Contents

The Changing Face of Pick's Disease

‘Pick's disease’ has been used in clinical work for many years to refer to patients with a distinct form of dementia that mainly affects the frontal lobes of the brain. This clinical type of dementia is believed to account for about 10% of all cases of dementia and is increasingly being called frontotemporal dementia in recognition that it can be caused by several different brain diseases. Pick's disease is now seen as only one of several diseases that causes clinical frontotemporal dementia. Indeed, patients with true 'Pick's Disease' are now regarded as being very uncommon compared to several other diseases that produce an identical clinical picture.

The main clinical symptoms of frontotemporal dementia are determined by which bits of the brain are affected by death of nerve cells. Three main clinical syndromes have been defined.

1. A behavioural syndrome referred to as frontotemporal dementia in which patients have emotional disturbances associated with disinhibition
2. A condition called progressive non-fluent aphasia in which patients have a difficult with speech production and ultimately become mute
3. Semantic dementia. is a condition where patients have difficulty in comprehending the meaning of what they see and hear. In contrast recall of personal day-to-day events and general 'memory' is usually well preserved.

Understanding of this group of diseases has only been possible through post mortem examination of the brain from patients who have died from disease.

Tau protein is a common factor in some cases
One important new concept has arisen from the realisation that several brain diseases causing dementia have a common factor - the accumulation of the same abnormal protein inside nerve cells. This protein is called tau and is a normal part of nerve cells where it acts to support the internal scaffolding of the nerve cell, and so gives a nerve cell its function. It is now apparent that several degenerative diseases of the brain result in the abnormal build up of tau protein inside nerve cells which is believed to stop the nerve cells working and possibly cause individual nerve cells to die.

Pick's disease is one of the conditions in which there is a build up of tau protein in nerve cells. In this type of disease the tau protein forms spherical lumps inside nerve cells which can be seen down the microscope called Pick Bodies. Nobody has got a clue why the tau protein wraps up into a ball but it is so distinctive that pathologists have little difficulty identifying that a person has had Pick's disease when brain tissue is examined down the microscope.

Other diseases causing frontotemporal dementia, not showing features of Pick's disease, also show an abnormal build up of tau protein in nerve cells and were originally given long and complex clinical names. Because these conditions all have the common theme of abnormal amounts of tau protein in the brain they have all been grouped as so-called tauopathies. Importantly, in rare families, a gene mutation has been shown to cause the abnormal build up of tau protein in the brain. The gene that normally codes for tau protein has been found to be abnormal in some families with frontotemporal dementia. Such cases are regarded as rare and often include clinical features similar to Parkinson's disease in affected patients. The gene for tau protein is on chromosome 17 so these rare familial cases are called frontotemporal dementia with parkinsonism linked to chromosome 17 - abbreviated to FTDP-17.

Non-Tau dementias are commoner than Pick's disease
When brains tissue is examined from patients who have had a frontotemporal dementia, often originally suspected to be Pick's disease, it is now apparent that the majority of cases do not show any abnormal build up of tau protein in the brain - they have other diseases.

These tau-negative diseases can be divided into three types on the basis of whether the brains show a build up of another protein in nerve cells called ubiquitin or whether patients have features in the brain that look like motor neurone disease. Motor neurone disease is another degenerative disorder that affects the brain and spinal cord and is characterised by weakness and wasting of the muscles. It is now appreciated that whatever causes motor neurone disease can also cause one form of frontotemporal dementia.

The three main types of disease causing frontotemporal dementia can be defined by a pathologist following examination of the brain after death but cannot be defined with any certainty in life by clinical examination or brain scans.

• Frontotemporal lobar degeneration with motor neurone disease (FTLD-MND)
• Frontotemporal lobar degeneration with ubiquitin-only-immunoreactive neuronal changes (FTLD-U)
• Frontotemporal degeneration (FTD)

Frontotemporal lobar degeneration with motor neurone disease (FTLD-MND)
This is a degenerative disease of the brain where a patient develops dementia as well as clinical features of motor neurone disease, such as muscle weakness or problems with swallowing. In some patients evidence that there is motor neurone disease may only be apparent on examining the brain after death under the microscope. Abnormal material accumulates in nerve cells containing the protein ubiquitin.

Frontotemporal lobar degeneration with ubiquitin-only-immunoreactive neuronal changes (FTLD-U).
This is a degenerative disease causing dementia in which nerve cells in the brain accumulate abnormal lumps of protein that contain the protein ubiquitin and which do not contain any tau protein.

Frontotemporal degeneration (FTD).
This is a degenerative disease causing dementia in which examination of the brain shows death of nerve cells in the frontal lobes but where a careful examination does not show any abnormal ubiquitin or tau protein build up.

Genetics
Approximately 50% of reported cases of frontotemporal degeneration are found to have a family history of dementia. In many of these there is what is called autosomal dominant transmission meaning that half of the children in a family would be expected to inherit the disease. With technical advances from the Human Genome Project it has been possible to narrow down the search for the gene causing this type of disease. There are at least three different genetic forms on chromosome 3, chromosome 9 and chromosome 17 at a site that is different from those associated with the tau gene. In the future it is expected that the precise genes will be discovered and that this will open up doors for new approaches to understanding and hopefully some new ideas about treatment.

Future directions
It is apparent that there is a relationship between some patients with frontotemporal dementia and some patients with motor neurone disease. It may be that research into motor neurone disease, rather than dementia, will give us an answer. It is clear that there are links between many of the so-called neurodegenerative diseases and that discoveries in one area may have a wider impact in seemingly unrelated diseases of the brain.

Post mortem examination of the brain is still an important part of medical practice. Without being able to examine the brain of patients who have died with these forms of dementia, often having been thought to have Pick's disease, we would not have been able to make these discoveries. Relating the changes seen in the brain to those which we can discover from advances in genetics promises to open up new approaches to understanding these diseases. There have been wide public concerns about the issues of organ retention and legislation in the UK will change in the near future. It is hoped that changes which will be put in place will not be such as to inhibit the progress of vital research into brain disease.

Acknowledgements
The families who gave permission for post mortem examinations and retention of brain for research are gratefully acknowledged. Without their forethought and generosity the understanding of the diseases described in this brief overview would have been impossible.

Jim Lowe
Professor of Neuropathology at the Queen’s Medical Centre,

Contact Details

Regional Contacts