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PubMed2005

ALS-IgG-induced selective motor neurone apoptosis in rat mixed primary spinal cord cultures.

There is evidence that in sporadic amyotrophic lateral sclerosis (ALS) immunological mechanisms may be involved in the pathophysiology of the disease. We tested whether purified IgG from ALS patients induce cell death in rat mixed primary spinal cord cultures and compared this with the effect of IgG purified from patients with Guillain-Barré syndrome (GBS) or from healthy donors. Treatment with ALS-IgG increases caspase-3 apoptosis when compared with control IgG or with GBS-IgG, but does not induce death by necrosis. Because ALS is characterized by the selective loss of motor neurones, we next assessed the differential effect of ALS-IgG on motor neurones or astrocytes. We showed, semiquantitatively, that motor neurones are more susceptible to apoptosis when cultures were treated with ALS-IgG compared with control-IgG. In conclusion, we have demonstrated in primary spinal cord cultures that IgG from patients with ALS induces apoptosis selectively in motor neurones, and that the caspase-3 pathway is involved. This suggests that immunological mechanisms may contribute to the selective loss of motor neurones in ALS.

Adolescent↗

PubMed1977

Studies on epidemiological, clinical, and etiological aspects of ALS disease in Sardinia, Southern Italy.

This investigation was conducted to clarify the epidemiology of ALS disease in Sardinia. During the years 1965-1974, the average annual incidence was found to be 0.64/100,000 inhabitants. On prevalence day, October 24th, 1974, the prevalence rate was 1.56/100,000 inhabitants. A significant male predominance was found, the average annual incidence rates for men and women being 0.88 and 0.40, respectively. The peak in both sexes was reached between 60 and 69 years. ALS distribution in the study area was uniform but its occurrence was significantly higher among agricultural workers (5.28/100,000). ALS started on average at 56.58 years and its duration was 2.5 years, being significantly longer in patients under 40-years-old. The distribution of the various clinical forms was: 66 per cent conventional forms, 20 percent bulbar and 14 per cent pseudo-polyneuritic. In the bulbar type, a female predominance was found. About 96 percent of cases were sporadic and 4 per cent familial. Familial cases presented no difference from sporadic cases. Trauma was present in 10.5 percent of the cases and gastrointestinal disfunction in 13 per cent. This probably reflects some relationship between trauma and ALS, and between malnutrition and ALS. No combination of ALS, dementia and parkinsonism was observed. Dementia was associated with ALS in four cases and Parkinson's disease in one case, separately. The combination of other disease states with ALS in the present study may be simple coincidence.

Adolescent↗

PubMed1999

Detection of Als proteins on the cell wall of Candida albicans in murine tissues.

A murine model of disseminated candidiasis was utilized to determine whether Candida albicans Als proteins are produced in vivo. The kidneys, spleen, heart, liver, and lungs were collected from mice inoculated with one of three C. albicans strains (SC5314, B311, or WO-1). Immunohistochemical analysis of murine tissues by using a rabbit polyclonal anti-Als serum indicated that Als proteins were produced by each C. albicans cell in the tissues examined. Patterns of staining with the anti-Als serum were similar among the C. albicans strains tested. These data indicated that Als protein production was widespread in disseminated candidiasis and that, despite strain differences in ALS gene expression previously noted in vitro, Als protein production in vivo was similar among C. albicans strains. The extensive production of Als proteins in vivo and their presence on the C. albicans cell wall position these proteins well for a role in host-pathogen interaction.

Animals↗

PubMed2005

The cost-effectiveness of early noninvasive ventilation for ALS patients.

BACKGROUND: Optimal timing of noninvasive positive pressure ventilation (NIPPV) initiation in patients with amyotrophic lateral sclerosis (ALS) is unknown, but NIPPV appears to benefit ALS patients who are symptomatic from pulmonary insufficiency. This has prompted research proposals of earlier NIPPV initiation in the ALS disease course in an attempt to further improve ALS patient quality of life and perhaps survival. We therefore used a cost-utility analysis to determine a priori what magnitude of health-related quality of life (HRQL) improvement early NIPPV initiation would need to achieve to be cost-effective in a future clinical trial. METHODS: Using a Markov decision analytic model we calculated the benefit in health-state utility that NIPPV initiated at ALS diagnosis must achieve to be cost-effective. The primary outcome was the percent utility gained through NIPPV in relation to two common willingness-to-pay thresholds: 50,000 dollars and 100,000 dollars per quality-adjusted life year (QALY). RESULTS: Our results indicate that if NIPPV begun at the time of diagnosis improves ALS patient HRQL as little as 13.5%, it would be a cost-effective treatment. Tolerance of NIPPV (assuming a 20% improvement in HRQL) would only need to exceed 18% in our model for treatment to remain cost-effective using a conservative willingness-to-pay threshold of 50,000 dollars per QALY. CONCLUSION: If early use of NIPPV in ALS patients is shown to improve HRQL in future studies, it is likely to be a cost-effective treatment. Clinical trials of NIPPV begun at the time of ALS diagnosis are therefore warranted from a cost-effectiveness standpoint.

Amyotrophic Lateral Sclerosis↗

PubMed2004

A clinical trial of creatine in ALS.

BACKGROUND: Mitochondrial dysfunction occurs early in the course of ALS, and the mitochondria may be an important site for therapeutic intervention. Creatine stabilizes the mitochondrial transition pore, and is important in mitochondrial ATP production. In a transgenic mouse model of ALS, administration of creatine prolongs survival and preserves motor function and motor neurons. METHODS: The authors conducted a randomized double-blind, placebo controlled trial on 104 patients with ALS from 14 sites to evaluate the efficacy of creatine supplementation in ALS. The primary outcome measure was maximum voluntary isometric contraction of eight upper extremity muscles, with secondary outcomes including grip strength, ALS Functional Rating Scale-Revised, and motor unit number estimates. Patients were treated for 6 months, and evaluated monthly. RESULTS: Creatine was tolerated well, but no benefit of creatine could be demonstrated in any outcome measure. CI analysis showed that the study, although powered to detect a 50% or greater change in rate of decline of muscle strength, actually made an effect size of greater than 23% unlikely. It was also demonstrated that motor unit number estimation was performed with acceptable reproducibility and tolerability, and may be a useful outcome measure in future clinical trials. CONCLUSION: Any beneficial effect of creatine at 5 g per day in ALS must be small. Other agents should be considered in future studies of therapeutic agents to address mitochondrial dysfunction in ALS. In addition, motor unit number estimation may be a useful outcome measure for future clinical trials in ALS.

Adolescent↗

PubMed2005

Cognitive change in ALS: a prospective study.

OBJECTIVES: To investigate longitudinally the profile of cognitive impairment in nondemented patients with ALS. METHODS: Twenty nondemented patients with ALS and 18 controls were interviewed at two time points separated by a 6-month interval. The extensive battery was designed to accommodate the range of physical disability present in ALS, and included measures of executive, memory, language, and visuospatial functions, everyday behavior, and emotion. RESULTS: On a test of simple word retrieval (Computerised Sentence Completion Test) patients with ALS became slower over time, while controls became faster at completing sentences with appropriate words. This effect remained when the analysis accommodated for progressive speech disability. Patients with ALS also displayed an impairment in both written and spoken verbal fluency indices (time to think of each word) at both time points, but there was no evidence of deterioration over time. On the Short Inventory of Minor Lapses, carers of patients with ALS displayed increased awareness of cognitive dysfunction in everyday behavior while controls' ratings of their partners decreased. In addition, patients displayed more depressive symptomology (although well below clinical levels) on the second interview vs controls. Patients with ALS also displayed emotional lability at both time points, although this did not increase over time. CONCLUSIONS: Cognitive deterioration in nondemented patients with ALS is a relatively slow process. Selective cognitive impairment in the form of verbal fluency deficits, most likely indicating executive dysfunction, appears relatively early on in the course of the disease, although language functions may become vulnerable as the disease progresses.

Adult↗

PubMed2005

A voxel-based morphometry study of patterns of brain atrophy in ALS and ALS/FTLD.

OBJECTIVE: To investigate the patterns of MRI brain atrophy in patients with ALS with and without clinically evident frontotemporal lobar dementia (FTLD) using voxel-based morphometry (VBM). METHODS: Voxel-based morphometry was used to compare T1-weighted MRI images obtained from ten ALS patients with FTLD, ten ALS patients who were cognitively and behaviorally normal, and 22 control subjects. Images from patients and controls were spatially pre-processed using a study-specific, customized template and a priori images. A statistical threshold of p < 0.05 corrected for multiple comparisons determined significance. RESULTS: A common pattern of gray matter atrophy was seen in both ALS and ALS/FTLD patients when compared to controls that involved the bilateral motor/premotor cortices, the left middle and inferior frontal gyri, the anterior portion of the superior frontal gyri, the superior temporal gyri, the temporal poles and left posterior thalamus. Most of the frontal regions were significantly more atrophied in the ALS/FTLD group than in the ALS group. No significant differences were found in white matter volumes. CONCLUSIONS: Patients with ALS and ALS associated with frontotemporal lobar degeneration exhibit widespread gray matter atrophy in frontotemporal regions. This finding supports the idea of a clinical and anatomic continuum between ALS and frontotemporal lobar degeneration.

Adult↗

PubMed2006

Axonal damage markers in cerebrospinal fluid are increased in ALS.

OBJECTIVE: To test whether biomarkers for axonal degeneration correlated with clinical subtypes and were of use in predicting progression of ALS. METHODS: Patients with ALS (n = 69), patients with Alzheimer disease (AD; n = 73), and age-matched controls (n = 33) were included in this prospective study. CSF levels of tau protein and neurofilaments (NfHSMI35) were measured using ELISA. In 49 patients with ALS, follow-up data were available (median follow-up 7 months). RESULTS: CSF levels of NfHSMI35 were five times higher in patients with ALS (1.7 ng/mL) than in controls (0.3 ng/mL, p < 0.001) and 10 times higher than in patients with AD (0.14 ng/mL, p < 0.001). NfHSMI35 values were also higher in patients with upper motor neuron-dominant ALS than in patients with typical ALS (upper motor neuron + lower motor neuron) at p = 0.02. Values of NfHSMI35 were higher in ALS of more rapid progression. The values of NfH and tau did not correlate with CSF protein content. CONCLUSIONS: The authors propose that axonal damage markers in CSF may discriminate between subtypes of ALS and that they could be used as markers for therapeutic trials. CSF NfH was superior to tau in these discriminations.

Adult↗

PubMed1998

Toward earlier diagnosis of amyotrophic lateral sclerosis: revised criteria. rhCNTF ALS Study Group.

We modified the World Federation of Neurology (WFN) diagnostic criteria for ALS to facilitate early diagnosis and used these criteria for enrollment of ALS patients in a clinical trial. The criteria developed required lower motor neuron (LMN) involvement in at least two limbs and upper motor neuron involvement in at least one region (bulbar, cervical, or lumbosacral). The EMG finding of fibrillation potentials was required for evidence of LMN involvement. Electrodiagnostic studies, neuroimaging, and laboratory studies were also used to exclude disorders that might mimic ALS. Using these criteria, the diagnosis of ALS was made at a mean time of 9.7 months from onset of symptoms, which compares favorably with the 12-month period cited in the literature. Using clinical assessment at completion of the trial, the diagnosis of ALS was believed to be accurate in those patients entered in the trial. However, pathologic confirmation of the diagnosis of ALS was not obtained. Based on our preliminary experience, we propose that these ALS diagnostic criteria will facilitate early diagnosis of ALS. Future studies should prospectively compare these criteria with the WFN criteria currently in use.

Amyotrophic Lateral Sclerosis↗

PubMed1999

Clustering of ALS patients in central Italy due to the occurrence of the L84F SOD1 gene mutation.

OBJECTIVE: To study three new apparently unrelated Italian families with ALS and several sporadic ALS patients living in the same rural area. BACKGROUND: One Italian family with ALS carrying a superoxide dismutase 1 (SOD1) gene mutation (G41S) and no regional ALS clustering has been reported in Italy. METHODS: Genetic analysis was performed by automated and manual sequencing of the SOD1 gene in 13 family members and in 6 of 10 unrelated patients with sporadic cases of ALS living in the same area. The authors also determined SOD1 activity in erythrocytes and lymphocytes. RESULTS: The three families included a total of 28 affected members distributed over six generations. Despite a wide variability in age at onset and disease duration, the clinical pattern is uniform, with onset in the lower limbs, ascending progression, and predominant lower motor neuron involvement in all subjects. Generational anticipation is evident in the last two generations. All familial ALS patients and one of the six sporadic patients carry the same L84F missense point mutation in exon 4 of the SOD1 gene. SOD1 enzyme activity and SOD1 protein levels were not decreased significantly in the L84F patients. CONCLUSION: The ALS patients carrying the L84F mutation derive from a common ancestor. This mutation is responsible for ALS clustering in the area. The L84F mutation does not modify SOD1-specific activity.

Adult↗

PubMed2000

Detection and cellular localization of enterovirus RNA sequences in spinal cord of patients with ALS.

OBJECTIVE: To investigate the possible association of persistent enterovirus (EV) infection with the development of ALS. BACKGROUND: Although ALS is a clinically well-defined motor neuron disease, little is known about the etiology and pathogenesis of the sporadic cases. Among the different causes that have been hypothesized, conflicting results have been reported about the possible role of persistent enteroviral infection. METHODS: Reverse transcriptase-PCR (RT-PCR) and direct RT in situ PCR (RT-IS-PCR) were performed in formaldehyde-fixed spinal cord samples of 17 patients with confirmed ALS and 29 control subjects with no history of motor neuron disease. When obtained, PCR products were sequenced subsequently. RESULTS: Using direct RT-IS-PCR, EV nucleic acid sequences were detected in 15 (88.3%) of 17 patients with ALS compared to 1 (3.4%) of 29 control subjects. PCR products were located in neuronal cell bodies of the anterior horns of the spinal cord. The RT-PCR products obtained in 13 of the 17 patients with ALS showed between 94% and 86% homology with echovirus 7 sequences. CONCLUSION: The 88.3% rate of detection of enterovirus (EV) nucleic acids in the neuronal cell bodies within the gray matter of the spinal cord of patients with ALS strongly suggests association between persistent EV RNA and ALS. Further work is required to confirm that the persisting EV sequences we detected are somehow involved in the development of ALS.

Amyotrophic Lateral Sclerosis↗

PubMed2003

Excess incidence of ALS in young Gulf War veterans.

BACKGROUND: Reported cases of ALS in young veterans of the 1991 Gulf War have suggested excess incidence. OBJECTIVE: To compare observed and expected incidence of ALS in Gulf War veterans diagnosed before age 45 years (young veterans). METHODS: Cases of ALS diagnosed from 1991 through 1998 were collected from military registries and a publicity campaign in late 1998. Diagnoses were established from neurologists' medical records using El Escorial criteria. Expected incidence was estimated from the age distribution of the Gulf War veteran population, weighted by age-specific death rates of the US population. Secular changes in nationwide ALS rates were assessed using calculations of the age-specific US population death rates from vital statistics data of 1979 to 1998. RESULTS: During 8 postwar years, 20 ALS cases were confirmed in approximately 690,000 Gulf War veterans, and 17 were diagnosed before age 45 years. All developed bulbar and spinal involvement, and 11 have died. In young veterans, the expected incidence increased from 0.93 cases/year in 1991 to 1.57 cases/year in 1998, but the observed incidence increased from 1 to 5 cases/year. The observed incidence was 0.94 (95% CI, 0.26 to 2.41) times that expected in the baseline period from 1991 to 1994 (4 vs 4.25 cases; p = 0.6); it increased to 2.27 (95% CI, 1.27 to 3.88) times that expected during the 4-year period from 1995 to 1998 (13 vs 5.72 cases; p = 0.006); and it peaked at 3.19 (95% CI, 1.03 to 7.43) times that expected in 1998 (5 vs 1.57 cases; p = 0.02). The magnitude of the excess of ALS cases over the expected incidence increased during the 8-year period (Poisson trend test, p = 0.05), and the increase was not explained by a change in the interval from onset to diagnosis or by a change in the US population death rate of ALS in those aged <45 years. CONCLUSIONS: The observed incidence of ALS in young Gulf War veterans exceeded the expected, suggesting a war-related environmental trigger.

Adult↗

PubMed1994

Inhibition of leukotriene production by N-[4-[4-(diphenylmethyl)-1- piperazinyl]butyl]-3-(6-methyl-3-pyridyl) acrylamide (AL-3264), a new antiallergic agent.

The effects of AL-3264, which exhibits a 5-lipoxygenase (5-LO) inhibiting property by blocking histamine H1-receptors and inhibition of histamine release, were examined on leukotriene (LT) production and LT-mediated responses. AL-3264 (1-30 microM) inhibited the A23,187-induced LT production from human leukocytes with almost the same potency as that of nordihydroguaiaretic acid. AL-3264 (30-100 mg/kg, p.o.) inhibited the antigen-induced LT production in the abdominal cavity of passively sensitized rats; its effect was as potent as that of AA-861, a 5-LO inhibitor. AL-3264 (30 microM) suppressed both the initial and sustained phases of the antigen-induced contractions in isolated trachea from actively sensitized guinea pig. Phenidone (3 microM), a dual inhibitor of 5-LO and cyclooxygenase (CO), suppressed the sustained phase, while indomethacin was without effect on either phase. AL-3264 (40-160 mg/kg, p.o.) suppressed the arachidonic acid-induced ear edema in mice, for which 5-LO inhibitors were effective but antihistamines were not. The anti-edematous effect of AL-3264 (160 mg/kg) was reduced by intradermal administration of LTC4 (0.1 microgram). These results suggest that AL-3264 suppresses LT production in vivo and in vitro by inhibiting 5-LO activity, and this property may contribute to the antiallergic effect of AL-3264.

Acrylamides↗

PubMed1998

In vitro modulation of AL-amyloid formation by human mesangial cells exposed to amyloidogenic light chains.

We have shown in vitro AL-amyloid formation by human mesangial cells (HMCs). AL-amyloid formation may require lysosomal processing of the light chains (LCs) by HMCs for amyloidogenesis to occur. Chloroquine inhibits lysosomal activity. TGF-beta mediates extracellular matrix formation in many glomerulopathies. Thrombospondin (TSP) has been proposed as a mediator of cell proliferation and a marker of early fibrosis. We investigated amyloid formation by HMCs exposed to AL-LCs in the absence of amyloid enhancing factor (AEF). The effects of TGF-beta, TSP and chloroquine on in vitro amyloid formation were studied. HMCs were incubated with two AL-LCs, a light chain deposition disease (LCDD)-LC, or one of two tubulopathic LCs (T-LCs). Additional cells were treated with an AL-LC and chloroquine, TGF-beta, or TSP. Amyloid formation was evaluated microscopically using hematoxylin and eosin, Congo red and Thioflavin-T stains, as well as ultrastructurally. Amyloid was formed only when HMCs were incubated with AL-LCs. Addition of TSP significantly enhanced amyloid formation. In contrast, exogenous TGF-beta and chloroquine significantly attenuated amyloid formation. These findings show that some AL-LCs do not require AEF for amyloidogenesis to occur, and that chloroquine, TGF-beta and sTSP modulate in vitro AL-amyloidosis.

Amyloid↗

PubMed1999

AL-8810: a novel prostaglandin F2 alpha analog with selective antagonist effects at the prostaglandin F2 alpha (FP) receptor.

A novel analog of prostaglandin F(2alpha) [AL-8810; (5Z, 13E)-(9S, 11S,15R)-9,15-dihydroxy-11-fluoro-15-(2-indanyl)-16,17,18,19, 20-pentanor-5,13-prostadienoic acid] has been discovered with uniquely low efficacy (E(max)) at the endogenous prostaglandin F(2alpha) receptors (FP receptors) of A7r5 rat thoracic aorta smooth muscle cells and Swiss mouse 3T3 fibroblasts, as assayed by stimulation of phospholipase C activity. AL-8810 has weak agonist potency (EC(50)) of 261 +/- 44 nM (n = 3) and E(max) = 19% (relative to the full FP receptor agonist cloprostenol) in A7r5 cells and EC(50) of 186 +/- 63 nM (n = 3) and E(max) = 23% in 3T3 fibroblasts. AL-8810 exhibited properties of an apparent competitive antagonist, i.e., produced parallel dextral shifts of the agonist concentration-response curves and no significant suppression of the maximal agonist-induced response, when the potent, selective FP receptor agonist fluprostenol was used. The inhibition parameters of AL-8810 were: pA(2) = 6.68 +/- 0.23 and 6.34 +/- 0.09 (n = 3-4) for A7r5 cells and 3T3 cells, respectively, with Schild slopes ranging from 0.80 to 0.92. AL-8810 concentration-dependently antagonized the response to 100 nM fluprostenol (K(i) = 426 +/- 63 nM; n = 5) in A7r5 cells. However, even at 10 microM concentration, AL-8810 did not significantly inhibit functional responses of TP, DP, EP(2), EP(4), receptor subtypes in various cell lines. AL-8810 also did not antagonize the phospholipase C-coupled V(1)-vasopressin receptor in A7r5 cells. These results suggest that AL-8810 is a unique, selective antagonist at the FP receptor, a heretofore unavailable pharmacological tool that should be valuable for studying FP receptor-mediated functional responses in complex biological systems.

3T3 Cells↗

PubMed1995

[AL amyloidosis].

AL amyloidosis is one type of systemic amyloidosis. AL represents Amyloid of Light chains (of Ig's) type. Diagnosis of amyloid must be carried out by patho-histological Congo-red stains of the biopsied materials under suspicion of amyloid deposits from patients with various clinical manifestations, including macroglossia, cardiac abnormalities, ECG abnormalities, GI tract problems or carpal-tunnel syndrome. Al amyloidosis may be also termed as plasma cell dyscrasia (PCD) associated amyloidosis, or monoclonal gammopathy associated amyloidosis. As to classification, AL amyloidosis consists of primary (or idiopathic) amyloidosis, and myeloma-associated (and then macroglobulinemia-associated) amyloidosis. As similarly to myeloma, patients with AL amyloidosis have monoclonal Ig's in the serum and-or in the urine. Furthermore, there have been known to be a higher incidence of Bence Jones proteins as well as more lambda than kappa among patients with AL amyloidosis compared with distributions of monoclonal Ig's among myeloma patients. It is also important for clinicians to recognize a data of a median survival of 12 months (only 4 months if cardiac amyloid occurred) in all patients with AL amyloid VS, a data of a median survival of about 36 months in myeloma patients. An attempt to clarify a way to an early diagnosis of AL amyloidosis should be investigated.

Amyloidosis↗

PubMed1996

The Amyotrophic Lateral Sclerosis Functional Rating Scale. Assessment of activities of daily living in patients with amyotrophic lateral sclerosis. The ALS CNTF treatment study (ACTS) phase I-II Study Group.

OBJECTIVES: To test the utility of a new, easy to administer instrument for assessing activities of daily living in patients with amyotrophic lateral sclerosis (ALS), to validate its accuracy, and to assess its ability to record disease progression in patients with ALS against other functional scales, quantitative isometric muscle testing, and global assessment scales. DESIGN: Serial assessments of patients who presented to four ALS treatment centers in two multicenter studies. PATIENTS: Study 1 (cross-sectional) evaluated 75 consecutive patients who presented to four ALS treatment centers during a 2-month period. Study 2 (longitudinal) evaluated the progression of 53 patients who were enrolled in a multicenter, phase I-II clinical trial of recombinant human ciliary neurotrophic factor for treatment of ALS. OUTCOME MEASURES: The ALS Functional Rating Scale (ALSFRS) was compared with quantitative myometry and with other measures of daily function in patients with ALS both cross-sectionally and longitudinally. RESULTS: The first study of 75 patients evaluated the internal consistency, the test-retest reliability, and the construct validity of the ALSFRS. Internal consistency and test-retest reliability were high. Patient self-rating of upper- and lower-extremity-dependent tasks were highly correlated with measures of upper- and lower-extremity strength, respectively. Thus, the ALSFRS has good construct validity. In the second study, ALSFRS scores declined in tandem with deterioration in motor and pulmonary function, indicating its sensitivity to change. CONCLUSIONS: The ALSFRS is a useful instrument for evaluation of functional status and functional change in patients with ALS. Its results are in close agreement with objective measures of muscle strength and pulmonary function. The ALSFRS may be used as a screening measure for entry into clinical trials, as a surrogate measure of function in situations in which muscle strength cannot be measured directly, or as an adjunct to myometry.

Activities of Daily Living↗

PubMed1997

[Similarities in calcium and magnesium metabolism between amyotrophic lateral sclerosis and calcification of the spinal cord in the Kii Peninsula ALS focus].

Current epidemiological surveys in the Western Pacific area and Kii Peninsula have suggested that low calcium (Ca), magnesium (Mg) and high aluminum (Al) and manganese (Mn) in river, soil and drinking water may be implicated in the pathogenetic process of amyotrophic lateral sclerosis (ALS) and parkinsonism-dementia (PD). The condition of unbalanced minerals was experimentally mimicked in this study using rats. Male Wistar rats, weighing 200 g, were maintained for 90 days on the following diets: (A) standard diet, (B) low Ca diet, (C) low Ca-Mg diet, (D) low Ca-Mg diet with high Al. In the groups maintained on unbalanced mineral diets, calcium and magnesium contents of the bones were lower than those fed with standard diet. On the other hand, Ca content of CNS showed higher values in the unbalanced diet groups (especially in spinal cord of the low Ca-Mg plus high Al diet group) than those in the standard diet group. This was determined by neutron activation analysis (NAA) at Research Reactor Institute, Kyoto University. Also, Ca content in soft tissues of rats given unbalanced mineral diets was higher than those on standard diet. Mg content of soft tissues and spinal cord of rats was markedly lower in the low Ca-Mg plus high Al diet group than the other three groups as determined by inductively coupled plasma emission spectrometry (ICP). Six Kii cases with amyotrophic lateral sclerosis (ALS) also showed higher Ca and lower Mg contents in the CNS tissues than those of neurologically normal controls. As of today, calcification of the spinal ligaments (CSL) has been reported in only 120 cases in the world and 28 cases of CSL in the Kii Peninsula have been found in the same foci as ALS. We analyzed Mg content of 7 spinal bones and 10 ligaments of the CSL and Ca content of 5 spinal bones compared with controls. The CSL showed lower values of Mg contents in bones and ligaments compared to controls. The Ca content in bones of CSL was significantly lower than that of controls. These results suggest that the environmental factor may contribute to the pathogenesis of CSL due to low Ca and Mg intake as well as for ALS.

Aged↗