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PubMed1997

Parvalbumin-immunoreactive neurons in the hippocampal formation of Alzheimer's diseased brain.

The number and topographic distribution of immunocytochemically stained parvalbumin interneurons was determined in the hippocampal formation of control and Alzheimer's diseased brain. In control hippocampus, parvalbumin interneurons were aspiny and pleomorphic, with extensive dendritic arbors. In dentate gyrus, parvalbumin cells, as well as a dense plexus of fibers and puncta, were associated with the granule cell layer. A few cells also occupied the molecular layer. In strata oriens and pyramidale of CA1-CA3 subfields, parvalbumin neurons gave rise to dendrites that extended into adjacent strata. Densely stained puncta and beaded fibers occupied stratum pyramidale, with less dense staining in adjacent strata oriens and radiatum. Virtually no parvalbumin profiles were observed in stratum lacunosum-moleculare or the alveus. Numerous polymorphic parvalbumin neurons and a dense plexus of fibers and puncta characterized the deep layer of the subiculum and the lamina principalis externa of the presubiculum. In Alzheimer's diseased hippocampus, there was an approximate 60% decrease in the number of parvalbumin interneurons in the dentate gyrus/CA4 subfield (P<0.01) and subfields CA1-CA2 (P<0.01). In contrast, parvalbumin neurons did not statistically decline in subfields CA3, subiculum or presubiculum in Alzheimer's diseased brains relative to controls. Concurrent staining with Thioflavin-S histochemistry did not reveal degenerative changes within parvalbumin-stained profiles. These findings reveal that parvalbumin interneurons within specific hippocampal subfields are selectively vulnerable in Alzheimer's disease. This vulnerability may be related to their differential connectivity, e.g., those regions connectionally related to the cerebral cortex (dentate gyrus and CA1) are more vulnerable than those regions connectionally related to subcortical loci (subiculum and presubiculum).

Adult↗

PubMed1997

The cerebral cortex is damaged in chronic alcoholics.

There is some controversy in the literature concerning whether chronic alcohol consumption damages the cerebral cortex. While decreased neuronal density in specific cortical regions is well described in chronic alcoholics, a recent study by Badsberg Jensen and Pakkenberg using unbiased stereological methods questions whether neurodegeneration occurs. In order to assess selective neurodegeneration in the cerebral cortex of chronic alcoholics, regional volumes and unbiased estimates of regional neuronal number (including neuronal identification with calcium-binding proteins) were calculated for 14 chronic alcoholics and 21 controls. Cases were carefully screened to exclude any interfering pathologies. Lifetime and maximum daily alcohol consumption was determined, and homogeneous groups were identified (four chronic alcoholics with Wernicke's encephalopathy and Korsakoff's psychosis, four chronic alcoholics with Wernicke's encephalopathy alone, six chronic alcoholics without Wernicke's encephalopathy or Korsakoff's psychosis, and 21 controls). Brain volume analysis revealed that discrete regions were significantly smaller in the chronic alcoholics compared to controls. As previously shown, white matter regions (particularly in the frontal lobe) were the most significantly reduced in volume. Alcoholics with Wernicke's encephalopathy (either alone or in combination with Korsakoff's psychosis) had significantly smaller white matter volumes than controls or alcoholics without these complications. Medial temporal lobe regions and the thalamus were also reduced in volume. Regression analyses revealed that the volume of both the white matter and thalamus negatively correlated with alcohol consumption. Consistent with the interpretation of previous neuronal density studies, selective neuronal loss was found in the superior frontal association cortex of chronic alcoholics, while no loss occurred from the motor cortex. The number of parvalbumin-, calbindin- and calretinin-immunoreactive neurons was found to be unaltered in chronic alcoholics, suggesting that the neurodegeneration is confined to the non-GABAergic pyramidal neurons. As neurodegeneration was observed in all alcoholic groups, damage to the frontal association cortex is not restricted to alcoholics with the amnesia of Korsakoff's psychosis. These results are consistent with the notion that chronic alcohol consumption is associated with selective neuronal vulnerability. The selective frontal neurodegeneration and the frontal focus of white matter atrophy are supported by neuropsychological, regional blood flow, and magnetic resonance imaging studies of frontal lobe dysfunction in chronic alcoholics and may correlate with abnormalities in working memory.

Adult↗

PubMed1998

Neuropathy target esterase: immunolocalization to neuronal cell bodies and axons.

Determination of the molecular mechanisms involved in organophosphate-induced axonopathy may help to elucidate those involved in normal axonal maintenance and in other neurodegenerative conditions. In this study we aimed to define the cellular distribution of neuropathy target esterase, the primary target protein for neuropathic organophosphates. A synthetic peptide corresponding to the sequence of a proteolytic fragment of neuropathy target esterase purified from chicken brain was used to raise a rabbit antiserum designated R28. The antiserum was shown by immunoprecipitation and western blotting of brain extracts to react with a polypeptide of the expected molecular size (155,000 mol. wt); this reaction was blocked by preincubating the antiserum with the immunizing peptide. Prominent intracellular immunostaining by R28 was seen in neuronal cell bodies and, in some cases, proximal axon segments in frozen sections of chicken brain cortex, optic tectum, cerebellum, spinal cord, and dorsal root ganglia. Cells with glial morphology were not immunostained, neither were normal sciatic nerve or motor end plates. However, 8-12 h following sciatic nerve ligation, immunoreactive material was seen to accumulate both proximal and, to a lesser extent, distal to the ligature, indicating that neuropathy target esterase undergoes fast axonal transport. No gross qualitative or quantitative changes in the above pattern of neuropathy target esterase immunoreactivity were detected in tissue obtained from chickens one or three days following treatment with a neuropathic organophosphate. The presence of neuropathy target esterase in essentially all neurons indicates that the selective vulnerability of long axons to neuropathic organophosphates is dependent on factors additional to the presence of the target protein.

Amino Acid Sequence↗

PubMed1999

Neuronal loss in functional zones of the cerebellum of chronic alcoholics with and without Wernicke's encephalopathy.

This study examines the effect of chronic alcohol consumption on the human cerebellum using operational criteria for case selection [Caine D. et al. (1997) J. Neurol. Neurosurg. Psychiat. 62, 51-60] and unbiased stereological techniques. We describe, for the first time, structural changes in different functional zones of the cerebellum of chronic alcoholics and correlate these changes with specific clinical symptoms. No consistent changes in the number of neurons or the structural volume for any cerebellar region were observed in the chronic alcoholics without the clinical signs of Wernicke's encephalopathy. In all cerebellar measures, these chronic alcoholics did not differ significantly from the non-alcoholic controls, suggesting that chronic alcohol consumption per se does not necessarily damage human cerebellar tissue. However, several cerebellar changes were noted in the thiamine-deficient alcoholics studied. There was a significant decrease in Purkinje cell density (reduced on average by 43%) and molecular layer volume (reduced by 32%) in the cerebellar vermis in all thiamine-deficient chronic alcoholics. A decrease in cell density and atrophy of the molecular layer, where the dendritic trees of the Purkinje cells are found, without significant cell loss suggests loss of cellular dendritic structure and volume. These thiamine-deficient alcoholics also had a significant decrease (36% loss) in the estimated Purkinje cell number of the flocculi, disrupting vestibulocerebellar pathways. These results indicate that cerebellar Purkinje cells are selectively vulnerable to thiamine deficiency. There is evidence that this damage contributes significantly to the clinical signs of Wernicke's encephalopathy. There was a 36% loss of Purkinje cells in the lateral lobe in alcoholics with mental state signs and 42% atrophy of vermal white matter in ataxic alcoholics. The finding of a 57% loss of Purkinje cells and a 43% atrophy of the molecular layer of the vermis in alcoholics with cerebellar dysfunction supports previous findings highlighting the importance of spinocerebellar pathways to these symptoms.

Adult↗

PubMed2000

Different receptors mediate motor neuron death induced by short and long exposures to excitotoxicity.

We compared the effect of short and long exposures of cultured motor neurons to glutamate and kainate (KA) and studied the receptors involved in these two types of excitotoxicity. There was no difference in the receptor type used between short and long glutamate exposures as activation of the N-methyl-D-asparate (NMDA) receptor was in both cases responsible for the motor neuron death. Cell death through activation of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors only became apparent when desensitization of these receptors was prevented. In such conditions, motor neurons became much more sensitive to excitotoxicity, and activation of different types of AMPA receptors mediated motor neuron death after short, compared to long, exposures to the non-desensitizing AMPA receptor agonist, KA. Short KA exposures selectively affected motor neurons containing Ca(2+)-permeable AMPA receptors, as the KA effect was completely inhibited by Joro spider toxin and only motor neurons that were positive for the histochemical Co(2+) staining were killed. A long exposure to KA affected motor neurons through both Ca(2+)-permeable and Ca(2+)-impermeable AMPA receptors. The selective death of motor neurons vs. dorsal horn neurons was observed after short KA exposures indicating that the selective vulnerability of motor neurons to excitotoxicity is related to the presence of Ca(2+)-permeable AMPA receptors.

6-Cyano-7-nitroquinoxaline-2,3-dione↗

PubMed2002

Models of repair mechanisms for future treatment modalities of Parkinson's disease.

Parkinson's disease is one of the most likely neurological disorders to be fully treatable by drugs and new therapeutic modalities. The age-dependent and multifactorial nature of its pathogenesis allows for many strategies of intervention and repair. Most data indicate that the selectively vulnerable dopaminergic neurons in the substantia nigra of patients that have developed Parkinson's disease can be modified by protective and reparative therapies. First, the oxidative stress, protein abnormalities, and cellular inclusions typically seen could be dealt with by anti-oxidants, trophic factors, and proteolytic enhancements. Secondly, if the delay of degeneration is not sufficient, then immature dopamine neurons can be placed in the parkinsonian brain by transplantation. Such neurons can be derived from stem cell sources or even stimulated to repair from endogenous stem cells. Novel molecular and cellular treatments provide new tools to prevent and alleviate Parkinson's disease.

Animals↗

PubMed2001

Neuroimaging studies in Rett syndrome.

Neuroimaging is a key instrument for determining structural and in vivo functional status of the brain, non-invasively. Multiple approaches can now determine aspects of anatomic and neurochemical changes in brain, and have been utilized effectively in Rett Syndrome patients to understand the biological basis of this neurodevelopmental disorder. Studies performed at our institute include volumetric analyses of MRI, magnetic resonance spectroscopy (MRS), diffusion tensor imaging (DTI), cerebral blood flow measurements with MRI, and positron emission tomography scans (PET). These studies have provided considerable insight into mechanisms underlying the clinical features of this disease. Volumetric analyses suggest that decreased brain volume in RS results from global reductions in both gray and white matter of the brain. A selective vulnerability of the frontal lobes is evidenced by the preferential reduction of blood flow, increased choline and reduced n-acetyl aspartate (NAA) by MRS, and increased glucose uptake in these same regions as shown by ((18)F)-fluorodeoxyglucose (FDG) PET scans. We hypothesize that the increased glucose uptake relates to increased glutamate cycling in synapses. The resulting neuroexcitotoxic injury to the developing brain contributes to the seizures, behavioral disturbance and respiratory irregularities commonly seen in phases 1 and 2 of this disorder.

Adolescent↗

PubMed1997

Hypoxic and ischemic disorders of infants and children. Lecture for 38th meeting of Japanese Society of Child Neurology, Tokyo, Japan, July 1996.

Hypoxia-ischemia damages selected regions of the immature at different ages. Prior to 32 weeks gestation the periventricular white matter is selectively vulnerable but in the last trimester the basal ganglia become especially vulnerable to injury. Hypoxia-ischemia causes injury by activating a series of biochemical events that unfolds over a period of hours to days following the initial insult and we are investigating the ways in which age modifies these events. The cascade includes release of glutamate, overstimulation of excitatory amino acid receptors and raised intracellular levels of calcium. Clinically this series is manifested by hypoxic-ischemic encephalopathy (HIE), a syndrome that includes coma, seizures, a burst suppression EEG, respiratory depression and severe hypotonia. Clinical studies have established a relationship between the severity of neonatal encephalopathy and later manifestations of brain damage or cerebral palsy. Potential neuroprotective therapies need to be effective when given after the insult but the 'therapeutic time window' for most N-methyl-D-aspartate (NMDA) glutamate antagonists is limited after injury. Using a model of hypoxic-ischemic injury and neonatal rats and hypothermic-circulatory arrest in dogs, we found that immunohistochemical staining for neuronal nitric oxide synthase (nNOS) is markedly increased from 6 to 24 h after the insult in the basal ganglia and cortex. The induction of nNOS preceded the time of maximal neuronal necrosis and during the time when many apoptotic nuclei were appearing. We have also found that a brief period of 2 h of mild hypothermia (32 degrees C) following hypoxia-ischemia in neonatal rats delayed neuronal necrosis by more than a week. We are determining whether this delay is related to a change in nNOS activation. Induction of nNOS in the post-insult period may contribute to expression of injury and signs of encephalopathy following a hypoxic-ischemic insult.

Animals↗

PubMed2000

Basal ganglia neurotoxins.

The epidemiology, clinical features, pathology, and mechanisms of action of basal ganglia neurotoxins are reviewed. Manganese, cyanide, hydrogen sulfide, methanol, carbon monoxide, 3-nitropropionic acid, MPTP, and annonaceae alkaloids are discussed. The probable mechanism of action for almost all basal ganglia neurotoxins is inhibition of mitochondrial function with destruction of the pallidum and putamen. MPTP produces selective loss of dopaminergic neurons because of selective uptake of a toxic metabolite in dopaminergic neurons. The basis for selective vulnerability of the putamen and pallidum is unknown.

Animals↗

PubMed2001

Hypoxic-ischemic injury results in acute disruption of myelin gene expression and death of oligodendroglial precursors in neonatal mice.

Studies of ischemic brain injury in neonatal rodents have focused upon the pathophysiology of neuronal damage. Much less consideration has been given to white matter injury, even though it is a major contributor to chronic neurological dysfunction in children. In the human neonate, particularly in those born prematurely, periventricular white matter is highly susceptible to hypoxic--ischemic (H--I) injury. To understand the basis for this selective vulnerability, we examined myelin gene expression and cell death in the subventricular layer and the surrounding white matter of neonatal mice following H--I insult. Using an in situ hybridization technique that gives high resolution and is very sensitive, we examined myelin basic protein and proteolipid protein gene expression three and twenty-four hours after a H-I insult. To elicit unilateral forebrain hypoxic and ischemic injury, 9--10-day-old mice underwent right carotid artery ligation followed by timed (40--70 min) exposure to 10% oxygen. Twenty-four hours following H--I, myelin basic protein and proteolipid protein transcripts were markedly reduced in striatum, external capsule, fornix, and corpus callosum in the injured side. Three hours after lesioning (ligation+70 min hypoxic exposure) myelin basic protein gene transcripts were visibly reduced in the ipsilateral white matter tracts. Interestingly, some cells in the subventricular layer expressed proteolipid protein transcripts, and 3 h after a H--I insult they were degenerating in the injured but not contralateral side. TUNEL staining showed an increase in the number of positive cells in the injured subventricular layer and corpus callosum but the adjacent striatum did not show a corresponding change in the number of TUNEL labeled cells. Ultrastructural studies of the subventricular zone and corpus callosum 3 h after H--I revealed that many subventricular cells, glial cells in the corpus callosum, and callosal axons in the injured side had already degenerated. However, the subventricular cells, glia and axons in the contralateral corpus callosum were spared. Many cells in the injured corpus callosum exhibited a apoptotic morphology; yet more mature oligodendrocytes in this region appeared normal. Our results show that a H--I insult causes a surprisingly swift and dramatic degenerative response in the subventricular layer and adjacent white matter. Within 3 h after H--I, the programmed cell death cascade was initiated; internucleosomal DNA degradation took place in subventricular and glial cells; oligodendrocyte progenitors died and axonal degeneration in the ipsilateral corpus callosum was extensive. The swiftness of the subventricular and glial cell degeneration suggests the H--I insult directly targets glia, as well as neurons, and raises the provocative question of whether glia exert damaging effects upon neurons and axons. Since the severity of the H--I insult can be modulated by varying the duration of hypoxia, the model is ideal to study whether oligodendrocyte progenitors are more susceptible to death than mature oligodendrocytes, whether mature oligodendrocytes de-differentiate and then are induced to remyelinate surviving axons, and/or whether oligodendrocyte progenitors in the subventricular layer can be stimulated to proliferate, migrate, and remyelinate the surviving axons.

Animals↗

PubMed1998

Identification of the mouse neuromuscular degeneration gene and mapping of a second site suppressor allele.

The nmd mouse mutation causes progressive degeneration of spinal motor neurons and muscle atrophy. We identified the mutated gene as the putative transcriptional activator and ATPase/DNA helicase previously described as Smbp2, Rip1, Gf1, or Catf1. Mutations were found in two alleles-a single amino acid deletion in nmdJ and a splice donor mutation in nmd2J. The selective vulnerability of motor neurons is striking in view of the widespread expression of this gene, although the pattern of degeneration may reflect a specific threshold since neither allele is null. In addition, the severity of the nmd phenotype is attenuated in a semidominant fashion by a major genetic locus on chromosome (Chr) 13. The identification of the nmd gene and mapping of a major suppressor provide new opportunities for understanding mechanisms of motor neuron degeneration.

Adenosine Triphosphatases↗

PubMed2003

Parkinson's disease: mechanisms and models.

Parkinson's disease (PD) results primarily from the death of dopaminergic neurons in the substantia nigra. Current PD medications treat symptoms; none halt or retard dopaminergic neuron degeneration. The main obstacle to developing neuroprotective therapies is a limited understanding of the key molecular events that provoke neurodegeneration. The discovery of PD genes has led to the hypothesis that misfolding of proteins and dysfunction of the ubiquitin-proteasome pathway are pivotal to PD pathogenesis. Previously implicated culprits in PD neurodegeneration, mitochondrial dysfunction and oxidative stress, may also act in part by causing the accumulation of misfolded proteins, in addition to producing other deleterious events in dopaminergic neurons. Neurotoxin-based models (particularly MPTP) have been important in elucidating the molecular cascade of cell death in dopaminergic neurons. PD models based on the manipulation of PD genes should prove valuable in elucidating important aspects of the disease, such as selective vulnerability of substantia nigra dopaminergic neurons to the degenerative process.

Animals↗

PubMed2000

Temporal profile of neuronal injury following pilocarpine or kainic acid-induced status epilepticus.

Systemic administration of pilocarpine and kainic acid (KA) has been extensively used to model temporal lobe epilepsy in rats. Here the regional distribution of selectively vulnerable neurons and the temporal evolution of such neuronal injury after status epilepticus (SE) are compared in both models. Using the silver staining technique of Gallyas, argyrophilic neurons were measured on a 0-3 (least-most) scale in 53 different brain areas. Few neurons were silver-stained 2.5 h after kainate-induced SE, but many silver-stained cells could be seen in most neocortical, hippocampal, amygdaloid and hypothalamic structures for pilocarpine group. In general, 8 or 24 h intervals between SE onset and perfusion times yielded the most intense neuronal silver-impregnation. Pilocarpine-induced neuronal silver impregnation was more prominent than that induced by kainate treatment for many areas in cortex, hippocampus, endopiriform nucleus, amygdaloid complex and hypothalamus. On the other hand, in the thalamus, some cortical areas, claustrum, lateral septum and caudoputamen, kainate-induced neuronal silver staining was also prominent, but occurred later than in pilocarpine-treated animals. Neuronal injury was found in almost the same brain areas in both models of SE but with different intensity levels and time course profiles. It was suggested that such differences in the temporal profile of cell damage should be taken into account when searching for neuroprotective agents.

Animals↗

PubMed1999

Clinical and brain 18fluoro-2-deoxyglucose positron emission tomographic findings in ethylmalonic aciduria, a progressive neurometabolic disease.

We report a 2-year-old boy with ethylmalonic aciduria and vasculopathy syndrome evaluated by 18fluoro-2-deoxyglucose positron emission tomographic (18FDG PET) brain scan, with intense uptake of 18FDG in the caudate nucleus and putamen bilaterally but with no morphological changes on magnetic resonance imaging (MRI). A repeat 18FDG PET brain scan 1 year later showed a significant bilateral decreased uptake of glucose in the putamen and the head of the caudate nucleus as well as a decreased uptake in the frontal lobes. On MRI, there was atrophy and watershed infarcts in the basal ganglia, explaining the loss of glucose uptake. These results reflect a selective vulnerability of the basal ganglia, their functional derangement, and ultimate degeneration.

Caudate Nucleus↗

PubMed1998

A fluorescence confocal assay to assess neuronal viability in brain slices.

Hippocampal slice models are used to study the mechanisms of ischemia-induced neurotoxicity and to assess the neuroprotective potential of novel therapeutic agents. A number of morphological and functional endpoints are available to assess neuronal viability. The slice model also allows the study of selectively vulnerable neuronal populations within the same preparation. The fluorescence procedure described here provides a method of assessing the viability of neurons in rat hippocampal slices exposed to hypoxic-hypoglycemic conditions. Control and/or treated slices that had been subjected to a 10 min oxygen-glucose deprivation insult are double stained with calcein-AM (4 microM), which stains live cells green, and ethidium homodimer (6 microM), which stains the nucleus of dead cells red. The stained slices are then imaged using confocal microscopy. Vulnerable neurons in the CA1 region of slices deprived of oxygen and glucose became increasingly permeant to ethidium homodimer over the 4 h reperfusion period. Exposure to low Ca2+ concentration (0.3 mM) or the N-, P- and Q-type Ca2+ channel antagonist MVIIC (100 nM), which have been shown to be neuroprotective in this model of ischemia using field evoked post-synaptic potential (EPSP) measures as an endpoint, were also shown to be protective using the fluorescence assay.

Animals↗

PubMed2000

Transient global ischemia specifically modulates visual P300 scalp distribution.

OBJECTIVE: Latency, amplitude, and scalp topography of the visual P300 component was examined in patients who had suffered from transient global ischemia (TGI) due to cardiac arrest and in age matched clinical and healthy controls in order to investigate the diagnostic value of this component. METHOD: Event-related potentials (ERPs) were recorded from 19 scalp electrodes in a visual oddball paradigm. RESULTS: Mean latency of the P300 component was prolonged in both patient groups. Changes in scalp distribution of the P300, however, appear to be specific to anoxic-ischemic encephalopathy. In particular, a selective reduction of the P300 amplitudes at posterior recording sites was observed in TGI patients. Moreover, examination of the auditory P300 in TGI patients revealed that this selective change seems to be restricted to the visual modality. CONCLUSION: The results are discussed with respect to selective vulnerability of brain tissue to hypoxic-ischemic injury. After TGI a modality-specific subset of P300 generators, probably located in the transitional parieto-occipital and extrastriate occipital cortex, appears to be affected. It is also noted, that the visual P300 component could serve as an additional marker of TGI especially in patients who do not show neuropathological changes in structural brain images.

Aged↗

PubMed2006

Vanishing white matter disease.

Vanishing white matter disease (VWM) is one of the most prevalent inherited childhood leucoencephalopathies. The classical phenotype is characterised by early childhood onset of chronic neurological deterioration, dominated by cerebellar ataxia. VWM is unusual because of its clinically evident sensitivity to febrile infections, minor head trauma, and acute fright, which may cause rapid neurological deterioration and unexplained coma. Most patients die a few years after onset. The phenotypic variation is extremely wide, including antenatal onset and early demise and adult-onset, slowly progressive disease. MRI findings are diagnostic in almost all patients and are indicative of vanishing of the cerebral white matter. The basic defect of this striking disease resides in either one of the five subunits of eukaryotic translation initiation factor eIF2B. eIF2B is essential in all cells of the body for protein synthesis and its regulation under different stress conditions. Although the defect is in housekeeping genes, oligodendrocytes and astrocytes are predominantly affected, whereas other cell types are surprisingly spared. Recently, undue activation of the unfolded-protein response has emerged as important in the pathophysiology of VWM, but the selective vulnerability of glia for defects in eIF2B is poorly understood.

Age of Onset↗

PubMed2001

Progress in clinical neurosciences: the evidence for ALS as a multisystems disorder of limited phenotypic expression.

Traditionally, amyotrophic lateral sclerosis (ALS) is considered to be a unique neurodegeneration disorder in which motor neurons are selectively vulnerable to a single disease process. Our current understanding of ALS, however, suggests that this is far too limited an approach. While motor neuron degeneration remains the central component to this process, there is considerable phenotypic variability including broad ranges in survivorship and the presence or absence of cognitive impairment. The number of familial variants of ALS for which unique genetic linkage has been identified is increasing, attesting further to the biological heterogeneity of the disorder. At the cellular level, derangements in cytoskeletal protein and glutamate metabolism, mitochondrial function, and in glial interactions are clearly evident. When considered in this fashion, ALS can be justifiably considered a disorder of multiple biological processes sharing in common the degeneration of motor neurons.

Amyotrophic Lateral Sclerosis↗