Rising mortality from motor neurone disease: an explanation

There is considerable debate about the increasing mortality from motor neurone disease (MND). However, examination of the relationship between increased life expectancy (through decreased general mortality) and increased mortality in both England and Wales and the United States indicates a close association between the two variables. Using a statistical model, defined sub-populations susceptible to MND can be identified in both countries. The size of such a sub-population has been estimated from the 1989 mortality data to be approximately 160 000 people in England and Wales. The proportion of this sub-population dying from MND has increased over the last 30 years, rather than, as previously, dying at an earlier age from other conditions. On this basis, deaths from MND are expected to increase by a further 20% in this sub-population between 1991-2021 because of continuing changes in life expectancy. MND is a condition made increasingly visible in mortality statistics through decreased general mortality, rather than one in which the underlying population at risk has substantially changed. Aetiological extrapolations from the data indicate that susceptibility to the disease is acquired early in life, and that it is unlikely, given the relative stability of the underlying sub-population, that either changed environmental circumstances or artifactual factors can account in themselves for the rise in mortality.     

Rising amyotrophic lateral sclerosis mortality in France 1968–1990: Increased life expectancy and inter-disease competition as an explanation

Gompertzian analysis is a statistical technique which has been successfully applied to the analysis of amyotrophic lateral sclerosis (ALS) mortality in England and Wales, Japan and the United States. This paper analyses the consistent trend of rising ALS mortality in France over the years 1968–1990, a period during which crude mortality rose from 400 deaths in 1968 to 950 deaths in 1990. The findings indicate that age-specific mortality rates have risen at ages older than 54 years for men and 53 years for women and decreased slightly at younger ages. The evolving ALS mortality pattern is attributable to changing inter-disease competition resulting from the increased life expectancy of the French population, rather than to changing environmental aetiopathogenic factors or to substantial artefact effects.     

Steadiness of amyotrophic lateral sclerosis in the province of Parma, Italy, 1960–1990

A clinical and epidemiological study on amyotrophic lateral sclerosis (ALS) was conducted in the province of Parma, Italy, from 1960–1990. A total of 121 cases were collected from hospital records. The average annual incidence was 0.98 per 100000 inhabitants, with a male/female ratio of 1.1. Age-specific incidence was maximal in the age group 60–69 years. No difference between rural and urban areas was found. Prevalence on October 26th, 1981 was 2.5 per 100000. Mean age at onset was 60 years, with no significant sex difference. Mean duration of the disease was 30 (sd 21.4) months. Bulbar forms were significantly (p<0.05) shorter than conventional forms, with a mean duration of 23.4 (sd 21.4) months. Age at onset did not influence prognosis. A comparison of three decades was made, to verify whether possible variations of the disease had occurred with time. From our data a definite stability was found in such epidemiological parameters as incidence, prevalence, mean duration and mortality of ALS in the period.     

The risk of motor neurone disease and multiple sclerosis is different in Estonians and Russians. Data from South Estonia

Epidemiological studies were performed in South Estonia to establish the prevalence rate of multiple sclerosis (MS) and motor neurone disease (MND). The case finding method included information from the hospital records of the central hospital in the region-the University Hospital (for MS from 1942 to 1989), from all neurologists in the region, from the Estonian MS Society and Association of Muscular Disorders, and from nursing homes in the region. The prevalence day was 31 December 1989. MND incidence was established for the period of 1986-1995. The results demonstrated high prevalence rates of MS among native Estonians (55.3 per 100 000), somewhat lower prevalence among native-born representatives of other nationalities (43.6 per 100 000) and the lowest prevalence rate of MS among non-Estonian immigrants (26.6 per 100 000). The differences were not statistically significant. The results for MND demonstrated the opposite pattern. The mean annual incidence rate of MND for 10 years was statistically significantly higher among people of other nationalities (2.5 per 100 000) and Russians (2.6 per 100 000), and lower in native-born Estonians (1.1 per 100 000). No differences in health care or clinical picture were established. The reasons for the demonstrated differences in MND incidence remain unclear.     

Ubiquitin-positive inclusions and progression of pathology in frontotemporal dementia and motor neurone disease identifies a group with mainly early pathology

Frontotemporal lobar degeneration (FTLD) with tau-negative, ubiquitin-positive inclusions has been a topic of major interest in recent years, with this group now accounting for the majority of tau-negative cases of frontotemporal degeneration. The severity of neurodegeneration in FTLD is dependent on the stage of disease and is substantial even in the earliest stages. Elucidating the pathogenesis of FTLD requires evaluation of changes during the earliest possible stage of disease. However, the long survival of most frontotemporal dementia cases means that cases with early neuropathology are not frequently encountered. Cases of FTLD with the shortest survival are those with coexisting motor neurone disease (FTLD + MND), making these the ideal group for studying early FTLD pathology. It is not clear, however, what the pathological contribution of MND is in these cases. This study evaluates the pathology of 20 cases of FTLD (11 with no clinical signs of MND and nine with FTLD + MND) as well as 10 cases of MND without dementia. Our findings indicate that the deposition of ubiquitin does not play a key role in the neurodegenerative process in FTLD, and that the severity of neurodegeneration in FTLD is similar in cases with and without clinical MND.     

Calbindin‐D28K is increased in the ventral horn of spinal cord by neuroprotective factors for motor neurons

Slow glutamate‐mediated neuronal degeneration is implicated in the pathophysiology of motor neuron diseases such as amyotrophic lateral sclerosis (ALS). The calcium‐binding proteins calbindin‐D_28K and parvalbumin have been reported to protect neurons against excitotoxic insults. Expression of calbindin‐D_28K is low in adult human motor neurons, and vulnerable motor neurons additionally may lack parvalbumin. Thus, it has been speculated that the lack of calcium‐binding proteins may, in part, be responsible for early degeneration of the population of motor neurons most vulnerable in ALS. Using a rat organotypic spinal cord slice system, we examined whether the most potent neuroprotective factors for motor neurons can increase the expression of calbindin‐D_28K or parvalbumin proteins in the postnatal spinal cord. After 4 weeks of incubation of spinal cord slices with 1) glial cell line‐derived neurotrophic factor (GDNF), 2) neurturin, 3) insulin‐like growth factor I (IGF‐I), or 4) pigment epithelium‐derived factor (PEDF), the number of calbindin‐D_28K‐immunopositive large neurons (>20 μm) in the ventral horn was higher under the first three conditions, but not after PEDF, compared with untreated controls. Under the same conditions, parvalbumin was not upregulated by any neuroprotective factor. The same calbindin increase was true of IGF‐I and GDNF in a parallel glutamate toxicity model of motor neuron degeneration. Taken together with our previous reports from the same model, which showed that all these neurotrophic factors can potently protect motor neurons from slow glutamate injury, the data here suggest that upregulation of calbindin‐D_28K by some of these factors may be one mechanism by which motor neurons can be protected from glutamate‐induced, calcium‐mediated excitotoxicity. © 2015 Wiley Periodicals, Inc.     

Morphological differences of intraneuronal ubiquitin‐positive inclusions in the dentate gyrus and parahippocampal gyrus of motor neuron disease with dementia

Semiquantitative morphological analysis of cerebral intraneuronal ubiquitin‐positive tau‐negative inclusions, a pathologic marker for motor neuron disease with dementia (MND‐D), was performed in the dentate gyrus and parahippocampal gyrus of 20 clinicopathologically confirmed patients with MND‐D. The forms of the inclusions were tentatively classified into three types: (i) C‐type, consisting of relatively large and intensely stained crescent or circular structures; (ii) L‐type, showing fine linear structures around the nuclei; and (iii) G‐type, showing faintly stained granular structures. The frequencies of the C‐type, L‐type and G‐type was 0.5–9.3%, 0.2–6.5% and 0–6.6% of dentate granule cells, respectively. In contrast to the dentate gyrus, almost all inclusions showed either the C‐type or L‐type form in the parahippocampal gyrus. A positive correlation was noted only between incidences of C‐type inclusion of the dentate gyrus and that of the parahippocampal gyrus (r = 0.69, P < 0.05). The morphological differences of the inclusions probably reflect different stages of their formation.     

Circulating cytokines and growth factors in professional soccer players: correlation with in vitro‐induced motor neuron death

Background: Professional soccer players are susceptible to amyotrophic lateral sclerosis. Strenuous physical activity has been associated with persistent inflammatory conditions and elevation of systemic cytokine levels, which could contribute to the vulnerability of these athletes. To investigate changes induced by playing soccer in the systemic profiles of growth factors and of the principal cytokines involved in the inflammatory response, we compared the serum concentrations of these factors in Italian professional soccer players and sedentary subjects. We also investigated the effects of the sera on primary cultured motor neurons in relation to their cytokine and growth factor content. Methods: Serum concentrations of cytokines and growth factors were measured by a biochip array analyzer. Neurotoxicity of sera was assessed by immunocytochemical assays in primary motor neuron cultures from mouse embryos. Results: Circulating levels of interleukin‐8, tumor necrosis factor‐alpha and interleukin‐4 were lower in soccer players than controls. However, the viability of primary cultured mouse motor neurons treated with sera from the two groups did not differ significantly. Vascular endothelial growth factor (VEGF) independently emerged as a systemic protective factor for motor neurons. Conclusions: We found significant alterations in circulating pro‐inflammatory cytokines in Italian professional soccer players, showing an unbalanced inflammatory condition in these subjects. VEGF was a protective serum factor affecting motor neuron survival.     

Review: The role of vitamin D in nervous system health and disease

Vitamin D and its metabolites have pleomorphic roles in both nervous system health and disease. Animal models have been paramount in contributing to our knowledge and understanding of the consequences of vitamin D deficiency on brain development and its implications for adult psychiatric and neurological diseases. The conflation of in vitro, ex vivo, and animal model data provide compelling evidence that vitamin D has a crucial role in proliferation, differentiation, neurotrophism, neuroprotection, neurotransmission, and neuroplasticity. Vitamin D exerts its biological function not only by influencing cellular processes directly, but also by influencing gene expression through vitamin D response elements. This review highlights the epidemiological, neuropathological, experimental and molecular genetic evidence implicating vitamin D as a candidate in influencing susceptibility to a number of psychiatric and neurological diseases. The strength of evidence varies for schizophrenia, autism, Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease, and is especially strong for multiple sclerosis.     

Ultra structure of pre-synaptic input to motor neurons in Onuf''s nucleus: controls and motor neuron disease

Ultrastructural analyses of sphincteric motoneurons in Onuf's nucleus at S2 were undertaken in human spinal cord obtained 3-6 h post-mortem from three subjects with no neurological disease ('controls') and five in which death was due to motor neuron disease (MND). Neurons in specified locations within Onuf's nucleus of control subjects ranged between 17.8 and 71.7 microns diameter (mean 38.6 microns). Analyses of synaptology revealed five ultrastructural classes of presynaptic terminal synapsing with the neuronal surface membrane. When classified by size, vesicle morphology, and synaptic site structure these conformed to the S, F, T, M and C-terminals defining somatic motoneurons. No terminals characteristic of autonomic motoneurons were found. In MND subjects, neurons in Onuf's nucleus at S2 were preserved despite a paucity of neurons in medial and lateral motor nuclei and were of similar size range to those in control subjects. The morphological classes of pre-synaptic terminal found in controls, also characterized sphincteric motoneurons in MND subjects, including the C-type terminal. The presence of C-terminals indicates (i) that sphincteric motoneurons are somatic alpha-motoneurons, and (ii) that hypotheses explaining the survival of sphincteric motoneurons in MND on the basis of Onuf's nucleus being an extension of the pre-ganglionic parasympathetic nucleus, or having intrinsic autonomic properties are incorrect.     

Human neural stem cell grafts in the spinal cord of SOD1 transgenic rats: Differentiation and structural integration into the segmental motor circuitry

Cell replacement strategies for degenerative and traumatic diseases of the nervous system depend on the functional integration of grafted cells into host neural circuitry, a condition necessary for the propagation of physiological signals and, perhaps, targeting of trophic support to injured neurons. We have recently shown that human neural stem cell (NSC) grafts ameliorate motor neuron disease in SOD1 transgenic rodents. Here we study structural aspects of integration of neuronally differentiated human NSCs in the motor circuitry of SOD1 G93A rats. Human NSCs were grafted into the lumbar protuberance of 8‐week‐old SOD1 G93A rats; the results were compared to those on control Sprague‐Dawley rats. Using pre‐embedding immuno‐electron microscopy, we found human synaptophysin (+) terminals contacting the perikarya and proximal dendrites of host α motor neurons. Synaptophysin (+) terminals had well‐formed synaptic vesicles and were associated with membrane specializations primarily in the form of symmetrical synapses. To analyze the anatomy of motor circuits engaging differentiated NSCs, we injected the retrograde transneuronal tracer Bartha‐pseudorabies virus (PRV) or the retrograde marker cholera toxin B (CTB) into the gastrocnemius muscle/sciatic nerve of SOD1 rats before disease onset and also into control rats. With this tracing, NSC‐derived neurons were labeled with PRV but not CTB, a pattern suggesting that PRV entered NSC‐derived neurons via transneuronal transfer from host motor neurons but not via direct transport from the host musculature. Our results indicate an advanced degree of structural integration, via functional synapses, of differentiated human NSCs into the segmental motor circuitry of SOD1‐G93A rats. J. Comp. Neurol. 514:297–309, 2009. © 2009 Wiley‐Liss, Inc.