Liver background uptake of [18F]FLT in PET imaging.

High liver uptake presents a problem for 3'-deoxy-3'-[18F]fluorothymidine ([18F]FLT) as a radiotracer for imaging cellular proliferation in the liver with positron emission tomography (PET). This investigation re-visited some issues related to the high liver background uptake of [18F]FLT with an animal model of woodchucks. Several enzymes involved in the hepatic catabolism of FLT, thymidine phosphorylase (TP, TYMP), uridine 5'-diphospho-glucuronosyl-transferases (UDP-GTs, short for UGTs), and ß-glucuronidase (GUSB), their homology as well as hepatic expression between the human and the woodchuck was examined. Inhibitors of these enzymes, TP inhibitor (TPI) tipiracil hydrochloride, UGT inhibitor probenecid, ß-glucuronidase inhibitor L-aspartate, were administered to the animals at human equivalent doses either intravenously (i.v.) and orally before the injection of tracer-dose [18F]FLT for PET imaging to examine any changes in liver uptake. Liver tissue samples were harvested from the animals after PET imaging and used to perform polymerase chain reaction (PCR) for TP expression or assays for enzymatic activities of TP and ß-glucuronidase. Non-radiolabeled (cold) FLT was also applied for enzyme saturation. Animals administered with TPI displayed lower radioactivity in the liver in comparison with the baseline scan. The application of probenecid did not change [18F]FLT liver uptake even though it reduced renal uptake. L-aspartate reduced the liver background uptake of [18F]FLT slightly. The application of cold FLT reduced overall uptake of [18F]FLT including the liver background. Therefore, the combined application of cold FLT and [18F]FLT merits further clinical investigation for reducing liver background uptake of [18F]FLT.

[18F] Clofarabine for PET Imaging of Hepatocellular Carcinoma.

Clinical diagnosis of hepatocellular carcinoma (HCC) relies heavily on radiological imaging. However, information pertaining to liver cancer treatment such as the proliferation status is lacking. Imaging tumor proliferation can be valuable in patient management. This study investigated 18F-labeled clofarabine ([18F]CFA) targeting deoxycytidine kinase (dCK) for PET imaging of dCK-dependent proliferation in HCC. Since clinical PET scans showed a high liver background uptake of [18F]CFA, the aim of this study was to reduce this liver background uptake. A clinically relevant animal model of spontaneously developed HCC in the woodchucks was used for imaging experiments. Several modifiers were tested and compared with the baseline PET scan: Forodesine, probenecid, and cold clofarabine, all applied before the hot [18F]CFA injection to evaluate the reduction in liver background uptake. Application of forodesine before hot [18F]CFA injection did not reduce the background uptake. Instead, it increased the background by 11.6-36.3%. Application of probenecid also increased the liver background uptake by 16.6-32.1%. Cold CFA application did reduce the liver background uptake of [18F]CFA, comparing to the baseline scan. Combining cold CFA with [18F]CFA for PET imaging of liver cancers is a promising strategy, worthy of further clinical evaluation.

Loss of dihydrotestosterone-inactivation activity promotes prostate cancer castration resistance detectable by functional imaging.

Androgens such as testosterone and dihydrotestosterone are a critical driver of prostate cancer progression. Cancer resistance to androgen deprivation therapies ensues when tumors engage metabolic processes that produce sustained androgen levels in the tissue. However, the molecular mechanisms involved in this resistance process are unclear, and functional imaging modalities that predict impending resistance are lacking. Here, using the human LNCaP and C4-2 cell line models of prostate cancer, we show that castration treatment-sensitive prostate cancer cells that normally have an intact glucuronidation pathway that rapidly conjugates and inactivates dihydrotestosterone and thereby limits androgen signaling, become glucuronidation deficient and resistant to androgen deprivation. Mechanistically, using CRISPR/Cas9-mediated gene ablation, we found that loss of UDP glucuronosyltransferase family 2 member B15 (UGT2B15) and UGT2B17 is sufficient to restore free dihydrotestosterone, sustained androgen signaling, and development of castration resistance. Furthermore, loss of glucuronidation enzymatic activity was also detectable with a nonsteroid glucuronidation substrate. Of note, glucuronidation-incompetent cells and the resultant loss of intracellular conjugated dihydrotestosterone were detectable in vivo by 18F-dihydrotestosterone PET. Together, these findings couple a mechanism with a functional imaging modality to identify impending castration resistance in prostate cancers.

Intestinal absorption of glucose in mice as determined by positron emission tomography.

KEY POINTS: The goal was to determine the importance of the sodium-glucose cotransporter SGLT1 and the glucose uniporter GLUT2 in intestinal glucose absorption during oral glucose tolerance tests (OGTTs) in mice. Glucose absorption was determined in mice using positron emission tomography and three non-metabolizable glucose probes: one specific for SGLTs, one specific for GLUTs, and one a substrate for both SGLTs and GLUTs. Absorption was determined in wild-type, Sglt1-/- and Glut2-/- mice. Gastric emptying was a rate-limiting step in absorption. SGLT1, but not GLUT2, was important in fast glucose absorption. In the absence of SGLT1 or GLUT2, the oral glucose load delivered to the small intestine was slowly absorbed. Oral phlorizin only inhibited the fast component of glucose absorption, but it contributed to decreasing blood glucose levels by inhibiting renal reabsorption. ABSTRACT: The current model of intestinal absorption is that SGLT1 is responsible for transport of glucose from the lumen into enterocytes across the brush border membrane, and GLUT2 for the downhill transport from the epithelium into blood across the basolateral membrane. Nevertheless, questions remain about the importance of these transporters in vivo. To address these questions, we have developed a non-invasive imaging method, positron emission tomography (PET), to monitor intestinal absorption of three non-metabolized glucose tracers during standard oral glucose tolerance tests (OGTTs) in mice. One tracer is specific for SGLTs (α-methyl-4-[18 F]fluoro-4-deoxy-d-glucopyranoside; Me-4FDG), one is specific for GLUTs (2-deoxy-2-[18 F]fluoro-d-glucose; 2-FDG), and one is a substrate for both SGLTs and GLUTs (4-deoxy-4-[18 F]fluoro-d-glucose; 4-FDG). OGTTs were conducted on adult wild-type, Sglt1-/- and Glut2-/- mice. In conscious mice, OGTTs resulted in the predictable increase in blood glucose that was blocked by phlorizin in both wild-type and Glut2-/- animals. The blood activity of both Me-4FDG and 4-FDG, but not 2-FDG, accompanied the changes in glucose concentration. PET imaging during OGTTs further shows that: (i) intestinal absorption of the glucose load depends on gastric emptying; (ii) SGLT1 is important for the fast absorption; (iii) GLUT2 is not important in absorption; and (iv) oral phlorizin reduces absorption by SGLT1, but is absorbed and blocks glucose reabsorption in the kidney. We conclude that in standard OGTTs in mice, SGLT1 is essential in fast absorption, GLUT2 does not play a significant role, and in the absence of SGLT1 the total load of glucose is slowly absorbed.

Positron emission tomography of sodium glucose cotransport activity in high grade astrocytomas.

A novel glucose transporter, the sodium glucose cotransporter 2 (SGLT2), has been demonstrated to contribute to the demand for glucose by pancreatic and prostate tumors, and its functional activity has been imaged using a SGLT specific PET imaging probe, α-methyl-4-[F-18]fluoro-4-deoxy-D-glucopyaranoside (Me-4FDG). In this study, Me-4FDG PET was extended to evaluate patients with high-grade astrocytic tumors. Me-4FDG PET scans were performed in four patients diagnosed with WHO Grade III or IV astrocytomas and control subjects, and compared with 2-deoxy-2-[F-18]fluoro-D-glucose (2-FDG) PET and magnetic resonance imaging (MRI) of the same subjects. Immunocytochemistry was carried out on Grade IV astrocytomas to determine the cellular location of SGLT proteins within the tumors. Me-4FDG retention was pronounced in astrocytomas in dramatic contrast to the lack of uptake into the normal brain, resulting in a high signal-to-noise ratio. Macroscopically, the distribution of Me-4FDG within the tumors overlapped with that of 2-FDG uptake and tumor definition using contrast-enhanced MRI images. Microscopically, the SGLT2 protein was found to be expressed in neoplastic glioblastoma cells and endothelial cells of the proliferating microvasculature. This preliminary study shows that Me-4FDG is a highly sensitive probe for visualization of high-grade astrocytomas by PET. The distribution of Me-4FDG within tumors overlapped that for 2-FDG, but the absence of background brain Me-4FDG resulted in superior imaging sensitivity. Furthermore, the presence of SGLT2 protein in astrocytoma cells and the proliferating microvasculature may offer a novel therapy using the SGLT2 inhibitors already approved by the FDA to treat type 2 diabetes mellitus.

Design, Syntheses, and in Vitro Evaluation of New Fluorine-18 Radiolabeled Tau-Labeling Molecular Probes.

Deposition of aggregates of hyperphosphorylated tau protein is a hallmark of tauopathies like Alzheimer and many other neurodegenerative diseases. A sensitive and selective method of in vivo detection of tau-aggregate presence and distribution could provide the means of an early diagnosis of tau-associated diseases. Furthermore, the use of selective molecular probes that enable histochemical differentiation of protein aggregates post-mortem would be advantageous for the insight into the properties of tau protein aggregates. We chose to design new molecular probes based on the structure of 2-(1-(6-((2-[18F]fluoroethyl)(methyl)amino)-2-naphthyl)ethylidene)malononitrile to investigate their likelihood of fitting into VQIVYK tau protein binding channel model. In a modular approach, using cross-coupling reactions, we synthesized a series of candidates, radiolabeled them with fluorine-18 radioisotope, and determined their physicochemical and in vitro binding properties. Herein we report the synthesis of a series of molecular probes capable of detection of tau protein deposits in vitro.

Dapagliflozin Binds Specifically to Sodium-Glucose Cotransporter 2 in the Proximal Renal Tubule.

Kidneys contribute to glucose homeostasis by reabsorbing filtered glucose in the proximal tubules via sodium-glucose cotransporters (SGLTs). Reabsorption is primarily handled by SGLT2, and SGLT2-specific inhibitors, including dapagliflozin, canagliflozin, and empagliflozin, increase glucose excretion and lower blood glucose levels. To resolve unanswered questions about these inhibitors, we developed a novel approach to map the distribution of functional SGLT2 proteins in rodents using positron emission tomography with 4-[18F]fluoro-dapagliflozin (F-Dapa). We detected prominent binding of intravenously injected F-Dapa in the kidney cortexes of rats and wild-type and Sglt1-knockout mice but not Sglt2-knockout mice, and injection of SGLT2 inhibitors prevented this binding. Furthermore, imaging revealed only low levels of F-Dapa in the urinary bladder, even after displacement of kidney binding with dapagliflozin. Microscopic ex vitro autoradiography of kidney showed F-Dapa binding to the apical surface of early proximal tubules. Notably, in vivo imaging did not show measureable specific binding of F-Dapa in heart, muscle, salivary glands, liver, or brain. We propose that F-Dapa is freely filtered by the kidney, binds to SGLT2 in the apical membranes of the early proximal tubule, and is subsequently reabsorbed into blood. The high density of functional SGLT2 transporters detected in the apical membrane of the proximal tubule but not detected in other organs likely accounts for the high kidney specificity of SGLT2 inhibitors. Overall, these data are consistent with data from clinical studies on SGLT2 inhibitors and provide a rationale for the mode of action of these drugs.

A semi-automated workflow solution for multimodal neuroimaging: application to patients with traumatic brain injury.

Traumatic brain injury (TBI) is a major cause of mortality and morbidity, placing a significant financial burden on the healthcare system worldwide. Non-invasive neuroimaging technologies have been playing a pivotal role in the study of TBI, providing important information for surgical planning and patient management. Advances in understanding the basic mechanisms and pathophysiology of the brain following TBI are hindered by a lack of reliable image analysis methods for accurate quantitative assessment of TBI-induced structural and pathophysiological changes seen on anatomical and functional images obtained from multiple imaging modalities. Conventional region-of-interest (ROI) analysis based on manual labeling of brain regions is time-consuming and the results could be inconsistent within and among investigators. In this study, we propose a workflow solution framework that combined the use of non-linear spatial normalization of structural brain images and template-based anatomical labeling to automate the ROI analysis process. The proposed workflow solution is applied to dynamic PET scanning with 15O-water (0-10 min) and 18F-FDDNP (0-6 min) for measuring cerebral blood flow in patients with TBI.

Revisiting the physiological roles of SGLTs and GLUTs using positron emission tomography in mice.

KEY POINTS: Glucose transporters are central players in glucose homeostasis. There are two major classes of glucose transporters in the body, the passive facilitative glucose transporters (GLUTs) and the secondary active sodium-coupled glucose transporters (SGLTs). In the present study, we report the use of a non-invasive imaging technique, positron emission tomography, in mice aiming to evaluate the role of GLUTs and SGLTs in controlling glucose distribution and utilization. We show that GLUTs are most significant for glucose uptake into the brain and liver, whereas SGLTs are important in glucose recovery in the kidney. This work provides further support for the use of SGLT imaging in the investigation of the role of SGLT transporters in human physiology and diseases such as diabetes and cancer. ABSTRACT: The importance of sodium-coupled glucose transporters (SGLTs) and facilitative glucose transporters (GLUTs) in glucose homeostasis was studied in mice using fluorine-18 labelled glucose molecular imaging probes and non-invasive positron emission tomography (PET) imaging. The probes were: α-methyl-4-[F-18]-fluoro-4-deoxy-d-glucopyranoside (Me-4FDG), a substrate for SGLTs; 4-deoxy-4-[F-18]-fluoro-d-glucose (4-FDG), a substrate for SGLTs and GLUTs; and 2-deoxy-2-[F-18]-fluoro-d-glucose (2-FDG), a substrate for GLUTs. These radiolabelled imaging probes were injected i.v. into wild-type, Sglt1(-/-) , Sglt2(-/-) and Glut2(-/-) mice and their dynamic whole-body distribution was determined using microPET. The distribution of 2-FDG was similar to that reported earlier (i.e. it accumulated in the brain, heart, liver and kidney, and was excreted into the urinary bladder). There was little change in the distribution of 2-FDG in Glut2(-/-) mice, apart from a reduction in the rate of uptake into liver. The major differences between Me-4FDG and 2-FDG were that Me-4FDG did not enter the brain and was not excreted into the urinary bladder. There was urinary excretion of Me-4FDG in Sglt1(-/-) and Sglt2(-/-) mice. However, Me-4FDG was not reabsorbed in the kidney in Glut2(-/-) mice. There were no differences in Me-4FDG uptake into the heart of wild-type, Sglt1(-/-) and Sglt2(-/-) mice. We conclude that GLUT2 is important in glucose liver transport and reabsorption of glucose in the kidney along with SGLT2 and SGLT1. Complete reabsorption of Me-4FDG from the glomerular filtrate in wild-type mice and the absence of reabsorption in the kidney in Glut2(-/-) mice confirm the importance of GLUT2 in glucose absorption across the proximal tubule.

Functional expression of sodium-glucose transporters in cancer.

Glucose is a major metabolic substrate required for cancer cell survival and growth. It is mainly imported into cells by facilitated glucose transporters (GLUTs). Here we demonstrate the importance of another glucose import system, the sodium-dependent glucose transporters (SGLTs), in pancreatic and prostate adenocarcinomas, and investigate their role in cancer cell survival. Three experimental approaches were used: (i) immunohistochemical mapping of SGLT1 and SGLT2 distribution in tumors; (ii) measurement of glucose uptake in fresh isolated tumors using an SGLT-specific radioactive glucose analog, α-methyl-4-deoxy-4-[(18)F]fluoro-D-glucopyranoside (Me4FDG), which is not transported by GLUTs; and (iii) measurement of in vivo SGLT activity in mouse models of pancreatic and prostate cancer using Me4FDG-PET imaging. We found that SGLT2 is functionally expressed in pancreatic and prostate adenocarcinomas, and provide evidence that SGLT2 inhibitors block glucose uptake and reduce tumor growth and survival in a xenograft model of pancreatic cancer. We suggest that Me4FDG-PET imaging may be used to diagnose and stage pancreatic and prostate cancers, and that SGLT2 inhibitors, currently in use for treating diabetes, may be useful for cancer therapy.

In vivo characterization of chronic traumatic encephalopathy using [F-18]FDDNP PET brain imaging.

Chronic traumatic encephalopathy (CTE) is an acquired primary tauopathy with a variety of cognitive, behavioral, and motor symptoms linked to cumulative brain damage sustained from single, episodic, or repetitive traumatic brain injury (TBI). No definitive clinical diagnosis for this condition exists. In this work, we used [F-18]FDDNP PET to detect brain patterns of neuropathology distribution in retired professional American football players with suspected CTE (n = 14) and compared results with those of cognitively intact controls (n = 28) and patients with Alzheimer's dementia (AD) (n = 24), a disease that has been cognitively associated with CTE. [F-18]FDDNP PET imaging results in the retired players suggested the presence of neuropathological patterns consistent with models of concussion wherein brainstem white matter tracts undergo early axonal damage and cumulative axonal injuries along subcortical, limbic, and cortical brain circuitries supporting mood, emotions, and behavior. This deposition pattern is distinctively different from the progressive pattern of neuropathology [paired helical filament (PHF)-tau and amyloid-ß] in AD, which typically begins in the medial temporal lobe progressing along the cortical default mode network, with no or minimal involvement of subcortical structures. This particular [F-18]FDDNP PET imaging pattern in cases of suspected CTE also is primarily consistent with PHF-tau distribution observed at autopsy in subjects with a history of mild TBI and autopsy-confirmed diagnosis of CTE.

Automated movement correction for dynamic PET/CT images: evaluation with phantom and patient data.

Head movement during a dynamic brain PET/CT imaging results in mismatch between CT and dynamic PET images. It can cause artifacts in CT-based attenuation corrected PET images, thus affecting both the qualitative and quantitative aspects of the dynamic PET images and the derived parametric images. In this study, we developed an automated retrospective image-based movement correction (MC) procedure. The MC method first registered the CT image to each dynamic PET frames, then re-reconstructed the PET frames with CT-based attenuation correction, and finally re-aligned all the PET frames to the same position. We evaluated the MC method's performance on the Hoffman phantom and dynamic FDDNP and FDG PET/CT images of patients with neurodegenerative disease or with poor compliance. Dynamic FDDNP PET/CT images (65 min) were obtained from 12 patients and dynamic FDG PET/CT images (60 min) were obtained from 6 patients. Logan analysis with cerebellum as the reference region was used to generate regional distribution volume ratio (DVR) for FDDNP scan before and after MC. For FDG studies, the image derived input function was used to generate parametric image of FDG uptake constant (Ki) before and after MC. Phantom study showed high accuracy of registration between PET and CT and improved PET images after MC. In patient study, head movement was observed in all subjects, especially in late PET frames with an average displacement of 6.92 mm. The z-direction translation (average maximum = 5.32 mm) and x-axis rotation (average maximum = 5.19 degrees) occurred most frequently. Image artifacts were significantly diminished after MC. There were significant differences (P<0.05) in the FDDNP DVR and FDG Ki values in the parietal and temporal regions after MC. In conclusion, MC applied to dynamic brain FDDNP and FDG PET/CT scans could improve the qualitative and quantitative aspects of images of both tracers.

A novel PSEN1 mutation (I238M) associated with early-onset Alzheimer's disease in an African-American woman.

Mutations in PSEN1 are the most common cause of autosomal dominant familial Alzheimer's disease (FAD). We describe an African-American woman with a family history consistent with FAD who began to experience cognitive decline at age 50. Her clinical presentation, MRI, FDG-PET, and PIB-PET scan findings were consistent with AD and she was found to have a novel I238M substitution in PSEN1. As this mutation caused increased production of Aß42 in an in vitro assay, was not present in two population databases, and is conserved across species, it is likely to be pathogenic for FAD.

Cerebral amyloid PET imaging in Alzheimer's disease.

The devastating effects of the still incurable Alzheimer's disease (AD) project an ever increasing shadow of burden on the health care system and society in general. In this ominous context, amyloid (Aß) imaging is considered by many of utmost importance for progress towards earlier AD diagnosis and for potential development of effective therapeutic interventions. Amyloid imaging positron emission tomography procedures offer the opportunity for accurate mapping and quantification of amyloid-Aß neuroaggregate deposition in the living brain of AD patients. This review analyzes the perceived value of current Aß imaging probes and their clinical utilization and, based on amyloid imaging results, offers a hypothesis on the effects of amyloid deposition on the biology of AD and its progression. It also analyzes lingering questions permeating the field of amyloid imaging on the apparent contradictions between imaging results and known neuropathology brain regional deposition of Aß aggregates. As a result, the review also discusses literature evidence as to whether brain Aß deposition is truly visualized and measured with these amyloid imaging agents, which would have significant implications in the understanding of the biological AD cascade and in the monitoring of therapeutic interventions with these surrogate Aß markers.

Amyloid-ß positron emission tomography imaging probes: a critical review.

The rapidly rising prevalence and cost of Alzheimer's disease in recent decades has made the imaging of amyloid-ß deposits the focus of intense research. Several amyloid imaging probes with purported specificity for amyloid-ß plaques are currently at various stages of FDA approval. However, a number of factors appear to preclude these probes from clinical utilization. As the available "amyloid specific" positron emission tomography imaging probes have failed to demonstrate diagnostic value and have shown limited utility for monitoring therapeutic interventions in humans, a debate on their significance has emerged. The aim of this review is to identify and discuss critically the scientific issues contributing to the extensive inconsistencies reported in the literature on their purported in vivo amyloid specificity and potential utilization in patients.

A transgenic Alzheimer rat with plaques, tau pathology, behavioral impairment, oligomeric aß, and frank neuronal loss.

Alzheimer's disease (AD) is hallmarked by amyloid plaques, neurofibrillary tangles, and widespread cortical neuronal loss (Selkoe, 2001). The "amyloid cascade hypothesis" posits that cerebral amyloid sets neurotoxic events into motion that precipitate Alzheimer dementia (Hardy and Allsop, 1991). Yet, faithful recapitulation of all AD features in widely used transgenic (Tg) mice engineered to overproduce Aß peptides has been elusive. We have developed a Tg rat model (line TgF344-AD) expressing mutant human amyloid precursor protein (APPsw) and presenilin 1 (PS1ΔE9) genes, each independent causes of early-onset familial AD. TgF344-AD rats manifest age-dependent cerebral amyloidosis that precedes tauopathy, gliosis, apoptotic loss of neurons in the cerebral cortex and hippocampus, and cognitive disturbance. These results demonstrate progressive neurodegeneration of the Alzheimer type in these animals. The TgF344-AD rat fills a critical need for a next-generation animal model to enable basic and translational AD research.

Postmortem 3-D brain hemisphere cortical tau and amyloid-ß pathology mapping and quantification as a validation method of neuropathology imaging.

This work is aimed at correlating pre-mortem [18F]FDDNP positron emission tomography (PET) scan results in a patient with dementia with Lewy bodies (DLB), with cortical neuropathology distribution determined postmortem in three physical dimensions in whole brain coronal sections. Analysis of total amyloid-ß (Aß) distribution in frontal cortex and posterior cingulate gyrus confirmed its statistically significant correlation with cortical [18F]FDDNP PET binding values (distribution volume ratios, DVR) (p < 0.001, R = 0.97, R2 = 0.94). Neurofibrillary tangle (NFT) distribution correlated significantly with cortical [18F]FDDNP PET DVR in the temporal lobe (p < 0.001, R = 0.87, R2 = 0.76). Linear combination of Aß and NFT densities was highly predictive of [18F]FDDNP PET DVR through all analyzed regions of interest (p < 0.0001, R = 0.92, R2 = 0.85), and both densities contributed significantly to the model. Lewy bodies were present at a much lower level than either Aß or NFTs and did not significantly contribute to the in vivo signal. [18F]FDG PET scan results in this patient were consistent with the distinctive DLB pattern of hypometabolism. This work offers a mapping brain model applicable to all imaging probes for verification of imaging results with Aß and/or tau neuropathology brain distribution using immunohistochemistry, fluorescence microscopy, and autoradiography.

PET imaging of neuropathology in tauopathies: progressive supranuclear palsy.

OBJECTIVE: Currently [18F]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 [18F]FDDNP labeling of brain neuropathology, primarily tau fibrillar aggregates, in patients with progressive supranuclear palsy (PSP), a human tauopathy usually lacking amyloid-ß deposits. METHODS: Fifteen patients with PSP received [18F]FDDNP PET scanning. [18F]FDDNP distribution volume ratios, in reference to cerebellar gray matter, were determined for cortical and subcortical areas and compared with those of patients with Parkinson's disease with short disease duration, and age-matched control subjects without neurodegenerative disorders. RESULTS: [18F]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 [18F]FDDNP binding were entirely consistent with the known pathology distribution for PSP. High midbrain and subthalamic region [18F]FDDNP binding was distinctive for PSP subjects and separated them from controls and patients with Parkinson's disease. CONCLUSIONS: These results provide evidence that [18F]FDDNP is a sensitive in vivo PET imaging probe to map and quantify the dynamic regional localization of tau fibrillar aggregates in PSP. Furthermore, [18F]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 [18F]FDDNP binding may also be useful in diagnosis early in disease presentation when clinical distinction among neurodegenerative disorders is often difficult.

Vascular risk and FDDNP-PET influence cognitive performance.

The relationship of cerebrovascular risk and Alzheimer's disease (AD) pathology to cognition in pre-dementia has been extensively investigated and is well-established. Cerebrovascular risk can be measured using a Framingham Stroke Risk Profile (FSRP) score, while positron emission tomography (PET) scans with 2-(1-{6-[(2-[F-18]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile (FDDNP) measure AD neuropathology (i.e., amyloid-ß plaques and tau tangles). Here we report results of 75 healthy non-demented subjects (mean age, 63 years) who underwent neuropsychological testing, physical assessments, and FDDNP-PET scans. Controlling for AD family history, education, and APOE4 status in a general linear model, higher FSRP risk and global FDDNP-PET binding were each associated with poorer cognitive functioning. The interaction of FSRP and global FDDNP-PET binding was not significant in the model, indicating that stroke risk and plaque and tangle burden each contributed to worse cognitive performance. Within our healthy volunteers, age, blood pressure, and antihypertensive medication use were vascular risks that contributed significantly to the above findings. These findings suggest that even mild cerebrovascular risk may influence the extent of cognitive dysfunction in pre-dementia, along with amyloid-ß and tau burden.

PET scanning of brain tau in retired national football league players: preliminary findings.

OBJECTIVE: Mild traumatic brain injury due to contact sports may cause chronic behavioral, mood, and cognitive disturbances associated with pathological deposition of tau protein found at brain autopsy. To explore whether brain tau deposits can be detected in living retired players, we used positron emission tomography (PET) scans after intravenous injections of 2-(1-{6-[(2-[F-18]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile (FDDNP). METHODS: Five retired National Football League players (age range: 45 to 73 years) with histories of mood and cognitive symptoms received neuropsychiatric evaluations and FDDNP-PET. PET signals in subcortical (caudate, putamen, thalamus, subthalamus, midbrain, cerebellar white matter) and cortical (amygdala, frontal, parietal, posterior cingulate, medial and lateral temporal) regions were compared with those of five male controls of comparable age, education, and body mass index. RESULTS: FDDNP signals were higher in players compared with controls in all subcortical regions and the amygdala, areas that produce tau deposits following trauma. CONCLUSIONS: The small sample size and lack of autopsy confirmation warrant larger, more definitive studies, but if future research confirms these initial findings, FDDNP-PET may offer a means for premorbid identification of neurodegeneration in contact-sports athletes.