Tau Positron Emission Tomographic Imaging in the Lewy Body Diseases

Abstract

Importance: The causes of cognitive impairment in dementia with Lewy bodies (DLB) and Parkinson disease (PD) are multifactorial. Tau pathologic changes are commonly observed at autopsy in individuals with DLB and PD dementia, but their contribution to these diseases during life is unknown.

Objective: To contrast tau aggregation in DLB, cognitively impaired persons with PD (PD-impaired), cognitively normal individuals with PD (PD-normal), and healthy persons serving as control participants, and to evaluate the association between tau aggregation, amyloid deposition, and cognitive function.

Design, setting, and participants: This cross-sectional study was conducted from January 1, 2014, to April 28, 2016, in a tertiary care center's memory and movement disorders units. Twenty-four patients with Lewy body disease (7 DLB, 8 PD-impaired, and 9 PD-normal) underwent multimodal brain imaging, cognitive testing, and neurologic evaluation, and imaging measures were compared with those of an independently acquired group of 29 controls with minimal brain amyloid burden as measured with carbon 11-labeled Pittsburgh Compound B ([11C]PiB) positron emission tomography (PET).

Exposures: Imaging with fluorine 18-labeled AV-1451 ([18F]AV-1451) (formerly known as [18F]T807), [11C]PiB PET, magnetic resonance imaging (MRI), neurologic examination, and detailed cognitive testing using the Mini-Mental State Examination (MMSE) and Clinical Dementia Rating scale.

Main outcomes and measures: Main outcomes were differentiation of diagnostic groups on the basis of [18F]AV-1451 binding, the association of [18F]AV-1451 binding with [11C]PiB binding, and the association of [18F]AV-1451 binding with cognitive impairment. All but 3 individuals underwent amyloid imaging with [11C]PiB PET. The hypotheses being tested were formulated before data collection. Mini-Mental State Examination (range, 0-30, with 30 being best) and Clinical Dementia Rating scale sum-of-boxes scale (range, 0-18, with 0 being best) were used for assessment of cognitive function.

Results: In patients with DLB, cortical [18F]AV-1451 uptake was highly variable and greater than in the controls, particularly in the inferior temporal gyrus and precuneus. Foci of increased [18F]AV-1451 binding in the inferior temporal gyrus and precuneus were also evident in PD-impaired patients. Elevated cortical [18F]AV-1451 binding was observed in 4 of 17 patients with Lewy body disease with low cortical [11C]PiB retention. For DLB and PD-impaired patients, greater [18F]AV-1451 uptake in the inferior temporal gyrus and precuneus was associated with increased cognitive impairment as measured with the MMSE and the Clinical Dementia Rating scale sum-of-boxes score.

Conclusions and relevance: Patients with Lewy body disease manifest a spectrum of tau pathology. Cortical aggregates of tau are common in patients with DLB and in PD-impaired patients, even in those without elevated amyloid levels. When present, tau deposition is associated with cognitive impairment. These findings support a role for tau copathology in the Lewy body diseases.

Figure 1

Distribution of [¹⁸F]AV-1451 binding in Lewy body disease subjects. A. Surface maps and PET images (coronal and axial views) of [¹⁸F]AV-1451 binding in two subjects with DLB (left, age 72, MMSE 17; right, age 61, MMSE 12). B. Surface maps and PET images of [¹⁸F]AV-1451 binding in two subjects with PD dementia (left, age 73, MMSE 20; right age 81, MMSE 19). In addition to gray matter binding of [¹⁸F]AV-1451, off-target binding to neuromelanin and a mucous retention cyst is also evident (24).

Figure 2

Surface renderings of group contrasts of DLB with NC, PD-impaired with NC, and PD-normal with NC (GLMs). Color bar shows significant binding at the p<0.01–0.0001 level.

Figure 3

Tau deposition varies across the diagnostic groups and is not dependent on amyloid. Inferior temporal gyrus [¹⁸F]AV-1451 SUVR values are displayed for each of the diagnostic groups, using the box-whiskers convention. Dots represent individual subject values. The horizontal line within each box is the group median [¹⁸F]AV-1451 SUVR value. As indicated by the asterisks, [¹⁸F]AV-1451 retention was higher in the DLB group than in the PD-normal (p=0.022, Wilcoxin test) and NC groups (p=0.004). Similarly, [¹⁸F]AV-1451 retention in the PD-impaired group was also higher than in the PD-normal (p=0.034, Wilcoxin test) and NC groups (p=0.022). Black circles (n=4) designate subjects with high [¹¹C]PiB (FLR > 1.15 SUVR); gray circles designate subjects with low [¹¹C]PiB; open circles (n=3) show cases who did not undergo [¹¹C]PiB PET. Note that 4 of the 6 impaired LBD subjects with elevated AV-1451 binding relative to NC were shown to have low amyloid burden.

Figure 4

Tau impacts global cognitive function in LBD subjects with cognitive impairment A. In the LBD-impaired group, comprised of DLB (open circles) and PD-impaired (closed circles), higher [¹⁸F]AV-1451 binding in the ITG was associated with greater impairment measured with the CDR sum-of-boxes score (Spearman r=0.68, p=0.006). In contrast, [¹⁸F]AV-1451 binding did not relate to the CDR sum of box score in the PD-normal or NC groups (p>0.05). B. Within the LBD-impaired group (r=−0.57, p=0.026), but not the other groups (p>0.05), higher ITG SUVR was associated with lower MMSE score. 95% confidence intervals are shown.