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Original Investigation |

Tau Positron Emission Tomographic Imaging in the Lewy Body Diseases ONLINE FIRST

Stephen N. Gomperts, MD, PhD1,2; Joseph J. Locascio, PhD2; Sara J. Makaretz, BS3; Aaron Schultz, PhD4; Christina Caso, BS3; Neil Vasdev, PhD5; Reisa Sperling, MD2,4,5; John H. Growdon, MD2; Bradford C. Dickerson, MD2,3,4; Keith Johnson, MD2,4,5
[+] Author Affiliations
1MassGeneral Institute for Neurodegenerative Disease, Charlestown, Massachusetts
2Alzheimer’s Disease Research Center, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown
3Frontotemporal Disorders Unit, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown
4Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital and Harvard Medical School, Charlestown
5Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston
JAMA Neurol. Published online September 19, 2016. doi:10.1001/jamaneurol.2016.3338
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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.

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Figure 1.
Distribution of Fluorine 18–Labeled AV-1451 ([18F]AV-1451) Binding in Patients With Lewy Body Disease

A, Surface maps and positron emission tomographic (PET) images (coronal and axial views) of [18F]AV-1451 binding in 2 individuals with dementia with Lewy bodies (left: age 72 years; Mini-Mental State Examination [MMSE] score, 17; right: age 61 years; MMSE score, 12). B, Surface maps and PET images of [18F]AV-1451 binding in 2 individuals with Parkinson disease dementia (left: age 73 years; MMSE score, 20; right: age 81 years; MMSE score, 19). In addition to gray matter binding of [18F]AV-1451, off-target binding to neuromelanin and a mucus retention cyst are also evident.24 SUVR indicates standardized uptake ratio. See the Methods section for a description of MMSE testing.

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Figure 2.
Surface Renderings of Group Contrasts

General linear models comparing individuals with normal cognition with patients who had dementia with Lewy bodies (A), Parkinson disease associated with cognitive impairment (PD-impaired) (B), and PD without cognitive impairment (PD-normal) (C). Color bar shows significant binding at the P = .01 to P = 1 × 10−4 levels.

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Figure 3.
Tau Deposition and Its Relation to Amyloid Burden Across the Diagnostic Groups

Inferior temporal gyrus fluorine 18–labeled AV-1451 ([18F]AV-1451) standardized uptake ratio (SUVR) values are displayed for each of the diagnostic groups using the box-whiskers convention. Dots represent individual participant values. The horizontal line within each box is the group median [18F]AV-1451 SUVR value. [18F]AV-1451 retention was higher in the dementia with Lewy bodies (DLB) group than in the Parkinson disease with normal cognition (PD-normal) (P = .022, Wilcoxon rank sum test) and normal control individuals (NC) (P = .004) groups. Similarly, [18F]AV-1451 retention in the PD group with impaired cognition (PD-impaired) was higher than in the PD-normal (P = .03, Wilcoxon rank sum test) and NC (P = .02) groups. Black circles (n = 4) designate participants with high carbon 11–labeled Pittsburgh Compound B ([11C]PiB) (frontal-lateral temporal-retrosplenial, >1.15 SUVR); gray circles designate participants with low [11C]PiB; and open circles (n = 3) show patients who did not complete [11C]PiB positron emission tomography. Four of the 6 cognitively impaired Lewy body disease individuals with elevated [18F]AV-1451 binding relative to NCs had low amyloid burden.

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Figure 4.
Effect of Tau Deposits on Global Cognitive Function in Patients With Lewy Body Disease (LBD)

A, In the group with LBD with cognitive impairment, composed of dementia with Lewy bodies (white circles) and Parkinson disease with cognitive impairment (PD-impaired) (dark gray circles), higher fluorine 18–labeled AV-1451 ([18F]AV-1451) binding in the inferior temporal gyrus (ITG) was associated with greater impairment as measured with the Clinical Dementia Rating (CDR) scale sum-of-boxes score (Spearman r = 0.68; P = .006). In contrast, [18F]AV-1451 binding did not relate to the CDR scale sum-of-boxes score in patients with Parkinson disease with normal cognition (PD-normal) or normal control individuals (NC) (P > .05). B, Within the LBD-impaired group (r = −0.57; P = .03) but not the other groups (P > .05), higher ITG SUVR was associated with a lower Mini-Mental State Examination (MMSE) score. Shaded areas indicate 95% CIs. See the Methods section for a description of CDR and MMSE testing.

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