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Objective: To assess the association of enteroviruses (EV) with ALS by applying a sensitive seminested reverse transcription (RT) PCR protocol to the detection of enteroviral RNA in a blinded set of archived tissues from ALS and control cases., Methods: The specimen set consisted of 24 frozen spinal cord samples from ALS cases, 17 frozen spinal cord samples from negative control (non-ALS) cases, and 5 frozen spinal cord positive control samples. The positive controls were two human spinal cord samples spiked with poliovirus (PV) and three spinal cords from PV-infected transgenic mice. A sensitive, EV-specific, seminested RT-PCR assay was used to detect EV genome in RNA extracted from the specimens and controls., Results: The assay detected EV RNA in a 10(-5) dilution of infected mouse tissue. EV RNA was not detected in the ALS specimens or in specimens from control cases, despite the presence of amplifiable RNA as assessed by amplification with control primers, whereas all of the positive control specimens yielded the expected PV amplification product., Conclusion: The reported association between EV infection and ALS was not confirmed by testing this set of specimens with these sensitive methods.

ts1 is a murine leukemia virus that causes rapidly evolving hindlimb paralysis in susceptible strains of mice. Following perinatal infection, three physical forms of unintegrated viral DNA were detected in the spinal cord by Southern blot hybridization. Linear and supercoiled closed-circle viral double-stranded DNAs were detected in both the central nervous system and non-central nervous system tissues. An elevated level of a novel minus-sense single-stranded form of viral DNA, which had a very high mobility in agarose gels, was correlated with the onset of symptoms of paralysis. As the severity of paralysis progressed, the level of this single-stranded form increased rapidly, with the highest level in the spinal cords of moribund mice. Since the virulence of a number of cytopathic retroviruses has been associated with the presence of increased amounts of unintegrated viral DNA in the tissues of the infected hosts, this novel form of highly mobile unintegrated single-stranded DNA may have a role in the neuropathogenesis of ts1.

Thyrotropin-releasing hormone-like immunoreactivity was demonstrated in neurons within the superficial laminae (I, II, III) of the mouse spinal dorsal horn by light-microscopic peroxidase immunocytochemistry. The immunoreactivity was distributed in a narrow dorsoventral band that enclosed the substantia gelatinosa (lamina II), with a higher concentration along the lamina II/III border. At present, the functional significance of these neurons is unknown. Their existence within the substantia gelatinosa suggests a role in sensory information processing.

Thyrotropin-releasing hormone (TRH) metabolism in NIH:N mouse cerebral cortex and spinal cord was studied with high pressure liquid chromatography. Degradation of added TRH was significantly (P less than 0.001) slower in the spinal cord (2.19 +/- 0.46%/min) than in the cerebral cortex (7.54 +/- 0.31%/min). Bacitracin, a non-competitive inhibitor of TRH deamidase, inhibited TRH degradation by 61.3 +/- 3.7% in the spinal cord but only by 35.9 +/- 1.0% in the cerebral cortex (P less than 0.001). Catabolism of TRH in the mouse spinal cord proceeds at a slower rate and predominantly via the TRH deamidase pathway.

Of the secondary messengers, cyclic quanosine monophosphate, but not cyclic adenosine monophosphate, was reduced by 80% in the cervical spinal cord and by 56% in the cerebellum of clinically affected homozygote "wobbler" mice compared to sex- and age-matched litter-mate clinically unaffected control mice. A neurotransmitter, gamma aminobutyric acid, and high-energy intermediates, adenosine triphosphate and phosphocreatine, were not significantly different in affected or unaffected mice.

Decreased cerebrospinal fluid concentrations of cyclic nucleotides in human motor neuron disease and decreased spinal cord concentrations of cyclic nucleotides in murine (Wobbler) motor neuron disease suggest that an abnormality in cyclic nucleotide metabolism may play a role in motor neuron degeneration. Retroviruses cause decreased cellular levels of cyclic nucleotides in infected cells. We induced a motor neuron degeneration with a neurotropic retrovirus, but not with a non-neurotropic retrovirus. In paralyzed mice, mean cAMP was decreased 21% in posterior horn segments and 34% in anterior horn segments compared to controls. The proportion of spinal cord phosphorylase a decreased 24% in paralyzed mice compared to controls. The content of cGMP decreased 48% in the cerebellum and 25% in both anterior and posterior horn segments of the spinal cords of paralyzed mice compared to controls. White matter content of these chemicals did not decrease in the posterior column of affected animals. Spinal cord content of ATP increased 20-22% in all three compartments, but the spinal cord content of phosphocreatine increased dramatically in white matter (46%), posterior horn gray matter (69%), and anterior horn gray matter (103%) compared to controls. Changes in high-energy phosphate intermediate and cyclic nucleotide metabolites occurred only in topographical regions showing neuronal and astrocyte pathological changes, but did not occur in the cerebral cortex.

The cerebral cortex reorganizes in response to central or peripheral lesions. Although basal ganglia and cerebellum are key components of the network dedicated to movement control, their role in motor reorganization remains elusive. We therefore tested if slowly progressive neurodegenerative motor disease alters the subcortical functional anatomy of the basal ganglia-thalamo-cerebellar circuitry. Ten patients with amyotrophic lateral sclerosis (ALS) and ten healthy controls underwent functional magnetic resonance imaging (fMRI), while executing a simple finger flexion task. Cued by an acoustic trigger, they squeezed a handgrip force transducer with their right hand at 10% of their maximum voluntary contraction force. Movement frequency, amplitude, and force were controlled. Statistical parametric mapping of task-related BOLD-response revealed increased activation in ALS patients as compared to healthy controls. The main activation increases were found in the supplementary motor area, basal ganglia, brainstem, and cerebellum. These findings suggest that degeneration of cortical and spinal motor neurons in ALS leads to a recruitment of subcortical motor structures. These subcortical activation patterns strongly resemble functional activation in motor learning and might therefore represent adaptations of cortico-subcortical motor loops as a—albeit finally ineffective—mechanism to compensate for the ongoing loss of motor neurons in ALS. [ABSTRACT FROM AUTHOR]