Classical ALS Research Articles

Cognition and motor phenotypes in ALS: a retrospective study

BackgroundAmyotrophic lateral sclerosis (ALS) is phenotypically heterogeneous in motor manifestations, and the extent of upper vs. lower motor neuron involvement is a widespread descriptor. This study aimed to examine cognition across different ALS motor phenotypes.MethodsALS patients (N = 124) were classified as classical (N = 66), bulbar (N = 13), predominant-upper motor neuron (PUMN; N = 19), and predominant-lower motor neuron (PLMN; N = 26) phenotypes. Cognition was assessed with the Edinburgh Cognitive and Behavioural ALS Screen (ECAS) and function with the ALS Functional Rating Scale—Revised (ALSFRS-R). Revised ALS-FTD consensus criteria were applied for cognitive/behavioral phenotyping.ResultsDefective ECAS-total scores were detected in all groups — bulbar: 15.4%, classical: 30.3%, PLMN: 23.1%, and PUMN: 36.8%. Classical and PUMN ALS patients performed worse than PLMN ones on ECAS-total, ALS-specific, Fluency, and Executive measures. No other difference was detected. Worse ASLFRS-R scores correlated with poorer ECAS-total scores in classical ALS patients.ConclusionsFrontotemporal cognitive deficits are more prevalent in PUMN and classical ALS and linked to disease severity in the latter, but occur also in PLMN phenotypes.

FUS mutation is probably the most common pathogenic gene for JALS, especially sporadic JALS.

Juvenile amyotrophic lateral sclerosis (JALS) is a rare and severe form of ALS. The development of gene sequencing methods has resulted in increased reports of JALS cases in recent years, and additional gene mutations in FUS have been identified. Fused in sarcoma (FUS) mutations, appeared rarely in classical ALS but indeed were the most frequent pathogenic mutations in JALS, especially in sporadic JALS. After studied the reports in the last 10 years about JALS cases, the case characteristics caused by FUS mutations and the commonality of the mutation sites were summarized in this review. FUS mutation associated with more than half of JALS and the very majority of sporadic JALS. It's worth noting that almost all of the mutations occur in nuclear localization signal (NLS) of FUS in sporadic JALS. This discovery emphasized a new perspective focus on NLS for the diagnosis and etiology of sporadic JALS as well as for further study about new treatment.

Cervical transverse MRI in ALS diagnosis and possible link to VEGF and MMP9 single nucleotide polymorphisms. Case Report

We report the case of a patient diagnosed with ALS and presenting with a “snake eyes” sign on axial cervical MRI. Given the peculiar radiological presentation and our patient’s young age, we decided to perform a genetic analysis to better investigate the molecular mechanisms underlying the pathogenesis of his clinical phenotype. In our study, we identified different polymorphisms of interest at the level of VEGF and MMP9 promoters that we suggest could contribute to neuronal sufferance by promoting vascular abnormalities and tissue hypoxia, in accordance with previous published papers. When combined with repetitive mechanical stress at cervical level, as evident in our patient’s case, the resultant radiological image appears to be the “snake eyes” sign in the anterior horns of the cervical spinal cord, while the clinical phenotype is that of an atypical ALS case, possibly an ALS-mimic. To correctly identify and diagnose such patients, in particular when disease course and neuroradiological data do not correspond to those of a classical ALS case, we underline the importance of axial cervical MRI studies and suggest the possibility of their implementation into routine clinical practice.

Prion-like properties of disease-relevant proteins in amyotrophic lateral sclerosis.

The hallmark of age-related neurodegenerative diseases is the appearance of cellular protein deposits and spreading of this pathology throughout the central nervous system. Growing evidence has shown the involvement and critical role of proteins with prion-like properties in the formation of these characteristic cellular aggregates. Prion-like domains of such proteins with their proposed function in the organization of membraneless organelles are prone for misfolding and promoting further aggregation. Spreading of these toxic aggregates between cells and across tissues can explain the progression of clinical phenotypes and pathology in a stereotypical manner, characteristic for almost every neurodegenerative disease. Here, we want to review the current evidence for the role of prion-like mechanisms in classical neurodegenerative diseases and ALS in particular. We will also discuss an intriguingly central role of the protein TDP-43 in the majority of cases of this devastating disease.

Comparative immunohistochemical study on the past and the recent kii amyotrophic lateral sclerosis patients

Background: Kii ALS is characterized neuropathologically by classical ALS pathology overlapped by widespread tau pathology including neurofibrillary tangles (NFT) and various glial inclusions. In recent years, the incidence of ALS has decreased in south Wakayama prefecture, and environmental changes have been suggested to play a role in the decline.

The neuropathology associated with repeat expansions in the C9ORF72 gene

An abnormal expansion of a GGGGCC hexanucleotide repeat in a non-coding region of the chromosome 9 open reading frame 72 gene (C9ORF72) is the most common genetic abnormality in familial and sporadic FTLD and ALS and the cause in most families where both, FTLD and ALS, are inherited. Pathologically, C9ORF72 expansion cases show a combination of FTLD-TDP and classical ALS with abnormal accumulation of TDP-43 into neuronal and oligodendroglial inclusions consistently seen in the frontal and temporal cortex, hippocampus and pyramidal motor system. In addition, a highly specific feature in C9ORF72 expansion cases is the presence of ubiquitin and p62 positive, but TDP-43 negative neuronal cytoplasmic and intranuclear inclusions. These TDP-43 negative inclusions contain dipeptide-repeat (DPR) proteins generated by unconventional repeat-associated translation of C9ORF72 transcripts with the expanded repeats and are most abundant in the cerebellum, hippocampus and all neocortex regions. Another consistent pathological feature associated with the production of C9ORF72 transcripts with expanded repeats is the formation of nuclear RNA foci that are frequently observed in the frontal cortex, hippocampus and cerebellum. Here, we summarize the complexity and heterogeneity of the neuropathology associated with the C9ORF72 expansion. We discuss implications of the data to the current classification of FTLD and critically review current insights from clinico-pathological correlative studies regarding the fundamental questions as to what processes are required and sufficient to trigger neurodegeneration in C9ORF72 disease pathogenesis.

ALS-Parkinsonism-Dementia complex of Kii and other related diseases in Japan

The ALS/parkinsonism-dementia complex (PDC) of Kii is an endemic disease with a diverse phenotypic expression characteristic of classical ALS, parkinsonism and dementia. Its clinical and neuropathological manifestations are similar to a syndrome found in Guam, sharing classical ALS pathology together with many neurofibrillary tangles in the brain. The incidence rates of ALS declined dramatically between the 1950s and 1980s. In the 1990 s, Kuzuhara found a high incidence of PDC with abundant neurofibrillary tangles, similar to Guamanian PDC. The incidence rates of PDC dramatically rose during the 1980s and 1990 s, and PDC replaced ALS. More than 70% of patients in the endemic region had a family history of ALS or PDC. We recently found a new gene OPTN causing ALS, and have extended its clinical survey in Japan. Two autopsied cases showed involvement of basal ganglia and/or cerebral cortex with neurofibrillary tangles. A few family members also showed dementia and parkinsonism without evidence of motor neuron disease. Moreover the penetrance seems to be incomplete. Despite these similarities, OPTN mutations were not found in the Kii patients. We speculate that the Kii/ALS-PDC could primarily be a genetic disease, and its clinical manifestation is modified by other genes or environmental factors.

Fus gene mutations in familial and sporadic amyotrophic lateral sclerosis

Mutations in the fused in sarcoma (FUS) gene have recently been found to cause familial amyotrophic lateral sclerosis (FALS). We screened FUS in a cohort of 200 ALS patients [32 FALS and 168 sporadic ALS (SALS)]. In one FALS proband, we identified a mutation (p.R521C) that was also present in her affected daughter. Their clinical phenotype was remarkably similar and atypical of classic ALS, with symmetric proximal pelvic and pectoral weakness. Distal weakness and upper motor neuron features only developed late. Neuropathological examination demonstrated FUS-immunoreactive neuronal and glial inclusions in the spinal cord and many extramotor regions, but no TDP-43 pathology. We also identified a novel mutation (p.G187S) in one SALS patient. Overall, FUS mutations accounted for 3% of our non-SOD1, non-TARDBP FALS cases and 0.6% of SALS. This study demonstrates that the phenotype with FUS mutations extends beyond classical ALS cases. Our findings suggest there are specific clinicogenetic correlations and provide the first detailed neuropathological description.

Clinical characteristics and survival pattern of 1153 patients with amyotrophic lateral sclerosis: Experience over 30 years from India

Amyotrophic Lateral Sclerosis is a progressive disease causing degeneration of upper and lower motor neurons with an average survival of 2 to 3 years. We retrospectively analyzed 1,153 patients of classical sporadic ALS seen over 30 years for the clinical manifestations and survival pattern. There were 855 (74.2%) men and 298 (25.8%) women with a M:F ratio of 3:1. The mean age of onset was 46.2+/-14.1 years (18-85) and the mean duration of illness at evaluation was 17.7+/-20.7 months (0.5-180). Mean age of onset for bulbar onset group was 52.8+/-11.6 and for limb onset was 43.7+/-14.1 (p<0.0001). One third of patients had onset before 40 years of age. The overall median survival duration (MSD) was 114.8+/-25.9(SE) months (3.3-194.4). Survival did not differ between the men [101.7+/-27.4(SE)] and women [118.9+/-6.3(SE)]. Information on death was available in 124 patients. The mean age at death was 52.95 years (25.7-82.6). The MSD for bulbar onset group was 55.9+/-2.9(SE) months and for limb onset group 177.9+/-3.2(SE) (p<0.0001). Gender did not have an effect on the survival period. The clinical manifestations are similar to findings from other developing countries with regards to age of onset, sex ratio and survival. When compared to studies among Caucasians the age of onset was one to two decades earlier and the male preponderance was more. The survival pattern is close to those reported from developing countries particularly from Africa and among Asian immigrants to the West, while it is significantly longer compared to Caucasians who generally have a dismal prognosis. Thus, Indians appear to have a relatively younger age of onset and prolonged survival suggesting the relatively slow course of ALS among Indian patients.

Attachment of monophosphoryl lipid A (MPL) to cells and liposomes augments antibody response to membrane-bound gangliosides.

Antibodies to gangliosides are found in low levels in normal individuals, and attempts to augment their production have had limited success. Murine studies suggest that the antibody response to membrane-bound cryptic antigens, such as phospholipids and gangliosides, can be induced and augmented by attaching lipid A to membranes. Therefore, we assessed the ability of monophosphoryl lipid A, a non-toxic derivative of lipid A, to augment antibody response against membrane-associated gangliosides. Anti-ganglioside antibodies were IgM after the first and second immunizations; in contrast, anti-phospholipid antibodies were IgM after the first immunization and IgG after the second immunization. Mice (BALB/c) immunized with MPL-attached human cells as well as mice (C57BL/6J) immunized with MPL-attached syngeneic tumor cells (B16 melanoma) produced a significant IgM response. Mice (C57BL/6J) immunized with MPL-attached liposomes containing GM3 developed significantly higher IgM responses than those immunized with purified gangliosides, MPL or MPL-free B16 cells. However, the antibody response after immunization with MPL-GM3-liposomes is similar to that after immunization with MPL-attached tumor cells, even though the MPL-liposomes contained a 27-fold higher level of gangliosides than the tumor cells. Our results emphasize that co-expression of MPL with membrane-bound gangliosides is necessary to augment the anti-ganglioside antibody response. These findings may shed light on the elevated titers of anti-ganglioside IgM antibodies found in patients with motor neuron diseases, various neuropathies and classical ALS, and are relevant to clearance of circulating immunosuppressive gangliosides in cancer patients.

Article Commentary: Acquired Equine Motor Neuron Disease

Equine motor neuron disease (EMND) is an acquired neuromuscular disease of horses that was first recognized in 1985 and reported in a preliminary report often horses in 1 990.3 The disease is characterized pathologically by degeneration of motor neurons in the ventral horns of the spinal cord and in selected brain stem nuclei. Death of motor neurons results in secondary axonal degeneration and denervation atrophy of skeletal muscle. Clinical signs of diffuse neuromuscular disease are seen in EMND and include marked weight loss due to muscle atrophy despite a normal appetite, generalized weakness with a short-strided gait, a characteristic stance with low head carriage and feet positioned well under the body, frequent shifting of weight from limb to limb, excessive recumbency, excessive sweating, especially following exercise, and muscle fasciculations. Involvement of neurons in the spinal ganglia is thought to be the basis of the hyperesthesia noted in some cases. Clinicopathologic features include mild to moderately increased serum levels of creatine kinase and/or aspartate aminotransferase and frequent increase in cerebrospinal fluid protein concentrations. Denervation potentials, primarily positive sharp waves, can be detected with concentric needle e l ec t r~myography .~ .~ .~ .~~ The clinical and pathologic features of the equine disorder closely resemble those of the motor neuron diseases of human beings, of which the most important is amyotrophic lateral sclerosis (ALS; “Lou Gehrig’s disease”). 1,23,14.18.22 This name is applied to a group of fatal, degenerative motor neuron disorders that are characterized by progressive degeneration of spinal and selected brain stem motor neurons ,~~2~8~14~18~22 with only mild involvement of sensory n e ~ r o n s . ~ J ~ The pathology of the human disorder differs from that of EMND, however, in that extensive degeneration of pyramidal tracts is seen in human beings with classical ALS. 1,2,8~14~Ig,22 Only mild degeneration of pyramidal tracts is present in horses with EMND. However, the pyramidal tracts are poorly developed, and less extensive, in ungulates as compared to human beings.I0 Alternatively, EMND may be more analogous to progressive muscular atrophy, a variant of ALS in which pyramidal tracts are spared. I Histopathologic and ultrastructural lesions in neurons of horses with EMND3 closely resemble those seen in ALS. 1,2,8,14,18320322 Immunocytochemical studies have shown that the swollen neurons in EMND contain dense aggregates of neur~filaments,~ a finding similar to those in ALS.17 This equine disorder is distinctly different, clinically and pathologically, from previously described diseases of the equine neuraxis. Equine degenerative myeloencephalopathy and cervical stenotic myelopathy are diseases of spinal cord white matter and result in clinical evidence of spastic paresis and ataxia. Protozoal encephalomyelitis may result in focal or multifocal degeneration of motor neurons and degeneration of the white matter of the brain and spinal cord, but the resulting lower motor neuron weakness is localized and frequently asymmetric. Rabies virus polioencephalomyelitis may initially produce signs suggestive of lower motor neuron disease. However, the rapid, diffuse spread of this lesion will be accompanied by other neurologic ~ i g n s . ~ J ~ The motor neuron degeneration seen in EMND is pathologically similar to that seen in a presumed inherited motor neuron disease of zebras (Equus burchelli),12 but EMND is clearly a sporadic acquired disorder affecting horses of all ages and breed^.^,^,^ Quarter Horses are overrepresented in the various breeds affected, and Thoroughbreds are also at increased risk. The risk of EMND increases with age, with a peak at 16 years of age.I6 At the time of this writing, 67 cases of EMND have been confirmed by pathologic and/or clinical and clinicopathologic findings, and many more are suspected. Most of the 67 recognized cases of EMND have occurred in the northeastern USA, the area from which most cases seen at the New York State College of Veterinary Medicine are drawn. However, cases have been confirmed in Ohio (four), Indiana (two), West Virginia (one), Maryland (one), Kentucky (one), Alaska (two), California (one), Oregon (one), Nebraska (one), Tennessee (one), Florida (one), and Ontario, Canada (one). Confirmation has relied on recognition of typical clinical and clinicopathologic findings and on frozen section histochemistry applied to muscle samples mailed by overnight carrier to appropriate laboratories. Additional cases are suspected in Great Britain.” At Cor-

Gangliosides Elicit a T-Cell Independent Antibody Response

Antibodies to glycolipids have recently been found to be elevated in a substantial proportion of patients with motor neuron diseases, various neuropathies and classical ALS. Several features of these antibody responses suggest that they may be produced by a T-cell independent B lymphocyte response: (1) antibodies are predominantly of IgM class; (2) antibodies against gangliosides are directed against the carbohydrate component of the gangliosides; and (3) antiganglioside antibodies are difficult to suppress. In this study we have asked whether gangliosides can induce T-independent responses, in T-cell deficient and T-cell competent mice. Homozygous nude mice (nu/nu), which lack T-cells, and heterozygous controls (nu/+) with intact T-cells, were immunized and rechallenged with the ganglioside GM1 in liposomes. Antibodies were measured by an ELISA method. Both nude mice and controls produced high titers of IgM class antibodies to the ganglioside GM1. The antibody titers peaked by 7 days after each immunization and declined by 14 days. The maximum titer rose progressively after each immunization. No significant amount of IgG antibody to GM1 was produced by either nu/nu or nu/+ mice, even after repeated immunization. These results suggest that gangliosides elicit prominent T-cell-independent antibody responses. The implications of these findings for neurologic disorders associated with anti-ganglioside antibodies are discussed.

Amyotrophic Lateral Sclerosis/Parkinsonism/Dementia: Clinico-Pathological Correlations Relevant to Guamanian ALS/PD

In a recent report on the clinical and pathological features of Guamanian ALS/PD and post-encephalitic parkinsonism/ALS a number of similarities were described, notably in the distribution of neurofibrillary tangles throughout the nervous system. In this account additional pathological features which these disorders share (and which differ from classical ALS, Parkinson's and Alzheimer's diseases) are described. These include atrophy of the globus pallidus and the entire substantia nigra, viz. pars compacta and pars reticulata. Moreover, neither Lewy bodies nor senile plaques are features of the Guamanian and post-encephalitic disorders. The significance of these observations and their relationship, more generally, to parkinsonism, ALS and dementia are discussed.

Receptor site specificity for the acute effects of DL(±)-BMAA in mice : Stuart E. Smith and Brian S. Meldrum, Department of Neurology, Institute of Psychiatry, De Crespigny Park, Denmark Hill, London SE5 8AF, U.K.

The ALS/parkinsonism-dementia complex (PDC) of Kii is an endemic disease with a diverse phenotypic expression characteristic of classical ALS, parkinsonism and dementia. Its clinical and neuropathological manifestations are similar to a syndrome found in Guam, sharing classical ALS pathology together with many neurofibrillary tangles in the brain. The incidence rates of ALS declined dramatically between the 1950s and 1980s. In the 1990s, Kuzuhara found a high incidence of PDC with abundant neurofibrillary tangles, similar to Guamanian PDC. The incidence rates of PDC dramatically rose during the 1980s and 1990s, and PDC replaced ALS. More than 70% of patients in the endemic region had a family history of ALS or PDC.We recently found a new gene OPTN causing ALS, and have extended its clinical survey in Japan. Two autopsied cases showed involvement of basal ganglia and/or cerebral cortex with neurofibrillary tangles. A few family members also showed dementia and parkinsonism without evidence of motor neuron disease. Moreover the penetrance seems to be incomplete. Despite these similarities, OPTN mutations were not found in the Kii patients. We speculate that the Kii/ALS-PDC could primarily be a genetic disease, and its clinical manifestation is modified by other genes or environmental factors.

Morphometric study of the sensory nerve in classical (or Charcot disease) and juvenile amyotrophic lateral sclerosis

Analysis of the superficial peroneal nerve sampled in 9 cases of classical amyotrophic lateral sclerosis (classical ALS, Charcot disease) and compared with 8 age-matched controls showed a very significant reduction of all myelinated fibres ( P < 0.001), affecting small-diameter ( P < 0.01) and large-diameter ( P < 0.02) fibres. Moreover, the small-diameter unmyelinated fibres were very significantly reduced ( P < 0.001) and the large-diameter fibres were highly increased ( P < 0.01). These results suggest a phenomenon of chronic axonal degeneration. Analysis of the same nerve in 7 patients suffering from juvenile ALS and compared with 4 age-matched controls showed a significant reduction ( P < 0.05) of myelinated fibres. The small-diameter and overall unmyelinated fibres were not significantly reduced while the large-diameter fibres, were significantly increased ( P < 0.01). The same analysis of 4 patients presenting an early-onset ALS compared with 3 controls showed lesions of a severity half-way between that of the classical and the juvenile form. Our study showed that the lesions of the sensory nerve are of the same type in classical ALS and in juvenile ALS, but of differing severity. The nosologic place of juvenile ALS compared with classical ALS and with heredodegenerative diseases of the nervous system is discussed.

Amyotrophic lateral sclerosis and parkinsonism-dementia complex of Guam. Neurological reevaluation.

This is the second paper of a series of four on recent investigations of the lateral sclerosis/parkinsonism-dementia (ALS/P-D) complex on the island of Guam. The objectives of this report are as follows: (1) to analyze in detail the neurological features of Guam ALS and P-D and compare them with classical ALS, Parkinson's disease, and other relevant disorders: (2) to show the unique relationship between the ALS and P-D syndromes, clinically and histologically; and (3) to report on pertinent laboratory studies. The data of this study were collected over a period of seven years (1957-1964). Related epidemiologic, neuropathologic, and genetic studies will be reported in separate papers. Historical Background The unusual prevalence of a hereditary paralysis on Guam was first reported in the medical literature in 1900. 1 The diagnosis of progressive muscular atrophy was recorded on local death certificates as early as 1904, and the diagnosis of amyotrophic lateral