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Cognitive findings in spinocerebellar ataxia type 2: relationship to genetic and clinical variables
Journal of the Neurological Sciences 201 (2002) 53 – 57 www.elsevier.com/locate/jns
Cognitive findings in spinocerebellar ataxia type 2: relationship to genetic and clinical variables Francesco Le Pira a,*, Giuseppe Zappala` b, Riccardo Saponara a, Elisabetta Domina a, Domenico A. Restivo a, Ester Reggio a, Alessandra Nicoletti a, Salvatore Giuffrida a a
Department of Neurosciences, University of Catania, Via S. Sofia 78, I-95125 Catania, Italy b Division of Neurology, Garibaldi Hospital Catania, Catania, Italy Received 3 December 2001; received in revised form 28 May 2002; accepted 3 June 2002
Abstract Several authors have recently reported a broad cognitive impairment in autosomal dominant cerebellar ataxias (ADCAs) patients. However, only a few studies on neuropsychological features in spinocerebellar ataxia type 2 (SCA2) patients are present in the current literature. The aim of this study is to evaluate the cognitive impairment in a wide sample of SCA2 patients and to verify the role of different disease-related factors (age of onset, disease duration, and clinical severity) on intellectual abilities. We administered a battery of neuropsychological tests assessing handedness, attention, short- and long-term verbal and visuo-spatial memory, executive functions, constructive abilities, general intellectual abilities and depression to 18 SCA2 patients belonging to eight families who came to our observation. Evidence of impaired verbal memory, executive functions and attention was found. The cognitive status was partially related to clinical severity rather than to disease duration or age at onset of symptoms. We partially confirmed data on cognitive defects already reported by others but we also found defective attention skills as well as significant lower performances in a nonverbal intelligence task. D 2002 Elsevier Science B.V. All rights reserved. Keywords: Autosomal dominant cerebellar ataxia; Spinocerebellar ataxia type 2; Cognitive impairment; Memory
1. Introduction Autosomal dominant cerebellar ataxias (ADCAs) represent a heterogeneous group of progressive neurodegenerative disorders with different clinical and neuropathological findings. Several genetic loci have been identified in ADCAs and named spinocerebellar ataxias (SCAs) [1]. One of the most common forms is spinocerebellar ataxia type 2 (SCA2) [2]. On clinical grounds, the SCAs are not easily distinguishable without genetic analysis. Mutation in SCA2 has been assigned to the long arm of chromosome 12 (12q23 –24,1) and an unstable cytosine – adenine – guanine (CAG) trinucleotide expansion has been identified [2,3]. Neuropathological data in SCA2 have shown that the typical pattern of olivopontocerebellar atrophy occurs early, and that an involvement of the neocortex is also present later [4]. Similar data were found in a large neuroradiological study
*
Corresponding author. Tel.: +39-95-330-943, +39-95-256-627; fax: +39-95-330-943. E-mail address: [email protected] (F. Le Pira).
where supratentorial atrophy was related to disease duration [5]. Some authors reported a cognitive impairment in ADCAs patients resembling subcortical dementia [6– 13]. However, most of these works were performed either on genetically not confirmed or on genetically heterogeneous patients. Only a few studies addressing neuropsychological features in SCA2 patients are present in current literature. Trojano et al. [10] found a significant relationship between clinical severity and verbal memory tasks in 15 SCA2 patients. Gambardella et al. [11] described a selective impairment of executive functions using Wisconsin Card Sorting Test (WCST) in 17 patients. Storey et al. [12] confirmed the same findings underlying a dis-executive syndrome among eight SCA2 patients without mention to learning and memory disturbances which may have afflicted these patients. However, in the same year, Bu¨rk et al. [13] investigated neuropsychological performances of 17 European SCA2 patients belonging to four families where, not only executive deficits were corroborated, but also verbal memory was significantly impaired with a relative sparing of visuo-spatial learning. In this study, we evaluated the cognitive impairment in a wide sample of SCA2 patients
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 1 9 4 - 6
54
F. Le Pira et al. / Journal of the Neurological Sciences 201 (2002) 53–57
attempting to verify the role of different disease related factors (age of onset, disease duration and clinical severity) on intellectual abilities.
2. Patients and methods Patients: 18 subjects out of eight families, all originating from Middle-Eastern Sicily, were diagnosed as having ADCA type I on the following criteria: autosomal dominant inheritance, progressive cerebellar ataxia variably associated with dysarthria, pyramidal or extrapyramidal signs, decreased vibration sense, ophthalmoplegia, and dementia. Blood sample was obtained with informed consent; molecular analysis performed with Rapid touchdown PCR assay [14] revealed SCA2 mutation in all of them. Severity of disease was scored according to the Inherited Ataxia Progression Scale (IAPS) (stage 1 = asymptomatic; stage 2 = mild symptoms; stage 3 = need of constant help and walking without support is impossible; stage 4 = wheelchair or bed) [15]. Furthermore, we evaluated upper limb ataxia and dysarthria using a scale ranging from 0 (absent) to 5 (most severe) [16]. Clinical and molecular data of these patients have been reported in a previous larger study [17]. Fourteen subjects (eight women and six men) without clinically evident neurological or psychiatric diseases were chosen as a control group; mean age was 49.93 F 12.43 years (range: 28 – 67) and the mean education was 7.93 F 3.41 years (range: 5 –13). Neuropsychological tests: a battery of neuropsychological tests assessing handedness, attention, short- and longterm verbal and visuo-spatial memory, executive functions, constructive abilities, general intellectual was administered to all patients. Presence of depression was evaluated by Hamilton Depression Scale. All tests were administered by the same observer (S.R.) who remained uninformed as to the exact molecular diagnosis of the individual being tested. Digit span: used in the Wechsler batteries (intelligence and memory), comprises two tests (digit forward and digits backward) which involve different abilities. The subject is asked to repeat random number sequences that the examiner reads. Repeating numbers forward seems to be related mostly to attention while the backward task is likely to involve working memory and mental tracking [18]. Corsi Block-tapping Test: it is a visuo-spatial test exploring attention and nonverbal working memory. It consists of nine cubes on a board; the subject is asked to tap the same cubes that the examiner had touched before in an increasing prearranged sequence [19]. Rey Complex Figure: copying this widely used picture allows to test constructional abilities [20]. Rey Complex Figure Test (recall administration): the immediate and delayed recall of this figure allows to measure short- and long-term nonverbal memory. For the three drawings, we used the same scoring system ranging from 0 to 36 [20].
California Verbal Learning Test (CVLT): it examines verbal memory and learning strategies together with conceptual abilities. The 16-word list is presented five times and each time the subject must repeat as many words as possible. After an interference trial, there is an immediate recall, a delayed recall (after 20 min) and a final trial of recognition of the 16 words from a longer list of words. The 16 words belong to four categories not known to the subjects (fruits, fishes, articles of clothing, tools) and the ability to make clusters (words of the same category recalled together) is, also, measured. We used the Italian version of the test where fishes took the place of herbs [21]. FAS: also-called Controlled Oral Word Association Test consists of three word-naming trials beginning with F, A and S; it gives a measure of verbal fluency [22]. Raven’s Progressive Matrices ’47 (RPM): we used the simplified 36-item format, which requires visual pattern matching and resolution of analogy problems; this test explores conceptual abilities using nonverbal material [23]. Edinburgh Handedness Inventory: a 10-item questionnaire assessing lateral preference in performing different activities [24]. Hamilton Depression Scale: the first version of this depression-rating test was used [25]. Statistical analysis. Statistical comparisons were conducted using Student’s two-tailed t-test, analysis of variance (ANOVA) and repeated measures ANOVA (MANOVA). A conservative correction factor (Bonferroni) was used because of the large number of variables. The CVLT items were first analyzed by MANOVA and after, if the multivariate tests were significant, by ANOVA. Differences were considered significant when p was < 0.05. Correlational analysis was conducted using Pearson correlation coefficient.
3. Results Eighteen subjects (nine men and nine women) were evaluated. The mean age was 48.06 F 12.18 years (range: Table 1 Neuropsychological performances (all tests but California Verbal Learning Test) of controls, and SCA2 patients
Digit forward Digit backward Corsi FAS RPM Rey (copy) Rey (STM) Rey (LTM) Hamilton
Controls (N = 14)
SCA2 patients (N = 18)
4.55 F 1.02 3.0 F 0.68 4.57 F 1.22 33 F 6.21 28.77 F 5.05 32.75 F 3.14 15 F 6.93 14.33 F 5.07 4.4 F 3.05
4.22 F 0.88 2.61 F 0.7 3.67 F 0.84 ( p = 0.02) 16.18 F 7.79 ( p = 0.0001) 23.11 F 5.53 ( p = 0.007) 30.89 F 4.14 10.14 F 4.95 11.5 F 5.9 5.53 F 6.11
STM = short-term memory; LTM = long-term memory. The p values in parentheses refer to comparisons between patients and controls.
F. Le Pira et al. / Journal of the Neurological Sciences 201 (2002) 53–57
26 –67), and mean education was 6.44 F 2.81 years (range: 4 –13). All subjects were right-handed but one. Mean age at onset, defined as the date at which the patients or relatives noticed the first appearance of symptoms, was 36.83 F 13.94 years. The mean duration of illness was 11.22 F 6.62. The pathological expanded alleles ranged from 34 to 46 repeats number (mean 40.33 F 3.05); the mean length of repeats was not different between male and female patients. Age at onset and repeat length were inversely correlated (r = 0.71; p < 0.0001). Statistical evaluation of cognitive performance between SCA2 patients and controls evidenced significant differences on visual – spatial attention (Block-tapping test: F = 6.15; p = 0.02), controlled verbal fluency (FAS: F = 36.23; p = 0.0001), abstract nonverbal reasoning (RPM: F = 8.48; p = 0.007) as well as on numerous subtests of the CVLT. The CVLT subtests were first analysed by MANOVA comparing separately controls and the experimental group. The tasks were clustered using two separate MANOVAs: the first one included the number of correct words (five learning trials, the short- and long-term memory and recognition trials), the second included the semantic clusters during the five learning trials, the short- and longterm memory trials. SCA2 patients’ performance on CVLT was significantly worse than controls almost on all subtests, both in the learning trials (number correct first –fifth), as well as during retrieval (short-term and long-term free recall); the same is true for their clustering ability (the ability to semantically categorize the word-list items to improve later recall). Recognition however did not reach significance. Comparison between SCA2 patients and controls are reported in Tables 1 and 2. We also studied the effects of some clinical variables (severity measured by IAPS, disease duration, age of onset) on neuropsychological performances. Statistical analysis revealed a significant Table 2 Neuropsychological performances (California Verbal Learning Test) of controls, and SCA2 patients
1j trial 2j trial 3j trial 4j trial 5j trial STM LTM Recognition 1j trial (cluster) 2j trial (cluster) 3j trial (cluster) 4j trial (cluster) 5j trial (cluster) STM (cluster) LTM (cluster)
Controls (N = 14)
SCA2 patients (N = 18)
6.31 F 2.1 9.15 F 2.79 9.92 F 3.07 10.3 F 1.97 11.77 F 2.45 10.23 F 2.8 10.46 F 2.29 14.15 F 1.4 1.38 F 1.32 2.92 F 1.93 3.31 F 2.36 2.77 F 1.09 3.992 F 2.72 4.31 F 2.63 4.54 F 2.96
3.65 F 1.37 ( p = 0.0001) 5.41 F 1.80 ( p = 0.0001) 6.82 F 2.13 ( p = 0.003) 7 F 2.24 ( p = 0.0001) 7.77 F 2.36 ( p = 0.0001) 5.94 F 3.4 ( p = 0.001) 6.71 F 2.99 ( p = 0.001) 12.71 F 2.28 0.53 F 0.62 ( p = 0.03) 1.06 F 1.2 ( p = 0.003) 1.47 F 1.59 ( p = 0.02) 1.53 F 1.37 ( p = 0.01) 1.65 F 1.22 ( p = 0.005) 1.65 F 1.93 ( p = 0.003) 2.23 F 2.11 ( p = 0.02)
STM = short-term memory; LTM = long-term memory. The p values in parentheses refer to comparisons between patients and controls.
55
correlation between IAPS and some items of CVLT (number of words: at the first trial: r = 0.68, p = 0.007; at the fourth trial: r = 0.74, p = 0.002; at the fifth trial: r = 0.56, p = 0.037; at the short-term memory trial: r = 0.55, p = 0.04; number of clusters: at the fourth trial: r = 0.59, p = 0.027; at the fifth trial: r = 0.53, p = 0.05; at the shortterm trial: r = 0.5, p = 0.04) while the age of onset and disease duration were not determinant. To rule out the possible influence of neurological deficits on neuropsychological performances, we correlated, respectively, limb ataxia to Block Tapping Test and dysarthria to CVLT and FAS results. No significant differences were found.
4. Discussion The discovery of the genetic abnormalities in ADCAs offers the opportunity to study homogenous samples of SCA2 subjects. In the last years, a small number of reports raised the issue of cognitive defects in genetically determined SCA2 patients. Defects in executive as well as verbal memory functions were recently reported in SCA2 subjects [10 –13]. Dementia is reported more frequently in SCA2 than in patients with SCA1, SCA3 or SCA6, supporting the notion that dementia is not a common feature of all genotypes. Cognitive disturbances have often been overlooked and formal neuropsychological evaluation has only been reported in a very few studies. General slowing, lower attentional skills, decreased executive functions, reduced verbal skills, have all been interpreted as an indirect evidence of cerebellar contribution to cognition. Based on previous results, subjects affected by SCA2 seem to show a neuropsychological pattern of disturbances not necessarily resembling dementia, rather a more or less marked profile of cognitive impairment whose interpretation is still difficult to attribute to a common substrate. Our data seem to confirm such significant cognitive impairment. Verbal learning and memory were highly significantly worse in SCA2 subjects on CVLT. Learning curve was flatter especially for number of clusters rather than correct words recall; short-term and long-term memory were significantly impaired but performance on recognition did not reach statistical significance, supporting the view of a retrieval defect rather than a storage problem [21]. The functional neuroanatomy of such discrepancy between free recall and recognition corroborates the involvement of anterior (mainly pre-frontal) rather than temporal (hippocampus) structures. Executive functions were found defective; significant lower performances were also found on nonverbal abstract reasoning test (RPM). In our group of SCA2 patients, the cognitive status was partially related to clinical severity rather than to disease duration or age at onset of symptoms. Kish et al. [9] in a genetically non-homogeneous group of ataxic patients found statistically significant correlations between severity of ataxia and performances on several neuropsychological tests and subtests. Bu¨rk et al. [13], however, failed to find
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F. Le Pira et al. / Journal of the Neurological Sciences 201 (2002) 53–57
such significant relationship between cognitive status and clinical severity. Interpretation of our results could be related to cerebellar involvement as suggested by others. Recent studies have extended the contribution of cerebellum to nonmotor functions, such as language, thought modulation and the organization of sequential activities [26,27]. There are also anatomic demonstrations that the cerebellar hemispheres are connected to the frontal and parietal cortex [28,29]. A cerebellar cognitive affective syndrome has been described in patients with cerebellar lesions which is characterized by deficits in executive functions, spatial cognition and linguistic processing [30]. The presence of cognitive changes even in SCA2 patients with short histories of disease and mild severity could also support the hypothesis of a significant contribution to cognition of cerebellum which is involved very early by the disease process. However, SCA2 neuropsychological studies cannot provide an ideal model to study cerebellar contributions to cognition because of subcortical and cortical degeneration, as demonstrated both in anatomo-pathological [4] and neuroradiological [5] studies. The pattern of neuropsychological defects that we demonstrated in the group of SCA2 patients resembles the typical profile of head injured victims [31], multiple sclerosis patients [32], normally aging subjects [33] where frontal subcortical diffuse axonal damage is predominant; it has been always interpreted as a ‘‘frontal’’ memory defect where learning per se is yet possible, organization of learned material is shallow and superficial, prone to interference of any kind, retrieval is defective but recognition is still possible because there remain traces of the earlier acquisitions upon confrontation. Recognition in fact, requires the identification of previously exposed material (verbal or nonverbal) with the same material presented later on via the same sensory input. In addition, the frontal lobes are strictly and highly connected to the cerebellum through the fronto-ponto-cerebellar pathways. Our results are in line with a functional disconnection syndrome where the disease rather quickly reduces the cognitive resources of these important cognitive networks with a rapid and significant slowing in the executive, organizational, and mnestic skills. The direct damage of the cerebellum by the disease makes an ‘‘anterograde’’ contribution to the general slowing of the cognitive process. In summary, SCA2 subjects have very low cognitive skills which often and rather inappropriately are termed dementia; their cognitive impairment is moderately severe and involves several aspects of cognition; previous and our findings support the view of a mainly ‘‘frontal’’ type of disorders, including reduced attention, reduced verbal fluency and, specifically, reduced verbal learning and memory. We also found an important and significant difference in performance between the experimental and the control group on two aspects of nonverbal neuropsychological functioning: visuo-spatial attention as measured by the
Corsi’s span and nonverbal abstract reasoning as measured by the RPM. The role of cerebellum in cognition is well documented. However, its contribution to the disease process is not clear at this point and deserves further investigation. References [1] Klockgether T, Wullner U, Spauschus A, Evert B. The molecular biology of the autosomal-dominant cerebellar ataxias. Mov Disord 2000;15:604 – 12. [2] Pulst SM, Nechiporuk A, Nechiporuk T, et al. Moderate expansion of a normally biallelic trinucleotide repeat in spinocerebellar ataxia type 2. Nat Genet 1996;14:269 – 76. [3] Sanpei K, Takano H, Igarashi S, et al. Identification of the spinocerebellar ataxia type 2 gene using a direct identification of repeat expansion and cloning technique, DIRECT. Nat Genet 1996;14:277 – 84. [4] Estrada S, Galagarra J, Orozco G, Nordase A, Auburger G. Spinocerebellar ataxia 2 (SCA2): morphometric analyses in 11 autopsies. Acta Neuropathol 1999;97(3):306 – 11. [5] Giuffrida S, Saponara R, Restivo DA, et al. Supratentorial atrophy in spinocerebellar ataxia type 2: MRI study of 20 patients. J Neurol 1999;246:383 – 8. [6] Hirono N, Yamadori A, Kameyama M, Mezaki T, Abe K. Spinocerebellar degeneration (SCD): cognitive disturbances. Acta Neurol Scand 1991;84:226 – 30. [7] Grafman J, Litvan MD, Massaquoi S, Stewart BA, Sirigu A, Hallett M. Cognitive planning deficit in patients with cerebellar atrophy. Neurology 1992;42:1493 – 6. [8] Apollonio IM, Grafman J, Schwartz V, Massaquoi S, Hallett M. Memory in patients with cerebellar degeneration. Neurology 1993; 43:1536 – 44. [9] Kish SJ, El-Awar M, Stuss D, et al. Neuropsychological test performance in patients with dominantly inherited spinocerebellar ataxia: relationship to ataxia severity. Neurology 1994;44:1738 – 46. [10] Trojano L, Chiacchio L, Grossi D, et al. Determinants of cognitive disorders in autosomal dominant cerebellar ataxia type 1. J Neurol Sci 1998;157:162 – 7. [11] Gambardella A, Annesi G, Bono F, et al. CAG repeat length and clinical features in three Italian families with spinocerebellar ataxia type 2 (SCA2): early impairment of Wisconsin Card Sorting Test and saccade velocity. J Neurol 1998;245:647 – 52. [12] Storey E, Forrest SM, Shaw JH, Mitchell P, Gardner RJ. Spinocerebellar ataxia type 2: clinical features of a pedigree displaying prominent frontal-executive dysfunction. Arch Neurol 1999;56:43 – 50. [13] Bu¨rk K, Globas C, Bosch S, et al. Cognitive deficits in spinocerebellar ataxia 2. Brain 1999;122:769 – 77. [14] Condorelli DF, Trovato Salinaro A, Spinella F, Valvo S, Saponara R, Giuffrida S. Rapid touchdown PCR assay for the molecular diagnosis of spinocerebellar ataxia type 2. Int J Clin Lab Res 1998;28:174 – 8. [15] Filla A, De Michele G, Banfi S, et al. Has spinocerebellar ataxia type 2 a distinct phenotype? Genetic and clinical study of an Italian family. Neurology 1995;45:793 – 6. [16] Klockgether T, Schroth G, Diener HC, Dichgans J. Idiopathic cerebellar ataxia of late onset: natural history and MRI morphology. J Neurol Neurosurg Psychiatry 1990;53:297 – 305. [17] Giuffrida S, Lanza S, Restivo DA, et al. Clinical and molecular analysis of 11 Sicilian SCA2 families: influence of gender in age at onset. Eur J Neurol 1999;6:301 – 7. [18] Wechsler D. A standardized memory scale for clinical use. J Psychol 1945;19:85 – 95. [19] Milner B. Interhemispheric differences in the localization of psychological processes in man. Br Med Bull 1971;27:272 – 7. [20] Rey A. L’examen psychologique dans les cas d’ence´phalopathie traumatique. Arch Psychol 1941;28:286 – 340.
F. Le Pira et al. / Journal of the Neurological Sciences 201 (2002) 53–57 [21] Delis DC, Kramer JH, Kaplan E, Ober BA. California Verbal Learning Test: Adult Version. San Antonio TX: The Psychological Corporation, 1987. [22] Benton AL, Hamsher K. de S. Multilingual Aphasia Examination. Iowa City, IA: AJA Associates, 1989. [23] Raven JC. Colored Progressive Matrices, revised. London: Hk Lewis, 1969. [24] Williams SM. Factor analysis of the Edinburgh Handedness Inventory. Cortex 1986;22:325 – 6. [25] Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry 1960;23:56 – 62. [26] Leiner HC, Leiner AL, Dow RS. Cognitive and language functions of the human cerebellum. [Review]. Trends Neurosci 1993;16:444 – 7. [27] Fiez JA. Cerebellar contribution to cognition. Neuron 1996;16:13 – 5. [28] Schmahmann JD, Pandya DN. Anatomical investigation of projections from thalamus to posterior parietal cortex in the rhesus monkey:
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a WGA-HRP and fluorescent tracer study. J Comp Neurol 1990;295: 299 – 326. Middleton FA, Strick P. Anatomical evidence for cerebellar and basal ganglia involvement in higher cognitive function. Science 1994;266: 458 – 61. Schmahmann JD, Sherman JC. The cerebellar cognitive affective syndrome. Brain 1998;121:561 – 79. Wiegner S, Donders J. Performance on the California Verbal Learning Test after traumatic brain injury. J Clin Exp Neuropsychol 1999; 21:159 – 70. Scarrabellotti M, Carroll M. Memory dissociation and metamemory in multiple sclerosis. Neuropsychologia 1999;37:1335 – 50. Wegesin DJ, Jacobs DM, Zubin NR, Ventura PR, Stern Y. Source memory and encoding strategy in normal aging. J Clin Exp Neuropsychol 2000;22:455 – 64.
Cognitive findings in spinocerebellar ataxia type 2: relationship to genetic and clinical variables Francesco Le Pira a,*, Giuseppe Zappala` b, Riccardo Saponara a, Elisabetta Domina a, Domenico A. Restivo a, Ester Reggio a, Alessandra Nicoletti a, Salvatore Giuffrida a a
Department of Neurosciences, University of Catania, Via S. Sofia 78, I-95125 Catania, Italy b Division of Neurology, Garibaldi Hospital Catania, Catania, Italy Received 3 December 2001; received in revised form 28 May 2002; accepted 3 June 2002
Abstract Several authors have recently reported a broad cognitive impairment in autosomal dominant cerebellar ataxias (ADCAs) patients. However, only a few studies on neuropsychological features in spinocerebellar ataxia type 2 (SCA2) patients are present in the current literature. The aim of this study is to evaluate the cognitive impairment in a wide sample of SCA2 patients and to verify the role of different disease-related factors (age of onset, disease duration, and clinical severity) on intellectual abilities. We administered a battery of neuropsychological tests assessing handedness, attention, short- and long-term verbal and visuo-spatial memory, executive functions, constructive abilities, general intellectual abilities and depression to 18 SCA2 patients belonging to eight families who came to our observation. Evidence of impaired verbal memory, executive functions and attention was found. The cognitive status was partially related to clinical severity rather than to disease duration or age at onset of symptoms. We partially confirmed data on cognitive defects already reported by others but we also found defective attention skills as well as significant lower performances in a nonverbal intelligence task. D 2002 Elsevier Science B.V. All rights reserved. Keywords: Autosomal dominant cerebellar ataxia; Spinocerebellar ataxia type 2; Cognitive impairment; Memory
1. Introduction Autosomal dominant cerebellar ataxias (ADCAs) represent a heterogeneous group of progressive neurodegenerative disorders with different clinical and neuropathological findings. Several genetic loci have been identified in ADCAs and named spinocerebellar ataxias (SCAs) [1]. One of the most common forms is spinocerebellar ataxia type 2 (SCA2) [2]. On clinical grounds, the SCAs are not easily distinguishable without genetic analysis. Mutation in SCA2 has been assigned to the long arm of chromosome 12 (12q23 –24,1) and an unstable cytosine – adenine – guanine (CAG) trinucleotide expansion has been identified [2,3]. Neuropathological data in SCA2 have shown that the typical pattern of olivopontocerebellar atrophy occurs early, and that an involvement of the neocortex is also present later [4]. Similar data were found in a large neuroradiological study
*
Corresponding author. Tel.: +39-95-330-943, +39-95-256-627; fax: +39-95-330-943. E-mail address: [email protected] (F. Le Pira).
where supratentorial atrophy was related to disease duration [5]. Some authors reported a cognitive impairment in ADCAs patients resembling subcortical dementia [6– 13]. However, most of these works were performed either on genetically not confirmed or on genetically heterogeneous patients. Only a few studies addressing neuropsychological features in SCA2 patients are present in current literature. Trojano et al. [10] found a significant relationship between clinical severity and verbal memory tasks in 15 SCA2 patients. Gambardella et al. [11] described a selective impairment of executive functions using Wisconsin Card Sorting Test (WCST) in 17 patients. Storey et al. [12] confirmed the same findings underlying a dis-executive syndrome among eight SCA2 patients without mention to learning and memory disturbances which may have afflicted these patients. However, in the same year, Bu¨rk et al. [13] investigated neuropsychological performances of 17 European SCA2 patients belonging to four families where, not only executive deficits were corroborated, but also verbal memory was significantly impaired with a relative sparing of visuo-spatial learning. In this study, we evaluated the cognitive impairment in a wide sample of SCA2 patients
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 1 9 4 - 6
54
F. Le Pira et al. / Journal of the Neurological Sciences 201 (2002) 53–57
attempting to verify the role of different disease related factors (age of onset, disease duration and clinical severity) on intellectual abilities.
2. Patients and methods Patients: 18 subjects out of eight families, all originating from Middle-Eastern Sicily, were diagnosed as having ADCA type I on the following criteria: autosomal dominant inheritance, progressive cerebellar ataxia variably associated with dysarthria, pyramidal or extrapyramidal signs, decreased vibration sense, ophthalmoplegia, and dementia. Blood sample was obtained with informed consent; molecular analysis performed with Rapid touchdown PCR assay [14] revealed SCA2 mutation in all of them. Severity of disease was scored according to the Inherited Ataxia Progression Scale (IAPS) (stage 1 = asymptomatic; stage 2 = mild symptoms; stage 3 = need of constant help and walking without support is impossible; stage 4 = wheelchair or bed) [15]. Furthermore, we evaluated upper limb ataxia and dysarthria using a scale ranging from 0 (absent) to 5 (most severe) [16]. Clinical and molecular data of these patients have been reported in a previous larger study [17]. Fourteen subjects (eight women and six men) without clinically evident neurological or psychiatric diseases were chosen as a control group; mean age was 49.93 F 12.43 years (range: 28 – 67) and the mean education was 7.93 F 3.41 years (range: 5 –13). Neuropsychological tests: a battery of neuropsychological tests assessing handedness, attention, short- and longterm verbal and visuo-spatial memory, executive functions, constructive abilities, general intellectual was administered to all patients. Presence of depression was evaluated by Hamilton Depression Scale. All tests were administered by the same observer (S.R.) who remained uninformed as to the exact molecular diagnosis of the individual being tested. Digit span: used in the Wechsler batteries (intelligence and memory), comprises two tests (digit forward and digits backward) which involve different abilities. The subject is asked to repeat random number sequences that the examiner reads. Repeating numbers forward seems to be related mostly to attention while the backward task is likely to involve working memory and mental tracking [18]. Corsi Block-tapping Test: it is a visuo-spatial test exploring attention and nonverbal working memory. It consists of nine cubes on a board; the subject is asked to tap the same cubes that the examiner had touched before in an increasing prearranged sequence [19]. Rey Complex Figure: copying this widely used picture allows to test constructional abilities [20]. Rey Complex Figure Test (recall administration): the immediate and delayed recall of this figure allows to measure short- and long-term nonverbal memory. For the three drawings, we used the same scoring system ranging from 0 to 36 [20].
California Verbal Learning Test (CVLT): it examines verbal memory and learning strategies together with conceptual abilities. The 16-word list is presented five times and each time the subject must repeat as many words as possible. After an interference trial, there is an immediate recall, a delayed recall (after 20 min) and a final trial of recognition of the 16 words from a longer list of words. The 16 words belong to four categories not known to the subjects (fruits, fishes, articles of clothing, tools) and the ability to make clusters (words of the same category recalled together) is, also, measured. We used the Italian version of the test where fishes took the place of herbs [21]. FAS: also-called Controlled Oral Word Association Test consists of three word-naming trials beginning with F, A and S; it gives a measure of verbal fluency [22]. Raven’s Progressive Matrices ’47 (RPM): we used the simplified 36-item format, which requires visual pattern matching and resolution of analogy problems; this test explores conceptual abilities using nonverbal material [23]. Edinburgh Handedness Inventory: a 10-item questionnaire assessing lateral preference in performing different activities [24]. Hamilton Depression Scale: the first version of this depression-rating test was used [25]. Statistical analysis. Statistical comparisons were conducted using Student’s two-tailed t-test, analysis of variance (ANOVA) and repeated measures ANOVA (MANOVA). A conservative correction factor (Bonferroni) was used because of the large number of variables. The CVLT items were first analyzed by MANOVA and after, if the multivariate tests were significant, by ANOVA. Differences were considered significant when p was < 0.05. Correlational analysis was conducted using Pearson correlation coefficient.
3. Results Eighteen subjects (nine men and nine women) were evaluated. The mean age was 48.06 F 12.18 years (range: Table 1 Neuropsychological performances (all tests but California Verbal Learning Test) of controls, and SCA2 patients
Digit forward Digit backward Corsi FAS RPM Rey (copy) Rey (STM) Rey (LTM) Hamilton
Controls (N = 14)
SCA2 patients (N = 18)
4.55 F 1.02 3.0 F 0.68 4.57 F 1.22 33 F 6.21 28.77 F 5.05 32.75 F 3.14 15 F 6.93 14.33 F 5.07 4.4 F 3.05
4.22 F 0.88 2.61 F 0.7 3.67 F 0.84 ( p = 0.02) 16.18 F 7.79 ( p = 0.0001) 23.11 F 5.53 ( p = 0.007) 30.89 F 4.14 10.14 F 4.95 11.5 F 5.9 5.53 F 6.11
STM = short-term memory; LTM = long-term memory. The p values in parentheses refer to comparisons between patients and controls.
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26 –67), and mean education was 6.44 F 2.81 years (range: 4 –13). All subjects were right-handed but one. Mean age at onset, defined as the date at which the patients or relatives noticed the first appearance of symptoms, was 36.83 F 13.94 years. The mean duration of illness was 11.22 F 6.62. The pathological expanded alleles ranged from 34 to 46 repeats number (mean 40.33 F 3.05); the mean length of repeats was not different between male and female patients. Age at onset and repeat length were inversely correlated (r = 0.71; p < 0.0001). Statistical evaluation of cognitive performance between SCA2 patients and controls evidenced significant differences on visual – spatial attention (Block-tapping test: F = 6.15; p = 0.02), controlled verbal fluency (FAS: F = 36.23; p = 0.0001), abstract nonverbal reasoning (RPM: F = 8.48; p = 0.007) as well as on numerous subtests of the CVLT. The CVLT subtests were first analysed by MANOVA comparing separately controls and the experimental group. The tasks were clustered using two separate MANOVAs: the first one included the number of correct words (five learning trials, the short- and long-term memory and recognition trials), the second included the semantic clusters during the five learning trials, the short- and longterm memory trials. SCA2 patients’ performance on CVLT was significantly worse than controls almost on all subtests, both in the learning trials (number correct first –fifth), as well as during retrieval (short-term and long-term free recall); the same is true for their clustering ability (the ability to semantically categorize the word-list items to improve later recall). Recognition however did not reach significance. Comparison between SCA2 patients and controls are reported in Tables 1 and 2. We also studied the effects of some clinical variables (severity measured by IAPS, disease duration, age of onset) on neuropsychological performances. Statistical analysis revealed a significant Table 2 Neuropsychological performances (California Verbal Learning Test) of controls, and SCA2 patients
1j trial 2j trial 3j trial 4j trial 5j trial STM LTM Recognition 1j trial (cluster) 2j trial (cluster) 3j trial (cluster) 4j trial (cluster) 5j trial (cluster) STM (cluster) LTM (cluster)
Controls (N = 14)
SCA2 patients (N = 18)
6.31 F 2.1 9.15 F 2.79 9.92 F 3.07 10.3 F 1.97 11.77 F 2.45 10.23 F 2.8 10.46 F 2.29 14.15 F 1.4 1.38 F 1.32 2.92 F 1.93 3.31 F 2.36 2.77 F 1.09 3.992 F 2.72 4.31 F 2.63 4.54 F 2.96
3.65 F 1.37 ( p = 0.0001) 5.41 F 1.80 ( p = 0.0001) 6.82 F 2.13 ( p = 0.003) 7 F 2.24 ( p = 0.0001) 7.77 F 2.36 ( p = 0.0001) 5.94 F 3.4 ( p = 0.001) 6.71 F 2.99 ( p = 0.001) 12.71 F 2.28 0.53 F 0.62 ( p = 0.03) 1.06 F 1.2 ( p = 0.003) 1.47 F 1.59 ( p = 0.02) 1.53 F 1.37 ( p = 0.01) 1.65 F 1.22 ( p = 0.005) 1.65 F 1.93 ( p = 0.003) 2.23 F 2.11 ( p = 0.02)
STM = short-term memory; LTM = long-term memory. The p values in parentheses refer to comparisons between patients and controls.
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correlation between IAPS and some items of CVLT (number of words: at the first trial: r = 0.68, p = 0.007; at the fourth trial: r = 0.74, p = 0.002; at the fifth trial: r = 0.56, p = 0.037; at the short-term memory trial: r = 0.55, p = 0.04; number of clusters: at the fourth trial: r = 0.59, p = 0.027; at the fifth trial: r = 0.53, p = 0.05; at the shortterm trial: r = 0.5, p = 0.04) while the age of onset and disease duration were not determinant. To rule out the possible influence of neurological deficits on neuropsychological performances, we correlated, respectively, limb ataxia to Block Tapping Test and dysarthria to CVLT and FAS results. No significant differences were found.
4. Discussion The discovery of the genetic abnormalities in ADCAs offers the opportunity to study homogenous samples of SCA2 subjects. In the last years, a small number of reports raised the issue of cognitive defects in genetically determined SCA2 patients. Defects in executive as well as verbal memory functions were recently reported in SCA2 subjects [10 –13]. Dementia is reported more frequently in SCA2 than in patients with SCA1, SCA3 or SCA6, supporting the notion that dementia is not a common feature of all genotypes. Cognitive disturbances have often been overlooked and formal neuropsychological evaluation has only been reported in a very few studies. General slowing, lower attentional skills, decreased executive functions, reduced verbal skills, have all been interpreted as an indirect evidence of cerebellar contribution to cognition. Based on previous results, subjects affected by SCA2 seem to show a neuropsychological pattern of disturbances not necessarily resembling dementia, rather a more or less marked profile of cognitive impairment whose interpretation is still difficult to attribute to a common substrate. Our data seem to confirm such significant cognitive impairment. Verbal learning and memory were highly significantly worse in SCA2 subjects on CVLT. Learning curve was flatter especially for number of clusters rather than correct words recall; short-term and long-term memory were significantly impaired but performance on recognition did not reach statistical significance, supporting the view of a retrieval defect rather than a storage problem [21]. The functional neuroanatomy of such discrepancy between free recall and recognition corroborates the involvement of anterior (mainly pre-frontal) rather than temporal (hippocampus) structures. Executive functions were found defective; significant lower performances were also found on nonverbal abstract reasoning test (RPM). In our group of SCA2 patients, the cognitive status was partially related to clinical severity rather than to disease duration or age at onset of symptoms. Kish et al. [9] in a genetically non-homogeneous group of ataxic patients found statistically significant correlations between severity of ataxia and performances on several neuropsychological tests and subtests. Bu¨rk et al. [13], however, failed to find
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such significant relationship between cognitive status and clinical severity. Interpretation of our results could be related to cerebellar involvement as suggested by others. Recent studies have extended the contribution of cerebellum to nonmotor functions, such as language, thought modulation and the organization of sequential activities [26,27]. There are also anatomic demonstrations that the cerebellar hemispheres are connected to the frontal and parietal cortex [28,29]. A cerebellar cognitive affective syndrome has been described in patients with cerebellar lesions which is characterized by deficits in executive functions, spatial cognition and linguistic processing [30]. The presence of cognitive changes even in SCA2 patients with short histories of disease and mild severity could also support the hypothesis of a significant contribution to cognition of cerebellum which is involved very early by the disease process. However, SCA2 neuropsychological studies cannot provide an ideal model to study cerebellar contributions to cognition because of subcortical and cortical degeneration, as demonstrated both in anatomo-pathological [4] and neuroradiological [5] studies. The pattern of neuropsychological defects that we demonstrated in the group of SCA2 patients resembles the typical profile of head injured victims [31], multiple sclerosis patients [32], normally aging subjects [33] where frontal subcortical diffuse axonal damage is predominant; it has been always interpreted as a ‘‘frontal’’ memory defect where learning per se is yet possible, organization of learned material is shallow and superficial, prone to interference of any kind, retrieval is defective but recognition is still possible because there remain traces of the earlier acquisitions upon confrontation. Recognition in fact, requires the identification of previously exposed material (verbal or nonverbal) with the same material presented later on via the same sensory input. In addition, the frontal lobes are strictly and highly connected to the cerebellum through the fronto-ponto-cerebellar pathways. Our results are in line with a functional disconnection syndrome where the disease rather quickly reduces the cognitive resources of these important cognitive networks with a rapid and significant slowing in the executive, organizational, and mnestic skills. The direct damage of the cerebellum by the disease makes an ‘‘anterograde’’ contribution to the general slowing of the cognitive process. In summary, SCA2 subjects have very low cognitive skills which often and rather inappropriately are termed dementia; their cognitive impairment is moderately severe and involves several aspects of cognition; previous and our findings support the view of a mainly ‘‘frontal’’ type of disorders, including reduced attention, reduced verbal fluency and, specifically, reduced verbal learning and memory. We also found an important and significant difference in performance between the experimental and the control group on two aspects of nonverbal neuropsychological functioning: visuo-spatial attention as measured by the
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