BRIEF REPORT
Semantic Corticobasal Dementia Challenging Nosology in Frontotemporal Lobe Degeneration Simona Luzzi, MD,* Katia Fabi, MD,* Viviana Cafazzo, MD,* Fabio M. Fringuelli, MD,w Carlo Reverberi, PhD,z Sara Baldinelli, MD,* Mauro Silvestrini, MD,* Leandro Provinciali, MD,* Giorgio Ascoli, MD,w Stuart Pickering-Brown, PhD,y David Mann, PhD,y David Neary, MD,y and Julie S. Snowden, PhDy
Key Words: semantic dementia, corticobasal syndrome, frontotemporal dementia, apraxia
(Alzheimer Dis Assoc Disord 2015;29:360–363)
S
emantic dementia (SD) is a multimodal disorder of conceptual knowledge associated with bilateral, albeit often asymmetric atrophy of the temporal lobes, and pathology of frontotemporal lobar degeneration (FTLD).1–3 The salient presenting features are typically a profound anomia, semantic paraphasias, and impaired single-word comprehension, occurring in the context of fluent, effortless speech output, and preserved phonology, syntax, and other nonsemantic aspects of cognition. SD is generally believed to be specifically associated with FTLD TPD-43 type C pathology.4,5 Whereas SD is both highly distinct and strongly predictive of a specific pathology, that is not case for corticobasal syndrome (CBS). The extrapyramidal, apraxic syndrome of CBS can be associated with a variety of pathologies,6,7 albeit most often tau-based. Conversely, the tau pathology of corticobasal degeneration (CBD) may present clinically not only as CBS but also as progressive supranuclear palsy, a frontal behavioral syndrome consistent with frontotemporal dementia, spatial Alzheimer disease (AD), and progressive nonfluent aphasia.8 The combination of pure SD and CBS would be unexpected. Indeed, current diagnostic criteria for CBD8 explicitly identify semantic breakdown as an exclusion criterion for probable and possible CBD. In the literature there is scant evidence for an association between SD and CBS. There is mention of 1 patient with CBD pathology who presented with word finding Received for publication August 25, 2014; accepted September 4, 2014. From the *Department of Clinical and Experimental Medicine, Polytechnic University of Marche; wNuclear Medicine Department, Ospedali Riuniti di Ancona, Ancona; zDepartment of Psychology, Milano-Bicocca University, Milano, Italy; and yMental Health and Neurodegeneration Research Group, University of Manchester, Manchester, UK. The authors declare no conflicts of interest. Reprints: Simona Luzzi, MD, Clinica Neurologica, Dipartimento di Medicina Sperimentale e Clinica, Universita` Politecnica delle Marche, Ospedali Riuniti di Ancona, Via Conca, 1, 60020, Torrette di Ancona, Italy (e-mails: [email protected]; simonaluzzi@ yahoo.it). Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Website, www.alzheimerjournal.com. Copyright r 2014 Wolters Kluwer Health, Inc. All rights reserved.
difficulty, and later showed deficits in object recognition, comprehension and naming, as well as apraxia and behavioral change.9 Extrapyramidal signs were late and atypical for CBD because of bilateral rigidity. Formal exploration of semantic memory impairment and visual agnosia was not performed. Another report10 described a woman presenting with behavioral problems, fluent aphasia, and mildly asymmetric (left > right) melokinetic and ideomotor apraxia. No follow-up or pathologic confirmation of diagnosis was available and the possibility of atypical AD could not be excluded. In 2012, we described a 69-year-old patient, M with CBS who also showed features of SD.11 Structural magnetic resonance imaging showed prominent asymmetric (left > right) bitemporal atrophy, single-photon emission computed tomography hypoperfusion in the same regions, and a dopamine transporter scan reduced dopamine transport in the basal ganglia. Genetic screening for mutations in the progranulin gene was negative. In the present paper, we describe a woman who presented with a highly selective semantic breakdown, consistent with SD. After a 2-year follow-up, she developed ideomotor apraxia confined to her right upper limb together with a mild extrapyramidal syndrome in keeping with CBS.
CASE REPORT: PATIENT L Clinical History, Neurology, and Investigations L, a 76-year-old right-handed female native Italian retired teacher, with 17 years of education, came to neurological attention complaining of a 2-year history of problems in language. She had begun to make semantic paraphasias in conversation and to substitute generic terms such as “thing” and “stuff” for precise substantives. Her family also reported that she had difficulty recognizing acquaintances and well-known television personalities and sometimes she mistook their identity. Her memory was reported as fairly good and she had never been disoriented in time and place. No behavioral changes were reported. Specifically, there was no report of loss of empathy, rigidity, obsessive/compulsive, or clockwatching behavior. The family history was unremarkable.
Neurological Examination Neurological examination was entirely normal. No primary sensory or motor problems were present. Pyramidal, extrapyramidal, and cerebellar signs were absent.
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Alzheimer Dis Assoc Disord
Volume 29, Number 4, October–December 2015
Ocular movements were normal. No involuntary movements were reported or observed.
Neuropsychology Neuropsychological evaluation (Table 1) revealed deficits exclusively pertaining to semantic memory, and involving both verbal and nonverbal information. In the language domain she showed significant anomia with occasional semantic paraphasias (eg, “dog” for “lion”), but no phonological errors. Category fluency was severely reduced, letter fluency to a lesser degree. Singleword comprehension was mildly affected, whereas grammatical comprehension was well preserved. Reading, TABLE 1. L’s General Neuropsychology
Test (Maximum Score) General abilities MMSE (30) Memory Bisyllabic word span Corsi block span Rey figure B delayed recall (31) Executive functions Weigl’s sorting test (15) Luria’s Motor Sequences (50) Perceptuospatial skills VOSP Shape detection test (20) Incomplete letters (20) Silhouettes (30) Object decision (20) Dot counting (10) Number location (10) Position discrimination (20) Cube analysis (10) Benton’s face discrimination (27) Famous faces (19)w Poppelreuleter Ghent’s overlapping figures test (9) Praxis Buccolinguofacial praxis (20) Ideomotor praxis (20) right hand Ideomotor praxis (20) left hand Ideomotor praxis (10) right lower limb Ideomotor praxis (10) left lower limb Rey figure B copy (31) Language “Easy” picture naming (40)w “Easy” word-picture matching (40)w Reading (40)w Writing (40)w Repetition (40)w Verbal fluency (3 categories 1 min each)w Letter fluency (F, A, S)w Pyramids and Palm tree test verbal version (30)w Pyramids and Palm tree test visual version (30)w Comprehension of grammar (60)
L’s Baseline
L’s Follow-up
28
28
7 6 24.5
5 5 18
42
36*
19 17 8* 16 8 10 20 10 26 6* 9
20 19 7* 14* 8 10 20 10 26 6* 9
20 20 20 20 20 27
20 16* 20 20 20 26
34* 40 40 40 40 29*
31* 40 40 40 40 27*
39 28
21* 26
25*
22*
58
58
*Abnormal performance. wThese tests were developed locally, the patient’s performance being compared with a reference group of healthy controls matched for age, sex, and education, the “easy” picture naming and word-picture matching tests were originally developed by Snowden and colleagues, translated into Italian, and adapted for Italian participants. MMSE indicate mini mental state examination.
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Semantic Corticobasal Dementia
writing, and repetition were in the normal range. In the visual domain, she showed profoundly impaired recognition of famous faces. By contrast she could discriminate between faces on the basis of perceptual features. This pattern was in keeping with an associative prosopagnosia. Her mini mental state examination was in the normal range, and she showed preservation of short-term and longterm memory. In summary, her neuropsychological profile was that of a multimodal semantic disorder, consistent with SD. She gave her consent to the administration of an experimental battery of apraxia tests aimed to explore in detail gesture comprehension and production in dementias (described in Appendix as on line supplement, Supplemental Digital Content 1, http://links.lww.com/WAD/ A98). All gestures are videotaped for scoring in terms of accuracy and quality of errors. L’s performance was consistent with her semantic disorder. She made some errors in matching tasks because of failure to recognize object stimuli. Similarly, action pantomime was compromised only when she did not recognize the object (eg, she manipulated drumsticks as if they were a ladle). Otherwise, performance was entirely normal. On imitation, all gestures were executed flawlessly.
Neuroimaging Structural magnetic resonance imaging revealed mild bitemporal atrophy more marked on the right. Resting state positron emission tomography (PET) imaging was carried out. The images were reconstructed as transaxial 256256 matrices, with a pixel size of about 3.5 mm. Images were normalized to the voxel of maximum activity. Two blind experienced observers evaluated PET images for presence, location, and intensity of relative abnormal flourodeoxiglucose uptake. PET imaging showed moderate hypometabolism, involving both temporal poles and anterior parts of the middle and inferior temporal gyri, more marked on the right. There was a suggestion also of a minimal area of hypometabolism in the left parietal cortex (Fig. 1). The clinical profile was consistent with a diagnosis of SD.
Follow-up History Approximately 2 years after the first assessment, L was reviewed following an urgent phone call from her daughter, precipitated by an incident in which L’s right hand picked up a plate from the table and threw it to the ground. L reported that the action had been totally unintentional and she referred to her hand as “totally crazy.” Over the preceding few months L had developed clumsiness in her right hand and slowing in her movements. No memory problems were reported.
Neurology Neurological examination revealed a mild extrapyramidal syndrome, with hypomimia, bradykinesia, and akinesia in her right upper limb. Pyramidal and cerebellar signs were absent. Ocular movements were normal. No myoclonic jerks were noted. No sphincter problems were present.
Neuropsychology Her language disorder was qualitatively similar to that demonstrated previously albeit more pronounced. General
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Luzzi et al
Volume 29, Number 4, October–December 2015
FIGURE 1. L’s PET scan showing bitemporal and left parietal hypometabolism (A) and 2-year L’s PET scan follow-up showing a more marked left parietal hypometabolism compared with baseline (B).
cognitive status was unchanged. However, in contrast to previous assessment she showed a striking right upper limb apraxia, which was independent of her semantic impairment (Table 1). Buccofacial, left upper limb, and left and right lower limb actions were well preserved. In summary, the neuropsychological profile was changed. In addition to the multimodal semantic disorder, consistent with SD, L had developed prototypical features of CBS.
Neuroimaging A repeat PET scan (Fig. 1) revealed more marked anterior temporal ypometabolism together with a more accentuated, localized area of hypometabolism in the left parietal lobe, compared with previous examination. No subcortical hypometabolism was detected.
Cerebrospinal Fluid b-amyloid protein was in the normal range (684 pg/ mL; normal range, 567 to 1027 pg/mL). Protein tau was elevated (643 pg/mL; normal range, 170 to 512 pg/mL), as was phospho-tau protein (70 pg/mL; normal range, 36 to 66 pg/mL).
Genetics The patient gave her written consent to genetic analyses for research purposes. Genetic screening for mutations in the C9orf72 and progranulin genes was negative.
DISCUSSION The patient L, reported here presents an unusual symptom profile, combining the circumscribed semantic
deficits of SD with the asymmetric extrapyramidal syndrome and limb apraxia of CBS. The SD syndrome clearly preceded the CBS syndrome: neuropsychological examination and detailed evaluation of praxis firmly excluded the presence of ideomotor apraxia on initial examination. The association between SD and CBS emerged only 2 years later. The presence of an increased left parietal area of hypometabolism on follow-up PET imaging was in keeping with the clinical findings. The present case complements the case of patient M, reported previously.11 However, in patient M, in contrast to patient L, the syndromes of SD and CBS developed apparently in parallel, albeit with the CBS syndrome predominating. In both patients structural and functional neuroimaging revealed bitemporal atrophy and hypometabolism/ hypoperfusion, with less severe changes in parietal regions. However, in the present case, patient L, the changes in temporal regions were more marked in the right hemisphere, in keeping with her early symptom of impaired face recognition, whereas in patient M they were more marked on the left. Motor symptoms in both patients were asymmetric. However, perhaps counter-intuitively, in patient L they were more marked in the right limb and in patient M the left. It is relevant in this regard that in patient L, the greater rightsided temporal lobe hypometabolism was combined with a discrete area of parietal metabolism on the left. These 2 cases of combined SD/CBS syndromes differ somewhat from “prototypical” cases of SD and CBS. In both patients there was a relatively slow progression of the semantic impairment, and deficits on semantic association tasks were only moderately impaired. Reading and writing were relatively preserved with no evident features of surface dyslexia or dysgraphia. (It should be noted, however, that Italian is a transparent language providing less opportunity for regularization errors
362 | www.alzheimerjournal.com Copyright r 2014 Wolters Kluwer Health, Inc. All rights reserved. Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved.
Alzheimer Dis Assoc Disord
Volume 29, Number 4, October–December 2015
than other languages.) There were no reports of prominent behavioral change, as found in many patients with SD, although it is possible that patients’ prominent physical disability overshadowed such changes. In terms of motor symptoms, patient L showed characteristic features of CBS, with asymmetric akinesia, rigidity and ideomotor apraxia, and striking alien limb phenomena. The underlying pathologic substrate remains opens to speculation. The relatively slow progression of symptoms in both patients suggests that CJD is unlikely. AD cannot be firmly ruled out. Semantic impairment may occur in AD. Moreover, AD can occasionally present with an asymmetric, apraxic syndrome.12 AD pathology is reported in 20% to 25% of patients with CBS.8 The cerebrospinal fluid profile, although not entirely typical of AD, does not exclude it unequivocally. Nevertheless, semantic impairment is typically seen in the context of episodic memory disorder. The highly circumscribed nature of the semantic/ apraxic disorder, absence of memory problems, and frankly asymmetric extrapyramidal and apraxic disorder would be unusual in AD. A form of FTLD seems most likely. In recent years there has been increasing recognition of the clinical and pathologic overlap between CBS and syndromes of FTLD.6–9 Patients may present with an apraxic syndrome that mimics CBS, yet display the pathology associated with frontotemporal dementia. Conversely, patients may present with the language disorder of primary progressive nonfluent aphasia yet have CBD pathology. Distinct pathologies underlie FTLD, tau, and TDP-43 pathologies accounting for the majority of cases. SD in its pure form is almost invariably associated with TDP-43 pathology, subtype C in which dystrophic neurites are the predominant histologic feature. By contrast, semantic impairment in the context of prominent frontal behavioral disorder has been associated with tau pathology and mutations in the tau gene. Progressive nonfluent aphasia has been associated with both tau and TDP-43 pathologies, the presence of speech apraxia being a predictor of the former. In view of the presence of ideomotor apraxia, a tau pathology might be predicted. Nevertheless, the possibility cannot be ruled out that the patient has mixed tau and
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TDP-43 pathology giving rise to the unusual clinical phenotype. Pathologic confirmation will be required to resolve the issue.
REFERENCES 1. Hodges JR, Patterson K, Oxbury S, et al. Semantic dementia. Progressive fluent aphasia with temporal lobe atrophy. Brain. 1992;115:1783–1806. 2. Snowden JS, Neary D, Mann D. Frontotemporal Lobar Degeneration: Frontotemporal Dementia, Progressive Aphasia, Semantic Dementia. London: Churchill Livingstone; 1996. 3. Gainotti G. Different patterns of famous people recognition disorders in patients with right and left anterior temporal lesions: a systematic review. Neuropsychologia. 2007;45:1591–1607. 4. Mackenzie IR, Neumann M, Bigio EH, et al. Nomenclature for neuropathologic subtypes of frontotemporal lobar degeneration: consensus recommendations: an update. Acta Neuropathol. 2010;119:1–4. 5. Mackenzie IRA, Neumann M, Baborie A, et al. A harmonized classification system for FTLD-TDP pathology. Acta Neuropathol. 2011;122:111–113. 6. Kertez A, Martinez-Lage P, Davidson W, et al. The corticobasal syndrome overlaps progressive aphasia and frontotemporal dementia. Neurology. 2000;55:1368–1375. 7. Boeve BF. The multiple phenotypes of corticobasal syndrome and corticobasal degeneration: implications for further study. J Mol Neurosci. 2011;45:350–353. 8. Armstrong MJ, Litvan I, Lang AE, et al. 2013 Criteria for the diagnosis of corticobasal de generation. Neurology. 2013; 80:496–503. 9. Kertez A, McMonagle P. Behavior and cognition in corticobasal degeneration and progressive supranuclear palsy. J Neurol Sci. 2010;289:138–143. 10. Raggi A, Marcone A, Iannaccone S, et al. The clinical overlap between the corticobasal syndrome and other diseases of the frontotemporal spectrum: three case reports. Behav Neurol. 2007;18:159–164. 11. Luzzi S, Cafazzo V, Silvestrini M, et al. Semantic dementia associated with corticobasal syndrome: a further variant of frontotemporal lobe degeneration? J Neurol. 2012;259:1478–1480. 12. Snowden JS, Thompson JC, Stopford CL, et al. Clinical diagnosis of early-onset dementias: diagnostic accuracy and clinicopathological relationships. Brain. 2011;134:2478–2492.
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363
Semantic Corticobasal Dementia Challenging Nosology in Frontotemporal Lobe Degeneration Simona Luzzi, MD,* Katia Fabi, MD,* Viviana Cafazzo, MD,* Fabio M. Fringuelli, MD,w Carlo Reverberi, PhD,z Sara Baldinelli, MD,* Mauro Silvestrini, MD,* Leandro Provinciali, MD,* Giorgio Ascoli, MD,w Stuart Pickering-Brown, PhD,y David Mann, PhD,y David Neary, MD,y and Julie S. Snowden, PhDy
Key Words: semantic dementia, corticobasal syndrome, frontotemporal dementia, apraxia
(Alzheimer Dis Assoc Disord 2015;29:360–363)
S
emantic dementia (SD) is a multimodal disorder of conceptual knowledge associated with bilateral, albeit often asymmetric atrophy of the temporal lobes, and pathology of frontotemporal lobar degeneration (FTLD).1–3 The salient presenting features are typically a profound anomia, semantic paraphasias, and impaired single-word comprehension, occurring in the context of fluent, effortless speech output, and preserved phonology, syntax, and other nonsemantic aspects of cognition. SD is generally believed to be specifically associated with FTLD TPD-43 type C pathology.4,5 Whereas SD is both highly distinct and strongly predictive of a specific pathology, that is not case for corticobasal syndrome (CBS). The extrapyramidal, apraxic syndrome of CBS can be associated with a variety of pathologies,6,7 albeit most often tau-based. Conversely, the tau pathology of corticobasal degeneration (CBD) may present clinically not only as CBS but also as progressive supranuclear palsy, a frontal behavioral syndrome consistent with frontotemporal dementia, spatial Alzheimer disease (AD), and progressive nonfluent aphasia.8 The combination of pure SD and CBS would be unexpected. Indeed, current diagnostic criteria for CBD8 explicitly identify semantic breakdown as an exclusion criterion for probable and possible CBD. In the literature there is scant evidence for an association between SD and CBS. There is mention of 1 patient with CBD pathology who presented with word finding Received for publication August 25, 2014; accepted September 4, 2014. From the *Department of Clinical and Experimental Medicine, Polytechnic University of Marche; wNuclear Medicine Department, Ospedali Riuniti di Ancona, Ancona; zDepartment of Psychology, Milano-Bicocca University, Milano, Italy; and yMental Health and Neurodegeneration Research Group, University of Manchester, Manchester, UK. The authors declare no conflicts of interest. Reprints: Simona Luzzi, MD, Clinica Neurologica, Dipartimento di Medicina Sperimentale e Clinica, Universita` Politecnica delle Marche, Ospedali Riuniti di Ancona, Via Conca, 1, 60020, Torrette di Ancona, Italy (e-mails: [email protected]; simonaluzzi@ yahoo.it). Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Website, www.alzheimerjournal.com. Copyright r 2014 Wolters Kluwer Health, Inc. All rights reserved.
difficulty, and later showed deficits in object recognition, comprehension and naming, as well as apraxia and behavioral change.9 Extrapyramidal signs were late and atypical for CBD because of bilateral rigidity. Formal exploration of semantic memory impairment and visual agnosia was not performed. Another report10 described a woman presenting with behavioral problems, fluent aphasia, and mildly asymmetric (left > right) melokinetic and ideomotor apraxia. No follow-up or pathologic confirmation of diagnosis was available and the possibility of atypical AD could not be excluded. In 2012, we described a 69-year-old patient, M with CBS who also showed features of SD.11 Structural magnetic resonance imaging showed prominent asymmetric (left > right) bitemporal atrophy, single-photon emission computed tomography hypoperfusion in the same regions, and a dopamine transporter scan reduced dopamine transport in the basal ganglia. Genetic screening for mutations in the progranulin gene was negative. In the present paper, we describe a woman who presented with a highly selective semantic breakdown, consistent with SD. After a 2-year follow-up, she developed ideomotor apraxia confined to her right upper limb together with a mild extrapyramidal syndrome in keeping with CBS.
CASE REPORT: PATIENT L Clinical History, Neurology, and Investigations L, a 76-year-old right-handed female native Italian retired teacher, with 17 years of education, came to neurological attention complaining of a 2-year history of problems in language. She had begun to make semantic paraphasias in conversation and to substitute generic terms such as “thing” and “stuff” for precise substantives. Her family also reported that she had difficulty recognizing acquaintances and well-known television personalities and sometimes she mistook their identity. Her memory was reported as fairly good and she had never been disoriented in time and place. No behavioral changes were reported. Specifically, there was no report of loss of empathy, rigidity, obsessive/compulsive, or clockwatching behavior. The family history was unremarkable.
Neurological Examination Neurological examination was entirely normal. No primary sensory or motor problems were present. Pyramidal, extrapyramidal, and cerebellar signs were absent.
360 | www.alzheimerjournal.com Alzheimer Dis Assoc Disord Volume 29, Number 4, October–December 2015 Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved.
Alzheimer Dis Assoc Disord
Volume 29, Number 4, October–December 2015
Ocular movements were normal. No involuntary movements were reported or observed.
Neuropsychology Neuropsychological evaluation (Table 1) revealed deficits exclusively pertaining to semantic memory, and involving both verbal and nonverbal information. In the language domain she showed significant anomia with occasional semantic paraphasias (eg, “dog” for “lion”), but no phonological errors. Category fluency was severely reduced, letter fluency to a lesser degree. Singleword comprehension was mildly affected, whereas grammatical comprehension was well preserved. Reading, TABLE 1. L’s General Neuropsychology
Test (Maximum Score) General abilities MMSE (30) Memory Bisyllabic word span Corsi block span Rey figure B delayed recall (31) Executive functions Weigl’s sorting test (15) Luria’s Motor Sequences (50) Perceptuospatial skills VOSP Shape detection test (20) Incomplete letters (20) Silhouettes (30) Object decision (20) Dot counting (10) Number location (10) Position discrimination (20) Cube analysis (10) Benton’s face discrimination (27) Famous faces (19)w Poppelreuleter Ghent’s overlapping figures test (9) Praxis Buccolinguofacial praxis (20) Ideomotor praxis (20) right hand Ideomotor praxis (20) left hand Ideomotor praxis (10) right lower limb Ideomotor praxis (10) left lower limb Rey figure B copy (31) Language “Easy” picture naming (40)w “Easy” word-picture matching (40)w Reading (40)w Writing (40)w Repetition (40)w Verbal fluency (3 categories 1 min each)w Letter fluency (F, A, S)w Pyramids and Palm tree test verbal version (30)w Pyramids and Palm tree test visual version (30)w Comprehension of grammar (60)
L’s Baseline
L’s Follow-up
28
28
7 6 24.5
5 5 18
42
36*
19 17 8* 16 8 10 20 10 26 6* 9
20 19 7* 14* 8 10 20 10 26 6* 9
20 20 20 20 20 27
20 16* 20 20 20 26
34* 40 40 40 40 29*
31* 40 40 40 40 27*
39 28
21* 26
25*
22*
58
58
*Abnormal performance. wThese tests were developed locally, the patient’s performance being compared with a reference group of healthy controls matched for age, sex, and education, the “easy” picture naming and word-picture matching tests were originally developed by Snowden and colleagues, translated into Italian, and adapted for Italian participants. MMSE indicate mini mental state examination.
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Semantic Corticobasal Dementia
writing, and repetition were in the normal range. In the visual domain, she showed profoundly impaired recognition of famous faces. By contrast she could discriminate between faces on the basis of perceptual features. This pattern was in keeping with an associative prosopagnosia. Her mini mental state examination was in the normal range, and she showed preservation of short-term and longterm memory. In summary, her neuropsychological profile was that of a multimodal semantic disorder, consistent with SD. She gave her consent to the administration of an experimental battery of apraxia tests aimed to explore in detail gesture comprehension and production in dementias (described in Appendix as on line supplement, Supplemental Digital Content 1, http://links.lww.com/WAD/ A98). All gestures are videotaped for scoring in terms of accuracy and quality of errors. L’s performance was consistent with her semantic disorder. She made some errors in matching tasks because of failure to recognize object stimuli. Similarly, action pantomime was compromised only when she did not recognize the object (eg, she manipulated drumsticks as if they were a ladle). Otherwise, performance was entirely normal. On imitation, all gestures were executed flawlessly.
Neuroimaging Structural magnetic resonance imaging revealed mild bitemporal atrophy more marked on the right. Resting state positron emission tomography (PET) imaging was carried out. The images were reconstructed as transaxial 256256 matrices, with a pixel size of about 3.5 mm. Images were normalized to the voxel of maximum activity. Two blind experienced observers evaluated PET images for presence, location, and intensity of relative abnormal flourodeoxiglucose uptake. PET imaging showed moderate hypometabolism, involving both temporal poles and anterior parts of the middle and inferior temporal gyri, more marked on the right. There was a suggestion also of a minimal area of hypometabolism in the left parietal cortex (Fig. 1). The clinical profile was consistent with a diagnosis of SD.
Follow-up History Approximately 2 years after the first assessment, L was reviewed following an urgent phone call from her daughter, precipitated by an incident in which L’s right hand picked up a plate from the table and threw it to the ground. L reported that the action had been totally unintentional and she referred to her hand as “totally crazy.” Over the preceding few months L had developed clumsiness in her right hand and slowing in her movements. No memory problems were reported.
Neurology Neurological examination revealed a mild extrapyramidal syndrome, with hypomimia, bradykinesia, and akinesia in her right upper limb. Pyramidal and cerebellar signs were absent. Ocular movements were normal. No myoclonic jerks were noted. No sphincter problems were present.
Neuropsychology Her language disorder was qualitatively similar to that demonstrated previously albeit more pronounced. General
2014 Wolters Kluwer Health, Inc. All rights reserved.
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Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved.
361
Alzheimer Dis Assoc Disord
Luzzi et al
Volume 29, Number 4, October–December 2015
FIGURE 1. L’s PET scan showing bitemporal and left parietal hypometabolism (A) and 2-year L’s PET scan follow-up showing a more marked left parietal hypometabolism compared with baseline (B).
cognitive status was unchanged. However, in contrast to previous assessment she showed a striking right upper limb apraxia, which was independent of her semantic impairment (Table 1). Buccofacial, left upper limb, and left and right lower limb actions were well preserved. In summary, the neuropsychological profile was changed. In addition to the multimodal semantic disorder, consistent with SD, L had developed prototypical features of CBS.
Neuroimaging A repeat PET scan (Fig. 1) revealed more marked anterior temporal ypometabolism together with a more accentuated, localized area of hypometabolism in the left parietal lobe, compared with previous examination. No subcortical hypometabolism was detected.
Cerebrospinal Fluid b-amyloid protein was in the normal range (684 pg/ mL; normal range, 567 to 1027 pg/mL). Protein tau was elevated (643 pg/mL; normal range, 170 to 512 pg/mL), as was phospho-tau protein (70 pg/mL; normal range, 36 to 66 pg/mL).
Genetics The patient gave her written consent to genetic analyses for research purposes. Genetic screening for mutations in the C9orf72 and progranulin genes was negative.
DISCUSSION The patient L, reported here presents an unusual symptom profile, combining the circumscribed semantic
deficits of SD with the asymmetric extrapyramidal syndrome and limb apraxia of CBS. The SD syndrome clearly preceded the CBS syndrome: neuropsychological examination and detailed evaluation of praxis firmly excluded the presence of ideomotor apraxia on initial examination. The association between SD and CBS emerged only 2 years later. The presence of an increased left parietal area of hypometabolism on follow-up PET imaging was in keeping with the clinical findings. The present case complements the case of patient M, reported previously.11 However, in patient M, in contrast to patient L, the syndromes of SD and CBS developed apparently in parallel, albeit with the CBS syndrome predominating. In both patients structural and functional neuroimaging revealed bitemporal atrophy and hypometabolism/ hypoperfusion, with less severe changes in parietal regions. However, in the present case, patient L, the changes in temporal regions were more marked in the right hemisphere, in keeping with her early symptom of impaired face recognition, whereas in patient M they were more marked on the left. Motor symptoms in both patients were asymmetric. However, perhaps counter-intuitively, in patient L they were more marked in the right limb and in patient M the left. It is relevant in this regard that in patient L, the greater rightsided temporal lobe hypometabolism was combined with a discrete area of parietal metabolism on the left. These 2 cases of combined SD/CBS syndromes differ somewhat from “prototypical” cases of SD and CBS. In both patients there was a relatively slow progression of the semantic impairment, and deficits on semantic association tasks were only moderately impaired. Reading and writing were relatively preserved with no evident features of surface dyslexia or dysgraphia. (It should be noted, however, that Italian is a transparent language providing less opportunity for regularization errors
362 | www.alzheimerjournal.com Copyright r 2014 Wolters Kluwer Health, Inc. All rights reserved. Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved.
Alzheimer Dis Assoc Disord
Volume 29, Number 4, October–December 2015
than other languages.) There were no reports of prominent behavioral change, as found in many patients with SD, although it is possible that patients’ prominent physical disability overshadowed such changes. In terms of motor symptoms, patient L showed characteristic features of CBS, with asymmetric akinesia, rigidity and ideomotor apraxia, and striking alien limb phenomena. The underlying pathologic substrate remains opens to speculation. The relatively slow progression of symptoms in both patients suggests that CJD is unlikely. AD cannot be firmly ruled out. Semantic impairment may occur in AD. Moreover, AD can occasionally present with an asymmetric, apraxic syndrome.12 AD pathology is reported in 20% to 25% of patients with CBS.8 The cerebrospinal fluid profile, although not entirely typical of AD, does not exclude it unequivocally. Nevertheless, semantic impairment is typically seen in the context of episodic memory disorder. The highly circumscribed nature of the semantic/ apraxic disorder, absence of memory problems, and frankly asymmetric extrapyramidal and apraxic disorder would be unusual in AD. A form of FTLD seems most likely. In recent years there has been increasing recognition of the clinical and pathologic overlap between CBS and syndromes of FTLD.6–9 Patients may present with an apraxic syndrome that mimics CBS, yet display the pathology associated with frontotemporal dementia. Conversely, patients may present with the language disorder of primary progressive nonfluent aphasia yet have CBD pathology. Distinct pathologies underlie FTLD, tau, and TDP-43 pathologies accounting for the majority of cases. SD in its pure form is almost invariably associated with TDP-43 pathology, subtype C in which dystrophic neurites are the predominant histologic feature. By contrast, semantic impairment in the context of prominent frontal behavioral disorder has been associated with tau pathology and mutations in the tau gene. Progressive nonfluent aphasia has been associated with both tau and TDP-43 pathologies, the presence of speech apraxia being a predictor of the former. In view of the presence of ideomotor apraxia, a tau pathology might be predicted. Nevertheless, the possibility cannot be ruled out that the patient has mixed tau and
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Semantic Corticobasal Dementia
TDP-43 pathology giving rise to the unusual clinical phenotype. Pathologic confirmation will be required to resolve the issue.
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