SHORT COMMUNICATION

Regional cortical thickness and cognitive functions innon-demented Parkinson�s disease patients: a pilot study

C. Pellicanoa,b, F. Assognac, F. Pirasc, C. Caltagironec,d, F. E. Pontieria,b,* and G. Spallettac,*aMovement Disorder Unit, Sant�Andrea Hospital, Rome; bDepartment of Neurology and Psychiatry, Sapienza University, Rome; cIRCCS

Santa Lucia Foundation, Rome; and dDepartment of Neuroscience, Tor Vergata University, Rome, Italy

Keywords:

cognitive functions, corti-

cal thickness, magnetic

resonance imaging,

non-motor symptoms,

Parkinson�s disease

Received 8 February 2011

Accepted 25 May 2011.

Background and purpose: The pathology of neuropsychological deficits in Parkinson�sdisease (PD) is incompletely defined.

Methods: We investigated cortical thickness and neuropsychological performances in

non-demented patients with PD and healthy controls.

Results: Patients showed significant cortical thinning in right middle temporal and

left fusiform cortices. Verbal memory performance was related with left fusiform

thinning.

Conclusions: Cognitive and cortical changes in non-demented patients with PD are

detectable and clearly related.

Introduction

Pathological studies [1] suggest that neurodegeneration

in Parkinson�s disease (PD) extends beyond the basal

ganglia, to produce motor and non-motor symptoms,

including cognitive deficits [2]. The brain pathology

underlying cognitive impairment in PD is incompletely

defined.

Voxel-based morphometry (VBM) studies on non-

demented patients with PD showed atrophy of frontal,

parietal and temporal areas [3,4]. More recently,

cortical thinning was measured in temporal, inferior

parietal, rostral frontal and orbitofrontal cortices in

non-demented patients with PD [5], but no attempt to

correlate cortical thinning with neuropsychological

functions was made. In this pilot study, we measured

cortical thickness (CTh) in non-demented patients with

PD and healthy controls (HC) and investigated its

relationship with neuropsychological performances.

Methods

Thirteen patients with PD, diagnosed according to

international guidelines [6] and treated with stable

dopaminergic therapy for at least 2 months without

motor fluctuations, and 13 HC matched for age, sex

and educational level were enrolled. All subjects were

right-handed. Inclusion criteria for both groups were

the following: (i) age between 40 and 80 years; (ii) Mini

Mental State Examination (MMSE) [7] score ‡26;(iii) suitability for magnetic resonance imaging (MRI)

scanning. Common exclusion criteria were as follows:

(i) major medical illnesses; (ii) comorbidity with psy-

chiatric (using DSM-IV-TR criteria [8]) or neurological

disorders and dementia or mild cognitive impairment

(MCI) diagnosis according with DSM-IV-TR [8] and

established MCI criteria [9], respectively. In particular,

no patients with PD suffered from mood disorders such

as major depressive or dysthymic disorders. Further,

two patients with PD suffered from the Minor form of

depression, according with the criteria sets provided for

further study listed in the DSM-IV-TR Appendix B;

(iii) history of alcoholism, drug dependence or abuse;

(iv) MRI evidence of significant focal cerebral abnor-

malities. The study was approved by the Santa Lucia

Foundation Ethical Committee, and each subject

signed an informed consent.

All subjects underwent the MMSE [7] for global

cognitive functions, the Rey-15 words Immediate and

Delayed Recall tests for short- and long-term verbal

memory [10], the Rey-Osterrieth Figure Immediate and

Delayed copy tests [11] for complex constructive praxis

and visual–spatial memory, the Stroop Word Color

Test [12] for frontal attention shifting and control, the

Wisconsin Card Sorting Test – Short Form [13] for

executive functions, and the Semantic and Phonologic

Verbal Fluency Test [10] for linguistic abilities.

Participants were then examined using a Siemens 3T

Allegra MR Imager with a standard quadrature head

Correspondence: Gianfranco Spalletta, MD, PhD, Neuropsychiatry

Laboratory, IRCCS Santa Lucia Foundation, Via Ardeatina, 306,

Rome – 00179, Italy (tel.: (+39) 06 51501575; fax (+39) 06 51501575;

e-mail g.spalletta@hsantalucia.it).

*These authors contributed equally to the work.

172� 2011 The Author(s)

European Journal of Neurology � 2011 EFNS

European Journal of Neurology 2012, 19: 172–175 doi:10.1111/j.1468-1331.2011.03465.x

coil. The MRI protocol included the following:

(i) whole-brain T1-weighted sequence obtained in the

sagittal plane using a modified driven equilibrium

Fourier transform sequence (MDEFT) [14] (echo time/

repetition time = 2.4/7.92 ms, flip angle 15�, voxel size1 · 1 · 1 mm3); (ii) standard clinical sequences (FLAIR,

DP-T2-weighted). All planar sequence acquisitions

were acquired along the Anterior Commissure-Poster-

ior Commissure (ACPC) line.

CTh was measured from the whole-brain T1-weigh-

ted images using Freesurfer 4.05 software package

(https://surfer.nmr.mgh.harvard.edu), detailed else-

where [15]. CTh was measured as the distance from the

gray/white matter boundary to the corresponding pial

surface. Misclassification of tissue type was corrected

by manual editing by a trained tracer (CP). Thirty-three

cortical regions were measured in each hemisphere.

Differences in CTh and neuropsychological values

between patients with PD and HC were analyzed by

paired t-test. For CTh values, Bonferroni�s correction

for multiple comparisons was applied with a signifi-

cance level of P < 0.0015 (P < 0.05/33 number of

comparisons in each hemisphere) to avoid false positive

results. The correlations between CTh and neuropsy-

chological scores in patients with PD were analyzed by

Pearson�s r. Because this was measured for the first

time, we accepted the false-positive risk, with a signifi-

cance uncorrected level set at P < 0.05.

Results

Despite no evidence of dementia or MCI diagnosis,

patients with PD had significantly lower MMSE score

than HC. Patients with PD showed lower performances

than HC in praxis, long-term verbal memory, frontal

attention and executive functions (Table 1). Also, visual

memory performance of patients tended (P = 0.06) to

be significantly impaired in comparison with that of

HC.

The significant differences of regional CTh between

patients with PD and HC are shown in Table 2. After

Bonferroni�s correction, significant CTh reduction in

patients with PD was found in the right middle tem-

poral and left fusiform regions.

Finally, significant correlations were found between

long-term verbal memory scores and CTh of the left

fusiform region (r = 0.682; P = 0.01) within patients

with PD.

Discussion

The present results indicate widespread cortical thin-

ning in non-demented patients with PD at the uncor-

rected statistical level. After Bonferroni�s correction,

only cortical thinning in right middle temporal and left

fusiform regions survived. This topographic pattern of

cortical thinning is similar to that reported recently [5]

on larger cohort of patients with PD and confirms the

preferential thinning in temporal regions in PD with-

out dementia. Such topographic distribution of corti-

cal thinning is rostral to posterior parietal and

occipital areas, where hypometabolism and hypoper-

fusion have been previously reported in non-demented

patients with PD [16,17]. Conversely, this distribution

overlaps discretely with the regions where cortical

Lewy bodies and neurites are found in patients with

Table 1 Demographics, clinical and neuropsychological features of the study cohort

PD (n = 13) HC (n = 13) d.f. T P

Sex (male) (%) 9 (69%) 8 (62%) 1 0.002 (chi-square) 0.96

Age (years) 58.8 ± 10.4 (40–72) 60.3 ± 10.4 (44–76) 12 0.39 0.70

Education (years) 11.8 ± 4.1 (8–18) 12.9 ± 2.8 (8–17) 12 0.96 0.40

UPDRS-III score 18.5 ± 7.7 (8–31) n/a n/a n/a n/a

Hoehn and Yahe score 1.9 ± 0.7 (1–3) n/a n/a n/a n/a

Disease duration (years) 4.3 ± 2.9 (1–10) n/a n/a n/a n/a

Mini Mental State Examination 28.4 ± 1.5 (26–30) 29.5 ± 0.9 (27–30) 12 2.48 0.03

Rey�s 15-word – Immediate Recall 40.6 ± 10.4 (30–61) 47.5 ± 10.2 (34–62) 12 1.58 0.14

Rey�s 15-word – Delayed Recall 8.1 ± 2.8 (3–13) 11.1 ± 3.5 (4–15) 12 2.37 0.03

Rey-Osterrieth Figure Copy Test – Immediate copy 28.5 ± 3.6 (22–35) 33.1 ± 2.1 (29–35) 12 3.68 0.01

Rey-Osterrieth Figure Copy Test – Delayed recall 14.7 ± 5.5 (8–25) 18.0 ± 6.9 (9–30) 12 2.07 0.06

Stroop Test – Interference Time (sec) 47.0 ± 15.9 (23–69) 34.2 ± 8.2 (25–52) 12 )2.91 0.01

Stroop Test – Interference Errors 1.2 ± 1.9 (0–5) 0.3 ± 0.4 (0–1) 12 )1.77 0.10

Wisconsin Card Sorting Test – non-persev. errors 2.15 ± 1.8 (0–5) 1.0 ± 1.1 (0–3) 12 )2.91 0.05

Wisconsin Card Sorting Test – persev. errors 0.8 ± 1.3 (0–4) 1.0 ± 2.0 (0–6) 12 0.17 0.87

Semantic Verbal Fluency Test 18.6 ± 4.9 (12–26) 21.5 ± 3.8 (17–28) 12 1.62 0.13

Phonologic Verbal Fluency Test 34.5 ± 10.8 (21–56) 39.0 ± 10.1 (25–61) 12 1.04 0.32

Data represent means ± SD. PD, patients with Parkinson�s disease; HC, healthy controls.

CTh in PD without dementia 173

� 2011 The Author(s)European Journal of Neurology � 2011 EFNS European Journal of Neurology 19, 172–175

more advanced PD (Braak�s stages 4 and 5) [18], who

generally display more severe cognitive and motor

deficits. These results support the hypothesis that

cortical thinning may occur early in PD, possibly

reflecting early and fine cortical processes such as

reduced size of neuronal cell bodies, reduced dendritic

arborization and/or loss of presynaptic terminals

rather than cortical neuronal cell loss.

Our preliminary results show a lack of significant

correlation between frontal- and parietal-mediated

cognitive performances and cortical thinning. However,

the small sample size and the statistical correction for

multiple comparisons here used to compare the cortical

thickness of the two groups have increased the risk of

false negative results. Thus, it is possible that more

cortical areas are implicated in PD and related to cog-

nitive deterioration. An alternative possibility is that

deficits of these cognitive domains may depend on

derangement of subcortical input to neocortical areas

rather than primary cortical damage. Conversely, cor-

tical thinning in the left fusiform region is associated in

our sample study with reduced verbal memory perfor-

mance in PD. Interestingly, left fusiform region is

activated by word and face recall tasks [19] and is

involved in successful encoding-related verbal memory

formation [20]. Thus, we suggest that cortical thinning

in left fusiform gyrus may represent a morphological

marker of verbal memory impairment in non-demented

patients with PD. Finally, we would like to point out

that our findings should be confirmed by further studies

on larger series using multimodal cortical thickness and

structural connectivity, such as Diffusion Tensor Ima-

ging (DTI), measurements to fully asses the entire pic-

ture of the relationship between cognition and cortical–

subcortical anatomy in PD.

Acknowledgements

Supported by grants from Italian Ministry of Health

RF 07 and 08 (GS) and MIUR (FEP).

Disclosure of conflicts of interest

The authors declare no financial or other conflict of

interests.

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Table 2 Cortical thickness (CTh) measurements

CTh (mm)

Patients with PD

(n = 13) (means ± SD)

HC (n = 13)

(means ± SD) % diff. d.f. t P

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174 C. Pellicano et al.

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CTh in PD without dementia 175

� 2011 The Author(s)European Journal of Neurology � 2011 EFNS European Journal of Neurology 19, 172–175