Ganglioside patterns in amyotrophic lateral sclerosis brain regions

In a search for evidence of biochemical disorders in regions of postmortem brain other than the motor cortex in amyotrophic lateral sclerosis (ALS), ganglioside patterns were also examined in the frontal, temporal, and parahippocampal gyrus cortex. In 21 ALS brains studied (20 sporadic, 1 familial), abnormal patterns were found in the frontal cortex (81%), temporal cortex (75%), motor cortex (70%), and parahippocampal gyrus cortex (71%). Patterns were established by measuring the percentage distribution of 12 ganglioside species. Two abnormal patterns were detected. One was based on low proportions of GD1b, GT1b, and GQ1b associated with high proportions of GM2 and GD3 (GM1, GD1a, GD2, and GT1a values were normal). The second abnormality was the appearance of Gx. Neither abnormality was seen in the 13 non-ALS control brains. The first, and predominant, abnormality was found in the frontal cortex in 14 brains, and the second was observed in 13 brains; 10 brains showed both abnormalities. These findings thus constitute evidence that the disease process in ALS extends beyond the motor cortex and involves neurons in several brain areas.     

Cognitive functioning in sporadic amyotrophic lateral sclerosis: a six month longitudinal study

OBJECTIVE: To observe changes in cognition over six months in subjects with recently diagnosed sporadic amyotrophic lateral sclerosis (ALS). METHODS: The study used a between-group and within-group longitudinal design. Nineteen ALS subjects and eight matched caregivers were recruited to participate in baseline neuropsychological assessments that were repeated six months later. Between group comparisons for these variables were undertaken at baseline and six months later. Within group/across time comparisons for these variables were carried out for both groups. Individual analyses for the neuropsychological variables using z scores were done for the ALS subjects using their baseline performance as the basis for comparison with their six month performance. RESULTS: The between-group and within-group comparisons did not show significant differences in cognitive function over time. In individual analyses, however, seven of 19 ALS subjects (36.84%) developed abnormal neuropsychological performance over six months. CONCLUSIONS: Early in the disease course, over one third of the ALS subjects developed cognitive deficits over six months. These findings support the hypothesis that cognitive deficits in ALS become more prominent over time.     

Quantitative motor assessment in amyotrophic lateral sclerosis

Reliable measurements are needed to document the natural history of ALS and to determine therapeutic efficacy. We have devised a standardized protocol that generates interval data sensitive to change-the Tufts Quantitative Neuromuscular Exam (TQNE). The TQNE consists of the following four major categories: pulmonary function, oropharyngeal function, timed functional activities, and isometric strength using an electronic strain gauge. The 29-item exam takes about 1 hour to administer and has excellent test-retest reliability.     

The motor cortex and amyotrophic lateral sclerosis

On theoretical grounds, abnormalities of the motor cortex in patients with amyotrophic lateral sclerosis (ALS) could lead to anterograde ("dying-forward") transneuronal degeneration of the anterior horn cells as suggested by Charcot. Conversely, retrograde ("dying-back") degeneration of the corticospinal tracts could affect the motor cortex. Evidence derived from clinical, neuropathological, static, and functional imaging, and physiological studies, favors the occurrence of anterograde degeneration. It is hypothesized that transneuronal degeneration in ALS is an active excitotoxic process in which live but dysfunctional corticomotoneurons, originating in the primary motor cortex, drive the anterior horn cell into metabolic deficit. When this is marked, it will result in more rapid and widespread loss of lower motor neurons. In contrast, slow loss of corticomotoneurons, as occurs in primary lateral sclerosis (PLS), precludes excitotoxic drive and is incompatible with anterograde degeneration. Preservation of slow-conducting non-M1 direct pathways in PLS is not associated with excitotoxicity, and anterior horn cells survive for long periods of time.     

Functional motor compensation in amyotrophic lateral sclerosis

The present study investigated the fMRI correlates of functional compensation/neural reorganization of the motor system in patients with amyotrophic lateral sclerosis (ALS). The hypothesis was that ALS patients would recruit additional brain regions compared with controls in a motor task and that activity in these regions would vary as a function of task difficulty. Patients and controls executed a motor task with two sequences (a simple and a more difficult one) of consecutive button presses. Patients and controls both activated brain regions known to be involved in motor execution and control. Activity in ipsilateral motor areas as well as difficulty-related activity in the left cerebellum could only be observed in patients. The behavioral data indicated that the motor task was much more difficult for patients than for controls. At nearly equal difficulty the observed patterns of hemodynamic activity in controls were very similar to those observed in ALS. The findings suggest that functional compensation in ALS relies on existing resources and mechanisms that are not primarily developed as a consequence of the lesion.     

A longitudinal study of the pathophysiological changes in single human thenar motor units in amyotrophic lateral sclerosis

The sequence of pathophysiological changes in amyotrophic lateral sclerosis (ALS) at the single motor unit (MU) level is not well understood. Using a recently described technique, a comprehensive range of physiological properties in two thenar MUs in ALS were intensively studied. In the first MU, despite a marked decline in the ability of the subject to voluntarily recruit the MU, the physiological properties of this MU remained remarkably stable over a 2-year period. In contrast, the physiological properties of the other MU declined rapidly over 5 months despite the fact that this MU could be recruited with ease throughout the study period. These differences between the progressively dysfunctional changes in these two MUs illustrates the value of such longitudinal studies of specific MUs in improving our understanding of the evolution of changes in single motoneurons in ALS. The broader application of longitudinally tracking the pathophysiological changes of the surviving MUs may prove to be a sensitive measure of disease progression and in evaluating the effectiveness of treatments. © 1998 John Wiley & Sons, Inc. Muscle Nerve 21: 1714–1723, 1998     

Minocycline in amyotrophic lateral sclerosis: a pilot study

Abstract Recent studies indicate that minocycline exerts neuroprotective effects in vitro and in vivo, and suggest that the drug may represent a novel therapeutic approach to amyotrophic lateral sclerosis (ALS). In this study we investigated the safety of combined treatment with minocycline and riluzole in ALS. Twenty ALS patients were randomised into two groups and administered either riluzole (50 mg b.i.d.) or riluzole and minocycline (100 mg i.d.) for 6 months. Disease progression was measured by means of the ALS-Functional Rating Scale score at monthly intervals. Respiratory function was measured at the beginning of the study and repeated after 3 and 6 months of treatment. Combined treatment with minocycline and riluzole was not followed by significant side effects. This pilot study shows that minocycline and riluzole can be taken safely together. Further trials are needed to assess efficacy of such treatment.     

Cortical inhibition in motor and non-motor regions: a combined TMS-EEG study

A number of studies using paired pulse transcranial magnetic stimulation (TMS) have demonstrated that cortical inhibition (CI) of the motor cortex can be recorded and also gauged through surface electromyography. However, recording CI from other brain regions that are more directly related with the pathophysiology of some neurologic and psychiatric disorders (e.g., dorsolateral prefrontal cortex (DLPFC) in schizophrenia) was previously fraught with technical difficulties. This study was therefore designed to examine, through a combination of TMS with EEG, whether CI could be measured directly from the motor cortex, DLPFC, and another non-motor region. To index CI, long interval cortical inhibition (LICI; a TMS paradigm) was used in the motor cortex and DLPFC in 14 healthy subjects, and in the parietal lobe in 5 of those subjects. In the motor cortex, LICI resulted in a significant suppression in mean cortical evoked activity on EEG (37.31 +/- 47.51%). In the DLPFC, LICI resulted in a significant suppression (32.45 +/- 47.86%) in mean cortical evoked activity and did not correlate with LICI in the motor cortex although they did not significantly differ. In the parietal lobe, LICI resulted in significant suppression (47.76 +/- 44.70%) in mean cortical evoked activity. In conclusion, CI in the dorsolateral prefrontal cortex, motor cortex and parietal cortex were similar at 120% of motor threshold. These data suggest that CI can be recorded by combining TMS with EEG and may facilitate future research attempting to ascertain the role of CI in the pathophysiology of several neurologic and psychiatric disorders.     

Multifocal motor nerve conduction abnormalities in amyotrophic lateral sclerosis.

Motor nerve conduction in motor neuron disease is considered normal until the terminal stages of the disease, a notable exception being lower motor neuron syndrome associated with anti-glycolipid antibodies. We reviewed the electrophysiological findings in all our patients who were diagnosed as having amyotrophic lateral sclerosis (ALS) during the last 6 years. Six patients, clinically indistinguishable from "classical" ALS patients, out of 31 (19%) displayed motor nerve conduction abnormalities. The most consistent finding, occurring in all 6, was prolonged distal latency or reduced conduction velocity in the distal segment of the median nerve, with normal sensory conduction, suggesting possible pressure proneness of motor nerve fibers in ALS. Additional abnormalities included multifocal motor conduction slowing (3 patients), and conduction blocks (4 patients). None of the patients had paraproteinemia and anti-GM1 and anti-GD1a antibodies were not detected. Thus, a subgroup of clinically indistinguishable ALS patients may have multifocal motor nerve conduction abnormalities, indicating motor nerve fiber involvement. The etiology and pathogenesis of the peripheral nerve involvement are presently unknown.     

Distal motor axonal dysfunction in amyotrophic lateral sclerosis

Nerve conduction slowing in amyotrophic lateral sclerosis (ALS) is usually caused by loss of fast motor axons. We studied the frequency, extent, and distribution of prominently prolonged distal motor latencies in ALS. We reviewed results of median, ulnar, and tibial nerve conduction studies in 91 patients with ALS, 24 with lower motor neuron disorders, and 36 with axonal neuropathy. Coincidental carpal tunnel syndrome was found for 4 (4.4%) of the ALS patients who were excluded from analyses. Markedly prolonged distal latencies (>125% of the upper limit of normal) were found only in the median nerve of ALS patients (9%), and in none of the disease controls. Excitability studies suggested membrane depolarization in some ALS patients. Our results show that approximately 10% of ALS patients shows prominently prolonged median distal latency, which cannot be explained by axonal loss and carpal tunnel lesion. The distal nerve conduction slowing may partly be caused by membrane depolarization possibly due to motor neuronal degeneration in ALS. We suggest that recognition of the pattern of distal motor axonal dysfunction predominant in the median nerve is clinically important, and could provide additional insights into the pathophysiology of ALS.     

Familial adult motor neuron disease: amyotrophic lateral sclerosis

We analyzed the medical records of 103 patients with familial adult motor neuron disease (MND). In the 72 families, 329 members were known to be affected. Observations were compared with the sporadic and Mariana forms of MND. Clinical and laboratory examinations of all three forms were similar in clinical course and findings, but there were minor variations in age at onset, sex ratio, survival, and the frequency with which onset occurred in the lower extremities. Recognition of the familial form still depends on diagnosis of the disease in more than one member of a family.     

Distal excitability changes in motor axons in amyotrophic lateral sclerosis.

OBJECTIVE: Previous axonal excitability studies in amyotrophic lateral sclerosis (ALS) have suggested that impaired potassium channel function could be responsible for the generation of fasciculations, but the ectopic activity arises predominantly from the motor nerve terminals. This study tested the hypothesis that dysfunction of potassium channels is more pronounced in the more distal parts of axons. METHODS: Threshold electrotonus was used to compare accommodation at the motor point of abductor pollicis brevis, and at the wrist portion of the median nerve, between 22 patients with ALS and 19 normal subjects. As target responses for motor point stimulation, movement-related potentials were recorded using an accelerometer. RESULTS: Compared to normal subjects, ALS patients showed greater threshold changes to depolarizing conditioning currents at both the motor point and wrist, suggesting less accommodation by potassium currents. Differences in the threshold electrotonus curves between the normal and ALS groups were much more prominent at the motor point than at the wrist. CONCLUSIONS: In ALS, axonal potassium channels are impaired more prominently in distal portions of axons than at the nerve trunk, and this is consistent with evidence that fasciculations mostly arise from the nerve terminals. SIGNIFICANCE: Excitability testing at the motor point provides additional information about the pathophysiology of ALS.