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Cognition in Friedreich Ataxia
Cognition in Friedreich Ataxia
DOI 10.1007/s12311-012-0363-9
ORIGINAL PAPER
Abstract Friedreich ataxia (FRDA) is the most frequent of have reported only mild anomalies in cerebral hemispheres.
the inherited ataxias. However, very few studies have exam- Thus, cognitive impairment in FRDA is probably caused by
ined the cognitive status of patients with genetically defined the interruption of the cerebro-cerebellar circuits that have
FRDA. Our aim was to study cognitive performance of FRDA been proposed as the anatomical substrate of the cerebellar
patients taking into account the motor problems characteristic involvement in cognition.
of this clinical population. Thirty-six FRDA patients were
administered a comprehensive neuropsychological battery Keywords Cerebellum . Cognition . Friedreich ataxia .
measuring multiple domains: processing speed, attention, Neuropsychology
working memory, executive functions, verbal and visual
memory, visuoperceptive and visuospatial skills, visuocon-
structive functions, and language. Thirty-one gender, age, Introduction
years of education, and estimated IQ-matched healthy partic-
ipants served as control subjects. All participants were native Traditionally, the cerebellum has been regarded as a motor
Spanish speakers. Patients showed decreased motor and men- mechanism, but this view of its function is being challenged
tal speed, problems in conceptual thinking, a diminished by observations from neuroanatomical, neuroimaging, and
verbal fluency, deficits in acquisition of verbal information neuropsychological studies, which suggest that it also plays
and use of semantic strategies in retrieval, visuoperceptive and a role in cognitive activity [1–6]. Friedreich ataxia (FRDA) is
visuoconstructive problems, and poor action naming. Scores the most frequent syndrome of the cerebellar ataxias. It is
on the depression inventory were significantly higher in caused in more than 95% of cases by a homozygous triplet
patients than controls, but depression did not account for GAA expansion in the first intron of the frataxin gene (FXN,
group differences in cognitive performance. The observed previously known as FRDA, X25) on chromosome 9q13,
pattern of neuropsychological impairment is indicative of while the remaining patients are compound heterozygotes
executive problems and parieto-temporal dysfunction. Neuro- for a GAA expansion in the disease-causing range in one
pathological and neuroimaging studies with FRDA patients FXN allele and another inactivating FXN point mutations in
the other allele [7]. Both types of mutations lead to a marked
deficiency of frataxin [8, 9]. Frataxin is a mitochondrial mem-
Electronic supplementary material The online version of this article
(doi:10.1007/s12311-012-0363-9) contains supplementary material, brane protein involved in iron distribution. Frataxin deficiency
which is available to authorized users. causes iron accumulation in mitochondria, fundamentally in
A. Nieto (*) : R. Correia : E. de Nóbrega : S. Hess : J. Barroso
cardiac muscle and in the cerebellar dentate nucleus [10],
School of Psychology, University of La Laguna, which, in turn, produces mitochondrial dysfunction [11]. This
38205, La Laguna, Tenerife, Spain is probably what is responsible for the degenerative changes in
e-mail: anieto@ull.es FRDA [9, 12, 13]. The neuropathological changes of FRDA
fundamentally involve the spinal cord, with degeneration of
F. Montón
Department of Neurology, Hospital N.S. La Candelaria, posterior columns and spinocerebellar tracts, and the dentate
S/C de Tenerife, Spain nucleus [13]. Pathological alteration of the cerebellum,
Cerebellum (2012) 11:834–844 835
especially the dentate nucleus, could interfere with cognition, of three Spanish hospitals: Ntra. Sra. Candelaria Universi-
affecting cerebellar–thalamic–cortical loops [14, 15]. tary Hospital (S/C de Tenerife), Marqués de Valdecillas
Although established as the most common cerebellar atax- Hospital (Cantabria), and La Paz Hospital (Madrid). All
ia, almost no attention has been paid to cognitive functions in patients fulfilled the diagnostic criteria of Friedreich ataxia
FRDA. Earlier studies in patients with clinical diagnosis of [25] and presented the molecular genotype of FRDA. They
FRDA have described deficits in several cognitive domains presented a large homozygous GAA triplet-repeat expan-
such as information processing speed, executive and mnesic sion in the first intron of the frataxin gene (X25, within the
functions, as well as some visuospatial and visuoconstructive critical region on chromosome 9). They showed progressive
functions [3, 16–19]. However, these studies were undertaken ataxia of limbs and gait, nystagmus, and dysarthria. Twenty-
prior to the identification of the FA mutations, or the clinical nine patients had typical FA (age of onset before 25 years
diagnosis was not confirmed by genetic molecular analysis. old) and seven cases had late onset FA. The mean duration
There are very few studies that examined the cognitive status of illness was 15.89 (SD08.63), and the mean age at disease
of patients with genetically defined FRDA and most of them onset was 18.06 years (SD09.40) (Table 1). All patients
have investigated specific cognitive functions. Our group ex- underwent a neurological examination. The Rankin Incapac-
amined verbal fluency in genetically proven FRDA using ity and the Nobile-Orazio Ataxia scales were used to quan-
different word retrieval [20]. We observed phonemic and action tify disease severity (score from 0—normal to 5—most
fluency impairments, suggesting a prefrontal dysfunction in impaired) [26, 27]. A Clinical Rating Scale modified from
FRDA. Corben et al. described impairment in motor program- Appollonio et al. [28] was used to quantify seven cerebellar
ming [21] and Klopper et al. [22] reported deficits in sustained signs (dysarthria, limb tone, postural tremor, upper and
volitional attention and working memory using the Test of lower limb ataxia, standing balance, and gait ataxia). Each
Everyday Attention [23]. To our knowledge, the only study of these was assigned a score from 0 (normal) to 4 (most
approaching a wide range of cognitive domains in FRDA is the
work published by Mantovan et al. [24]. In this study, 13 Table 1 Demographic characteristics and clinical features of patients
individuals with genetically proven FRDA were examined. and normal controls
Patients showed slowed information processing, reduced verbal
FA patients Controls p
span and visual memory, deficits in verbal fluency and alter-
(n036) (n031)
ation in complex visuoperceptual and visuoconstructive abili- Mean (SD) Mean (SD)
ties. Nonetheless, the interpretation of these results might be
hampered by the fact that the FRDA group showed an average Age 33.94 (12.23) 30.35 (8.34) 0.172
IQ lower than controls and two patients had an IQ below Education (years) 12.39 (4.09) 13.55 (3.23) 0.208
normal range. In addition, some conclusions reached by these Sexa 20/16 17/14 0.953
authors regarding specific cognitive functions (e.g., visual Handednessb 32/4 29/2 0.505
memory, visuoconstructive abilities, concrete thinking, and MMSE 28.81 (1.30) 29.23 (1.05) 0.157
poor capacity in concept formation) are supported by data that Information subtest 9.31 (3.36) 10.42 (2.50) 0.134
are not explicitly reported in their published manuscript. BDI 12.47 (10.27) 6.03 (6.31) 0.003c
In sum, given the current lack of results, more compre- Age at disease onset (years) 18.06 (9.40) – –
hensive neuropsychological explorations are needed to fur- Disease duration (years) 15.89 (8.63) – –
ther understand the cognitive impairment profile in FRDA. Rankin Incapacity Scale 3.00 (0.89) – –
Thus, our aim is to study these patients’ cognitive function- Nobile-Orazio Ataxia Scale 4.31 (1.01) – –
ing in a wide range of cognitive domains, trying to mitigate Appollonio CRS 13.47 (5.18) – –
the possible effects of their motor disturbances on their A. CRS dysarthria 1.72 (0.81) – –
performance in neuropsychological tasks. In addition, we A. CRS limb tone 0.72 (0.75) – –
examine a larger patient sample than that usually found in A. CRS postural tremor 0.32 (0.48) – –
FRDA studies, which might help to reduce inter-subject A. CRS upper limb ataxia 1.96 (0.84) – –
variability in the neuropsychological data. A. CRS lower limb ataxia 2.26 (0.91) – –
A. CRS standing balance 2.76 (1.09) – –
A. CRS gait ataxia 3.08 (1.04) – –
Methods A. CRS oculomotion 1.95 (1.59) – –
impaired). In addition, the following abnormalities in ocular Table 2 Neuropsychological test administered grouped by cognitive
domains
movements were each scored as 1 when present: dysmetria,
nystagmus in the horizontal or vertical plane, slowed or Global screening
absent saccades, and saccadic breakdown of pursuit. Total Mini-Mental State Examination (MMSE)
scores on this scale ranged from 0 to 32; the higher the Information Subtest (WAIS-III)
score, the worse the dysfunction. Magnetic resonance imag- Beck’s Depression Inventory (BDI)
ing was performed on every patient. MR images were clin- Reaction Time, Attention, and Working Memory (WM)
ically assessed by an experienced neuroradiologist. All Simple Reaction Time (Pc-Vienna System)
patients presented spinal cord atrophy, and two of them Choice Reaction Time (Pc-Vienna System)
presented mild cerebellar atrophy. Neither cerebral atrophy Continuous Performance Test (CPT-IP)
nor focal lesions were observed. Stroop Word and Color Test
The control group consisted of 31 subjects. Control par- Digit Span (WMS-III)
ticipants were free of neurological disease/injury, drug ad- Spatial Span (WMS-III)
diction, and psychiatric illness histories. General cognition Executive functions
was tested with a modified version of the Mini-Mental State Wisconsin Card Sorting Test (WCST)
Examination [29]. The Information subtest of the Wechsler Similarities Subtest (WAIS-III)
Adult Intelligence Scale (WAIS)-III [30] was also adminis- Verbal fluency (FAS, animals, and actions)
tered as a general intelligence estimation measure. Patient
Memory and learning
and control groups did not differ with respect to age, level of
Logical Memory (WMS-III)
education, Mini-Mental State Examination (MMSE) score,
California Verbal Learning Test (CVLT)
and Information score (WAIS-III). Depression was assessed
10/36 Spatial Recall Test (10/36 SRT)
by the Beck Depression Inventory (BDI) [31].
Visuoperceptive, visuospatial, and visuoconstructive abilities
Both groups of participants were informed about the aim of
Judgment Line Orientation Test (JLOT)
the investigation and participated voluntarily. All subjects
Facial Recognition Test (FRT)
gave their informed consent. The data included in the manu-
Minnesota Test
script were obtained in accordance with the regulations of the
Block Design (WAIS-III)
ethics committees of the University of La Laguna and in
Language
compliance with the Helsinki Declaration for human research.
Noun and action naming
Anaphora comprehension
Materials
subject’s performance in the other two neutral conditions making two designs, one four-block design and one nine-
(Word and Color sheets). To calculate the interference index block design, with all the red faces of the blocks at the top.
(I), it is first required to calculate an expected score (ES) Language was assessed with a naming task by visual
from subject’s performance in the word and the color con- confrontation of pictorial stimuli and an anaphora comprehen-
ditions [ES 0 (word × color)/(word + color)] and then to sion task. These tasks were designed by our group with the aim
calculate the interference index by subtracting the expected of measuring both language production and comprehension.
score from number of corrected responses emitted in the The naming task consists of 40 stimuli representing elements
third condition (I 0 word−color − ES). (noun naming) and 20 stimuli depicting action scenes (action
Working memory was tested with digit span and spatial naming). Nouns and actions were paired in those variables
span [forward and backwards; Wechsler Memory Scale known to affect naming: every action item was paired with
(WMS-III)] [35]. two noun items in word frequency [44] and nominal agreement
Executive functions were tested with the Wisconsin Card [45]. Stimuli are line drawings of objects in black and white,
Sorting Test (WCST) [36], Similarities subtest of the WAIS- taken from the work of Cuetos et al. [46], from the Interna-
III [30], and Verbal fluency tasks. These tasks consist of tional Picture Naming Project [47] and the materials of Druks
asking the participants to rapidly generate words beginning and Masterson [48]. Stimuli presentation was computerized
by a given letter (phonemic fluency —FAS) [37], to generate using E-Prime v1.1 [49]. The participants were instructed to
only animals (semantic fluency), and to rapidly generate verbs recall the name of the concept represented (either the noun
(action fluency) [38]. corresponding to the element drawn or the verb corresponding
Verbal memory was tested with the Logical Memory to the action depicted). Hits were recorded.
subtest (immediate and delayed free recall and recognition The anaphora comprehension task consisted of 20 senten-
of two prose passages) of the WMS-III [35] and the Spanish ces with anaphoric expressions, ten non-ambiguous and ten
adaptation of the California Verbal Learning Test (learning ambiguous. Ambiguity is defined in terms of gender, thus
over five-trial presentation of a 16-word list, free and cued when it is possible to discriminate the antecedent based solely
delayed recall, recognition) [39, 40]. Visual memory was on its gender, the anaphora resolution is easier than when there
tested with a modified 10/36 Spatial Recall Test (10/36) is more than one word in the sentence which agrees in gender
[41], a spatial memory test that does not require good motor with the anaphoric pronoun. Thus, in our design, we consider
control. A ten-dot pattern was displayed on a 6×6 grid. two types of pronominal anaphora: (1) non-ambiguous, in
Participants studied this arrangement for 10 s. Afterwards, which the anaphora is resolved by the gender key (e.g., Alba
the pattern was removed and the participants reproduced it gave a painkiller to Eduardo as he had a headache) and (2)
from memory on an empty grid using poker chips. This ambiguous, where gender does not solve the ambiguity, re-
learning task continued over five trials and delayed visual quiring a semantic interpretation of the sentence to solve
recall was assessed at 30 min. Visual recognition was mea- it (e.g., Alba gave a painkiller to Mercedes as she had a
sured employing a forced choice procedure in which four headache). Since pronominal anaphors are very common lin-
grids with ten-dot patterns were presented. The participants guistic expressions that give coherence and continuity to
attempted to pick the grid with the correct pattern. This speech, the aim of this task is to assess the ability to make
forced choice procedure was given twice. the necessary inferences to comprehend sentences involving
Visuoperceptive skills were tested with the Facial Recog- anaphora. All sentences were presented in auditory format by
nition Test (FRT) [42]. Abbreviated versions of the Judg- E-Prime computer software. Participants were instructed to
ment of Line Orientation Test (JLOT—15 items) [42] and a listen to a series of sentences and to look at the computer
task of mental spatial rotation, the Minnesota Paper Form screen where two words would appear during each sentence
Board Test [43], were used to assess visuospatial function- auditory presentation. These words correspond to the charac-
ing. Finally, for the assessment of visuoconstructive skills, a ters in the opening sentence, that is, the subject (Alba) and the
Modified Block Design subtest of the WAIS-III was select- object (Eduardo) of the sentence. After each sentence presen-
ed. This subtest was administered as described in the manual tation, the participants were asked to answer a question re-
[30] except that if the design was not correctly completed garding either the subject (Who gave a painkiller?) or the
within the standard administration time, we allowed the object (Who had a headache?) of the sentence. Responses
subject to work on the problem for one extra minute. The were registered by means of a two-button panel and partic-
number of correct blocks was recorded without any kind of ipants were instructed to press the button corresponding to the
speed credits in order to take into account the motor deficits correct answer (either right button if the correct answer is the
of patients. A motor baseline task was also administered and word present at the right side of the screen or left button for the
execution time was recorded. This task was equivalent to the word at the left side). In some cases, due to motor impairment,
original Block Design Test in motor demand but had mini- the patients responded orally and the tester registered the
mal perceptive and planning requirements. It consisted of response. We recorded the number of hits and errors.
838 Cerebellum (2012) 11:834–844
dysarthria score from the Appollonio Clinical Rating Scale Visuoperceptual, Visuospatial, and Visuoconstructive
and the patients’ performance on every verbal fluency task. Abilities
Only action fluency showed a significant correlation (FAS,
r0−0.219, p00.206; animal, r0−0.294, p00.087; action, As shown in Table 7, FRDA patient scores were significantly
r0−0.333, p00.050). However, it did not show a significant lower than the controls only in FRT. In addition, there was no
effect as a covariable when the subsequent analysis of significant correlation between the FRT score and the presence
covariance (ANCOVA) was performed [F(1, 63)03.168, of oculomotor disturbances assessed by the Appollonio
p00.080]. On the other hand, we decided also to divide Clinical Rating Scale (r00.128, p00.838).
the FRDA group into patients without dysarthria or with In the Block Design subtest, we found significant
only mild dysarthria (non-dysarthric patients) and patients between-groups differences on both standard and extended
with moderate or severe dysarthria according to the dysar- time conditions (Table 8). As suggested by Lezak et al. [51],
thria item of the Appollonio Clinical Rating Scale. Perform- we grouped trials in easy and complex designs and found
ances on fluency measures were reanalyzed for control that FRDA patients had significantly poorer performance
participants and non-dysarthric FRDA. These two groups than controls in the complex but not the easy designs
did not significant differ in age, education, and MMSE. (Table 8). Significant between-groups differences were
Non-dysarthric FRDA patients also performed significantly also found on the baseline motor task administered.
worse than controls in the three verbal fluency measures Moreover, performance in this control task correlated
(Table 5). with accuracy in total (r0−0.568, p<0.0001) and complex
In addition, although moderate and significant correla- designs (r0−0.573, p<0.0001). Therefore, we performed
tions were found between total reaction time and each of the subsequent ANCOVA analyses. Nonetheless, participants’
verbal fluency measures (FAS, r0−0.463, p00.001; animal, performance in control designs was not a significant covariant
r0−0.330, p00.020; action, r0−0.430, p00.002), total re- in the analyses performed [total extended time, F(1, 49)0
action time did not show a significant effect when subse- 0.766, p00.386; complex extended time, F(1, 49)00.858,
quent ANCOVA was performed [FAS, F(1, 46)01.327, p0 p00.359]. Neither was FRDA patients’ performance in
0.255; animal, F(1, 46)00.790, p00.379; action, F(1, 46)0 the complex designs correlated with their performance
1.541, p 00.221]. Thus, reaction time does not explain in FRT (total, r00.498, p00.070; complex designs, r00.509,
between-groups differences in verbal fluency measures. p00.063).
Patients scored significantly worse than controls on imme- We conducted a repeated measures analysis in order to
diate in the Logical Memory subtest. Although they also analyze both differences between groups and the effect of
scored worse on the delayed recall, there were no significant the naming category (noun vs. action) on participants’ per-
differences between groups on the retention percentage and formance in naming tasks. There was a significant effect of
the recognition trial of this subtest. Significant differences the between-subjects variable group [F(1, 57)06.930, p0
between patients and controls were also found on cued short 0.011)]. We did not find a significant effect of the within-
delay recall in California Verbal Learning Test (CVLT). No subjects variable naming category [F(1, 57)03.943, p0
significant differences were found between groups on visual 0.052] but the interaction between both independent varia-
memory measures (Table 6). bles was significant [F(1, 57)04.901, p00.031]. As shown
in Fig. 1, the controls performed similarly in every naming
task but patients showed a significantly higher performance
in noun compared to action naming. In addition, FRDA
Table 5 Performance by non-dysarthric patients and normal controls patients and controls did not significantly differ in noun
in verbal fluency measures
naming, but in action naming, the controls exhibited a
FRDA (n021) Controls (n031) superior performance to that of the patients (Fig. 1).
Mean (SD) Mean (SD) p Since the participants had a lower performance than the
controls in FRT, we studied the relationship between partic-
FAS 26.24 (8.92) 37.87 (7.71) 0.0001ab
ipants’ performances on FRT and both naming tasks. We did
Animal 19.95 (5.14) 23.77 (4.18) 0.005ab
not find a significant relationship between FRT and these
Action 14.14 (4.28) 20.23 (5.45) 0.0001ab
naming tasks (nouns, r00.226, p00.094; actions, r00.229,
a
Significance level of α/300.0160 p00.089).
b
Significant differences according to Bonferroni-adjusted α values A repeated measures analysis of variance was also per-
(α/n) formed to analyze participant performance in the anaphora
840 Cerebellum (2012) 11:834–844
Regarding the comprehension task, patients solved correctly in the Test of Everyday Attention [23]. Nonetheless, the tasks
both non-ambiguous and ambiguous anaphora to comprehend included in Klopper’s work have an important switching
the meaning of the sentences presented. attention component [53, 54] or a considerable working mem-
In sum, FRDA patients showed slowed processing speed, ory load. In fact, the only task included considered to be a pure
impaired concept formation and verbal fluency, deficits in sustained attention measure is the elevator counting condition
acquisition of verbal information and use of semantic strate- [53–56] where FRDA patients had a preserved performance.
gies in retrieval, visuoperceptive and visuoconstructive prob- Therefore, in our opinion, the ability to self-sustain attention is
lems, and poor action naming. Attentional functions, working not a characteristic deficit of FRDA but difficulties might arise
memory, visual memory, and language comprehension are in more complex tasks where other cognitive processes (work-
preserved. ing memory, flexibility, switching, etc.) are also involved.
In general, the cognitive deficits observed in the present Impairment observed in conceptual thinking and verbal
study are in line with those observed in previous studies about fluency is indicative of deficits in prefrontal functions, at least
cognitive performance in genetically confirmed FRDA in its executive component. The characteristics of other deficits
patients. Impaired information processing speed is a consis- showed by FRDA patients, in the present study, also suggest an
tent result in the scarce cognitive research on FRDA [20, 21, interpretation in terms of executive dysfunction. Whereas
24]. Our results are also concordant with reports regarding patients showed a good performance in immediate recall of
impairment in concept formation, verbal fluency, and visuo- the words list of the CVLT, they were impaired on the imme-
perceptive and visuoconstructive functions [20, 24]. In addi- diate recall of texts. This suggests that difficulties in text recall
tion, the procedures followed in our study allowed us to may be due to an inappropriate use of organizing strategies for
explore more deeply explanations for task results with a encoding the abundant information contained in the texts. In
difficult interpretation such as verbal fluency or visuocon- addition, problems with the proper use of semantic strategies to
structive skills. Regarding declarative memory, the only study retrieve a list of words seem also to be the cause of the poor
that has examined memory performance in FRDA reported a performance in CVLT delayed cued recall. On the other hand,
poorer overall performance (memory quotient) but did not visuoperceptive and visuoconstructional impairments are in-
report differences between FRDA patients and control partic- dicative of a dysfunction in right temporo-parietal systems [42,
ipants in specific memory tasks [24]. Action naming has not 51]. In addition, the fact that poor performance in block
been studied to date, but the preservation of noun naming is in designs was observed only in more complex designs points
line with results obtained by Mantovan et al. [24]. to a difficulty in self-generating strategies for problem solving
On the other hand, the preservation of working memory and a lack of the flexibility needed to perceive components of a
and attention is partially discrepant with results obtained in gestalt and then integrate them as a particular block arrange-
previous studies. Impairment in verbal working memory, as ment. All these results are indicative of impairments in the
assessed by digit tasks, was reported by Mantovan et al. [24], more executive components of these different tasks. In agree-
but in that study, patients presented an average IQ lower than ment with this, results in naming tasks indicate that patients
controls and 2 of 13 patients had an IQ below normal average. have difficulties only in action naming, a task that has been
Attention is a complex function that consists of different especially associated with frontal lobe functioning [57–59].
subsystems that perform different but interrelated functions There is converging evidence from anatomical, physio-
[52]. In the present study, we focused on two of these sub- logical, and clinical approaches to recognize the cerebellum
systems: selective attention and sustained attention. Selective as a critical component of the distributed neural circuits
attention, conceptualized as the capacity to select relevant subserving cognition [60]. Inputs to the cerebellum arise
stimuli and inhibit irrelevant ones, was assessed with the from multiple cortical areas, such as the frontal, parietal,
Stroop Test. In agreement with Corben et al. [21], FRDA and temporal lobes. Outputs from the deep cerebellar nuclei
patients were not impaired. Mantovan et al. [24] reported a project to a diverse set of thalamic nuclei and, in turn, these
different result. However, they used a modification of the nuclei project to cortical areas other than the motor cortex
Stroop paradigm that does not actually examine selective [1, 61, 62]. Particularly, prefrontal and parietal areas are
attention but the perception of the consistency or inconsisten- cortical targets of cerebello–thalamo–cortical pathway from
cy between stimuli features. Sustained attention, the ability to the dentate nucleus [63–65]. This deep cerebellar nucleus is,
self-sustain attention in the absence of external manipulators precisely, the one especially affected in FRDA, showing
of attention such as novelty, was assessed with a paradigm of increased iron and severe neuronal degeneration. Thus, the
CPT-IP. FRDA patients showed a preserved performance in deficits shown by FRDA patients may relate to the disruption of
this task. To our knowledge, no other study has used a CPT cerebro-cerebellar circuits, especially those linking cerebellum
paradigm to assess sustained attention in FRDA before. with prefrontal and parieto-temporal cortex.
Klopper et al. [22] reported sustained attention deficit in Another explanation for these deficits is that they are
this clinical population based on their impaired performance caused by a primary cerebral damage. Similarly to the neurons
Cerebellum (2012) 11:834–844 843
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Acknowledgments The authors thank Dr. Berciano (Hospital Marques impairment in semantic, phonemic, and action fluency perfor-
de Valdecillas, Santander) and Dr. Arpa (Hospital La Paz, Madrid) for mance in Friedreich’s ataxia: possible evidence of prefrontal dys-
providing access to patients and for their helpful assistance. They also function. J Int Neuropsychol Soc. 2007;13(06):944–52.
thank Margaret Guillon for linguistic review of the manuscript. This 21. Corben LA, Delatycki MB, Bradshaw JL, Horne MK, Fahey MC,
research has been partially supported by a research grant from Ministerio Churchyard AJ, et al. Impairment in motor reprogramming in
de Ciencia e Innovacion (PSI2011-24665) and Proyecto Estructurante Friedreich ataxia reflecting possible cerebellar dysfunction. J Neurol.
Neurocog, financed by the ACIISI and cofinanced by FEDER funds and 2010;257(5):782–91.
the University of La Laguna. 22. Klopper F, Delatycki MB, Corben LA, Bradshaw JL, Rance G,
Georgiou-Karistianis N. The test of everyday attention reveals
Conflict of Interest The authors declare that they have no competing significant sustained volitional attention and working memory
personal or financial interests. deficits in friedreich ataxia. J Int Neuropsychol Soc. 2011;17
(1):196–200.
23. Robertson IH, Ward A, Ridgeway V, Nimmo-Smith I. The test of
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