Alzheimer Disease and Frontotemporal Dementias

Behavioral Distinctions
Morgan L. Levy, MD; Bruce L. Miller, MD; Jeffrey L. Cummings, MD; Lynn A. Fairbanks, PhD; Anne Craig, MD

Background: Frontotemporal dementia (FTD) is a syn-
degeneration of the temporal
drome produced by lobar
and/or frontal lobes.
Objectives: To quantify the behavioral disturbances
of FTD and compare them with behavioral changes
observed in Alzheimer disease (AD).
Design: Cross-sectional comparison of 2 groups de-
fined by research diagnostic criteria and single photon emis-
sion computed tomography. Behaviors were assessed us-
ing a standardized rating scale\p=m-\Neuropsychiatric
Inventory. Groups were matched for dementia severity.
Setting: Patients were seen at 2 university-based outpatient
dementia clinics and a Veterans Affairs medical center.
Participants: Twenty-two patients with FTD and 30
patients with AD.
Results: Patients with FTD had significantly greater to-
tal Neuropsychiatric Inventory scores than patients with
AD and exhibited more apathy, disinhibition, euphoria,
and aberrant motor behavior. The Neuropsychiatric In-
ventory accurately assigned 77% of patients with FTD
and 77% of patients with AD to the correct diagnostic
group using disinhibition, apathy, and depression. Pa-
tients with FTD had higher levels of disinhibition and
apathy with relatively lower levels of depression com-
pared with patients with AD.
Conclusions: The Neuropsychiatric Inventory pro-
vides a behavioral profile that differentiates patients
with FTD from patients with AD. Patients with FTD are
more behaviorally disturbed but are often less
depressed than patients with AD relative to their level
of apathy.
Arch Neurol. 1996;53:687-690

From the Departments of
Psychiatry and Biobehavioral
Sciences (Drs Levy,
Cummings, and Fairbanks)
and Neurology
(Dr Cummings), University of
California at Los Angeles
School of Medicine, West Los
Angeles Veterans Affairs
Medical Center Psychiatry
Service (Drs Levy, Cummings,
and Craig), and Department of
Neurology, Harbor-University
of California at Los Angeles
Medical Center (Dr Miller),
Los Angeles, Calif.
Arnold
Pick1 in 1892, de¬
scribed the first case of
dementia associated with
lobar atrophy. Pick disease
became synonymous with
frontotemporal dementia (FTD) until the re¬
cent recognition that several degenerative
disorders can produce selective frontotem¬
poral atrophy. Pick disease with classic Pick-
type histopathologic features, Pick disease
without Pick cells, amyotrophic lateral scle¬
rosis dementia, dementia lacking distinctive
histological features, and frontal lobe degen¬
eration ofnon-Alzheimer type are all names
used recently to describe degenerative dis¬
orders with selective frontal and temporal at¬
rophy. This group ofdisorders may be more
common than previously thought, compris¬
ing 10% to 15% of some autopsy series of
degenerative dementias.2
Many cases found at autopsy to have
FTD were misdiagnosed as Alzheimer dis¬
ease (AD) during life.3 The reasons for this
high rate of diagnostic inaccuracy in¬
clude the failure of computed tomogra-
phy or magnetic resonance imaging to
identify the localized atrophy of FTD and
the failure of clinical diagnostic criteria for
AD to distinguish the 2 disorders. Func¬
tional neuroimaging has been more suc¬
cessful in distinguishing FTD and AD; pa¬
tients with FTD have predominantly
anterior alterations, while those with AD
have more marked posterior changes.4"10
Differentiating FTD and AD has become
more imperative as therapies specifically
for AD emerge and FTD-specific treat¬
ments are sought. our study, we de¬
In
fined the 2 populations using research
criteria and single photon emission com¬
puted tomography (SPECT) and then
sought behavioral differences between
them using the Neuropsychiatrie Inven¬
tory (NPI) scale.11
See Subjects and Methods
on next
page

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SUBJECTS AND METHODS
All patients were referred for dementia assessment
to 1 of 2 university specialty clinics or to a memory
disorders clinic at a Veterans Affairs medical center.
Patients were screened for chronic mental illness, head
trauma, vascular dementia, extrapyramidal disor¬
ders, vitamin deficiency, hypothyroidism, syphilis,
and other medical conditions. Thirty patients re¬
ceived a clinical diagnosis of AD based on criteria es¬
tablished by the National Institute of Neurological
and Communicative Disorders and Stroke-
Alzheimer's Disease and Related Disorders Associa¬
tion. 12 There were 19 women and 11 men with a mean
age of 73.5 years (range, 54-85 years). Their mean
Mini-Mental State Examination (MMSE)13 score was
17.5 (SD, 7.0; range, 0-27). Seventeen patients re¬
ceived a clinical diagnosis of FTD based on criteria
developed by the Lund and Manchester Groups.H This
group included 6 women and 11 men with a mean
age of 65 years (range, 52-81 years). Their mean
MMSE score was 14.9 (SD, 9.2; range, 0-28). Every
patient underwent magnetic resonance imaging and
technetium Tc 99m hexamethyl propylenamine ox-
ime SPECT as part of their diagnostic assessment. All
patients included in the FTD group had predomi¬
nantly anterior cerebral hypoperfusion and all pa¬
tients with AD had predominantly posterior cere¬
bral hypoperfusion. Patients were included in the
study only if they met clinical diagnostic criteria and
had compatible SPECT findings for a diagnosis of
AD FTD.
or
Behavioral data collected
were during care¬
giver interviewsusing the NPI. This instrument
assesses 10 behaviors occurring in dementing
illnesses, including delusions, hallucinations, agita¬
tion, depression, anxiety, euphoria, apathy, disinhi¬
bition, irritability, and aberrant motor behavior (in¬
cluding pacing, rummaging, and compulsions). A
frequency rating (1-4) multiplied by a severity rat¬
ing (1-3) produces a subscale score for each behav¬
ior and the summation of subscale scores produces
the total NPI score. All interviews were performed
within 3 months of the diagnostic assessment and in
most cases they were done on the same day. The NPI
has been shown to be valid when compared with a
variety of other diagnostic approaches and to have
high interrater and test-retest reliability.11
We compared the mean total NPI scores and sub-
scale scores between the FTD and AD groups for each
behavior using t tests. In addition, a stepwise dis¬
criminative function analysis with an F to enter of
4.0 was performed to determine the degree to which
patients could be assigned to the correct diagnostic
group using the NPI subscale scores. Informed con¬
sent for all procedures was obtained from both pa¬
tients and caregivers.
RESULTS
Patients with FTD were significantly younger than pa¬
tients with AD. Patients with FTD had a mean age of 65
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years (SD, 8.1 years) compared with patients with AD
whose mean age was 73.5 years (SD, 8.4 years) (P<.001).
The MMSE scores were not significantly different be¬
tween the 2 groups (mean FTD MMSE score, 14.9 [SD,
9.9] and mean AD MMSE score, 17.5 [SD, 7.0], not sig¬
nificant). The total NPI scores were significantly differ¬
ent. Patients with FTD hadamean score of 23.2 (SD, 17.0)
compared with patients with AD who had a mean score
of 15.7 (SD, 11.6) (P<.05).
Comparing mean NPI subscale scores, patients with
FTD had significantly more disinhibition (t, 2.71; P=.01),
euphoria (t, 2.55; P<.05), apathy (t, 2.89; P-C01), and
aberrant motor behavior (t, 2.04; P<.05) than patients
with AD (Figure 1 ). There were no statistically signifi¬
cant differences between 6 of the 10 mean subscale scores
including delusions, hallucinations, agitation, depres¬
sion, anxiety, and irritability.
Contrasting the percentage of patients with spe¬
cificbehaviors, we found differences between FTD and
AD (Figure 2). Disinhibition and euphoria were much
more common in patients with FTD (68% and 36%)
than in patients with AD (23% and 7%) (P<.01 for
both). Apathy was common in both groups but was
more common in patients with FTD (95%) than in
patients with AD (80%), although this difference did
not reach statistical significance. Likewise, aberrant
motor behavior and anxiety occurred in both groups
but were more common in patients with FTD (73% and
59%) than in patients with AD (47% and 43%); these
differences also failed to reach statistical significance.
Delusions and hallucinations occurred in a larger per¬
centage of patients with AD (33% and 7%) than in
patients with FTD (23% and 0%), but the differences
were not statistically significant. Depression, irritability,
and agitation occurred in similar proportions in both
groups.
A stepwise discriminate function analysis was
performed to identify the subset of NPI behaviors that
best discriminated patients with FTD from patients
with AD. Disinhibition was the first variable to enter
the discriminate analysis (F to enter, 9.49; Wilks ,
0.84; canonical coefficient, 0.27), followed by apathy
(F to enter, 6.11; Wilks 1 , 0.75; canonical coefficient,
0.22). Euphoria and aberrant motor activity, which
were significantly different between groups when
assessed independently, were positively correlated
with the first 2 variables and did not add significantly
to the discrimination. A new variable, depression,
which did not appear in the independent analyses,
added significantly to the prediction of diagnostic
group once disinhibition and apathy had been taken
into account (F to enter, 5.92; Wilks , 0.67; canoni¬
cal coefficient, —0.38). Patients who had high-scale
scores for disinhibition and apathy and relatively low
scores for depression were members of the FTD group.
The final equation using these 3 variables accurately
assigned 77% of the patients with FTD and 77% of the
patients with AD to the correct diagnostic groups.
Jackknifed classification was 73% accurate for patients
with FTD and 67% accurate for patients with AD.
On average, the patients with FTD were younger
than the patients with AD. To assess whether the con-
 Figure 1. Mean composite subscale scores (frequency severity) for
behavioral symptoms in patients with frontotemporal dementia (FTD) and
in patients with Alzheimer disease (AD) measured by the Neuropsychiatrie
Inventory (NPI). Apa indicates apathy; AbM, aberrant motor behavior; Dis,
disinhibition; Eup, euphoria; Hal, hallucinations; Del, delusions; Dep,
depression; Irr, irritability; Anx, anxiety; Agi, agitation; and error bars, SD.
founding of age with diagnosis biased the above results,
Pearson correlations of patients' ages with subscale
scores were computed within the AD group for each of
the variables that differentiated the patients with FTD
from the patients with AD. The magnitude of the corre¬
lations ranged from —0.10 to 0.17 and none was statis¬
tically significant. This indicates that the difference in
neurobehavioral symptoms found between the 2 groups
is unlikely to be because of the younger age of the
patients with FTD.
Finally, 2 general types of behaviors have been as¬
sociated with frontal lobe dysfunction: disinhibition and
apathy. The data were analyzed to see if 2 distinct types
of FTD were identifiable. Of 15 patients with disinhibi-
tion, the mean apathy score was 3.1 (SD, 3.6) compared
with 7 patients without disinhibition whose mean apa¬
thy score was 8.6 (SD, 2.8) (P<.05). Thus, patients with
marked disinhibition were less apathetic than those with¬
out, supporting the suggestion of 2 subgroups of pa¬
tients.
COMMENT
Standardized assessment of behavioral symptoms pro¬
vides a means of characterizing neuropsychiatrie
syndromes associated with different neurologic condi¬
tions. Numerous articles3'7·914"17 describe behavioral
differences between FTD and other dementias includ¬
ing AD, but instruments for quantitative assessment and
differentiation have been lacking. The NPI is a new be¬
havioral rating scale that measures symptoms common
in a variety of dementing syndromes including FTD and
has been shown to be both valid and reliable.11 Using the
NPI, highly significant differences between AD and FTD
were identified.
Disinhibition, apathy, aberrant motor behavior, eu¬
phoria, and total NPI scores were significantly more
elevated in the FTD group, consistent with previous
descriptions of behavioral differences between FTD and
AD. Barber et al13 described similar differences based on
a retrospective questionnaire given to close relatives of
autopsy-proven patients with FTD and AD, demonstrat-
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Figure 2. The percentage of patients with frontotemporal dementia (FTD)
and Alzheimer disease (AD) with non-0 scores for each subscale. Asterisks
indicate 2, P<.01 (see Figure 1 for expansion of abbreviations).
ing that these findings are robust even in a retrospective
study.
Disinhibited behaviors suchas acting impulsively
or making socially inappropriate remarks have been
reported to help differentiate patients with FTD from
patients with AD.9 Starkstein et al7 demonstrated ante¬
rior hypoperfusion with SPECT in patients who were
defined as "mildly demented with disinhibition," and
Miller et al18 reported 5 cases of FTD with behavioral
disinhibition and noted a specific association with right
frontal lobe hypoperfusion. This study confirms the
relationship of anterior hypoperfusion with disinhibi-
tion.
Aberrant motorbehavior was significantly more
common patients with FTD than in patients with
in
AD. The character of the motor activity was not specifi¬
cally studied in this investigation, but previous reports
indicate that the behaviors exhibited by the 2 diagnostic
groups differ. Patients with FTD manifest stereotyped
behaviors ranging from overt compulsions to elemen¬
tary repetitions such as repeatedly eating the same
food.19 Patients with AD are more likely to pace, move
furniture, unpack closets, and rummage through draw¬
ers. The nature of the aberrant motor behavior
may
help distinguish the 2 groups and warrants further
study.
Apathy is commonly reported in patients with AD,20
but it is more prominent in patients with FTD and oc¬
curs at earlier stages of the disease. Apathy is commonly
mistaken for depression and a number of patients re¬
ceived treatment for depression in the years just prior to
being diagnosed with FTD, when apathy had become ap¬
parent. Our results show that patients with FTD have sig¬
nificantly more apathy, but relatively less depression for
their level of apathy.
Euphoria, in the form of elevated mood or inap¬
propriate jocularity, was reported by Gustafson21 in
about one third of his patients with FTD, and he noted
that when euphoria occurs in conjunction with restless¬
ness, these symptoms could closely mimic hypomania
or mania. We found that 8 of 22 patients with FTD had
euphoria compared with only 2 of 30 patients with AD.
Thus, the presence of euphoria is unusual in AD and is
common in FTD. This diagnosis should be seriously
considered in patients with euphoric dementia and in
 patients presenting with late-onset mood disorders with
manic features.
The NPI provided an accurate means of differenti¬
ating FTD from AD in this sample. Seventy-seven per¬
cent of patients were accurately classified using the NPI
when compared with current "gold standard" research
clinical and SPECT criteria. This is well above the accu¬
racy rates of clinical diagnosis of FTD reported from
brain banks where only 14% of patients (3 of 21) were
recognized.3 Thus, the NPI may provide a useful means
of identifying these patients for involvement in FTD-
specific research or as a means of eliminating them
from AD research projects and trials of an ti-AD drugs.
We have obtained postmortem histopathologic confir¬
mation of the diagnosis of 3 of the 22 patients with FTD
and all of them had lobar atrophy with Pick bodies and
without AD-type pathological changes.
The FTDs are a heterogeneous group of disorders
with varying degrees of anatomical and physiological
dysfunction in the right or left frontal or temporal
regions. Even within the frontal lobes there is heteroge¬
neity of regional involvement and some patients show
intense changes in the cingulum, while others demon¬
strate more severe orbitobasal or dorsolateral alter¬
ations. Additionally, there is significant variability in
the neurochemical deficits associated with FTD with
individual differences in the severity of serotonin defi¬
ciency. This anatomical and biochemical heterogeneity
may account for the variability in behavioral profile
exhibited by patients with FTD.
These results must be considered preliminary be¬
cause of the relatively small sample size. In addition, some
patients with AD may have significant frontal involve¬
ment and the ability of the NPI to distinguish FTD from
these patients remains to be investigated. We conclude
that the NPI reliably differentiates degenerative syn¬
dromes with anterior or posterior cerebral involvement
and helps distinguish the behavioral syndromes of FTD
and AD.
Accepted for publication March 18, 1996.
This study was supported by grant AG10123 from
the Department of Veterans Affairs, a National Institute
on Aging Alzheimer's Disease Center, Bethesda, Md, and
the Irving and Helga Cooper Geriatric Research Award of
the UCLA Center on Aging, Los Angeles, Calif.
Reprints: Jeffrey L. Cummings, MD, UCLA Neuro¬
psychiatrie Institute, 760 Westwood Plaza, Room 37-431,
Los Angeles, CA 90024.
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REFERENCES
1. Pick A. On the relation between aphasia and senile atrophy of the brain (1892).
In: Rottenberg DA, Hochberg FH, eds; Schoene WC, trans. Neurological Clas-
sics in Modern Translation. New York, NY: Hafner Press; 1977:35-40.
2. Brun A. Frontal lobe degeneration of non-Alzheimer type, I: neuropathology.
Arch Gerontol Geriatr. 1987;6:193-208.
3. Mendez MF, Selwood A, Mastri AR, Frey WH. Pick's disease versus Alzhei-
mer's disease: a comparison of clinical characteristics. Neurology. 1993;43:
289-292.
4. Read SL, Miller BL, Mena I, Kim R, Itabashi H, Darby A. SPECT in dementia:
clinical and pathological correlation. J Am Geriatr Soc. 1995;43:243-247.
5. Frisoni GB, Pizzolato G, Geroldi C, Rossato A, Bianchetti A, Trabucchi M. Dementia
of the frontal type: neuropsychological and [99Tc]-HM-PAO SPECT features.
J Geriatr Psychiatry Neurol. 1995;8:42-48.
6. Herholz K. FDG PET and differential diagnosis of dementia. Alzheimer Dis As-
soc Disord. 1995;9:6-16.
7. Starkstein SE, Migliorelli R, Teson A, et al. Specificity of changes in cerebral
blood flow in patients with frontal lobe dementia. J Neurol Neurosurg Psy-
chiatry. 1994;57:790-796.
8. Risberg J, Passant U, Warkentin S, Gustafson L. Regional cerebral blood flow
in frontal lobe dementia of non-Alzheimer type. Dementia. 1993;4:186-187.
9. Miller BL, Cummings JL, Villanueva-Meyer J, et al. Frontal lobe degeneration:
clinical, neuropsychological, and SPECT characteristics. Neurology. 1991;41:
1374-1382.
10. Neary D, Snowden JS, Shields RA, et al. Single photon emission tomography
using 99mTc-HM-PAO in the investigation of dementia. J Neurol Neurosurg Psy-
chiatry. 1987;50:1101-1109.
11. Cummings JL, Mega M, Gray K, Rosenberg-Thompson S, Carusi DA, Gorn-
bein J. The Neuropsychiatric Inventory: comprehensive assessment of psy-
chopathology in dementia. Neurology. 1994;44:2308-2314.
12. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clini-
cal diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA work group
under the auspices of Department of Health and Human Services Task Force
on Alzheimer's Disease. Neurology. 1984;34:939-944.
13. Folstein MF, Folstein SE, McHugh PR. Mini-Mental State: a practical method
for grading the cognitive state of patients for the clinician. J Psychiatr Res.
1975;12:189-198.
14. Brun A, Englund B, Gustafson L, et al. Consensus statement: clinical and neu-
ropathological criteria for frontotemporal dementia: the Lund and Manchester
Groups. J Neurol Neurosurg Psychiatry. 1994;57:416-418.
15. Barber R, Snowden JS, Craufurd D. Frontotemporal dementia and Alzheimer's
disease: retrospective differentiation using information from informants. J Neu-
rol Neurosurg Psychiatry. 1995;59:61-70.
16. Gustafson L. Clinical picture of frontal lobe degeneration of non-Alzheimer type.
Dementia. 1993;4:143-148.
17. Neary D, Snowden JS, Northen B, Goulding P. Dementia of frontal lobe type.
J Neurol Neurosurg Psychiatry. 1988;51:353-361.
18. Miller BL, Chang L, Mena I, Boone K, Lesser IM. Progressive right frontotem-
poral degeneration: clinical, neuropsychological and SPECT characteristics.
Dementia. 1993;4:204-213.
19. Ames D, Cummings JL, Wirshing WC, Quinn B, Mahler M. Repetitive and com-
pulsive behavior in frontal lobe degenerations. J Neuropsychiatry Clin Neuro-
sci. 1994;6:100-113.
20. Mega MS, Cummings JL, Fiorello T, Gorbein J. The spectrum of behavioral
changes in Alzheimer's disease. Neurology. 1996;46:130-135.
21. Gustafson L. Frontal lobe degeneration of non-Alzheimer type, II: clinical pic-
ture and differential diagnosis. Arch Gerontol Geriatr. 1987;6:209-223.