BackgroundHuntington's disease (HD) is a fatal inherited neurodegenerative disease, caused by a

Huntington's disease (HD) is a neurodegenerative disease for which there is no curative treatment available. Given that the endocannabinoid system is involved in the pathogenesis of HD mouse models, stimulation of specific targets within this signaling system has been investigated as a promising therapeutic agent in HD. We conducted a double-blind, randomized, placebo-controlled, cross-over pilot clinical trial with Sativex(®), a botanical extract with an equimolecular combination of delta-9-tetrahydrocannabinol and cannabidiol. Both Sativex(®) and placebo were dispensed as an oral spray, to be administered up to 12 sprays/day for 12 weeks. The primary objective was safety, assessed by the absence of more severe adverse events (SAE) and no greater deterioration of motor, cognitive, behavioral and functional scales during the phase of active treatment. Secondary objectives were clinical improvement of Unified Huntington Disease Rating Scale scores. Twenty-six patients were randomized and 24 completed the trial. After ruling-out period and sequence effects, safety and tolerability were confirmed. No differences on motor (p = 0.286), cognitive (p = 0.824), behavioral (p = 1.0) and functional (p = 0.581) scores were detected during treatment with Sativex(®) as compared to placebo. No significant molecular effects were detected on the biomarker analysis. Sativex(®) is safe and well tolerated in patients with HD, with no SAE or clinical worsening. No significant symptomatic effects were detected at the prescribed dosage and for a 12-week period. Also, no significant molecular changes were observed on the biomarkers. Future study designs should consider higher doses, longer treatment periods and/or alternative cannabinoid combinations.Clincaltrals.gov identifier: NCT01502046.

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Spain has several characteristics that make it adequate for such studies. Although in the past Spain has seen significant waves of immigration, in the last millennium immigration has not occurred at high enough levels to influence the genetic background of its population. Spain also has high-quality standards of universally free healthcare. Several studies have been published as meta-analyses 5 or local population studies. [6][7][8][9] In this article we review some of these and other, more recent, studies. Environmental Risk ModifiersA summary of the available data is shown in AgeAs in other studies around the world, epidemiological investigations performed in Spain have confirmed the increased risk associated with age in AD. This effect is almost exponential until >90 years of age, when it appears to reduce its impact. 10,15Education Illiteracy and poor schooling are associated with an increased risk of dementia and AD in most studies in which the population has a mixed (assorted) educational background. 3,10,13,14 The same findings are reported in Spain. 5-9 However, most of these studies did not differentiate between education and its co-variates, such as low socioeconomic status, possible pre-natal and developmental nutrition, lack of social and familial intellectual stimulation and others. 16-19 GenderThe majority of population-based studies performed in Spain haveshown an increased risk of AD in females. 6,8,9 In the Neurological Disorders in Central Spain (NEDICES) study this relationship was not found. 7 This has been proposed as the basis for a neuro-protective role of oestrogens, even prompting the use of these compounds in clinical trials, but a very confusing factor is the fact that senile females (around the turn of the millennium this was defined as >65 years of age) had a much lower level of education than contemporary males. Studies such as the Ashkelon study where gender was corrected for by education have not shown a difference in the risk at different ages. As a meta-analysis pointed out, 10 there AbstractAlzheimer's disease is a complex neurodegenerative disorder of unknown aetiology, and an important number of cases are sporadic. To date, only some of the genetic and environmental risk factors for Alzheimer's disease have been identified. It is very important to understand the role of environmental and genetic risk factors in Alzheimer's disease in order to develop therapeutic strategies. For sporadic cases of Alzheimer's disease, many environmental and genetic risk factor modifiers have been described, but -with a few exceptions -most of them remain controversial. In this article we review some studies of these risk factors in a Spanish population to identify a few directives for future studies.

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