Very Early Semantic Dementia with Progressive Temporal Lobe Atrophy an 8-Year Longitudinal Study

OBSERVATION Very Early Semantic Dementia With Progressive Temporal Lobe Atrophy An 8-Year Longitudinal Study

Kathrin Czarnecki, MD; Joseph R. Duffy, PhD; Carissa R. Nehl, PhD; Shelley A. Cross, MD; Jennifer R. Molano, MD; Clifford R. Jack Jr, MD; Maria M. Shiung, BA; Keith A. Josephs, MD, MST; Bradley F. Boeve, MD

Background: Semantic dementia is a syndrome within mal but subtle left anterior temporal lobe atrophy was the spectrum of frontotemporal lobar degenerations char- present. During the follow-up period of 8 years, she de- acterized by fluent progressive aphasia (particularly ano- veloped profound anomia and loss of word meaning as- mia) and loss of word meaning. sociated with progressive left anterior temporal lobe atrophy, consistent with semantic dementia. In more recent Objective: To report a unique case of very early seman- years, anterograde memory impairment and mild prosop- tic dementia with a slowly progressive course, allowing agnosia evolved in association with left hippocampal at- insights into the early natural history of this disorder. rophy and subtle atrophy in the homologous gyri of the right anterior temporal lobe. She remains functionally in- Design: Case report. dependent despite her current deficits. Setting: A tertiary care center. Conclusions: Early identification of patients who will develop semantic dementia is difficult and might be missed Patient: A 62-year-old woman who presented with with standard clinical, neuropsychological, and struc- “memory loss” complaints. tural neuroimaging evaluations. Recognition of this rela- Main Outcome Measures: Clinical course, neuropsy- tively rare syndrome is important for early diagnosis and chological data, and magnetic resonance imaging results. prognostication and particularly for therapeutic inter- ventions in the future. Results: The patient was first evaluated when the results of standard neuropsychological measures were nor- Arch Neurol. 2008;65(12):1659-1663

N 1982, MESULAM1 FIRST DE- semantic dementia have ubiquitin- scribed a series of patients who positive, tau-negative inclusions as the cor- had aphasia without dementia; he relate of their disease.5 More recent analy- later named this syndrome pri- ses6 have shown that such inclusions mary progressive aphasia. Such immunostain with TAR-DNA binding pro- patientsI can be distinguished on the ba- tein 43 (TDP-43). There also have been re- sis of fluency of speech, having either pro- ports of tauopathies and Alzheimer dis- gressive nonfluent or fluent aphasia. The ease in patients with semantic dementia,7 term semantic dementia refers to fluent although differentiating features might be Author Affiliations: aphasia with additional loss of word mean- found on neuropsychological testing and 2 8 Departments of Neurology ing. Clinically, patients have impair- brain imaging. The early natural course (Drs Czarnecki, Duffy, Cross, ment in language function and object rep- of semantic dementia is largely un- Josephs, and Boeve), Psychiatry resentation with preservation of episodic known, and many patients only come to and Psychology (Dr Nehl), and memory and absence of deficits in other medical attention when either profound Diagnostic Radiology (Dr Jack cognitive domains during the first 2 years anomia is already established or addi- and Ms Shiung), Mayo Clinic, of the illness.3 Imaging studies4 reveal dis- tional behavioral symptoms have devel- and Robert H. and Clarice tinct focal atrophy involving the infero- oped. We describe a unique patient who Smith and Abigail Van Buren Alzheimer’s Disease Research lateral temporal lobes, usually in an asym- presented to our clinic early in her illness Program of the Mayo metric distribution. There have been and developed slowly progressive seman- Foundation (Drs Jack, Josephs, advances in determining the underlying tic dementia with typical clinical and ra- and Boeve), Rochester, neuropathologic features of frontotempo- diologic features, allowing insights into the Minnesota. ral dementia, and most patients with early natural history of the disorder.

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©2008 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 METHODS plaints, her husband reported that she was substituting words, speaking in a circumlocutory manner, and mak- The patient was evaluated once yearly for 8 years by compre- ing semantic and frequent spelling errors. Formal speech hensive neurologic examination,9 neuropsychological testing, evaluation by an experienced speech pathologist (J.R.D.) and magnetic resonance imaging (MRI) of the brain as a par- demonstrated normal motor speech, verbal comprehen- ticipant in the Mayo Alzheimer Disease Research Center pro- sion and retention, verbal expression, and reading and writ- gram, a Mayo Foundation institutional review board– ing skills but a marked deficit in word retrieval (less than approved research program. the fifth percentile on the Boston Naming Test). Further- more, she often did not recognize missed target words when NEUROPSYCHOLOGICAL TESTING they were provided to her. During the following years, the patient had progression of anomia as documented by de- The patient underwent serial neuropsychological testing, in- cline in scores on the Boston Naming Test and category cluding assessment of global functioning (Folstein Mini- fluency. In contrast, scores remained average to above av- Mental State Examination),10 Kokmen Short Test of Mental erage for attention/executive functioning and visuospa- Status,11 learning and memory (Logical Memory and Visual Re- tial tasks. She performed near or above generally ac- productions subtests of the Wechsler Memory Scale–Revised, Per- cepted cutoff scores on screening measures (eg, Ն24 on cent Retention on the Auditory Verbal Learning Test), execu- the Folstein Mini-Mental State Examination and Ն29 on tive functioning (Trail Making Test parts A and B), Digit Symbol subtest of the Wechsler Adult Intelligence Scale–Revised, lan- the Kokmen Short Test of Mental Status). Anterograde guage functioning (Boston Naming Test, Controlled Oral Word memory performance was variable across follow-up with Association Test, category fluency), and visuospatial function- generally impaired visual reproductions of the Wechsler ing (Block Design subtest of the Wechsler Adult Intelligence Scale– Memory Scale–Revised and percent retention on the Rey Revised, Rey-Osterrieth Complex Figure Test, and Judgment of Auditory Verbal Learning Test performance for the last 3 Line Orientation). Mayo Older American Normative Studies to 5 years. In the most recent evaluation, all measures of norms were used to determine scaled scores for these tests, in anterograde memory were impaired (Figure 1). On serial which 10 represents the mean and 3 the SD.12-15 language examinations, she developed surface dyslexia, loss of word meaning, and difficulties in recognizing famous BRAIN IMAGING faces; she clearly met criteria for semantic dementia.3 Se- rial MRIs document progressive left anterior inferolateral The MRIs were performed using a Signa MRI scanner (General temporal lobe atrophy with relative sparing of the hippo- Electric Medical Systems, Waukesha, Wisconsin) at 1.5 Tesla, and campus until age 68 (Figure 2). On the most recent MRIs, images of the brain were obtained in sagittal (T1-weighted), axial there is evidence of right temporal lobe atrophy in a strik- (proton-density, T2-weighted, fluid-attenuated inversion recov- ingly similar pattern of topography compared with the left ery), and coronal (T1-weighted) planes. side. From a behavioral standpoint, the patient has become slightly more rigid mentally but remains indepen- REPORT OF A CASE dent in her simple and complex activities of daily living.

A 62-year-old woman was referred to our behavioral neurology clinic with a 6-month history of “memory loss,” COMMENT specified as problems recalling names of people and ob- jects. She had mild difficulties in organizational skills and We report a case of very early semantic dementia with complex decision making, such as cooking a meal follow- longitudinal neuropsychological and radiologic following a detailed recipe, but was highly functional in her ac- up, allowing insights into the early natural course of this tivities of daily living and engaged in various social activi- syndrome. Our patient exemplifies the way that subjec- ties. Her medical history was significant for treated tive “memory loss” complaints precede objective evi- pernicious anemia and hypothyroidism. The patient had dence of cognitive impairment by standard testing meth- recently retired from teaching and led a health-conscious ods. Her course during 8 years was remarkably slow in lifestyle. She reported that several second-degree family its progression, compared with previously published data, members had been diagnosed as having late-onset Alzhei- which gave an estimated mean survival time of 8 years mer disease. The results of general neurologic examina- after diagnosis.16 On initial evaluation, both her neuro- tion and standard laboratory workup were unremark- psychological assessment and imaging findings were be- able. Her mental status examination revealed a score of lieved to be normal, although in hindsight subtle atro- 33/38 on the Kokmen Short Test of Mental Status, recall- phy of the left collateral sulcus and superior temporal gyrus ing 3 of 4 items correctly on delay. On detailed neuropsy- was present on MRI. The striking asymmetry of tempo- chological testing, performance on learning and memory, ral lobe atrophy with predilection for the dominant hemi- language, and other cognitive domains was within the low sphere has been well described,4,17,18 and relative sparing average to average range (Figure 1). The results of the of the mesial temporal lobe structures seems to account initial MRI of the brain were considered normal for the for preservation of episodic memory, at least during the patient’s age, although in retrospect, subtle widening of initial years. Later in the course, the opposite homolo- the collateral sulcus and thinning of the superior tempo- gous temporal lobe regions tend to become atrophic in ral gyrus in the left anterior temporal lobe were present the exact same topography, as seen in our patient. The (Figure 2). The patient was seen on return visits for the underlying mechanisms of focal atrophy and eventual ho- following 8 years. Two years after onset of her com- mologous opposite hemisphere involvement in seman-

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35 25 30 20 25

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Total Score Total 15 10 10 5 5

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MOANS Scaled Score 4 4 BNT WMS-LM COWAT WMS-VR 2 2 Category Fluency AVLT-PR

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MOANS Scaled Score 4 4 TMT-A WAIS-BD TMT-B REY-O 2 2 Digit Symbol JLO

0 0 1 2 3 4 5 6 7 1 2 3 4 5 6 7 Evaluation Evaluation

Figure 1. Longitudinal performance in screening mental status examinations and key cognitive domains for specific neuropsychological tests. Tests covered the following areas: A, Folstein Mini-Mental State Examination; B, language; C, attention/executive; D, Kokmen Short Test of Mental Status; E, memory; and F, visuospatial. All raw scores were converted to scaled scores based on Mayo Older American Normative Studies (MOANS) norms (mean,10; SD, 3). Shaded areas represent scores in the abnormal range. Note that impaired performance on the Boston Naming Test preceded impairment on semantic fluency, and impairment in verbal and visual memory coincided with impaired naming. By history, a decline in the patient’s episodic memory was only noted at evaluation 7. AVLT-PR indicates percentage of retention on the Auditory Verbal Learning Test; BNT, Boston Naming Test; COWAT, Controlled Oral Word Association Test; JLO, Judgment of Line Orientation; ROCF, Rey-Osterrieth Complex Figure Test; TMT, Trail Making Test; WAIS-BD, Block Design subtest of the Wechsler Adult Intelligence Scale –Revised; WMS-LM, Logical Memory of the Wechsler Memory Scale –Revised; and WMS-VR, Visual Reproductions of the Wechsler Memory Scale –Revised.

tic dementia are unknown, but one could hypothesize nostic biomarkers. Furthermore, correlating the clini- that apoptosis and/or transcallosal degeneration is at play. cal dementia syndrome with underlying pathophysi- Making an early diagnosis and differentiating among ologic changes has proven to be difficult in frontotemporal the various dementia syndromes remain challenging even lobar degenerations.19 In a postmortem study,5 seman- for behavioral neurologists, stressing the need for diag- tic dementia has been shown to be associated with

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Figure 2. Magnetic resonance images (MRIs) showing progressive left anterior temporal lobe atrophy. Left column, Serial coronal T1-weighted images. Right column, Axial fluid-attenuated inversion recovery (FLAIR) images. Note subtle widening of the left collateral sulcus and thinning of the superior temporal gyrus on early MRIs with clear progression to atrophy, a hazy increased signal in the left mesial temporal lobe on FLAIR images, and development of atrophy in homologous regions in the right anterior temporal lobe over more recent MRIs. Numbers on the left represent the patient’s age (in years) corresponding to that row of images.

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©2008 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 tau-negative, ubiquitin-positive inclusions in 13 of 18 3. Neary D, Snowden J, Gustafson L, et al. Frontotemporal lobar degeneration: a cases. The ubiquitinated protein recently has been iden- consensus on clinical diagnostic criteria. Neurology. 1998;51(6):1546-1554. 4. Garrard P, Hodges JR. Semantic dementia: clinical, radiological and pathologi- tified as TDP-43, raising hope for future treatment strat- cal perspectives. J Neurol. 2000;247(6):409-422. 6 egies targeting TDP-43 pathophysiologic mechanisms. 5. Davies RR, Hodges JR, Kril J, et al. The pathological basis of semantic dementia. Treatment is most likely to be beneficial the earlier it is Brain. 2005;128(9):1984-1995. instituted but, as exemplified by this case, early diagno- 6. Neumann M, Sampathu DM, Kwong LK, et al. Ubiquitinated TDP-43 in fronto- sis will be challenging using standard neuropsychologi- temporal lobar degeneration and amyotrophic lateral sclerosis. Science. 2006; cal measures and MRI. 314(5796):130-133. 7. Knibb JA, Xuereb JH, Patterson K, et al. Clinical and pathological characteriza- tion of progressive aphasia. Ann Neurol. 2006;59(1):156-165. Accepted for Publication: March 11, 2008. 8. Josephs KA, Whitwell JL, Duffy JR, et al. Progressive aphasia secondary to Alz- Correspondence: Bradley F. Boeve, MD, Department of heimer disease vs FTLD pathology. Neurology. 2008;70(1):25-34. Neurology, Mayo Clinic, 200 First Street SW, Roches- 9. Wiebers DO, Dale AJD, Kokmen E, Swanson JW. Mayo Clinic Examinations in ter, MN 55905 ([email protected]). Neurology. 7th ed. St Louis, MO: Mosby–Year Book; 1998. Author Contributions: Study concept and design: Czarnecki 10. Folstein MF, Folstein S, McHugh P. “Mini-Mental State”: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975; and Boeve. Acquisition of data: Czarnecki, Duffy, Cross, 12(3):189-198. Molano, Jack, Shiung, and Boeve. Analysis and interpre- 11. Kokmen E, Smith G, Petersen R, Tangalos E, Ivnik R. The Short Test of Mental tation of data: Czarnecki, Nehl, Molano, Josephs, and Status: correlations with standardized psychometric testing. Arch Neurol. 1991; Boeve. Drafting of the manuscript: Czarnecki and Boeve. 48(7):725-728. Critical revision of the manuscript for important intellec- 12. Ivnik R, Malec J, Smith G, et al. Mayo’s Older American Normative Studies: WAIS-R, WMS-R, and AVLT norms for ages 56-97. Clin Neuropsychol. 1992;6(suppl): tual content: Duffy, Nehl, Cross, Molano, Jack, Shiung, 1-104. Josephs, and Boeve. Obtained funding: Jack. Administra- 13. Ivnik R, Malec J, Smith G, Tangalos E, Petersen R. Neuropsychological tests’ tive, technical, and material support: Jack, Shiung, and norms above age 55: COWAT, BNT, MAE Token, WRAT-R reading, AMNART, Boeve. Study supervision: Boeve. STROOP, TMT and JLO. Clin Neuropsychol. 1996;10:262-278. Financial Disclosure: None reported. 14. Lucas JA, Ivnik RJ, Smith GE, et al. Mayo’s Older Americans Normative Studies: Funding/Support: This research is supported by grants category fluency norms. J Clin Exp Neuropsychol. 1998;20(2):194-200. 15. Machulda MM, Ivnik RJ, Smith GE, et al. Mayo’s Older Americans Normative Stud- AG16574 and AG11378 from the National Institute on ies: Visual Form Discrimination and copy trial of the Rey-Osterrieth Complex Figure. Aging and the Robert H. and Clarice Smith and Abigail J Clin Exp Neuropsychol. 2007;29(4):377-384. Van Buren Alzheimer’s Disease Research Program of the 16. Hodges JR, Davies R, Xuereb J, Kril J, Halliday G. Survival in frontotemporal Mayo Foundation. dementia. Neurology. 2003;61(3):349-354. 17. Gorno-Tempini ML, Dronkers NF, Rankin KP, et al. Cognition and anatomy in three variants of primary progressive aphasia. Ann Neurol. 2004;55(3):335- REFERENCES 346. 18. Desgranges B, Matuszewski V, Piolino P, et al. Anatomical and functional alter- 1. Mesulam MM. Slowly progressive aphasia without generalized dementia. Ann ations in semantic dementia: a voxel-based MRI and PET study. Neurobiol Aging. Neurol. 1982;11(6):592-598. 2007;28(12):1904-1913. 2. Hodges JR, Patterson K, Oxbury S, Funnell E. Semantic dementia. Brain. 1992; 19. Boeve BF. A review of the non-Alzheimer dementias. J Clin Psychiatry. 2006;67 115(6):1783-1806. (12):1985-2001.

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