Primary progressive aphasia: analisys of 16 cases

Arq Neuropsiquiatr 2001;59(3-A):512-520 PRIMARY PROGRESSIVE APHASIA Analisys of 16 cases Márcia Radanovic1, Mirna Lie Hosogi Senaha2, Letícia Lessa Mansur3, Ricardo Nitrini4, Valéria Santoro Bahia5, Maria Teresa Carthery6, Flávia Nóbrega Freire Aires7, Sandra Christina Mathias8, Paulo Caramelli9 ABSTRACT - Primary progressive aphasia (PPA) is an intriguing syndrome, showing some peculiar aspects that differentiate it from classical aphasic pictures caused by focal cerebral lesions or dementia. The slow and progressive deterioration of language occurring in these cases provides an interesting model to better understand the mechanisms involved in the linguistic process. We describe clinical and neuroimaging aspects found in 16 cases of PPA. Our patients underwent language and neuropsychological evaluation, magnetic resonance imaging (MRI) and single photon emission computerized tomography (SPECT). We observed a clear distinction in oral expression patterns; patients were classified as fluent and nonfluent. Anomia was the earliest and most evident symptom in both groups. Neuroimaging pointed to SPECT as a valuable instrument in guiding the differential diagnosis, as well as in making useful clinical and anatomical correlations. This report and a comparison to literature are an attempt to contribute to a better understanding of PPA. KEY WORDS: primary progressive aphasia, focal cortical degeneration, cerebral perfusion, neuroimaging. Afasia progressiva primária: análise de 16 casos RESUMO - A afasia progressiva primária (APP) é uma síndrome que tem despertado grande interesse devido a aspectos particulares que a diferenciam das afasias clássicas (secundárias a lesões cerebrais focais) e dos quadros demenciais. A deterioração lenta e progressiva da linguagem presente nesses casos fornece um interessante modelo de observação dos mecanismos subjacentes ao processamento linguístico. Descrevemos as características clínicas e de neuroimagem de 16 casos de APP. Os pacientes foram submetidos a exame de linguagem, neuropsicológico, ressonância magnética (RM) e tomografia computadorizada por emissão de fóton único (SPECT). Clinicamente pudemos observar uma nítida distinção nos padrões de produção oral, sendo os pacientes agrupados em fluentes e não-fluentes. Anomia foi o sintoma mais precoce e evidente nos dois subgrupos. Os achados de neuroimagem permitem destacar a sensibilidade do SPECT como instrumento diagnóstico. O registro e a comparação destes casos aos da literatura são uma tentativa de contribuir para a compreensão da APP. PALAVRAS-CHAVE: afasia progressiva primária, degeneração focal cortical, perfusão cerebral, neuroimagem. Progressive language impairment in patients with relative preservation of other cognitive functions is called primary progressive aphasia (PPA); it is a clinical syndrome with several aspects still open to question, for example language profile characterization and clinical and neuroimaging diagnostic criteria. The first description of isolated progressive loss of language was reported by Pick, in 18921, describing a patient with severe language disturbance associated with atrophy in the left temporo-polar region and posterior two thirds of the frontal lobe. Later, the same author described other patients with temporal2, parietal and frontal lobe atrophy3. The term “Pick’s disease” was later used for any similar progressive atrophic diseases, especially those with predominant behavioral disturbances. Other authors have also described predominant language alterations, under the name “aphasic dementia” or “pure verbal deafness evolving to sensorial aphasia”4-6. Perhaps due to greater frequency, Alzheimer’s dis- Behavioral and Cognitive Neurology Unit, Department of Neurology (DN); Department of Physiotherapy, Speech Pathology and Occupational Therapy (DP), University of São Paulo School of Medicine, São Paulo SP, Brazil: 1M.D., Consultant Neurologist (DN); 2MSc in Neurosciences (DN); 3PhD, Assistant Professor (DP); 4MD, Associate Professor (DN); 5Post graduate student (DN); 6MSc in Neurosciences (DN); 7Speech Pathologist (DP); 8M.D., Consultant Neurologist (DN); 9M.D., Assistant Professor (DN) Received 22 January 2001, received in final form 26 April 2001. Accepted 30 April 2001. Dra. Márcia Radanovic - R. Cristiano Viana, 163 / 92 - 05411-000 São Paulo SP – Brasil. E-mail: mgomes@tecway.com.br Arq Neuropsiquiatr 2001;59(3-A) ease was liberally diagnosed to many clinical conditions, including those that could be considered PPA. In 1982, Mesulam7 described six patients with isolated and long lasting language deterioration, naming these clinical pictures as slowly progressive aphasia without dementia, later called PPA. Some of these patients, in spite of serious limitations to oral and written communication, were able to maintain autonomy in daily life activities. More than a hundred similar cases have been reported in literature8. In Brazil, Oliveira et al.9 were the first to report a case of PPA. To date, some 33 cases of PPA have undergone pathologic examination, showing predominantly (in approximately 60% of cases) signs of non-specific focal degeneration with neuronal loss, gliosis and spongiform alterations in superficial cortical layers10-12. Alterations compatible with Pick’s disease were seen in about 20% of the patients13-15, whereas the remaining 20% had Alzheimer’s disease16. There is a report of Creutzfeldt-Jakob disease manifesting itself as PPA in its fluent form17. It is nowadays accepted that PPA constitutes a syndrome including different etiologies and whose diagnosis is clinical and based on the presence of progressive language deficit, which during the first two years is either the only affected cognitive function or is the most important function involved. Although usually isolated, PPA may coexist with disorders such as acalculia, ideomotor or constructional apraxia, indicative of left hemisphere damage18,8. These clinical manifestations emerge in the absence of morphologic alterations (excluding atrophy) both in computerized tomography (CT) and magnetic resonance imaging (MRI). Atrophy usually appears in left frontal, temporal or perisylvian cortices19. Clinical presentations similar to PPA can occasionally be found such as in pure progressive verbal deafness, described in a patient with left superior temporal atrophy20 and pure progressive aphemia21. The purpose of this paper is to report clinical, linguistic and neuroimaging characteristics found in 16 PPA cases diagnosed and accompanied by the Behavioral and Cognitive Neurology Unit of the Neurological Division, Hospital das Clínicas of the University of São Paulo School of Medicine. METHOD Sixteen patients were studied, whose demographic data are presented in Table 1. Language evaluation was performed using Montreal-Toulouse (BETA version)22 and Boston Diagnostic Aphasia Examination (BDAE)23 protocols, with patients classified as fluent and nonfluent. Seven 513 patients were evaluated longitudinally. The remaining cognitive functions were evaluated using the Mini-Mental State Examination (MMSE)24 and complementary neuropsychological tests. Cranial MRI was performed on all patients. Ten patients were also submitted to single photon emission computerized tomography (SPECT). RESULTS Our series comprised nine females and seven males, with ages varying between 39 and 83 years (average 62.8 years) and an educational level between two and 20 years (average 10.7 years). Six patients spoke other languages besides Portuguese (see Table 1). Neuropsychological evaluation results are shown in Table 2. Performance in language tests, repeated after a one to two year interval in seven cases, is presented in Table 3. Neuroimaging exam results are described in Table 4. Figure 1 shows a comparison in language performances between fluent and nonfluent groups. Figures 2 and 3 show the speech characteristics profile scales for each group and its evolution over time. These profiles are useful in identifying similarities and differences between fluent form and Broca’s aphasia (Fig 2) or between nonfluent form and Wernicke’s aphasia (Fig 3). Figures 4 and 5 illustrate the neuroimaging (SPECT and MRI) findings in a fluent and a nonfluent patient, respectively. These figures include speech samples from the same patients. Differential diagnosis and evolution of cases The clinical course, although restricted in some cases, can cast further light on the differential diagnosis between correlate syndromes such as semantic dementia, as observed in case 14. In this case, the family’s report on the progression of linguistic changes suggests steady reduction, and their first description approached transcortical motor aphasia. Oral comprehension began worsening three years after the disease had manifested, where aspects most preserved were word repetition and reading. The patient’s evolution showed marked comprehension difficulties, which differentiates it from a typical anterior cerebral lesion profile. In this case, one can speculate on the presence of semantic dementia (given that the family’s description of language reduction was somewhat vague). This hypothesis does not persist given the verification of a residual comprehension capacity, aptitude for isolated words in naming tests and also evidenced by the ability to treat information semantically when visual stimuli were supplied, such as in reading tests. Besides, there were no difficulties in manipulating objects. 514 Arq Neuropsiquiatr 2001;59(3-A) Table 1. Demographic data and presenting symptoms. Patient Age schooling ∆T 1st eval (years) (months) Language presenting problem 1 82 9 18 Portuguese naming 2 52 15 60 Portuguese naming 3 63 5 24 Portuguese naming 4 45 11 60 Portuguese “asking strange questions and forgetting the answers” 5 77 15 18 Czech Portuguese recent memory word finding 6 59 15 24 Spanish Portuguese word finding 7 72 9 18 Portuguese expression and word finding 8 72 5 24 Portuguese word finding 9 70 16 30 Italian Portuguese naming: proper names 10 60 20 12 Portuguese Japanese word finding 11 67 11 48 Portuguese expression memory loss depression 12 60 11 24 Portuguese “forgetfulness” word finding 13 39 11 72 Norwegian Portuguese writing 14 60 2 48 Portuguese Spanish expression in Spanish (mother tongue) and slowness in Portuguese 15 68 4 24 Portuguese oral production oral and speech apraxia 16 60 12 24 Portuguese English “stuttering” expression difficulties ,T 1st eval : time from onset of symptoms to first evaluation Fig 1. Average performance on language tests. Arq Neuropsiquiatr 2001;59(3-A) 515 Table 2. Neuropsychological evaluation and deficit evolution. Patient MMSE / NP alterations (first evaluation) deficit evolution 1 NT / mild memory impairment oral comprehension and reading after one year 2 22 / verbal and non-verbal memory oral comprehension after one year memory, apathy, irritability, obsessive behavior after five years FTD after eight years 3 9/ digit span anomia 4 9/ memory, digit span and calculation pragmatic communication disturbance 5 20 / normal oral comprehension depression 6 26 / verbal memory anomia 7 22 / NT memory transient behavioral disturbances (nocturnal fears, “strangeness of environment”) after three years 8 25/ NT recent memory 9 23 / anterograde episodic memory and visuospatial abilities naming in general 10 22 / initiation, perseveration, verbal and visual memory and conceptualization reading and calculation impaired lexical access, phrase reformulation 11 12 / Mattis34: 87/144 (attention, memory, constructional praxis and executive functions) symptoms worsening 12 25/ Mattis: 116/144 (executive functions and verbal episodic memory) agraphia slowness in talking 13 24 / constructional praxis, acalculia and non-verbal memory agraphia after four years expression and recent memory after five years 14 NT / normal oral production in both languages 15 29 / normal dementia after five years 16 20/ Mattis: 97/144 (attention, constructional praxis and executive functions) expression difficulties worsening NP: neuropsychological evaluation; NT: not tested; FTD: frontotemporal dementia. Fig 2. Speech characteristics profile scale (Goodglass and Kaplan, 1985). PPA patients, nonfluent form. Red line: patient with less than 36 months of disease; blue line: average for patients with more than 36 months of disease; dotted line: Broca’s aphasia profile. 516 Arq Neuropsiquiatr 2001;59(3-A) Table 3. Language examination. Performance in tests is expressed in terms of percentage of correct answers. Patient 1 2 3 fluency F F F ,t (yrs) 1 2 1 oral reading compr compr naming repetition reading writing protocol (dictate) 73.3 46.7 70.9 78.7 100 53.8 Beta 62.5 69.2 66.6 86.6 86.6 ND Beta 86 75 24 90 70 85 Beta 49.1 55 8.3 93.3 53.3 ND Beta 21.4 40 43 62.5 60 42.7 BDAE 36.2 61.5 35.5 90.9 81.8 ND Beta 4 F NA 26.1 30 45.8 54.3 40 0 BDAE 5 F NA 52.5 59.5 11.7 45.8 100 55,7 Beta / BN 6 F NA 97.2 100 94.5 91.6 100 96.6 BDAE 7 F 1 86.3 85 92 82.5 100 84.7 Beta 75.3 68.3 56.6 62.5 82.5 64.5 BDAE 8 F NA 100 100 84 100 100 ND Beta 9 F NA 96.3 68.3 64 100 96.7 ND Beta 10 F NA 97.2 90 86.7 42.5 66.7 42.3 BDAE 11 F NA 87.7 73 13.8 66.6 55.5 ND Beta / BN 12 F 1 76.6 89.5 66.7 97.8 100 92.7 Beta 84.8 91.66 75 70.8 100 88.2 Beta 60.9 75 49.3 57.8 74.5 0 Beta 59.6 58.9 76 62.3 55 0 Beta 13 NF 1 14 NF NA 28.3 36.6 2.75 43.3 13.3 0 BDAE 15 NF 2 100 100 100 100 100 ND Beta 87 87 78 48 45 ND Beta 68.3 47 28.3 31.1 93.7 ND Beta / BN 16 NF NA ,t: interval between first and second evaluation ; compr: comprehension; NA: not applicable; ND: not done; BN: Boston naming test. Neuroimaging Considering the MRI findings, we noted that 15 patients in our series presented predominant left hemisphere atrophy. In three cases (2, 4 and 16), the atrophy was bilateral, although predominant in the left side. The temporal region was the most affected, with atrophy present in 11 cases; one with temporo-parietal atrophy (Case 6), two with fronto-temporal atrophy (Cases 15 and 16) and one with volumetric reduction of left hippocampus (Case 5). Perisylvian atrophy was reported in three cases (1, 7 e 8), thus implying frontal and/or temporal degeneration (these cases are considered separately because we can not describe the site of anomaly accurately). One case (13) presented diffuse cortical and subcortical atrophy. Regarding perfusion studied with SPECT, of the 13 patients that underwent the exam, ten presented CBF abnormalities in the left hemisphere only. Bilateral CBF abnormalities existed in Cases 4, 13 and 16, being focal in two cases (4 and 16) and generalized in one (13). In eight cases, the temporal region was the most affected, being isolated in one case (2), or associated with frontal (Cases 3 and 14), parietal (Cases 7, 10 and 16) or fronto-parietal (cases 5 and 12). Three patients had homogeneous left fronto-temporo-parietal CBF abnormalities (Cases 6, 11 and 15). The perfusion abnormalities were more pronounced than those found in MRI, both in extension and intensity. Arq Neuropsiquiatr 2001;59(3-A) 517 Table 4. Neuroimaging results. Patient MRI SPECT 1 mild asymmetry of sylvian fissures (L > R) not performed 2 diffuse atrophy, mainly in left temporal region left temporal hypo perfusion 3 sectorial enlargement of left insular cistern and enlargement of cortical sulci in left temporal region left temporal hypo perfusion with mild left frontal extension 4 mild cortico-subcortical atrophy slightly larger on left side left parietal and occipital hypo perfusion plus right parietal 5 left cortical atrophy / left hippocampal volumetric reduction severe left temporal hypo perfusion with left frontal and parietal extension 6 left inferior parietal and temporal atrophy left fronto-temporo-parietal hypo perfusion 7 ventricular asymmetry (L > R) left temporo-parietal hypo perfusion 8 ventricular asymmetry (L > R) not performed 9 left temporal atrophy not performed 10 left temporo-parietal atrophy left temporo-parietal hypo perfusion 11 left temporal atrophy moderate left fronto-temporo-parietal 12 left temporal atrophy left fronto-parietal, anterior temporal and basal ganglia hypo perfusion 13 cortico-subcortical atrophy bi-hemispheric hypo perfusion, mainly on left side 14 severe hemispheric asymmetry with left temporal atrophy left temporal hypo perfusion with mild left frontal extension 15 left fronto-temporal atrophy left fronto-temporo-parietal hypo perfusion 16 bilateral cortical atrophy, predominating in left fronto-temporal region left mesial temporal and bilateral parietal hypo perfusion L: left; R: right Fig 3. Speech characteristics profile scale (Goodglass and Kaplan, 1985). PPA patients, fluent form. Red line: average for two patients with less than 36 months of disease; blue line: average for patients with more than 36 months of disease; dotted line: Wernicke’s aphasia profile. 518 Arq Neuropsiquiatr 2001;59(3-A) Impairment of lexical access in a fluent patient (case 6) P – My apartment has 3 rooms has a... has a big living room, has a big sacada with a...churrasqueira that is to keep Argentine habits. It has a kitchen, it has a small room for breakfeast and also when we are alone we use it as...as...to have lunch and dinner... The words in italic refer to names that the patient couldn’t access in his mother tongue (Spanish) and were spoken in Portuguese. Fig 4. Case 6 - SPECT and MRI showing mild hypoperfusion and atrophy in left parieto-temporal region. Agrammatism found in a nonfluent patient (case 15) Illustrations sequence: in this story, a woman leaves her car with two children inside. The children start driving and the car crashes in a lamppost. Patient’s description: car guide womun (woman) car exits womun car break fall car fall break the boy guide aumobile (automobile) womun.. (unintelligible).. count (crash) pasts (posts) womun beak (break) Fig 5. Case 15 - SPECT and MRI showing mild hypoperfusion and atrophy in left fronto-temporal region DISCUSSION Our results disclosed different and peculiar patterns of language impairment among the patients, to be expected, especially considering the differing progressions of the disease over time. The anatomical distribution of abnormalities in neuroimaging is similar to that described in literature . The first possible consideration, analyzing language data, is including these cases in the classical aphasic syndromes. Using generic taxonomy, we chose to divide the cases into fluent and nonfluent and to identify the isolated aphasic symptoms, given that one of the difficulties in regard to classification, stems from the fact that the patients were diagnosed when the intensity, combination and sum of alterations surpassed the classical aphasic syndrome definitions. The attempt to recoup evolution from clinical history provided by family proved unsuccessful, given the overlapping interpretations of memory and language alterations, exemplified by frequent indications of “word forgetting” for anomia, or the generic descriptions of “pronunciation alterations”. As new cases of PPA were being described, it became evident that the clinical features are complex and heterogeneous. This has led several authors to attempt a classification of the patients into subgroups with similar clinical characteristics. One of the first attempts was to categorize into nonfluent (where expression alterations such as agrammatism, emission reduction and phonologic alterations predominate) and fluent, where the semantic impairment is more evident. One of the most intriguing discussions arises from similarities and differences that may exist between fluent PPA and “semantic dementia”25,26. In the latter condition, however, the impairment of cognition seems to be more prevalent, affecting the recognition of words and objects, traits usually associated with bilateral temporal lobe dysfunction. The subdivision into nonfluent and fluent groups proved insufficient to include all new data observed by researchers. Principally due to the overlapping of symptoms between patients in both groups, as well as features shared by PPA and other degenerative diseases with lobar atrophy, such as frontotemporal dementia (FTD) 27,25. The existence of pathologic alterations that are present both in FTD and PPA reinforces the hypothesis of both manifestations representing a non-Alzheimer degenerative process, with the occurrence of a different distribution of the pa- Arq Neuropsiquiatr 2001;59(3-A) thological process, either predominantly in the frontal or temporal lobes. Due to this overlapping of clinical and pathological characteristics, Kertesz et al. 28,29 proposed the term “Pick complex” to include the clinical conditions currently described as FTD, PPA, Pick’s disease and corticobasal degeneration. Weintraub and Mesulam30 proposed a classification of degenerative dementia based on four clinical profiles, each in turn having more probability of association with a specific cerebral disease. This classification takes into account the neuropsychological profile exhibited by the patient during the first two years of disease. PPA is one of these profiles (Progressive Language Network Syndrome). In our series, it was not possible to classify the patients into classical aphasic syndromes, although a resemblance to predominantly frontal dysfunction (agrammatism), or temporal (marked comprehension disturbances) is admissible. That said, symptoms also described in dementia occurred alongside the language primary deficit. Regarding fluency, which is a referential for subgroup identification, we did not notice any remarkably positive characteristics, such as hyper fluency. Reduction in fluency and quantitative emission predominated, and were shared by the patients with clinical symptoms compatible with both frontal and temporal dysfunction. Absence of language production occurred when extra-language cognitive symptoms intensified. Anomia was the earliest and most notable symptom, being present in all patients. Disturbances of repetition were also frequent and could be found in the fluent and nonfluent groups. We can notice in Figures 2 and 3 that the nonfluent group presents greater similarities to Broca’s aphasia profile as the disease evolves, except for comprehension, which is more impaired in our data. In the fluent group, independent of evolution time, the profile is more akin to that found in Wernicke’s aphasia, except for the occurrence of fewer semantic paraphasias in language production. One of the main goals in the research field of degenerative cerebral diseases is to find a method with enough specificity to allow the elaboration of a prognosis, bearing in mind the great number of years necessary to reach a clinical diagnosis with reasonable acuity. Toward this goal, several groups have striven to establish relations between perfusion and neuroimaging, and the probable clinical evolution for each profile. Talbot et al.31 described the correlation between standard perfusion with SPECT in 363 519 patients studied prospectively for 3 years. They found positive correlation between the presence of posterior bilateral alterations and Alzheimer’s disease, and between anterior bilateral alterations and FTD. Other perfusion patterns, such as patchy distribution and generalized or unilateral (anterior or posterior) alterations, showed less correlation and therefore were less useful for the characterization of a diagnosis. Neuroimaging findings in PPA keep certain correlation with the clinical variant. In nonfluent cases, there is left frontal and perisylvian atrophy in cranial CT and MRI, with CBF abnormalities in the same areas in SPECT. In fluent cases, the cortical atrophy and CBF abnormalities are located predominantly in the left temporal lobe, hippocampus and parahippocampal gyrus32. In a review article of 112 cases, Westbury and Bub33 found the following distribution: of 59 cases that performed PET or SPECT, 39 (66.1%) had CBF abnormalities exclusively in the left hemisphere and 18 (30.5%) had bilateral CBF abnormalities; perfusion was normal only in two cases (3.4%). In the left hemisphere, for 27.3% of cases the CBF abnormalities were located in the fronto-temporal region, 21.2% in the temporal region, 12.1% in the frontal region, and the remaining 39.4% were distributed between frontal, temporal and parietal lesions combined. In those cases for which MRI was performed (105), 49 (46.7%) had atrophy in the left side only, 38 (36.2%) had bilateral atrophy and in 17 (16.2%) the exams were normal. The anatomical distribution found in our cases was similar to that documented in literature, namely: predominance in the left hemisphere and, within this, in the temporal and frontal regions or combination of the two. We observed that the abnormalities were more apparent in SPECT than in MRI findings, generally showing areas of CBF abnormalities that were larger and more evident than those seen in MRI. We think this feature of SPECT might be helpful, especially in the earlier stages of the disease when MRI shows only mild diffuse atrophy or asymmetry of Sylvian fissures, in providing a useful clue for correct diagnosis. CONCLUSION We found elements in our series that suggest the need to seek an analysis model for the clinical picture of PPA. We think that the description of symptomatology from a longitudinal and cross-sectional point of view is very important to improve our ability to diagnose PPA in its initial phase. Moreover, it will allow refinement of the tools used to identify 520 Arq Neuropsiquiatr 2001;59(3-A) the symptoms that are typical of this phase. Furthermore, this description can aid to identification of those symptoms that overlap in language disorders and other cognitive losses. 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