Registro nacional de esclerosis lateral amiotrófica: prueba piloto, junio de 2015 a mayo de 2016 / Amyotrophic Lateral Sclerosis National Registry: Pilot Test, June 2015 to May 2016

INTRODUCCIÓN La esclerosis lateral amiotrófica (ELA) es una enfermedad neurodegenerativa, que causa el deterioro de las neuronas motoras superiores e inferiores y lleva a la muerte al 50% de los enfermos en los primeros 3 años posteriores al diagnóstico, siendo la más frecuente de estas condiciones en los adultos. Se estima que la tasa de incidencia de la ELA para todas las edades es de 1,6 personas por cada 100.000 habitantes, cifra que aumenta a 5 personas por cada 100.000 en la séptima década de la vida. La incidencia estimada en Argentina es de 2 por 100.000 habitantes por año, pero no existen cifras oficiales. La ELA no es una enfermedad de declaración obligatoria a nivel nacional, por cuya razón surge la necesidad de realizar un estudio que describa el comportamiento de la enfermedad en el país. OBJETIVOS A nivel general, desarrollar e implementar como prueba piloto el Registro Nacional de Esclerosis Lateral Amiotrófica (ReNELA) en Argentina. De manera específica, construir y consolidar una base de datos unificada para los efectores involucrados, realizar un análisis epidemiológico descriptivo de la base de datos construida y evaluar el registro y su alcance respecto de la población afectada en el período seleccionado. MÉTODOS Se elaboró un registro anónimo, que incluyó a pacientes vivos con residencia en el territorio nacional y diagnóstico de ELA basado en historias clínicas. El instrumento fue una base de datos construida para volcar los datos pertinentes al registro y analizarlos posteriormente. RESULTADOS Se logró construir una base con datos de 215 personas que padecen ELA. Dado que se estudió a la población alcanzada por la red de neurólogos y no fue posible tomar una muestra representativa, no cabe realizar inferencias estadísticas generalizables a la población del país. DISCUSIÓN Esta experiencia permitió identificar posibles factores que facilitarían la consolidación del registro y su continuidad para establecerse como una herramienta capaz de caracterizar epidemiológicamente la ELA en el país.

Potential Biomarkers with Plasma Cortisol, Brain-derived Neurotrophic Factor and Nitrites in Patients with Acute Ischemic Stroke.

BACKGROUND: Acute Ischemic Stroke (AIS) represents an economic challenge for health systems all over the globe. Changes of neuroactive steroids have been found in different neurological diseases. We have previously demonstrated that old patients with AIS show changes of plasma cortisol and estradiol concentrations, in that increased steroid levels are associated with a deterioration of neurological status and a worse cognitive decline. OBJECTIVE: The present study assessed in patients with AIS if changes of behavior, Brain-Derived Neurotrophic Factor (BDNF) and Nitrites (NO-2) bear a relationship with the degree of hypercortisolism. METHODS: We recruited patients hospitalized within the first 24 hours of AIS. Subjects were divided into two groups, each one composed of 40 control subjects and 40 AIS patients, including men and women. The neurological condition was assessed using the National Institute of Health Stroke Scale (NIHSS) and the cognitive status with the Montreal Cognitive Assessment (MoCA). The emotional status was evaluated using the Montgomery-Asberg Depression Rating Scale (MADRS), whereas the Modified Rankin Scale (MRS) was used to determine the functional condition. BDNF and NO-2 plasma levels were measured by ELISA and the Griess reaction method, respectively. RESULTS: We found that in AIS patients, increased plasma cortisol was negatively correlated with plasma BDNF and NO-2 levels, neurological condition, cognition, functional responses and emotional status, suggesting a relationship between the declines of clinical, behavioral and blood parameters with stress-induced cortisol elevation. CONCLUSION: Nitrites and BDNF may represent potential biomarkers for cortisol negative effects on the area of cerebral ischemia and penumbra, potentiating ischemic cell damage.

Expression and cellular localization of the classical progesterone receptor in healthy and amyotrophic lateral sclerosis affected spinal cord.

BACKGROUND AND PURPOSE: Previous studies have suggested that elevated progesterone levels are associated with a slower disease course in amyotrophic lateral sclerosis (ALS). Given that the effects of progesterone are mediated in part by the classical progesterone receptor (PR), the expression and cellular localization of the A and B isoforms (PR-A and PR-B, respectively) of the PR in control (neuropathologically normal) and ALS-affected spinal cord (SC) were examined. METHODS: Semi-quantitative RT-PCR, immunohistochemistry and immunofluorescence analyses of the cervical and lumbar SC of post-mortem ALS patients (n = 19) and control subjects (n = 10) were performed. Primers and antibodies used allowed the detection of both PR-A and PR-B isoforms together (PR-A+B) or PR-B isoform alone. RESULTS: Lumbar PR-A+B and cervical PR-B mRNA expression were significantly higher in ALS than controls. In both ALS and controls, PR-A+B immunoreactivity (IR) was occasionally detected in motor neurons. In contrast, PR-A+B IR was prominent in axonal processes and vessels. This was more evident in nerve roots and large arteries in ALS compared with controls. Colocalization of PR-A+B with markers of neurons, axonal processes and vascular endothelium was also observed. CONCLUSIONS: Evidence that both PR-A and PR-B isoforms are expressed in the human SC is provided, with some regional variation in isoform expression between ALS and controls. The IR was more prominent in nerve roots and large arteries in ALS, suggesting a potential role in the degenerative process.

Circulating gonadal and adrenal steroids in amyotrophic lateral sclerosis: possible markers of susceptibility and outcome.

Although changes of circulating steroids have been reported in patients with sporadic amyotrophic lateral sclerosis (ALS), a full comparison of the adrenal and gonadal steroid profile between control subjects and ALS patients is lacking. Considering that respiratory failure is the most frequent cause of death in ALS, we looked into whether a relationship emerged between circulating steroids and respiratory parameters. Serum levels of adrenal and gonadal steroids were measured in 52 age- and gender-matched subjects (28 ALS and 24 controls) using radioimmunoassay techniques. We also evaluated respiratory parameters in ALS patients, including forced vital capacity (FVC), maximal inspiratory pressure (MIP), and maximal expiratory pressure (MEP). We found increased levels of testosterone in female ALS patients compared to healthy female subjects. Furthermore, control subjects showed a significant decline of testosterone, dehydroepiandrosterone and its sulfate, and a borderline decline of progesterone with increasing age. Instead, testosterone did not decline with increasing age in ALS patients. We also found that the dehydroepiandrosterone sulfate/cortisol ratio was positively associated with FVC, MIP, and MEP. Moreover, ALS patients showing higher testosterone levels and lower progesterone/free testosterone ratio presented a more rapid worsening of the monthly FVC. In conclusion, first our study revealed a differential steroid profile with age and gender in ALS patients relative to controls. Second, we demonstrated an association between some steroids and their ratios with respiratory function and disease progression. Thus, we hypothesize that the endogenous steroid profile could be a marker of susceptibility and prognosis in ALS patients.

Progesterone protective effects in neurodegeneration and neuroinflammation.

Progesterone is a neuroprotective, promyelinating and anti-inflammatory factor for the nervous system. Here, we review the effects of progesterone in models of motoneurone degeneration and neuroinflammation. In neurodegeneration of the Wobbler mouse, a subset of spinal cord motoneurones showed increased activity of nitric oxide synthase (NOS), increased intramitochondrial NOS, decreased activity of respiratory chain complexes, and decreased activity and protein expression of Mn-superoxide dismutase type 2 (MnSOD2). Clinically, Wobblers suffered several degrees of motor impairment. Progesterone treatment restored the expression of neuronal markers, decreased the activity of NOS and enhanced complex I respiratory activity and MnSOD2. Long-term treatment with progesterone increased muscle strength, biceps weight and survival. Collectively, these data suggest that progesterone prevented neurodegeneration. To study the effects of progesterone in neuroinflammation, we employed mice with experimental autoimmune encephalomyelitis (EAE). EAE mice spinal cord showed increased mRNA levels of the inflammatory mediators tumour necrosis factor (TNF)α and its receptor TNFR1, the microglial marker CD11b, inducible NOS and the toll-like receptor 4. Progesterone pretreatment of EAE mice blocked the proinflammatory mediators, decreased Iba1+ microglial cells and attenuated clinical signs of EAE. Therefore, reactive glial cells became targets of progesterone anti-inflammatory effects. These results represent a starting point for testing the usefulness of neuroactive steroids in neurological disorders.

Progesterone attenuates several hippocampal abnormalities of the Wobbler mouse.

It is now recognised that progesterone plays a protective role for diseases of the central nervous system. In the Wobbler mouse, a model of motoneurone degeneration, progesterone treatment prevents spinal cord neuropathology and clinical progression of the disease. However, neuropathological and functional abnormalities have also been discovered in the brain of Wobbler mice and patients with amyotrophic lateral sclerosis. The present study examined the hippocampus of control and afflicted Wobbler mice and the changes in response to progesterone treatment. Mice received either a single progesterone implant (20 mg for 18 days). We found that the hippocampal pathology of the untreated Wobblers involved a decreased expression of brain-derived neurotrophic factor (BDNF) mRNA, decreased astrogliosis in the stratum lucidum, stratum radiatum and stratum lacunosum-moleculare, decreased doublecortin (DCX)-positive neuroblasts in the subgranular zone of the dentate gyrus and a decreased density of GABA immunoreactive hippocampal interneurones and granule cells of the dentate gyrus. Although progesterone did not change the normal parameters of control mice, it attenuated several hippocampal abnormalities in Wobblers. Thus, progesterone increased hippocampal BDNF mRNA expression, decreased glial fibrillary acidic protein-positive astrocytes and increased the number of GABAergic interneurones and granule cells. The number of DCX expressing neuroblasts and immature neurones remained impaired in both progesterone-treated and untreated Wobblers. In conclusion, progesterone treatment exerted beneficial effects on some aspects of hippocampal neuropathology, suggesting its neuroprotective role in the brain, in agreement with previous data obtained in the spinal cord of Wobbler mice.

Regional spread pattern predicts survival in patients with sporadic amyotrophic lateral sclerosis.

BACKGROUND AND PURPOSE: Sporadic amyotrophic lateral sclerosis (sALS) is a disease with a focal clinical onset and contiguous spread. We examined patterns of disease spread following symptoms onset in sALS and whether the pattern of spread predicted survival. METHODS: Review of medical records (2003-2009) at London Ontario and Buenos Aires clinic cohorts retrieved 318 patients with sporadic sALS. According to patient self-report, we determined eight spread patterns: rostro-caudal, caudo-rostral, crossed, circular, superior interposed, middle interposed, inferior interposed and isolated. The variables studied were as follows: age, gender, sALS phenotypes, time from onset to diagnosis and time and direction of the spreading to the first region. Survival from symptoms onset was analysed by Kaplan-Meier, Tarone-Ware and Cox proportional hazards methods. RESULTS: The direction of first spread was horizontal in 33%, rostral to caudal in 32% and caudal to rostral in 21%, whereas spread to remote regions was observed in 14% of patients. Survival curves and 3- and 5-year survival rates favoured patients with an isolated and caudo-rostral pattern of spread compared to patients progressing to distant regions without involvement in the intervening region, or 'superior and inferior interposed patterns' (Tarone-Ware P = 0.001, χ(2) = 0.002 and χ(2) = 0.006, respectively). Factors affecting survival were gender, time to diagnosis, flail arm phenotype and age at diagnosis. CONCLUSIONS: We have provided evidence that not all spread in ALS is contiguous and that the nature of symptom progression influences survival. Patients with sALS with 'interposed patterns' had a worse prognosis, whereas patients with caudo-rostral pattern fared better than the rest.

Progesterone effects on neuronal brain-derived neurotrophic factor and glial cells during progression of Wobbler mouse neurodegeneration.

Previous results have shown a depletion of brain-derived neurotrophic factor (BDNF) mRNA in the degenerating motoneurons from clinically afflicted Wobbler mice, whereas progesterone treatment reverts this depletion. We now compared progesterone regulation of BDNF in motoneurons and oligodendrocytes of Wobbler mice at the progressive (EP, 1-3 months), symptomatic (SYM, 5-8 months old), and late stages (LS, 12-13 months). As controls we used NFR/NFR mice. Controls and Wobbler mice of different ages remained untreated or received a 20 mg progesterone pellet during 18 days. BDNF mRNA was determined in the ventral, intermediolateral, and dorsal gray matter by film autoradiography and in motoneurons using in situ hybridization. A depletion of BDNF mRNA already occurred at the EP stage of Wobblers, but progesterone was inactive at this period. In contrast, progesterone upregulated the low levels of BDNF mRNA in SYM Wobblers in the three gray matter regions analyzed. Progesterone also increased BDNF mRNA in LS Wobblers, according to grain counting procedures. BDNF protein analyzed by enzyme-linked immunosorbent assay (ELISA) in ventral horns or immunostaining of motoneurons was normal in steroid-naive SYM Wobblers. BDNF protein was decreased by progesterone, suggesting increased anterograde transport and/or release of neuronal BDNF. Wobbler mice also showed depletion of CC1-immunopositive oligodendrocytes, whereas progesterone treatment enhanced the density of BDNF+ and CC1+ oligodendrocytes in EP, SYM, and LS Wobblers. Our results suggest that BDNF could be involved in progesterone effects on motoneurons at the SYM and LS periods, whereas effects on oligodendrocytes occurred at all stages of the Wobbler disease. These steroid actions may be important to arrest the ongoing neurodegeneration.

Experimental and clinical evidence for the protective role of progesterone in motoneuron degeneration and neuroinflammation.

Far beyond its role in reproduction, progesterone exerts neuro-protective, promyelinating, and anti-inflammatory effects in the nervous system. These effects are amplified under pathological conditions, implying that changes of the local environment sensitize nervous tissues to steroid therapy. The present survey covers our results of progesterone neuroprotection in a motoneuron neurodegeneration model and a neuroinflammation model. In the degenerating spinal cord of the Wobbler mouse, progesterone reverses the impaired expression of neurotrophins, increases enzymes of neurotransmission and metabolism, prevents oxidative damage of motoneurons and their vacuolar degeneration (paraptosis), and attenuates the development of mitochondrial abnormalities. After long-term treatment, progesterone also increases muscle strength and the survival of Wobbler mice. Subsequently, this review describes the effects of progesterone in mice with induced experimental autoimmune encephalomyelitis (EAE), a commonly used model of multiple sclerosis. In EAE mice, progesterone attenuates the clinical severity, decreases demyelination and neuronal dysfunction, increases axonal counts, reduces the formation of amyloid precursor protein profiles, and decreases the aberrant expression of growth-associated proteins. These actions of progesterone may be due to multiple mechanisms, considering that classic nuclear receptors, extranuclear receptors, and membrane receptors are all expressed in the spinal cord. Although many aspects of progesterone action in humans remain unsolved, data provided by experimental models makes getting to this objective closer than previously expected.

Endogenous progesterone is associated to amyotrophic lateral sclerosis prognostic factors.

UNLABELLED: 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.

Síntomas iniciales de esclerosis lateral amiotrófica / No disponible

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