Sleep microstructure and neurodegeneration as measured by [<Superscript>123</Superscript>I]β-CIT SPECT in treated patients with Parkinson’s disease

Abstract Objectives Along with spindles, K-complexes are well known hallmarks of stage 2 (S2) sleep. However, little is known about their quantity in S2 sleep of patients with Parkinsons disease (PD). Setting Sleep laboratory, Department of Neurology, University of Vienna, Austria. Patients and methods Whole-night polysomnography (PSG) was performed in twelve treated PD patients and ten healthy controls without history of sleep complaints. The quantity of spontaneous K-complexes, K-alpha-complexes, and sleep spindles in one hour S2 sleep, distributed in four epochs of 15 minutes all through the night, were visually selected and analysed. The quantity and the temporal course of these phasic events were compared with the quantity in age-matched healthy controls. Nine of the twelve PD patients underwent [¹²³I]-CIT SPECT for calculating dopamine transporter binding in the striatum and serotonin transporter density in the thalamus-hypothalamus region. Results There was no difference between the quantity of K-complexes, K-alpha-complexes, and sleep spindles in PD patients and in the healthy control group. K-complexes but not sleep spindles decreased over the night in both groups. The number of sleep spindles did not correlate with the dopamine transporter binding in the striatum or the serotonin binding in the thalamic/hypothalamic region. Conclusion K-complexes and sleep spindles are not reduced and do not seem to be related to the degree of dopaminergic degeneration in treated PD patients.This research was supported in part by the European Commission, DG XII (Project Biomed-2 BMH4-CT97–2040 SIESTA) and by the Austrian National Bank (Project 7870). Svenja Happe, MD, was recipient for a fellowship stipend of the European Neurological Society (ENS).     

Comparison of α-dihydroergocryptine and levodopa monotherapy in Parkinson’s disease: assessment of changes in DAT binding with [<Superscript>123</Superscript>I]IPT SPECT

Summary. Putative neurotoxic actions of levodopa and neuroprotective effects of dopamine agonists, as indicated by laboratory and animal studies, provide the rationale to study their effect on the progression of Parkinsons disease. Aim of this pilot study was to compare the effects of monotherapy with the dopamine agonist -dihydroergocryptine (DEC) versus monotherapy with levodopa on nigrostriatal dopaminergic neurons as measured with dopamine transporter (DAT) SPECT. 25 PD patients (H&Y stages 1 to 2.5) entered this study and were treated in a randomized fashion either with DEC (101±39mg) or levodopa (369±51mg) monotherapy. 16/25 patients (8 per group) terminated the study after 52 weeks. In each patient SPECT investigations with [¹²³I]IPT were performed at baseline and after 52 weeks to assess changes of specific DAT binding over time. Changes in clinical symptoms were assessed by UPDRS score. The mean annual decline rate in striatal IPT-binding was lower in the DEC group (8.4%) compared to the levodopa group (10.4%). The difference was most accentuated in the putamen (DEC: 7.3%; levodopa: 16.2%; p=0.16). Due to the small sample size and the relatively short observation period, however, group differences did not reach a statistical significant level. The results of this pilot study suggest that as compared to levodopa monotherapy DEC may have beneficial effects on decline of dopamine transporter binding similar to those recently described for pramipexole.     

New perspectives on neurochemical effects of amantadine in the brain of parkinsonian patients: a PET – [<Superscript>11</Superscript>C]raclopride study

Summary. Amantadine, is a non competitive NMDA receptors antagonist that has been proved beneficial in Parkinson's disease. However its mechanism of action at therapeutic doses is still under discussion. Aim of this study was to evaluate the effect of repeated administration of amantadine on striatal dopaminergic system by measuring [¹¹C]raclopride binding to striatal D₂ dopamine receptors, in patients with moderate idiopathic Parkinson's disease. Eight patients completed the study undergoing a PET scan, before and after 10–14 days treatment with Amantadine (200 mg/day). Patients were on treatment with L-DOPA, which was suspended 1 night before each PET scans, and free from dopaminergic agonists, anticholinergic and antidepressants. Amantadine treatment significantly increased [¹¹C-]Raclopride binding (caudate: 10% p = 0.04; putamen 11% p = 0.01). A slight reduction (−7.3%, p = 0.062) of UPDRS total scores was also observed. The increased availability of striatal D₂ receptors, is likely to be caused by drug induced modification of receptors expression. This hypothesis is consistent with previous experiments, indicating an increase in striatal D₂ receptors in rats treated with amantadine or other non competitive NMDA antagonists and suggests that the neo-synthesis of D₂ receptors may represent a reinforcing mechanism of drug efficacy. Received October 17, 2001; accepted January 3, 2002 Published online June 28, 2002     

Down-regulation of the AMPA glutamate receptor subunits GluR1 and GluR2/3 in the rat cerebellum following pre- and perinatal Δ<Superscript>9</Superscript>-tetrahydrocannabinol exposure

This paper reports the effects of pre- and perinatal exposure to delta9-tetrahydrocannabinol (THC) on expression levels of specific AMPA glutamate receptor subunits (GluR1 and GluR2/3) in the cerebellum of male and female rats. Pregnant rats were administered saline or THC from gestational day 5 (ED5) to postnatal day 20 (PD20). Expression of the GluR1 and GluR2/3 subunits of AMPA glutamate receptors was analyzed by immunohistochemistry in THC-exposed rats at three postnatal ages: PD20 (still exposed to THC) to study the direct effect of drug exposure, and PD30 and PD70 (10 and 50 days following THC withdrawal) to analyze the long-term effects of prenatal exposure. Compared to controls, pre- and perinatal THC exposure decreased the immunoreactivity levels of the GluR1 subunit in Bergmann glial cells, as well as levels of the GluR2/3 subunit in Purkinje neurons at PD20. These changes in AMPA receptor subunit levels may correlate with the decreased excitatory neurotransmission described in the cerebellum after cannabinoid treatment, which could play a significant role in the biochemical effects of THC. In addition, the reduced glutamate receptor expression observed at PD20 did not return to normal even after THC withdrawal (PD30 and PD70). The results support the idea that THC exposure during critical stages of cerebellar development may alter the glutamatergic system, not only during the drug exposure period itself but also in adults following THC withdrawal. The decreased expressions of glutamate receptors induced by developmental THC exposure could lead to functional alterations through the inhibition of glutamatergic neurotransmission, and clearly demonstrate an interaction between cannabinoids and the glutamatergic system.     

Changes in Binding of [<Superscript>123</Superscript>I]CLINDE,a High-Affinity Translocator Protein 18 kDa (TSPO) Selective Radioligand in a Rat Model of Traumatic Brain Injury

After traumatic brain injury (TBI), secondary injuries develop, including neuroinflammatory processes that contribute to long-lasting impairments. These secondary injuries represent potential targets for treatment and diagnostics. The translocator protein 18 kDa (TSPO) is expressed in activated microglia cells and upregulated in response to brain injury and therefore a potential biomarker of the neuroinflammatory processes. Second-generation radioligands of TSPO, such as [¹²³I]CLINDE, have a higher signal-to-noise ratio as the prototype ligand PK11195. [¹²³I]CLINDE has been employed in human studies using single-photon emission computed tomography to image the neuroinflammatory response after stroke. In this study, we used the same tracer in a rat model of TBI to determine changes in TSPO expression. Adult Sprague–Dawley rats were subjected to moderate controlled cortical impact injury and sacrificed at 6, 24, 72 h and 28 days post surgery. TSPO expression was assessed in brain sections employing [¹²³I]CLINDE in vitro autoradiography. From 24 h to 28 days post surgery, injured animals exhibited a marked and time-dependent increase in [¹²³I]CLINDE binding in the ipsilateral motor, somatosensory and parietal cortex, as well as in the hippocampus and thalamus. Interestingly, binding was also significantly elevated in the contralateral M1 motor cortex following TBI. Craniotomy without TBI caused a less marked increase in [¹²³I]CLINDE binding, restricted to the ipsilateral hemisphere. Radioligand binding was consistent with an increase in TSPO mRNA expression and CD11b immunoreactivity at the contusion site. This study demonstrates the applicability of [¹²³I]CLINDE for detailed regional and quantitative assessment of glial activity in experimental models of TBI.     

Surgical resection plus stereotactic <Superscript>125</Superscript>I brachytherapy in adult patients with eloquently located supratentorial WHO grade II glioma – Feasibility and outcome of a combined local treatment concept

Objective

The current pilot study analyzed feasibility, risk and effectiveness of 1) microsurgery plus stereotactic iodine-125 (¹²⁵I) brachytherapy (SBT) for large (diameter > 4 cm), circumscribed, and complex located WHO grade II glioma and 2) SBT alone for small (diameter < 4 cm), and complex located recurrences.

Methods

Lowactivity temporary ¹²⁵I seeds were used. The applied reference dose was 54 Gy and the dose rate was low (median, 10 cGy/h). Time to progression and time to additional external beam radiation (EBR) and/or chemotherapy were estimated with the Kaplan-Meier method. Any adverse sequel potentially attributable to treatment was classified as morbidity. Treatment effects of SBT were estimated according to the modified MacDonald criteria.

Results

Thirtyone patients (de novo group: n = 18, recurrence group: n = 13) were included. The median tumor volume before surgery was 66 ml. A planned partial tumor resection achieved eligibility for SBT in all patients. Transient morbidity of microsurgery and SBT was 27.8 % and 6.4 %, respectively. There was no permanent morbidity. Radiogenic complications did not occur. Complete response, partial response, and stable disease were seen in 8, 9, and 14 patients, respectively. Ten patients exhibited tumor progression (overall 5-year progression- free survival > 60 %). The 5-year probability to receive chemotherapy and/or EBR was 18 %.

Conclusion

A planned partial tumor resection of large and complex located WHO grade II glioma is safe. SBT of small and complex located residual of recurrent tumors is safe and minimally invasive. Combined treatment may provide the possibility to withhold EBR and/or chemotherapy for a considerable number of patients and deserves further prospective evaluation.

     

Loss of thalamic serotonin transporters in early drug-naïve Parkinson’s disease patients is associated with tremor: an [<Superscript>123</Superscript>I]β-CIT SPECT study

In vitro studies revealed serotonin transporter (5-HTT) decline in Parkinson’s disease (PD). Yet, few studies investigated thalamic 5-HTT in vivo and its effect on PD heterogeneity. We analyzed thalamic [¹²³I]β-CIT binding (mainly reflecting 5-HTT binding) in 32 drug-naïve PD patients and 13 controls with SPECT. Twenty-six patients were examined twice (17 months apart). Based on UPDRS scores, we identified subgroups of patients with moderate/severe tremor (PD_T) and without tremor (PD_WT) at the time of clinical diagnosis. Additionally, depressive symptoms were evaluated using the Beck Depression Inventory (BDI) at baseline. Mean thalamic specific to non-specific [¹²³I]β-CIT binding ratio was lower in patients when compared to controls, and further decreased during follow-up. At baseline, average thalamic ratio was significantly lower in the PD_T than in the PD_WT subgroup. No correlation was found between BDI scores and thalamic binding ratios. Our findings show decline of [¹²³I]β-CIT binding to thalamic 5-HTT in PD and its possible contribution to tremor onset.     

C-myb Plays an Essential Role in the Protective Function of IGF-1 on Cytotoxicity Induced by Aβ<Subscript>25–35</Subscript> via the PI3K/Akt Pathway

The main pathological feature of Alzheimer’s disease (AD) is the formation of abundant amyloid-β (Aβ) plaques in the human brain. Studies have reported that Aβ from the AD brain is resistant to proteolytic digestion, which may explain why Aβ cannot be readily eliminated from this organ. However, there are only a few studies that address this important question. We used the AD transgenic mouse (APP/PS1) model to show that Aβ derived from the brain of the old mouse is resistant to proteolytic digestion. This was in contrast to the proteinase K-sensitive human Aβ peptide, whose amino acid sequence was identical to that of AD mouse-derived Aβ but whose conformation was different (i.e., the native protein, but not the peptide, folded into a three-dimensional conformation). To address this question, we denatured AD mouse-derived Aβ with urea and found that Aβ became proteinase K-sensitive. This phenomenon was concentration-dependent, and these results were confirmed by another protein denaturant, guanidinium hydrochloride. We recovered the conformation of the denatured AD mouse-derived Aβ by eliminating urea and adding the human Aβ peptide, and we found that human Aβ was converted to the proteinase K-resistant form in the presence of partially undenatured AD mouse-derived Aβ. However, upon the addition of the rat Aβ peptide, there were no Aβ proteinase K-resistant fragments. Our results show that the resistance of AD mouse-derived Aβ to proteolytic digestion is dependent on the three-dimensional conformation of Aβ. In summary, this study provides new insights on why Aβ plaques fail to be degraded in the human brain.