Effects of subthalamic deep brain stimulation on striatal metabolic connectivity in a rat hemiparkinsonian model.

Deep brain stimulation (DBS) in the subthalamic nucleus (STN) has been successfully used for the treatment of advanced Parkinson's disease, although the underlying mechanisms are complex and not well understood. There are conflicting results about the effects of STN-DBS on neuronal activity of the striatum, and its impact on functional striatal connectivity is entirely unknown. We therefore investigated how STN-DBS changes cerebral metabolic activity in general and striatal connectivity in particular. We used ipsilesional STN stimulation in a hemiparkinsonian rat model in combination with [18F]FDOPA-PET, [18F]FDG-PET and metabolic connectivity analysis. STN-DBS reversed ipsilesional hypometabolism and contralesional hypermetabolism in hemiparkinsonian rats by increasing metabolic activity in the ipsilesional ventrolateral striatum and by decreasing it in the contralesional hippocampus and brainstem. Other STN-DBS effects were subject to the magnitude of dopaminergic lesion severity measured with [18F]FDOPA-PET, e.g. activation of the infralimbic cortex was negatively correlated to lesion severity. Connectivity analysis revealed that, in healthy control animals, left and right striatum formed a bilateral functional unit connected by shared cortical afferents, which was less pronounced in hemiparkinsonian rats. The healthy striatum was metabolically connected to the ipsilesional substantia nigra in hemiparkinsonian rats only (OFF condition). STN-DBS (ON condition) established a new functional striatal network, in which interhemispheric striatal connectivity was strengthened, and both the dopamine-depleted and the healthy striatum were functionally connected to the healthy substantia nigra. We conclude that both unilateral dopamine depletion and STN-DBS affect the whole brain and alter complex interhemispheric networks.

Motor impairment and compensation in a hemiparkinsonian rat model: correlation between dopamine depletion severity, cerebral metabolism and gait patterns.

BACKGROUND: In Parkinson's disease (PD), cerebral dopamine depletion is associated with PD subtype-specific metabolic patterns of hypo- and hypermetabolism. It has been hypothesised that hypometabolism reflects impairment, while hypermetabolism may indicate compensatory activity. In order to associate metabolic patterns with pathophysiological and compensatory mechanisms, we combined resting state [18F]FDG-PET (to demonstrate brain metabolism in awake animals), [18F]FDOPA-PET (dopamine depletion severity) and gait analysis in a unilateral 6-hydroxydopamine rat model. RESULTS: We found unilateral nigro-striatal dopaminergic loss to decrease swing speed of the contralesional forelimb and stride length of all paws in association with depletion severity. Depletion severity was found to correlate with compensatory changes such as increased stance time of the other three paws and diagonal weight shift to the ipsilesional hind paw. [18F]FDG-PET revealed ipsilesional hypo- and contralesional hypermetabolism; metabolic deactivation of the ipsilesional network needed for sensorimotor integration (hippocampus/retrosplenial cortex/lateral posterior thalamus) was solely associated with bradykinesia, but hypometabolism of the ipsilesional rostral forelimb area was related to both pathological and compensatory gait changes. Mixed effects were also found for hypermetabolism of the contralesional midbrain locomotor region, while contralesional striatal hyperactivation was linked to motor impairments rather than compensation. CONCLUSIONS: Our results indicate that ipsilesional hypo- and contralesional hypermetabolism contribute to both motor impairment and compensation. This is the first time when energy metabolism, dopamine depletion and gait analysis were combined in a hemiparkinsonian model. By experimentally increasing or decreasing compensational brain activity, its potential and limits can be further investigated.

A Practical One-Pot Synthesis of Positron Emission Tomography (PET) Tracers via Nickel-Mediated Radiofluorination.

Invited for this months cover picture is the group of Professor Bernd Neumaier at the Institute of Radiochemistry and Experimental Molecular Imaging at the University Clinic of Cologne. The cover picture shows the differences in brain metabolism of a healthy young and a healthy old subject, as well as a patient suffering from Parkinsons disease (left to right) uncovered by 6-[(18)F]FDOPA-positron emission tomography (PET). Morbus Parkinson occurs when nerve cells that produce dopamine begin to die. The shortage of dopamine leads to movement problems in affected individuals. 6-[(18)F]FDOPA is extensively used to evaluate the progression of Parkinsons disease. Bold stick projections of this PET tracer, as well as a neuronal network, are seen in the background. Unfortunately, conventional procedures to produce 6-[(18)F]FDOPA are cumbersome. Thus, several recent developments aim at the simplification of this radiosynthesis. In our work, we studied the applicability of the recently reported Ni-mediated radiofluorination approach for daily routine production of 6-[(18)F]FDOPA. For more details, see the Full Paper on p. 457 ff.

A Practical One-Pot Synthesis of Positron Emission Tomography (PET) Tracers via Nickel-Mediated Radiofluorination.

Recently a novel method for the preparation of (18)F-labeled arenes via oxidative [(18)F]fluorination of easily accessible and sufficiently stable nickel complexes with [(18)F]fluoride under exceptionally mild reaction conditions was published. The suitability of this procedure for the routine preparation of clinically relevant positron emission tomography (PET) tracers, 6-[(18)F]fluorodopamine (6-[(18)F]FDA), 6-[(18)F]fluoro-l-DOPA (6-[(18)F]FDOPA) and 6-[(18)F]fluoro-m-tyrosine (6-[(18)F]FMT), was evaluated. The originally published base-free method was inoperative. However, a "low base" protocol afforded protected radiolabeled intermediates in radiochemical conversions (RCCs) of 5-18 %. The subsequent deprotection step proceeded almost quantitatively (>95 %). The simple one-pot two-step procedure allowed the preparation of clinical doses of 6-[(18)F]FDA and 6-[(18)F]FDOPA within 50 min (12 and 7 % radiochemical yield, respectively). In an unilateral rat model of Parkinsons disease, 6-[(18)F]FDOPA with high specific activity (175 GBq µmol(-1)) prepared using the described nickel-mediated radiofluorination was compared to 6-[(18)F]FDOPA with low specific activity (30 MBq µmol(-1)) produced via conventional electrophilic radiofluorination. Unexpectedly both tracer variants displayed very similar in vivo properties with respect to signal-to-noise ratio and brain distribution, and consequently, the quality of the obtained PET images was almost identical.

Copper-mediated aromatic radiofluorination revisited: efficient production of PET tracers on a preparative scale.

Two novel methods for copper-mediated aromatic nucleophilic radiofluorination were recently reported. Evaluation of these methods reveals that, although both are efficient in small-scale experiments, they are inoperative for the production of positron emission tomography (PET) tracers. Since high base content turned out to be responsible for low radiochemical conversions, a "low base" protocol has been developed which affords (18)F-labeled arenes from diaryliodonium salts and aryl pinacol boronates in reasonable yields. Furthermore, implementation of our "minimalist" approach to the copper-mediated [(18)F]-fluorination of (mesityl)(aryl)iodonium salts allows the preparation of (18)F-labeled arenes in excellent RCCs. The novel radiofluorination method circumvents time-consuming azeotropic drying and avoids the utilization of base and other additives, such as cryptands. Furthermore, this procedure enables the production of clinically relevant PET tracers; [(18)F]FDA, 4-[(18)F]FPhe, and [(18)F]DAA1106 are obtained in good isolated radiochemical yields. Additionally, [(18)F]DAA1106 has been evaluated in a rat stroke model and demonstrates excellent potential for visualization of translocator protein 18 kDa overexpression associated with neuroinflammation after ischemic stroke.