Félix F. Cruz-Sánchez

Cerebellar Cortex Delayed Maturation in Sudden Infant Death Syndrome

The cerebellum shows afferent and efferent connections with intrinsic bulbar nuclei and plays an important role in respiration and cardiovascular control. Pathological and neurochemical abnormalities of bulbar nuclei including the arcuate nucleus have been postulated in sudden infant death syndrome (SIDS). Most of these abnormalities have been related to impairment in brain development. The cerebellar cortex has a well-documented evolution from fetal life until infancy; thus, it may be a very good model to assess brain maturation in SIDS. The present study was conducted to investigate changes in the cerebellar cortex in 19 SIDS cases compared with 12 age-related controls using morphological, quantitative, and statistical approaches. Five-μm paraffin sections from the midsagittal cerebellar vermis were stained with hematoxylin and eosin (H&E). Immunohistochemical staining was carried out using a polyclonal antiserum to glial fibrillary acidic protein (GFAP). Each case consisted of a 25-μm parallel paraffin section stained with H&E, where the cerebellar external granular layer (EGL) cell density was obtained in one field magnification (X 1,000) using an optical dissector procedure on the basis of a stereological method. A statistically significant high EGL cell density, mostly related to the presence of immature bipolar, elongated neuronal cells of the premigratory zone with hyperchromatic, oval or poor differentiated nuclei, was observed in SIDS. In these cases, EGL expressed immunoreactivity for GFAP mainly in the subpial and the postmitotic zone. These findings demonstrate a delayed or slower decline in the number of EGL neurons in SIDS, suggesting either a prolongation of the growth phase related to postnatal cerebellar foliation or a delay in inward migration. These results suggest that in SIDS there is delayed maturation of the cerebellar cortex/EGL, which may support the hypothesized cardiopulmonary control dysfunction, leading to death in a vulnerable period of postnatal development.

Differentiation in embryonal neuroepithelial tumors of the central nervous system

Ninety‐six embryonal neuroectodermal tumors were studied histologically and immunohistologically with a panel of antibodies including glial, neuronal, epithelial, mesodermal, and myelin markers. In 71 tumors there was glial and neuronal differentiation and expression both of an S (photoreceptor) antigen and vimentin. In five tumors there was only glial differentiation and in 20 tumors only neuronal differentiation. No reactivity for myelin and epithelial markers was found. Histologic and immunohistologic findings identified various degrees of differentiation in different tumors, which was bipolar (glial and neuronal) in most tumors and unipolar in the remainder. The authors suggest that their findings may be the result of normal or aberrant oncogenic differentiation, agreeing with the nomenclature of the World Health Organization classification for these tumors with and the inclusion of a category for ependymoblastoma.

STIFF-MAN SYNDROME WITH VACUOLAR DEGENERATION OF ANTERIOR HORN MOTOR NEURONS

Sirs: Stiff-man syndrome (SMS) is a rare neurological disorder characterized by progressive muscular rigidity predominantly of the trunk muscles with superimposed spasms [5, 10]. The pathophysiology of SMS is unknown. SMS could result from an imbalance between excitatory (catecholaminergic), and inhibitory (GABAergic) pathways controlling α-motoneuron activity [7]. The presence of autoantibodies against glutamic acid decarboxylase (GAD) in the serum and CSF of approximately 60% of SMS patients might be important in the pathophysiology of SMS since this enzyme catalyzes the conversion of glutamate to GABA [15]. Only a few postmortem studies of SMS patients have been reported, with findings that range from a normal nervous system to changes that overlap with those found in encephalomyelitis with rigidity, a syndrome that shares some clinical features with SMS [3, 4, 8, 9, 16]. We present a SMS patient with GAD autoantibodies who died 8 month after the onset of the disease, and whose autopsy showed unusual findings which may be relevant to establishing the physiopathological mechanism of this nosological entity. A 65-year-old man noticed painful deviation of his right foot in March 1996. He was admitted a few days later because of a marked increase in pain and dystonic posture with spasms of the right leg and lower trunk. The spasms were spontaneous, aggravated by stimuli, and accompanied by autonomic hyperactivity. Past medical history was significant only for non-insulin-dependent diabetes mellitus diagnosed at 50 years of age. On neurological examination there was equinus deformity of the right foot, and the leg was markedly rigid, particularly distally. Voluntary movements of the right leg and tactile stimuli often precipitated a painful spasm that occasionally affected the left leg. The rest of the neurological examination was normal. Electromyography revealed continuous motor unit activity at rest in both legs and lumbar paraspinal muscles, more prominent on the right side. The silent period in the tibialis anterior muscle of both legs was normal. Results of magnetic resonance imaging of the brain and spinal cord and of routine laboratory analysis were normal. The presence of GAD autoantibodies (GAD-Ab) were detected by immunohistochemistry, radioimmunoassay (3.225 U/ml in serum and 272 U/ml in CSF) and confirmed by immunoblot of GAD65 recombinant protein [12]. At limiting dilutions containing similar IgG levels, the CSF dilution still showed anti-GAD immunoreactivity when the serum dilution was negative. These data suggested an intrathecal synthesis of GAD-Ab. The patient also had pancreatic islet-cell and thyroglobulin antibodies. CSF examination was normal except for the presence of oligoclonal IgG bands, which were absent in the serum. The spasms greatly improved with diazepam and baclofen. One month later the patient was readmitted because the spasms became more severe and frequent, involving both legs, and he was unable to stand because of severe stiffness of both hips and thighs. Symptoms did not improve with increased doses of diazepam or the addition of tizanidine and phenytoin. Finally, treatment with intrathecal baclofen by implanted pump was initiated; this led to remission of the spasms and partial improvement in the rigidity. A LETTER TO THE EDITORS J Neurol (1999) 246 :858–860

Clinical and pathological study of two patients with progressive supranuclear palsy and Alzheimer's changes. Antigenic determinants that distinguish cortical and subcortical neurofibrillary tangles

Two cases with classical clinical manifestations of progressive supranuclear palsy (PSP) showed severe progressive dementia as an additional clinical feature. Neuropathological study demonstrated typical features of PSP in the brainstem. Additionally, histological criteria of Alzheimers disease (AD) were observed. A topographic and immunohistological study (with neurofilament subunit and Tau and Ubiquitin antibodies) of the distribution of neurofibrillary tangles (NFTs) was performed in order to compare the characteristics of NFTs from cortex and brainstem. NFTs from cortex were positive with all antibodies used and were predominantly distributed in cortical layers III and V and affected medium size neurons. Brainstem NFTs were positive only for neurofilament subunits and Tau. Cortical and brainstem NFTs showed immunohistological differences. Cortical NFTs in our two cases had a similar distribution as in control AD cases. On the basis of our observations we believe (1) that cortical tangles in our PSP cases are related to Alzheimers disease and (2) that the cortical NFTs of PSP and AD are morphologically and immunohistologically distinct. Mechanisms concerned with the production of cortical and brainstem NFTs in PSP and AD are discussed.

Neuronal Changes in the Substantia Nigra with Aging: A Golgi Study

In order to recognize substantia nigra neuronal changes occurring in aging, 20 human control brains from 13 males and 7 females with a mean age of 61 years (range 20 to 93 years) without neurological disease were examined using the Golgi method. A quantitative study of dendrites and dendritic spines was performed as well as a statistical analysis of obtained data. Parallel sections to the impregnated material were histologically and immunohistologically studied with the aim to identify possible neuronal cytoskeletal abnormalities. Results were compared to changes of substantia nigra reported in other conditions such as Parkinsons disease (PD) and methyl-4-phenylpyridine (MPTP) experimental toxicity. Three different substantia nigra neuronal types were observed. Morphological changes during aging consisted of distorted profile of the cell body and swelling and beading of dendritic branches. The quantitative assessment of changes observed in neuronal types showed a significant loss of dendrites and dendritic spines, especially in the oldest cases. These findings were similar to those previously described in other cerebral areas during aging, but a specific vulnerability of the largest substantia nigra neuronal type could be observed. Nodulations and beaded aspects of dendrites are reminiscent of those changes previously described in MPTP toxicity. Dendritic varicosities found in the oldest cases have also been found in dendrites of large substantia nigra neurons in PD. Cytoskeletal abnormalities have been described in PD but were not found in the present study. Therefore, other pathophysiological mechanisms different from the cytoskeletal compromise occurring in some neurodegenera-tive diseases should be involved in aging.

Enolase Activity and Isoenzyme Distribution in Human Brain Regions and Tumors

Abstract: The distribution of enolase (EC 4.2.1.11) activity and isoenzymes in various regions of human brain at different ages (from 23 weeks of gestation to 95 years) and in brain tumors has been determined. Total enolase activity increased in all regions with age. No significant differences were found in the relative proportions of αα‐, αγ‐, and γγ‐enolase isoenzymes in the various brain regions, determined by agarose gel electrophoresis. Type αα‐enolase was the predominant isoenzyme, and αγ‐enolase represented a substantial proportion of the total enolase activity. Astrocytomas, anaplastic astrocytomas, glioblastomas, and meningiomas possessed lower enolase activity than normal brain. Among astrocytic tumors, total enolase activity correlated with malignancy. Astrocytomas possessed the lowest and glioblastomas the highest enolase activity. All tumors possessed a higher proportion of αα‐enolase and a lower proportion of γγ‐enolase than the normal human brain. Among astrocytic tumors, glioblastomas were the tumors with the highest proportion of αα‐enolase and lowest proportion of γγ‐enolase.

Plasticity of the nigrostriatal system in MPTP-treated mice : a biochemical and morphological correlation

In order to compare the recovery capacity of the nigrostriatal system between adult and old mice, MPTP hydrochloride was administered to 48 BL/C57 male mice, which were sacrificed 24 h or 10 d after the second dose. The animals were divided into four groups, based on age (adult or old) and moment of sacrifice (24 h or 10 d). The detailed morphology of the neurons and the cellular processes of the substantia nigra pars compacta and the striatum were studied using the Golgi method. Immunostaining with a polyclonal glial fibrillary acidic protein antiserum using the peroxidase-antiperoxidase technique was performed to study the glial response. Striatal catecholamines were determined to correlate the biochemical data with the morphological changes. Significant neuronal changes of cellular processes were observed in substantia nigra pars compacta from all MPTP-treated mice, consisting of swelling and distortion of cellular bodies, discontinuous thickness, and nodulations of dendrites with baded aspect. Axons showing focal swelling and nodulations were also found in the neuropil of silver impregnated striata. Marked gliosis with reactive astrocytes in substantia nigra and striatum from all the old treated mice was found. Recovery was only observed in adult mice sacrificed 10 d after withdrawal. At this time, all the old MPTP-treated mice showed marked neuronal changes and a persistent marked gliosis. As expected, 24 h after the MPTP treatment, a marked depletion of dopamine and its metabolites was found in all the animals; at 10 d, the depletion was partially reversed in the adult group. These data correlate well with the observed morphological changes. Our results suggest that, in mice, deterioration of dendritic and axonal neuropil constitutes a significant causal factor of the MPTP neurotoxicity. These features are related to the age of the animals and the integrity of the plasticity phenomena, which appear to be altered in old mice.

Brain lesions following combined treatment with methotrexate and craniospinal irradiation

SummaryEight patients with meningeal seeding by carcinoma or lymphomas were treated with intravenous (i.v.) and/or intrathecal (i.th.) Methotrexate (MTX). Seven patients received additional craniospinal irradiation and in all seven a fatal encephalopathy developed.On the bases of clinical and morphological findings we identified an acute and a delayed form of encephalopathy and concluded that the concurrent administration of Methotrexate and of craniospinal irradiation increases considerably the risk of brain damage.

Immunohistological study of grumose degeneration of the dentate nucleus in progressive supranuclear palsy

The grumose degeneration observed in the dentate nuclei of 7 cases of progressive supranuclear palsy (PSP) was studied with a panel of antibodies which included 2 neurofilaments, Tau and ubiquitin. Dentate nucleus neurons were negative with all antibodies except ubiquitin which showed a slightly positive homogeneous pattern of staining. The amorphous material surrounding swollen or normal neurons was strongly positive for neurofilament and subunits and numerous torpedoes were observed in the granular layer of the cerebellar cortex. Our results confirm that grumose degeneration consists in degeneration of terminal axons of Purkinje cells in the dentate nucleus. The positivity of dentate nucleus neurons for ubiquitin may support the concept of synaptic dysfunction between Purkinje cells and dentate nucleus neurons.

Aging and the nigro-striatal pathway

Aging is associated with a progressive impairment in motor function. This feature, together with the decline in mental function, could be considered as an aging syndrome which may finally compromise the ability of the elderly to maintain an active, independent life-style. In the present paper a wide variety of morphological aspects, which have been classically related to brain aging and others such as cytoskeletal changes, the role of growth factors and molecular changes, will be reviewed focusing on aging of the nigrostriatal pathway. In addition to sharing features of aging common to other structures, it is likely that the nigrostriatal pathway has specific characteristics derived from its particular molecular characteristics and/or from a selective vulnerability to aging. To gain further insight into the aging syndrome, the acquisition of rigorous criteria for selecting control cases is paramount. The improvement of methods for the preservation of human tissue is also crucial.