Evaluation of Vascular Cognitive Impairment: To White Matter and Beyond

Cognitive impairment and dementia have become a pervasive reality with the rapidly growing number of elderly individuals living to greater than 80 years of age in the majority of developed countries. Dementia is projected to affect approximately 6.4% of the population, and the vascular contributions to cognitive impairment and dementia account for about 25% of the dementia subtypes.[1] Vascular contributions to declining cognition have been referenced under many different names over the years, including multiinfarct dementia, vascular dementia (VaD) and even poststroke dementia.[2,3] However, it is this ambiguity and heterogeneity in terminology that necessitated further evaluation by the authors. Gorelick and colleagues explored the spectrum of vascular contributions to cognitive impairment and dementia, and created a scientific statement from the American Heart Association/American Stroke Association to serve as a guide to practitioners on the prevention, diagnosis, and treatment of vascular cognitive impairment.[4]

The initial step was to develop a uniform definition that incorporated all previous terminology. The umbrella term vascular cognitive impairment (VCI) was utilized by the authors to describe the varying degrees of clinical cognitive impairment that are associated with cerebrovascular disease (CVD) or injury.[5] VCI is characterized by the presence of a cognitive disorder confirmed by neuropsychological testing and either a clinical or a neuroimaging diagnosis of vascular disease that is suggestive of a connection between the cognitive disorder and the vascular disease.[4] The spectrum ranges from VaD, the most severe form of VCI, to vascular mild cognitive impairment, the mildest form of VCI. The authors are quick to point out that VaD can coincide with other types of cognitive disorders, particularly Alzheimer dementia (AD).[6] Unlike AD, memory impairment is not required for the diagnosis of VCI and is often associated with impairment of executive function.[7] The complexity of VCI can make identification challenging, but the implementation of a standard language allows for more consistent investigation into the neuropathophysiology, risk factors, prevention, treatment options, and research initiatives in VCI.

Cerebral infarcts are the most common cerebrovascular abnormality contributing to VCI.[8] The extent to which infarct volume and infarct location contribute to VCI, however, remains a controversial topic. Cerebral infarcts also appear to augment the affects of AD pathology by causing cognitive decline and increasing the susceptibility of developing dementia.[9] Other cerebrovascular abnormalities addressed by the authors include white matter degeneration and primary vessel disease, but further clinical studies are required to determine if they serve as a primary contributor or a marker of VCI.[10] Neuroimaging plays a substantial role in identifying cerebrovascular pathology. However, more data is needed to determine the significance of microscopic changes that are not appreciated on current neuroimaging modalities and to clarify the relationship between overlapping pathologic changes seen in both VCI and AD.[11] It is evident, however, that neurovascular dysfunction plays a significant role in the development of VCI and AD.[12]

The authors highlight the association between VCI and cerebral amyloid angiopathy (CAA). There may be multiple pathophysiologic mechanisms that contribute to this association.[13,14] Hereditary small vessel syndromes, specifically cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), are another cause of VCI.[15] Although more research is needed to establish specific disease modifying therapies, the authors conclude that it is reasonable to treat cardiovascular risk factors in cases of suspected CAA or CADASIL (Class IIa, Level of Evidence C). It remains unclear if early vascular aging significantly contributes to VCI, but noninvasive evaluations of arteries such as measurements of intima-media thickness may play a promising role in determining the significance.[16] Magnetic resonance imaging of the brain is used to evaluate the CVD-associated brain injury (CVBI), which includes white matter lesions (WML), brain atrophy and silent cerebral infarctions (SCI). Although the relationship between CVBI and VCI remains hazy, it is suggested based on prospective studies that the progression of SCI and WML may act as a marker for VCI.[17,18] The authors conclude that is it reasonable to use brain imaging in constructing a diagnosis of VCI (Class IIb, Level of Evidence B).

To evaluate the risk factors associated with VCI, the authors reviewed studies that confirmed VCI according to NINDS-CSVCI harmonization standards [5] and studies that provided Class I evidence. It is not surprising that VCI appears to be more common with increasing age, similar to AD.[19] The identification of genetic factors may eventually play an important role in the diagnosis of VCI. As expected, multiple studies have shown that smoking increases the risk of cognitive impairment.[20] In addition to smoking cessation (Class IIa, Level of Evidence A), the authors also conclude that moderate alcohol consumption, weight control, and physical activity are reasonable interventions for individuals at risk for VCI (Class IIb, Level of Evidence B).

Other notable physiologic risk factors for VCI include hypertension, hyperglycemia, and hypercholesterolemia. Treatment of hypertension is recommended, particularly in middle-age individuals, although few large clinical blood pressure trials have actually included cognitive assessments as part of the trial.[21,22] Treatment of hyperglycemia and hypercholesterolemia may be reasonable for individuals at risk of VCI; however the usefulness of treatment to prevent dementia is uncertain.[23,24] These vascular risk factors also appear to be risk factors for AD.[25] Stroke increases the risk of VCI, which is due to both direct and indirect causes.[26] Other concomitant diseases that have an association with VCI are CAD, peripheral vascular disease, atrial fibrillation, and cardiac failure. Studies suggest that treating vascular risk factors in midlife rather than late life is beneficial.[22,27]

There have been multiple clinical trials in VCI over the past decade. However, pharmacologic trials to date have been relatively disappointing and only show modest benefit in cognitive measures.[28] These findings are likely the result of the aforementioned challenges to identify VCI and subsequently exclude concomitant AD. Future trials will surely benefit from the updated clinical guidelines and advancement in diagnostic testing. Few nonpharmacologic studies have been completed, but the authors suggest refreshing ideas for alternative interventions such as acupuncture and cognitive rehabilitation.

As health care costs in the United States continue to rise, the prevention and treatment of dementia become an important public health care agenda. VCI can be challenging to identify, but the authors have provided a rigorous review highlighting the improved understanding of VCI pathophysiology and risk factors in recent years. However, despite these advancements, large prospective clinical trials are needed to identify vascular biomarkers, prevention strategies, and both pharmacologic and nonpharmacologic treatments. The authors acknowledge these limitations and effectively provide the impetus to establish future research programs in VCI.