HHS Public Access Author manuscript Author Manuscript
JAMA Neurol. Author manuscript; available in PMC 2017 November 01. Published in final edited form as: JAMA Neurol. 2016 November 01; 73(11): 1334–1341. doi:10.1001/jamaneurol.2016.3338.
Tau PET imaging in the Lewy body diseases Stephen Gomperts, M.D., Ph.D.1,2, Joseph J. Locascio, Ph.D.2, Sara J. Makaretz, B.S.3, Aaron Schultz, Ph.D.1, Christina Caso, B.S.3, Neil Vasdev, Ph.D.4, Reisa Sperling, M.D.2,4,5, John H. Growdon, M.D.2, Bradford C. Dickerson, M.D.2,3,5, and Keith Johnson, M.D.2,4,5 1MassGeneral
Institute for Neurodegenerative Disease (MIND), 114 16th Street, Charlestown, MA
02129
Author Manuscript
2Alzheimer’s
Disease Research Center, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, 149 13th St., Charlestown, MA 02129 3Frontotemporal
Disorders Unit, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, 149 13th St., Charlestown, MA 02129
4Division
of Nuclear Medicine and Molecular Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, 55 Fruit St., Boston, MA 02114
5Athinoula
A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital and Harvard Medical School, 149 13th St., Charlestown, MA 02129
Abstract Author Manuscript
Importance—The causes of cognitive impairment in dementia with Lewy bodies (DLB) and Parkinson disease (PD) are multifactorial. Tau pathology is commonly observed at autopsy in DLB and PD dementia, but its contribution during life to these diseases is unknown. Objective—To contrast tau aggregation in DLB, cognitively impaired PD (PD-impaired), cognitively normal PD (PD-normal), and normal control (NC) subjects and to evaluate the relationship between tau aggregation, amyloid deposition, and cognitive function. Design—This cross-sectional study was conducted from 2014 to 2016.
Author Manuscript
Corresponding Author: Stephen N. Gomperts, M.D., Ph.D., MassGeneral Institute for Neurodegenerative Disease (MIND), 114 16th Street, Room 2004, Charlestown, MA 02129, Tel: (617) 726-5570; Fax:(617) 726-5760, [email protected]. Author Contributions SNG contributed to conceptualization of the study, analysis and interpretation of data, drafting and revision of the report, and statistical analysis. KAJ contributed to conceptualization of the study, interpretation of data, and drafting and revision of the report. JHG and BCD contributed to interpretation of data and drafting and revision of the report. JL contributed to analysis and interpretation of data, drafting and revision of the report, and the statistical analysis. RAS contributed to acquisition of data and drafting and revision of the report. SM, CC, and AS contributed to acquisition, analysis of data, drafting and revision of the report, and provided technical support. NV contributed to acquisition of data and drafting and revision of the report. Conflicts of interest BCD has provided consulting services for Merck DSMB, Forum, Ionis, Piramal, and receives royalties from Oxford University Press. RAS has provided providing consulting services for Roche, Genentech, Biogen and Bracket, Abbvie, received support from a joint NIH-Lilly-sponsored clinical trial (A4 Study – U19AG10483), and research funding from the National Institutes of Health/National Institute on Aging (R01 AG046396, P01 AG036694, P50 AG00513421) and the Alzheimer’s Association. KJ has provided consulting services for Lilly, Novartis, Janssen, Roche, Piramal, GE Healthcare, Siemens, ISIS Pharma, AZTherapy, Abbvie, Lundbeck, and Biogen, received support from a joint NIH-Lilly-sponsored clinical trial (A4 Study – U19AG10483), and received research support from National Institutes of Health/National Institute on Aging (R01 AG046396, P01 AG036694, P50 AG00513421, U19AG10483, U01AG024904-S1), Fidelity Biosciences, the Michael J. Fox Foundation, the Marr Foundation, and the Alzheimer’s Association.
Gomperts et al.
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Author Manuscript
Setting—Subjects were recruited from a tertiary care center’s Memory and Movement Disorders Units. Participants—24 patients with Lewy body disease (7 DLB, 8 PD-impaired, and 9 PD-normal) underwent multimodal brain imaging, cognitive testing, and neurological evaluation, and imaging measures were compared to those of an independently acquired group of 29 NC subjects with minimal brain amyloid burden, as measured with [11C]PiB PET. Exposures for observational studies—[18F]AV-1451 (formerly known as [18F]T807), [11C]PiB PET, MRI, detailed cognitive testing, and neurological examination.
Author Manuscript
Main Outcomes and Measures—Subjects underwent tau PET imaging with [18F]AV-1451, MRI, detailed cognitive testing, and neurological examination. All but 3 subjects also underwent amyloid imaging with [11C]PiB PET. The hypotheses being tested were formulated before data collection. Results—In DLB, cortical [18F]AV-1451 uptake was highly variable and greater than in NC, particularly in the inferior temporal gyrus (ITG) and precuneus. Foci of increased [18F]AV-1451 binding in the ITG and precuneus were also evident in PD-impaired subjects. Elevated cortical [18F]AV-1451 binding was observed in 4/17 Lewy body disease cases with low cortical [11C]PiB retention. For DLB and PD-impaired subjects, greater [18F]AV-1451 uptake in the ITG and precuneus was associated with increased cognitive impairment, as measured with the MMSE and the CDR 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 DLB and PD-impaired patients, even in patients without elevated amyloid. When present, tau deposition is associated with cognitive impairment. These findings support a role for tau co-pathology in the Lewy body diseases.
Author Manuscript
Keywords dementia with Lewy bodies; Parkinson; [18F] AV1451; [11C] PiB; biomarker
Introduction
Author Manuscript
Dementia with Lewy bodies (DLB), Parkinson disease (PD), and PD dementia (PDD) together comprise the Lewy body diseases (LBD), which are defined neuropathologically by Lewy body intracellular inclusions that are rich in α-synuclein (1). In individuals with DLB and PDD, co-existent Alzheimer’s disease (AD) pathology, in the form of extracellular amyloid plaques and intracellular paired helical filaments of tau, is commonly observed at autopsy (2–6). The relevance of these protein aggregates to the course of these diseases has been based primarily on clinico-pathological correlations. Now, with the advent of PET molecular imaging, it is possible to examine both the timing and extent to which amyloid and tau affect cognition during life in the course of disease (7,8). Molecular imaging of neuropathological aggregates began with the introduction of Pittsburgh compound B ([11C]PiB), and has enabled research studies to show that cortical Aβ deposition is common in PD and PDD, that high levels of Aβ are observed in most cases of DLB (9–12), and that greater deposition of Aβ is a risk factor for cognitive impairment in JAMA Neurol. Author manuscript; available in PMC 2017 November 01.
Gomperts et al.
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Author Manuscript
PD, accelerating cognitive decline once established (13,14). These findings were consonant with prior neuropathological reports (reviewed in 7).
Author Manuscript
In AD, disease progression occurs in the context of high Aβ and is associated with spread of tau deposits from the medial temporal lobe to the basal temporal neocortex and then to other neocortical regions (15–17), in association with regional neuronal loss (18). Neuropathologic studies have also linked tau deposition to the LBD, with the following observations. In both DLB and PDD, the presence of tau pathology in combination with Aβand α-synuclein has been shown to potentiate dementia (5). Furthermore, as in AD (19,20), tau aggregates in PD have been found to correlate with the severity of cognitive impairment (3,4), and tau aggregates measured at autopsy, late in the course of disease, are commonly observed in both PDD and DLB. However, greater tau burden has been observed in DLB than PDD tissue (21), raising the possibility of a difference during life. The contribution of brain tau aggregates during life to the clinical manifestations and course of these diseases has been difficult to evaluate, as the ability to image tau in living humans has been lacking until recently.
Author Manuscript
In this study, we selected the radioligand [18F]AV-1451, also known as [18F]T807, to image tau in the LBD, based on its high affinity, selectivity and favorable kinetics for imaging tau (22,23). Recent work with postmortem tissue has confirmed that [18F]AV-1451 binds strongly to tau in neurofibrillary tangles and neurites without binding Aβ and has shown, critically, that [18F]AV-1451 does not bind α-synuclein aggregates or Lewy bodies (24,25). Based on these favorable characteristics, we conducted a study to evaluate the contribution of tau to clinical phenotype and to cognitive function in LBD. Based on neuropathological observations (3–5,21), we hypothesized that among diagnostic groups [18F]AV-1451 uptake would be highest in DLB and that uptake would be related in our sample to the severity of cognitive impairment.
Methods Study design
Author Manuscript
Seven DLB, 8 PD with a broad range of cognitive impairment (PD-impaired) ranging from mild (PD-MCI, n=4) to severe (PDD, n=4), and 9 cognitively normal PD (PD-normal) subjects were recruited from Massachusetts General Hospital’s Movement and Memory Disorder Units. Subjects with DLB met clinical consensus criteria for probable DLB of the DLB consortium (26), with the presence of at least two of the following: parkinsonism, visual hallucinations, and fluctuations of cognition. All had a history suggestive for REM sleep behavioral disorder. PD subjects met the diagnostic criteria for idiopathic PD of the UKPDSBBRC (27). Cognitive function in PD-normal subjects was well-preserved, exceeding criteria for PD-MCI (28). PD-impaired subjects met current criteria for either PDMCI or PDD (29), with subjective complaints and objective impairment on at least two cognitive tests. Interviews with caregivers were acquired in all cases. [18F]AV-1451 PET and MRI were acquired in all subjects; [11C]PiB PET was acquired in 5 DLB, 7 PD-impaired (either PD-MCI or PDD), and 9 PD-normal subjects. As AD co-pathology in some NC subjects could obscure findings in LBD, acquired data were contrasted with identical test data collected from a separately acquired cohort of 29 normal control (NC) subjects with JAMA Neurol. Author manuscript; available in PMC 2017 November 01.
Gomperts et al.
Page 4
Author Manuscript
low cortical amyloid (27. All participants gave written informed consent according to the protocols approved by the Institutional Review Board of Partners Healthcare, Inc, and received a small stipend for participation. Clinical evaluation
Author Manuscript
Cognitive evaluation included the CDR scale, Mayo fluctuations screen (31), Mayo sleep questionnaire (32), visual form discrimination, and the tests of the National Alzheimer’s Consortium Uniform Dataset (UDS; 33). Cognitive testing was conducted in the on-state to minimize the contribution of motor impairment. Evaluations of motor function included the Unified Parkinson Disease Rating Scale (UPDRS) part III (34) and Hoehn and Yahr (H&Y) staging (35). The interval between cognitive/motor testing and [18F]AV-1451 PET was 67±16 days for disease groups and 115±26 days for NC. Group demographics Subjects had similar ages and education, but gender was nonsignificantly skewed towards males in the disease groups (Table 1). MMSE and CDR sum-of-boxes scores were similarly impaired for DLB and PD-impaired groups, and greater than PD-normal and NC groups (for each contrast, p0.05 for each contrast). Imaging acquisition
Author Manuscript
MRI—An MP-RAGE sequence optimized for use with Freesurfer software (http:// surfer.nmr.mgh.harvard.edu) was acquired on a Siemens 3T Tim Trio system to generate high-resolution anatomic data for morphometric analyses. PET imaging—Synthesis, preparation and administration of [18F]AV-1451 were conducted as previously described (36). [18F]AV-1451 and [11C]PiB data were acquired on a Siemens/CTI ECAT HR+ scanner (63 parallel planes; axial FOV: 15.2 cm; in-plane resolution: 4.1 mm full-width at half-maximum; slice width: 2.4 mm). For [18F]AV-1451, administration of 10 mCi of radiotracer was followed by a 20-minute acquisition, beginning at 80 minutes post-injection. [11C]PiB data were acquired using a 39-frame dynamic protocol (8×15s, 4×60s, and 27×120s), reconstructed and corrected for scatter, attenuation and randoms with vendor-supplied software. Image analyses
Author Manuscript
PET—[18F]AV-1451 and [11C]PiB data were co-registered to each subject’s MP-RAGE MR. Each subject’s [18F]AV-1451 and [11C]PiB PET data were spatially transformed into the PET native space using Statistical Parametric Mapping (SPM8). For anatomically-based analyses, we used Freesurfer to identify volumes and vertices (37,38) as performed previously (39,40). We expressed [18F]AV-1451 data as the standardized uptake ratio (SUVR) with cerebellar grey reference, as reported (23,39), and [11C]PiB as the distribution volume ratio (DVR) with cerebellar reference(37,38,41). We expected atrophy to have an
JAMA Neurol. Author manuscript; available in PMC 2017 November 01.
Gomperts et al.
Page 5
Author Manuscript
impact on PET measures and therefore chose to assess the ROI SUVRs with and without partial volume (PV) correction with the GTM method (42; results with PV corrected data are reported below; results with non-PV corrected data are reported in the Supplement). Whole-brain group contrasts of PET data included Freesurfer-based assessments of cortical binding at vertices (43). Findings from the surface-based analyses were confirmed using inferior temporal gyrus (ITG) and precuneus regions of interest (ROI), according to the Desikan FS parcellation (39,44). Each group’s [18F]AV-1451 SUVR and [11C]PiB DVR ROI measures are shown in eTable 1 of the Supplement. Data Analysis
Author Manuscript
For general linear models (GLMs), backward elimination of an initial full model of simultaneous predictor terms, including pertinent interactions and covariates, was employed using a cutoff of p=0.01. Post hoc tests adjusting for multiplicity of the tests were run as called for. Model residuals were checked for fit and conformance to assumptions. We used Spearman bivariate correlations to avoid violation of assumptions for the significance test of the Pearsons test and the excessive influence of some outliers. Analyses were run using SAS/JMP.
Results Tau deposition
Author Manuscript
DLB patients had greater cortical retention of [18F]AV-1451 than NC particularly prominent in the inferior and lateral temporal lobe and precuneus (exemplified in Figure 1A, with vertex maps in Figure 2, peak p
JAMA Neurol. Author manuscript; available in PMC 2017 November 01. Published in final edited form as: JAMA Neurol. 2016 November 01; 73(11): 1334–1341. doi:10.1001/jamaneurol.2016.3338.
Tau PET imaging in the Lewy body diseases Stephen Gomperts, M.D., Ph.D.1,2, Joseph J. Locascio, Ph.D.2, Sara J. Makaretz, B.S.3, Aaron Schultz, Ph.D.1, Christina Caso, B.S.3, Neil Vasdev, Ph.D.4, Reisa Sperling, M.D.2,4,5, John H. Growdon, M.D.2, Bradford C. Dickerson, M.D.2,3,5, and Keith Johnson, M.D.2,4,5 1MassGeneral
Institute for Neurodegenerative Disease (MIND), 114 16th Street, Charlestown, MA
02129
Author Manuscript
2Alzheimer’s
Disease Research Center, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, 149 13th St., Charlestown, MA 02129 3Frontotemporal
Disorders Unit, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, 149 13th St., Charlestown, MA 02129
4Division
of Nuclear Medicine and Molecular Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, 55 Fruit St., Boston, MA 02114
5Athinoula
A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital and Harvard Medical School, 149 13th St., Charlestown, MA 02129
Abstract Author Manuscript
Importance—The causes of cognitive impairment in dementia with Lewy bodies (DLB) and Parkinson disease (PD) are multifactorial. Tau pathology is commonly observed at autopsy in DLB and PD dementia, but its contribution during life to these diseases is unknown. Objective—To contrast tau aggregation in DLB, cognitively impaired PD (PD-impaired), cognitively normal PD (PD-normal), and normal control (NC) subjects and to evaluate the relationship between tau aggregation, amyloid deposition, and cognitive function. Design—This cross-sectional study was conducted from 2014 to 2016.
Author Manuscript
Corresponding Author: Stephen N. Gomperts, M.D., Ph.D., MassGeneral Institute for Neurodegenerative Disease (MIND), 114 16th Street, Room 2004, Charlestown, MA 02129, Tel: (617) 726-5570; Fax:(617) 726-5760, [email protected]. Author Contributions SNG contributed to conceptualization of the study, analysis and interpretation of data, drafting and revision of the report, and statistical analysis. KAJ contributed to conceptualization of the study, interpretation of data, and drafting and revision of the report. JHG and BCD contributed to interpretation of data and drafting and revision of the report. JL contributed to analysis and interpretation of data, drafting and revision of the report, and the statistical analysis. RAS contributed to acquisition of data and drafting and revision of the report. SM, CC, and AS contributed to acquisition, analysis of data, drafting and revision of the report, and provided technical support. NV contributed to acquisition of data and drafting and revision of the report. Conflicts of interest BCD has provided consulting services for Merck DSMB, Forum, Ionis, Piramal, and receives royalties from Oxford University Press. RAS has provided providing consulting services for Roche, Genentech, Biogen and Bracket, Abbvie, received support from a joint NIH-Lilly-sponsored clinical trial (A4 Study – U19AG10483), and research funding from the National Institutes of Health/National Institute on Aging (R01 AG046396, P01 AG036694, P50 AG00513421) and the Alzheimer’s Association. KJ has provided consulting services for Lilly, Novartis, Janssen, Roche, Piramal, GE Healthcare, Siemens, ISIS Pharma, AZTherapy, Abbvie, Lundbeck, and Biogen, received support from a joint NIH-Lilly-sponsored clinical trial (A4 Study – U19AG10483), and received research support from National Institutes of Health/National Institute on Aging (R01 AG046396, P01 AG036694, P50 AG00513421, U19AG10483, U01AG024904-S1), Fidelity Biosciences, the Michael J. Fox Foundation, the Marr Foundation, and the Alzheimer’s Association.
Gomperts et al.
Page 2
Author Manuscript
Setting—Subjects were recruited from a tertiary care center’s Memory and Movement Disorders Units. Participants—24 patients with Lewy body disease (7 DLB, 8 PD-impaired, and 9 PD-normal) underwent multimodal brain imaging, cognitive testing, and neurological evaluation, and imaging measures were compared to those of an independently acquired group of 29 NC subjects with minimal brain amyloid burden, as measured with [11C]PiB PET. Exposures for observational studies—[18F]AV-1451 (formerly known as [18F]T807), [11C]PiB PET, MRI, detailed cognitive testing, and neurological examination.
Author Manuscript
Main Outcomes and Measures—Subjects underwent tau PET imaging with [18F]AV-1451, MRI, detailed cognitive testing, and neurological examination. All but 3 subjects also underwent amyloid imaging with [11C]PiB PET. The hypotheses being tested were formulated before data collection. Results—In DLB, cortical [18F]AV-1451 uptake was highly variable and greater than in NC, particularly in the inferior temporal gyrus (ITG) and precuneus. Foci of increased [18F]AV-1451 binding in the ITG and precuneus were also evident in PD-impaired subjects. Elevated cortical [18F]AV-1451 binding was observed in 4/17 Lewy body disease cases with low cortical [11C]PiB retention. For DLB and PD-impaired subjects, greater [18F]AV-1451 uptake in the ITG and precuneus was associated with increased cognitive impairment, as measured with the MMSE and the CDR 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 DLB and PD-impaired patients, even in patients without elevated amyloid. When present, tau deposition is associated with cognitive impairment. These findings support a role for tau co-pathology in the Lewy body diseases.
Author Manuscript
Keywords dementia with Lewy bodies; Parkinson; [18F] AV1451; [11C] PiB; biomarker
Introduction
Author Manuscript
Dementia with Lewy bodies (DLB), Parkinson disease (PD), and PD dementia (PDD) together comprise the Lewy body diseases (LBD), which are defined neuropathologically by Lewy body intracellular inclusions that are rich in α-synuclein (1). In individuals with DLB and PDD, co-existent Alzheimer’s disease (AD) pathology, in the form of extracellular amyloid plaques and intracellular paired helical filaments of tau, is commonly observed at autopsy (2–6). The relevance of these protein aggregates to the course of these diseases has been based primarily on clinico-pathological correlations. Now, with the advent of PET molecular imaging, it is possible to examine both the timing and extent to which amyloid and tau affect cognition during life in the course of disease (7,8). Molecular imaging of neuropathological aggregates began with the introduction of Pittsburgh compound B ([11C]PiB), and has enabled research studies to show that cortical Aβ deposition is common in PD and PDD, that high levels of Aβ are observed in most cases of DLB (9–12), and that greater deposition of Aβ is a risk factor for cognitive impairment in JAMA Neurol. Author manuscript; available in PMC 2017 November 01.
Gomperts et al.
Page 3
Author Manuscript
PD, accelerating cognitive decline once established (13,14). These findings were consonant with prior neuropathological reports (reviewed in 7).
Author Manuscript
In AD, disease progression occurs in the context of high Aβ and is associated with spread of tau deposits from the medial temporal lobe to the basal temporal neocortex and then to other neocortical regions (15–17), in association with regional neuronal loss (18). Neuropathologic studies have also linked tau deposition to the LBD, with the following observations. In both DLB and PDD, the presence of tau pathology in combination with Aβand α-synuclein has been shown to potentiate dementia (5). Furthermore, as in AD (19,20), tau aggregates in PD have been found to correlate with the severity of cognitive impairment (3,4), and tau aggregates measured at autopsy, late in the course of disease, are commonly observed in both PDD and DLB. However, greater tau burden has been observed in DLB than PDD tissue (21), raising the possibility of a difference during life. The contribution of brain tau aggregates during life to the clinical manifestations and course of these diseases has been difficult to evaluate, as the ability to image tau in living humans has been lacking until recently.
Author Manuscript
In this study, we selected the radioligand [18F]AV-1451, also known as [18F]T807, to image tau in the LBD, based on its high affinity, selectivity and favorable kinetics for imaging tau (22,23). Recent work with postmortem tissue has confirmed that [18F]AV-1451 binds strongly to tau in neurofibrillary tangles and neurites without binding Aβ and has shown, critically, that [18F]AV-1451 does not bind α-synuclein aggregates or Lewy bodies (24,25). Based on these favorable characteristics, we conducted a study to evaluate the contribution of tau to clinical phenotype and to cognitive function in LBD. Based on neuropathological observations (3–5,21), we hypothesized that among diagnostic groups [18F]AV-1451 uptake would be highest in DLB and that uptake would be related in our sample to the severity of cognitive impairment.
Methods Study design
Author Manuscript
Seven DLB, 8 PD with a broad range of cognitive impairment (PD-impaired) ranging from mild (PD-MCI, n=4) to severe (PDD, n=4), and 9 cognitively normal PD (PD-normal) subjects were recruited from Massachusetts General Hospital’s Movement and Memory Disorder Units. Subjects with DLB met clinical consensus criteria for probable DLB of the DLB consortium (26), with the presence of at least two of the following: parkinsonism, visual hallucinations, and fluctuations of cognition. All had a history suggestive for REM sleep behavioral disorder. PD subjects met the diagnostic criteria for idiopathic PD of the UKPDSBBRC (27). Cognitive function in PD-normal subjects was well-preserved, exceeding criteria for PD-MCI (28). PD-impaired subjects met current criteria for either PDMCI or PDD (29), with subjective complaints and objective impairment on at least two cognitive tests. Interviews with caregivers were acquired in all cases. [18F]AV-1451 PET and MRI were acquired in all subjects; [11C]PiB PET was acquired in 5 DLB, 7 PD-impaired (either PD-MCI or PDD), and 9 PD-normal subjects. As AD co-pathology in some NC subjects could obscure findings in LBD, acquired data were contrasted with identical test data collected from a separately acquired cohort of 29 normal control (NC) subjects with JAMA Neurol. Author manuscript; available in PMC 2017 November 01.
Gomperts et al.
Page 4
Author Manuscript
low cortical amyloid (27. All participants gave written informed consent according to the protocols approved by the Institutional Review Board of Partners Healthcare, Inc, and received a small stipend for participation. Clinical evaluation
Author Manuscript
Cognitive evaluation included the CDR scale, Mayo fluctuations screen (31), Mayo sleep questionnaire (32), visual form discrimination, and the tests of the National Alzheimer’s Consortium Uniform Dataset (UDS; 33). Cognitive testing was conducted in the on-state to minimize the contribution of motor impairment. Evaluations of motor function included the Unified Parkinson Disease Rating Scale (UPDRS) part III (34) and Hoehn and Yahr (H&Y) staging (35). The interval between cognitive/motor testing and [18F]AV-1451 PET was 67±16 days for disease groups and 115±26 days for NC. Group demographics Subjects had similar ages and education, but gender was nonsignificantly skewed towards males in the disease groups (Table 1). MMSE and CDR sum-of-boxes scores were similarly impaired for DLB and PD-impaired groups, and greater than PD-normal and NC groups (for each contrast, p0.05 for each contrast). Imaging acquisition
Author Manuscript
MRI—An MP-RAGE sequence optimized for use with Freesurfer software (http:// surfer.nmr.mgh.harvard.edu) was acquired on a Siemens 3T Tim Trio system to generate high-resolution anatomic data for morphometric analyses. PET imaging—Synthesis, preparation and administration of [18F]AV-1451 were conducted as previously described (36). [18F]AV-1451 and [11C]PiB data were acquired on a Siemens/CTI ECAT HR+ scanner (63 parallel planes; axial FOV: 15.2 cm; in-plane resolution: 4.1 mm full-width at half-maximum; slice width: 2.4 mm). For [18F]AV-1451, administration of 10 mCi of radiotracer was followed by a 20-minute acquisition, beginning at 80 minutes post-injection. [11C]PiB data were acquired using a 39-frame dynamic protocol (8×15s, 4×60s, and 27×120s), reconstructed and corrected for scatter, attenuation and randoms with vendor-supplied software. Image analyses
Author Manuscript
PET—[18F]AV-1451 and [11C]PiB data were co-registered to each subject’s MP-RAGE MR. Each subject’s [18F]AV-1451 and [11C]PiB PET data were spatially transformed into the PET native space using Statistical Parametric Mapping (SPM8). For anatomically-based analyses, we used Freesurfer to identify volumes and vertices (37,38) as performed previously (39,40). We expressed [18F]AV-1451 data as the standardized uptake ratio (SUVR) with cerebellar grey reference, as reported (23,39), and [11C]PiB as the distribution volume ratio (DVR) with cerebellar reference(37,38,41). We expected atrophy to have an
JAMA Neurol. Author manuscript; available in PMC 2017 November 01.
Gomperts et al.
Page 5
Author Manuscript
impact on PET measures and therefore chose to assess the ROI SUVRs with and without partial volume (PV) correction with the GTM method (42; results with PV corrected data are reported below; results with non-PV corrected data are reported in the Supplement). Whole-brain group contrasts of PET data included Freesurfer-based assessments of cortical binding at vertices (43). Findings from the surface-based analyses were confirmed using inferior temporal gyrus (ITG) and precuneus regions of interest (ROI), according to the Desikan FS parcellation (39,44). Each group’s [18F]AV-1451 SUVR and [11C]PiB DVR ROI measures are shown in eTable 1 of the Supplement. Data Analysis
Author Manuscript
For general linear models (GLMs), backward elimination of an initial full model of simultaneous predictor terms, including pertinent interactions and covariates, was employed using a cutoff of p=0.01. Post hoc tests adjusting for multiplicity of the tests were run as called for. Model residuals were checked for fit and conformance to assumptions. We used Spearman bivariate correlations to avoid violation of assumptions for the significance test of the Pearsons test and the excessive influence of some outliers. Analyses were run using SAS/JMP.
Results Tau deposition
Author Manuscript
DLB patients had greater cortical retention of [18F]AV-1451 than NC particularly prominent in the inferior and lateral temporal lobe and precuneus (exemplified in Figure 1A, with vertex maps in Figure 2, peak p
