α-Synuclein-containing glial cytoplasmic inclusions (GCIs) originating in oligodendrocytes are the characteristic hallmark for neuropathological diagnosis of multiple system atrophy (MSA). α-Synuclein can be degraded either by the proteasomal machinery or by autophagy, a lysosomal pathway which involves the formation of autophagosomes. The autophagosome takes up polyubiquitinated proteins via the autophagosomal protein LC3 and the ubiquitin binding protein p62. In the present study, neuropathological examination of seven MSA cases revealed that LC3-immunoreactivity is found to be associated with α-synuclein-positive GCIs. These are also prominently stained by antibodies against p62 and ubiquitin, indicating that the autophagic pathway is upregulated during pathogenesis, which might be due to a persistent downregulation of proteasomal activity. To further address this question in a cellular context, we have investigated whether proteasomal inhibition in cultured rat brain oligodendrocytes promotes the recruitment of LC3 and p62 to protein aggregates. The data show that the autophagic marker LC3-II is upregulated and LC3 is recruited to the growing protein aggregates in cultured oligodendrocytes when the proteasome is impaired. However, aggregated proteins remain in the oligodendroglial cytoplasm and cannot be cleared efficiently. In conclusion, autophagy and the ubiquitin proteasome system are closely connected, and the presence of LC3-positive vesicles in GCIs indicates that macroautophagy participates in MSA pathogenesis.

The presence and distribution of apoptotic cell death in multiple system atrophy (MSA) and morphologically related diseases were investigated by means of a modified terminal deoxynucleotidyl transferase-mediated nick end labeling method, comparing their distribution with that of glial cytoplasmic inclusions, immunohistochemically demonstrated bcl-2 protein, bax protein, CD95, TNFalpha, and p53-protein expression, as well as activated microglia. Apoptosis occurred almost exclusively in oligodendrocytes in multiple system atrophy and its general distribution was comparable to the already known oligodendroglial pathology in this disorder. Additionally, in about a quarter of glial cytoplasmic inclusions, there was upregulation of bcl-2-protein and coexpression with ubiquitin, suggesting a final attempt of involved cells to counteract apoptotic cell death. Bax protein was also demonstrated in oligodendroglial cells. A significant neuronal apoptosis was not observed in MSA; these cells might be destroyed secondarily to oligodendroglial apoptosis by necrosis or other forms of programmed cell death. These results emphasize the central role of oligodendroglial pathology in multiple system atrophy, making this disease unique among neurodegenerative diseases.

We investigated the age-related location, gender distribution, and histology of 107 brain tumors in children under 4 years of age seen in our department between 1984 and 1997. The male-to-female ratio was 1.4 (62/45 cases) with a prevalence of supratentorial tumors (60/47 = 1.3); the main histological entity was astrocytoma (33.6%), followed by ependymoma (14.0%). In the 1st year of life 22 cerebral neoplasms became clinically apparent. A higher ratio for supratentorial tumors was revealed (17/5 = 3.4), but without gender preference, and primitive neuroectodermal tumors (PNET) were the most frequent (5/22). In the 2nd year 25 tumors were found. The male-to-female ratio was 1.5 (15/10) and the supratentorial-to-infratentorial ratio, 1.1 (13/12). The two most common entities were astrocytoma and ependymoma (6 cases each). In addition, a survey of previously published investigations into this subject was performed and a compilation of data on 1960, 545 and 1084 tumors in children below the age of 1, 2 and 4 years, respectively, was prepared, which makes it the most extensive review of brain tumors of infancy and early childhood yet undertaken.

Prostaglandins (PGs) are critical mediators of physiologic processes and inflammation. They are produced by two different isoforms of the cyclooxygenase (COX) enzyme, namely COX-1 and COX-2. In particular COX-2 was demonstrated to be crucial for PG-synthesis in inflammation. Recently, inhibition of COX-2 was shown to prevent the loss of motor neurons in a model of amyotrophic lateral sclerosis (ALS). Furthermore, spinal COX-2 expression was shown to be increased in transgenic mice that produce an ALS-like syndrome. Therefore, we investigated the expression of COX-1 and COX-2 in the spinal cord of seven human sporadic ALS patients by means of immunohistochemistry. Specimens from seven patients without any neurological disease served as controls. COX-2 expression was dramatically increased in the spinal cord of patients with ALS. Its protein was found in motor neurons, interneurons and glial cells. Statistical analysis showed a significantly higher expression of COX-2 in ALS for both neurons and glia. In contrast, COX-1 expression was predominantly confined to microglia and no apparent difference was detected between controls and ALS. In addition, we studied the concentration of prostaglandin E2 (PG E2) as a marker for COX activity in the cerebrospinal fluid of nine patients diagnosed for ALS and compared the results with those from nine patients without motor neuron disease. PG E2 levels were markedly increased in ALS cases (45.8 +/- 35.1 pg/mL) compared to the non-ALS specimens (15.8 +/- 3.7 pg/mL). The results of our study corroborate a potential role for COX-2 in the pathogenesis of motor neuron death in ALS. Selective COX-2 inhibition might therefore offer a new possibility in the treatment of human ALS. However, to determine the exact role of COX-2 in human ALS will require further research.

We present the first case of cerebral splenosis, occurring in a 20-year-old man 15 years after posttraumatic splenectomy. He became symptomatic through seizures and was operated on for suspected meningioma of the right occipital pole. Histologic evaluation of the lesion revealed splenic tissue with matching immunohistochemical results. Because no penetrating head injuries were reported at the time of trauma, a hematogenous spread of splenic tissue has to be assumed.