Primary Lateral Sclerosis Research Articles

Hexanucleotide repeat expansions in C9ORF72 in the spectrum of motor neuron diseases

To assess the frequency and phenotype of hexanucleotide repeat expansions in C9ORF72 in a large cohort of patients of Dutch descent with familial (fALS) and sporadic (sALS) amyotrophic lateral sclerosis (ALS), progressive muscular atrophy (PMA), and primary lateral sclerosis (PLS). Included were 78 patients with fALS, 1,422 with sALS, 246 with PMA, and 110 with PLS, and 768 control subjects. Repeat expansions were determined by a repeat primed PCR. Familial aggregation of dementia and Parkinson disease (PD) was examined among patients with ALS who carried the repeat expansion. The expanded repeat was found in 33 (37%) of all patients with fALS, in 87 (6.1%) patients with sALS, in 4 (1.6%) patients with PMA, and in 1 (0.9%) patient with PLS. None of the controls carried the mutation. Patients with ALS with the repeat expansion had an earlier age at onset (median 59.3 vs 61.9 years, hazard ratio 1.55, p = 5 × 10(-5)) and shorter survival (median 2.5 vs 2.7 years, hazard ratio 1.46, p = 8 × 10(-4)). Dementia, but not PD, occurred nearly twice as often in relatives of patients with the expansion compared to all patients with ALS or controls (p = 9 × 10(-4)). The hexanucleotide repeat expansion in C9ORF72 is a major cause of fALS and apparently sporadic ALS in the Netherlands. Patients who carry the repeat expansion have an earlier onset, shorter survival, and familial aggregation of dementia. These results challenge the classic definition of fALS and may justify genetic testing in patients with sALS.

The expansions of ALS

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative condition of upper and lower motor neurons. Clinical presentation is heterogeneous and is usually segregated by site of onset (bulbar vs spinal). Extreme phenotypes with better prognosis include primary lateral sclerosis (PLS) (pure upper motor neuron involvement) and progressive muscular atrophy (PMA) (pure lower motor neuron involvement).1 Although primarily a disorder of the motor system, ALS also has nonmotor features. Cognitive impairment occurs in up to 50% of cases, and 1 patient in 8 develops frank frontotemporal dementia (FTD).2 There is some evidence that ALS and FTD may form part of a disease continuum, with “pure” ALS at one extreme and “pure” FTD at the other.

Beta-band intermuscular coherence: a novel biomarker of upper motor neuron dysfunction in motor neuron disease

In motor neuron disease, the focus of therapy is to prevent or slow neuronal degeneration with neuroprotective pharmacological agents; early diagnosis and treatment are thus essential. Incorporation of needle electromyographic evidence of lower motor neuron degeneration into diagnostic criteria has undoubtedly advanced diagnosis, but even earlier diagnosis might be possible by including tests of subclinical upper motor neuron disease. We hypothesized that beta-band (15–30 Hz) intermuscular coherence could be used as an electrophysiological marker of upper motor neuron integrity in such patients. We measured intermuscular coherence in eight patients who conformed to established diagnostic criteria for primary lateral sclerosis and six patients with progressive muscular atrophy, together with 16 age-matched controls. In the primary lateral sclerosis variant of motor neuron disease, there is selective destruction of motor cortical layer V pyramidal neurons and degeneration of the corticospinal tract, without involvement of anterior horn cells. In progressive muscular atrophy, there is selective degeneration of anterior horn cells but a normal corticospinal tract. All patients with primary lateral sclerosis had abnormal motor-evoked potentials as assessed using transcranial magnetic stimulation, whereas these were similar to controls in progressive muscular atrophy. Upper and lower limb intermuscular coherence was measured during a precision grip and an ankle dorsiflexion task, respectively. Significant beta-band coherence was observed in all control subjects and all patients with progressive muscular atrophy tested, but not in the patients with primary lateral sclerosis. We conclude that intermuscular coherence in the 15–30 Hz range is dependent on an intact corticospinal tract but persists in the face of selective anterior horn cell destruction. Based on the distributions of coherence values measured from patients with primary lateral sclerosis and control subjects, we estimated the likelihood that a given measurement reflects corticospinal tract degeneration. Therefore, intermuscular coherence has potential as a quantitative test of subclinical upper motor neuron involvement in motor neuron disease.

Motor unit firing in amyotrophic lateral sclerosis and other upper and lower motor neurone disorders

ObjectiveMotor unit recruitment order and firing rate was investigated in healthy subjects, and in small numbers of patients 50years ago. We aimed to investigate firing rate in different disorders, testing the same target muscle with normal strength, to evaluate possible application in diagnosing upper motor neuron (UMN) lesion. MethodsWe studied motor unit firing in the tibialis anterior muscle in six groups of subjects; normal subjects (n=45), patients with amyotrophic lateral sclerosis (ALS) (n=36), primary lateral sclerosis (PLS) (n=21), progressive muscular atrophy (PMA) (n=14), various upper motor neurone lesions (n=16) and polyneuropathy (n=42). In all these subjects the tibialis anterior muscle was of normal strength. Motor units were recruited during slight contraction in order to study 2–5 motor units at each recording site, using a standard concentric needle electrode, so that 20–22 motor units were recorded in each muscle. We analysed the coefficient of variation (CV) for amplitude, area, duration and firing rate in these motor units, and the correlation between motor unit potential size and recruitment order. ResultsThe mean MU firing rate in this task was similar in each group. No recruitment order was disclosed within the limits of the study task. The CV of firing rate was decreased in UMN and PLS groups. ALS patients with marked spasticity showed a lower CV of motor unit firing rate. The CV of amplitude, area and duration was similar between groups. ConclusionsThese results in tibialis anterior indicate that physiological modulation of lower motor neuron (LMN) firing rate is decreased in patients with lower limb spasticity. The variability of MU discharges tends to be greater in diseases affecting the LMN. SignificanceThese results suggest that, notwithstanding the simplicity of the task we have used, the physiological variability of motor unit firing may be a useful variable in assessing UMN involvement in motor system disorders.

Neuroanatomical patterns of cerebral white matter involvement in different motor neuron diseases as studied by diffusion tensor imaging analysis

This study was designed to investigate differences of white matter (WM) involvement patterns in various motor neuron disorders (MND) by use of diffusion tensor imaging (DTI).DTI was acquired in ALS (n = 20), primary lateral sclerosis (n = 20), pure hereditary spastic paraparesis (HSP) (n = 20), and complicated HSP (n = 12). The data analysis was performed by voxelwise comparison of fractional anisotropy (FA) maps at group level together with fibre tracking in regions of interest (ROI) accompanied by tractwise fractional anisotropy statistics. DTI analysis revealed widespread patterns of alterations with a predominant deterioration of the motor system. These alterations encompassed, as the key structures, not only the corticospinal tracts (CST) but also distinct areas of the corpus callosum (CC), in particular its motor segment III. In conclusion, whole brain-based and tract-based DTI analysis was able to define a distinct WM pathoanatomy of different MND. These results may serve as an additional guidance in the identification of MRI-based parameters by showing a consistent CST and CC involvement, with differences in the extent of pathology, across a range of clinically different disorders. For potential future developments in MRI diagnostics in MND, a (perhaps multiparametric) ROI-based approach should include CST and the CC motor segment.

Novel <emph type="ital">FUS</emph> Deletion in a Patient With Juvenile Amyotrophic Lateral Sclerosis

Juvenile amyotrophic lateral sclerosis (JALS) refers to a form of amyotrophic lateral sclerosis (ALS) in which a progressive upper and lower motor neuron degeneration begins before 25 years of age. It is generally associated with slow disease progression. During the past decade, a number of genes have been reported to cause JALS. Mutations in the ALSIN gene cause JALS type 2 (ALS2) as well as juvenile primary lateral sclerosis and infantile-onset ascending spastic paralysis. Mutations in the SETX gene can also sometimes lead to JALS. Conversely, mutations in SOD1, TARDBP, and FUS typically cause pure ALS, with adult onset between 46 and 56 years of age and usually rapid progression over 3 to 5 years. Recently, a few mutations in FUS have been associated with juvenile-onset of ALS characterized by a very rapid progression. To investigate the genetics of a patient with juvenile-onset ALS. We sequenced all the coding exons of SOD1, TARDBP, and FUS in a 19-year-old patient experiencing rapid degeneration of upper and lower motor neurons. A novel 1-base pair deletion was detected in exon 14 of the FUS gene, leading to a frameshift and the integration of 33 new amino acids. The variant p.R495QfsX527 is located in the highly conserved, extreme C terminal of the FUS protein, where most of the mutations in FUS have been identified. The variant was also identified in the unaffected 47-year-old mother of the patient, who remains asymptomatic. Our finding, along with other research, further confirms that FUS mutations can lead to an early-onset malignant form of ALS. In addition, our data lend additional support to the notion that disruption of the conserved C terminal of FUS is critical for developing ALS.

White Matter Damage in Amyotrophic Lateral Sclerosis and Primary Lateral Sclerosis: A Tract-Based Spatial Statistics Study (P03.162)

White Matter Damage in Amyotrophic Lateral Sclerosis and Primary Lateral Sclerosis: A Tract-Based Spatial Statistics Study (P03.162)

The Role of Diffusion Tensor Imaging To Uncover Primary Lateral Sclerosis Masquerading as Progressive Supranuclear Palsy (P03.118)

The Role of Diffusion Tensor Imaging To Uncover Primary Lateral Sclerosis Masquerading as Progressive Supranuclear Palsy (P03.118)

Primary lateral sclerosis as progressive supranuclear palsy: Diagnosis by diffusion tensor imaging

Evaluating the integrity of white matter tracts with diffusion tensor imaging may differentiate primary lateral sclerosis from progressive supranuclear palsy. Thirty-three prospectively recruited subjects had standardized evaluations and diffusion tensor imaging: 3 with primary lateral sclerosis who presented with features suggestive of progressive supranuclear palsy, 10 with probable or definite progressive supranuclear palsy, and 20 matched controls. We compared fractional anisotropy of the corticospinal tract, superior cerebellar peduncles, and body of the corpus callosum between groups. Both the primary lateral sclerosis and progressive supranuclear palsy subjects showed reduced fractional anisotropy in superior cerebellar peduncle and body of the corpus callosum compared with controls, but only primary lateral sclerosis subjects showed reductions in the corticospinal tracts. A ratio of corticospinal tract/superior cerebellar peduncle best distinguished the disorders (P < .02). The corticospinal tract/superior cerebellar peduncle ratio is a marker to differentiate primary lateral sclerosis from progressive supranuclear palsy.

Adolf von Strümpell: a key yet neglected protagonist of neurology

German internist and neurologist Adolf von Strümpell (1853-1925) was a leading figure in German neurosciences around 1900 and helped to establish neurology as a discipline in its own right. He made contributions that were crucial to the development of the subject and in many cases his were the first descriptions of complex diseases such as Bechterew disease (ankylosing spondylitis), primary lateral sclerosis, hereditary spastic paraplegia, and syphilis. His Textbook of Special Pathology and Therapy of Internal Diseases, published in English as Text-book of Medicine for Students and Practitioners, and in particular the subvolume on neurological diseases, were the guiding manuals for the training in neurology for decades. However, despite his pioneering achievements, his name has almost become unknown within medical terminology. This article, therefore, wishes to revive an awareness not only of the most important stages in Strümpell's life in Erlangen, Leipzig, Breslau (Wrocław), and Vienna, but also of his scientific achievements, focusing primarily on his neurological studies. To this end, the article reviews his most important publications on the subject and seeks to evaluate their and hence Strümpell's impact on the understanding of certain illnesses.

AAV2 mediated retrograde transduction of corticospinal motor neurons reveals initial and selective apical dendrite degeneration in ALS

Corticospinal motor neurons (CSMN) are the cortical component of motor neuron circuitry, which controls voluntary movement and degenerates in diseases such as amyotrophic lateral sclerosis, primary lateral sclerosis and hereditary spastic paraplegia. By using dual labeling combined with molecular marker analysis, we identified AAV2–2 mediated retrograde transduction as an effective approach to selectively target CSMN without affecting other neuron populations both in wild-type and hSOD1G93A transgenic ALS mice. This approach reveals very precise details of cytoarchitectural defects within vulnerable neurons in vivo. We report that CSMN vulnerability is marked by selective degeneration of apical dendrites especially in layer II/III of the hSOD1G93A mouse motor cortex, where cortical input to CSMN function is vastly modulated. While our findings confirm the presence of astrogliosis and microglia activation, they do not lend support to their direct role for the initiation of CSMN vulnerability. This study enables development of targeted gene replacement strategies to CSMN in the cerebral cortex, and reveals CSMN cortical modulation defects as a potential cause of neuronal vulnerability in ALS.

Nigro-striatal involvement in primary progressive freezing gait: Insights into a heterogeneous pathogenesis

Primary progressive freezing gait (PPFG) is a clinical syndrome underlain by diverse neurodegenerative diseases and characterized by early occurrence of gait freezing. Either degeneration or integrity of the nigrostriatal terminals have been found by SPECT and PET studies. In this retrospective study, we evaluated 123I-FP-CIT SPECT findings in a consecutive series of 13 PPFG patients with detailed clinical evaluation over time (mean follow-up duration: 3.1 ± 1.2 years). In all patients, 123I-FP-CIT SPECT has been performed at the time of first clinical evaluation (1.7 ± 1.4 years after disease onset) and was compared with data from 23 age- and sex-matched healthy subjects. PPFG patients were categorized as having abnormal (n = 8) or normal (n = 5) SPECT. At disease onset, PPFG with abnormal SPECT had more frequent hypophonia, higher UPDRS-III scores and partial levodopa responsiveness. By contrast, PPFG with normal SPECT had more frequent bilateral plantar responses and no response to levodopa. At latest follow-up, initial diagnosis in the abnormal SPECT group was revised (n = 5) to progressive supranuclear palsy (n = 4) and pure akinesia with gait freezing (n = 1). Among the five patients with normal SPECT, follow-up evaluation disclosed corticobasal syndrome (n = 2) and primary lateral sclerosis (n = 1). Dopamine transporter imaging can capture the clinical heterogeneity of PPFG and might have a value to predict possible disease progression.

Tongue's motor evoked potentials in the diagnosis of Primary Lateral Sclerosis (PLS): Preliminary report

BackgroundPrimary Lateral Sclerosis (PLS) is an adult-onset neurodegenerative disorder due to a selective loss of precentral pyramidal neurons. Our purpose was to evaluate preferential impairment of pyramidal tract to bulbar muscles in patients with PLS and identify a valuable electrophysiological method to help clinicians in the differential diagnosis from Amyotrophic Lateral Sclerosis (ALS). Materials and methodsWe recorded Motor Evoked Potentials (MEPs) from tongue's and anterior tibialis muscles in six patients with PLS and compared the results, in terms of Central Motor Conduction Time (CMCT), amplitude of MEPs and duration of controlateral silent period (cSP), with those obtained both from ten age-matched healthy volunteers and ten patients affected by ALS. ResultsFor lower limbs, CMCT resulted significantly increased in PLS and ALS samples compared with healthy subjects (p<0.01); we did not disclose any difference between ALS and PLS groups (p=0.417). Instead for tongue's recordings, CMCT, absolute amplitude of MEPs and cSP were significantly altered in PLS patients towards both ALS patients and healthy volunteers. ConclusionsWe showed that tongue's MEPs are selectively impaired in PLS. This technique could be helpful to differentiate patients with PLS from those affected by upper motor neuron-predominant variants of ALS. Tongue's MEPs could represent an interesting electrodiagnostic test, potentially useful for the diagnosis of PLS.

161 15–30 Hz intermuscular coherence as a potential biomarker of upper motor neuron dysfunction in motor neuron disease

Motor neuron disease (MND) involves the degeneration of variable proportions of upper and lower motor neurons (UMNs, LMNs). Electrophysiological tests for LMN degeneration are well established but an analogous biomarker...

090 The phenotype of Voltage Gated Potassium Channel (VGKC) antibody positive patients at the Walton Centre for neurology and neurosurgery. A retrospective analysis of 52 patients

A patient presented to the Walton Centre for Neurology and Neurosurgery (WCNN) with non-specific fatigue. A voltage gated potassium channel (VGKC) antibody assay was requested, among other investigations. A titre...

Tissue Engineering Approaches for Motor Neuron Pathway Regeneration

Tissue Engineering Approaches for Motor Neuron Pathway Regeneration During fetal development, a tightly-regulated spatio-temporal pattern of guidance cues directs and maintains motor neuron axonal growth along specific pathways to reach the target cells and tissues. However, an inflammatory environment resulting from an injury (e.g., trauma, stroke) or disease [e.g., amyotrophic lateral sclerosis (ALS), primary lateral sclerosis (PLS), and hereditary spastic paraplegia (HSP)] leads to progressive degeneration of motor neurons and destruction of axonal tracts in the adult CNS.

"Wine-glass appearance" of pyramidal tracts in a patient with primary lateral sclerosis

"Wine-glass appearance" of pyramidal tracts in a patient with primary lateral sclerosis

Speech synthesis technologies for individuals with vocal disabilities: Voice banking and reconstruction

In this invited paper, we overview the clinical applications of speech synthesis technologies and explain a few selected researches. We also introduce the University of Edinburgh’s new project ‘‘Voice Banking and reconstruction’’ for patients with degenerative diseases, such as motor neurone disease and Parkinson’s disease and show how speech synthesis technologies can improve the quality of life for the patients. 1.1. Speech Disorder and Impairment Speech disorders have a variety of causes. The major neurological degenerative diseases resulting in severe speech disorders include Motor Neurone Disease (MND), Parkinson’s, and Multiple Sclerosis; non-progressive conditions resulting in such disorders include Stroke and Cerebral Palsy. Speech impairment may also be caused by conditions such as cancer of the vocal cords, resulting in laryngectomy. MND, also known in the USA as Amyotrophic Lateral Sclerosis (ALS) or Lou Gehrig’s disease, is a debilitating neurological disease that results from the degeneration and death of the large motor neurones in the brain and spinal cord. This causes a worsening muscle weakness that leads to loss of mobility and difficulties with swallowing, breathing and speech production. Approximately 75% of MND patients are unable to speak by the time of their death [1]. There are four types of MNDs. Most cases of ALS and Progressive Bulbar Palsy are recorded in over 60’s. Age of onset of Primary Lateral Sclerosis is fifty years. Age of onset of Progressive Muscular Atrophy is usually under fifty years. About 100 new cases of MND are diagnosed in Scotland, U.K. each year.

Primary lateral sclerosis: Upper‐motor‐predominant amyotrophic lateral sclerosis with frontotemporal lobar degeneration – immunohistochemical and biochemical analyses of TDP‐43

Primary lateral sclerosis (PLS) is clinically defined as a disorder selectively affecting the upper motor neuron (UMN) system. However, recently it has also been considered that PLS is heterogeneous in its clinical presentation. To elucidate the association of PLS, or disorders mimicking PLS, with 43-kDa TAR DNA-binding protein (TDP-43) abnormality, we examined two adult patients with motor neuron disease, which clinically was limited almost entirely to the UMN system, and was followed by progressive frontotemporal atrophy. In the present study, the distribution and severity, and biochemical profile of phosphorylated TDP-43 (pTDP-43) in the brains and spinal cords were examined immunohistochemically and biochemically. Pathologically, in both cases, frontotemporal lobar degeneration with ubiquitin inclusions (FTLD-U) was evident, with the most severe degeneration in the motor cortex. An important feature in both cases was the presence of Bunina bodies and/or ubiquitin inclusions, albeit very rarely, in the well preserved lower motor neurons. The amygdala and neostriatum were also affected. pTDP-43 immunohistochemistry revealed the presence of many positively stained neuronal cytoplamic inclusions (NCIs) and dystrophic neurites/neuropil threads in the affected frontotemporal cortex and subcortical gray matter. By contrast, such pTDP-43 lesions, including NCIs, were observed in only a few lower motor neurons. pTDP-43 immunoblotting revealed that fragments of ∼25-kDa were present in the cortices, but not in the spinal cord in both cases. Genetically, neither of the patients had any mutation in the TDP-43 gene. In conclusion, we consider that although PLS may be a clinically significant disease entity, at autopsy, the majority of such clinical cases would present as upper-motor-predominant amyotrophic lateral sclerosis with FTLD-TDP.

Brain Fludeoxyglucose F 18 Positron Emission Tomography Hypometabolism in Magnetic Resonance Imaging–Negative X-Linked Adrenoleukodystrophy

A38-YEAR-OLD MAN presented with progressive gait difficulties and urinary and erectile dysfunction of 10 years’ duration. Clinical examination showed right-sided predominant spastic paraparesis, bilateral Babinski signs, hyperreflexia, impaired vibration sensitivity in the distal legs, slight cerebellar dysfunction, and normal cognition. Brain (Figure) and spinal magnetic resonance imaging (MRI) findings were normal, as were copper and vitamins B12 and E levels and results of electromyography and a lumbar puncture. Differential diagnoses included primary lateral sclerosis (although the impaired vibration sensitivity and cerebellar dysfunction were atypical), familial spastic paraparesis, and hereditary leukodystrophy. Brain fludeoxyglucose F 18 positron emission tomography (FDG-PET) showed bilateral hypometabolism (confirmed by z scores between �3 and �4 SDs) in the paramedian frontal, anterior parietal, temporal polar, and cerebellar lobes, making primary lateral sclerosis unlikely. Predominant hypometabolism in the left lower limb motor cortex and both cerebellar lobes corresponded well with the right-sided predominance of the spastic paraparesis and the bilateral cerebellar dysfunction in our pa