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J Alzheimers Dis. Author manuscript; available in PMC 2013 June 6.
Published in final edited form as:
PMCID: PMC3674205
NIHMSID: NIHMS468740

PET Imaging of Neuropathology in Tauopathies: Progressive Supranuclear Palsy

Vladimir Kepe, PhD,a Yvette Bordelon, MD, PhD,b Adam Boxer, MD, PhD,e Sung-Cheng Huang, DSc,a Jie Liu, PhD,a Frederick C. Thiede, BSc,b John C. Mazziotta, MD, PhD,b Mario F. Mendez, MD, PhD,b,c,f Natacha Donoghue, MA,c,d Gary W. Small, MD,c and Jorge R. Barrio, PhD*

Abstract

Objective

Currently [F-18]FDDNP is the only PET imaging probe with the ability to visualize hyperphosphorylated tau fibrillar aggregates in living subjects. In this work, we evaluate in vivo [F-18]FDDNP labeling of brain neuropathology, primarily tau fibrillar aggregates, in patients with progressive supranuclear palsy (PSP), a human tauopathy usually lacking β-amyloid deposits.

Methods

Fifteen patients with PSP received [F-18]FDDNP PET scanning. [F-18]FDDNP distribution volume ratios (DVR), in reference to cerebellar gray matter, were determined for cortical and subcortical areas and compared with those of patients with Parkinson’s disease (PD) with short disease duration, and age-matched control subjects without neurodegenerative disorders.

Results

[F-18]FDDNP binding was present in subcortical areas (e.g., striatum, thalamus, subthalamic region, midbrain and cerebellar white matter) regardless of disease severity, with progressive subcortical and cortical involvement as disease severity increased. Brain patterns of [F-18]FDDNP binding were entirely consistent with the known pathology distribution for PSP. High midbrain and subthalamic region [F-18]FDDNP binding was distinctive for PSP subjects and separated them from controls and patients with PD.

Conclusions

These results provide evidence that [F-18]FDDNP is a sensitive in vivo PET imaging probe to map and quantify the dynamic regional localization of tau fibrillar aggregates in PSP. Furthermore, [F-18]FDDNP PET may provide a tool to detect changes in tau pathology distribution either associated with disease progression or as a treatment biomarker for future tau-specific therapies. Patterns of [F-18]FDDNP binding may also be useful in diagnosis early in disease presentation when clinical distinction among neurodegenerative disorders is often difficult.

Keywords: Key-words: positron emission tomography, FDDNP, progressive supranuclear palsy, Parkinson’s disease, neuropathology, hyperphosphorylated tau aggregates, tauopathy

INTRODUCTION

In vivo imaging of neuropathological insoluble protein aggregates with positron emission tomography (PET) can aid in early diagnosis of neurodegenerative diseases before extensive neuronal loss and clinical symptoms become evident [1]. It can also serve as an indicator of treatment efficacy for interventions aimed at preventing or slowing protein aggregate deposition if it possesses sufficient sensitivity to detect changes in protein lesion loads resulting from disease progression or from effective targeted therapies.

During the last decade, investigators have introduced numerous imaging probes with purported specificity for β-amyloid plaques, [C-11]PiB, [F-18]3′-fluoro-PiB ([F-18]flutemetamol, [C-11]SB-13, [F-18]BAY94-9172 ([F-18]florbetaben), [F-18]AV45 ([F-18]florbetapir), BF-227, among others [2]; however, only 2-(1-{6-[(2-[F-18]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile ([F-18]FDDNP) has been shown capable of detecting tau protein deposits in the living human brain. [F-18]FDDNP is specific for the β-pleated sheet conformation present in amyloid fibrils of all types, both in vitro [3] and in vivo in Alzheimer’s disease (AD) and mild cognitive impairment [4,5], in Gerstmann-Sträussler-Scheinker disease and other prion diseases [6,7], as well as tau neuropathology in fronto-temporal lobe dementia (FTLD) [8]. [F-18]FDDNP PET in AD has shown a pattern of cortical binding that includes both β-amyloid senile plaque (SP) and hyperphosphorylated tau neurofibrillary tangle (NFT) rich areas of the AD brain compared with no cortical binding in cognitively normal controls [4,5]. Recently, a number of [F-18]fluorinated molecular imaging probes have shown in vitro ability to label tau aggregates and to possess selectivity for tau over β-amyloid aggregates, i.e. THK523 [9, 10] and T807 [11], and they are now being evaluated for human use with PET [12, 13].

The ability of [F-18]FDDNP to label fibrillar tau in NFT rich areas in AD points to its potential as an in vivo tau marker in neurodegenerative disorders characterized by tau pathology, usually in the absence of β-amyloid aggregates. These disorders include progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), FTLD with tau pathology, and argyrophilic grain disease [14]. Of these, PSP offers an excellent human model of brain tauopathies for evaluation of [F-18]FDDNP PET for in vivo detection of fibrillar tau aggregates in subcortical, and in some cases, also cortical areas of the brain. In contrast to AD, where fibrillar tau is found predominately in the form of neuronal NFTs in the cortex, tau fibrillar aggregates in PSP occur in neurons (NFTs), astrocytes (tuft-shaped astrocytes) and oligodendrocytes (coiled bodies) in both cortical and subcortical regions [15, 16].

With this work we tested the hypothesis that 1) [F-18]FDDNP PET is a sensitive in vivo imaging method for neurodegenerative tau lesions in PSP patients; and 2) [F-18]FDDNP brain regional deposition in these patients will be increased in subcortical and cortical areas known to have progressive deposition of tau pathology. Comparison was made with another neurodegenerative disorder with similar clinical symptomatology early on in disease course, Parkinson disease (PD). Lewy body pathology characteristic of PD, and also detected in vitro by FDDNP based on the fibrillar structure of α-synuclein aggregates, present different brain distribution patterns and lower densities than tau pathology in PSP. This allows separation of these two conditions based on their distinctive in vivo [F-18]FDDNP brain binding patterns.

MATERIALS AND METHODS

Written, informed consent was obtained from subjects in accordance with procedures of the Office of the Human Research Protection Program (OHRPP) of the University of California, Los Angeles, under strict, standard ethics guidelines. Capacity to provide informed consent was determined for each subject in the presence of a spouse or caregiver by questioning the subject’s understanding of key elements of the study including risks and benefits. If a subject was deemed not able to provide informed consent, the legal representative (in these cases, the spouses) provided informed consent while the subject agreed to participation. Fifteen patients with a diagnosis of clinically probable PSP according to NINDS criteria (gradually progressive disorder, age of onset >40 and either vertical supranuclear gaze paresis or both slowing of vertical saccades and prominent postural instability with falls in the first year) [17], were enrolled from the Movement Disorders and Memory Disorders Clinics at University of California, Los Angeles and the Memory and Aging Center at University of California, San Francisco. Subjects underwent examination that included the PSP Rating Scale (PSPRS) [18] and Mini-Mental State Examination (MMSE) [19]. No PSP subject had symptoms of cerebellar ataxia. The subject group consisted of 7 female and 8 male patients aged 59–86 years (mean±SD: 68.3±7.5 years) with duration of disease lasting 2–8 years (mean±SD: 4.7±2.0 years). Eight patients with idiopathic PD with short duration of disease (<5 years, mean 2.4±1.1years) were recruited from the UCLA Movement Disorders Clinic and underwent examination that included the Unified Parkinson Disease Rating Scale (UPDRS) [20] and the MMSE. Demographics for all patient groups are shown in Table 1 (data for individual subjects from all groups are shown in the Supplementary Materials Table S1). Five age matched control subjects without history of neurological disorders and dementia were recruited from a larger study on [F-18]FDDNP PET imaging in aging and AD conducted at UCLA [5].

Table 1
Cumulative demographic and clinical data for PSP, PD, and control subject groups.

PET Imaging Protocol

[F-18]FDDNP was prepared as previously described [21] following currently FDA-mandated regulatory requirements for chemistry, manufacture and control. All PET scans were performed at the UCLA Ahmanson Biomedical Imaging Center using either ECAT HR+ PET camera or Biograph PET/CT camera (both Siemens/CTI, Knoxville, TN). Patients lying in supine position on the tomography bed were injected with 10 mCi of [F-18]FDDNP as a bolus intravenous injection following a 10 min attenuation scan. The dynamic data acquisition was started at the time of injection. The following time frames were collected: 6x30 sec, 4x180 sec, and 10x300 sec (total duration: 65 min). All PET scans were decay corrected and reconstructed using filtered back-projection (Hann filter, 5.5 mm FWHM) with scatter correction and measured attenuation correction. The resulting images from the PET camera contained 63 contiguous slices with the plane-to-plane separation of 2.42 mm and images from the PET/CT camera contained 109 contiguous slices with the plane-to-plane separation of 2.0 mm. No significant differences between images from the two scanners were observed. Motion correction was performed as described previously [22].

Imaging Analysis

Logan graphical analysis [23] with the cerebellar grey matter as the reference region was performed on dynamic [F-18]FDDNP data sets and parametric images of the distribution volume ratios (DVR) using time frames from 30 min to 65 min were prepared as described previously [4,24]. Cerebellar grey matter is a suitable reference region for analysis of [F-18]FDDNP PET data in PSP subjects since, in the absence of ataxia, only sporadic tau deposition in this area has been observed [25]. No atrophy correction of the PET data was performed. Partial volume effects result in reduction of the PET signal due to brain atrophy and, if performed, this correction would increase the intensity of [F-18]FDDNP brain signal even further.

[F-18]FDDNP DVR Quantification

Regional [F-18]FDDNP distribution volume ratio (DVR) values were extracted from DVR parametric images using regions-of-interest (ROIs) drawn on the [F-18]FDDNP perfusion image, obtained during the first six minutes of the scan [24]. ROI sets included subcortical areas (striatum, thalamus, subthalamic region, midbrain, cerebellar white matter including deep nuclei, and cortical areas [frontal, parietal, medial temporal (limbic regions, including the hippocampus, parahippocampal areas and entorhinal cortex), lateral temporal and posterior cingulate gyrus]. ROIs were drawn bilaterally on each region, with the exception of the midbrain where only one ROI was placed. Each regional DVR value was calculated as an average of the left and right regions and global cortical DVR values were calculated as averages of the values for all cortical regions (frontal, parietal, medial temporal, lateral temporal and posterior cingulate gyrus).

Statistical Analysis

ANOVA analysis was conducted to assess whether there were significant differences in regional [F-18]FDDNP binding (DVR values) between PSP, PD, and control groups. Spearman rank correlation (rS) was used to determine the correlation between frontal [F-18]FDDNP DVR values and PSPRS scores in PSP subjects with available PSPRS scores. Student t-tests were used to determine whether there were significant differences in regional [F-18]FDDNP binding (DVR values) in all subject groups compared with controls.

RESULTS

The PSP cohort included four patients with lower MMSE scores in the range of DSM criteria for dementia [21] (MMSE score <25; range 13–23; mean±SD: 18.7±3.3) and nine subjects with higher MMSE scores (MMSE score ≥25; range 25–29; mean±SD: 26.8±1.4) (Supplementary Materials Table S1). The MMSE score was not available for two PSP patients. All PSP patients with MMSE <25 also had high PSPRS scores (range: 41–61; mean±SD: 46.5±9.7) (Supplementary Materials Table S1 and Figure S2).

[F-18]FDDNP binding in PSP subjects differed significantly from that of all other subject groups in several subcortical regions, which are the areas with a higher density of tau aggregates: subthalamic area (F[3,26] = 33.01, P<0.0001), midbrain region (F[3,26] = 24.12, P<0.0001), and cerebellar white matter (F[3,26] = 11.84, P<0.0001) (Figure 1, Figure S3, Table 2). Neocortical regions were affected only in a subset of PSP subjects with more severe clinical symptoms (Table 1) and pattern variability prevalent with binding primarily in the frontal lobe and less frequently in temporal lobes and posterior cingulate gyrus. In the frontal lobe [F-18]FDDNP binding was correlated with PSPRS score as a measure of severity of symptoms (Figure S4, rS = 0.53, P<0.05).

Figure 1
Coronal (A) and transaxial (B) brain [F-18]FDDNP DVR images sections of human subjects showing the distribution of [F-18]FDDNP DVR signal in a PSP subject (PSP12; upper row in each view) and a typical control (CTRL3; lower row in each view). DVR values ...
Table 2
Regional [F-18]FDDNP DVR values

DISCUSSION

The observed patterns of subcortical [F-18]FDDNP binding in PSP (Figure 2) correlated well with (i) known patterns of brain areas frequently affected by different subtypes of tau aggregates (NFTs, tufted astrocytes, coiled bodies) throughout PSP disease progression, and (ii) symptomatology, as motor symptoms are typically more prominent in this disease. Variable patterns of cortical [F-18]FDDNP binding, e.g., frontal lobe (Figure S4), were observed in PSP subjects, with higher levels observed in patients with more severe disease. Especially in the earliest states of PSP, [F-18]FDDNP brain imaging shows distinctive differences in subcortical areas compared with early PD, with which it may be overlapping clinically (Figures 2 and and3).3). Early in disease presentation subjects with PSP are often misdiagnosed with PD given the similarity in syndromes with patients exhibiting bradykinesia, rigidity, and gait and postural instability. Only after disease progression will the diagnosis of PSP become more certain. Comparing this pattern with the patterns of [F-18]FDDNP binding in other neurodegenerative diseases, it is clear that [F-18]FDDNP binding in the subthalamic area, midbrain and cerebellar areas is specific to PSP and not observed in other disorders and thus, could be a valuable diagnostic aid. Earlier diagnosis is critical particularly as tau-specific therapies become available in the future.

Figure 2
Representative examples of [F-18]FDDNP binding patterns observed in PSP with longer duration (advanced PSP, left column), in PSP with shorter duration without cortical signal (early PSP, middle column), and in Parkinson’s disease (right column). ...
Figure 3
Detailed views of [F-18]FDDNP DVR parametric images shown in coronal and transaxial orientation are shown for three PSP patients. PD5 subject is shown for comparison. Subthalamic areas are indicated by arrowheads.

As stated earlier, only [F-18]FDDNP has currently the ability to visualize in vivo tau-aggregate-rich brain regions in patients with AD (i.e., medial temporal lobe) [4,5] and tau-positive frontotemporal dementia (frontal and temporal lobes) [8]. The ability of [F-18]FDDNP to label both β-amyloid and hyperphosphorylated tau aggregates in AD is based on the recognition of β-pleated sheet secondary structures in rigid fibrils present in both types of pathological protein deposits. Additional in vitro line of evidence supporting FDDNP tau binding includes co-crystallization of the DDNP moiety with VQIVYK segments from the tau protein repeat domain at atomic resolution [27] (Figure 4), [F-18]FDDNP binding to K183K280 tau fibrils (KD = 36.7 ± 11.6 nM) [10], FDDNP labeling of cells transfected with SY5Y tau constructs, and tau aggregates in NFTs in MAPT transgenic mice, both detected by fluorescence microscopy (Cole et al, unpublished observations), as well as tau labeling in AD brain specimens [5]. With the apparent exception of globose neurofibrillary tangles [3], these in vitro and in vivo results demonstrate the ability of the 2-dicyanopropenyl-6-dialkylaminonaphthalene scaffold to bind tightly to structures formed by tau fragments.

Figure 4
Models of DDNP bound to a tau segment (VQIVYK fiber) based on undifferentiated electron density. Panel A shows micro-crystals of VQIVYK co-crystallized with DDNP. In the structure of the complexes with DDNP (B–C), VQIVYK is packed in a form having ...

Our findings with PSP subjects suggest that [F-18]FDDNP offers promise as a tool in the clinical evaluation of patients with neurodegenerative diseases including the tauopathies. These disorders are characterized by a spectrum of clinical symptoms ranging from motor dysfunction to dementia as a result of extensive neuronal loss in specific vulnerable neuronal populations [28]. Observed differences in clinical presentation of various tauopathies are based on structural, physiological and functional alterations of different brain circuits brought forth by underlying cellular and tau-induced degenerative changes. Although the relationships among these tau pathological changes, neuronal loss and clinical symptoms are complex and not well understood, it is clear that hyperphosphorylation of tau proteins, their polymerization and formation of cellular inclusions is required for full disease evolution. [29, 30].

Neuropathology reports in PSP have shown that the subthalamic nucleus, substantia nigra (midbrain) and globus pallidus internus are consistently affected, even in cases with the mildest clinical symptoms and the lowest lesion burden [15]. Analysis of different cellular types of tau aggregates has revealed that all types found commonly in PSP, i.e., neurofibrillary tangles, tufted astrocytes and coiled bodies in oligodendrocytes, are composed of straight fibrils formed predominatly by four repeat isoforms [31]. Total tau pathology load varies considerably among brain regions and within patients with PSP. NFTs are most abundant in the basal ganglia and brainstem structures; tufted astrocytes are most abundant in the cortices, putamen and caudate nucleus; and coiled bodies and tau threads, which are the major contributors to the overall tau load, are most numerous in the subthalamic nucleus, substantia nigra and globus pallidus internus and least dense in cortical regions [15]. This is again entirely consistent with the observed [F-18]FDDNP brain distribution observed in the living brain of these patients and [F-18]FDDNP’s ability to detect four repeat isoforms of these tau fibrillar aggregates.

In addition to typical PSP as defined by NINDS clinical [17] and neuropathological [32] criteria, up to six atypical subtypes have been described. These can be largely subdivided into cortical predominant and brain stem predominant PSP subtypes [30]. Regardless of its clinical variability, early pathology deposition in PSP seems to occur first in a progressive fashion in subcortical areas, most specifically in globus pallidus, subthalamic structures, brain stem and cerebellar white matter spreading to the cortex in later stages of the disease. Observations with this PSP patient population reveal consistent [F-18]FDDNP subcortical involvement and a variable pattern of cortical involvement possibly reflecting different pathological stages of the disease (Table 2), which is evident as increased [F-18]FDDNP binding in cortical areas is observed in more symptomatic PSP subjects (higher PSPRS score)(Figure S4). Although symptoms included in PSPRS score are not cortical they serve as indication of disease severity. In the absence of pathology results from these more affected subjects it is not possible to exclude the presence of concurrent AD pathology in some of the PSP subjects presenting cortical [F-18]FDDNP binding.

Figure 2 and Table 2 demonstrate the different [F-18]FDDNP distribution reflecting the differential patterns of subcortical binding in PSP and PD. This consistent subcortical [F-18]FDDNP binding to tau pathological aggregates may be of help to clinicians in the differential diagnosis of PSP, even the PSP-Parkinsonism variant, and PD [15]. These findings confirm previous reports on in vivo [F-18]FDDNP imaging of tau fibrillar deposits [33, 34], but the small number of PSP subjects in this intial study and the lack of confirmed pathology in these subjects present a limitation for a more general interpretation of the imaging results. However, recent work on [F-18]FDDNP imaging with retired football players with possible chronic traumatic encephalopathy (CTE) [35] offers confirmatory evidence of the utility of [F-18]FDDNP as an in vivo tau marker in neurodegenerative tauopathies, with sufficient sensitivity to detect variable patterns of regional tau pathology load. On a more general note, this work with PSP subjects also demonstrates that the pi-conjugation of a dialkylamino group, as the electron donor, with a 2-cyano acrylate unit in the dialkylamino naphthalenyl-2-cyanoacrylate motif, as the electron acceptor (e.g., in 2-dicyanopropenyl-6-dialkylaminonaphthalenes as [F-18]FDDNP), does produce tau-binding molecules with significant sensitivity for in vivo detection of tau aggregation in humans. Of importance is that the tau binding properties of such a motif as well as its specificity for tau (e.g., vs. Aβ binding) could be fine-tuned by modifying the electronic density and extent of conjugation between the donor and acceptor units. This approach offers a framework for the development and testing of new neurofibrillary tau specific imaging probes in parallel with X-ray microcrystallography at atomic resolution in co-crystallization experiments [27].

Supplementary Material

SUpplementary-Materials

Acknowledgments

Supported by National Institutes of Health (P01-AG025831, R01AG038791, R01AG031278, R01AG034499, P50 AG 16570) and by the Tau Research Consortium. JRB gratefully acknowledges support from the Elizabeth and Thomas Plott Endowment in Gerontology. No company provided support of any kind for this study. Special thanks also to N. Satyamurthy and cyclotron staff and J. Williams and the Nuclear Medicine Clinic staff for their support with the scanning protocols.

Footnotes

Contributors. VK, YB, AB, SCH, JCM, MFM, GWS, JRB designed the study. YB, AB, MFM, FT, ND, GWS recruited and evaluated subjects. JL performed radiosynthesis. VK analyzed the imaging data. VK, YB, SCH, MFM, GWS and JRB interpreted the data. VK, YB, JL, MFM, and JRB prepared the initial manuscript. All authors contributed to the final version of the manuscript.

Conflict of Interest. The University of California, Los Angeles (UCLA), owns a U.S. patent, “Methods for Labeling β-Amyloid Plaques and Neurofibrillary Tangles” (6,274,119), that uses the approach outlined in this article. Drs. Huang, Small, and Barrio, are listed among the inventors. All other authors report that they have no conflict of interest.

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