The Dopamine Transporter Is Absent in Parkinsonian Putamen and Reduced in the Caudate Nucleus

Abstract

The neuronal dopamine transporter/uptake site can be covalently labeled with the photoaffinity probe 1-(2-[bis-(4-fluorophenyl) methoxy]ethyl)-4-[2-(4-azido-3-[125I]iodophenyl)ethyl]piperazine [( 125I]FAPP) and visualized following sodium dodecyl sulfate polyacrylamide gel electrophoresis and autoradiography. Upon photolysis, [125I]FAPP specifically incorporated into a polypeptide of apparent Mr = 62,000 in membranes from both the putamen and the caudate nucleus of control, Alzheimer's, schizophrenia, and Huntington's diseased brain, and following complete deglycosylation, migrated as an Mr approximately 48,000 polypeptide. In parkinsonian postmortem putamen, however, there was no detectable photoincorporation of [125I]FAPP into the ligand binding subunit of the dopamine transporter. [125I]FAPP did specifically label the Mr 62,000 polypeptide of parkinsonian caudate, although with efficiencies of 20-50% of control. The asymmetrical loss of the dopamine transporter in Parkinson's diseased striatum was confirmed in reversible receptor binding experiments using [3H]GBR-12935 (3H-labeled 1-[2-(diphenylmethoxy) ethyl]-4-(3-phenylpropyl)piperazine). In parkinsonian putamen, mazindol competitively inhibited the binding of [3H]GBR-12935 with an estimated affinity (Ki approximately 2,000 nM) 10 times lower than in controls (Ki approximately 30 nM), while the affinity of maxindol for [3H]GBR-12935 binding in the caudate was equal to that seen with controls (Ki approximately 50 nM). The proportion of [3H]GBR-12935 binding sites recognized by mazindol with high affinity in Parkinson's diseased caudate was, however, reduced by 50-80%.(ABSTRACT TRUNCATED AT 250 WORDS)

Validation of a Standardized Normalization Template for Statistical Parametric Mapping Analysis of 123I-FP-CIT Images

“…An unresolved question is the minimal number of images required to obtain a reliable template. For example, the CBF (H 2 15 O) template provided within the SPM99 software was created with 12 normal scans. Most templates created for other brain tracers were obtained with a small number of subjects (i.e., 10215 subjects) (20,33,35,36).…”

“…Conclusion: SPM normalization was accurate even in subjects with low striatal 123 I-FP-CIT uptake, making it a promising approach for automaticParki nson's disease (PD) is characterized by the progressive degeneration of nigrostriatal dopaminergic neurons. This neurodegenerative process is associated with a loss of striatal dopamine transporters (DATs) as shown by postmortem studies (1,2). Therefore, in vivo measurement of DAT density with PET or SPECT is an early marker of the dopaminergic cell loss in subjects with parkinsonian symptoms or in asymptomatic carriers of genetic mutations causing PD (3)(4)(5)(6)(7).…”

Thalamic Deep Brain Stimulation for Parkinson’s Disease

“…Interestingly, increases in regional CBF and metabolism are also found in the Vim nucleus ipsilateral to the stimulation site (Rezai et al, 1999;Perlmutter et al, 2002;Haslinger et al, 2003;Fukuda et al, 2004;Mure et al, 2011). SPECT using Iodine-123 fluoropropyl-carbomethoxy-3 ([ 123 I]FP-CIT SPECT) targets the dopamine transporter and is used to determine ongoing loss of dopaminergic neurons in PD patients (Kaufman & Madras., 1991;Niznik et al, 1991;Seibyl et al, 1998). [ 123 I]FP-CIT SPECT shows significantly higher uptake in the putamen and caudate nucleus in tremor-dominant PD than in akinesia/rigidity-dominant PD (Spiegel et al, 2007;Eggers et al, 2011).…”

Validation of Simple Quantification Methods for 18F-FP-CIT PET Using Automatic Delineation of Volumes of Interest Based on Statistical Probabilistic Anatomical Mapping and Isocontour Margin Setting

“…Parkinson's disease is a progressive neurodegenerative disorder of nigrostriatal dopaminergic neurons [1]. Nuclear imaging methods for the dopaminergic system using SPECT or PET are reliable and objective diagnostic tools for Parkinson's syndromes.…”