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Autopsy-Proven, Sporadic Pick Disease With Onset at Age 25 Years
Landon W. Coleman, MD;
Kathleen B. Digre, MD;
Gary M. Stephenson, MD;
Jeannette J. Townsend, MD
Arch Neurol. 2002;59:856-859.
ABSTRACT
Context Pick disease is uncommon and accounts for less than 2% of adult-onset
dementias. Reports of Pick disease in young adults have apparently increased
in the last decade.
Objective To document the presentation and course of a patient with tau-positive
Pick disease presenting at an extremely young age.
Setting A university hospital.
Patient A white woman with cognitive impairment that began at age 25 years.
She experienced progressive dementia over an 8-year period with radiographic
evidence of severe cerebral atrophy of the frontotemporal lobes. Autopsy findings
confirmed the diagnosis of Pick disease characterized by tau-positive Pick
bodies in the neurons of the fascia dentata.
Conclusion Pick disease should be considered in the differential diagnosis of young
adults presenting with behavioral symptoms, especially those of frontal impairment.
INTRODUCTION
AN OFTEN-CONFUSED term,1 Pick disease
is uncommon and accounts for less than 2% of adult-onset dementias. The peak
age of onset occurs between 45 and 60 years and is rarely seen after age 75.
The average disease duration is 5 to 10 years. Women are slightly more afflicted
than men. Although some patients have a clear family history, usually with
a dominant inheritance pattern, more than 80% of cases are sporadic in nature.2
Patients present with progressive personality and behavior changes,
memory loss, and progressive fluent aphasia. Typically, patients develop severe
lobar atrophy that involves the frontotemporal lobes.2
The confusion associated with the term Pick disease causes debate in the literature.1 In this case, we use the term to describe a pathological
entity of tau-positive intraneuronal inclusions with clinical and radiographic
features similar to those just described. We present a patient who, to our
knowledge, is the youngest woman to be described with sporadic Pick disease.
The diagnosis of her condition was confirmed at autopsy. She developed symptoms
at age 25 years and was severely demented by age 29.
REPORT OF A CASE
A white woman had normal development and was known as a high achiever
in high school and college. The member of a large family, there was no family
history of dementia or other neurological disorders. She began to develop
memory problems at the age of 25. Initially, she was unable to recall the
details necessary to function at work. Her job required attention to fine
detail and strong interpersonal skills. Over the next 2 years, stark personality
changes and behavioral problems were noted. She began smoking and drinking
heavily and neglected normal daily activities such as bathing and eating.
She was unable to remember the date without a watch. A computed tomographic
scan of the brain at age 27 showed no abnormalities. Results of a visit to
a physician showed vitamin B12 deficiency. She was appropriately
treated with no improvement in mental function. She lost her job at age 28
because of progressive memory problems and lack of trustworthiness.
A psychological evaluation at age 29, because of continued alcohol abuse,
demonstrated severe memory impairment and behavioral disinhibition that interfered
significantly with her ability to function independently. On a Wechsler Adult
Intelligence Scale–Revised, her verbal IQ score was 87; the performance
IQ, 82; and the full-scale IQ, 83. She was unable to learn new information
despite repeated trials. Although it was felt that these symptoms could be
due to Korsakoff syndrome or alcoholic dementia, the rapidity of onset, along
with the disinhibition, perseveration, loose associations, and flight of ideas
suggested possible frontal lobe involvement.
Multiple laboratory tests were done at this time to look for possible
viral diseases, toxins, or clotting abnormalities. Findings from tests for
herpes simplex viruses 1 and 2, measles, cytomegalovirus, varicella-zoster
virus, and Epstein-Barr virus were negative, and the examination of the cerebral
spinal fluid gave normal results. The VDRL test findings were negative. Test
results for anti-cardiolipin antibodies and an anti-nuclear antibody were
negative. The levels of folate, vitamin B12, thyroxine, and triiodothyronine
were normal. Toxicology screening was positive for ethanol at 103.2 mg/dL,
but it was negative for benzodiazepines, opiates, salicylates, acetaminophen,
tricyclic antidepressants, stimulant amines, cocaine, and barbiturates.
Three months after this evaluation, she began wandering off and was
admitted to a hospital because of her progressive dementia and inability to
take care of herself. A high-resolution magnetic resonance imaging (MRI) study
showed significant volume loss involving the mesial temporal structures and
frontal lobes bilaterally in a symmetric fashion. These included the hippocampal
gyri bilaterally, the uncus, the anterior aspect of the temporal lobes, and
the white matter (Figure 1 and Figure 2). There was some generalized cerebral
and cerebellar atrophy.
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Figure 1. A T1-weighted sagittal magnetic
resonance image demonstrating marked atrophy of the frontotemporal lobes.
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Figure 2. A T1-weighted coronal magnetic
resonance image demonstrating marked atrophy of the temporal lobes. The right
side of the brain is on the left side of the figure; left side of the brain,
on the right.
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Over the next 2 years, she continued to decline and would commonly pace
while mumbling, repeating random numbers and her birthdate. She was under
constant supervision. She was unable to dress herself or shower without being
told each step. She refused to stop repeating numbers and, thus, had a difficult
time eating. Another hospitalization at age 31 documented continued deterioration.
She slept only 1 to 3 hours per night and would continually do repetitive
tasks such as applying chapstick, blowing bubbles, or repeating numbers. At
this time, findings from an electroencephalogram were within normal limits,
while another MRI showed severe cerebral atrophy of the frontotemporal lobes.
She died 1 year 9 months later.
PATHOLOGICAL FINDINGS
At postmortem examination the brain weighed 1170 g. There was marked
atrophy of both frontal and temporal lobes with knifelike gyri. Coronal sections
revealed severe cortical atrophy in the frontotemporal lobes (Figure 3). There was marked ex vacuo dilatation of the ventricles.
The substantia nigra was pale. Histologically on hematoxylin-eosin–stained
sections, the frontotemporal lobe cortices demonstrated severe loss of neurons
with gliosis. Scattered ballooned Pick cells were found (Figure 4). Occasional Pick bodies were seen in the frontotemporal
lobe sections. The hippocampi showed neuronal loss with numerous Pick bodies
in the neurons of the fascia dentata (Figure
5). Numerous Pick bodies in the hippocampus demonstrated strongly
positive expression when stained with antibodies to tau protein (monoclonal
mouse anti–human paired helical filaments-tau, clone AT8 (Autogenbioclear,
Calne, Wiltshire, United Kingdom) by immunohistochemistry (Figure 6). No senile plaques or neurofibrillary tangles were found.
Both caudate nuclei demonstrated moderate neuronal loss with marked gliosis.
The putamen and globus pallidus were mildly involved with neuronal loss and
gliosis. The thalamus showed focal gliosis medially with mild neuronal loss.
Severe neuronal loss and gliosis were present in the insular cortex. The substantia
nigra showed severe loss of neurons with pigmentary incontinence and gliosis
in the pars compacta. There was gliosis around the aqueduct of Sylvius. No
Lewy bodies were found. Sections of the pons and the cerebellum were normal.
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Figure 3. The coronal section of the brain
shows severe atrophy of the temporal lobes and marked ex vacuo dilatation
of the temporal horns. The right side of the brain is on the right side of
the figure; left side of the brain, on the left.
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Figure 4. Photomicrograph showing a ballooned
Pick cell in the cortex (hematoxylin-eosin, original magnification x1000).
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Figure 5. Photomicrograph demonstrating
a Pick body (arrow) in the cytoplasm of a neuron in the fascia dentata of
the hippocampus (hematoxylin-eosin, original magnification x1000).
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Figure 6. Antibody to tau demonstrates numerous
positive Pick bodies in the neurons of the fascia dentata (peroxidase with
antibody to tau, original magnification x1000).
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COMMENT
To our knowledge, this patient represents the youngest woman with sporadic
Pick disease reported in the literature. Her diagnosis was confirmed by autopsy.
Because of her young age, the diagnosis of Pick disease was not entertained
until late in the disease course. By that time, many other possible causes
had been ruled out and striking symmetrical atrophy of the frontotemporal
lobes was obvious on MRI.
In general, the peak incidence of Pick disease is in the sixth decade
of life, and unlike Alzheimer disease (AD), patients present before 65 years
of age.3 This relationship was further supported
by the European Concerted Action on Pick's Disease Consortium's data4 that showed in 50 cases of histologically confirmed
Pick disease an earlier onset of disease than that found in AD. They also
documented that Pick disease was relatively uncommon after 70 years of age.4
There are 2 reports of familial Pick disease in which the patients,
2 brothers, were 21 and 25 years old when symptoms began.5-6
Several sporadic cases in younger individuals have been reported. Jacob et
al7 described a woman who presented at age
27 and on biopsy had tau-positive inclusions. A 27-year-old man with biopsy-proven
Pick disease was reported by Stewart et al.8
A third case reported by Mowadat et al9 described
a 28-year-old woman with clinical and scanning evidence for Pick disease,
but histological confirmation was not obtained. These 3 cases of sporadic
Pick disease were all reported in the 1990s suggesting that Pick disease is
being more frequently recognized in younger patients possibly because of better
imaging techniques, lower risk of biopsy, and the ability to rule out other
possible disorders.
Several studies have suggested features more commonly seen in young
patients with Pick disease. These include a high incidence of familial occurrence,
a short and progressive clinical course, severe basal ganglia disease, selective
degeneration of the substantia nigra, and strong positive expression of tau
protein in Pick bodies.10 Our patient with
sporadic Pick disease died 8 years following the onset of symptoms and had
marked involvement of the caudate and substantia nigra with neuronal loss
and gliosis. The putamen was also mildly involved. Diffuse Pick bodies revealed
strong tau protein expression by immunohistochemistry.
Degenerative dementia with early onset is rare. It is possible that
past cases have eluded detection or have been confused with psychiatric disorders
or other organic disease processes. The differential diagnosis in a young
patient presenting with dementia includes a long list of possible causes.
This list includes not only the degenerative diseases but also metabolic imbalances,
psychiatric illnesses, neoplasms, infections, posttraumatic sequelae, and
vascular disease. The history and clinical workup will eliminate most of these
causes and identify any treatable cause for the dementia.
After other diagnoses have been eliminated, Pick disease can often be
suspected by lobar atrophy detected in radiographic studies. Importantly,
Pick disease should be considered in the differential diagnosis of young adults
presenting with behavioral symptoms, especially those of frontal impairment.
AUTHOR INFORMATION
Accepted for publication January 15, 2002.
Author contributions: Study concept and design (Drs Coleman and Townsend); acquisition of data (Drs Coleman, Digre, Stephenson, and Townsend); analysis and interpretation
of data (Drs Coleman and Townsend); drafting of the
manuscript (Drs Coleman and Townsend); critical revision
of the manuscript for important intellectual content (Drs
Coleman, Digre, Stephenson, and Townsend); administrative, technical,
and material support (Drs Coleman and Digre); study
supervision (Drs Coleman, Digre, Stephenson, and Townsend).
Corresponding author: Jeannette J. Townsend, MD, Department of Pathology,
University of Utah Health Sciences Center, 30 N 1900 East, Salt Lake City,
UT 84132-2501 (e-mail: jeannette.townsend{at}hsc.utah.edu).
From the Departments of Pathology (Drs Coleman and Townsend), Neurology
(Dr Digre), and Psychiatry (Dr Stephenson), University of Utah Health Sciences
Center, Salt Lake City.
REFERENCES
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4. European Concerted Action on Pick's Disease (ECAPD) Consortium. Provisional and clinical and neuroradiological criteria for the diagnosis
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