Cognition in FA.pdf

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The Cerebellum

ISSN 1473-4222

Volume 11

Number 4

Cerebellum (2012) 11:834-844

DOI 10.1007/s12311-012-0363-9

Cognition in Friedreich Ataxia

Antonieta Nieto, Rut Correia, Erika de

Nbrega, Fernando Montn, Stephany

Hess & Jose Barroso


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ORIGINAL PAPER

Cognition in Friedreich Ataxia

Antonieta Nieto &Rut Correia &Erika de Nbrega &Fernando Montn &Stephany Hess &Jose Barroso

Published online: 16 February 2012# Springer Science+Business Media, LLC 2012

Abstract Friedreich ataxia (FRDA) is the most frequent of

the inherited ataxias. However, very few studies have exam-ined the cognitive status of patients with genetically defined

FRDA. Our aim was to study cognitive performance of FRDA

patients taking into account the motor problems characteristic

of this clinical population. Thirty-six FRDA patients were

administered a comprehensive neuropsychological battery

measuring multiple domains: processing speed, attention,

working memory, executive functions, verbal and visual

memory, visuoperceptive and visuospatial skills, visuocon-

structive functions, and language. Thirty-one gender, age,

years of education, and estimated IQ-matched healthy partic-

ipants served as control subjects. All participants were native

Spanish speakers. Patients showed decreased motor and men-

tal speed, problems in conceptual thinking, a diminished

verbal fluency, deficits in acquisition of verbal information

and use of semantic strategies in retrieval, visuoperceptive and

visuoconstructive problems, and poor action naming. Scores

on the depression inventory were significantly higher in

patients than controls, but depression did not account for

group differences in cognitive performance. The observed

pattern of neuropsychological impairment is indicative of

executive problems and parieto-temporal dysfunction. Neuro-

pathological and neuroimaging studies with FRDA patients

have reported only mild anomalies in cerebral hemispheres.

Thus, cognitive impairment in FRDA is probably caused bythe interruption of the cerebro-cerebellar circuits that have

been proposed as the anatomical substrate of the cerebellar

involvement in cognition.

Keywords Cerebellum . Cognition . Friedreich ataxia.

Neuropsychology

Introduction

Traditionally, the cerebellum has been regarded as a motor

mechanism, but this view of its function is being challenged

by observations from neuroanatomical, neuroimaging, and

neuropsychological studies, which suggest that it also plays

a role in cognitive activity [16]. Friedreich ataxia (FRDA) is

the most frequent syndrome of the cerebellar ataxias. It is

caused in more than 95% of cases by a homozygous triplet

GAA expansion in the first intron of the frataxin gene (FXN,

previously known as FRDA, X25) on chromosome 9q13,

while the remaining patients are compound heterozygotes

for a GAA expansion in the disease-causing range in one

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-

brane protein involved in iron distribution. Frataxin deficiency

causes iron accumulation in mitochondria, fundamentally in

cardiac muscle and in the cerebellar dentate nucleus [10],

which, in turn, produces mitochondrial dysfunction [11]. This

is probably what is responsible for the degenerative changes in

FRDA [9,12,13]. The neuropathological changes of FRDA

fundamentally involve the spinal cord, with degeneration of

posterior columns and spinocerebellar tracts, and the dentate

nucleus [13]. Pathological alteration of the cerebellum,

Electronic supplementary material The online version of this article

(doi:10.1007/s12311-012-0363-9) contains supplementary material,

which is available to authorized users.

A. Nieto (*) : R. Correia: E. de Nbrega:S. Hess :J. Barroso

School of Psychology, University of La Laguna,

38205, La Laguna, Tenerife, Spain

e-mail: [email protected]

F. Montn

Department of Neurology, Hospital N.S. La Candelaria,

S/C de Tenerife, Spain

Cerebellum (2012) 11:834844

DOI 10.1007/s12311-012-0363-9
http://dx.doi.org/10.1007/s12311-012-0363-9http://dx.doi.org/10.1007/s12311-012-0363-9


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especially the dentate nucleus, could interfere with cognition,

affecting cerebellarthalamiccortical loops [14,15].

Although established as the most common cerebellar atax-

ia, almost no attention has been paid to cognitive functions in

FRDA. Earlier studies in patients with clinical diagnosis of

FRDA have described deficits in several cognitive domains

such as information processing speed, executive and mnesic

functions, as well as some visuospatial and visuoconstructivefunctions [3,1619]. However, these studies were undertaken

prior to the identification of the FA mutations, or the clinical

diagnosis was not confirmed by genetic molecular analysis.

There are very few studies that examined the cognitive status

of patients with genetically defined FRDA and most of them

have investigated specific cognitive functions. Our group ex-

amined verbal fluency in genetically proven FRDA using

different word retrieval [20]. We observed phonemic and action

fluency impairments, suggesting a prefrontal dysfunction in

FRDA. Corben et al. described impairment in motor program-

ming [21] and Klopper et al. [22] reported deficits in sustained

volitional attention and working memory using the Test ofEveryday Attention [23]. To our knowledge, the only study

approaching a wide range of cognitive domains in FRDA is the

work published by Mantovan et al. [24]. In this study, 13

individuals with genetically proven FRDA were examined.

Patients showed slowed information processing, reduced verbal

span and visual memory, deficits in verbal fluency and alter-

ation in complex visuoperceptual and visuoconstructive abili-

ties. Nonetheless, the interpretation of these results might be

hampered by the fact that the FRDA group showed an average

IQ lower than controls and two patients had an IQ below

normal range. In addition, some conclusions reached by these

authors regarding specific cognitive functions (e.g., visual

memory, visuoconstructive abilities, concrete thinking, and

poor capacity in concept formation) are supported by data that

are not explicitly reported in their published manuscript.

In sum, given the current lack of results, more compre-

hensive neuropsychological explorations are needed to fur-

ther understand the cognitive impairment profile in FRDA.

Thus, our aim is to study these patientscognitive function-

ing in a wide range of cognitive domains, trying to mitigate

the possible effects of their motor disturbances on their

performance in neuropsychological tasks. In addition, we

examine a larger patient sample than that usually found in

FRDA studies, which might help to reduce inter-subject

variability in the neuropsychological data.

Methods

Participants

Thirty-six FRDA patients participated in this study. The

patients were consecutively recruited from the ataxia units

of three Spanish hospitals: Ntra. Sra. Candelaria Universi-

tary Hospital (S/C de Tenerife), Marqus de Valdecillas

Hospital (Cantabria), and La Paz Hospital (Madrid). All

patients fulfilled the diagnostic criteria of Friedreich ataxia

[25] and presented the molecular genotype of FRDA. They

presented a large homozygous GAA triplet-repeat expan-

sion in the first intron of the frataxin gene (X25, within the

critical region on chromosome 9). They showed progressiveataxia of limbs and gait, nystagmus, and dysarthria. Twenty-

nine patients had typical FA (age of onset before 25 years

old) and seven cases had late onset FA. The mean duration

of illness was 15.89 (SD08.63), and the mean age at disease

onset was 18.06 years (SD09.40) (Table 1). All patients

underwent a neurological examination. The Rankin Incapac-

ity and the Nobile-Orazio Ataxia scales were used to quan-

tify disease severity (score from 0normal to 5most

impaired) [26, 27]. A Clinical Rating Scale modified from

Appollonio et al. [28] was used to quantify seven cerebellar

signs (dysarthria, limb tone, postural tremor, upper and

lower limb ataxia, standing balance, and gait ataxia). Eachof these was assigned a score from 0 (normal) to 4 (most

Table 1 Demographic characteristics and clinical features of patients

and normal controls

FA patients

(n036)

Controls

(n031)

p

Mean (SD) Mean (SD)

Age 33.94 (12.23) 30.35 (8.34) 0.172

Education (years) 12.39 (4.09) 13.55 (3.23) 0.208

Sexa 20/16 17/14 0.953

Handednessb 32/4 29/2 0.505

MMSE 28.81 (1.30) 29.23 (1.05) 0.157

Information subtest 9.31 (3.36) 10.42 (2.50) 0.134

BDI 12.47 (10.27) 6.03 (6.31) 0.003c

Age at disease onset (years) 18.06 (9.40)

Disease duration (years) 15.89 (8.63)

Rankin Incapacity Scale 3.00 (0.89)

Nobile-Orazio Ataxia Scale 4.31 (1.01)

Appollonio CRS 13.47 (5.18)

A. CRS dysarthria 1.72 (0.81)

A. CRS limb tone 0.72 (0.75)

A. CRS postural tremor 0.32 (0.48)

A. CRS upper limb ataxia 1.96 (0.84)

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)

A. CRS oculomotion 1.95 (1.59)

CRSclinical rating scaleaSex (men/women)b Handedness (right/left)c Significant differences

Cerebellum (2012) 11:834844 835


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impaired). In addition, the following abnormalities in ocular

movements were each scored as 1 when present: dysmetria,

nystagmus in the horizontal or vertical plane, slowed or

absent saccades, and saccadic breakdown of pursuit. Total

scores on this scale ranged from 0 to 32; the higher the

score, the worse the dysfunction. Magnetic resonance imag-

ing was performed on every patient. MR images were clin-

ically assessed by an experienced neuroradiologist. Allpatients presented spinal cord atrophy, and two of them

presented mild cerebellar atrophy. Neither cerebral atrophy

nor focal lesions were observed.

The control group consisted of 31 subjects. Control par-

ticipants were free of neurological disease/injury, drug ad-

diction, and psychiatric illness histories. General cognition

was tested with a modified version of the Mini-Mental State

Examination [29]. The Information subtest of the Wechsler

Adult Intelligence Scale (WAIS)-III [30] was also adminis-

tered as a general intelligence estimation measure. Patient

and control groups did not differ with respect to age, level of

education, Mini-Mental State Examination (MMSE) score,and Information score (WAIS-III). Depression was assessed

by the Beck Depression Inventory (BDI) [31].

Both groups of participants were informed about the aim of

the investigation and participated voluntarily. All subjects

gave their informed consent. The data included in the manu-

script were obtained in accordance with the regulations of the

ethics committees of the University of La Laguna and in

compliance with the Helsinki Declaration for human research.

Materials

Participants completed an extensive battery of neuropsycho-

logical tests administered by an experienced clinical neuro-

psychologist over two sessions. Every session consisted of

2 h of assessment with a 20-min break between the first and

the second hour. Tests were chosen to examine cognitive

functioning in various cognitive domains (Table 2). In ad-

dition, all the tests were selected in such a way that no or

only limited movements had to be carried out by the patient.

Additionally, motor baseline tasks and statistical methods

were used to control for the differences in motor coordination

deficits, psychomotor slowness, and dysarthria. Only

nonstandard procedures will be described here.

Reaction Times Simple and choice reaction time tasks of the

Reaction Unit/Vienna System (RT) were used [32]. This

system permits the dissociation of the cognitive component

[decision time (DT)] and the motor component [motor time

(MT)]. Simple reaction time: A yellow light appeared ran-

domly, at which time the subject was instructed to remove

his/her index finger of the dominant hand from a rest button

and press another key as quickly as possible. Choice reac-

tion time: A red light appeared randomly in a background of

distractor stimuli. DT is the time interval between the ap-

pearance of the stimuli and release of the finger. MT is the

time interval between release of the finger and depression of

the second key. DT is a cognitive measure of information

processing speed. Motor time reflects motor and coordination

deficit [18]. Total reaction time is the sum of both components

(DT and MT).

Attention A computerized version of the Continuous Perfor-

mance Test-Identical pairs (CPT-IP) paradigm [33] was

administered in order to measure sustained attention. One

hundred fifty digits were auditory presented with an inter-

stimulus interval of 1 s. The subjects were instructed to

press the response button every time two identical letters

appeared consecutively (15% target stimuli). The total num-

ber of correct responses and omiss ion and commission

errors were obtained. Selective attention was assessed with

the Stroop Color and Word Test [34]. This Stroop Test

version includes an index to assess the interference related

to the wordcolor conflict by comparing the subjects per-

formance in the third sheet (WordColor), with the same

Table 2 Neuropsychological test administered grouped by cognitive

domains

Global screening

Mini-Mental State Examination (MMSE)

Information Subtest (WAIS-III)

Becks Depression Inventory (BDI)

Reaction Time, Attention, and Working Memory (WM)

Simple Reaction Time (Pc-Vienna System)

Choice Reaction Time (Pc-Vienna System)

Continuous Performance Test (CPT-IP)

Stroop Word and Color Test

Digit Span (WMS-III)

Spatial Span (WMS-III)

Executive functions

Wisconsin Card Sorting Test (WCST)

Similarities Subtest (WAIS-III)

Verbal fluency (FAS, animals, and actions)

Memory and learning

Logical Memory (WMS-III)California Verbal Learning Test (CVLT)

10/36 Spatial Recall Test (10/36 SRT)

Visuoperceptive, visuospatial, and visuoconstructive abilities

Judgment Line Orientation Test (JLOT)

Facial Recognition Test (FRT)

Minnesota Test

Block Design (WAIS-III)

Language

Noun and action naming

Anaphora comprehension

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subjects performance in the other two neutral conditions

(Word and Color sheets). To calculate the interference index

(I), it is first required to calculate an expected score (ES)

from subjects performance in the word and the color con-

ditions [ES 0 (word color)/(word + color)] and then to

calculate the interference index by subtracting the expected

score from number of corrected responses emitted in the

third condition (I 0wordcolor ES).Working memory was tested with digit span and spatial

span [forward and backwards; Wechsler Memory Scale

(WMS-III)] [35].

Executive functions were tested with the Wisconsin Card

Sorting Test (WCST) [36], Similarities subtest of the WAIS-

III [30], and Verbal fluency tasks. These tasks consist of

asking the participants to rapidly generate words beginning

by a given letter (phonemic fluency FAS) [37], to generate

only animals (semantic fluency), and to rapidly generate verbs

(action fluency) [38].

Verbal memory was tested with the Logical Memory

subtest (immediate and delayed free recall and recognitionof two prose passages) of the WMS-III [35] and the Spanish

adaptation of the California Verbal Learning Test (learning

over five-trial presentation of a 16-word list, free and cued

delayed recall, recognition) [39, 40]. Visual memory was

tested with a modified 10/36 Spatial Recall Test (10/36)

[41], a spatial memory test that does not require good motor

control. A ten-dot pattern was displayed on a 66 grid.

Participants studied this arrangement for 10 s. Afterwards,

the pattern was removed and the participants reproduced it

from memory on an empty grid using poker chips. This

learning task continued over five trials and delayed visual

recall was assessed at 30 min. Visual recognition was mea-

sured employing a forced choice procedure in which four

grids with ten-dot patterns were presented. The participants

attempted to pick the grid with the correct pattern. This

forced choice procedure was given twice.

Visuoperceptiveskills were tested with the Facial Recog-

nition Test (FRT) [42]. Abbreviated versions of the Judg-

ment of Line Orientation Test (JLOT15 items) [42] and a

task of mental spatial rotation, the Minnesota Paper Form

Board Test [43], were used to assess visuospatial function-

ing. Finally, for the assessment of visuoconstructive skills, a

Modified Block Design subtest of the WAIS-III was select-

ed. This subtest was administered as described in the manual

[30] except that if the design was not correctly completed

within the standard administration time, we allowed the

subject to work on the problem for one extra minute. The

number of correct blocks was recorded without any kind of

speed credits in order to take into account the motor deficits

of patients. A motor baseline task was also administered and

execution time was recorded. This task was equivalent to the

original Block Design Test in motor demand but had mini-

mal perceptive and planning requirements. It consisted of

making two designs, one four-block design and one nine-

block design, with all the red faces of the blocks at the top.

Language was assessed with a naming task by visual

confrontation of pictorial stimuli and an anaphora comprehen-

sion task. These tasks were designed by our group with the aim

of measuring both language production and comprehension.

The naming task consists of 40 stimuli representing elements

(noun naming) and 20 stimuli depicting action scenes (actionnaming). Nouns and actions were paired in those variables

known to affect naming: every action item was paired with

two noun items in word frequency [44] and nominal agreement

[45]. Stimuli are line drawings of objects in black and white,

taken from the work of Cuetos et al. [46], from the Interna-

tional Picture Naming Project [47] and the materials of Druks

and Masterson [48]. Stimuli presentation was computerized

using E-Prime v1.1 [49]. The participants were instructed to

recall the name of the concept represented (either the noun

corresponding to the element drawn or the verb corresponding

to the action depicted). Hits were recorded.

The anaphora comprehension task consisted of 20 senten-ces with anaphoric expressions, ten non-ambiguous and ten

ambiguous. Ambiguity is defined in terms of gender, thus

when it is possible to discriminate the antecedent based solely

on its gender, the anaphora resolution is easier than when there

is more than one word in the sentence which agrees in gender

with the anaphoric pronoun. Thus, in our design, we consider

two types of pronominal anaphora: (1) non-ambiguous, in

which the anaphora is resolved by the gender key (e.g., Alba

gave a painkiller to Eduardo as he had a headache) and (2)

ambiguous, where gender does not solve the ambiguity, re-

quiring a semantic interpretation of the sentence to solve

it (e.g., Alba gave a painkiller to Mercedes as she had a

headache). Since pronominal anaphors are very common lin-

guistic expressions that give coherence and continuity to

speech, the aim of this task is to assess the ability to make

the necessary inferences to comprehend sentences involving

anaphora. All sentences were presented in auditory format by

E-Prime computer software. Participants were instructed to

listen to a series of sentences and to look at the computer

screen where two words would appear during each sentence

auditory presentation. These words correspond to the charac-

ters in the opening sentence, that is, the subject (Alba) and the

object (Eduardo) of the sentence. After each sentence presen-

tation, the participants were asked to answer a question re-

garding either the subject (Who gave a painkiller?) or the

object (Who had a headache?) of the sentence. Responses

were registered by means of a two-button panel and partic-

ipants were instructed to press the button corresponding to the

correct answer (either right button if the correct answer is the

word present at the right side of the screen or left button for the

word at the left side). In some cases, due to motor impairment,

the patients responded orally and the tester registered the

response. We recorded the number of hits and errors.

Cerebellum (2012) 11:834844 837


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Data Analysis

All the statistical analyses were performed with Statistical

Package for Social Sciences (SPSS, Chicago, IL) version

15.0 for Windows. Groups were compared using univariate

and repeated measures analysis of variance (ANOVA), ort

test where appropriate. Violations of equality of variance

between groups were established using Levenes test, andthus, Welch correction was used when necessary. Statistical

significance was taken as p0.05 and Bonferroni test cor-

rection was applied to account for multiple comparisons

among means within each task, adjusting the to /n,

where n is the number or comparisons performed [50].

Analysis has been performed to account for the effect of

possible covariables. Correlations between variables were

determined by Pearsons coefficientr.

Results

Reaction Time, Attention, and Working Memory

As Table3shows, significant differences were found in both

decision and motor reaction times. In contrast, there were no

significant differences in any of the CPT accuracy measures,

Digit, and Spatial Span Tests.

With regard to subjects performance in the Stroop Test,

FRDA patients significantly differed from the controls in the

three task trials (word, F(1, 62)073.25,p


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dysarthria score from the Appollonio Clinical Rating Scale

and the patients performance on every verbal fluency task.

Only action fluency showed a significant correlation (FAS,

r00.219, p00.206; animal, r00.294, p00.087; action,

r00.333,p00.050). However, it did not show a significant

effect as a covariable when the subsequent analysis of

covariance (ANCOVA) was performed [F(1, 63)03.168,

p00.080]. On the other hand, we decided also to dividethe FRDA group into patients without dysarthria or with

only mild dysarthria (non-dysarthric patients) and patients

with moderate or severe dysarthria according to the dysar-

thria item of the Appollonio Clinical Rating Scale. Perform-

ances on fluency measures were reanalyzed for control

participants and non-dysarthric FRDA. These two groups

did not significant differ in age, education, and MMSE.

Non-dysarthric FRDA patients also performed significantly

worse than controls in the three verbal fluency measures

(Table5).

In addition, although moderate and significant correla-

tions were found between total reaction time and each of theverbal fluency measures (FAS, r00.463,p00.001; animal,

r00.330, p00.020; action, r00.430, p00.002), total re-

action time did not show a significant effect when subse-

quent ANCOVA was performed [FAS, F(1, 46)01.327,p 0

0.255; animal,F(1, 46)00.790,p 00.379; action,F(1, 46)0

1.541, p00.221]. Thus, reaction time does not explain

between-groups differences in verbal fluency measures.

Memory and Learning

Patients scored significantly worse than controls on imme-

diate in the Logical Memory subtest. Although they also

scored worse on the delayed recall, there were no significant

differences between groups on the retention percentage and

the recognition trial of this subtest. Significant differences

between patients and controls were also found on cued short

delay recall in California Verbal Learning Test (CVLT). No

significant differences were found between groups on visual

memory measures (Table6).

Visuoperceptual, Visuospatial, and Visuoconstructive

Abilities

As shown in Table7, FRDA patient scores were significantly

lower than the controls only in FRT. In addition, there was no

significant correlation between the FRT score and the presence

of oculomotor disturbances assessed by the Appollonio

Clinical Rating Scale (r00.128, p00.838).In the Block Design subtest, we found significant

between-groups differences on both standard and extended

time conditions (Table8). As suggested by Lezak et al. [51],

we grouped trials in easy and complex designs and found

that FRDA patients had significantly poorer performance

than controls in the complex but not the easy designs

(Table 8). Significant between-groups differences were

also found on the baseline motor task administered.

Moreover, performance in this control task correlated

with accuracy in total (r00.568, p


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comprehension task. There was a significant effect of the

within-subjects variable anaphora ambiguity [F(1, 56)0

30.908, p


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color instead of reading the word printed) but also in the

reading and color naming conditions. Moreover, when in-

terference indices were calculated and groups were compared,

no significant differences were found between them. Thus,

impaired performance on Stroop trials might be interpreted as

the result of reduced processing speed or dysarthric speech

rather than due to a selective attention deficit.

FRDA patients and controls performed similarly inWCST. However, patients showed poor performance in the

similarities test, indicating verbal concept formation prob-

lems. Although this result could be attributed to a global

intellectual deficit, FRDA patients did not differ from the

controls in their IQ estimated from the Information subtest

scores. Therefore, this result seems to be a deficit circumscribed

to verbal conceptual thinking.

Patients showed a diminished verbal fluency perfor-

mance at the three modalities assessed. Although verbal

fluency tasks are good measures of executive functioning,

performance can also be affected by articulatory problems

and slowed processing speed. Regarding the first confound-ing factor, the two different approaches followed converged

in showing significant differences between FRDA patients

and controls, even after dysarthria effects were controlled.

Regarding the second one, processing speed was not a

significant covariant when ANCOVA analyses were per-

formed. Taking into account these results, it could be con-

sidered that FRDA patients showed a primary verbal fluency

deficit that could not be explained by either dysarthria or a

generalized slowing.

In regards to memory, FRDA patients showed poor per-

formance on immediate and delayed recall of prose texts.

However, since nonsignificant differences were found be-

tween patients and controls in the retention percentage,

differences observed in delayed recall seem to be better

explained by previous poor acquisition. The results on

CVLT showed that patients preserved the ability to learn

lists of words but presented difficulties in cued delayed

recall. In this last trial, the examiner asks the subject to

recall items by each of the categories of the word list (tools,

fruits, spices, and clothes). The impaired performance on

cued recall suggests that patients failed to benefit from this

cueing, indicating difficulties in the use of semantic associ-

ations as a strategy to retrieve stored information. Visual

learning and memory, as assessed by 10/36 Spatial Recall

test, is preserved in FRDA patients.

Comparable performances of patients and normal con-

trols on JLOT and Minnesota Test were obtained, suggesting

unimpaired visuospatial functioning in FRDA. On the con-

trary, patients showed poorer performance than controls onFRT. The lack of a significant correlation between FRT and

ocular motor scores and the fact that other tasks involving

visual analysis are correctly performed, suggest that ocular

motion impairment is not playing a determinant role in FRT

impairment. Patients also showed a poor performance on

block design. The interpretation of block design results in

cerebellar ataxia (as in any other movement disorder) is

always complicated. We have designed an assessment pro-

cedure (including baseline motor trials, softening time

restrictions, and eliminating time credits) and performed

different statistical analysis to address this issue and to try

to clarify the interpretation of results. So, although we didnot give time credits and increased the time for the task

execution by an extra minute, FRDA patients showed im-

paired performance in the block design. Therefore, FRDA

deficits in this task cannot be solely explained by the speed

requirements. In addition, administering a baseline motor/

manipulative task allowed us to show that the motor/manip-

ulative component does not account for the poorer perfor-

mance of patients in the block design. Thirdly, we

distinguished between easy and complex design in terms

of their visuoperceptivevisuoconstructive complexity, and

patients and controls only differed significantly in those

more complex designs. Finally, given the visuoperceptive

difficulties assessed with FRT, we studied the possible rela-

tionship between this impairment and performance in the

block design task. There was no significant relationship

between both variables. Therefore, after following the pro-

cedure depicted above, it seems that the impaired FRDA

patient performance in block design is not due to motor

slowness, coordination, nor visuoperceptive deficits. More-

over, the fact that significant differences appear only in

complex designs suggests an impairment of the components

related to structuring and organizing the materials and planning

the visuoconstructive task.

With respect to language, our assessment protocol includes

a naming task where participants are required to name both

nouns and actions and an anaphora comprehension task.

FRDA patients and controls did not differ significantly in

nouns but they did in action naming. In addition, while the

performance of the control group is comparable between both

naming conditions, patients showed a significantly lower per-

formance in action compared to noun naming. These FRDA

patients difficulties in naming by visual confrontation of

pictorial stimuli are not related to visuoperceptive deficits.

Fig. 1 Performance by FRDA patients and normal controls on nouns

and actions naming tasks

Cerebellum (2012) 11:834844 841


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Regarding the comprehension task, patients solved correctly

both non-ambiguous and ambiguous anaphora to comprehend

the meaning of the sentences presented.

In sum, FRDA patients showed slowed processing speed,

impaired concept formation and verbal fluency, deficits in

acquisition of verbal information and use of semantic strate-

gies in retrieval, visuoperceptive and visuoconstructive prob-

lems, and poor action naming. Attentional functions, workingmemory, visual memory, and language comprehension are

preserved.

In general, the cognitive deficits observed in the present

study are in line with those observed in previous studies about

cognitive performance in genetically confirmed FRDA

patients. Impaired information processing speed is a consis-

tent result in the scarce cognitive research on FRDA [20,21,

24]. Our results are also concordant with reports regarding

impairment in concept formation, verbal fluency, and visuo-

perceptive and visuoconstructive functions [20,24]. In addi-

tion, the procedures followed in our study allowed us to

explore more deeply explanations for task results with adifficult interpretation such as verbal fluency or visuocon-

structive skills. Regarding declarative memory, the only study

that has examined memory performance in FRDA reported a

poorer overall performance (memory quotient) but did not

report differences between FRDA patients and control partic-

ipants in specific memory tasks [24]. Action naming has not

been studied to date, but the preservation of noun naming is in

line with results obtained by Mantovan et al. [24].

On the other hand, the preservation of working memory

and attention is partially discrepant with results obtained in

previous studies. Impairment in verbal working memory, as

assessed by digit tasks, was reported by Mantovan et al. [24],

but in that study, patients presented an average IQ lower than

controls and 2 of 13 patients had an IQ below normal average.

Attention is a complex function that consists of different

subsystems that perform different but interrelated functions

[52]. In the present study, we focused on two of these sub-

systems: selective attention and sustained attention. Selective

attention, conceptualized as the capacity to select relevant

stimuli and inhibit irrelevant ones, was assessed with the

Stroop Test. In agreement with Corben et al. [21], FRDA

patients were not impaired. Mantovan et al. [24] reported a

different result. However, they used a modification of the

Stroop paradigm that does not actually examine selective

attention but the perception of the consistency or inconsisten-

cy between stimuli features. Sustained attention, the ability to

self-sustain attention in the absence of external manipulators

of attention such as novelty, was assessed with a paradigm of

CPT-IP. FRDA patients showed a preserved performance in

this task. To our knowledge, no other study has used a CPT

paradigm to assess sustained attention in FRDA before.

Klopper et al. [22] reported sustained attention deficit in

this clinical population based on their impaired performance

in the Test of Everyday Attention [23]. Nonetheless, the tasks

included in Kloppers work have an important switching

attention component [53,54] or a considerable working mem-

ory load. In fact, the only task included considered to be a pure

sustained attention measure is the elevator counting condition

[5356] where FRDA patients had a preserved performance.

Therefore, in our opinion, the ability to self-sustain attention is

not a characteristic deficit of FRDA but difficulties might arisein more complex tasks where other cognitive processes (work-

ing memory, flexibility, switching, etc.) are also involved.

Impairment observed in conceptual thinking and verbal

fluency is indicative of deficits in prefrontal functions, at least

in its executive component. The characteristics of other deficits

showed by FRDA patients, in the present study, also suggest an

interpretation in terms of executive dysfunction. Whereas

patients showed a good performance in immediate recall of

the words list of the CVLT, they were impaired on the imme-

diate recall of texts. This suggests that difficulties in text recall

may be due to an inappropriate use of organizing strategies for

encoding the abundant information contained in the texts. Inaddition, problems with the proper use of semantic strategies to

retrieve a list of words seem also to be the cause of the poor

performance in CVLT delayed cued recall. On the other hand,

visuoperceptive and visuoconstructional impairments are in-

dicative of a dysfunction in right temporo-parietal systems [42,

51]. In addition, the fact that poor performance in block

designs was observed only in more complex designs points

to a difficulty in self-generating strategies for problem solving

and a lack of the flexibility needed to perceive components of a

gestalt and then integrate them as a particular block arrange-

ment. All these results are indicative of impairments in the

more executive components of these different tasks. In agree-

ment with this, results in naming tasks indicate that patients

have difficulties only in action naming, a task that has been

especially associated with frontal lobe functioning [5759].

There is converging evidence from anatomical, physio-

logical, and clinical approaches to recognize the cerebellum

as a critical component of the distributed neural circuits

subserving cognition [60]. Inputs to the cerebellum arise

from multiple cortical areas, such as the frontal, parietal,

and temporal lobes. Outputs from the deep cerebellar nuclei

project to a diverse set of thalamic nuclei and, in turn, these

nuclei project to cortical areas other than the motor cortex

[1, 61, 62]. Particularly, prefrontal and parietal areas are

cortical targets of cerebellothalamocortical pathway from

the dentate nucleus [6365]. This deep cerebellar nucleus is,

precisely, the one especially affected in FRDA, showing

increased iron and severe neuronal degeneration. Thus, the

deficits shown by FRDA patients may relate to the disruption of

cerebro-cerebellar circuits, especially those linking cerebellum

with prefrontal and parieto-temporal cortex.

Another explanation for these deficits is that they are

caused by a primary cerebral damage. Similarly to the neurons

842 Cerebellum (2012) 11:834844


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of the dorsal root ganglia, spinal cord, or dentate nucleus,

other neural systems may be affected by the frataxin deficien-

cy, although in a subtler way [24]. There are some neuropath-

ological reports of atrophy of cerebral gyri, but these changes

were considered as secondary to hypoxia resulting from epi-

sodes of heart failure [66, 67]. Lamarche [68] examined

postmortem material from six FRDA cases and he found no

neuropathological changes in cerebral cortex. Neuroimagingstudies of FRDA with genetic diagnosis have reported mild

white matter anomalies in cerebral hemispheres, but volume

loss in gray matter has not been observed [6971]. Thus, while

the possibility of a primary cortical dysfunction is interesting,

further studies are needed to support this interpretation.

Conclusions

The findings of the present study demonstrate mild cognitive

impairments in a large sample (n036) of patients with FRDA

genetically confirmed. Impairments were observed in process-

ing speed, conceptual thinking, verbal fluency, acquisition of

verbal information, use of semantic strategies in retrieval,

visuoperceptive and visuoconstructive functions, and action

naming. These deficits cannot be attributed to motor impair-

ment or depressed mood. Taken together, these results point to

a dysfunction of prefrontal and temporo-parietal systems that

may be caused by the affectation of the cerebro-cerebellar

circuits proposed as the anatomical substrate of the

cerebellums involvement in cognition.

Acknowledgments The authors thank Dr. Berciano (Hospital Marques

de Valdecillas, Santander) and Dr. Arpa (Hospital La Paz, Madrid) for

providing access to patients and for their helpful assistance. They also

thank Margaret Guillon for linguistic review of the manuscript. This

research has been partially supported by a research grant from Ministerio

de Ciencia e Innovacion (PSI2011-24665) and Proyecto Estructurante

Neurocog, financed by the ACIISI and cofinanced by FEDER funds and

the University of La Laguna.

Conflict of Interest The authors declare that they have no competing

personal or financial interests.

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