Journal of the Neurological Sciences 310 (2011) 70–74

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Journal of the Neurological Sciences

j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / j n s

Brain structural MRI correlates of cognitive dysfunctions in Parkinson's disease

Naroa Ibarretxe-Bilbao a, b, c, d,⁎, Carme Junque a, b, Maria J. Marti a, c, Eduardo Tolosa a, c
a
Centro de Investigación en Red de Enfermedades Neurodegenerativas (CIBERNED), Hospital Clínic de Barcelona, Spain
b
Department of Psychiatry and Clinical Psychobiology, University of Barcelona, Spain
c
Movement Disorders Unit, Neurology Service, Institut Clínic de Neurociències (ICN), Hospital Clínic de Barcelona, Spain
d
Department of Methods and Experimental Psychology, Faculty of Psychology and Education, University of Deusto, Spain

a r t i c l e i n f o a b s t r a c t

Article history: Cognitive dysfunction occurs at early stages of Parkinson's disease (PD). Initial studies reported that cognitive
Received 29 March 2011 dysfunction in early PD only affected fronto-striatal circuits, provoking a marked executive dysfunction.
Received in revised form 28 July 2011 Memory impairment in PD was thought to depend on a problem in retrieving stored information, therefore
Accepted 30 July 2011
also reflecting a fronto-striatal dysfunction. However, there is increasing structural MRI evidence of medial
Available online 23 August 2011
temporal lobe atrophy in PD, which may be responsible for memory dysfunction. Other neuropsychological
Keywords:
functions usually impaired in PD are semantic fluency, visuoperceptual and visuospatial functions, decision-
Parkinson's disease making and recognition of facial emotions; and impairments in these functions are associated with cortical
Cognition structural changes assessed by MRI. Overall, although the literature on the topic is scarce, there is increasing
Memory evidence of brain structural changes, detectable by MRI, which can explain the neuropsychological deficits
Magnetic resonance imaging early in the clinical disease course before dementia develops. In this review, we summarize the papers that
have used structural MRI to study the neuroanatomical correlates of cognitive dysfunctions in PD.
© 2011 Elsevier B.V. All rights reserved.

1. Introduction 2. Neuroanatomical correlates of cognitive dysfunctions in PD

Cognitive dysfunctions occur at early stages of Parkinson's disease 2.1. Memory

(PD) and mostly involve impairment of memory, executive and
visuoperceptual functions [1–4]. Neuroimaging techniques, specifically
the use of structural MRI, have proved useful for assessing the
neuroanatomical correlates of these cognitive dysfunctions. The
methods most widely used to assess structural MRI changes in PD are
volumetric region-of-interest (ROI) and voxel-based morphometry
(VBM). Combining these neuroimaging techniques and neuropsycho-
logical testing may identify the cerebral substrate for cognitive changes
occurring in PD before the onset of dementia. In this review, we
summarize the cross-sectional MRI papers that study the neuroana-
tomical correlates of cognitive dysfunctions in PD patients (see Table 1).
A systematic literature search using MEDLINE database was carried out
on papers published in English between 1998 and March 2011. We
included the studies in PD that performed: i) analyses of T1-weighted
structural MRI brain data; ii) neuropsychological assessment; and
iii) correlation analyses between the neuropsychological data and
structural MRI brain data.
⁎ Corresponding author at: Department of Methods and Experimental Psychology,
Faculty of Psychology and Education, University of Deusto, Avenida de las Universidades
24, 48007 Bilbao, Spain. Tel.: + 34 94 413 90 00x2891.
E-mail address: naroa.ibarretxe@deusto.es (N. Ibarretxe-Bilbao).
Cognitive dysfunction in early stages of PD is much more extended
than previously believed and is not only limited to executive
dysfunction. Initial studies reported that cognitive dysfunction in
early PD only affected fronto-striatal circuits, provoking a marked
executive dysfunction [5]. Memory problems associated with PD have
traditionally been reported to be secondary to retrieval deficits and
therefore also reflect fronto-striatal dysfunction [6]. However, there is
increasing evidence of a learning and recognition memory deficit in
both demented and non-demented PD patients, which is inconsistent
with this retrieval deficit hypothesis [7,8]. MRI studies suggest that
medial temporal lobe atrophy may be responsible for memory
dysfunction in PD. Using an ROI approach, Riekkinen et al. [9] reported
that right and left hippocampus volume correlated with memory
accuracy on the Delayed Matching to Sample Test (DMTS) in a group of
non-demented PD. Using a visual scale, Bruck et al. [10] reported that
early PD patients had more atrophy in the hippocampus and prefrontal
cortex than controls, and that atrophy of the left hippocampus
correlated with verbal memory score. Tam et al. [11] also used a
visual scale and reported medial temporal lobe atrophy in PD patients
compared to controls, but no correlation between atrophy and cogni-
tive impairment was found. Camicioli et al. [12] showed a progressive
hippocampal volume loss in PD and found that verbal memory,
assessed by the CERAD recognition memory test, was associated with
left but not right hippocampal atrophy. Junque et al. [13] showed that

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 N. Ibarretxe-Bilbao et al. / Journal of the Neurological Sciences 310 (2011) 70–74 71

Table 1
Summary of main MRI studies on neuroanatomical correlates of cognitive dysfunctions in PD.

Study Participants Matched control Assessment MRI analysis Neuropsychological test Correlation with
(mean age) group?a of VH? technique (impaired or not?)b brain structure

Memory
Riekkinen et al. 1998 20 mild PD (60) No control group No Manual ROI DMTS memory L and R hippocampus
15 UM severe PD (64) accuracy (Yes)
8 IM severe PD (65)
Camicioli et al. 2003 10 PD (73.3) Yes No Manual ROI CERAD recognition L hippocampus
10 PDD (74.7) (Yes)
11 AD (74.4)
12 controls (73.9)
Bruck et al. 2004 20 early PD (61.3) Yes No Visual scale VEM (not specified) L hippocampus
22 controls (65.7)
Junque et al. 2005 16 PD (72.8) Yes No Manual ROI RAVLT Learning (Yes) Amygdala hippocampus
16 PDD (70.1)
16 controls (71.3)
Bouchard et al. 2007 44 PD (71.1) Yes No Manual ROI CVLT-II (No) L and R amygdala
13 PDD (71.9) L hippocampal head
44 controls (71.1) BVMT-R (No) L hippocampal head
Ibarretxe-Bilbao et al. 2008 9 PDD (69.8) Yes Yes: 16 PD VBM RAVLT Learning (Yes) L and R hippocampal head
16 PD with VH (73.5) with VH
19 PD no-VH (72.5)
56 Controls (73)
c
Dalaker et al. 2011 11 MCI PD (67.5) Yes No Volumetric automatic CVLT-II (not specified) Fourth ventricle
32 non-MCI PD (63.3) segmentation
41 controls (64.2)

Executive function
Nagano-Saito et al. 2005 39 PD (61.8) Yes: only age matched. Yes: none VBM RCPM (not specified) Dorsolateral PFC
9 PDD (67.3) with VH
31 Controls (63.5) Parahippocampus
Camicioli et al. 2008 43 PD (70.7) Yes No VBM Index of executive Caudate, middle temporal
43 Controls (71.0) functiond gyri, precuneus cerebellume
Ibarretxe-Bilbao et al. 2009 24 early PD (56.1) Yes Yes: none VBM IGT (Yes) L lateral OFC f
24 controls (57.6) with VH

Verbal fluency
Pereira et al. 2009 32 PD (73.1) No control group Yes: 14 PD VBM Semantic fluency Inferior and middle frontal
with VH (Not specified) gyrus Temporal lobe

Visuoperceptual and visuospatial functions

Pereira et al. 2009 36 PD (73.2) Yes Yes: 18 PD VBM BFRT (yes) Fusiform gyrus
20 controls (72.7) with VH VFDT (yes) L and R superior parietal

Recognition of facial expressions of emotions

f
Ibarretxe-Bilbao et al. 2009 24 early PD (56.1) Yes Yes: none VBM Ekman test (yes) Bilateral OFC
24 controls (57.6) with VH

Others (negative results or correlations with general cognitive measures)

Apostolova et al. 2010 12 PD (68.4) Yes No Radial distance MMSE (yes) Head of the caudate
8 MCI PD (78) mapping
15 PDD (73.4) Inferior and posterior lateral
20 controls (73.6) ventricle horns
Tam et al. 2005 33 PD (75.4) Yes No Visual scale CAMCOG (yes) No significant correlations
31 PDD (71.8) (MTA rating)
25 DLB (75.3)
31 AD (78.7)
39 Controls (75.2)
Tinaz et al. 2011 15 early PD (59.7) Yes No Cortical thickness (Not impaired) No significant correlations
15 controls (59.8)

Abbreviations: BFRT = Benton's facial recognition test; BVMT-R = Brief visuospatial memory test, revised; CAMCOG = Cambridge Cognitive Examination; CERAD = Consortium to
Establish a Registry for Alzheimer's Disease; CVLT-II = California Verbal Learning Test; DMTS = Delayed Matching to Sample Test; GM = gray matter; ICV = intracranial volume; IGT =
Iowa Gambling Task; L = left; MCI = mild cognitive impairment; MI = memory impaired; MTA = medial temporal lobe atrophy; OFC = orbitofrontal cortex; PD = Parkinson's disease
patients without dementia; PDD = Parkinson's disease patients with dementia; PFC = prefrontal cortex; R = right; RAVLT = Rey's auditory verbal learning test; RCPM = Raven colored
progressive matrices; ROI = region-of-interest; UM = unimpaired memory; VBM = voxel-based morphometry; VEM = Wechsler memory scale-revised (WMS-R) test for verbal
memory; VFDT = visual form discrimination test; VH = visual hallucinations.
a
Age-, gender-, education-matched control group.
b
The table only includes the neuropsychological tests associated with brain structure.
c
Correlation corrected for age, gender and education.
d
Executive function index includes: Stroop interference, TMT A and B; digit ordering.
e
Correlation corrected for age, gender and ICV.
f
Correlation corrected for total GM volume.

verbal memory scores not only correlated with the volume of the associated hippocampal atrophy in PD. In the whole PD sample, left
hippocampus but also with the volume of the amygdala in PD patients. hippocampal volume, specifically the volume of the head of the hip-
Using an ROI method Bouchard et al. [14] reported significant age- pocampus, correlated with recall on the California Verbal Learning Test
72 N. Ibarretxe-Bilbao et al. / Journal of the Neurological Sciences 310 (2011) 70–74
(CVLT-II) and the Brief Visuospatial Memory Test, revised (BVMT-R).
In addition, they also found a correlation between amygdala volumes
and CVLT-II recall. Using VBM, Ibarretxe-Bilbao et al. [15] showed a
pattern of hippocampal atrophy affecting the head and the tail of this
structure in demented PD patients, but restricted just to the hippo-
campal head in patients at risk for dementia (patients with visual
hallucinations). When PD patients participating in the study were
considered altogether, a significant correlation was found between
RAVLT learning scores and GM density in the head of left and right
hippocampus [15].
Not only limbic atrophy but ventricular enlargement as well has
been associated with memory dysfunctions in PD. Using freesurfer
Dalaker et al. [16] found that fourth ventricle volume correlated with
memory scores assessed by CLVT-II after including age, sex and
education as covariates. In another study, the enlargement of the
inferior and posterior lateral ventricle horns correlated with MMSE
scores in PD [17]; and a longitudinal study showed that ventricular
change over 36 months correlated with change in dementia rating
scale (DRS) and MMSE in patients with PD [18]. Ventricular
enlargement and its relation to cognition in PD patients could be
interpreted as a sign of brain GM and WM loss due to progressive
neurodegeneration.
2.2. Executive functions
Executive dysfunction in PD is frequently attributed to the
dopamine loss in the striatum that may affect frontal lobe function
by disrupting activity within basal ganglia–thalamocortical circuits
[19]. However, MRI studies show that morphological brain structural
changes may also be involved. Camicioli et al. [20] assessed executive
functions in PD using a composite measure which included the Stroop
test, Trail Making Test, and digit ordering test; and significant
correlations were found between this composite executive function
measure and GM volume in bilateral caudate, bilateral middle
temporal gyri, precuneus and cerebellum. On the other hand, in
early PD one VBM study [21] found a significant correlation between
decision-making, assessed by the Iowa Gambling Task (IGT), and
atrophy in left lateral orbitofrontal cortex (OFC), which is considered
to be the limbic association cortex. Decision-making is usually
discussed in the context of executive dysfunction. However, a recent
review showed that only 4 out of 12 studies reported a correlation
between executive functions and performance on decision-making
tasks in PD [22]. Finally, we also included in this review as depicted in
Table 1, one study [23] that reported an association between the
performance on the Raven Colored Progressive Matrices (RCPM) and
dorsolateral PFC and parahippocampal atrophy. The authors of this
study suggested this test as a measure of executive and visuospatial
functions. However, the RCPM should be better considered as a
measure of visual inductive reasoning and/or a measure for evaluating
general intelligence.
2.3. Verbal fluency
Impairment in verbal fluency is frequently observed in PD and
occurs at the early stages of the disease [24]. Verbal fluency includes
semantic and phonemic fluency, and early impairment in semantic
fluency is a predictor of conversion to dementia in PD [25]. Deficits in
phonemic and semantic fluencies are considered secondary to frontal
lobe dysfunctions, as both types of fluency are impaired in patients
with structural frontal lesions. Semantic fluency is, however, more
closely related to temporal damage than phonemic fluency [24]. In
terms of language organization, recent data points to a role for the
posterior lateral superior temporal lobe in analyzing phonemic and
lexical features of speech, with more anterior regions playing some
role in higher order sentence level processing [26]. Only one study
[27] has investigated the neuroanatomical correlates of phonemic and
semantic deficits in PD patients. The most interesting results of that
study were that semantic fluency scores in non-demented PD patients
correlated with GM density in the inferior and middle frontal gyrus
(BA 10, 46) and in several areas in the temporal lobe (BA 20, 21, 22,
38), assessed by VBM. On the other hand, no significant correlation
was found between global brain GM density and phonemic fluency
scores. These results suggest that semantic fluency tests reflect
cortical dysfunctions in PD better than phonemic fluency.
2.4. Visuospatial and visuoperceptual functions
Pereira et al. [28] evaluated visuoperceptual functions with
Benton's facial recognition test (BFRT) in a group of non-demented
PD patients and found that performance on this test correlated with
GM density in the fusiform gyrus (BA 19, 36), parahippocampus, the
middle occipital gyrus (BA 19), and the inferior frontal gyrus. Patients
were also assessed by means of the Visual Form Discrimination Test
(VFDT), a test that not only evaluates visuoperceptual functions but
involves visuospatial abilities as well, and correlations between
performance in this test and GM density in bilateral parietal regions
(BA 7, 40) were observed. Other significant GM correlations were
detected in the superior occipital (BA19), middle frontal (BA 9), and
inferior frontal gyrus. Taken together, these findings suggest that
visuospatial and visuoperceptual dysfunctions in PD patients mainly
reflect structural GM changes in posterior cerebral regions, specifi-
cally in temporo-parietal cortical regions.
2.5. Recognition of facial emotions
Several studies have reported impairment of recognition of facial
expressions of emotions in PD [21,29–33]. Specifically, Sprengelmeyer
et al. [33] reported that de novo PD patients scored significantly lower
in recognizing sadness and fear than healthy controls. These results
suggested that recognition of these emotions is impaired very early in
the disease and is independent of treatment. In a group of early PD
patients we found atrophy of bilateral OFC and amygdala using VBM
[21]. The bilateral OFC atrophy correlated with the scores in the Ekman
60 faces test, a measure of recognition of facial emotions, in the PD
group. Another MRI study [34] also reported degeneration of the
OFC in early PD patients but no significant correlations between the
behavioral tests and the imaging data were found.
3. Discussion
We reviewed MRI studies aimed at identifying brain morphological
changes associated with neuropsychological dysfunctions in PD; and
most of these studies provided evidence of specific structural brain
changes associated with specific neuropsychological deficits in PD. The
most consistent finding refers to memory function. Structural MRI
studies using different techniques have shown reduced hippocampal
and amygdalar volumes in PD patients, and atrophy of these limbic
structures has been related to verbal memory deficits in PD. This
review also shows that other neuropsychological functions usually
impaired in early stages of PD are associated with cortical structural
changes detectable by MRI.
Pathological explanations for cognitive decline in PD include
coexistent Lewy body degeneration and Alzheimer-type changes
[35]. All these changes might lead to morphological brain changes,
including atrophy, which can be detected in vivo by structural MRI
studies. The six-stage system of brain pathology in PD proposed by
Braak et al. [36] suggests a predictable sequence of topographically
ascending LB pathology. As the disease progresses, components of the
autonomic, limbic, and somatomotor systems become pathologically
involved. During stages 1–2, inclusion body pathology is confined to
the medulla oblongata/pontine tegmentum and olfactory bulb/
anterior olfactory nucleus. These stages are thought to correspond to
 N. Ibarretxe-Bilbao et al. / Journal of the Neurological Sciences 310 (2011) 70–74
the so called premotor phase of the disease [37]. In stages 3–4, the
substantia nigra and other nuclear grays of the midbrain and forebrain
become the main focus of pathology. At this point, most individuals
probably cross the threshold to the symptomatic motor phase of the
illness. In Braak et al. stages 5–6, the process extends to the neocortex.
Dementia in PD has been shown to occur frequently, but not always, in
patients eventually found to have on pathological examination
abundant cortical LBs as it occurs in Braak et al. stages 5 and 6 [38].
VBM studies agree with Braak et al. staging in the sense that non-
demented PD patients have limbic (amygdala and hippocampus) as
well as paralimbic (cingulate cortex) and prefrontal GM reductions.
However, in patients with early stages of motor impairment (Hoehn
and Yahr I and II), which one would presume to reflect Braak et al.
stages 3 and 4, correlation between cognitive deficits and GM
reductions are observed in the OFC but not in the medial temporal
lobe [21].
On the other hand, cognitive dysfunctions in PD, mainly executive
dysfunctions, have been usually attributed to dopamine depletion
affecting fronto-striatal circuits. MRI studies reviewed here show
degeneration of brain regions involved in other circuits such as
brainstem nuclei, limbic structures, and cerebral cortex that may
reflect degeneration of other systems including noradrenergic,
serotoninergic, and cholinergic projections which are also known to
be involved in the cognitive dysfunction in PD [39]. Finally, it should
be borne in mind that a combination of Lewy- and Alzheimer-type
pathologies is a robust pathological correlate of dementia in PD [40].
However, none of the MRI studies included in this manuscript used
cases validated by autopsy. The combination of both post-mortem
pathologic studies and in vivo MRI studies would be crucial to
understand the neuroanatomical correlates of cognitive dysfunctions
in PD.
The main methodological problems in the MRI studies discussed in
the current review are as follows: Firstly, the heterogeneity of samples
studied; it is not always well defined whether the PD patients
included in the study are impaired in the specific neuropsychological
test and/or if they present VH. For example, from papers reviewed in
Table 1 only 5 assessed whether patients presented VH. Patients with
VH and/or cognitive impairment usually present greater atrophy
compared to patients without these characteristics and therefore not
taking into consideration these variables may bias the results.
Secondly, the inconsistency in controlling the influence of age, gender
and education in the correlation analyses between brain and function.
Most of the studies did not control the confounding effect of these
sociodemographic variables in the analyses. Finally, the limitations of
structural MRI analyses techniques. On the one hand, manual ROI
method takes into consideration the variability across subjects, but it
also depends on the subjective criteria of the investigator. For this
reason, inter- and intra-rater validations should be mandatory in this
kind of analysis, but this is not always the case. On the other hand,
automatic MRI measures such as VBM provide a non-biased measure.
However, the normalization stage within the VBM analysis, which is
required to ensure that the same brain regions can be compared
between subjects, transforms the shape of the brain image and may
distort the abnormal tissue and artificially inflate the atrophied areas
[41]. Surface-based methods and 3D modeling analyses still scarce in
PD are proving successful.
Further studies are needed to corroborate the results of the studies
reviewed here. Major challenges that remain in the field of structural
MRI studies in PD are the need to identify brain structures which are
vulnerable to early degeneration and which could be considered as
biomarkers predicting different disease outcomes.
Conflict of interest
None.
73
Acknowledgments
This work was supported by Generalitat de Catalunya [2009 SGR
0941 to C.J., 2009 SGR 0836 to E.T., PSI2010-16174 to C. J.]; CIBERNED
and University of Deusto.
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