Brain, Vol. 122, No. 4, 769-777,
April 1999
© 1999 Oxford University Press
Cognitive deficits in spinocerebellar ataxia 2
1 Department of Neurology, University of Tübingen, 2 Department of Clinical Neuropsychology, University of Bochum, Germany, 3 Department of Neurology, University of Innsbruck, Austria and 4 INSERM U 289, Hôpital de la Salpêtrière, Paris, France
Correspondence to:
K. Bürk, MD, Department of Neurology, University of Tübingen, Hoppe-Seyler-Strasse 3, D-72076 Tübingen, Germany E-mail: buerk{at}uni-tuebingen.de
 |
Abstract |
|---|
 Top Abstract IntroductionPatients and methodsResultsDiscussionReferences |
|---|
This is one of the first studies assessing the pattern of cognitive impairment in spinocerebellar ataxia 2 (SCA2). Cognitive function was studied in 17 patients with genetically confirmed SCA2 and 15 age- and IQ- matched controls using a neuropsychological test battery comprising tests for IQ, attention, verbal and visuospatial memory, as well as executive functions. Twenty-five percent of the SCA2 subjects showed evidence of dementia. Even in non-demented SCA2 subjects, there was evidence of verbal memory and executive dysfunction. Tests of visuospatial memory and attention were not significantly impaired in the non-demented group compared with controls. There was no relationship between test performance and motor disability, repeat length or age of onset, while disease duration was shown to be inversely correlated with two tests reflecting the progression of cognitive deficits during the course of the disease. Intellectual impairment should therefore not be interpreted as a secondary effect of progressive motor disability, but represents an important and independent part of the SCA2 phenotype.
spinocerebellar ataxia; neuropsychology; autosomal dominant cerebellar ataxia
ADCA = autosomal dominant cerebellar ataxia; MMS = Mini-Mental State TestM; SCA2 = spinocerebellar ataxia 2; WCST = Wisconsin Card Sorting Test; WMS = Wechsler Memory Scale—Revised
|
Introduction |
|---|
|
TopAbstractIntroductionPatients and methodsResultsDiscussionReferences |
|---|
The autosomal dominant cerebellar ataxias (ADCAs) are a heterogeneous group of dominantly inherited neurological disorders characterized by progressive ataxia that results from degeneration of the cerebellum and its afferent and efferent connections. In most families, there is clinical and neuropathological evidence for additional involvement of the brainstem, basal ganglia, spinal cord and peripheral nervous system (Greenfield, 1954
; Harding, 1982). Clinically, several types of ADCA can be distinguished, the most frequent of which, ADCA I, is characterized by various combinations of ataxia with cognitive impairment, optic atrophy, ophthalmoplegia, pyramidal tract signs, basal ganglia symptoms, sensory loss and amyotrophy. ADCA II is distinct in having the feature of retinal degeneration, while ADCA III is a pure cerebellar disorder (Harding, 1982). Recently, genetic heterogeneity of ADCA I has been established, with disease loci assigned to chromosomes 6p (SCA1), 12q (SCA2), 14q (SCA3) and 16q (SCA4) (Zoghbi et al., 1991; Gispert et al., 1993; Stevanin et al., 1994; Flanigan et al., 1996). Three of the genes, SCA1, SCA2 and SCA3, have been cloned, and the mutations have been shown to be unstable CAG trinucleotide repeat expansions present within coding regions of the respective genes (Orr et al., 1993; Kawaguchi et al., 1994; Imbert et al., 1996; Pulst et al., 1996; Sanpei et al., 1996). Some aspects of the clinical phenotype of SCA mutations are directly influenced by the length of the CAG repeat. Patients carrying longer CAG repeats show earlier disease onset, have faster disease progression and are often more severely affected (Orr et al., 1993; Maciel et al., 1995; Klockgether et al., 1996). In ADCA I, the frequency and severity of cognitive deficits appear to depend in part on the underlying mutation. While cognitive deterioration is usually absent in SCA4, it may occur in a minority of SCA1 and SCA3 patients, mainly during late stages of the disease (Kish et al., 1988a, 1994; Flanigan et al., 1996; Maruff et al., 1996). In clinical investigations, the frequency of cognitive deficits in SCA2 varies from 5 to 19% (Wadia, 1984; Dürr et al., 1995; Bürk et al., 1997; Cancel et al., 1997). None of the earlier studies systematically addressed the issue of cognitive function in SCA2 by means of comprehensive neuropsychological testing. Therefore, cognitive impairments could have escaped the examiner's notice when only clinical ratings were used.
During recent years, there has been increasing awareness of the non-motor role of the cerebellum: clinical reports of patients with lesions confined to the cerebellum have implicated the cerebellum in higher cognitive functions (Akshoomoff and Courchesne, 1992; Grafman et al., 1992; Leiner et al., 1995; Gao et al., 1996; Schmahmann and Sherman, 1998). This hypothesis has been supported by functional neuroimaging studies demonstrating cerebellar activation in tests of working memory (Desmond et al., 1997), verbal memory (Grasby et al., 1993), linguistic processing (Petersen et al., 1989; Klein et al., 1995), motor learning (Jenkins et al., 1994), executive function (Kim et al., 1994), classical conditioning (Logan and Grafton, 1995) and attention (Allen et al., 1997). On the contrary, other investigators have failed to provide clear evidence for cognitive deficits in patients with cerebellar syndromes. Many of these studies suffered from methodological shortcomings concerning patient selection, such as the inclusion of patients with additional extracerebellar damage. In SCA2, the degenerative process is not restricted to the cerebellum but additionally involves the brainstem, basal ganglia and cerebral hemispheres (Orozco et al., 1989). Regarding the widespread degeneration in SCA2, the pattern of cognitive impairment present in SCA2 individuals cannot be clearly attributed to cerebellar dysfunction and therefore does not allow clearcut conclusions to be drawn about the specific role of the cerebellum in cognition.
The present study aimed (i) to determine the profile of cognitive impairment in patients carrying the SCA2 mutation, (ii) to define the frequency of dementia in SCA2 using neuropsychological testing, and (iii) to investigate the influence of disease duration, motor disability, dysarthria, age of onset and CAG repeat length on neuropsychological test performance.
|
Patients and methods |
|---|
|
TopAbstractIntroductionPatients and methodsResultsDiscussionReferences |
|---|
Patients and controls
Seventeen patients from four families (10 males, 7 females; mean age, 44.5 ± 15.0 years, range 24–65 years; mean age of onset 32.4 ± 13.2 years, range 18–58 years; mean disease duration 12.1 ± 8.7 years, range 2–32 years) with a molecular diagnosis of SCA2 were interviewed personally and clinically examined by one of us (K.B. or S.B.) using a standard examination procedure. Patients received clinical and neuropsychological testing at their homes. Severities of upper limb ataxia and dysarthria were rated on a scale ranging from 0 (absent) to 5 (most severe) (Klockgether et al., 1990
). Genetic testing for CAG repeat expansion and haplotype analysis were performed as described elsewhere (Bürk et al., 1996; Imbert et al., 1996). The control group consisted of paid volunteers recruited from advertisements or personal contact (10 males, 10 females; mean age 43.4 ± 14.0 years). The control subjects were selected from a larger pool to ensure that their ages and IQs were similar to those of the non-demented SCA2 patients (see Results). None of these subjects had a history of neurological disease and/or psychiatric symptoms or was taking medication at the time of testing. All subjects gave consent to completion of the neurophysiological tests. The study was approved by the Ethics Committee of The University of Tübingen.
Neuropsychological assessment
Subjects were administered the battery of neurophysiological tests as described in the following paragraphs. The methodological details of these tests have been extensively reported in the literature. Their administration in the current study was according to a standard protocol. The same number of tests was applied for each subject. In accordance with ethical committee requirements, patients were instructed that they could discontinue participation at any stage. All patients completed the entire battery of tests.
Mini-Mental State Test and IQ
The Mini-Mental State Test (MMS) was used to assess dementia: patients who scored 23 out of 30 or less on the MMS (Folstein et al., 1975) were studied separately in all subsequent subtests. Estimates of verbal and performance IQ were derived from the Similarities and Picture Completion subtests of a short version of the German version of the Wechsler Adult Intelligence Scale (WIP) (Dahl, 1972).
Attention
Attention was tested with the subtest Digit Span of the Wechsler Memory Scale—Revised (WMS). Subjects were asked to verbally reproduce series of numbers read out by the examiner. Forward and backward reproduction were tested separately (Wechsler, 1987). The number of correctly reproduced items was noted.
Verbal memory
For measures of verbal memory, subjects were tested for the immediate and delayed recall of 16-item categorized and uncategorized word lists (Channon et al., 1989). The consecutive categories list contained words belonging to four superordinate semantic categories (e.g. animals), presented sequentially so that all words belonging to one category followed each other. In the randomized categories list, four members of four different categories were presented in randomized order; the uncategorized list contained 16 unrelated words. The items in the three lists were matched for word length and word frequency. Subjects were asked to recall each list immediately after presentation and after a delay of 30 min. List order was randomized across subjects.
Free recall of verbal information was further tested using a prose passage from the Wechsler Memory Scale (Dahl, 1972). The subject was asked to reproduce a short story directly and 30 min after presentation. The number of correctly reproduced details was analysed.
Visuospatial memory
Copying and delayed reproduction of a complex geometrical figure, the Rey–Osterrieth Complex Figure (Rey, 1942; Osterrieth, 1944), was used to assess visuospatial processing and long-term memory. Subjects were asked to copy the figure that contained 47 single elements. After a delay of 40 min, subjects were asked to draw the figure from memory, and the proportion of correctly reproduced elements was analysed. Although copying problems may indicate apraxia, poor performance on delayed recall indicates poor visuospatial memory.
Executive functions
A modified version of the Wisconsin Card Sorting Test (WCST) (Nelson, 1976) was administered as a measure of executive function. The WCST assesses the ability to form and shift cognitive sets. The subject was asked to determine rules (colour, shape, number of symbols) by which he or she could sort a set of cards. The subject had to change rules when a change was indicated by the experimenter. Perseverative errors occurred when the subject continued to sort according to the `old' rule (Nelson, 1976).
To assess verbal fluency, the subject was asked to name as many items as possible from a semantic category (countries), a phonemic category (nouns starting with the letter `b') and a condition which required switching between semantic categories (male first names/vegetables) within a time limit of 1 min each task (Daum et al., 1996).
Statistical analysis
Statistical comparisons were conducted using Student's two-tailed t test or one-way ANOVA (analysis of variance), or repeated measures ANOVA where appropriate with the fixed factor group. Differences were considered significant when P was <0.05. Post hoc paired-group comparisons were explored using Tukey's honestly significant difference. For correlation studies we used the Pearson correlation coefficient. In order to achieve a global significance level of 5%, the P values were corrected applying the Bonferroni–Holm adjustment.
|
Results |
|---|
|
TopAbstractIntroductionPatients and methodsResultsDiscussionReferences |
|---|
Subject variables: MMS and IQ
The clinical features of the SCA2 patients are summarized in Table 1
. The number of CAG repeats varied from 36 to 44 (controls, 14–31). All families had the same haplotype for the flanking markers, with an expected frequency of <1.5% in a Caucasian control population. Hence, a common founder of all four kindreds has strongly to be assumed. For further details see Bürk et al. (1996, 1997).
|
MMS was used to distinguish between demented and non-demented SCA2 patients. Four (23.5%) patients scored below 23, indicating the presence of dementia. These patients were studied separately through the entire test battery (demented SCA2 patients: n = 4, mean age 52 ± 12.2 years, mean age of onset 28.8 ± 9.0 years, mean disease duration 23.3 ± 6.5 years).
SCA2 subjects without dementia (n = 13, mean age 42.2 ± 15.0 years, mean age of onset 33.5 ± 14.2 years, mean disease duration 8.7 ± 5.7 years) did not differ significantly from controls with regard to age (P = 0.833) or estimated IQ (verbal IQ estimate, P = 0.410; performance IQ estimate, P = 0.829). The analysis of IQ estimates yielded impairments in the demented SCA2 patient group compared with normal controls and the non-demented subjects (all P < 0.005), while there were no significant age differences (Table 2).
|
Neuropsychological deficits in non-demented SCA2 subjects
Attention: digit span
Analysis of attention measures did not reveal significant differences between non-demented SCA2 patients subjects and controls (forward, P = 0.735; backward, P = 0.525) (Table 2
).
Verbal memory: word lists and WMS
Word list recall was analysed by repeated measures ANOVA with group (non-demented SCA2 subjects versus controls), list type (uncategorized, randomized categories, consecutive categories) and delay (immediate versus delayed recall) as factors. The interaction between group and list type was significant [F(2,50) = 3.66, P < 0.05]. Further analysis showed that both the patients and the controls recalled more items from the consecutive categories list compared with the uncategorized list; the recall differences between the two lists did not differ between the groups. Control subjects also recalled more words from the random categories list compared with the uncategorized list (P < 0.001). Memory performance of the non-demented SCA2 patients patients, on the other hand, did not differ significantly between the uncategorized and randomized categories lists (P = 0.151). This pattern indicates that the non-demented SCA2 patients patients did not use categorization spontaneously or as efficiently as the controls (Fig. 1A and B).
|
Verbal memory measures of the prose passage from the WMS were both significantly reduced in non-demented SCA2 patients compared with controls (immediate recall, P < 0.005; delayed recall, P < 0.05) (Table 2
).
Visuospatial memory
Non-demented SCA2 patients and controls did not differ with respect to copying (immediate copy, P = 0.427) or the delayed recall of the Rey–Osterrieth Complex Figure (absolute recall, P = 0.329; percentage recall of the initial copy, P = 0.299) (Table 2).
Executive functions
Non-demented SCA2 individuals did not differ significantly from controls with regard to number of categories, number of random errors and number of perseveration errors on the WCST (P = 0.779, P = 0.352 and P = 0.120, respectively) (Table 2).
Analysis of the three verbal fluency tests yielded no significant difference between controls and non-demented SCA2 subjects in the generation of nouns from a single semantic category (P = 0.195), while the phonemic and the switching tasks were significantly impaired in non-demented SCA2 patients (phonemic category, switching semantic categories, P < 0.05) (Fig. 2).
|
Neuropsychological deficits in demented SCA2 subjects
The demented SCA2 patients patients were impaired on all neuropsychological measures compared with the control subjects. The following sections present the data for the comparison of the two patient groups. Because of the large differences in IQ estimates between demented and non-demented patients, these findings have to be treated with caution.
Attention: digit span
Compared with non-demented SCA2 patients, both attention measures were reduced in demented SCA2 patients patients (forward, P = 0.108; backward, P < 0.005) (Table 2).
Verbal memory: word lists and WMS
Comparison of the two patient groups revealed general impairment of the immediate and delayed recall of all list types in demented SCA2 patients. Statistical analysis yielded a significant difference in the immediate recall of uncategorized and randomized categories lists (P < 0.05) and the delayed recall of consecutive categories list type (P < 0.01) (Fig. 1A and B).
In demented SCA2 subjects, verbal memory measures of the WMS were even more impaired than in non-demented SCA2 patients (immediate recall, P < 0.05; delayed recall, P = 0.068) (Table 2).
Visuospatial memory
In demented SCA2 patients, the immediate copies of the Rey–Osterrieth Complex Figure lacked more details than those produced by the non-demented SCA2 group (P < 0.001), while two recall measures did not yield significant differences between the two patient groups (absolute recall, P = 0.087; percentage recall of the initial copy, P = 0.117) (Table 2).
Executive functions
Demented SCA2 patients patients attained fewer categories and made more random errors than non-demented SCA2 subjects in the WCST (number of categories and number of random errors, P < 0.001; number of perseveration errors, P < 0.005) (Table 2).
Demented SCA2 individuals presented more severe deficits in all three verbal fluency tests compared with the non-demented SCA2 group (semantic category, P < 0.005; phonemic category, P < 0.05; switching semantic categories, P < 0.01) (Fig. 2).
Correlation with disease duration, neurological status, age of onset and CAG repeat length
The cognitive status was not related to the severity of cerebellar symptoms (limb ataxia and dysarthria, P > 0.05 for all tests), the age of onset (P > 0.05 for all tests) or the CAG repeat length (P > 0.05 for all tests), while the test performance of two verbal subtests (word lists: consecutive categories list, immediate recall; verbal fluency: switching semantic categories) was inversely correlated with the disease duration (r = –0.78 and r = –0.74, respectively; P < 0.05).
|
Discussion |
|---|
|
TopAbstractIntroductionPatients and methodsResultsDiscussionReferences |
|---|
This is one of the first studies assessing the pattern of cognitive impairment in SCA2 individuals. Using a battery of neuropsychological tests, we showed that ~25% of the SCA2 patients tested were demented. In addition, we provide evidence of impaired verbal memory and executive functions in non-demented SCA2 patients and additional visuospatial dysfunction in demented SCA2 individuals.
In patients suffering from movement disorders, motor dysfunction may interfere with neuropsychological test performance. In the present study, such interference appears negligible since test performance was not correlated with the severity of cerebellar symptoms. In addition, inattentiveness and poor motivation could be ruled out as interacting variables since SCA2 subjects had a similar or even better performance on attentional tasks compared with controls. Reduced scores of the demented SCA2 subgroup may have been due to loss of memory rather than to inattentiveness.
Dementia, as defined by a score of <23 in the MMS, was present in almost 25% of our patients. The frequency of general intellectual impairment in our sample is thus higher than in most clinical studies (Wadia, 1984; Dürr et al., 1995; Bürk et al., 1997; Cancel et al., 1997). Molecular genetic testing indicated a common ancestor for all SCA2 individuals studied. Therefore, this sample of patients is probably not representative. However, Pulst et al. (1996) reported a SCA2 kindred characterized by predominant dementia and a mild cerebellar syndrome (Cancel et al., 1997). These findings suggest a causative role for the SCA2 mutation in the development of intellectual impairment, while the extent of dementia is likely to be influenced by factors other than the mutation itself. In the present sample, disease duration in the demented SCA2 subgroup was considerably longer than in the non-demented subgroup (mean, 23.3 ± 6.5 years versus 8.7 ± 5.7 years). The fact that test performance was related to disease duration but not to the repeat number or the age of onset also points to a gradual increase in cognitive impairment during the course of the disease independent of CAG repeat length.
In cerebellar syndromes, several investigators have documented general intellectual impairment by means of reduced scores in the Wechsler Adult Intelligence Scale (Kish et al., 1988a; Bracke-Tolkmitt et al., 1989). Other groups described scores in the normal or even the superior range (Fiez et al., 1992; Appollonio et al., 1993; Daum et al., 1993). In the latter studies, the lesions were mostly confined to the cerebellum, whereas patients with dementia had additional extracerebellar damage. Hence, general intellectual impairment is more likely to be contingent upon the involvement of extracerebellar structures.
The finding of impaired immediate and delayed recall of the WMS in the non-demented SCA2 subjects provides evidence for deficient verbal memory not related to general intellectual impairment. In Alzheimer's disease, degeneration occurs in the basal forebrain cholinergic system, which provides the major cholinergic innervation to the neocortex, hippocampus and amydala. The `cholinergic hypothesis' of dementia has been supported by post-mortem and functional imaging studies demonstrating reduced acetylcholinesterase activity in the cerebral cortex of patients with Alzheimer's disease (Fishman et al., 1986; Zubenko et al., 1989; Iyo et al., 1997). By analogy, having observed general cognitive dysfunction in SCA1 patients, Kish et al. (1988a, b) analysed cholinergic marker enzymes in the cortices of SCA1 brains and found them considerably reduced. Cholinergic marker enzymes have not yet been studied in SCA2 brains. Regarding the close correspondence of SCA1 and SCA2 in every respect, the cholinergic hypothesis should be taken into consideration to explain the memory deficits and general intellectual impairment present in SCA2.
Feedforward and feedback links between the cerebellum and the parietal cortex form the theoretical basis for cerebellar involvement in visuospatial organization (Allen and Tsukahara, 1974; Brodal, 1978; Schmahmann and Pandya, 1989). The finding of deficient visuospatial recall (Bracke-Tolkmitt et al., 1989) and impaired visuospatial manipulations (Wallesch and Horn, 1990; Schmahmann and Sherman, 1998) in patients with cerebellar syndromes indicates cerebellar involvement in visuospatial organization. Other investigators have failed to demonstrate impairment of visuospatial processing in cerebellar patients (Appollonio et al., 1993; Daum et al., 1993). In the present study, deficient copying of visuospatial material was restricted to demented SCA2 subjects. Despite considerable cerebellar damage, non-demented SCA2 individuals did not differ significantly from controls in either copying or delayed visuospatial recall, as measured with the Rey–Osterrieth Complex Figure. Since recall measures did not yield significant differences between demented and non-demented SCA2 patients, impaired copying does not result from memory loss in the demented patients, but points to difficulties of visuospatial organization. Given the small number of demented SCA2 patients, further analysis of a larger patient sample will be needed to address the issue of the nature of visuospatial deficits in SCA2.
SCA2 subjects scoring above the threshold for dementia in the MMS demonstrated deficits on a range of memory tests involving both structured and unrelated material. The deficit was particularly apparent when self-generated strategies could be used to help encoding and retrieval. SCA2 subjects appeared to have impaired ability to generate such strategies. Deficient use of semantic organization in encoding and retrieval has been ascribed to executive dysfunction (della Rocchetta, 1986; Daum et al., 1993). Additionally, SCA2 subjects presented impaired set shifting when generating nouns from alternating semantic categories, which is in accordance with executive problems (Daum et al., 1995). Inspection of the WCST data indicates that non-demented SCA2 patients also showed numerically higher error rates for both random and perseverative errors, even though the statistical comparison with the control subjects did not reach significance. Disturbances of executive functions are usually associated with damage of the prefrontal cortex. The hypothesis that SCA2 patients have frontal deficits is in accordance with the clinical finding of a positive palmomental reflex in 64.7% or a positive grasp reflex in 11.8% of our patients. One possible explanation for the cognitive deficits in SCA2 is to assume that parts of the cerebral cortex undergo degeneration in parallel to the pontocerebellar system. Indeed, post mortem studies of SCA2 brains reported severe gyral atrophy prominent in the frontotemporal lobes with mild neuronal loss (Wadia, 1993; Dürr et al., 1995). Another explanation for the cognitive deficits in cerebellar disease is the disruption of cerebrocerebellar connections. This circuitry consists of a feedforward limb (corticopontine and pontocerebellar) and a feedback limb (cerebellothalamic and thalamocortical). There is evidence from anatomical investigations that prefrontal association areas are linked to the cerebellum (Allen and Tsukahara, 1974; Schmahmann and Pandya, 1995, 1997a). Efferent connections arising from the dentate nucleus and projecting to the prefrontal cortex thus represent the feedback limb of the cerebrocerebellar circuitry (Middleton and Strick, 1994, 1997; Schmahmann and Pandya, 1997b). Imaging studies demonstrating cerebellar activation during performance of executive tasks reflect the close functional relationship between the cerebellum and the frontal cortex (Kim et al., 1994). Therefore, the problems of SCA2 individuals in shifting attention between modalities are consistent with impaired cerebrocerebellar interactions with deficient implementation of the frontal plan to change attentional behaviour. Since the degenerative process is not restricted to the cerebellum but also involves basal ganglia (Orozco et al., 1989; Wadia, 1993; Dürr et al., 1995) an alternative explanation would be that the observed executive deficits are due to degeneration of subcortical structures. Such an assumption is made to explain `subcortical dementia' in basal ganglion disorders. The idea behind the concept of subcortical dementia in basal ganglion disorders is that disruption of the corticostriatothalamic loop at the level of the striatum leads to frontal lobe dysfunction although the frontal lobe is morphologically intact (Owen et al., 1992). However, in contrast to SCA3, in SCA2 striatal degeneration is not a neuropathological feature (Orozco et al., 1989; Dürr et al., 1995). There is loss of dopaminergic neurons of the substantia nigra in SCA2, but these neurons are not directly involved in the circuit outlined above (Orozco et al., 1989).
Other SCA mutations are characterized by similar cognitive deficits. Kish et al. (1988a) reported impaired test performance in the WCST in SCA1. In SCA3, Maruff et al. (1996) found evidence of specific deficits in visual attentional function under high demands of detection and discrimination while visual memory and learning were normal. They interpreted the slowing of the processing of visual information as an inability to shift attention to previously irrelevant stimulus dimensions, which has also been ascribed to damage of the frontal lobe or its connections to subcortical structures (Owen et al., 1992). General intellectual impairment has been restricted to SCA1 subjects (Kish et al., 1988a; Maruff et al.). Taken together, the evidence indicates that different types of SCA may present with executive dysfunction, but comparative neuropsychological studies have not yet been performed.
|
References |
|---|
|
TopAbstractIntroductionPatients and methodsResultsDiscussionReferences |
|---|
Akshoomoff NA, Courchesne E. A new role for the cerebellum in cognitive operations. Behav Neurosci 1992; 106: 731–8.[Web of Science][Medline]
Allen GI, Tsukahara N. Cerebrocerebellar communication systems. [Review]. Physiol Rev 1974; 54: 957–1006.
Allen G, Buxton RB, Wong EC, Courchesne E. Attentional activation of the cerebellum independent of motor involvement. Science 1997; 275: 1940–3.
Appollonio IM, Grafman J, Schwartz V, Massaquoi S, Hallett M. Memory in patients with cerebellar degeneration. Neurology 1993; 43: 1536–44.
Bracke-Tolkmitt R, Linden A, Canavan AG, Rockstroh B, Scholz E, Wessel K, et al. The cerebellum contributes to mental skills. Behav Neurosci 1989; 103: 442–6.[Web of Science]
Brodal P. The corticopontine projection in the rhesus monkey. Origin and principles of organization. Brain 1978; 101: 251–83.
Bürk K, Abele M, Fetter M, Dichgans J, Skalej M, Laccone F, et al. Autosomal dominant cerebellar ataxia type I clinical features and MRI in families with SCA1, SCA2 and SCA3. Brain 1996; 119: 1497–505.
Bürk K, Stevanin G, Didierjean O, Cancel G, Trottier Y, Skalej M, et al. Clinical and genetic analysis of three German kindreds with autosomal dominant cerebellar ataxia type I linked to the SCA2 locus. J Neurol 1997; 244: 256–61.[Web of Science][Medline]
Cancel G, Dürr A, Didierjean O, Imbert G, Bürk K, Lezin A, et al. Molecular and clinical correlations in spinocerebellar ataxia 2: a study of 32 families. Hum Mol Genet 1997; 6: 709–15.
Channon S, Daum I, Polkey CE. The effect of categorization on verbal memory after temporal lobectomy. Neuropsychologia 1989; 27: 777–85.[Web of Science][Medline]
Dahl G. WIP Reduzierter Wechsler-Intelligenztest. [Reduced Wechsler Intelligence Test] Meisenheim/Glan: Hain; 1972.
Daum I, Ackermann H, Schugens MM, Reimold C, Dichgans J, Birbaumer N. The cerebellum and cognitive functions in humans. Behav Neurosci 1993; 107: 411–9.[Web of Science][Medline]
Daum I, Schugens MM, Spieker S, Poser U, Schönle PW, Birbaumer N. Memory and skill acquisition in Parkinson's disease and frontal lobe dysfunction. Cortex 1995; 31: 413–32.[Web of Science][Medline]
Daum I, Gräber S, Schugens MM, Mayes AR. Memory dysfunction of the frontal type in normal ageing. Neuroreport 1996; 7: 2625–8.[Web of Science][Medline]
della Rocchetta AI. Classification and recall of pictures after unilateral frontal or temporal lobectomy. Cortex 1986; 22: 189–211.[Web of Science][Medline]
Desmond JE, Gabrieli JD, Wagner AD, Ginier BL, Glover GH. Lobular patterns of cerebellar activation in verbal working-memory and finger-tapping tasks as revealed by functional MRI. J Neurosci 1997; 17: 9675–85.
Dürr A, Smadja D, Cancel G, Lezin A, Stevanin G, Mikol J, et al. Autosomal dominant cerebellar ataxia type I in Martinique (French West Indies). Clinical and neuropathological analysis of 53 patients from three unrelated SCA2 families. Brain 1995; 118: 1573–81.
Fiez JA, Petersen SE, Cheney MK, Raichle ME. Impaired non-motor learning and error detection associated with cerebellar damage. A single case study. Brain 1992; 115: 155–78.
Fishman EB, Siek GC, MacCallum RD, Bird ED, Volicer L, Marquis JK. Distribution of the molecular forms of acetylcholinesterase in human brain: alterations in dementia of the Alzheimer type. Ann Neurol 1986; 19: 246–52.[Web of Science][Medline]
Flanigan K, Gardner K, Alderson K, Galster B, Otterud B, Leppert MF, et al. Autosomal dominant spinocerebellar ataxia with sensory axonal neuropathy (SCA4): clinical description and genetic localization to chromosome 16q22.1. Am J Hum Genet 1996; 59: 392–9.[Web of Science][Medline]
Folstein MF, Folstein SE, McHugh PR. MMST Mini-Mental-Status-Test—Deutschsprachige Fassung. [German version of the Mini-Mental State Test]. Kessler J, Folstein SE, Denzler P. Weinheim: Beltz; 1975.
Gao JH, Parsons LM, Bower JM, Xiong J, Li J, Fox PT. Cerebellum implicated in sensory acquisition and discrimination rather than motor control [see comments]. Science 1996; 272: 545–7. Comment in: Science 1996; 272: 482–3.[Abstract]
Gispert S, Twells R, Orozco G, Brice A, Weber J, Heredero L, et al. Chromosomal assignment of the second locus for autosomal dominant cerebellar ataxia (SCA2) to chromosome 12q23–24.1. Nat Genet 1993; 4: 295–9.[Web of Science][Medline]
Grafman J, Litvan I, Massaquoi S, Stewart M, Sirigu A, Hallett M. Cognitive planning deficit in patients with cerebellar atrophy [see comments]. Neurology 1992; 42: 1493–6. Comment in: Neurology 1993; 43: 2153–4.
Grasby PM, Frith CD, Friston KJ, Bench C, Frackowiak RS, Dolan RJ. Functional mapping of brain areas implicated in auditory–verbal memory function. Brain 1993; 116: 1–20.
Greenfield J. The spino-cerebellar degenerations. Springfield (IL): Charles C. Thomas; 1954.
Harding AE. The clinical features and classification of the late onset autosomal dominant cerebellar ataxias. A study of 11 families, including descendants of `the Drew family of Walworth'. Brain 1982; 105: 1–28.
Imbert G, Saudou F, Yvert G, Devys D, Trottier Y, Garnier JM, et al. Cloning of the gene for spinocerebellar ataxia 2 reveals a locus with high sensitivity to expanded CAG/glutamine repeats [see comments]. Nat Genet 1996; 14: 285–91. Comment in: Nat Genet 1996; 14: 237–8.[Web of Science][Medline]
Iyo M, Namba H, Fukushi K, Shinotoh H, Nagatsuka S, Suhara T, et al. Measurement of acetylcholinesterase by positron emission tomography in the brains of healthy controls and patients with Alzheimer's disease. Lancet 1997; 349: 1805–9.[Web of Science][Medline]
Jenkins IH, Brooks DJ, Nixon PD, Frackowiak RS, Passingham RE. Motor sequence learning: a study with positron emission tomography. J Neurosci 1994; 14: 3775–90.[Abstract]
Kawaguchi Y, Okamoto T, Taniwaki M, Aizawa M, Inoue M, Katayama S, et al. CAG expansions in a novel gene for Machado–Joseph disease at chromosome 14q32.1 [see comments]. Nat Genet 1994; 8: 221–8. Comment in: Nat Genet 1994; 8: 213–5.[Web of Science][Medline]
Kim SG, Ugurbil K, Strick PL. Activation of a cerebellar output nucleus during cognitive processing. Science 1994; 265: 949–51.
Kish SJ, el Awar M, Schut L, Leach L, Oscar-Berman M, Freedman M. Cognitive deficits in olivopontocerebellar atrophy: implications for the cholinergic hypothesis of Alzheimer's dementia. Ann Neurol 1988a; 24: 200–6.[Web of Science][Medline]
Kish SJ, Schut L, Simmons J, Gilbert J, Chang LJ, Rebbetoy M. Brain acetylcholinesterase activity is markedly reduced in dominantly-inherited olivopontocerebellar atrophy. J Neurol Neurosurg Psychiatry 1988b; 51: 544–8.
Kish SJ, el Awar M, Stuss D, Nobrega J, Currier R, Aita JF, et al. Neuropsychological test performance in patients with dominantly inherited spinocerebellar ataxia: relationship to ataxia severity. Neurology 1994; 44: 1738–46.
Klein D, Milner B, Zatorre RJ, Meyer E, Evans AC. The neural substrates underlying word generation: a bilingual functional-imaging study. Proc Natl Acad Sci USA 1995; 92: 2899–903.
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.
Klockgether T, Kramer B, Lüdtke R, Schöls L, Laccone F. Repeat length and disease progression in spinocerebellar ataxia type 3 [letter]. Lancet 1996; 348: 830.[Web of Science][Medline]
Kolb B, Whishaw IQ, editors. Fundamentals of human neuropsychology. 3rd ed. New York: W.H. Freeman; 1990.
Leiner HC, Leiner AL, Dow RS. The underestimated cerebellum. Hum Brain Mapp 1995; 2: 244–54.
Logan CG, Grafton ST. Functional anatomy of human eyeblink conditioning determined with regional cerebral glucose metabolism and positron-emission tomography. Proc Natl Acad Sci USA 1995; 92: 7500–4.
Maciel P, Gaspar C, DeStefano AL, Silveira I, Coutinho P, Radvany J, et al. Correlation between CAG repeat length and clinical features in Machado–Joseph disease. Am J Hum Genet 1995; 57: 54–61.[Web of Science][Medline]
Maruff P, Tyler P, Burt T, Currie B, Burns C, Currie J. Cognitive deficits in Machado–Joseph disease. Ann Neurol 1996; 40: 421–7.[Web of Science][Medline]
Middleton FA, Strick PL. Anatomical evidence for cerebellar and basal ganglia involvement in higher cognitive function. Science 1994; 266: 458–61.
Middleton FA, Strick PL. Dentate output channels: motor and cognitive components. [Review]. Prog Brain Res 1997; 114: 553–66.[Web of Science][Medline]
Nelson HE. A modified card sorting test sensitive to frontal lobe defects. Cortex 1976; 12: 313–24.[Web of Science][Medline]
Orozco G, Estrada R, Perry TL, Arana J, Fernandez R, Gonzalez-Quevedo A, et al. Dominantly inherited olivopontocerebellar atrophy from eastern Cuba. Clinical, neuropathological, and biochemical findings. J Neurol Sci 1989; 93: 37–50.[Web of Science][Medline]
Orr HT, Chung MY, Banfi S, Kwiatkowski TJ Jr, Servadio A, Beaudet AL, et al. Expansion of an unstable trinucleotide CAG repeat in spinocerebellar ataxia type 1. Nat Genet 1993; 4: 221–6.[Web of Science][Medline]
Osterrieth PA. Le test de copie d'une figure complex. Arch Psychol 1944; 30: 206–356.
Owen AM, James M, Leigh PN, Summers BA, Marsden CD, Quinn NP, et al. Fronto-striatal cognitive deficits at different stages of Parkinson's disease. Brain 1992; 115: 1727–51.
Petersen SE, Fox PT, Posner MI, Mintum MA, Raichle ME. Positron emission tomographic studies of the processing of single words. J Cogn Neurosci 1989; 1: 153–70.
Pulst SM, Nechiporuk A, Nechiporuk T, Gispert S, Chen XN, Lopes-Cendes I, et al. Moderate expansion of a normally biallelic trinucleotide repeat in spinocerebellar ataxia type 2 [see comments]. Nat Genet 1996; 14: 269–76. Comment in: Nat Genet 1996; 14: 237–8.[Web of Science][Medline]
Rey A. L'examen psychologique dans les cas d'encephalopathie traumatique. Arch Psychol 1941; 28: 286–340.
Sanpei K, Takano H, Igarashi S, Sato T, Oyake M, Sasaki H, et al. Identification of the spinocerebellar ataxia type 2 gene using a direct identification of repeat expansion and cloning technique, DIRECT [see comments]. Nat Genet 1996; 14: 277–84. Comment in: Nat Genet 1996; 14: 237–8.[Web of Science][Medline]
Schmahmann JD, Pandya DN. Anatomical investigation of projections to the basis pontis from posterior parietal association cortices in rhesus monkey. J Comp Neurol 1989; 289: 53–73.[Web of Science][Medline]
Schmahmann JD, Pandya DN. Prefrontal cortex projections to the basilar pons in rhesus monkey: implications for the cerebellar contribution to higher function. Neurosci Lett 1995; 199: 175–8.[Web of Science][Medline]
Schmahmann JD, Pandya DN. Anatomic organization of the basilar pontine projections from prefrontal cortices in rhesus monkey. [Review]. J Neurosci 1997a; 17: 438–58.
Schmahmann JD, Pandya DN. The cerebrocerebellar system. [Review]. Int Rev Neurobiol 1997b; 41: 31–60.[Web of Science][Medline]
Schmahmann JD, Sherman JC. The cerebellar cognitive affective syndrome [see comments]. Brain 1998; 121: 561–79. Comment in: Brain 1998; 121: 545–6.
Stevanin G, Le Guern E, Ravise N, Chneiweiss H, Dürr A, Cancel G, et al. A third locus for autosomal dominant cerebellar ataxia type I maps to chromosome 14q24.3-qter: evidence for the existence of a fourth locus. Am J Hum Genet 1994; 54: 11–20.[Web of Science][Medline]
Wadia NH. A variety of olivopontocerebellar atrophy distinguished by slow eye movements and peripheral neuropathy. Adv Neurol 1984; 41: 149–77.[Medline]
Wadia NH. A common variety of hereditary ataxia in India. In: Lechtenberg R, editor. Handbook of cerebellar diseases. New York: Marcel Dekker; 1993. p. 373–88.
Wallesch CW, Horn A. Long-term effects of cerebellar pathology on cognitive functions. Brain Cogn 1990; 14: 19–25.[Web of Science][Medline]
Wechsler D. WMS-R Wechsler Memory Scale_Revised. Manual. San Antonio (TX): The Psychological Corporation; 1987.
Zoghbi HY, Jodice C, Sandkuijl LA, Kwiatkowski TJ Jr, McCall AE, Huntoon SA, et al. The gene for autosomal dominant spinocerebellar ataxia (SCA1) maps telomeric to the HLA complex and is closely linked to the D6S89 locus in three large kindreds. Am J Hum Genet 1991; 49: 23–30.[Web of Science][Medline]
Zubenko GS, Moossy J, Martinez AJ, Rao GR, Kopp U, Hanin I. A brain regional analysis of morphologic and cholinergic abnormalities in Alzheimer's disease. Arch Neurol 1989; 46: 634–8.
Received October 23, 1998. Accepted December 7, 1998.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  M Suenaga, Y Kawai, H Watanabe, N Atsuta, M Ito, F Tanaka, M Katsuno, H Fukatsu, S Naganawa, and G Sobue Cognitive impairment in spinocerebellar ataxia type 6 J. Neurol. Neurosurg. Psychiatry, May 1, 2008; 79(5): 496 - 499. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. M. Zaroff, O. Neudorfer, C. Morrison, G. M. Pastores, H. Rubin, and E. H. Kolodny Neuropsychological assessment of patients with late onset GM2 gangliosidosis Neurology, June 22, 2004; 62(12): 2283 - 2286. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. M. Levenson, S. Choi, S.-Y. Lee, Y. A. Cao, H. J. Ahn, K. C. Worley, M. Pizzi, H.-C. Liou, and J. D. Sweatt A Bioinformatics Analysis of Memory Consolidation Reveals Involvement of the Transcription Factor c-Rel J. Neurosci., April 21, 2004; 24(16): 3933 - 3943. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 U. Rub, D. Del Turco, K. Del Tredici, R. A. I. de Vos, E. R. Brunt, G. Reifenberger, C. Seifried, C. Schultz, G. Auburger, and H. Braak Thalamic involvement in a spinocerebellar ataxia type 2 (SCA2) and a spinocerebellar ataxia type 3 (SCA3) patient, and its clinical relevance Brain, October 1, 2003; 126(10): 2257 - 2272. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Burk, S. Bosch, C. A. Muller, A. Melms, C. Zuhlke, M. Stern, I. Besenthal, M. Skalej, P. Ruck, S. Ferber, et al. Sporadic cerebellar ataxia associated with gluten sensitivity Brain, May 1, 2001; 124(5): 1013 - 1019. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||