Lars-Olof Ronnevi

Amyotrophic Lateral Sclerosis in Sweden, 1991-2005

OBJECTIVES To investigate the temporal trend of amyotrophic lateral sclerosis (ALS) incidence in Sweden between January 1, 1991, and December 31, 2005, and to explore incidence variations according to major demographic factors. DESIGN Population-based study. SETTING Academic research. PARTICIPANTS All incident cases of ALS identified through the Swedish Inpatient Register between January 1, 1991, and December 31, 2005. MAIN OUTCOME MEASURE Age-standardized incidence rates were calculated by applying the observed age-specific incidence rates to the age distribution of the Swedish population in 1991. A linear regression model was used to assess the potential trend of the incidence during calendar years. We also followed up the entire population registered in the 1990 Population and Housing Census for incidence of ALS. Relative risk and 95% confidence interval of ALS associated with demographic variables were estimated using Poisson regression models. RESULTS The age-standardized incidence rates increased from 2.32 per 100,000 person-years in 1991-1993 to 2.98 per 100,000 person-years in 2003-2005, representing an annual increase of approximately 2% during the 15 years (P value for trend, .002). The age-specific incidence rates increased in all age groups except those younger than 50 years. The observed increase remained significant when restricting the analysis to individuals born in Sweden (P value for trend, <.001). Compared with individuals born from April through June, those born from October through December were at 11% increased risk of ALS (95% confidence interval, 1.01-1.23). CONCLUSIONS The incidence of ALS has been increasing during the last 15 years in Sweden. Further studies are warranted to explore the underlying reasons for this observed trend.

An ultrastructural study of the synaptic contacts of α-motoneurone axon collaterals. I. Contacts in lamina IX and with identified α-motoneurone dendrites in lamina VII

Horseradish peroxidase (HRP) was injected intracellularly in triceps surae alpha-motoneurones. The axons and axon collaterals of these neurones were traced light and electron microscopically. Synaptic boutons of collaterals, in Rexeds lamina IX or in synaptic contact with HRP-stained motoneurone dendrites in lamina VII, were studied ultrastructurally. The boutons exhibited spherical synaptic vesicles and made synaptic contacts of two different types with HRP-stained alpha-motoneurone dendrites in lamina IX and VII, dendrites and cell bodies of large neurones in lamina IX, dendrites of unknown origin in lamina IX and with one cell body of a medium size neurone in lamina IX. The observations are discussed in relation to earlier qualitative and quantitative studies on the synaptology of cat spinal alpha-motoneurones.

Origin of the glial processes responsible for the spontaneous postnatal phagocytosis of boutons on cat spinal motoneurons

SummaryPrevious studies have demonstrated that astrocyte processes are responsible for a spontaneously occurring phagocytosis of boutons on cat spinal motoneurons during the second postnatal week. In the present investigation, the astrocytes and the astrocyte processes in contact with the motoneurons were studied qualitatively and quantitatively during the early postnatal period. It could be concluded that the cells responsible for the phagocytosis of boutons are immature astrocytes. These cells were present not only during the period of phagocytosis but also prior to this period. The type of process responsible for the phagocytosis was present not only during the period of phagocytosis but also prior to and after that period although the relative contribution of such processes to the glia-covered membrane area of the motoneurons was reduced in the older animals. On the basis of these results, the possible specificity of the immature astrocyte as the element responsible for the phagocytosis of boutons during normal development is discussed.

Spontaneous phagocytosis of boutons on spinal motoneurons during early postnatal development. An electron microscopical study in the cat

SummaryThe boutons making synaptic contact with different regions of spinal motoneurons have been studied during the early postnatal period. The observations suggest that a spontaneous glial phagocytosis of boutons of different types occurs mainly during the second postnatal week. This finding is discussed in relation to the previously demonstrated disappearance of boutons from the initial axon segment of spinal motoneurons during the same period of development and also in relation to other degenerative and eliminatory phenomena associated with the normal development of the nervous system.The boutons making synaptic contact with different regions of spinal motoneurons have been studied during the early postnatal period. The observations suggest that a spontaneous glial phagocytosis of boutons of different types occurs mainly during the second postnatal week. This finding is discussed in relation to the previously demonstrated disappearance of boutons from the initial axon segment of spinal motoneurons during the same period of development and also in relation to other degenerative and eliminatory phenomena associated with the normal development of the nervous system.

Abnormal tissue distribution of lead in amyotrophic lateral sclerosis

The lead content of cerebrospinal fluid (CSF) was found to be significantly elevated in 12 patients with amyotrophic lateral sclerosis, when compared to 28 control subjects having non-degenerative neurological disorders. The difference could not be explained as being merely secondary to blood-CSF barrier damage. A hypothetical model of the pathogenesis of the disease is advanced and the results are discussed in relation to this model.

An ultrastructural study of the synaptic contacts ofα1-motoneuron axon collaterals. II. Contacts in lamina VII

Horseradish peroxidase (HRP) was injected intracellularly in triceps surae alpha-motoneurons. The axons and axon collaterals of these neurons were traced light and electron microscopically. Synaptic boutons of collaterals in the ventral part of Rexeds lamina VII were studied ultrastructurally. The boutons exhibited spherical synaptic vesicles and made synaptic contacts with cell bodies and proximal dendrites of neurons assumed to be Renshaw cells and with dendrites of unknown origin. The observations are discussed in relation to earlier qualitative and quantitative studies on the other known synaptic contacts of the alpha-motor axons, both in the central and peripheral nervous system.

Spontaneous phagocytosis of c-type synaptic terminals by spinal α-motoneurons in newborn kittens. An electron microscopic study

The cell bodies and proximal dendrites of spinal alpha-motoneurons were studied electron microscopically with the aid of serial sections during the first postnatal week in the cat. The observations suggested that some of the synaptic terminals of the so-called C-type on the cell bodies and dendrites are phagocytosed by the motoneurons during the first few days after birth. This finding is discussed in relation to the earlier demonstrated postnatal loss of synaptic terminals on the motoneurons after birth and differences demonstrated between different functional types of spinal motoneurons with respect to the number and distribution of C-type terminals in the adult cat.

An ultrastructural study of serially sectioned renshaw cells. I. Architecture of the cell body, axon hillock, initial axon segment and proximal dendrites

Seventeen neurons which were postsynaptic to axon collateral boutons of intracellularly HRP-stained triceps surae alpha-motoneurons were studied ultrastructurally. All 17 neurons were situated in lamina VII, ventro-medially to the main motor nuclei. This and other facts support the assumption that the observed neurons are morphological correlates to the physiologically defined Renshaw cells. The contours of the cell bodies, as observed in the midnucleolus plane, were elongated. The axons originated either from the cell bodies or from dendrites. The number of dendrites of each neuron varied between 3 and 7. The appearance of the presumed Renshaw cells was also compared with that of a larger sample of neurons from the ventral part of lamina VII which was studied light microscopically in semithin sections. It was suggested that the Renshaw cells belong to the larger and more elongated neurons in the area.

Amyotrophic lateral sclerosis and cancer: a register-based study in Sweden.

Abstract Comorbidity of cancer with ALS has been studied previously. Detailed description of the temporal relationship between cancer and ALS is, however, lacking. We conducted a nested case-control study of ALS in Sweden during 1987−2009, including 5481 cases of ALS identified from the Swedish Patient Register and 27,405 controls randomly selected from the general Swedish population. Odds ratios (ORs) for association of ALS with previous cancer diagnosis and incidence rate ratios (IRRs) of cancer after diagnosis were calculated to compare ALS patients with ALS-free individuals. Overall, a previous cancer diagnosis was not associated with subsequent risk of ALS (OR 1.00; 95% CI 0.91−1.10). No overall association was observed for any specific cancer type. An increased risk of ALS was observed during the first year after cancer diagnosis (OR 1.50; 95% CI 1.17−1.92). In contrast, a lower risk of cancer was observed in ALS patients after diagnosis compared with ALS-free individuals (IRR 0.84; 95% CI 0.69−1.02). The risk reduction was seen primarily two or more years after ALS diagnosis (IRR 0.64; 95% CI 0.45−0.88). Our results provide no evidence for comorbidity of cancer and ALS overall. Surveillance biases seem the most likely explanation for the limited associations detected.

Infection of the Central Nervous System, Sepsis and Amyotrophic Lateral Sclerosis

Background Severe infections may lead to chronic inflammation in the central nervous system (CNS) which may in turn play a role in the etiopathogenesis of amyotrophic lateral sclerosis (ALS). The relentless progression and invasive supportive treatments of ALS may on the other hand induce severe infections among ALS patients. Methodology and Principal Findings The present study included 4,004 ALS patients identified from the Swedish Patient Register during 1991–2007 and 20,020 age and sex matched general population controls. Conditional logistic regression was used to estimate the odds ratios (ORs) of ALS given a previous hospitalization for CNS infection or sepsis. Cox models were used to estimate the hazard ratios (HRs) of hospitalization for CNS infection or sepsis after ALS diagnosis. Overall, previous CNS infection (OR: 1.3, 95% confidence interval [CI]: 0.8, 2.4) or sepsis (OR: 1.2, 95% CI: 0.9, 1.6) was not associated with ALS risk. However, compared to ALS free individuals, ALS cases were more likely to be hospitalized for sepsis after diagnosis (HR: 2.6, 95% CI: 1.9, 3.5). We did not observe a higher risk of CNS infection after ALS diagnosis. Conclusions/Significance Our results suggest that acute and severe infections unlikely contribute to the development of ALS; however, ALS patients are at a higher risk of sepsis after diagnosis, compared to ALS free individuals.