José A. Luchsinger, MD, MPH, Florence Irving Associate Professor of Medicine and Epidemiology in the Gertrude H. Sergievsky Center and Taub Institute at NYPH/CUMC Columbia University, discusses his paper, "Subcortical cerebrovascular disease in mild cognitive impairment," which was recently published in Neurology® (2009; 73:450-456). He spoke with AAN.com Science editor, José G. Merino, MD, MPhil.
AAN.com: Dr. Luchsinger, thank you for the opportunity to discuss your paper. Can you please summarize the major findings of your study?
Luchsinger: We used MRI and neuropsychological tests to study 679 elderly people without dementia living in the community. We found that the presence of cerebral infarcts and white matter changes on MRI was associated with mild cognitive impairment (MCI). These lesions had different effects on cognitive function. The volume of white matter hyperintensities (WMH) was strongly related to memory impairment (amnestic MCI), while the presence of cerebral infarcts was associated with impairment in executive, visuospatial, and language functions (non-amnestic MCI).
AAN.com: What is mild cognitive impairment and how do you differentiate it from occasional cognitive lapses that are common at any age at one extreme and early dementia at the other?
Luchsinger: MCI is a transitional stage between normal cognition and dementia. It is defined by the presence of cognitive complaints and objective impairment on neuropsychological tests but without functional impairment. The latter is a feature of dementia. MCI may be a precursor (but not invariably so) of subsequent dementia. The cutoff most commonly used in cognitive tests to define impairment in a cognitive domain, and the one we used in the study, is performance 1.5 standard deviations below the norms for age- and sex-matched controls. We diagnosed amnestic MCI when an individual met the cognitive impairment criterion in memory tests, and non-amnestic MCI when an individual met this criterion in tests of executive function, language, and visuospatial ability.
AAN.com: What is the relationship between MCI and vascular cognitive impairment (VCI)?
Luchsinger: VCI is a term used when cognitive deficits of any severity (from MCI to severe dementia) are present in patients with vascular risk factors or vascular disease. While in many instances the cognitive profile of patients with mild VCI is similar to that seen in patients with non-amnestic MCI, some definitions of VCI include patients with amnestic MCI with a vascular contribution.
AAN.com: White matter hyperintensities (WMH) and cerebral infarcts are often considered surrogate markers for cerebrovascular disease, and in earlier studies both types of lesions were associated with impairment in executive function rather than memory loss. Why do you think that, in your study, cerebral infarcts and WMH led to different patterns of cognitive impairment? What do your findings imply about the etiology of white matter hyperintensities?
Luchsinger: We do not fully understand the mechanisms by which WMH lead to cognitive impairment. The traditional view is that small vessel disease leads to ischemia of the white matter, and that the lesions lead to cognitive impairment by interrupting cortical-subcortical circuits that are critical for cognition, particularly executive function. It is increasingly recognized, however, that WMH are heterogeneous; they have multiple etiologies and pathological correlates. They may be caused by vascular, neurodegenerative, or other factors. There is a growing literature, for example, on the association between WMH and cerebral amyloid angiopathy, and WMH are an important correlate of Alzheimer's disease. I think that the assumption that WMH on MRI are surrogate markers of ischemia needs to be revised, and we need to conduct more research to differentiate the various types of WMH. It is possible that in our sample, some of the WMH were due to neurodegeneration and other processes that accompany Alzheimer's disease, such as cerebral amyloid angiopathy, rather than small vessel disease induced ischemia.
AAN.com: Did the location or extent of white matter lesions and cerebral infarcts affect the cognitive profile?
Luchsinger: We did not have data to address this issue. As mentioned above, lesions that interrupt cortical-subcortical circuits may lead to cognitive and behavioral changes. Presumably, lesions in the hippocampus lead to memory impairment. We are currently conducting analyses examining if the location of white matter lesions is related to different types of cognitive impairment.
AAN.com: Can you comment on the association of cerebrovascular pathology and Alzheimer's disease?
Luchsinger: There is a growing awareness that Alzheimer's disease and VCI are two ends of a spectrum, and that most patients with cognitive impairment have vascular and neurodegenerative pathology. Vascular lesions are very common in the brains of the elderly. Hypertension, diabetes, inflammation, and other vascular diseases are risk factors for developing Alzheimer's disease. Infarcts seem to lower the threshold of brain amyloid pathology necessary to manifest dementia. The role of WMH is less clear, in my opinion.
AAN.com: From your study, can you draw any inferences about the etiology of MCI and the progression to dementia?
Luchsinger: Our study is cross-sectional, and we cannot make inferences about progression to dementia. We are following this sample and should be able to address this question in the future. Prior studies have shown that stroke-free individuals with MCI are more likely than age-matched controls with normal cognition to develop Alzheimer's disease. Studies with patients with cerebrovascular disease also show that those with cognitive impairment shortly after a stroke are more likely than those without cognitive changes to develop dementia five years later. These findings highlight the fact that MCI is not benign. With regards to the etiology of MCI, we need to conduct more research to clarify the etiology of the WMH.
AAN.com: What are the clinical implications of your findings? Should all patients who have moderate or severe white matter hyperintensities or silent infarcts on MRI undergo formal neuropsychological testing?
Luchsinger: Clinicians should be aware that patients who have infarcts or extensive WMH on brain imaging, even in the absence of a stroke history, are at high risk of having MCI. These patients, and their families, should be questioned for evidence of impairment in memory, language, visuospatial ability, and executive function. Their clinical examination should include tests for impairment in these domains. We need to conduct trials to assess whether more aggressive treatment of vascular risk factors in these persons leads to better outcomes. The evidence, however, does not yet warrant recommendations or guidelines requiring formal neuropsychological testing for all these patients.
Within the past 24 months, Dr. Luchsinger served as Associate Editor for the Journal of Alzheimer's Disease. In the last five years, he has also received research support from NIH, ADA, Alzheimer's Association, Fidelity Foundation, and the Institute for the Study of Aging.
Dr. Merino performed a one-time consultation with staff from Bell, Falla and Associates.