Clinical staging and disease progression in frontotempo...

Clinical staging and disease progression in frontotemporal dementia

OBJECTIVE:

We aimed to develop a novel tool capable of staging disease severity in frontotemporal dementia (FTD) based upon functional dependence and behavioral changes, and to assess change over time in the 3 main FTD variants (behavioral variant FTD [bvFTD]; progressive nonfluent aphasia [PNFA]; and semantic dementia [SemD]).

METHODS:

The Frontotemporal Dementia Rating Scale (FRS) was developed in a validation cohort of 77 consecutive clinic attendees (bvFTD = 29; PNFA = 20; SemD = 28) and applied to an independent sample of 75 patients (bvFTD = 28; PNFA = 21; SemD = 26) to establish intergroup differences. Assessments from 42 patients followed up after 12 months were used to determine annual progression. Finally, a combined sample (n = 152) was used to determine length of symptoms in each severity category.

RESULTS:

Six severity stages were identified and operationalized based upon a 30-item questionnaire (very mild to profound). The cross-sectional study revealed much greater levels of impairment in bvFTD than in the language variants, with limited correlation with general cognitive measures. Patients with SemD showed the closest association between length of symptoms and stage, taking, on average, 10 years to reach the severe stage. Patients with bvFTD appear to move most quickly between stages and patients with PNFA were intermediate. The FRS was capable of detecting functional deterioration in all 3 variants over 12 months.

CONCLUSIONS:

Disease progression differs across frontotemporal dementia (FTD) variants. Patients with behavioral variant FTD progress rapidly whereas those with semantic dementia progress more slowly. The Frontotemporal Dementia Rating Scale can aid in staging and determining disease progression. Length of symptoms and global cognitive assessments alone do not reflect disease severity and progression in FTD.


Mioshi E, Hsieh S, Savage S, Hornberger M, Hodges JR. Clinical staging and disease progression in frontotemporal dementia. Neurology. 2010 May 18;74(20):1591-7.


Frontotemporal dementia (FTD) refers to 3 distinctive clinical syndromes with heterogeneous
neuropathology: behavioral variant FTD (bvFTD), semantic dementia (SemD), and progres-
sive nonfluent aphasia (PNFA).1 bvFTD patients present with marked change in personality
and social conduct,2 whereas symptoms in SemD and PNFA remain language related, at least
initially.3-6 Recent studies have established that FTD impacts considerably on everyday activi-
ties, which cannot be attributed to language deficits even in those with SemD and PNFA.7
These changes in behavior, language, and functional abilities lead to progressive disability7-10
and, consequently, high levels of stress and burden on carers.11-13

There is no consistent method of deter-
mining disease stage or severity in FTD. Cli-
nicians may use a combination of cognitive, behavioral, imaging, and activities of daily liv-
ing (ADL)–based data. To complicate mat-
ters, patients with FTD present at different
stages in terms of severity of dementia but
these stages have not been well-defined to
date. Moreover, no tool has yet been devel-
oped that is capable of delineating the stages
of FTD severity, or its rate of disease progres-
sion. The majority of the FTD studies have
relied on Alzheimer disease (AD) staging
tools,9,14,15 such as the Clinical Dementia Rat-
ing Scale (CDR).16 An adapted CDR (FTLD-
modified CDR) was recently developed for
use in clinical trials,17 and showed superior
ability to the standard CDR. The modified
CDR, however, did not detect differences be-
tween FTD subgroups, or rates of progression
in each variant.

The objectives of this study were to 1)
identify stages or levels of dementia across the
3 main clinical variants of FTD using a novel
staging tool, the Frontotemporal Dementia
Rating Scale (FRS); 2) identify annual rate of
decline in the FRS; and 3) investigate the rela-
tionship between length of symptoms and
FRS stages.


METHODS

Patient criteria. Patients were included if they
1) fulfilled criteria for FTD1; 2) had an informant who could
give a reliable account of the patient’s routine; 3) had no physical
disability that could confound assessment of activities of daily
living; 4) had absence of major depression as assessed by a psy-
chiatrist; and 5) had undergone an Addenbrooke’s Cognitive
Examination Revised (ACE-R)18 and a CDR16 within 60 days of
the functional assessment (patients were included irrespective of
ACE-R scores). All patients underwent MRI scan and were ex-
cluded if they had evidence of significant cerebrovascular disease
(infarcts or confluent white matter change). Cognitive testing
was given by a senior research nurse or a research assistant. All
patients were assessed by an experienced research occupational
therapist (E.M.) and a senior behavioral neurologist (J.R.H.) at
the research clinics in Cambridge or Sydney. Diagnoses were
made on the basis of a multidisciplinary consensus (neurologist,
neuropsychiatrist, and neuropsychologist), and measures de-
scribed here were not included in the diagnostic process. Patients
with clinical symptoms of bvFTD but without brain atrophy or
progression, so called phenocopy cases, were also excluded.19-21
Duration of disease was estimated by onset of symptoms as re-
ported by the informant at the time of diagnosis. Note that in
Cambridge and Sydney we have used the general label FTD to
encompass all variants described above (bvFTD, SemD, PNFA),
rather than frontotemporal lobar degeneration (FTLD).4,22-23

An initial cohort of 77 patients with FTD was used to de-
velop the FRS, as shown in figure 1 (sample 1). For this analysis
the ratings on each FRS question were based on existent data
from the Cambridge Behavioral Inventory (CBI)24 and the Dis-
ability Assessment for Dementia (DAD).25 An independent sam-
ple of 75 patients with FTD (sample 2: bvFTD28; SemD26;
PNFA21) were included in the analysis. For the analysis
of annual change, we used a subgroup of 42 patients with base-
line and 1-year follow-up assessments (sample 3). Sample 2 and
3 caregivers were interviewed by an occupational therapist
(E.M.) or neurologist (J.R.H.) who administered the FRS. Fi-
nally, to investigate the impact of the length of symptoms on
FRS staging, we combined 2 sets of data: the sample that vali-
dated the scale (n=77) and the sample mentioned above (n
75), resulting in 152 patient assessments (sample 4).

Controls. Twenty age-matched controls (10 male and 10 fe-
male) were recruited at the MRC Cognition and Brain Science
Unit, Cambridge, UK (table 1).

Instruments. FRS. A total of 77 patients with FTD were in-
cluded (sample 1: bvFTD=29; SemD=28; PNFA=20), following the
same inclusion criteria reported in Methods. The
77 patients represented a consecutive sample assessed in Cam-
bridge. Patients were matched for age and length of disease (table
e-1 on the Neurology® Web site at www.neurology.org). We in-
tended to create a staging scale specific for FTD, capable of char-
acterizing disease severity and nuances of change with disease,
avoiding the floor effects inherent in standard cognitive tests.
These can be misleading in moderate patients, especially those
with language problems.

A total of 75 questions were initially identified from the CBI
and DAD,25 which had previously been shown to capture the
behavioral changes and impairment in ADLs that characterize
FTD syndromes.7,24 Rasch modeling26 was applied to the set of
75 questions in 77 patients (sample 1). Rasch analysis converts
ordinal raw data to interval measures, placing questions and pa-
tients along the same hierarchy.27,28 In other words, Rasch analy-
sis ranks patients according to their level of ability (from able to
disabled), while examining the hierarchy of questions according
to their level of complexity (from difficult to easy). In this way it
identifies which questions best describe patient capacity based on
the whole sample, eliminating those questions that do not cap-
ture the sample characteristics as a continuum.

The Rasch analysis was conducted iteratively until the initial
75 items were reduced to a smaller set that would demonstrate
construct validity, unidimensionality, and good internal reliabil-
ity. To verify construct validity, items were excluded if they
failed to fit recommended limits of infit and outfit values
(MNSQ=0.60 to 1.49 and Z=2 to 2).

The resulting scale comprises 30 questions. Mean infit statis-
tics (M=1.01; Z=0.0, SD±0.8) and outfit statistics (M=0.94; Z
0.0, SD±0.7) confirmed that, overall, this choice of
items produced a smooth continuum without outliers.27

To verify unidimensionality, which is a trait that assures that
the scale is measuring one construct only, in this case disease
severity, a principal component analysis (PCA) of the residuals
was performed. This produced good Eigen values for the 5 con-
trasts (1.8–3.5). The raw variance explained was 46.4%, which
was very close to the desired 50%.27 Further comparison of posi-
tive and negative loaded variables confirmed the unidimension-
ality of the scale.

Test consistency was 0.93, almost reaching the desirable
Cronbach α=0.95.29 The item separation index of the scale was
3.68, which was close to the desired level of 3.0.28 Interrater test
reliability was conducted on a subsample of 23 patients, whose
FRSs were scored by 4 independent raters (94 ratings). The in-
traclass reliability coefficient was 0.994 (absolute agreement),
with figures closer to 1 demonstrating high agreement.

In the resultant scale, a score of 30 denotes full functional
ability and no behavior change, whereas lower scores denote de-
cline in everyday abilities and marked behavior change. Item
difficulty is shown in figure e-1. Item difficulty was defined by
logit values, with higher logit values representing more difficult
items.

Once a score is obtained, it has to be converted to a percent-
age (raw score/number of applicable questions). This step avoids
gender or cultural bias, respecting a patient’s premorbid abilities
(e.g., no points are lost if the person has never managed finances
or if cooking was not part of his or her routine prior to disease
onset). This percentage score is then checked against a logit ta-
ble, where a logit score is obtained. This step aids in spreading
the patients across the different severity categories. Logit scores
were subdivided into 6 equal categories to facilitate clinical inter-
pretation: very mild (4.12), mild (4.11 to 1.92), moderate
(1.91 to 0.40), severe (0.39 to 2.58), very severe (2.57
to 4.99), and profound (below 4.99). Higher scores on the
FRS denote higher functioning.

The FRS is available for free download via the Frontier Web
site (http://www.ftdrg.org).

ACE-R. The ACE-R assesses 5 cognitive domains: attention/
orientation, memory, verbal fluency, and language and visuospa-
tial abilities. The total score is 100; higher scores reflect better
ability. The ACE-R was designed to be sensitive to early stages of
dementia, and incorporates the MMSE. Not all patients could
perform an ACE-R due to disease severity (n=56).

CDR. The CDR16 is a clinical staging instrument of demen-
tia that combines 6 domains of cognitive and functional perfor-
mance: memory, orientation, judgment and problem solving,
community affairs, home and hobbies, and personal care. An
algorithm allows the calculation of a total score; a score of zero
reflects no dementia and higher scores denote greater impair-
ment. Not all patients had a CDR administered (n=53).

Standard protocol approvals, registrations, and patient
consents. The study was approved by the Addenbrooke’s Hos-
pital Ethics Committee in Cambridge and the South Eastern
Sydney/Illawara Area Health Service in Sydney. Patient or family
consent was obtained from each participant.

Statistical analysis. Data were analyzed using SPSS 17.0
(SPSS Inc., Chicago, IL). A priori, variables were plotted and
checked for normal distribution by Kolmogorov-Smirnov tests.
Parametric demographic data (age, education), as well as scores
on the FRS, were compared via one-way analyses of variance
(ANOVA), followed by Tukey HSD post hoc tests. Correlations
between the FRS, cognitive assessments, CDR, and length of
symptoms were done via Spearman correlation because ACE-R
and MMSE scores were not normally distributed for PNFA and
bvFTD. Change on FRS scores was analyzed using t tests.


RESULTS

Profiles of FTD variants on the FRS. Data
from 75 patients with FTD were used to compare
profiles across clinical variants (bvFTD=28;
SemD=26; PNFA=21). As shown in the table 1, the
patient groups were well-matched for age and
length of disease.

Profiles of impairment according to logit scores
are shown in figure 2A. A one-way ANOVA identi-
fied a group effect (F=12.509, df=74, p=0.001)
and post hoc tests revealed that the bvFTD group
scored lower than the SemD (p=0.001) and PNFA
groups (p=0.05), with no difference between the 2
language variants. For controls, mean logit staging
score was 5.07 (SD±0.56).

We also examined the groups according to their
distribution of severity scores.

As shown in figure 3A, virtually all patients with
bvFTD fell within the moderate, severe, very severe,
or profound categories, whereas for the PNFA and
SemD groups 25% fell within the mild category, and
none were very severe or profound. The proportion
of patients with PNFA in the severe category was
about double in comparison to patients with SemD.

The FRS and cognitive measures, CDR, and length of
symptoms. There was a correlation between the FRS
and MMSE for bvFTD (r=0.482; p=0.05) and
PNFA (r=0.675; p=0.05) groups. The PNFA
group also showed a correlation between the FRS
and ACE-R (r=0.695; p=0.05).

To verify concurrent validity, we compared FRS
and CDR scores. There was an overall negative asso-
ciation between the FRS and the CDR (r=0.713, p=0.001).
Figure 3B compares performance on the
FRS and CDR. Interestingly, a proportion of pa-
tients with minimal or mild dementia on the CDR
(0.5 or 1) had moderate or even severe ratings on the
FRS.

In terms of disease progression and length of
symptoms, only patients with SemD showed a corre-
lation (r=0.556; p=0.03).

Nature of disease staging and progression. As in AD,
overall FTD affects complex ADLs (instrumental
ADLs) initially, with changes in basic ADLs later in
the course of the disease. Table e-2 outlines the basic
and instrumental ADL loss and changes in behavior
at the various stages of FTD.

Length of symptoms in each severity category. To an-
alyze the relationship between length of symptoms
and staging, we combined the FRS assessments from
the initial cohort (sample 1: n=77) and the second
cohort (sample 2: n=75), resulting in a total of 152
assessments (sample 4). As shown in figure 4, the
SemD group showed the clearest relationship be-
tween length of symptoms and severity categories,
whereas the bvFTD and PNFA groups showed
greater variability.

Since none of the patients with language variants
were beyond severe, we have considered the time be-
tween symptom onset and reaching mild, moderate,
and severe across the variants. It can be seen from
figure 4 that for bvFTD the time to reach mild, mod-
erate, and severe stages was very similar, and that by 5
years the vast majority have severe impairment. By
contrast, progression in SemD appears much slower,
taking on average 10 years to reach the severe stage.
PNFA was somewhat intermediate, with an average
around 3 years between mild, moderate, and severe
stages.

Rate of decline. Twelve-month follow-up data were
available for 42 patients (sample 3: bvFTD=17;
SemD=15; PNFA=10). Mean follow-up time
was 13.1 months (6–27 months). All subgroups
showed marked decline on the FRS (p=0.005 for
all), which was greater for the bvFTD group (fig-
ure 2B).


DISCUSSION

We were able to identify 6 clinical
severity stages in FTD, and to characterize the fea-
tures of each stage based on a novel instrument, the
FRS. These behavioral and functional changes were
identified using Rasch modeling. The bvFTD group
were the most severely impaired and showed the
most rapid progression through the stages.

This study confirms the devastating nature of
bvFTD, which produces greater functional loss and
behavioral change than SemD and PNFA, even after
controlling for length of symptoms.7-9 Patients with
SemD were the least impaired, with 70% of patients
within very mild, mild, and moderate stages, al-
though a recent study using different measures found
PNFA to be the least impaired FTD variant.17 Our
results showed that the functional level of the PNFA
group was intermediate between bvFTD and SemD,
perhaps in line with the pathologic heterogeneity5,30;
those presenting with lower scores may have underly-
ing AD pathology.31 It is notable that half of the
patients with PNFA fell in the severely impaired
stage, which strengthens the case to use an ADL and
behavioral scale. The reasons for this marked decline
are unclear: one plausible explanation is the develop-
ment of apraxia, which is common in PNFA32 and
likely to impact everyday life.33,34 A proportion of
patients with PNFA develop full-blown corticobasal
syndrome as the disease progresses.5,32 The severity
level of the PNFA group highlights the disabling na-
ture of this variant, and that patients with PNFA
have more general cognitive impairment than is
commonly recognized.

Determining disease severity is controversial.
There is currently a lack of consensus in how to de-
fine severity in dementia—different studies use cog-
nitive measures, length of disease, or even AD staging
tools.9,14,15,17 Our study shows that severity can be
measured using a unidimensional tool, which ap-
pears to characterize FTD well as a condition that
ultimately causes loss of ability and changes in behav-
ior. In addition, the FRS provided further under-
standing of disease progression in FTD by showing
which abilities are lost first and last, without the lim-
itation of cognitive assessments that are language
driven.

The FRS also demonstrated statistically signifi-
cant decline over a 12-month period in all 3 clinical
variants. Longitudinal studies are few in FTD, and
have reached varied conclusions especially in terms of
survival. One study showed that patients with
bvFTD declined faster than those with AD, but the
SemD group did not differ from AD.35 Another
study showed a similar rate of deterioration in both
bvFTD and AD.36 The slow progression in SemD is
in keeping with the prolonged survival shown in a
consecutive series of 100 patients from Cambridge.37

The lack of consistent correlation between the
FRS and cognitive measures is of interest. It shows
that our staging tool is not biased toward language
abilities. For instance, several patients were mute but
still high-functioning and independent, and there-
fore obtained scores within the mild stage. More im-
portantly, it highlights the relevance of a staging tool
that focuses on functional decline, which, as shown
in AD studies, can be very sensitive to change in drug
trials.38,39 In addition, the detailed clinical informa-
tion provided by the FRS can guide families and cli-
nicians in making important practical decisions in
financial, legal, and long-term care issues.

There was, as expected, a negative association be-
tween the CDR and FRS in that advanced stages on
the FRS correlated with worsening dementia on the
CDR. More interestingly, it appears that the CDR
underrates disease severity since a proportion of pa-
tients rated as having minimal or mild dementia
(CDR=0.5 or 1.0) had moderate or severe levels of
disability as rated by the FRS. There was an overall
trend for length of symptoms to correlate with sever-
ity levels on the FRS: most patients with long
disease history fall into the severe categories. Con-
versely, however, not everyone within these catego-
ries had a long disease history. This is especially true
for patients with bvFTD, who may be at a moderate
stage early in the disease. Moreover, this finding
demonstrates that length of symptoms does not nec-
essarily reflect dementia severity in FTD, and should
be used with caution when matching different de-
mentia groups.

Our study had certain limitations. We did not
have pathologic confirmation of the patients as-
sessed, which would clearly take a number of years,
but prior studies have demonstrated that the major-
ity of patients with bvFTD and SemD have pat-
hology within the FTLD spectrum although a
proportion of those with PNFA have Alzheimer pa-
thology.31 In addition, a longer follow-up period
would provide even more detailed information on
disease staging and progression. We have established
excellent interrater reliability but retest data should
ideally be collected to verify test stability.

This is the first study to describe the specific as-
pects of disease staging in the variants of FTD. The
loss of these abilities can be captured in the FRS, a
novel staging tool, which in turn can guide clinicians
in determining disease severity and in making prog-
nosis for patients and families.


AUTHOR CONTRIBUTIONS

Statistical analysis was conducted by Dr. E. Mioshi.


ACKNOWLEDGMENT

The authors thank Lindy Clemson (Occupational Therapy Faculty of
Health Sciences, Sydney University) and Mike Linacre (Winsteps.com)
for their advice on Rasch analysis, and Kate Dawson (Department of
Clinical Neurosciences, University of Cambridge) and Hilary Green
(MRC Cognition and Brain Sciences Unit, Cambridge) for administering
cognitive assessments.


DISCLOSURE

Dr. Mioshi serves on the editorial board of Dementia and Geriatric Cogni-
tive Disorders. Dr. Hsieh, Dr. Savage, and Dr. Hornberger report no dis-
closures. Dr. Hodges serves on editorial boards of Aphasiology, Cognitive
Neuropsychiatry, and Cognitive Neuropsychology; receives royalties from
publication of Cognitive Assessment for Clinicians (Oxford University
Press, 2007) and Frontotemporal Dementia Syndromes (Cambridge Uni-
versity Press, 2007); and receives fellowship support from the Australian
Research Council Federation.
Received September 15, 2009. Accepted in final form February 3, 2010.


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