Typical Amyotrophic Lateral Sclerosis Research Articles

Endothelial nitric oxide synthase overexpression by neuronal cells in neurodegeneration: a link between inflammation and neuroprotection

The roles of neuronal and inducible nitric oxide synthases in neurones have been extensively investigated; by contrast, the biological significance of endothelial nitric oxide synthase (eNOS) overexpression that occurs in several pathological conditions has not yet been studied. We have started addressing this issue in a cell model of neurodegeneration, i.e. human SKNBE neuroblastoma cells transfected with a mutant form of alsin, a protein causing an early-onset type of amyotrophic lateral sclerosis, ALS2. We found that eNOS, which is endogenously expressed by these cells, was activated by tumour necrosis factor-alpha (TNF-alpha), a proinflammatory cytokine that plays important roles in ALS2 and several neurodegenerative diseases. The TNF-alpha-dependent eNOS activation occurred through generation, by sphingosine-kinase-1, of sphingosine-1-phosphate, stimulation of its membrane receptors and activation of Akt, as determined using small interference RNA and dominant negative constructs specific for the enzymes and receptors. eNOS activation by TNF-alpha conferred cytoprotection from excitotoxicity and neurotoxic cues such as reactive oxygen species, endoplasmic reticulum stress, DNA damage, and mutated alsin itself. Our results suggest that overexpression of eNOS by neurones is a broad-range protective mechanism activated during damage and establish a link of pathophysiological relevance between this enzyme and inflammation accompanying neurodegenerative diseases. These findings also question the concept that high NO output in the presence of oxidative stress leads always to peroxynitrite formation contributing to neurodegeneration.

VAPB interacts with and modulates the activity of ATF6

A mis-sense point mutation in the human VAPB gene is associated with a familial form of motor neuron disease that has been classified as Amyotrophic Lateral Sclerosis type VIII. Affected individuals suffer from a spinal muscular atrophy (SMA), amyotrophic lateral sclerosis (ALS) or an atypical slowly progressing form of ALS. Mammals have two homologous VAP genes, vapA and vapB. VAPA and VAPB share 76% similar or identical amino acid residues; both are COOH-terminally anchored membrane proteins enriched on the endoplasmic reticulum. Several functions have been ascribed to VAP proteins including membrane trafficking, cytoskeleton association and membrane docking interactions for cytoplasmic factors. It is shown here that VAPA and VAPB are expressed in tissues throughout the body but at different levels, and that they are present in overlapping but distinct regions of the endoplasmic reticulum. The disease-associated mutation in VAPB, VAPB(P56S), lies within a highly conserved N-terminal region of the protein that shares extensive structural homology with the major sperm protein (MSP) from nematodes. The MSP domain of VAPA and VAPB is found to interact with the ER-localized transcription factor ATF6. Over expression of VAPB or VAPB(P56S) attenuates the activity of ATF6-regulated transcription and the mutant protein VAPB(P56S) appears to be a more potent inhibitor of ATF6 activity. These data indicate that VAP proteins interact directly with components of ER homeostatic and stress signalling systems and may therefore be parts of a previously unidentified regulatory pathway. The mis-function of such regulatory systems may contribute to the pathological mechanisms of degenerative motor neuron disease.

Progressive Muskelatrophie

Progressive muscle atrophy (PMA) is a degenerative disease of the lower motor neuron. The course of the illness and the fatal prognosis correspond to those of amyotrophic lateral sclerosis (ALS). Neuropathologic and genetic findings support categorizing PMA within the spectrum of ALS, even though no clinical sign of a disorder of the upper motor neuron is demonstrable. The diagnosis of PMA is based on advanced extremity pareses and atrophies with a high progression rate. Respiratory insufficiency is determinative of the prognosis. Absent or late affection of bulbar functions is characteristic of the disease. Intraneuronal bunina bodies and ubiquitine-positive inclusions, which are established morphologic characteristics of ALS, are found post mortem. The treatment options of riluzol medication, respiratory therapy, and nutrition are analogous to those for typical ALS.

Muscle Nogo‐a expression is a prognostic marker in lower motor neuron syndromes

A proportion of patients with pure lower motor neuron syndrome (LMNS) progress to amyotrophic lateral sclerosis (ALS). Early detection of this progression is impossible, which delays the patient's access to treatment. Muscle expression of Nogo-A is a new candidate marker of ALS. We tested whether detection of Nogo-A in a muscle biopsy from patients with LMNS predicts progression to ALS. Thirty-three patients who had undergone a muscle biopsy during the diagnostic workup of spinal LMNS were observed for 12 months. Nogo-A expression was measured by Western blot in muscle biopsy samples and compared with the final diagnosis. Nogo-A expression was detected in 17 patients and was absent in 16 patients. The detection of Nogo-A in muscle biopsy samples from LMNS patients correctly identified patients who further progressed to ALS with 91% accuracy, 94% sensitivity, and 88% specificity. In patients who later developed typical ALS, Nogo-A may be detected as early as 3 months after the onset of symptoms. Nogo-A test is able to identify ALS early in the course of the disease when diagnosis is difficult, requiring further progression. Use of the test in clinical practice may shorten the delay before introduction of neuroprotective drugs or inclusion in clinical trials.

Progress in Clinical Neurosciences: Frontotemporal Dementia-Pick's Disease

Frontotemporal dementia (clinical Pick's disease) is a relatively common, but underdiagnosed degenerative disease in the presenium. Estimated prevalence ranges from 6-12% of dementias. The behavioural, aphasic and extrapyramidal presentations are labeled FTD-behavioural variant, Primary Progressive Aphasia (PPA) and Corticobasal Degeneration/Progressive Supranuclear Palsy (CBD/PSP). The diagnostic features and course of each are described and their overlap in the evolution of the illness is emphasized. The neuropathology ranges from the most common tau negative ubiquitin positive amyotrophic lateral sclerosis (ALS) type inclusions to the tau positive classical Pick bodies and more or less distinct changes of PSP and CBD. The genetics of the relatively frequent tau mutations and the yet unsolved problem of tau negative families are discussed. The tau negative cases tend to be associated with the behavioural presentation and semantic dementia and the tau positive ones with PPA and the CBD/PSP syndrome. However the overlap is too great to split the disease. A glossary to navigate the proliferating terminology is included.

P3-146: Marked increase of parkinsonism-dementia (P-D) phenotypes in the high incidence amyotrophic lateral sclerosis (ALS) focus in the Kii peninsula of Japan

A small village in the southern coast of the Kii peninsula of Japan, with a population of 1,400 is one of the high incidence ALS focus together with Guam. Marked increase of Mariana dementia in contrast to marked decline of ALS and P–D have been reported in Chamorros on Guam. To review the recent epidemiology of ALS–parkinsonism–dementia syndrome in the Kii peninsula ALS focus in Japan. 34 cases of ALS–parkinsonism–dementia (14 men and 20 women) including 6 autopsy cases, in that the onset of the disease was in 1985 or later were analyzed. Clinical phenotypes included 7 cases of pure ALS (20.6%), 6 cases of ALS plus dementia (17.6%) consisting of ALS–dementia (ALS–D) and P–D superimposed by ALS, and 21 cases of P–D (61.8%) . The average ages were 56.6 +/– 4.5 years in ALS, 66.2 +/– 5.0 years in ALS plus dementia, and 66.3 +/– 8.2 years in P–D. Family history of ALS–dementia–parkinsonism syndrome was positive in more than 75% of the patients. Neuropathologically, ALS–D and P–D showed similar findings characterized by many neurofibrillar tangles (NFTs) and ALS pathology, while pure ALS phenotype cases showed typical ALS pathology and NFTs of mild to moderate degree, suggesting that these phenotypes are of the same entity. In contrast to the marked decline of ALS/P–D on Guam, the incidence rates of ALS/P–D remain unchanged for these 50 years in the Kii peninsula ALS focus, suggesting some genetic factor may be the primary cause. ALS–D and P–D had been very rare in the Kii ALS focus before 1980. Some environmental and socio–economical changes of the residents of the Kii ALS focus, particularly aging of the population and westernization of food may have modified the disease, and have induced marked increase of P–D and ALS–D phenotypes and mild decline of pure ALS phenotypes. More and more attention paid to the cognitive and motor dysfunctions of the old people in recent years may be another factor that has increased the incidence rates of P–D phenotypes.

Creatine as a Potential Treatment for Amyotrophic Lateral Sclerosis

Key words: Creatine; amyotrophic lateral sclerosis; clinical trials; neurotherapeutics; transgenic mouse models; ALS functional rating scale. Introduction Amyotrophic lateral sclerosis (ALS) is a rare degenerative disorder of large motor neurons that results in progressive wasting and paralysis of voluntary muscles of the extremities, bulbar regions and respiratory apparatus (Rowland, 1994; Mulder, 1982). The incidence of ALS is currently approximately 2/100 000/year (Chio & Silani, 2001; Haverkamp et al ., 1995) with a prevalence of approximately 5/100 000. The lifetime ALS risk is 1 in 600 to 1 in 1000. Fifty percent of ALS cases die within 3 years of onset of symptoms and 90% die within 5 years (Shefner, 1996; Kurtzke & Kurland, 1989). The median age of onset is 55 years. In sporadic disease, males are at slightly greater risk, while the male/female ratio is 1 : 1 in most cases of familial disease. Ten Percent of patients have a history of the disease in first degree relatives; about 20% of these patients have a mutation in the gene encoding cytosolic copper–zinc superoxide dismutase (SOD1) have been robustly identified as causing typical familial ALS (fALS) (Rosen et al ., 1993). Patients with ALS typically present with focal weakness of an arm, a leg, or of facial and bulbar muscles. The weakness typically progresses regionally and ultimately involves all muscles of voluntary movement. Both lower motor neurons (spinal) and upper (cortical) motor neurons are involved, so that patients display signs of atrophy, fasciculations, cramps and weakness in combination with spasticity, increased stretch reflexes and incoordination. Although there is sometimes pathologic evidence of sensory neuron loss, clinically, sensory signs are sparse or absent (Shefner et al ., 1991).

Diffusion-Tensor MR Imaging of Corticospinal Tract in Amyotrophic Lateral Sclerosis and Progressive Muscular Atrophy

To prospectively evaluate several diffusion-tensor magnetic resonance (MR) imaging indexes (mean diffusivity [MD], fractional anisotropy [FA], and eigenvalues) of corticospinal tract impairment in patients with progressive muscular atrophy (PMA) and patients with amyotrophic lateral sclerosis (ALS). This study had institutional review board approval, and written informed consent was obtained from all subjects. Eight male patients with PMA (mean age, 63 years +/- 13 [standard deviation]), eighteen patients with ALS (14 men and four women; mean age, 64 years +/- 7), and twelve control subjects (four men and eight women; mean age, 65 years +/- 6) underwent diffusion-tensor MR imaging at which 25 spin-echo echo-planar imaging diffusion-weighted images (b = 1000 sec/mm2) were acquired along noncollinear directions. MD and FA were measured along the corticospinal tracts in each patient and subject. Changes in diffusion along and orthogonal to fiber bundles in patients were evaluated by using diffusion-tensor eigenvalues. Differences in diffusion-tensor imaging indexes between patients with PMA and those with ALS, as compared with these indexes in control subjects, were evaluated with Mann-Whitney testing. Correlations between diffusion-tensor imaging indexes and clinical variables were estimated with Pearson and Spearman rank correlation testing. As compared with MD (697.1 x 10(-6) mm2/sec +/- 28.1) and FA (0.585 +/- 0.032) in control subjects, MD was typically significantly increased (734.7 x 10(-6) mm2/sec +/- 41.2, P = .035) and FA significantly decreased (0.534 +/- 0.053, P = .037) along the corticospinal tracts in patients with ALS, while these parameters showed no significant change in patients with PMA (MD, 707.0 x 10(-6) mm2/sec +/- 44.2; FA, 0.559 +/- 0.028). Estimation of diffusion-tensor eigenvalues revealed normal diffusion along fiber tracts in all patients, while diffusion was increased orthogonal to fiber tracts only in patients with typical ALS. In patients with ALS, MD correlated with disease duration while FA correlated with disease severity. Diffusion-tensor MR imaging reveals corticospinal tract impairment in ALS but not in PMA.

A common founder for amyotrophic lateral sclerosis type 8 (ALS8) in the Brazilian population

The P56S mutation in the VAPB gene causes ALS8. Eight families, comprising more than 1,500 individuals of whom about 200 are affected, are now known to carry this mutation. Seven are of Portuguese-Brazilian ancestry and one of African-Brazilian ancestry. Haplotype analysis shows a common founder for all families regardless of ancestry, with a founding event 23 generations ago (95% CI 13-39), consistent with the Portuguese colonization of Brazil.

Virus‐delivered small RNA silencing sustains strength in amyotrophic lateral sclerosis

Mutations in superoxide dismutase cause a subset of familial amyotrophic lateral sclerosis and provoke progressive paralysis when expressed in mice. After retrograde transport to the spinal cord following injection into muscles, an adeno-associated virus carrying a gene that encodes a small interfering RNA was shown to target superoxide dismutase messenger RNA for degradation. The corresponding decrease in mutant superoxide dismutase in spinal motor neurons preserved grip strength. This finding provides proof of principle for the selective reduction of any neuronal protein and supports intramuscular injections of a small interfering RNA-encoding virus as a viable therapy for this type of familial amyotrophic lateral sclerosis.

Intervention Decision-Making for Persons with Amyotrophic Lateral Sclerosis

Intervention Decision-Making for Persons with Amyotrophic Lateral Sclerosis

A Mutation in the Vesicle-Trafficking Protein VAPB Causes Late-Onset Spinal Muscular Atrophy and Amyotrophic Lateral Sclerosis

Motor neuron diseases (MNDs) are a group of neurodegenerative disorders with involvement of upper and/or lower motor neurons, such as amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), progressive bulbar palsy, and primary lateral sclerosis. Recently, we have mapped a new locus for an atypical form of ALS/MND (atypical amyotrophic lateral sclerosis [ALS8]) at 20q13.3 in a large white Brazilian family. Here, we report the finding of a novel missense mutation in the vesicle-associated membrane protein/synaptobrevin-associated membrane protein B (VAPB) gene in patients from this family. Subsequently, the same mutation was identified in patients from six additional kindreds but with different clinical courses, such as ALS8, late-onset SMA, and typical severe ALS with rapid progression. Although it was not possible to link all these families, haplotype analysis suggests a founder effect. Members of the vesicle-associated proteins are intracellular membrane proteins that can associate with microtubules and that have been shown to have a function in membrane transport. These data suggest that clinically variable MNDs may be caused by a dysfunction in intracellular membrane trafficking.

A therapeutic role for cyclooxygenase-2 inhibitors in a transgenic mouse model of amyotrophic lateral sclerosis.

Recent studies indicate that the proinflammatory enzyme cyclooxygenase (COX)-2, an enzyme involved in inflammatory cascades but also normal neuronal activities, is elevated in the brain and spinal cord of amyotrophic lateral sclerosis (ALS) patients and ALS mouse model systems. On the basis of this evidence, we explored the impact of COX-2 inhibition on the onset and progression of ALS-like disease in the G93A human superoxide dismutase (SOD)1 mouse model of ALS. We found that prophylactic administration of nimesulide, a preferential COX-2 inhibitor, in the feed resulted in a significant delay in the onset of ALS type motor impairment. This delay of ALS symptomatology temporally overlapped with the inhibition of prostaglandin E2 elevation in the spinal cord of SOD1-G93A transgenic mice relative to untreated SOD1-G93A controls. This study strongly supports a role for COX-2 in the pathophysiology of ALS and provides the first experimental evidence that prophylactic treatment with COX-2 inhibitors can significantly delay the onset of motor dysfunction in the SOD1-G93A transgenic mouse model of ALS.

Neuropathology with clinical correlations of sporadic amyotrophic lateral sclerosis: 102 autopsy cases examined between 1962 and 2000.

Sporadic amyotrophic lateral sclerosis (ALS) is a fatal neurological disorder affecting adults. We studied the neuropathology and clinical correlations in 102 autopsy cases of ALS. The age at onset of the disease was significantly higher for the bulbaronset form (30 cases) than for the limb-onset form (72 cases). Dementia was confirmed in 7 cases. These 102 cases were divided into 4 pathological subgroups: typical ALS (59 cases), lower-motor-predominant ALS (23 cases), ALS with temporal lesions (18 cases), and ALS with pallido-nigro-luysian degeneration (2 cases). The age at onset was significantly higher for lower-motor-predominant ALS and ALS with temporal lesions than for typical ALS. In the lower motor neurons, Bunina bodies were detected in 88 cases, whereas ubiquitin-immunoreactive skein and/or spherical inclusions were detected in all 102 cases. Of the 100 available cases, 50 and 16 also showed ubiquitin-immunoreactive inclusions in the neostriatal and temporal small neurons, respectively. Ubiquitin-immunoreactive dystrophic neurites were also observed in the neostriatum in 3 of the 50 cases with neostriatal inclusions, and in the temporal cortex in 4 of the 16 cases with temporal inclusions. There was a significant association between the bulbar-onset form, temporal lesions, neostriatal inclusions and temporal inclusions, and between dementia, temporal lesions and temporal inclusions. Neostriatal and temporal dystrophic neurites were associated with dementia and bulbar-onset form through temporal lesions and temporal inclusions. The present findings may be helpful for designing further studies on the mechanisms underlying the development of ALS.

Overexpression of SOD1 protects vulnerable motor neurons after spinal cord injury by attenuating mitochondrial cytochrome c release.

Defective Cu,Zn-superoxide dismutase (SOD1) is responsible for some types of amyotrophic lateral sclerosis, and ventral horn motor neurons (VMN) have been shown to die through a mitochondria-dependent apoptotic pathway after chronic exposure to high levels of reactive oxygen species (ROS). VMN are also selectively vulnerable to mild spinal cord injury (SCI); however, the involvement of SOD1, ROS, and apoptosis in their death has not been clarified. Mild compression SCI was induced in SOD1-overexpressing transgenic rats and wild-type littermates. Superoxide production, mitochondrial release of cytochrome c, and activation of caspase-9 were examined, and apoptotic DNA injury was also characterized. In the wild-type animals, increased superoxide production, mitochondrial release of cytochrome c, and cleaved caspase-9 were observed exclusively in VMN after SCI. Subsequently, a majority of VMN (75%) selectively underwent delayed apoptotic cell death. Transgenic animals showed less superoxide production, mitochondrial cytochrome c release, and caspase-9 activation, resulting in death of only 45% of the VMN. These results suggest that the ROS-initiated mitochondrial signaling pathway possibly plays a pivotal role in apoptotic VMN death after SCI and that increased levels of SOD1 in VMN reduce oxidative stress, thereby attenuating the activation of the pathway and delayed cell death.

Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND).

Riluzole has been approved for treatment of patients with amyotrophic lateral sclerosis (ALS) in some countries but not others. Questions persist about its clinical utility because of high cost, modest efficacy and concern over adverse effects. To examine the efficacy of riluzole in prolonging survival, and in delaying the use of surrogates (tracheostomy and mechanical ventilation) to sustain survival. Search of the Cochrane Neuromuscular Disease Group Register for randomized trials and enquiry from authors of trials and other experts in the field. The most recent search was conducted in June 1999. Types of studies: randomized trials adults with a diagnosis of ALS Types of interventions: treatment with riluzole or placebo Types of outcome measures: Primary: per cent mortality at 12 months with riluzole 100 mg Secondary: per cent mortality as a function of time with 100 mg and with all doses of riluzole, scales of neurologic function, quality of life, muscle strength and adverse events. We identified two randomized trials. Each reviewer graded them for methodological quality. Data extraction was performed by a single reviewer and checked by the other two. We obtained some missing data from investigators. We performed meta-analyses with RevMan software using a fixed effects model. The two eligible trials included a total of 794 riluzole treated patients and 320 placebo treated patients. The methodological quality was acceptable and the trials were easily comparable. There were significant differences between the riluzole and placebo groups of both trials, in terms of the primary outcome measure, which was per cent mortality at 12 months with the 100 mg dose of riluzole. The odds ratio for the combined studies was 0.57 (95%CI 0.41 to 0.80) at 12 months. In the secondary outcome measures, there was a survival advantage with riluzole 100 mg at six, nine, 12 and 15 months, but not at three or 18 months. Pooled data from the 50, 100 and 200mg dose groups in the larger trial showed a lower per cent mortality with riluzole compared to placebo only at 12 months (odds ratio (OR) 0.64, 95% CI 0.47 to 0.88). There was no beneficial effect on bulbar function, or muscle strength. There were scant data on quality of life, but patients treated with riluzole remained in a more moderately affected health state significantly longer than placebo-treated patients (weighted mean difference (WMD) 35.5 days, 95% CI 5.9 to 65. 0). A threefold increase in serum alanine transferase was more frequent in riluzole treated patients than controls (WMD 2.65, 95% CI 1.51 to 4.65). Riluzole 100 mg per day appears to be modestly effective in prolonging survival for patients with ALS.

ALS with variable phenotypes in a six-generation family caused by leu144phe mutation in the SOD1 gene

Background: amyotrophic lateral sclerosis (ALS) is a progressive neurological disorder. The mutations of Cu/Zn superoxide dismutase gene ( SOD1) are responsible for familial ALS. We investigated a large family of Istro-Rumanian origin characterized by an autosomal dominant ALS occurring in 18 cases (three of which are still alive) throughout six generations. Methods: clinical data were available for nine patients from the 2nd generation onward, among which one contained the neuropathological details. The mean age at onset of the disease (±SD) was 57.3±8.9 years (range 49–72), while the duration of the disease spanned over a length of time equal to 4.9±1.96 years (range 1.5–7). The analysis of the coding region of SOD1 was done by PCR and direct sequencing. The SOD1 activity was measured by using the red and mononuclear cells belonging to three of the patients. Results: the leu144phe mutation of SOD1 was identified in four patients while a normal sequence was found in five healthy related subjects. The molecular defect was responsible for a decrease in SOD1 activity. Most of patients in this family presented clinical manifestations of ALS (in particular, the lower limb onset variant) not as severe as typical ALS caused by other SOD1 mutations. However, one patient suffering from hyperthyroidism for 17 years, showed an early onset and a rapidly progressing ALS coupled with dementia. Conclusions: we described a large family with a relatively not severe phenotype of ALS (due to a leu144phe SOD1 mutation) that was compromised in one patient by a concomitant hyperthyroidism.

The RNA of the glutamate transporter EAAT2 is variably spliced in amyotrophic lateral sclerosis and normal individuals.

Impaired re-uptake of synaptic glutamate, and a reduced expression of the glutamate transporter EAAT2 have been found in the motor cortex of patients with amyotrophic lateral sclerosis (ALS). Two splice forms of the EAAT2 RNA resulting from retention of intronic sequences (EAAT2/Int) and deletion of one protein coding exon (EAAT2/C1) have been reported to account for the EAAT2 protein loss in ALS. In this study we investigated the presence of two known (EAAT2/C1; EAAT2/Int) and three novel (EAAT2/C2-4) EAAT2 RNA in motor cortex of 17 ALS cases and 11 controls. Reverse transcription and PCR were carried out to amplify the complementary DNA of the complete and variably spliced EAAT2 transcripts. Nested PCR was followed to generate amplicons specific for EAAT2/C1-4 and EAAT2/Int. EAAT2/Int was detected in 59% of ALS specimens as compared to 36% of controls showing a trend but no statistical significance of a more frequent expression in ALS (Type I error 24.6%). EAAT2/C1-4 were found to be equally expressed in ALS patients and controls. Our results indicate that the involvement of EAAT2 transcripts in ALS is unlikely to be primary, and more complex than previously recognized. Alterations of quantitative expression of distinct EAAT2 splice forms in ALS cannot be excluded from this study and remain to be investigated.

Frontal type dementia preceding amyotrophic lateral sclerosis: a neuropsychological and SPECT study of five clinical cases.

Between 1993 and 1995, we observed five sporadic cases of frontotemporal dementia (FTD) which in all cases preceded the appearance of typical amyotrophic lateral sclerosis (ALS). The FTD rapidly became severe (within 12-18 months) and the delay between the presumed onset of mental change and ALS was short (12-26 months). The frontal dysfunction was characteristic (disinhibited, jocular, impatient, gluttonous, stereotypical gestures). The language impairment (less talkative, persistent errors, fantastic and semantic paraphasia, neologistic errors, echolalia) was constant. Single photon emission computed tomography (SPECT) with 99 Tcm HMPAO (hexamethyl propylamine oxime) was done at the same time as neuropsychological testing in four cases and showed serious diffuse bifrontal defect, sometimes with less serious internal temporal hypofixation. All patients died with bulbar ALS complications. The total course can last from 14-48 months. Most of the reported cases suggested a relationship between dementia-ALS and frontal dysfunction. The mechanism underlying dementia-ALS remains to be solved. Our five cases resemble those reported by Mitsuyama (1993), who suggested that dementia-ALS has the same clinicopathological entity.

Diagnosis and progression of ALS

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by loss of upper and lower motor neurons, leading to progressive loss of motor function. The disease is almost always fatal, and approximately 50% of patients die within 3 to 4 years after onset of symptoms. [1,2] ALS is more common in men than in women (until age 70, when the rate becomes equal) and, although the average age of onset is in the mid-fifties, the disease can occur at anytime after the teen years. [2-4] The disease is a distinct syndrome characterized by a combination of upper motor neuron (UMN) and lower motor neuron (LMN) dysfunction and by generalized distribution and relentless progression. No specific blood test is available to provide an unequivocal diagnosis of ALS, and the clinical diagnosis is usually based on results of physical and neurologic examinations that identify the signs and symptoms of the disease. Because UMN and LMN symptoms associated with a variety of other disorders mimic those seen in ALS patients, an integral part of diagnosing ALS involves excluding other possible causes of the signs and symptoms exhibited by the patients. Diagnostic tests, such as electromyography (EMG), neuroimaging, blood and urine tests and, if indicated, muscle and nerve biopsy, are therefore used in this process. Although ALS was first described more than 120 years ago by Charcot, [5] it has remained an enigmatic disease. Recently, however, as the result of intense research during the past decade, significant advances have been made in understanding the pathogenesis and etiology of ALS and in identifying potential management strategies for the disease. More than 90% of ALS cases are classified as classical, a type of sporadic ALS, and are characterized by a combination of UMN and LMN involvement. [2] Among classical ALS patients, more than two-thirds present with …