysarthria, abulia, pseudobulbar affect) but a history of hypertension and extensive subcortical white matter changes on MRI should help to distinguish subcortical vascular cognitive impairment. In addition, progressive supranuclear palsy patients are more likely to experience early falls, to have vertical gaze palsy, and to have a reduced midbrain to pons ratio on MRI (61).

Patients with systemic lupus erythematosus have been shown to have a high burden of small vessel disease features on MRI, even though they had fewer vascular risk factors than age-matched stroke controls (109). In particular, they had many enlarged perivascular spaces.

Diagnostic workup

MRI. Because a wide range of conditions can resemble subcortical vascular dementia radiologically, appropriate findings on the history and clinical examination are mandatory. Neuroimaging is required and in advanced cases may demonstrate extensive white matter changes involving most of the centrum semiovale and sparing the U-fiber region, corpus callosum, and internal capsule. Extensive caps on the horns of the lateral ventricles and prominent periventricular rims of white matter change on MRI are not sufficient to make a diagnosis of subcortical vascular dementia but are compatible with the early subcortical vascular cognitive impairment.

Lacunar infarcts in the deep white matter and basal ganglia are common. There is almost no correlation between focal histopathological change and MRI findings, all degrees of histopathological change short of infarction appearing broadly the same on MRI. Consequently, there is no close correlation between the location of white matter lesions and frontal and executive cognitive impairment. Microbleeds, best detected using T2*-weighted MRI, are associated with small vessel cerebrovascular disease and correlate with increased cognitive impairment and are common, rising from 6.5% in those aged under 50 years to over a third in those 80 years or older (71). Cerebral microbleeds are especially common in patients with cerebral amyloid angiopathy (03), but other risk factors for microbleeds besides cerebral amyloid angiopathy are increased age and the APOE-e4 allele (31; 58). Other vascular disease may coexist, but cortical infarcts, infarcts outside the centrum semiovale and large white matter infarcts (as distinct from confluent lesions) are not part of subcortical vascular dementia alone and suggest the presence of additional patterns of vascular dementia. It is always difficult to be sure that the white matter changes seen, especially on MRI, and the history of stroke are the only causes of cognitive decline. In cases of hereditary cerebral amyloid angiopathy, MRI scans can show white matter hyperintensities, cerebral microbleeds, and microinfarcts before cognitive or neuropsychiatric symptoms develop (100; 03).

Lumbar puncture. The removal of at least 20 cm³ of cerebrospinal fluid may help identify normal-pressure hydrocephalus, if indicated by the history and neurologic examination. CSF examination for IgG index and oligoclonal bands should be done if there is any question of multiple sclerosis. There are no diagnostic positive findings in the CSF in subcortical vascular dementia. A slightly raised protein may be seen occasionally (the CSF protein level should be no higher than the patient’s age). Further investigation of the brain is rarely required and should be directed to the differential diagnosis in the case in question.

Other tests. Other treatable causes of dementia should be excluded with biochemistry, hematology, thyroid function, vitamin B12, and vitamin D. The cardiovascular system should not be neglected. To identify modifiable vascular risk factors, electrocardiography, echocardiography, and carotid duplex Doppler examination should be performed. Genetic testing for the NOTCH 3 mutation is indicated if CADASIL is suspected (14). Amyloid PET is a potential biomarker for cerebral amyloid angiopathy because the amyloid ligand is capable of labeling vascular amyloid. Binding of the amyloid ligand to vascular amyloid takes place to a lesser degree than to the amyloid plaques of Alzheimer disease (84; 62).

Management

Antihypertensive medications. Blood pressure reduction in the early predementia stage of subcortical vascular cognitive impairment is recommended because the SPRINT-MIND study showed that intensive blood pressure management of less than 120 systolic (vs. standard management of less than 140 systolic) was effective in reducing the risk of mild cognitive impairment in hypertensive older adults over a 5-year follow-up period (108). Nevertheless, this trial demonstrated no benefit of intensive blood pressure management in reducing risk of dementia. It is possible that these aggressive blood pressure management efforts were ineffective for preventing dementia once subcortical vascular cognitive impairment was already established. In fact, tight blood pressure control may actually be harmful for chronically hypertensive individuals who have lost the ability to autoregulate as a way to maintain normal cerebral perfusion pressure. The findings of the SPRINT study were consistent with the earlier results of PROGRESS, where use of perindopril reduced the risk of mild vascular cognitive impairment by 19% but had no effect on risk of dementia (42). These authors suggested that standard blood pressure control in vascular cognitive impairment patients was still recommended for the sake of stroke prevention.

Cholinesterase inhibitors. Twelve placebo-controlled studies have been performed with cholinesterase inhibitors in vascular dementia patients who had been free of any dementia drugs for at least 6 weeks prior to the trial (12). The clinical trials of donepezil (doses of 5-10 mg/day) showed significant cognitive benefit using the ADAS-cog as an endpoint. Galantamine trials were also successful but the rivastigmine trials (only 2) did not show any cognitive benefit. These rivastigmine trials did, however, demonstrate behavioral benefit. In 1 long-term prospective study of subcortical vascular dementia patients treated with rivastigmine (n = 245), improvement was seen in behavioral symptoms, as measured by the BEHAVE-AD scale (48). Another 26-week trial showed significant behavioral improvement with rivastigmine (6 mg/d) in subcortical vascular dementia patients using the neuropsychiatric inventory scale (NPI) as an endpoint. Donepezil provided little cognitive benefit for vascular cognitive impairment patients with CADASIL (20). In that study, there were no significant differences between the effects of donepezil and placebo on change in the primary endpoint at 18 weeks (vascular-ADAS-cog score). There were significant changes, however, in 2 of the secondary outcome measures (both executive function scores).

Other behavioral treatments. Emotionalism (pseudobulbar affect) is common in patients with subcortical vascular cognitive impairment. The Cochrane Database performed a systematic review on this topic, identifying 7 trials (239 participants) where emotionalism appeared following stroke. It found moderate quality of evidence that antidepressants significantly reduced tearfulness and that the effect was not specific to any given drug (01). When pseudobulbar cases are more difficult to treat, there is also the alternative of dextromethorphan/quinidine, although the price is often prohibitive (83). Some patients with subcortical vascular dementia experience psychosis and agitation, especially when mixed dementia is present (15; 16). These authors reviewed strategies of optimizing doses of cholinesterase inhibitors and memantine, as well as using sequential trials of citalopram, gabapentin, and atypical antipsychotic drugs, such as quetiapine, to manage agitation and other disruptive behaviors. When psychotic symptoms develop in dementia patients, it is important to investigate potential underlying factors, such as pain, sleep disturbances, and total number of medications (34).

Nonpharmacological treatments. Physical activity (at least 30 minutes of activity on at least 3 days per week) reduces the risk of cognitive impairment and vascular dementia in older adults, independent of age, education, or severity of subcortical white matter changes (102).

Special considerations

Anesthesia

There is no specific information. As the deep white matter may have limited autoregulatory reserve, avoidance of hypotension, hypoxia, and drugs that impair autoregulation is prudent.