Neurodesarrollo frente a neurodegeneración: hipótesis neuroanatómicas de la esquizofrenia / Neurodevelopment versus neurodegeneration: neuroanatomical hypothesis of schizophrenia

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Manifestaciones psiquiátricas como inicio de una degeneración corticobasal / Psychiatric manifestations as the debut of a corticobasal degeneration

La degeneración corticobasal (DCB) es un proceso neurodegenerativo poco frecuente, de etiología desconocida y de curso progresivo, cuya edad de inicio se sitúa entre los 60 y 70 años. El síndrome clínico suele caracterizarse por signos de disfunción cortical y trastornos del movimiento, característicamente asimétricos. Las descripciones más recientes sugieren que los síntomas demenciales son probablemente la forma de presentación más común de la DCB. Debido a la heterogeneidad en su presentación clínica y a las diferentes formas de inicio, proponemos incluir a la DCB en el diagnóstico diferencial de aquellos pacientes que se presenten con un deterioro cognitivo lentamente progresivo asociado a síntomas afectivos característicos. En este trabajo describimos un caso de DCB que se inicia con sintomatología psiquiátrica aislada (AU)

Expression of c-Jun protein in degenerating retinal ganglion cells after optic nerve lesion in the rat.

Axonal lesions to the optic nerve (ON) induce c-Jun expression in retinal ganglion cells (RGCs) of the rat in vivo. Detailed investigations using retrograde tracers, and double labeling studies for c-Jun and regeneration-associated factors, such as the growth-associated protein GAP-43, have suggested that this upregulation of c-Jun is part of a cell body response in an abortive attempt of affected RGCs to survive and regenerate an axon. On the other hand, prolonged expression of c-Jun protein has in several paradigms of neurodegeneration been linked to the induction of apoptotic cell death. In the present study, we examined the time course and subcellular localization of c-Jun protein by immunocytochemistry on retinal sections after optic nerve crush and carried out double labeling for c-Jun protein and DNA strand breaks to detect apoptosis on the same sections. Several days after ON lesion, a subpopulation of RGCs was detected in which c-Jun protein was not confined to the nucleus, but also located in the cytoplasm. In addition, RGCs were seen that displayed morphological signs of apoptosis, DNA strand breaks, and c-Jun immunoreactivity at the same time. Therefore, c-Jun expression is not confined to intact or regenerating ganglion cells, but also occurs in cells that are destined to die. Our results suggest that the decision to undergo either fate depends on additional signaling events that modulate the transcriptional actions of c-Jun.

Neuronal degeneration by suicide transport following injection of volkensin into rat cerebral cortex.

We have examined the time course of neurodegeneration in subcortical nuclei and other cortical areas known to project to the rat parietal cortex, following unilateral injection of the suicide transport agent, volkensin, into the cortex of one side. Degenerating neurons, visualized by Gallyas silver staining were most prominent 21 days after injection. At this time darkly staining neurons were present in nuclei and areas known to project to the injected cortical area but not in other sites. Affected subcortical nuclei included the ipsilateral ventral thalamus and intralaminar nuclei, the basal nucleus of Meynert and claustrum of the same side, and the dorsal median raphé nucleus of both sides. Within the cortex degenerating pyramidal neurons were visible in the contralateral parietal cortex and in the frontal cortex of the same side. The distribution of degenerating cells is in agreement with the conclusion that only neurons projecting to the injection site were affected. The time course of the appearance of the degeneration and its distribution are in keeping with axonal transport rather than spread by diffusion of the toxin. Neuronal counts in Nissl-stained sections of the contralateral SMI confirmed significant neuronal loss 28 days after injection. In situ hybridization studies using an oligonucleotide probe directed against GAD mRNA and counts of GAD mRNA-positive neurons in the contralateral cortex confirmed that this population of cortical interneurons, which do not project to the injection site, were unaffected.

Motonuclear changes after cranial nerve injury and regeneration.

Little is known about the mechanisms at play in nerve regeneration after nerve injury. Personal studies are reported regarding motonuclear changes after regeneration of injured cranial nerves, in particular of the facial and oculomotor nerves, as well as the influence that the natural molecule acetyl-L-carnitine (ALC) has on post-axotomy cranial nerve motoneuron degeneration after facial and vagus nerve lesions. Adult and newborn animal models were used. Massive motoneuron response after nerve section and reconstruction was observed in the motonuclei of all nerves studied. ALC showed to have significant neuroprotective effects on the degeneration of axotomized motoneurons. Complex quantitative, morphological and somatotopic nuclear changes occurred that sustain new hypotheses regarding the capacities of motoneurons to regenerate and the possibilities of new neuron proliferation. The particularities of such observations are described and discussed.

Detection of pyramidal tract lesions in amyotrophic lateral sclerosis with magnetization-transfer measurements.

PURPOSE: To determine the presence of small lesions in the pyramidal tract in patients with amyotrophic lateral sclerosis (ALS) by using magnetization-transfer (MT) measurements and MR imaging. METHODS: MT ratios (MTRs) were measured in the posterior limb of the internal capsule in nine patients with ALS and in nine healthy volunteers. RESULTS: The mean value of MTRs (%) in patients with ALS was 15.76 +/- 1.48, while that of the control subjects was 19.83 +/- 1.54. The difference was statistically significant. CONCLUSIONS: MT measurements are useful for detecting abnormalities associated with degeneration of the pyramidal tract in patients with ALS.

Neurodegeneration and gliosis in transgenic mice overexpressing a carboxy-terminal fragment of Alzheimer amyloid-beta protein precursor.

In order to study the properties of beta-amyloid in vivo, we generated a total of 28 transgenic founder mice that harbored the gene for the 17-amino acid signal sequence and the 99-amino acid carboxy-terminal fragment (CTF) of the human amyloid-beta protein precursor (beta APP) linked to the cytomegalovirus enhancer and chicken beta-actin promoter. Two of these founders, termed 0304 and 0809, exhibited decreased behavioral activity with gliosis and neurodegeneration in the hippocampus at 2.5 and 9 months of age. Both mice had also decreased levels of synaptophysin, a presynaptic marker, but no evidence for beta-amyloid deposition in their brains. Neurodegeneration in the hippocampus was transmitted to the offspring of mouse 0304, although the frequency was low (5 of 44 mice examined) and the time of onset of the disorder was rather later than that in the founder mouse. This is probably due to reduced levels of the transgene-derived products in the offspring of mouse 0304. The 0809 line failed to produce its offspring. The other remaining transgenic founders appeared normal and had lesser amounts of the CTF mRNA and protein in their brains than did 0304 and 0809 founders, though some mice died in earlier stages or exhibited hydrocephalus. These findings suggest that overexpression of the CTF of human beta APP has the potential to elicit neurodegeneration in vivo without appreciable production of beta-amyloid fibrils.

Global ischemia induces downregulation of Glur2 mRNA and increases AMPA receptor-mediated Ca2+ influx in hippocampal CA1 neurons of gerbil.

Transient, severe forebrain or global ischemia leads to delayed cell death of pyramidal neurons in the hippocampal CA1. The precise molecular mechanisms underlying neuronal cell death after global ischemia are as yet unknown. Glutamate receptor-mediated Ca2+ influx is thought to play a critical role in this cell death. In situ hybridization revealed that the expression of mRNA encoding GluR2 (the subunit that limits Ca2+ permeability of AMPA-type glutamate receptors) was markedly and specifically reduced in gerbil CA1 pyramidal neurons after global ischemia but before the onset of neurodegeneration. To determine whether the change in GluR2 expression is functionally significant, we examined the AMPA receptor-mediated rise in cytoplasmic free Ca2+ level ([Ca2+]i) in individual CA1 pyramidal neurons by optical imaging with the Ca2+ indicator dye fura-2 and by intracellular recording. Seventy-two hours after ischemia, CA1 neurons that retained the ability to fire action potentials exhibited a greatly enhanced AMPA-elicited rise in [Ca2+]i. Basal [Ca2+]i in these neurons was unchanged. These findings provide evidence for Ca2+ entry directly through AMPA receptors in pyramidal neurons destined to die. Downregulation of GluR2 gene expression and an increase in Ca2+ influx through AMPA receptors in response to endogenous glutamate are likely to contribute to the delayed neuronal death after global ischemia.

Degeneration of cocultures of spinal muscular atrophy muscle cells and rat spinal cord explants is not due to secreted factors and cannot be prevented by neurotrophins.

We have shown recently that cocultures of muscle cells from infantile spinal muscular atrophy (SMA) patients innervated by motoneurons of normal rat spinal cord explants undergo a degeneration process, suggesting that muscle may play a role in this atrophy, which previously has been considered to be a pure motoneuron disease. Conditional media of SMA cocultures did not affect control healthy nerve muscle cocultures. Conversely, conditioned media of control cocultures were unable to prevent degeneration of SMA cocultures. Moreover, neurotrophic factors, thought to be of help in motoneuron disease treatment, did not protect SMA cocultures from premature death. Our results suggest that the abnormal phenotype observed in nerve-muscle coculture (1) is not due to the release of a toxic factor nor to the lack of a secreted survival factor, and (2) does not respond to neurotrophin treatment.

Age-related neuronal loss in the nucleus centralis superior of the rhesus monkey.

The effect of age on the number of neurons in the nucleus centralis superior (NCS) was determined in 11 behaviorally tested rhesus monkeys of 7-32 years of age, There was a significant age-related decrease in both cell packing density and in the total number of neurons. This decrease in number of neurons appeared to effect two different populations of cell in the NCS, one of which corresponded in size to the serotonergic cells in this nucleus and the other to a smaller-sized cell. Comparisons of the changes in the cell packing density with behavioral testing, showed significant correlations with the overall test performance as well as with individual tests of memory function and of executive system functions. These findings suggest that neuronal loss in the NCS may play a significant role in mediating cognitive changes seen in normal aging.

Rediscovering an old friend, IGF-I: potential use in the treatment of neurodegenerative diseases.

Insulin-like growth factor-I (IGF-I) is a pleiotropic protein that acts on many tissues and organs. As it is one of the major trophic factors in the circulation, its actions in peripheral tissues are well established. It has been used for the treatment of several diseases, including growth deficiency, osteoporosis, catabolic disorders and diabetes. Recent evidence supports the significance of IGF-I in the maintenance of the integrity and homeostasis of the nervous system. The widespread distribution of its receptor allows IGF-I to affect the survival of numerous populations of neurones and glial cells in both the CNS and the PNS. Most recently, a clinical trial has revealed the beneficial effects of IGF-I in amyotrophic lateral-sclerosis (ALS), a degenerative disease of the motoneurones. We review briefly here experimental and clinical information that suggests the potential usefulness of IGF-I in the treatment of certain neurodegenerative diseases, including ALS, Alzheimer's disease, various neuropathies and brain trauma. The rather unique propensity of IGF-I to act on a variety of neuronal cells might provide a general means of reducing or slowing down neuronal losses that occur following various brain insults.

MR appearance of trigeminal and hypoglossal motor denervation.

PURPOSE: To illustrate and describe the appearance of both long-standing and relatively recently occurring motor denervation of the hypoglossal nerve and of the third (mandibular) division of the trigeminal nerve (V3), with emphasis on findings particular to MR imaging. METHODS: Findings from 11 patients with V3 denervation and from seven patients with hypoglossal denervation resulting from a variety of abnormalities were reviewed retrospectively. The motor denervation appearance and functional compromise of the affected musculature are described in terms of the chronicity of the denervation process. RESULTS: The appearance of V3 and hypoglossal motor denervation varies with the chronicity of the process. Long-standing denervation results in extensive fatty replacement and a decrease in the size of the affected musculature. Relatively recently occurring denervation results in abnormal contrast enhancement and edemalike signal changes in the denervated musculature. Fatty replacement was observed acutely in hypoglossal denervation but did not manifest until the subacute stage in V3 denervation. Increased volume of the denervated musculature may also accompany acute denervation signal changes. CONCLUSION: V3 and hypoglossal denervation have a variable appearance depending on the chronicity of the process. Recognition of MR imaging patterns of denervation may allow earlier diagnosis of a denervating lesion and may help to distinguish denervation from similar-appearing processes, such as infection or neoplasia.

Microglia responses in the CNS following sciatic nerve transection in C57BL/Wld(s) and BALB/c mice.

The present study employed C57BL/Wld(s) mice to investigate whether a delay in microglia reaction would occur similar to the delay that occurs in macrophage response after sciatic neurectomy. The results were compared with control BALB/c mice. The observations showed that in both strains of mice there was no delayed microglia response around lesioned motoneurons and around the central processes of the dorsal root ganglion cells after sciatic neurectomy in the adult. The increased Mac-1 staining appeared as early as 1 day postoperation (dpo). This indicates that microglial cells and macrophages respond to different signals generated by neurectomy. In both strains of mice, the number of microglia in the neonate was much less than that in the adult and the increase in Mac-1 staining was detectable only at 3 dpo in both strains of mice. A significant loss of motoneurons was detected after sciatic neurectomy in the neonate. However, there were no significant differences in the mean percentages of motoneuron loss between the two strains of mice at 5, 10, and 15 dpo. It is surmised that the lack of an adequate number of mature microglia in the neonates and their tardy expression of CR3 antigenicity may contribute to the motoneuron loss.

Apoptosis in neurodegenerative disorders.

We review here recent reports pertaining to the issue of apoptosis in neurodegenerative diseases. Tissue culture models, animal models and human pathological studies are discussed. At present, there is supportive, but not definitive, evidence for apoptosis in a number of neurodegenerative disorders.

Neuropsychology and advances in memory function.

Recent developments in the functional and neural bases of several aspects of memory are described including long term cortical memory storage, the transition from immediate to permanent memory mediated by medial temporal structures, working memory, memory retrieval, and implicit memory. These are linked to current data on the nature of anterograde and retrograde amnesia in the degenerative diseases, and also to issues in the clinical diagnosis of memory impairments. Understanding the bases of memory can inform the diagnosis of memory impairments in degenerative diseases, and the patterns of impairment seen in the degenerative diseases can help contribute to knowledge of the mechanisms of normal memory.

[Coma-associated neuropathy]. / Komaassoziierte Neuropathie.

To evaluate signs of peripheral nerve dysfunction, over a period of 31 months all patients treated for more than 14 days in our intensive care unit (ICU) had clinical and electrophysiological examination. The results of 78 patients were analysed: 53 had diseases of the central nervous system, 25 suffered from general cerebral hypoxia, mainly after cardiopulmonary reanimation. 54 showed bilateral signs of denervation activity, additionally 10 patients had fibrillation potentials unilateral to their spastic hemiparesis. 19 patients had denervation potentials only in proximal muscles of the upper limbs. Generalized denervation activity developed mainly after septic organ failure. On the other hand 35 patients showed denervation potentials already between day 14 and 21, suggesting an affection of peripheral nerve function in the first week of ICU treatment. Time course, pattern of distribution and frequency of electrophysiological abnormalities are not generally consistent with alterations of nutrition, metabolism or hypoxia in the course of ICU treatment. Clinical signs of peripheral nerve dysfunction were present in 40% of the patients showing denervation in the EMG.

Diverse effects of Purkinje cell loss on deep cerebellar and vestibular nuclei neurons in Purkinje cell degeneration mutant mice: a possible compensatory mechanism.

The genetic defect in the Purkinje cell degeneration (PCD) mutant mouse completely disrupts the cerebellar corticonuclear connection through intrinsic action on the final integrating unit of the cerebellar cortex, the Purkinje cell (PC). The postsynaptic target neurons of the PC in the deep cerebellar nuclei (DCN) and the vestibular nuclei (VN) are denervated by this PC loss by more than two-thirds of their total y-aminobutyric acid (GABA)-ergic innervation. This massive disinhibition should be reflected in an increased and thus electrophysiologically detectable activity of the respective neurons. To address this question, we performed extracellular recordings of PCD mutant and corresponding wild-type VN neurons under sinusoidal vestibular stimulation. The response amplitudes (neuronal response to sinusoidal rotation) of VN neurons in PCD mutant mice showed a decrease rather than the expected increase. The same was true for the mean resting rate, whereas the phase relationships were unaffected for the most part. This finding is a clear indication of compensatory reactions in the VN that substitute quantitatively for the lost PC inhibition. The expression of the calcium-binding protein parvalbumin (Parv) is assumed to correlate with the physiological activity of neurons, and Parv is localized predominantly in inhibitory neurons. Because inhibitory inter- or projecting neurons are also largely denervated by the PC loss, Parv immunocytochemistry also was performed. In wild-type mice, only very few Parv-immunopositive (Parv+) somata were present in the VN, and none were present in the DCN. In PCD mutant mice, a substantial number of Parv+ neuronal somata were visible in the VN, and even more were visible in the DCN. This increase in Parv+ somata in PCD mutant mice is closely related temporally and spatially to the extent of denervation caused by the PCD. Parv+ neuronal somata are first visible in the dentate nucleus at postnatal day (P) 24 and appear in the other cerebellar and VN up to P29. Direct double labeling of Parv and GABA and of Parv and glycine reveals that the large majority of Parv + neurons colocalize GABA, glycine, or both inhibitory transmitters. These results show that neurons that are postsynaptic to cerebellar PC develop diverse physiological and biochemical reactions in the course of genetically determined PCD. These mechanisms are likely to contribute to the phenotypically mild motor disturbances observed in PCD mutant mice.

Selective induction of c-Jun and NGF in reactive astrocytes after cholinergic degenerations in rat basal forebrain.

Cholinergic basal forebrain neurons are the major source of cortical cholinergic innervation. The number of these neurons is regulated by the availability of nerve growth factor (NGF) during development while in adulthood their cholinergic activity is modulated by NGF. In previous studies we have shown that cholinergic immunolesions of basal forebrain neurons increase local immediate early gene expression and NGF synthesis in the regions of degeneration. In this study we identify the cellular source of c-Jun and NGF expression using dual immunolabeling of c-Jun and NGF in combination with neuronal and glial markers. We demonstrate that both c-Jun and NGF are exclusively expressed in reactive astrocytes but not in microglia or in GABAergic basal forebrain neurons. These observations support the hypothesis that reactive astrocytes synthesize neurotrophic substances in vivo in response to neuronal degeneration in the basal forebrain.

Progressive formation of neuritic plaques and neurofibrillary tangles is exponentially related to age and neuronal size. A morphometric study of three geographically distinct series of aging people.

Neuronal size and the incidence of neuritic plaques (NPs) and neurofibrillary tangles (NFTs) were morphometrically and quantitatively studied in the entorhinal cortex of 300 autopsied individuals without dementia in three geographically distinct series (Brazil, Germany and Japan), and an additional series including 30 clinically diagnosed Alzheimer's disease patients. The mean ages at onset of NPs and NFTs were similar between the three normal series, and the incidence of NPs and NFTs increased exponentially with age, but at different rates. A correlation was found between larger neuronal size and higher incidence of NPs and NFTs. Neuronal size distribution largely seemed to account for the differences between the series. While the onset of neurodegeneration may be tightly programmed, i.e., in a species-specific manner, our data support the idea that the incidence of NPs and NFTs and the progression from NPs to NFTs may vary remarkably, depending on neuronal size.