We found elevated PIB PET in almost a third of patients with Lewy body-associated dementia, but PIB binding did not distinguish between DLB and PDD patients. Increased PIB uptake was associated with increased severity of global cognitive impairment but not with any other specific clinical or neuropsychological features. Furthermore, there were no differences in progression of cognitive impairment at follow-up based on PIB binding.
Our rate of elevated PIB binding in PDD patients (27%) is consistent with previous studies (range 17–33%)13, 15, 33
. Our rate in DLB patients (33%) is strikingly lower than previous studies in which DLB samples were recruited primarily from dementia centers (85–88%)13, 14
but more comparable to that of a recent study conducted in a movement disorders center (44%)15
. Others have found higher PIB binding in DLB compared to PDD13, 14
, but we did not. Our results suggest considerable overlap between the neuropathological features of DLB and PDD and support using a single disorder model when studying the underlying pathobiology of Lewy body-associated dementia34
. However, the differences among PIB PET studies in this population also illustrate the potential for bias due to recruitment source. Individuals presenting to dementia centers have a higher risk for AD than those presenting to movement disorders centers. In addition, all of the DLB participants in our cohort had parkinsonism; in dementia clinics, 10–15% of individuals meeting criteria for DLB lack significant parkinsonian motor findings35
. Differences in the pretest probability of AD and the diagnostic accuracy of DLB across settings may produce varying PIB PET results.
Similar to other PIB studies, we did not correct our PET data for partial volume effects, which could cause an underestimation of amyloid burden in patients with brain atrophy that is worse with more severe dementia. The association between PIB binding and dementia severity suggests this did not play a major role in our analysis. Consistent with previous studies14, 15, 36
, we found that higher PIB uptake was associated with greater cognitive impairment in patients with MCI or dementia. These results suggest that amyloid burden may modify dementia severity in Lewy body disorders, potentially by altering the pathophysiology or effects of α-synucleinopathy8, 9
. We also found an association between greater cognitive impairment and increased caudate, but not cortical, PIB uptake within MCI, suggesting that the striatum may be an early site for amyloid deposition in Lewy body dementias13
The large proportion of Lewy body-associated dementia patients without elevated PIB binding (71%) and the lack of association between PIB binding and neuropsychological test performance or progression of cognitive impairment in our study suggest that amyloid deposition is not central to the pathogenesis of dementia in Lewy body disorders. This interpretation is in concordance with clinicopathological examinations, which conclude that diffuse Lewy body pathology is the main substrate of dementia, as it is present in nearly all cases and correlates better with cognitive decline than amyloid plaque burden1, 5
Amyloid plaques may nonetheless influence the evolution of dementia in individuals with Lewy body disease. They are commonly found in patients with DLB and PDD and are positively correlated with cortical Lewy body counts, suggesting the two pathologies share common origins or interact6, 7
. Increased cortical PIB uptake has been associated with faster development of the full DLB clinical phenotype36
. Understanding the role of amyloid pathology in Lewy body dementias will increase in importance as anti-amyloid agents become available for therapeutic investigations and clinical application.
Given the small sample, subgroup differences (or lack thereof) should be interpreted with caution and remain to be confirmed in a larger study. Increased statistical power is needed to definitively exclude amyloid deposition as a feature that distinguishes Lewy body-associated disorders. Likewise, our limited follow-up does not permit us to determine the utility of PIB PET as an antecedent marker for dementia in PD, as has been indicated for AD37
Amyloid burden may contribute to an increased severity of cognitive impairment in Lewy body disease; however, neuropathological features other than amyloid, such as α-synucleinopathy, likely underlie most of the associated dementia. Further investigations in larger cohorts are needed to determine the role of amyloid deposition in the pathogenesis and clinical course of Lewy body-associated dementia and the clinical utility of PIB PET in Lewy body diseases. Improved understanding of synucleinopathy and its association with cognitive decline is also required.