Endogenous protectant kynurenic acid in amyotrophic lateral sclerosis

OBJECTIVES: Excitotoxicity may play a role in neurodegeneration in amyotrophic lateral sclerosis (ALS). Kynurenic acid (KYNA), an endogenous antagonist of excitatory amino acid receptors, may inhibit excitotoxic lesions. The aim of this study was to determine the concentration of KYNA in ALS patients. MATERIAL AND METHODS: KYNA was measured by high-performance liquid chromatography in the serum and cerebrospinal fluid (CSF) from ALS and control patients. RESULTS: Our study revealed that CSF KYNA concentration was significantly higher in patients with bulbar onset of ALS compared to controls, and compared to patients with limb onset of the disease. CSF KYNA was also higher in patients with severe clinical status compared to controls. Serum KYNA was significantly lower in ALS patients with severe clinical status compared to controls, and compared to patients with mild clinical status. There were no significant differences in CSF and serum KYNA concentration between the whole ALS group of patients and controls. There was no difference in CSF KYNA concentration between males and females, and there was no correlation between KYNA concentration and age of patients, and duration of ALS. CONCLUSIONS: An increased CSF KYNA concentration in patients with bulbar onset of ALS and in patients with severe clinical status may indicate neuroprotective role of KYNA against excitotoxicity. The difference of KYNA concentration in CSF of patients with bulbar and limb onset of ALS suggests that these two variants of motor neuron disease may have different etiopathogenetic mechanisms.     

Effect of reproductive factors and postmenopausal hormone use on the risk of amyotrophic lateral sclerosis

OBJECTIVE: To examine the associations of reproductive factors and postmenopausal hormone use with the risk of amyotrophic lateral sclerosis (ALS) among women. METHODS: This case-control study was conducted within the Kaiser Permanente Medical Care Program (KPMCP) of Northern California during the years 1996-2000. Among the 193 postmenopausal women, 62 were incident ALS cases and 131 were controls randomly selected from KPMCP members and frequency matched by age and respondent type (self versus proxy) to the cases. Statistical analyses were carried out using logistic regression. RESULTS: Reproductive factors such as age at menarche, age at final menstrual period, parity, oral contraceptive use, and type of menopause (natural vs. hysterectomy with or without oophorectomy) were not associated with risk of ALS. Postmenopausal hormone use was positively, but not significantly, associated with the risk of ALS (adjusted OR 1.9, 95% CI 0.9-3.8). CONCLUSIONS: Reproductive factors were not associated with ALS risk. There is no evidence that suggests a protective effect of postmenopausal hormone use against the development of ALS. However, due to insufficient power, we cannot rule out a possible increase in ALS risk associated with postmenopausal hormone use.     

Environmental risk factors for amyotrophic lateral sclerosis

In order to evaluate reported associations of environmental risk factors with amyotrophic lateral sclerosis (ALS), consideration is given first to robust clinical and epidemiologic observations. These are observations which have persisted in time, have been replicated consistently and likely reflect the reality of the disease. Sporadic, familial and Western Pacific ALS are considered. In contrast, other associations appear to have emerged due to chance, sometimes compounded by faulty study design, and have dissipated once greater attention was given to methodological rigor. Current data suggest that there are no robust environmental risk factors for sporadic ALS.     

Endogenous progesterone is associated to amyotrophic lateral sclerosis prognostic factors

Gargiulo Monachelli G, Meyer M, Rodríguez GE, Garay LI, Sica REP, De Nicola AF, González Deniselle MC. Endogenous progesterone is associated to amyotrophic lateral sclerosis prognostic factors.
Acta Neurol Scand: 2011: 123: 60–67.
© 2010 John Wiley & Sons A/S. Negative prognostic factors in amyotrophic lateral sclerosis include advanced age, shorter time from disease onset to diagnosis, bulbar onset and rapid progression rate. Objective – To compare progesterone (PROG) and cortisol serum levels in patients and controls and ascertain its relationship to prognostic factors and survival. Methods – We assessed serum hormonal levels in 27 patients and 21 controls. Results – Both hormones were 1.4‐fold higher in patients. PROG showed a negative correlation with age, positive correlation with survival and positive trend with time to diagnosis. Increased PROG was observed in spinal onset and slow progression patients. No correlation was demonstrated with cortisol. Conclusion – Increased hormonal levels in patients are probably due to hypothalamic–pituitary–adrenal axis activation. Nevertheless, in this preliminary report only PROG correlated positively with factors predicting better prognosis and survival. We hypothesize endogenous PROG and cortisol may be engaged in differential roles, the former possibly involved in a neuroprotective response.     

Prior medical conditions and the risk of amyotrophic lateral sclerosis

Sporadic amyotrophic lateral sclerosis (ALS) is believed to be a complex disease in which multiple exogenous and genetic factors interact to cause motor neuron degeneration. Elucidating the association between medical conditions prior to the first symptoms of ALS could lend support to the theory that specific subpopulations are at risk of developing ALS and provide new insight into shared pathogenic mechanisms. We performed a population-based case–control study in the Netherlands, including 722 sporadic ALS patients and 2,268 age and gender matched controls. Data on medical conditions and use of medication were obtained through a structured questionnaire. Multivariate analyses showed that hypercholesterolemia (OR 0.76, 95 % CI 0.63–0.92, P = 0.006), the use of statins (OR 0.45, 95 % CI 0.35–0.59, P = 1.86 × 10^?9) or immunosuppressive drugs (OR 0.26, 95 % CI 0.08–0.86, P = 0.03) were associated with a decreased risk of ALS. Head trauma was associated with an increased ALS susceptibility (OR 1.95, 95 % CI 1.11–3.43, P = 0.02). No association was found with autoimmune diseases, cancer, psychiatric disorders or cardiovascular diseases, or survival. The lower frequency of hypercholesterolemia and less use of statins in ALS patients indicate a favorable lipid profile prior to symptom onset in at least a subpopulation of ALS. Prior head trauma is a risk factor for ALS and the significantly lower use of immunosuppressive drugs in ALS patients could suggest a protective effect. The identification of specific subpopulations at risk for ALS may provide clues towards possible pathogenic mechanisms.     

Vitamin E intake and risk of amyotrophic lateral sclerosis

Oxidative stress may contribute to the pathogenesis of amyotrophic lateral sclerosis (ALS). We therefore examined prospectively whether individuals who regularly use supplements of the antioxidant vitamins E and C have a lower risk of ALS than nonusers. The study population comprised 957,740 individuals 30 years of age or older participating in the American Cancer Society's Cancer Prevention Study II. Information on vitamin use was collected at time of recruitment in 1982; participants then were followed up for ALS deaths from 1989 through 1998 via linkage with the National Death Index. During the follow-up, we documented 525 deaths from ALS. Regular use of vitamin E supplements was associated with a lower risk of dying of ALS. The age- and smoking-adjusted relative risk was 0.99 (95% confidence interval [CI], 0.69-1.41) among occasional users, 0.59 (95% CI, 0.36-0.96) in regular users for less than 10 years, and 0.38 (95% CI, 0.16-0.92) in regular users for 10 years or more as compared with nonusers of vitamin E (p for trend = 0.004). In contrast, no significant associations were found for use of vitamin C or multivitamins. These results suggest that vitamin E supplementation could have a role in ALS prevention.     

Familial amyotrophic lateral sclerosis

The increasing complexity of the pathways implicated in the pathogenesis of familial amyotrophic lateral sclerosis (ALS) has stimulated intensive research in many directions. Genetic analysis of familial ALS has yielded six loci and one disease gene (SOD1), initially suggesting a role for free radicals in the disease process, although the mechanisms through which the mutant exerts toxicity and results in selective motor neuron death remain uncertain. Numerous studies have focused on structural elements of the affected cell, emphasizing the role of neurofilaments and peripherin and their functional disruption in disease. Other topics examined include cellular homeostasis of copper and calcium, particularly in the context of oxidative stress and the processes of protein aggregation, glutamate excitotoxicity, and apoptosis. It has become evident that there is considerable interplay between these mechanisms and, as the role of each is established, a common picture may emerge, enabling the development of more targeted therapies. This study discusses the main areas of investigation and reviews the findings.     

Hereditary amyotrophic lateral sclerosis

A Spanish family transmits, as an autosomal dominant trait, a form of amyotrophic lateral sclerosis characterized by an unusually prolonged evolution of the disease in all affected members. Precocity and persistence of muscle cramps, presence of unilateral proximal segmental myoclonus and early abolition of ankle jerks are other clinical features conspicuous in this family. This type of hereditary ALS of non-Chamorro origin and prolonged evolution is rare.     

Juvenile amyotrophic lateral sclerosis

This paper presents two juvenile cases of familial amyotrophic lateral sclerosis. They are the first and fourth child in a family with seven children from the eastern part of Finland. All seven children, as well as the parents, were examined by our group. In the first case the disease showed a rather mild course, while in the second a noticeable progression was observed even during a period of 10 months. The patients come from a rural area with a stable population and low immigration, which may favor an enrichment of certain genes and therefore support the possible hereditary basis for the disease.