Primary Lateral Sclerosis Research Articles

Alfa-class prefoldin protein UXT is a novel interacting partner of Amyotrophic Lateral Sclerosis 2 (Als2) protein

Mutations in Als2 gene cause several autosomal recessive forms of motor neuron diseases including Juvenile Amyotrophic Lateral Sclerosis (JALS), Juvenile Primary Lateral Sclerosis (PLSJ) and Infantile-onset Ascending Hereditary Spastic Paralysis (IAHSP). To find novel protein–protein interactions of Als2 protein we performed a yeast two hybrid screen and fished out the Ubiquitously Expressed Transcript (UXT) protein. UXT is a novel gene encoding for an α-class prefoldin type chaperone which acts as a co-activator for various transcriptional factors such as Nf-κB and AR. The interaction between Als2 and UXT was confirmed by co-immunoprecipitation. Co-localization between endogenous Als2 and UXT was mainly found in the cytoplasm of neuronal Neuro2a cells with immunofluorescence microscopy. Cell cycle arrest of Neuro2a cells showed that Als2 and Uxt transcriptional levels are synchronously changing. Our results suggest that Als2 is a binding partner of Uxt and Als2/Uxt interaction could be important for the activation of Nf-κB pathway. These results provides basis for future research to investigate the role of Nf-κB pathway in the development of motor neuron diseases.

White matter alterations differ in primary lateral sclerosis and amyotrophic lateral sclerosis

Primary lateral sclerosis is a sporadic disorder characterized by slowly progressive corticospinal dysfunction. Primary lateral sclerosis differs from amyotrophic lateral sclerosis by its lack of lower motor neuron signs and long survival. Few pathological studies have been carried out on patients with primary lateral sclerosis, and the relationship between primary lateral sclerosis and amyotrophic lateral sclerosis remains uncertain. To detect in vivo structural differences between the two disorders, diffusion tensor imaging of white matter tracts was carried out in 19 patients with primary lateral sclerosis, 18 patients with amyotrophic lateral sclerosis and 19 age-matched controls. Fibre tracking was used to reconstruct the intracranial portion of the corticospinal tract and three regions of the corpus callosum: the genu, splenium and callosal fibres connecting the motor cortices. Both patient groups had reduced fractional anisotropy, a measure associated with axonal organization, and increased mean diffusivity of the reconstructed corticospinal and callosal motor fibres compared with controls, without changes in the genu or splenium. Voxelwise comparison of the whole brain white matter using tract-based spatial statistics confirmed the differences between patients and controls in the diffusion properties of the corticospinal tracts and motor fibres of the callosum. This analysis further revealed differences in the regional distribution of white matter alterations between the patient groups. In patients with amyotrophic lateral sclerosis, the greatest reduction in fractional anisotropy occurred in the distal portions of the intracranial corticospinal tract, consistent with a distal axonal degeneration. In patients with primary lateral sclerosis, the greatest loss of fractional anisotropy and mean diffusivity occurred in the subcortical white matter underlying the motor cortex, with reduced volume, suggesting tissue loss. Clinical measures of upper motor neuron dysfunction correlated with reductions in fractional anisotropy in the corticospinal tract in patients with amyotrophic lateral sclerosis and increased mean diffusivity and volume loss of the corticospinal tract in patients with primary lateral sclerosis. Changes in the diffusion properties of the motor fibres of the corpus callosum were strongly correlated with changes in corticospinal fibres in patients, but not in controls. These findings indicate that degeneration is not selective for corticospinal neurons, but affects callosal neurons within the motor cortex in motor neuron disorders.

Alterations of the Corpus Callosum as an MR Imaging–Based Hallmark of Motor Neuron Diseases

In motor neuron diseases (MNDs) such as amyotrophic lateral sclerosis (ALS) and primary lateral sclerosis (PLS), the definition of disease-related MR imaging characteristics is still ongoing. MR imaging approaches based on conventional and advanced techniques are frequently reported, aiming at the

Upper and extra-motoneuron involvement in early motoneuron disease: a diffusion tensor imaging study

Motoneuron disease is a term encompassing three phenotypes defined largely by the balance of upper versus lower motoneuron involvement, namely amyotrophic lateral sclerosis, primary lateral sclerosis and progressive muscular atrophy. However, neuroradiological and pathological findings in these phenotypes suggest that degeneration may exceed the neuronal system upon which clinical diagnosis is based. To further delineate the phenotypes within the motoneuron disease spectrum, this controlled study assessed the upper- and extra-motoneuron white matter involvement in cohorts of patients with motoneuron disease phenotypes shortly after diagnosis by comparing diffusion tensor imaging data of the different cohorts to those of healthy controls and directly between the motoneuron disease phenotypes (n = 12 for each cohort). Furthermore, we acquired follow-up data 6 months later to evaluate fractional anisotropy changes over time. Combined use of diffusion tensor tractography of the corticospinal tract and whole-brain voxel-based analysis allowed for comparison of the sensitivity of these techniques to detect white matter involvement in motoneuron disease. The voxel-based analysis demonstrated varying extents of white matter involvement in different phenotypes of motoneuron disease, albeit in quite similar anatomical locations. In general, fractional anisotropy reductions were modest in progressive muscular atrophy and most extensive in primary lateral sclerosis. The most extensive patterns of fractional anisotropy reduction were observed over time in the voxel-based analysis, indicating progressive extra-motor white matter degeneration in limb- and bulbar onset amyotrophic lateral sclerosis and in progressive muscular atrophy. The observation of both upper motor and extra-motoneuron involvement in all phenotypes of motoneuron disease shortly after diagnosis suggests that these are all part of a single spectrum of multisystem neurodegenerative disease. Voxel-based analysis was more sensitive to detect longitudinal changes than diffusion tensor tractography of the corticospinal tract. Voxel-based analyses may be particularly valuable in the evaluation of motor and extra-motor white matter involvement in the early symptomatic stages of motoneuron disease, and for monitoring the spread of pathology over time.

Dysregulation of the ALS-associated gene TDP-43 leads to neuronal death and degeneration in mice

Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are characterized by cytoplasmic protein aggregates in the brain and spinal cord that include TAR-DNA binding protein 43 (TDP-43). TDP-43 is normally localized in the nucleus with roles in the regulation of gene expression, and pathological cytoplasmic aggregates are associated with depletion of nuclear protein. Here, we generated transgenic mice expressing human TDP-43 with a defective nuclear localization signal in the forebrain (hTDP-43-ΔNLS), and compared them with mice expressing WT hTDP-43 (hTDP-43-WT) to determine the effects of mislocalized cytoplasmic TDP-43 on neuronal viability. Expression of either hTDP-43-ΔNLS or hTDP-43-WT led to neuron loss in selectively vulnerable forebrain regions, corticospinal tract degeneration, and motor spasticity recapitulating key aspects of FTLD and primary lateral sclerosis. Only rare cytoplasmic phosphorylated and ubiquitinated TDP-43 inclusions were seen in hTDP-43-ΔNLS mice, suggesting that cytoplasmic inclusions were not required to induce neuronal death. Instead, neurodegeneration in hTDP-43 and hTDP-43-ΔNLS-expressing neurons was accompanied by a dramatic downregulation of the endogenous mouse TDP-43. Moreover, mice expressing hTDP-43-ΔNLS exhibited profound changes in gene expression in cortical neurons. Our data suggest that perturbation of endogenous nuclear TDP-43 results in loss of normal TDP-43 function(s) and gene regulatory pathways, culminating in degeneration of selectively vulnerable affected neurons.

Neuropsychological Functioning in PLS: A Comparison with ALS

In order to characterize the nature and extent of neuropsychological dysfunction in primary lateral sclerosis (PLS), we studied prospectively cognitive, emotional, and behavioral functioning in PLS, and compared performances to functioning in amyotrophic lateral sclerosis (ALS). Eighteen patients with PLS and 13 patients with ALS completed a neuropsychological test battery assessing both cognitive skills and emotional/behavioral functioning. Both PLS and ALS groups scored broadly within normal limits (mean T-scores greater than 40) on all cognitive measures and no significant between-group differences were found with the exception of one variable. However, when examined on a case by case basis, the data revealed considerable heterogeneity amongst patients in both groups. Overall, 39% of PLS patients and 31% of ALS patients were considered cognitively impaired. Ahigher than expected frequency of abnormal scores was noted for several tests of executive function in both groups, and a majority of PLS patients also exhibited abnormal behavioural symptoms. There was no relationship in PLS or ALS groups between cognitive functioning and disease duration, current site of disease, site of onset, functional status, and respiratory variables. Comparison between the PLS and ALS groups indicated virtually no differences in cognitive test scores and overall emotional/behavioural symptoms. We observed deficits in cognition and behaviour in a significant proportion of PLS patients which were comparable to those observed in ALS cases. Although deficits were not in the range of frontotemporal dementia, both ALS and PLS cases demonstrated deficits most prominently on tests of executive functioning.

Voxel-based diffusion tensor imaging detects pyramidal tract degeneration in primary lateral sclerosis

Primary lateral sclerosis (PLS) is a progressive degenerative disorder affecting upper motor neurons and requires a clinical diagnosis. Diffusion tensor imaging (DTI) is a quantitative method for assessing white matter fibre integrity. The purpose of the study was to evaluate the involvement of upper motor neurons by using DTI in PLS. A patient with PLS was compared with eight age-matched controls. Differences in fractional anisotropy (FA) index were assessed using DTI on a voxel-by-voxel basis. Decreased FA was observed in the proximal part of the pyramidal tract bilaterally, which indicated degeneration of the pyramidal cells. Voxel-based DTI could be used as an objective marker for detecting upper motor neuron degeneration in PLS.

Magnetic resonance imaging and diffusion tensor imaging in primary lateral sclerosis

Magnetic resonance imaging and diffusion tensor imaging in primary lateral sclerosis

Hereditary primary lateral sclerosis with cone dysfunction

Purpose: To describe the clinical phenotype and electroretinographic changes in two siblings with primary hereditary lateral sclerosis.Materials and methods: Case series of two male siblings from a consanguineous family. A clinical evaluation and full field electroretinography according to International Society for Clinical Electrophysiology of Vision (ISCEV) standards was performed.Results: Both siblings had reduced central vision without nystagmus and a normal fundus examination. The electroretinogram showed cone dysfunction with markedly reduced amplitude 30-Hz flicker, and broad, delayed photopic single flash of normal amplitude. The rod driven electroretinography (ERG) b-waves were within the normal range.Conclusions: Cone dysfunction has not been reported previously in patients with primary lateral sclerosis. Although it is possible this is a chance association it is more likely that the retinal dysfunction is caused by the same genetic mutation causing the neurological disease. Investigation of other cases will be helpful in delineating the phenotype. The association may also help prioritize candidate gene analysis in the search for the underlying genetic mutation causing primary lateral sclerosis.

P7-10 Asymmetry of motor unit number estimation (MUNE) in patients with amyotrophic lateral sclerosis

Objective: Development of an electrophysiological biomarker of corticospinal tract (CST) degeneration for application as an electrodiagnostic test in Amyotrophic Lateral Sclerosis (ALS). ALS is a sporadic, progressive and fatal neurodegenerative disorder, which is characterised by loss of motoneurones within the brainstem and spinal cord, and degeneration of corticospinal tract (CST) neurons. While electrodiagnostic techniques for identifying motoneurone degeneration in ALS are well established, those for CST disease are not. We now have evidence from experiments in macaque monkeys that 15 30Hz intermuscular coherence (IMC), which is a measure of coupling between two EMG signals in the 15 30Hz frequency range, can be used to assess the integrity of the CST. We have therefore begun investigating the utility of IMC as an electrodiagnostic test in ALS patients. Methods: IMC was measured in 23 patients with ALS, including 10 patients with primary lateral sclerosis (PLS), the pure upper motor neurone variant of ALS in which there is only CST degeneration, and 6 patients with progressive muscular atrophy (PMA) the pure lower motor neurone variant of ALS. We also performed similar measures on healthy age-matched controls. Results: Significant 15 30Hz IMC was found in all patients with PMA, all age-matched controls (n = 15) and all non age-matched controls (n = 20) tested to date. However, none of the patients with PLS had significant 15 30Hz IMC. Conclusions: 15 30Hz IMC is dependent upon an intact CST and appears to be an inexpensive, simple and robust measure of CST degeneration in ALS. We are now investigating the diagnostic sensitivity and specificity of 15 30Hz IMC prospectively in a group of patients with clinically suspected/possible ALS, in which a significant proportion are likely to have an ALS mimic syndrome.

P7-7 The condition of bone marrow-MSCs of ALS patients is strongly associated with their prognosis

Objective: Development of an electrophysiological biomarker of corticospinal tract (CST) degeneration for application as an electrodiagnostic test in Amyotrophic Lateral Sclerosis (ALS). ALS is a sporadic, progressive and fatal neurodegenerative disorder, which is characterised by loss of motoneurones within the brainstem and spinal cord, and degeneration of corticospinal tract (CST) neurons. While electrodiagnostic techniques for identifying motoneurone degeneration in ALS are well established, those for CST disease are not. We now have evidence from experiments in macaque monkeys that 15 30Hz intermuscular coherence (IMC), which is a measure of coupling between two EMG signals in the 15 30Hz frequency range, can be used to assess the integrity of the CST. We have therefore begun investigating the utility of IMC as an electrodiagnostic test in ALS patients. Methods: IMC was measured in 23 patients with ALS, including 10 patients with primary lateral sclerosis (PLS), the pure upper motor neurone variant of ALS in which there is only CST degeneration, and 6 patients with progressive muscular atrophy (PMA) the pure lower motor neurone variant of ALS. We also performed similar measures on healthy age-matched controls. Results: Significant 15 30Hz IMC was found in all patients with PMA, all age-matched controls (n = 15) and all non age-matched controls (n = 20) tested to date. However, none of the patients with PLS had significant 15 30Hz IMC. Conclusions: 15 30Hz IMC is dependent upon an intact CST and appears to be an inexpensive, simple and robust measure of CST degeneration in ALS. We are now investigating the diagnostic sensitivity and specificity of 15 30Hz IMC prospectively in a group of patients with clinically suspected/possible ALS, in which a significant proportion are likely to have an ALS mimic syndrome.

Parkinsonism and motor neuron diseases: Twenty‐seven patients with diverse overlap syndromes

It has long been recognized that signs of motor neuron disease (MND) may accompany clinical evidence of parkinsonism in different neurodegenerative conditions. By using the Columbia University Division of Movement Disorders database, we reviewed data from 5,500 cases of parkinsonism and recorded the presence of upper motor neuron (UMN) dysfunction, lower motor neuron (LMN) dysfunction, or both. Among the 27 patients so identified, we counted those with autonomic dysfunction, cerebellar dysfunction, or dementia. Among the 27 cases, seven had UMN signs and LMN signs as well as parkinsonism and were diagnosed with amyotrophic lateral sclerosis (ALS)-parkinsonism (Brait-Fahn disease). Three of the seven had dementia that was not deemed to be frontotemporal dementia (FTD). Six other patients had no LMN signs but had UMN signs and parkinsonism and were classified as having primary lateral sclerosis (PLS)-parkinsonism. Four patients had both UMN and LMN signs with parkinsonism as well as the characteristic dementia of FTD; they were diagnosed with FTD-parkinsonism-ALS. Seven patients had MND, parkinsonism, and autonomic or cerebellar dysfunction, a combination compatible with multiple system atrophy (MSA). Three patients had syndromes compatible with hereditary spastic paraplegia (HSP). In sum, we found that MND occurs in association with diverse parkinsonian syndromes; some are heritable, others sporadic and causes are uncertain. Having MND may be a risk factor for parkinsonism. A prospective study may elucidate this possibility.

Clinicopathological characteristics of FTLD-TDP showing corticospinal tract degeneration but lacking lower motor neuron loss

The presence of frontotemporal lobar degeneration with TDP-43-positive inclusions (FTLD-TDP) showing corticospinal tract (CST) degeneration but lacking lower motor neuron (LMN) loss has been reported, and the term primary lateral sclerosis (PLS) is used to distinguish motor neuron disease (MND) of these cases from amyotrophic lateral sclerosis (ALS). To date, however, details of clinicopathological findings of FTLD-MND-PLS type (FTLD-MND-P) have not been reported. We evaluated medical records and histopathological findings of ten cases of FTLD-MND-P, in comparison with those of six FTLD-MND-ALS type (FTLD-MND-A) cases. The mean age at onset and disease duration of FTLD-MND-P cases were 54 and 12 years, respectively. The first symptoms were frontotemporal dementia showing behavioral abnormality and/or personality change in five cases, semantic dementia in three cases, progressive non-fluent aphasia in one case, and auditory hallucination in one case. Upper motor neuron signs were clinically identified in six of the ten cases. There were no LMN signs throughout the clinical course in any case. Histopathologically, there was no obvious LMN loss or Bunina bodies in the hypoglossal nucleus or spinal cord in any case, whereas the CST was involved in all cases. The cerebral cortex of the six cases showed type 1 of TDP-43 histology defined by Cairns et al., whereas three cases showed type 3 histology, and one case showed type 2 histology. In all cases, TDP-43 positive neuronal cytoplasmic inclusions were absent or rare in the LMNs, while TDP-43 positive round structures were frequently identified in the neuropil of the spinal cord anterior horn in some cases. This study clarified that FTLD-MND-P cases have characteristic clinicopathological features distinct from those of FTLD-MND-A.

Langsam progressive Dysarthrophonie bei primärer Lateralsklerose

Slowly progressive dysarthria over many years may be the only sign of primary lateral sclerosis (PLS). Clinically it presents as pseudobulbar palsy which can be differentiated from amyotrophic lateral sclerosis (ALS) by the longer disease duration (> or =4 years), central pathological magnetic-evoked potentials to the tongue and lack of denervation in EMG. In contrast, hereditary spastic paraplegia (HSP) is characterized by a primary spasticity of the lower limbs, mostly later onset, the fact that other family members are affected and in isolated cases by positive genetic testing for mutations.

Marked accumulation of 27-hydroxycholesterol in SPG5 patients with hereditary spastic paresis

Patients with a recessively inherited "pure" hereditary spastic paresis (SPG5) have mutations in the gene coding for the oxysterol 7 alpha hydroxylase (CYP7B1). One of the expected metabolic consequences of such mutations is accumulation of oxysterol substrates due to decreased enzyme activity. In accordance with this, we demonstrate here that four patients with the SPG5 disease have 6- to 9-fold increased plasma levels of 27-hydroxycholesterol. A much higher increase, 30- to 50-fold, was found in cerebrospinal fluid. The plasma levels of 25-hydroxycholesterol were increased about 100-fold. There were no measurable levels of this oxysterol in cerebrospinal fluid. The pattern of bile acids in serum was normal, suggesting a normal bile acid synthesis. The findings are discussed in relation to two transgenic mouse models with increased levels of 27-hydroxy cholesterol in the circulation but without neurological symptoms: the cyp27a1 transgenic mouse and the cyp7b1 knockout mouse. The absolute plasma levels of 27-hydroxycholesterol in the latter models are, however, only about 20% of those in the SPG5 patients. If the accumulation of 27-hydroxycholesterol is an important pathogenetic factor, a reduction of its levels may reduce or prevent the neurological symptoms. A possible strategy to achieve this is discussed.

Towards a user-friendly brain–computer interface: Initial tests in ALS and PLS patients

Patients usually require long-term training for effective EEG-based brain-computer interface (BCI) control due to fatigue caused by the demands for focused attention during prolonged BCI operation. We intended to develop a user-friendly BCI requiring minimal training and less mental load. Testing of BCI performance was investigated in three patients with amyotrophic lateral sclerosis (ALS) and three patients with primary lateral sclerosis (PLS), who had no previous BCI experience. All patients performed binary control of cursor movement. One ALS patient and one PLS patient performed four-directional cursor control in a two-dimensional domain under a BCI paradigm associated with human natural motor behavior using motor execution and motor imagery. Subjects practiced for 5-10min and then participated in a multi-session study of either binary control or four-directional control including online BCI game over 1.5-2h in a single visit. Event-related desynchronization and event-related synchronization in the beta band were observed in all patients during the production of voluntary movement either by motor execution or motor imagery. The online binary control of cursor movement was achieved with an average accuracy about 82.1+/-8.2% with motor execution and about 80% with motor imagery, whereas offline accuracy was achieved with 91.4+/-3.4% with motor execution and 83.3+/-8.9% with motor imagery after optimization. In addition, four-directional cursor control was achieved with an accuracy of 50-60% with motor execution and motor imagery. Patients with ALS or PLS may achieve BCI control without extended training, and fatigue might be reduced during operation of a BCI associated with human natural motor behavior. The development of a user-friendly BCI will promote practical BCI applications in paralyzed patients.

Whole brain‐based analysis of regional white matter tract alterations in rare motor neuron diseases by diffusion tensor imaging

Different motor neuron disorders (MNDs) are mainly defined by the clinical presentation based on the predominance of upper or lower motor neuron impairment and the course of the disease. Magnetic resonance imaging (MRI) mostly serves as a tool to exclude other pathologies, but novel approaches such as diffusion tensor imaging (DTI) have begun to add information on the underlying pathophysiological processes of these disorders in vivo. The present study was designed to investigate three different rare MNDs, i.e., primary lateral sclerosis (PLS, N = 25), hereditary spastic paraparesis (HSP, N = 24), and X-linked spinobulbar muscular atrophy (X-SBMA, N = 20), by use of whole-brain-based DTI analysis in comparison with matched controls. This analysis of white matter (WM) impairment revealed widespread and characteristic patterns of alterations within the motor system with a predominant deterioration of the corticospinal tract (CST) in HSP and PLS patients according to the clinical presentation and also in patients with X-SBMA to a lesser degree, but also WM changes in projections to the limbic system and within distinct areas of the corpus callosum (CC), the latter both for HSP and PLS. In summary, DTI was able to define a characteristic WM pathoanatomy in motor and extra-motor brain areas, such as the CC and the limbic projectional system, for different MNDs via whole brain-based FA assessment and quantitative fiber tracking. Future advanced MRI-based investigations might help to provide a fingerprint-identification of MNDs.

Slowly progressive dysarthria (pseudobulbar palsy) in primary lateral sclerosis

Slowly progressive dysarthria (pseudobulbar palsy) in primary lateral sclerosis

A pilot study of the prevalence of psychiatric disorders in PLS and ALS

The prevalence of psychiatric disorders in primary lateral sclerosis (PLS) is currently unknown. In the present study, we compared the prevalence of psychiatric illness in patients with PLS and amyotrophic lateral sclerosis (ALS). We hypothesized that if the psychosocial stress of motor neuron disease predisposes patients to depressive disorders, patients with ALS (with a poorer prognosis and more disability than patients with PLS) should have a higher prevalence of depressive disorders than patients with PLS. We administered the gold standard of psychiatric assessment, the SCID, to 19 PLS and 13 ALS patients. We found a prevalence of current depressive disorders in PLS patients that was, by a non-significant trend, lower than that of ALS patients. The prevalence of current depressive disorders in the ALS patients was higher than previously reported and similar to that observed in non-neurological medical disorders. Other psychiatric disorders were rare. In conclusion, depressive disorders were the most commonly observed psychiatric disorders in both PLS and ALS. By a non-significant trend, the PLS patients had a lower current prevalence of depressive disorders than the ALS patients. These data are consistent with the hypothesis that the psychosocial stress of MND is a risk factor for depression.

Primary lateral sclerosis may occur within familial amyotrophic lateral sclerosis pedigrees

Primary lateral sclerosis (PLS) is considered to be a specific sporadic motor neuron disorder, but some reports have shown familial history of motor neuron disorders that may comprise PLS cases. Here we report a novel pedigree highlighting an intrafamilial occurrence of PLS and amyotrophic lateral sclerosis (ALS) cases. These observations strengthen the hypothesis that PLS may represent an ALS phenotype with a long evolution and strongly suggest the involvement of common genetic factors that can lead to upper and lower motor neuron death.