Molecular Imaging Validated for Evaluation of Patients with Lewy Body Diseases

Because of overlapping pathologic findings, the differential diagnosis between Alzheimer's disease (AD), Parkinson's disease (PD) with dementia and Lewy bodies dementia is often uncertain. Several research teams have made initial steps in developing biomarkers of Lewy body diseases, including:

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• Amyloid imaging with positron emission tomography radioligand [11C]Pittsburgh compound B (PiB)
• Dopamine transporter (DAT) imaging with [11C]Altropane positron emission tomography

Stephen N. Gomperts, MD, PhD, director of the Lewy Body Dementia Unit of the Department of Neurology at Massachusetts General Hospital, and colleagues recently reported in Neurology that they have validated those two biomarkers against postmortem neuropathologic findings.

Study Subjects

The researchers analyzed data on 18 deceased patients with a Lewy body disease who had participated in a longitudinal study from 2006 to 2011. All 18 had undergone [11C]PiB imaging, and 10 had also undergone DAT imaging with [11C]Altropane.

By the time of death, all participants were cognitively impaired. At the last study visit, the clinical diagnoses were dementia with Lewy bodies (DLB) in 10 patients, PD with mild cognitive impairment in four (PD-MCI), and PD with dementia (PDD) in four.

Postmortem Assessments

• AD-related neuropathologic changes were scored according to National Institute on Aging–Alzheimer's Association's guidelines with the ABC rating scale
• A is the Thal phase of amyloid deposition
• B is the Braak stage of neurofibrillary tangles
• C is the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) neuritic plaque score
• The severity of cerebral amyloid angiopathy was rated with the Vonsattel score
• The severity of Lewy body pathology was scored with the Braak staging system

Accuracy of Clinical Diagnoses

• In all 18 patients, the clinical diagnosis of PD or DLB was confirmed on the basis of extensive neuronal loss in the substantia nigra with Lewy bodies
• All patients had Braak Lewy body scores ≥3, and the Braak stage was significantly higher in the DLB group than in the PD-MCI or PDD groups
• [11C]Altropane uptake was decreased in all 10 patients in whom it was performed, with no differences across diagnostic groups
• There were no differences between diagnostic groups in ABC scores or in estimates of cerebral amyloid angiopathy

Neuritic Plaque Burden

• Seventeen participants had evidence of amyloid deposits (CERAD score ≥1 and Thal phase ≥1)
• In most cases, [11C]PiB uptake accurately reflected the extent of amyloid deposits. However, in four mismatched cases, low [11C]PiB uptake was observed in patients with sparse or moderate neuritic plaque burden
• [11C]PiB uptake was significantly correlated with CERAD scores of amyloid burden
• Contradicting studies of AD patients, [11C]PiB uptake was not significantly correlated with the Thal phase, a measure of the distribution of amyloid deposits across brain regions over the course of AD.
• Accordingly, the pattern of amyloid distribution in Lewy body diseases may be distinct from the characteristic pattern in AD

Total Amyloid Burden

The researchers emphasize that PiB binds all fibrillar forms of amyloid, both cored neuritic plaques and the non-neuritic fibrillar diffuse plaques that are frequently present in both PDD and DLB. In contrast, the CERAD score reflects only neuritic plaques. Therefore, the team suspected that the CERAD score underestimates total amyloid burden.

When the researchers measured both neuritic and non-neuritic amyloid in four cortical regions, [11C]PiB retention was significantly correlated with the total plaque score averaged over the four regions. When each region was analyzed individually, [11C]PiB retention remained significantly correlated with total plaque score in the occipital region.

Non-Amyloid Pathologic Changes

• [11C]PiB uptake was strongly correlated with the Braak stage of neurofibrillary tangles. Neuritic plaques and neurofibrillary tangles have been significantly correlated in postmortem studies of patients with DLB, and this finding validates [11C]PiB imaging for detecting this relationship in living patients
• [11C]PiB uptake was significantly and directly correlated with the Braak Lewy body score. This observation, too, is consistent with underlying pathologic changes known from postmortem research on patients who had DLB
• [11C]Altropane uptake was not significantly correlated with the Braak Lewy body score

These correlations support the previously proposed view that amyloid, tau and α-synuclein can promote each other's aggregation. The researchers conclude that [11C]PiB shows promise as a surrogate marker of neurofibrillary tangles and Lewy bodies in patients with PDD or DLB.

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