Vascular Cognitive Impairment - Vascular Cognitive Impa...

Vascular Cognitive Impairment

Cognitive impairment commonly accompanies clinical syndromes associated with vascular disease of the brain. Because of evolving definitional criteria, however, the frequency of cognitive impairment attributable to cerebrovascular disease is difficult to determine. Dementia occurs in up to one-third of elderly patients with stroke, a subset of whom have Alzheimer's disease (AD) rather than a pure vascular dementia syndrome. In fact, pure vascular dementia has been shown to be uncommon in most large autopsy series. A mixed etiology of AD and cerebrovascular disease is thought to become more common with increasing age, although no clinical criteria for the diagnosis of AD with cerebrovascular disease are currently available. Epidemiological studies have implicated subcortical small-vessel disease as a risk factor for cognitive impairment and dementia, but the cognitive expression and clinical significance of MRI white matter changes in individual patients is difficult to establish. The frequency of specific neuropathologic features of vascular cognitive impairment depends largely on study inclusion criteria. Cerebral meningocortical microangiopathies with distinctive clinicopathological profiles are associated with dementia in both sporadic cases and familial syndromes. In patients with AD, the contribution of amyloid-β protein to the degree of cognitive impairment has not been clearly defined.


Selnes OA, Vinters HV. Vascular Cognitive Impairment. Nat Clin Pract Neurol. 2006;2(10):538-547.

Introduction

Cognitive impairment is part of the clinical presentation of several conditions associated with cerebrovascular disease, but the precise frequency of vascular cognitive disorders is difficult to ascertain. Clinicopathological studies of various selected or unselected populations have shown a remarkable heterogeneity of vascular and brain parenchymal lesions,[1-3] and classification schemes based on clinical,[4] radiological[5] and neuropathologic[1,6] criteria have been proposed. In this Review, only the major subtypes of vascular cognitive impairment will be considered.[4]

Diagnostic criteria for vascular dementia have evolved over the past two decades,[7] but several obstacles to widespread acceptance of these definitions are recognized. Modeled after Alzheimer's disease (AD), early definitions of vascular dementia (VaD) disproportionately emphasized deficits of new learning and memory, rather than the pattern of motor slowing and executive deficits typically associated with VaD. The requirement that patients with VaD should have cognitive impairment of sufficient severity to interfere with activities of daily living is now acknowledged as too restrictive, because it does not allow cases to be identified early enough for diagnostic interventions. The severity and type of lesions on neuroimaging required for a diagnosis of VaD remain controversial, and the requirement of a temporal link between the onset of cognitive changes and neuroimaging changes restricts case identification predominantly to VaD secondary to infarcts.[8]

The term 'vascular cognitive disorder' was proposed by Sachdev[9] to define vascular cognitive deficits of sufficient severity to meet criteria for a diagnosable disorder. It was intended as an umbrella term to include the spectrum of impairment from mild 'vascular cognitive impairment' (VCI) to VaD.[10] The development of a single, uniform set of criteria that apply to all subtypes of VCI has clearly been challenging, and some experts have recommended that separate criteria be developed for certain subtypes, such as non-infarct-related subcortical small-vessel disease.[11] The aim of this Review is to provide a brief overview of the current state of scientific knowledge in the field of VCI, with an emphasis on its neurocognitive and neuropathologic aspects.


Subtypes of Vascular Cognitive Impairment


Post-stroke Dementia

The prognosis for recovery of cognitive symptoms, including aphasia, after an initial stroke is generally favorable, but some patients do not show the expected recovery, and instead develop persistent or progressive cognitive decline.[12] Because older patients at risk for stroke have an increased risk of dementia even in the absence of a stroke, the inclusion of elderly controls is crucial for interpreting the results of post-stroke dementia (PSD) studies.[13,14] PSD has long been considered the prototypical subtype of VaD, and it might therefore be expected that all patients with PSD would meet the criteria for VaD. Surprisingly, however, only one-third of such patients have been reported to meet the diagnostic criteria for AD.[12,15] This finding is consistent with epidemiological data showing that risk factors for cerebrovascular disease are common in patients with AD,[16] and also that many patients diagnosed with PSD have cognitive impairment even before their stroke.[12,17]

The most important demographic predictor of PSD is age; the association with stroke risk factors is less robust.[12] Degree of pre-existing subcortical white matter disease, infarct volume, and global and medial temporal lobe atrophy, have been identified as some of the relevant imaging determinants of post-stroke dementia,[18] and cortical hypoperfusion might also play an important role.[14] Stroke characteristics, such as lesion volume and location, appear to be less predictive of PSD. A greater degree of severity of cognitive impairment after stroke has been associated with increased risk of PSD.[15,19] The apolipoprotein E ε4 allele is a risk factor for AD, but it does not appear to be associated with increased risk of PSD.[20]

Strategic Infarct Dementia. The view that a certain threshold volume of brain tissue loss (e.g. >50-100 ml) predictably causes dementia is no longer widely accepted; smaller infarcts in particular regions, for example in the deep central gray matter, might have an equally important role in causing dementia.[1] Lacunar infarcts involving the thalamus, internal capsule and basal ganglia are sometimes associated with surprisingly widespread cognitive effects, including confusion and memory impairment.[21] Infarcts involving the dorsomedial and anterior thalamus might also produce significant executive symptoms and profound amnesia, which can persist in some cases.[22] Prospective follow-up studies have shown that, although initially quite severe, cognitive symptoms associated with strategic infarcts are often reversible by 12 months, and they are therefore not a common cause of persistent dementia.[23]

In summary, there is substantial evidence that stroke in the context of advanced age confers an increased risk of dementia. Nonetheless, the risk of PSD appears to be more closely related to the severity of pre-existing white matter abnormalities, atrophy and hemodynamic factors than to the stroke characteristics themselves. Although generally easily recognized clinically, PSD represents only the proverbial 'tip of the iceberg' of the spectrum of VCI.[24]


Alzheimer's Disease With Cerebrovascular Disease

Determining the neurobehavioral and neuroimaging correlates of ischemic brain lesions occurring in the context of significant AD alterations can be a daunting task, and the usefulness of the traditional strict dichotomization between AD and VaD has recently been challenged.[25] Evidence is accumulating that AD is commonly associated with vascular risk factors, including diabetes,[26] hypertension and smoking.[16] Whether these associations are causal or coincidental co-occurrences of common age-associated conditions is not known.

Many individuals with AD, especially those beyond 85 years of age, show significant vascular comorbidity, to the extent that they are more accurately characterized as having mixed vascular-AD dementia.[27] In longitudinal studies and large clinicopathological series with necropsy confirmation, the observed morpho-anatomical substrates are largely determined by study entry criteria. Autopsy investigations in individuals who develop dementia after large cortical or subcortical cystic infarcts will show different patterns of lesions from studies in which patients are selected for a high likelihood of deep lacunar infarcts or subcortical white matter alterations, including leukoaraiosis.[6,28] Such populations of patients are also likely to differ in their clinical progression; those with small deep lacunar infarcts (especially within the white matter) or multiple microinfarcts are less likely to show a stepwise progression of cognitive impairment than are those with regions of substantial cystic encephalomalacia. In one large autopsy series, 'pure' VaD was seen in 9.4% of 900 individuals with dementia, but in only 2.9% of patients with the clinical diagnosis of probable or possible AD.[29] Some investigators suggest that VaD might account for only 2-3% of dementias,[30] and others claim that 'pure' VaD is almost nonexistent in large dementia series, even when careful necropsies are performed.[31] Even though a mixed etiology is likely to be more common than either pure AD or VaD among older patients, there are no current clinical criteria for ante-mortem diagnosis of mixed dementia.[4]


Subcortical Small-vessel Ischemic Disease

White matter hyperintensities and lacunar infarcts demonstrated by MRI are generally considered to be evidence of small-vessel or microvascular ischemic disease, although some are related to dilated perivascular spaces.[1] White matter abnormalities on MRI are common in otherwise healthy community-dwelling individuals.[32] The prevalence of these abnormalities increases sharply with age, and other risk factors include hypertension, diabetes and genetic factors.[33,34] In patients with known cardiovascular disease, such as candidates for coronary artery bypass grafting, the prevalence has been reported to be as high as 50%.[35] Pathologically, MRI white matter signal abnormalities reflect focal and diffuse lesions of the subcortical and periventricular white matter, as well as lacunes and microinfarcts of the central gray matter.[36]

Because white matter abnormalities are so common in otherwise asymptomatic individuals, they are often considered to be benign. There is increasing evidence, however, that white matter abnormalities on MRI are associated with an increased risk of dementia. In cross-sectional studies, individuals with more-severe white matter lesions had a twofold increased risk of dementia.[37] In prospective studies, the presence of periventricular white matter lesions at baseline was found to double the risk of future dementia.[21] There is also evidence that progression of white matter disease is accompanied by a decline in cognitive performance, supporting an etiological link between the white matter changes and cognitive decline.[32,38]

Although epidemiological studies have clearly established an association of subcortical white matter lesions with poorer performance in specific cognitive domains,[39] the cognitive expression of subcortical small vessel disease in individual patients is highly variable. In a patient who presents with mild cognitive impairment and mild subcortical white matter lesions, the etiological significance of the white matter lesions cannot be easily determined. Neither a history of risk factors for cerebrovascular disease nor the clinical presentation can establish that the cognitive symptoms are causally related to the white matter findings. On the one hand, there are case reports of patients with MRI-documented widespread white matter disease whose cognitive functioning is normal even by detailed neuropsychological testing.[40] On the other hand, it is also well known that white matter abnormalities are commonly seen in patients with AD.[41]

Although there is no cognitive profile that is entirely specific for subcortical vascular disease, neuropsychological testing can nevertheless identify whether the overall pattern is predominantly cortical or subcortical. In patients who present with cognitive changes in the context of risk factors for cerebrovascular disease, and with MRI findings of subcortical white matter disease, the finding of a predominantly subcortical profile will significantly increase the likelihood that the cognitive symptoms are of vascular origin. The profile of neuropsychological test findings alone cannot rule out possible primary or coexisting AD, but if follow-up testing demonstrates stable or relatively minor change over time, this can further support a diagnosis of VCI.

An important but unresolved question is whether subcortical small-vessel disease by itself can lead to cognitive impairment of sufficient severity to meet the criteria for dementia. Overall, the cognitive expression of isolated white matter hyperintensities appears to be limited to mild motor and psychomotor slowing rather than a pervasive, severe degree of cognitive impairment.[42] There is growing evidence, however, that the subcortical white matter changes visualized on conventional MRI might be incomplete markers of more-widespread, 'covert' hypoxia-ischemia-related injury.[43,44] With improvements in the ability to quantify the overall burden of vascular disease affecting the brain, including the presence of hypoperfusion,[45,46] microinfarcts[47,48] and amyloid angiopathy,[49] a more-precise assessment of the relationship between cerebrovascular changes and cognitive impairment might become possible.


Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary non-amyloid type of small-vessel disease that is commonly associated with cognitive impairment or dementia.[50,51] It results from either a gain or a loss of one or three cysteine residues in the extracellular N-terminal region of the NOTCH3 gene, which is located on chromosome 19p13.[52] Affected deep cerebral arteries show destruction of the smooth cell layer in their media, accompanied by progressive wall thickening, and luminal narrowing caused by this thickening and fibrosis. Clinically, the condition is characterized by recurrent subcortical strokes in patients aged between 40 years and 60 years. The clinical manifestations include cognitive impairment and psychiatric symptoms, with a generally variable clinical course.[53] Some patients may initially present with only migraine headaches and no cognitive symptoms. The diagnosis is made by a combination of characteristic MRI findings and genetic testing.


Neurocognitive Considerations

There has been considerable debate with respect to the specificity of the cognitive profile associated with VCI. Some people have argued that there is significant overlap between the cognitive profiles of subcortical vascular disease and cortical dementias such as AD.[54,55] Others have suggested that the cognitive profile of subcortical vascular disease can be distinguished from that of AD principally by milder memory impairment but more-pronounced impairment of executive functions.[56,57]

For several reasons, it has been difficult to resolve the question of the specificity of the cognitive profile of VCI. First, if all etiologies of VCI are considered together, there is little reason to expect a consistent cognitive profile. The cognitive profile of dementia secondary to large cortical infarcts might depend on both the location and volume of the lesion, and would consequently be highly variable. Second, because comprehensive cognitive testing cannot easily be performed in large clinical or community samples, many of the studies with detailed testing have been limited by modest sample sizes.[58,59] A third reason why some investigators have not found consistent differences between the cognitive profiles of vascular and AD-type cognitive impairment is that not all cognitive domains have been explored in sufficient detail. One of the more robust neuropsychological characteristics of patients with subcortical disease is a slowing of motor and psychomotor speed,[39] a feature that is not typically associated with cortical dementias. Because most studies have not included measures of motor speed in their test battery, however, psychomotor speed has not generally been considered to be a unifying feature of VCI.[55,59]

Studies that have focused on patients with VCI of sufficient severity to meet the criteria for dementia have generally found impairments across most cognitive domains, with more similarities to than differences from AD. These studies are likely to have included a subset of patients with dementia of mixed etiology.[55,60] In patients with less-severe cognitive impairment, a more distinctive cognitive profile might be discernable. Garrett and colleagues reported that the neuropsychological performance of a small group of patients with cognitive impairment (but no dementia) was characterized by disproportionate executive dysfunction and deficits in verbal retrieval.[59] Data from Looi and colleagues[61] also confirm an overall profile of less-severe memory impairment and greater executive impairment in VaD. Several investigators have reported a profile of memory impairment that includes better preservation of recognition memory performance relative to free recall in patients with VCI.[58,62] In studies of patients with CADASIL, who are generally younger and therefore less likely to have concomitant AD pathologic changes, speed of processing has consistently been identified as impaired, with somewhat less-pronounced but significant deficits in areas of executive performance and attention. It has been suggested that this pattern of impairment represents the core of the cognitive syndrome associated with small-vessel subcortical ischemic disease.[63-65]

Only a few studies have examined the cognitive profile of autopsy-confirmed cases of VCI and dementia.[66] These studies have emphasized considerable variability in the clinical presentation and the profile of neuropsychological test findings.

Although the cognitive profile of subcortical VCI might vary somewhat according to both etiology and severity of the disease, the pattern of relative preservation and impairment is nonetheless helpful in a clinical setting. In a patient in whom the history, imaging findings and clinical presentation are otherwise consistent with subcortical vascular disease, a neurocognitive profile of relatively preserved language and recognition memory, but with significant motor and psychomotor slowing and impaired executive performance, can be considered to be supportive of a diagnosis of probable VCI rather than AD.


Neuropathologic Substrates of Vascular Cognitive Impairment

From a neuropathologic perspective, the problem of studying ischemic VaD can be reduced—with the understanding that this is a huge oversimplification—to examining three major inter-related, yet functionally separable, pathophysiologic components: cerebrovascular disease, systemic mediators of ischemic brain necrosis (which of course might interact with cerebrovascular disease), and the CNS parenchymal lesions that we recognize as being the result of cerebrovascular disease and systemic factors. Once irreversible parenchymal injury has occurred, there are downstream and retrograde effects in the CNS that result from the insult—as a function of Wallerian, trans-synaptic and other types of degeneration (Figure 1)— which almost certainly affect subsequent neurobehavioral morbidity in ways that we do not yet understand.[4,67] Subcortical axonal injury and loss might be key elements in VaD pathogenesis and progression.[68] The identity of the neuropathologic substrates of leukoaraiosis, which also affects subcortical white matter, is still controversial, but might include apoptosis of oligodendroglia.[69]

Figure 1. Conceptual framework for etiology and pathogenesis of ischemic vascular dementia, taking into account cerebrovascular disease, systemic factors and ischemic necrosis of the brain, as well as retrograde or downstream effects of focal ischemic lesions. Abbreviations: AS = arteriosclerosis; CAA = cerebral amyloid angiopathy; CADASIL = cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy; FMD = fibromuscular dysplasia; LH = lipohyalinosis; spor/fam = sporadic/familial.

Ischemic parenchymal lesions in patients with VaD vary in size. In a longitudinal California-wide study of patients pre-selected for a high likelihood of subcortical ischemic lesions, especially lacunar infarcts (based on ante-mortem neuroimaging studies), we have arbitrarily subcategorized infarcts seen at autopsy as cystic infarcts (larger than 1.0 cm in greatest dimension), lacunar infarcts (grossly visible on cut sections of the brain but smaller than 1.0 cm in size), and microinfarcts (not seen on gross inspection of the cut brain, but identified by microscopy; see Figure 2).[6] Immunohistochemical stains that are especially helpful for demonstrating microinfarcts include those using primary antibodies against CD68 or other macrophage-microglial markers, and those using primary antibodies against glial fibrillary acidic protein (GFAP). Both of these stains highlight areas of localized proliferation of cells that react to irreversible ischemic injury. The roles of astrocytes and microglia—and the factors that they secrete—in the progression of subinfarctive ischemia are not yet known. Abundant old cortical microinfarcts render the cortical surface irregular; an affected brain is sometimes described as showing 'granular atrophy', even though the causal lesions are infarctive rather than atrophic.

Figure 2. Microscopic appearance of brain lesions commonly encountered in the brains of individuals with cerebrovascular disease and dementia. (A,B) Two small arteries with marked 'onion skin'-type thickening in the brain of a 68-year-old man. (C) A slit-like microinfarct (arrows) perpendicular to the pial surface (left), with a larger triangular region of necrosis at its base near the cortex-white matter junction. (D) Small old linear parenchymal infarct (arrows) filled with macrophages.

Cystic infarcts often result from occlusion of large meningeal arteries affected by atherosclerosis, sometimes as a result of atheroemboli that lodge within them—such atheroemboli might also originate in severely atherosclerotic carotid or vertebral arteries in the neck.[70] Cystic infarcts can also occur as wedge-shaped regions of encephalomalacia in the border zone between two large territories of supply by cerebral arteries. As discussed above, strategically placed small infarcts might be just as likely to lead to dementia as larger infarcts.[1,71]

Lacunar infarcts have historically been attributed to arteriosclerotic microangiopathy affecting cerebral parenchymal arteries, a process sometimes described as lipohyalinosis and linked etiologically to longstanding hypertension, although that association has recently been called into question.[28,72] Therefore, the term 'hypertensive microvascular disease' as a synonym for lipohyalinosis is best avoided. Lacunar infarcts (Figure 3) have been further classified into various subtypes on the basis of their neuropathologic components; the different types include Ia (small cystic cavity containing small blood vessels and a few macrophages), Ib (incomplete necrosis with perivascular rarefaction and patchy astrocytic gliosis), and II (an old microhemorrhage with abundant hemosiderin-laden macrophages).[72] Hippocampal injury, often resembling hippocampal sclerosis, identified in the medial temporal lobes of patients with intractable temporal lobe epilepsy (with severe segmental neuron loss in the CA1 segment of the pyramidal cell layer and frequent preservation of CA2) is now recognized as a common neuropathologic finding in the CNS of elderly patients with dementia, and should probably be considered as part of the spectrum of VaD.[6,73]

Figure 3. Lacunar infarcts. (A) Lacunar infarct (arrowhead) in the left basal ganglia of a patient with dementia. Larger cystic infarcts (arrows) are seen at the junction of the right basal ganglia with the adjacent white matter, and in the white matter of the right centrum semiovale. (B) Lacunar infarcts in the pons of a different patient (arrows). Lacunar infarcts are thought to be one consequence of longstanding hypertension, although the strength of this association has recently been questioned.


Cerebral Amyloid Angiopathy

Cerebral amyloid angiopathy (CAA) describes an enigmatic microangiopathy that affects meningeal and cortical arterioles, venules and capillaries, whereby the normal vessel wall becomes replaced by fibrillar amyloid.[74-76] The most common form of CAA is an age-related vasculopathy that appears to be confined to the brain. CAA is strongly associated with AD, such that almost all AD patients have some degree of CAA when this is diligently sought by multiple sections from autopsy brains.[77-79] In rare cases, individuals with prominent CAA lack other neuropathologic characteristics of AD (senile plaques and neurofibrillary tangles), and might not show signs of dementia during their lifetime.[80] Severe CAA, in which the medial layer of many or most cortical arterioles is completely replaced by amyloid, is also comparatively rare. Replacement of the smooth muscle cell layer of the arteriolar media by fibrillar amyloid renders the vessel susceptible to spontaneous rupture, which can occur with mild increases in intravascular pressure or when thrombolytic agents are administered.[76] This can result in nontraumatic lobar cerebral hemorrhage, although this is an infrequent occurrence considering the vast numbers of individuals who have some degree of CAA.[74,77] In biopsy or autopsy brain specimens, antibodies to amyloid-β (Aβ) protein (especially Aβ1-40, as opposed to Aβ1-42) effectively immunolabel arteriolar and capillary walls, showing that vascular amyloid in CAA is similar to the amyloid in senile plaques.[75]

A small subset of patients with sporadic or age-related CAA develop superimposed vasculitis. This granulomatous vasculitis, often with a significant giant cell component, appears to result from amyloid deposition in arteriolar walls, rather than being a cause of amyloid deposition.[81] Recent studies have indicated that vasculitis with CAA might present with a clinically distinctive syndrome of rapid cognitive decline and seizures, rather than cerebral hemorrhage.[82] There is also growing interest in the likelihood that patients with severe CAA might represent an underappreciated variant of VaD (Figure 4).[83] In our California-wide longitudinal study of individuals at high risk for VaD, as many as 8-10% of those examined at necropsy showed severe CAA, often with associated cortical microinfarcts, severe subcortical leukoencephalopathy or both. It might be predicted that all of these individuals would also have advanced (Braak stage V-VI) AD, but instead, a subset of them showed 'Alzheimerization' of the CNS that did not extend to the isocortical stage. Further characterization of this interesting patient group is in progress. In large case-control studies, Aβ CAA has been established as a risk factor for cerebral ischemic infarcts.[84]

Figure 4. Cerebral amyloid angiopathy, sporadic, with extensive old microinfarcts throughout the CNS. The specimens were taken from a 77-year-old patient who was considered clinically to have Alzheimer's disease (AD), and who showed significant AD changes in the hippocampus and neocortex at autopsy. (A,B) Hematoxylin and eosin-stained sections (at low and high magnification, respectively) show severe thickening of cerebral parenchymal arterioles, in which the media has been replaced by eosinophilic 'glassy' hyaline material (arrows). (C) Amyloid-β (Aβ) immunohistochemistry shows replacement of many arteriolar walls by Aβ-immunoreactive material (arrows). (D) Multiple remote microinfarcts (similar to those indicated by arrows) and microhemorrhages were found throughout all areas of the cortex. (E) Infarcts were highlighted by CD68 and glial fibrillary acidic protein (GFAP) immunohistochemistry (this panel shows anti-GFAP immunoreactivity).

An autosomal dominant syndrome of dementia and stroke (cerebral hemorrhage), characterized by extensive, often overwhelming and widely distributed meningocortical CAA, results from a point mutation in codon 693 of the gene that codes for amyloid precursor protein (APP). The resulting disease, which is observed in circumscribed regions of the Netherlands, is described as hereditary cerebral hemorrhage with amyloidosis, Dutch-type (HCHWA-D).[74,85] Interestingly, dementia in these patients clearly appears to be linked to the severity or burden of CAA rather than to the density of senile plaques and neurofibrillary tangles.[86] This indicates that sporadic, age-related or AD-associated CAA, especially when severe, might be a significant—perhaps even defining—factor in the cognitive decline in this disorder. Other familial syndromes in which Aβ-immunoreactive CAA is a dominant neuropathologic finding result from mutations in codons 692-694 of the APP gene.[74,76] Very recently, a neuropathologically 'pure' form of CAA was identified in association with an autosomal dominant APP L705V point mutation within the Aβ sequence.[87]


Conclusions

The field of cerebrovascular disease and cognitive impairment has made significant progress over the past decade, including the discovery of CADASIL, the first genetic form of a vascular cognitive disorder. Several challenges lie ahead, however. Population-based epidemiological studies suggest a continuum of AD-type pathology and vascular brain disease, and the relatively arbitrary separation of AD and vascular dementia may no longer be the most productive approach. Improvements in neuroimaging have demonstrated that brain microvascular disease becomes increasingly common with advancing age, but the poor correlation with degree of cognitive impairment indicates that better measures to capture the total burden of vascular disease of the brain are needed. Ultimately, the importance of better understanding of the pathophysiology of dementia with cerebrovascular disease is the potential that some of the risk factors might be treatable, so that the incidence of this age-related disorder might eventually be reduced.


Sidebar: Key Points

* Several clinical subtypes of vascular cognitive impairment due to vascular disease are now recognized, ranging in severity from mild cognitive impairment to dementia

* The risk of dementia after stroke is increased in older patients and in those with pre-existing cognitive impairment or cerebrovascular disease

* The cognitive consequences of subcortical small-vessel disease is variable, suggesting that the subcortical white matter changes visualized on conventional MRI might be incomplete markers of the total burden of cerebrovascular disease

* The cognitive profile of vascular cognitive impairment is predominantly subcortical, with prominent psychomotor slowing and executive deficits, but relatively preserved language and recognition memory

* From a neuropathologic perspective, the morphologic substrates or correlates of vascular dementia are extremely heterogeneous

* Cerebral microvascular diseases, both sporadic and genetically determined, including cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and cerebral amyloid angiopathy, are instructive in terms of providing pathologic models of age-related arteriopathies and their consequences for brain parenchyma

* The brains of aged individuals are likely to show impaired function as a consequence of combined 'Alzheimerization' and cerebrovascular disease


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Acknowledgments

Technical assistance provided by Justine Pomakian and Negar Khanlou. We thank Pamela Talalay for her editorial assistance.
Reprint Address

Division of Cognitive Neuroscience, Johns Hopkins University School of Medicine, Reed Hall East 2, 1620 McElderry Street, Baltimore, MD 21205-1910, USA. Email: oselnes@jhmi.edu

Nat Clin Pract Neurol. 2006;2(10):538-547. © 2006 Nature Publishing Group