The n e w e ng l a n d j o u r na l of
Case Records of the Massachusetts General Hospital
From the Department of Neurology,
McLean Hospital, Belmont, MA (B.H.P.);
and the Departments of Neurology
(B.H.P., D.L.P.), Psychiatry (D.L.P.), Radi‑
ology (O.R.), and Pathology (D.H.O.),
Massachusetts General Hospital, and
the Departments of Neurology (B.H.P.,
D.L.P.), Radiology (O.R.), and Pathology
(D.H.O.), Harvard Medical School —
both in Boston.
N Engl J Med 2020;383:2666-75.
DOI: 10.1056/NEJMcpc1916251
Copyright © 2020 Massachusetts Medical Society.
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m e dic i n e
Founded by Richard C. Cabot
Eric S. Rosenberg, M.D., Editor
Virginia M. Pierce, M.D., David M. Dudzinski, M.D., Meridale V. Baggett, M.D.,
Dennis C. Sgroi, M.D., Jo‑Anne O. Shepard, M.D., Associate Editors
Kathy M. Tran, M.D., Assistant Editor
Matthew B. Roberts, M.B., B.S., Case Records Editorial Fellow
Emily K. McDonald, Tara Corpuz, Production Editors
Case 41-2020: A 62-Year-Old Man
with Memory Loss and Odd Behavior
Bruce H. Price, M.D., David L. Perez, M.D., M.M.Sc., Otto Rapalino, M.D.,
and Derek H. Oakley, M.D., Ph.D.​​
Pr e sen tat ion of C a se
Dr. David L. Perez: A 62-year-old, left-handed man was seen in the memory disorders
clinic of this hospital because of memory loss, personality changes, and odd be-
havior.
Approximately 5 years before this evaluation, the patient’s wife noticed that the
patient was becoming more forgetful and napped frequently during the day. She
also noticed that he lacked initiative in his professional work; for example, he was
not charging or collecting payments for services. The patient’s coworkers observed
that he was having difficulty focusing and frequently required redirection when
interacting with clients. The patient had no concerns other than intermittent mild
headaches.
During the next few years, the patient’s wife noticed that he became distant
with family, was less talkative, and lacked interest in activities that he had previ-
ously enjoyed. He made numerous costly errors at work and also had odd behav-
iors. For example, he entered the kitchen of a local restaurant without permission;
on another occasion, he inadvertently borrowed a vehicle from a colleague without
first notifying that person. In another instance, while the patient’s vehicle was
stopped for a routine traffic infraction, he became irritable and briefly evaded
police, incurring several legal violations.
One year before this evaluation, the patient was seen in the neurology and
psychiatry clinics of another hospital at his wife’s request. He had no concerns
about his neurocognitive state. He noted that he was sleeping as little as 2 to 3 hours
per night but had a good energy level. He reported intermittent mild headaches.
He had no sinus pain, numbness, tingling, or constitutional symptoms. On exami-
nation, the patient was alert and oriented, with some inattention and confabula-
tion. The remainder of the neurologic examination was normal. A complete blood
count and blood levels of electrolytes and glucose were normal, as were results of
tests of kidney, liver, and thyroid function. Tests for antinuclear antibodies and for
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The New England Journal of Medicine
 Case Records of the Massachuset ts Gener al Hospital
Lyme disease were negative. The patient received
diagnoses of attention deficit–hyperactivity dis-
order, adjustment disorder, and avoidant person-
ality traits. Psychotherapy was initiated, and mela-
tonin and dextroamphetamine–amphetamine
were prescribed.
The patient had ongoing personality changes
and difficulties with organization and daily
functioning, and he was evaluated in the mem-
ory disorders clinic of this hospital at his wife’s
request. She reported that dextroamphetamine–
amphetamine had not improved his overall orga-
nizational abilities. Although he was physically
capable of conducting activities of daily living,
he required prompting to perform tasks to main-
tain basic hygiene, such as bathing. He no lon-
ger participated in the management of family
finances; he was unable to maintain employ-
ment and was receiving disability payments. He
had new odd behaviors, such as urinating in
public on a few occasions and frequently and
unexpectedly visiting family members’ workplaces
and neighbors’ homes at late hours. He also had
obsessive behaviors, such as calling his children
multiple times to confirm details before a
scheduled gathering. The patient was unaware of
his inappropriate and unusual behaviors. He did
not report having anxiety, depression, or percep-
tual disturbances.
Approximately 10 years before the current
evaluation, the patient had received a diagnosis
of Waldenström’s macroglobulinemia. Because
he was asymptomatic, treatment was deferred.
Two years before the current evaluation, com-
puted tomography (CT) of the chest, abdomen,
and pelvis was performed for disease surveil-
lance. There were multiple enlarged hilar and
retrocrural lymph nodes, measuring up to 1.2 cm
in greatest dimension, with no evidence of or-
ganomegaly or focal osseous lesions. The patient
attended routine oncology appointments for dis-
ease monitoring. Two months before the current
evaluation, a complete blood count and a basic
metabolic panel were normal. The blood IgM
level was 2850 mg per deciliter (reference range,
40 to 230), and the β2-microglobulin level 2.8 mg
liter (reference range, 0 to 2.7); these values had
been stable since the diagnosis of Waldenström’s
macroglobulinemia was established.
Other medical history included mitral regur-
gitation, nephrolithiasis, benign prostatic hyper-
plasia, bilateral knee osteoarthritis, and spinal
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stenosis. There was no history of head trauma,
stroke, or seizure. Medications included a multi-
vitamin and fish oil; there were no known aller-
gies to medications. The patient did not drink
alcohol, smoke tobacco, or use illicit drugs. He
lived with his wife, and his daughters and
grandchildren lived nearby. He had graduated
from high school and trade school before serv-
ing in the navy for 2 years; he did not serve in a
combat role or have known exposure to toxins.
Both of his parents had heart disease, a sister
had depression, and a maternal uncle had throat
cancer. There was no family history of dementia,
neurologic disorders, or psychiatric disorders.
On examination, the patient was well groomed,
pleasant, and cooperative. Physical appearance
was normal. His Mini–Mental State Examination
score was 23 on a scale ranging from 0 to 30
(with higher scores indicating better cognitive
function), and his Montreal Cognitive Assess-
ment (MoCA) score was 15 on a scale ranging
from 0 to 30 (with higher scores indicating bet-
ter cognitive function).
Orientation was intact except for an error in
recalling the date. On testing of attention, the
patient had difficulty with serial sevens calcula-
tions and with the digit-span test, in which a
sequence of numbers is read by the examiner
and repeated by the patient; he repeated only
four digits of the forward span correctly. On
testing of memory, he repeated five out of five
words after two trials and did not spontane-
ously recall any of the words after 5 minutes; he
recalled three of the words when selecting from
a written list of word choices. Spontaneous speech
production was diminished. On testing of con-
frontation naming, he identified a camel when
shown a picture of a giraffe. On testing of se-
mantic and phonemic fluency, he spontaneously
generated six animal names over a 1-minute
period, as well as one word that begins with the
letter “F” over a 1-minute period. The clock-
drawing test showed good organization. The
letter–number sequencing test (also known as
the alternating trail-making test) revealed im-
paired set shifting, and Luria’s three-step test
revealed impaired motor sequencing. On testing
of verbal abstraction, when the patient was
asked to describe how a train and a bicycle are
similar, he stated, “A train is bigger than a bi-
cycle and would crush the bicycle.” Judgment
and insight were markedly impaired.
2667
 The n e w e ng l a n d j o u r na l
An evaluation of cranial nerve function, sen-
sation, power, bulk, tone, coordination, and gait
was normal. Deep-tendon reflexes were normal,
and the toes were downgoing bilaterally. Bilat-
eral grasp reflexes and palmomental reflexes
were present. Testing for syphilis was negative.
The blood folate level was 8.2 ng per milliliter
(19 nmol per liter; reference range, >4.7 ng per
milliliter [11 nmol per liter]), and the vitamin B12
level 258 pg per milliliter (190 pmol per liter;
reference range, >231 pg per milliliter [170 pmol
per liter]).
On neuropsychological assessment, social en-
gagement was limited, with a few moments of
giggling that was incongruent with the context.
Spontaneous speech was fluent but impoverished.
There was frequent use of the word “thing” to
replace lower-frequency words and periodic use
of phonemic paraphasias such as “a fenco type
of thing.” Thoughts were coherent but impover-
ished, tangential, and perseverative. Attention and
executive functioning were markedly impaired
during assessments of verbal fluency, divided
attention, abstract reasoning, and inhibitory
control. Visual memory was relatively intact, but
verbal memory was impaired in terms of encod-
ing and retrieval. When the patient was asked to
describe an image, written language was severely
impaired but oral language was relatively intact.
A diagnostic test was reviewed, and a diagno-
sis was made.
Differ en t i a l Di agnosis
Dr. Bruce H. Price: This 62-year-old man had clini-
cally significant memory loss and personality
and behavioral changes that progressively im-
paired his ability to function professionally and
personally over the course of 5 years. The fea-
tures of his presentation fit criteria for dementia
characterized by an insidious onset with pro-
gression over time. I will develop a differential
diagnosis of dementia that focuses on the inter-
section of neurologic and psychiatric disease.1
Assessment of Findings
The initial findings observed in this patient were
forgetfulness, difficulty focusing, disrupted sleep,
apathy, and a lack of concern followed by con-
fabulation. Disturbance of the circadian rhythm
that leads to disruption or loss of nighttime
sleep is increasingly associated with early de-
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of m e dic i n e
mentia.2 Apathy implies a decrease in or loss of
motivation, as compared with the previous level
of functioning, a feature that is not consistent
with the patient’s age or culture.3 Spontaneous
confabulation, defined as the generation of false
narratives with the absence of doubt in forming
and expressing the beliefs,4 is primarily associ-
ated with amnestic dementia but can also be
seen with neurosyphilis, hypoxemia, disorders
of thought, and affective psychoses.
The patient’s inexorable disease progression
led to frank disinhibition and impulsivity, as
well as compulsive behaviors.5 Four years into
the disease course, he received psychiatric diag-
noses of attention deficit–hyperactivity disorder,
adjustment disorder, and avoidant personality
traits. He eventually became unable to work and
was no longer involved in family decisions. He
had a decline in his personal hygiene, a lack of
awareness of his deficits and unusual behaviors
(including inadvertent theft and public urination),
and normal results on serial elementary neuro-
logic examinations, except for the presence of
grasp reflexes and palmomental reflexes, which
are nonspecific findings.5,6
Montreal Cognitive Assessment
Five years into the disease course, the patient
underwent the MoCA, which was illuminating.7
Attention, motivation, and effort are crucial to
establish validity of the assessment. The process,
not just the final score, is important for inter-
pretation of the results. The patient was unable
to successfully complete the letter–number se-
quencing test. He made no effort at self-correc-
tion, which implies apathy and a lack of aware-
ness. He had mild inattention, was able to recite
only four digits of the forward span on the digit-
span test, and generated only 1 word that begins
with the letter “F” over a 1-minute period,
whereas high school graduates normally gener-
ate 11 words or more. Verbal abstraction was
interpreted concretely. On testing of verbal
memory, the patient learned 5 words during a
second trial and spontaneously recalled none of
the words after a time delay. Yet, when he was
given multiple written choices, he correctly re-
called 3 of the words, a finding that suggests
some memory retention. A plausible interpreta-
tion is that the MoCA results do not suggest
primary amnesia but instead reflect secondary
amnesia due to an apathetic, disengaged, and
 Case Records of the Massachuset ts Gener al Hospital
unconcerned state. A formal neuropsychological
assessment conducted 5 years after disease onset
revealed limited engagement with the testing, a
flat affect, incongruent giggling, fluent speech
and language with impoverished content and
paraphasic errors, markedly impaired attention
and executive functioning, and impaired verbal
memory with relatively intact visual memory.
Patient History
A relevant patient history, with a focus on the
time before the onset of illness, was obtained.
The patient had graduated from high school and
trade school, which suggests that he had normal
baseline cognitive functioning. He had received a
diagnosis of Waldenström’s macroglobulinemia,
which was described as stable without treat-
ment. Lymphoplasmacytic lymphoma can cause
central nervous system disease that results in
cognitive decline and psychiatric symptoms, al-
though this manifestation is rare.8 However, this
diagnosis is usually accompanied by motor defi-
cits and cranial nerve palsies, which were not
present in this patient. Furthermore, a surveil-
lance chest CT scan obtained 2 years before the
current evaluation showed no evidence of organo-
megaly or focal bone lesions; these results re-
duce the likelihood of cancer or paraneoplastic
brain involvement.
Frontal Network Dysfunction
Many common neurologic conditions are associ-
ated with frontal network dysfunction, which
causes clinically significant changes in person-
ality and behavior. Frontal–subcortical circuitry
carries projections from the thalami to the fron-
tal lobes and connects the frontal lobes to the
basal ganglia. Disruptions in nonmotor frontal–
subcortical circuits are specifically linked to
apathy, disinhibition, and executive dysfunction
— prominent features of this patient’s presenta-
tion (Fig. 1).
Causes of Dementia Associated with Brain
Lesions
This patient’s normal results on serial neuro-
logic examinations would not typically be con-
sistent with diagnoses associated with brain le-
sions. However, atypical presentations are not
uncommon with these diagnoses, and clinical
judgment remains paramount in ruling them out.
One such diagnosis is vascular brain disease; the
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patient had no known vascular risk factors, al-
though it would be important to ascertain his
body-mass index and determine whether he had
obstructive sleep apnea. Huntington’s disease is
another possibility, given that its peak incidence
is in the fourth and fifth decades of life, but this
patient, now in his seventh decade of life, did
not have a family history of Huntington’s dis-
ease and had not reported a movement disorder
5 years into the disease course.9
Lewy-body dementia is an unlikely diagnosis
in this patient because he did not have parkinso-
nian features, postural instability, autonomic
dysfunction, repeated falls, delusions, or visual
hallucinations. Tauopathies, such as progressive
supranuclear palsy, can be ruled out on the basis
of the normal results on serial neurologic exami-
nations, including intact extraocular movements,
which were observed 5 years into the disease
course. White-matter disease, such as multiple
sclerosis, is a possibility, but he had none of the
typical signs or symptoms. Slow-growing tumors,
including meningiomas emanating from the falx
cerebri or cribriform plate and pituitary tumors
invading suprasellar structures, should also be
considered but are unlikely.
The patient’s clinical presentation could be
consistent with normal pressure hydrocephalus,
but his normal gait and the absence of inconti-
nence are not consistent with this diagnosis.
Common infections such as human immunode-
ficiency virus infection and syphilis should al-
ways be considered in the differential diagnosis
of progressive neurocognitive decline, but test-
ing for syphilis was negative, he had no risk fac-
tors for infection, and his neurologic examination
was unremarkable. Prion diseases, particularly
variant Creutzfeldt–Jakob disease,10 should be
considered in this patient, although the mean
age at disease onset is 29 years; furthermore, he
did not have myoclonus, pyramidal or extrapyra-
midal features, or cerebellar signs and he had
survived much longer than would be expected
with this illness.
Spontaneous intracranial hypotension can
cause frontotemporal brain sagging syndrome11
with frontal–subcortical disconnection, but the
symptoms usually depend on the patient’s posi-
tion. Hashimoto’s encephalopathy should also
be considered in this case, but laboratory test
results were reportedly normal and there were
no physical findings consistent with thyroid
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 The n e w e ng l a n d j o u r na l of m e dic i n e

Executive dysfunction

DL
Dorsolateral
prefrontal cortex Caudate
nucleus
LDM
Globus
pallidus

Thalamus

MD

VA

Disinhibition

Caudate
nucleus
VM
MDM
Globus
pallidus

Orbitofrontal
cortex Thalamus

MD

VA

Apathy

Caudate
nucleus
NA–VM
Anterior
cingulate cortex

Putamen

Globus
pallidus
V

Thalamus MD

VA

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 Case Records of the Massachuset ts Gener al Hospital
Figure 1 (facing page). Brain Anatomy Associated with
This Patient’s Early Neurobehavioral (Neuropsychiatric)
Symptoms.
The brain is composed of anatomical regions with
unique architectural properties that are arranged geo‑
graphically throughout the cortical and subcortical areas
and linked with topographic precision. DL denotes dorso‑
lateral, LDM lateral dorsomedial, MD mediodorsal, MDM
medial dorsomedial, NA nucleus accumbens, V ventral,
VA ventral anterior, and VM ventromedial.
disease, such as tremors, seizures, myoclonus, or
ataxia.
Behavioral Variant of Frontotemporal
Dementia
The two most likely diagnoses in this case are
the behavioral variant of frontotemporal dementia
(bvFTD)12 and the frontal variant of Alzheimer’s
disease (fvAD).13 It can be difficult to distinguish
fvAD with disproportional frontal features from
bvFTD. The occurrence of prominent early mem-
ory loss with bvFTD can further blur the distinc-
tion. This patient had five of the six major
symptoms of bvFTD (Table 1): early behavioral
disinhibition, apathy, loss of sympathy or empa-
thy, compulsive or ritualistic behaviors, and
deficits in executive functioning with relative
sparing of memory and visuospatial abilities.14
Hyperorality (excessive chewing, sucking, or lip
smacking) and changes associated with food
preference or diet (e.g., binge eating, weight
gain, or eating inedible objects) are likely to oc-
cur in patients with bvFTD, but no such changes
were reported in this case. Patients with bvFTD
are often referred for psychiatric evaluation15
and may have normal results on neuroimaging
early in the disease course; the disease can
manifest either symmetrically or asymmetrical-
ly, both clinically and on neuroimaging.
Several features of this patient’s presentation
favor a diagnosis of bvFTD. He was 57 years of
age at disease onset; the frequency of early dis-
ease onset (at <65 years of age) among patients
with bvFTD is similar to or higher than the
frequency among those with fvAD. He had early
profound changes in personality and behavior.
Apathy is the most common initial symptom of
bvFTD and is more frequent and severe among
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Table 1. Diagnostic Criteria for the Behavioral Variant of Frontotemporal
Dementia.*
Present in
Criterion This Patient
Possible diagnosis: three of the following persistent or recur‑
rent features
Early behavioral disinhibition Yes
Early apathy or inertia Yes
Early loss of empathy or sympathy Yes
Early perseveration or stereotyped, compulsive, or ritual‑ Yes
istic behaviors
Hyperorality and dietary changes No
Deficits in executive functioning with relative sparing of Yes
memory and visuospatial abilities
Probable diagnosis: all the following features
Criteria needed for possible diagnosis Yes
Clinically significant functional decline Yes
Neuroimaging results consistent with the disease
Evidence of atrophy involving the frontal or anterior Yes
temporal lobe on MRI or CT
Evidence of hypoperfusion involving the frontal or Unknown
anterior temporal lobe on SPECT or hypometabo‑
lism on PET
Definite diagnosis with FTLD: two of the following features
Criteria needed for either possible or probable diagnosis Yes
One of the following:
Histopathological evidence of FTLD on biopsy or Yes
autopsy
Pathogenic mutation known to cause FTLD Yes
* Adapted from Seeley12 and Rascovsky et al.14 CT denotes computed tomogra‑
phy, FTLD frontotemporal lobar degeneration, MRI magnetic resonance imag‑
ing, PET positron-emission tomography, and SPECT single-photon-emission
computed tomography.
patients with bvFTD than among those with
fvAD.16 Criminal behaviors, such as theft, are
more common among patients with bvFTD. This
patient’s MoCA score, which indicated major
executive and behavioral dysfunction possibly
without primary amnesia, and his asymmetric
neuropsychological profile, which indicated im-
paired verbal memory with relatively intact visual
memory, also favor a diagnosis of bvFTD. The
clinical syndrome of bvFTD involves selective
neuroanatomy but may not be predictive of the
precise underlying pathological features. To es-
tablish the diagnosis of bvFTD, I would recom-
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 The n e w e ng l a n d j o u r na l of m e dic i n e

Figure 2. MRI of the Head. A

A sagittal fluid‑attenuated inversion recovery (FLAIR)
image (Panel A) shows disproportional volume loss,
which is more prominent in the cortical sulci along the
anterior and medial aspects of the left frontal lobe (ar‑
rowheads) than in the parietal and occipital sulci. Axial
FLAIR images through the frontal and temporal lobes
(Panels B and C, respectively) show asymmetric vol‑
ume loss, which is more prominent on the left side
(arrows) than on the right side.

B
mend magnetic resonance imaging (MRI) of the
head to assess for atrophy of the frontotemporal
lobes.

Dr . Bruce H. Pr ice’s Di agnosis

Behavioral variant of frontotemporal dementia.

Im aging S t udie s
Dr. Otto Rapalino: MRI of the head, performed
before and after the administration of intrave-
nous contrast material (Fig. 2), revealed dispro-
portional volume loss that was most prominent
in the frontal and temporal lobes and greater on
the left side than on the right side, with involve-
ment of the anterior cingulate gyri and ex vacuo
dilatation of the adjacent frontal and temporal
horns of the lateral ventricles. There was no ce-
rebral infarct, intracranial mass, abnormal intra- C
cranial enhancement, or evidence of previous
hemorrhage. This pattern of parenchymal vol-
ume loss was compatible with the clinical diag-
nosis of frontotemporal dementia.

Discussion of M a nagemen t
Dr. Perez: On the basis of this patient’s clinical
presentation and the frontotemporal-predominant
atrophy on MRI, the initial management strat-
egy was focused on providing counseling and
support for the patient and his wife.12 Counsel-
ing included a review of the core symptoms and
natural history of bvFTD (including disinhibi-
tion, apathy, loss of empathy, development of
stereotyped or ritualistic behaviors, hyperorality,
dietary changes, and executive dysfunction),14 as
well as a discussion of the striking loss of in-

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 Case Records of the Massachuset ts Gener al Hospital

sight that commonly accompanies this condi-

A
tion.17 As is common practice in the manage-
ment of neurodegenerative diseases for which
disease-modifying therapies are not yet avail-
able, outpatient follow-up clinic visits were
scheduled to provide the patient’s wife and other
family members with ongoing emotional sup-
port. There was also a review of available online
resources and social work services.
For pharmacologic management, sertraline, a
selective serotonin-reuptake inhibitor, was pre-
scribed to target impulsivity and emerging com-
pulsive behaviors.18 Trazodone was prescribed to
alleviate insomnia. Over several follow-up visits,
nonpharmacologic behavioral management strat-
egies were discussed with the patient’s wife.19
During the 3 years after the patient’s initial
visit, his neurocognitive condition continued to
decline. He began to have repetitive motor be- B
haviors, including frequent tapping of the knees
and grinding of the teeth.14 Unusual eating pat-
terns also emerged; he ate coffee grounds on
one occasion and became fixated on drinking
one particular brand of coffee. The patient’s wife
and other family members noticed that he had a
marked loss of empathy. There was a clinically
significant decline in speech output; at times,
he would respond to questions with only “yes” C
or “no,” and after subsequent progression, he
would respond with “aha.” He was referred to an
adult day program, which reportedly was a posi-
tive experience for the patient.20 By 66 years of
age, he required full care and no longer returned
to the clinic. He died at 69 years of age. With the
permission of his family, an autopsy was per-
formed.
Figure 3. Photographs of the Brain at Autopsy.
Pathol o gic a l Discussion The inferior surface of the brain (Panel A) shows atrophy
of the frontal and anterior temporal lobes that is greater
Dr. Derek H. Oakley: An autopsy that was limited to on the left side than on the right side. Coronal sections
examination of the brain was performed. On of the anterior frontal lobe and anterior temporal lobe
gross examination (Fig. 3), the brain weighed (Panel B) show severe atrophy, along with ventricular dil‑
910 g (normal range, 1250 to 1400) and had atation. More‑posterior coronal sections (Panel C) show
relative sparing of the superior temporal gyrus (arrow‑
severe atrophy of the frontal lobes and the ante-
heads) and posterior aspects of the frontal lobe.
rior portion of the temporal lobes that was
greater on the left side than on the right side.
There was severe cortical thinning in areas of discolored and firm. There was a notable ab-
atrophy and focal separation of the cortical band sence of atrophy in the posterior portion of the
from the underlying white matter, which was superior temporal gyrus. The amygdalae and

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 The n e w e ng l a n d j o u r na l of m e dic i n e

A B Figure 4. Brain Specimens at Autopsy.

Luxol fast blue–hematoxylin and eosin staining of the
inferior frontal cortex at low and high magnification
(Panels A and B, respectively) shows status spongio‑
sis, astrogliosis, and neuronal loss in the cortex. There
is also loss of Luxol fast blue myelin staining in the
underlying white matter due to axonal degeneration
(Panel A). A rare remaining cortical neuron is visible
(Panel B, arrowhead). Luxol fast blue–hematoxylin and
eosin staining of the hippocampal dentate gyrus at
high magnification (Panel C) shows numerous round‑
ed eosinophilic cytoplasmic inclusions, known as Pick
bodies (arrowheads). On immunohistochemical stain‑
ing of the hippocampal dentate gyrus (Panel D), the
Pick bodies are positive for tau (in brown). Immuno‑
histochemical staining of the parahippocampal gyrus
C D
at low and high magnification (Panels E and F, respec‑
tively) shows numerous rounded tau‑positive Pick bod‑
ies and dystrophic neurites (Panel F, arrowhead). Im‑
munohistochemical staining of the cingulate gyrus at
high magnification (Panel G) shows swollen tau‑posi‑
tive neurons, known as Pick cells (arrowheads), as well
as rounded tau‑positive Pick bodies.

hippocampi were mildly atrophic. The remain-

der of the gross examination of the brain was
unremarkable.
Microscopic examination (Fig. 4) revealed
severely degenerated cortex in the grossly affected
E F
areas of the brain, with status spongiosis, astro-
gliosis, and nearly complete neuronal loss.
Rounded eosinophilic cytoplasmic inclusions were
present in many neurons of the hippocampal
dentate gyrus and scattered throughout other
cortical areas. There were occasional swollen
neurons. Cerebrovascular disease was also pres-
ent, with mild atherosclerosis of the internal
carotid arteries and mild arteriolosclerosis of
vessels in the leptomeninges and white matter.
The pattern of gross atrophy strongly sug-
gests an underlying diagnosis of frontotemporal
lobar degeneration (FTLD). The atrophy was
G more restricted than would be expected in a
patient with Alzheimer’s disease and did not
stay within vascular territories, as would be ex-
pected in a patient with ischemic injury. The
gross findings are fully supported by the micro-
scopic changes in the affected cortical regions.
FTLD is characterized by ubiquitinated pro-
tein aggregates, most commonly in neurons.
Subtypes are based on the specific proteinopathy
and include FTLD-tau (with tau-positive inclu-
sions; subcategories include Pick’s disease, MAPT
mutation, and others), FTLD-TDP (with inclusions

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 Case Records of the Massachuset ts Gener al Hospital

positive for TAR DNA-binding protein 43), FTLD-
FUS (with inclusions positive for fused in sarco-
ma protein), FTLD-UPS (with inclusions positive
for ubiquitin proteasome system markers), and
FTLD-ni (with no inclusions).21 To determine the
subtype of this patient’s disease, immunohisto-
chemical staining was performed (Fig. 4). Stain-
ing revealed numerous rounded tau-positive in-
traneuronal inclusions (Pick bodies) in grossly
affected cortical regions, including the frontal
cortex, hippocampal dentate gyrus, and parahip-
pocampal gyrus. Swollen tau-positive neurons
(Pick cells) and dystrophic neurites were also
identified. The presence of tau-positive Pick bod-
ies and Pick cells is diagnostic of Pick’s disease,
a subcategory of FTLD-tau that is characterized
by aggregation of 3R tau isoforms. Additional
stains for phosphorylated TDP-43 and α-synuclein
were negative. A stain for β-amyloid revealed
rare, diffuse plaques in the hippocampus and neo-
cortex, a finding consistent with normal aging.
On the basis of the clinical, radiologic, and histo-
logic features identified in this patient, the final
diagnosis is FTLD consistent with Pick’s disease.
Fina l Di agnosis
Frontotemporal lobar degeneration with tau-
positive inclusions (FTLD-tau) consistent with
Pick’s disease.
This case was presented at Neurology Grand Rounds.
No potential conflict of interest relevant to this article was
reported.
Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.

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