BARCELONA – Preliminary evidence of brain amyloid-beta deposition in patients with Parkinson’s disease and varying degrees of cognitive impairment suggests that the timing and amount of Alzheimer’s pathology present may influence when and if dementia symptoms arise.
"Accepting this model leads to some new directions for potential treatment," said Dr. John Growdon, director of the memory and movement disorders clinic at Massachusetts General Hospital, Boston. "If there is evidence of concomitant Alzheimer’s pathology, as imaged by [Pittsburgh compound B], we should consider applying some of the antiamyloid treatments under development for Alzheimer’s in our Parkinson’s disease dementia patients."
Dr. Growdon presented the results of a longitudinal cohort study of 74 patients, which included 26 of 41 patients who were initially evaluated in a 2008 cross-sectional study. This original group of 41 patients included 8 with dementia with Lewy bodies (DLB), 7 with Parkinson’s disease dementia, 11 Parkinson’s disease patients with normal cognition, 15 with Alzheimer’s disease, and 37 control subjects (Neurology 2008;71:903-10). They all underwent PET imaging with Pittsburgh compound B (PiB) and cognitive and neuropsychological testing. PiB binds to amyloid-beta plaques in the brain.
He differentiated DLB and Parkinson’s dementia by the timing of the onset of dementia symptoms: "When someone goes from Parkinson’s over the years to develop dementia, we call it Parkinson’s disease dementia. If the dementia starts simultaneously with or before the motor symptoms, we call it dementia with Lewy bodies."
That initial cross-sectional study found that amyloid burden in the DLB group was similar to that in the Alzheimer’s group. Amyloid burden in the Parkinson’s dementia group was similar to that found in the cognitively normal Parkinson’s patients and the normal controls.
Imaging in the initial study also revealed that amyloid in the Parkinson’s disease patients aggregated in the lateral parietal, precuneus, and posterior cingulate region and was related to visuospatial impairment.
"When we pulled together all the data we accumulated in the initial study, we saw PiB binding varied significantly across the diagnostic groups," Dr. Growdon said at the meeting. "There was an apparent clean separation of PiB uptake in Lewy body dementia and Parkinson’s disease dementia, and we wondered whether amyloid burden might contribute in a meaningful way to both the behavior and cognitive problems seen in Lewy body dementia."
He said the investigators were also "struck by the fact that half our nondemented Parkinson’s patients had substantial PiB uptake, raising the question that these individuals might be on the path to developing dementia."
In the current cohort of 74 patients (33 Parkinson’s disease patients with normal cognition, 10 with Parkinson’s disease and mild cognitive impairment [MCI], 12 with Parkinson’s disease dementia, and 19 with DLB), the subjects have now been followed for a mean of 3.5 years, with annual PiB-PET imaging, and physical, cognitive, and neuropsychological testing.
After the follow-up period of 2-5 years, Dr. Growdon found that 11 patients have progressed in cognitive decline. Of the 33 Parkinson’s disease patients who had normal cognition, 6 now have MCI. Of the 10 who had Parkinson’s and MCI, 5 have progressed to Parkinson’s dementia.
"While PiB was not significantly related to that decline, there was a clear trend. Those with minimal PiB burden at baseline remained relatively stable, while those with an initially high amyloid burden tended to lose their normal cognitive status."
The "marginal" relationship between PiB burden and change over time was related only to executive function, the loss of which was low in the group with moderate PiB binding and higher in the group with high PiB binding. "The correlation was still weak, although there was a trend in that direction," he said. A longer follow-up time may see more significant changes, he added, because cognitive status in Parkinson’s disease declines much slower than it does in Alzheimer’s disease.
While treatment with an antiamyloid for patients who experience early amyloid deposition may someday be recommended, Dr. Growdon suggested that a different path might be appropriate for DLB patients, who show early alpha-synuclein deposition. "We need to think about ways to prevent this accumulation, whether by a chaperone for the molecule or antibodies aimed against alpha-synuclein oligomers and aggregates."
During the discussion, Dr. Agneta Nordberg, cochair of the session and head of Alzheimer’s neurobiology at the Karolinska Institute, Stockholm, asked whether amyloid imaging would have any practical application in Parkinson’s disease patients.
"If you mean as a way of identifying people who might be at risk for cognitive decline, I think we need to follow this cohort longer and see what the predictive value of the amyloid is," Dr. Growdon said. "It’s clear that in Alzheimer’s mild cognitive impairment, if you have amyloid you are on your way to Alzheimer’s dementia. The time course for Parkinson’s to dementia is several times slower than that. We only see about a 4% annual incidence of Parkinson’s progressing to dementia, so we do need to follow these patients longer."