Association of Ideomotor Apraxia with Frontal Gray Matter Volume Loss in Corticobasal Syndrome

ORIGINAL CONTRIBUTION Association of Ideomotor Apraxia With Frontal Gray Matter Volume Loss in Corticobasal Syndrome

Edward D. Huey, MD; Matteo Pardini, MD; Alyson Cavanagh, BS; Eric M. Wassermann, MD; Dimitrios Kapogiannis, MD; Salvatore Spina, MD; Bernardino Ghetti, MD; Jordan Grafman, PhD

Objective: To determine the brain areas associated with matter volume in the left supplemental motor area, pre- specific components of ideomotor apraxia (IMA) in cor- motor cortex, and caudate nucleus of patients with CBS. ticobasal syndrome (CBS). The overall degree of apraxia was independent of the side of motor impairment. Praxis to imitation (vs command) Design: Case-control and cross-sectional study. was particularly impaired in the patients with CBS. Pa- tients demonstrated equal impairment in transitive and Participants: Forty-eight patients with CBS and 14 con- intransitive praxis. trol subjects. Conclusions: In patients with CBS, IMA is associated with Intervention: Administration of the Test of Oral and left posterior frontal cortical and subcortical volume loss. Limb Apraxia. Despite showing left frontal volume loss associated with IMA, patients with CBS have particularly impaired imita- Main Outcome Measures: Differences between pa- tion of gestures. These findings suggest either that the IMA tients with CBS and healthy controls and associations be- of CBS affects a route of praxis that bypasses motor en- tween areas of gray matter volume and IMA determined grams or that motor engrams are affected but that they ex- by voxel-based morphometry in patients with CBS. ist in areas other than the inferior parietal cortex.

Results: Overall, IMA was associated with decreased gray Arch Neurol. 2009;66(10):1274-1280

ORTICOBASAL SYNDROME parts as objects),9 ideational (failure to se- (CBS) is a rare neurologic quence task elements correctly),7,10 and con- disorder characterized by ceptual (failure to use tools correctly).11 progressive asymmetric Ideomotor apraxia is the most commonly apraxia and rigidity with observed type of apraxia in CBS,5,6 as well otherC findings of cortical (eg, alien limb, cor- asthemoststudied.10 Severalresearchershave tical sensory loss, myoclonus, and mirror proposedthatsuccessfulpraxisofteninvolves movements) and basal ganglia (eg, brady- the use of motor engrams.12-14 The term en- kinesia and increased resistance to passive gram has been variably defined in the litera- movement) dysfunction.1,2 Corticobasal syn- ture. In this study, we define an engram as drome is defined as a clinical syndrome aris- a “visuokinesthetic motor memory” of a pre- ing from dysfunction of specific brain areas. viously performed action that facilitates re- It is associated with the neuropathological production of the action.13,15 It has been pro- changes of corticobasal degeneration3; how- posed that these engrams are contained in ever, the clinical syndrome of CBS can be the left inferior parietal lobe13,16 and com- observed with other underlying pathologi- municated to premotor and motor areas that cal conditions.4 are important in programming the move- Apraxia is a core clinical feature of ments coded for by the parietal representa- CBS1,2,5-8 and is defined as impaired pro- tion.13 In support of this theory, the left pa- duction of purposeful skilled movements rietal lobe is the lesion site most commonly that is not explained by deficits in elemen- associated with apraxia,17-22 and the left pa- tal motor functions, sensation, cognition, rietal lobe is activated with praxis in healthy or language.6 Apraxia has been classified individuals.23 However, damage to the left into different types: oral, limb-kinetic (loss frontalcortex,especiallytheleftmiddlefron- of hand and finger dexterity), ideomotor talgyrus,19 andsubcorticalstructures24 isalso (IMA) (deficits in executing goal-directed sufficient to cause IMA in the absence of pa- movements characterized by the presence rietal lesions.18 Author Affiliations are listed at of temporal and/or spatial errors as well as If motor engrams are damaged (from the end of this article. improper spatial orientation and use of body injury to the left inferior parietal lobe), pa-

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Patients With CBS Healthy Controls ␹2 or t Value (n=48) (n=14) for Difference P Value Sex, No. M/F 25/23 8/6 ␹2=0.001 .98 Age at onset, mean (SD), y 61 (9) NA NA NA Age at testing, mean (SD), y 66 (9) 60 (6) t=2.44 .02 Handedness, No. R/L/ambidextrous 43/4/1 14/0/0 ␹2=1.586 .45 Education, mean (SD), y 15 (3) 17 (4) t=1.99 .051 MDRS2 total raw score, mean (SD) (total possible, 144) 116 (24) 139 (3) t=3.65 .006a Initial side of symptoms, No. L/R/unclear 25/21/2 NA NA NA Side tested, No. L/R/both 33/13/2 NA NA NA

Abbreviations: CBS, corticobasal syndrome; L, left; MDRS2, Mattis Dementia Rating Scale 2; NA, not applicable; R, right. a Significant at a Bonferroni-corrected level of PϽ.05.

tients should have impairment of gesture recognition, imitation and equal impairment in the production of whereas frontal lesions should be associated with apraxia meaningful and meaningless gestures (ie, representa- with preserved gesture recognition.13,14 Thus, patients with tional IMA). If their IMA is more associated with frontal IMA from frontal damage should be able to recognize ges- dysfunction, they should show an advantage in produc- tures and perform them to imitation more easily than to ing gestures to imitation compared with command and command.13,25 Two studies found that patients with CBS meaningful gestures compared with meaningless ges- had IMA to command to a greater degree than to imita- tures (ie, dynamic IMA). tion or recognizing actions, suggesting a relative preser- 6,14 vation of movement representations, implicating fron- METHODS tal rather than parietal damage (although this was not directly tested). A deficit of functions associated with the frontal lobe in patients with CBS has been linked with SUBJECTS apraxia.6,26,27 In the 2-route model,9,28,29 separate routes are pro- Forty-eight patients with CBS seen consecutively in the Na- posed for gesture production and imitation depending tional Institute of Neurological Disorders and Stroke Cogni- tive Neuroscience Section clinic participated. All were en- on whether the gesture has meaning. The indirect or “lexi- rolled in an ongoing natural history study of CBS and related cal” route, associated with the inferior parietal lobe, is disorders. Patients were referred by outside physicians or self- used to process meaningful gestures and has access to referred. The diagnosis was confirmed by a neurologist with information about the gesture, including engrams. Dam- expertise in movement disorders and behavioral neurology age to this route can produce “representational” IMA char- (E.M.W.) and a neuropsychologist (J.G.) according to pub- acterized by greater impairment of transitive (involving lished criteria.1 All patients assigned durable power of attor- objects or tools) than intransitive (symbolic) gestures and ney before enrollment and assignees gave written informed con- equal impairment in the imitation of meaningful and sent for the study, which was approved by the institutional meaningless gestures.29 The direct route, associated with review board of the National Institute of Neurological Disor- frontoparietal structures, is used for the processing of ders and Stroke. Demographic and clinical data are presented in Table 1. Five patients died and their brains were obtained meaningless gestures and bypasses engramatic informa- at autopsy. All of them had a neuropathological diagnosis of tion. Damage to this route can produce “dynamic” IMA, corticobasal degeneration, according to standard criteria.3 The which is characterized by equal impairment of transi- healthy control subjects were recruited from the local commu- tive and intransitive gestures, but an advantage in imi- nity by advertisement and were age and education matched to tating meaningful gestures.29 This model is similar to that the patients (Table 1). All healthy controls underwent an in- proposed for language processing in which patients with terview and neurologic examination. The exclusion criteria for transcortical sensory aphasia can repeat words without the patients with CBS included a diagnosis of any neurodegen- understanding them.9 Other researchers have also pro- erative illness other than CBS, lack of a caregiver who could posed models of praxis that posit the utilization of sepa- assist with participation in the study, behavioral symptoms that rate systems of action knowledge and perceptual and mo- would preclude data collection, and any other medical or so- 30 cial condition that would, in the opinion of the investigators, tor processes to perform actions. preclude participation. The exclusion criteria for the healthy This study attempts to better characterize IMA in CBS controls included any active neurologic or psychiatric condi- and elucidate its neuroanatomic basis. Corticobasal syn- tion, use of any neurologic or psychiatric medications, and sig- drome is a good system in which to examine the relative nificant abnormalities on neurologic examination, magnetic reso- contributions of frontal and parietal cortices to IMA be- nance imaging, or neuropsychological testing. cause the patients often have both posterior frontal and parietal dysfunction. A second goal is to integrate these APRAXIA ASSESSMENT findings into current theories of IMA. Specifically, we hy- pothesize that if the patients have IMA associated with The measure of apraxia used in this study was the Test of Oral and dysfunction of engrams contained in the inferior pari- Limb Apraxia (TOLA).31 In the TOLA, each subject was asked to etal cortex, they should have especially poor praxis to perform each gesture first to verbal command (eg, “show me how

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Mean (SD) Comparison Between CBS and Standardization Groups Healthy Patients Standardization Test Controls With CBS Sample t Test P Value TOLA composite standard score 121b 100 (9) 100 (15) 0 Ͼ.99 Imitation standard score 14 (0.40) 8 (2) 10 (3) 4.31 .01 Command standard score 15 (0.10) 10 (2) 10 (3) 0 Ͼ.99 Oral standard score 14 (0.03) 10 (3) 10 (3) 0 Ͼ.99 Limb standard score 14 (0.30) 8 (2) 10 (3) 4.31 .01

Abbreviations: CBS, corticobasal syndrome; TOLA, Test of Oral and Limb Apraxia. a Scores on the TOLA composite and subtests for the 48 patients with CBS compared with the standardized sample and healthy controls of the TOLA standardization sample.31 The standardization sample was composed of 145 patients with ideomotor apraxia, mostly from stroke. The healthy control sample was composed of 21 healthy volunteers.31 A higher score reflects more intact praxis. b The normative data do not allow the computation of a standard deviation on this derived measure for the healthy controls.

you would wave ‘goodbye’”) and then to imitation (eg, “I want To determine whether severity of apraxia differed between you to imitate the following gesture”). The gestures were all mean- patients with CBS with predominantly left vs right hand af- ingful (ie, nonsense gestures were not evaluated). The TOLA31 con- fected, the TOLA composite standard score was compared in sists of 6 categories of tasks performed to both command and imi- right-handed subjects with left-hand impairment (25 pa- tation: proximal intransitive (eg, salute), proximal transitive (eg, tients) vs right-handed subjects with right-hand impairment stir a gallon of paint), distal intransitive (eg, make an “OK” sign), (21 patients) by the use of a 2-tailed t test. distal transitive (eg, dial a telephone), oral nonrespiratory (eg, bite an apple), and oral respiratory (eg, blow out a candle). In addi- IMAGING tion, subjects were shown pictures of an object and told, “Now I’m going to show you some pictures. Each picture shows an ob- A 1.5-T magnetic resonance imager (GE Medical Systems, Mil- ject that can be represented with a gesture. For example, here is waukee, Wisconsin) and standard quadrature head coil were a picture of a pen. If I were to represent it with a gesture without used to obtain all images. A T1-weighted spoiled gradient- talking, I would do this.” (Make an appropriate gesture.) “Now, echo sequence was used to generate 124 contiguous 1.5-mm- you make a gesture to represent this picture.”31 For this “gestured thick axial sections (repetition time, 6.1 milliseconds; echo time, pictures”task,3categoriesweretested:proximal(eg,ameatgrinder), minimum full; flip angle, 20°; field of view, 240 mm; 124 sec- distal (eg, tweezers), and oral (eg, toothbrush). Patients were in- tions; section thickness, 1.5 mm; matrix size, 256ϫ256ϫ124). structed to use the nondominant hand to perform the actions. If Voxel-based morphometry (VBM) analysis of the data was per- this hand was too impaired to perform the task, the dominant hand formed with SPM5 (http://www.fil.ion.ucl.ac.uk/spm/software was used. Table 1 shows the distribution of hands tested. On all /spm5) and followed the principles outlined by Ridgway et al.33 transitive oral gestures (eg, licking an ice cream cone), the patient Except as noted subsequently, all default SPM5 options were used. was restrained from cueing himself or herself by pretending to hold Images were segmented into gray matter, white matter, and ce- the object. The TOLA was administered and scored by trained rebrospinal fluid. In SPM5, spatial normalization, segmentation, bachelor’s- to master’s-level research assistants (including A.C.). and modulation are processed by means of a unified segmenta- All subject gestures were given a score of 0 to 3, where 3 repre- tion algorithm.32 This algorithm, in contrast to optimized VBM sents normal performance; 2 represents noticeable errors, hesi- used in SPM2 (in which the steps are completed sequentially), tancy, or self-correction; 1 represents a movement that retains some simultaneously calculates image registration, tissue classifica- basic elements but is largely disordered; and 0 represents a move- tion, and bias correction by using our participants’ structural mag- ment that lacks all crucial elements of the gesture. The TOLA has netic resonance images combined with the tissue probability maps been tested on healthy controls and patients with apraxia and has provided in SPM5. The segmented and modulated normalized gray been demonstrated to have content, predictive, concurrent, and matter images were smoothed with a 12-mm full-width at half- construct validity for the measurement of IMA.31 Patients who did maximum gaussian kernel. An explicit mask encompassing the not appear to understand the TOLA instructions were not included entire brain was used in the analyses to control for background in the analysis, although this excluded only 1 subject. signal outside the brain. This mask was downloaded from the SPM5 In a previous study, the TOLA was normed in a sample of Anatomic Automatic Labeling toolbox (http://www.cyceron.fr 145 patients with apraxia (139 from stroke, 6 from other causes) /web/aal__anatomical_automatic_labeling.html). A 0.05 ex- and 21 healthy subjects.31 A “standard score” was developed plicit absolute threshold for masking was used in the SPM second- for the total score and several subtests (see Table 2 for a com- level model interface.34 Total intracranial volume was calculated parison of the patients with CBS from our study with the pa- in SPM5 from the unsmoothed, modulated gray matter, white mat- tients and healthy controls from the normative TOLA sample). ter, and cerebrospinal fluid images from each patient and used The TOLA composite standard score is derived from the raw as a nuisance variable to account for the possible effect of vary- scores and assigned a mean of 100 and a standard deviation of ing brain volumes. We corrected the statistical significance thresh- 15 in the normative patient sample. The standard subscores have olds for multiple comparisons correction by 2 methods widely a mean of 10 and a standard deviation of 3 in the normative used in the neuroimaging community: the false discovery rate and patient sample. We compared the patients with CBS vs the the family-wise error correction. The false discovery rate is the healthy controls and patient populations from the TOLA nor- proportion of false-positive results among those tests for which mative sample with 1-tailed (between patients with CBS and the null hypothesis is rejected,35 whereas the family-wise error healthy controls) and 2-tailed (between patients with CBS and correction, which computes a correction for all voxels control- the standardization sample of patients) t tests on 5 of the TOLA ling for the chance of any false-positive results, is the most strin- summary measures (Table 2). gent correction for multiple comparisons available in SPM.36

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©2009 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/23/2021 Figure 2. Areas of reduced gray matter volume associated with reduced score on the Test of Oral and Limb Apraxia. With the areas from Figure 1 used as the region of interest, the gray matter densities in the areas shown negatively correlated significantly with the Test of Oral and Limb Apraxia composite standard score. Areas displayed in red are significant at an uncorrected PϽ.001 level with a threshold of 20 voxels and survive false discovery rate correction.

t=11.4, P=.01; oral: t=6.1, P=.01; limb: t=13.6, P=.01). We were unable to perform a t test on the TOLA composite standard score between the patients with CBS and healthy controls because the normative data do not allow the computation of a standard deviation on this derived measure for the healthy controls. However, the mean for the healthy controls on this measure is greater than 2 standard deviations above that of the patients with CBS. When compared with the TOLA standardization sample, patients with CBS had significantly lower scores on the imitation (t=4.31, P=.01) and limb (t=4.31, P=.01) measures. Within the CBS patient group, the limb scores were depressed compared with the oral scores (t=6.3, PϽ.05) Figure 1. Areas of significantly reduced gray matter volume in patients with and the imitation scores were depressed compared with corticobasal syndrome compared with healthy control subjects. Threshold Ͻ was 50 voxels; areas significant when corrected for multiple comparisons the command scores (t=10.3, P .05). No other signifi- with the family-wise error correction at the .05 level are shown in red. cant differences were observed. No significant difference (t=0.89, P=.38) in TOLA composite standard score was observed between right- First, the images from the patient group were compared with the images of a group of 14 age-matched healthy controls by handed patients with primarily right-hand impairment means of a 2-sample t test. Statistical threshold for this analy- (mean [SD] score, 98.4 [9.0]) and right-handed sis was set at PϽ.05, family-wise error–corrected for multiple patients with primarily left-hand impairment (101.3 comparisons. All subsequent analyses were limited to these areas [11.3]). of significant gray matter volume reduction. Especially stringent significance and voxel thresholds were used when pa- IMAGING tients with CBS were compared with healthy controls because the differences between the patients with CBS and the con- The VBM analysis showed patients with CBS to have re- trols were sufficiently large that using less stringent signifi- duced gray matter volume in the posterior frontal lobes cance and voxel thresholds resulted in much of the brain being (including supplemental motor area and dorsal premo- detected as significantly different between patients and controls. Figure 1 shows images and areas of significant differ- tor and prefrontal cortex) and anterior parietal lobes (in- ences between the patients with CBS and the healthy controls. cluding postcentral gyrus and superior parietal lobule) The relationship between voxel values and TOLA composite compared with healthy controls (Figure 1, Table 3). standard score was examined by means of a separate 1-tailed t Significantly reduced gray matter densities were also test, assuming that worsening praxis would be associated with found in the superior temporal and fusiform gyri, cau- decreased tissue volume. Total intracranial volume was added date nucleus, thalamus, and cerebellum (Figure 1, as a covariate of no interest. For this analysis, we considered Table 3). as significant those voxels surviving a threshold of both PϽ.001 The TOLA composite standard score (total IMA) cor- Ͻ uncorrected at voxel level and P .05 false discovery rate– related with decreased gray matter volume in the left corrected for multiple comparisons. All clusters reported were middle frontal and precentral gyri and the left caudate composed of at least 20 voxels (Figure 2). nucleus of patients with CBS (Figure 2, Figure 3, and Table 3). The TOLA limb score showed areas of de- RESULTS creased gray matter very similar to those associated with the TOLA composite standard score, likely reflecting the APRAXIA ASSESSMENT large contribution of limb IMA to total IMA. The VBM analyses of TOLA proximal, distal, transitive, intransi- As shown in Table 2, patients with CBS performed sig- tive, and oral scores did not show associations with areas nificantly worse than the healthy controls on the TOLA of gray matter volume loss that survived false discovery measures (TOLA imitation: t=13.6, P=.01; command: rate correction (data not shown).

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Cluster Dimension, Voxels Voxel T Value Voxel Z Value Peak MNI Coordinates x, y, z Anatomic Localization In Patients With CBS vs Healthy Controls (Figure 1)a 5690 7.68 6.37 0, 2, 64 Left cerebrum, superior frontal gyrus, BA 6 7.42 6.21 −2, −46, 66 Left paracentral lobule, BA 5 7.37 6.18 0, −14, 62 Left medial frontal gyrus, BA 6 501 7.10 6.01 58, −62, −30 Right cerebrum, fusiform gyrus, BA 37 5.43 4.87 52, −66, −20 Right fusiform gyrus, BA 19 801 6.55 5.66 28, −2, 68 Right cerebrum, middle frontal gyrus, BA 6 5.82 5.15 58, −4, 50 Right cerebrum, precentral gyrus, BA 6 799 6.52 5.64 6, 10, 12 Right caudate nucleus 5.63 5.02 2, −18, 14 Right thalamus 66 6.13 5.37 −26, 18, −44 Left cerebrum, superior temporal gyrus, BA 38 125 6.12 5.37 −68, −20, 14 Left postcentral gyrus, BA 40 5.12 4.63 −68, −18, 22 Left postcentral gyrus, BA 43 5.02 4.57 −68, −30, 22 Left inferior parietal lobule, BA 40 683 5.80 5.14 −40, 12, −12 Left insula, BA 13 127 5.59 4.99 −58, 2, 42 Left cerebrum, middle frontal gyrus, BA 6 5.23 4.72 −50, −2, 54 Left precentral gyrus, BA 6 4.90 4.47 −52, −12, 54 Left postcentral gyrus, BA 3 538 5.57 4.97 44, −8, 6 Right insula, BA 13 73 5.52 4.94 70, −20, 18 Right postcentral gyrus, BA 43 Associated With TOLA Composite Standard Score (Figure 2)b 44 4.55 4.08 −38, 10, 60 Left middle frontal gyrus, BA 6 49 4.03 3.69 −6, −2, 12 Left caudate nucleus 3.98 3.65 −62, −2, 38 Left precentral gyrus, BA 6

Abbreviations: BA, Brodmann area; CBS, corticobasal syndrome; MNI, Montreal Neurological Institute; TOLA, Test of Oral and Limb Apraxia. a Areas significant at a threshold of 50 voxels when corrected for multiple comparisons with the family-wise error correction at the .05 level. b Areas significant at an uncorrected P Ͻ .001 level and a threshold of 20 voxels that survived false discovery rate correction.

monly affected in CBS, cerebellar atrophy is less commonly 0.40 observed.1

0.35 Within the regions found to have decreased gray matter volume in the patients with CBS compared with healthy 0.30 controls, greater total IMA was associated with lower vol- 0.25 ume in the left supplemental motor area, dorsal premotor cortex, and caudate nucleus (Figures 2 and 3, and 0.20 Table 3). The predominance of left hemisphere findings 0.15 in Figure 2 (even though, as seen in Figure 1, the patients Gray Matter Density 0.10 with CBS as a group showed bilateral volume changes) is consistent with the dominant role of the left hemisphere 0.05 in praxis,18 especially since the left hand was tested in most patients (Table 1). Damage to the left posterior frontal lobe 0 0.4 0.8 1.2 1.6 (see Leiguarda and Marsden18 for a review) and basal gan- TOLA Total Composite Score glia24 have been associated with apraxia in illnesses other than CBS. The specific role of the basal ganglia in apraxia Figure 3. Correlation between Test of Oral and Limb Apraxia (TOLA) composite standard score and gray matter density in patients with remains unclear. However, damage to the basal ganglia usu- corticobasal syndrome in brain areas found to have significantly reduced ally results in apraxia with preservation of imitation and volume associated with the TOLA composite standard score in the discrimination, suggesting that the basal ganglia do not voxel-based morphometry analysis (r=0.53, P=.01). The TOLA composite contain motor engrams.24 The lack of significant imaging standard scores have been normalized to the mean. findings associated with most of the TOLA submeasures may reflect that this study did not have sufficient sub- COMMENT jects to adequately power these analyses. Future studies may disclose informative associations between these mea- Our data are consistent with previous imaging1,37-39 and sures and gray matter volume. autopsy1,3 studies on patients with CBS; compared with Previous studies of IMA (mostly from patients with the healthy subjects, the patients showed the greatest de- stroke) have found the strongest association between left crease of gray matter surrounding the dorsal precentral inferior parietal damage and IMA.18 Our data suggest that and postcentral gyri bilaterally, with additional volume patients with CBS have a more “frontal” form of IMA than decreases in the caudate nucleus, cerebellum, and fron- patients who are apraxic secondary to other neurologic tal, temporal, and parietal lobes. The frontal and occipi- disorders. However, the patients with CBS did not show tal poles were spared. Although the basal ganglia are com- preservation of praxis to imitation compared with the stan-

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©2009 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/23/2021 dardization TOLA apraxia sample. This finding sup- and apart from the attitudes of the sponsor. Study con- ports the report of Pazzaglia et al,40 which showed a simi- cept and design: Huey and Grafman. Acquisition of data: lar finding in patients with left frontal lesions. A difference Huey, Cavanagh, Wassermann, Kapogiannis, Spina, and between the current study and that of Pazzaglia et al40 is Ghetti. Analysis and interpretation of data: Huey, Par- that the lesions most associated with gestural compre- dini, and Grafman. Drafting of the manuscript: Huey and hension deficits in that study were more inferior in the Grafman. Critical revision of the manuscript for impor- frontal cortex than found in the present study. This could tant intellectual content: Huey, Pardini, Cavanagh, Wasser- reflect that the left frontal lesion distribution in that study mann, Kapogiannis, Spina, Ghetti, and Grafman. Statis- was more inferior than the atrophy observed in our pa- tical analysis: Huey and Pardini. Obtained funding: Spina, tients with CBS (Figure 1). Several previous studies have Ghetti, and Grafman. Administrative, technical, and ma- shown damage to the dorsal frontal cortex, as found in terial support: Ghetti and Grafman. Study supervision: the present study, to be more associated with IMA than Wassermann and Grafman. damage to the inferior frontal cortex.18,19,41-44 The only other Financial Disclosure: None reported. study to our knowledge that used VBM in CBS showed Funding/Support: This study was supported by the in- frontal and parietal volume loss associated with IMA in tramural program of the National Institutes of Health/ CBS, but did not analyze IMA to command vs imitation.45 National Institute of Neurological Disorders and Stroke The findings of this study are compatible with the (NIH/NINDS), grant 5R00NS060766 from the NINDS (Dr 2-route model of IMA29 because the patients demon- Huey), grant 5P30AG010133 from the National Insti- strated IMA associated with frontal atrophy and equal im- tute on Aging (Dr Ghetti), and the Litwin-Zucker Cen- pairment of transitive and intransitive gesture produc- ter for Research on Alzheimer’s Disease and Memory Dis- tion (ie, dynamic IMA). A processing advantage for orders (Dr Huey). meaningful gestures and an intact hand posture compo- Additional Contributions: We thank Nicole Arm- nent of transitive gesture production are also associated strong, BA, for manuscript preparation; Michael C. Tier- with this type of IMA29 but cannot be tested with the data ney, MA, and Karen Detucci, MA, for patient testing; the collected in this study and should be tested in a future study. National Institute of Neurological Disorders and Stroke/ In conclusion, this study suggests that IMA is associ- Clinical Center nurses for patient care; and Roland Zahn, ated with left posterior frontal and caudate atrophy in MD, PhD, for comments. CBS and is associated with a lack of preservation of praxis to imitation and equal impairment of transitive and intransitive gesture production. These findings suggest either REFERENCES that the IMA of CBS affects a route of praxis that bypasses motor engrams or that motor engrams are af- 1. Boeve BF. 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