Evaluation of N‐benzyl‐N‐[11C]methyl‐2‐ (7‐methyl‐8‐oxo‐2‐phenyl‐7,8‐dihydro‐9H‐purin‐9‐yl)acetamide ([11C]DAC) as a novel translocator protein (18 kDa) radioligand in kainic acid‐lesioned rat

The aim of this study was to evaluate N‐benzyl‐N‐[¹¹C]methyl‐2‐(7‐methyl‐8‐oxo‐2‐phenyl‐7,8‐dihydro‐9H‐purin‐9‐yl)acetamide ([¹¹C]DAC) as a new translocator protein (18 kDa) [TSPO, formerly known as the peripheral‐type benzodiazepine receptor (PBR)] positron emission tomography (PET) ligand in normal mice and unilateral kainic acid (KA)‐lesioned rats. DAC is a derivative of AC‐5216, which is a potent and selective PET ligand for the clinical investigation of TSPO. The binding affinity and selectivity of DAC for TSPO were similar to those of AC‐5216, and DAC was less lipophilic than AC‐5216. The distribution pattern of [¹¹C]DAC was in agreement with TSPO distribution in rodents. No radioactive metabolite of [¹¹C]DAC was found in the mouse brain, although it was metabolized rapidly in mouse plasma. Using small‐animal PET, we examined the in vivo binding of [¹¹C]DAC for TSPO in KA‐lesioned rats. [¹¹C]DAC and [¹¹C]AC‐5216 exhibited similar brain uptake in the lesioned and nonlesioned striatum, respectively. The binding of [¹¹C]DAC to TSPO was increased significantly in the lesioned striatum, and [¹¹C]DAC showed good contrast between the lesioned and nonlesioned striatum (the maximum ratio was about threefold). In displacement experiments, the uptake of [¹¹C]DAC in the lesioned striatum was eventually blocked using an excess of either unlabeled DAC or PK11195 injected. [¹¹C]DAC had high in vivo specific binding to TSPO in the injured rat brain. Therefore, [¹¹C]DAC is a useful PET ligand for TSPO imaging, and its specific binding to TSPO is suitable as a new biomarker for brain injury. Synapse 63:961–971, 2009. © 2009 Wiley‐Liss, Inc.     

Evidence of oligodendrogliosis in 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP)‐induced Parkinsonism

V. Annese, C. Barcia, F. Ros‐Bernal, A. Gómez, C. M. Ros, V. De Pablos, E. Fernández‐Villalba, M.‐E. De Stefano and M. T. Herrero (2013) Neuropathology and Applied Neurobiology 39, 132–143 Evidence of oligodendrogliosis in 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP)‐induced Parkinsonism Aims: Mice and nonhuman primates administered with 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) represent elective experimental models of Parkinsonism, in which degeneration of the nigrostriatal dopaminergic pathway is associated with prominent neuroinflammation, characterized by activated microglia and astrocytes in both substantia nigra (SN) and striatum. To date, it is unknown whether oligodendrocytes play a role in these events. Methods: We performed a detailed qualitative and quantitative analysis of oligodendrocyte‐associated changes induced by acute and chronic MPTP treatment, in the SN and striatum of mice and macaques respectively. Oligodendrocytes were immunolabelled by cell‐specific markers and analysed by confocal microscopy. Results: In both experimental models, MPTP treatment induces an increase in oligodendrocyte cell number and average size, as well as in the total area occupied by this cell type per tissue section, accompanied by evident morphological changes. This multifaceted array of changes, herein referred to as oligodendrogliosis, significantly correlates with the reduction in the level of dopaminergic innervation to the striatum. Conclusions: This event, associated with early damage of the dopaminergic neurone axons and of the complex striatal circuits of which they are part, may result in an important, although neglected, aspect in the onset and progression of Parkinsonism.     

Poly(ADP‐ribose)polymerase inhibitor can attenuate the neuronal death after 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine‐induced neurotoxicity in mice

An excessive expression of poly(ADP‐ribose)polymerase (PARP) has been demonstrated to play a key role in the pathogenesis of Parkinson's disease (PD). Here we investigated the therapeutic effect of the PARP inhibitor benzamide against 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) neurotoxicity in mice. In our HPLC and Western blot analysis, pretreatment with benzamide showed a neuroprotective effect against MPTP neurotoxicity in mice. Posttreatment with benzamide also attenuated MPTP neurotoxicity in mice. Furthermore, our immunohistochemical study showed that posttreatment with benzamide significantly prevented neuronal damage by suppressing overexpression of neuronal, microglial, and astroglial PARP after MPTP treatment. These findings have important implications for the therapeutic time window and choice of PARP inhibitors in PD patients. Our present findings provide further evidence that PARP inhibitor may offer a novel therapeutic strategy for PD. © 2009 Wiley‐Liss, Inc.     

Anterior pituitary gland synthesises dopamine from l‐3,4‐dihydroxyphenylalanine (l‐dopa)

Prolactin (PRL) is a hormone principally secreted by lactotrophs of the anterior pituitary gland. Although the synthesis and exocytosis of this hormone are mainly under the regulation of hypothalamic dopamine (DA), the possibility that the anterior pituitary synthesises this catecholamine remains unclear. The present study aimed to determine if the anterior pituitary produces DA from the precursor l ‐3,4‐dihydroxyphenylalanine (l ‐dopa). Accordingly, we investigated the expression of aromatic l ‐amino acid decarboxylase (AADC) enzyme and the transporter vesicular monoamine transporter 2 (VMAT2) in the anterior pituitary, AtT20 and GH3 cells by immunofluorescence and western blotting. Moreover, we investigated the production of DA from l ‐dopa and its release in vitro. Then, we explored the effects of l ‐dopa with respect to the secretion of PRL from anterior pituitary fragments. We observed that the anterior pituitary, AtT20 and GH3 cells express both AADC and VMAT2. Next, we detected an increase in DA content after anterior pituitary fragments were incubated with l ‐dopa. Also, the presence of l ‐dopa increased DA levels in incubation media and reduced PRL secretion. Likewise, the content of cellular DA increased after AtT20 cells were incubated with l ‐dopa. In addition, l ‐dopa reduced corticotrophin‐releasing hormone‐stimulated adrenocorticotrophic hormone release from these cells after AADC activity was inhibited by NSD‐1015. Moreover, DA formation from l ‐dopa increased apoptosis and decreased proliferation. However, in the presence of NSD‐1015, l ‐dopa decreased apoptosis and increased proliferation rates. These results suggest that the anterior pituitary synthesises DA from l ‐dopa by AADC and this catecholamine can be released from this gland contributing to the control of PRL secretion. In addition, our results suggest that l ‐dopa exerts direct actions independently from its metabolisation to DA.     

Insulin treatment restores glutamate (α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid) receptor function in the hippocampus of diabetic rats

Type 1 diabetes is associated with cognitive dysfunction. Cognitive processing, particularly memory acquisition, depends on the regulated enhancement of expression and function of glutamate receptor subtypes in the hippocampus. Impairment of memory was been detected in rodent models of type 1 diabetes induced by streptozotocin (STZ). This study examines the functional properties of synaptic α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) receptors and the expression of synaptic molecules that regulate glutamatergic synaptic transmission in the hippocampus of STZ‐diabetic rats. The AMPA receptor‐mediated miniature excitatory postsynaptic currents (mEPSCs) and single‐channel properties of synaptosomal AMPA receptors were examined after 4 weeks of diabetes induction. Results show that amplitude and frequency of mEPSCs recorded from CA1 pyramidal neurons were decreased in diabetic rats. In addition, the single‐channel properties of synaptic AMPA receptors from diabetic rat hippocampi were different from those of controls. These impairments in synaptic currents gated by AMPA receptors were accompanied by decreased protein levels of AMPA receptor subunit GluR1, the presynaptic protein synaptophysin, and the postsynaptic anchor protein postsynaptic density protein 95 in the hippocampus of diabetic rats. Neural cell adhesion molecule (NCAM), an extracellular matrix molecule abundantly expressed in the brain, and the polysialic acid (PSA) attached to NCAM were also downregulated in the hippocampus of diabetic rats. Insulin treatment, when initiated at the onset of diabetes induction, reduced these effects. These findings suggest that STZ‐induced diabetes may result in functional deteriorations in glutamatergic synapses in the hippocampus of rats and that these effects may be reduced by insulin treatment. © 2015 Wiley Periodicals, Inc.     

N‐methyl‐d‐aspartate (NMDA) receptor antibodies encephalitis mimicking an autistic regression

Expressive dysphasia and mutism are common clinical features in children and adults with N‐methyl‐d ‐aspartate receptor antibodies (NMDAR‐Ab) encephalitis, and are likely to result from NMDAR hypofunction. A prodromal loss of social and communication skills can typify that of an autistic regression, particularly when presenting under the age of 3 years. Here we describe two toddlers who presented with developmental regression, particularly of their social communication skills, mimicking an autistic regression, who were found to have NMDAR‐Ab in the serum and cerebrospinal fluid. Although both patients had some other neurological features, they were subtle, which resulted in delayed diagnosis of NMDAR‐Ab encephalitis. Importantly, immunotherapy was beneficial in both patients, with significant improvement of their language skills and behaviour.     

Anti–N‐methyl‐D‐aspartate receptor (NMDAR) encephalitis in children and adolescents

Objective

To report the clinical features of anti–N‐methyl‐D‐aspartate receptor (NMDAR) encephalitis in patients ≤ 18 years old.

Methods

Information was obtained by the authors or referring physicians. Antibodies were determined by immunocytochemistry and enzyme‐linked immunosorbent assay (ELISA) using HEK293 cells ectopically expressing NR1.

Results

Over an 8‐month period, 81 patients (12 male) with anti‐NMDAR encephalitis were identified. Thirty‐two (40%) were ≤18 years old (youngest 23 months, median 14 years); 6 were male. The frequency of ovarian teratomas was 56% in women >18 years old, 31% in girls ≤18 years old (p = 0.05), and 9% in girls ≤14 years old (p = 0.008). None of the male patients had tumors. Of 32 patients ≤18 years old, 87.5% presented with behavioral or personality change, sometimes associated with seizures and frequent sleep dysfunction; 9.5% with dyskinesias or dystonia; and 3% with speech reduction. On admission, 53% had severe speech deficits. Eventually, 77% developed seizures, 84% stereotyped movements, 86% autonomic instability, and 23% hypoventilation. Responses to immunotherapy were slow and variable. Overall, 74% had full or substantial recovery after immunotherapy or tumor removal. Neurological relapses occurred in 25%. At the last follow‐up, full recovery occurred more frequently in patients who had a teratoma that was removed (5/8) than in those without a teratoma (4/23; p = 0.03).

Interpretation

Anti‐NMDAR encephalitis is increasingly recognized in children, comprising 40% of all cases. Younger patients are less likely to have tumors. Behavioral and speech problems, seizures, and abnormal movements are common early symptoms. The phenotype resembles that of the adults, although dysautonomia and hypoventilation are less frequent or severe in children. Ann Neurol 2009;66:11–18     

Minocycline 1‐year therapy in multiple‐system‐atrophy: Effect on clinical symptoms and [11C] (R)‐PK11195 PET (MEMSA‐trial)

The aim of the study was to investigate the efficacy of the antibiotic minocycline as a drug treatment in patients with Multiple‐System‐Atrophy Parkinson‐type (MSA‐P). Sixty‐three patients were randomized to minocycline 200 mg/d (n = 32) or a matching placebo (n = 31). The primary outcome variable was the change in the value of the motor score of the Unified Multiple‐System‐Atrophy Rating‐Scale (UMSARSII) from baseline to 48 weeks. Secondary outcome variables included subscores and individual Parkinsonian symptoms as determined by the UMSARS and the Unified‐Parkinson's‐Disease Rating‐Scale (UPDRS). Health‐related quality of life (HrQoL) was assessed using the EQ‐5D and SF‐12. “Progression rate” was assumed to be reflected in the change in motor function over 48 weeks. At 24 weeks and 48 weeks of follow‐up, there was a significant deterioration in motor scores in both groups, but neither the change in UMSARSII nor in UPDRSIII differed significantly between treatment groups, i.e. “progression rate” was considered to be similar in both treatment arms. HrQoL did not differ among the two treatment arms. In a small subgroup of patients (n = 8; minocycline = 3, placebo = 5)[¹¹C](R)‐PK11195‐PET was performed. The three patients in the minocycline group had an attenuated mean increase in microglial activation as compared to the placebo group (P = 0.07) and in two of them individually showed decreased [11C](R)‐PK11195 binding actually decreased. These preliminary PET‐data suggest that minocycline may interfere with microglial activation. The relevance of this observation requires further investigation. This prospective, 48 week, randomized, double‐blind, multinational study failed to show a clinical effect of minocycline on symptom severity as assessed by clinical motor function. © 2009 Movement Disorder Society     

Construction and validation of the chronic acquired polyneuropathy patient‐reported index (CAP‐PRI): A disease‐specific,health‐related quality‐of‐life instrument

Introduction: Generic health‐related quality‐of‐life (HRQOL) patient‐reported outcome measures have been used in patients with chronic immune‐mediated polyneuropathies. We have created a disease‐specific HRQOL instrument. Methods: The chronic acquired polyneuropathy patient‐reported index (CAP‐PRI) was developed and validated in multiple steps. Items were initially generated through patient and specialist input. The performance of the preliminary 20 items was analyzed via a prospective, 5‐center study involving chronic immune‐mediated polyneuropathy patients. Results: Data analysis suggested modification to a 15‐item scale with 3 response categories rather than 5. The final CAP‐PRI was validated in another prospective, 5‐center study. The CAP‐PRI appeared to be a unidimensional outcome measure that fit the Rasch model in our multicenter cohort. It correlated appropriately with outcome measures commonly used in this patient population. Conclusions: The CAP‐PRI is a simple disease‐specific HRQOL measure that appears to be useful for clinical care and possibly also for clinical trials. Muscle Nerve 54 : 9–17, 2016     

The Inventory of Depressive Symptomatology (IDS): Clinician (IDS‐C) and Self‐Report (IDS‐SR) ratings of depressive symptoms

This paper describes the rationale and methods entailed in developing the Inventory of Depressive Symptomatology (IDS) in both clinician‐rated (IDS‐C) and self‐reported (IDS‐SR) formats. Psychometric features of the both the IDS‐C and IDS‐SR are presented. These scales are compared to the Hamilton Rating Scale for Depression (HRS‐D) in the detection of symptom change in patients with major depressive (n = 184) or bipolar disorder (n = 141). The face validity and established psychometric features of the IDS‐C and IDS‐SR indicate that either may be useful in detecting symptom change, as well as in detecting residual symptoms in depressed patients. Further efforts to shorten each measure are indicated. Copyright © 2000 Whurr Publishers Ltd.     

Cyclooxygenase‐2 (Cox‐2) expression and angiogenesis in glioblastoma

Cyclooxygenase‐2 (Cox‐2), the key enzyme that catalyzes the first steps in the biosynthesis of the prostaglandins from arachidonic acid, appears to play a role in the regulation of progression, invasiveness and angiogenesis of various neoplasms. We analyzed the immunohistochemical expression of Cox‐2 and angiogenic parameters (microvessel density (MVD) and vascular patterns) in 54 glioblastomas. We also examined their relation with prognosis. Cox‐2 immunohistochemical expression was observed in 48 tumors (89%). There was no staining in six tumors (11%). On univariate analysis, MVD was correlated with a poor outcome (MVD > 70; hazard ratio, 0.441; 95% confidence interval, 0.200–0.975, P = 0.041). But MVD showed no prognostic impact on multivariate analysis. Neither Cox‐2 expression nor vascular pattern showed prognostic value. The difference in Cox‐2 expression between the classical and bizarre vascular pattern in glioblastomas was statistically significant (P = 0.047). However, no correlation was found between Cox‐2 expression and MVD. These findings suggest that Cox‐2 is heterogeneously expressed in glioblastomas without a significant association with MVD. However, Cox‐2 expression may be related to vascular pattern in glioblastomas.