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Cortex Thickness Provides Possible Marker for Alzheimer Disease Progression



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In imaging studies, the change in the thickness of the cortex was a strong marker for progression to Alzheimer disease.

Investigators at Harvard's Massachusetts General Hospital, in collaboration with a group at the Washington University's Alzheimer's Disease Research Center, in St. Louis, have identified cortical areas that are atrophying in people with only possible hints that dementia may be on the horizon.

Bradford C. Dickerson, MD, who heads a neuroimaging laboratory and is an associate professor of neurology at Harvard Medical School, and his colleagues wanted to see whether people with mild cognitive impairment (MCI) had a “cortical signature” that could help identify those who would develop AD.

The St. Louis team, led by John C. Morris, MD, PhD, analyzed structural MRIs from 49 people with MCI, or questionable AD. The investigators identified nine regions of interest using the data from previous studies in patients with mild Alzheimer dementia. [See figure 1]. They compared cortical thickness in these regions in those with MCI with previous imaging scans done with 29 patients with mild AD and 115 older healthy controls.


INVESTIGATORS FOCUSED ON NINE REGIONS OF INTEREST based on earlier data and studies: the medial temporal cortex (A), inferior temporal gyrus (B), temporal pole (C), angular gyrus (D), superior front gyrus (E), superior parietal lobule (F), supramarginal gyrus (G), precuneus (H), and inferior frontal sulcus (I).

About two and a half years later, 20 of the 49 people with MCI had progressed to mild Alzheimer dementia. The others remained stable. At baseline, all 49 subjects had a mild degree of cortical thinning compared to older adults who had no symptoms according to neuropsychological tests. Those who progressed showed temporal and parietal thinning compared to those who had no change in cognition.

The investigators reported that the change in the thickness of the cortex was a strong marker for progression to AD — predicting progression to mild AD with 83 percent sensitivity and 65 percent sensitivity, according to the findings published online Dec. 24 ahead of the print March 24 Neurology.

Many previous MRI studies of brain structure focused on changes in the entorhinal cortex and the hippocampus — the two areas hit early in the disease. But although entorhinal-hippocampal measures may still be valuable markers, this new “cortical signature” may provide additional value in predicting disease progression, said Dr. Dickerson, because AD also affects other brain regions early in the course.

“Such an approach employing disease-signature cortical regions of interest is powerful in that it enables hypotheses to be tested about the sequence of involvement of cortical regions in AD progression through comparison of effect sizes from cross-sectional data from patients at different clinical stages in the disease,” the study authors wrote.

Cortical thinning was seen before clinical signs of Alzheimer disease emerged, they added. “Neurologists and psychiatrists know that most patients with mild Alzheimer disease have cognitive problems beyond memory — including executive functioning, language, and processing visual-spatial information,” Dr. Dickerson said. Indeed, they found thinning in multiple cortical regions associated with those abilities in patients with early AD — and the same regions had started to thin years before a diagnosis could be made.

The findings raise many questions. How do these cortical abnormalities relate to the symptoms in these patients who, at the time of scanning, had only the faintest hints of cognitive trouble? Does imaging these cortical regions of interest add more to the predictive features of scans that measure the volume of the hippocampus, the entorhinal cortex, or the whole brain?

In the study, Dr. Dickerson and his colleagues found strong relationships between the average thickness of the nine AD-signature regions and the MMSE (Mini-Mental State Examination) performance as well as CDR-SB (Clinical Dementia Rating) scale. This was of interest, the authors said, especially since some people have symptoms of cognitive decline in daily life but can still perform fairly well on testing, especially in the earliest stages of the disease. The CDR-SB scores correlated with the thickness of the ventromedial temporal and lateral parietal regions and the MMSE scores matched with changes in the superior frontal and lateral parietal thickness. Dr. Dickerson said that these relationships connect the imaging measures with clinical features of the disease that many doctors understand, providing validation.

The investigators admit that one of the main limitations of the study is that the diagnosis of AD was not confirmed by either autopsy or other imaging markers. When they followed up more than two years later, they did not perform another MRI. Such tests would be useful to provide additional evidence that each person in fact has Alzheimer disease, and studies are ongoing to obtain that kind of information.

For David S. Knopman, MD, professor of neurology at the Mayo Clinic in Rochester, MN, the most interesting aspect of the finding was that the brain scans were able to track changes in the cerebral cortex that matched the disease progression that the study doctors were observing clinically. “This confirms what has been seen in autopsy studies, the observation that Alzheimer progresses from the medial temporal cortex to the neo-cortex as patients move from memory problems to more pervasive cognitive difficulties.”

Ultimately, such a technology may be useful in helping test new treatments aimed at slowing this degenerative process, he added. “If a therapy could delay the pathology, this tool would be able to detect whether it was working to slow the progression of the disease.”

While the finding is potentially important, “it needs to be replicated,” said Michael W. Weiner, MD, director of the Center for Imaging of Neurodegenerative Disease at the VA Medical Center and professor of medicine, radiology, psychiatry, and neurology at University of California-San Francisco. As principal investigator of the Alzheimer's Disease Neuroimaging Initiative (ADNI), Dr. Weiner said that the federally-funded initiative that shares its data online would be a perfect dataset to test Dr. Dickerson's hypothesis of cortical thinning. ADNI has brain scans from over 800 elderly people. Dr. Weiner said that the idea for measuring cortical thinning became possible in the past few years.


• Bakkour A, Morris JC, Dickerson BC. The cortical signature of prodromal AD: Regional thinning predicts mild AD dementia. Neurology 2008: E-pub 2008 Dec. 24.