Paper of the Month: White matter change as early MRI markers of cognitive decline

This month's featured paper is from the laboratory of Dr. Lisa Silbert, and is titled, "Trajectory of white matter hyperintensity burden preceding mild cognitive impairment." It was published in the journal Neurology. The research in this paper was conducted by investigators in the OHSU Department of Neurology and the Department of Neurology, Portland Veterans Affairs Medical Center.

“This analysis from the NIA/Layton Aging & Alzheimer’s Disease Center neuroimaging lab is a fabulous example of how carefully designed and conducted cohort studies can provide important insights into disease causation and progression. The OHSU research team has been the source of many advances in the neuroscience of aging.”
- Eric Orwoll, M.D.
Associate Dean for Clinical Science

Dementia is a medical disorder characterized by loss of brain function such as thinking, memory, and judgment that interfere with a person's daily life. In the later stages of the condition affected persons may be disoriented to time, place and person. It occurs more frequently in the elderly, though is not considered a normal part of aging. The most common form of dementia is Alzheimer's disease, which affects about 5.4 million people in the United States alone.

Mild cognitive impairment (MCI) is a precursor to dementia. Unlike
MCI is defined by memory loss that does not significantly impact daily functioning, and may be minimal to mild and hardly noticeable to the individual.People with MCI have an increased risk of eventually developing Alzheimer's or another type of dementia.

Scientists in the Lisa Silbert Lab are focused on MCI, and how the progression of white matter burden might signal the early onset of dementia.

Previous studies, according to Dr. Silbert, have shown that increased rate of hippocampal and brain volume loss, and increased rate of ventricular cerebrospinal fluid (vCSF) volume expansion are MRI markers that can predict cognitive decline.

The Silbert team measured dementia risk by examining white matter lesions in elderly patients as it developed over the course of several years.

"White matter lesions that show up as areas of high signal intensity on T2 or FLAIR MRI sequences are extremely common in older individuals, and are thought to be due, in part, to small vessel ischemic disease," said Dr. Silbert. "Few previous studies have looked at white matter change as a potential early indicator of cognitive decline risk. Results from our investigation put a focus on the timing of white matter hyperintensity (WMH) burden acceleration in relationship to MCI, a potential precursor to Alzheimer's and other forms of dementia. It's a significant step forward in understanding the emergence of cognitive impairment in the elderly."

brain92512Unlike other scientists in the U.S. and world, the team had an exceptionally long duration of longitudinal MRI data available to them—19.6 years of data—thanks to the Oregon Brain Aging Study (OBAS, PI Dr. Jeffrey Kaye).

Using this data, the Silbert team examined the yearly MRIs of 181 cognitively intact elderly OBAS men and women, tracking rates of WMH progression in relation to the onset of MCI, and reported their findings in a recent paper titled, Trajectory of white matter hyperintensity burden preceding mild cognitive impairment (Neurology).

In previous cross-sectional studies, the team found that baseline WMH burden was associated with poorer cognitive and motor function, and increased risk of cognitive decline. Additionally, greater rates of WMH progression were discovered to be associated with increased risk of MCI.

In this latest study, the data showed that of the 181 subjects participating in the investigation, 134 of them eventually converted to the MCI stage. MRI analysis of these individuals revealed that an acceleration in WMH volume increase occurred 10.6 years before MCI onset. In contrast, acceleration in the vCSF volume model occurred 3.7 years before the onset of the disorder.

Of those with MCI who converted to dementia, most had a clinical diagnosis of Alzheimer's disease. Of those with dementia who eventually had brain autopsy, only 45 percent had AD pathology as the sole etiology of their dementia, with almost just as many subjects having coexisting vascular pathology.

Dr. SilbertResults from this study show that WMH burden acceleration predates the onset of MCI by many years (as much as a decade), and occurs prior to changes in other brain volumes, thus demonstrating that white matter integrity disruption is a very early marker of MCI. "The fact that a minority of those with autopsy who subsequently converted to dementia had AD as their sole pathology highlights the importance of co-pathologies, particularly cerebrovascular disease, in the etiology of dementia in the elderly," said Dr. Silbert.

Furthermore, WMH acceleration occurring 10.6 years prior to MCI conversion also raises the question as to whether these white matter lesions may partially represent axonal degeneration secondary to cortical beta-amyloid deposition, as prior studies have estimated a temporal lag of approximately 10 years between the deposition of Abeta and the clinical syndrome of AD.

"I think in the field of dementia research, there is a recent increased interest in the effects of other pathologies on the clinical expression of dementia in older populations," said Dr. Silbert. "I would like to continue to pursue this line of research, with a focus on white matter integrity change."

Results from this study support the idea that WMH progression is an important predictor of cognitive decline, and that this could be used as a very early MRI marker of dementia risk. Dr. Silbert said future studies will be needed to determine whether these MRI-detected white matter lesions are related to atherosclerotic or neurodegenerative disease, or whether there is some component of both involved. "Ultimately, identification of factors that decrease WMH accumulation over time could be used in treatment and prevention trials aimed at preserving cognitive health in our growing elderly population."

The team's findings were published in the journal Neurology.

Photos: (top) Commonly observed age-related white matter hyperintensity lesions detected by brain MRI; (bottom) Lisa Silbert, M.D.

*Paper Authors

Lisa Silbert, M.D., MCR (1, 2)
Hiroko Dodge, Ph.D. (1)
Louie Perkins, B.S. (1)
Lena Sherbakov, M.S. (1)
David Lahna, B.A. (1)
Deniz Erten-Lyons, M.D. (1, 2)
Randall Woltjer, M.D., Ph.D. (1)
Lynne Shinto, N.D. (1)
Jeffrey Kaye, M.D. (1, 2)


(1) OHSU Department of Neurology

(2) Department of Neurology, Veterans Affairs Medical Center, Portland, OR.


The School of Medicine newsletter spotlights a recently published faculty research paper in each issue. The goals are to highlight the great research happening at OHSU and to share this information across departments, institutes and disciplines. The monthly paper summary is selected by Associate Dean for Basic Science Mary Stenzel-Poore, PhD.

More Published Papers

The entire list of OHSU papers published this month is here.