The establishment of a brain bank in New Zealand for undertaking diagnostic studies on Huntington's Disease was first suggested to Professor Faull in 1981 by the late Professor Arthur Veale. Professor Veale knew of Professor Faull's interest in the region of the brain which was affected in Huntington's Disease (i.e. in the basal ganglia, a region at the base of the brain where brain cells die in Huntington's Disease). With enthusiastic support from the Huntington's Disease Association, Professor Veale established and organized procedures for the bequest of brains from patients throughout New Zealand who died with a diagnosis of Huntington's Disease. During the first three years of operation, the objective was to establish techniques for conclusively diagnosing Huntington's Disease and to investigate the pattern of brain cell death in the basal ganglia. These initial studies were undertaken with the expert assistance of Dr Beth Synek, Neuropathologist at the Auckland Medical School. In the early years resources to undertake detailed research studies on the human brain were not available but these studies provided an important diagnostic service to the families of the deceased.

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2. Development of Diagnostic and Research Studies

Over the last ten years Professor Faull's studies have progressed considerably and the research group has gradually grown to a present size of 7 scientific staff. The studies have expanded with the successful development of techniques for investigating the distribution of chemicals and genes in the brain. The human brain consists of several billion nerve cells which communicate with each other by the release of specific chemicals called neurotransmitters. One of the major advances in our understanding of the brain in recent years has been the demonstration that around 70-80 different neurotransmitters may be present in the brain. Furthermore, recent research has suggested that in Huntington's Disease, the group of cells which degenerate in the basal ganglia utilize certain specific chemical neurotransmitters. It occurred to Professor Faull that if they could determine exactly which chemicals were affected in Huntington's Disease, then patients with this disease could possibly be helped by replacing the depleted chemicals using specific drugs. An example of how this type of research can benefit patients is shown by the results of studies in Parkinson's Disease. Research in Parkinson's Disease has demonstrated that this disease is caused primarily by the degeneration of a group of cells in the brain which utilize dopamine as their neurotransmitter. The subsequent use of drugs to replace the low levels of dopamine in the brains of patients suffering from Parkinson's Disease has, in many cases, resulted in a marked improvement of the symptoms of the disease.

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3. Results of Chemical Studies

The results of the chemical studies on Huntington's brains, which have been bequeathed to the research group from all over New Zealand, have demonstrated very specific chemical changes which have now been shown to be characteristic of this disease. What is especially interesting is the finding that some of these chemical changes appear to develop before any brain cells die. In fact, it now appears that in comparison to pathological studies the chemical tests provide a very sensitive and reliable method of diagnosing the disease in the post-mortem brain; this finding is the first major result of Professor Faull's research studies and is of considerable practical importance for the diagnosis of this condition. Using these chemical methods and specialised genetical studies (see section 5), they are able to conclusively diagnose whether or not the person died with Huntington's Disease. Once they have completed the analysis of each brain, Professor Faull phones the relatives to discuss the results, and if requested a copy of the diagnostic report is sent to the next of kin detailing the results. The clinical geneticists in Auckland (Dr Ingrid Winship) and Wellington (Dr Joanne Dixon) and Genetic Services Staff are always available for back-up and for expert interpretation of the significance of the results to other family members (see page 8 for contact addresses and phone numbers). Because of the nature of the chemical and genetic studies, the analysis of each brain can take at least 9 months for completion. In most cases the results confirm that the person had Huntington's Disease, but occasionally the studies clearly demonstrate that the person didn't have Huntington's Disease, but some other neurological condition (e.g. Pick's Disease or Alzheimer's Disease). The results of these studies are thus of critical importance to the families and next of kin. Not only are they able to confirm or deny the diagnosis of Huntington's Disease for the family of the deceased, but they also learn more about the cell and chemical changes and the genetics of the disease.

Another of the major findings from these studies is the demonstration that there is a marked loss of the chemical g -aminobutyric acid (known as GABA) in the basal ganglia of Huntington's brains. Unfortunately, giving GABA to patients with Huntington's Disease has not proved to be a successful treatment. GABA acts by inhibiting or "slowing" the activity of nerve cells throughout the brain. Giving the chemical GABA to Huntington's patients not only results in replacing the depleted store of GABA in the basal ganglia, but also results in an excess of GABA in other "normal" parts of the brain thus causing a generalised "slowing" or inhibition of the activity of cells in widespread regions of the brain. Thus replenishing the depleted stores of GABA in this way is not a desirable method of treatment. However, perhaps patients could be helped if GABA was selectively replaced in the region of the brain affected in Huntington's disease - i.e. in the basal ganglia. As detailed below, Professor Faull's research group are investigating this possibility using an animal model of the disease and studying the effects of transplanting brain cells which make GABA.

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4. Studies on an animal model of Huntington's disease and brain cell transplants

Based on the results of the human studies, over the last 3 years they have established an animal model of Huntington's Disease in the rat. They have shown that the same cell and chemical changes that are seen in the Huntington's diseased brains can be mimicked almost exactly in the rat brain by placing a small injection of a chemical toxin (quinolinic acid) into the basal ganglia. This chemical has been shown by some investigators to be present in higher than normal concentrations in Huntington's brains and it has been suggested that it may play a role in initiating the disease process.

In an attempt to replace the lost chemicals in the basal ganglia of the animal model, they have transplanted GABA producing brain cells from a fetal rat into the animal model. The results to date show that the transplanted cells survive, grow and make GABA and other chemicals. Further detailed studies still have to be carried out, but the results of the preliminary studies are sufficiently encouraging to suggest that the transplantation of such brain cells may help patients with Huntington's Disease. These developments in their research are very exciting. The transplanting of cells into human brains has already been shown to be possible in patients with Parkinson's Disease. Over the last 2 years in North America and Europe over 100 patients with Parkinson's Disease have been given transplants into the basal ganglia of "dopamine producing" fetal brain cells. The results have been variable - from minimal to marked improvement - and it is still too early to conclude whether or not this type of treatment will produce long term benefits for the patient or whether it will halt the progression of the disease. Clearly more research is still needed on the effects of cell transplants in the animal brain - and they intend to continue their studies in the animal model of Huntington's Disease.

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5. Genetic studies

Apart from these animal studies, Professor Faull's research group has much to learn by continuing their anatomical and chemical studies on the Huntington's human brain. They have recently developed specialized techniques for studying the activity of the genes in brain cells which control the production of the chemicals in the brain. By applying these techniques to the Huntington's diseased brain, they hope to be able to show which neurotransmitter genes are affected in the disease, and most importantly, to determine how early in the disease these genes are affected.

It is now known that the gene for Huntington's Disease is located on the short arm of chromosome 4 and contains an "expansion mutation" comprising a number of "CAG" repeats. This is a highly repetitive area of DNA, analogous to a typing error, in the human genome. DNA studies of this region reveal the

number of CAG repeats. Affected individuals have 36 or more repeats; less than 30 would confirm that one is unaffected, while an intermediate form of 30-35 repeats is equivocal.

In order to fully understand and to document the HD gene in each case, it is important to undertake the genetic studies on the brain and also on other tissues of the body (blood and small tissue samples from other organs of the body). Permission to take other tissue samples is therefore also requested on the attached postmortem consent form.

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6. Future studies

Other new studies being planned with Dr Lynette Tippett (Neuropsychologist, Department of Psychology, University of Auckland) involve investigating clinical changes in three areas (thinking processes [for example, concentration, memory, planning], mood and emotions, and movement problems), in individuals in whom the diagnosis of Huntington's disease is suspected or confirmed. Information from this research will be used in conjunction with results from the anatomical, chemical and genetic studies. The aim is to understand and answer questions about the relation between behavioural and mood changes and the specific chemical alterations, and loss of particular groups of brain cells in the basal ganglia. For example, are the behavioural and mood changes closely related to early stage chemical changes in the brain, or do they only emerge with the death of brain cells? Are the different patterns of difficulties or symptoms experienced by individuals with Huntington's Disease caused by the death of different and distinct types of brain cells in the basal ganglia? Are different patterns of symptoms related to different time courses of the progression of Huntington's Disease? How do these patterns of symptoms relate to gene characteristics? Answers to these questions will help in the areas of prognosis and treatment of individuals with Huntington's Disease.

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7. Who should consider the bequest of brain tissue

(i) Brain tissue should be bequeathed from any person in whom the diagnosis of Huntington's Disease is suspected. The studies will provide for a confirmation or an exclusion of the diagnosis of Huntington's Disease.

(ii) Brain tissue should also be bequeathed from a person who dies who is at risk of Huntington's Disease but hasn't developed symptoms, particularly if that person has had pre-symptomatic testing confirming the presence of the gene.

(iii) Brain tissue should also be bequeathed from any person who has a family history of Huntington's disease but who doesn't have the HD gene. This type of tissue will provide invaluable control information which will help clarify how the HD gene affects the brain.

One of the important questions Professor Faull wants to answer is, do the chemical changes in the brain appear before any brain cells die? To answer this question, they need to examine not only the brains of patients who die with Huntington's Disease, but also those who are at risk of or have the gene for Huntington's Disease (but who have not yet developed the disease) and who die of other causes.

In order to undertake the genetic studies, it is essential that they receive the brains as soon after death as possible, preferably within 6-12 hours, although diagnostic tests and useful research can still be undertaken on brains received within 24 hours of death.

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8. Procedures for the bequest of brains to the Brain Bank

The procedures for bequeathing brains to the Brain Bank are quite straight forward.

(i) First, at some time before death it is important that the immediate next of kin and the donor (if possible) have discussed this matter since it is only with the approval of all of the next of kin that the bequest can be accepted. The donor or relatives should complete the form "OFFER OF BRAIN and other RELEVANT TISSUES" which is attached and send it to:

The Huntington's Disease Brain Bank
Department of Anatomy
University of Auckland
School of Medicine
Private Bag 92019
Auckland
New Zealand.

The Brain Bank will then acknowledge receipt of the form and keep the details on file.

(ii) The form "AUTHORITY FOR POST MORTEM EXAMINATION" should also be completed by the next-of-kin and placed in the donor's hospital notes or, if the patient is not hospitalized, kept securely by the next-of-kin.

Additional copies of the "OFFER OF BRAIN and other RELEVANT TISSUES" forms are included for the patient's medical notes, doctor and the family as required.

(iii) At the time of death or preferably when death is imminent, it is important for a member of the nursing or medical staff, or for a member of the family to contact Professor Faull or a member of the Brain Bank staff in the Anatomy Department at the Auckland Medical School (phone no: 09-3737-599 ext. 6703) or at home (phone 09-8492-009) so that arrangements for the bequest can be discussed in detail. If you are unable to contact Professor Faull or a member of the Brain Bank Staff then a representative of the local Huntington's Disease Association should be contacted. The specific arrangements will vary considerably depending on whether the patient is located in Auckland or in some other part of New Zealand. In all cases, at the time of death arrangements will have to be made for a postmortem examination to remove the brain and other relevant tissue and for the rapid transportation of the tissue to the Auckland Medical School; arrangements for this are best handled at that time.

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9. Processing, Analysis and Storage of Brain Tissue

The brain tissue is processed for pathological, chemical and genetic studies. The detailed anatomical, chemical and genetic studies are undertaken first to confirm the diagnosis of Huntington's Disease and also for research purposes. These studies normally take at least 9 months, and often up to one year. At the conclusion of these studies the next-of-kin will be contacted and a copy of the final report is sent to the family and to the family doctor.

Tissue is retained for future studies and analysis, i.e. as new techniques become available, stored tissue can be used as a source of DNA for family and genetic studies as requested by the family.

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10. Confidentiality

All information, including personal identification and clinical details will be regarded as strictly confidential and only used for research purposes under the conditions of The Privacy Act 1993 and Health Information Code 1994; that is, tissue and personal information will be identified only by code number and not by name.

Finally, Professor Faull and his research group would like to express their appreciation to all the various branches of the Huntington's Disease Association throughout New Zealand and to the families of the Huntington's patients who have enthusiastically supported the Brain Bank since its establishment in 1981. To date they have received over 60 brains for analysis. It is only through these efforts that they have been able to successfully establish a broad research programme on Huntington's Disease and to make important scientific contributions which they hope will provide a more effective treatment for the sufferers of this tragic disease. Professor Faull is always willing to discuss any aspects of their studies with members of Huntington's families or to provide further details to families who have made bequests.

If you have any further queries on brain tissue donation, please write directly to:

Professor RLM Faull
Huntington's Disease Brain Bank
Department of Anatomy
School of Medicine
University of Auckland
Private Bag 92019
AUCKLAND

If you have any questions about other aspects of Huntington's Disease please contact your nearest HD Field Officer.