In the July, 2008 Journal of Experimental Medicine Dr M. Bjorquist, S. Tabrizi and collaborators reported on their findings of immune activation and inflammation in Huntington's. They showed that several inflammatory markers called cytokines are found very early in the disease process and strongly correlate with disease progression. These findings are valuable to Huntington families because cytokines may become important biomarkers; and even more importantly this work adds to the growing evidence that inflammation is a highly important disease mechanism, which in turn makes it a key pathway for drug targeting.

What is inflammation?
When cells are damaged by infection, trauma or other harmful events, immune cells of different types produce a variety of products that can attack the offending virus or other agent. A visible example of protective inflammation includes the red swollen response to a skin infection. Inflammation is a complex process that includes the early action of cytokine proteins that are released from immune cells. Cytokines communicate with other immune cells to both initiate and perpetuate the inflammatory process. In many cases -- like the skin infection -- this inflammatory immune response is protective. However in immune-related diseases like rheumatoid arthritis or Lupus, chronic long-term inflammation is destructive.

Simply Stated

The human factor tells us that finding a drug to combat this critically important disease mechanism is vital.

In neurodegenerative disease, immune cells in the periphery (bloodstream or any area outside of brain) and immune cells of the nervous system (neuroglia and others) are activated and are involved in promoting a chronic inflammatory process in brain that involves the release of cytokines.

Neuroinflammation in Huntington's: In their recent study Dr. Bjorquist and collaborators found that elevated levels of cytokines are present in blood (peripheral system) and spinal fluid (brain system) of Huntington individuals as early as 16 years before expected symptom onset, and that these levels increase with the stage of disease, both before and after symptom development [Björkqvist M 2008]. They also showed that immune cells from Huntington's individuals and model mice are primed, and have an exaggerated response to an inflammatory stimulus when compared to normal cells. This means that mutant huntingtin protein- by some unknown mechanism - causes both a low level of constant inflammation and a hyperactive response to a new inflammatory stimulus.

Neuroinflammation is not unique to Huntington's disease, and has been described in others including Alzheimer's [Reale M 2008], prion disease (Mad Cow is one of the prion diseases) [Eikelenboom P 2002], and Parkinson's [Sawada M 2006]. Though less well characterized than in Huntington's, inflammatory cytokines are present and increase with disease stage in these disorders as well [Galimberti D 2006].

Effect of peripheral inflammation on the brain: Dr. Bjorquist and colleagues suggest that mutant huntingtin induces parallel dysfunction in both the periphery and the brain, but do not comment whether an inflammatory stimulus in one area could affect the other. However, in experiments done in prion disease rat models, scientists have shown that an inflammatory stimulus in the periphery outside of brain can trigger greater inflammation in brain with harmful short term and long term consequences. Scientists showed that brain cytokine levels increased after the peripheral stimulus causing a short term rapid decline in cognitive and motor function -- that in turn was followed by an greater rate of disease progression than was present before the peripheral stimulus [Cunningham C 2009].

This happens in people too: It is well known that systemic infection outside of brain can trigger delirium, and that this is more common in the elderly and those with neurodegenerative disease [Konsman JP 2002]. There is also human data suggesting that systemic inflammation accelerates rate of disease progression and loss of functional ability [McCusker J 2001].

Up close and personal: One of the HDDW trials participants – whose test scores and function had been stable for more than a year -- had high fever and delirium following a flu and pneumonia vaccine. After this event he had an abrupt worsening of function (and test scores) which persisted after his recovery from fever. Further, over the following years he has had steady decline in test scores and function. In fact, this pattern of abrupt decline followed by more rapid disease progression is often described in Huntington patients after infection, trauma or other events that trigger inflammatory responses.

Why these clinical observations in people are important: We know that mutant huntingtin protein caused damage in many systems (energy, transcription, excitation, etc.), but scientific experiments in models have not shown us which ones are more important. However, these clinically apparent observations in Huntington's patients tell us that neuroinflammation is a very important component of disease progression -- one that can be seen over short periods of time. In my patient it was seen in a week's time.

Finding a drug that works early and effectively in this system could affect disease progression in a major way . . more in Part 2.

References

Björkqvist M, Wild EJ, Thiele J, Silvestroni A, Andre R, Lahiri N, Raibon E, Lee RV, Benn CL, Soulet D, Magnusson A, Woodman B, Landles C, Pouladi MA, Hayden MR, Khalili-Shirazi A, Lowdell MW, Brundin P, Bates GP, Leavitt BR, Möller T, Tabrizi SJ. A novel pathogenic pathway of immune activation detectable before clinical onset in Huntington's disease. J Exp Med. 2008 Aug 4;205(8):1869-77. doi: 10.1084/jem.20080178. Epub 2008 Jul 14. PubMed abstract

Reale M, Iarlori C, Feliciani C, Gambi D. Peripheral chemokine receptors, their ligands, cytokines and Alzheimer's disease. J Alzheimers Dis. 2008 Jun;14(2):147-59. PubMed abstract

Eikelenboom P, Bate C, Van Gool WA, Hoozemans JJ, Rozemuller JM, Veerhuis R, Williams A. Neuroinflammation in Alzheimer's disease and prion disease. Glia. 2002 Nov;40(2):232-9. PubMed abstract

Sawada M, Imamura K, Nagatsu T. Role of cytokines in inflammatory process in Parkinson's disease. J Neural Transm Suppl. 2006;(70):373-81. PubMed abstract

Galimberti D, Schoonenboom N, Scheltens P, Fenoglio C, Bouwman F, Venturelli E, Guidi I, Blankenstein MA, Bresolin N, Scarpini E. Intrathecal chemokine synthesis in mild cognitive impairment and Alzheimer disease. Arch Neurol. 2006 Apr;63(4):538-43. PubMed abstract

Cunningham C, Campion S, Lunnon K, Murray CL, Woods JF, Deacon RM, Rawlins JN, Perry VH. Systemic inflammation induces acute behavioral and cognitive changes and accelerates neurodegenerative disease. Biol Psychiatry. 2009 Feb 15;65(4):304-12. doi: 10.1016/j.biopsych.2008.07.024. Epub 2008 Sep 18. PubMed abstract

Konsman JP, Parnet P, Dantzer R. Cytokine-induced sickness behaviour: mechanisms and implications. Trends Neurosci. 2002 Mar;25(3):154-9. PubMed abstract

McCusker J, Cole M, Dendukuri N, Belzile E, Primeau F. Delirium in older medical inpatients and subsequent cognitive and functional status: a prospective study. CMAJ. 2001 Sep 4;165(5):575-83. PubMed abstract