Dementia is already a significant problem not just in the UK but on a global scale. In the UK dementia affects between 750,000 and 800,000 people (this includes one in 20 in the over-65s and one in five over the age of 80 years).1,2 However, dementia is not only a concern in the ageing population. Of those, around 18,000 are under the age of 65 years2 with reports suggesting this number could be significantly higher. Early onset dementia is a complex problem that has special requirements, and therefore specialist services are vital to manage their multifaceted needs. The specialist requirements are related to the fact that these patients may be at work at the time of diagnosis or have a dependent family.

Even among those under the age of 65 years, Alzheimer’s still represents the highest proportion accounting for over 30%. In this age group, fronto-temporal dementia (FTD) accounts for the second highest proportion with around 20% thought to be affected.1 Other causes include vascular and dementia with Lewy bodies. The focus of this particular prevalence study will be FTD.

FTD affects males and females in equal proportion and can affect those as young as 30 years.3 The condition was first classified as Pick’s disease following post-mortems carried out by Alois Alzheimer (who named the condition after the German physician Arnold Pick). The term frontotemporal dementia is much preferred now as only a small proportion of patients exhibit the characteristic histopathological changes associated with Pick’s disease.4

FTD involves predominantly changes in personality, behaviour and language with early preservation of visuo-spatial skills and memory. It is these character and behavioural changes that play the most significant part in making a clinical diagnosis of FTD.

FTD is rather like a syndrome, which can be further subdivided into the behavioural (frontal) variant, temporal variant (semantic dementia) and progressive non-fluent aphasia. The latter two are more predominantly concerned with language. It is the behavioural disorder that accounts for close to 50% of cases of FTD. Neary et al published the most recognised diagnostic criteria, which include behavioural changes (such as hyperorality, inflexibility distractibility, stereotyped and perseverative behaviours), affective changes (including disinhibition and apathy), alterations in speech (echolalia, perseverative and stereotypy of speech) and neurological signs (Parkinsonian syndrome).3,5,6,7 The onset of all three subtypes is typically insidious and progressive. However, the clinical presentation for pre-senile FTD remains heterogeneous thereby the exact prevalence remains difficult to ascertain.

FTD is largely the result of atrophy of the frontal and/or temporal lobes. It is thought that somewhere between 30 and 50% of patients with FTD report a positive family history in the behavioural variant of the disorder.8 This number is somewhat reduced in the two language variants. In the rest of patients, the cases are thought to be sporadic in nature. The typical inheritance pattern appears to be autosomal dominant.5 Therefore, genetic research is fundamental in understanding the nature of this condition. Unfortunately at present understanding the genetics of FTD is as complex as the clinical picture. Much of the research is linked to chromosome 17 and in particular, the tau gene (although chromosomes 3 and 9 have been hypothesized). Abnormal tau accumulations are associated with several neurodegenerative conditions including Alzheimer’s disease, frontotemporal dementia, cortico-basal degeneration and progressive supranuclear palsy.9

There are now somewhere between 25 and 30 mutations which have been identified in the tau gene thought to be implicated in FTD.10 However, there are cases where the tau gene is not the source of the genetic change yet they suffer with FTD. Further mutations have been found in the progranulin (GRN) genes, valosin containing protein (VCP), TAR-DNA binding protein (TARDP) and fused in sarcoma (FUS) genes.8 Even with this there are still some mutations which are yet to be identified. Therefore, research is continuing in finding alternate genes thought to be responsible.

Methodology

The total number of patients under the care of the Younger People with Dementia Service in the Shropshire area was first ascertained. The sample size was then cut down to give those patients on the register as suffering with FTD between the ages of 45–64 years. Then a review of the case notes of the patients suffering with FTD in the Shropshire area was conducted. A more detailed analysis was carried out to ascertain the evidence for a genetic cause for FTD in those patients. In those patients identified with a positive family history, further efforts were made to identify the nature of the gene implicated including the various institutions whereby the genetic testing was undertaken.

Results

The total number of patients in the catchment area of Shropshire suffering with early onset dementia is 150. There were 23 patients listed on the register as suffering with FTD. However, after performing an in-depth review of case notes, this number was reduced to 17. Two of those excluded were found to have alternative diagnoses including progressive supranuclear palsy (PSP) and non-progressive fluent aphasia. A further four were excluded on the basis that they were not found to have a definitive diagnosis but rather a possible one.

Out of 17 patients, it was determined that there were two (11.76% of total FTD cases) with a positive family history. The total prevalence of FTD within the younger onset dementia service is 1.33% (2/150) and the prevalence within Shropshire (those within the 45–64 age group) is 0.0023% (2/87,100).11 The prevalence of FTD on the whole was found to be 0.0195% (17/87,100). Upon genetic testing the two patients were found to have a mutation in the MAPT gene (exons 10+16) present on chromosome 17. This gene is responsible for encoding the tau protein. The two patients were in actual fact siblings. The chance therefore of one of their children or siblings inheriting the mutation is 50%.

Discussion

The aim of this particular study was to determine the prevalence of familial FTD in the Shropshire area. The study demonstrated the prevalence of familial FTD (within the 45–64 age groups) in the Shropshire area was 0.0023%. Prevalence studies of familial FTD are rare but there have been population-based studies on the prevalence of the condition as a whole. Two such studies have been carried out in two cities in the UK which included those patients referred to specialist services for their dementia. The prevalence rates found in these studies showed figures of 15 per 100,000 inhabitants.12,13 In Shropshire it was found to be 17 out of 87,100 patients had frontotemporal dementia. These figures clearly indicate the condition is more common than was once thought.

Numerous cases of FTD are familial, predominantly in an autosomal dominant inheritance pattern. This study found only a small proportion of patients (11.76%) with evidence of family history out of the total FTD cases. Whether, the remaining cases are sporadic in nature or there was simply insufficient information available on family history remains to be seen. The mutation found in the two individuals involved the MAPT gene (microtubule-associated protein tau). The result of the mutation is either an overproduction of tau isoforms or a reduction in its ability to interact with microtubulin.9 Both of these can lead to the condition frontotemporal dementia. More than 30 different mutations in this gene have been identified. Although abnormal accumulations of tau are due to mutations in the tau gene, not all patients on neuropathological studies exhibit this tau change which is why this is a focus for continuing research.14 In the majority of familial frontotemporal dementia cases it is chromosome 17 (the tau and progranulin gene) that is implicated but there is evidence to suggest chromosome 3 and 9 may play a role.

It is clear that this is a complex disorder both in terms of clinical presentation and with regard to determining genetics. A recent paper failed to find any significant difference in presentation between genetic and sporadic cases but determining the exact genetic cause in several familial cases appears inconclusive. Nonetheless, there is a definite need for specialist services with a multidisciplinary approach in order to manage this highly complex and challenging condition and support services in place for those with a genetic predisposition.

Conflict of interest: none declared

References

 

1. Jones RW. Drug Treatment in Dementia. Blackwell Science Limited. 2000.
2. Knapp M, Prince M. Dementia UK: The full report. A report into the prevalence and cost of dementia prepared by the Personal Social Services Research Unit (PSSRU) at the London School of Economics and the Institute of Psychiatry at King’s College London, for the Alzheimer’s Society. Alzheimer’s Society 2007

3. Whalley LJ, Breitner CS. Fast Facts – Dementia. Health Press Limited. 2002

4. Weder ND, Aziz R, Wilkins K and Tampi RR. Frontotemporal Dementias: A Review. Annals of General Psychiatry 2007: 15 
5. Piguet O, et al. Similar early clinical presentations in familial and non-familial frontotemporal dementia. J NeurolNeurosurg Psychiatry 2004; 75: 1743–45

6. Brun A, Englund B, Gustafson L, et al. Clinical and neuropathological criteria for frontotemporal dementia. The Lund and Manchester Groups. J NeurolNeurosurg Psychiatry 1994; 57: 416–18

7. Graham A, et al. Pathologically proven frontotemporal dementia presenting with severe amnesia. Brain 2005; 128 (3): 597–605.

8. Seelaar H, Rohrer JD,  Pijnenburg YAL, Fox NC, Swieten JC. Clinical, genetic and pathological heterogeneity of frontotemporal dementia: a review. J Neurol Neurosurg Psychiatry 2011; 82: 476–86

9. Goedert M, Spillantini MG. Tau mutations in frontotemporal dementia FTDP-17 and their relevance for Alzheimer’s disease. Biochim Biophys Acta 2000; 1502(1): 110-21

10. Deerlin VMV, LH Gill,  Farmer  JM, et al. Familial Frontotemporal Dementia: From Gene Discovery to Clinical Molecular Diagnostics. Clinical Chemistry October 2003; 49(10): 1717–25

11. Source: 2011 Census, Office for National Statistics

12. Ratnavalli E, Brayne C, Dawson K, Hodges JR. The prevalence of frontotemporal dementia. Neurology 2002; 58:1615–21

13. Harvey RJ, Skelton-Robinson M, Rossor MN. The prevalence and causes of dementia in people under the age of 65 years. J Neurol Neurosurg Psychiatry 2003; 74: 1206–9

14. Mackenzie IR, et al. Familial frontotemporal dementia with neuronal intranuclear inclusions is not a polyglutamine expansion disease. BMC Neurology 2006, 6: 32 doi:10.1186/1471-2377-6-32