The metabolic brain network in patients with Parkinson's disease based on (18)F-FDG PET imaging: evaluation of neuronal injury and regeneration.

Different metabolic patterns analysis of Parkinsonism on the 18F-FDG PET

18[F]-FDG PET study on the Idiopathic Parkinson's disease from several parkinsonian-plus syndromes

The aims in this study were to evaluate the role of brain F-FDG PET imaging in differential diagnosis of parkinsonism and to correlate brain metabolism findings with patients' clinical findings. Brain F-FDG PET images were evaluated both visually and quantitatively using the NeuroQ software in 21 parkinsonism patients in whom final clinical diagnoses were established. Final clinical diagnoses were idiopathic Parkinson disease in 7, multisystem atrophy (MSA) in 7, progressive supranuclear palsy (PSP) in 4, corticobasal degeneration in 2, and Lewy body disease in 1 patient. Asymmetrical cortical hypometabolism was observed in most of the patients in frontal and parietotemporal regions. Fifteen of 21 patients had basal ganglia involvement, which was bilateral in patients with MSA and more frequently unilateral in patients with idiopathic Parkinson disease and PSP. Four patients with PSP and 1 patient with corticobasal degeneration had thalamic hypometabolism. Cerebellar hypometabolism was observed in 4 patients with MSA. The Unified Parkinson Disease Rating Scale motor and bradykinesia scores were higher in patients with basal ganglia involvement. Brain F-FDG PET findings in subcortical nuclei and cerebellum were found to be useful in differential diagnosis of patients with parkinsonism. The extent of cerebral cortical and basal ganglia hypometabolism showed correlation with the presentation and severity of clinical findings.

Parkinson's disease (PD) and Parkinsonian syndromes; Progressive supranuclear palsy (PSP), and Multiple system atrophy (MSA) are debilitating neurodegenerative disorders. Fractalkine is a chemokine involved in neuroinflammation, whereas, 3-nitrotyrosine (3-NT) is a marker of early neurodegenerative cellular-damage. We measured Fractalkine and 3-NT levels in the serum of these patients to examine the neuroinflammation hypothesis and also to decipher the propensity of these biologics to be used as early (5years from onset) biochemical markers in neurodegenerative Parkinsonism. The diagnoses of PD, PSP and MSA were performed as per the respective clinical criteria. 21 PD, 9 PSP and 8 MSA patients along with controls participated in this study. Serum concentrations of Fractalkine and 3-NT were measured by ELISA. Fractalkine levels were increased in PD, PSP and MSA cohorts in comparison with controls with p < 0.001, p < 0.05 and p < 0.05 respectively. Levels of 3-NT also showed elevation in PD (p < 0.01) vs. controls. However, Pearson plot showed that Fractalkine levels were high in the patients with unified Parkinson's disease rating scale (UPDRS) part III motor score of 1, meaning slight disability, but gradually dropped in patients with motor score of 4, which is a measure of severe motor disability. This negative correlation (- .565, p < .0.01) also accentuates the neuroprotectant/anti-inflammatory nature of Fractalkine in PD. Continuous rise of 3-NT in PD, positively correlating (.512, p < 0.05) with worsening motor symptoms points to deleterious consequences of nitrosative stress. To our knowledge, this is the first report providing evidence that serum Fractalkine and 3-NT have early diagnostic/prognostic significance as PD biomarkers.

Objective To investigate the value of statistical parametric mapping (SPM) analysis of 18F-fluorodeoxyglucose (FDG) PET imaging in the differential diagnosis of Parkinsonism in single-case level. Methods SPM software was used to retrospectively analyze the 18F-FDG PET images of 160 patients (104 males, 56 females, age: 30-82 years) who were suspected with Parkinsonism at baseline and were clinical confirmed by follow-up from April 2010 to December 2017. 18F-FDG PET images of patients was compared with those of age-matched healthy controls in single-case level using two-sample t test in SPM software to obtain the imaging diagnosis. By comparing imaging diagnosis with the final clinical diagnosis, the diagnostic accuracy of SPM in the overall cohort as well as the early subcohort (duration of disease less than 2 years (56 males, 22 females, age: 50-82 years)) were calculated respectively. Results Among 160 patients with Parkinsonism, 146(91.2%) had the same 18F-FDG PET diagnosis as their final clinical diagnosis. The diagnostic sensitivity for Parkinson′s disease (PD), multiple system atrophy (MSA), progressive supranuclear palsy (PSP) and cortical basal ganglia degeneration (CBD) were 93.5%(86/92), 92.3%(24/26), 84.0%(21/25) and 15/17, respectively. The specificity were 95.6%(65/68), 95.5%(128/134), 96.3%(130/135) and 100%(143/143), respectively. In the early subcohort, the analysis also achieved similar differential diagnosis effectiveness(92.3%). Conclusion The single-case 18F-FDG PET imaging SPM analysis can be helpful in the early differential diagnosis of Parkinsonism effectively. Key words: Parkinsonian disorders; Positron-emission tomography; Diagnosis, differential; Deoxyglucose

Objective To validate PD-related pattern (PDRP) network as a measure of PD by 18F-FDG PET imaging.Methods Thirty-two PD patients with different severities and 32 healthy controls matched by age and gender were recruited in studies of resting-state brain 18F-FDG PET imaging.To obtain the PDRP,principal component analysis (PCA) was used.The correlations between PDRP expression and the severities of PD (classified by unified PD rating scale (UPDRS) motor scores and Hoehn & Yahr stages) were investigated.The two-sample t test and Pearson correlation analysis were used for statistical analysis.Results PDRP was characterized by relative metabolic increases in the putamen,globus pallidus (GP),thalamus,pons,cerebellum and primary motor cortex,and was associated with decreases in the premotor and posterior parietal areas.The value of PDRP expression in PD group (1.605±0.655) was significantly higher than that of healthy controls (0.000±0.523 ; t =10.829,P＜0.001).The value of PDRP expression also correlated significantly with UPDRS motor scores (r=0.760,P＜0.001) and Hoehn & Yahr stages in PD group (r=0.736,P＜0.001).Conclusion The PDRP based on 18F-FDG PET imaging can be useful for identification of PD patients from healthy controls and correlates well with the severity of the disease. Key words: Parkinson disease; Brain; Metabolism; Tomography, emission-computed; Deoxyglucose

Cholinergic projections to cerebral cortical and subcortical regions are decreased in Parkinson disease (PD), but not evaluated in the parkinsonian syndromes of multiple system atrophy (MSA-P) and progressive supranuclear palsy (PSP). We studied cholinergic innervation in these disorders as compared to age-appropriate normal control subjects. We used PET with [(11)C]PMP to measure acetylcholinesterase (AChE) activity in multiple cerebral cortical and subcortical regions. We studied 22 normal controls, 12 patients with PD, 13 patients with MSA-P, and 4 patients with PSP. We found significantly decreased AChE activity in most cerebral cortical regions in PD and MSA-P, and a similar but nonsignificant decrease in PSP. No differences were found between PD and MSA-P. Significantly decreased AChE activity was found in PD in striatum, cerebellum, and thalamus, with a marginally significant decrease in mesencephalon and no change in pons. Significantly greater declines in AChE activity in all subcortical regions were seen in MSA-P and PSP vs in PD. Decreased AChE activity in brainstem and cerebellum of all 3 disorders correlated with disturbances of balance and gait. Cerebral cortical cholinergic activity is decreased to a similar level in Parkinson disease (PD), parkinsonian syndromes of multiple system atrophy (MSA-P), and progressive supranuclear palsy (PSP) as compared to normal controls. Subcortical cholinergic activity is significantly more decreased in MSA-P and PSP than in PD. The more substantial decrease reflects greater impairment in the pontine cholinergic group, which is important in motor activity, particularly gait. These differences may account for the greater gait disturbances in the early stages of MSA-P and PSP than in PD.

Progressive supranuclear palsy (PSP) is a rare movement disorder and often difficult to distinguish clinically from Parkinson's disease (PD) and multiple system atrophy (MSA) in early phases. In this study, we report reproducible disease-related topographies of brain network and regional glucose metabolism associated with PSP in clinically-confirmed independent cohorts of PSP, MSA, and PD patients and healthy controls in the USA and China. Using 18 F-FDG PET images from PSP and healthy subjects, we applied spatial covariance analysis with bootstrapping to identify a PSP-related pattern (PSPRP) and estimate its reliability, and evaluated the ability of network scores for differential diagnosis. We also detected regional metabolic differences using statistical parametric mapping analysis. We produced a highly reliable PSPRP characterized by relative metabolic decreases in the middle prefrontal cortex/cingulate, ventrolateral prefrontal cortex, striatum, thalamus and midbrain, covarying with relative metabolic increases in the hippocampus, insula and parieto-temporal regions. PSPRP network scores correlated positively with PSP duration and accurately discriminated between healthy, PSP, MSA and PD groups in two separate cohorts of parkinsonian patients at both early and advanced stages. Moreover, PSP patients shared many overlapping areas with abnormal metabolism in the same cortical and subcortical regions as in the PSPRP. With rigorous cross-validation, this study demonstrated highly comparable and reproducible PSP-related metabolic topographies at network and regional levels across different patient populations and PET scanners. Metabolic brain network activity may serve as a reliable and objective marker of PSP, although cross-validation applying recent diagnostic criteria and classification is warranted.

Objectives To assess the value of external anal sphincter electromyography (EASEMG) in evaluating the related autonomic dysfunction in Parkinson's disease ( PD), parkinsonism dominant multiple system atrophy (MSA-P) and progressive supranuclear palsy (PSP). Methods From the records of EAS-EMG collected in our lab (total 562 cases), 60 PD (male 41, female 19), 68 MSA-P (male 35,female 33) and 13 PSP (male 10, female 3) were included in the analysis in this study. Mean duration,polyphasic ratio and satellite potential occurrence rate were comparable among the groups. Mean duration prolongation were graded as normal ( ＜ 10.0 ms), mild ( 10.0-11.9 ms), moderate ( 12.0-13.9 ms)and severe ( ≥ 14.0 ms). Results Among all related autonomic symptoms, the occurrence rate of constipation, urinary incontinence, urgency and frequency in patients with MSA-P(95.8% (23/24) ,94.6% (53/56) ,87.7% ( 50/57 ), 85.7% (42/49), 76.5% ( 39/51 ) ) were higher than that of PD ( 61.5%(16/26), 62.3% (33/53), 30.6% (15/49), 46.2% (24/52), 45.7% (21/46)) and PSP (75.0%(3/4) , 62.5% (5/8), 50.0% (4/8), 42.9% (3/7), 42.9% (3/7)). The abnormal rate of EAS-EMG in PD, MSA-P and PSP were 60.0%, 94.2% and 84.6%, accordingly. Mean duration ( PD ( 12.0 ± 1.6)ms, MSA-P (15.4±3.0) ms, PSP (13.8±1.8) ms), polyphasic ratio (PD 46.2% ±19.2%, MSA-P 63.9% ± 15.8%, PSP 51.5% ± 12.1% ) and satellite potential occurrence rate ( PD 9.5% ± 8.3%,MSA-P 26.5% ± 15.9%, PSP 19.2% ± 12.5% ) varied significantly different among the groups ( F =31.724, F = 17.412, x2 =45. 335, all P ＜0.01 ). Severe mean duration prolongation was overwhelming in MSA-P (66.2% ) , compared with mild 10.3% and moderate 23.5%. The predominant prolongation degree was moderate in PSP (61.5%, mild 7.7%, severe 30.8% ), and mild in PD (36.7%, moderate 36.7% ,severe 11.7%, normal 15.0% ). Conclusions EAS-EMG could play a role in evaluating the related autonomic dysfunctions in PD, MSA-P and PSP. The EAS-EMG impairment was severe and frequent in MSA-P, mild and infrequent in PD, moderate in PSP. The spectrum of mean duration prolongation suggested the possibility of Onuf's nucleus involvement in these diseases. Key words: Parkinson disease; Multiple system atrophy; Supranuelear palsy progressive; Anal canal; Electromyography; Autonomic nervous system

BackgroundAn early clinical differentiation between Parkinson's disease (PD) and multiple system atrophy (MSA) or progressive supranuclear palsy (PSP) remains a challenge. The purpose of this study was to evaluate the usefulness of the combination use of midbrain-to-pontine ratio (M/P ratio) from magnetic resonance imaging (MRI) with cardiac 123I-metaiodobenzylguanidine (MIBG) uptake for differentiating PD from MSA and PSP. MethodsNinety-six parkinsonian patients (70 PD, aged 68.5 ± 9.5 years; 16 MSA, aged 67.9 ± 7.5 years; 10 PSP, aged 70.4 ± 9.4 years) who underwent MRI and cardiac MIBG scintigraphy were included in this study. Receiver operating characteristic (ROC) curve analysis was used to assess the sensitivity and specificity for distinguishing PD from MSA and PSP patients. The diagnostic accuracy of these tests was also assessed among patients at the early disease stage (defined as patients with a disease duration of 3 years or less). ResultsThe individual diagnostic sensitivity of the M/P ratio and cardiac MIBG scintigraphy was 87.1% and 67.1% in PD vs. MSA and 78.6% and 67.1% in PD vs. PSP, respectively. The diagnostic specificity of the M/P ratio and cardiac MIBG scintigraphy was 56.3% and 100% in PD vs. MSA and 70.0% and 90% in PD vs. PSP, respectively. With the optimal cutoff values, at least one positive result (either the M/P ratio or cardiac MIBG revealed abnormalities) improved sensitivity (95.7%) without decrease of specificity (56.3%) in PD vs. MSA, as well as in PD vs. PSP (100% sensitivity, 70.0% specificity). In contrast, both positive results of two tests had good specificity but low sensitivity in PD vs. MSA (60.0% sensitivity and 100% specificity) and in PD vs. PSP (47.1% sensitivity and 90% specificity). Similar trends were observed in early-stage patients. ConclusionAlthough M/P ratio alone was potentially useful for distinguishing PD from MSA or PSP, the combined use with cardiac MIBG scintigraphy can further improve the diagnostic accuracy of PD from MSA or PSP.

To prospectively assess sensitivity and specificity of magnetic resonance (MR) imaging measurements of midbrain, pons, middle cerebellar peduncles (MCPs), and superior cerebellar peduncles (SCPs) for differentiating progressive supranuclear palsy (PSP) from Parkinson disease (PD) and Parkinson variant of multiple system atrophy (MSA-P), with established consensus criteria as reference standard. All study participants provided informed consent; study was approved by the institutional review board. Pons area, midbrain area, MCP width, and SCP width were measured in 33 consecutive patients with PSP (16 possible, 17 probable), 108 consecutive patients with PD, 19 consecutive patients with MSA-P, and 50 healthy control participants on T1-weighted MR images. The pons area-midbrain area ratio (P/M) and MCP width-SCP width ratio (MCP/SCP) were also used, and an index termed MR parkinsonism index was calculated [(P/M).(MCP/SCP)]. Differences in MR imaging measurements among groups were evaluated with Kruskal-Wallis test, Mann-Whitney U test, and Bonferroni correction. Midbrain area and SCP width in patients with PSP (23 men, 10 women; mean age, 69.3 years) were significantly (P < .001) smaller than in patients with PD (62 men, 46 women; mean age, 65.8 years), patients with MSA-P (five men, 14 women; mean age, 64.0 years), and control participants (25 men, 25 women; mean age, 66.6 years). P/M and MCP/SCP were significantly larger in patients with PSP than in patients in other groups and control participants. All measurements showed some overlap of values between patients with PSP and patients from other groups and control participants. MR parkinsonism index value was significantly larger in patients with PSP (median, 19.42) than in patients with PD (median, 9.40; P < .001), patients with MSA-P (median, 6.53; P < .001), and control participants (median, 9.21; P < .001), without overlap of values among groups. No patient with PSP received a misdiagnosis when the index was used (sensitivity and specificity, 100%). The MR parkinsonism index can help distinguish patients with PSP from those with PD and MSA-P on an individual basis.

BackgroundNon-motor symptoms (NMS) are compulsory clinical features for the clinical diagnosis of multiple system atrophy (MSA), some of which precede motor symptoms onset. To date, few studies have systematically investigated NMS in MSA and the timing of presenting NMS as the disease progresses. Clinically, MSA is difficult to be differentiated from Parkinson's disease (PD) and progressive supranuclear palsy (PSP), and the differences in NMS between MSA and PD/PSP remain unclear. The aim of this study was to compare the burden of NMS between MSA and PD/PSP and to delineate the timing of NMS presentation relative to the onset of motor symptoms in MSA.MethodsA total of 61, 87, and 30 patients with MSA, PD, and PSP, respectively, were enrolled in this study. NMS was systematically assessed in all patients using the NMS scale (NMSS), and the onset of NMS relative to the onset of motor symptoms in MSA was investigated.ResultsMSA group had higher total NMSS scores (82.15 ± 46.10) than the PD (36.14 ± 30.78) and PSP (50.30 ± 55.05) groups (p < 0.001 overall). The number distribution pattern of the NMS was significantly different among the three parkinsonian disorders (p < 0.001 overall). In total, 85.2% of patients with MSA had more than 10 NMS, which was significantly higher than PD (28.7%) and PSP (33.3%). The frequency and scores of many NMSS subdomains and symptoms were higher in MSA than in PD and PSP (all p < 0.05). Multivariate logistic regression analysis revealed that patients with fainting, lack of motivation, swallowing, and loss of sexual interest could be attributed to MSA rather than PD or PSP, while patients with loss of concentration and forgetfulness were characteristic features of PD or PSP rather than MSA. REM-sleep behavior disorder (RBD), constipation, problems having sex, and loss of sexual interest preceded the motor symptoms onset of MSA by 2.81 ± 4.51, 1.54 ± 6.32, 1.35 ± 4.70, and 0.45 ± 3.61 years, respectively.ConclusionThe NMS spectrum in MSA differs from that of PD and PSP. Patients with MSA have a higher NMS burden than patients with PD or PSP. RBD, constipation, problems having sex, and loss of sexual interest may become early diagnostic clinical markers of MSA.

Objective To discuss the correlation between 18F-fluorodeoxyglucose (FDG) imaging and arterial spin labeling perfusion weighted imaging (ASL-PWI) using synchronous PET/MR, and explore the feasibility of 18F-FDG PET and ASL for differential diagnosis in Parkinsonism (PS). Methods A retrospective analysis was performed in 24 patients with Parkinson′s disease (PD), 10 patients with multiple system atrophy (MSA) and 6 patients with progressive supranuclear palsy (PSP) who all underwent 18F-FDG PET/MR imaging from October 2017 to December 2018 (15 males, 25 females, age: 34-77 years). Synchronously acquired data, including MRI T1, 18F-FDG PET and three dimensional (3D) ASL-PWI were extracted. T1 structure image was used to register with standard brain template, and the personalized brain template of each patient was obtained. Then, the templates were matched to the corresponding PET and ASL-PWI images, and the mean standardized uptake value (SUVmean) and mean cerebral blood flow (CBFmean) of each brain region could be extracted. Pearson correlation analysis was used to evaluate the correlation between SUVmean and CBFmean of the whole brain and the regions of interest (ROI; caudate nucleus, putamen, midbrain, pons and cerebellum). One-way analysis of variance and least significant difference t test were used to evaluate the characteristics of SUVmean and CBFmean in different diagnostic groups. The diagnostic values of SUVmean and CBFmean in different ROI were evaluated with receiver operating characteristic (ROC) curve analysis. Results A total of 2 800 pairs of SUVmean and CBFmean were obtained from 40 cases in 3 groups. The overall correlation between them was good (r=0.468, P<0.01). There were also significant correlations between SUVmean and CBFmean in caudate nucleus, putamen, pons and cerebellum (r values: 0.346-0.492, all P<0.05). The CBFmean of cerebellum in MSA group was significantly lower than that in PD group ((36.92±11.35) vs (47.92±10.75) ml·100 g-1·min-1;F=4.817, t=2.675, P<0.05). Compared to the PSP group, CBFmean in caudate nucleus was higher in PD group ((30.02±3.51) vs (40.21±8.13) ml·100 g-1·min-1;F=5.393, t=2.969, P<0.05). The similar results were obtained for SUVmean. To differentiate PD with MSA, CBFmean of cerebellum possessed the highest diagnostic efficiency, with the area under ROC curve (AUC), sensitivity and specificity reaching 0.792, 83.3% and 70.0% respectively. To differentiate PSP with PD or MSA, CBFmean in caudate nucleus had the highest diagnostic efficiency, and the AUC were 0.903 and 0.933 respectively. Conclusions In patients with PD, MSA and PSP, the level of 18F-FDG glucose metabolism is in good agreement with the ASL cerebral blood flow perfusion obtained by synchronous PET/MR. The distribution characteristics of specific ROI in both PET and MR imaging can be helpful to the differential diagnosis of PS. Key words: Parkinsonian disorders; Positron-emission tomography; Magnetic resonance imaging; Diagnosis, differential; Deoxyglucose

The value of novel MRI techniques in Parkinson-plus syndromes: Diffusion tensor imaging and anatomical connectivity studies

ObjectiveThis study examined grip force and cognition in Parkinson’s disease (PD), Parkinsonian variant of multiple system atrophy (MSAp), progressive supranuclear palsy (PSP), and healthy controls. PD is characterized by a slower rate of force increase and decrease and the production of abnormally large grip forces. Early-stage PD has difficulty with the rapid contraction and relaxation of hand muscles required for precision gripping. The first goal was to determine which features of grip force are abnormal in MSAp and PSP. The second goal was to determine whether a single variable or a combination of motor and cognitive measures would distinguish patient groups. Since PSP is more cognitively impaired relative to PD and MSAp, we expected that combining motor and cognitive measures would further distinguish PSP from PD and MSAp.MethodsWe studied 44 participants: 12 PD, 12 MSAp, 8 PSP, and 12 controls. Patients were diagnosed by a movement disorders neurologist and were tested off anti-Parkinsonian medication. Participants completed a visually guided grip force task wherein force pulses were produced for 2 s, followed by 1 s of rest. We also conducted four cognitive tests.ResultsPD, MSAp, and PSP were slower at contracting and relaxing force and produced longer pulse durations compared to controls. PSP produced additional force pulses during the task and were more cognitively impaired relative to other groups. A receiver operator characteristic analysis revealed that the combination of number of pulses and Brief Test of Attention (BTA) discriminated PSP from PD, MSAp, and controls with a high degree of sensitivity and specificity.ConclusionsSlowness in contracting and relaxing force represent general features of PD, MSAp, and PSP, whereas producing additional force pulses was specific to PSP. Combining motor and cognitive measures provides a robust method for characterizing behavioral features of PSP compared to MSAp and PD.