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Primary progressive aphasia and Pick complex
Journal of the Neurological Sciences 206 (2003) 97 – 107 www.elsevier.com/locate/jns
Primary progressive aphasia and Pick complex Andrew Kertesz a,*, David G. Munoz b,c a
Department of Clinical Neurological Sciences, University of Western Ontario, St. Joseph’s Health Care London, 268 Grosvenor Street, London, Ontario, Canada N6A 4V2 b Department of Pathology and Clinical Neurological Sciences, University of Western Ontario, London, Ontario, Canada c Banco de Tejidos para Investigacion Neurolo´gica, Universidad Autonoma, Madrid, Spain Received 16 July 2002; accepted 10 September 2002
Abstract Ten autopsied patients from a prospectively followed, clinically defined, neuropsychologically and radiologically documented cohort with primary progressive aphasia were histologically characterized. All were variants of frontotemporal degeneration (Pick complex): Pick body dementia, n = 3, corticobasals degeneration (CBD), n = 4, and tau and synuclein negative ubiquitinated inclusions of the motor neuron disease type, n = 3. All shared superficial cortical spongiosis, neuronal loss, and gliosis. Although most patients had fluent anomic aphasia at onset, all progressed to a nonfluent or mute state. Comprehension, episodic memory, and activities of daily living were initially preserved. Three cases with Pick body dementia had verbal apraxia and stuttering at onset. Two of the patients with CBD pathology were older than the average primary progressive aphasia (PPA). All patients developed secondary syndromes either of frontotemporal dementia (FTD) and/or extrapyramidal-apraxic manifestations (CBD). By the time autopsy was obtained, the pathology appeared outside the language areas. Progressive aphasias secondary to Alzheimer’s disease (AD) were excluded on the basis of early loss of memory and comprehension. Rather than the previously emphasized histological heterogeneity, clinically probable PPA has a predictive value of a group of related pathologies, collectively named frontotemporal degeneration, or Pick complex. This series of autopsied cases provides evidence for the clinical and pathological overlap of PPA with FTD and CBD, and contributes to the diagnostic and neuropsychological definition of PPA. D 2002 Elsevier Science B.V. All rights reserved. Keywords: Primary progressive aphasia; Frontotemporal dementia; Corticobasal degeneration; Pick’s disease
1. Introduction Since the description of primary progressive aphasia (PPA) as a distinct clinical entity by Mesulam [1], the neuropathological basis of the disease has been considered heterogenous. Autopsied cases described as Pick’s disease (PID), or had neuronal achromasia, cortical spongiosis, and Alzheimer’s disease (AD) [2]. ‘‘Dementia Lacking Distinctive Histology’’ (DLDH) [3] was considered the most common underlying pathology of PPA in subsequent reviews [4]. Progressive language disorder was considered part of non-Alzheimer lobar atrophy [5]. We have published three cases with autopsy representing a spectrum of pathology, and suggested the concept of ‘‘Pick complex’’ to encompass the syndromes of PPA, frontotemporal dementia * Corresponding author. Tel.: +1-519-646-6032; fax: +1-519-6466226. E-mail address: [email protected] (A. Kertesz).
(FTD), corticobasal degeneration (CBD), and the underlying pathologic substrates [6]. The concept of PPA being part of FTD became accepted by various consensus groups [7,8]. Most clinicopathological correlations consist of a few cases, and reviews of the material from different centers suffer from the lack of consistency of the clinical and the pathological descriptions. Recently, familial FTD and Parkinsonism have been linked to chromosome 17 (FTDP-17) [9]. Many patients of several kindreds of FTDP-17 had progressive aphasia, though not necessarily primary [9,10]. Mutations in the tau gene have been identified in aphasic phenotypes along with other patterns such as behavioral disorders [10]. However, not all familial FTD express tau or are linked to mutations in the tau gene. Tau negative hereditary dysphasic disinhibition dementia (HDDD) and some sporadic cases of DLDH with prominent language and behavioral deficit have been more recently attributed to the loss of tau in the brain with the same effect as the ‘‘tauopathies’’ with tau positive pathology [11].
0022-510X/02/$ - see front matter D 2002 Elsevier Science B.V. All rights reserved. PII: S 0 0 2 2 - 5 1 0 X ( 0 2 ) 0 0 3 4 5 - 3
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In this study, we describe the pathological features of seven new cases of PPA and add three previously published [6] re-examined with updated histochemistry from a population of 70 clinically defined ‘‘probable’’ PPA, in order to analyze the spectrum of underlying pathology.
2. Methods We prospectively followed 70 cases of probable PPA, defined as a primary progressive language disorder with initial preservation of memory, comprehension, visuospatial function, and activities of daily living. Yearly neuropsychological testing included language, memory, visuospatial, and praxis items from the first visit until they were untestable. Most patients received two to three consecutive yearly clinical neuropsychological and neuroimaging assessments. Neuroimaging was carried out usually with an MRI and HMPAO-SPECT, and occasionally CT scan. Neuropsychological scores were from the Western Aphasia Battery (WAB), Modified Block Design from the WAIS-R, Raven’s Coloured Progressive Matrices (RCPM), and tests of calculation, drawing, and praxis. Progressive aphasics with early or primary memory impairment (n = 18) were excluded from this cohort. Brains obtained at autopsy were fixed in formalin for 2 weeks, and blocks embedded in paraffin. H&E, Bielchowsky, and Gallyas stains were complemented with immunostains for phosphorylated neurofilament, tau (tau-2 antibody), ubiquitin, chromogranin A, and a-synuclein. The criteria used for histological diagnosis have been described in detail
previously [12 – 18]. In summary for the type of neuronal cytoplasmic inclusion, the requirements are as follows: for Dementia with Pick bodies: Bielchowsky+, tau+, Gallyas ; for MND-type Dementia Bielchowsky , tau , synuclein , Gallyas , ubiquitin+ (also called ITSNU: Inclusion, Tau and Synuclein Negative, Ubiquintinated); for CBD Bielchowsky+, tau+, Gallyas+, plus astrocytic (glial plaque) and oligodendrocytic (coiled body) tau+, Gallyas+ inclusions. In the absence of these inclusions, a diagnosis of DLDH was reached. Three representative cases from the histological variants are presented in detail. The clinical, neuropsychological, and neuroimaging features of the others are summarized in Tables 1 and 2.
3. Case reports 3.1. Case 1 This 64-year-old retired engineer began to experience word finding difficulties, mixing up words, and stuttering. His speech gradually worsened, but he continued driving, gardening, banking, bookkeeping, and had no difficulty remembering appointments or recent events. He sometimes made spelling and grammatical errors in his diary. The initial diagnosis was stroke, but because of continuing deterioration, he was referred for further investigation. Four years after onset, he was fully oriented, pleasant, and cooperative. He stumbled on initial syllables, frequently repeating, and often distorting them, sometimes unintelli-
Table 1 Clinicopathological summary Number in text – sex Age of onset Presenting feature Initial diagnosis
Secondary syndrome Tertiary syndrome Memory Spatial functions Early apraxia ADL preserved (years) Neuroimaging Duration of illness (years) Age at death Histology
1–M
2–F
3–F
4–F
5–F
64 aphemic stuttering stroke
65 aphemic stuttering anxiety
55 stuttering
64 logopenic
CBDs (4)
CBDs (4)
49 62 logopenic anomia agrammatic depression depression depression Alzheimer’s hysterical PPA conversion mute CBDs (1) FTD (3) FTD (1) FTD (2)
FTD (8)
FTD (4)
FTD (7)
preserved
visual preserved preserved mild 5
preserved
impaired
preserved yes 5
7–M
8–M
9–M
10 – M
57 66 72 logopenic circumlocutory logopenic agrammatic PPA Alzheimer’s PPA
82 anomia paraphasias Alzheimer’s
FTD (3)
FTD (5)
CBDs (3)
CBDs (6)
–
CBDs (4)
CBDs (4)
–
–
preserved
preserved
impaired
impaired
preserved
impaired no 2
visual preserved preserved yes 2
preserved no 6
preserved no 5
impaired moderate 2
impaired mild 5
preserved no 2
LFCP LFCP L/R F CT & MRI CT & MRI CT 11 7 10
L FT CT 7
LFT CT & MRI 5
LT CT 9
LCT CT 5
LFT CT 10
LFCP CT 7
on autopsy LP 3
75 DPB
71 ITSNU
54 ITSNU
71 ITSNU
63 CBD
76 CBD
79 CBD
85 CBD
preserved yes 6
72 DPB
65 DPB
–
6–M
–
R = Right, L = Left, F = Frontal, T = Temporal, P = Parietal, C = Central, DPB = Dementia with Pick bodies, ITSNU = Inclusions, tau and synuclein negative, ubiquitin positive.
Table 2 Longitudinal cognitive scores 1
Time from onset (years)
Year 4
Year 5
Year 6
(10)a (10) (60)
9 5 60
6 4 60
0 0 51
(60)
56
50
(80)
36
(100) (60) (20) (10)
Speech content Speech fluency Comprehension yes/no Word recognition Sentence comprehension Repetition Object naming Word fluency Sentence completion Responsive speech AQ Reading Writing Praxis Drawing Block design Calculations RCPM
2 Year 2
4
5
7
8
9
Year 3
Year 4
Year 3
Year 4
Year 3
Year 4
Year 4.5
Year 3
Year 4
Year 2
Year 3
Year 3
Year 4
Year 5
8 9 60
7 5 60
0 0 24
9 8 57
5 8 51
6 4 45
2 0 36
0 0 42
8 2 51
3 2 45
4 8 45
2 4 18
9 6 60
5 6 54
3 4 30
22
60
60
57
52
32
52
18
19
58
48
15
7
60
58
43
47
0
80
80
76
42
34
45
27
11
38
48
29
4
72
65
56
70 45 5 9
55 20 3 8
0 0 0 0
100 60 11 10
56 46 8 10
0 0 0 0
86 21 0 4
84 9 0 2
27 17 1 4
0 0 0 0
0 0 0 0
30 54 10 4
15 28 6 6
94 10 0 2
50 3 0 2
97 59 5 10
96 56 1 8
77 50 0 8
(10)
9
4
0
10
8
0
6
6
2
0
0
8
6
4
0
8
10
4
(100) (100) (100) (60) (30) (9) (24) (37)
71 49 50 16 9 5 24 29
54 64 35 18 14 3 22 28
7.3 15 0 2 – – – 16
92 100 100 56 30 – 24 26
70 86 88 51 27 9 24 22
16 59 62 – 18 5 24 21
72.5 83 91 44 17.5 0 12 17
58 – – – 5 0 6 9
44 54 55 40 25 7 20 26
12.1 – – 25 10 7 16 24
7.2 30 0 15 – – – 23
57 79 81 59 27 6 24 32
36 51 54 48 20 7 24 31
55 44 26 39 12 2 2 7
26 5 1 8 0 0 0 0
85 79 – 49 19 – 24 21
74 80 – 47 21 – 24 19
55 – – 15 – – 16 0
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Patient number in text
AQ = Aphasia Quotient, a weighted language total score of the Western Aphasia Battery (WAB); RCPM = Raven’s Coloured Progressive Matrices, a test of nonverbal, visuospatial analogies. a Maximum scores in brackets.
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gibly. He had major word finding difficulty and often produced incomplete sentences or merely single word answers. When he used full sentences, they were very segmented with each word separately emphasized so that the normal fluency and melodic line were interrupted. His comprehension was good, except for complex commands. Naming was slightly impaired. He had significant buccofacial and limb apraxia. His neuropsychological test scores are summarized in Table 2. CT scan showed left hemispheric atrophy. The MRI, 6 years post-onset, showed asymmetric atrophy of the ventricles. The proton T2 weighted intermediate images illustrate the thinness of the cortex of the left posterior frontal lobe and the temporal lobe on the more inferior cuts, and the parietal lobe in (Fig. 1). Eight years post-onset, stiffness and immobility of the right hand were observed, and he had trouble turning and shifting position. He communicated by pointing, but this was inconsistent. He could not write or draw objects put in his hands to demonstrate object use. Nine years after the onset, he developed urinary incontinence, and a year later, bowel incontinence and began falling. He was admitted to a nursing home and died 11 years after the onset of his illness.
insula bilaterally, and to a lesser extent, in the frontal cortex. Areas where the atrophy was less severe demonstrated superficial linear spongiosis. Ballooned neurons (Pick cells) and Pick bodies were widely distributed. These bodies were well demonstrated with the Bielchowsky, but not the Gallyas stain. They were labelled by immunostains for tau and chromogranin A, as well as ubiquitin (Fig. 2a– d). They were mostly located in the small neurons of the temporal lobe, as well as insular cortex and parietal cortex, hippocampus, dentate gyrus, subiculum, and entorrhinal cortex. They were also present in the thalamus, amygdala, nucleus basalis, nucleus accumbens, and the locus coeruleus. Thorny astrocytes highlighted on Bielchowsky, tau, and Gallyas stains were identified within the temporal lobe and hippocampus, and in the caudate. Glial plaques were absent. Globose, PSP-type tangles were identified in the neurons of the putamen, as well as in the thalamus. A small number of neuritic plaques and tangles were seen in the hippocampus. The microscopic diagnosis was classical PiD or dementia with Pick bodies.
3.2. Neuropathology
This 64-year-old woman began having word finding difficulty and forgetfulness 3 years before being seen. The beginning of her illness was unclear, but questioning the family revealed the speech problem preceded her forgetfulness. There was also some depression before her illness began, and the initial clinical diagnosis was ‘‘pseudodementia’’. Although her speech difficulty progressed considerably, she could still remember dates and could give the names of all her children and grandchildren, manage her banking, cooking, and other household chores. She was referred as a case of PPA. Three years after the onset, she also developed personality changes of apathy, spontaneity, rigidity, and concreteness in her thinking, and dependency on certain routines. She wanted to do things right away when she thought it was time. She became disinhibited in approaching strangers with compliments, gushing remarks, and unexpectedly friendly behavior. She stroked the beard of a strange man. She also had difficulty organizing complex meals and her housekeeping had slipped. She developed occasional unexplained urinary incontinence. On examination, she had marked word finding difficulty, her speech was empty and often inadequate to express her thoughts. On formal language testing with the WAB, she was only able to name seven out of twenty objects, but her repetition was intact for single words and phrases. Her comprehension was relatively preserved, except for multicomponent commands. She had difficulty generating words in a category in a verbal fluency task. Her writing had paraphasic errors. Praxis testing showed more ideational than limb apraxia. Neuroimaging showed focal atrophy of the left frontal lobe on CT and the temporal lobe on the MRI (Fig. 3), as
The brain weighed 1060 g. Severe atrophy of the frontal and temporal lobes and mild atrophy of the parietal lobes were seen bilaterally. Microscopy revealed severe cortical atrophy, massive cortical neuronal loss, and exuberant astrocytosis, most marked in the temporal lobes and the
Fig. 1. Case 1: MRI, 6 years post-onset, left hemispheric, cortical atrophy, and ventricular dilatation.
3.3. Case 4
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Fig. 2. Case 1: (a) Pick bodies (arrows) CA1 section of the hippocampus; H&E 100 8. (b) Pick bodies (some marked with arrows). CA1 sector of the hippocampus. Bielchowsky stain; 40 1. (c) Pick bodies (some marked with arrows). Dentate gyrus. Tau-2 immunostain with hematoxylin counterstain; 40 1. (d) Pick bodies (some marked with arrows). Dentate gyrus. Chromogranin A immunostain with hematoxylin counterstain; 40 1. Case 4: (e) Frontal cortex demonstrating severe atrophy, gliosis, and widespread spongiosis; H&E 10 2. (f) Numerous dystrophic neurites in the lower layers of the cortex, occipitotemporal gyrus, ubiquitin immunostain; 20. (g) Numerous ITSNU (some marked with arrows) in the dentate gyrus. Ubiquitin immunostain; 20 1. (h) Two ITSNU (arrows) occupy the cytoplasm of neurons in the granule cell layer of the dentate gyrus. Ubiquitin immuonstain; 100 1.
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Fig. 4. Case 7: Written note by patient, better preserved than spoken output, reflects relatively intact cognition, except language.
Fig. 3. Case 4: MRI scan, left temporal atrophy.
well as decreased perfusion on HMPAO-SPECT. She was treated with Paroxetene and this seemed to help her mood, but not her language problem. After further deterioration, she was admitted to a nursing home, and died 10 years postonset.
positive (ITSNU) in the cytoplasm of dentate granule neurons (Fig. 2g,h). Other neuronal cytoplasmic inclusions of the same MND-type were found in the temporal neocortex, accompanied by numerous spindle-shaped neurites (Fig. 2f). Sections through the basal ganglia demonstrated unremarkable nucleus basalis of Meynert. There was neuronal loss and gliosis of the caudate nucleus, whereas the putamen
3.4. Neuropathology The brain weighed 1010 g. Atrophy was accentuated in the temporal lobes, much greater on the left side than on the right. Microscopic examination showed severe neuronal loss (more than 90%) and gliosis, resulting in marked narrowing of the cortical ribbon. On the right side, the loss was less severe, affecting predominantly the superficial layers, manifested as superficial linear spongiosis (Fig. 2e). The left frontal lobe showed a degree of neuronal loss comparable to that of the right temporal lobe. Bielchowsky stain demonstrated a small number of neuritic plaques in both the temporal and frontal neocortex. No neurofibrillary tangles were found in the neocortex or the entorrhinal cortex. The white matter of the left temporal lobe showed marked rarefaction and gliosis. The hippocampus had spongiosis in CA1 and complete loss of neurons in the subiculum, which were replaced by a dense glial scar. Tau immunostains revealed only a very rare neurofibrillary tangle. Ubiquitin immunostains, however, demonstrated numerous round inclusions, tau and synuclein negative, ubiquitin
Fig. 5. Case 7: MRI, left predominant cortical atrophy.
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Fig. 6. Case 7: (a) Superficial linear spongiosis. Left superior temporal gyrus; H&E 4. (b) Tau-2 immunostain demonstrating both neuronal inclusions (black arrows) and glial plaques (two confluent ones delineated by open arrowheads). Left middle frontal gyrus; 25. (c) Gallyas stain, showing solid neuronal inclusions (black arrow) and the processes of a glial plaque from which thin threads originate (open arrows). Left superior temporal gyrus; 100. (d) Gallyas stain, showing typical ring-shaped neuronal inclusions (black arrows). Left superior temporal gyrus; 100. (e) Numerous ballooned neurons demonstrated by immunostain for phosphorylated neurofilament. Layer 6 of left superior temporal gyrus; 20. (f) Numerous neurons in the granular cell layer of the dentate gyrus express cytoplasmic tau in a diffuse pattern (arrows). Tau-2 immunostain; 25. (g) Pervasive threads (black arrow) in the absence of neuronal inclusions (open arrows mark counter stained neurons). Gallyas stain. CA1 sector of the hippocampus; 40. (h) The substantia nigra shows globose neurofibrillary tangles (black arrow) and clusters of pigment-laden macrophages (open arrows) representing neuronal tombstones. Gallyas stain; 40.
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was minimally affected. The external segment of the globus pallidus appeared unremarkable, but the inner segment demonstrated marked neuronal loss and gliosis. 3.5. Case 7 This 57-year-old man developed word finding difficulty and he would reach for a paper to write a word he could not say (Fig. 4). Despite worsening language involvement, he remained well oriented, continued driving, shopping, mowing his lawn, and banking. Three years after onset, he began having changes in his personality. He did not pay his bills, and neglected his appearance and personal hygiene, although he had been a neat person before. His wife suspected that his shopping trips to another town were wasteful, but he became irritable when questioned. His mother was said to have been demented at the age of 73, but there was no history of similar language deterioration. On examination, 3 years after onset, he was severely anomic and paraphasic. Although he did not have articulatory difficulty, he produced incomplete and agrammatical sentences or responses were one word. Although he had better ‘‘yes –no comprehension’’ and word recognition, he was impaired for sequential commands containing grammatical variables. He also had difficulty repeating longer phrases and sentences, but his object naming was quite good. He could utilize phonemic cues for the missed items. He did well on nonverbal tasks. He could copy designs and his scores for attention initiation, construction, and memory were normal on the MDRS. His WAIS-R performance IQ was 101, which was average, but the verbal items could not be scored because of his aphasia. His visual memory span was nine, which was better than average, his visual reproduction score of 36 was in the 95th percentile, and his score of 31 on the RCPM was in the 92nd percentile. Neurological examination, including eye movements, was normal. MRI showed cortical atrophy, which was more marked on the left frontotemporal region (Fig. 5). Bilateral hypodensities were noted in the striatum. Later, in the fifth year of his illness, he stopped eating, developed vomiting, diarrhea, and was found to have stomach cancer 6 weeks before he died. 3.6. Neuropathology Post-mortem examination showed a brain weight of 1240 g. Mild cortical atrophy was more prominent in the frontal convexities and in the superior and middle temporal gyri. Microscopic sections showed superficial layer spongiosis, severe neuronal loss, and astrogliosis (Fig. 6a). Ballooned achromatic neurons were scattered in the deep layers of the cortex (Fig. 6e). There were many welldefined round, kidney-, ring-, or flame-shaped cytoplasmic inclusions in the cortical neurons staining with Bielchowsky, Gallyas, and tau immunostains (Fig. 6b – d). The neuropil showed many abnormal processes, threads, and
grains on the Gallyas and tau stains (Fig. 6g). Some of the processes were clustered crown-like around a central space where sometimes a glial nucleus could be seen (so-called glial plaque) (Fig. 6b,c). Under high-power hairlike projections originated from these processes (Fig. 6c). Several neuronal inclusions in the hippocampus and amygdala were round, but were stained by Gallyas, as well as Bielchowsky, and thus were not Pick bodies by definition. These structures also showed very abundant neuropil threads. There were no round inclusions in the dentate gyrus, but many neurons demonstrated diffuse cytoplasmic tau immunoreactivity (Fig. 6f). Mild gliosis, scattered neuronal globose neurofibrillary tangles (Fig. 6h), and skein-like cytoplasm inclusions in the neurons were seen in the basal ganglia and substantia nigra. Pick cells (ballooned neurons), abnormal processes, and grains were demonstrated in the hippocampus and amygdala. Neuritic plaques or neurofibrillary tangles of the Alzheimer-type were absent. Although numerous neuronal inclusions could be classified as Pick bodies on Bielchowsky stains and tau immunostains alone, the case fits the pathological pattern of CBD.
4. Results The clinical features and demographics of the 10 cases that were clinically diagnosed as probable PPA are summarized in Table 1. Three of these cases [3,6,10] have been previously published in some detail [6], but their histology was re-examined. The average age of onset was 63.5 (10.4), not statistically different from the population of PPA patients, who did not come to autopsy [n = 60, x¯ = 63.4 (7.5)]. By definition, they had only aphasia initially, although secondary syndromes developed within a year in two patients. The duration of predominant aphasia before the development of significant behavior and other cognitive deficits ranges from 1 to 6 years with an average of 3.1 (2.3) n = 10. The initial diagnosis varied between anxiety, depression, conversion reaction in three, and AD in three. One patient was diagnosed as a stroke, and three of the patients were referred as PPA before coming to the clinic. The presenting features were verbal apraxia and stuttering in three out of ten patients and logopenia, or decreased speech output, with relatively preserved articulation in the rest. All patients began with word finding difficulty or anomia, whether or not they were aphemic or logopenic, the difference being the amount of stuttering behavior and verbal apraxia which characterized the aphemic variety. Two patients, who were initially logopenic, were noted to develop agrammatism resembling Broca’s aphasia. All patients progressed to mutism, or to a severely logopenic, near mute state, but comprehension remained preserved on serial language examinations (Table 2). The duration of illness until death ranged from 3 to 11 years, with an average of 7.1 years.
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Three aphemic and two logopenic presentations developed apractic, extrapyramidal symptoms compatible with the corticobasal degeneration syndrome (CBDs). The other half of the cases, all logopenic presentation, developed significant behavioral and personality changes similar to FTD. A third syndrome developed in half of the cases, FTD in three, and CBDs in two (Table 1). CBDs and FTD appeared simultaneously in Case 2. Neuroimaging showed left frontal, central, and temporal atrophy in most cases (Table 1). At times, this was only frontotemporal, while at other times, predominantly perisylvian and temporal atrophy were seen. In two cases with Pick bodies and in two cases with CBD, parietal atrophy on the dominant side was significant. Neuropsychological test results of longitudinal follow-up in seven patients are summarized in Table 2. The deterioration is significant for the Aphasia Quotient (AQ) on repeated measures in all patients. All expressive subtests declined, except in patients 4 and 5, in whom repetition was preserved in the first 2 years. Word (category) fluency was initially impaired and reached floor effect early in all. Comprehension and its subtests, such as yes –no questions and word recognition tended to remain preserved over several follow-up years with significant drop in patients 3 and 6 only. This corresponded to the preservation of activities of daily living, allowing these patients a relatively independent existence, longer than it is usual for AD of the same duration. Several patients were severely logopenic and even mute when they were still performing tests of comprehension and visuospatial analogies (RCPM) at a remarkably high level. Neuropathological features are summarized in Table 1. Three patients had dementia with Pick bodies (classical PiD) (Cases 1, 2, and 3), three had frontotemporal degeneration with MND-type inclusions (ITSNU) (Cases 4, 5, and 6), and four showed CBD pathology (Cases 7, 8, 9, and 10). All cases shared neuronal loss, gliosis, and superficial linear spongiosis. No cases of ‘‘Dementia Lacking Distinctive Histology’’ were found, although all the MND-type cases would have fallen into this category had the appropriate stains not been done. Two of the patients with CBD histology were older at onset than the average of this population. Altogether, the clinical features were similar across the histological varieties.
5. Discussion This series of patients was referred to our clinic in the context of a larger population of various memory disorders and dementias. Several patients participated in a Canadian cohort study of related dementias (ACCORD). Typical cases of PPA represent a distinct syndrome which can be easily recognized. The difficulties in the differential diagnosis occur when a patient with a predominantly aphasic picture is seen at a later stage of the illness, which may have begun
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with memory problems. Most of these cases are older, have comprehension difficulties, early loss of memory and activities of daily living. Such cases with ‘‘possible PPA’’ usually have atypical, focally distributed AD histology [19,20]. We have seen 18 such cases, but excluded them from this series, on the basis of their clinical presentation. Four such cases came to autopsy and showed focal AD histology (in preparation). An initial 2 years of ‘‘relatively isolated language disorder’’ and ‘‘relative’’ absence of deficits in other domains, as a definition of PPA [21], is a useful guideline. In our experience, however, a behavioral or extrapyramidal disorder may be superimposed shortly after onset, and we felt such cases should not be excluded. Although most of our patients had preserved memory, visuospatial function, and activities of daily living, several had significant impairment in one or two of these domains by the time they came to us. Furthermore, language impairment commonly interfered with the neuropsychological test results. These difficulties in isolating the language impairment have been acknowledged by Mesulam [22] in a recent review. Neuroimaging confirmation of asymmetrical atrophy is important for diagnosis and was present in all but one of our cases. As the disease progresses, however, the asymmetry may lessen and may not be as evident on autopsy. Patients presenting with left frontotemporal atrophy and corresponding progressive aphasia often develop right temporal or bifrontal atrophy later, exhibiting disinhibition dementia or stereotypic compulsive behaviors, described in FTD. Variations in presentation as aphasic or behavioral in cases selected for one or the other side being atrophied first were renamed as the right and left variants of frontotemporal dementia [23]. In our PPA cases, the disease seemed to affect the language dominant frontotemporal and parietal areas first, but subsequent progression to other areas of the brain and variable subcortical involvement was observed in all autopsied cases. All three cases, which were characterized histologically by having Pick bodies, had ‘‘aphemic’’ presentation with stuttering and articulatory difficulty. Articulatory or aphemic presentation has been described in several individual case reports and in families without autopsy, and in two cases with DLDH [24]. The stuttering, dysarthric, often hypophonic speech in a younger patient may lead to the diagnosis of conversion reaction, such as in Case 3. The aphemic patients also progressed toward increasing word finding difficulty, logopenia, and eventually, mutism. A number of sporadic reports of PPA with CBD histology in the literature are in line with our observations [25,26]. The largest number of our cases had CBD-type of pathology, but they were not distinguishable clinically from the rest of the probable PPA population. None of the four cases with CBD histology started with the extrapyramidal apractic syndrome. One of them did not have any extrapyramidal features, and the others developed CBDs as a secondary syndrome. Conversely, in several series which examined
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patients with clinical CBD syndrome (CBDs), a variety of underlying histological types of the Pick complex was found [27,28]. Three cases lacked the tau positive neuronal and glial deposits seen in PiD and CBD pathology. Two of these were classified as DLDH originally, until the distinctive inclusions of the FTD –MND-type were revealed by ubiquitin immunostains. They were characteristically located in the dentate gyrus (see Fig. 2a –h), in a similar distribution to Pick bodies. Identical inclusions in the dentate gyrus and neocortex appear in MND with dementia and in some MND cases without dementia. They share immunoreactivity with the inclusions seen in the brainstem and spinal cord in MND. However, many cases with FTD have inclusions only in the cortex and not in the spinal cord or brainstem and clinically do not have MND. Recently, cases of PPA and semantic dementia (aphasia) were found to have MND-type pathology [29,30] in addition to cases of MND associated with aphasia [31]. Our cases of PPA with histology of the MND-type were not distinguishable clinically from the tau positive varieties. The occurrence of secondary syndromes of FTD and CBDs in PPA confirms the cohesiveness of the major clinical components of the Pick complex. Apparently, PPA does not remain isolated in most cases, although death or lack of follow-up may preclude the observation of the other symptoms. The clinical distinction of PPA, FTD, and CBDs is important for diagnosis, but should not obscure their cohesion. The concept of their relatedness appears to be the best approximation to fit the current evidence and it allows a better perspective of the syndrome, which continues to be under-diagnosed despite its estimated frequency of about 15 –20% of degenerative dementias (higher in the presenile group) [27,32,33]. The clinical variation within families with a single gene mutation is similar to the variation in the sporadic cases. On the other hand, different mutations in the same gene and possibly in different genes can also cause the same clinical phenotype. Genetic and clinicopathological studies are complementary in clarifying the nature of this disorder.
Acknowledgements We would like to thank Bonita Stevenson for secretarial and Marybelle Lozanski for technical assistance, the physicians who referred patients, and the caregivers and patients, above all, who taught us a great deal. This study was supported in part by the Medical Research Council of Canada, Grant No. C94-0493.
References [1] Mesulam M-M. Slowly progressive aphasia without generalized dementia. Ann Neurol 1982;11:592 – 8.
[2] Mesulam MM, Weintraub S. Primary progressive aphasia: sharpening the focus on a clinical syndrome. In: Boller F, Forette F, Khachaturian Z, Poncet M, Christen Y, editors. Heterogeneity of Alzheimer’s disease. Berlin: Springer; 1992. p. 43 – 66. [3] Knopman DS, Mastri AR, Frey WH, Sung JH, Rustan T. Dementia lacking distinctive histologic features: a common non-Alzheimer degenerative dementia. Neurology 1990;40:251 – 6. [4] Turner RS, Kenyon LC, Trojanowski JQ, Gonatas N, Grossman M. Clinical, neuroimaging, and pathologic features of progressive nonfluent aphasia. Ann Neurol 1996;39:166 – 73. [5] Snowden JS, Neary D, Mann DMA, Goulding PJ, Testa HJ. Progressive language disorder due to lobar atrophy. Ann Neurol 1992;31: 174 – 83. [6] Kertesz A, Hudson L, Mackenzie IRA, Munoz DG. The pathology and nosology of primary progressive aphasia. Neurology 1994;44: 2065 – 72. [7] Neary D, Snowden JS, Gustafson L, Passant U, Stuss D, Black S, et al. Frontotemporal lobar degeneration—a consensus on clinical diagnostic criteria. Neurology 1998;51:1546 – 54. [8] McKhann GM, Albert MS, Grossman M, Miller B, Dickson D, Trojanowski JQ. Clinical and pathological diagnosis of frontotemporal dementia. Arch Neurol 2001;58:1803 – 9. [9] Wilhelmsen KC, Lynch T, Pavlou E, Higgins M, Nygaard TG. Localization of disinhibition dementia parkinsonism amyotrophy complex to 17q21 – 22. Am J Hum Genet 1994;55:1159 – 65. [10] Bird TD, Nochlin D, Poorkaj P, et al. A clinical pathological comparison of three families with frontotemporal dementia and identical mutations in the tau gene (P301L). Brain 1999;122: 741 – 56. [11] Zhukareva V, Vogelsberg-Ragaglia V, Van Deerlin V, et al. Loss of brain tau defines novel sporadic and familial tauopathies with frontotemporal dementia. Ann Neurol 2001;49:165 – 75. [12] Munoz DG. The pathology of Pick complex. In: Kertesz A, Munoz DG, editors. Pick’s disease and Pick complex. New York: Wiley; 1998. p. 211 – 41. [13] Cooper PN, Jackson M, Lennox G, Lowe J, Mann DMA. t, Ubiquitin, and aB-crystallin—immunohistochemistry define the principal causes of degenerative frontotemporal dementia. Arch Neurol 1995;52: 1011 – 5. [14] Feany MB, Mattiace LA, Dickson DW. Neuropathologic overlap of progressive supranuclear palsy, Pick’s disease and corticobasal degeneration. J Neuropathol Exp Neurol 1996;55:53 – 67. [15] Jackson M, Lowe J. The new neuropathology of degenerative frontotemporal dementias. Acta Neuropathol 1996;91:127 – 34. [16] Dickson DW. Pick’s disease: a modern approach. Brain Pathol 1998; 8:339 – 54. [17] Iseki E, Li F, Odawara T, et al. Ubiquitin-immunohistochemical investigation of atypical Pick’s disease without Pick bodies. JNS 1998; 159:194 – 201. [18] Komori T. Tau-positive glial inclusions in progressive supranuclear palsy, corticobasal degeneration and Pick’s disease. Brain Pathol 1999;9:663 – 79. [19] Karbe H, Kertesz A, Polk M. Profiles of language impairment in primary progressive aphasia. Arch Neurol 1993;50:193 – 201. [20] Galton CJ, Patterson K, Xuereb JH, Hodges JR. Atypical and typical presentations of Alzheimer’s disease: a clinical, neuropsychological, neuroimaging and pathological study of 13 cases. Brain 2000;123: 484 – 98. [21] Weintraub S, Rubin NP, Mesulam M-M. Primary progressive aphasia: longitudinal course, neuropsychological profile, and language features. Arch Neurol 1990;47:1329 – 35. [22] Mesulam MM. Primary progressive aphasia. Ann Neurol 2001;49: 425 – 32. [23] Edwards-Lee T, Miller BL, Benson F, Cummings JL, Russell GL, Boone K, et al. The temporal variant of frontotemporal dementia. Brain 1997;120:1027 – 40. [24] Broussolle E, Bakchine S, Tommasi M, et al. Slowly progressive
A. Kertesz, D.G. Munoz / Journal of the Neurological Sciences 206 (2003) 97–107
[25]
[26]
[27] [28]
[29]
anarthria with late anterior opercular syndrome: a variant form of frontal cortical atrophy syndromes. JNS 1996;144:44 – 58. Lang AE. Cortico-basal ganglionic degeneration presenting with ‘‘progressive loss of speech output and orofacial dyspraxia’’. J Neurol Neurosurg Psychiatry 1992;55:1101. Mimura M, Oda T, Tsuchiya K, Kato M, Ikeda K, Hori K, et al. Corticobasal degeneration presenting with nonfluent primary progressive aphasia: a clinicopathological study. JNS 2001;183:19 – 26. Kertesz A, Munoz DG. Pick’s Disease and Pick Complex. New York: Wiley-Liss; 1998. Boeve BF, Maraganore DM, Parisi JE, et al. Pathologic heterogeneity in clinically diagnosed corticobasal degeneration. Neurology 1999; 53:795 – 800. Kinoshita A, Tomimoto H, Tachibana N, et al. A case of primary
[30]
[31]
[32]
[33]
107
progressive aphasia with abnormally ubiquitinated neurites in the cerebral cortex. Acta Neuropathol 1996;92:520 – 4. Rossor MN, Revesz T, Lantos PL, Warrington EK. Semantic dementia with ubiquitin-positive tau-negative inclusion bodies. Brain 2000; 123:267 – 76. Bak TH, O’Donovan DG, Xuereb JH, Boniface S, Hodges JR. Selective impairment of verb processing associated with pathological changes in Brodmann areas 44 and 45 in the motor neuron disease – dementia – aphasia syndrome. Brain 2001;124:103 – 20. Gustafson L. Frontal lobe degeneration of non-Alzheimer type: II. Clinical picture and differential diagnosis. Arch Gerontol Geriatr 1987;6:209 – 23. Ratnavalli E, Brayne C, Dawson K, Hodges JR. The prevalence of frontotemporal dementia. Neurology 2002;58:1615 – 21.
Primary progressive aphasia and Pick complex Andrew Kertesz a,*, David G. Munoz b,c a
Department of Clinical Neurological Sciences, University of Western Ontario, St. Joseph’s Health Care London, 268 Grosvenor Street, London, Ontario, Canada N6A 4V2 b Department of Pathology and Clinical Neurological Sciences, University of Western Ontario, London, Ontario, Canada c Banco de Tejidos para Investigacion Neurolo´gica, Universidad Autonoma, Madrid, Spain Received 16 July 2002; accepted 10 September 2002
Abstract Ten autopsied patients from a prospectively followed, clinically defined, neuropsychologically and radiologically documented cohort with primary progressive aphasia were histologically characterized. All were variants of frontotemporal degeneration (Pick complex): Pick body dementia, n = 3, corticobasals degeneration (CBD), n = 4, and tau and synuclein negative ubiquitinated inclusions of the motor neuron disease type, n = 3. All shared superficial cortical spongiosis, neuronal loss, and gliosis. Although most patients had fluent anomic aphasia at onset, all progressed to a nonfluent or mute state. Comprehension, episodic memory, and activities of daily living were initially preserved. Three cases with Pick body dementia had verbal apraxia and stuttering at onset. Two of the patients with CBD pathology were older than the average primary progressive aphasia (PPA). All patients developed secondary syndromes either of frontotemporal dementia (FTD) and/or extrapyramidal-apraxic manifestations (CBD). By the time autopsy was obtained, the pathology appeared outside the language areas. Progressive aphasias secondary to Alzheimer’s disease (AD) were excluded on the basis of early loss of memory and comprehension. Rather than the previously emphasized histological heterogeneity, clinically probable PPA has a predictive value of a group of related pathologies, collectively named frontotemporal degeneration, or Pick complex. This series of autopsied cases provides evidence for the clinical and pathological overlap of PPA with FTD and CBD, and contributes to the diagnostic and neuropsychological definition of PPA. D 2002 Elsevier Science B.V. All rights reserved. Keywords: Primary progressive aphasia; Frontotemporal dementia; Corticobasal degeneration; Pick’s disease
1. Introduction Since the description of primary progressive aphasia (PPA) as a distinct clinical entity by Mesulam [1], the neuropathological basis of the disease has been considered heterogenous. Autopsied cases described as Pick’s disease (PID), or had neuronal achromasia, cortical spongiosis, and Alzheimer’s disease (AD) [2]. ‘‘Dementia Lacking Distinctive Histology’’ (DLDH) [3] was considered the most common underlying pathology of PPA in subsequent reviews [4]. Progressive language disorder was considered part of non-Alzheimer lobar atrophy [5]. We have published three cases with autopsy representing a spectrum of pathology, and suggested the concept of ‘‘Pick complex’’ to encompass the syndromes of PPA, frontotemporal dementia * Corresponding author. Tel.: +1-519-646-6032; fax: +1-519-6466226. E-mail address: [email protected] (A. Kertesz).
(FTD), corticobasal degeneration (CBD), and the underlying pathologic substrates [6]. The concept of PPA being part of FTD became accepted by various consensus groups [7,8]. Most clinicopathological correlations consist of a few cases, and reviews of the material from different centers suffer from the lack of consistency of the clinical and the pathological descriptions. Recently, familial FTD and Parkinsonism have been linked to chromosome 17 (FTDP-17) [9]. Many patients of several kindreds of FTDP-17 had progressive aphasia, though not necessarily primary [9,10]. Mutations in the tau gene have been identified in aphasic phenotypes along with other patterns such as behavioral disorders [10]. However, not all familial FTD express tau or are linked to mutations in the tau gene. Tau negative hereditary dysphasic disinhibition dementia (HDDD) and some sporadic cases of DLDH with prominent language and behavioral deficit have been more recently attributed to the loss of tau in the brain with the same effect as the ‘‘tauopathies’’ with tau positive pathology [11].
0022-510X/02/$ - see front matter D 2002 Elsevier Science B.V. All rights reserved. PII: S 0 0 2 2 - 5 1 0 X ( 0 2 ) 0 0 3 4 5 - 3
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In this study, we describe the pathological features of seven new cases of PPA and add three previously published [6] re-examined with updated histochemistry from a population of 70 clinically defined ‘‘probable’’ PPA, in order to analyze the spectrum of underlying pathology.
2. Methods We prospectively followed 70 cases of probable PPA, defined as a primary progressive language disorder with initial preservation of memory, comprehension, visuospatial function, and activities of daily living. Yearly neuropsychological testing included language, memory, visuospatial, and praxis items from the first visit until they were untestable. Most patients received two to three consecutive yearly clinical neuropsychological and neuroimaging assessments. Neuroimaging was carried out usually with an MRI and HMPAO-SPECT, and occasionally CT scan. Neuropsychological scores were from the Western Aphasia Battery (WAB), Modified Block Design from the WAIS-R, Raven’s Coloured Progressive Matrices (RCPM), and tests of calculation, drawing, and praxis. Progressive aphasics with early or primary memory impairment (n = 18) were excluded from this cohort. Brains obtained at autopsy were fixed in formalin for 2 weeks, and blocks embedded in paraffin. H&E, Bielchowsky, and Gallyas stains were complemented with immunostains for phosphorylated neurofilament, tau (tau-2 antibody), ubiquitin, chromogranin A, and a-synuclein. The criteria used for histological diagnosis have been described in detail
previously [12 – 18]. In summary for the type of neuronal cytoplasmic inclusion, the requirements are as follows: for Dementia with Pick bodies: Bielchowsky+, tau+, Gallyas ; for MND-type Dementia Bielchowsky , tau , synuclein , Gallyas , ubiquitin+ (also called ITSNU: Inclusion, Tau and Synuclein Negative, Ubiquintinated); for CBD Bielchowsky+, tau+, Gallyas+, plus astrocytic (glial plaque) and oligodendrocytic (coiled body) tau+, Gallyas+ inclusions. In the absence of these inclusions, a diagnosis of DLDH was reached. Three representative cases from the histological variants are presented in detail. The clinical, neuropsychological, and neuroimaging features of the others are summarized in Tables 1 and 2.
3. Case reports 3.1. Case 1 This 64-year-old retired engineer began to experience word finding difficulties, mixing up words, and stuttering. His speech gradually worsened, but he continued driving, gardening, banking, bookkeeping, and had no difficulty remembering appointments or recent events. He sometimes made spelling and grammatical errors in his diary. The initial diagnosis was stroke, but because of continuing deterioration, he was referred for further investigation. Four years after onset, he was fully oriented, pleasant, and cooperative. He stumbled on initial syllables, frequently repeating, and often distorting them, sometimes unintelli-
Table 1 Clinicopathological summary Number in text – sex Age of onset Presenting feature Initial diagnosis
Secondary syndrome Tertiary syndrome Memory Spatial functions Early apraxia ADL preserved (years) Neuroimaging Duration of illness (years) Age at death Histology
1–M
2–F
3–F
4–F
5–F
64 aphemic stuttering stroke
65 aphemic stuttering anxiety
55 stuttering
64 logopenic
CBDs (4)
CBDs (4)
49 62 logopenic anomia agrammatic depression depression depression Alzheimer’s hysterical PPA conversion mute CBDs (1) FTD (3) FTD (1) FTD (2)
FTD (8)
FTD (4)
FTD (7)
preserved
visual preserved preserved mild 5
preserved
impaired
preserved yes 5
7–M
8–M
9–M
10 – M
57 66 72 logopenic circumlocutory logopenic agrammatic PPA Alzheimer’s PPA
82 anomia paraphasias Alzheimer’s
FTD (3)
FTD (5)
CBDs (3)
CBDs (6)
–
CBDs (4)
CBDs (4)
–
–
preserved
preserved
impaired
impaired
preserved
impaired no 2
visual preserved preserved yes 2
preserved no 6
preserved no 5
impaired moderate 2
impaired mild 5
preserved no 2
LFCP LFCP L/R F CT & MRI CT & MRI CT 11 7 10
L FT CT 7
LFT CT & MRI 5
LT CT 9
LCT CT 5
LFT CT 10
LFCP CT 7
on autopsy LP 3
75 DPB
71 ITSNU
54 ITSNU
71 ITSNU
63 CBD
76 CBD
79 CBD
85 CBD
preserved yes 6
72 DPB
65 DPB
–
6–M
–
R = Right, L = Left, F = Frontal, T = Temporal, P = Parietal, C = Central, DPB = Dementia with Pick bodies, ITSNU = Inclusions, tau and synuclein negative, ubiquitin positive.
Table 2 Longitudinal cognitive scores 1
Time from onset (years)
Year 4
Year 5
Year 6
(10)a (10) (60)
9 5 60
6 4 60
0 0 51
(60)
56
50
(80)
36
(100) (60) (20) (10)
Speech content Speech fluency Comprehension yes/no Word recognition Sentence comprehension Repetition Object naming Word fluency Sentence completion Responsive speech AQ Reading Writing Praxis Drawing Block design Calculations RCPM
2 Year 2
4
5
7
8
9
Year 3
Year 4
Year 3
Year 4
Year 3
Year 4
Year 4.5
Year 3
Year 4
Year 2
Year 3
Year 3
Year 4
Year 5
8 9 60
7 5 60
0 0 24
9 8 57
5 8 51
6 4 45
2 0 36
0 0 42
8 2 51
3 2 45
4 8 45
2 4 18
9 6 60
5 6 54
3 4 30
22
60
60
57
52
32
52
18
19
58
48
15
7
60
58
43
47
0
80
80
76
42
34
45
27
11
38
48
29
4
72
65
56
70 45 5 9
55 20 3 8
0 0 0 0
100 60 11 10
56 46 8 10
0 0 0 0
86 21 0 4
84 9 0 2
27 17 1 4
0 0 0 0
0 0 0 0
30 54 10 4
15 28 6 6
94 10 0 2
50 3 0 2
97 59 5 10
96 56 1 8
77 50 0 8
(10)
9
4
0
10
8
0
6
6
2
0
0
8
6
4
0
8
10
4
(100) (100) (100) (60) (30) (9) (24) (37)
71 49 50 16 9 5 24 29
54 64 35 18 14 3 22 28
7.3 15 0 2 – – – 16
92 100 100 56 30 – 24 26
70 86 88 51 27 9 24 22
16 59 62 – 18 5 24 21
72.5 83 91 44 17.5 0 12 17
58 – – – 5 0 6 9
44 54 55 40 25 7 20 26
12.1 – – 25 10 7 16 24
7.2 30 0 15 – – – 23
57 79 81 59 27 6 24 32
36 51 54 48 20 7 24 31
55 44 26 39 12 2 2 7
26 5 1 8 0 0 0 0
85 79 – 49 19 – 24 21
74 80 – 47 21 – 24 19
55 – – 15 – – 16 0
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Patient number in text
AQ = Aphasia Quotient, a weighted language total score of the Western Aphasia Battery (WAB); RCPM = Raven’s Coloured Progressive Matrices, a test of nonverbal, visuospatial analogies. a Maximum scores in brackets.
99
100
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gibly. He had major word finding difficulty and often produced incomplete sentences or merely single word answers. When he used full sentences, they were very segmented with each word separately emphasized so that the normal fluency and melodic line were interrupted. His comprehension was good, except for complex commands. Naming was slightly impaired. He had significant buccofacial and limb apraxia. His neuropsychological test scores are summarized in Table 2. CT scan showed left hemispheric atrophy. The MRI, 6 years post-onset, showed asymmetric atrophy of the ventricles. The proton T2 weighted intermediate images illustrate the thinness of the cortex of the left posterior frontal lobe and the temporal lobe on the more inferior cuts, and the parietal lobe in (Fig. 1). Eight years post-onset, stiffness and immobility of the right hand were observed, and he had trouble turning and shifting position. He communicated by pointing, but this was inconsistent. He could not write or draw objects put in his hands to demonstrate object use. Nine years after the onset, he developed urinary incontinence, and a year later, bowel incontinence and began falling. He was admitted to a nursing home and died 11 years after the onset of his illness.
insula bilaterally, and to a lesser extent, in the frontal cortex. Areas where the atrophy was less severe demonstrated superficial linear spongiosis. Ballooned neurons (Pick cells) and Pick bodies were widely distributed. These bodies were well demonstrated with the Bielchowsky, but not the Gallyas stain. They were labelled by immunostains for tau and chromogranin A, as well as ubiquitin (Fig. 2a– d). They were mostly located in the small neurons of the temporal lobe, as well as insular cortex and parietal cortex, hippocampus, dentate gyrus, subiculum, and entorrhinal cortex. They were also present in the thalamus, amygdala, nucleus basalis, nucleus accumbens, and the locus coeruleus. Thorny astrocytes highlighted on Bielchowsky, tau, and Gallyas stains were identified within the temporal lobe and hippocampus, and in the caudate. Glial plaques were absent. Globose, PSP-type tangles were identified in the neurons of the putamen, as well as in the thalamus. A small number of neuritic plaques and tangles were seen in the hippocampus. The microscopic diagnosis was classical PiD or dementia with Pick bodies.
3.2. Neuropathology
This 64-year-old woman began having word finding difficulty and forgetfulness 3 years before being seen. The beginning of her illness was unclear, but questioning the family revealed the speech problem preceded her forgetfulness. There was also some depression before her illness began, and the initial clinical diagnosis was ‘‘pseudodementia’’. Although her speech difficulty progressed considerably, she could still remember dates and could give the names of all her children and grandchildren, manage her banking, cooking, and other household chores. She was referred as a case of PPA. Three years after the onset, she also developed personality changes of apathy, spontaneity, rigidity, and concreteness in her thinking, and dependency on certain routines. She wanted to do things right away when she thought it was time. She became disinhibited in approaching strangers with compliments, gushing remarks, and unexpectedly friendly behavior. She stroked the beard of a strange man. She also had difficulty organizing complex meals and her housekeeping had slipped. She developed occasional unexplained urinary incontinence. On examination, she had marked word finding difficulty, her speech was empty and often inadequate to express her thoughts. On formal language testing with the WAB, she was only able to name seven out of twenty objects, but her repetition was intact for single words and phrases. Her comprehension was relatively preserved, except for multicomponent commands. She had difficulty generating words in a category in a verbal fluency task. Her writing had paraphasic errors. Praxis testing showed more ideational than limb apraxia. Neuroimaging showed focal atrophy of the left frontal lobe on CT and the temporal lobe on the MRI (Fig. 3), as
The brain weighed 1060 g. Severe atrophy of the frontal and temporal lobes and mild atrophy of the parietal lobes were seen bilaterally. Microscopy revealed severe cortical atrophy, massive cortical neuronal loss, and exuberant astrocytosis, most marked in the temporal lobes and the
Fig. 1. Case 1: MRI, 6 years post-onset, left hemispheric, cortical atrophy, and ventricular dilatation.
3.3. Case 4
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Fig. 2. Case 1: (a) Pick bodies (arrows) CA1 section of the hippocampus; H&E 100 8. (b) Pick bodies (some marked with arrows). CA1 sector of the hippocampus. Bielchowsky stain; 40 1. (c) Pick bodies (some marked with arrows). Dentate gyrus. Tau-2 immunostain with hematoxylin counterstain; 40 1. (d) Pick bodies (some marked with arrows). Dentate gyrus. Chromogranin A immunostain with hematoxylin counterstain; 40 1. Case 4: (e) Frontal cortex demonstrating severe atrophy, gliosis, and widespread spongiosis; H&E 10 2. (f) Numerous dystrophic neurites in the lower layers of the cortex, occipitotemporal gyrus, ubiquitin immunostain; 20. (g) Numerous ITSNU (some marked with arrows) in the dentate gyrus. Ubiquitin immunostain; 20 1. (h) Two ITSNU (arrows) occupy the cytoplasm of neurons in the granule cell layer of the dentate gyrus. Ubiquitin immuonstain; 100 1.
102
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Fig. 4. Case 7: Written note by patient, better preserved than spoken output, reflects relatively intact cognition, except language.
Fig. 3. Case 4: MRI scan, left temporal atrophy.
well as decreased perfusion on HMPAO-SPECT. She was treated with Paroxetene and this seemed to help her mood, but not her language problem. After further deterioration, she was admitted to a nursing home, and died 10 years postonset.
positive (ITSNU) in the cytoplasm of dentate granule neurons (Fig. 2g,h). Other neuronal cytoplasmic inclusions of the same MND-type were found in the temporal neocortex, accompanied by numerous spindle-shaped neurites (Fig. 2f). Sections through the basal ganglia demonstrated unremarkable nucleus basalis of Meynert. There was neuronal loss and gliosis of the caudate nucleus, whereas the putamen
3.4. Neuropathology The brain weighed 1010 g. Atrophy was accentuated in the temporal lobes, much greater on the left side than on the right. Microscopic examination showed severe neuronal loss (more than 90%) and gliosis, resulting in marked narrowing of the cortical ribbon. On the right side, the loss was less severe, affecting predominantly the superficial layers, manifested as superficial linear spongiosis (Fig. 2e). The left frontal lobe showed a degree of neuronal loss comparable to that of the right temporal lobe. Bielchowsky stain demonstrated a small number of neuritic plaques in both the temporal and frontal neocortex. No neurofibrillary tangles were found in the neocortex or the entorrhinal cortex. The white matter of the left temporal lobe showed marked rarefaction and gliosis. The hippocampus had spongiosis in CA1 and complete loss of neurons in the subiculum, which were replaced by a dense glial scar. Tau immunostains revealed only a very rare neurofibrillary tangle. Ubiquitin immunostains, however, demonstrated numerous round inclusions, tau and synuclein negative, ubiquitin
Fig. 5. Case 7: MRI, left predominant cortical atrophy.
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Fig. 6. Case 7: (a) Superficial linear spongiosis. Left superior temporal gyrus; H&E 4. (b) Tau-2 immunostain demonstrating both neuronal inclusions (black arrows) and glial plaques (two confluent ones delineated by open arrowheads). Left middle frontal gyrus; 25. (c) Gallyas stain, showing solid neuronal inclusions (black arrow) and the processes of a glial plaque from which thin threads originate (open arrows). Left superior temporal gyrus; 100. (d) Gallyas stain, showing typical ring-shaped neuronal inclusions (black arrows). Left superior temporal gyrus; 100. (e) Numerous ballooned neurons demonstrated by immunostain for phosphorylated neurofilament. Layer 6 of left superior temporal gyrus; 20. (f) Numerous neurons in the granular cell layer of the dentate gyrus express cytoplasmic tau in a diffuse pattern (arrows). Tau-2 immunostain; 25. (g) Pervasive threads (black arrow) in the absence of neuronal inclusions (open arrows mark counter stained neurons). Gallyas stain. CA1 sector of the hippocampus; 40. (h) The substantia nigra shows globose neurofibrillary tangles (black arrow) and clusters of pigment-laden macrophages (open arrows) representing neuronal tombstones. Gallyas stain; 40.
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was minimally affected. The external segment of the globus pallidus appeared unremarkable, but the inner segment demonstrated marked neuronal loss and gliosis. 3.5. Case 7 This 57-year-old man developed word finding difficulty and he would reach for a paper to write a word he could not say (Fig. 4). Despite worsening language involvement, he remained well oriented, continued driving, shopping, mowing his lawn, and banking. Three years after onset, he began having changes in his personality. He did not pay his bills, and neglected his appearance and personal hygiene, although he had been a neat person before. His wife suspected that his shopping trips to another town were wasteful, but he became irritable when questioned. His mother was said to have been demented at the age of 73, but there was no history of similar language deterioration. On examination, 3 years after onset, he was severely anomic and paraphasic. Although he did not have articulatory difficulty, he produced incomplete and agrammatical sentences or responses were one word. Although he had better ‘‘yes –no comprehension’’ and word recognition, he was impaired for sequential commands containing grammatical variables. He also had difficulty repeating longer phrases and sentences, but his object naming was quite good. He could utilize phonemic cues for the missed items. He did well on nonverbal tasks. He could copy designs and his scores for attention initiation, construction, and memory were normal on the MDRS. His WAIS-R performance IQ was 101, which was average, but the verbal items could not be scored because of his aphasia. His visual memory span was nine, which was better than average, his visual reproduction score of 36 was in the 95th percentile, and his score of 31 on the RCPM was in the 92nd percentile. Neurological examination, including eye movements, was normal. MRI showed cortical atrophy, which was more marked on the left frontotemporal region (Fig. 5). Bilateral hypodensities were noted in the striatum. Later, in the fifth year of his illness, he stopped eating, developed vomiting, diarrhea, and was found to have stomach cancer 6 weeks before he died. 3.6. Neuropathology Post-mortem examination showed a brain weight of 1240 g. Mild cortical atrophy was more prominent in the frontal convexities and in the superior and middle temporal gyri. Microscopic sections showed superficial layer spongiosis, severe neuronal loss, and astrogliosis (Fig. 6a). Ballooned achromatic neurons were scattered in the deep layers of the cortex (Fig. 6e). There were many welldefined round, kidney-, ring-, or flame-shaped cytoplasmic inclusions in the cortical neurons staining with Bielchowsky, Gallyas, and tau immunostains (Fig. 6b – d). The neuropil showed many abnormal processes, threads, and
grains on the Gallyas and tau stains (Fig. 6g). Some of the processes were clustered crown-like around a central space where sometimes a glial nucleus could be seen (so-called glial plaque) (Fig. 6b,c). Under high-power hairlike projections originated from these processes (Fig. 6c). Several neuronal inclusions in the hippocampus and amygdala were round, but were stained by Gallyas, as well as Bielchowsky, and thus were not Pick bodies by definition. These structures also showed very abundant neuropil threads. There were no round inclusions in the dentate gyrus, but many neurons demonstrated diffuse cytoplasmic tau immunoreactivity (Fig. 6f). Mild gliosis, scattered neuronal globose neurofibrillary tangles (Fig. 6h), and skein-like cytoplasm inclusions in the neurons were seen in the basal ganglia and substantia nigra. Pick cells (ballooned neurons), abnormal processes, and grains were demonstrated in the hippocampus and amygdala. Neuritic plaques or neurofibrillary tangles of the Alzheimer-type were absent. Although numerous neuronal inclusions could be classified as Pick bodies on Bielchowsky stains and tau immunostains alone, the case fits the pathological pattern of CBD.
4. Results The clinical features and demographics of the 10 cases that were clinically diagnosed as probable PPA are summarized in Table 1. Three of these cases [3,6,10] have been previously published in some detail [6], but their histology was re-examined. The average age of onset was 63.5 (10.4), not statistically different from the population of PPA patients, who did not come to autopsy [n = 60, x¯ = 63.4 (7.5)]. By definition, they had only aphasia initially, although secondary syndromes developed within a year in two patients. The duration of predominant aphasia before the development of significant behavior and other cognitive deficits ranges from 1 to 6 years with an average of 3.1 (2.3) n = 10. The initial diagnosis varied between anxiety, depression, conversion reaction in three, and AD in three. One patient was diagnosed as a stroke, and three of the patients were referred as PPA before coming to the clinic. The presenting features were verbal apraxia and stuttering in three out of ten patients and logopenia, or decreased speech output, with relatively preserved articulation in the rest. All patients began with word finding difficulty or anomia, whether or not they were aphemic or logopenic, the difference being the amount of stuttering behavior and verbal apraxia which characterized the aphemic variety. Two patients, who were initially logopenic, were noted to develop agrammatism resembling Broca’s aphasia. All patients progressed to mutism, or to a severely logopenic, near mute state, but comprehension remained preserved on serial language examinations (Table 2). The duration of illness until death ranged from 3 to 11 years, with an average of 7.1 years.
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Three aphemic and two logopenic presentations developed apractic, extrapyramidal symptoms compatible with the corticobasal degeneration syndrome (CBDs). The other half of the cases, all logopenic presentation, developed significant behavioral and personality changes similar to FTD. A third syndrome developed in half of the cases, FTD in three, and CBDs in two (Table 1). CBDs and FTD appeared simultaneously in Case 2. Neuroimaging showed left frontal, central, and temporal atrophy in most cases (Table 1). At times, this was only frontotemporal, while at other times, predominantly perisylvian and temporal atrophy were seen. In two cases with Pick bodies and in two cases with CBD, parietal atrophy on the dominant side was significant. Neuropsychological test results of longitudinal follow-up in seven patients are summarized in Table 2. The deterioration is significant for the Aphasia Quotient (AQ) on repeated measures in all patients. All expressive subtests declined, except in patients 4 and 5, in whom repetition was preserved in the first 2 years. Word (category) fluency was initially impaired and reached floor effect early in all. Comprehension and its subtests, such as yes –no questions and word recognition tended to remain preserved over several follow-up years with significant drop in patients 3 and 6 only. This corresponded to the preservation of activities of daily living, allowing these patients a relatively independent existence, longer than it is usual for AD of the same duration. Several patients were severely logopenic and even mute when they were still performing tests of comprehension and visuospatial analogies (RCPM) at a remarkably high level. Neuropathological features are summarized in Table 1. Three patients had dementia with Pick bodies (classical PiD) (Cases 1, 2, and 3), three had frontotemporal degeneration with MND-type inclusions (ITSNU) (Cases 4, 5, and 6), and four showed CBD pathology (Cases 7, 8, 9, and 10). All cases shared neuronal loss, gliosis, and superficial linear spongiosis. No cases of ‘‘Dementia Lacking Distinctive Histology’’ were found, although all the MND-type cases would have fallen into this category had the appropriate stains not been done. Two of the patients with CBD histology were older at onset than the average of this population. Altogether, the clinical features were similar across the histological varieties.
5. Discussion This series of patients was referred to our clinic in the context of a larger population of various memory disorders and dementias. Several patients participated in a Canadian cohort study of related dementias (ACCORD). Typical cases of PPA represent a distinct syndrome which can be easily recognized. The difficulties in the differential diagnosis occur when a patient with a predominantly aphasic picture is seen at a later stage of the illness, which may have begun
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with memory problems. Most of these cases are older, have comprehension difficulties, early loss of memory and activities of daily living. Such cases with ‘‘possible PPA’’ usually have atypical, focally distributed AD histology [19,20]. We have seen 18 such cases, but excluded them from this series, on the basis of their clinical presentation. Four such cases came to autopsy and showed focal AD histology (in preparation). An initial 2 years of ‘‘relatively isolated language disorder’’ and ‘‘relative’’ absence of deficits in other domains, as a definition of PPA [21], is a useful guideline. In our experience, however, a behavioral or extrapyramidal disorder may be superimposed shortly after onset, and we felt such cases should not be excluded. Although most of our patients had preserved memory, visuospatial function, and activities of daily living, several had significant impairment in one or two of these domains by the time they came to us. Furthermore, language impairment commonly interfered with the neuropsychological test results. These difficulties in isolating the language impairment have been acknowledged by Mesulam [22] in a recent review. Neuroimaging confirmation of asymmetrical atrophy is important for diagnosis and was present in all but one of our cases. As the disease progresses, however, the asymmetry may lessen and may not be as evident on autopsy. Patients presenting with left frontotemporal atrophy and corresponding progressive aphasia often develop right temporal or bifrontal atrophy later, exhibiting disinhibition dementia or stereotypic compulsive behaviors, described in FTD. Variations in presentation as aphasic or behavioral in cases selected for one or the other side being atrophied first were renamed as the right and left variants of frontotemporal dementia [23]. In our PPA cases, the disease seemed to affect the language dominant frontotemporal and parietal areas first, but subsequent progression to other areas of the brain and variable subcortical involvement was observed in all autopsied cases. All three cases, which were characterized histologically by having Pick bodies, had ‘‘aphemic’’ presentation with stuttering and articulatory difficulty. Articulatory or aphemic presentation has been described in several individual case reports and in families without autopsy, and in two cases with DLDH [24]. The stuttering, dysarthric, often hypophonic speech in a younger patient may lead to the diagnosis of conversion reaction, such as in Case 3. The aphemic patients also progressed toward increasing word finding difficulty, logopenia, and eventually, mutism. A number of sporadic reports of PPA with CBD histology in the literature are in line with our observations [25,26]. The largest number of our cases had CBD-type of pathology, but they were not distinguishable clinically from the rest of the probable PPA population. None of the four cases with CBD histology started with the extrapyramidal apractic syndrome. One of them did not have any extrapyramidal features, and the others developed CBDs as a secondary syndrome. Conversely, in several series which examined
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patients with clinical CBD syndrome (CBDs), a variety of underlying histological types of the Pick complex was found [27,28]. Three cases lacked the tau positive neuronal and glial deposits seen in PiD and CBD pathology. Two of these were classified as DLDH originally, until the distinctive inclusions of the FTD –MND-type were revealed by ubiquitin immunostains. They were characteristically located in the dentate gyrus (see Fig. 2a –h), in a similar distribution to Pick bodies. Identical inclusions in the dentate gyrus and neocortex appear in MND with dementia and in some MND cases without dementia. They share immunoreactivity with the inclusions seen in the brainstem and spinal cord in MND. However, many cases with FTD have inclusions only in the cortex and not in the spinal cord or brainstem and clinically do not have MND. Recently, cases of PPA and semantic dementia (aphasia) were found to have MND-type pathology [29,30] in addition to cases of MND associated with aphasia [31]. Our cases of PPA with histology of the MND-type were not distinguishable clinically from the tau positive varieties. The occurrence of secondary syndromes of FTD and CBDs in PPA confirms the cohesiveness of the major clinical components of the Pick complex. Apparently, PPA does not remain isolated in most cases, although death or lack of follow-up may preclude the observation of the other symptoms. The clinical distinction of PPA, FTD, and CBDs is important for diagnosis, but should not obscure their cohesion. The concept of their relatedness appears to be the best approximation to fit the current evidence and it allows a better perspective of the syndrome, which continues to be under-diagnosed despite its estimated frequency of about 15 –20% of degenerative dementias (higher in the presenile group) [27,32,33]. The clinical variation within families with a single gene mutation is similar to the variation in the sporadic cases. On the other hand, different mutations in the same gene and possibly in different genes can also cause the same clinical phenotype. Genetic and clinicopathological studies are complementary in clarifying the nature of this disorder.
Acknowledgements We would like to thank Bonita Stevenson for secretarial and Marybelle Lozanski for technical assistance, the physicians who referred patients, and the caregivers and patients, above all, who taught us a great deal. This study was supported in part by the Medical Research Council of Canada, Grant No. C94-0493.
References [1] Mesulam M-M. Slowly progressive aphasia without generalized dementia. Ann Neurol 1982;11:592 – 8.
[2] Mesulam MM, Weintraub S. Primary progressive aphasia: sharpening the focus on a clinical syndrome. In: Boller F, Forette F, Khachaturian Z, Poncet M, Christen Y, editors. Heterogeneity of Alzheimer’s disease. Berlin: Springer; 1992. p. 43 – 66. [3] Knopman DS, Mastri AR, Frey WH, Sung JH, Rustan T. Dementia lacking distinctive histologic features: a common non-Alzheimer degenerative dementia. Neurology 1990;40:251 – 6. [4] Turner RS, Kenyon LC, Trojanowski JQ, Gonatas N, Grossman M. Clinical, neuroimaging, and pathologic features of progressive nonfluent aphasia. Ann Neurol 1996;39:166 – 73. [5] Snowden JS, Neary D, Mann DMA, Goulding PJ, Testa HJ. Progressive language disorder due to lobar atrophy. Ann Neurol 1992;31: 174 – 83. [6] Kertesz A, Hudson L, Mackenzie IRA, Munoz DG. The pathology and nosology of primary progressive aphasia. Neurology 1994;44: 2065 – 72. [7] Neary D, Snowden JS, Gustafson L, Passant U, Stuss D, Black S, et al. Frontotemporal lobar degeneration—a consensus on clinical diagnostic criteria. Neurology 1998;51:1546 – 54. [8] McKhann GM, Albert MS, Grossman M, Miller B, Dickson D, Trojanowski JQ. Clinical and pathological diagnosis of frontotemporal dementia. Arch Neurol 2001;58:1803 – 9. [9] Wilhelmsen KC, Lynch T, Pavlou E, Higgins M, Nygaard TG. Localization of disinhibition dementia parkinsonism amyotrophy complex to 17q21 – 22. Am J Hum Genet 1994;55:1159 – 65. [10] Bird TD, Nochlin D, Poorkaj P, et al. A clinical pathological comparison of three families with frontotemporal dementia and identical mutations in the tau gene (P301L). Brain 1999;122: 741 – 56. [11] Zhukareva V, Vogelsberg-Ragaglia V, Van Deerlin V, et al. Loss of brain tau defines novel sporadic and familial tauopathies with frontotemporal dementia. Ann Neurol 2001;49:165 – 75. [12] Munoz DG. The pathology of Pick complex. In: Kertesz A, Munoz DG, editors. Pick’s disease and Pick complex. New York: Wiley; 1998. p. 211 – 41. [13] Cooper PN, Jackson M, Lennox G, Lowe J, Mann DMA. t, Ubiquitin, and aB-crystallin—immunohistochemistry define the principal causes of degenerative frontotemporal dementia. Arch Neurol 1995;52: 1011 – 5. [14] Feany MB, Mattiace LA, Dickson DW. Neuropathologic overlap of progressive supranuclear palsy, Pick’s disease and corticobasal degeneration. J Neuropathol Exp Neurol 1996;55:53 – 67. [15] Jackson M, Lowe J. The new neuropathology of degenerative frontotemporal dementias. Acta Neuropathol 1996;91:127 – 34. [16] Dickson DW. Pick’s disease: a modern approach. Brain Pathol 1998; 8:339 – 54. [17] Iseki E, Li F, Odawara T, et al. Ubiquitin-immunohistochemical investigation of atypical Pick’s disease without Pick bodies. JNS 1998; 159:194 – 201. [18] Komori T. Tau-positive glial inclusions in progressive supranuclear palsy, corticobasal degeneration and Pick’s disease. Brain Pathol 1999;9:663 – 79. [19] Karbe H, Kertesz A, Polk M. Profiles of language impairment in primary progressive aphasia. Arch Neurol 1993;50:193 – 201. [20] Galton CJ, Patterson K, Xuereb JH, Hodges JR. Atypical and typical presentations of Alzheimer’s disease: a clinical, neuropsychological, neuroimaging and pathological study of 13 cases. Brain 2000;123: 484 – 98. [21] Weintraub S, Rubin NP, Mesulam M-M. Primary progressive aphasia: longitudinal course, neuropsychological profile, and language features. Arch Neurol 1990;47:1329 – 35. [22] Mesulam MM. Primary progressive aphasia. Ann Neurol 2001;49: 425 – 32. [23] Edwards-Lee T, Miller BL, Benson F, Cummings JL, Russell GL, Boone K, et al. The temporal variant of frontotemporal dementia. Brain 1997;120:1027 – 40. [24] Broussolle E, Bakchine S, Tommasi M, et al. Slowly progressive
A. Kertesz, D.G. Munoz / Journal of the Neurological Sciences 206 (2003) 97–107
[25]
[26]
[27] [28]
[29]
anarthria with late anterior opercular syndrome: a variant form of frontal cortical atrophy syndromes. JNS 1996;144:44 – 58. Lang AE. Cortico-basal ganglionic degeneration presenting with ‘‘progressive loss of speech output and orofacial dyspraxia’’. J Neurol Neurosurg Psychiatry 1992;55:1101. Mimura M, Oda T, Tsuchiya K, Kato M, Ikeda K, Hori K, et al. Corticobasal degeneration presenting with nonfluent primary progressive aphasia: a clinicopathological study. JNS 2001;183:19 – 26. Kertesz A, Munoz DG. Pick’s Disease and Pick Complex. New York: Wiley-Liss; 1998. Boeve BF, Maraganore DM, Parisi JE, et al. Pathologic heterogeneity in clinically diagnosed corticobasal degeneration. Neurology 1999; 53:795 – 800. Kinoshita A, Tomimoto H, Tachibana N, et al. A case of primary
[30]
[31]
[32]
[33]
107
progressive aphasia with abnormally ubiquitinated neurites in the cerebral cortex. Acta Neuropathol 1996;92:520 – 4. Rossor MN, Revesz T, Lantos PL, Warrington EK. Semantic dementia with ubiquitin-positive tau-negative inclusion bodies. Brain 2000; 123:267 – 76. Bak TH, O’Donovan DG, Xuereb JH, Boniface S, Hodges JR. Selective impairment of verb processing associated with pathological changes in Brodmann areas 44 and 45 in the motor neuron disease – dementia – aphasia syndrome. Brain 2001;124:103 – 20. Gustafson L. Frontal lobe degeneration of non-Alzheimer type: II. Clinical picture and differential diagnosis. Arch Gerontol Geriatr 1987;6:209 – 23. Ratnavalli E, Brayne C, Dawson K, Hodges JR. The prevalence of frontotemporal dementia. Neurology 2002;58:1615 – 21.