Abnormalities In Amyotrophic Lateral Sclerosis Research Articles

Tractography in amyotrophic lateral sclerosis using a novel probabilistic tool: A study with tract-based reconstruction compared to voxel-based approach

Diffusion tensor imaging (DTI) is one of the most sensitive MRI tools for detecting subtle cerebral white matter abnormalities in amyotrophic lateral sclerosis (ALS). Nowadays a plethora of DTI tools have been proposed, but very few methods have been translated into clinical practice. The aim of this study is to validate the objective measurement of fiber tracts as provided by a new unbiased and automated tractography reconstruction tool named as TRActs Constrained by UnderLying Anatomy (TRACULA). The reliability of this tract-based approach was evaluated on a dataset of 14 patients with definite ALS compared with 14 age/sex-matched healthy controls. To further corroborate these measurements, we used a well-known voxelwise approach, called tract-based spatial statistics (TBSS), on the same dataset. TRACULA showed specific significant alterations of several DTI parameters in the corticospinal tract of the ALS group with respect to controls. The same finding was detected using the well-known TBSS analysis. Similarly, both methods depicted also additional microstructural changes in the cingulum. DTI tractography metrics provided by TRACULA perfectly agree with those previously reported in several post-mortem and DTI studies, thus demonstrating the accuracy of this method in characterizing the microstructural changes occurring in ALS. With further validation (i.e. considering the heterogeneity of other clinical phenotypes), this method has the potential to become useful for clinical practice providing objective measurements that might aid radiologists in the interpretation of MR images and improve diagnostic accuracy of ALS.

7‐T MRI of the spinal cord can detect lateral corticospinal tract abnormality in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder affecting lower and upper motor neurons. Degeneration of the lateral corticospinal tract (CST) is a key finding in ALS cervical spinal cord autopsies. We hypothesized that in vivo ultra-high-field MRI of the cervical spinal cord can detect abnormality in the CST. A patient with ALS (disease duration 23 months) and a healthy control were scanned at 7-T MRI using a 19-channel coil. Multi-echo T2*-weighted imaging was performed in the spinal cord, covering C2-C6. Cross-sectional resolution was 0.37 × 0.37 mm(2). We detected clear signal hyperintensity in both segments of the lateral CST in the ALS patient, which was significant when compared with the normal control subject (P < 10(-7)). We believe there are potential benefits of 7-T MRI for increased sensitivity and spatial accuracy in characterizing pathology in the spinal cord.

Whole-Brain Analysis of Amyotrophic Lateral Sclerosis by Using Echo-Planar Spectroscopic Imaging

To detect regional metabolic differences in amyotrophic lateral sclerosis (ALS) with whole-brain echo-planar spectroscopic imaging. Sixteen patients with ALS (nine men, seven women; mean age, 56.6 years), five persons suspected of having ALS (four men, one woman; mean age, 62.6 years), and 10 healthy control subjects (five men, five women; mean age, 56.1 years) underwent echo-planar spectroscopic imaging after providing informed consent. The study was approved by the institutional review board and complied with HIPAA. Data were analyzed with the Metabolic Imaging and Data Analysis System software, and processed metabolite maps were coregistered and normalized to a standard brain template. Metabolite maps of creatine (Cr), choline (Cho), and N-acetylaspartate (NAA) were segmented into 81 regions with Automated Anatomical Labeling software to measure metabolic changes throughout the brains of patients with ALS. Statistical analysis involved an unpaired, uncorrected, two-sided Student t test. The NAA/Cho ratio across six regions was significantly lower by a mean of 23% (P ≤ .01) in patients with ALS than in control subjects. These regions included the caudate, lingual gyrus, supramarginal gyrus, and right and left superior and right inferior occipital lobes. The NAA/Cr ratio was significantly lower (P ≤ .01) in eight regions in the patient group, by a mean of 16%. These included the caudate, cuneus, frontal inferior operculum, Heschl gyrus, precentral gyrus, rolandic operculum, and superior and inferior occipital lobes. The Cho/Cr ratio did not significantly differ in any region between patient and control groups. Whole-brain echo-planar spectroscopic imaging permits detection of regional metabolic abnormalities in ALS, including not only the motor cortex but also several other regions implicated in ALS pathophysiologic findings.

P20 Frontal white matter connections and cognitive change in amyotrophic lateral sclerosis: a DTI-tractography study

<h3>Objective</h3> Traditionally considered a motor-neuron disorder, cognitive and behavioural impairments in a subset of non-demented amyotrophic lateral sclerosis (ALS) patients are now well-acknowledged. This study aimed to define the structural basis of cognitive abnormalities in ALS, by clarifying the involvement of specific cognitive domains and the respective contribution of white matter damage to the integrity of the uncinate (UF), inferior longitudinal (ILF) and inferior-frontal occipital (IFOF) fasciculi. <h3>Method</h3> 26 ALS patients and 27 healthy controls underwent a detailed neuropsychological assessment and a whole brain diffusion tensor imaging (DTI) scan. The two groups were matched for age, IQ, years of education, and anxiety and depression scores. Individual neuropsychological test scores were converted into four composite scores, measuring executive functions, language, memory and visuospatial ability. Changes in fractional anisotropy (FA) and mean diffusivity (MD) were measured along the UF, ILF, and the IFOF using a two-region of interest approach. <h3>Results</h3> ALS patients were found to exhibit impaired performance on the executive and language composite test scores, but not on memory and visuospatial composite test scores. DT-MRI investigations of the white matter association tracts (ie, UF, ILF and IFOF) identified no significant differences in ALS-patients compared to healthy controls with respect to mean FA values, indicating that water diffusion within these tracts still followed the main axonal direction. MD values however were found to be significantly increased within the uncinate fasciculus of ALS-patients compared to healthy controls. This is associated with neurodegeneration, as an increased MD typically arises from reduced barriers of diffusion, indicating weak axonal myelination. Correlational analysis did not find significant relationships between white matter tracts and neuropsychological composite scores. <h3>Conclusion</h3> The findings confirm the presence of executive dysfunction in ALS patients and also suggest that language deficits maybe more extensive and prevalent than has been suggested by previous research. These results suggest involvement of the UF within the disease-profile of ALS, however correlations to significant deficits remain to be found. If confirmed in a larger study this frontal white matter change could represent an important biomarker for trials in ALS.

7. Predominant motor involvement in the electrophysiological diagnosis of carpal tunnel syndrome

Objective: Analysis of the distribution of clinical and electrodiagnostic abnormalities in amyotrophic lateral sclerosis (ALS) may assist in planning an electrodiagnostic study of highest diagnostic yield and in determining the mechanisms of spread of motor system dysfunction. Methods: Clinical and electrophysiological data were prospectively acquired in a cohort of 142 patients with early ALS. Electrophysiological testing included detailed nerve conduction studies (NCS) and widespread electromyographic (EMG) sampling. Results: Significant rostral-caudal gradients of weakness were evident in lower limb and bulbar onset ALS. Upper limb onset groups demonstrated significant predominance of weakness ipsilateral to the limb of onset. Motor nerves were more frequently abnormal in upper than lower limbs, with neurophysiological evidence of the split hand phenomenon frequent. Terminal latency, conduction velocity, and minimum F-wave latency significantly correlated with CMAP amplitude in all nerve-muscle systems. In terms of high yield muscles, active and chronic denervation was most frequent in tibialis anterior (TA), abductor pollicis brevis (APB), first dorsal interosseous (FDI) and biceps brachii (BB). There was little side-to-side or rostral-caudal variation in EMG abnormalities between onset groups. Conclusions: Nerve conduction parameters confirmed the association between amplitude reduction and conduction slowing. Based on the findings from the present study, the highest diagnostic yield may be achieved through incorporation of NCS of tibial and median motor nerves, including F-wave responses, with EMG of TA, APB or FDI, and biceps bilaterally. While there may be apparently random progression of clinical weakness in patients with ALS, spread of pathology within cortical and spinal foci appears linked.

Iron Accumulation in Deep Cortical Layers Accounts for MRI Signal Abnormalities in ALS: Correlating 7 Tesla MRI and Pathology

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by cortical and spinal motor neuron dysfunction. Routine magnetic resonance imaging (MRI) studies have previously shown hypointense signal in the motor cortex on T2-weighted images in some ALS patients, however, the cause of this finding is unknown. To investigate the utility of this MR signal change as a marker of cortical motor neuron degeneration, signal abnormalities on 3T and 7T MR images of the brain were compared, and pathology was obtained in two ALS patients to determine the origin of the motor cortex hypointensity. Nineteen patients with clinically probable or definite ALS by El Escorial criteria and 19 healthy controls underwent 3T MRI. A 7T MRI scan was carried out on five ALS patients who had motor cortex hypointensity on the 3T FLAIR sequence and on three healthy controls. Postmortem 7T MRI of the brain was performed in one ALS patient and histological studies of the brains and spinal cords were obtained post-mortem in two patients. The motor cortex hypointensity on 3T FLAIR images was present in greater frequency in ALS patients. Increased hypointensity correlated with greater severity of upper motor neuron impairment. Analysis of 7T T2 *-weighted gradient echo imaging localized the signal alteration to the deeper layers of the motor cortex in both ALS patients. Pathological studies showed increased iron accumulation in microglial cells in areas corresponding to the location of the signal changes on the 3T and 7T MRI of the motor cortex. These findings indicate that the motor cortex hypointensity on 3T MRI FLAIR images in ALS is due to increased iron accumulation by microglia.

Localized Muscle Impedance Abnormalities in Amyotrophic Lateral Sclerosis

To assess changes in electrical impedance myography (EIM) parameters in amyotrophic lateral sclerosis (ALS). Ten patients with ALS and a cohort of normal subjects underwent EIM testing of tibialis anterior. Montages using voltage and current electrodes placed at a distance (far) and in close proximity (near) were compared. The EIM parameters, resistance (R), reactance (X), and phase (theta) in the patients with ALS, were compared with normal values. theta measured at 50 kHz using the near montage was most sensitive to the presence of ALS, with 9 of 10 patients with ALS having smaller theta values than the calculated lower limit of normal. theta using the far montage and X using both the near and far montages were also sensitive to disease, whereas R did not seem to be useful. EIM is sensitive to muscle abnormalities in ALS, with theta measured with near montages providing the best results.

Specific electron transport chain abnormalities in amyotrophic lateral sclerosis

In an amyotrophic lateral sclerosis (ALS) patient who also had an IgA gammopathy, autopsy studies identified the IgA in the surviving motor neurons. Further, the IgA bound the surface of isolated bovine motor neurons and inhibited neuronal proliferation in culture. To determine the pathologic basis of this IgA interaction with motor neurons, a neuroblastoma cDNA library was generated and screened with the IgA monoclonal antibody. Reactive clones were identified as flavin adenine dinucleotide (FAD) synthetase. To extend this finding to ALS in general, quantitative RT-PCRs were performed on blood samples from 26 ALS and 30 control blood samples to determine mRNA expression levels of FAD synthetase and other electron transport chain proteins, specifically riboflavin kinase (RFK), cytochrome C1 (CYC1), and succinate dehydrogenase complex subunit B (SDHB). All expression levels were measured against a control enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Expression levels for a non-respiratory chain protein (beta-actin) were also measured. We found that FAD synthetase expression levels were decreased in ALS samples compared to expression levels in controls (P = 0.0151). Expression levels for RFK, CYC1, and SDHB were also significantly decreased in the ALS group (P = 0.0025, P = 0.0002, and P < 0.0001, respectively). As control, expression levels for beta-actin did not show a significant difference between ALS and control groups (P = 0.2118). Our data show that a reduction in electron transport proteins, namely FAD synthetase, RFK, CYC1, and SDHB, is seen in patients with ALS. It is possible that this may have an effect on oxygen-dependent metabolic pathways. Human motor neurons may be particularly susceptible to injury if there is sub-optimal oxidative metabolism.

Focal transplantation–based astrocyte replacement is neuroprotective in a model of motor neuron disease

Cellular abnormalities in amyotrophic lateral sclerosis (ALS) are not limited to motor neurons. Astrocyte dysfunction occurs in human ALS and SOD1G93A animal models. Therefore, the value of focal enrichment of normal astrocytes was investigated using transplantation of lineage-restricted astrocyte precursors, Glial-Restricted Precursors (GRPs). GRPs were transplanted around cervical spinal cord respiratory motor neuron pools, the principal cells responsible for death in this neurodegenerative disease. GRPs survived in diseased tissue, differentiated efficiently into astrocytes, and reduced microgliosis in SOD1G93A rat cervical spinal cord. GRPs extended survival and disease duration, attenuated motor neuron loss, and slowed declines in fore-limb motor and respiratory physiological function. Neuroprotection was mediated in part by the primary astrocyte glutamate transporter, GLT1. These findings demonstrate the feasibility and efficacy of transplantation-based astrocyte replacement, and show that targeted multi-segmental cell delivery to cervical spinal cord is a promising therapeutic strategy for slowing focal motor neuron loss associated with ALS.

Clinical, electrophysiologic, and pathologic evidence for sensory abnormalities in ALS

Amyotrophic lateral sclerosis (ALS) is a progressive degenerative disease of upper and lower motor neurons. Reports of the nature and frequency of sensory nerve involvement in ALS have varied. We reviewed the Emory University motor neuron disease registry between 1997 and 2004 to identify 103 patients with ALS without coexisting diseases that might cause sensory abnormalities and for whom electrodiagnostic studies were available for review. Neurophysiologic studies were interpreted based on age-adjusted normative data from our laboratory. Twelve control biopsies were evaluated alongside 22 samples from patients with ALS to ensure blinded evaluation of pathologic specimens. Sensory symptoms or signs were present in 32% of patients, sural sensory nerve action potential amplitudes were abnormal in 27%, and pathologic abnormalities were present in 91% of patients. Large-caliber myelinated fibers were predominantly affected (reduced in 73%) and small-caliber myelinated fibers were affected less often (23%). Thinly myelinated fibers were present in 95% and regenerating clusters in 77% of the biopsies. Teased fiber analysis showed an increased frequency of axonal degeneration and regeneration as well as excessive myelin irregularity. Morphometry confirmed the loss of large-caliber fibers. These data indicate that one third of patients with amyotrophic lateral sclerosis report sensory symptoms and sural sensory response amplitudes are reduced in a similar proportion of subjects. Pathologic evidence of sensory nerve pathology was present in 91% of patients who underwent sural nerve biopsy. The electrophysiologic and pathologic findings indicate a pattern of axonal loss that predominantly affects large-caliber myelinated fibers.

Motor cortex abnormalities in amyotrophic lateral sclerosis with transcranial direct‐current stimulation

The aim of this study was to identify a neurophysiological marker of upper motoneuron involvement in patients with sporadic amyotrophic lateral sclerosis (ALS). For this purpose we evaluated the after-effects of transcranial direct-current stimulation (tDCS) on excitability of the motor cortex of eight ALS patients and eight healthy controls. Healthy controls showed a transient polarity-specific change in corticospinal excitability of about +/-45%, with anodal tDCS inducing facilitation and cathodal tDCS leading to inhibition, whereas no change could be induced in ALS patients after either type of tDCS. It is likely that the lack of tDCS after-effects in ALS is the result of alterations of the motoneuronal membrane or, alternatively, may represent an electrophysiological correlate of disordered glutamate neurotransmission. Further studies are warranted to confirm these results. The present findings may lead to a new, reliable electrophysiological marker of upper motoneuronal involvement in ALS.

Comparative proteomic profiling of cerebrospinal fluid between living and post mortem ALS and control subjects

Neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), lack definitive diagnostic tests or biomarkers of disease progression. Most studies that investigate protein abnormalities in ALS have used biofluids such as blood or cerebrospinal fluid (CSF), while some have used post mortem tissue or CSF samples. Since ALS disease progression and post mortem effects probably induce significant alterations to protein modifications or proteolysis, we directly examined the CSF proteome from ALS subjects at various lengths of time from symptom onset and at autopsy by mass spectrometry based proteomics. CSF was also obtained from both healthy age-matched control subjects and at autopsy from healthy and Alzheimer's disease (AD) controls. We identified significant differences in the CSF proteome between living and post mortem ALS subjects, as well as living and post mortem control subjects. We also noted differences in the CSF proteome of ALS subjects that have exhibited symptoms for varying lengths of time and between ALS and AD subjects at end-stage of disease. This is the first study describing differences in the CSF proteome from post mortem and living ALS subjects using a mass spectrometric approach. These differences highlight the importance of utilizing CSF from living ALS subjects near the time of symptom onset for the identification of early protein biomarkers, although some protein alterations that occur early in the disease process are maintained throughout the course of disease and in post mortem samples.

Implementation of X-ray Fluorescence Microscopy for Investigation of Elemental Abnormalities in Amyotrophic Lateral Sclerosis

The abnormalities of metallochemical reactions may contribute to the pathogenesis of Amyotrophic Lateral Sclerosis (ALS). In the present work, an investigation of the elemental composition of the gray matter, nerve cells and white matter from spinal cord tissues representing three ALS cases and five non-ALS controls was performed. This was done with the use of the synchrotron microbeam X-ray fluorescence technique (micro-SRXRF). The following elements were detected in the tissue sections: P, S, Cl, K, Ca, Fe, Cu, Zn and Br. A higher accumulation of Cl, K, Ca, Zn and Br was observed in the nerve cell bodies than in the surrounding tissue. Contrary to all other elements, Zn accumulation was lower in the white matter areas than in the gray matter ones. The results of quantitative analysis showed that there were no general abnormalities in the elemental accumulation between the ALS and the control group. However, for individual ALS cases such abnormalities were observed for the nerve cells. We also demonstrated differences in the elemental accumulation between the analyzed ALS cases.

Word retrieval in amyotrophic lateral sclerosis: a functional magnetic resonance imaging study.

The cognitive impairment revealed in some non- demented amyotrophic lateral sclerosis (ALS) patients is characterized by executive dysfunction with widely repeated deficits on tests of verbal (letter) fluency. However, conflicting evidence exists of an impairment on other word retrieval tasks, such as confrontation naming, which do not place heavy demands on executive processes. Previous research has demonstrated intact confrontation naming in the presence of verbal fluency deficits, although naming deficits have been described in other studies. In this investigation, functional MRI (fMRI) techniques were employed to explore whether word retrieval deficits and underlying cerebral abnormalities were specific to letter fluency, which are more likely to indicate executive dysfunction, or were also present in confrontation naming, indicating language dysfunction. Twenty-eight non-demented ALS patients were compared with 18 healthy controls. The two groups were matched for age, intelligence quotient, years of education, and anxiety and depression scores. Two compressed-sequence overt fMRI activation paradigms were employed, letter fluency and confrontation naming, which were developed for use with an older and potentially impaired population. In ALS patients relative to controls, the letter fluency fMRI task revealed significantly impaired activation in the middle and inferior frontal gyri and anterior cingulate gyrus, in addition to regions of the parietal and temporal lobes. The confrontation naming fMRI task also revealed impaired activation in less extensive prefrontal regions, including the inferior frontal gyrus and regions of the temporal, parietal and occipital lobes. These changes were present despite matched performance between patients and controls during each activation paradigm. The pattern of dysfunction corresponded to the presence of cognitive deficits on both letter fluency and confrontation naming in the ALS group. This study provides evidence of cerebral abnormalities in ALS in the network of regions involved in language and executive functions. Moreover, the findings further illustrate the heterogeneity of cognitive and cerebral change in ALS.

The natural history of central motor abnormalities in amyotrophic lateral sclerosis.

Degeneration of spinal motoneurons has been well documented in amyotrophic lateral sclerosis (ALS), but the evolution of central motor abnormalities is largely unknown. It has been suggested that glutamate-mediated neuroexcitotoxicity may be involved in the pathogenesis of ALS and that this may be manifest as an increase in corticomotor excitability early in the disease. Serial measurements of corticomotor threshold, central motor conduction time (CMCT), silent period duration and the amplitude of compound muscle action potentials (CMAPs) from ulnar nerve stimulation in the right and left first dorsal interosseous muscles were made in 76 patients with idiopathic ALS, 49 of whom were followed from presentation to death. Threshold to transcranial magnetic stimulation was determined by standard methods and CMCT was measured using the F-wave method. Silent period was estimated during a small background contraction of the muscle. Patients were classified according to the region of onset and the physical signs in the hands. The region of onset was bulbar in 17 patients, lower limb in 31 patients and upper limb in 28 patients. At presentation, 23 patients had no abnormal physical signs in the hands, 25 had lower motoneuron signs only, 14 had upper motoneuron signs only and the remainder (14) had mixed upper and lower motoneuron signs in the hands. Evolution of the central conduction parameters was determined in relation to time from onset of symptoms and also as a function of normalized total disease duration in the patients who had died. Corticomotor threshold and CMCT showed no change as the disease evolved except for patients with mixed signs, who had a terminal increase in threshold and prolongation of CMCT. Silent period duration was shorter than normal early in the disease and showed progressive lengthening throughout the illness, but nevertheless remained within the normal range regardless of the region of onset. CMAP amplitude showed a linear decline over the course of the disease. There was therefore no evidence of a phase of increased corticomotor hyperexcitability at any stage of disease progression. The early shortening of silent period, however, probably represents a shift in the balance of excitatory and inhibitory inputs to the cortical output cells responsible for voluntary action, and could be a reflection of degeneration of cortical interneurons. None of the measures of central motor function in ALS are likely to be useful for monitoring patients in a clinical trial setting.

Motor responses evoked by transcranial magnetic stimulation and peripheral nerve stimulation in the ulnar innervation in amyotrophic lateral sclerosis: the effect of upper and lower motor neuron lesion

We studied the upper (UMN) and lower motor neuron (LMN) innervations of 159 hands from 81 patients with amyotrophic lateral sclerosis (ALS). Eleven patients with various chronic LMN disorders causing weakness in the abductor digiti minimi (ADM) muscle served as LMN controls. Thirty healthy subjects served as normal controls. Cortical motor threshold, central conduction time (CMCT), and motor-evoked response amplitude (MEP) after transcranial magnetic stimulation (TMS) were studied, and the MEP/M wave ratio was calculated. The data was analyzed in the ALS subjects in groups defined by ADM muscle strength and by the presence or absence of clinical signs of UMN involvement. CMCT was not increased in the ALS or LMN disease groups. The threshold was higher in limbs with both weak ADM muscles and UMN signs. The MEP/M wave amplitude ratio was increased in weak muscles in the ALS patients, notably in limbs with no UMN signs, and also in weak muscles in patients with other chronic LMN disorders. It was frequently decreased in strong muscles. There was no difference between bulbar-onset and limb-onset ALS groups, and there was no correlation between threshold and disease duration. We suggest that expressing the data as an index and utilising the MEP/M wave amplitude ratio as a variable is a sensitive method for detecting UMN abnormality in ALS in particular in early affected muscles.

Subtle involvement of the sympathetic nervous system in amyotrophic lateral sclerosis.

The literature on the involvement of the autonomic nervous system (ANS) in amyotrophic lateral sclerosis (ALS) is conflicting. We therefore investigated several aspects of autonomic function, namely muscle sympathetic nerve activity (MSNA), blood pressure, cardiac function (electrocardiogram; ECG), and respiration in 16 patients with sporadic ALS and in 12 age-matched healthy volunteers, both at rest and during sympathoexcitatory stimulation. We measured MSNA by provoking venous pooling during short-lasting lower body negative pressure (LBNP) and during the cold pressor test (CPT). To assess the vagal (baroreflex) control of heart rate (HR), we measured spontaneous baroreflex sensitivity (BRS). To assess the involvement of the ANS beyond the cardiovascular system, we measured the sympathetic skin response (SSR). The stand-up test showed that none of the subjects had orthostatic intolerance. In comparison with the control group, the ALS patients had an increased HR and a decreased BRS at rest, and a reduced MSNA response to LBNP. The CPT response was normal and the total MSNA at rest did not differ significantly from that of controls. The latencies of the palmar and plantar SSR were prolonged, and in 3 ALS patients there was no plantar SSR. The results indicate that the sympathetic nervous system shows subtle abnormalities in ALS, predominantly sympathetic overactivity. They also point to the involvement of the preganglionic sympathetic column as the cause of the higher sympathetic activity and the absence of SSR. The higher sympathetic activity is postulated to be due to changes in modulation of the sympathetic system, whereas the absence of the SSR is probably caused by disruption of the reflex pathway.

Neurophysiological evaluation of cortical function in the early diagnosis of ALS.

The corticomotoneuronal system is selectively vulnerable in amyotrophic lateral sclerosis (ALS). In the past it has been difficult to evaluate the upper motor neuron component of this system. Recent studies using functional imaging and neurophysiological methods are now available as potential surrogate markers in the early diagnosis of ALS. We have used peristimulus time histograms (PSTHs) to evaluate the integrity of the motor cortex in ALS and in particular the cortical colonies that synapse with single anterior horn cells. The motor cortex in ALS becomes hyperexcitable early in the course of the disease and this may persist for some time. This is reflected in the PSTH by a desynchronized, complex response. Evidence indicates that this prime abnormality in ALS is supraspinal in origin and probably due to increased repetitive firing of the corticomotoneuron. The hyperexcitability is likely to be due to a combination of increased excitation at the level of the motor cortex and decreased inhibition due to dysfunction of the cortical inhibitory interneurones that modulate the output of the corticomotoneurone.

ALS-linked Cu/Zn-SOD mutation impairs cerebral synaptic glucose and glutamate transport and exacerbates ischemic brain injury.

Although degeneration of lower motor neurons is the most striking abnormality in amyotrophic lateral sclerosis (ALS), more subtle alterations may occur in the brain. Mutations in copper/zinc superoxide dismutase (Cu/Zn-SOD) are responsible for some cases of inherited ALS, and expression of mutant Cu/Zn-SOD in transgenic mice results in progressive motor neuron loss and a clinical phenotype similar to that of ALS patients. It is now reported that Cu/Zn-SOD mutant mice exhibit increased vulnerability to focal ischemic brain injury after transient occlusion of the middle cerebral artery. Levels of glucose and glutamate transport in cerebral cortex synaptic terminals were markedly decreased, and levels of membrane lipid peroxidation were increased in Cu/Zn-SOD mutant mice compared to nontransgenic mice. These findings demonstrate that mutant Cu/Zn-SOD may endanger brain neurons by a mechanism involving impairment of glucose and glutamate transporters. Moreover, our data demonstrate a direct adverse effect of the mutant enzyme on synaptic function.

Chapter 59 Are motor evoked potentials (MEPs) helpful in the differential diagnosis of spondylotic cervical myelopathy (SCM)?

Publisher Summary Motor evoked potentials (MEPs) exhibit an excellent sensitivity in various disorders affecting the upper motor neuron but are of limited value in the differential diagnosis. Only in amyotrophic lateral sclerosis (ALS), a normal central motor conduction time and normal threshold may indicate that a co-existing spondylotic myelopathy is of no relevance. Cervical spondylotic myelopathy (SCM or CSM) is the most serious manifestation of cervical spondylosis and the most common cause of myelopathy over the age of 60 years. The differential diagnosis of spondylotic cervical myelopathy (SCM) includes multiple sclerosis, ALS, primary lateral sclerosis (PLS), spinal tumors, and syringomyelia. Spinal tumors and syringomyelia can easily be detected with conventional imaging methods. The high frequency of spondylosis in the elderly population implies that quite a few patients with ALS and PLS can have spondylosis if not cervical myelopathy as well. In ALS, however, the pattern of MEP abnormalities is different. The central motor conduction time is usually reported as normal or marginally prolonged. The characteristic abnormality in ALS is a reduced MEP amplitude and abnormal morphology. Early in the disease, the cortical threshold is reduced. This implies that in an ALS patient with radiological evidence of cervical spondylosis or myelopathy, a normal central motor conduction time and normal or reduced threshold, is likely to lead to the conclusion that the spondylosis or myelopathy is of no clinical relevance. Such patient should not be selected for surgical treatment.