Abnormal metabolic pattern associated with cognitive impairment in Parkinson's disease: a validation study

Cognitive deficits in Parkinson''s disease (PD) have been associated with a specific metabolic covariance pattern. Although the expression of this PD cognition-related pattern (PDCP) correlates with neuropsychological performance, it is not known whether the PDCP topography is reproducible across PD populations. We therefore sought to identify a PDCP topography in a new sample comprised of 19 Dutch PD subjects. Network analysis of metabolic scans from these individuals revealed a significant PDCP that resembled the original network topography. Expression values for the new PDCP correlated (P=0.001) with executive dysfunction on the Frontal Assessment Battery (FAB). Subject scores for the new PDCP correlated (P<0.001) with corresponding values for the original pattern, which also correlated (P<0.005) with FAB scores in this patient group. For further validation, subject scores for the new PDCP were computed in an independent group of 86 American PD patients. In this cohort, subject scores for the new and original PDCP topographies were closely correlated (P<0.001); significant correlations between pattern expression and cognitive performance (P<0.05) were observed for both PDCP topographies. These findings suggest that the PDCP is a replicable imaging marker of PD cognitive dysfunction.     

Brain metabolic correlates of fatigue in Parkinson's disease: a PET study

Purpose: The neural bases of fatigue in Parkinson's disease (PD) remain uncertain. We aimed to assess the brain metabolic correlates of fatigue in patients with PD.

Patients and methods: Twenty-seven PD patients without clinically relevant depression (17-item Hamilton Depression Rating Scale (HAMD) score ≥ 14), apathy (Apathy Scale (AS) score ≥ 14) and excessive daytime somnolence (Epworth Sleepiness Scale (ESS) score ≥ 10) were evaluated with Fatigue Severity Scale (FSS). Each patient had an F-18 fluorodeoxyglucose positron emission tomography (FDG-PET) scan. Motor symptoms were measured with the Unified Parkinson's Disease Rating Scale motor part. Levodopa equivalent daily dose for each patient was also calculated. The PET images were analyzed using statistical parametric mapping software. We introduced the age, educational level, HAMD scores, AS scores and ESS scores as covariates.

Results: High FSS scores were associated with brain hypermetabolism in areas including the right middle temporal gyrus (Brodmann area (BA) 37) and left middle occipital gyrus (BA 19). Increased FSS scores correlated with hypometabolism in regions such as the right precuneus (BA 23), left inferior frontal gyrus (BA 45) and left superior frontal gyrus (orbital part, BA 11).

Conclusion: This study demonstrates that brain areas including frontal, temporal and parietal regions indicative of emotion, motivation and cognitive functions are involved in fatigue in PD patients.     

Dopaminergic correlates of metabolic network activity in Parkinson's disease

Parkinson's disease (PD) is associated with distinct metabolic covariance patterns that relate to the motor and cognitive manifestations of the disorder. It is not known, however, how the expression of these patterns relates to measurements of nigrostriatal dopaminergic activity from the same individuals. To explore these associations, we studied 106 PD subjects who underwent cerebral PET with both ¹⁸F‐fluorodeoxyglucose (FDG) and ¹⁸F‐fluoro‐L‐dopa (FDOPA). Expression values for the PD motor‐ and cognition‐related metabolic patterns (PDRP and PDCP, respectively) were computed for each subject; these measures were correlated with FDOPA uptake on a voxel‐by‐voxel basis. To explore the relationship between dopaminergic function and local metabolic activity, caudate and putamen FDOPA PET signal was correlated voxel‐wise with FDG uptake over the entire brain. PDRP expression correlated with FDOPA uptake in caudate and putamen (P < 0.001), while PDCP expression correlated with uptake in the anterior striatum (P < 0.001). While statistically significant, the correlations were only of modest size, accounting for less than 20% of the overall variation in these measures. After controlling for PDCP expression, PDRP correlations were significant only in the posterior putamen. Of note, voxel‐wise correlations between caudate/putamen FDOPA uptake and whole‐brain FDG uptake were significant almost exclusively in PDRP regions. Overall, the data indicate that PDRP and PDCP expression correlates significantly with PET indices of presynaptic dopaminergic functioning obtained in the same individuals. Even so, the modest size of these correlations suggests that in PD patients, individual differences in network activity cannot be explained solely by nigrostriatal dopamine loss. Hum Brain Mapp 36:3575–3585, 2015. © 2015 Wiley Periodicals, Inc.     

Regional metabolic changes in parkinsonian patients with normal dopaminergic imaging.

Dopaminergic imaging has been found to be normal in approximately 15% of parkinsonian patients enrolled in neuroprotective trials. We used (18)F-fluorodeoxyglucose positron emission tomography (FDG PET) to determine the metabolic basis for this finding. We reviewed scans from 185 patients with clinical signs of Parkinson's disease (PD) who underwent (18)F-fluorodopa PET imaging for diagnostic confirmation. Of this group, 27 patients (14.6%) had quantitatively normal scans; 8 of these patients were additionally scanned with FDG PET. Pattern analysis was performed on an individual scan basis to determine whether the metabolic changes were consistent with classic PD. Computer-assisted single-case assessments of the FDG PET scans of these 8 patients did not disclose patterns of regional metabolic change compatible with classical PD or an atypical parkinsonian variant. Similarly, network quantification revealed that PD-related pattern expression was not elevated in these patients as it was in an age- and duration-matched cohort with classical PD (P < 0.0001). None of these patients developed clinical signs of classical PD or of an atypical parkinsonian syndrome at a follow-up visit conducted 3 years after imaging. The results suggest that parkinsonian subjects with normal dopaminergic imaging do not have evidence of classical PD or an atypical parkinsonian syndrome.     

Brain PET substrate of impulse control disorders in Parkinson's disease: A metabolic connectivity study

Impulse control disorders (ICDs) have received increased attention in Parkinson's disease (PD) because of potentially dramatic consequences. Their physiopathology, however, remains incompletely understood. An overstimulation of the mesocorticolimbic system has been reported, while a larger network has recently been suggested. The aim of this study is to specifically describe the metabolic PET substrate and related connectivity changes in PD patients with ICDs. Eighteen PD patients with ICDs and 18 PD patients without ICDs were evaluated using cerebral 18F‐fluorodeoxyglucose positron emission tomography. SPM‐T maps comparisons were performed between groups and metabolic connectivity was evaluated by interregional correlation analysis (IRCA; p < .005, uncorrected; k > 130) and by graph theory (p < .05). PD patients with ICDs had relative increased metabolism in the right middle and inferior temporal gyri compared to those without ICDs. The connectivity of this area was increased mostly with the mesocorticolimbic system, positively with the orbitofrontal region, and negatively with both the right parahippocampus and the left caudate (IRCA). Moreover, the betweenness centrality of this area with the mesocorticolimbic system was lost in patients with ICDs (graph analysis). ICDs are associated in PD with the dysfunction of a network exceeding the mesocorticolimbic system, and especially the caudate, the parahippocampus, and the orbitofrontal cortex, remotely including the right middle and inferior temporal gyri. This latest area loses its central place with the mesocorticolimbic system through a connectivity dysregulation.     

Executive processes in Parkinson's disease: FDG-PET and network analysis

It is assumed widely that the clinical expression of Parkinson's Disease (PD), both motor and cognitive, is subtended by topographically distributed brain networks. However, little is known about the functional neuroanatomy of executive dysfunction in PD. Our objective was to validate further in a PD group the use of network analysis to assess the relationship between executive processes and pathological disorganization of frontostriatal networks. We studied 15 patients with idiopathic PD, and 7 age-matched normal controls, using resting [(18)F]fluorodeoxyglucose (FDG) and high-resolution positron emission tomography (PET). We carried out network analysis on regional metabolic data to identify specific covariation patterns associated with motor and executive dysfunction. We detected two independent patterns relating respectively to the two clinical abnormalities. The first pattern (principal component 1) was topographically similar to that described previously in other PD populations. Subject scores for this pattern discriminated patients from controls and correlated significantly with bradykinesia ratings (P = 0.013, r = 0.655) in PD patients. The second pattern (principal component 2) was characterized by relative ventromedial frontal, hippocampal, and striatal hypometabolism, associated with mediodorsal thalamic hypermetabolism. In the PD group, scores from this pattern correlated with scores on the conditional associative learning (CAL; P = 0.01, r = 0.690) and the Brown Peterson paradigm (BPP; P = 0.017, r = -0.651) tests, respectively assessing strategy and planning, and working memory. According to these findings, the networks subserving bradykinesia and executive dysfunction in PD seems to be topographically distinct and to involve different aspects of subcortico-cortical processing.     

Fatigue in Parkinson's disease: a review.

Fatigue is a common problem in Parkinson's disease (PD), often the most troubling of all symptoms. It is poorly understood, generally under-recognized, and has no known treatment. This article reviews what is known about the symptom, putting it into the context of fatigue in other disorders, and outlines a program for developing better understanding and therapy.     

Atypical clinical presentation of pathologically proven Parkinson's disease: The role of Parkinson's disease related metabolic pattern

Regional changes in brain metabolism upgraded with measurements of specific metabolic brain patterns and automated diagnostic algorithms can help to differentiate among neurodegenerative parkinsonisms, but with few reports on pathological confirmation. Here we describe a parkinsonian patient with atypical presentation and ¹⁸F-FDG-PET imaging consistent with idiopathic Parkinson's disease. The latter was confirmed at the pathohistological examination.     

Association of dysphagia with altered brain glucose metabolism in Parkinson's disease

Aims

Dysphagia is a major clinical concern in Parkinson's disease (PD). However, the relationship between the development of phase-specific dysphagia and the regional brain glucose metabolism remains unclear. Our objective was to investigate the distributions of brain glucose metabolism specific to oral and pharyngeal phases of dysphagia in PD.

Methods

In this retrospective cross-sectional study, patients with PD who underwent videofluoroscopic swallowing study (VFSS) and ¹⁸F-fluorodeoxy-glucose positron emission tomography at intervals of <1 month were included. Each swallow was assessed by the binarized Videofluoroscopic Dysphagia Scale with 14 subitems, seven each for the oral and pharyngeal phases. Metabolism mapping was performed by superimposing significant clusters of subitems belonging to each of the two phases using voxel-wise Firth's penalized binary logistic regression model, adjusting for age and PD duration at VFSS.

Results

Eighty-two patients with PD who met the inclusion criteria were included in the analysis. The oral phase dysphagia-specific overlap map showed hypermetabolism in the right inferior temporal gyrus, bilateral cerebellum, superior frontal gyrus, and anterior cingulate cortices. Hypometabolism in the bilateral orbital and triangular parts of the inferior to middle frontal gyrus was also correlated with the occurrence of oral phase dysphagia. The development of pharyngeal phase dysphagia was related to hypermetabolism of posterior aspects of the bilateral parietal lobes, cerebellum, and hypometabolism of the mediodorsal aspects of anterior cingulate and middle to superior frontal gyri.

Conclusion

These findings suggest that phase-specific distribution of brain glucose metabolism may explain the dysphagia of PD.     

Fatigue in Parkinson's disease: concepts and clinical approach

Parkinson's disease (PD) is a progressive neurological disorder characterized by a large number of motor and non‐motor features. Fatigue is one of the most common and most disabling symptoms among patients with PD, and it has a significant impact on their quality of life. Although fatigue has been recognized for a long time, its pathophysiology remains poorly understood, and there is no evidence to support any therapeutic approach in PD patients. Expert consensus on case definition and diagnostic criteria for PD‐related fatigue have been recently published, and although they still need to be adequately validated, they provide a great step forward in the study of fatigue. The goal of this article is to provide relevant information for the identification and management of patients with fatigue.     

Direct comparison between regional cerebral metabolism in progressive supranuclear palsy and Parkinson's disease.

The differentiation between progressive supranuclear palsy (PSP) and Parkinson's disease (PD) may be difficult, especially in the early stages of disease. Positron emission tomography potentially provides a tool for making such a distinction. To identify key features in the spatial distributions of cerebral glucose metabolism, 18F-fluorodeoxyglucose (FDG) measurements of 10 patients with probable or possible PSP were directly compared with those of 9 PD patients. This analysis was done with statistic parametric mapping. After normalization of global brain uptake, in PSP, relative uptake of FDG was reduced in the caudal (motor) part of the anterior cingulate gyrus (Brodmann's area BA 24; P < 0.05, corrected for multiple comparisons). At a lower threshold, an additional decrease was present in the dorsal mesencephalon. In PD, relative hypometabolism was seen in extrastriate visual, ventrolateral temporal, posterior parietal, and orbitofrontal regions. Only reduction in the right fusiform gyrus and the lateral extrastriate visual cortex reached statistical significance. We concluded that particularly the reduction of medial frontal metabolism may be a valuable diagnostic imaging parameter in distinguishing PSP from PD. For PD, a possible association between occipitotemporal FDG decrease and vulnerability to hallucinations is suggested.     

Cognitive changes in prodromal Parkinson's disease: A review

Although other nonmotor phenomena representing possible prodromal symptoms of Parkinson's disease have been described in some detail, the occurrence and characteristics of cognitive decline in this early phase of the disease are less well understood. The aim of this review is to summarize the current state of research on cognitive changes in prodromal PD. Only a small number of longitudinal studies have been conducted that examined cognitive function in individuals with a subsequent PD diagnosis. However, when we consider data from at‐risk groups, the evidence suggests that cognitive decline may occur in a substantial number of individuals who have the potential for developing PD. In terms of specific cognitive domains, executive function in particular and, less frequently, memory scores are reduced. Prospective longitudinal studies are thus needed to clarify whether cognitive, and specifically executive, decline might be added to the prodromal nonmotor symptom complex that may precede motor manifestations of PD by years and may help to update the risk scores used for early identification of PD. © 2017 International Parkinson and Movement Disorder Society     

Fatigue in Japanese patients with Parkinson's disease: A study using Parkinson fatigue scale

The objective of this multicenter cross‐sectional study was to determine the prevalence of fatigue and factors contributing to it in a large sample of Japanese patients with Parkinson's disease (PD). We used the 16‐item Parkinson Fatigue Scale (PFS‐16), which was designed to assess fatigue exclusively associated with PD. We carried out this study using PFS‐16, the Unified Parkinson's Disease Rating Scale, Zung's Self‐Rating Depression Scale, Parkinson's Disease Sleep Scale (PDSS), and the PD quality of life (QOL) scale (PDQ‐39) by interview using questionnaires and physical examination by neurologists in 361 nondemented PD patients. Fatigue (an average PFS score of 3.3 or greater) was revealed in 151 patients (41.8%). Multiple logistic regression analysis indicated that the significant independent variables related to the presence of fatigue were the scores of PDSS and PDQ‐39. Depression score was not a significant contributing factor. Our study revealed that the prevalence of fatigue in Japanese PD patients is as high as that in Western countries, and that fatigue is a relatively independent symptom, although sleep disturbance may be associated with fatigue. Since fatigue is significantly related to QOL reduction, therapeutic interventions including treatment of sleep disturbance are important. © 2009 Movement Disorder Society     

Changes in Glucose Metabolism in Cerebral Cortex and Cerebellum Correlate With Tremor and Rigidity Control by Subthalamic Nucleus Stimulation in Parkinson's Disease: A Positron Emission Tomography Study

Objective. Employing [¹⁸F]fluorodeoxyglucose (FDG) positron emission tomography (PET) to assess the correlation between the effect of deep brain stimulation (DBS) on the subthalamic nucleus (STN) and the regional cerebral metabolic rate of glucose (rCMRGlc) in advanced Parkinson's disease patients (N = 8). Materials and Methods. On the basis of patients’ diary records, we performed FDG‐PET during the off‐period of motor activity with on‐ or off‐stimulation by STN‐DBS on separate days and analyzed the correlation between changes in motor symptoms and alterations in the rCMRGlc. Result. When FDG‐PET was performed, the motor score on the unified Parkinson's disease rating scale (UPDRS) was 64% lower with on‐stimulation than with off‐stimulation (p < 0.001, Wilcoxon single‐rank test). STN‐DBS increased the rCMRGlc in the posterior part of the right middle frontal gyrus, which corresponded to the premotor area, and the right anterior lobe of the cerebellum (p < 0.005, paired t‐test). No region exhibited a decrease in rCMRGlc. Among the items of the UPDRS motor score, the changes in resting tremor and rigidity of the left extremities showed a significant correlation with the changes in rCMRGlc observed in the right premotor area (p < 0.02 and p < 0.05, respectively, Spearman's rank correlation). Conclusions. STN‐DBS either activates the premotor area or normalizes the deactivation of the premotor area. These FDG‐PET findings obtained are consistent with the idea that STN‐DBS modifies the activities of neural circuits involved in motor control.     

Regional homogeneity changes in patients with Parkinson's disease

Resting state brain activity in Parkinson's disease (PD) can give clues to the pathophysiology of the disorder, and might be helpful in diagnosis, but it has never been explored using functional MRI (fMRI). In the current study, we used a regional homogeneity (ReHo) method to investigate PD-related modulations of neural activity in the resting state. FMRIs were acquired in 22 patients with PD at both before and after levodopa administration, as well as in 22 age- and sex-matched normal controls. In the PD group compared with the healthy controls, we found ReHo decreased in extensive brain regions, including the putamen, thalamus, and supplementary motor area; and increased in some other areas, including the cerebellum, primary sensorimotor cortex, and premotor area. The ReHo off medication was negatively correlated with the Unified Parkinson's Disease Rating Scale (UPDRS) in the putamen and some other regions, and was positively correlated with the UPDRS in the cerebellum. Administration of levodopa relatively normalized ReHo. Our findings demonstrate that neural activity in the resting state is changed in patients with PD. This change is secondary to dopamine deficiency, and related to the severity of the disease. The different neuronal activity at the baseline state should be considered in explaining fMRI findings obtained during tasks.     

Cortical hypometabolism assessed by a metabolic ratio in Parkinson's disease primarily reflects cognitive deterioration—[18F]FDG‐PET

In Parkinson's disease patients with cognitive deterioration, regional cortical hypometabolism has been observed with [¹⁸F]fluorodeoxyglucose‐positron emission tomography (FDG‐PET). Our aim was to develop a robust method to subsume the overall degree of metabolic deterioration in Parkinson's disease by means of a single index and to investigate which of the clinical features correlates best with hypometabolism. Twenty‐two Parkinson's patients (10 demented) and seven controls underwent FDG‐PET. A metabolic index (mean relative uptake in typically affected regions) was calculated for each patient and compared with scores for cognition [Minimental State Examination (MMSE)], motor performance [Unified Parkinson's Disease Rating Scale (UPDRS III)” and behavior (Neuropsychiatric Inventory). In stepwise linear regression analysis, MMSE (P < 0.001) score showed the only significant effect. Estimated sensitivity and specificity for DSM‐IV diagnosis of dementia were high for the metabolic index (MI), with 91 and 100%. Taken together, the presented data indicate that cerebral hypometabolism in Parkinson's disease is primarily associated with cognitive impairment. © 2009 Movement Disorder Society     

Motor subtype changes in early Parkinson's disease

IntroductionDistinct motor subtypes of Parkinson's disease (PD) have been described through both clinical observation and through data-driven approaches. However, the extent to which motor subtypes change during disease progression remains unknown. Our objective was to determine motor subtypes of PD using an unsupervised clustering methodology and evaluate subtype changes with disease duration.MethodsThe Parkinson's Progression Markers Initiative database of 423 newly diagnosed PD patients was utilized to retrospectively identify unique motor subtypes through a data-driven, hierarchical correlational clustering approach. For each patient, we assigned a subtype to each motor assessment at each follow-up visit (time points) and by using published criteria. We examined changes in PD subtype with disease duration using both qualitative and quantitative methods.ResultsFive distinct motor subtypes were identified based on the motor assessment items and these included: Tremor Dominant (TD), Axial Dominant, Appendicular Dominant, Rigidity Dominant, and Postural and Instability Gait Disorder Dominant. About half of the patients had consistent subtypes at all time points. Most patients met criteria for TD subtype soon after diagnosis. For patients with inconsistent subtypes, there was an overall trend to shift away from a TD phenotype with disease duration, as shown by chi-squared test, p < 0.001, and linear regression analysis, p < 0.05.ConclusionThese results strongly suggest that classification of motor subtypes in PD can shift with increasing disease duration. Shifting subtypes is a factor that should be accounted for in clinical practice or in clinical trials.     

The patterns of EEG changes in early-onset Parkinson's disease patients

The aim of this study was to investigate the patterns of brain activity changes in early-onset Parkinson's disease (EOPD) patients and its relationship with the severity of disease and motor deterioration. Electroencephalography (EEG) was performed in a sample of 52 nondemented EOPD patients and 20 healthy controls with similar age. All patients underwent a battery to assess PD severity and motor deterioration. The EEG data were rated by visual and quantitative analyses with the grant total EEG (GTE) score and NicoletOne Software. The parameters of relative band power and coherences for various frequency bands were calculated. In addition, all parameters were compared between groups and examined for correlations with the severity of disease and motor deterioration. The GTE score and two subscores including “Diffuse Slow Waves” and “Frequency of Rhythmic Background Activity” of EOPD increased comparing to control group. The relative beta band powers in seven regions (O1,O2,T5,T6,P3,P4 and C3) indicated significant decreases in EOPD patients and obvious increases in interhemispheric beta coherences were observed in the midtemporal area and frontal area (T3T4 and F3F4). Furthermore, correlation analyses revealed that longer duration was associated with the subscore of “background wave frequency”. The beta frequency bands in the right posterior temporal (T6) showed negative relationship with the modified Hoehn–Yahr grading scores. This study is the first to depict the patterns of EEG changes in EOPD patients without dementia and offer a better understanding of the pathophysiological mechanisms underlying and prognostic purposes in EOPD. Some of these changes could serve as useful biomarkers in the study of EOPD.