Nonprogressive behavioural frontotemporal dementia: recent developments and clinical implications of the 'bvFTD phenocopy syndrome'

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PURPOSE OF REVIEW:

The clinical features of behavioural variant frontotemporal dementia (bvFTD) are well established; however, recent work has identified patients fulfilling diagnostic criteria for the disease who do not appear to progress clinically. This review describes means of distinguishing this group at an early stage from patients who are likely to deteriorate.

RECENT FINDINGS:

Despite indistinguishable clinical profiles, studies in a cohort of bvFTD patients showed a particularly good prognosis in a subgroup of predominantly male patients in whom initial structural imaging was normal. This could not be explained by differences in disease duration, and was confirmed by subsequent PET studies. Retrospective review of clinical data in these groups verified that the current clinical diagnostic criteria are both insensitive to true progressive bvFTD, particularly in the early stages, and also poorly specific. In contrast, measures of activity of daily living performance, executive function and tests of social cognition appear to have better discriminatory value for patients who show clear clinical progression, with many individual diagnoses verified by post mortem examination in this group.

SUMMARY:

It remains doubtful that the nonprogressive group have a neurodegenerative disease. The implication for the current clinical diagnostic criteria and their proposed revision is discussed.


Kipps CM, Hodges JR, Hornberger M. Nonprogressive behavioural frontotemporal dementia: recent developments and clinical implications of the 'bvFTD phenocopy syndrome'. Curr Opin Neurol. 2010 Dec;23(6):628-32.


Introduction

Behavioural variant frontotemporal dementia (bvFTD) is
the most common presentation of frontotemporal demen-
tia (FTD) [1,2]. Patients usually present with changes in
behaviour and personality, including alterations of mood, motivation and inhibition, which are recognized in the
current diagnostic criteria [3] (Table 1). These clinical
diagnostic criteria have, in the past, been shown to
reliably detect and discriminate bvFTD from other
dementias [4]; however, they have never been prospec-
tively validated. Recent studies [5,6] have also ques-
tioned whether there are patients who fulfill the bvFTD
diagnostic criteria without an underlying neurodegenera-
tive condition. Such patients are considered to have a
bvFTD ‘phenocopy syndrome’, manifesting character-
istic behavioural features without actively progressing to
frank dementia. This raises concern that application of
the current clinical criteria (or their revision) may identify
patients without a neurodegenerative disorder. In the
following article we will review recent evidence for the
bvFTD phenocopy syndrome, highlight the diagnostic
challenges for clinicians, recommend diagnostic steps
and discuss the implications for the clinical diagnostic
criteria of bvFTD.

Phenocopy syndrome

Researchers at the Cambridge Dementia Group became
aware of a group of bvFTD patients in whom there did
not appear to be disease progression following clinical
diagnosis despite a clear history from caregivers of initial
personality and behavioural changes. Using a visual scale
to rate the degree of atrophy in frontal and temporal
lobes, it became clear that there was a distinct lack of
frontotemporal atrophy on structural imaging in many of
those patients [6]. Crucially, imaging changes are not
currently mandatory for definite bvFTD diagnosis. More
importantly, Kipps and colleagues [6] noted that other
frontotemporal syndromes (particularly semantic demen-
tia, but also progressive nonfluent aphasia), invariably
showed significant atrophy by the time of diagnosis. By
contrast, over half of the bvFTD patients had scans that
overlapped with the control range (0–1) (see Fig. 1).

Moreover, a retrospective survival analysis of a bvFTD
cohort [5] showed that those patients with abnormal scans
were largely dead or institutionalized within 3 years, in
line with median survival time in pathologically proven
cases of bvFTD [7 ]. However, patients with scan ratings
in the control range had a significantly better disease
prognosis, with some patients surviving for 10 years or
longer. Importantly, disease duration was controlled for
between both groups and therefore was unlikely to
contribute to the findings. To our knowledge, there
are no pathologically verified studies of such bvFTD
phenocopy cases; however, two cases from the
Cambridge sample have since come to autopsy and did
not show frontotemporal lobar degeneration (FTLD)
specific pathology. In addition, two single cases diag-
nosed clinically as bvFTD, but lacking pathological
changes at post mortem, have been reported as asides
in other studies [8,9] highlighting again the importance of
detecting such phenocopy cases at a clinical level.

Clinical features

Nonprogressive bvFTD cases are a concern as they
mimic the clinical characteristics of frank bvFTD. A
study by Hornberger and colleagues [10 ] investigated
whether the diagnostic criteria for the Cambridge
bvFTD patients were inappropriately applied, or
whether the clinical diagnosis in the nonprogressive
group of patients was insufficiently rigorous. The entire
bvFTD cohort of the Cambridge Dementia Group was
assessed retrospectively [10 ], including 71 patients in
whom follow-up information was available for at least 3
years to be certain of the disease progression. Impor-
tantly, clinical features at presentation were extracted
blind to knowledge about imaging and subsequent out-
come. Characteristics defined by the consensus criteria,
those from earlier lists of diagnostic formulations, and a
number of frontal behavioural characteristics derived
from behavioural rating scales were noted. Of these
patients, 32 had died, and 18 of these had post mortem
data which confirmed the clinical diagnosis. The results
confirmed the inability of the clinical diagnostic criteria to
separate progressive cases from those that remained
stable after clinic presentation. More specifically, pro-
gressive bvFTD and phenocopy cases were virtually
identical on the core bvFTD diagnostic criteria and
only showed significant differences for a few supportive
diagnostic features [distractibility, stereotypic speech,
impaired activities of daily living (ADLs) and current
depression].

Carer and functional information

One factor which is likely to have influenced the identical
behavioural presentation in both groups is the lack of
insight many bvFTD patients show. Clinicians need to
rely heavily on information provided by carers to corro-
borate symptoms, and in few other diseases is the clin-
ician so dependent on the carer in reaching a diagnosis. In
the studies mentioned above, behavioural symptoms
reported by carers, and rated using behavioural inven-
tories such as the Cambridge Behavioural Inventory and
Neuropsychiatric Inventory, were indistinguishable in
real and phenocopy bvFTD patients [11 ], with all
caregivers being adamant that there had been both a
distinct change in behaviour, and progression over time.

By contrast, functional assessments of ADLs show differ-
ential performance in phenocopy and bvFTD cases.
Mioshi et al. [12] showed that a detailed assessment of
ADLs was effective at identifying those patients in whom
performance was truly compromised; this group over-
whelmingly comprised patients from the progressive
bvFTD patient group. In a follow-up study [13 ], it
was shown that only bvFTD patients with significantly
impaired ADLs decline functionally over a 12-month
period, whereas phenocopy patients do not deteriorate
functionally over the same time frame.

Neuroimaging

In addition to the sensitivity of visual scan ratings,
functional imaging studies have shown excellent
discrimination of phenocopy and real bvFTD cases. An
18-FDG-PET study to measure regional metabolic rates
in frontotemporal regions was conducted in two apparent
bvFTD patients in whom detailed longitudinal neuro-
psychological assessments were available [14]. Despite
both having a clinical history entirely compatible with
bvFTD, and neuropsychological assessment that was
in keeping with the diagnosis at presentation, one
patient had marked hypometabolism and deteriorated,
whilst the other, whose PET scan showed no changes,
remained clinically stable. A subsequent group study was
performed in a much larger cohort, and with few excep-
tions, only those patients with MRI changes had con-
cordant hypometabolism on their PET scans [11 ].

Neuropsychology and social cognition

Sophisticated imaging modalities such as PET and MRI
are not always readily available, and although patients
with bvFTD often end up in specialist dementia clinics,
diagnosis may be delayed, or confused with psychiatric
syndromes [15]. Neuropsychological assessments are
often performed as a means of establishing whether a
neurodegenerative process is occurring or not. In particu-
lar, executive function performance in phenocopy and
real bvFTD patients has provided useful insights into
which tests are most useful in diagnosing each group at
clinic presentation.

In a retrospective study of executive tests, phenocopies
performed at control levels, whereas real bvFTD patients
were usually impaired [16]. In particular, the Verbal
(letter) Fluency task, Digit Span Backwards, the Hayling
test of Inhibition and the Trail making Test Part B
(Trails B) were good discriminators [16], with Hayling
and Digit Span Backwards alone correctly classifying 85%
of patients at first clinic presentation. Global cognitive
screening measures such as the Addenbrooke’s Cognitive
Examination (ACE-R) [17] were also capable of monitor-
ing cognitive decline, with 10–12 points expected loss
per annum on this scale in progressors, compared with
comparative stability in those patients with normal ima-
ging [18]. On a cautionary note, up to 25% of patients
shown to subsequently progress had normal neuropsy-
chology at clinic presentation [16], implying that normal
neuropsychological performance is not a reliable exclu-
sion criterion for the disease and that such measures
should be corroborated by imaging or ADL performance
when possible.

Interestingly, the admixture of phenocopy and real
bvFTD patients might have contributed to earlier contra-
dictory neuropsychology findings in bvFTD as the ratio
of each group in a study would have the potential to affect
the outcome. This might explain the previously mixed
results in executive functioning in bvFTD, and was
recently proposed as an explanation for the variability
of reported memory problems at presentation in bvFTD.
For example, a study by Hornberger and colleagues [19 ]
showed that real bvFTD patients were impaired to a
similar degree as Alzheimer disease patients on episodic
memory tests, whereas phenocopies showed near normal
performance.

Measurement of performance on tasks assessing social
dysfunction has provided a further means for discrimi-
nating both patient groups at presentation. Patients with
bvFTD have well-documented impairment of their abil-
ity to interpret emotion in others – they lack empathy, and
have defective ability to represent the mental states
of others (Theory of Mind) [20,21]. A behavioural study
looking at emotion and sarcasm interpretation showed
that there was particularly impaired negative emotion
recognition in those bvFTD patients who had imaging
changes [22 ]. Similarly, sarcasm interpretation, requiring
mental state attribution and the interpretation of emotion
signals, showed that bvFTD patients with imaging
changes on MRI and PET performed badly on this
measure as well [22 ]. It is not clear at this stage whether
such social cognition tests can be applied in everyday
clinical practice, as normative age-related data are not
available for most tests, however social cognition assess-
ment seems a promising avenue for future bvFTD diag-
nostic assessment.

Clinical diagnosis

On a purely practical level, how should the above phe-
nocopy evidence guide or influence clinical diagnostic
practice? Since these patients have not yet come to post
mortem in convincing numbers, we cannot state with
certainty that there is no neurodegenerative process
occurring. However, it would seem unlikely in view of
the normal imaging many years after symptoms onset; the
lack of clinical progression when under medical review;
and near-normal neuropsychological and ADL perform-
ance. Identification on clinical characteristics alone is
problematic, and should be supported by the results of
executive function tests, ADL assessment and concor-
dant imaging changes in the frontal and/or temporal lobes
(see Fig. 2). In those bvFTD patients with globally
abnormal executive function and impaired ADLs as well
as clear imaging evidence, the diagnosis is likely to be a
pathological form of bvFTD. In patients who do not show
impairment in these domains, despite a convincing set of
other clinical criteria, one should maintain a strong degree
of caution if the imaging findings are normal (see Fig. 2).
In these patients, it would be sensible to carefully re-visit
the history and attempt to corroborate it independently.
Where doubt remains, a period of monitoring without
confirming a degenerative process seems sensible, fol-
lowed by re-examination of executive function and ima-
ging measures to verify disease progression after an
interval of at least 12 months.

Implications for bvFTD diagnostic criteria

The studies reported above have important implications
for the current diagnostic criteria and their recently
proposed revision [23]. As mentioned earlier, the current
criteria do not reliably distinguish real bvFTD and phe-
nocopy patients [10 ], with limitations of both sensitivity
and specificity [3]. Importantly, they also miss the most
salient features in real bvFTD patients. In a study by
Piguet and Hornberger [24 ], it was shown that of 45
bvFTD patients for whom there was clear clinical pro-
gression and imaging evidence of frontotemporal dys-
function or atrophy, only half exhibited all five core
diagnostic criteria needed for diagnosis at presentation,
with some patients never showing some of the core
criteria over the entire disease history. Of the supportive
features, only impaired executive function, hyperorality,
mental inflexibility and distractibility were present in
over half the patients at presentation.

New diagnostic bvFTD criteria have been proposed (see
Table 2) [23] and are in the process of being validated
across multiple sites worldwide. These criteria incor-
porate levels of clinical certainty into the diagnosis
(possible, probably, definite) and more rigorously define
the nature of the included clinical characteristics. Work
is still ongoing as to how many criteria are needed for
diagnosis, but both imaging findings and neuropsycho-
logical performance on executive tests will have more
weight in the diagnosis. Tests of social cognition and
assessment of ADLs, however, are not included in the
revision.

___
Table 2 Revised diagnostic criteria [23] for behavioural variant frontotemporal dementia; currently under validation

Possible bvFTD
- Shows progressive deterioration of behaviour and/or cognition by observation or history
- Early (3 years) behavioral disinhibition
- Early (3 years) apathy or inertia
- Early (3 years) loss of sympathy and empathy
- Early (3 years) perseverative, stereotyped or compulsive/ritualistic behavior
- Hyperorality and dietary changes
- Neuropsychological profile: executive/generation deficits with relative sparing of memory and
visuospatial functions

Probable bvFTD
- Meets criteria for possible bvFTD
- Exhibits significant functional decline
- Imaging results consistent with bvFTD

bvFTD with definite FTLD disorder
- Meets criteria for possible or probable bvFTD
- Histopathological evidence of FTLD on biopsy or at post mortem
- Presence of a known pathogenic mutation

bvFTD, behavioural variant frontotemporal dementia.
___


Conclusion

The underlying explanation for the phenocopy cases
remains unclear, but is quite likely to be heterogeneous.
At this point, very few phenocopy cases have come to post
mortem, and none of those that have died appear to have
evidence of FTLD neuropathology. In view of the appar-
ent normal life expectancy of these patients, it may be
some time before there is a full understanding of the
pathological basis of their disorder. Many of the features
of FTD overlap with those seen in neuropsychiatric con-
ditions, and it is likely that a number of the phenocopy
cases have decompensated personality disorders, or autism
spectrum disorders such as Asperger’s syndrome manifest
at a level below the threshold for formal psychiatric diag-
nosis. In the absence of biological markers for these
conditions, this is, however, difficult to prove.

More importantly, the evidence for such phenocopy
patients has influenced both the sensitivity and speci-
ficity of the clinical diagnosis of bvFTD, which is
reflected in the revised diagnostic criteria. On a clinical
level, clinicians can be reasonably confident that patients
who display a bvFTD-like syndrome with normal ima-
ging and neuropsychological profile have a low risk of
progression and good life expectancy. This is vitally
important prognostic information for both patients and
carers.

Acknowledgements
JRH is currently supported by an Australian Research Council
Federation Fellowship (FF0776229).


References and recommended reading

Papers of particular interest, published within the annual period of review, have
been highlighted as:
of special interest
of outstanding interest

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19
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Kipps CM, Nestor PJ, Acosta-Cabronero J, et al. Understanding social
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This study looked at emotion and sarcasm performance in bvFTD and phenocopy
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