High-oligomeric and low-total-?-synuclein cerebrospinal fluid (CSF) levels have been found in Parkinson's disease (PD), but with inconsistent or limited data, particularly on their clinical and structural correlates in earliest (premotor) or latest (dementia) PD stages. We determined CSF oligomeric- and total-?-synuclein in 77 subjects: 23 with idiopathic REM-sleep behaviour disorder (iRBD, a condition likely to include a remarkable proportion of subjects in the premotor stage of PD) and 41 with PD [21 non-demented (PDND) + 20 demented (PDD)], intended to reflect the premotor-motor-dementia PD continuum, along with 13 healthy controls. The study protocol also included the Unified PD Rating Scale motor-section (UPDRS-III), mini mental state examination (MMSE), neuropsychological cognitive testing, 3T brain MRI for cortical-thickness analyses, CSF ? and CSF A?. CSF oligomeric-?-synuclein was higher in PDND than iRBD and in PDD than iRBD and controls, and correlated with UPDRS-III, MMSE, semantic fluency and visuo-perceptive scores across the proposed premotor-motor-dementia PD continuum (iRBD + PDND + PDD). CSF total-?-synuclein positively correlated with age, CSF A?, and, particularly, CSF ?, tending towards lower levels in PD (but not iRBD) vs. controls only when controlling for CSF ?. Low CSF total-?-synuclein was associated with dysfunction in phonetic-fluency (a frontal-lobe function) in PD and with frontal cortical thinning in iRBD and PDND independently of CSF ?. Conversely, the associations of high (instead of low) CSF total-?-synuclein with posterior-cortical neuropsychological deficits in PD and with posterior cortical thinning in PDD were driven by high CSF ?. These findings suggest that CSF oligomeric- and total-?-synuclein have different clinical, neuropsychological and MRI correlates across the proposed premotor-motor-dementia PD continuum. CSF total-?-synuclein correlations with CSF ? and A? support the hypothesis of an interaction among these proteins in PD, with CSF ? probably influencing the presence of high (instead of low) CSF total-?-synuclein and its correlates mostly in the setting of PD-related dementia.
The current study investigates both gray and white matter changes in non-demented Parkinson's disease (PD) patients with varying degrees of mild cognitive deficits and elucidates the relationships between the structural changes and clinical sequelae of PD. Twenty-six PD patients and 15 healthy controls (HCs) were enrolled in the study. Participants underwent T1-weighted and diffusion tensor imaging (DTI) scans. Their cognition was assessed using a neuropsychological battery. Compared with HCs, PD patients showed significant cortical thinning in sensorimotor (left pre- and postcentral gyri) and cognitive (left dorsolateral superior frontal gyrus [DLSFG]) regions. The DLSFG cortical thinning correlated with executive and global cognitive impairment in PD patients. PD patients showed white matter abnormalities as well, primarily in bilateral frontal and temporal regions, which also correlated with executive and global cognitive impairment. These results seem to suggest that both gray and white matter changes in the frontal regions may constitute an early pathological substrate of cognitive impairment of PD providing a sensitive biomarker for brain changes in PD.
The aim of this study was to investigate patterns of cortical atrophy associated with mild cognitive impairment in a large sample of nondemented Parkinson's disease (PD) patients, and its relation with specific neuropsychological deficits. Magnetic resonance imaging (MRI) and neuropsychological assessment were performed in a sample of 90 nondemented PD patients and 32 healthy controls. All underwent a neuropsychological battery including tests that assess different cognitive domains: attention and working memory, executive functions, memory, language, and visuoperceptual-visuospatial functions. Patients were classified according to their cognitive status as PD patients without mild cognitive impairment (MCI; n?=?43) and PD patients with MCI (n?=?47). Freesurfer software was used to obtain maps of cortical thickness for group comparisons and correlation with neuropsychological performance. Patients with MCI showed regional cortical thinning in parietotemporal regions, increased global atrophy (global cortical thinning, total gray matter volume reduction, and ventricular enlargement), as well as significant cognitive impairment in memory, executive, and visuospatial and visuoperceptual domains. Correlation analyses showed that all neuropsychological tests were associated with cortical thinning in parietotemporal regions and to a lesser extent in frontal regions. These results provide neuroanatomic support to the concept of MCI classified according to Movement Disorders Society criteria. The posterior pattern of atrophy in temporoparietal regions could be a structural neuroimaging marker of cognitive impairment in nondemented PD patients. All of the neuropsychological tests reflected regional brain atrophy, but no specific patterns were seen corresponding to impairment in distinct cognitive domains.
The prevalence of obesity is increasing worldwide. Previous research has shown a relationship between obesity and both executive functioning alterations and frontal cortex volume reductions. The Brain Derived Neurotrophic Factor val66met polymorphism, involved in eating behavior, has also been associated with executive functions and prefrontal cortex volume, but to date it has not been studied in relation to obesity. Our aim is to elucidate whether the interaction between the Brain Derived Neurotrophic Factor val66met polymorphism and obesity status influences executive performance and frontal-subcortical brain structure. Sixty-one volunteers, 34 obese and 27 controls, age range 12-40, participated in the study. Participants were assigned to one of two genotype groups (met allele carriers, n?=?16, or non-carriers, n?=?45). Neuropsychological assessment comprised the Trail Making Test, the Stroop Test and the Wisconsin Card Sorting Test, all tasks that require response inhibition and cognitive flexibility. Subjects underwent magnetic resonance imaging in a Siemens TIM TRIO 3T scanner and images were analyzed using the FreeSurfer software. Analyses of covariance controlling for age and intelligence showed an effect of the obesity-by-genotype interaction on perseverative responses on the Wisconsin Card Sorting Test as well as on precentral and caudal middle frontal cortical thickness: obese met allele carriers showed more perseverations on the Wisconsin Card Sorting Test and lower frontal thickness than obese non-carriers and controls. In conclusion, the Brain Derived Neurotrophic Factor may play an important role in executive functioning and frontal brain structure in obesity.
Graph-theoretical analyses of functional networks obtained with resting-state functional magnetic resonance imaging (fMRI) have recently proven to be a useful approach for the study of the substrates underlying cognitive deficits in different diseases. We used this technique to investigate whether cognitive deficits in Parkinson's disease (PD) are associated with changes in global and local network measures. Thirty-six healthy controls (HC) and 66 PD patients matched for age, sex, and education were classified as having mild cognitive impairment (MCI) or not based on performance in the three mainly affected cognitive domains in PD: attention/executive, visuospatial/visuoperceptual (VS/VP), and declarative memory. Resting-state fMRI and graph theory analyses were used to evaluate network measures. We have found that patients with MCI had connectivity reductions predominantly affecting long-range connections as well as increased local interconnectedness manifested as higher measures of clustering, small-worldness, and modularity. The latter measures also tended to correlate negatively with cognitive performance in VS/VP and memory functions. Hub structure was also reorganized: normal hubs displayed reduced centrality and degree in MCI PD patients. Our study indicates that the topological properties of brain networks are changed in PD patients with cognitive deficits. Our findings provide novel data regarding the functional substrate of cognitive impairment in PD, which may prove to have value as a prognostic marker.
The ability to dynamically use various aspects of cognition is essential to daily function, and reliant on dopaminergic transmission in cortico-striatal circuitry. Our aim was to investigate both striatal and cortical dopaminergic changes in patients with Parkinsons disease with mild cognitive impairment, who represent a vulnerable group for the development of dementia. We hypothesized severe striatal dopamine denervation in the associative (i.e. cognitive) region and cortical D2 receptor abnormalities in the salience and executive networks in Parkinsons disease with mild cognitive impairment compared with cognitively normal patients with Parkinsons disease and healthy control subjects. We used positron emission tomography imaging with dopaminergic ligands (11)C-dihydrotetrabenazine, to investigate striatal dopamine neuron integrity in the associative subdivision and (11)C-FLB 457, to investigate cortical D2 receptor availability in patients with Parkinsons disease (55-80 years of age) with mild cognitive impairment (n = 11), cognitively normal patients with Parkinsons disease (n = 11) and age-matched healthy control subjects (n = 14). Subjects were administered a neuropsychological test battery to assess cognitive status and determine the relationship between dopaminergic changes and cognitive performance. We found that patients with mild cognitive impairment had severe striatal dopamine depletion in the associative (i.e. cognitive) subdivision as well as reduced D2 receptor availability in the bilateral insula, a key cognitive hub, compared to cognitively normal patients and healthy subjects after controlling for age, disease severity and daily dopaminergic medication intake. Associative striatal dopamine depletion was predictive of D2 receptor loss in the insula of patients with Parkinsons disease with mild cognitive impairment, demonstrating interrelated striatal and cortical changes. Insular D2 levels also predicted executive abilities in these patients as measured using a composite executive z-score obtained from neuropsychological testing. Furthermore we assessed cortical thickness to ensure that D2 receptor changes were not confounded by brain atrophy. There was no difference between groups in cortical thickness in the insula, or any other cortical region of interest. These findings suggest that striatal dopamine denervation combined with insular D2 receptor loss underlie mild cognitive impairment in Parkinsons disease and in particular decline in executive function. Furthermore, these findings suggest a crucial and direct role for dopaminergic modulation in the insula in facilitating cognitive function.
Tourette syndrome (TS) is a heritable neuropsychiatric disorder that presents in childhood with a constellation of motor and nonmotor symptoms. Many of the earliest efforts to elucidate the anatomic substrate of TS focused on the contribution of the basal ganglia to the disorder. Simultaneously, however, a substantial body of evidence has accrued to implicate dysfunction of regions outside the basal ganglia in the generation of tics. In particular, while activation studies have shown evidence for cortico-striato-thalamo-cortical circuit abnormalities in TS, several other functional imaging reports have suggested that a dysregulation of striatal dopamine both at the presynaptic and postsynaptic level may play a primary role in TS. In addition, new radiotracers allowing for the investigation of extrastriatal dopamine seem to support the involvement of cortical structures as well.
Obesity depends on homeostatic and hedonic food intake behavior, mediated by brain plasticity changes in cortical and subcortical structures. The aim of this study was to investigate cortical thickness and subcortical volumes of regions related to food intake behavior in a healthy young adult sample with obesity. Thirty-seven volunteers, 19 with obesity (age=33.7±5.7 (20-39) years body-mass index (BMI)=36.08±5.92 (30.10-49.69)kg/m(2)) and 18 controls (age=32.3±5.9 (21-40) years; BMI=22.54±1.94 (19.53-24.97)kg/m(2)) participated in the study. Patients with neuropsychiatric or biomedical disorders were excluded. We used FreeSurfer software to analyze structural magnetic resonance images (MRI) and obtain global brain measures, cortical thickness and subcortical volume estimations. Finally, correlation analyses were performed for brain structure data and obesity measures. There were no between-group differences in age, gender, intelligence or education. Results showed cortical thickness reductions in obesity in the left superior frontal and right medial orbitofrontal cortex. In addition, the obesity group had lower ventral diencephalon and brainstem volumes than controls, while there were no differences in any other subcortical structure. There were no statistically significant correlations between brain structure and obesity measures. Overall, our work provides evidence of the structural brain characteristics associated with metabolically normal obesity. We found reductions in cortical thickness, ventral diencephalon and brainstem volumes in areas that have been implicated in food intake behavior.
OBJECTIVE The authors sought to assess the efficacy of functional remediation, a novel intervention program, on functional improvement in a sample of euthymic patients with bipolar disorder. METHOD In a multicenter, randomized, rater-blind clinical trial involving 239 outpatients with DSM-IV bipolar disorder, functional remediation (N=77) was compared with psychoeducation (N=82) and treatment as usual (N=80) over 21 weeks. Pharmacological treatment was kept stable in all three groups. The primary outcome measure was improvement in global psychosocial functioning, measured blindly as the mean change in score on the Functioning Assessment Short Test from baseline to endpoint. RESULTS At the end of the study, 183 patients completed the treatment phase. Repeated-measures analysis revealed significant functional improvement from baseline to endpoint over the 21 weeks of treatment (last observation carried forward), suggesting an interaction between treatment assignment and time. Tukeys post hoc tests revealed that functional remediation differed significantly from treatment as usual, but not from psychoeducation. CONCLUSIONS Functional remediation, a novel group intervention, showed efficacy in improving the functional outcome of a sample of euthymic bipolar patients as compared with treatment as usual.
In non-demented older persons, smell dysfunction, measured premortem, has been associated with postmortem brain degeneration similar to that of Alzheimers disease. We hypothesized that distinct measures of gray and white matter integrity evaluated through magnetic resonance imaging (MRI) techniques could detect degenerative changes associated with age-related olfactory dysfunction. High-resolution T1-weighted images and diffusion-tensor images (DTI) of 30 clinically healthy subjects aged 51-77 were acquired with a 3-Tesla MRI scanner. Odor identification performance was assessed by means of the University of Pennsylvania Smell Identification Test (UPSIT). UPSIT scores correlated with right amygdalar volume and bilateral perirhinal and entorhinal cortices gray matter volume. Olfactory performance also correlated with postcentral gyrus cortical thickness and with fractional anisotropy and mean diffusivity levels in the splenium of the corpus callosum and the superior longitudinal fasciculi. Our results suggest that age-related olfactory loss is accompanied by diffuse degenerative changes that might correspond to the preclinical stages of neurodegenerative processes.
One fundamental question concerning brain reward mechanisms is to determine how reward-related activity is influenced by the nature of rewards. Here, we review the neuroimaging literature and explicitly assess to what extent the representations of primary and secondary rewards overlap in the human brain. To achieve this goal, we performed an activation likelihood estimation (ALE) meta-analysis of 87 studies (1452 subjects) comparing the brain responses to monetary, erotic and food reward outcomes. Those three rewards robustly engaged a common brain network including the ventromedial prefrontal cortex, ventral striatum, amygdala, anterior insula and mediodorsal thalamus, although with some variations in the intensity and location of peak activity. Money-specific responses were further observed in the most anterior portion of the orbitofrontal cortex, supporting the idea that abstract secondary rewards are represented in evolutionary more recent brain regions. In contrast, food and erotic (i.e. primary) rewards were more strongly represented in the anterior insula, while erotic stimuli elicited particularly robust responses in the amygdala. Together, these results indicate that the computation of experienced reward value does not only recruit a core "reward system" but also reward type-dependent brain structures.
We aimed to investigate changes in the verbal recognition memory network in patients with early Parkinsons disease (PD) without overt recognition memory alteration. Verbal recognition memory was assessed in 24 PD patients in early stages of the disease and a control group of 24 healthy subjects during fMRI data acquisition. Participants were presented with a list of 35 words before imaging, and later during fMRI scanning they were required to recognize these previously presented words. Both model-based (FEAT) and model-free (MELODIC) analyses of the fMRI data were carried out with FSL software. Memory was also assessed by means of Reys Auditory Verbal Learning Test (RAVLT). PD patients showed no difference in the fMRI recognition memory task and recognition memory assessed by the RAVLT compared to healthy controls. Model-based analysis did not show significant differences between groups. On the other hand, model-free analysis identified components that fitted the task-model and were common to all the participants, as well as components that differed between PD and healthy controls. PD patients showed decreased task-related activations in areas involved in the recognition memory network and decreased task-related deactivations in the default mode network in comparison with controls. In conclusion, model-free fMRI analysis detected alterations in functional cerebral networks involved in a verbal memory task in PD patients without evident recognition memory deficit.
Metabolic Syndrome (MetSd) is a cluster of vascular risk factors that may influence cerebrovascular pathology during aging. Recently, microstructural white matter (WM) changes detected by diffusion tensor imaging (DTI) and processing speed deficits have been reported in MetSd patients. We aimed to test the relationship between WM alteration and cognitive impairment in these patients.
Metabolic Syndrome is a cluster of vascular risk factors which has been related to dementia and cognitive decline. The aim of this study was to describe the neuropsychological profile of metabolic syndrome patients. An extensive neuropsychological protocol was administered to 55 patients and 35 controls assessing memory, executive, visuoperceptual and visuoconstructive functions, language and speed of processing. There were differences between groups in speed of processing and some executive functions after controlling for the influences of education and gender. The results suggest that metabolic syndrome may be a prodromal state of vascular cognitive impairment.
Impulsivity is a complex behaviour composed of different domains encompassing behavioural dis-inhibition, risky decision-making and delay discounting abnormalities. To investigate regional brain correlates between levels of individual impulsivity and grey matter volume, we performed voxel-based morphometric correlation analysis in 34 young, healthy subjects using impulsivity scores measured with Barratt Impulsivity Scale-11 and computerized Kirbys delay discounting task. The VBM analysis showed that impulsivity appears to be reliant on a network of cortical (medial prefrontal cortex and dorsolateral prefrontal cortex) and subcortical (ventral striatum) structures emphasizing the importance of brain networks associated with reward related decision-making in daily life as morphological biomarkers for impulsivity in a normal healthy population. While our results in healthy volunteers may not directly extend to pathological conditions, they provide an insight into the mechanisms of impulsive behaviour in patients with abnormalities in prefrontal/frontal-striatal connections, such as in drug abuse, pathological gambling, ADHD and Parkinsons disease.
The aim of this study was to investigate the progression of cortical thinning and gray-matter (GM) volume loss in early Parkinsons disease (PD). MRI and neuropsychological assessment were obtained at baseline and follow-up (mean ± standard deviation = 35.50 ± 1.88 months) in a group of 16 early-PD patients (H & Y stage ?II and disease duration ?5 years) and 15 healthy controls matched for age, gender, and years of education. FreeSurfer software was used for the analysis of cortical thickness as well as for cortical and subcortical volumetric analyses. Voxel-based morphometry analysis was performed using SPM8. Compared to controls, PD patients showed greater regional cortical thinning in bilateral frontotemporal regions as well as greater over-time total GM loss and amygdalar volume reduction. PD patients and controls presented similar over-time changes in cognitive functioning. In early-PD patients, global GM loss, amygdalar atrophy, and cortical thinning in frontotemporal regions are specifically associated with the PD-degenerative process.
In a previous functional MRI (fMRI) study, we found that patients with Parkinsons disease (PD) presented with dysfunctions in the recruitment of recognition memory networks. We aimed to investigate the changes in these networks over time.
Obesity is a multifactorial disease caused by the interaction between genotype and environment, and it is considered to be a type of addictive alteration. The A1 allele of the DRD2/ANKK1-TaqIA gene has been associated with addictive disorders, with obesity and with the performance in executive functions. The 7 repeat allele of the DRD4 gene has likewise been associated with the performance in executive functions, as well as with addictive behaviors and impulsivity. Participants were included in the obesity group (N?=?42) if their body mass index (BMI) was equal to or above 30, and in the lean group (N?=?42) if their BMI was below 25. The DRD2/ANKK1-TaqIA and DRD4 VNTR polymorphisms were obtained. All subjects underwent neuropsychological assessment. Eating behavior traits were evaluated. The DRD2/ANKK1-TaqIA A1-allele status had a significant effect on almost all the executive variables, but no significant DRD4 7R-allele status effects were observed for any of the executive variables analyzed. There was a significant group x DRD2/ANKK1-TaqIA A1-allele status interaction effect on LN and group x DRD4 7R-allele status interaction effect on TMT B-A score. Being obese and a carrier of the A1 allele of DRD2/ANKK1-TaqIA or the 7R allele of DRD4 VNTR polymorphisms could confer a weakness as regards the performance of executive functions.
Obesity is a major health problem in modern societies. It has been related to abnormal functional organization of brain networks believed to process homeostatic (internal) and/or salience (external) information. This study used resting-state functional magnetic resonance imaging analysis to delineate possible functional changes in brain networks related to obesity. A group of 18 healthy adult participants with obesity were compared with a group of 16 lean participants while performing a resting-state task, with the data being evaluated by independent component analysis. Participants also completed a neuropsychological assessment. Results showed that the functional connectivity strength of the putamen nucleus in the salience network was increased in the obese group. We speculate that this abnormal activation may contribute to overeating through an imbalance between autonomic processing and reward processing of food stimuli. A correlation was also observed in obesity between activation of the putamen nucleus in the salience network and mental slowness, which is consistent with the notion that basal ganglia circuits modulate rapid processing of information.
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