Delusions and Hallucinations in Frontotemporal Dementia
A Clinicopathologic Case Report
Maria Carmela Tartaglia, MD,* Andrew Kertesz, MD,w and Lee-Cyn Ang, MDz
Background: Frontotemporal dementia (FTD) is associated with
marked behavior changes, but hallucinations and delusions are
Objective: To report a case of FTD with early and persistent
delusions, including de Clerambault syndrome.
Design: We describe the clinical, neuroradiologic, and neuro-
pathologic findings of a 76-year-old woman with an 11-year
course of FTD with bizarre delusions and hallucinations.
Results: The patient’s autopsy examination of the brain revealed
pathology consistent with frontotemporal lobar degeneration with
ubiquitin-positive and transactive response (TAR)-DNA–binding
protein-43–positive inclusions and hippocampal sclerosis.
Conclusions: Delusions and hallucinations can occur in proven
Key Words: frontotemporal lobar degeneration with ubiquitin-
positive and TDP-43–positive inclusions, delusions, hippocam-
(Cog Behav Neurol 2008;21:107–110)
years, after Alzheimer disease (AD).1Clinically, FTD is
characterized by behavioral and/or language dysfunc-
tion.2The behavioral variant of FTD usually begins with
an early change in social and personal conduct, and is
often associated with disinhibition, resulting in impulsive
or inappropriate behavior. Delusions and hallucinations
are uncommon in FTD.3–5We present a case of
pathologically confirmed frontotemporal lobar degenera-
tion with ubiquitin-positive and transactive response
rontotemporal dementia (FTD) is the second most
common form of dementia in those under the age of 65
inclusions (FTLD-U-TDP-43) wherein hallucinations
and delusions, including a de Clerambault delusion,
Y.B. was 65-year-old when her children first noticed
behavioral changes. Initially, they noted neglect of household
chores and indifference toward her appearance and hygiene.
Over time, she stopped paying her bills, lost interest in her
hobbies, and on several occasions, withdrew large sums of
money but could not recall what she had done with it.
Furthermore, she became rude and uncaring toward others
and could be heard hollering on the street, making rude gestures,
and threatening to hit people. Her eating habits changed, she
became disinhibited, and would often appear topless in front of
her son. She developed delusions early on in her disease course,
claiming her son was ‘‘part of a cult.’’ About 4 years into her
illness, she began insisting that a bishop had married her to a
local priest and she had many children with this man. At times,
she would claim having up to 45 children and on occasion, she
presented to the emergency room claiming she was in labor. She
would display baskets with a towel inside and say, ‘‘how do you
like my baby?’’ She stated that the priest and she were madly in
love and so had many babies. She kissed mirrors and said she
was kissing her husband or the priest and went into public with
only her undergarments, but insisted she was dressed. She slept
on the floor stating there was not enough room in her bed
because of all the other people in it. She also hallucinated
pythons in her room.
Neuropsychologic testing performed 5 and 6 years after
disease onset revealed poor attention and concentration and
difficulty with visual and verbal memory, but no aphasia. Her
testing with the Frontal Assessment Battery revealed frontal
lobe dysfunction. The second evaluation, 1 year later, revealed
worsened cognitive function and more frontal lobe impairment
in keeping with a FTD, but no aphasia. Her Frontal Behavior
Inventory score was 46 (diagnostic cut-off of 27 for FTD) 6
years after disease onset. She was diagnosed as FTD although
the delusions were felt to be atypical. Physical examination was
essentially normal without evidence of weakness or Parkinson-
ism. Sensory coordination and gait were also normal. She had
no history of alcohol or drug abuse and no family history of
dementia, amyotrophic lateral sclerosis (ALS), or Parkinsonism.
Other medical problems included hypertension and diabetes.
She died of respiratory distress approximately 11 years after
Neuroimaging showed diffuse atrophy in frontal,
temporal, and parietal lobes that worsened over a 1-year
interval (Fig. 1A). Autopsy revealed marked cerebral
Copyrightr2008 by Lippincott Williams & Wilkins
Received for publication October 14, 2007; accepted March 26, 2008.
From the *Department of Clinical Neurological Sciences, Division of
Neurology; zDepartment of Pathology, London Health Sciences
Centre; and wDepartment of Cognitive Neurology, St Joseph’s
Hospital, University of Western Ontario, Ontario, Canada.
The authors have full access to all of the data in the study and take
responsibility for the integrity of the data and the accuracy of the
Reprints: Maria Carmel Tartaglia, MD, Department of Clinical
Neurological Sciences, Division of Neurology, University of Western
Ontario, B7-005, 339 Windermere Road, London, Ontario N6A
5A5, Canada (e-mail: email@example.com).
Cog Behav Neurol?Volume 21, Number 2, June 2008
atrophy (weight: 842g), worse in the anterior frontal
lobe and superior temporal gyri (Fig. 1B). Both lateral
ventricles were dilated with bilateral atrophy of the
caudate head. Brainstem sections showed pallor of the
substantia nigra and pontine atrophy. Microscopic
examination revealed marked neuronal loss, gliosis, and
superficial microvacuolation involving the frontal (middle
and inferior gyri and poles) and temporal (superior and
middle gyri and poles) cortex (Fig. 2A). Infrequent
ballooned neurons were noted in the frontal cortex.
Ubiquitin-positive cytoplasmic neuronal inclusions and
neurites were present in the anterior cingulate and frontal
and temporal cortices, especially in the poles. The
parietal, occipital, and posterior cingulate cortex dis-
played less neuronal loss and fewer ubiquitin-positive
inclusions. Infrequent neurofibrillary tangles without
neuritic plaques were noted in the frontal and temporal
cortex. Both hippocampi showed severe neuronal loss
with gliosis in CA1 consistent with hippocampal sclerosis
(Fig. 2B). The subiculum was gliotic. Neurofibrillary
tangles were rare in the hippocampal neurons but
granulovacuolar degeneration was noted in CA1 and
CA2. Moderate numbers of neurofibrillary tangles were
noted in the entorhinal cortex. Dotlike ubiquitin-positive
cytoplasmic inclusions were noted in the granular neurons
of the dentate gyrus (Fig. 2C). These neuronal inclusions
also exhibited TDP-43 immunoreactivity (Fig. 2D). The
amygdala showed scattered neurofibrillary tangles and
FIGURE 1. A, Sagittal and axial MRI taken at year 5 and 6 after disease onset show diffuse atrophy that worsened over 1 year.
B, Right and left hemispheres at autopsy with marked atrophy of frontal lobe and anterior temporal gyrus. MRI indicates magnetic
Tartaglia et al Cog Behav Neurol ?Volume 21, Number 2, June 2008
r2008 Lippincott Williams & Wilkins
neuropil threads and moderate density of ubiquitin-
positive neuronal inclusions and neurites.
Moderate neuronal loss with gliosis of the caudate
was noted in the putamen, anterior nucleus, medial
dorsal, and lateral dorsal of the thalamus. The globus
pallidi showed numerous enlarged perivascular spaces.
The substantia nigra showed significant neuronal loss
with pigmentary incontinence. There was patchy Purkinje
cell loss in the superior vermis folial crest. No Lewy
bodies were seen in any of the sections stained with
hematoxylin and eosin. In addition, a-synuclein staining
in the pons, midbrain, hippocampus with entorhinal
cortex, cingulate, or amygdala also did not reveal any
Lewy bodies. TDP-43 staining in the hypoglossal nuclei in
the medulla revealed no abnormal cytoplasmic or nuclear
The neuropathologic diagnosis was FTLD-U-TDP-
43. There was also bilateral hippocampal sclerosis,
infrequent neocortical neurofibrillary tangles, and cere-
The behavioral variant of FTD features primarily
dysfunction of social and personal conduct with disin-
hibition as a common, early feature. As the disease
progresses, there may be poor judgment, impulsive
buying, self-destructive behaviors, inappropriate sexual
behavior, and frank criminal behavior. Changes in
dietary habits and disregard for personal hygiene are
common signs. There is very little insight with striking
lack of empathy and concern for others. Obsessive-
compulsive and stereotyped behaviors are common.6
Against this background of impairment, there is notable
sparing of episodic memory. The pathologic designation
frontotemporal lobar degeneration (FTLD) reflects the
prominent frontal and temporal lobe atrophy associated
with neuronal loss and gliosis. Immunohistochemically,
FTLD can be broadly divided into 2 categories: (1)
predominant t-positive inclusions and (2) predominant
ubiquitin-positive and TDP-43-positive, t-negative, and
synuclein-negative inclusions termed FTLD-U-TDP-43,
which is the most common neuropathologic subtype of
FTLD. Our patient fits in the FTLD-U-TDP-43 group as
ubiquitin-positive and TDP-43-positive inclusions were
numerous, and although there were a few t-positive
neurofibrillary tangles attributable to aging, there were no
other t-positive inclusions.
Clinically, our patient is unusual in that prominent
delusions and hallucinations appeared early on in the
disease and persisted. Delusions and hallucinations are
uncommon in FTLD, unlike Diffuse Lewy Body demen-
tia (DLB), where they are part of the diagnostic criteria.
Hirono et al4looked at psychiatric disturbances in DLB,
AD, and FTD and found that both persecutory delusions
and misidentification delusions were less common in the
FTD group than in the AD and the DLB groups.
Hallucinations were more common in the DLB group
than in the AD and FTD groups. Harciarek et al7
reviewed the incidence and nature of reduplicative
phenomena, delusions, and misidentification syndromes
and found delusional misidentification in 2 patients with
semantic dementia and none in the behavioral variety
of FTD. Our patient showed an unusual delusion,
de Clerambault delusion, also known as erotomania, a
syndrome characterized by the delusional belief that
another person (in our patient’s case, a celibate priest)
who is socially unobtainable because of an unbridgeable
FIGURE 2. Histology sections. A, H&E
marked superficial microvacuolation. B,
NeuN stain of hippocampus shows se-
vere neuronal loss with gliosis consistent
with hippocampal sclerosis. C, Dotlike
ubiquitin-positive cytoplasmic inclusions
seen in the granular neurons of the
dentate gyrus. D, The cytoplasmic inclu-
sions were TDP-43 positive. TDP-43
DNA–binding protein-43; H&E, hema-
toxylin and eosin.
Cog Behav Neurol ?Volume 21, Number 2, June 2008 FTD—Delusions and Hallucinations
r 2008 Lippincott Williams & Wilkins
gap in social and financial status passionately loves this Download full-text
person. This is rare among elderly patients but has been
reported in conjunction with dementia, epilepsy, subar-
achnoid hemorrhage, and traumatic brain injury.8A case
report of FTD and motor neuron disease (MND) with de
Clerambault syndrome was reported, but no pathologic
confirmation was included.9
patient (same age and demographics with a similar love
interest) was reported as having de Clerambault syn-
drome secondary to a cerebrovascular accident.10A case
of de Clerambault syndrome with AD and 1 case with
vascular dementia are reported, but the authors could
not find any shared central nervous system correlates to
account for the symptom.11The anatomic substrates of
delusions are unclear. Sultzer et al12found a significant
relationship between the severity of delusional thoughts
and metabolic rate in the right prefrontal cortex in AD
patients with delusions. It is, however, difficult to ascribe
this as a cause in FTD, given the rarity of delusions and
hallucinations in FTD despite the severity of the frontal
lobe pathology. A report on 3 cases of FTD and MND
exhibiting hallucinations and delusions propose primarily
temporal lobe involvement as the pathogenetic factor.13
Pathologically, there was bilateral hippocampal
sclerosis (HS) in our patient, which has been observed
as a concomitant neuropathologic finding in a number of
dementias, including AD, FTD, DLB, and vascular
dementia (VD).14–15The etiology of HS is unknown,
but is postulated to be either secondary to hypoxic-
ischemic injury or to selective neurodegeneration of
vulnerable neurons in CA1 and subiculum.16,17One
autopsy series reported that of 18 HS dementia cases,
11 displayed ubiquitinated neuronal inclusions in the
dentate gyrus granule neurons, similar to those of MND
inclusion dementia.18They felt that most patients with
pathologic findings of HS dementia might actually have
the MND inclusion dementia variant of FTD. HS has
also been observed in FTLD with ubiquitin immunor-
Recently, TDP-43, an abnormal protein, was found
in both FTLD with ubiquitin-positive inclusions with
and without MND and in MND/ALS linking these 2
entities.20TDP-43 is a ubiquitously expressed, chromo-
some 1 encoded, DNA and RNA binding protein. Its
function is unclear, but it may be involved in transcrip-
tion. This protein was found to accumulate abnormally in
postmortem brain tissue from FTD and ALS patients.
Recently, criteria for neuropathologic diagnosis of FTLD
have included TDP-43 staining.21TDP-43 immunolabel-
ing in the hippocampal section highlighted its expression
in dentate granule cells.
This case demonstrates some interesting features,
such as the presence of delusions and hallucinations that
are rarely seen in FTD. Hallucinations and delusions can
be seen in temporal lobe seizures, and perhaps, more
severe temporal lobe involvement in FTD can result in
psychotic symptoms. Both frontal and temporal lobes
were severely atrophied in our patient and this may have
contributed to her psychosis. Further clinicopathologic
Interestingly, a similar
studies are required to clarify if different levels of
temporal lobe or frontal lobe pathology can result in
prominent psychotic symptoms in FTD.
1. 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;74:1206–1209.
2. Neary D, Snowden JS, Gustafson L, et al. Frontotemporal lobar
degeneration: a consensus on clinical diagnostic criteria. Neurology.
3. Mendez MF, McMurtray A, Chen AK, et al. Functional
neuroimaging and presenting psychiatric features in frontotemporal
dementia. J Neurol Neurosurg Psychiatry. 2006;77:4–7.
4. Hirono N, Mori E, Tanimukai S, et al. Distinctive neurobehavioral
features among neurodegenerative dementias. J Neuropsychiatry
Clin Neurosci. 1999;11:498–503.
5. Hodges JR, Davies RR, Xuereb JH, et al. Clinicopathological
correlates in frontotemporal dementia. Ann Neurol. 2004;56:
6. Hodges JR, Miller B. The neuropsychology of frontal variant
frontotemporal dementia and semantic dementia. Introduction to
the special topic papers: part II. Neurocase. 2001;7:113–121.
7. Harciarek M, Kertesz A. The prevalence of misidentification
syndromes in neurodegenerative diseases. Alzheimer Dis Assoc
Disorders. 2008. In press.
8. el Gaddal YY. De Clerambault’s syndrome (erotomania) in organic
delusional syndrome. Br J Psychiatry. 1989;154:714–716.
9. Olojugba C, de Silva R, Kartsounis LD, et al. De Clerambault’s
syndrome (erotomania) as a presenting feature of fronto-temporal
dementia and motor neuron disease (FTD-MND). Behav Neurol.
10. Das A, Mathur S, Orrell M. Erotomania secondary to cerebrovas-
cular accident in frontotemporal impairment. Ir J Psych Med.
11. Brune M, Schroder SG. Erotomania variants in dementia. J Geriatr
Psychiatry Neurol. 2003;16:232–234.
12. Sultzer DL, Brown CV, Mandelkern MA, et al. Delusional thoughts
and regional frontal/temporal cortex metabolism in Alzheimer’s
disease. Am J Psychiatry. 2003;160:341–349.
13. Nitrini R, Rosemberg S. Psychotic symptoms in dementia associated
with motor neuron disease: a pathophysiological hypothesis.
J Neuropsychiatry Clin Neurosci. 1998;10:456–458.
14. Corey-Bloom J, Sabbagh MN, Bondi MW, et al. Hippocampal
sclerosis contributes to dementia in the elderly. Neurology.
15. Dickson DW, Davies P, Bevona C, et al. Hippocampal sclerosis: a
common pathological feature of dementia in very old (>or=80y
of age) humans. Acta Neuropathol (Berl). 1994;88:212–221.
16. Barker WW, Luis CA, Kashuba A, et al. Relative frequencies of
Alzheimer disease, Lewy body, vascular and frontotemporal
dementia, and hippocampal sclerosis in the State of Florida Brain
Bank. Alzheimer Dis Assoc Disord. 2002;16:203–212.
17. Zarow C, Vinters HV, Ellis WG, et al. Correlates of hippocampal
neuron number in Alzheimer’s disease and ischemic vascular
dementia. Ann Neurol. 2005;57:896–903.
18. Hatanpaa KJ, Blass DM, Pletnikova O, et al. Most cases of
dementia with hippocampal sclerosis may represent frontotemporal
dementia. Neurology. 2004;63:538–542.
19. Amador-Ortiz C, Ahmed Z, Zehr C, et al. Hippocampal sclerosis
dementia differs from hippocampal sclerosis in frontal lobe
degeneration. Acta Neuropathol (Berl). 2007;113:245–252.
20. Neumann M, Sampathu DM, Kwong LK, et al. Ubiquitinated
TDP-43 in frontotemporal lobar degeneration and amyotrophic
lateral sclerosis. Science. 2006;314:130–133.
21. Cairns NJ, Bigio EH, Mackenzie IR, et al. Neuropathologic
diagnostic and nosologic criteria for frontotemporal lobar degen-
eration: consensus of the Consortium for Frontotemporal Lobar
Degeneration. Acta Neuropathol. 2007;114:5–22.
Tartaglia et al Cog Behav Neurol ?Volume 21, Number 2, June 2008
r2008 Lippincott Williams & Wilkins