Dimitrios Kanakis

Immunohistochemical evidence for impaired neuregulin-1 signaling in the prefrontal cortex in schizophrenia and in unipolar depression.

Abstract:u2002 In the central nervous system (CNS), neuregulin‐1 (NRG‐1) proteins function in neuronal migration, differentiation, and survival of oligodendrocytes. The NRG‐1 gene codes for at least 15 different isoforms, which may be classified on the basis of their molecular structure. At least two different haplotypes of the NRG‐1 gene may be associated with schizophrenia. An abnormal expression pattern of NRG‐1 mRNA was found in the prefrontal cortex of schizophrenic patients in comparison to controls. We here show that the NRG‐1α isoform is significantly reduced in white matter of the prefrontal cortex in schizophrenia but not in affective disorder. In the prefrontal gray matter, the density of NRG‐1α expressing neurons was reduced in individuals with schizophrenia and in unipolar patients. We studied brains of 22 schizophrenics, 12 patients with affective disorders (7 unipolar and 5 bipolar), and 22 matched controls. NRG‐1α immunoreactive material was detected with a polyclonal antiserum against the synthetic peptide from α‐type EGF‐like domain of human NRG. The demonstrated decreased number of NRG‐1 immunoreactive neurons in the brains of schizophrenics and patients with unipolar depression points to an important role of this NRG‐1α splice variant in neuropsychiatric disorders. Reduced NRG‐1α protein concentrations were found in brains of schizophrenics after Western blot analysis. The diminished expression of NRG‐1α strongly supports an early neurodevelopmental component to schizophrenia.

Localization of neuregulin-1α (heregulin-α) and one of its receptors, ErbB-4 tyrosine kinase, in developing and adult human brain

Abstract Using immunohistochemistry, Western blot analysis, and RT-polymerase chain reaction, we studied the distribution of neuregulin-1 splice variant α (NRG-1α) and one of its putative receptors, ErbB-4 tyrosine kinase, in human brain. In the pre- and perinatal human brain immunoreactivity was confined to numerous neurons, with the highest cell density found in cortical gray matter, hypothalamus and cerebellum. In the adult brain, single cortical gray and white matter neurons showed NRG-1α immunoreactivity. Occasionally, immunoreactive oligodendrocytes were observed. NRG-1α-expressing neurons were also found in the hypothalamus, hippocampus, basal ganglia and brain stem. Application of two antibodies recognizing α and β isoforms revealed a different distribution pattern in that many cortical and hippocampal pyramidal neurons were labeled. ErbB-4 immunoreactivity was expressed in both neurons and oligodendrocytes. Our data show that NRG-1α expression is lower in the adult human brain than in the developing brain, and, therefore, support a role for NRG-1α in brain development.

Paraneoplastic necrotizing myelopathy with hypertrophy of the cauda equina.

Sirs: Recently, Burton et al. [1] described clinical and radiological characteristics of two patients presenting with hypertrophic radiculopathy of the cauda equina. Because removal of a bronchial carcinoid in one patient led to clinical improvement, a paraneoplastic origin was suggested. We report clinical and autopsy data of a patient with non-small cell lung cancer (SCLC), who developed a paraneoplastic necrotizing myelopathy [7] together with hypertrophic radiculopathy. A 71-year-old male patient with non-SCLC had been treated with chemotherapy leading to remission. Two years later he presented with pain in his lumbar spine and both legs, difficulty in walking, constipation, and impaired micturition. Neurological examination revealed paraparesis (right 2/5, left 4/5 MRC) with abolished tendon reflexes, flexor plantar responses, and a sensory level at D10. Prior to admission, EMG had shown chronic denervation of leg muscles. Sensory and motor conduction velocities and action potentials were in the lower normal range, F-wave latencies of the posterior tibial and peroneal nerve in the upper normal range. Tibial somatosensory evoked potentials could not be elicited. While no classical onconeural antibodies were found (immunoblot against cerebellar extract, blots against recombinant Hu-, Yo-, and Ri-antigens), serum antibodies against oligodendrocytes and Purkinje cells not identical with anti-CV2 could be detected by immunohistochemistry. CSF showed normal values for total protein, IgG, and lactate, but an increased cell count (16/μl) without tumour cells. Myelography of the lumbar and thoracic spine ruled out compression of the spinal cord and nerve roots. Within five weeks, continuous deterioration resulted in complete paraplegia and subsequent ascension of the transverse syndrome to a cervical level. The patient died of bronchopneumonia and septicaemia. Postmortem examination revealed necrotic areas in the central part of the cord throughout its whole length. The leptomeninges were unremarkable. Histologically, necrosis of the white and gray matter, demyelination, and focal accumulation of macrophages were present, most pronounced in the lumbar segments (Fig. 1). Intraspinal vessels were normal. Examination of the cauda equina demonstrated thickening of several nerve roots in a randomly distributed fashion (Fig. 2A). The tumourlike lesions were of firm consistency without necroses or haemorrhages. Microscopy showed proliferation of connective tissue, resulting in irregular separation of the nerve fibres (Fig. 2B). However, the cellularity of the Schwann cells was not increased, and no schwannoma or neurofibroma was observed. Mitotic figures were absent, and no proliferation was detected by Ki67-immunostaining. Only occasionally were single T lymphoctes observed within the nerve roots. Again blood vessels were normal. Semithin sections of a sural nerve sample showed a slightly reduced density of myelinated nerve fibres, but no acute demyelination, onion bulb formation, inflammatory infiltrates, or vasculitis. The brain was unremarkable except for moderate widening of the perivascular spaces in the basal ganglia. Autopsy also disclosed radiologically undetected remnants of the non-SCLC. Although no MRI could be performed (because the patient had a cardiac pacemaker), the pathomorphological findings of the cauda hypertrophy correspond well with the radiological features described by Burton et al. [1]. In contrast to LETTER TO THE EDITORS

Sudden progression of a glioblastoma in partial remission

There are only sparse data on viral CNS infections in patients with malignant glioma. We report a case of fatal herpes encephalitis in a patient with glioblastoma in partial remission and provide a short review of the literature.

ADAM 12: a putative marker of oligodendrogliomas?

ADAM 12 (meltrin alpha) belongs to a large family of molecules, consisting of members with both disintegrin and metalloproteinase properties. ADAMs have been implicated in several cell physiological processes including cell adhesion, cell fusion, proteolysis and signalling. ADAM 12 is widely expressed, including skeletal muscle, testis, bone, intestine, heart and kidney. In addition, a variety of tumours show elevated expression of ADAM12; among them being breast-, colon-, gastric- and lung-carcinoma. As to the brain, ADAM 12 has been shown previously to be expressed in rat and human oligodendrocytes. However, little is known about the expression of this protease in brain tumours. This study demonstrates the presence of ADAM 12 in non-neoplastic oligodendroglial cells of normal human brain as well as in neoplastic oligodendroglia and minigemistocytes arising from four pure oligodendrogliomas and three mixed oligoastrocytomas. Double stainings revealed a notable preference of ADAM 12 for the oligodendroglial over astroglial components. The results of immunohistochemistry are in accordance with the results obtained from the RT-PCR, which further demonstrated a mild difference concerning the mRNA concentration of ADAM 12 between similar grades of eight astrocytomas and eight oligodendrogliomas (namely four astrocytomas grade II versus four oligodendrogliomas grade II and four astrocytomas grade III versus four oligodendrogliomas grade III). Both cellular immunostaining for ADAM 12 and ADAM 12 mRNA content decrease with higher histologic grade of the tumour. Surprisingly, the latter parameter (ADAM12 mRNA) showed a significant opposite correlation to the degree of histologic tumour malignancy. From our data showing that ADAM 12 is highly expressed in, but not restricted to, oligodendrogliomas, we conclude that ADAM 12 immunohistochemistry may be a helpful tool in the diagnosis of brain tumours.

Pseudotrisomy 13: clinical findings and genetic implications.

The combination of holoprosencephaly, postaxial polydactyly, and normal karyotype has been termed pseudotrisomy 13 syndrome. Here, we report the prenatal diagnosis of pseudotrisomy 13 in three siblings suggesting autosomal recessive inheritance of this syndrome. Clinical overlap with hydrolethalus syndrome, Smith-Lemli-Opitz syndrome, Meckel syndrome, and Pallister-Hall syndrome is discussed.