Increased oxidative stress in patients with amyotrophic lateral sclerosis/Parkinsonism‐dementia complex in the Kii peninsula,Japan

Amyotrophic lateral sclerosis and Parkinsonism‐dementia complex of the Kii peninsula (Kii ALS/PDC) is an endemic and a tauopathy, which shows clinical symptoms of amyotrophy, parkinsonism, and dementia. The objective of this study was to report the role of oxidative stress on Kii ALS/PDC using biochemical analysis. Urinary 8‐hydroxydeoxyguanosine (8‐OHdG)/creatinine ratio was analyzed in 11 patients with Kii ALS/PDC and 8 normal controls. The mean level of urinary 8‐OHdG/creatinine ratio of the patients with Kii ALS/PDC was significantly higher than that of control subjects. Oxidative stress may be implicated in pathogenesis of Kii ALS/PDC. © 2008 Movement Disorder Society     

Geographical distribution of amyotrophic lateral sclerosis with neurofibrillary tangles in the Kii peninsula of Japan

Between 1984 and 1996 we histopathologically examined 26 autopsy cases of amyotrophic lateral sclerosis (ALS) from the Mie Prefecture in eastern and southern Kii Peninsula, which includes the Hohara ALS focus. Four of the individuals had a moderate number of neurofibrillary tangles in the locus coeruleus, substantia nigra, raphe nucleus, periaqueductal grey and hippocampus in addition to the histological changes of ALS. All four came from the vicinity of Hohara; symptoms of ALS developed in 1979, 1987, 1991 and 1993. Two had family history of ALS, and one, of parkinsonism-dementia. These findings confirm that Kii type ALS occurs continuously in and near the Hohara focus. Received: 23 November 1999 / Received in revised form: 25 April 2000 / Accepted: 28 May 2000     

Diagnostic problems and delay of diagnosis in amyotrophic lateral sclerosis

Objective

Initial symptoms of amyotrophic lateral sclerosis (ALS) mimic several neurological syndromes that may decelerate a correct diagnosis. The aim of our study was to investigate if diagnostic and therapeutic parameters have influence on the time of diagnosis.

Methods

We retrospectively reviewed the medical records of 100 consecutive ALS patients focusing on clinical and diagnostic data, the timing of diagnosis and treatments attributed to the onset of symptoms of ALS.

Results

Among 100 consecutive patients with ALS, 12% underwent surgery due to symptoms retrospectively attributable to ALS. The comparison of duration from first symptoms to correct diagnosis showed a significant difference between operated and non-operated patients. 35% of all ALS patients had bulbar onset symptoms. The mean time from first symptoms to diagnosis was 9 months in this group. In patients without bulbar onset it was 16.4 months which also represents a significant difference. In 44% of patients other diagnoses were considered and medically treated previous to correct diagnosis, but there was no significant delay of diagnosis.

Conclusion

Our study confirms that diagnosis of ALS is still a common clinical problem and shows the need of sensitive and specific diagnostic tests.     

Degeneration of the human Betz cell due to amyotrophic lateral sclerosis.

The giant pyramidal cell of Betz is known to be partially affected in cases of amyotrophic lateral sclerosis (ALS). Though biochemical, physiologic, and histologic properties of the diseased Betz soma have been investigated, the morphologic status of the largest portion of cell membrane, that of its vast dendritic array, has not. Precentral cortex from six patients, ages 51 to 64 years, who had succumbed to the sequelae of ALS was examined using variants of the Golgi techniques. ALS is shown to be a degenerative disorder which causes a decline in the integrity of the Betz dendritic arbor as well as of the soma of origin. Dendritic fragmentation occurs and numerous irregularities appear, while the number of dendritic spines declines. Concomitantly, a reactive gliosis encroaches upon the soma and may extend onto initial dendritic segments. These observations are remarkably similar to those of the Betz cell in normal aging. The correlation of qualitative histologic data in these conditions is meaningful in light of suggestions that aging and ALS may be related processes. This could provide some clue as to the etiology of Betz cell degeneration and of motor neuron disease.     

Emotional responding in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal disease, leaving the patient in a partially or completely deafferented state. In an explorative study, we investigated responses to visual socio–emotional stimuli in ALS patients. Pictures from the International Affective Picture System (IAPS) were verbally judged by 12 moderately affected ALS patients with a spinal onset and a slow progression and 18 age–matched controls, and data were compared with psychophysiological responses. Verbal emotional judgments of patients were more positive than ratings of controls. Regarding arousal, patients neutralized extreme pictures, in that they rated calm pictures as more exciting than controls and exciting pictures as more calm. These changes of emotional processing were unrelated to depression or frontal lobe dysfunction. There were no major differences between patients and controls concerning physiological responses to emotional stimuli. We conclude that emotional responses of ALS patients tend to be altered towards positive valence and towards a more balanced arousal state in early stages of the disease. These findings contradict assumptions of a generally negative impact of the disease on the emotional disposition and may indicate compensatory cognitive or neuroplastic changes.     

Duration of amyotrophic lateral sclerosis is age dependent

Since 1985, we prospectively followed 246 patients with ALS. The relation ship between the age of developing neurological impairment and disease duration was analyzed in 138 patients (86 men and 52 women) who died. Mean disease duration was 4.0 ± 3.8 years for men and 3.2 ± 2.5 years for women. There was an inverse, exponential, relationship between onset age and duration (goodness-of-fit P > 0.05). Mean duration at onset age 40 years was 8.2 ± 5.0 years compared with 2.6 ± 1.4 years for patients aged 61 to 70 years (P > 0.001). The ratio of young (40 years) men to women was 3.6:1. When matched for age, disease duration was the same for patients with bulbar and nonbulbar onsets. We conclude that onset age, but no sex, is the most significant predictor determining disesae duration in ALS. Longer survival in younger patients probably reflects their greater neuronal reserve. © 1993 John Wiley & Sons, Inc.     

Genotype–phenotype relationships in familial amyotrophic lateral sclerosis with FUS/TLS mutations in Japan

Introduction: We investigated possible genotype–phenotype correlations in Japanese patients with familial amyotrophic lateral sclerosis (FALS) carrying fused in sarcoma/translated in liposarcoma (FUS/TLS) gene mutations. Methods: A consecutive series of 111 Japanese FALS pedigrees were screened for copper/zinc superoxide dismutase 1 (SOD1) and FUS/TLS gene mutations. Clinical data, including onset age, onset site, disease duration, and extramotor symptoms, were collected. Results: Nine different FUS/TLS mutations were found in 12 pedigrees. Most of the patients with FUS/TLS‐linked FALS demonstrated early onset in the brainstem/upper cervical region, and relatively short disease duration. A few mutations exhibited phenotypes that were distinct from typical cases. Frontotemporal dementia was present in 1 patient. Conclusions: This study revealed a characteristic phenotype in FUS/TLS‐linked FALS patients in Japan. FUS/TLS screening is recommended in patients with FALS with this phenotype. Muscle Nerve 54 : 398–404, 2016     

Sporadic amyotrophic lateral sclerosis resembling primary lateral sclerosis: Report of an autopsy case and a review of the literature

This report describes the clinicopathological findings of a case of sporadic amyotrophic lateral sclerosis (ALS) resembling primary lateral sclerosis (PLS). A Japanese man developed muscle weakness in the distal part of the right upper extremity at age 59. At age 60 he presented with bradycinesia and rigidity. A neurological examination revealed fasciculation and increased deep tendon reflexes in the extremities. He developed decubitus and vesicorectal disturbance 2 months before his death at age 61. The neuropathological examination revealed not only prom-inent degeneration of the pyramidal tracts, evident in the internal capsule, but also loss of Betz's cells in the motor cortex. There was relative preservation of the neurons in the hypoglossal nuclei and anterior horns of the cervical and lumbar cord. In the anterior horn of the first sacral cord, there were small aggregates of lipofuscin-laden macrophages in locations from which large cells had presumably been lost. Bunina bodies and ubiquitin-immunoreactive neuronal inclusions were present in the anterior horn cells of the spinal cord. On the basis of these clinicopathological findings, we concluded that this case was one of sporadic ALS with predominant involvement of the upper motor neuron system and exhibiting features of PLS.     

Determination of urine thiocyanate in patients with amyotrophic lateral sclerosis

It has been reported that amyotrophic lateral sclerosis-Parkinsonism-dementia in Guam might be related to the eating of Cycas seeds, which contain cyanide. Based on this assumption, we determined the urinary thiocyanate excretion level in patients with ALS and compared this with that of other neurological diseases. The assay method was designed to use column chromatography with Amberlite IRA 402. The thiocyanate level was determined using pyridine-barbiturate method. The 24-h thiocyanate level was higher in the ALS patients of the middle stages than in the normal control group (Wilcoxon's test, P less than 0.02). There were no significant differences between the ALS patient groups of the early and terminal stages, Kugelberg-Welander disease group, Duchenne type muscular dystrophy group and control group. From these results, we concluded that ALS patients were contaminated with cyanide or thiocyanate and that, along with rapid muscular atrophy, the thiocyanate excretion levels were high.     

Frontal-lobe mediated behavioral dysfunction in amyotrophic lateral sclerosis

Background:  Cognitive impairment secondary to frontal lobe atrophy exists in 40–60% of Amyotrophic Lateral Sclerosis (ALS) cases. We aimed to determine the prevalence of frontal-lobe mediated behavioral impairment in (ALS) and to ascertain its relationship to cognitive impairment.
Methods:  Two-hundred and twenty five patients diagnosed with sporadic ALS were evaluated for behavioral dysfunction using the Frontal Systems Behavior Scale (FrSBe), a validated measure used to examine frontal-lobe mediated behaviors, specifically apathy , executive dysfunction and disinhibition ; a total behavior score is also provided. Additionally, a subset of patients also underwent a comprehensive neuropsychological evaluation.
Results:  Changes in the total FrSBe scores were observed in 24.4% of the patients and 39.6% of the patients had impairment in at least one behavioral domain with symptoms of Apathy being the most common (31.1%). Cognitively impaired ALS patients had worse total ( P  = 0.05) and apathy scores ( P  < 0.01); however, behavioral dysfunction was also present in 16% of the cognitively intact patients. Half of the behaviorally intact patients exhibited cognitive impairment. Significant correlations were observed for performance on certain neuropsychological tests (Animal fluency, Block Design, Logical Memory I and Verbal Series Attention Test) and severity of behavioral dysfunction on certain FrSBe sub scores.
Conclusions:  Frontal-lobe mediated behavioral dysfunction appears to be common in ALS. Cognitively impaired ALS patients had greater behavioral dysfunction. Recognition of behavioral and cognitive dysfunction may assist health-care providers and care-givers recognize changes in decision-making capacity and treatment compliance of patients with ALS.     

Reassessment of motor-behavioural test analyses enables the detection of early disease-onset in a transgenic mouse model of amyotrophic lateral sclerosis

As a model for amyotrophic lateral sclerosis (ALS), transgenic hSOD1^G93A mice constitute the standard tool for evaluating future therapeutic strategies. Due to axonal retraction from neuromuscular junctions, the animals suffer from muscle wasting leading to weakness and paralysis of the extremities, which in early stages can be detected by measuring weight loss. Suspecting that underlying mechanisms might yield subtle neuromuscular abnormalities ahead of weight loss onset, we wanted to determine a behavioural test to detect disease onset time earlier. We compared the monitoring of weight with the “forced” examination of grip strength and the investigation of freely behaving animals within an open field. Additionally, we compared two different data analysis methods: (1) two-way ANOVA with Bonferroni correction (2) break point analysis calculating symptom onset time points for each animal. Break point analysis revealed onset times that significantly preceded those obtained by standard two-way ANOVA. Open field analysis of freely moving animals could not give an advantage over weight loss measurements. Grip strength assessment of hindlimbs detected disease onset 36 days before the first evidence of weight loss, providing a maximal treatment window of 84 days on average before the death of male animals. We conclude that grip strength analysis of hindlimbs is a very sensitive and reproducible motor behavioural test, which can even be applied to small cohorts of animals. Combined with break point analysis, it represents the method of choice to detect early disease onset in hSOD1^G93A mice.     

肌萎缩侧索硬化患者的重复神经电刺激特点

目的探讨肌萎缩侧索硬化(ALS)患者重复神经电刺激(RNS)特点,及其在ALS诊断和鉴别诊断中的应用价值。方法收集2008-05-2009-04在北京协和医院神经科门诊或住院确诊或拟诊的ALS患者101例,另选择同期门诊就诊的非ALS肌肉萎缩患者40例为对照。记录患者的临床资料。所有患者行肌电图和RNS检查。比较ALS患者和非ALS肌萎缩患者RNS阳性率的差异。比较ALS患者不同神经RNS阳性率及递减幅度差异,并分析性别、年龄、病程、尺神经波幅、临床疾病分级对RNS阳性率的影响。结果 (1)ALS患者和非ALS肌萎缩无力患者RNS检查低频递减阳性率分别为53.5%和7.5%,两组间比较差异有统计意义(P0.05),未出现高频递增患者。(2)所检测神经低频递减阳性率从高至低依次为腋神经(30.6%)副神经(25%)桡神经(15.5%)尺神经(7.8%)面神经(1.0%)胫神经(0%)。(3)ALS患者RNS检测低频递减阳性率与性别、年龄、病程、临床疾病分级无关(均P0.05),肢体起病者较球部起病者RNS低频递减阳性率高(P0.05)。结论 ALS患者RNS检测低频递减阳性率较非ALS肌无力萎缩患者高,RNS检测有助于ALS的诊断和鉴别诊断。ALS患者RNS检测低频递减阳性与性别、年龄、病程、临床疾病分级均无关。     

Amyotrophic lateral sclerosis with dementia

Four patients with amyotrophic lateral sclerosis (ALS) and dementia are reported. Mental symptoms antedated motor signs and were investigated with a neuropsychology battery, which brought out different patterns of cognitive impairment. A case presented with frontal dementia, another with a predominant aphasic, apraxic, amnesic syndrome, while the remainders showed cognitive decline in association with blunt affect. Motor signs were characterized by a precocious involvement of the upper motor system.     

Needle electromyography of the rectus abdominis in patients with amyotrophic lateral sclerosis

We examined the role of needle electromyography (EMG) of the rectus abdominis (RA) in assessing thoracic involvement in amyotrophic lateral sclerosis (ALS). Needle EMG of the RA was performed in 67 patients with sporadic ALS and 110 healthy controls. The presence of abnormal spontaneous activity, configuration of motor unit action potentials (MUAPs), and recruitment pattern of motor unit potentials were examined. In ALS patients, MUAPs in the RA were of prolonged duration, large amplitude, and showed increased prevalence of polyphasic waveforms compared to controls. Significant differences in MUAP parameters, presence of abnormal spontaneous potentials, and interference patterns were noted between ALS patients and controls. Additionally, we found that active denervation was more frequent in the RA of ALS patients with dyspnea than those without dyspnea. Thus, conventional needle EMG of the RA is a valuable electrophysiological method to assess clinical and subclinical involvement of thoracic lower motor neurons in patients with suspected ALS.     

Time for optimism in amyotrophic lateral sclerosis

Background and purpose

Amyotrophic lateral sclerosis (ALS) is among the most common motor neuron diseases in adults. Nevertheless, ALS remains fatal, despite decades of research and clinical trials, which has led to negative conclusions until recently in regard to four specific treatments. It is well known that we can learn from failures, and we consider that the time has come to present positive insight on this disease.

Methods

We did a literature search using PubMed and Scopus for articles published in English from 1 January 2016, to 30 June 2022 dealing with “amyotrophic lateral sclerosis”, diagnosis, treatment, and biomarkers.

Results

A comprehensive review of the literature on diagnosis, monitoring, and treatment of this condition showed convincing evidence that we are now able to diagnose earlier as well as to better monitor and treat ALS.

Conclusions

Although ALS is often difficult to diagnose and remains incurable, there are many indications that an optimistic view of ALS management in the coming years is now realistic.     

Epidemiology of amyotrophic lateral sclerosis in the province of Modena, Italy. Influence of environmental exposure to lead

A retrospective study of all admissions to the University of Modena Neurological Department from 1976-1986; 51 cases of amyotrophic lateral sclerosis (ALS) were found. ALS mean annual incidence was 0.78/100,000 inhabitants, while prevalence was 2.35/100,000. Mean age at onset was 61.43 years, mean and median duration of illness were, respectively, 28.83 and 24.5 months, and survival at 5 years post-onset was 24.4%. A tendency to higher incidence and prevalence of ALS in the ceramic district, when compared with those of the rest of the province was found. However, the small number of cases did not allow any conclusive statistical correlation between environmental exposure to lead and frequency of ALS.     

Amyotrophic lateral sclerosis with dementia showing clinical parkinsonism and severe degeneration of the substantia nigra: Report of an autopsy case

An autopsy case of amyotrophic lateral sclerosis with dementia (ALS‐D) showing clinically overt parkinsonism and severe degeneration of the substantia nigra is reported. The patient was a 78‐year‐old man who died after a 2‐year clinical course characterized by parkinsonism that was responsive to Levodopa (L‐DOPA) treatment. Motor neuron symptoms and dementia were not apparent ante‐mortem. The autopsy demonstrated the severe degeneration of the substantia nigra without α‐synucleinopathy‐related changes. Finely granular mineralization of necrotic neurons was a unique finding in the substantia nigra. The mild loss of spinal anterior horn cells, the appearance of several Bunina bodies and the degeneration of the hippocampal subiculum and temporal cortex were also noted. A small number of ubiquitinated intra‐cytoplasmic inclusions were found in neurons of the dentate fascia of the hippocampus and the temporal and frontal cortices. Although the degeneration of the substantia nigra is a common finding in ALS‐D, patients seldom develop clinically overt parkinsonism. This case indicates that patients with ALS‐D rarely present with predominantly parkinsonian clinical features and these symptoms and signs can be improved by L‐DOPA treatment.