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Functional disconnection of thalamic and cerebellar dentate nucleus networks in progressive supranuclear palsy and corticobasal syndrome
Accepted Manuscript Functional disconnection of thalamic and cerebellar dentate nucleus networks in progressive supranuclear palsy and corticobasal syndrome Neeraj Upadhyay, PhD, Antonio Suppa, MD PhD, Maria Cristina Piattella, MD PhD, Costanza Gianni, MD, Matteo Bologna, MD PhD, Flavio Di Stasio, MD, Nikolaos Petsas, PhD, Francesca Tona, MD, Giovanni Fabbrini, MD, Alfredo Berardelli, MD, Patrizia Pantano, MD PII:
S1353-8020(17)30103-7
DOI:
10.1016/j.parkreldis.2017.03.008
Reference:
PRD 3266
To appear in:
Parkinsonism and Related Disorders
Received Date: 19 October 2016 Revised Date:
10 February 2017
Accepted Date: 13 March 2017
Please cite this article as: Upadhyay N, Suppa A, Piattella MC, Gianni C, Bologna M, Di Stasio F, Petsas N, Tona F, Fabbrini G, Berardelli A, Pantano P, Functional disconnection of thalamic and cerebellar dentate nucleus networks in progressive supranuclear palsy and corticobasal syndrome, Parkinsonism and Related Disorders (2017), doi: 10.1016/j.parkreldis.2017.03.008. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Functional Disconnection of Thalamic and Cerebellar Dentate Nucleus
Networks in Progressive Supranuclear Palsy and Corticobasal Syndrome
Neeraj Upadhyay PhD1, Antonio Suppa MD PhD1-2, Maria Cristina Piattella MD PhD1, Costanza
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Gianni MD1, Matteo Bologna MD PhD1-2, Flavio Di Stasio MD2, Nikolaos Petsas PhD1, Francesca Tona MD1, Giovanni Fabbrini MD1-2, Alfredo Berardelli MD1-2 and Patrizia Pantano MD1-2 1
Department of Neurology and Psychiatry, “Sapienza” University of Rome, Italy, 2IRCCS
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Neuromed Institute, Pozzilli (IS), Italy.
thalamus, dentate nucleus.
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Keywords: progressive supranuclear palsy, corticobasal syndrome, functional connectivity,
Running head: Thalamic and dentate nucleus functional connectivity in PSP and CBS. Number of words (Abstract): 202
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Number of words (Introduction): 620 Number of words (Discussion): 1001
Number of words (excluding references and abstract): 3197
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Number of Figures: 2
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Number of Tables: 2
Corresponding author: Prof. Patrizia Pantano
Department of Neurology and Psychiatry, Sapienza University of Rome Viale dell’Università, 30, 00185 Rome, Italy Telephone number: +39- 0649914719 Fax+39- 0649914903 E-mail: [email protected]
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ABSTRACT
Aim: To assess functional rearrangement following neurodegeneration in the thalamus and dentate nucleus in patients with progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS).
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Methods: We recruited 19 patients with PSP, 11 with CBS and 14 healthy subjects. All the subjects underwent resting-state (rs) fMRI using a 3T system. Whole brain functional connectivity of the thalamus and dentate nucleus were calculated by means of a seed-based approach with FEAT script
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in FSL toolbox. Thalamic volume was calculated by means of FIRST, and the dentate area by means of Jim software.
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Results: Both thalamic volume and dentate area were significantly smaller in PSP and CBS patients than in healthy subjects. No significant difference emerged in thalamic volume between PSP and CBS patients, whereas dentate area was significantly smaller in PSP than in CBS. Thalamic functional connectivity was significantly reduced in both patient groups in various cortical, subcortical and cerebellar areas. By contrast, changes in dentate nucleus functional connectivity
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differed in PSP and CBS: it decreased in subcortical and prefrontal cortical areas in PSP, but increased asymmetrically in the frontal cortex in CBS.
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Conclusions: Evaluating the dentate nucleus size and its functional connectivity may help to
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differentiate patients with PSP from those with CBS.
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INTRODUCTION
Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are 4R-tauopathies characterized by neuronal loss and accumulation of filamentous tau inclusions within neurons and
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glia [1-3]. CBD is pathologically characterized by a prominent and asymmetrical involvement of the fronto-parietal cortex, whereas PSP mainly involves subcortical structures, the midbrain and the cerebellum [1-3]. Clinically, PSP and CBD are characterized by parkinsonism and a combination of
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additional motor, cognitive and behavioral symptoms. In PSP, motor symptoms include
parkinsonism, vertical supranuclear gaze palsy, postural instability and early falls, whereas
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cognitive and behavioral symptoms mainly include a frontal dysexecutive syndrome associated with apathy, impulsivity, and visuospatial and memory function impairment [4-7]. The most frequent clinical presentation of CBD is instead corticobasal syndrome (CBS), which is characterized by parkinsonism, dystonia, myoclonus, cortical sensory loss, ideomotor apraxia, alien-limb phenomena with a characteristically asymmetrical distribution, and additional cognitive and behavioral
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impairment [5,8]. Since the clinical features in PSP and CBS patients may overlap, particularly in the early disease stages [1,4], new imaging biomarkers that may be used to differentiate PSP from
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CBS are of great importance.
MRI studies have extensively demonstrated differences between PSP and CBS patients in
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structural damage in the gray (GM) and white matter (WM). PSP is characterized by damage to infratentorial structures, i.e. the midbrain and cerebellum [9]. Severe asymmetrical atrophy of the perirolandic cortex is typical of CBS, whereas the frontal cortex atrophy observed in PSP is symmetrical [10]; moreover, basal ganglia and thalamic atrophy have been reported in both CBS and PSP [9,10]. A recent longitudinal MRI study in which patients were examined at 6-12 month intervals, demonstrated greater volume loss in CBS than in PSP in the basal ganglia as well as in several cortical regions, including the precentral gyrus, whereas the degree of atrophy in the brainstem was comparable [11]. Similarly, recent diffusion tensor imaging (DTI) longitudinal
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studies have shown that WM changes are prominent in CBS [12], whereas the involvement of the dentate-rubro-thalamic tract is greater in patients with PSP [13], a finding that is in keeping with neuropathological studies [2,3]. Resting-state fMRI (rs-fMRI) is used to investigate functional connectivity between
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different brain structures during spontaneous neuronal activity at rest [14]. This activity is assessed by identifying slow fluctuations in the blood oxygen level-dependent (BOLD) signal and is depicted by means of spatial correlation maps (functional connectivity maps) [14]. The seed-based approach,
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which is one of the possible methods available to analyze fMRI data in a region-of-interest, is performed by correlating the time course of a region chosen a priori with that of all the other brain
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voxels [15]. Three recent seed-based studies have explored functional connectivity in PSP and demonstrated functional disruption of the caudate, putamen, pallidum, dorsal midbrain tegmentum and, more prominently, of the thalamus [16-18]. Only one previous study by Seeley and colleagues [19], who compared brain functional patterns in several types of neurodegenerative disorders, including CBS, demonstrated abnormal asymmetrical resting state activity in the sensori-motor
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network in patients with CBS.
To the best of our knowledge, no studies have yet investigated dentate nucleus functional
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connectivity in PSP, nor have any specifically investigated thalamic and dentate nucleus functional connectivity in CBS. We believe that an evaluation and comparison of thalamic and dentate nucleus
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functional connectivity changes in patients with PSP and CBS may provide a better understanding of the pathophysiology of these two conditions and thereby help to differentiate between them. The aim of our work was to investigate functional connectivity changes in brain regions selected a priori, i.e. the thalamus and the dentate nucleus, in PSP and CBS. We also measured structural abnormalities in thalamus and dentate seeds in order to identify any association between neuronal loss and functional rearrangement in these two clinical conditions.
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MATERIALS AND METHODS
Subjects We recruited 19 patients with a diagnosis of probable PSP (9 females, mean age ± standard
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deviation: 69.4±4.9), 11 patients with a diagnosis of probable CBS (8 females, 68.0±6.9) and 12 age-matched healthy subjects (9 females, 69.3±5.2). All the patients were referred to the Movement Disorders outpatient clinic of the Department of Neurology and Psychiatry at Sapienza University
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of Rome (Italy). A movement disorder specialist made the diagnosis of probable PSP and probable CBS on the basis of the most recent clinical criteria [4, 5]. The clinical features of all the PSP
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patients were characteristic of Richardson’s syndrome. The asymmetrical clinical features in the CBS patients consisted of predominantly right-side symptoms in 6 of the patients and predominantly left-side symptoms in the other 5. Table 1 shows the demographic and clinical features of the participants, all of whom were right-handed. Motor signs were scored using part III of the Italian version of the Movement Disorder Society-Unified Parkinson’s Disease Rating Scale
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(MDS-UPDRS-III) [20], the Hoehn & Yahr (H&Y) scale [21]; patients with probable PSP were also assessed by means of the PSP-Rating Scale (PSP-RS) [22]. Cognitive functions were evaluated
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by means of the Mini-Mental State Evaluation (MMSE) [23] and Frontal Assessment Battery (FAB) [24]. Depression was evaluated by means of the Hamilton Depression Scale (HAM-D) [25].
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Patients suffering from dementia or depression, defined according to the Diagnostic and Statistical Manual of Mental Disorders (DSM IV-TR) criteria, were excluded, as were any patients with other neurological, psychiatric and systemic diseases or general contraindications to MRI. Patients were asked to suspend L-dopa treatment or any other drugs known to act on the central nervous system at least twelve hours before the MRI examination. Participants gave their written informed consent, and the study was approved by the institutional review board and conformed to the Declaration of Helsinki.
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MRI acquisition
All the patients underwent a multimodal MRI study on a 3.0 T Siemens scanner (Verio, Siemens AG, Erlangen, Germany) that included rs-fMRI and volumetric imaging. The manufacturer’s 12channel head coil designed for parallel imaging (GRAPPA) was used for signal reception. A multi-
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planar T1-weighted localizer with slice orientation parallel to the subcallosal line was acquired at the beginning of each MRI examination. The following sequences were acquired for all the
subjects: a) BOLD single-shot echo-planar images (TR=3,000 ms, TE=30 ms, flip angle=89°,
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FOV=192, matrix=64x64, 50 axial slices 3 mm thick, no gap, 120 volumes, acquisition time=7 minutes), with all the patients and healthy subjects being instructed to close their eyes and stay
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awake during the rs-fMRI acquisitions; b) high-resolution 3D, T1-weighted (T1-3D) MPRAGE sequence (TR=1,900 ms, TE=2.93 ms, flip angle=9°, FOV=260 mm, matrix=256x256, 176 sagittal slices 1 mm thick, no gap); c) dual turbo spin-echo, proton density (PD) and T2-weighted images (TR=3,320 ms, TE=10/103ms, FOV=220 mm, matrix=384x384, 25 axial slices 4 mm thick, 30%
MRI data analysis
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Structural MRI
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due to concomitant diseases.
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gap). The dual turbo spin-echo sequences were obtained to exclude subjects with brain alterations
T1-3D images were processed using SIENAX (http://fsl.fmrib.ox.ac.uk/fsl/fslwiki/SIENA), a fully automated and accurate method for measuring cross-sectional changes in brain volume [26]. Sub-cortical volumes of the thalamus were estimated by means of FMRIB’s Integrated Registration and Segmentation Tool (FIRST) [18]. Thalamic volumes were corrected for individual differences in intracranial volume using an individual scale factor obtained from Sienax. The dentate nuclei were identified in every patient as hypo-intense regions on T2-weighted images located in anatomical sites defined according to a cerebellar reference atlas (SUIT,
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http://www.diedrichsenlab.org/imaging/suit.htm), and were delineated using a semi-automated software (Xinapse Systems Ltd., West Bergholt, UK, http://www.xinapse.com/j-im-7-software/) that also indicated their area.
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Functional MRI Data were analyzed using FSL (FMRIB’s Software Library) tools v 4.1.9
(http://www.fmrib.ox.ac.uk/fsl). Single-subject preprocessing and group analysis were performed
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using FEAT (FMRI Expert Analysis Tool) version 5.98. The first 3 volumes of the 140 resting-state BOLD volumes were discarded to obtain a steady-state BOLD signal. In brief, preprocessing
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consisted of head motion correction, brain extraction, spatial smoothing using a Gaussian kernel of FWHM (full width at half maximum) 5 mm and high pass temporal filtering. Functional data were registered to structural images (within-subject) and MNI standard space (to allow higher level group comparisons) using both linear (FMRIB's Linear Image Registration Tool, FLIRT) and non-linear (FNIRT) registration tools [18].
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As the clinical and MRI features of CBS are asymmetrical, the MR images were flipped in the X dimension so that the more severely affected hemisphere (contralateral to the more affected body
previous study [10].
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side) was positioned on the left side for all the subjects, according to the method adopted in a
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Individual seed region-of-interest (ROI) masks of the thalami were obtained from each subject using an automatic sub-cortical segmentation program. Each image was visually inspected in the coronal plane to ensure accuracy. Left and right masks of the thalamus were merged to obtain a single bilateral mask. In addition, a 4 mm-radius spherical ROI was placed on each of the dentate nuclei and centered according to the coordinates (left -18, -58, -36; right 18, -56, -36) of the probabilistic SUIT cerebellar atlas included in the FSL tool package. After visual inspection to ensure location of the dentate nucleus was correct, the left and right dentate masks were merged to obtain a single bilateral mask. The thalamic and dentate masks were then registered to functional
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coordinate space and used to extract the related time course from preprocessed fMRI data. Time series were averaged across all voxels for each seed. After having been separately fed into FEAT, each time series yielded individual participant-level correlation maps of all voxels that were either positively or negatively correlated with each seed. The general linear model (GLM) was applied to
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test for group averages and differences between patient groups and healthy subjects using the twosample unpaired t-test. The Z-statistic images were thresholded using clusters determined by Z > 2.3, and a whole brain family-wise-error (FWE) corrected clusters were thresholded for a
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significance level of p < 0.05. The anatomical location of significant clusters was established according to the standard atlas included in the FSL (http://www.fmrib.ox.ac.uk/fsl/data/atlas-
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descriptions.html).
Potential indeterminate noise [27], seeds of cerebrospinal fluid (CSF) and white matter (WM) were also identified on each individual functional image, and their time courses were added as covariates of no-interest into each of the seed voxel-wise correlation analyses to remove non-neural contributions to the BOLD signal. Similarly, the study participants’ age, thalamic volume and
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dentate nucleus area were entered as nuisance covariates. Finally, structural maps were used as additional covariates on a voxel-by-voxel basis to account for potential gray matter volume
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two patient groups.
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differences. Lastly, we correlated the functional connectivity of each seed with clinical scores in the
Statistical Analysis
The statistical analysis was carried out using SPSS software, version 16.0 (SPSS, Chicago, Illinois, USA). All values are reported as mean ±standard deviation (SD). ANOVA, post-hoc t test and chisquare were used to detect any differences between groups. Clinico-radiological correlations were performed using Spearman rank correlation. All the results are reported at p<0.05 after correction for multiple comparisons.
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Both the ANOVA and the chi-square test showed that age (p=0.12) and gender (χ (1) =3.12,
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p=0.21) were comparable in all 3 groups (patients with PSP, CBS and healthy subjects). Moreover, the MDS-UPDRS-III scores (p=0.47), disease duration (p=0.49) and H&Y scores (p=0.41) were comparable in CBS and PSP patients. MMSE and FAB scores were significantly lower in PSP and
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CBS patients than in healthy subjects (p<0.001). The MMSE scores were comparable in PSP and CBS (p>0.05), whereas the FAB scores were significantly lower in PSP than in CBS patients
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(p=0.004). Lastly, the HAM-D scores were not only higher in PSP and CBS patients than in controls (p<0.000), but also significantly higher in CBS than in PSP patients (p=0.04).
Structural MRI
Thalamic volume was significantly smaller in patients with PSP and CBS than in healthy subjects
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(p=0.003), with no difference being detected between PSP and CBS patients (Table 2). The dentate nucleus area was significantly smaller in both PSP and CBS patients than in healthy subjects
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(p=0.0001) (Table 2). Post-hoc analysis showed a greater reduction in the dentate nucleus area in
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patients with PSP than in those with CBS (p=0.0001).
Functional MRI
No significant differences in thalamic functional connectivity were observed between PSP and CBS patients; thalamic functional connectivity was lower in both patient groups than in healthy subjects. The areas affected to the greater extent by decreased thalamic functional connectivity were the basal ganglia, dorsolateral prefrontal cortex (DLPFC), anterior cingulate cortex (ACC), supplementary motor area (SMA), bilaterally, and left cerebellum in PSP, and the right basal ganglia, left DLPFC, ACC and SMA, and cerebellum bilaterally in CBS (Fig 1).
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Dentate nucleus functional connectivity significantly differed between PSP and CBS patients, as well as between both these groups of patients and healthy subjects. In particular, PSP patients displayed lower dentate nucleus functional connectivity with the basal ganglia, thalamus and prefrontal cortex bilaterally than either CBS patients or healthy subjects. By contrast, if
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compared with PSP patients and healthy subjects, CBS patients displayed increased dentate nucleus functional connectivity with the ACC, SMA, primary motor cortex and prefrontal cortex,
bilaterally, though predominantly in the more affected hemisphere (contralateral to the body side
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affected most) (Fig. 2).
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Clinico-radiological correlations
No significant correlations emerged between functional connectivity changes within the thalamic and dentate seed regions and the clinical scores in either patient group even when the MDS-UPDRS
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DISCUSSION
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subscores that are specific for bradykinesia, rigidity and tremor alone were considered.
In this study, we used a seed-based rs-fMRI approach to explore thalamic and dentate nucleus
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functional connectivity in patients with PSP and CBS. Thalamic connectivity was lower in both PSP and CBS patients than in healthy subjects, whereas dentate connectivity was reduced in PSP and increased in CBS. We also found a difference in the dentate size between PSP and CBS, with a smaller dentate area in PSP than in CBS patients. Our results provide new neuroimaging data that may help to differentiate the functional connectivity patterns of the thalamic and cerebellar dentate networks in PSP patients from those in CBS patients.
Thalamic networks: functional connectivity changes in PSP and CBS
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We found decreased functional connectivity between the thalamus and several cortical, subcortical and cerebellar areas in patients with PSP and CBS. Patients with PSP were characterized by decreased thalamic functional connectivity with the basal ganglia, the dorsolateral and mesial frontal cortices bilaterally and the left cerebellar hemisphere. These findings confirm and extend
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previous observations in patients with PSP [16-18]. Similarly to PSP patients, CBS patients displayed decreased thalamic functional connectivity with the right basal ganglia as well as with the dorsal and mesial frontal cortices and cerebellum, bilaterally. We found a similar thalamic volume
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reduction in PSP and CBS when compared with healthy subjects, confirming previous
morphometric results [9,10,28-31]. Our findings raise the hypothesis that decreased thalamic
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functional connectivity reflects neuronal degeneration in the thalamic nuclei in both PSP and CBS [1-3]. Accordingly, we speculate that thalamic neuronal loss leads to a functional disconnection between the thalamo-cortical, thalamo-basal ganglia and thalamo-cerebellar networks in PSP and CBS. This hypothesis is in agreement with the results of previous neuropathological studies that
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revealed a cortico-subcortical disconnection in both PSP and CBS patients [1-3].
Dentate nucleus networks: functional connectivity changes in PSP and CBS
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We found that dentate nucleus functional connectivity was altered in both patient groups; however, the specific pattern of brain regions affected and the direction of the functional connectivity changes
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differed in PSP and CBS. Lower dentate nucleus functional connectivity with the basal ganglia, thalamus and prefrontal cortex, bilaterally, was observed in PSP than in CBS patients and healthy subjects. Conversely, greater dentate nucleus functional connectivity with the ACC, SMA, primary motor cortex and prefrontal cortex was observed in CBS patients than in either PSP patients or healthy subjects; furthermore, the distribution of the increased dentate nucleus functional connectivity was asymmetrical in CBS patients, with greater functional connectivity being observed in the cerebral hemisphere contralateral to the body side affected most.
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The decreased dentate nucleus functional connectivity in PSP may be due to neurodegenerative processes in the dentate nucleus. This hypothesis is supported by the observation that the dentate nucleus area was smaller in patients with PSP than in those with CBS or in healthy subjects. Accordingly, we speculate that dentate nucleus neuronal degeneration in PSP leads to a
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disconnection in the cerebello-cortical network. Several mechanisms may explain the increased cerebello-cortical functional connectivity in CBS. In animal models, dentate nucleus neuronal activity depends on the balance between direct excitatory glutamatergic projections from mossy
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fibers (spino-cerebellar and cortico-ponto-cerebellar tracts) and from climbing fibers (from the inferior olive) and inhibitory GABA-ergic projections from Purkinje cells [32]. One hypothesis that
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may explain the increased dentate nucleus functional connectivity we observed in CBS is that an abnormal Purkinje cells activity leads to dentate nucleus disinhibition, as has been suggested on the basis of animal models of dystonia [33]. However, this hypothesis appears to be contradicted by the fact that patients with PSP, unlikely those with CBS, displayed prominent dentate degeneration but decreased functional connectivity. An alternative hypothesis is that increased functional
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connectivity in the dentate nucleus networks in patients with CBS is a compensatory mechanism through which dentate nucleus neuronal reorganization helps to overcome motor and non-motor
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symptoms [34,35]. This hypothesis is based on a recent model that interprets hyper-connectivity in brain networks as a common consequence of neurological disruption [34,36]. According to this
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model, hyper-connectivity results from interactions between situational/transient demands, from the degree of challenge posed by the specific neurological disruption and, lastly, from the resource availability [34,36]. Indeed, the decreased functional connectivity we observed in the dentate nucleus networks of patients with PSP, in whom we found a markedly smaller dentate nucleus surface area than in CBS patients, might reflect the lack of resources available to compensate for the degree of neurological disruption in PSP [34,36]. Although we failed to detect any clinico-radiological correlation, the more severe cognitive impairment (as assessed by FAB) observed in PSP than in CBS patients [37] might depend on the
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functional connectivity reduction in both the thalamic and dentate nucleus networks as well as on the lack of compensatory mechanisms resulting from the greater neuronal loss in the dentate nucleus of PSP patients than in that of CBS patients. A possible limitation of the present study is that the cases we studied were not
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pathologically proven and that the sample enrolled is limited in size. Lastly, as the functional connectivity maps do not provide information on the directionality of the connectivity, it is difficult to ascertain whether the differences we observed in connectivity are due to afferent or efferent
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abnormalities with respect to the seed regions.
Conclusion
This study provides evidence of thalamic and dentate nucleus functional connectivity changes in patients with PSP and CBS. Our observations indicate that the functional and structural changes that occur in the thalamus in PSP and CBS are similar, whereas those that occur in the dentate nucleus
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are different. A recent pathological study detected no significant differences in tau burden between PSP and CBD in the thalamus, but a higher tau burden in cerebellar structures in PSP than in CBD
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[3]. These observations are in keeping with previous neuroimaging data showing that dentatethalamic structural connections differentiate patients with PSP from those with other atypical
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parkinsonisms [13]. The different dentate nucleus structural and functional changes that occur in PSP and CBS patients may represent an imaging biomarker for an in vivo diagnosis.
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ABBREVIATIONS
AD: Alzheimer disease; ANOVA: analysis of variance; CBS: corticobasal syndrome; DN: dentate nucleus; DSM IV-TR: Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text
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Revision; FAB: frontal assessment battery; FTLD: fronto-temporal lobar degeneration; GLM: general linear model; GM: gray matter; HAM-D: Hamilton depression scale; MDS-UPDRS-III: movement disorder society-unified Parkinson’s disease rating scale, part III; MMSE: mini-mental
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state evaluation; PD: Parkinson disease; PSP: progressive supranuclear palsy; rsfMRI: resting-state functional magnetic resonance imaging; RSN: resting-state networks; RS: Richardson syndrome;
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WM: white matter.
REFERENCES
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[1] K.A. Josephs, Key emerging issues in progressive supranuclear palsy and corticobasal degeneration, J Neurol. 262 (2015) 783–791.
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[2] N. Kouri, M.E. Murray, A. Hassan, R. Rademakers, R.J. Uitti, B.F. Boeve, N.R. Graff-Radford, Z.K. Wszolek, I. Litvan, K.A. Josephs, D.W. Dickson, Neuropathological features of corticobasal
3275.
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degeneration presenting as corticobasal syndrome or Richardson syndrome, Brain.134 (2011) 3264–
[3] H. Ling, H. Ling, R. de Silva, L.A. Massey, R. Courtney, G. Hondhamuni, N. Bajaj, J. Lowe, J.L. Holton, A. Lees, T. Revesz, Characteristics of progressive supranuclear palsy presenting with corticobasal syndrome: a cortical variant, Neuropathol. Appl. Neurobiol. 40 (2014) 149–163. [4] I. Litvan, Y. Agid, D. Calne, G. Campbell, B. Dubois, R.C. Duvoisin, C.G. Goetz, L.I. Golbe, J. Grafman, J.H. Growdon, M. Hallett, J. Jankovic, N.P. Quinn, E. Tolosa, D.S. Zee, Clinical research
14
ACCEPTED MANUSCRIPT
criteria for the diagnosis of progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome) Report of the NINDS-SPSP International Workshop, Neurology. 47 (1996) 1–9. [5] M.J. Armstrong, I. Litvan, A.E. Lang, T.H. Bak, K.P. Bhatia, B. Borroni, A.L. Boxer, D.W. Dickson, M. Grossman, M. Hallett, K.A. Josephs, A. Kertesz, S.E. Lee, B.L. Miller, S.G. Reich,
corticobasal degeneration, Neurology. 80 (2013) 496–503.
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D.E. Riley, E. Tolosa, A.I. Tröster, M. Vidailhet, W.J. Weiner, Criteria for the diagnosis of
[6] C. Colosimo, T.H. Bak, M. Bologna, A. Berardelli, Fifty years of progressive supranuclear
SC
palsy, J. Neurol. Neurosurg. Psychiatry 85 (2013) 938-944.
[7] T. Rittman, M. Rubinov, P.E. Vértes, A.X. Patel, C.E. Ginestet, B.C.P. Ghosh, R.A. Barker, M.
M AN U
Spillantini, E.T. Bullmore, J.B. Rowe, Regional expression of the MAPT gene is associated with loss of hubs in brain networks and cognitive impairment in Parkinson disease and progressive supranuclear palsy. Neurobiol Aging. 48 (2016) 153–160.
[8] S.K. Alexander, T. Rittman, J.H. Xuereb, T.H. Bak, J.R. Hodges, J.B. Rowe, Validation of the new consensus criteria for the diagnosis of corticobasal degeneration, J Neurol Neurosurg
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Psychiatry. 85 (2014) 925–929.
[9] K.A. Josephs, J.L. Whitwell, D.W. Dickson, B.F. Boeve, D.S. Knopman, R.C. Petersen, J.E.
29 (2008) 280–289.
EP
Parisi, C.R. Jack, Voxel-based morphometry in autopsy proven PSP and CBD, Neurobiol. Aging.
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[10] J.L. Whitwell, C.R. Jack, B.F. Boeve, J.E. Parisi, J.E. Ahlskog, D.A. Drubach, M.L. Senjem, D.S. Knopman, R.C. Petersen, D.W. Dickson, Imaging correlates of pathology in corticobasal syndrome, Neurology. 75 (2010) 1879–1887. [11] S. Dutt , R.J. Binney, H.W. Heuer, P. Luong, S. Attygalle, P. Bhatt, G.A. Marx, J. Elofson, M.C. Tartaglia, I. Litvan, S.M. McGinnis, B.C. Dickerson, J. Kornak, D. Waltzman, L. Voltarelli, N. Schuff, G.D. Rabinovici, J.H. Kramer, Jr. C.R. Jack, B.L. Miller, H.J. Rosen, A.L. Boxer; AL108-231 investigators, Progression of brain atrophy in PSP and CBS over 6 months and 1 year, Neurology. 87 (2016) 2016-2025.
15
ACCEPTED MANUSCRIPT
[12] Y. Zhang, R. Walter, P. Ng, P.N. Luong, S. Dutt, H. Heuer, J.C. Rojas-Rodriguez, R. Tsai, I. Litvan, B.C. Dickerson, M.C. Tartaglia, G. Rabinovici, B.L. Miller, H.J. Rosen, N. Schuff, A.L. Boxer, Progression of Microstructural Degeneration in Progressive Supranuclear Palsy and Corticobasal Syndrome: A Longitudinal Diffusion Tensor Imaging Study, PLoS One. 11(2016):
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e0157218. [13] Y. Surova, M. Nilsson, J. Lätt, B. Lampinen, O. Lindberg, S. Hall, H. Widner, C. Nilsson, D. van Westen, O. Hansson, Disease-specific structural changes in thalamus and dentatorubrothalamic
SC
tract in progressive supranuclear palsy, Neuroradiology. 57 (2015) 1079–1091.
[14] M.D. Fox, M.E. Raichle, Spontaneous fluctuations in brain activity observed with functional
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magnetic resonance imaging, Nat. Rev. Neurosci. 8 (2007) 700–711.
[15] M.H. Lee, C.D. Smyser, J.S. Shimony, Resting-State fMRI: A Review of Methods and Clinical Applications, Am. J. Neuroradiol. 34 (2013) 1866–1872.
[16] J.L. Whitwell, R. Avula, A. Master, P. Vemuri, M.L. Senjem, D.T. Jones, C.R. Jack, K.A. Josephs, Disrupted thalamocortical connectivity in PSP: A resting-state fMRI, DTI, and VBM
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study, Parkinsonism Relat. Disord. 17 (2011) 599–605. [17] R.C. Gardner, A.L. Boxer, A. Trujillo, J.B. Mirsky, C.C. Guo, E.D. Gennatas, H.W. Heuer, E.
EP
Fine, J. Zhou, J.H. Kramer, B.L. Miller, W.W. Seeley, Intrinsic connectivity network disruption in progressive supranuclear palsy: Network Disruption in PSP, Ann. Neurol. 73 (2013) 603–616.
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[18] M.C. Piattella, F. Tona, M. Bologna, E. Sbardella, A. Formica, N. Petsas, N. Filippini, A. Berardelli, P. Pantano, Disrupted Resting-State Functional Connectivity in Progressive Supranuclear Palsy, Am. J. Neuroradiol. 36 (2015) 915–921. [19] W.W. Seeley, R.K. Crawford, J. Zhou, B.L. Miller, M.D. Greicius, Neurodegenerative Diseases Target Large-Scale Human Brain Networks, Neuron. 62 (2009) 42–52. [20] A. Antonini, G. Abbruzzese, L. Ferini-Strambi, B. Tilley, J. Huang, G.T. Stebbins, C.G. Goetz, P. Barone; MDS-UPDRS Italian Validation Study Group, M. Bandettini di Poggio, G. Fabbrini, F. Di Stasio, M. Tinazzi, T. Bovi, S. Ramat, S. Meoni, G. Pezzoli, M. Canesi, P. Martinelli, CL. Maria
16
ACCEPTED MANUSCRIPT
Scaglione, A. Rossi, N. Tambasco, G. Santangelo, M. Picillo, L. Morgante, F. Morgante, R. Quatrale, M. Sensi, M. Pilleri, R. Biundo, G. Nordera, A. Caria, C. Pacchetti, R. Zangaglia, L. Lopiano, M. Zibetti, M. Zappia, A. Nicoletti, A. Quattrone, M. Salsone, G. Cossu, D. Murgia, A. Albanese, F. Del Sorbo, Validation of the Italian version of the Movement Disorder Society-Unified
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Parkinson’s Disease Rating Scale, Neurol. Sci. 34 (2012) 683-690. [21] M.M. Hoehn, M.D. Yahr, Parkinsonism: onset, progression and mortality, Neurology. 17 (1967) 427–442.
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[22] L.I. Golbe, P.A. Ohman-Strickland, A clinical rating scale for progressive supranuclear palsy, Brain. 130 (2007) 1552–1565.
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[23] M.F. Folstein, S.E. Folstein, P.R. McHugh, “Mini-mental state”: A practical method for grading the cognitive state of patients for the clinician, J. Psychiatr. Res. 12 (1975) 189–198. [24] B. Dubois, A. Slachevsky, I. Litvan, B. Pillon, The FAB: a Frontal Assessment Battery at bedside, Neurology. 55 (2000) 1621–1626.
(1967) 278–296.
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[25] M. Hamilton, Development of a rating scale for primary depressive illness, Clin. Psychol. 6
[26] S.M. Smith, M. Jenkinson, M.W. Woolrich, C.F. Beckmann, T.E.J. Behrens, H. Johansen-
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Berg, P.R. Bannister, M. De Luca, I. Drobnjak, D.E. Flitney, R.K. Niazy, J. Saunders, J. Vickers, Y. Zhang, N. De Stefano, J.M. Brady, P.M. Matthews, Advances in functional and structural MR
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image analysis and implementation as FSL, NeuroImage. 23, Supplement 1 (2004) S208–S219. [27] P.M. Macey, K.E. Macey, R. Kumar, R.M. Harper, A method for removal of global effects from fMRI time series, Neuroimage. 22 (2004) 360–366 [28] M.C. Piattella, N. Upadhyay, M. Bologna, E. Sbardella, F. Tona, A. Formica, N. Petsas, A. Berardelli, P. Pantano, Neuroimaging evidence of gray and white matter damage and clinical correlates in progressive supranuclear palsy, J. Neurol. 262 (2015) 1850–1858.
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[29] C.P. Hess, C.W. Christine, A.C. Apple, W.P. Dillon, M.J. Aminoff, Changes in the thalamus in atypical parkinsonism detected using shape analysis and diffusion tensor imaging, AJNR Am. J. Neuroradiol. 35 (2014) 897–903. [30] N. Upadhyay, A. Suppa, M.C. Piattella, F. Di Stasio, N. Petsas, C. Colonnese, C. Colosimo, A.
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Berardelli, P. Pantano, Gray and white matter structural changes in corticobasal syndrome, Neurobiol. Aging. 37 (2016) 82–90.
[31] N. Upadhyay, A. Suppa, M.C. Piattella, M. Bologna, F. Di Stasio, A. Formica, F. Tona, C.
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Colosimo, A. Berardelli, P. Pantano, MRI gray and white matter measures in progressive supranuclear palsy and corticobasal syndrome, J Neurol. (2016).
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[32] V. Steuber and D. Jaeger, Modeling the Generation of Output by the Cerebellar Nuclei, Neural Netw. 47 (2013) 112–119.
[33] R.S. Raike, C.E. Pizoli, C. Weisz, A.M.J.M. van den Maagdenberg, H.A. Jinnah, E.J. Hess, Limited regional cerebellar dysfunction induces focal dystonia in mice, Neurobiol. Dis. 49 (2013) 200–210.
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[34] M. Küper, A. Dimitrova, M. Thürling, S. Maderwald, J. Roths, H.G. Elles, E.R. Gizewski, M.E. Ladd, J. Diedrichsen, D. Timmann, Evidence for a motor and a non-motor domain in the
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human dentate nucleus--an fMRI study, Neuroimage. 54 (2011) 2612-2622. [35] T. Wu, M. Hallett, The cerebellum in Parkinson’s disease, Brain. 136 (2013) 696–709.
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[36] F.G. Hillary, C.A. Roman, U. Venkatesan, S.M. Rajtmajer, R. Bajo, N.D. Castellanos, Hyperconnectivity is a fundamental response to neurological disruption, Neuropsychology. 29 (2015) 59–75.
[37] J.R. Burrell, J.R. Hodges, J.B. Rowe, Cognition in corticobasal syndrome and progressive supranuclear palsy: a review, Mov. Disord. 29 (2014) 684–693.
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FIGURE LEGENDS
Figure 1. Maps of functional connectivity obtained from the thalamus of 12 healthy subjects (redyellow) (one-sample t-test, p<0.05, corrected for family wise error - FWE); maps of differences in
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the functional connectivity (FC) of the thalamus (blue) between 19 patients with progressive supranuclear palsy (PSP) and 12 healthy subjects, and between 11 patients with cortical-basal syndrome (CBS) and 12 healthy subjects (two-sample t-test, p<0.05, corrected for FWE). L: left
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hemisphere; R: right hemisphere.
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Figure 2. Maps of functional connectivity obtained from the dentate nucleus of 12 healthy subjects (red-yellow) (one-sample t-test, p<0.05, corrected for family wise error - FWE); maps of differences in the functional connectivity (FC) of the dentate nucleus (red) between 19 patients with progressive supranuclear palsy (PSP) (blue) and 12 healthy subjects, and between 11 patients with cortical-basal syndrome (CBS) and 12 healthy subjects (two-sample t-test, p<0.05, corrected for
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FWE). L: left hemisphere; R: right hemisphere.
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CBS
P-value
(n=12)
(n=19)
(n=11)
(<0.05)
Age (yrs)
69.3±5.2
68.35 ± 5.8
68±6.9
0.125
Sex, M:F
5:7
10:9
3:8
0.210
Disease duration (yrs)
-
3.21 ± 1.8
2.64 ± 1.3
H&Y
-
2.9 ± 1.0
2.3 ± 1.7
PSPRS
-
35.82 ± 17.0
MDS-UPDRS-III
-
27.62 ± 17.9 36.09 ± 23.4 0.417
0.561
0.410
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MMSE
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HS
-
29.4±0.9
24.33 ± 3.9
26.81 ±0.9
0.000+
-
11.19 ± 3.8
15.45 ± 1.4
0.0038*
4.7±3.8
8.8 ± 3.6
11.63 ± 3.4
0.000*+
FAB
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HAM-D
HS: healthy subjects; PSP: progressive supranuclear palsy; CBS: corticobasal syndrome; H&Y: Hoehn & Yahr scale; PSPRS: Progressive Supranuclear Palsy rating
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scale, MDS-UPDRS-III: Unified Parkinson’s disease rating scale, part III; MMSE: mini-mental state examination; FAB: frontal assessment battery, HAM-D: Hamilton
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depression scale.
Significant p values are in bold. * Indicates significant difference between patient groups while
+
indicates p values that were significantly different in both patients
group from those of HS.
ACCEPTED MANUSCRIPT Table 2 Radiological characteristics of 19 patients with PSP, of 11 patients with CBS and of 12 healthy subjects (HS).
8.829 ± 1.15
CBSa (n=11)
P Value b
9.23 ± 1.648
p=0.003
Dentate A.
99.30 ± 18.62
p<0.0001
GM V.
764.39 ± 72.83 724.79 ± 65.77 712.14 ± 52.93
p=0.133
WM V.
790.36 ± 82.96 752.23 ± 58.35 705.71 ± 63.78* p=0.017
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59.970 ± 19.87 74.45 ± 23.708
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Thalamus V. 11.13 ± 2.26
PSP a (n=19)
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HSa (n=12)
V.= volume (mm3); A.=area (mm2).
Left and right values of subcortical volumes are averaged. Values are reported as mean ± standard deviation
b
Differences between groups were assessed by Kruskal-Wallis non-parametric Anova
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a
and posthoc pairwise comparisons.
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ACCEPTED MANUSCRIPT Highlights •
Decreased thalamic functional connectivity in Progressive supranuclear palsy (PSP) Decreased thalamic functional connectivity in Corticobasal syndrome (CBS).
•
Decreased dentate nucleus functional connectivity in PSP.
•
Increased dentate nucleus functional connectivity in CBS.
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•
S1353-8020(17)30103-7
DOI:
10.1016/j.parkreldis.2017.03.008
Reference:
PRD 3266
To appear in:
Parkinsonism and Related Disorders
Received Date: 19 October 2016 Revised Date:
10 February 2017
Accepted Date: 13 March 2017
Please cite this article as: Upadhyay N, Suppa A, Piattella MC, Gianni C, Bologna M, Di Stasio F, Petsas N, Tona F, Fabbrini G, Berardelli A, Pantano P, Functional disconnection of thalamic and cerebellar dentate nucleus networks in progressive supranuclear palsy and corticobasal syndrome, Parkinsonism and Related Disorders (2017), doi: 10.1016/j.parkreldis.2017.03.008. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Functional Disconnection of Thalamic and Cerebellar Dentate Nucleus
Networks in Progressive Supranuclear Palsy and Corticobasal Syndrome
Neeraj Upadhyay PhD1, Antonio Suppa MD PhD1-2, Maria Cristina Piattella MD PhD1, Costanza
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Gianni MD1, Matteo Bologna MD PhD1-2, Flavio Di Stasio MD2, Nikolaos Petsas PhD1, Francesca Tona MD1, Giovanni Fabbrini MD1-2, Alfredo Berardelli MD1-2 and Patrizia Pantano MD1-2 1
Department of Neurology and Psychiatry, “Sapienza” University of Rome, Italy, 2IRCCS
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Neuromed Institute, Pozzilli (IS), Italy.
thalamus, dentate nucleus.
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Keywords: progressive supranuclear palsy, corticobasal syndrome, functional connectivity,
Running head: Thalamic and dentate nucleus functional connectivity in PSP and CBS. Number of words (Abstract): 202
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Number of words (Introduction): 620 Number of words (Discussion): 1001
Number of words (excluding references and abstract): 3197
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Number of Figures: 2
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Number of Tables: 2
Corresponding author: Prof. Patrizia Pantano
Department of Neurology and Psychiatry, Sapienza University of Rome Viale dell’Università, 30, 00185 Rome, Italy Telephone number: +39- 0649914719 Fax+39- 0649914903 E-mail: [email protected]
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ABSTRACT
Aim: To assess functional rearrangement following neurodegeneration in the thalamus and dentate nucleus in patients with progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS).
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Methods: We recruited 19 patients with PSP, 11 with CBS and 14 healthy subjects. All the subjects underwent resting-state (rs) fMRI using a 3T system. Whole brain functional connectivity of the thalamus and dentate nucleus were calculated by means of a seed-based approach with FEAT script
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in FSL toolbox. Thalamic volume was calculated by means of FIRST, and the dentate area by means of Jim software.
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Results: Both thalamic volume and dentate area were significantly smaller in PSP and CBS patients than in healthy subjects. No significant difference emerged in thalamic volume between PSP and CBS patients, whereas dentate area was significantly smaller in PSP than in CBS. Thalamic functional connectivity was significantly reduced in both patient groups in various cortical, subcortical and cerebellar areas. By contrast, changes in dentate nucleus functional connectivity
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differed in PSP and CBS: it decreased in subcortical and prefrontal cortical areas in PSP, but increased asymmetrically in the frontal cortex in CBS.
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Conclusions: Evaluating the dentate nucleus size and its functional connectivity may help to
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differentiate patients with PSP from those with CBS.
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INTRODUCTION
Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are 4R-tauopathies characterized by neuronal loss and accumulation of filamentous tau inclusions within neurons and
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glia [1-3]. CBD is pathologically characterized by a prominent and asymmetrical involvement of the fronto-parietal cortex, whereas PSP mainly involves subcortical structures, the midbrain and the cerebellum [1-3]. Clinically, PSP and CBD are characterized by parkinsonism and a combination of
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additional motor, cognitive and behavioral symptoms. In PSP, motor symptoms include
parkinsonism, vertical supranuclear gaze palsy, postural instability and early falls, whereas
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cognitive and behavioral symptoms mainly include a frontal dysexecutive syndrome associated with apathy, impulsivity, and visuospatial and memory function impairment [4-7]. The most frequent clinical presentation of CBD is instead corticobasal syndrome (CBS), which is characterized by parkinsonism, dystonia, myoclonus, cortical sensory loss, ideomotor apraxia, alien-limb phenomena with a characteristically asymmetrical distribution, and additional cognitive and behavioral
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impairment [5,8]. Since the clinical features in PSP and CBS patients may overlap, particularly in the early disease stages [1,4], new imaging biomarkers that may be used to differentiate PSP from
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CBS are of great importance.
MRI studies have extensively demonstrated differences between PSP and CBS patients in
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structural damage in the gray (GM) and white matter (WM). PSP is characterized by damage to infratentorial structures, i.e. the midbrain and cerebellum [9]. Severe asymmetrical atrophy of the perirolandic cortex is typical of CBS, whereas the frontal cortex atrophy observed in PSP is symmetrical [10]; moreover, basal ganglia and thalamic atrophy have been reported in both CBS and PSP [9,10]. A recent longitudinal MRI study in which patients were examined at 6-12 month intervals, demonstrated greater volume loss in CBS than in PSP in the basal ganglia as well as in several cortical regions, including the precentral gyrus, whereas the degree of atrophy in the brainstem was comparable [11]. Similarly, recent diffusion tensor imaging (DTI) longitudinal
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studies have shown that WM changes are prominent in CBS [12], whereas the involvement of the dentate-rubro-thalamic tract is greater in patients with PSP [13], a finding that is in keeping with neuropathological studies [2,3]. Resting-state fMRI (rs-fMRI) is used to investigate functional connectivity between
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different brain structures during spontaneous neuronal activity at rest [14]. This activity is assessed by identifying slow fluctuations in the blood oxygen level-dependent (BOLD) signal and is depicted by means of spatial correlation maps (functional connectivity maps) [14]. The seed-based approach,
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which is one of the possible methods available to analyze fMRI data in a region-of-interest, is performed by correlating the time course of a region chosen a priori with that of all the other brain
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voxels [15]. Three recent seed-based studies have explored functional connectivity in PSP and demonstrated functional disruption of the caudate, putamen, pallidum, dorsal midbrain tegmentum and, more prominently, of the thalamus [16-18]. Only one previous study by Seeley and colleagues [19], who compared brain functional patterns in several types of neurodegenerative disorders, including CBS, demonstrated abnormal asymmetrical resting state activity in the sensori-motor
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network in patients with CBS.
To the best of our knowledge, no studies have yet investigated dentate nucleus functional
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connectivity in PSP, nor have any specifically investigated thalamic and dentate nucleus functional connectivity in CBS. We believe that an evaluation and comparison of thalamic and dentate nucleus
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functional connectivity changes in patients with PSP and CBS may provide a better understanding of the pathophysiology of these two conditions and thereby help to differentiate between them. The aim of our work was to investigate functional connectivity changes in brain regions selected a priori, i.e. the thalamus and the dentate nucleus, in PSP and CBS. We also measured structural abnormalities in thalamus and dentate seeds in order to identify any association between neuronal loss and functional rearrangement in these two clinical conditions.
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MATERIALS AND METHODS
Subjects We recruited 19 patients with a diagnosis of probable PSP (9 females, mean age ± standard
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deviation: 69.4±4.9), 11 patients with a diagnosis of probable CBS (8 females, 68.0±6.9) and 12 age-matched healthy subjects (9 females, 69.3±5.2). All the patients were referred to the Movement Disorders outpatient clinic of the Department of Neurology and Psychiatry at Sapienza University
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of Rome (Italy). A movement disorder specialist made the diagnosis of probable PSP and probable CBS on the basis of the most recent clinical criteria [4, 5]. The clinical features of all the PSP
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patients were characteristic of Richardson’s syndrome. The asymmetrical clinical features in the CBS patients consisted of predominantly right-side symptoms in 6 of the patients and predominantly left-side symptoms in the other 5. Table 1 shows the demographic and clinical features of the participants, all of whom were right-handed. Motor signs were scored using part III of the Italian version of the Movement Disorder Society-Unified Parkinson’s Disease Rating Scale
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(MDS-UPDRS-III) [20], the Hoehn & Yahr (H&Y) scale [21]; patients with probable PSP were also assessed by means of the PSP-Rating Scale (PSP-RS) [22]. Cognitive functions were evaluated
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by means of the Mini-Mental State Evaluation (MMSE) [23] and Frontal Assessment Battery (FAB) [24]. Depression was evaluated by means of the Hamilton Depression Scale (HAM-D) [25].
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Patients suffering from dementia or depression, defined according to the Diagnostic and Statistical Manual of Mental Disorders (DSM IV-TR) criteria, were excluded, as were any patients with other neurological, psychiatric and systemic diseases or general contraindications to MRI. Patients were asked to suspend L-dopa treatment or any other drugs known to act on the central nervous system at least twelve hours before the MRI examination. Participants gave their written informed consent, and the study was approved by the institutional review board and conformed to the Declaration of Helsinki.
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MRI acquisition
All the patients underwent a multimodal MRI study on a 3.0 T Siemens scanner (Verio, Siemens AG, Erlangen, Germany) that included rs-fMRI and volumetric imaging. The manufacturer’s 12channel head coil designed for parallel imaging (GRAPPA) was used for signal reception. A multi-
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planar T1-weighted localizer with slice orientation parallel to the subcallosal line was acquired at the beginning of each MRI examination. The following sequences were acquired for all the
subjects: a) BOLD single-shot echo-planar images (TR=3,000 ms, TE=30 ms, flip angle=89°,
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FOV=192, matrix=64x64, 50 axial slices 3 mm thick, no gap, 120 volumes, acquisition time=7 minutes), with all the patients and healthy subjects being instructed to close their eyes and stay
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awake during the rs-fMRI acquisitions; b) high-resolution 3D, T1-weighted (T1-3D) MPRAGE sequence (TR=1,900 ms, TE=2.93 ms, flip angle=9°, FOV=260 mm, matrix=256x256, 176 sagittal slices 1 mm thick, no gap); c) dual turbo spin-echo, proton density (PD) and T2-weighted images (TR=3,320 ms, TE=10/103ms, FOV=220 mm, matrix=384x384, 25 axial slices 4 mm thick, 30%
MRI data analysis
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Structural MRI
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due to concomitant diseases.
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gap). The dual turbo spin-echo sequences were obtained to exclude subjects with brain alterations
T1-3D images were processed using SIENAX (http://fsl.fmrib.ox.ac.uk/fsl/fslwiki/SIENA), a fully automated and accurate method for measuring cross-sectional changes in brain volume [26]. Sub-cortical volumes of the thalamus were estimated by means of FMRIB’s Integrated Registration and Segmentation Tool (FIRST) [18]. Thalamic volumes were corrected for individual differences in intracranial volume using an individual scale factor obtained from Sienax. The dentate nuclei were identified in every patient as hypo-intense regions on T2-weighted images located in anatomical sites defined according to a cerebellar reference atlas (SUIT,
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http://www.diedrichsenlab.org/imaging/suit.htm), and were delineated using a semi-automated software (Xinapse Systems Ltd., West Bergholt, UK, http://www.xinapse.com/j-im-7-software/) that also indicated their area.
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Functional MRI Data were analyzed using FSL (FMRIB’s Software Library) tools v 4.1.9
(http://www.fmrib.ox.ac.uk/fsl). Single-subject preprocessing and group analysis were performed
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using FEAT (FMRI Expert Analysis Tool) version 5.98. The first 3 volumes of the 140 resting-state BOLD volumes were discarded to obtain a steady-state BOLD signal. In brief, preprocessing
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consisted of head motion correction, brain extraction, spatial smoothing using a Gaussian kernel of FWHM (full width at half maximum) 5 mm and high pass temporal filtering. Functional data were registered to structural images (within-subject) and MNI standard space (to allow higher level group comparisons) using both linear (FMRIB's Linear Image Registration Tool, FLIRT) and non-linear (FNIRT) registration tools [18].
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As the clinical and MRI features of CBS are asymmetrical, the MR images were flipped in the X dimension so that the more severely affected hemisphere (contralateral to the more affected body
previous study [10].
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side) was positioned on the left side for all the subjects, according to the method adopted in a
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Individual seed region-of-interest (ROI) masks of the thalami were obtained from each subject using an automatic sub-cortical segmentation program. Each image was visually inspected in the coronal plane to ensure accuracy. Left and right masks of the thalamus were merged to obtain a single bilateral mask. In addition, a 4 mm-radius spherical ROI was placed on each of the dentate nuclei and centered according to the coordinates (left -18, -58, -36; right 18, -56, -36) of the probabilistic SUIT cerebellar atlas included in the FSL tool package. After visual inspection to ensure location of the dentate nucleus was correct, the left and right dentate masks were merged to obtain a single bilateral mask. The thalamic and dentate masks were then registered to functional
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coordinate space and used to extract the related time course from preprocessed fMRI data. Time series were averaged across all voxels for each seed. After having been separately fed into FEAT, each time series yielded individual participant-level correlation maps of all voxels that were either positively or negatively correlated with each seed. The general linear model (GLM) was applied to
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test for group averages and differences between patient groups and healthy subjects using the twosample unpaired t-test. The Z-statistic images were thresholded using clusters determined by Z > 2.3, and a whole brain family-wise-error (FWE) corrected clusters were thresholded for a
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significance level of p < 0.05. The anatomical location of significant clusters was established according to the standard atlas included in the FSL (http://www.fmrib.ox.ac.uk/fsl/data/atlas-
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descriptions.html).
Potential indeterminate noise [27], seeds of cerebrospinal fluid (CSF) and white matter (WM) were also identified on each individual functional image, and their time courses were added as covariates of no-interest into each of the seed voxel-wise correlation analyses to remove non-neural contributions to the BOLD signal. Similarly, the study participants’ age, thalamic volume and
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dentate nucleus area were entered as nuisance covariates. Finally, structural maps were used as additional covariates on a voxel-by-voxel basis to account for potential gray matter volume
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two patient groups.
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differences. Lastly, we correlated the functional connectivity of each seed with clinical scores in the
Statistical Analysis
The statistical analysis was carried out using SPSS software, version 16.0 (SPSS, Chicago, Illinois, USA). All values are reported as mean ±standard deviation (SD). ANOVA, post-hoc t test and chisquare were used to detect any differences between groups. Clinico-radiological correlations were performed using Spearman rank correlation. All the results are reported at p<0.05 after correction for multiple comparisons.
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Both the ANOVA and the chi-square test showed that age (p=0.12) and gender (χ (1) =3.12,
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p=0.21) were comparable in all 3 groups (patients with PSP, CBS and healthy subjects). Moreover, the MDS-UPDRS-III scores (p=0.47), disease duration (p=0.49) and H&Y scores (p=0.41) were comparable in CBS and PSP patients. MMSE and FAB scores were significantly lower in PSP and
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CBS patients than in healthy subjects (p<0.001). The MMSE scores were comparable in PSP and CBS (p>0.05), whereas the FAB scores were significantly lower in PSP than in CBS patients
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(p=0.004). Lastly, the HAM-D scores were not only higher in PSP and CBS patients than in controls (p<0.000), but also significantly higher in CBS than in PSP patients (p=0.04).
Structural MRI
Thalamic volume was significantly smaller in patients with PSP and CBS than in healthy subjects
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(p=0.003), with no difference being detected between PSP and CBS patients (Table 2). The dentate nucleus area was significantly smaller in both PSP and CBS patients than in healthy subjects
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(p=0.0001) (Table 2). Post-hoc analysis showed a greater reduction in the dentate nucleus area in
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patients with PSP than in those with CBS (p=0.0001).
Functional MRI
No significant differences in thalamic functional connectivity were observed between PSP and CBS patients; thalamic functional connectivity was lower in both patient groups than in healthy subjects. The areas affected to the greater extent by decreased thalamic functional connectivity were the basal ganglia, dorsolateral prefrontal cortex (DLPFC), anterior cingulate cortex (ACC), supplementary motor area (SMA), bilaterally, and left cerebellum in PSP, and the right basal ganglia, left DLPFC, ACC and SMA, and cerebellum bilaterally in CBS (Fig 1).
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Dentate nucleus functional connectivity significantly differed between PSP and CBS patients, as well as between both these groups of patients and healthy subjects. In particular, PSP patients displayed lower dentate nucleus functional connectivity with the basal ganglia, thalamus and prefrontal cortex bilaterally than either CBS patients or healthy subjects. By contrast, if
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compared with PSP patients and healthy subjects, CBS patients displayed increased dentate nucleus functional connectivity with the ACC, SMA, primary motor cortex and prefrontal cortex,
bilaterally, though predominantly in the more affected hemisphere (contralateral to the body side
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affected most) (Fig. 2).
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Clinico-radiological correlations
No significant correlations emerged between functional connectivity changes within the thalamic and dentate seed regions and the clinical scores in either patient group even when the MDS-UPDRS
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DISCUSSION
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subscores that are specific for bradykinesia, rigidity and tremor alone were considered.
In this study, we used a seed-based rs-fMRI approach to explore thalamic and dentate nucleus
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functional connectivity in patients with PSP and CBS. Thalamic connectivity was lower in both PSP and CBS patients than in healthy subjects, whereas dentate connectivity was reduced in PSP and increased in CBS. We also found a difference in the dentate size between PSP and CBS, with a smaller dentate area in PSP than in CBS patients. Our results provide new neuroimaging data that may help to differentiate the functional connectivity patterns of the thalamic and cerebellar dentate networks in PSP patients from those in CBS patients.
Thalamic networks: functional connectivity changes in PSP and CBS
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We found decreased functional connectivity between the thalamus and several cortical, subcortical and cerebellar areas in patients with PSP and CBS. Patients with PSP were characterized by decreased thalamic functional connectivity with the basal ganglia, the dorsolateral and mesial frontal cortices bilaterally and the left cerebellar hemisphere. These findings confirm and extend
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previous observations in patients with PSP [16-18]. Similarly to PSP patients, CBS patients displayed decreased thalamic functional connectivity with the right basal ganglia as well as with the dorsal and mesial frontal cortices and cerebellum, bilaterally. We found a similar thalamic volume
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reduction in PSP and CBS when compared with healthy subjects, confirming previous
morphometric results [9,10,28-31]. Our findings raise the hypothesis that decreased thalamic
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functional connectivity reflects neuronal degeneration in the thalamic nuclei in both PSP and CBS [1-3]. Accordingly, we speculate that thalamic neuronal loss leads to a functional disconnection between the thalamo-cortical, thalamo-basal ganglia and thalamo-cerebellar networks in PSP and CBS. This hypothesis is in agreement with the results of previous neuropathological studies that
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revealed a cortico-subcortical disconnection in both PSP and CBS patients [1-3].
Dentate nucleus networks: functional connectivity changes in PSP and CBS
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We found that dentate nucleus functional connectivity was altered in both patient groups; however, the specific pattern of brain regions affected and the direction of the functional connectivity changes
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differed in PSP and CBS. Lower dentate nucleus functional connectivity with the basal ganglia, thalamus and prefrontal cortex, bilaterally, was observed in PSP than in CBS patients and healthy subjects. Conversely, greater dentate nucleus functional connectivity with the ACC, SMA, primary motor cortex and prefrontal cortex was observed in CBS patients than in either PSP patients or healthy subjects; furthermore, the distribution of the increased dentate nucleus functional connectivity was asymmetrical in CBS patients, with greater functional connectivity being observed in the cerebral hemisphere contralateral to the body side affected most.
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The decreased dentate nucleus functional connectivity in PSP may be due to neurodegenerative processes in the dentate nucleus. This hypothesis is supported by the observation that the dentate nucleus area was smaller in patients with PSP than in those with CBS or in healthy subjects. Accordingly, we speculate that dentate nucleus neuronal degeneration in PSP leads to a
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disconnection in the cerebello-cortical network. Several mechanisms may explain the increased cerebello-cortical functional connectivity in CBS. In animal models, dentate nucleus neuronal activity depends on the balance between direct excitatory glutamatergic projections from mossy
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fibers (spino-cerebellar and cortico-ponto-cerebellar tracts) and from climbing fibers (from the inferior olive) and inhibitory GABA-ergic projections from Purkinje cells [32]. One hypothesis that
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may explain the increased dentate nucleus functional connectivity we observed in CBS is that an abnormal Purkinje cells activity leads to dentate nucleus disinhibition, as has been suggested on the basis of animal models of dystonia [33]. However, this hypothesis appears to be contradicted by the fact that patients with PSP, unlikely those with CBS, displayed prominent dentate degeneration but decreased functional connectivity. An alternative hypothesis is that increased functional
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connectivity in the dentate nucleus networks in patients with CBS is a compensatory mechanism through which dentate nucleus neuronal reorganization helps to overcome motor and non-motor
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symptoms [34,35]. This hypothesis is based on a recent model that interprets hyper-connectivity in brain networks as a common consequence of neurological disruption [34,36]. According to this
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model, hyper-connectivity results from interactions between situational/transient demands, from the degree of challenge posed by the specific neurological disruption and, lastly, from the resource availability [34,36]. Indeed, the decreased functional connectivity we observed in the dentate nucleus networks of patients with PSP, in whom we found a markedly smaller dentate nucleus surface area than in CBS patients, might reflect the lack of resources available to compensate for the degree of neurological disruption in PSP [34,36]. Although we failed to detect any clinico-radiological correlation, the more severe cognitive impairment (as assessed by FAB) observed in PSP than in CBS patients [37] might depend on the
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functional connectivity reduction in both the thalamic and dentate nucleus networks as well as on the lack of compensatory mechanisms resulting from the greater neuronal loss in the dentate nucleus of PSP patients than in that of CBS patients. A possible limitation of the present study is that the cases we studied were not
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pathologically proven and that the sample enrolled is limited in size. Lastly, as the functional connectivity maps do not provide information on the directionality of the connectivity, it is difficult to ascertain whether the differences we observed in connectivity are due to afferent or efferent
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abnormalities with respect to the seed regions.
Conclusion
This study provides evidence of thalamic and dentate nucleus functional connectivity changes in patients with PSP and CBS. Our observations indicate that the functional and structural changes that occur in the thalamus in PSP and CBS are similar, whereas those that occur in the dentate nucleus
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are different. A recent pathological study detected no significant differences in tau burden between PSP and CBD in the thalamus, but a higher tau burden in cerebellar structures in PSP than in CBD
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[3]. These observations are in keeping with previous neuroimaging data showing that dentatethalamic structural connections differentiate patients with PSP from those with other atypical
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parkinsonisms [13]. The different dentate nucleus structural and functional changes that occur in PSP and CBS patients may represent an imaging biomarker for an in vivo diagnosis.
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ABBREVIATIONS
AD: Alzheimer disease; ANOVA: analysis of variance; CBS: corticobasal syndrome; DN: dentate nucleus; DSM IV-TR: Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text
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Revision; FAB: frontal assessment battery; FTLD: fronto-temporal lobar degeneration; GLM: general linear model; GM: gray matter; HAM-D: Hamilton depression scale; MDS-UPDRS-III: movement disorder society-unified Parkinson’s disease rating scale, part III; MMSE: mini-mental
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state evaluation; PD: Parkinson disease; PSP: progressive supranuclear palsy; rsfMRI: resting-state functional magnetic resonance imaging; RSN: resting-state networks; RS: Richardson syndrome;
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WM: white matter.
REFERENCES
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[1] K.A. Josephs, Key emerging issues in progressive supranuclear palsy and corticobasal degeneration, J Neurol. 262 (2015) 783–791.
EP
[2] N. Kouri, M.E. Murray, A. Hassan, R. Rademakers, R.J. Uitti, B.F. Boeve, N.R. Graff-Radford, Z.K. Wszolek, I. Litvan, K.A. Josephs, D.W. Dickson, Neuropathological features of corticobasal
3275.
AC C
degeneration presenting as corticobasal syndrome or Richardson syndrome, Brain.134 (2011) 3264–
[3] H. Ling, H. Ling, R. de Silva, L.A. Massey, R. Courtney, G. Hondhamuni, N. Bajaj, J. Lowe, J.L. Holton, A. Lees, T. Revesz, Characteristics of progressive supranuclear palsy presenting with corticobasal syndrome: a cortical variant, Neuropathol. Appl. Neurobiol. 40 (2014) 149–163. [4] I. Litvan, Y. Agid, D. Calne, G. Campbell, B. Dubois, R.C. Duvoisin, C.G. Goetz, L.I. Golbe, J. Grafman, J.H. Growdon, M. Hallett, J. Jankovic, N.P. Quinn, E. Tolosa, D.S. Zee, Clinical research
14
ACCEPTED MANUSCRIPT
criteria for the diagnosis of progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome) Report of the NINDS-SPSP International Workshop, Neurology. 47 (1996) 1–9. [5] M.J. Armstrong, I. Litvan, A.E. Lang, T.H. Bak, K.P. Bhatia, B. Borroni, A.L. Boxer, D.W. Dickson, M. Grossman, M. Hallett, K.A. Josephs, A. Kertesz, S.E. Lee, B.L. Miller, S.G. Reich,
corticobasal degeneration, Neurology. 80 (2013) 496–503.
RI PT
D.E. Riley, E. Tolosa, A.I. Tröster, M. Vidailhet, W.J. Weiner, Criteria for the diagnosis of
[6] C. Colosimo, T.H. Bak, M. Bologna, A. Berardelli, Fifty years of progressive supranuclear
SC
palsy, J. Neurol. Neurosurg. Psychiatry 85 (2013) 938-944.
[7] T. Rittman, M. Rubinov, P.E. Vértes, A.X. Patel, C.E. Ginestet, B.C.P. Ghosh, R.A. Barker, M.
M AN U
Spillantini, E.T. Bullmore, J.B. Rowe, Regional expression of the MAPT gene is associated with loss of hubs in brain networks and cognitive impairment in Parkinson disease and progressive supranuclear palsy. Neurobiol Aging. 48 (2016) 153–160.
[8] S.K. Alexander, T. Rittman, J.H. Xuereb, T.H. Bak, J.R. Hodges, J.B. Rowe, Validation of the new consensus criteria for the diagnosis of corticobasal degeneration, J Neurol Neurosurg
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Psychiatry. 85 (2014) 925–929.
[9] K.A. Josephs, J.L. Whitwell, D.W. Dickson, B.F. Boeve, D.S. Knopman, R.C. Petersen, J.E.
29 (2008) 280–289.
EP
Parisi, C.R. Jack, Voxel-based morphometry in autopsy proven PSP and CBD, Neurobiol. Aging.
AC C
[10] J.L. Whitwell, C.R. Jack, B.F. Boeve, J.E. Parisi, J.E. Ahlskog, D.A. Drubach, M.L. Senjem, D.S. Knopman, R.C. Petersen, D.W. Dickson, Imaging correlates of pathology in corticobasal syndrome, Neurology. 75 (2010) 1879–1887. [11] S. Dutt , R.J. Binney, H.W. Heuer, P. Luong, S. Attygalle, P. Bhatt, G.A. Marx, J. Elofson, M.C. Tartaglia, I. Litvan, S.M. McGinnis, B.C. Dickerson, J. Kornak, D. Waltzman, L. Voltarelli, N. Schuff, G.D. Rabinovici, J.H. Kramer, Jr. C.R. Jack, B.L. Miller, H.J. Rosen, A.L. Boxer; AL108-231 investigators, Progression of brain atrophy in PSP and CBS over 6 months and 1 year, Neurology. 87 (2016) 2016-2025.
15
ACCEPTED MANUSCRIPT
[12] Y. Zhang, R. Walter, P. Ng, P.N. Luong, S. Dutt, H. Heuer, J.C. Rojas-Rodriguez, R. Tsai, I. Litvan, B.C. Dickerson, M.C. Tartaglia, G. Rabinovici, B.L. Miller, H.J. Rosen, N. Schuff, A.L. Boxer, Progression of Microstructural Degeneration in Progressive Supranuclear Palsy and Corticobasal Syndrome: A Longitudinal Diffusion Tensor Imaging Study, PLoS One. 11(2016):
RI PT
e0157218. [13] Y. Surova, M. Nilsson, J. Lätt, B. Lampinen, O. Lindberg, S. Hall, H. Widner, C. Nilsson, D. van Westen, O. Hansson, Disease-specific structural changes in thalamus and dentatorubrothalamic
SC
tract in progressive supranuclear palsy, Neuroradiology. 57 (2015) 1079–1091.
[14] M.D. Fox, M.E. Raichle, Spontaneous fluctuations in brain activity observed with functional
M AN U
magnetic resonance imaging, Nat. Rev. Neurosci. 8 (2007) 700–711.
[15] M.H. Lee, C.D. Smyser, J.S. Shimony, Resting-State fMRI: A Review of Methods and Clinical Applications, Am. J. Neuroradiol. 34 (2013) 1866–1872.
[16] J.L. Whitwell, R. Avula, A. Master, P. Vemuri, M.L. Senjem, D.T. Jones, C.R. Jack, K.A. Josephs, Disrupted thalamocortical connectivity in PSP: A resting-state fMRI, DTI, and VBM
TE D
study, Parkinsonism Relat. Disord. 17 (2011) 599–605. [17] R.C. Gardner, A.L. Boxer, A. Trujillo, J.B. Mirsky, C.C. Guo, E.D. Gennatas, H.W. Heuer, E.
EP
Fine, J. Zhou, J.H. Kramer, B.L. Miller, W.W. Seeley, Intrinsic connectivity network disruption in progressive supranuclear palsy: Network Disruption in PSP, Ann. Neurol. 73 (2013) 603–616.
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[18] M.C. Piattella, F. Tona, M. Bologna, E. Sbardella, A. Formica, N. Petsas, N. Filippini, A. Berardelli, P. Pantano, Disrupted Resting-State Functional Connectivity in Progressive Supranuclear Palsy, Am. J. Neuroradiol. 36 (2015) 915–921. [19] W.W. Seeley, R.K. Crawford, J. Zhou, B.L. Miller, M.D. Greicius, Neurodegenerative Diseases Target Large-Scale Human Brain Networks, Neuron. 62 (2009) 42–52. [20] A. Antonini, G. Abbruzzese, L. Ferini-Strambi, B. Tilley, J. Huang, G.T. Stebbins, C.G. Goetz, P. Barone; MDS-UPDRS Italian Validation Study Group, M. Bandettini di Poggio, G. Fabbrini, F. Di Stasio, M. Tinazzi, T. Bovi, S. Ramat, S. Meoni, G. Pezzoli, M. Canesi, P. Martinelli, CL. Maria
16
ACCEPTED MANUSCRIPT
Scaglione, A. Rossi, N. Tambasco, G. Santangelo, M. Picillo, L. Morgante, F. Morgante, R. Quatrale, M. Sensi, M. Pilleri, R. Biundo, G. Nordera, A. Caria, C. Pacchetti, R. Zangaglia, L. Lopiano, M. Zibetti, M. Zappia, A. Nicoletti, A. Quattrone, M. Salsone, G. Cossu, D. Murgia, A. Albanese, F. Del Sorbo, Validation of the Italian version of the Movement Disorder Society-Unified
RI PT
Parkinson’s Disease Rating Scale, Neurol. Sci. 34 (2012) 683-690. [21] M.M. Hoehn, M.D. Yahr, Parkinsonism: onset, progression and mortality, Neurology. 17 (1967) 427–442.
SC
[22] L.I. Golbe, P.A. Ohman-Strickland, A clinical rating scale for progressive supranuclear palsy, Brain. 130 (2007) 1552–1565.
M AN U
[23] M.F. Folstein, S.E. Folstein, P.R. McHugh, “Mini-mental state”: A practical method for grading the cognitive state of patients for the clinician, J. Psychiatr. Res. 12 (1975) 189–198. [24] B. Dubois, A. Slachevsky, I. Litvan, B. Pillon, The FAB: a Frontal Assessment Battery at bedside, Neurology. 55 (2000) 1621–1626.
(1967) 278–296.
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[25] M. Hamilton, Development of a rating scale for primary depressive illness, Clin. Psychol. 6
[26] S.M. Smith, M. Jenkinson, M.W. Woolrich, C.F. Beckmann, T.E.J. Behrens, H. Johansen-
EP
Berg, P.R. Bannister, M. De Luca, I. Drobnjak, D.E. Flitney, R.K. Niazy, J. Saunders, J. Vickers, Y. Zhang, N. De Stefano, J.M. Brady, P.M. Matthews, Advances in functional and structural MR
AC C
image analysis and implementation as FSL, NeuroImage. 23, Supplement 1 (2004) S208–S219. [27] P.M. Macey, K.E. Macey, R. Kumar, R.M. Harper, A method for removal of global effects from fMRI time series, Neuroimage. 22 (2004) 360–366 [28] M.C. Piattella, N. Upadhyay, M. Bologna, E. Sbardella, F. Tona, A. Formica, N. Petsas, A. Berardelli, P. Pantano, Neuroimaging evidence of gray and white matter damage and clinical correlates in progressive supranuclear palsy, J. Neurol. 262 (2015) 1850–1858.
17
ACCEPTED MANUSCRIPT
[29] C.P. Hess, C.W. Christine, A.C. Apple, W.P. Dillon, M.J. Aminoff, Changes in the thalamus in atypical parkinsonism detected using shape analysis and diffusion tensor imaging, AJNR Am. J. Neuroradiol. 35 (2014) 897–903. [30] N. Upadhyay, A. Suppa, M.C. Piattella, F. Di Stasio, N. Petsas, C. Colonnese, C. Colosimo, A.
RI PT
Berardelli, P. Pantano, Gray and white matter structural changes in corticobasal syndrome, Neurobiol. Aging. 37 (2016) 82–90.
[31] N. Upadhyay, A. Suppa, M.C. Piattella, M. Bologna, F. Di Stasio, A. Formica, F. Tona, C.
SC
Colosimo, A. Berardelli, P. Pantano, MRI gray and white matter measures in progressive supranuclear palsy and corticobasal syndrome, J Neurol. (2016).
M AN U
[32] V. Steuber and D. Jaeger, Modeling the Generation of Output by the Cerebellar Nuclei, Neural Netw. 47 (2013) 112–119.
[33] R.S. Raike, C.E. Pizoli, C. Weisz, A.M.J.M. van den Maagdenberg, H.A. Jinnah, E.J. Hess, Limited regional cerebellar dysfunction induces focal dystonia in mice, Neurobiol. Dis. 49 (2013) 200–210.
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[34] M. Küper, A. Dimitrova, M. Thürling, S. Maderwald, J. Roths, H.G. Elles, E.R. Gizewski, M.E. Ladd, J. Diedrichsen, D. Timmann, Evidence for a motor and a non-motor domain in the
EP
human dentate nucleus--an fMRI study, Neuroimage. 54 (2011) 2612-2622. [35] T. Wu, M. Hallett, The cerebellum in Parkinson’s disease, Brain. 136 (2013) 696–709.
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[36] F.G. Hillary, C.A. Roman, U. Venkatesan, S.M. Rajtmajer, R. Bajo, N.D. Castellanos, Hyperconnectivity is a fundamental response to neurological disruption, Neuropsychology. 29 (2015) 59–75.
[37] J.R. Burrell, J.R. Hodges, J.B. Rowe, Cognition in corticobasal syndrome and progressive supranuclear palsy: a review, Mov. Disord. 29 (2014) 684–693.
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FIGURE LEGENDS
Figure 1. Maps of functional connectivity obtained from the thalamus of 12 healthy subjects (redyellow) (one-sample t-test, p<0.05, corrected for family wise error - FWE); maps of differences in
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the functional connectivity (FC) of the thalamus (blue) between 19 patients with progressive supranuclear palsy (PSP) and 12 healthy subjects, and between 11 patients with cortical-basal syndrome (CBS) and 12 healthy subjects (two-sample t-test, p<0.05, corrected for FWE). L: left
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hemisphere; R: right hemisphere.
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Figure 2. Maps of functional connectivity obtained from the dentate nucleus of 12 healthy subjects (red-yellow) (one-sample t-test, p<0.05, corrected for family wise error - FWE); maps of differences in the functional connectivity (FC) of the dentate nucleus (red) between 19 patients with progressive supranuclear palsy (PSP) (blue) and 12 healthy subjects, and between 11 patients with cortical-basal syndrome (CBS) and 12 healthy subjects (two-sample t-test, p<0.05, corrected for
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FWE). L: left hemisphere; R: right hemisphere.
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ACCEPTED MANUSCRIPT Table 1. Demographic and clinical features of all the participants. PSP
CBS
P-value
(n=12)
(n=19)
(n=11)
(<0.05)
Age (yrs)
69.3±5.2
68.35 ± 5.8
68±6.9
0.125
Sex, M:F
5:7
10:9
3:8
0.210
Disease duration (yrs)
-
3.21 ± 1.8
2.64 ± 1.3
H&Y
-
2.9 ± 1.0
2.3 ± 1.7
PSPRS
-
35.82 ± 17.0
MDS-UPDRS-III
-
27.62 ± 17.9 36.09 ± 23.4 0.417
0.561
0.410
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MMSE
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HS
-
29.4±0.9
24.33 ± 3.9
26.81 ±0.9
0.000+
-
11.19 ± 3.8
15.45 ± 1.4
0.0038*
4.7±3.8
8.8 ± 3.6
11.63 ± 3.4
0.000*+
FAB
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HAM-D
HS: healthy subjects; PSP: progressive supranuclear palsy; CBS: corticobasal syndrome; H&Y: Hoehn & Yahr scale; PSPRS: Progressive Supranuclear Palsy rating
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scale, MDS-UPDRS-III: Unified Parkinson’s disease rating scale, part III; MMSE: mini-mental state examination; FAB: frontal assessment battery, HAM-D: Hamilton
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depression scale.
Significant p values are in bold. * Indicates significant difference between patient groups while
+
indicates p values that were significantly different in both patients
group from those of HS.
ACCEPTED MANUSCRIPT Table 2 Radiological characteristics of 19 patients with PSP, of 11 patients with CBS and of 12 healthy subjects (HS).
8.829 ± 1.15
CBSa (n=11)
P Value b
9.23 ± 1.648
p=0.003
Dentate A.
99.30 ± 18.62
p<0.0001
GM V.
764.39 ± 72.83 724.79 ± 65.77 712.14 ± 52.93
p=0.133
WM V.
790.36 ± 82.96 752.23 ± 58.35 705.71 ± 63.78* p=0.017
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59.970 ± 19.87 74.45 ± 23.708
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Thalamus V. 11.13 ± 2.26
PSP a (n=19)
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HSa (n=12)
V.= volume (mm3); A.=area (mm2).
Left and right values of subcortical volumes are averaged. Values are reported as mean ± standard deviation
b
Differences between groups were assessed by Kruskal-Wallis non-parametric Anova
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a
and posthoc pairwise comparisons.
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Decreased thalamic functional connectivity in Progressive supranuclear palsy (PSP) Decreased thalamic functional connectivity in Corticobasal syndrome (CBS).
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Decreased dentate nucleus functional connectivity in PSP.
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Increased dentate nucleus functional connectivity in CBS.
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