Timothy M. Shoup

Imaging amyloid deposition in Lewy body diseases

Background: Extrapyramidal motor symptoms precede dementia in Parkinson disease (PDD) by many years, whereas dementia occurs early in dementia with Lewy bodies (DLB). Despite this clinical distinction, the neuropsychological and neuropathologic features of these conditions overlap. In addition to widespread distribution of Lewy bodies, both diseases have variable burdens of neuritic plaques and neurofibrillary tangles characteristic of Alzheimer disease (AD). Objectives: To determine whether amyloid deposition, as assessed by PET imaging with the β-amyloid–binding compound Pittsburgh Compound B (PiB), can distinguish DLB from PDD, and to assess whether regional patterns of amyloid deposition correlate with specific motor or cognitive features. Methods: Eight DLB, 7 PDD, 11 Parkinson disease (PD), 15 AD, and 37 normal control (NC) subjects underwent PiB-PET imaging and neuropsychological assessment. Amyloid burden was quantified using the PiB distribution volume ratio. Results: Cortical amyloid burden was higher in the DLB group than in the PDD group, comparable to the AD group. Amyloid deposition in the PDD group was low, comparable to the PD and NC groups. Relative to global cortical retention, occipital PiB retention was lower in the AD group than in the other groups. For the DLB, PDD, and PD groups, amyloid deposition in the parietal (lateral and precuneus)/posterior cingulate region was related to visuospatial impairment. Striatal PiB retention in the DLB and PDD groups was associated with less impaired motor function. Conclusions: Global cortical amyloid burden is high in dementia with Lewy bodies (DLB) but low in Parkinson disease dementia. These data suggest that β-amyloid may contribute selectively to the cognitive impairment of DLB and may contribute to the timing of dementia relative to the motor signs of parkinsonism. GLOSSARY: AAL = Automated Anatomic Labeling; AD = Alzheimer disease; ADRC = Alzheimer’s Disease Research Center; AMNART = American version of the National Adult Reading Test; ANCOVA = analysis of covariance; BDS = Blessed Dementia Scale; CAA = cerebral amyloid angiopathy; CDR = Clinical Dementia Rating; CDR-SB = Clinical Dementia Rating Sum of Boxes; DLB = dementia with Lewy bodies; DVR = distribution volume ratio; FCSRT = Cued Selective Reminding Test; FRSRT = Free Selective Reminding Test; H&Y = Hoehn and Yahr; MGH = Massachusetts General Hospital; MMSE = Mini-Mental State Examination; NC = normal control; NFT = neurofibrillary tangle; NPIQ = Neuropsychiatric Inventory Questionnaire; NS = not significant; PD = Parkinson disease; PDD = Parkinson disease dementia; PiB = Pittsburgh Compound B; ROI = region of interest; SPM2 = Statistical Parametric Mapping; UKPDSBRC = UK Parkinson’s Disease Society Brain Bank Research Center; UPDRS = United Parkinson’s Disease Rating Scale; WAIS-R = Wechsler Adult Intelligence Scale–Revised.

Tau positron emission tomographic imaging in aging and early Alzheimer disease

Detection of focal brain tau deposition during life could greatly facilitate accurate diagnosis of Alzheimer disease (AD), staging and monitoring of disease progression, and development of disease‐modifying therapies.

Tau PET imaging in aging and early Alzheimer's disease

Detection of focal brain tau deposition during life could greatly facilitate accurate diagnosis of Alzheimer disease (AD), staging and monitoring of disease progression, and development of disease‐modifying therapies.

Polymer-encapsulated PC-12 cells demonstrate high-affinity uptake of dopamine in vitro and 18F-dopa uptake and metabolism after intracerebral implantation in nonhuman primates

Intracranial implantation of polymer-encapsulated PC-12 cells has been shown to improve motor behavioral performance in animal models of Parkinsons disease. The purpose of this blinded study was to examine whether such improvement is associated with the active uptake and metabolism of dopamine precursors by intracerebrally implanted polymer-encapsulated PC-12 cells. In an in vitro experiment we demonstrate that 3H-dopamine uptake by PC-12 cells was 10(8) fmol/min x 10(6) cells, and that this uptake can be specifically blocked 88% by the addition of 10nM of nomifensine. In the in vivo experiments, polymer-encapsulated PC-12 cells were implanted in four MPTP-treated monkeys into the left deep parietal white matter (R1) or left striatum (R2-4). A fifth MPTP-treated monkey (R5) served as a control and received left striatal implants of empty capsules. 18-F-Dopa Positron Emission Tomography (PET) imaging was performed on each monkey before and after implantation surgery by blinded investigators. PET images obtained 5-13 wk after implantation demonstrated well delineated focal areas of high 18F-dopa uptake in R1, R2, and R4. The focal area of high 18F-dopa uptake in R1 precisely coregistered on a brain magnetic resonance image to the site of implantation. R3 (in whom the polymer-encapsulated PC-12 cells demonstrated poor cell survival upon explantation) and R5 (empty capsules) failed to demonstrate any area of increased 18F-dopa uptake in their PET images. Histological examination of the host brain revealed no sprouting of dopaminergic nerve terminals around the implantation sites of the polymer-encapsulated PC-12 cells. These results indicate that the previously noted behavioral improvement after intrastriatal implantation of polymer encapsulated PC-12 cells is at least in part due to their highly specific uptake and metabolism of dopamine precursors. Furthermore, these data suggest that polymer-encapsulated PC-12 cells can store, reuptake, and functionally replenish dopamine and therefore, may be an effective treatment for Parkinsons disease.

Dopamine terminal loss and onset of motor symptoms in MPTP-treated monkeys : a positron emission tomography study with 11C-CFT

We studied the time course of dopamine (DA) terminal loss in three macaca fascicularis injected with MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) intravenously every 10-14 days for up to 389 days. Striatal DA terminal loss was monitored in vivo by positron emission tomography using 11C-CFT (WIN 35,428), a cocaine derivative that labels the DA transporter. The 11C-CFT uptake rate constant in the striatum of MPTP-treated monkeys decreased exponentially over time, with the putamen significantly more affected than the caudate. Spontaneous locomotor activity decreased in parallel with the decline of the 11C-CFT uptake rate; however, overt parkinsonian signs appeared only after the 11C-CFT uptake rate had declined to about 30% of the pretreatment values. We conclude that a long-term intermittent mode of administration of MPTP can lead to a pattern of terminal loss that closely resembles idiopathic Parkinson disease.

Synthesis of [F‐18]‐1‐amino‐3‐fluorocyclobutane‐1‐carboxylic acid (FACBC): a PET tracer for tumor delineation

Fluorine-18 labeled 1-amino-3-fluorocyclobutane-1-carboxylic acid (FACBC), a new tumor-avid amino acid, was synthesized for positron emission tomography. [18F]FACBC was prepared with high specific activity by nucleophilic displacement with an overall radiochemical yield of 12% (EOB). Synthesis of the triflate precursor was accomplished in nine steps starting from the reaction of benzyl bromide with epichlorohydrin which gave 1-chloro-2-benzyloxy-3-brompropane. A key step involves conversion of 3-benzyloxy-cyclobutane-1,1-dicarboxylate diamide to a mixture of diastereomeric 2-benzyloxycyclobutane hydantoins. Copyright

A concise radiosynthesis of the tau radiopharmaceutical, [18F]T807

Fluorine-18 labeled 7-(6-fluoropyridin-3-yl)-5H-pyrido[4,3-b]indole ([(18) F]T807) is a potent and selective agent for imaging paired helical filaments of tau and is among the most promising PET radiopharmaceuticals for this target in early clinical trials. The present study reports a simplified one-step method for the synthesis of [(18) F]T807 that is broadly applicable for routine clinical production using a GE TRACERlab™ FXFN radiosynthesis module. Key facets of our optimized radiosynthesis include development and use of a more soluble protected precursor, tert-butyl 7-(6-nitropyridin-3-yl)-5H-pyrido[4,3-b]indole-5-carboxylate, as well as new HPLC separation conditions that enable a facile one-step synthesis. During the nucleophilic fluorinating reaction with potassium cryptand [(18) F]fluoride (K[(18) F]/K222 ) in DMSO at 130 °C over 10 min the precursor is concurrently deprotected. Formulated [(18) F]T807 was prepared in an uncorrected radiochemical yield of 14 ± 3%, with a specific activity of 216 ± 60 GBq/µmol (5837 ± 1621 mCi/µmol) at the end of synthesis (60 min; n = 3) and validated for human use. This methodology offers the advantage of faster synthesis in fewer steps, with simpler automation that we anticipate will facilitate widespread clinical use of [(18) F]T807.

PET- and MRI-Based Assessment of Glucose Utilization, Dopamine Receptor Binding, and Hemodynamic Changes after Lesions to the Caudate-Putamen in Primates

In vivo physiological changes associated with striatal pathology were determined by measurement of glucose utilization, binding to D1 receptors and dopamine reuptake sites, regional blood flow, and behavior before and after unilateral quinolinate infusions into caudate-putamen in three nonhuman primates (Macaca fascicularis and Macaca mulatta). Following the quinolinate lesion, symptoms similar to those of Huntingtons disease could be induced by dopamine agonist treatment. In addition, all animals showed a long-term decrease in glucose utilization in the caudate by [19F]fluoro-2-deoxy-D-glucose positron emission tomography (PET). At 4-6 weeks following the lesion the average decrease in glucose utilization in the caudate-putamen was between 40 and 50% of the prelesion values in primates with large lesions. Corresponding caudate-putamen regional blood volume in these animals showed a 61 and 74% decrease as studied by magnetic resonance imaging with somewhat smaller changes observed in an index of cerebral blood flow. The caudate-putamen uptake rate constants for D1 receptors reflected neuronal loss and decreased by an average 40 and 48%, as determined by 11C-labeled Schering compound (SCH 39 166) and PET. Dopamine reuptake sites and fibers assessed by the 11C-labeled cocaine analog, WIN 35 428 compound, and PET showed a temporary decrease in areas with mild neuronal loss and a long-term decrease in striatal regions with severe destruction. These results, which were consistent with behavioral changes and neuropathology seen at postmortem examination, can be related to in vivo physiological studies of Huntingtons disease patients.

Detection of inflamed atherosclerotic lesions with diadenosine-5′,5‴-P1,P4-tetraphosphate (Ap4A) and positron-emission tomography

Diadenosine-5′,5‴-P1,P4-tetraphosphate (Ap4A) and its analog P2,P3-monochloromethylene diadenosine-5′,5‴-P1,P4-tetraphosphate (AppCHClppA) are competitive inhibitors of adenosine diphosphate-induced platelet aggregation, which plays a central role in arterial thrombosis and plaque formation. In this study, we evaluate the imaging capabilities of positron-emission tomography (PET) with P2,P3-[18F]monofluoromethylene diadenosine-5′,5‴-P1,P4-tetraphosphate ([18F]AppCHFppA) to detect atherosclerotic lesions in male New Zealand White rabbits. Three to six months after balloon injury to the aorta, the rabbits were injected with [18F]AppCHFppA, and microPET imaging showed rapid accumulation of this radiopharmaceutical in the atherosclerotic abdominal aorta, with lesions clearly visible 30 min after injection. Computed tomographic images were coregistered with PET images to improve delineation of aortoiliac tracer activity. Plaque macrophage density, quantified by immunostaining with RAM11 against rabbit macrophages, correlated with PET measurements of [18F]AppCHFppA uptake (r = 0.87, P < 0.0001), whereas smooth-muscle cell density, quantified by immunostaining with 1A4 against smooth muscle actin, did not. Biodistribution studies of [18F]AppCHFppA in normal rats indicated typical adenosine dinucleotide behavior with insignificant myocardial uptake and fast kidney clearance. The accumulation of [18F]AppCHFppA in macrophage-rich atherosclerotic plaques can be quantified noninvasively with PET. Hence, [18F]AppCHFppA holds promise for the noninvasive characterization of vascular inflammation.

Pharmacokinetic Evaluation of the Tau PET Radiotracer 18F-T807 (18F-AV-1451) in Human Subjects

18F-T807 is a PET radiotracer developed for imaging tau protein aggregates, which are implicated in neurologic disorders including Alzheimer disease and traumatic brain injury (TBI). The current study characterizes 18F-T807 pharmacokinetics in human subjects using dynamic PET imaging and metabolite-corrected arterial input functions. Methods: Nine subjects (4 controls, 3 with a history of TBI, 2 with mild cognitive impairment due to suspected Alzheimer disease) underwent dynamic PET imaging for up to 120 min after bolus injection of 18F-T807 with arterial blood sampling. Total volume of distribution (VT) was estimated using compartmental modeling (1- and 2-tissue configurations) and graphical analysis techniques (Logan and multilinear analysis 1 [MA1] regression methods). Reference region–based methods of quantification were explored including Logan distribution volume ratio (DVR) and static SUV ratio (SUVR) using the cerebellum as a reference tissue. Results: The percentage of unmetabolized 18F-T807 in plasma followed a single exponential with a half-life of 17.0 ± 4.2 min. Metabolite-corrected plasma radioactivity concentration fit a biexponential (half-lives, 18.1 ± 5.8 and 2.4 ± 0.5 min). 18F-T807 in gray matter peaked quickly (SUV > 2 at ∼5 min). Compartmental modeling resulted in good fits, and the 2-tissue model with estimated blood volume correction (2Tv) performed best, particularly in regions with elevated binding. VT was greater in mild cognitive impairment subjects than controls in the occipital, parietal, and temporal cortices as well as the posterior cingulate gyrus, precuneus, and mesial temporal cortex. High focal uptake was found in the posterior corpus callosum of a TBI subject. Plots from Logan and MA1 graphical methods became linear by 30 min, yielding regional estimates of VT in excellent agreement with compartmental analysis and providing high-quality parametric maps when applied in voxelwise fashion. Reference region–based approaches including Logan DVR (t* = 55 min) and SUVR (80- to 100-min interval) were highly correlated with DVR estimated using 2Tv (R2 = 0.97, P < 0.0001). Conclusion: 18F-T807 showed rapid clearance from plasma and properties suitable for tau quantification with PET. Furthermore, simplified approaches using DVR (t* = 55 min) and static SUVR (80–100 min) with cerebellar reference tissue were found to correlate highly with compartmental modeling outcomes.