A framework for differential diagnosis of three of the most common dementia disorders using analysis of structural MRI of the brain was proposed by Mayo Clinic investigators in Rochester, MN, at the International Conference on Alzheimer's Disease in Vienna, Austria, in July.
The technique appears to be a promising way to differentiate Alzheimer disease (AD), frontotemporal lobar degeneration (FTLD), and Lewy body disease (LBD).
The investigators calculated the overall pattern of lost gray matter in each person, producing the “STructural Abnormality iNDex” or STAND-Map. Each neurodegenerative disorder was studied using pathologically confirmed cases. The researchers found that each type was associated with a unique pattern of atrophy. That pattern could then be applied prospectively to new patients.
They mined their database for autopsy cases with a confirmed diagnosis of one of the three dementias and looked at scans that had been obtained when people were alive. They found that the STAND-Maps for each type of dementia mirrored the known anatomic distribution of pathological neurodegeneration as recorded in the literature.
“We have a lot of cases in our database, beginning in 1990,” said Prashanthi Vemuri, PhD, a senior research fellow at the Mayo Clinic aging and dementia imaging research lab and the lead author of the study. Dr. Vemuri said that “at this point, we are only looking at the gray matter, and this performs reasonably well” in this preliminary work to distinguish among the three types of dementia in living patients. Currently we can only confirm the type of dementia postmortem, she added.
All 90 patients had brain imaging at initial evaluation and had subsequent tissue confirmation of only one dementia type at postmortem examination. Forty-forty patients had AD, 18 LBD, and 28 FTLD. FTLD was restricted to the behavioral variant, which affects social skills, personal conduct, and self-awareness. Patients may show such behavioral symptoms as stubbornness, emotional coldness, apathy, and selfishness.
The accuracy of differential diagnosis based on the patterns of atrophy for AD was 81 percent, for FTLD 90 percent, and 88 percent for LBD, said Dr. Vemuri. “I would say the numbers are good especially for LBD.”
Dr. Vemuri said that FTLD is often clinically distinct from the other two dementias, yet a behavioral issue that appears to signal FTD can turn out to be due to Alzheimer disease. “There is a lot of syndromic overlap,” she said.
None of the patients had mild cognitive impairment; all had dementia. Dr. Vemuri said that eventually the team hopes to see if MCI could be classified as an early stage of any of the dementias.
Study co-author Ronald Petersen, MD, PhD, professor of neurology, and research director of the Alzheimer's Disease Research Center at the Mayo Clinic College of Medicine in Rochester, MN, noted that the imaging pattern that emerged validated the STAND-Map approach. “The scans did have predictable patterns,” Dr. Petersen said.
In Alzheimer dementia, the disease affects the medial temporal lobe, he explained. The damage in FTLD is most pronounced in the frontal and temporal lobes. In Lewy body dementia the degeneration is apparent in the medial temporal lobes, more subtle in other brain regions.
“The naked eye is pretty good especially in trained observers, but the changes can be subtle. This technique gives you an actual score,” Dr. Petersen said. “STAND-Map also gives values for an individual subject,” he added, “whereas in most clinical trials for these disorders, data are reported for groups.”
“It needs replication by others but it is an important step in that direction,” Dr. Petersen said.
“If this approach is confirmed in a larger series of patients, it could significantly improve accuracy in identifying specific dementias pre-mortem,” said Erik P. Pioro, MD, PhD, director of the section of ALS and related disorders at the Neurological Institute of the Cleveland Clinic. Dr. Pioro, who commented by e-mail, uses neuroimaging in ALS and ALS-FTD patients.
“Although available treatment of these dementias is limited at present, this will hopefully change,” Dr. Pioro added. He noted, “in order to perform clinical trials with the correct types of patients, an accurate pre-mortem diagnosis is critical.”
He added that even if a cure is unavailable, knowing the correct diagnosis is important in coping with what the future will bring, for patients and for families.
“Presently, the accuracy of premortem diagnosis of dementia is limited and usually requires pathologic confirmation by postmortem examination. This means that frequently, the diagnosis of dementia and specifically what type of dementia it is, is incorrect until the specific brain pathology is revealed by postmortem examination,” Dr. Pioro said.
The unique aspect of this study was that the investigators obtained pathological confirmation in patients who had been scanned when they were suspected to have one of the three most common dementias.
“We definitely think an earlier and more accurate diagnosis is critical,” said Maria Carrillo, PhD, director of medical and scientific affairs for the Alzheimer's Association, “as the diagnosis is now based on exclusionary criteria. Patients and families put quite a bit of effort into neuropsychological tests and brain imaging scans to exclude other diagnoses. We know we need something better, at minimum a diagnosis not as time-consuming for the person and the caregiver, and health professional.” Dr. Carrillo noted that the process can take months, and patients may need to schedule return visits to repeat tests to observe whether their cognitive status has declined further.
Structural MRI with a volumetric determination is considered one of the leading possible biomarkers in dementia, said Dr. Carrillo. As compared to an aggregate of six to ten hours of testing required for a diagnosis today, Carrillo said, “one session and one STAND-Map would be an advantage, if an accurate diagnosis could be based on this technology.”
“Though there are no disease-modifying drugs available today,” Dr. Carrillo said, “there are opportunities for people with early stage to benefit, particularly in clinical trials, which provide participants with better health care, and potential therapies that are experimental and only available through trials.”