Specific cerebellar and cortical degeneration correlates with ataxia severity in spinocerebellar ataxia type 7

Abstract

Spinocerebellar ataxia type 7 (SCA7) is a progressive neurodegenerative disorder that is accompanied by loss of motor control and macular degeneration. Previous studies have shown cerebellar and pons atrophy as well as functional connectivity changes across the whole brain. Although different MRI modalities have been used to study the degenerative process, little is known about the relationship between the motor symptoms and cerebral atrophy. Twenty-four patients with molecular diagnosis of SCA7 where invited to participate in this study. Ataxia severity was evaluated using the scale for the assessment and rating of ataxia (SARA). Structural magnetic resonance imaging (MRI) brain images were used to obtain the grey matter volume of each participant. As expected, we found a significant negative correlation between the SARA score and the grey matter volume in distinct regions of the cerebellum in the patient group. Additionally, we found significant correlations between the ataxia degree and the degeneration of specific cortical areas in these patients. These findings provide a better understanding of the relationship between gray matter atrophy and ataxia related symptoms that result from the SCA7 mutation.

Full text

BRIEF COMMUNICATION
Specific cerebellar and cortical degeneration correlates
with ataxia severity in spinocerebellar ataxia type 7
Carlos R. Hernandez-Castillo
1
&Victor Galvez
2
&Rosalinda Diaz
3
&
Juan Fernandez-Ruiz
2,3
#Springer Science+Business Media New York 2015
Abstract Spinocerebellar ataxia type 7 (SCA7) is a progres-
sive neurodegenerative disorder that is accompanied by loss
of motor control and macular degeneration. Previous studies
have shown cerebellar and pons atrophy as well as functional
connectivity changes across the whole brain. Although differ-
ent MRI modalities have been used to study the degenerative
process, little is known about the relationship between the
motor symptoms and cerebral atrophy. Twenty-four patients
with molecular diagnosis of SCA7 where invited to participate
in this study. Ataxia severity was evaluated using the scale for
the assessment and rating of ataxia (SARA). Structural mag-
netic resonance imaging (MRI) brain images were used to
obtain the grey matter volume of each participant. As expect-
ed, we found a significant negative correlation between the
SARA score and the grey matter volume in distinct regions of
the cerebellum in the patient group. Additionally, we found
significant correlations between the ataxia degree and the de-
generation of specific cortical areas in these patients. These
findings provide a better understanding of the relationship
between gray matter atrophy and ataxia related symptoms that
result from the SCA7 mutation.
Keywords Spinocerebellar ataxia .Motor impairment .
VBM .Cerebellum .Precentral gyrus
Background
Spinocerebellar ataxia 7 (SCA7) is a neurodegenerative
disorder caused by the abnormal expansion of the
cytosine-adenine-guanine (CAG) trinucleotide encoding
the protein ataxin7 (Garden and La Spada 2008). SCA7
is characterized by a combination of cerebellar ataxia and
macular degeneration that causes permanent blindness
(Michalik et al. 2004; Miller et al. 2009). Furthermore,
patients may eventually develop other neurological defi-
cits, including loss of manual dexterity, speech dysar-
thria, dysphagia and eye movement abnormalities
(Hugosson et al. 2009). Brain atrophy associated with
SCA7 has been documented in different neuropathologi-
cal studies using both postmortem and imaging tech-
niques. These techniques have identified severe neuronal
loss in a broad range of cerebellar and cerebral regions,
including the cerebellar cortex, the inferior olivary com-
plex tracts, the subthalamic nucleus, the pallidum, and
the substantia nigra. SCA7 is also associated with degen-
eration of cortical regions such as the pre/postcentral
gyri, cuneus, precuneus, inferior occipital gyrus, insula,
and inferior frontal gyrus (Alcauter et al. 2011;Bang
et al. 2004; Döhlinger et al. 2008; Hernandez-Castillo
et al. 2013; Masciullo et al. 2007). Resting state func-
tional magnetic resonance imaging (fMRI) techniques
have been used to analyze the effect of SCA7 related
degeneration on functional connectivity patterns, finding
synchrony changes between degenerated and non-
degenerated areas across the brain (Hernandez-Castillo
et al. 2013,2014). However, there is a lack of
Electronic supplementary material The online version of this article
(doi:10.1007/s11682-015-9389-1) contains supplementary material,
which is available to authorized users.
*Juan Fernandez-Ruiz
jfr@unam.mx
1
Consejo Nacional de Ciencia y Tecnología –Cátedras - Instituto de
Neuroetologia, Universidad Veracruzana, Xalapa, México
2
Instituto de Neuroetologia, Universidad Veracruzana,
Xalapa, México
3
Departamento de Fisiología, Facultad de Medicina, Universidad
Nacional Autónoma de México, Distrito Federal, México
Brain Imaging and Behavior
DOI 10.1007/s11682-015-9389-1

information regarding the relationship between brain at-
rophy and the motor impairments in SCA7. Therefore,
we correlated gray matter volume in specific brain areas
targeted by SCA7 pathology with measures of ataxia
severity using the scale for the assessment and rating of
ataxia (SARA) in a large set of people with SCA7.
Methods
Participants
Twenty-four patients with a molecular diagnosis of SCA7 and
a CAG expansion higher than 40 participated in this study (11
female; right-handed; mean age/SD, 39.4/14.7 years). Motor
impairment was measured using the Scale for the assessment
and rating of ataxia (SARA) (Schmitz-Hübsch et al. 2006).
The SARA has eight items, including tests of gait, stance,
sitting, and speech, as well as the finger-chase test, finger-
nose test, fast alternating movements, and heel-shin test. The
control group consisted of 24 healthy volunteers that were
matched for age and sex to the SCA7 group (Further
demographic information of the two groups can be found
in supplementary Table 1). The procedures carried out were
in accordance with the ethical standards of the committees
on human experimentation of the Universidad Nacional
Autonoma de Mexico.
Image acquisition
All images were acquired using a 3.0-T Achieva MRI scanner
(Phillips Medical Systems, Eindhoven, The Netherlands) at
the Instituto Nacional de Psiquiatria BRamon de la Fuente
Muñiz^in Mexico City. The high-resolution anatomical ac-
quisition consisted of a 3-D T1 Fast Field-Echo sequence,
with TR/TE of 8/3.7 ms, FOVof 256×256 mm, and an acqui-
sition and reconstruction matrix of 256×256, resulting in an
isometric resolution of 1×1×1 mm.
Voxel-based morphometry
Gray matter volume measurements were performed using
voxel based morphometry (VBM) (Ashburner and Friston
2000) implemented on FSL (Smith et al. 2004). First, voxels
that did not represent cerebral tissue were excluded. Then,
tissues were segmented into grey matter, white matter, and
cerebrospinal fluid. The images corresponding to the gray
matter were aligned to Neurological Institute of Montreal
MNI152 standard space by means of a nonlinear co-registra-
tion. The average of these co-registered images was obtained
to generate a specific standard for this study. The individual
gray matter images were co-registered to this specific standard
space through a non-linear co-registration, and local changes
in expansion or contraction were corrected through a process
known as modulation (Good et al. 2002). Smoothing was
applied with a Gaussian isotropic kernel with a sigma of
2 mm. Using the FSL randomise tool, (Winkler et al. 2014)
atwo-samplettest was performed between the SCA7 group
and controls . Significance was defined as p<0.05 after
correcting for multiple comparisons using the randomized per-
mutation method (Hayasaka and Nichols 2004). For the SCA7
group, whole-brain correlation maps were created by calculat-
ing the Pearson’s partial correlation between the gray matter
volume (GMV) and SARA scores. Since prior studies using
imaging measures have described age-associated changes
across the cerebral cortex (Raz 1997; Salat et al. 2004), we
included the age data in the partial correlation. The standard-
ized SCA7 GMV images were loaded in MATLAB 2014a
(The Mathworks, Inc., Natick, MA) and a voxelwise partial
correlation were calculated using in-house functions. Partial
correlation maps were corrected for multiple comparisons by
using the false discovery rate (FDR) with a pvalue< 0.05. For
every significant cluster in the final map, GMV values were
extracted for each participant using a Bsphere^of 15 voxels
centered in the peak correlation voxel.
Results
The VBM analysis showed extensive regions of decreased
brain volumein patients with SCA7 in comparison to controls,
involving both neocortical and allocortical regions. As previ-
ously reported, the right anterior cerebellum showed the
greatest amount of atrophy, followed by the left posterior cer-
ebellum. Other regions showing gray matter decreases in the
SCA7 group compared to controls were the cuneus,
precuneus, pre/post central gyri, inferior frontal gyrus, and
temporal regions (Fig. 1a).
Significant negative correlations were found between
GMV and SARA scores in the SCA7 group (Table 1and
Fig. 1b). These regions include the bilateral anterior and pos-
terior cerebellum, the left parahippocampal gyrus, bilateral
precentral gyri, bilateral cingulate gyri, bilateral insula, and
bilateral inferior frontal gyri. Scatter plots of the significant
correlations are shown in the supplementary Fig. 1.
Discussion
In this study we analyzed the relationship between gray matter
loss and SARA scores in people with SCA7. As expected,
significant negative correlations between SARA scores and
GMV were found in the cerebellum and precentral gyri, but
also in the parahippocampal, cingulate, insular and inferior
frontal cortices.
Brain Imaging and Behavior

The cerebellum, which is fundamental for movement and
balance (Middleton and Strick 1998), is the most structurally
affected region in SCA7 (Alcauter et al. 2011; Horton et al.
2013). Different studies have shown motor deficits after dam-
age to the cerebellum (Schmahmann 2014). A number of
SCAs studies including SCA1 and SCA7 have reported that
the extent of cerebellar neurodegeneration correlates with a
variety of clinical motor features, like ataxia scores and extra-
pyramidal signs (Goel et al. 2011; Lasek et al. 2006; Reetz
et al. 2011). Our results show a significant correlation between
ataxia severity and decreased GMV in the anterior and poste-
rior cerebellar hemispheres, bilaterally. Previous studies have
measure the amount of cerebellar atrophy in SCA7 (Alcauter
et al. 2011;Hernandez-Castilloetal.2013), but our results
show for the first time the close relationship between cerebel-
lar volume and the motor impairment in people with SCA7.
A number of cortical areas where GMV correlated with the
SARA score could reflect the motor deficits in gait and gen-
eral movement in people with SCA7 (Martin 2012). As ex-
pected, based on previous volumetric studies, volume of the
precentral gyrus showed significant correlation with higher
SARA scores in the SCA7 group. Another region where
GMV correlated with SARA scores was the anterior cingulate
cortex. This region has been related to emotional self-control,
Fig. 1 Comparison of brain
regions showing gray matter
atrophy and SARA-GMV
correlation. aSignificant gray
matter atrophy in patients
compared with controls; b
significant partial correlations
between patients’GMV and
SARA controlling for age. Warm
colors indicate for a)thetvalue
and b) the Pearson’spartial
correlation coefficient pr value.
Parametric maps corrected at
p<0.05 (see Methods)
Tab l e 1 Significant correlations between gray matter volume and
SARA score
Anatomical region X Y Z pr BA
Right anterior cerebellum culmen 22 −62 −22 −0.817 –
Left parahippocampal gyrus −24 −56 −4−0.805 19
Left precentral gyrus −46 −432−0.799 6
Right cingulate gyrus 4 20 40 −0.793 32
Right insula 36 18 8 −0.773 13
Right precentral gyrus 32 −12 52 −0.761 4
Left anterior cerebellum culmen −30 −52 −18 −0.759 –
Right precentral gyrus 60 12 4 −0.742 44
Right posterior cerebellum tonsil 24 −52 −46 −0.740 –
Right inferior frontal gyrus 38 30 −14 −0.725 47
Left cingulate gyrus −14 −34 38 −0.724 –
Right inferior frontal gyrus 54 10 26 −0.723 9
Left insula −32 8 12 −0.696 13
Left posterior cerebellum semi-lunar −30 −68 −44 −0.640 –
Coordinates for peak correlations in MNI space in mm. Anatomical
regions and BA were obtained using Talairach daemon
BA Brodmann Area
p<0.05 FDR corrected
Brain Imaging and Behavior

focused problem solving, error recognition, and adaptive re-
sponse to changing conditions, and is also known to have
numerous projections to motor systems (Allman et al. 2006).
The motor areas of the cingulate cortex have connections not
only to the spinal cord and red nucleus, but also to the primary
motor cortex and the supplementary motor area (Devinsky
et al. 1995). Patients with lesions in this area often show def-
icits in spontaneous initiation of movement and speech, as
well as inability to suppress externally triggered motor sub-
routines (Paus et al. 2001). Like the cingulate and primary
motor cortices, insula GMV also correlated with SARA
scores. Structurally, the anterior insular cortex is connected
with limbic and paralimbic regions including the anterior cin-
gulate area and anterior inferior frontal cortex, whereas the
posterior insula cortex is more densely connected with poste-
rior temporal, parietal, and frontal areas including somatosen-
sory, motor, and premotor cortices (Cerliani et al. 2012;Jakab
et al. 2012). Moreover, the insula also supports pre-
articulatory functions of speech motor control such as the
Bprogramming^of vocal tract gestures (Ackermann and
Riecker 2004). Another region where GMV correlates with
SARA scores was the inferior frontal cortex. This area con-
tributes to different cognitive processes including decision
making, response inhibition, stimulus-based switching of at-
tention (Freedman 1998;Szatkowskaetal.2007), as well as
performance on go/no go tasks (Aron et al. 2003). Aside from
response inhibition (Swick et al. 2008), the left inferior frontal
gyrus is extremely important for language production and
verb comprehension (Costafreda et al. 2006). Overall, loss
of gray matter volume in these areas probably represents an
advanced stage of the neurodegenerative process, the clinical
consequences of which are gait, speech, and coordination def-
icits that worsen with disease progression.
The significant correlation between SARA scores and
GMV found in the left parahippocampal gyrus was unexpect-
ed. This area has been associated with many cognitive pro-
cesses, including visuospatial processing and episodic mem-
ory (Aminoff et al. 2013). For example, the parahippocampal
gyrus is involved in the visuospatial storage of stimulus rep-
resentations across long delays (Maguire et al. 2003)andin
the production of allocentric sense of position. Lesions in this
region can lead to topographical disorientation (Aguirre et al.
1996; Bohbot et al. 1998). Taking into account that the
parahippocampal area is affected in different subtypes of
SCAs such SCA2, SCA6, SCA7 (Hernandez-Castillo et al.
2013;Ishikawaetal.1999;Mercadilloetal.2014) and that
it has been related to the progression of motor symptoms in
SCA17 (Reetz et al. 2010), we believe that its possible in-
volvement in the ataxia severity should be explored further.
Finally, it is important to note that significant decreases in
GMV in the SCA7 group compared to controls were found in
other brain regions including the occipital, parietal and tem-
poral cortices (Fig. 1a). However, in those cases GMV loss did
not correlate with SARA scores (Fig. 1b), suggesting that not
all the areas that degenerate during the SCA7 course are relat-
ed to ataxia severity.
Conclusion
Our results show specific brain regions where GMV correlates
with the severity of ataxia in SCA7. All of these regions, with
the exception of the parahippocampal cortex, are closely re-
lated to movement coordination and speech deficits that pa-
tients with SCA7 usually develop. Our results provide novel
and relevant information for the understanding of SCA7.
Acknowledgments This study was supported in part by: Universidad
Nacional Autonoma de Mexico (PAPIIT IN221413) and Consejo
Nacional de Ciencia y Tecnologia (220871) grants to Juan Fernandez
Ruiz, as well as the National Ataxia Foundation (USA) grant to Carlos
R. Hernandez-Castillo.
Conflict of Interest Carlos R. Hernandez-Castillo, Victor Galvez,
Rosalinda Diaz, and Juan Fernandez-Ruiz declare that they have no con-
flicts of interest.
Informed consent All procedures followed were in accordance with
the ethical standards of the responsible committee on human experimen-
tation (institutional and national) and with the Helsinki Declaration of
1975, and the applicable revisions at the time of the investigation.
Informed consent was obtained from all patients for being included in
the study.
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