Cognitive and motor assessment in autopsy-proven corticobasal degeneration

Transcription

1 Cognitive and motor assessment in autopsy-proven corticobasal degeneration R. Murray, BS; M. Neumann, MD; M.S. Forman, MD, PhD; J. Farmer, MSc; L. Massimo, LPN; A. Rice, BS; B.L. Miller, MD; J.K. Johnson, PhD; C.M. Clark, MD; H.I. Hurtig, MD; M.L. Gorno-Tempini, MD, PhD; V.M.-Y. Lee, MD, PhD; J.Q. Trojanowski, MD, PhD; and M. Grossman, MD Abstract Objective: To investigate the clinical features of autopsy-proven corticobasal degeneration (CBD). Methods: We evaluated symptoms, signs, and neuropsychological deficits longitudinally in 15 patients with autopsy-proven CBD and related these observations directly to the neuroanatomic distribution of disease. Results: At presentation, a specific pattern of cognitive impairment was evident, whereas an extrapyramidal motor abnormality was present in less than half of the patients. Follow-up examination revealed persistent impairment of apraxia and executive functioning, worsening language performance, and preserved memory. The motor disorder emerged and worsened as the condition progressed. Statistical analysis associated cognitive deficits with tau-immunoreactive pathology that is significantly more prominent in frontal and parietal cortices and the basal ganglia than temporal neocortex and the hippocampus. Conclusion: The clinical diagnosis of corticobasal degeneration should depend on a specific pattern of impaired cognition as well as an extrapyramidal motor disorder, reflecting the neuroanatomic distribution of disease in frontal and parietal cortices and the basal ganglia. NEUROLOGY 2007;68: Corticobasal degeneration (CBD) is a neurodegenerative condition characterized by atrophy, gliosis, and tau-immunoreactive pathology in the gray matter and white matter of the neocortex, basal ganglia, and substantia nigra. Corticobasal syndrome (CBS), first described in 1968, 1 is a clinical disorder linked to the large family of akinetic-rigid diseases because of extrapyramidal motor features such as dystonia, myoclonus, gait impairment, and alien hand phenomena. Clinical identification of pathologically confirmed CBD can be difficult. 2-4 In this clinicopathologic report, we examine the clinical syndrome associated with autopsy-proven CBD. Cognitive deficits are said to emerge later in the course of CBS. 5,6 One proposed set of diagnostic criteria suggests that early dementia should be an exclusionary criterion for CBS. 7 Case descriptions of autopsy-proven CBD nevertheless report dementia early in the clinical course More recently, Grimes et al. 16 described 13 cases of pathologically confirmed CBD often presenting with dementia, although only Additional material related to this article can be found on the Neurology Web site. Go to and scroll down the Table of Contents for the April 17 issue to find the title link for this article. four of these cases carried the clinical diagnosis of CBS. Since this seminal work, several studies of patients with apparent CBS highlight impairments in multiple areas of cognition, including language, praxis, visuospatial functioning, calculation, and a social disorder. 13,14,17-22 However, the overwhelming majority of patients in these studies do not have neuropathologic confirmation that their deficits are due to CBD. In this report, we examine the spectrum of cognitive and motor features in 15 consecutively evaluated cases of pathologically confirmed CBD. Although we expect an extrapyramidal motor disorder, neuroimaging studies 19,20,23-28 and observations of gross pathology 2,16,29 suggest that we should also observe difficulties associated with impairments of gestural, language, executive, social, and visuospatial functioning. Methods. Subjects. A large multicenter registry of neurodegenerative disease autopsies performed at the University of Pennsylvania between 1995 and 2005 (n 114) 30 was examined to identify patients with the pathologic diagnosis of CBD. This search generated a list of 15 consecutively evaluated patients with CBD. Nine cases were evaluated clinically at the University of Pennsylvania and six at the University of California at San Francisco. Clinic visits occurred from 1988 through One case was seen clinically only once, and the data from this case were included with the initial evaluation. Patients with a complaint of From the Departments of Neurology (R.M., L.M., A.R., C.M.C., M.G.) and Pathology (M.S.F., V.M.-Y.L., J.Q.T.) and Center for Neurodegenerative Disease Research (M.N., M.S.F., J.F., V.M.-Y., J.Q.T.), University of Pennsylvania School of Medicine, Philadelphia, PA; and Department of Neurology (B.L.M., J.K.J., H.I.H., M.L.G.T.), University of California at San Francisco, San Francisco, CA. This work was supported in part by National Institutes of Health (NS44266, AG17586, AG15116, AG09215, AG10124, AG19724, and AG23501) and the Dana Foundation. Disclosure: The authors report no conflicts of interest. Received June 29, Accepted in final form December 11, Address correspondence and reprint requests to Dr. Murray Grossman, Department of Neurology, 2 Gibson, University of Pennsylvania School of Medicine, 3400 Spruce Street, Philadelphia, PA ; mgrossma@mail.med.upenn.edu 1274 Copyright 2007 by AAN Enterprises, Inc.

2 depression or who showed depression during the examination were treated with a nonsedating antidepressant such as sertraline. We also identified from this cohort a brain-damaged control group consisting of 21 autopsy-identified patients with a neurodegenerative disease not due to CBD. Control dementia patients were identified on the basis of having comparable clinical and neuropsychological data as well as similar demographic characteristics. The control group included patients with frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U, n 10), Alzheimer disease (AD, n 8), frontotemporal dementia with parkinsonism due to a mutation on chromosome 17 of the region coding tau (FTD-17, n 1), Pick s disease (PiD, n 1), and argyrophilic grain disease (AGD, n 1). Clinical data. Each chart was scored for the chief complaint, the presence of symptoms (reported by the subject or caregiver), and evidence of signs (as reported in the neurologic examination noted by the physician) from among those identified in a literature review of features reported in CBS. If a symptom or sign was not mentioned, it was scored as absent. Data from each patient s initial clinic visit and all subsequent follow-up visits were recorded. To ensure rater reliability, two examiners independently scored 67% of the charts. These raters achieved an overall agreement on symptom and sign data of 92.6% ( 0.76). Discrepancies between reviewers were resolved through open discussions. Neuropsychological testing. Data from cognitive assessments included as part of the routine evaluation at each institution were also examined. We assessed the following domains: Executive functioning. Digit span was assessed in both a forward and reverse direction. 31 Category fluency was assessed for both animals and letters (F-A-S), 32 although letter fluency for five patients was assessed using the number of D words. 33 We scored the average number of novel target words generated in 1 minute. Performance on the Stroop color-word interference task 34 examined the average number of correctly answered items per minute (to a maximum of 300 seconds). Language. Visual confrontation naming was assessed with an abbreviated version of the Boston Naming Test. 35 A 12-item oral sentence comprehension task was administered to assess grammatic comprehension. 36 Semantic memory was assessed by asking patients to make semantic category membership decisions about 24 pictures and 24 words, where half of the stimuli were members of the target category and half were foils, 36 and by assessment of semantic association between a target stimulus and one of two available choice stimuli presented as words or as pictures. 37 Visuospatial and constructional abilities. The constructional praxis portion of the Committee to Establish a Registry for Alzheimer s Disease (CERAD) was used to assess patients ability to copy four geometric shapes: a circle, a rectangle, a diamond, and a cube. 38 Memory. Episodic memory was assessed using a supraspan list learning task. 33,39 Nine words were presented to each patient in four successive trials or 10 words were presented in three successive trials. Participants recalled as many words as possible following a 2-minute filled period. Recognition of the target words, intermixed randomly with an equal number of new words, was then assessed. Three measures were examined: the total number of words registered across all trials (prorated to a total of 30 words), the percentage of words spontaneously recalled after a delay, and the percentage of words correctly recognized after a delay. Neuropathologic assessment. As described in detail elsewhere, 30 representative tissue obtained at the time of autopsy was fixed in both neutral-buffered formalin and 70% ethanol in 150 mmol/l NaCl, ph 7.4, paraffin embedded, and cut into 6- to 10- m thick sections. Sections were stained with hematoxylin and eosin, and thioflavin S. Immunohistochemistry was performed on sections of neocortex (mid-prefrontal gyrus, superior temporal gyrus, angular gyrus), hippocampus, putamen, globus pallidus, cerebellum, and midbrain including substantia nigra pars compacta. Immunohistochemistry was performed with antibodies to tau, ubiquitin, and -synuclein. The avidin-biotin-peroxidase method with 3,3=-diaminobenzidine for color development was used for all immunostaining. The neuropathologic diagnosis of CBD was made using criteria that emphasize tau-immunoreactive lesions in cortical and subcortical regions in a characteristic distribution. 29 This includes taupositive inclusions in cell bodies of neuronal and glial cells, astrocytic plaques, and extensive tau-immunoreactive cell processes in gray matter, white matter, and subcortical regions. The neuropathologic diagnosis of CBD was confirmed in all 15 cases. None of the cases with CBD fulfilled criteria for other neurodegenerative disorders such as AD, FTDL-U, PiD, Lewy body disease, or progressive supranuclear palsy. To characterize the severity of pathology, nerve cell loss, spongiosis, and gliosis were assessed semiquantitatively on a0to3scale as absent, mild, moderate, or severe. We related patient clinical features statistically to the severity and anatomic distribution of tau pathology using the semiquantitative grading of tau-immunoreactive lesions in cortical gray matter, white matter, and subcortical regions. Several of these cases were included in the autopsy series described by Forman et al., 30,40 and one patient (Case 11) was described by Gorno- Tempini et al. 41 Statistical analysis. Interrater reliability for the chart reviews was reported as the percentage of agreement. Cohen s statistic was used to evaluate interrater reliability. Performance on each measure of cognitive function is reported as a z score relative to 26 age- and education-matched healthy seniors. Significance was set at 2.32, equivalent to p 0.01 (two tailed), unless otherwise noted. Statistical evaluations of autopsy samples were performed with nonparametric techniques such as Friedman s analysis of variance by ranks, 2 test, and the Wilcoxon signed ranks test. All analyses were performed using SPSS statistical software package, version 12.0 (SPSS, Chicago, IL). Results. Demographic characteristics, chief presenting complaint, and final diagnosis. Table 1 shows that patients with CBD present at a relatively young age and that a majority of cases do not have a motor complaint at presentation. The mean age at onset in these patients was 60.9 years (range, 51 to 73 years). This is a little more than 4 years younger than the autopsy control group and more than 10 years younger than in AD (mean age at onset, 71.4 years), based on a cohort of 80 patients with a clinical and pathologic diagnosis of AD followed at the University of Pennsylvania Alzheimer s Disease Center. Disease duration of CBD, based on the family and patient report of first symptom onset, was 64.9 months (range, 24 to 96 months). This is approximately 9 months briefer than the autopsy control group, but considerably briefer on average than in AD, where we find a mean disease duration in the 80 autopsy-confirmed cases of AD at University of Pennsylvania of months. There was no gender preference in CBD. Family history was obtained in 14 cases, and a definite or probable family history of an FTD spectrum disorder was present in two (14%) of these 14 patients. We evaluated the number of patients with a chief presenting complaint related to motor difficulty compared to those complaining of cognitive disturbances (table 1). Eight (53.3%) of the patients presented exclusively with a cognitive complaint, whereas three (20%) of the patients presented with a motor complaint only. Four patients reported both cognitive and motor complaints at presentation. A final clinical diagnosis was available for all 15 patients in this cohort. Some cases carried more than one possible diagnosis. A clinical diagnosis of CBD was rendered in only six (40%) of the patients. Five of these six cases had motor signs at initial testing, compared to four of nine patients who were not diagnosed with CBD. Six patients carried a clinical diagnosis of FTD prior to death, two of whom also had the diagnosis of progressive nonfluent aphasia. Both patients who carried a clinical diagnosis of progressive supranuclear palsy (PSP) at the time of death demonstrated a vertical gaze palsy at initial examination. April 17, 2007 NEUROLOGY

3 Table 1 Demographic features, chief complaint, and final diagnosis* Case Gender Final clinical Dx Age at onset, y Disease duration, mo Education, y Family history Chief complaint(s) 1 F FTD-PNFA None Expressive speech difficulties. 2 M AD None Deterioration of memory and cognitive skills 3 M Atypical dementia None Decreased visual acuity. 4 M FTD Definite Agitation, unusual behavior, social withdrawal, depression 5 M Atypical PSP N/A Slow speech and walking, agitation, forgetfulness 6 F PSP Probable Less social, difficulty completing sentences, irritability, and depression 7 F CBD or FTD Possible Difficulty moving right arm and hand 8 M CBD or DLB None Difficulty speaking, handwriting difficulty, limb clumsiness 9 M FTD None Diminished speech, slowed movement, memory problems 10 F FTD-PNFA Possible Speech difficulties 11 F CBD None Difficulty expressing her thoughts, unable to say things quickly 12 M CBD N/A None Visual changes, gait difficulties, coordination difficulty 13 F CBD None Disturbance in right hand function, visuospatial difficulties 14 F CBD None Dead right foot, will not do what she wants it to; falls 15 F FTD-PNFA N/A None Speech and language difficulties Mean CBD 8 F/7 M Mean dementia controls 7 F/14 M * Age at onset was derived from patient charts as indicated by caregiver or physician. Disease duration was taken from onset date to date of death. Family history was determined according to a strict set of guidelines available form the authors. Chief complaint was obtained from patient charts. FTD-PNFA frontotemporal dementia progressive nonfluent aphasia; AD Alzheimer disease; PSP progressive supranuclear palsy; CBD corticobasal degeneration; DLB dementia with Lewy bodies; N/A not available. Longitudinal clinical assessment. Longitudinal clinical assessments of symptoms and signs are summarized in table 2. Symptoms and signs in individual patients with CBD are provided in table E-1 (available on the Neurology Web site at A variety of extrapyramidal motor features emerges at some point during the course of CBD, but signs ( ; p 0.05) become noticeably more frequent in CBD than in the autopsy control cohort only at the final clinical evaluation. At presentation, motor complaints were related most frequently to a gait disturbance. One patient attributed his gait difficulty to impaired visuospatial functioning rather than a motor disorder. Motor signs at presentation were most commonly unilateral limb rigidity or axial rigidity. All patients with CBD exhibited at least one extrapyramidal motor sign by the time of death. Unlike demented patients without CBD, rigidity and a gait disturbance were evident in a majority of patients with CBD prior to death. Involuntary movements such as dystonia, myoclonus, and alien hand phenomena were observed only in 20% of patients with CBD 1276 NEUROLOGY 68 April 17, 2007 at presentation, and any one of these findings was present on neurologic examination in only approximately one-third of patients at some point prior to death. The symptoms and signs summarized in table 2 also emphasize prominent gestural, executive, social, language, and visuospatial difficulties at onset in CBD, whereas episodic memory functioning is relatively preserved. Complaints and signs of apraxia were present in almost half of the patients with CBD, more commonly than in the autopsy control group (p 0.01, according to the binomial test). Apraxia in CBD interfered with manipulating an implement or dressing. Upper limb complaints were most common, although one patient presented with an initial complaint of a dead right foot. On examination, limb apraxia was commonly described as ideomotor. Oral apraxia was distinguished from dysarthria and anomia and may have contributed to the effortful speech seen in some patients. Although executive and social complaints occurred in CBD, they were not as common as in the dementia autopsy

4 Table 2 Longitudinal clinical symptoms and neurologic signs* Symptoms (%) Signs (%) Onset Prior to death Onset Prior to death CBD Other CBD Other CBD Other CBD Other Motor Axial rigidity Limb stiffness/rigid tone Falls/gait difficulty Resting tremor Masked facies Motor slowing/bradykinesia Diplopia/gaze palsy Dystonia Myoclonus Alien limb phenomena Apraxia Limb apraxia Oral apraxia Dressing apraxia Executive and social Inattention Impaired planning/mental search Perseverative behavior Disinhibition Behavioral changes Impaired insight Depression Language Effortful speech Word-finding difficulty/anomia Dysarthria Comprehension impairment Handwriting difficulty Apractic agraphia Visuospatial Lateralized neglect Visuospatial difficulty Left/right discrimination difficulty Cortical sensory loss Other Memory impairment Acalculia * Symptoms reflect patient or caregiver reports recorded in the chart. Signs reflect features specifically observed by a neurologist or a neuropsychologist. Data included in the prior to death column were mentioned in the clinic notes any time after the initial assessment. CBD corticobasal degeneration. group (p 0.01, according to the binomial test). Caregivers complaints about executive impairment in CBD focused on inattention and planning difficulty. An executive and social impairment was noted during the neurologic examination of more than half of the patients with CBD at presentation, as often as in the autopsy control group, but this worsened noticeably only in the non-cbd autopsy group ( ; p 0.05). All patients with CBD nevertheless developed a disorder of executive functioning at some point prior to death. Changes in social behavior were occasionally mentioned in patients with CBD. These difficulties included disinhibition, increased agitation, aggres- April 17, 2007 NEUROLOGY

5 1278 NEUROLOGY 68 April 17, 2007 siveness, hypersexuality, hyperorality, and inappropriate laughter. Although one patient was reported to have poor insight into his disease, many patients were noted to have intact insight despite significant impairments in other aspects of cognitive functioning. Language dysfunction was the most commonly reported complaint early in CBD, although this was not as common as in the non-cbd autopsy group ( ; p 0.05). CBD patients noted impaired word finding, effortful speech, and handwriting difficulty. Examination of patients with CBD revealed worsening naming and language output as the disease progressed (p 0.01, according to the binomial test), and five patients became so impaired that they were eventually said to be mute. Some patients with CBD were specifically observed to have apractic agraphia. Language comprehension was preserved initially in CBD, but this too appeared to worsen as the disease approached an end stage. When comprehension impairments were noted, they appeared to be caused by a deficit in understanding grammatically complex sentences rather than an impairment of single-word knowledge. Visuospatial complaints in CBD were less common than impairments in other domains, although one patient presented solely with a decline of visually mediated functioning. Another patient with CBD was said to have lateralized neglect, and visual agnosia also was observed. Visuospatial difficulty was seen on examination in half of the patients with CBD at some point prior to death, more commonly than in the non-cbd autopsy group (p 0.05, according to the binomial test). Cortical sensory loss may be underrepresented due to infrequent assessment. Difficulties with calculations in CBD were reported by caregivers as an impairment with money transactions. Detailed assessment of calculation demonstrated acalculia in some patients, but an assessment of calculations was not performed uniformly and thus may be underrepresented. In the context of this broad range of difficulties, episodic memory was relatively preserved in CBD. Although memory impairment was a frequent complaint of patients with CBD and caregivers, this occurred less commonly than in non-cbd autopsy controls (p 0.01, according to the binomial test). Although many of these patients with CBD had relatively intact episodic memory on neurologic examination, memory functioning worsened noticeably in the autopsy controls (p 0.01, according to the binomial test). Longitudinal neuropsychological assessment. Performance on neuropsychological tests, summarized in table 3, confirms difficulty in executive, language, and visuospatial domains and relatively preserved episodic memory in CBD. Despite numerous cognitive difficulties documented by the initial neurologic assessment, patients with CBD on average had a Mini-Mental State Examination (MMSE) score that was not within the demented range at presentation. During the subsequent years prior to death, the MMSE score in CBD decreased on average by approximately 3 points each year, similar to the rate of decline in the non-cbd autopsy group. Nevertheless, at a point only approximately 9 months prior to death when many patients had profound cognitive deficits, the MMSE suggested that patients with CBD were only moderately demented. Assessment of executive functioning revealed significant difficulty on multiple measures at the first examination in CBD, although there was only modest decline over time. This paralleled performance in the non-cbd autopsy group. Neuropsychological testing demonstrated few areas of significant language impairment in CBD early in the disease course. Although confrontation naming and comprehension worsened noticeably as the disease progressed in CBD, this was less than in the non-cbd autopsy group. Visuospatial functioning, assessed formally in only approximately half of the patients with CBD, was impaired initially in CBD but not in the non-cbd autopsy controls. Although ascertainment involved visuospatial constructions that include a motor component, visuospatial displacement errors were observed in the constructions of several patients with CBD that could not be explained by a motor limitation. In contrast to impairments in executive, language, and visuospatial functioning, formal episodic memory testing in CBD did not differ significantly from controls at the initial visit. Indeed, at the final testing session, when there was difficulty repeating words during the learning trials complicated by effortful speech and word-finding difficulty, there was no impairment in delayed memory recall or recognition in CBD. By comparison, memory difficulty was found in the non-cbd autopsy group, and this worsened noticeably over time. Neuroanatomic distribution of pathology. Histopathologic abnormalities were most prominent in frontal and parietal regions, although variable pathology was also present in other brain regions. Table E-2 summarizes atrophy grading and amount of tau pathology in cortical regions (mid-frontal gyrus, superior temporal gyrus, angular gyrus), hippocampal CA1 region, basal ganglia (putamen and globus pallidus), and substantia nigra on a scale ranging from 0 to 3. The pathology is illustrated in figure 1. All patients showed moderate to severe tau pathology in frontal gray matter and white matter (mean gray matter pathology grade 2.47; mean white matter pathology grade 2.40), whereas the inferior parietal lobule showed mild to severe tau pathology (mean gray matter pathology grade 2.07; mean white matter pathology grade 2.00). Most cases showed mild or no neuronal loss in the temporal lobe (mean gray matter pathology grade 1.73; mean white matter pathology grade 1.80] and CA1 region of the hippocampus (mean pathology grade 1.58), associated with relatively mild tau pathology. Nevertheless, occasional cases demonstrated more prominent cell loss and tau pathology in these regions. The basal ganglia (mean pathology grade 2.50) and the substantia nigra (mean pathology grade 2.40) were moderately to severely affected in most patients. However, Case 7 showed only mild midbrain tau pathology, and four patients showed only mild neuronal loss and gliosis in the substantia nigra. Statistical analysis confirmed the prominent tauimmunoreactive pathology in frontal and parietal regions relative to temporal and hippocampal regions, consistent with the profile of cognitive difficulty seen in these cases. Analysis of tau-immunoreactive histopathology from cortical and subcortical regions thus demonstrated a difference between gray matter regions ( ; p ) and a difference between white matter regions ( ; p 0.004). According to Wilcoxon signed ranks tests, temporal cortex and hippocampal regions had the least pathology (each contrast significant at least at the p 0.05 level,

6 Table 3 Longitudinal neuropsychological assessment* Initial evaluation Second evaluation CBD Other CBD Other Age, y 63.6 (7.9) 65.7 (12.5) 66.3 (7.9) 68.1 (9.7) Time after symptom onset, mo (13.4) 39.6 (34.1) 55.4 (18.7) 73.5 (40.3) MMSE (max 30) 25.7 (2.8) 23.2 ( 6.4) 16.7 (9.0) 17.0 (9.9) Executive Forward Digit Span 0.33 (13) 0.57 (20) 1.07 (9) 2.20 (17) Reverse Digit Span 1.08 (13) 0.97 (20) 2.25 (12) 2.56 (16) Animal fluency 2.92 (13) 2.06 (18) 3.44 (10) 3.40 (17) FAS or D/minute 2.35 (12) 1.42 (18) 2.73 (7) 2.91 (8) Stroop time, sec 4.64 (5) 4.12 (7) 7.27 (3) 7.06 (7) Stroop correct/min 2.41 (7) 2.81 (7) 3.15 (6) 3.99 (7) Language Boston Naming Test 0.76 (11) 2.35 (19) 3.31 (10) 7.44 (16) Sentence comprehension total 1.70 (5) 1.54 (16) 1.19 (4) 2.90 (13) Single written word comprehension 1.43 (5) 1.62 (16) 2.03 (4) 4.66 (12) Single picture comprehension 0.99 (5) 2.84 (17) 2.10 (4) 6.09 (12) Pyramid and Palm Trees pictures 1.58 (3) 8.07 (6) 8.91 (4) (2) Pyramid and Palm Trees written 3.35 (3) (5) (4) (2) Visuospatial Constructional praxis 4.73 (6) 1.56 (19) 5.01 (6) 3.24 (17) Memory List learning total 0.93 (12) 2.63 (20) 2.90 (10) 4.68 (17) Word list recall 1.03 (13) 2.46 (21) 1.52 (13) 3.57 (17) Word list recognition 0.94 (11) 2.13 (21) 1.33 (9) 4.23 (17) * All data are z scores except for mean ( SD) age and education, and raw MMSE score. z Scores compared mean group performance to 26 age-matched healthy seniors; we set a threshold of significant impairment at z less than 2.32 (p 0.01, two tailed). Neuropsychological data were obtained from focused testing and bedside examination. When multiple testing dates were available, the data with the most complete battery of tests that fell closest to the initial evaluation or time of death were used. CBD corticobasal degeneration; MMSE Mini-Mental State Examination; FAS or D/minute letter-guided category naming fluency. relative to frontal, parietal, and subcortical regions), although the temporal cortex and hippocampal regions did not differ from each other. White matter of the temporal lobe also showed less tau pathology than frontal white matter (z 3.00; p 0.005). Discussion. Our findings support growing evidence that CBD presents with cognitive difficulties that are as prominent as their motor deficits. The cognitive picture that emerges in our study highlights a characteristic impairment of gestural, executive, social, language, and visuospatial functioning, but relative sparing of episodic memory, even late in the disease. This pattern of selective cognitive impairment appears to forecast the anatomic distribution of pathology, with relatively prominent frontal and parietal disease in addition to basal ganglia pathology, but modest involvement of the temporal lobe and hippocampus. We conclude that the characteristic clinical features of CBS should be modified to reflect the cognitive impairment as well as the motor disorder associated with the histopathologic diagnosis of CBD. We discuss the clinical features consistent with a pathologic diagnosis of CBD in greater detail below. CBD is classically described as an akinetic-rigid syndrome with asymmetric motor features such as rigidity, dystonia, and myoclonus. 1,6,42 Four large series of autopsy-confirmed CBD have been reported. These studies emphasize rigidity, bradykinesia and a gait disorder, 15 a useless arm, 6 limb clumsiness and tremor, 43 and asymmetric extrapyramidal features that help distinguish CBS from other conditions such as PSP and FTD. 44 Virtually all patients in our cohort exhibit at least some extrapyramidal motor features prior to death, and we observe the same spectrum of motor difficulty as described in the literature. The most common extrapyramidal motor signs in the present series include axial rigidity associated with gait difficulty and asymmetric limb rigidity. Other features include alien hand phenomena, dysto- April 17, 2007 NEUROLOGY

7 Figure. Topographic distribution and variability of tau pathology in corticobasal degeneration. (A to H) Case 11 presented with decreased language output and also had executive impairments on neuropsychological assessment. Her clinical course changed abruptly 4 years later, and she developed an alien limb. Although cognitive and language function continued to decline, the extrapyramidal disorder became her major source of disability. Language output deteriorated to the point where she was characterized as functionally mute. This pattern of clinical impairment was associated with moderate to severe tau pathology including neuronal cytoplasmic inclusions (arrowhead in A), extensive tau-positive cell processes, astrocytic plaques (arrows in A) and oligodendroglial cytoplasmic inclusions (inset in B) in the frontal (A, B), temporal (C, D), and parietal (E, F) lobes as well as in the globus pallidus (G). In the CA1 region of the hippocampus, only modest numbers of tau-positive neuronal inclusions and cell processes were detectable (H). (I to P) Case 10 initially presented with hesitant, effortful speech that was self-described as due to difficultly with initiation. She was clinically diagnosed with progressive nonfluent aphasia shortly after presenting to clinic and was noted to have surprisingly good comprehension until relatively late in the disease course. No motor symptoms were observed clinically until almost 4 years after the onset of her language difficulties, when she developed rigidity, gait difficulty, and executive impairments manifested clinically as echolalia. This was associated with moderate tau pathology in the frontal (I, J) and parietal lobes (M, N), but only mild involvement of the temporal lobe (K, L). The globus pallidus was moderately affected (O). The hippocampus showed only few tau-positive inclusions (P). Tau immunostains, PHF1. Fg frontal gray; Fw frontal white; Tg temporal gray; Tw temporal white; Pg parietal gray; Pw parietal white. Scale bar in A: 50 m NEUROLOGY 68 April 17, 2007 nia, myoclonus, and tremor. We also find a supranuclear gaze palsy in approximately one-third of patients. 5,45 The motor disorder presumably is related to frontal disease as well as involvement of the striatum and the brainstem. 2,46-48 Regardless of the neuroanatomic basis for these motor difficulties, the typical pattern of motor impairment underlines that this cohort does not represent an unusual sampling of cases with CBD. Less than half of the patients in this series present with motor-related complaints. Even with the observation of a motor impairment, the diagnosis of CBD was considered in less than half of the patients. This is true of other clinicopathologic series as well. 2,4,16,49 Some of the difficulty identifying CBD clinically may be the delayed onset of motor features and misdiagnosis as another akinetic-rigid disorder such as Parkinson disease or PSP. In this context, early identification of CBS can be enhanced by recognition that a specific pattern of cognitive impairment is an essential characteristic of this disorder. Patients with CBS are often said to have few cognitive deficits. 1,5,6 Cognitive symptoms are featured less prominently than motor deficits at presentation, according to this view, but cognitive signs may emerge late in the course of the disease process. We find instead the reverse order of occurrence. Cognitive deficits thus often precede the motor difficulties as the disease evolves clinically. Neuroimaging studies 19,20,23-28 and descriptions of gross pathology 2,16,29 emphasize a neuroanatomic distribution of disease centered in frontal and parietal lobes. The profile of cognitive difficulty appears to correspond to this distribution of disease. Apraxia is said to be a hallmark of CBS, 50 due in part to its presence in patients with autopsy-proven CBD. 2,6,16,43 In the present cohort, complaints about implement use and dressing difficulty are not uncommon. Neurologic examination reveals ideomotor apraxia in almost half of the patients. Apraxia is often asymmetric in nature: Apraxia presenting primarily in the dominant hand seems to be associated with an ideomotor disorder executing meaningful movements, but apraxia presenting primarily in the nondominant hand often includes spatial errors during reproduction of a nonmeaningful gesture relating body parts to each other. The disorder of apraxia in CBS corresponds to the significant pathology that we observe in frontal and parietal brain regions. This is consistent with an imaging study associating limb apraxia in CBS with a glucose metabolic PET defect in the contralateral supplementary motor area and superior parietal lobule. 25 Significant executive difficulty in the present re-

8 port appears to be related to prominent frontal pathology in CBD. There are few reports of executive dysfunction in autopsy-confirmed cases of CBD, but executive difficulties such as impaired planning, poor inhibitory control, and limited mental search are documented in patients with clinically diagnosed CBS. 13,28,51,52 In the current series, patients and their caregivers rarely complain of executive difficulty. However, deficits in mental search are present in a majority of patients at the initial examination. This is confirmed by neuropsychological assessments showing significant deficits on measures of category naming fluency and the Stroop test. These findings should be interpreted cautiously because deficits on verbally mediated measures may be due in part to their language difficulty. Regardless of the basis for an executive impairment, this disorder persists throughout the course of the disease. A disorder of social comportment and personality is described in patients with pathologically confirmed CBD, including bizarre behavior, personality change, and apathy. 16,43 Behavioral changes such as these are observed in the present study as well, although less frequently than in the non-cbd autopsy group. However, many patients with CBS in this series have good insight into their disease, perhaps contributing to the frequent observation of depression. 21 Although depression may contribute to cognitive difficulty in CBD, the frequency of depression does not differ between CBD and the control group, and depression alone is unlikely to explain the qualitatively distinct neuropsychological characteristics of CBD patients compared to the control groups. Frontal and parietal involvement also may play a role in the pattern of language impairment seen in CBD. In a comprehensive review of the literature, 44% of patients with pathologically confirmed CBD are said to have some form of language difficulty. 53 Patients with autopsy-confirmed CBD may present with a speech and language disorder, 8,12,14,16,41,54 although dysarthria or agraphia may be due in part to a motor disorder. 5,55,56 In the present series, patients frequently complain of speech and handwriting difficulty. Neurologic examination confirms the common occurrence of effortful speech and dysarthria, consistent with previous observations. 14,54 Neuropsychological evaluation shows that patients with CBD have a mild deficit in naming and single-word comprehension at presentation. The grammatic comprehension deficit observed in some patients may be due in part to a limitation in executive resources needed to understand a complex sentence. Moreover, language impairments worsen noticeably as the disease progresses. Although difficulty on measures of apraxia and visuospatial functioning may be helpful in the initial diagnosis of CBD, performance on language measures thus may be useful for tracking disease progression. Visuospatial difficulties also are reported in patients with pathologically confirmed CBD. 57 Visuospatial complaints and signs are common in the present series, including one patient who presented with a visuospatial disorder and ultimately developed visual agnosia. Neuropsychological measures of visual construction show a significant impairment. Although these tasks have a motor component, spatial errors underline the contribution of parietal disease. The planning component of a visual construction also may be related to frontal pathology. 58 The present study also reveals domains of relatively preserved cognitive functioning in CBS. This emphasizes the selective nature of cognitive impairment in this condition. Although memory difficulty is a common complaint, clinical examination and neuropsychological testing demonstrate normal recall and recognition memory even late in the course of CBS. Postmortem analysis of the brains of all patients with CBD in this study show the characteristic pathologic lesions of this condition, 29 including taupositive inclusions in cell bodies of neuronal and glial cells, astrocytic plaques, and extensive tauimmunoreactive cell processes in both gray matter and white matter associated with neuron loss and atrophy. In accordance with previous work, 40 the pathology is present throughout frontal, parietal, and temporal cortical regions as well as the hippocampus, basal ganglia, and substantia nigra. However, statistical analysis indicates that the burden of disease is not equally distributed across these brain regions. The most severe pathology is observed in the frontal cortex and frontal white matter, whereas significantly less atrophy and tau-immunoreactivity is seen in hippocampal and temporal regions. Pathology in the parietal lobe is intermediate in severity. However, the severity of parietal pathology may be underestimated in the present series because the available samples are from the inferior parietal lobule and not from the superior parietal lobule that is often more severely affected in CBD. It is important to interpret clinicopathologic correlations cautiously because of the months to years that may intervene between clinical ascertainment and pathologic analysis. In this series, clinical and pathologic observations are separated by approximately 9 months. The anatomic distribution of pathology nevertheless is consistent with clinical and neuropsychological examinations. There is a clear relationship between relatively preserved memory and modest hippocampal and temporal lobe pathology. Likewise, deficits in apraxia, executive functioning, visuospatial processing, and language are compatible with prominent frontal and parietal pathology. This study was conducted retrospectively over many years at two institutions, and as a result, all cases were not subjected to the same battery of tests at the same time points. Although data from clinical records are dependent on individual physician assessment, the consistency of motor findings with other reported cases of CBD and the uniformity of results across the two institutions suggest that these April 17, 2007 NEUROLOGY

9 data are reliable and reproducible even in this small series. There is a potential referral bias in this series, with many cases coming from clinics assessing patients with a cognitive disorder. The observed clinical and neuropsychological pattern may be seen with other neurodegenerative diseases affecting the same frontal and parietal areas. 2,4 Depression in CBS may worsen cognitive functioning, although this clearly cannot account for the deficit pattern seen in these patients. Because this cognitive impairment profile may not be specific for CBS, other biomarkers are needed to help confirm the diagnosis of CBD during life. With these caveats in mind, we conclude from this pathologically proven series that CBS is associated with apraxia, executive dysfunction, a social disorder, language deficits, and visuospatial difficulty, reflecting frontal and parietal disease. 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