‘Unpicking’ Pick’s disease: working towards accurate diagnoses of frontotemporal dementia
Among the members of the dementia family, Alzheimer’s disease (AD) is the oldest and easily the best known. But as the graph below illustrates, one of AD’s lesser known siblings is slowly emerging from obscurity and beginning to make a name for itself.
Ten years ago, few people outside dementia research circles had heard of frontotemporal dementia (FTD). Clinicians and textbooks often referred to it as ‘Pick’s disease’, after Czech psychiatrist Arnold Pick, who in the 1890’s, described distinctive structures he noticed in the brains of some of his patients who had died with dementia. The structures still bear Pick’s name, but have now been ‘un-Picked’: they contain tau – a protein that helps healthy nerve cells keep their internal structure.
There are many reasons for greater FTD awareness, not least the media reports of notable people living with the condition, such as Monty Python star Terry Jones and David Baddiel’s father, Colin.
Another factor is the development of imaging techniques that can show diagnostic changes in the brains of living patients – changes that could previously only be observed after death. Imaging techniques are now reliable enough that a negative amyloid PET scan can effectively exclude a diagnosis of Alzheimer’s disease.
But not having Alzheimer’s disease doesn’t necessarily mean having FTD. To detect FTD we need a test that shows that the disease-causing tau protein is present. The good news is that trials are being done to see how useful tau PET scans are. At best, though, a tau PET scan will diagnose only about 50% of FTD cases, as there is a second variant, which is as common as FTD-with-tau, but caused by a different protein.
Patients with FTD come in two broad types: one group suffers changes in personality (behavioural variant FTD, or bvFTD) and the other difficulties producing and understanding language – primary progressive aphasia (PPA).
Behavioural change can be hard to describe, let alone measure, but there are three easily recognized features: loss of inhibition, apathy, and obsessionality. Disinhibited patients are energetic, impulsive, and (embarrassingly or engagingly) over-familiar. It is painfully hard work to extract information from an apathetic patient. The obsessional patient’s stereotypical movements or verbalizations make them uneasy company in a consultation room.
When FTD presents with language problems it is referred to as primary progressive aphasia (PPA). PPA has three main forms: progressive nonfluent aphasia (PNFA), semantic dementia (SD), ‘Logopenic’ PPA (LPA).
- People with PNFA have distorted speech but can usually understand spoken words. They sometimes have difficulty following sentences.
- Those with SD have fluent but ‘empty’ speech, and do not understand the words they hear. At a recent clinical assessment, I asked one of my patients with more advanced fluent PPA whether she still enjoyed listening to music. Her reply was diagnostic: “What’s music?”
- LPA tends to have a milder effect on speech, but patients have trouble repeating spoken sentences.
The essential differences between these three PPA subtypes are summarised below:
FTD is not common – estimates of its prevalence average around the 20 per 100,000 mark. FTD is currently untreatable and the different brain proteins causing FTD will almost certainly require different approaches to treatment. But the challenge of making an accurate diagnosis of FTD will make it difficult to find enough participants to take part in the clinical trials that will, in time, be required.
It turns out that PPA could provide the best chance of identifying probable cause and type of FTD at an early stage. This is because post mortem analyses suggest that the two proteins causing most FTDs correlate broadly with the two main types of PPA.
So how can we capitalise on this correlation to work towards efficient and reliable classifications of PPA, and of FTD more widely?
One challenge is to provide standardised definitions based on the known differences between different types of PPA. Another is to try to identify additional dimensions that could be used to refine the classification further. Finally, because large groups of patients are essential, we need a way of translating these measures into languages other than English, to facilitate and encourage international collaborative research into what is, after all, an increasingly global problem.
With these aims in mind, the Medical Research Council have recently funded a three-year, multi-centre study of PPA, at the end of which a fully validated clinical test – the Mini Linguistic State Examination (MLSE) – will be available for use by medical staff.
The aim is to use pattern recognition software to consistently distinguish the three PPA types from one another using a common set of criteria and to monitor levels of severity over time. It is intended that the MSLE will be comprehensive yet brief, and capable of being administered by clinicians without special expertise in language assessment. The MLSE will also support and enhance other essential ongoing dementia research.
Researchers at St George’s, University of London, the Universities of Cambridge and Manchester and the Istituto Universitario di Studi Superiore in Pavia, Italy, are looking for patients with all forms of PPA, whether as a symptom of FTD, or other disorders (such as corticobasal degeneration, progressive supranuclear palsy and ‘classical’ post stroke aphasic syndromes) to create and validate equivalent English and Italian versions of the test.
The relative rarity of these conditions will mean that recruitment through the NIHR Clinical Research Network and Join Dementia Research will be of more than usual value, and I am grateful to colleagues in Wessex and Thames Valley for their early interest.
I encourage you to follow the progress of the project on our website www.mlsexam.com where you’ll find updates on development in other languages, publications, and a project blog.
*NIHR is running a campaign to mark World Alzheimer’s Month. Find out more on the NIHR website.
There are a number of FTD studies throughout the UK that are looking for participants through Join Dementia Research. You can see if you are eligible by logging into your Join Dementia Research account.
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