Acute methotrexate-induced encephalopathy--causal relation to homozygous allelic state for MTR c.2756A>G (D919G)?

Methotrexate (MTX) is widely used in the treatment of hematological diseases. The typical side-effects of high-dose MTX chemotherapy on the CNS range from asymptomatic white matter changes to severe CNS demyelination. MTX neuro - toxicity has been described to be associated with homocysteine and folate levels as well as genetic variants affecting methionine metabolism. Here we describe a case of severe, acute MTX-induced encephalopathy in a patient who was found to be homozygous for the rare missense variant methionine synthase (MTR) c.2756A>G (D919G), which may have modified the effect of MTX on homocysteine metabolism. This finding encourages further studies to determine to what extent the individual conditions of folate and methionine metabolism influence the effects or side-effects of MTX treatment.

Role of pontine nuclei damage in smooth pursuit impairment of progressive supranuclear palsy: a clinical-pathologic study.

We performed a quantitative study of the pontine nuclei in the basis pontis and a semiquantitative study of extrapontine structures involved in smooth pursuit in four patients with severe impairment of horizontal smooth pursuit and histopathologically confirmed diagnosis of progressive supranuclear palsy (PSP). There were only slight changes in the extrapontine structures involved in smooth pursuit, but there was a significant neuronal loss--massive in three patients and mild in one patient--in all nuclei of the basis pontis. Our results suggest that degenerative lesions affecting the pontine nuclei are largely responsible for the horizontal smooth pursuit impairment in PSP.

Cholinergic markers in ALS spinal cord.

We analyzed binding sites for quinuclidinyl benzilate (QNB) and hemicholinium-3 (HC-3) by quantitative slice autoradiography and the activities of choline acetyltransferase (ChAT) and acetylcholinesterase (AChE) in spinal cord of 5-7 patients with amyotrophic lateral sclerosis (ALS). In the ventral horn, QNB binding sites were markedly reduced (38% of controls; P less than 0.001), whereas HC-3 binding sites were only moderately affected (76%, P less than 0.01). Losses in cholinergic marker enzymes were inconsistent. The loss of muscarinic binding sites in the ventral horn was the most reliable cholinergic disease marker in ALS.

Amyotrophic lateral sclerosis: changes of noradrenergic and serotonergic transmitter systems in the spinal cord.

Noradrenaline (NA), dopamine (DA), serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) were measured in discrete subdivisions of cervical, thoracic and lumbar spinal cord segments obtained at autopsy of 4 subjects with amyotrophic lateral sclerosis (ALS) and 7 control patients. NA concentrations in thoracic and lumbar spinal cord of ALS patients were 2- to 4-fold higher compared with values obtained in control patients. 5-HT levels were unchanged at the cervical and thoracic level and slightly above normal in lumbar spinal cord, while the concentration of 5-HIAA was lowered in cervical and thoracic, but within the control range, in lumbar spinal cord. As a result, the molar ratios of 5-HT/5-HIAA were increased at all spinal levels in ALS. No difference in spinal DA concentration was found between ALS and control patients. The changes in the noradrenergic and serotonergic transmitter systems reported here most probably reflect a decreased release of these transmitter substances in ALS spinal cord. Since lack of the facilitatory monoaminergic influence would necessitate an increase in the excitatory, potentially neurotoxic glutamatergic input onto the motoneurones, we hypothesize that this could contribute to the progressive loss of spinal motoneurones in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis: glutamate dehydrogenase and transmitter amino acids in the spinal cord.

Measurements were taken of the activity of glutamate dehydrogenase (GDH) and the levels of transmitter amino acids in anatomically dissected regions of cervical and lumbar spinal cord in eight patients dying with amyotrophic lateral sclerosis (ALS) and in 11 neurologically normal controls. GDH activity was considerably increased in lateral and ventral white matter and in the dorsal horn of the ALS cervical spinal cord, but normal in the ventral horn and the dorsal columns. Similar, although less pronounced, GDH changes were found in the lumbar enlargement. The mean concentrations of aspartate and glutamate were reduced in all regions of ALS spinal cord investigated. Taurine concentrations were significantly increased in several subdivisions of cervical spinal cord, but normal in lumbar regions. Glycine levels were significantly reduced in lumbar ventral and dorsal horns. There was no striking change in spinal cord GABA levels in our ALS patients. It is suggested that the reduced levels of glutamate and aspartate as well as the elevated GDH activity in the spinal cord of ALS patients may reflect an overactivity of the neurons releasing these potentially excitotoxic amino acids and thus may be causally related to the spinal neuro-degenerative changes characteristic of ALS.

Progressive supranuclear palsy: loss of choline-acetyltransferase-like immunoreactive neurons in the pontine reticular formation.

We performed a quantitative immunocytochemical study using a polyclonal antibody directed against choline acetyltransferase (ChAT) in the lower pontine reticular formation in four control subjects and three patients with progressive supranuclear palsy (PSP). In the normal brains, there was detectable ChAT-like immunoreactivity in the nucleus papillioformis, a precerebellar reticular nucleus, and in the nucleus pontis centralis caudalis. In PSP patients, the mean estimated total number of ChAT-like immunoreactive cells was 54% of controls in nucleus papillioformis and 40% of controls in nucleus pontis centralis caudalis. The demonstration of ChAT-like immunoreactivity in nucleus papillioformis is consistent with studies suggesting an extrinsic cholinergic innervation of the cerebellar cortex. Loss of cholinergic cells in nucleus pontis centralis caudalis that corresponds largely to the paramedian pontine reticular formation may be related to disturbances of horizontal saccades in PSP patients.

Technetium-99m-d,1-hexamethylpropyleneamine oxime (HMPAO) uptake and glutathione content in brain tumors.

Technetium-d, HMPAO SPECT was performed in 70 patients suffering from intracerebral tumors of various histologic types (glioma n = 30, meningioma n = 19, metastases n = 10, angioma n = 3, neuroma n = 2, lymphoma n = 2, neurocytoma n = 1, epidermoid n = 1, gliosis n = 1, cholesteatoma n = 1). Tumor classification was histologically verified in all subjects except in two cases with inoperable angiomas. SPECT was performed under resting state conditions with a dual-head rotating camera (SIEMENS ZLC 37) following intravenous injection of 18-25 mCi 99mTc-d, 1-HMPAO. Regional tracer deposit was expressed in terms of a cerebellar index (CBI). Significantly higher regional HMPAO uptake was found in meningiomas when compared with gliomas of different malignancy (ANOVA p less than 0.05). Within gliomas, regional uptake increased with malignancy (n.s.). In 23 patients, a total of 32 tumor specimens were obtained for histochemical analysis of glutathione (GSH) content using high-pressure liquid chromatography. A significant correlation (least square method, p less than 0.001) between CBIs and GSH values was found, supporting the hypothesis that GSH is the predominant factor for the conversion of the lipophilic complex to hydrophilic derivates.

Differential vulnerability of cholinergic projections to the mediodorsal nucleus of the thalamus in senile dementia of Alzheimer type and progressive supranuclear palsy.

The cholinergic innervation of the mediodorsal nucleus of the thalamus, which is thought to originate primarily in the laterodorsal tegmental nucleus and the substantia innominata, was studied by acetylcholinesterase histochemistry and immunohistochemistry with a polyclonal antiserum against human choline acetyltransferase on autopsy tissue from eight control subjects, five patients with progressive supranuclear palsy and four patients with senile dementia of Alzheimer type. In controls, cholinergic innervation of the mediodorsal nucleus of the thalamus was distributed heterogeneously in densely labelled patches surrounded by less heavily stained matrix. In patients with progressive supranuclear palsy, the density of choline acetyltransferase-positive varicosities decreased by 75% in the matrix and 60% in the patches. The number of choline acetyltransferase-positive cell bodies decreased by 84% in the laterodorsal tegmental nucleus, but more moderately (-33%) in the substantia innominata. In patients with senile dementia of Alzheimer type, choline acetyltransferase-positive varicosities decreased by 34% in the matrix, but 46% in the patches. Choline acetyltransferase-labelled cell bodies were spared in the laterodorsal tegmental nucleus, whereas severe loss (-80%) was observed in the substantia innominata. These results suggest that cholinergic innervation of mediodorsal nucleus matrix derives mainly from the laterodorsal tegmental nucleus and mediodorsal nucleus patches from the substantia innominata. Differential loss of innervation to the matrix and patches in progressive supranuclear palsy and senile dementia of Alzheimer type may in turn differentially affect mediodorsal nucleus innervation of the frontal cortex, resulting in dissimilar symptomatologies.

Mesencephalic cholinergic nuclei in progressive supranuclear palsy.

Using an antibody against choline acetyltransferase (ChAT), mesencephalic cholinergic cell nuclei were studied in autopsy material from 3 cases of progressive supranuclear palsy (PSP) and 4 controls. ChAT-immunoreactive neurons were quantified in sections that spanned the rostrocaudal extent of each nucleus. In PSP, there was a significant decrease in the number of neurons with detectable immunoreactivity for ChAT in and adjacent to the central gray substance in the following nuclei: the nucleus of Edinger-Westphal (69%); the rostral interstitial nucleus of the medial longitudinal fasciculus (97%); the interstitial nucleus of Cajal (78%). A cell loss was also evident in a group of neurons found in the deep layers of the superior colliculus (93%). In contrast, the estimated number of ChAT-immunoreactive cell bodies in cranial nerves III and IV, in the mesencephalic reticular formation, and in the parabigeminal nucleus was not different from that of controls. The results are compatible with the notion that, in PSP, there is a regionally selective destruction of cholinergic neurons.

Catecholaminergic systems in the medulla oblongata in parkinsonian syndromes: a quantitative immunohistochemical study in Parkinson's disease, progressive supranuclear palsy, and striatonigral degeneration.

We investigated tyrosine-hydroxylase (TH)-immunoreactive neurons in the medulla oblongata corresponding to the A1 and A2 cell groups in autopsy tissue of patients with Parkinson's disease (PD) (n = 3), progressive supranuclear palsy (PSP) (n = 3), striatonigral degeneration (SND) (n = 2), and in controls (n = 4). The estimated total number of TH-positive neurons in the A1 and the A2 regions was normal in PD and PSP patients. The sparing of medullary catecholaminergic cells in PD and PSP may be related to their minor degree of melanization and the possibility that intermediate compounds associated with the oxidative catabolism of norepinephrine and epinephrine may be less cytotoxic than those generated by degradation of dopamine. Patients with SND showed a marked loss of TH-immunoreactive cells in the A1 and the A2 groups, which may contribute to the impairment of vasomotor control characteristic of the disease.