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Could Fractional Anisotropy Reveal Premotor Parkinson’s Disease?


 

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PHILADELPHIA—The midportion of the nigra may be significantly different on fractional anisotropic analysis in patients with Parkinson’s disease, compared with controls, according to research presented at the 66th Annual Meeting of the American Academy of Neurology. Fractional anisotropic analysis may also reveal differences between controls and patients with REM sleep behavior disorder, who are at increased risk of developing Parkinson’s disease.

Investigators are seeking a biomarker for the early detection of Parkinson’s disease because diagnosis occurs too late for neurologists to intervene effectively with neuroprotective or neurorestorative strategies, said Matthew Brodsky, MD, Associate Professor of Neurology at Oregon Health and Science University in Portland. Patients with REM sleep behavior disorder are a valuable cohort to consider because the onset of this disorder typically predates the onset of motor symptoms in Parkinson’s disease by a decade or more, he added.

“Our hypothesis was that fractional anisotropic analysis of the posterior lateral portion of the nigra pars compacta would be reduced in patients with Parkinson’s disease, and that a smell identification test and this imaging finding might be reduced in a subset of patients with REM sleep behavior disorder who ultimately develop Parkinson’s disease,” said Dr. Brodsky.

Comparing Three Patient Groups
To test their hypothesis, Dr. Brodsky and colleagues recruited patients with REM sleep behavior disorder and age-matched healthy controls from the community. The researchers also enrolled patients with Parkinson’s disease who presented to their clinic in Portland. REM sleep behavior disorder was confirmed with polysomnography according to criteria in the International Classification of Sleep Disorders. All participants underwent various tests, including the University of Pennsylvania Smell Identification Test (UPSIT) and the Unified Parkinson’s Disease Rating Scale (UPDRS).

Two blinded neuroradiologists drew three 29-mm3 regions of interest to be examined on imaging. The regions divided the nigra into thirds just below the red nucleus. Patients underwent diffusion tensor MRI on a 3-T scanner, and a blinded research assistant performed fractional anisotropic calculations. For each patient, the researchers analyzed the three regions of interest, as well as the entire nigra. For patients with Parkinson’s disease, the investigators also analyzed the more affected side of the brain, based on the side of the body that symptoms and signs were present. All participants were followed up for two years.

One Patient Developed Parkinson’s Disease During Follow-Up
Data were available for three patients with Parkinson’s disease, three participants with REM sleep behavior disorder, and three controls, but several outcomes were statistically significant, said Dr. Brodsky. Participants’ ages ranged from the late 30s to the mid-50s. Disease onset occurred between nine and 20 months before enrollment for patients with Parkinson’s disease. These individuals had mild to moderate disease.

The most lateral segment of the nigra had no significant change in patients with Parkinson’s disease, compared with controls. This finding was a surprise, said Dr. Brodsky, based on a previous investigation. The investigators did observe a trend, however, toward a reduction in this segment in patients with Parkinson’s disease, compared with controls.

One patient with REM sleep behavior disorder had an UPSIT score of 11, and the other two patients with REM sleep behavior disorder had UPSIT scores in the mid-30s, which is closer to normal. The patient with the lowest UPSIT score had no additional symptoms at one year but had an asymmetric rest tremor and bradykinesia on finger tapping at two years. In addition, the patient’s total and motor UPDRS scores were much higher than those of the controls and other subjects with REM sleep behavior disorder and suggested early Parkinson’s disease.

Results May Indicate Cell Loss in Nigrosome 1
The pilot data demonstrated changes in the midportion of the nigra in patients with early Parkinson’s disease, compared with age-matched controls, based on fractional anisotropic analysis with diffusion tensor imaging (DTI). This finding “may be consistent with loss of tissue in nigrosome 1,” said Dr. Brodsky. “Although on average we did not see new changes in our subjects [with REM sleep behavior disorder], it was interesting to find that this one patient who went on to develop signs of Parkinson’s disease had significantly reduced fractional anisotropic values, highlighting the potential utility of this technique.”

Other researchers recently have examined fractional anisotropic analysis with diffusion tensor MRI in asymptomatic people at risk of Parkinson’s disease. One study of agricultural workers found a difference in FA values on DTI between patients with Parkinson’s disease and controls. A separate meta-analysis suggested that evidence does not support the utility of fractional anisotropy with DTI for identifying patients with early Parkinson’s disease. Nevertheless, an imaging biomarker is a necessary step toward earlier neuroprotective interventions in Parkinson’s disease, Dr. Brodsky concluded.

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