<Superscript>123</Superscript>I-β-CIT binding and recovery from depression

Abstract. Eighteen depressive outpatients were investigated using single-photon emission computerized tomography (SPECT) with a high-affinity dopamine (DA) and serotonin transporter (SERT) specific radioligand, ¹²³I-labeled -CIT (2-carbomethoxy-3-(4-iodophenyl)-tropane). The patients were tested at the beginning of the study and on follow-up after six months. The severity of depression was evaluated using the 17-item Hamilton Rating Scale of Depression (HRSD). Eight of the eighteen patients had an HRSD score below the median (12 points) on follow-up, and they had a significantly greater increase in ¹²³I--CIT binding in the midbrain region compared with those patients who did not recover (ANCOVA: F = 8.12; df = 1, 14; p = 0.013). These results indicate that recovery from depression is associated with an increase in ¹²³I--CIT binding in the midbrain.     

Amyloid-Positronenemissionstomographie mit [<Superscript>18</Superscript> F]-Florbetaben in der Demenzdiagnostik

Background

To this day the definite diagnosis of Alzheimer’s disease still relies on post-mortem histopathological detection of neurofibrillary tangles and beta-amyloid deposits. Amyloid positron emission tomography (PET) is a new diagnostic tool that enables the in vivo quantification of pathological beta-amyloid deposits. The aim of the current study was to evaluate to what extent ¹⁸F-florbetaben-PET (FBB-PET) influences the diagnosis of patients with dementia.

Material and methods

Imaging with FBB-PET was performed on 33 patients from our outpatient department for cognitive neurology. Beforehand all patients underwent a comprehensive clinical, neuropsychiatric and laboratory examination as well as imaging by means of magnetic resonance imaging (MRI) and fluorodeoxyglucose-PET. The working diagnoses before and after FBB-PET imaging were compared.

Results

17 out of 33 patients were scored as FBB-PET positive. In four cases the initial diagnosis had to be changed to Alzheimer’s disease (three cases) and cerebral amyloid angiopathy (one case) due to the positive FBB-PET scan. 16 patients showed a negative FBB-PET scan. In three patients the initial diagnosis of Alzheimer’s disease could be ruled out due to the negative FBB-PET scan. Overall, in 7 out of 33 examined patients the initial diagnosis had to be changed because of the findings of the FBB-PET scan. In 24 patients the initial diagnosis was confirmed by the results of the FBB-PET scan.

Conclusion

Amyloid-PET is currently no standard procedure in the diagnosis of dementia; however, it can be a helpful additional diagnostic tool when used according to the “Appropriate Use Criteria” and the S3 guidelines on dementia in cases of unclear clinical presentation, atypically early age of onset as well as in patients with persistent or progressive unexplained mild cognitive impairment. By facilitating early diagnosis amyloid-PET imaging allows patient selection for therapeutic drug trials.

     

<Emphasis Type="Italic">N</Emphasis><Superscript>ε</Superscript>-Carboxymethyllysine in diabetic and non-diabetic polyneuropathies

Increased oxidative stress and advanced glycosylation are important factors in the development of diabetic neuropathy. In non-diabetic neuropathies their influence has not been investigated in detail so far. We studied the localisation of N(epsilon)-carboxymethyllysine (CML) - a biomarker for oxidative stress - by immunohistochemistry in sural nerve biopsies of 31 patients with different polyneuropathies [diabetic polyneuropathy (n=5), alcohol-associated polyneuropathy (n=4), vitamin B12-deficient polyneuropathy (n=6), chronic inflammatory demyelinating polyneuropathy (CIDP) (n=6), vasculitic neuropathy (n=6), Charcot-Marie-Tooth disease type I (CMT I) (n=4)] and 4 normal controls. CML was detected in the perineurium of patients with diabetic, alcohol-associated, vitamin B12-deficient and vasculitic polyneuropathies. Epineurial, perineurial and endoneurial vessels were CML positive in diabetic, vitamin B12-deficient and vasculitic polyneuropathies. CML was also found in mononuclear inflammatory cells in vasculitic neuropathy. In CIDP and normal controls there was only marginal perineurial CML deposition in 2/6 and 1/4 cases. In CMT I no CML was detected. Immunohistochemical results were confirmed by immunoblot. Our data suggest a role of oxidative stress in the pathogenesis not only of diabetic but also of alcohol-associated, vitamin B12-deficient and vasculitic polyneuropathies. It may be a minor pathogenetic factor in CIDP and may not be involved in CMT I. Underlying causes for increased oxidative stress may be an elevated production of reactive oxygen species and an impairment of antioxidative defences. Therefore, an antioxidative treatment should be considered in alcohol-associated, vitamin B12-deficient and vasculitic polyneuropathy.     

Measuring the potency labelling of onabotulinumtoxinA (Botox<Superscript>®</Superscript>) and incobotulinumtoxinA (Xeomin<Superscript>®</Superscript>) in an LD50 assay

The biological potency of botulinum toxin (BT) drugs is determined by a standardised LD50 assay. However, the potency labelling varies vary amongst different BT drugs. One reason for this may be differences in the LD50 assays applied. When five unexpired batches of onabotulinumtoxinA (Botox^®) and incobotulinumtoxinA (Xeomin^®) are compared in the Xeomin^® batch release assay, the potency variability of both BT drugs fell within the range allowed by the European Pharmacopoiea. Statistical analyses failed to detect differences in the potency labelling of both products. Although the existence of a conversion ratio has been questioned recently, our experimental data are in line with previous clinical experience showing that Botox^® and Xeomin^® can be compared using a 1:1 conversion ratio. Identical potency labelling allows easy exchange of both BT drugs in a therapeutic setting, and direct comparison of efficacy, adverse effects and costs.     

Sapphire<Superscript>®</Superscript> platinum detachable coil experience in a tertiary-care facility

Background

The Guglielmi Detachable Coil introduced by the Boston Scientific Corporation has been widely used for endovascular coiling of aneurysm. Recently, Sapphire® platinum detachable coils (eV3, Irvine, CA) have been introduced for aneurysm coiling. Herein, we report our clinical experience with the Sapphire® coil to evaluate the incidence of coil related complications and the rate of aneurysm occlusion.

Methods

Consecutive patients who underwent embolization with Sapphire® detachable coils were prospectively enrolled from January 2004 to September 2004 and the data were retrospectively analyzed. Patient demographics, including age, gender, presenting symptoms, Hunt and Hess grade, Fisher grade and locations of the vascular anomalies were collected. Additionally, complications associated with the coils and rates of aneurysm occlusion were observed and the data compiled.

Results

29 patients underwent Sapphire® coil embolization for intracranial aneurysms. Mean age was 50 ± 18 (mean ± SD) years with 81% being females. Aneurysm neck reconstruction was required in 7 cases, 6 with Neuroform stent (5 unruptured aneurysms) and 1 with balloon assistance (ruptured aneurysm). In 7 cases, Sapphire® coils were used along with other coils. There were no events of thromboembolism or ruptures of aneurysms during coil embolization. However, multi-diameter coils demonstrated stretching in 4 stent-assisted cases without any adverse consequences. Complete occlusion of the aneurysm was achieved in 79.31% of the patients, neck remnant in 6.89, and partial coiling was achieved in 13.79%.

Conclusion

The Sapphire® coil could safely be used in the treatment of both ruptured and unruptured aneurysms. However, multi-diameter non-stretch resistant coils may be associated with coil stretching when used in conjunction with a stent. Further study is still required for definitive results.

     

Distribution of Peripherally Injected Peptide YY ([<Superscript>125</Superscript>I] PYY (3–36)) and Pancreatic Polypeptide ([<Superscript>125</Superscript>I] hPP) in the CNS: Enrichment in the Area Postrema

The mechanism by which blood-borne peptide YY (3-36) (PYY(3-36)) and pancreatic polypeptide (PP) inhibit food intake is not clear and could implicate peripheral (vagal afferent pathways) and/or central (direct action on specific brain nuclei) mechanisms. To identify the primary brain structure(s) that could be activated after a peripheral injection of neuropeptide Y-related peptides, we investigated the distribution of radioactive materials using whole body autoradiography and coronal brain sections. Rats were injected with [125I] porcine (p) PYY(3-36) (i.p., 10 microCi) and killed after 30 min, 1, 2, or 4 h. After i.p. administration, significant amounts of radioactive materials were rapidly (<30 min) detected in the blood circulation and various tissues including the kidneys, liver, lung, heart, bone marrow, gastrointestinal tract, and thyroid gland, whereas in the brain, low but significant amounts of radioactive materials were detected at the level of the area postrema. Next, we investigated the distribution of radioactive labeling in the brain after i.v. injections of [125I]pPYY(3-36) (Y2 and Y5 subtypes), [125I] human (h) PP (Y4 and Y5 receptors), and [125I][Leu(31), Pro(34)] pPYY (Y1, Y4 and Y5 classes) in the rat brain. Fifteen minutes post injection, autoradiograms revealed positive signals only in the area postrema after the injection of [125I]-hPP and [125I][Leu(31), Pro(34)]pPYY. Whereas the presence of [125I]pPYY(3-36)-related labeling was detected in the area postrema, subfornical organ, and median eminence. In all other brain structures, including all hypothalamic nuclei and other circumventricular organs, near background level signals were detected. These data suggest that the inhibition of food intake observed after peripheral injections of pPYY(3-36) and hPP could involve receptor activation preferentially located at the level of the area postrema, a structure well-known to be involved in the modulation of food intake.     

Reduced cardiac <Superscript>123</Superscript>I-MIBG uptake reflects cardiac sympathetic dysfunction in de novo Parkinson’s disease

It remains unclear whether cardiac iodine-123-labeled metaiodobenzylguanidine (¹²³I-MIBG) uptake is clinically related to autonomic dysfunction on conventional autonomic function testing in de novo Parkinson’s disease (PD). We therefore studied the relation between cardiac ¹²³I-MIBG uptake and cardiovascular autonomic dysfunction in patients with de novo PD. The subjects were 26 patients with de novo PD. The ratio of the average pixel count in the heart to that in the mediastinum was calculated to derive the cardiac ¹²³I-MIBG uptake. Cardiovascular autonomic function was evaluated on the basis of cardiovascular autonomic response on the Valsalva maneuver (VM), and systolic blood pressure response (SBP) on head-up tilt-table testing (HUT). Patients with de novo PD had significantly reduced cardiac ¹²³I-MIBG uptake as compared with controls (1.58 ± 0.43 vs. 2.25 ± 0.34, p = 0.0001) and cardiovascular autonomic response on the VM. No significant difference in the fall in SBP on HUT was found between patients with de novo PD and the controls. Cardiac ¹²³I-MIBG uptake in de novo PD was not significantly related to vasomotor sympathetic function, baroreceptor reflex gain, cardiac parasympathetic function, or the changes in SBP on HUT. Cardiac ¹²³I-MIBG uptake was, however, significantly related to the blood pressure overshoot in phase IV of the VM (r = 0.648, p = 0.0003). Cardiac ¹²³I-MIBG uptake began to decrease in association with the reduction in the overshoot of phase IV on the VM. Cardiac ¹²³I-MIBG uptake clinically reflects cardiac sympathetic dysfunction in de novo PD.     

∆<Superscript>9</Superscript>-Tetrahydrocannabinol Decreases NOP Receptor Density and mRNA Levels in Human SH-SY5Y Cells

Several studies demonstrated a cross-talk between the opioid and cannabinoid system. The NOP receptor and its endogenous ligand nociceptin/orphanin FQ represent an opioid-related functional entity that mediates some non-classical opioid effects. The relationship between cannabinoid and nociceptin/NOP system is yet poorly explored. In this study, we used the neuroblastoma SH-SY5Y cell line to investigate the effect of delta-9-tetrahydrocannabinol (∆⁹-THC) on nociceptin/NOP system. Results revealed that the exposure to ∆⁹-THC (100, 150, and 200 nM) for 24 h produces a dose-dependent NOP receptor B _max down-regulation. Moreover, ∆⁹-THC caused a dose-dependent decrease in NOP mRNA levels. The selective cannabinoid receptor CB1 antagonist AM251 (1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-1-piperidinyl-1H-pyrazole-3-carboxamide) reduces both effects, suggesting that ∆⁹-THC activation of CB1 receptor is involved in the observed effects. These data show evidence of a cross-talk between NOP and CB1 receptors, thus suggesting a possible interplay between cannabinoid and nociceptin/NOP system.     

Pharmacological Effects on Ceroid Lipofuscin and Neuronal Structure in <Emphasis Type="Italic">Cln3</Emphasis><Superscript><Emphasis Type="Italic">∆ex7/8</Emphasis></Superscript> Mouse Brain Cultures

Juvenile Batten disease (JBD) is an inherited disorder that is characterized by the development of blindness, seizures, and progressive motor, psychiatric, and cognitive impairment. A model of JBD expressing the predominant human mutation (Cln3 ^?ex7/8 ) has been explored. Dissociated brain cultures from Cln3 ^?ex7/8 knock-in mice were compared to wild type (WT) for effects on granules of ceroid lipofuscin (CL) and neuronal structure. Utilizing high content image analysis of CL granules identified with antibodies to mitochondrial ATP synthase subunit c or tripeptidyl peptidase-1, significant increases in the areas for both immunoreactive granules were observed in Cln3 ^?ex7/8 cultures in comparison to WT. CL granules also exhibit autofluorescence at 488 and 560 nm, and the areas of these autofluorescent spots were found to be significantly increased in Cln3 ^?ex7/8 cultures in comparison to WT. Progressive increases in CL granule area in Cln3 ^?ex7/8 cultures were observed during culture development. Because current therapies for JBD provide only symptomatic support, a therapeutic strategy has been explored based on the observations that JBD-related tissues are deficient in β-galactosyl ceramide. Treatment of cultures for 40 h with a potent analog of β-galactosyl ceramide (SNB-4050) produced significant decreases in CL granule area in the Cln3 ^?ex7/8 cultures; whereas identical studies on WT cultures produced no detectible changes. Significant decreases in average neurite length and neurite branch point number were also observed in the Cln3 ^?ex7/8 cultures that were attenuated by treatment with 1 nM SNB-4050. These studies indicate Cln3 ^?ex7/8 brain cultures may be useful to screen therapeutic agents for treatment of JBD.     

Reduced hippocampal neurogenesis in the GR<Superscript>+/−</Superscript> genetic mouse model of depression

Glucocorticoid receptor (GR) heterozygous mice (GR^+/− ) represent a valuable animal model for major depression. GR^+/− mice show a depression-related phenotype characterized by increased learned helplessness on the behavioral level and neuroendocrine alterations with hypothalamo-pituitary-adrenal (HPA) axis overdrive characteristic of depression. Hippocampal brain-derived neurotrophic factor (BDNF) levels have also been shown to be reduced in GR^+/− animals. Because adult hippocampal neurogenesis has been implicated in the pathophysiology of affective disorders, we studied here the effects of the GR^+/− genotype on neurogenesis in vivo. In a 2 × 2 design, GR^+/− mice and GR^+/+ littermate controls were either subjected to 1 h of restraint stress or left undisturbed in their home cages after intraperitoneal injection of BrdU. Stress exposure and BrdU injections were performed once daily for 7 days and neurogenesis analyzed 4 weeks later. BrdU cell counts were significantly reduced as an effect of GR^+/− genotype and as an effect of stress. Majority of the BrdU+ cells showed co-labeling with mature neuronal marker NeuN or astrocytic marker S100β with no further significant effect of either experimental condition or of genotype. In sum, this results in reduced neurogenesis in GR^+/− mice which is further repressed by restraint stress. Our results, thus, reinforce the link between reduced neurogenesis, stress, neurotrophins, and behavioral symptoms of and susceptibility to depression.     

Delta-9-Tetrahydrocannabinol (∆<Superscript>9</Superscript>-THC) Induce Neurogenesis and Improve Cognitive Performances of Male Sprague Dawley Rats

Neurogenesis is influenced by various external factors such as enriched environments. Some researchers had postulated that neurogenesis has contributed to the hippocampal learning and memory. This project was designed to observe the effect of Delta-9-tetrahydrocannabinol (?⁹-THC) in cognitive performance that influenced by the neurogenesis. Different doses of ?⁹-THC were used for observing the neurogenesis mechanism occurs in the hippocampus of rats. The brains were stained with antibodies, namely BrdU, glial fibrillary acidic protein (GFAP), nestin, doublecortin (DCX) and class III β-tubulin (TuJ-1). The cognitive test was used novel-object discrimination test (NOD) while the proteins involved, DCX and brain-derived neurotrophic factor (BDNF), were measured. Throughout this study, ?⁹-THC enhanced the markers involved in all stages of neurogenesis mechanism. Simultaneously, the cognitive behaviour of rat also showed improvement in learning and memory functions observed in behavioural test and molecular perspective. Administration of ?⁹-THC was observed to enhance the neurogenesis in the brain, especially in hippocampus thus improved the cognitive function of rats.     

Discrimination of white matter lesions and multiple sclerosis plaques by short echo quantitative <Superscript>1</Superscript>H—magnetic resonance spectroscopy

Multiple sclerosis (MS) plaques and age related white matter lesions (WML) are of similar morphological appearance on T2 weighted MRI. Therefore their differentiation is sometimes crucial. Proton magnetic resonance spectroscopy (¹H–MRS) adds metabolic information to conventional imaging and may help to distinguish inflammatory MS plaques from vascular related WML. This study was performed to evaluate the metabolite pattern in MS plaques and WML. 15 MS patients, 14 elderly individuals with WML and 16 controls were investigated by conventional MRI and short echo quantitative ¹H–MRS (TE: 30ms, TR: 3000ms). The mean metabolite concentrations in normal control white matter (NCWM), MS plaques and WML were: t–NAA: 8.96 mmol/l (SD:0.93) vs 6.79 mmol/l (SD: 1.99) vs 7.18 mmol/l (SD: 1.41); Cho: 1.66 mmol/l (SD: 0.4) vs 1.49 mmol/l (SD: 0.45) vs 1.46 mmol/l (SD: 0.34); PCr: 5.64 mmol/l (SD: 0.83) vs 4.9mmol/l (SD: 1.3) vs 4.95 mmol/l (SD: 0.86); myo–Ins: 4.57 mmol/l (SD:1.05) vs 6.34 mmol/l (SD: 2.03) vs 4.5 mmol/l (SD: 0.96). t–NAA reduction in MS plaques and WML was significant compared with controls (p ≤ 0.001). MS plaques showed significantly elevated myo– Ins concentrations compared with controls (p = 0.002) and to WML (p = 0.003). In summary MS plaques and WML show a decrease in their t–NAA concentrations compared with controls. Elevated concentrations of myo–Ins in MS plaques but not in WML makes this metabolite of special interest for their differentiation.     

Muscarinic acetylcholine receptor status in Alzheimer’s disease assessed using (R,R) <Superscript>123</Superscript>I-QNB SPECT

Abstract Background One of the most characteristic changes in Alzheimer's disease (AD) is a deficit in cortical cholinergic neurotransmission and associated receptor changes. Objective To investigate differences in the distribution of M1/M4 receptors using (R, R) ¹²³I-iodo-quinuclidinyl-benzilate (QNB) and single photon emission computed tomography (SPECT) in patients with mild/moderate AD and agematched controls. Also, to compare ¹²³I-QNB uptake to the corresponding changes in regional cerebral blood flow (rCBF) in the same subjects. Methods Forty two subjects (18 AD and 24 healthy elderly controls) underwent ¹²³IQNB and perfusion ^99mTc-exametazime SPECT scanning. Image analysis was performed using statistical parametric mapping (SPM99) following intensity normalisation of each image to its corresponding mean whole brain uptake. Group differences and correlations were assessed using two sample t-tests and linear regression respectively. Results Significant reductions in ¹²³I-QNB uptake were observed in regions of the frontal rectal gyrus, right parahippocampal gyrus, left hippocampus and areas of the left temporal lobe in AD compared to controls (height threshold of p ≤ 0.001 uncorrected). Such regions were also associated with marked deficits in rCBF. No significant correlations were identified between imaging data and clinical variables. Conclusion Functional impairment as measured by rCBF is more widespread than changes in M1/M4 receptor density in mild/moderate AD, where there was little or no selective loss of M1/M4 receptors in these patients that was greater than the general functional deficits shown on rCBF scans.     

<Superscript>18</Superscript>F-FP-CIT PET imaging and SPM analysis of dopamine transporters in Parkinson’s disease in various Hoehn &; Yahr stages

To investigate the usefulness of 18F-FP-CIT PET for assessing the severity of Parkinson’s disease (PD) at various clinical stages, 41 patients with PD were divided into early (Hoehn&Yahr I-II, n = 23) and advanced (Hoehn&Yahr III-IV, n = 18) subgroups. 18F-FP-CIT PET was performed in these patients and 12 normal subjects. 18F-FP-CIT uptake in striatal subregions and its correlation with UPDRS were first evaluated by ROI analysis, and between-group differences were also analyzed by Statistical Parametric Mapping (SPM). Our results showed that striatal 18F-FP-CIT binding were significantly reduced to 70.9% (caudate), 46.8% (anterior putamen) and 24.0% (posterior putamen) in early PD compared with that of the control, and to 52.0%, 34.5% and 16.5% correspondingly in advanced PD, respectively. There was significant negative correlation between total motor UPDRS score of all parkinsonian patients and 18F-FP-CIT uptake in caudate nucleus (r = −0.53, p < 0.001), anterior putamen (r = −0.53, p < 0.001) and posterior putamen (r = −0.61, p < 0.001). SPM comparison of 18F-FP-CIT uptake between early or advanced PD and the control group showed significant decline in striatum, predominantly localized on the contralateral side and in the dorsal-posterior putamen. These results indicate that 18F-FP-CIT PET can serve as a suitable biomarker to represent the severity of PD in early and advanced stages. Received in revised form: 11 June 2006     

CCL2 transgene expression in the central nervous system directs diffuse infiltration of CD45<Superscript>high</Superscript>CD11b<Superscript>+</Superscript> monocytes and enhanced Theiler’s murine encephalomyelitis virus-induced demyelinating disease

CCL2 is a member of the CC chemokine family that mediates the migration and recruitment of monocytes and T cells and has been identified in the central nervous system (CNS) during several neuroinflammatory diseases. In order to examine the biological effect of constitutive CCL2 expression in the CNS, the authors engineered a mouse that expressed CCL2 in the CNS under control of the human glial fibrillary acidic protein (hGFAP) promoter. The results demonstrated that transgenic expression of CCL2 in the CNS resulted in diffuse CNS monocyte infiltration and accumulation. Transgenic CCL2 expression did not alter normal development, differentiation, or function of T cells. There was no evidence of overt CNS disease or other pathologic phenotype when mice were left unchallenged with antigen or uninfected. However, when CCL2 transgenic mice were given a peripheral challenge of lipopolysaccharide (LPS), an inflammatory infiltrate with organized perivascular lesions developed. Infection of the transgenic mice with Theiler's murine encephalomyelitis virus (TMEV) resulted in accelerated onset and increased severity of clinical and histological disease. These results suggest that CCL2 expression in the CNS is a major pathogenic factor that drives macrophage accumulation in the development of CNS inflammatory disease.     

Identification of N<Superscript>ɛ</Superscript>-(carboxymethyl)lysine-positive cells in astroglia-rich primary cultures

Summary. Astroglia-rich primary cultures from rat brain were used to investigate the presence in glial cells of N-(carboxymethyl)lysine (CML), an advanced glycation endproduct. Westernblot analysis of homogenates of rat brain as well as of astroglia-rich cultures demonstrated the presence of CML-modified proteins in these samples. Immunocytochemical staining of astroglia-rich cultures revealed that only a minority of the cells in these cultures were intensively stained for CML. The staining intensity of CML-positive cells was strongly reduced, if the cells were not permeabilized, indicating that intracellular proteins were CML-modified. The CML-positive cells were identified as astrocytes and oligodendrocytes by double-labelling immunocytochemical staining for CML and the cellular markers galactocerobroside, myelin basic protein and glial fibrillary acidic protein. In contrast to other glial cells, microglial cells in astroglia-rich cultures were CML-negative. The finding that only a minority of cells in astroglia-rich cultures contains high amounts of intracellular CML-modified proteins indicates that specific properties of these CML-positive cells are responsible for the CML-formation in these cells.Received January 28, 2003; accepted April 22, 2003 Published online June 30, 2003     

The murine <Emphasis Type="Italic">Bis1</Emphasis> seizure gene and the <Emphasis Type="Italic">Kcnab2</Emphasis> gene encoding the β2-subunit of the K<Superscript>+</Superscript> channel are different

Received: April 22, 1999 / Accepted: August 30, 1999 / Published online: January 10, 2000     

Chorea-acanthocytosis in monozygotic twins: clinical findings and neuropathological changes as detected by diffusion tensor imaging,FDG-PET and <Superscript>123</Superscript>I-<Emphasis Type="Italic">β</Emphasis>-CIT-SPECT

Abstract We report on two 33 years old monozygotic twins with chorea-acanthocytosis (ChAc) misdiagnosed as schizophrenia and Tourette syndrome, respectively. Although the patients shared several clinical similarities, there were also some clear differences: twin 1 presented initially with an acute episode of a paranoid schizophrenia, while twin 2 suffered from generalized epileptic seizures. In both twins, MRI demonstrated caudate nucleus atrophy and an increased apparent diffusion coefficient (ADC) in the striatum bilaterally with right sided predominance. ¹⁸F-FDG PET showed bilaterally reduced glucose utilization in the striatum with clearly pronounced reduction on the right side compared to the left and in twin 1 compared to twin 2. Ratios of binding to striatal dopamine transporters (DAT) and serotonin transporters in the hypothalamus midbrain area as determined using ¹²³I-β-CIT-SPECT fell within the normal ranges. However, in twin 1 a significant difference in binding to presynaptic DAT with marked reduction on the right hemisphere was observed. Right hemispheric accentuated changes measured by MRI, FDG-PET, and ¹²³I-β-CITSPECT correspond to more severe hyperkinetic movements on the left part of the body in both twins. Different neuro-psychiatric features in this monocygotic twin pair suggest that not only genetic but also environmental factors contribute to the clinical symptomatology. Our findings suggest that the main neuropathological process in ChAc is located in the striatum, involving microstructural alterations, and disturbance of metabolism and dopaminergic neurotransmission.     

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     

The BDNF Val<Superscript>66</Superscript>Met polymorphism has a gender specific influence on planning ability in Parkinson’s disease

Parkinson’s disease (PD) patients show a range of cognitive deficits,which may relate to abnormalities in dopaminergic transmission in fronto–striatal circuitry. In this study, we have investigated the impact of brainderived neurotrophic factor (BDNF) val⁶⁶met polymorphisms on performance of the Tower of London (TOL) test of planning by PD patients. This polymorphism significantly influences BDNF secretion in the CNS, and BDNF is known to influence dopaminergic neurons and cognitive processes. Patients with PD totalling 291 who had undergone detailed motor and cognitive assessments as part of a population–based study of PD were genotyped for the BDNF val⁶⁶met polymorphism. The impact of this polymorphism on cognitive ability was determined using multivariate analysis to adjust for possible confounding variables. Patients with low rates of BDNF secretion (met alleles) performed significantly better at the TOL task than those with high rates of secretion (val alleles). Furthermore, subgroup analyses revealed that the effect is most apparent in women and among patients with prior dopaminergic exposure. We speculate that BDNF may interact with dopaminergic transmission and dopamine receptor stimulation in the frontostriatal circuitry, with subsequent consequences on cognition in Parkinson’s disease.