Tau levels do not influence human ALS or motor neuron degeneration in the SOD1G93A mouse.

BACKGROUND: The microtubule-associated protein tau is thought to play a pivotal role in neurodegeneration. Mutations in the tau coding gene MAPT are a cause of frontotemporal dementia, and the H1/H1 genotype of MAPT, giving rise to higher tau expression levels, is associated with progressive supranuclear palsy, corticobasal degeneration, and Parkinson disease (PD). Furthermore, tau hyperphosphorylation and aggregation is a hallmark of Alzheimer disease (AD), and reducing endogenous tau has been reported to ameliorate cognitive impairment in a mouse model for AD. Tau hyperphosphorylation and aggregation have also been described in amyotrophic lateral sclerosis (ALS), both in human patients and in the mutant SOD1 mouse model for this disease. However, the precise role of tau in motor neuron degeneration remains uncertain. METHODS: The possible association between ALS and the MAPT H1/H2 polymorphism was studied in 3,540 patients with ALS and 8,753 controls. Furthermore, the role of tau in the SOD1(G93A) mouse model for ALS was studied by deleting Mapt in this model. RESULTS: The MAPT genotype of the H1/H2 polymorphism did not influence ALS susceptibility (odds ratio = 1.08 [95% confidence interval 0.99-1.18], p = 0.08) and did not affect the clinical phenotype. Lowering tau levels in the SOD1(G93A) mouse failed to delay disease onset (p = 0.302) or to increase survival (p = 0.557). CONCLUSION: These findings suggest that the H1/H2 polymorphism in MAPT is not associated with human amyotrophic lateral sclerosis, and that lowering tau levels in the mutant SOD1 mouse does not affect the motor neuron degeneration in these animals.

Pigmented creatine deposits in Amyotrophic Lateral Sclerosis central nervous system tissues identified by synchrotron Fourier Transform Infrared microspectroscopy and X-ray fluorescence spectromicroscopy.

Amyotrophic Lateral Sclerosis (ALS) is an untreatable, neurodegenerative disease of motor neurons characterized by progressive muscle atrophy, limb paralysis, dysarthria, dysphagia, dyspnae and finally death. Large motor neurons in ventral horns of spinal cord and motor nuclei in brainstem, large pyramidal neurons of motor cortex and/or large myelinated axons of corticospinal tracts are affected. In recent synchrotron Fourier Transform Infrared microspectroscopy (sFTIR) studies of ALS CNS autopsy tissue, we discovered a small deposit of crystalline creatine, which has a crucial role in energy metabolism. We have now examined unfixed, snap frozen, post-autopsy tissue sections of motor cortex, brain stem, spinal cord, hippocampus and substantia nigra from six ALS and three non-degenerated cases with FTIR and micro-X-ray fluorescence (XRF). Heterogeneous pigmented deposits were discovered in spinal cord, brain stem and motor neuron cortex of two ALS cases. The FTIR signature of creatine has been identified in these deposits and in numerous large, non-pigmented deposits in four of the ALS cases. Comparable pigmentation and creatine deposits were not found in controls or in ALS hippocampus and substantia nigra. Ca, K, Fe, Cu and Zn, as determined by XRF, were not correlated with the pigmented deposits; however, there was a higher incidence of hot spots (Ca, Zn, Fe and Cu) in the ALS cases. The identity of the pigmented deposits remains unknown, although the absence of Fe argues against both erythrocytes and neuromelanin. We conclude that elevated creatine deposits may be indicators of dysfunctional oxidative processes in some ALS cases.

Profile of laryngological abnormalities in patients with amyotrophic lateral sclerosis.

Few studies have described laryngological evaluation of patients with amyotrophic lateral sclerosis. We assessed the laryngological abnormalities of 35 such patients (24 bulbar onset and 11 limb onset). In nine limb onset patients, we discovered signs of early vagal nerve dysfunction, prior to any clinical presentation of bulbar failure. However, in all bulbar onset patients studied, we noticed changes in the uni/bilateral position of the vocal folds and in the voice quality.

Paraoxonase gene polymorphisms and sporadic ALS.

BACKGROUND: The human paraoxonase (PON) gene family consists of three members, PON1, PON2, and PON3, located adjacent to each other on chromosome 7. PON catalytic activity may be influenced by frequent amino acid variants. Chronic exposure to certain chemicals or to environmental factors causing enhanced lipid peroxidation metabolized by paraoxonases may be a risk factor for sporadic ALS (sALS). OBJECTIVE: The aim of this study was to examine the association between PON1 Q192R, PON1 L55M, and PON2 C311S functional polymorphisms and the risk of sALS in a Polish population. METHODS: The authors included 185 patients with a definite or probable diagnosis of sALS (El Escorial Criteria) and 437 healthy controls of similar age and gender. The paraoxonase polymorphisms were studied by PCR and restriction enzyme digestion. RESULTS: Using logistic regression analyses, the C allele of the C311S polymorphism was associated with sALS in dominant and additive models, whereas the R allele of the Q192R polymorphism was associated with sALS in recessive, additive, and dominant models. The authors compared the distribution of haplotypes between cases and controls. The R-C haplotype was overrepresented among cases (odds ratio 3.44, 95% CI: 1.55 to 7.62, p = 0.002). CONCLUSIONS: Frequent amino acid variants in the paraoxonase 1 and paraoxonase 2 genes are associated with sporadic ALS in a Polish population.

Implementation of X-ray fluorescence microscopy for investigation of elemental abnormalities in amyotrophic lateral sclerosis.

The abnormalities of metallochemical reactions may contribute to the pathogenesis of Amyotrophic Lateral Sclerosis (ALS). In the present work, an investigation of the elemental composition of the gray matter, nerve cells and white matter from spinal cord tissues representing three ALS cases and five non-ALS controls was performed. This was done with the use of the synchrotron microbeam X-ray fluorescence technique (micro-SRXRF). The following elements were detected in the tissue sections: P, S, Cl, K, Ca, Fe, Cu, Zn and Br. A higher accumulation of Cl, K, Ca, Zn and Br was observed in the nerve cell bodies than in the surrounding tissue. Contrary to all other elements, Zn accumulation was lower in the white matter areas than in the gray matter ones. The results of quantitative analysis showed that there were no general abnormalities in the elemental accumulation between the ALS and the control group. However, for individual ALS cases such abnormalities were observed for the nerve cells. We also demonstrated differences in the elemental accumulation between the analyzed ALS cases.

EFNS task force on management of amyotrophic lateral sclerosis: guidelines for diagnosing and clinical care of patients and relatives.

Despite being one of the most devastating diseases known, there is little evidence for diagnosing and managing patients with amyotrophic lateral sclerosis (ALS). Although specific therapy is lacking, correct early diagnosis and introduction of symptomatic and specific therapy can have a profound influence on the care and quality of life of the patient and may increase survival time. This document addresses the optimal clinical approach to ALS. The final literature search was performed in the spring of 2005. Consensus recommendations are given graded according to the EFNS guidance regulations. Where there was lack of evidence but consensus was clear we have stated our opinion as good practice points. People affected with possible ALS should be examined as soon as possible by an experienced neurologist. Early diagnosis should be pursued and a number of investigations should be performed with high priority. The patient should be informed of the diagnosis by a consultant with a good knowledge of the patient and the disease. Following diagnosis, the patient and relatives should receive regular support from a multidisciplinary care team. Medication with riluzole should be initiated as early as possible. PEG is associated with improved nutrition and should be inserted early. The operation is hazardous in patients with vital capacity < 50%. Non-invasive positive pressure ventilation improves survival and quality of life but is underused. Maintaining the patients ability to communicate is essential. During the entire course of the disease, every effort should be made to maintain patient autonomy. Advance directives for palliative end of life care are important and should be fully discussed early with the patient and relatives respecting the patients social and cultural background.

The antibodies against Bordetella pertussis in sera of patients with Parkinson's disease and other non-neurological diseases.

OBJECTIVES: It has been reported that the prevalance of parkinsonism might be associated with exposure to whooping cough. METHODS: Examination of levels of antibodies against Bordetella pertussis in serum using enzyme-linked immunosorbent assay (ELISA) tests [presence of IgG antibodies against filamentous hemagglutinin and pertussis toxin (PT)] were performed in 81 persons (including 45 patients with controls) (age-matched groups). RESULTS: Positive results were found in patients with Parkinson's disease (PD), patients with other non-inflammatory diseases, and controls (about 40-45% in each group). A detailed examination of separate responses (IgG and IgA antibodies against PT, and a whole cell immune response) and of the serum level of immunoglobulins IgG, IgA and IgM was also performed. CONCLUSION: Our results demonstrate numerous cases of whooping cough serum antibodies among the adult population (also among PD patients). The results of our research, i.e. a common occurrence of Bordetella pertussis infection do not provide evidence of relationship between PD and the above-mentioned infection.

Progressive multifocal leukoencephalopathy (PML) in a patient with silicosis treated previously with steroids. A report of a case with JC virus infection confirmed immunohistochemically and by electron microscopy.

We present a case of progressive multifocal leukoencephalopathy (PML) diagnosed at autopsy, in which JC virus infection of the central nervous system was confirmed by means of electron microscopy and immunohistochemistry. The patient had been receiving steroid hormones due to suspected sarcoidosis or pneumoconiosis. Diffuse silicosis in lungs and in hilar and mediastinal lymph nodes was diagnosed at autopsy. Intranuclear inclusions, ultrastructurally typical of JC virus were found in some oligodendrocytes in the white matter. However the strongest immunopositive viral deposits were found in the cerebellar cortex, also within Purkinje cells. Numerous apparently apoptotic cells seen in white matter suggest that this mechanism of cell elimination plays an important role in PML pathogenesis and hence anti-apoptotic treatment may alleviate the symptoms and prolong survival.

[The application of dysarthria profile tests in ALS patients for the detection of speech disturbances]. / Przydatnosc testów profilu dyzartrii do wykrywania zaburzen mowy u chorych ze stwardnieniem bocznym zanikowym.

Dysarthria is an invalidating disability in ALS patients with motor neuron degeneration in the bulbar region. The methods to assess dysarthric disorders in ALS are seldom described in publications. This study was performed in 43 patients who had definite (n = 23) or probable (n = 20) ALS (of the bulbar group n = 15, of the limb group n = 28, mean age = 57.07 (range: 36-69 yr.)) according to WFN criteria. The method based on quantitative tests of dysarthria profile (by Robertson, 1986) was used and the results were compared with 37 age, sex-matched, healthy control subjects. Our study showed the existence of disturbances in all dysarthria profile tests which were of the statistic significance and more frequent as compared to the control subjects (p < 0.01). The analysis showed that quantitative assessment of some dysarthria profile tests (5 out of 8) might be useful in clinical practice to detect dysarthria in ALS patients. Using the dysarthria profile tests we also demonstrated that preclinical dysarthric processes occur among the limb ALS group.

Phenotypic differences between African and white patients with motor neuron disease: a case-control study.

There is increasing evidence that race may affect the phenotype in some neurodegenerative diseases. To investigate this in motor neuron disease a retrospective case-control study has been carried out on 15 negroid African and 45 white patients with the disease seen over 8 years. Each African was compared with three age and sex matched white patients with motor neuron disease. There were no statistically significant differences in age of onset or the mean duration of disease in the two groups. The chance of presenting with the "flail arm" variant of motor neuron disease was four times as high in the African group than the white group (odds ratio 4.33, p=0. 05, 95% confidence interval 0.99-18.92). Although no overall differences in survival were seen between the two groups, in those with the flail arm variant, four out of the six African patients had died whereas all six white arm patients were alive at the censoring date of 1 January 1999 (median follow up 38.5 months). It is concluded that race may influence the phenotype and progression of motor neuron disease.

ALS-Plus syndrome. A clinical and neuropathological case study.

ALS-Plus syndrome occurs rarely and usually presents typical ALS phenotype associated with dementia, Parkinsonism or both. We reported a case of sporadic, definite ALS with pseudobulbar palsy, emotional lability and selective cognitive deficit in the presence of frontal lobe dementia. Neuropsychological tests predominantly demonstrated perserveration and dynamic apraxia, CT and MRI scans showed widened subarachnoideal spaces in the frontal and temporal regions. The neuropathological findings confirmed ALS processes i.e. atrophy of motor nuclei in brainstem and anterior horns of cervical spinal cord and showed mild atrophy and status spongiosus in the frontal lobes. These findings suggest the co-occurrence of sporadic ALS and frontal lobe dementia: ALS-Plus syndrome.

[Evaluation of dysarthria with the assistance of acoustic speech analysis in patients with amyotrophic lateral sclerosis]. / Ocena dyzartrii za pomoca analizy akustycznego sygnalu mowy u chorych z stwardnieniem bocznym zanikowym.

The aim of the study was to assess dysarthria in ALS subjects using acoustic speech analysis. The study was performed in 47 definite or probable ALS patients aged 29-76 years (mean age 53.7 yr.) and in 30 age and sex matched healthy control subjects. Neurological examination showed 15 dysarthric ALS subjects. Acoustic speech analysis is a quantitative, computer-acoustic method estimating dysarthria and based on assessing of sound distance from speech sound tests. In both group the mean sound distance between chosen sounds was compared to a basic pattern and was measured on time-frequency computer acoustic analyses (delta f = 125 Hz, delta T = 9 ms, delta s = 0.5 dB). Our results demonstrated that all sounds were incorrect in all ALS subjects. These abnormalities were significantly increased in the dysarthric ALS subjects. The mean sound distances which separated ALS from control subjects is 0.2 (by Euclidian principle) in 4 out of 5 measured sounds. We suggest that it is possible to detect and measure dysarthria in ALS patients based on the acoustic speech analysis, also in the limb onset ALS subjects.

Acoustic analysis of dysarthria profile in ALS patients.

Dysarthria is a leading disability in ALS patients with motor neurone degeneration in the bulbar region. Although different approaches have been tried in the past, currently, no test is available to detect and follow the progression of dysarthria. We studied 53 patients with definite (n=27) or probable (n=26) ALS (the bulbar onset group n=15, the limb onset group n=38, mean age 53. 66/29-76 years/) according to El Escorial criteria. Each patient was seen by a neurologist every 10-12 weeks and clinical performance was assessed using the Norris scale. To evaluate dysarthria we developed a computer-based acoustic method. All patients had computer-analysed speech sound tests done three times. The most significantly affected vowels were selected for further studies. A method based on the Euclidian principle was used and the results were compared with 30 age, sex-matched, healthy control subjects. Our results demonstrated the existence of a specific dysarthria profile in ALS patients with most significantly affected vowels: 'B', 'O', 'I', 'W', 'T' in the bulbar group, and: 'B', 'I', 'T', 'W', 'O' in the limb group. This study suggests that it is possible to detect and monitor the progression of the disease based on the acoustic analysis of only several sounds. Abnormalities detected in the dysarthria profile may appear prior to any clinical symptoms of the disease.

[Assessment of the efficacy of treatment with pimozide in patients with amyotrophic lateral sclerosis. Introductory notes]. / Ocena skutecznosci pimozydu u chorych ze stwardnieniem bocznym zanikowym. Doniesienie wstepne.

The aim of the study was to assess the effect of pimozide voltage-dependent calcium channel blocker on the progression of ALS patients as compared to the potentially neuroprotective drugs, selegiline and vitamin E. There were 44 patients (17 females and 27 males, aged from 30 to 80 years, mean age: 56.2 years) diagnosed as either definite or possible ALS. The study design was open randomised. Patients were treated 3-12 months; the daily dose of pimozide was 1 mg. The disease progression index was calculated as a difference between scores of Norris scale before and after treatment. Statistical analysis showed a significant decrease of the index of progression of the disease in pimozide treated patients as compared to the others. This effect was neither related to the progression of the disease nor advance of the disease at the beginning of treatment.

[Prognostic significance of transient hyperglycemia in acute phase of ischemic stroke]. / Prognostyczne znaczenie przejsciowej hiperglikemii w ostrej fazie udaru niedokrwiennego mózgu.

Experimental studies of different stroke models equivocally showed that hyperglycaemia is responsible for the increase of infarct volume and mortality. Similar results were obtained in several, but not all clinical studies. The aim of the study was to assess the occurrence and prognosis of transient hyperglycaemia in non-diabetic, acute ischaemic stroke patients. A consecutive series of 204 patients admitted to the Stroke Unit within 48 hours after the onset of the first-ever hemispheric ischaemic stroke, confirmed by CT and/or autopsy, were included in the study. Blood samples for determination of glucose level were obtained immediately after admission, on the 1-st, 2-nd, 3-rd, 5-th, 7-th and 14-th day of stroke. The fructosamine and HbA1 measurements were used to exclude patients with previous glucose intolerance. The severity of stroke was assessed according to Scandinavian Neurological Stroke Scale on admission, on the first, 7-th, 14-th and 30-th day of stroke. Transient hyperglycaemia, defined as at least one elevated glucose level in the first week of stroke with normal level of HbA1 and fructosamine was found in 65 (31.9%) of patients. Patients with transient hyperglycaemia did not differ from diabetics and normoglycaemic according to age, gender, history of hypertension and other risk factors. 30 day mortality in the group of patients with transient hyperglycaemia was significantly higher than in normoglycaemic ( p. < 0.001) and diabetic patients. Transient hyperglycaemic patients died earlier, mainly on the 7-th day after admission whereas patients with normoglycaemia died mainly on the 18-th day (p < 0.0001). The main reason of death in hyperglycaemic patients were cardiac complications (15/20), in normoglycaemic--the consequences of immobility (8/11) (< 0.01). The results of our study showed that the transient hyperglycaemia occurred in about one third of acute ischaemic stroke patients and resulted in higher 30-day mortality.

[The effect of amitriptyline on the pathological crying and other pseudobulbar signs]. / Wplyw amitriptyliny na patologiczny placz oraz inne objawy zespolu rzekomoopuszkowego.

The efficacy and tolerability of amitriptyline on the pathologic crying and other pseudobulbar signs were investigated in 22 consecutive patients diagnosed mostly as ALS. The occurrence and intensity of pathologic crying, dysarthria, dysphagia, jaw reflex and primitive reflexes (snout, palmo-mental and oral), were assessed before and after 3 and 6 weeks of amitriptyline treatment. The drug administered in low dose (30-100 mg, mean 64 +/- 17.6 mg) significantly decreased the frequency of pathologic crying in 17 patients after 3 weeks and in 20 patients after 6 weeks of treatment. There were no changes in the intensity of the other pseudobulbar signs. Only few mild and transient side effects were observed. The authors conclude, that amitriptyline is an effective treatment of pathologic crying in ALS patients.