Review: Hypocretin and Neurological Disorders

The paper reviewed here is ‘Hypocretin/orexin Disturbances in Neurological Disorders’ by Rolf Fronczek and colleagues. The search strategy is not described, but the authors state in the abstract

In this paper we first review the current methods to measure the integrity of the hypocretin system in human patients

and also write that they will be looking at the findings in a number of neurological disorders. There is a relatively brief introduction before the authors discuss the form and function of the hypocretin system including the alternative name of orexin and the production of hypocretin within the dorsolateral hypothalamus. They then discuss the techniques for assessing the function of hypocretin and here the reader is able to see the complexity involved as measurements in the CSF, in brain tissue and assessment of hypocretin containing neurons all have their own difficulties. Further there are reasons why there may not be a simple relationship between these measures and the function of hypocretin. Indeed it becomes apparent through the review that the issue of partial depletion of hypocretin does not always result in the expected physiological consequences.

They then look at a number of disorders starting with Narcolepsy. Essentially the findings of an association between hypocretin deficiency and narcolepsy. In particular the authors note that it is narcolepsy with cataplexy that hypocretin deficiency is strongly associated. They then look at a number of disorders included amongst which are Huntington’s Disease, Parkinson’s Disease, Alzheimer’s Disease, Lewy Body Dementia and Progressive Supranuclear Palsy. From their discussion I found the described results of a reduction in hypocretin in late stage Parkinson’s Disease and in post-mortem studies in Alzheimer’s Disease the most convincing. They cite one study of reduced hypocretin levels in multiple sclerosis with hypothalamic involvement, with the levels increasing after treatment with steroids. They also discuss Guillan Barre syndrome and traumatic brain injury.

They finish with a discussion of the possible functional relevance of partial hypocretin depletion and point out the difficulties of fully establishing a causal pathway between the reduction in hypocretin and physiological associations. They suggest that studies with a hypocretin agonist would be useful in this regards. I thought this was a well written article which introduces the reader to the subject area and provides a clear structure for reviewing the research that has taken place. The association with narcolepsy with cataplexy seems quite convincing and the associations with Parkinson’s Disease and Alzheimer’s Disease were quite interesting although this would be one of many pathophysiological pathways in these conditions.


Fronczek R, Baumann C, Lammers G, Bassetti C and Overeem S. Hypocretin/orexin Disturbances in Neurological Disorders. Sleep Medicine Reviews. 2009. 13. 9-22.


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