Parameters from site classification to harmonize MRI clinical studies: Application to a multi-site Parkinson's disease dataset.

Multi-site MRI datasets are crucial for big data research. However, neuroimaging studies must face the batch effect. Here, we propose an approach that uses the predictive probabilities provided by Gaussian processes (GPs) to harmonize clinical-based studies. A multi-site dataset of 216 Parkinson's disease (PD) patients and 87 healthy subjects (HS) was used. We performed a site GP classification using MRI data. The outcomes estimated from this classification, redefined like Weighted HARMonization PArameters (WHARMPA), were used as regressors in two different clinical studies: A PD versus HS machine learning classification using GP, and a VBM comparison (FWE-p < .05, k = 100). Same studies were also conducted using conventional Boolean site covariates, and without information about site belonging. The results from site GP classification provided high scores, balanced accuracy (BAC) was 98.39% for grey matter images. PD versus HS classification performed better when the WHARMPA were used to harmonize (BAC = 78.60%; AUC = 0.90) than when using the Boolean site information (BAC = 56.31%; AUC = 0.71) and without it (BAC = 57.22%; AUC = 0.73). The VBM analysis harmonized using WHARMPA provided larger and more statistically robust clusters in regions previously reported in PD than when the Boolean site covariates or no corrections were added to the model. In conclusion, WHARMPA might encode global site-effects quantitatively and allow the harmonization of data. This method is user-friendly and provides a powerful solution, without complex implementations, to clean the analyses by removing variability associated with the differences between sites.

Retinal Thickness Predicts the Risk of Cognitive Decline in Parkinson Disease.

OBJECTIVE: This study was undertaken to analyze longitudinal changes of retinal thickness and their predictive value as biomarkers of disease progression in idiopathic Parkinson's disease (iPD). METHODS: Patients with Lewy body diseases were enrolled and prospectively evaluated at 3 years, including patients with iPD (n = 42), dementia with Lewy bodies (n = 4), E46K-SNCA mutation carriers (n = 4), and controls (n = 17). All participants underwent Spectralis retinal optical coherence tomography and Montreal Cognitive Assessment, and Unified Parkinson's Disease Rating Scale score was obtained in patients. Macular ganglion cell-inner plexiform layer complex (GCIPL) and peripapillary retinal nerve fiber layer (pRNFL) thickness reduction rates were estimated with linear mixed models. Risk ratios were calculated to evaluate the association between baseline GCIPL and pRNFL thicknesses and the risk of subsequent cognitive and motor worsening, using clinically meaningful cutoffs. RESULTS: GCIPL thickness in the parafoveal region (1- to 3-mm ring) presented the largest reduction rate. The annualized atrophy rate was 0.63µm in iPD patients and 0.23µm in controls (p < 0.0001). iPD patients with lower parafoveal GCIPL and pRNFL thickness at baseline presented an increased risk of cognitive decline at 3 years (relative risk [RR] = 3.49, 95% confidence interval [CI] = 1.10-11.1, p = 0.03 and RR = 3.28, 95% CI = 1.03-10.45, p = 0.045, respectively). We did not identify significant associations between retinal thickness and motor deterioration. INTERPRETATION: Our results provide evidence of the potential use of optical coherence tomography-measured parafoveal GCIPL thickness to monitor neurodegeneration and to predict the risk of cognitive worsening over time in iPD. ANN NEUROL 2021;89:165-176.

Predictors of health-related quality of life in Parkinson's disease: the impact of overlap between health-related quality of life and clinical measures.

PURPOSE: This study aimed to determine predictors of health-related quality of life (HRQoL) in Parkinson's disease (PD) and to explore their predictive value before and after controlling overlapping items between HRQoL and clinical variables. METHODS: One hundred and eight PD patients underwent motor, anxiety, depression, apathy, fatigue, and neurocognition assessment. HRQoL was assessed by the Parkinson's Disease Questionnaire-39 (PDQ-39). In order to determine predictors of HRQoL in PD, stepwise multiple regression analyses were performed in two ways: before and after removing the emotional well-being dimension from PDQ-39 to control the overlap between depression and anxiety, and HRQoL. RESULTS: HRQoL total index was predicted by anxiety, fatigue, motor symptoms, and depression, explaining 26.9%, 7.2%, 2.8%, and 1.9% of the variance. However, after removing overlapping items, HRQoL total index was predicted by fatigue (16.5%), anxiety (6.1%), motor symptoms (3.9%), and neurocognition (2.5%), but not depression. Regarding HRQoL dimensions, mobility and activities of daily living were predicted by fatigue (19.7% and 5%) and UPDRS-III (4% and 10.2%); emotional well-being by fatigue (7.9%); social support by anxiety (12.2%) and UPDRS-III (8.6%); communication by neurocognition (5.3%) and UPDRS-III (3.4%); cognition by anxiety (10.6%) and bodily discomfort by anxiety (23%) and fatigue (4.1%). CONCLUSION: These findings showed the importance of identifying and controlling overlapping items of HRQoL and clinical measures to perform an accurate interpretation. HRQoL dimensions showed different predictors before and after controlling the overlap. Based on these results fatigue, anxiety, motor symptoms, and neurocognition, but not depression are the main predictors of HRQoL in PD patients.

Metabolic Network Abnormalities in Drug-Naïve Parkinson's Disease.

BACKGROUND: An ideal imaging biomarker for a neurodegenerative disorder should be able to measure abnormalities in the earliest stages of the disease. OBJECTIVE: We investigated metabolic network changes in two independent cohorts of drug-naïve Parkinson's disease (PD) patients who have not been exposed to dopaminergic medication. METHODS: We scanned 85 de novo, drug-naïve PD patients and 85 age-matched healthy control subjects from Italy (n = 96) and the United States (n = 74) with [18 F]-fluorodeoxyglucose PET. All patients had clinical follow-ups to verify the diagnosis of idiopathic PD. Spatial covariance analysis was used to identify and validate de novo PD-related metabolic patterns in the Italian and U.S. cohorts. We compared the de novo PD-related metabolic patterns to the original PD-related pattern that was identified in more advanced patients who had been on chronic dopaminergic treatment. RESULTS: De novo PD-related metabolic patterns were identified in each of the two independent cohorts of drug-naïve PD patients, and each differentiated PD patients from healthy control subjects. Expression values for these disease patterns were elevated in drug-naïve PD patients relative to healthy controls in the identification as well as in each of the validation subgroups. The two de novo PD-related metabolic patterns were topographically very similar to each other and to the original PD-related pattern. CONCLUSIONS: Reproducible PD-related patterns are expressed in de novo, drug-naïve PD patients. In PD, disease-related metabolic patterns have stereotyped topographies that develop independently of chronic levodopa treatment. © 2019 International Parkinson and Movement Disorder Society.

Parafoveal thinning of inner retina is associated with visual dysfunction in Lewy body diseases.

BACKGROUND: Retinal optical coherence tomography findings in Lewy body diseases and their implications for visual outcomes remain controversial. We investigated whether region-specific thickness analysis of retinal layers could improve the detection of macular atrophy and unravel its association with visual disability in Parkinson's disease. METHODS: Patients with idiopathic Parkinson's disease (n = 63), dementia with Lewy bodies (n = 8), and E46K mutation carriers in the α-synuclein gene (E46K-SNCA) (n = 4) and 34 controls underwent Spectralis optical coherence tomography macular scans and a comprehensive battery of visual function and cognition tests. We computed mean retinal layer thicknesses of both eyes within 1-, 2-, 3-, and 6-mm diameter macular discs and in concentric parafoveal (1- to 2-mm, 2- to 3-mm, 1- to 3-mm) and perifoveal (3- to 6-mm) rings. Group differences in imaging parameters and their relationship with visual outcomes were analyzed. A multivariate logistic model was developed to predict visual impairment from optical coherence tomography measurements in Parkinson's disease, and cutoff values were determined with receiver operating characteristic analysis. RESULTS: When compared with controls, patients with dementia with Lewy bodies had significant thinning of the ganglion cell-inner plexiform layer complex within the central 3-mm disc mainly because of differences in 1- to 3-mm parafoveal thickness. This parameter was strongly correlated in patients, but not in controls, with low contrast visual acuity and visual cognition outcomes (P < .05, False Discovery Rate), achieving 88% of accuracy in predicting visual impairment in Parkinson's disease. CONCLUSION: Our findings support that parafoveal thinning of ganglion cell-inner plexiform complex is a sensitive and clinically relevant imaging biomarker for Lewy body diseases, specifically for Parkinson's disease. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

A multi-site study on sex differences in cortical thickness in non-demented Parkinson's disease.

Clinical, cognitive, and atrophy characteristics depending on sex have been previously reported in Parkinson's disease (PD). However, though sex differences in cortical gray matter measures in early drug naïve patients have been described, little is known about differences in cortical thickness (CTh) as the disease advances. Our multi-site sample comprised 211 non-demented PD patients (64.45% males; mean age 65.58 ± 8.44 years old; mean disease duration 6.42 ± 5.11 years) and 86 healthy controls (50% males; mean age 65.49 ± 9.33 years old) with available T1-weighted 3 T MRI data from four international research centers. Sex differences in regional mean CTh estimations were analyzed using generalized linear models. The relation of CTh in regions showing sex differences with age, disease duration, and age of onset was examined through multiple linear regression. PD males showed thinner cortex than PD females in six frontal (bilateral caudal middle frontal, bilateral superior frontal, left precentral and right pars orbitalis), three parietal (bilateral inferior parietal and left supramarginal), and one limbic region (right posterior cingulate). In PD males, lower CTh values in nine out of ten regions were associated with longer disease duration and older age, whereas in PD females, lower CTh was associated with older age but with longer disease duration only in one region. Overall, male patients show a more widespread pattern of reduced CTh compared with female patients. Disease duration seems more relevant to explain reduced CTh in male patients, suggesting worse prognostic over time. Further studies should explore sex-specific cortical atrophy trajectories using large longitudinal multi-site data.

Brain Degeneration in Synucleinopathies Based on Analysis of Cognition and Other Nonmotor Features: A Multimodal Imaging Study.

BACKGROUND: We aimed to characterize subtypes of synucleinopathies using a clustering approach based on cognitive and other nonmotor data and to explore structural and functional magnetic resonance imaging (MRI) brain differences between identified clusters. METHODS: Sixty-two patients (n = 6 E46K-SNCA, n = 8 dementia with Lewy bodies (DLB) and n = 48 idiopathic Parkinson's disease (PD)) and 37 normal controls underwent nonmotor evaluation with extensive cognitive assessment. Hierarchical cluster analysis (HCA) was performed on patients' samples based on nonmotor variables. T1, diffusion-weighted, and resting-state functional MRI data were acquired. Whole-brain comparisons were performed. RESULTS: HCA revealed two subtypes, the mild subtype (n = 29) and the severe subtype (n = 33). The mild subtype patients were slightly impaired in some nonmotor domains (fatigue, depression, olfaction, and orthostatic hypotension) with no detectable cognitive impairment; the severe subtype patients (PD patients, all DLB, and the symptomatic E46K-SNCA carriers) were severely impaired in motor and nonmotor domains with marked cognitive, visual and bradykinesia alterations. Multimodal MRI analyses suggested that the severe subtype exhibits widespread brain alterations in both structure and function, whereas the mild subtype shows relatively mild disruptions in occipital brain structure and function. CONCLUSIONS: These findings support the potential value of incorporating an extensive nonmotor evaluation to characterize specific clinical patterns and brain degeneration patterns of synucleinopathies.

Multimodal visual system analysis as a biomarker of visual hallucinations in Parkinson's disease.

Visual hallucinations (VH) are present in up to 75% of Parkinson's disease (PD) patients. However, their neural bases and participation of the visual system in VH are not well-understood in PD. Seventy-four participants, 12 PD with VH (PDVH), 35 PD without VH (PDnoVH) and 27 controls underwent a battery of primary visual function and visual cognition tests, retinal optical coherence tomography and structural and resting-state functional brain MRI. We quantified cortical thickness with Freesurfer and functional connectivity (FC) of Visual (VIS), Fronto-Parietal (FP), Ventral Attention (VAN) and Dorsal Attention (DAN) networks with CONN toolbox. Group comparisons were performed with MANCOVA. Area Under the Curve (AUC) was computed to assess the ability of visual variables to differentiate PDVH and PDnoVH. There were no significant PDVH vs PDnoVH differences in disease duration, motor manifestations, general cognition or dopamine agonist therapy (DA) use. Compared to PDnoVH and HC, and regardless of DA use, PDVH showed significantly reduced contrast sensitivity, visuoperceptive and visuospatial abilities, increased retina photoreceptor layer thickness, reduced cortical thickness mostly in right visual associative areas, decreased between-network VIS-VAN and VAN-DAN connectivity and increased within-network DAN connectivity. The combination of clinical and imaging variables that best discriminated PDVH and PDnoVH (highest AUC), where within-network DAN FC, photoreceptor layer thickness and cube analysis test from Visual Object and Space Perception Battery (accuracy of 81.8%). Compared to PDnoVH, PDVH have specific functional and structural abnormalities within the visual system, which can be quantified non-invasively and could potentially constitute biomarkers for VH in PD.

Effectiveness of Cognitive Rehabilitation in Parkinson's Disease: A Systematic Review and Meta-Analysis.

Cognitive deficits influence the quality of life of Parkinson's disease (PD) patients. In order to reduce the impact of cognitive impairment in PD, cognitive rehabilitation programs have been developed. This study presents a systematic review and meta-analysis regarding the effectiveness of cognitive rehabilitation in non-demented PD patients. Twelve articles were selected according to PRISMA guidelines. The systematic review showed that attention, working memory, verbal memory, executive functions and processing speed were the most frequently improved domains. Meta-analysis results showed moderate effects on global cognitive status (g = 0.55) and working memory (g = 0.50); small significant effects on verbal memory (g = 0.41), overall cognitive functions (g = 0.39) and executive functions (g = 0.30); small non-significant effects on attention (g = 0.36), visual memory (g = 0.29), verbal fluency (g = 0.27) and processing speed (g = 0.24); and no effect on visuospatial and visuoconstructive abilities (g = 0.17). Depressive symptoms showed small effect (g = 0.24) and quality of life showed no effect (g = -0.07). A meta-regression was performed to examine moderating variables of overall cognitive function effects, although moderators did not explain the heterogeneity of the improvement after cognitive rehabilitation. The findings suggest that cognitive rehabilitation may be beneficial in improving cognition in non-demented PD patients, although further studies are needed to obtain more robust effects.

Visual dysfunction is associated with cognitive impairment in Parkinson's disease.

INTRODUCTION: Visual dysfunction and cognitive impairment are common in Parkinson's disease (PD) but the precise contribution of lower-level visual impairment to visual-input based cognitive performance has not been extensively characterized in PD. METHODS: We included 49 PD patients and 22 healthy controls (HC). Lower-level visual function tests [high and low contrast visual acuity (HCVA and LCVA) and contrast sensitivity (CS)] and a neuropsychological battery (involving visual cognition) were performed. Pairwise correlations between lower-level visual functions and visual cognition were computed and stepwise linear regressions were fitted introducing age, Geriatric Depression Scale, and lower-level visual functions in the model to calculate their predicted effect on visual cognition. RESULTS: Compared to controls, patients presented a significant impairment in all cognitive domains (visual attention, visual processing speed and visual perception, visuospatial abilities, visuoconstructive abilities, and visual memory), and lower-level visual functions. HCVA and LCVA were significantly associated with visual cognition in PD. HCVA explained up to 49.3% and 34.2% of the variability in visual perception and visuospatial abilities, respectively, whereas LCVA was mainly associated with short- and long-term visual memory and visuospatial abilities. CONCLUSION: Lower-level visual dysfunction is highly associated with cognitive performance in PD, when cognitive tests are based on visual input. Our results support that lower-level visual functions should be considered when assessing cognitive status of PD patients and might be useful for predicting cognitive deterioration.

Contributions of sex, depression, and cognition on brain connectivity dynamics in Parkinson's disease.

Alterations in time-varying functional connectivity (FC) have been found in Parkinson's disease (PD) patients. To date, very little is known about the influence of sex on brain FC in PD patients and how this could be related to disease severity. The first objective was to evaluate the influence of sex on dynamic FC characteristics in PD patients and healthy controls (HC), while the second aim was to investigate the temporal patterns of dynamic connectivity related to PD motor and non-motor symptoms. Ninety-nine PD patients and sixty-two HC underwent a neuropsychological and clinical assessment. Rs-fMRI and T1-weighted MRI were also acquired. Dynamic FC analyses were performed in the GIFT toolbox. Dynamic FC analyses identified two States: State I, characterized by within-network positive coupling; and State II that showed between-network connectivity, mostly involving somatomotor and visual networks. Sex differences were found in dynamic indexes in HC but these differences were not observed in PD. Hierarchical clustering analysis identified three phenotypically distinct PD subgroups: (1) Subgroup A was characterized by mild motor symptoms; (2) Subgroup B was characterized by depressive and motor symptoms; (3) Subgroup C was characterized by cognitive and motor symptoms. Results revealed that changes in the temporal properties of connectivity were related to the motor/non-motor outcomes of PD severity. Findings suggest that while in HC sex differences may play a certain role in dynamic connectivity patterns, in PD patients, these effects may be overcome by the neurodegenerative process. Changes in the temporal properties of connectivity in PD were mainly related to the clinical markers of PD severity.

Autonomic dysfunction is associated with neuropsychological impairment in Lewy body disease.

OBJECTIVE: This study aimed to analyze the association of autonomic dysfunction with cognition, depression, apathy, and fatigue in Lewy body disease (LBD). METHODS: We included 61 patients [49 with idiopathic Parkinson's disease, 7 with dementia with Lewy bodies, and 5 E46K-SNCA mutation carriers] and 22 healthy controls. All participants underwent a comprehensive battery of neuropsychological and clinical measures, autonomic symptom assessment with the SCOPA-AUT, analysis of non-invasive hemodynamic parameters during deep breathing, the Valsalva maneuver, and a 20-min tilt test, and electrochemical skin conductance measurement at rest (Sudoscan). Student's t tests were used to assess group differences, and bivariate correlations and stepwise linear regressions to explore associations between autonomic function, cognition, depression, apathy, and fatigue. RESULTS: Compared to controls, patients who had significant impairment (p < 0.05) in cognition, higher depression, apathy, and fatigue, more autonomic symptoms and objective autonomic dysfunction, reduced deep breathing heart rate variability [expiratory-to-inspiratory (E/I) ratio], prolonged pressure recovery time, and lower blood pressure in Valsalva late phase II and phase IV, while 24.1% had orthostatic hypotension in the tilt test. Autonomic parameters significantly correlated with cognitive and neuropsychiatric outcomes, systolic blood pressure during the Valsalva maneuver predicting apathy and depression. The E/I ratio was the main predictor of cognitive performance (17.6% for verbal fluency to 32.8% for visual memory). CONCLUSION: Cardiovascular autonomic dysfunction is associated with cognitive and neuropsychiatric impairment in LBD, heart rate variability during deep breathing and systolic blood pressure changes during the Valsalva procedure are the main predictors of neuropsychological performance and depression/apathy symptoms, respectively.

A Neuropsychological Rehabilitation Program for Cognitive Impairment in Psychiatric and Neurological Conditions: A Review That Supports Its Efficacy.

Neuropsychological rehabilitation has been the focus of much scientific research over the past decades due to its efficacy in different pathologies. Advances in the neuropsychology field have led to improvements and changes in neuropsychological interventions, which in turn have given rise to different approaches and rehabilitation programs. REHACOP is an integrative neuropsychological rehabilitation program designed by specialist neuropsychologists. With an integrated bottom-up and top-down approach, REHACOP includes neurocognition, social cognition, and daily living tasks hierarchically organized on an increasing level of difficulty. Task arrangement is addressed to maximize improvements and transfer effects into participant's daily living. To date, REHACOP has been implemented on different clinical samples such as patients with schizophrenia, multiple sclerosis (MS), and Parkinson's disease (PD). This manuscript presents the efficacy data of REHACOP across these three populations and discusses it in the context of the available literature. Overall, the magnitude of improvements obtained by means of REHACOP ranged from medium to high across samples. These changes were not restricted to specific neurocognitive domains since participants attending the REHACOP program also showed changes in social cognition and daily functioning variables by means of both direct and transfer effects. Results regarding REHACOP's efficacy in psychiatric and neurological conditions have contributed to expanding the existing evidence about the use of structured neuropsychological rehabilitation. In addition, the results obtained after its implementation highlighted the need and importance of designing and implementing integrative neuropsychological rehabilitation programs that are focused not only on cognition per se but also on participants' performance in daily living.

Apathy and brain alterations in Parkinson's disease: a multimodal imaging study.

OBJECTIVE: Apathy is a common nonmotor symptom in Parkinson's disease (PD) affecting 40% of patients. The aim of the study was to investigate brain changes and correlates of frontal, striatal, and limbic pathways related to subclinical symptoms of apathy in PD patients. METHODS: Thirty-two PD patients divided into low-subclinical symptoms of apathy (LSA) (n = 18) and high-subclinical symptoms of apathy (HSA) (n = 14) and 25 healthy controls (HC) underwent a T1-weighted, diffusion-weighted, and resting-state functional MRI. Apathy was evaluated with the Lille Apathy Rating Scale. Voxel-based morphometry, tract-based spatial statistics, and resting-state functional connectivity (FC) analyses were performed with a region-of-interest approach. RESULTS: HSA-PD showed increased white matter axial and mean diffusivity compared with HC and increased white matter axial diffusivity compared with LSA-PD. HSA-PD showed decreased fronto-striatal and fronto-limbic FC compared with HC and decreased fronto-striatal FC compared with LSA-PD. LSA-PD showed decreased fronto-limbic but increased fronto-striatal FC (hyperconnectivity) compared with HC. No significant differences in grey matter were found. Fronto-striatal FC and white matter axial and mean diffusivity were associated with symptoms of apathy in HSA-PD. The fronto-striatal hyperconnectivity was associated with lower symptoms of apathy in LSA-PD. INTERPRETATION: Findings suggest distinct brain alterations in PD groups with subclinical symptoms of apathy. The increased pattern of activation in LSA-PD, accompanied with lower apathetic symptomatology, might be the initial manifestation of compensatory mechanisms for dysfunctional limbic pathway. The same pattern of hyperconnectivity has been found in other pathologies and the implication of these abnormalities as a cross-disease model for initial apathy symptomatology is further discussed.

Increased brain connectivity and activation after cognitive rehabilitation in Parkinson's disease: a randomized controlled trial.

Cognitive rehabilitation programs have demonstrated efficacy in improving cognitive functions in Parkinson's disease (PD), but little is known about cerebral changes associated with an integrative cognitive rehabilitation in PD. To assess structural and functional cerebral changes in PD patients, after attending a three-month integrative cognitive rehabilitation program (REHACOP). Forty-four PD patients were randomly divided into REHACOP group (cognitive rehabilitation) and a control group (occupational therapy). T1-weighted, diffusion weighted and functional magnetic resonance images (fMRI) during resting-state and during a memory paradigm (with learning and recognition tasks) were acquired at pre-treatment and post-treatment. Cerebral changes were assessed with repeated measures ANOVA 2 × 2 for group x time interaction. During resting-state fMRI, the REHACOP group showed significantly increased brain connectivity between the left inferior temporal lobe and the bilateral dorsolateral prefrontal cortex compared to the control group. Moreover, during the recognition fMRI task, the REHACOP group showed significantly increased brain activation in the left middle temporal area compared to the control group. During the learning fMRI task, the REHACOP group showed increased brain activation in the left inferior frontal lobe at post-treatment compared to pre-treatment. No significant structural changes were found between pre- and post-treatment. Finally, the REHACOP group showed significant and positive correlations between the brain connectivity and activation and the cognitive performance at post-treatment. This randomized controlled trial suggests that an integrative cognitive rehabilitation program can produce significant functional cerebral changes in PD patients and adds evidence to the efficacy of cognitive rehabilitation programs in the therapeutic approach for PD.

Altered functional connectivity in the default mode network is associated with cognitive impairment and brain anatomical changes in Parkinson's disease.

OBJECTIVE: To assess whether functional neural connectivity is disrupted between the regions of the default mode network (DMN) in Parkinson's disease (PD) and how this connectivity is related to cognition, brain gray matter structure and white matter integrity and diffusivity. METHODS: Thirty-seven PD patients and 16 healthy controls were evaluated, using resting-state functional magnetic resonance imaging (MRI), T1-weighted MRI, diffusion-weighted imaging and a battery of cognitive tests. Functional connectivity between the regions of the DMN, specifically in the precuneus, anterior and posterior cingulate, medial prefrontal and temporal and inferior parietal cortices was assessed with seed-to-voxel connectivity; gray matter volume and white matter values were determined using voxel-based morphometry and tract-based spatial statistics. RESULTS: Reduced functional connectivity was observed between the posterior cingulate and medial temporal lobe in PD. Lower cognitive performance, gray matter loss in posterior, medial temporal and parietal areas, and fractional anisotropy reduction in the white matter adjacent to DMN regions were also observed in PD patients compared with healthy controls. Lower DMN functional connectivity correlated with lower verbal and visual memory and visual abilities performance in PD. In addition, lower DMN functional connectivity correlated with lower gray matter volume in the posterior cingulate and precuneus, and with lower white matter fractional anisotropy of the inferior longitudinal and posterior cingulate fasciculi in PD. CONCLUSIONS: By combining different neuroimaging techniques and cognitive data, results showed that functional connectivity alteration between the regions of the DMN is associated with lower cognitive performance and gray and white matter abnormalities in PD.

Verbal Memory in Parkinson's Disease: A Combined DTI and fMRI Study.

BACKGROUND: While significant progress has been made to determine the functional role of specific gray matter areas underlying verbal memory in Parkinson's disease (PD), very little is known about the relationship between these regions and their underlying white matter structures. OBJECTIVE: The objectives of this study were (1) to investigate verbal memory, fractional anisotropy and brain activation differences between PD patients and healthy controls (HC), (2) to explore the neuroanatomical and neurofunctional correlates of verbal memory in PD, and (3) to investigate the relationship between these neuroanatomical and neurofunctional verbal memory correlates in PD. METHODS: Functional magnetic resonance imaging (fMRI) while performing a verbal memory paradigm and diffusion tensor imaging data (DTI), were acquired in 37 PD patients and 15 age-, sex-, and education-matched HC. RESULTS: PD patients showed verbal recognition memory impairment, lower fractional anisotropy in the anterior cingulate tract, and lower brain activation in the inferior orbitofrontal cortex compared to HC. Brain activation in the inferior orbitofrontal cortex correlated significantly with verbal recognition memory impairment in PD patients. In addition, a relationship between brain activation in the inferior orbitofrontal cortex and fractional anisotropy of the uncinate fasciculus was found in PD. CONCLUSIONS: These results reveal that deficits in verbal memory in PD are accompanied by functional brain activation changes, but also have specific structural correlates related to white matter microstructural integrity.