Cortical Macro- and Microstructural Changes in Parkinson's Disease with Probable Rapid Eye Movement Sleep Behavior Disorder.

BACKGROUND: Evidence regarding cortical atrophy patterns in Parkinson's disease (PD) with probable rapid eye movement sleep behavior disorder (RBD) (PD-pRBD) remains scarce. Cortical mean diffusivity (cMD), as a novel imaging biomarker highly sensitive to detecting cortical microstructural changes in different neurodegenerative diseases, has not been investigated in PD-pRBD yet. OBJECTIVES: The aim was to investigate cMD as a sensitive measure to identify subtle cortical microstructural changes in PD-pRBD and its relationship with cortical thickness (CTh). METHODS: Twenty-two PD-pRBD, 31 PD without probable RBD (PD-nonpRBD), and 28 healthy controls (HC) were assessed using 3D T1-weighted and diffusion-weighted magnetic resonance imaging on a 3-T scanner and neuropsychological testing. Measures of cortical brain changes were obtained through cMD and CTh. Two-class group comparisons of a general linear model were performed (P < 0.05). Cohen's d effect size for both approaches was computed. RESULTS: PD-pRBD patients showed higher cMD than PD-nonpRBD patients in the left superior temporal, superior frontal, and precentral gyri, precuneus cortex, as well as in the right middle frontal and postcentral gyri and paracentral lobule (d > 0.8), whereas CTh did not detect significant differences. PD-pRBD patients also showed increased bilateral posterior cMD in comparison with HCs (d > 0.8). These results partially overlapped with CTh results (0.5 < d < 0.8). PD-nonpRBD patients showed no differences in cMD when compared with HCs but showed cortical thinning in the left fusiform gyrus and lateral occipital cortex bilaterally (d > 0.5). CONCLUSIONS: cMD may be more sensitive than CTh displaying significant cortico-structural differences between PD subgroups, indicating this imaging biomarker's utility in studying early cortical changes in PD. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

COVID-19 severity is related to poor executive function in people with post-COVID conditions.

Patients with post-coronavirus disease 2019 (COVID-19) conditions typically experience cognitive problems. Some studies have linked COVID-19 severity with long-term cognitive damage, while others did not observe such associations. This discrepancy can be attributed to methodological and sample variations. We aimed to clarify the relationship between COVID-19 severity and long-term cognitive outcomes and determine whether the initial symptomatology can predict long-term cognitive problems. Cognitive evaluations were performed on 109 healthy controls and 319 post-COVID individuals categorized into three groups according to the WHO clinical progression scale: severe-critical (n = 77), moderate-hospitalized (n = 73), and outpatients (n = 169). Principal component analysis was used to identify factors associated with symptoms in the acute-phase and cognitive domains. Analyses of variance and regression linear models were used to study intergroup differences and the relationship between initial symptomatology and long-term cognitive problems. The severe-critical group performed significantly worse than the control group in general cognition (Montreal Cognitive Assessment), executive function (Digit symbol, Trail Making Test B, phonetic fluency), and social cognition (Reading the Mind in the Eyes test). Five components of symptoms emerged from the principal component analysis: the "Neurologic/Pain/Dermatologic" "Digestive/Headache", "Respiratory/Fever/Fatigue/Psychiatric" and "Smell/ Taste" components were predictors of Montreal Cognitive Assessment scores; the "Neurologic/Pain/Dermatologic" component predicted attention and working memory; the "Neurologic/Pain/Dermatologic" and "Respiratory/Fever/Fatigue/Psychiatric" components predicted verbal memory, and the "Respiratory/Fever/Fatigue/Psychiatric," "Neurologic/Pain/Dermatologic," and "Digestive/Headache" components predicted executive function. Patients with severe COVID-19 exhibited persistent deficits in executive function. Several initial symptoms were predictors of long-term sequelae, indicating the role of systemic inflammation and neuroinflammation in the acute-phase symptoms of COVID-19." Study Registration: www.ClinicalTrials.gov , identifier NCT05307549 and NCT05307575.

Structural brain changes in post-acute COVID-19 patients with persistent olfactory dysfunction.

OBJECTIVE: This research aims to study structural brain changes in patients with persistent olfactory dysfunctions after coronavirus disease 2019 (COVID-19). METHODS: COVID-19 patients were evaluated using T1-weighted and diffusion tensor imaging (DTI) on a 3T MRI scanner, 9.94 ± 3.83 months after COVID-19 diagnosis. Gray matter (GM) voxel-based morphometry was performed using FSL-VBM. Voxelwise statistical analysis of the fractional anisotropy, mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity was carried out with the tract-based spatial statistics in the olfactory system. The smell identification test (UPSIT) was used to classify patients as normal olfaction or olfactory dysfunction groups. Intergroup comparisons between GM and DTI measures were computed, as well as correlations with the UPSIT scores. RESULTS: Forty-eight COVID-19 patients were included in the study. Twenty-three were classified as olfactory dysfunction, and 25 as normal olfaction. The olfactory dysfunction group had lower GM volume in a cluster involving the left amygdala, insular cortex, parahippocampal gyrus, frontal superior and inferior orbital gyri, gyrus rectus, olfactory cortex, caudate, and putamen. This group also showed higher MD values in the genu of the corpus callosum, the orbitofrontal area, the anterior thalamic radiation, and the forceps minor; and higher RD values in the anterior corona radiata, the genu of the corpus callosum, and uncinate fasciculus compared with the normal olfaction group. The UPSIT scores for the whole sample were negatively associated with both MD and RD values (p-value ≤0.05 FWE-corrected). INTERPRETATION: There is decreased GM volume and increased MD in olfactory-related regions explaining prolonged olfactory deficits in post-acute COVID-19 patients.

Neuropsychological impairment in post-COVID condition individuals with and without cognitive complaints.

One of the most prevalent symptoms of post-COVID condition is cognitive impairment, which results in a significant degree of disability and low quality of life. In studies with large sample sizes, attention, memory, and executive function were reported as long-term cognitive symptoms. This study aims to describe cognitive dysfunction in large post-COVID condition individuals, compare objective neuropsychological performance in those post-COVID condition individuals with and without cognitive complaints, and identify short cognitive exams that can differentiate individuals with post-COVID symptoms from controls. To address these aims, the Nautilus project was started in June 2021. During the first year, we collected 428 participants' data, including 319 post-COVID and 109 healthy controls (18-65 years old) from those who underwent a comprehensive neuropsychological battery for cognitive assessment. Scores on tests assessing global cognition, learning and long-term memory, processing speed, language and executive functions were significantly worse in the post-COVID condition group than in healthy controls. Montreal Cognitive Assessment, digit symbol test, and phonetic verbal fluency were significant in the binomial logistic regression model and could effectively distinguish patients from controls with good overall sensitivity and accuracy. Neuropsychological test results did not differ between those with and without cognitive complaints. Our research suggests that patients with post-COVID conditions experience significant cognitive impairment and that routine tests like the Montreal Cognitive Assessment, digit symbol, and phonetic verbal fluency test might identify cognitive impairment. Thus, the administration of these tests would be helpful for all patients with post-COVID-19 symptoms, regardless of whether cognitive complaints are present or absent. Study registration: www.ClinicalTrials.gov, identifiers NCT05307549 and NCT05307575.

Inhibitory framing in hypersexual patients with Parkinson's disease. An fMRI pilot study.

Hypersexuality in medicated patients with PD is caused by an increased influence of motivational drive areas and a decreased influence of inhibitory control areas due to dopaminergic medication. In this pilot study, we test a newly developed paradigm investigating the influence of dopaminergic medication on brain activation elicited by sexual pictures with and without inhibitory contextual framing. Twenty PD patients with and without hypersexuality were examined with fMRI either OFF or ON standardized dopaminergic medication. The paradigm consisted of a priming phase where either a neutral context or an inhibitory context was presented. This priming phase was either followed by a sexual or a neutral target. Sexual, compared to neutral pictures resulted in a BOLD activation of various brain regions implicated in sexual processing. Hypersexual PD patients showed increased activity compared to PD controls in these regions. There was no relevant effect of medication between the two groups. The inhibitory context elicited less activation in inhibition-related areas in hypersexual PD, but had no influence on the perception of sexual cues. The paradigm partially worked: reactivity of motivational brain areas to sexual cues was increased in hypersexual PD and inhibitory contextual framing lead to decreased activation of inhibitory control areas in PD. We could not find a medication effect and the length of the inhibitory stimulus was not optimal to suppress reactivity to sexual cues. Our data provide new insights into the mechanisms of hypersexuality and warrant a replication with a greater cohort and an optimized stimulus length in the future.

Brain atrophy pattern in de novo Parkinson's disease with probable RBD associated with cognitive impairment.

Rapid eye movement sleep behavior disorder (RBD) is associated with high likelihood of prodromal Parkinson's disease (PD) and is common in de novo PD. It is associated with greater cognitive impairment and brain atrophy. However, the relation between structural brain characteristics and cognition remains poorly understood. We aimed to investigate subcortical and cortical atrophy in de novo PD with probable RBD (PD-pRBD) and to relate it with cognitive impairment. We analyzed volumetry, cortical thickness, and cognitive measures from 79 PD-pRBD patients, 126 PD without probable RBD patients (PD-non pRBD), and 69 controls from the Parkinson's Progression Markers Initiative (PPMI). Regression models of cognition were tested using magnetic resonance imaging measures as predictors. We found lower left thalamus volume in PD-pRBD compared with PD-non pRBD. Compared with controls, PD-pRBD group showed atrophy in the bilateral putamen, left hippocampus, left amygdala, and thinning in the right superior temporal gyrus. Specific deep gray matter nuclei volumes were associated with impairment in global cognition, phonemic fluency, processing speed, and visuospatial function in PD-pRBD. In conclusion, cognitive impairment and gray matter atrophy are already present in de novo PD-pRBD. Thalamus, hippocampus, and putamen volumes were mainly associated with these cognitive deficits.

Sex differences in brain atrophy and cognitive impairment in Parkinson's disease patients with and without probable rapid eye movement sleep behavior disorder.

BACKGROUND: The presence of rapid eye movement sleep behavior disorder (RBD) contributes to increase cognitive impairment and brain atrophy in Parkinson's disease (PD), but the impact of sex is unclear. We aimed to investigate sex differences in cognition and brain atrophy in PD patients with and without probable RBD (pRBD). METHODS: Magnetic resonance imaging and cognition data were obtained for 274 participants from the Parkinson's Progression Marker Initiative database: 79 PD with pRBD (PD-pRBD; male/female, 54/25), 126 PD without pRBD (PD-non pRBD; male/female, 73/53), and 69 healthy controls (male/female, 40/29). FreeSurfer was used to obtain volumetric and cortical thickness data. RESULTS: Males showed greater global cortical and subcortical gray matter atrophy than females in the PD-pRBD group. Significant group-by-sex interactions were found in the pallidum. Structures showing a within-group sex effect in the deep gray matter differed, with significant volume reductions for males in one structure in in PD-non pRBD (brainstem), and three in PD-pRBD (caudate, pallidum and brainstem). Significant group-by-sex interactions were found in Montreal Cognitive Assessment (MoCA) and Symbol Digits Modalities Test (SDMT). Males performed worse than females in MoCA, phonemic fluency and SDMT in the PD-pRBD group. CONCLUSION: Male sex is related to increased cognitive impairment and subcortical atrophy in de novo PD-pRBD. Accordingly, we suggest that sex differences are relevant and should be considered in future clinical and translational research.

Differentiation of multiple system atrophy subtypes by gray matter atrophy.

BACKGROUND AND PURPOSE: Multiple system atrophy(MSA) is a rare adult-onset synucleinopathy that can be divided in two subtypes depending on whether the prevalence of its symptoms is more parkinsonian or cerebellar (MSA-P and MSA-C, respectively). The aim of this work is to investigate the structural MRI changes able to discriminate MSA phenotypes. METHODS: The sample includes 31 MSA patients (15 MSA-C and 16 MSA-P) and 39 healthy controls. Participants underwent a comprehensive motor and neuropsychological battery. MRI data were acquired with a 3T scanner (MAGNETOM Trio, Siemens, Germany). FreeSurfer was used to obtain volumetric and cortical thickness measures. A Support Vector Machine (SVM) algorithm was used to assess the classification between patients' group using cortical and subcortical structural data. RESULTS: After correction for multiple comparisons, MSA-C patients had greater atrophy than MSA-P in the left cerebellum, whereas MSA-P showed reduced volume bilaterally in the pallidum and putamen. Using deep gray matter volume ratios and mean cortical thickness as features, the SVM algorithm provided a consistent classification between MSA-C and MSA-P patients (balanced accuracy 74.2%, specificity 75.0%, and sensitivity 73.3%). The cerebellum, putamen, thalamus, ventral diencephalon, pallidum, and caudate were the most contributing features to the classification decision (z > 3.28; p < .05 [false discovery rate]). CONCLUSIONS: MSA-C and MSA-P with similar disease severity and duration have a differential distribution of gray matter atrophy. Although cerebellar atrophy is a clear differentiator between groups, thalamic and basal ganglia structures are also relevant contributors to distinguishing MSA subtypes.

Disrupted functional connectivity in PD with probable RBD and its cognitive correlates.

Recent studies associated rapid eye movement sleep behavior disorder (RBD) in Parkinson's disease (PD) with severe cognitive impairment and brain atrophy. However, whole-brain functional connectivity has never been explored in this group of PD patients. In this study, whole-brain network-based statistics and graph-theoretical approaches were used to characterize resting-state interregional functional connectivity in PD with probable RBD (PD-pRBD) and its relationship with cognition. Our sample consisted of 30 healthy controls, 32 PD without probable RBD (PD-non pRBD), and 27 PD-pRBD. The PD-pRBD group showed reduced functional connectivity compared with controls mainly involving cingulate areas with temporal, frontal, insular, and thalamic regions (p < 0.001). Also, the PD-pRBD group showed reduced functional connectivity between right ventral posterior cingulate and left medial precuneus compared with PD-non pRBD (p < 0.05). We found increased normalized characteristic path length in PD-pRBD compared with PD-non pRBD. In the PD-pRBD group, mean connectivity strength from reduced connections correlated with visuoperceptual task and normalized characteristic path length correlated with processing speed and verbal memory tasks. This work demonstrates the existence of disrupted functional connectivity in PD-pRBD, together with abnormal network integrity, that supports its consideration as a severe PD subtype.

Structural and functional magnetic resonance imaging in isolated REM sleep behavior disorder: A systematic review of studies using neuroimaging software.

Isolated rapid eye movement sleep behavior disorder (iRBD) is a harbinger for developing clinical synucleinopathies. Magnetic resonance imaging (MRI) has been suggested as a tool for understanding the brain bases of iRBD and its evolution. This review systematically analyzed original full text articles on structural and functional MRI in patients with video-polysomnography-confirmed iRBD according to systematic procedures suggested by Reviews and Meta-analyses (PRISMA). The literature search was conducted via the PubMed database for articles related to structural and functional MRI in iRBD from 2000 to 2020. Investigations to date have been diverse in terms of methodology, but most agree that patients with iRBD have structural changes in deep gray matter nuclei, cortical gray matter atrophy, and disrupted functional connectivity within the basal ganglia, the cortico-striatal and cortico-cortical networks. Furthermore, there is evidence that MRI detects structural and functional brain changes associated with the motor and non-motor symptoms of iRBD. The current review highlights the need for larger multicenter and longitudinal studies, using complex approaches based on data-driven and unsupervised machine learning that will help to identify structural and functional patterns of brain degeneration. In turn, this may even allow for the prediction of subsequent phenoconversion from iRBD to the clinically defined synucleinopathies.

Impaired Structural Connectivity in Parkinson's Disease Patients with Mild Cognitive Impairment: A Study Based on Probabilistic Tractography.

Background: Probabilistic tractography, in combination with graph theory, has been used to reconstruct the structural whole-brain connectome. Threshold-free network-based statistics (TFNBS) is a useful technique to study structural connectivity in neurodegenerative disorders; however, there are no previous studies using TFNBS in Parkinson's disease (PD) with and without mild cognitive impairment (MCI). Materials and Methods: Sixty-two PD patients, 27 of whom classified as PD-MCI, and 51 healthy controls (HC) underwent diffusion-weighted 3T magnetic resonance imaging. Probabilistic tractography, using FMRIB Software Library (FSL), was used to compute the number of streamlines (NOS) between regions. NOS matrices were used to find group differences with TFNBS, and to calculate global and local measures of network integrity using graph theory. A binominal logistic regression was then used to assess the discrimination between PD with and without MCI using non-overlapping significant tracts. Tract-based spatial statistics were also performed with FSL to study changes in fractional anisotropy (FA) and mean diffusivity. Results: PD-MCI showed 37 white matter connections with reduced connectivity strength compared with HC, mainly involving temporal/occipital regions. These were able to differentiate PD-MCI from PD without MCI with an area under the curve of 83-85%. PD without MCI showed disrupted connectivity in 18 connections involving frontal/temporal regions. No significant differences were found in graph measures. Only PD-MCI showed reduced FA compared with HC. Discussion: TFNBS based on whole-brain probabilistic tractography can detect structural connectivity alterations in PD with and without MCI. Reduced structural connectivity in fronto-striatal and posterior cortico-cortical connections is associated with PD-MCI.

Sex Differences in Brain and Cognition in de novo Parkinson's Disease.

Background and Objective: Brain atrophy and cognitive impairment in neurodegenerative diseases are influenced by sex. We aimed to investigate sex differences in brain atrophy and cognition in de novo Parkinson's disease (PD) patients. Methods: Clinical, neuropsychological and T1-weighted MRI data from 205 PD patients (127 males: 78 females) and 69 healthy controls (40 males: 29 females) were obtained from the PPMI dataset. Results: PD males had a greater motor and rapid eye movement sleep behavior disorder symptomatology than PD females. They also showed cortical thinning in postcentral and precentral regions, greater global cortical and subcortical atrophy and smaller volumes in thalamus, caudate, putamen, pallidum, hippocampus, and brainstem, compared with PD females. Healthy controls only showed reduced hippocampal volume in males compared to females. PD males performed worse than PD females in global cognition, immediate verbal recall, and mental processing speed. In both groups males performed worse than females in semantic verbal fluency and delayed verbal recall; as well as females performed worse than males in visuospatial function. Conclusions: Sex effect in brain and cognition is already evident in de novo PD not explained by age per se, being a relevant factor to consider in clinical and translational research in PD.

Differentiation of multiple system atrophy from Parkinson's disease by structural connectivity derived from probabilistic tractography.

Recent studies combining diffusion tensor-derived metrics and machine learning have shown promising results in the discrimination of multiple system atrophy (MSA) and Parkinson's disease (PD) patients. This approach has not been tested using more complex methodologies such as probabilistic tractography. The aim of this work is assessing whether the strength of structural connectivity between subcortical structures, measured as the number of streamlines (NOS) derived from tractography, can be used to classify MSA and PD patients at the single-patient level. The classification performance of subcortical FA and MD was also evaluated to compare the discriminant ability between diffusion tensor-derived metrics and NOS. Using diffusion-weighted images acquired in a 3 T MRI scanner and probabilistic tractography, we reconstructed the white matter tracts between 18 subcortical structures from a sample of 54 healthy controls, 31 MSA patients and 65 PD patients. NOS between subcortical structures were compared between groups and entered as features into a machine learning algorithm. Reduced NOS in MSA compared with controls and PD were found in connections between the putamen, pallidum, ventral diencephalon, thalamus, and cerebellum, in both right and left hemispheres. The classification procedure achieved an overall accuracy of 78%, with 71% of the MSA subjects and 86% of the PD patients correctly classified. NOS features outperformed the discrimination performance obtained with FA and MD. Our findings suggest that structural connectivity derived from tractography has the potential to correctly distinguish between MSA and PD patients. Furthermore, NOS measures obtained from tractography might be more useful than diffusion tensor-derived metrics for the detection of MSA.

Disrupted structural connectivity of fronto-deep gray matter pathways in progressive supranuclear palsy.

BACKGROUND: Structural connectivity is a promising methodology to detect patterns of neural network dysfunction in neurodegenerative diseases. This approach has not been tested in progressive supranuclear palsy (PSP). OBJECTIVES: The aim of this study is reconstructing the structural connectome to characterize and detect the pathways of degeneration in PSP patients compared with healthy controls and their correlation with clinical features. The second objective is to assess the potential of structural connectivity measures to distinguish between PSP patients and healthy controls at the single-subject level. METHODS: Twenty healthy controls and 19 PSP patients underwent diffusion-weighted MRI with a 3T scanner. Structural connectivity, represented by number of streamlines, was derived from probabilistic tractography. Global and local network metrics were calculated based on graph theory. RESULTS: Reduced numbers of streamlines were predominantly found in connections between frontal areas and deep gray matter (DGM) structures in PSP compared with controls. Significant changes in structural connectivity correlated with clinical features in PSP patients. An abnormal small-world architecture was detected in the subnetwork comprising the frontal lobe and DGM structures in PSP patients. The classification procedure achieved an overall accuracy of 82.23% with 94.74% sensitivity and 70% specificity. CONCLUSION: Our findings suggest that modelling the brain as a structural connectome is a useful method to detect changes in the organization and topology of white matter tracts in PSP patients. Secondly, measures of structural connectivity have the potential to correctly discriminate between PSP patients and healthy controls.

Progression of Parkinson's disease patients' subtypes based on cortical thinning: 4-year follow-up.

BACKGROUND: Three cortical atrophy patterns were previously identified in non-demented Parkinson's disease patients using a data-driven approach based on cortical thickness data: i) parieto-temporal pattern of atrophy with worse cognitive performance (pattern 1), ii) occipital and frontal cortical atrophy with younger disease onset (pattern 2), and iii) non-detectable cortical atrophy (pattern 3). We aimed to investigate the evolution of these three patterns over time. METHODS: Magnetic resonance imaging and neuropsychological assessment were obtained at baseline and follow-up (3.8 ±â€¯0.4 year apart) in a group of 45 Parkinson's disease patients and 22 healthy controls. FreeSurfer was used for cortical thickness analysis and global atrophy measures. RESULTS: Temporo-parietal cortical thinning occurred in pattern 2, 3 and controls groups, and patients showed decline in processing speed (as measured by the Stroop Word-Color test, the Symbol Digits Modalities test and the Trail Making Test Part B) and in semantic fluency (animals). Pattern 3 patients showed more progressive cortical thinning in the left prefrontal cortex than controls and more right occipital thinning than pattern 2 patients over time. Pattern 1 patients had greater compromise in activities of the daily living and suffered higher attrition rate. CONCLUSION: The Parkinson's disease phenotypes identified using cluster analysis of cortical thickness data showed different progression over time. The presence of prefrontal thinning and younger disease onset at baseline was associated to less cortical degeneration, while non-atrophic patients progressed showing a temporo-parietal cortical thinning.

Cortical Gray Matter and Hippocampal Atrophy in Idiopathic Rapid Eye Movement Sleep Behavior Disorder.

Objective: In this study we investigate cortical and subcortical gray matter structure in patients with Idiopathic REM-sleep behavior disorder (IRBD), and their relation to cognitive performance. Methods: This study includes a sample of 20 patients with polysomnography-confirmed IRBD and 27 healthy controls that underwent neuropsychological and T1-weighted MRI assessment. FreeSurfer was used to estimate cortical thickness, subcortical volumetry (version 5.1), and hippocampal subfields segmentation (version 6.0). FIRST, FSL's model-based segmentation/registration tool was used for hippocampal shape analysis. Results: Compared with healthy subjects, IRBD patients showed impairment in facial recognition, verbal memory, processing speed, attention, and verbal naming. IRBD patients had cortical thinning in left superior parietal, post-central, and fusiform regions, as well as in right superior frontal and lateral occipital regions. Volumetric and shape analyses found right hippocampal atrophy in IRBD, specifically in posterior regions. Hippocampal subfields exploratory analysis identified significant differences in the right CA1, molecular layer, granule cell layer of dentate gyrus, and CA4 of this patients. No correlations were found between cognitive performance and brain atrophy. Conclusion: This work confirms the presence of posterior based cognitive dysfunction, as well as cortical and right hippocampal atrophy in IRBD patients.

Cerebellar resting-state functional connectivity in Parkinson's disease and multiple system atrophy: Characterization of abnormalities and potential for differential diagnosis at the single-patient level.

BACKGROUND: Recent studies using resting-state functional connectivity and machine-learning to distinguish patients with neurodegenerative diseases from other groups of subjects show promising results. This approach has not been tested to discriminate between Parkinson's disease (PD) and multiple system atrophy (MSA) patients. OBJECTIVES: Our first aim is to characterize possible abnormalities in resting-state functional connectivity between the cerebellum and a set of intrinsic-connectivity brain networks and between the cerebellum and different regions of the striatum in PD and MSA. The second objective of this study is to assess the potential of cerebellar connectivity measures to distinguish between PD and MSA patients at the single-patient level. METHODS: Fifty-nine healthy controls, 62 PD patients, and 30 MSA patients underwent resting-state functional MRI with a 3T scanner. Independent component analysis and dual regression were used to define seven resting-state networks of interest. To assess striatal connectivity, a seed-to-voxel approach was used after dividing the striatum into six regions bilaterally. Measures of cerebellar-brain network and cerebellar-striatal connectivity were then used as features in a support vector machine to discriminate between PD and MSA patients. RESULTS: MSA patients displayed reduced cerebellar connectivity with different brain networks and with the striatum compared with PD patients and with controls. The classification procedure achieved an overall accuracy of 77.17% with 83.33% of the MSA subjects and 74.19% of the PD patients correctly classified. CONCLUSION: Our findings suggest that measures of cerebellar functional connectivity have the potential to distinguish between PD and MSA patients.

Differential Progression of Regional Hippocampal Atrophy in Aging and Parkinson's Disease.

Hippocampal subfields have different vulnerability to the degenerative processes related to aging, amnestic mild cognitive impairment (MCI) and Alzheimer's disease (AD), but the temporal evolution in Parkinson's disease (PD) is unknown. The purposes of the current work are to describe regional hippocampal changes over time in a sample of PD patients classified according to their baseline cognitive status and to relate these changes to verbal memory loss. T1-weighted images and verbal memory assessment were obtained at two separate time points (3.8 ± 0.4 years apart) from 28 PD with normal cognition (PD-NC), 16 PD with MCI (PD-MCI) and 21 healthy controls (HCs). FreeSurfer 6.0 automated pipeline was used to segment the hippocampus into 12 bilateral subregions. Memory functions were measured with Rey's Auditory Verbal learning test (RAVLT). We found significant reductions in cornu ammonis 1 (CA1) over time in controls as well as in PD subgroups. Right whole-hippocampal volumes showed time effects in both PD groups but not in controls. PD-NC patients also displayed time effects in the left hippocampal tail and right parasubiculum. Regression analyses showed that specific hippocampal subfield volumes at time 1 predicted almost 60% of the variability in RAVLT delayed-recall score decline. Changes in several hippocampal subregions also showed predictive value for memory loss. In conclusion, CA1 changes in PD were similar to those that occur in normal aging, but PD patients also had more decline in both anterior and posterior hippocampal segments with a more pronounced atrophy of the right hemisphere. Hippocampal segments are better predictors of changes in memory performance than whole-hippocampal volumes.

Gray/White Matter Contrast in Parkinson's Disease.

Gray/white matter contrast (GWC) decreases with aging and has been found to be a useful MRI biomarker in Alzheimer's disease (AD), but its utility in Parkinson's disease (PD) patients has not been investigated. The aims of the study were to test whether GWC is sensitive to aging changes in PD patients, if PD patients differ from healthy controls (HCs) in GWC, and whether the use of GWC data would improve the sensitivity of cortical thickness analyses to differentiate PD patients from controls. Using T1-weighted structural images, we obtained individual cortical thickness and GWC values from a sample of 90 PD patients and 27 controls. Images were processed with the automated FreeSurfer stream. GWC was computed by dividing the white matter (WM) by the gray matter (GM) values and projecting the ratios onto a common surface. The sample characteristics were: 52 patients and 14 controls were males; mean age of 64.4 ± 10.6 years in PD and 64.7 ± 8.6 years in controls; 8.0 ± 5.6 years of disease evolution; 15.6 ± 9.8 UPDRS; and a range of 1.5-3 in Hoehn and Yahr (H&Y) stage. In both PD and controls we observed significant correlations between GWC and age involving almost the entire cortex. When applying a stringent cluster-forming threshold of p < 0.0001, the correlation between GWC and age also involved the entire cortex in the PD group; in the control group, the correlation was found in the parahippocampal gyrus and widespread frontal and parietal areas. The GWC of PD patients did not differ from controls', whereas cortical thickness analyses showed thinning in temporal and parietal cortices in the PD group. Cortical thinning remained unchanged after adjusting for GWC. GWC is a very sensitive measure for detecting aging effects, but did not provide additional information over other parameters of atrophy in PD.

Cortical atrophy patterns in early Parkinson's disease patients using hierarchical cluster analysis.

INTRODUCTION: Cortical brain atrophy detectable with MRI in non-demented advanced Parkinson's disease (PD) is well characterized, but its presence in early disease stages is still under debate. We aimed to investigate cortical atrophy patterns in a large sample of early untreated PD patients using a hypothesis-free data-driven approach. METHODS: Seventy-seven de novo PD patients and 50 controls from the Parkinson's Progression Marker Initiative database with T1-weighted images in a 3-tesla Siemens scanner were included in this study. Mean cortical thickness was extracted from 360 cortical areas defined by the Human Connectome Project Multi-Modal Parcellation version 1.0, and a hierarchical cluster analysis was performed using Ward's linkage method. A general linear model with cortical thickness data was then used to compare clustering groups using FreeSurfer software. RESULTS: We identified two patterns of cortical atrophy. Compared with controls, patients grouped in pattern 1 (n = 33) were characterized by cortical thinning in bilateral orbitofrontal, anterior cingulate, and lateral and medial anterior temporal gyri. Patients in pattern 2 (n = 44) showed cortical thinning in bilateral occipital gyrus, cuneus, superior parietal gyrus, and left postcentral gyrus, and they showed neuropsychological impairment in memory and other cognitive domains. CONCLUSIONS: Even in the early stages of PD, there is evidence of cortical brain atrophy. Neuroimaging clustering analysis is able to detect two subgroups of cortical thinning, one with mainly anterior atrophy, and the other with posterior predominance and worse cognitive performance.