Autopsy-Proven, Sporadic Pick Disease with Onset at Age 25 Years

OBSERVATION 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

Context: Pick disease is uncommon and accounts for began at age 25 years. She experienced progressive de- less than 2% of adult-onset dementias. Reports of Pick mentia over an 8-year period with radiographic evi- disease in young adults have apparently increased in the dence of severe cerebral atrophy of the frontotemporal last decade. lobes. Autopsy findings confirmed the diagnosis of Pick disease characterized by tau-positive Pick bodies in the Objective: To document the presentation and course neurons of the fascia dentata. of a patient with tau-positive Pick disease presenting at an extremely young age. Conclusion: Pick disease should be considered in the differential diagnosis of young adults presenting with behav- Setting: A university hospital. ioral symptoms, especially those of frontal impairment.

Patient: A white woman with cognitive impairment that Arch Neurol. 2002;59:856-859

1 N OFTEN-CONFUSED term, REPORT OF A CASE Pick disease is uncommon and accounts for less A white woman had normal develop- than 2% of adult-onset de- ment and was known as a high achiever mentias. The peak age of in high school and college. The member onsetA occurs between 45 and 60 years and of a large family, there was no family his- is rarely seen after age 75. The average dis- tory of dementia or other neurological disease duration is 5 to 10 years. Women are orders. She began to develop memory slightly more afflicted than men. Al- problems at the age of 25. Initially, she was though some patients have a clear family unable to recall the details necessary to history, usually with a dominant inherit- function at work. Her job required atten- ance pattern, more than 80% of cases are tion to fine detail and strong interper- sporadic in nature.2 sonal skills. Over the next 2 years, stark Patients present with progressive per- personality changes and behavioral prob- sonality and behavior changes, memory lems were noted. She began smoking and loss, and progressive fluent aphasia. Typi- drinking heavily and neglected normal cally, patients develop severe lobar atro- daily activities such as bathing and eat- phy that involves the frontotemporal ing. She was unable to remember the date lobes.2 The confusion associated with the without a watch. A computed tomo- term Pick disease causes debate in the lit- graphic scan of the brain at age 27 showed erature.1 In this case, we use the term to no abnormalities. Results of a visit to a phy- describe a pathological entity of tau- sician showed vitamin B12 deficiency. positive intraneuronal inclusions with She was appropriately treated with no im- clinical and radiographic features similar provement in mental function. She lost her to those just described. We present a pa- job at age 28 because of progressive From the Departments of tient who, to our knowledge, is the young- memory problems and lack of trustwor- Pathology (Drs Coleman and Townsend), Neurology est woman to be described with sporadic thiness. (Dr Digre), and Psychiatry Pick disease. The diagnosis of her condi- A psychological evaluation at age 29, (Dr Stephenson), University tion was confirmed at autopsy. She devel- because of continued alcohol abuse, dem- of Utah Health Sciences Center, oped symptoms at age 25 years and was onstrated severe memory impairment and Salt Lake City. severely demented by age 29. behavioral disinhibition that interfered sig-

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/25/2021 Figure 1. A T1-weighted sagittal magnetic resonance image demonstrating marked atrophy of the frontotemporal lobes.

nificantly 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 Figure 2. A T1-weighted coronal magnetic resonance image demonstrating symptoms could be due to Korsakoff syndrome or alco- marked atrophy of the temporal lobes. The right side of the brain is on the holic dementia, the rapidity of onset, along with the dis- left side of the figure; left side of the brain, on the right. inhibition, perseveration, loose associations, and flight of ideas suggested possible frontal lobe involvement. ing chapstick, blowing bubbles, or repeating numbers. Multiple laboratory tests were done at this time to At this time, findings from an electroencephalogram were look for possible viral diseases, toxins, or clotting ab- within normal limits, while another MRI showed severe normalities. Findings from tests for herpes simplex vi- cerebral atrophy of the frontotemporal lobes. She died 1 ruses 1 and 2, measles, cytomegalovirus, varicella- year 9 months later. zoster virus, and Epstein-Barr virus were negative, and the examination of the cerebral spinal fluid gave normal PATHOLOGICAL FINDINGS results. The VDRL test findings were negative. Test results for anti-cardiolipin antibodies and an anti-nuclear At postmortem examination the brain weighed 1170 g. antibody were negative. The levels of folate, vitamin B12, There was marked atrophy of both frontal and temporal thyroxine, and triiodothyronine were normal. Toxicol- lobes with knifelike gyri. Coronal sections revealed se- ogy screening was positive for ethanol at 103.2 mg/dL, vere cortical atrophy in the frontotemporal lobes but it was negative for benzodiazepines, opiates, salicy- (Figure 3). There was marked ex vacuo dilatation of lates, acetaminophen, tricyclic antidepressants, stimu- the ventricles. The substantia nigra was pale. Histologi- lant amines, cocaine, and barbiturates. cally on hematoxylin-eosin–stained sections, the fron- Three months after this evaluation, she began wan- totemporal lobe cortices demonstrated severe loss of neu- dering off and was admitted to a hospital because of her rons with gliosis. Scattered ballooned Pick cells were found progressive dementia and inability to take care of her- (Figure 4). Occasional Pick bodies were seen in the fron- self. A high-resolution magnetic resonance imaging (MRI) totemporal lobe sections. The hippocampi showed neu- study showed significant volume loss involving the me- ronal loss with numerous Pick bodies in the neurons of sial temporal structures and frontal lobes bilaterally in a the fascia dentata (Figure 5). Numerous Pick bodies in symmetric fashion. These included the hippocampal gyri the hippocampus demonstrated strongly positive expres- bilaterally, the uncus, the anterior aspect of the tempo- sion when stained with antibodies to tau protein (mono- ral lobes, and the white matter (Figure 1 and Figure 2). clonal mouse anti–human paired helical filaments-tau, There was some generalized cerebral and cerebellar at- clone AT8 (Autogenbioclear, Calne, Wiltshire, United rophy. Kingdom) by immunohistochemistry (Figure 6). No se- Over the next 2 years, she continued to decline and nile plaques or neurofibrillary tangles were found. Both would commonly pace while mumbling, repeating ran- caudate nuclei demonstrated moderate neuronal loss with dom numbers and her birthdate. She was under con- marked gliosis. The putamen and globus pallidus were stant supervision. She was unable to dress herself or mildly involved with neuronal loss and gliosis. The thala- shower without being told each step. She refused to stop mus showed focal gliosis medially with mild neuronal repeating numbers and, thus, had a difficult time eat- loss. Severe neuronal loss and gliosis were present in the ing. Another hospitalization at age 31 documented con- insular cortex. The substantia nigra showed severe loss tinued deterioration. She slept only 1 to 3 hours per night of neurons with pigmentary incontinence and gliosis in and would continually do repetitive tasks such as apply- the pars compacta. There was gliosis around the aque-

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/25/2021 Figure 3. The coronal section of the brain shows severe atrophy of the Figure 5. Photomicrograph demonstrating a Pick body (arrow) in the temporal lobes and marked ex vacuo dilatation of the temporal horns. cytoplasm of a neuron in the fascia dentata of the hippocampus The right side of the brain is on the right side of the figure; left side (hematoxylin-eosin, original magnification ϫ1000). of the brain, on the left.

Figure 4. Photomicrograph showing a ballooned Pick cell in the cortex Figure 6. Antibody to tau demonstrates numerous positive Pick bodies (hematoxylin-eosin, original magnification ϫ1000). in the neurons of the fascia dentata (peroxidase with antibody to tau, original magnification ϫ1000).

duct of Sylvius. No Lewy bodies were found. Sections of There are 2 reports of familial Pick disease in which the pons and the cerebellum were normal. the patients, 2 brothers, were 21 and 25 years old when symptoms began.5,6 Several sporadic cases in younger 7 COMMENT individuals have been reported. Jacob et al described a woman who presented at age 27 and on biopsy had tau- To our knowledge, this patient represents the youngest positive inclusions. A 27-year-old man with biopsy- woman with sporadic Pick disease reported in the litera- proven Pick disease was reported by Stewart et al.8 A ture. Her diagnosis was confirmed by autopsy. Because third case reported by Mowadat et al9 described a of her young age, the diagnosis of Pick disease was not 28-year-old woman with clinical and scanning evidence entertained until late in the disease course. By that time, for Pick disease, but histological confirmation was not many other possible causes had been ruled out and strik- obtained. These 3 cases of sporadic Pick disease were all ing symmetrical atrophy of the frontotemporal lobes was reported in the 1990s suggesting that Pick disease is obvious on MRI. being more frequently recognized in younger patients In general, the peak incidence of Pick disease is in possibly because of better imaging techniques, lower the sixth decade of life, and unlike Alzheimer disease (AD), risk of biopsy, and the ability to rule out other possible patients present before 65 years of age.3 This relation- disorders. ship was further supported by the European Concerted Several studies have suggested features more com- Action on Pick’s Disease Consortium’s data4 that showed monly seen in young patients with Pick disease. These in 50 cases of histologically confirmed Pick disease an include a high incidence of familial occurrence, a short earlier onset of disease than that found in AD. They also and progressive clinical course, severe basal ganglia dis- documented that Pick disease was relatively uncom- ease, selective degeneration of the substantia nigra, and mon after 70 years of age.4 strong positive expression of tau protein in Pick bod-

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/25/2021 ies.10 Our patient with sporadic Pick disease died 8 years tent (Drs Coleman, Digre, Stephenson, and Townsend); following the onset of symptoms and had marked in- administrative, technical, and material support (Drs volvement of the caudate and substantia nigra with neu- Coleman and Digre); study supervision (Drs Coleman, ronal loss and gliosis. The putamen was also mildly in- Digre, Stephenson, and Townsend). volved. Diffuse Pick bodies revealed strong tau protein Corresponding author: Jeannette J. Townsend, MD, De- expression by immunohistochemistry. partment of Pathology, University of Utah Health Sciences Degenerative dementia with early onset is rare. It is Center, 30 N 1900 East, Salt Lake City, UT 84132-2501 possible that past cases have eluded detection or have been (e-mail: [email protected]). confused with psychiatric disorders or other organic disease processes. The differential diagnosis in a young pa- REFERENCES tient presenting with dementia includes a long list of possible causes. This list includes not only the degenerative diseases but also metabolic imbalances, psychiatric ill- 1. Rossor MN. Pick’s disease: a clinical overview. Neurol. 2001;56(suppl 4):S3- nesses, neoplasms, infections, posttraumatic sequelae, and S5. 2. Esiri MM, Hyman BT, Beyreuther K, Masters CL. Ageing and dementia. In: Gra- vascular disease. The history and clinical workup will ham DI, Lantos PL, eds. Greenfield’s Neuropathology: Sixth Edition. Vol 2. Lon- eliminate most of these causes and identify any treat- don, England: Oxford University Press, Inc; 1997:192-198. able cause for the dementia. 3. Dickenson DW. Pick’s disease: a modern approach. Brain Pathol. 1998;8:339- After other diagnoses have been eliminated, Pick dis- 354. ease can often be suspected by lobar atrophy detected in 4. European Concerted Action on Pick’s Disease (ECAPD) Consortium. Provisional and clinical and neuroradiological criteria for the diagnosis of Pick’s disease. Eur radiographic studies. Importantly, Pick disease should J Neurol. 1998;5:519-520. be considered in the differential diagnosis of young adults 5. Lo¨wenberg K, Boyd DA Jr, Salon DD. Occurrence of Pick’s disease in early adult presenting with behavioral symptoms, especially those years. Arch Neurol Psychiatr. 1939;41:1004-1020. of frontal impairment. 6. Malamud N, Waggoner RW. Genealogic and clinicopathologic study of Pick’s disease. Arch Neurol Psychiatr. 1943;50:288-303. 7. Jacob J, Revesz T, Thom M, Rossor MN. A case of sporadic pick disease with Accepted for publication January 15, 2002. onset at 27 years. Arch Neurol. 1999;56:1289-1291. Author contributions: Study concept and design (Drs 8. Stewart JT, Ware MR, Bauer RM, Hoffman MK, Lefler LA. A case of early-onset Coleman and Townsend); acquisition of data (Drs Cole- Pick’s disease [letter]. J Clin Psychiatry. 1992;53:380. man, Digre, Stephenson, and Townsend); analysis and 9. Mowadat HR, Kerr EE, St Clair D. Sporadic Pick’s disease in a 28-year-old woman. Br J Psychiatry. 1993;162:259-262. interpretation of data (Drs Coleman and Townsend); draft- 10. Kobayashi K, Hayashi M, Fukutani Y, et al. KP1 expression of ghost Pick bodies, ing of the manuscript (Drs Coleman and Townsend); criti- amyloid P-positive astrocytes and selective nigral degeneration in early onset cal revision of the manuscript for important intellectual con- Picks disease. Clin Neuropathol. 1999;18:240-250.

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