What causes people to develop the ‘phenocopy’ syndrome of FTD?

In a study published recently, Gossink and colleagues investigated the link between psychiatric and psychological factors in people who develop a disorder which has been termed the behavioural variant FTD ‘phenocopy’ syndrome, and identified a variety of psychiatric and psychosocial factors which may contribute to the manifestation of this condition.

What is the bvFTD phenocopy syndrome?

The behavioural variant of FTD (bvFTD) is characterized mainly by changes in behaviour and personality. However, there are also deficits in planning and problem solving (executive function) and social and emotional processing. In 2011 international diagnostic criteria were developed to classify patients into possible, probable and definite bvFTD based on genetic, pathological, neuroimaging, cognitive and behavioural features.

To reach a diagnosis of possible bvFTD patients must exhibit three of six core behavioural and cognitive features: apathy, disinhibition, stereotypic/compulsive behaviours, sweet preference, loss of empathy and a problems with executive function. To reach probable bvFTD, evidence of worsening day-to-day function and an abnormal brain scan must also be present. Only when genetic findings during life or pathological confirmation at autopsy are demonstrated is the diagnosis considered definite.

While many patients with possible bvFTD move into a probable or definite category over time, there remains a proportion of cases that remain possible over a number of years and are termed the ‘phenocopy syndrome’. These patients show a range of behavioural changes identical to standard bvFTD patients. In contrast to standard bvFTD the progression is often slow and indolent spanning decades, and they lack the typical frontal and temporal lobe abnormalities on brain scans. These patients represent a diagnostic conundrum for clinicians, and many theories exist regarding the possible aetiology, including loss of brain cells (neurodegeneration) similar to standard bvFTD but occurring very slowly, a psychiatric disorder, or some form of late-onset autism. Despite recognition of the ‘phenocopy syndrome’ until now there have been no studies exploring the link with psychiatric and psychosocial factors.

How was the study conducted?

Gossink and colleagues used a two-pronged approach to characterise the characteristics of a group of probable and possible bvFTD patients who were seen over at least a one-year period. Those in the possible group who did not progress or develop imaging changes were termed ‘phenocopy syndrome’. A strength of this study lies in the use of validated criteria: the international diagnostic criteria for bvFTD, and the DSM-IV for psychiatric diagnoses. The authors then categorized psychiatric and psychological problems into themes, consisting of depression, bipolar disorder, anxiety, alcohol abuse, recent intense life events, personality traits, autism spectrum disorder, intellectual disability and relationship problems. They then used statistical measures to quantify the differences between the two groups.

What were the results?

In keeping with other studies on the phenocopy syndrome, this study found that the majority of patients (94%) were male and were also significantly younger than those with probable bvFTD. It is striking that 86% of phenocopy cases had psychiatric or psychological symptoms or diagnoses in comparison to 47% of the probable bvFTD group. Of the phenocopy cases 36% experienced a recent serious life event compared to only 5% of probable cases, and 30% had intense relationship problems compared to 10.5% of probable cases. Certain personality traits, composed of dependent or obsessive-compulsive personality traits, were also common in phenocopy cases. In contrast, major depressive disorders, anxiety, bipolar disorder and alcohol abuse were similar across groups. The authors make note that previous studies have shown a high rate of depression and compulsive behaviours such as alcohol consumption in patients with neurodegenerative conditions. The majority of phenocopy syndrome cases exhibited more than one psychiatric or psychological trait. However, only one case satisfied criteria for autism spectrum disorder.

This study does have a number of limitations that should be considered. Firstly, the length of follow-up is short. The minimum follow-up is one year and given that progression in bvFTD is variable, it seems possible that cases classified as phenocopy cases may have progressed or developed imaging changes had the follow-up been longer. Similarly, C9orf72 testing was not performed in these cases. Recent studies of C9orf72 bvFTD have demonstrated that up to one-half of these patients are classified as possible bvFTD at presentation, and can show a slower progression than sporadic cases. This suggests that some of these cases may have harboured this genetic expansion, and as such may have satisfied criteria for definite bvFTD. Finally, pathological confirmation was not performed.

What does this tell us about the cause of the phenocopy syndrome?

This novel study found that patients with the phenocopy syndrome were significantly more likely to have psychiatric or psychological conditions than probable bvFTD patients. Overall the results suggest that the phenocopy syndrome manifests when a complex interaction of psychiatric and psychological factors exist. In accordance with the views of the authors, it seems essential that neurology and psychiatry work together to ensure these patients have access to appropriate diagnostic and interventional services in a timely fashion.

References

Gossink FT, Dols A, Kerssens CJ, Krudop WA, Kerklaan BJ, Scheltens P, et al. Psychiatric diagnoses underlying the phenocopy syndrome of behavioural variant frontotemporal dementia. Journal of neurology, neurosurgery, and psychiatry. 2015.

Piguet O, Hornberger M, Mioshi E, Hodges JR. Behavioural-variant frontotemporal dementia: diagnosis, clinical staging, and management. The Lancet Neurology. 2011;10:162-72.

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