Huntington's Disease
Huntington's disease is a devastating degenerative neurological disorder characterized by progressive involuntary choreiform movements, psychological disturbances, and dementia. First symptoms occur at approximately age 40; a relentless course leads to death in an average of 17 years. There is an animal model of HD which, some researchers claim, may be useful in searching for therapeutic modalities. This model's validity, however, is doubtful.
Background: Huntington's Disease
Huntington's disease (HD) is an autosomal dominant condition with complete penetrance, but patients' age at onset and durations of the disease's course vary. Behavioral changes are often the first symptoms, later followed by worsening involuntary choreiform movements and dementia. Depression is the most frequent initial complaint; patients can also suffer psychotic delusions of grandeur or paranoia.
HD's complicated neuropathology is poorly understood. Cell loss is greatest in the striatum (caudate and putamen), but many neurons also die in the globus pallidus and the cerebral cortex. In different parts of the brain, neurotransmitter levels, biosynthetic enzymes, and receptor-binding sites undergo many local changes. Some alterations may relate to HD's primary pathology, which is still unknown, but most are probably secondary to neuronal degradation. It is not known whether HD's clinical symptoms are primary degenerative changes or secondary effects. Our understanding of HD has been hampered by a multitude of central nervous system (CNS) changes, limited information on the progression of these changes, and incomplete knowledge of the clinical relevance of many documented biochemical and anatomical abnormalities found on autopsy.
Background: Animal Models
The leading animal models of HD have involved injection of neurotoxins into the striatum of rats, which causes local destruction of this area of the brain. Two earlier neurotoxins were kainic acid and ibotenic acid,(1,2) synthetic analogues of glutamic acid that excite receptor neurons and, in excess, lead to excitotoxic death. In 1983, Schwarcz et al. found that injection of quinolinic acid (QA) into the striatum of rats produced a similar excitotoxic effect.(3) QA is an endogenous neurotransmitter normally found in human and rat brains.(4) Reported similarities between QA toxicity and HD have raised the possibility that QA may be primarily responsible for HD,(5,6) but these findings have been disputed.(7-9)
Part 1: Comparison of the Animal Models to Huntington's Disease Clinical Presentation
Most of the similarities between HD and the animal models are histological and biochemical. The classic triad of human HD -- involuntary chorea, psychiatric disturbances, and dementia -- have not been described in the animal models. Schwarcz et al. have noted: "Unilateral intrastriatal application of . . . quinolinic acid resulted in tonic-clonic movements of the contralateral forelimb. . . . The behavior, which was dose-dependent and was usually accompanied by episodic barrel-like rotations, was virtually indistinguishable from that seen after identical treatments with nanomole amounts of kainic or iboteriic acids."(3) Such epileptiform movements appear to have little in common with the choreiform movements that characterize HD. The psychiatric disturbances and dementia seen in HD would be difficult, if not impossible, to assess in non-human animals.
HD decreases the striatum's levels of GABA and substance P but increases the measured concentration of somatostatin and neuropeptide Y.(5) The increased somatostatin and neuropeptide Y are thought to reflect relative sparing of neurons that release these transmitters.(5) Scientists disagree on the neurotransmitter abnormalities found in the animal model. Kainic acid and ibotenic acid do not selectively spare somatostatin and neuropeptide Y. However, Beal and colleagues have reported sparing of somatostatin and neuropeptide Y after QA,(5,6) 1-homocysteic acid,(10) or N-methyl-D,L-aspartate (11) injection, similar to the neurochemical findings in HD. Other investigators have had conflicting results using QA.(7-9) While the details of this debate are complicated, a brief overview of the main points is helpful. Davies and Roberts have written:
The observation of a sparing of large cholinergic cells suggests that all three toxins (kainic acid, ibotenic acid and quinolinic acid) produce patterns of cell loss reminiscent of those found in the neurodegenerative disorder Huntington's disease. The failure of these three compounds to spare somatostatin-, neuropeptide Y- and NADPH-diaphorase-containing cells is, however, in marked contrast to the sparing of these cells found in Huntington's disease.(8)
Beal and colleagues agree that QA is non-selective in neuron destruction at the injection site, where its concentration is greatest. However, they have maintained that, in a transition zone where only some neurons die, the cells with somatostatin and neuropeptide Y are selectively spared. Davies and Roberts have denied that such a transition zone exists; "Transition zones exhibiting selective sparing of subtypes of neurons . . . appear not to be a feature of quinolinic acid-induced neurotoxicity."(8) The controversy remains unresolved.
Pathogenesis
HD is an inherited degenerative disorder, and the underlying abnormality has not been characterized. Perhaps, as animal models have suggested, an excess of a neurotoxin, such as QA, slowly kills neurons. Other possibilities include abnormalities of neuron receptors or a metabolic defect. The animal models involve direct injection of neurotoxins into the brain, leading to rapid cell death. In contrast, HD typically has a course of about 17 years, presumably reflecting slow loss of neurons.
HD's natural history differs considerably from the QA toxicity induced in animal models. Work by Davies and Roberts has indicated that cellular protective mechanisms must be overwhelmed in order for QA toxicity to occur. Studies in HD patients have indicated elevated levels of the enzyme that synthesizes QA, but the preliminary findings have not been conclusive. However, this could be secondary to the pattern of cell loss in HD rather than a primary event.(12) In addition, autopsy studies have shown that QA levels in HD patients are similar to those of normal individuals.(13)
Recently, Young et al. reported that HD patients showed a relatively selective loss of neurons with NMDA receptors. This finding supports the excitotoxicity theory.(14) Young et al. have reasoned, "If NMDA receptors are involved in the pathogenesis of HD, cells with high density of NMDA receptors should be preferentially lost in HD striatum, and NMDA receptor density should decline concomitantly."(1) Such decline appears to be the case. As regards HD pathogenesis, however, they can only speculate on a number of possibilities:
The large decreases observed in striatal NMDA receptors in HD striatum could be due to several different mechanisms including overproduction of an endogenous neurotoxin such as quinolinic acid or a primary genetic defect in striatal NMDA receptors. Alternatively, HD may produce another defect such as inipaired energy metabolism in a subset of striatal neurons. Cells with an abnormal ability to maintain adequate energy stores may be more vulnerable to excitotoxic damage. If so, the neurotoxic mechanisms, although secondary, might accelerate the course of the disorder. If any of the above mechanisms do play a role in HD, then blockade of NMDA receptors could retard the progression of the disease.(14)
In summary, scientists need more information on basic neuroanatomy and on HD's neuropathology in order to assess the relevance of the QA toxicity animal model for HD. Schwarcz et al. have observed: "an assessment of the validity of intracerebral excitotoxin injections for the production of animal models is compromised by a lack of sufficient knowledge concerning both the neuropathology of the human disorders and the functional organization of the rat brain."(15)
Part 2: Clinical Review Articles
In 1986, Martin and Gusella published a major review of HD research in the New England Journal of Medicine. Work with animal models was discussed in the following passage:
Local injection of high concentrations of glutamate or of other more potent excitatory analogues, such as kainic and ibotenic acid, produce neuronal degeneration in the striatum of laboratory animals... .. Such findings have suggested that the degeneration found in Huntington's disease may be caused by an endogenous substance that interacts with glutamate receptors. Recently, baclofen, which appears to inhibit the release of excitatory transmitters, including glutamate, has been tested as a therapeutic agent in Huntington's disease. Benefits have been reported, and long-term clinical trials are now under way.(16)
The long-term clinical trials, however, did not show any benefit from baclofen.(17)
Part 3: Clinically Important Questions
Clinicians are trying to address several important questions in order to assist HD patients. First, what is HD's pathogenesis? The animal models suggest excitotoxity, but the human data have failed to confirm this to date, and there are other plausible theories. Neurotoxicity is one of the few ways by which a CNS lesion may be created in animals. It is much more difficult, if not impossible, to reproduce a metabolic defect, neuron receptor abnormality, or other cellular defect -- any of which may account for HD. While excitotoxicity is more amenable to experimental studies, there is no strong evidence at this time that excitotoxins cause HD. It is likely that continuation of ongoing human clinical investigation will prove most valuable in efforts to understand HD etiology. For example, while animal studies initially pointed to QA accumulation as the underlying pathological defect, QA excess has not been found in autopsied HD patient brains.(13) Rather, autopsy studies have implicated kynurenic acid deficiency (18) or glutamic acid toxicity.(19) The use of non-invasive scanning measures, such as CAT,(20) PET,(21,22) and SPECT (23) scans offers exciting possibilities for the study of ongoing pathological changes in living HD patients.
A second important question is, "What treatment modalities will ameliorate HD symptoms?" Inspired by human clinical data of neurotransmitter abnormalities in HD, attempts to alter GABA levels or to restore the balance between dopamine and acetyicholine have failed.(16) Beal and colleagues have suggested that a compound that blocks QA in the CNS may be helpful. They have found that MK-801, an NMDA antagonist, protects rats from QA toxicity.(6) Other investigators have reported that MK-801 can protect against other types of excitotoxic injury by blocking NMDA receptors.(24,25) However, this analogue of phencyclidine (PCP, "angel dust") would probably have unacceptable side-effects.(12) Also MK-801 would help HD patients only if HD were due to excitotoxicity acting on NMDA receptors.(14) As discussed above, the first trial of a drug that antagonizes excitatory neurotransmitters was not successful. We need to know more about HD in humans in order to choose between a multitude of possible therapeutic strategies, particularly if some options pose considerable risks of side-effects.
How can we know which people carry the HD gene? Because the average age of HD onset is 41, gcnetic tests are needed to help potential carriers decide whether to have children. Such tests, involving DNA mapping and derived from human genetics research, are already available and are 95% accurate.(16) Prenatal HD tests have also been performed;(26) further research to improve test accuracy will necessarily use human genetic material.
Conclusions
The value of excitotoxin animal models remains to be seen. At present, there is little clinical data to support the claim that HD is due to excitotoxicity. Improvements in our understanding and treatment of HD are mostly likely to derive from human clinical investigation. Schwarcz et al. have noted that experimental excitotoxic lesions have not yet been demonstrated to be relevant to HD etiology.
References
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