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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.

Progressive CSF lymphocytic pleocytosis and intrathecal IgG-synthesis occurred late in familial amyotrophy, neuropathy, chorea, and dementia with spherocytosis. Immunoblotting showed a serum and CSF antibody apparently directed against glial fibrillary acidic protein. A secondary autoimmune response was probably triggered during the evolution of the neurodegenerative process.

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]

Motor fatigue, during 30 seconds of maximum voluntary isometric contraction (MVIC) was simultaneously evaluated by the decline in mechanical force output, and from the compression in the power spectrum obtained from surface electromyogram (sEMG). Measurements were performed in patients diagnosed with amyotrophic lateral sclerosis (ALS) and normal control (NC) in two muscle groups, elbow flexors (EF) and ankle dorsiflexors (DF). The decline in force output, as a manifestation of mechanical fatigue, was digitally calculated online by partitioning the force versus time curve to determine the percent of MVIC reduction over a 30 sec period and was expressed as force fatigue index (FFI). The compression in the sEMG power spectrum, as a manifestation of myoelectrical fatigue, was tracked by calculating the median frequency shift (MFS) from the first 5 sec to the last 5 sec of the 30 sec MVIC using digital Fast Fourier Transformation. In ALS patients, the significantly higher reduction in mechanical force output during the 30 sec MVIC (higher FFI) was accompanied with significantly less compression in the sEMG power spectrum (less MFS) as compared to NC ( P ≤0.005) in the two muscle groups. This dissociation between the mechanical and myoelectrical manifestation of muscle fatigue in ALS indicates that a reduction in muscle fiber conduction velocity (MFCV) may be a contributing peripheral factor in the pathogenesis of muscle fatigue in ALS. Alterations in motor unit functionality, especially in type II fast motor unit muscle fibers, and structural damage in denervated muscle fibers may contribute to the lower MFCV during motor fatigue in ALS patients. [ABSTRACT FROM AUTHOR]