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.
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.
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.
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.
eAppendix. Findings Without Partial Volume Correction (PVC) of [18F]AV-1451 Retention
eTable. [18F]AV-1451 Binding and [11C]PiB Binding in Select ROIs Across the Diagnostic Groups
eFigure 1. Partial Volume Uncorrected Estimates of Tau Deposition in the Inferior Temporal Gyrus
eFigure 2. Scatterplot of PV Corrected [18F]AV-1451 Binding in the ITG and [11C]PiB Binding Across Subjects
eFigure 3. Tau Deposition in Lewy Body Disease Subjects With Low Amyloid Burden Tau Deposition in Lewy Body Disease Subjects With Low Amyloid Burden
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Gomperts SN, Locascio JJ, Makaretz SJ, Schultz A, Caso C, Vasdev N, Sperling R, Growdon JH, Dickerson BC, Johnson K. Tau Positron Emission Tomographic Imaging in the Lewy Body Diseases. JAMA Neurol. 2016;73(11):1334–1341. doi:10.1001/jamaneurol.2016.3338
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Do tau pathologic changes relate to clinical status and amyloid deposition in the Lewy body diseases?
In this cross-sectional positron emission tomographic imaging study of 24 patients with Lewy body disease (including participants with dementia with Lewy bodies [DLB], as well as cognitively impaired and cognitively normal individuals with Parkinson disease [PD]) and 29 healthy individuals with low brain amyloid levels, cortical fluorine 18–labeled AV-1451 ([18F]AV-1451) uptake was increased in patients with DLB and PD and related to greater cognitive functional impairment. Elevated neocortical tau was observed in some patients with low amyloid burden, imaged with carbon 11–labeled Pittsburgh Compound B.
Neocortical tau pathology is common in DLB- and PD-impaired patients, even in the absence of elevated brain amyloid deposition, and contributes to cognitive impairment.
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.
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).
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.
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.
Dementia with Lewy bodies (DLB), Parkinson disease (PD), and PD dementia (PDD) together compose the Lewy body diseases, which are defined neuropathologically by Lewy body intracellular inclusions that are rich in α-synuclein.1 In individuals with DLB and PDD, coexistent Alzheimer disease (AD) pathologic changes, in the form of extracellular amyloid plaques and intracellular paired helical filaments of tau, are commonly observed at autopsy.2-6 The relevance of these protein aggregates to the course of the diseases has been based primarily on clinicopathologic correlations. With the advent of positron emission tomographic (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 neuropathologic aggregates began with the introduction of carbon 11–labeled Pittsburgh Compound B ([11C]PiB) and has enabled research studies to show that cortical β amyloid (Aβ) deposition is common in individuals with 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 patients with PD, accelerating cognitive decline once established.13,14 These findings were consonant with prior neuropathologic reports.7
In AD, disease progression occurs in the context of high Aβ levels and is associated with the spread of tau deposits from the medial temporal lobe to the basal temporal neocortex and then to other neocortical regions15-17 in association with regional neuronal loss.18 Neuropathologic studies have also linked tau deposition to the Lewy body diseases, with the following observations. In both patients with DLB and those with PDD, the presence of tau pathologic changes in combination with Aβ and α-synuclein has been shown5 to potentiate dementia. Furthermore, as in patients with AD,19,20 tau aggregates in those with 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 patients with PDD and those with DLB. However, greater tau burden has been noted in the tissue of patients with DLB than in those with PDD,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 since the ability to image tau in living humans has been lacking until recently.
In the present study, we selected the radioligand fluorine 18–labeled AV-1451 ([18F]AV-1451), also known as [18F]T807, to image tau in patients with the Lewy body diseases because of its high affinity, selectivity, and favorable kinetics for imaging tau.22,23 Recent work24,25 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. Because of these favorable characteristics, we conducted a study to evaluate the contribution of tau to clinical phenotype and cognitive function in the Lewy body diseases. Based on neuropathologic observations,3-5,21 we hypothesized that, among diagnostic groups, [18F]AV-1451 uptake would be highest in patients with DLB and that uptake would be related in our sample to the severity of cognitive impairment.
Seven participants with DLB; 8 with PD with a broad range of cognitive impairment (PD-impaired), including 4 with mild cognitive impairment (PD-MCI) and 4 with severe cognitive impairment (PDD); and 9 cognitively normal individuals with PD (PD-normal) were recruited from Massachusetts General Hospital’s Movement and Memory Disorder Units. Patients with DLB met clinical consensus criteria for probable DLB developed by the DLB consortium,26 with the presence of at least 2 of the following factors: parkinsonism, visual hallucinations, and fluctuations of cognition. All of these individuals had a history suggestive for rapid eye movement sleep behavioral disorder. Patients with PD met the clinical diagnostic criteria for idiopathic PD of the UK Parkinson’s Disease Society Brain Bank.27 Cognitive function in PD-normal persons was well preserved, exceeding criteria for PD-MCI.28 The PD-impaired participants met current criteria29 for either PD-MCI or PDD, with subjective symptoms and objective impairment demonstrated on at least 2 cognitive tests. Interviews with caregivers were acquired in all cases. PET and magnetic resonance imaging with [18F]AV-1451 were performed in all participants, and [11C]PiB PET was acquired in 5 individuals with DLB, in 7 PD-impaired patients (either PD-MCI or PDD), and in 9 PD-normal persons. Because AD copathology in some people with normal cognition could obscure findings in the Lewy body diseases, acquired data were contrasted with identical test data collected from a separate cohort of 29 normal control (NC) individuals with low cortical amyloid levels (<1.15 distribution volume ratio, measured in the frontal-lateral temporal-retrosplenial regions30) who were participating in a study of aging (R01 AG046396). The NC group had normal neurologic examination results and normal cognition (global Clinical Dementia Rating [CDR] scale, 0; Mini-Mental State Examination [MMSE], >27). The protocols for this study were approved by the institutional review board of Partners Healthcare, Inc, and all participants gave written informed consent and received a small stipend for participation.
Cognitive evaluation included the CDR sum-of-boxes scale (sum-of-boxes score ranges from 0 to 18; 0 reflects optimum cognitive function), MMSE (score ranges from 0-30, with 30 being best), Mayo fluctuations screen (score ranges from 0 to 4; 0 reflects absence and 4 reflects maximum severity of fluctuations of arousal or attention),31 Mayo Sleep Questionnaire,32 visual form discrimination (score ranges from 0 to 32; 32 reflects optimum performance), and the tests of the National Alzheimer Consortium Uniform Data Set.33 Cognitive testing was conducted in the on-state to minimize the contribution of motor impairment. Evaluations of motor function included the Unified Parkinson’s Disease Rating Scale part III (grades are assigned to each motor element of parkinsonism; score ranges from 0 to 108, with 108 being the worst score possible)34 and Hoehn and Yahr staging (score ranges from 0 to 5, with 5 indicative of the most advanced disease).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.
Participants had similar ages and education, but sex was nonsignificantly skewed toward men in the disease groups (Table). The MMSE and CDR sum-of-boxes scores were similarly impaired for DLB and PD-impaired groups and more greatly impaired than PD-normal and NC groups (for each contrast; P < .01). Motor function was similar across the disease groups (for both Unified Parkinson’s Disease Rating Scale and Hoehn and Yahr scale; P > .05 for each contrast) (Table).
A magnetization prepared–rapid acquisition gradient-echo (MP-RAGE) sequence optimized for use with FreeSurfer, version 5.3 software (http://surfer.nmr.mgh.harvard.edu) was acquired (3T Tim Trio system; Siemens) to generate high-resolution anatomic data for morphometric analyses.
Synthesis, preparation, and administration of [18F]AV-1451 were conducted as previously described.36 Data obtained using [18F]AV-1451 and [11C]PiB were acquired on a scanner (CTI ECAT HR+; Siemens) with 63 parallel planes; axial field of view, 15.2 cm; in-plane resolution, 4.1-mm full-width at half-maximum; and section 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 after injection. The [11C]PiB data were acquired using a 39-frame dynamic protocol (8 × 15 seconds, 4 × 60 seconds, and 27 × 120 seconds), reconstructed and corrected for scatter, attenuation, and randoms with vendor-supplied software (CTI PET Systems Inc).
Data from [18F]AV-1451 and [11C]PiB were coregistered to each participant’s MP-RAGE magnetic resonance imaging and were spatially transformed into the PET native space using Statistical Parametric Mapping (SPM8; Wellcome Trust Centre for Neuroimaging). For anatomically based analyses, we used FreeSurfer to identify volumes and vertices37,38 as performed previously.39,40 We expressed [18F]AV-1451 data as the standardized uptake ratio (SUVR) with cerebellar gray reference, as reported,23,39 and [11C]PiB as the distribution volume ratio with cerebellar reference.37,38,41 We expected atrophy to have an effect on PET measures and therefore chose to assess the region-of-interest (ROI) SUVRs with and without partial volume correction with the geometric transfer matrix method42 (results with partial volume–corrected data are reported below; results with nonpartial volume–corrected data are reported in the eAppendix 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 ROIs, according to the Desikan FreeSurfer parcellation.39,44 Each group’s [18F]AV-1451 SUVR and [11C]PiB distribution volume ratio ROI measures are reported in the eTable in the Supplement.
For general linear models, backward elimination of an initial full model of simultaneous predictor terms, including pertinent interactions and covariates, was applied using a cutoff level of P = .01. Post hoc tests adjusting for multiplicity of the tests were run as needed. 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 Pearson test and the excessive influence of some outliers. Analyses were run using SAS, version 9.4, and JMP, version Pro 10 (SAS Institute Inc).
Patients with DLB had greater cortical retention of [18F]AV-1451 than did NC participants that was particularly prominent in the inferior and lateral temporal lobe and precuneus (exemplified in Figure 1A with vertex maps in Figure 2, peak uncorrected P = 1 × 10−4, false-discovery rate corrected, P = .005; mean [SD] group difference in SUVR at maximum vertices: inferior temporal lobe, 0.233 [0.043] [left], 0.190 [0.040] [right]; precuneus, 0.219 [0.042] [left], 0.181 [0.034] [right]). A similar anatomy of high SUVR was observed in PD-impaired patients but with lower magnitude and extent (Figure 1B and Figure 2), which did not survive the false-discovery rate correction (mean [SD] group difference in SUVR: inferior temporal, 0.158 [0.036] [left], 0.137 [0.031] [right]; precuneus, 0.163 [0.040] [left], 0.124 [0.030] [right]). In contrast, peak mean distribution volume ratio did not differ significantly between PD-normal and NC individuals (Figure 2).
Confirmatory analyses using ITG (Figure 3) and precuneus ROIs (eTable in the Supplement) showed that the mean SUVRs in both ITG and precuneus differed by diagnostic group (for each ROI, main effect of group, P < .005; Kruskal-Wallis test, partial volume corrected). Between diagnostic groups, ITG and precuneus SUVRs were higher in DLB compared with NC participants (P < .004; Wilcoxon rank sum test) and PD-normal patients (P < .02) but did not differ significantly from SUVRs in PD-impaired patients (P > .30). The PD-impaired patients’ ITG and precuneus SUVRs were higher than those in NC participants (P < .02), but only the ITG SUVR was greater in PD-impaired compared with PD-normal persons (P < .03). The variance of ITG SUVR was greater in the DLB group than in any of the other groups (P < .05; F test). Similar results with somewhat smaller effects were observed without partial volume correction (eFigure 1 in the Supplement).
Age was not associated with either ITG SUVR or precuneus SUVR in any diagnostic group (P > .05). In the DLB group alone, shorter duration of disease was associated with greater SUVR in the ITG (r = −0.86, P = .01) and precuneus (r = −0.82, P = .02).
Of 21 patients with Lewy body diseases, 17 participants (81%) had [11C]PiB retention that was lower than a distribution volume ratio of 1.15, a cut point typically used in our laboratory to classify low amyloid burden. Across and within diagnostic groups, [11C]PiB retention and [18F]AV-1451 SUVR were uncorrelated, assessed either in ITG or precuneus (across groups, ITG r = −0.05; P = .74; precuneus r = 0.22; P = .13; within each Lewy body disease group, P > .05) (eFigure 2 in the Supplement). Consistent with this observation, 4 of 17 (23.5%) of the Lewy body disease cases with low [11C]PiB had ITG [18F]AV-1451 binding exceeding that of all NC persons (Figure 3 and eFigure 3 in the Supplement). Thus, high amyloid status was not necessary for [18F]AV-1451 binding in the cognitively impaired Lewy body disease groups; however, small foci of cortical amyloid were observed in 2 of these 4 cognitively impaired Lewy body disease individuals with low amyloid levels (eFigure 3 in the Supplement).
Given the shared anatomy of tau pathology in the DLB and PD-impaired groups, we aggregated these diagnostic groups to evaluate the effect of tau on cognitive function. In the aggregate DLB/PD-impaired group, performance on the CDR sum-of-boxes scale was significantly correlated with both ITG SUVR (r = 0.68; P = .006) (Figure 4A) and precuneus SUVR (r = 0.82; P = .0002). Similarly, the MMSE score in the DLB/PD-impaired group was significantly correlated with both ITG SUVR (r = −0.57; P = .03 (Figure 4B) and precuneus SUVR (r = −0.69; P = .005). Correlations were not significant in the PD-normal and NC groups, where the range of the cognitive functional measures was restricted.
When we analyzed the DLB and PD-impaired groups separately using a general linear model containing all diagnostic groups, we observed a significant interaction of ITG and precuneus SUVR with the diagnostic groups in their association to the CDR scale sum-of-boxes score (P = 1 × 10−4), with backward elimination of nonsignificant age and educational level. Specifically, higher SUVR was associated with greater impairment on the CDR scale sum-of-boxes score in the DLB group in the ITG and precuneus (P = 1 × 10−4) and in the PD-impaired group in the precuneus (P = .001). In contrast, associations were essentially flat for the PD-normal and NC groups. Consistent with these findings, in a second set of general linear model analyses for MMSE, ITG and precuneus SUVR each interacted with diagnostic group (P = 1 × 10−4 and P = .01, respectively; age and educational level were nonsignificant). Specifically, a significant negative association between SUVR and MMSE was observed in the DLB group (P < .002) in both the ITG and precuneus and in the PD-impaired group in the precuneus (P < .001), whereas the association was flat for the other groups.
Across the sample as a whole, [11C]PiB retention did not correlate with the CDR scale sum-of-boxes score (r = 0.07; P = .65) or the MMSE (r = −0.05, P = .74), and within-group correlations were also nonsignificant (P > .05 for each group).
Although α-synuclein deposition in Lewy bodies is the core neuropathologic feature of the Lewy body diseases, tau and Aβ copathologies are commonly observed in most patients with DLB and PDD at autopsy.2-6 Neuropathologic studies3-5 of patients with DLB and PDD have tied both tau and Aβ to the severity of dementia, which supports their contribution to cognitive function in these diseases. To identify tau in living patients with Lewy body diseases and evaluate its contribution to their course, we used [18F]AV-1451 PET imaging.
The results of this study support a role for tau accumulation in patients with DLB and in patients with PD with cognitive impairment. In whole-brain and ROI analyses, we found that [18F]AV-1451 retention was higher in the DLB and PD-impaired groups than in low-amyloid NCs, consistent with expected patterns reported in pathologic45 and tau PET studies of patients with AD.39,46-48 Even so, the amount of cortical [18F]AV-1451 binding in the DLB patients and PD-impaired participants was substantially lower than that reported in patients with AD,39,46-48 which typically ranges from 1.5 to greater than 2, consistent with neuropathologic reports.3-6,26
We also observed that the anatomic localization for abnormal [18F]AV-1451 binding in both patients with DLB and PD-impaired participants was similar to that reported in individuals with AD, including inferolateral temporal and parietal/precuneus regions. This finding suggests that neuropathologic processes that drive accumulation of tau deposits in patients with DLB and in PD-impaired patients are subject to the same regional vulnerabilities as those driving tau deposition in individuals with AD. Tau deposition was more variable in patients with DLB and was lower in magnitude and extent in the PD-impaired group. In contrast, the PD-normal participants did not demonstrate evidence for tau deposition. These observations are consistent with the variability of tau described in neuropathologic studies2-6,21 of DLB and PD and support the concept that tau copathology is common in Lewy body diseases but is not necessary for the presumptive driving neuropathology of α-synuclein aggregation.
In contrast to prior studies of individuals with advanced DLB,9-12 in which Aβ burden is often high, most cases of DLB in the present study had low amyloid burden. This difference may be due to the relatively modest cognitive impairment of individuals with DLB in the present study and may have obscured a correlation of amyloid burden with cognitive function. Nevertheless, the low Aβ burden in our DLB sample was often associated with high levels of abnormal [18F]AV-1451 binding in the neocortex, a finding that is in marked contrast to PET findings in individuals with MCI and AD, in which the 2 pathologies are well correlated in the neocortex and in which it is theorized that high Aβ burden is a critical factor in the expansion of tau pathologic changes into the neocortex.39,46,48 Thus, in Lewy body diseases, tau can accumulate in the neocortex without demonstrably elevated fibrillar amyloid. Whether Aβ is necessary for tau accumulation in the Lewy body diseases remains to be determined, however, because small foci of cortical amyloid were present in some patients, as previously demonstrated in Lewy body disease,9 and soluble Aβ oligomers and nonfibrillar amyloid in diffuse plaques could also contribute.7 This distinction between AD and the Lewy body diseases may reflect the synergistic association between α-synuclein aggregation and tau pathologic changes.49,50
Consistent with the hypothesis that tau deposition is deleterious to cognition in Lewy body disease, as previously demonstrated in AD,15,39,46-48 in an aggregate cohort of participants with DLB and PD-impaired participants, those with greater [18F]AV-1451 binding in inferior temporal and precuneus regions showed greater cognitive impairment. This result is consistent with a model in which neuropathologic cascades that involve tau accumulation might act through local synaptic and cell loss,18 likely in concert with α-synuclein toxic effects,51 to impair cognition in the Lewy body diseases.
In this study, we sought to contrast Lewy body disease groups with an age-matched NC group with no evidence of amyloid proteinopathy. Many cognitively normal individuals have high levels of cortical amyloid, however, and a small proportion of these people has recently been shown39 to have elevated neocortical tau in the inferior temporal gyrus. Compared with these individuals, tau deposition in the DLB and PD-impaired groups would not be as evident. Even so, the levels of neocortical tau deposition observed in several of the DLB and PD-impaired participants exceed levels of tau observed in cognitively normal persons with high amyloid and tau levels, and tau deposition in patients with Lewy body disease was associated with cognitive impairment.
Strengths of this study include acquisition of multimodal PET molecular imaging and inclusion of well-characterized patients across the spectrum of Lewy body disease. The use of an NC cohort with low amyloid burden increases the sensitivity to detect AD neurofibrillary tangle copathology in the diagnostic groups. A limitation of this study is the small group sizes; future studies with more participants will be required to confirm these observations. An additional limitation is the use of clinical diagnosis without neuropathologic confirmation. Reported off-target binding of [18F]AV-1451 to melanin and brain hemorrhagic lesions24 is unlikely to affect the results of the study.
The results of this study suggest that deposits of tau are common in the Lewy body diseases, especially in DLB; can arise in the absence of significant amyloid burden; and contribute to cognitive impairment. These observations highlight the contribution of noncanonical, extra-synuclein tau copathology to cognition in the Lewy body diseases.
Corresponding Author: Stephen N. Gomperts, MD, PhD, MassGeneral Institute for Neurodegenerative Disease, 114 16th St, Room 2004, Charlestown, MA 02129 (email@example.com).
Accepted for Publication: July 9, 2016.
Published Online: September 19, 2016. doi:10.1001/jamaneurol.2016.3338
Author Contributions: Dr Gomperts had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: Gomperts, Sperling, Growdon, Johnson.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: Gomperts, Locascio, Johnson.
Critical revision of the manuscript for important intellectual content: All authors.
Statistical analysis: Gomperts, Locascio, Makaretz, Sperling, Johnson.
Obtaining funding: Gomperts, Sperling, Johnson.
Administrative, technical, or material support: Makaretz, Caso, Sperling, Growdon, Dickerson, Johnson.
Study supervision: Gomperts, Growdon, Dickerson, Johnson.
Conflict of Interest Disclosures: Dr Sperling has provided paid consulting services for Roche, Genentech, Biogen and Bracket, and Abbvie; received support from a joint National Institutes of Health (NIH)-Lilly–sponsored clinical trial; and research funding from the NIH/National Institute on Aging and the Alzheimer’s Association. Dr Dickerson has provided paid consulting services for Merck DSMB, Forum, Ionis, and Piramal and receives royalties from Oxford University Press. Dr Johnson has provided paid 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; and received research support from NIH/National Institute on Aging, Fidelity Biosciences, the Michael J. Fox Foundation, the Marr Foundation, and the Alzheimer’s Association.
Funding/Support: This study was supported by grants R21 NS 090243 and R21 NS084156 from the NIH/National Institute of Neurological Disorders and Stroke; R01 AG046396, P01 AG036694, and P50 AG00513421 from the National Institute on Aging; and the National Parkinson’s Foundation.
Role of the Funder/Sponsor: These funding organizations played no role in the design and conduct of the study; collection, management, analysis, and interpretation of data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Additional Contributions: Musab Zorlu, MD, and Parisa Oviedo, BS (Massachusetts General Hospital), assisted with data management. There was no financial compensation. We thank the patients and families who participated in this study and the staff involved in coordinating study visits and assessments.