Caudate Uptake Research Articles

Exploring the Distinct Effect of Age at Onset and Caudate Denervation on Cognitive Deficits in Early Parkinson's Disease.

Older age at onset and baseline caudate dopaminergic denervation are recognized risk factors for cognitive impairment in Parkinson's disease (PD), posing challenges in identifying their relative contribution to cognitive outcomes. The objective of this study was to assess the distinct contribution of age at onset and baseline caudate dopaminergic binding to the early cognitive deficits in PD patients. We examined the relationship between baseline dopaminergic striatal dysfunction (measured using [123I]-FP-CIT SPECT), age at disease onset and neuropsychological performance in 128 drug-naive PD patients, utilizing putaminal and caudate binding values of 77 healthy controls (HC) for a comparative exploration of age-dependent loss of DAT availability. Additionally, we investigated whether age at onset and DAT binding value of the caudate could independently predict cognitive changes over a median of 7-year follow-up. [123I]-FP-CIT-SPECT binding values had a significant negative correlation with age in both PD and HC, but in PD, aging was linked with a steeper slope for the caudate than the putamen. Older age at onset and lower caudate uptake were associated with worse global cognitive function and performance in specific neuropsychological tests at baseline and demonstrated to be significant independent predictors of cognitive dysfunction at follow-up. Our findings confirm a differential age effect on [123I]-FP-CIT binding in the striatal subregions of de novo PD patients. Notably, we found less age-related attrition of dopaminergic binding in the putamen than in the caudate, reflecting likely the superimposition of putaminal compensatory mechanisms and an increased predisposition of old onset PD patients to develop cognitive disturbances.

Motor progression phenotypes in early-stage Parkinson’s Disease: A clinical prediction model and the role of glymphatic system imaging biomarkers

BackgroundSubstantial heterogeneity of motor symptoms in Parkinson’s disease (PD) poses a challenge to disease prediction. ObjectivesThe aim of this study was to construct a nomogram model that can distinguish different longitudinal trajectories of motor symptom changes in early-stage PD patients. MethodsData on 90 patients with 5-years of follow-up were collected from the Parkinson’s Progression Marker Initiative (PPMI) cohort. We used a latent class mixed modeling (LCMM) to identify distinct progression patterns of motor symptoms, and backward stepwise logistic regression with baseline information was conducted to identify the potential predictors for motor trajectory and to develop a nomogram. The performance of the nomogram model was then evaluated using the optimism-corrected C-index for internal validation, the area under the curve (AUC) of the receiver operating characteristic (ROC) curve for discrimination, the calibration curve for predictive accuracy, and decision curve analysis (DCA) for its clinical value. ResultsWe identified two trajectories for motor progression patterns. The first, Class 1 (Motor deteriorated group), was characterized by sustained, continuously worsening motor symptoms, and the second, Class 2 (Motor stable group), had stable motor symptoms throughout the follow-up period. The best combination of 7 baseline variables was identified and assembled into the nomogram: Scopa-AUT [odds ratio (OR), 1.11; p = 0.091], Letter number sequencing (LNS) (OR, 0.76; p = 0.068), the asymmetry index of putamen (OR, 0.95; p = 0.034), mean caudate uptake (OR, 0.14; p = 0.086), CSF pTau/α-synuclein (OR, 0.00; p = 0.011), CSF tTau/Aβ (OR, 25434806; p = 0.025), and the index for diffusion tensor image analysis along the perivascular space (ALPS-index) (OR, 0.02; p = 0.030). The nomogram achieved good discrimination, with an original AUC of 0.901 (95% CI, 0.813–0.989), and the bias-corrected concordance index (C-index) with 1,000 bootstraps was 0.834. The calibration curve and DCA also suggested both the high accuracy and clinical usefulness of the nomogram, respectively. ConclusionsThis study proposes an effective nomogram to predict different motor progression patterns in early-stage PD. Furthermore, the imaging biomarker indicating glymphatic function could be an independent predictive factor for PD motor progression.

Association between 18F – FDG uptake and global cognitive performance in individuals at risk of dementia

AbstractBackgroundCardiometabolic disorders (CMD) and Mild Cognitive Impairment (MCI) have been associated with an increased risk of developing dementia. However, brain glucose metabolism has not been compared between patients with CMD and MCI, and little is known about its associations with global cognitive performance. Here we examined regional brain 18F – FDG uptake in patients with CMD and MCI, and analyzed its potential associations with global cognitive performance.Methods55 patients with increased risk for developing dementia were recruited (MCI = 22; CMD = 33) in this cross‐sectional study. As a measure of brain glucose metabolism, PET/CT was performed and the mean uptake value in brain regions of interest (ROI) was obtained and standardized by whole brain uptake. Global cognitive performance was examined using the Mini‐Mental State Examination (MMSE). Group differences in brain metabolism and cognitive performance were examined. We conducted separate linear regression models considering standardized MMSE as the dependent variable, and mean 18F – FDG uptake in each of the ROI (and its CMD/MCI group‐interactions) as independent variables. Our models were adjusted by age, gender, years of education, and presence of at least one APOE e4 allele, and corrected for multiple testing with the False Discovery Ratio (FDR < 0.01).ResultsThe CMD and MCI groups were comparable in age, gender, education, and mean 18F‐FDG uptake across all the ROIs, but significantly different in MMSE (Table 1). Adjusted models for global cognitive performance showed significant group interactions with the mean 18F – FDG uptake in bilateral caudate and hippocampus, as well as in left‐hemisphere amygdala, cuneus, fusiform gyrus, and opercular part of the inferior frontal gyrus. Thus, significant negative associations of 18F – FDG uptake in the above ROIs and cognitive performance was observed in the MCI group (Figure 1 & Table 2).ConclusionsIn MCI patients, reduced global cognitive performance was significantly associated with high brain glucose metabolism in bilateral caudate and hippocampus, and with the left fusiform gyrus, cuneus, and inferior frontal gyrus (opercular part). These asymmetric associations between high metabolism and low cognitive performance could suggest compensatory effects in MCI patients but further research is needed to confirm this hypothesis.

Relationship between [123I]FP-CIT SPECT data and peripheral CD4 + T cell profile in newly-diagnosed drug-naïve Parkinson's disease patients.

Dysregulation of the CD4 + T cell compartment occurs in Parkinson's Disease (PD). Nonetheless, the exact relationship with dopamine transporter (DAT) SPECT denervation patterns is currently unknown. Expression of transcription factors and levels of circulating CD4 + T cell subsets were assessed in peripheral blood mononuclear cells (PBMC) from 23 newly diagnosed drug-naïve PD patients. Semi-quantitative [123I]-FP-CIT SPECT data, i.e. uptake in the most and least affected putamen (maP, laP) and caudate (maC, laC), total striatal binding ratio (tSBR), and total putamen-to-caudate ratio (tP/C) were obtained. FOXP3 mRNA levels correlated with the uptake in maC (r = - 0.542, P = 0.011), laP (r = - 0.467, P = 0.033), and tSBR (r = - 0.483, P = 0.027). Concerning flow cytometry analysis of circulating CD4 + T cell subsets, a significant relationship between tP/C, caudate uptake, and the levels of both T helper (Th)1 and 2, was detected. Furthermore, we found significant correlations between the uptake in maP and the total count of naïve and activated T regulatory cells (Treg) (r = - 0.717, P = 0.001; r = - 0.691, P = 0.002), which were confirmed after the Benjamini-Hochberg correction for multiple comparisons using a false discovery rate at level q = 0.10. Levels of circulating naïve Treg were higher (P = 0.014) in patients with more extensive dopaminergic denervation, suggesting a compensatory phenomenon. Peripheral CD4 + T cell immunity is involved in early-stage PD and novel correlations with striatal DAT loss were observed.

Longitudinal changes in dopamine transporter uptake scans in progressive apraxia of speech

PurposeTo describe qualitative and quantitative longitudinal changes in dopamine transporter uptake (DaT) scan findings in progressive apraxia of speech (PAOS) patients. MethodsDaTQUANT software was used to quantify uptake in the left and right caudate and putamen in DaT scans of 39 patients with PAOS, 19 with repeat scans. Clinical radiologic impressions were used as the gold standard for evaluating whether quantitative measures (z-score of left and right putamen and caudate uptake) aligned with gestalt impressions of DaT abnormalities and clinical impairments, cross-sectionally. Measures at first and last available DaT were used to evaluate change over time and the influence of qualitative abnormality at first visit on change over time. ResultsCross-sectionally, 16/39 patients had abnormal DaT scans on visual read, with differences in all quantitative DaT measures between those with (ab)normal scans, but without differences in any clinical measures (apraxia of speech, aphasia, or parkinsonism). Three patients that had normal DaT scans at baseline were read as abnormal at subsequent visits, with coinciding change in quantitative measures. At the group level, across the 19 patients with repeat imaging, no statistical change in left or right caudate or putamen scores was observed despite progression of clinical indices. Abnormality at first visit did not statistically influence the rate of change over time, although trends were observed. ConclusionsApproximately 40–50% of patients with PAOS have or will develop DaT scans that may be visually read as abnormal. Quantitative measures of DaT match visual reads cross-sectionally, but may not map to clinical progression, including of parkinsonism, observed in these patients.

Diagnosis of Parkinson syndrome and Lewy-body disease using 123I-ioflupane images and a model with image features based on machine learning

Objectives123I-ioflupane has been clinically applied to dopamine transporter imaging and visual interpretation assisted by region-of-interest (ROI)-based parameters. We aimed to build a multivariable model incorporating machine learning (ML) that could accurately differentiate abnormal profiles on 123I-ioflupane images and diagnose Parkinson syndrome or disease and dementia with Lewy bodies (PS/PD/DLB).MethodsWe assessed 123I-ioflupane images from 239 patients with suspected neurodegenerative diseases or dementia and classified them as having PS/PD/DLB or non-PS/PD/DLB. The image features of high or low uptake (F1), symmetry or asymmetry (F2), and comma- or dot-like patterns of caudate and putamen uptake (F3) were analyzed on 137 images from one hospital for training. Direct judgement of normal or abnormal profiles (F4) was also examined. Machine learning methods included logistic regression (LR), k-nearest neighbors (kNNs), and gradient boosted trees (GBTs) that were assessed using fourfold cross-validation. We generated the following multivariable models for the test database (n = 102 from another hospital): Model 1, ROI-based measurements of specific binding ratios and asymmetry indices; Model 2, ML-based judgement of abnormalities (F4); and Model 3, features F1, F2 and F3, plus patient age. Diagnostic accuracy was compared using areas under receiver-operating characteristics curves (AUC).ResultsThe AUC was high with all ML methods (0.92–0.96) for high or low uptake. The AUC was the highest for symmetry or asymmetry with the kNN method (AUC 0.75) and the comma-dot feature with the GBT method (AUC 0.94). Based on the test data set, the diagnostic accuracy for a diagnosis of PS/PD/DLB was 0.86 ± 0.04 (SE), 0.87 ± 0.04, and 0.93 ± 0.02 for Models 1, 2 and 3, respectively. The AUC was optimal for Model 3, and significantly differed between Models 3 and 1 (p = 0.027), and 3 and 2 (p = 0.029).ConclusionsImage features such as high or low uptake, symmetry or asymmetry, and comma- or dot-like profiles can be determined using ML. The diagnostic accuracy of differentiating PS/PD/DLB was the highest for the multivariate model with three features and age compared with the conventional ROI-based method.

A tissue-fraction estimation-based segmentation method for quantitative dopamine transporter SPECT.

Quantitative measures of dopamine transporter (DaT) uptake in caudate, putamen, and globus pallidus (GP) derived from dopamine transporter-single-photon emission computed tomography (DaT-SPECT) images have potential as biomarkers for measuring the severity of Parkinson's disease. Reliable quantification of this uptake requires accurate segmentation of the considered regions. However, segmentation of these regions from DaT-SPECT images is challenging, a major reason being partial-volume effects (PVEs) in SPECT. The PVEs arise from two sources, namely the limited system resolution and reconstruction of images over finite-sized voxel grids. The limited system resolution results in blurred boundaries of the different regions. The finite voxel size leads to TFEs, that is, voxels contain a mixture of regions. Thus, there is an important need for methods that can account for the PVEs, including the TFEs, and accurately segment the caudate, putamen, and GP, from DaT-SPECTimages. Design and objectively evaluate a fully automated tissue-fraction estimation-based segmentation method that segments the caudate, putamen, and GP from DaT-SPECTimages. The proposed method estimates the posterior mean of the fractional volumes occupied by the caudate, putamen, and GP within each voxel of a three-dimensional DaT-SPECT image. The estimate is obtained by minimizing a cost function based on the binary cross-entropy loss between the true and estimated fractional volumes over a population of SPECT images, where the distribution of true fractional volumes is obtained from existing populations of clinical magnetic resonance images. The method is implemented using a supervised deep-learning-basedapproach. Evaluations using clinically guided highly realistic simulation studies show that the proposed method accurately segmented the caudate, putamen, and GP with high mean Dice similarity coefficients of ∼ 0.80 and significantly outperformed ( ) all other considered segmentation methods. Further, an objective evaluation of the proposed method on the task of quantifying regional uptake shows that the method yielded reliable quantification with low ensemble normalized root mean square error (NRMSE) < 20% for all the considered regions. In particular, the method yielded an even lower ensemble NRMSE of ∼ 10% for the caudate andputamen. The proposed tissue-fraction estimation-based segmentation method for DaT-SPECT images demonstrated the ability to accurately segment the caudate, putamen, and GP, and reliably quantify the uptake within these regions. The results motivate further evaluation of the method with physical-phantom and patientstudies.

Multi-Atlas MRI-Based Striatum Segmentation for 123I-FP-CIT SPECT (DAT-SPECT) Compared With the Bolt Method and SPECT-Atlas-Based Segmentation Method Toward the Accurate Diagnosis of Parkinson's Disease/Syndrome.

Aims: This study aimed to analyze the performance of multi-atlas MRI-based parcellation for 123I-FP-CIT SPECT (DAT-SPECT) in healthy volunteers. The proposed method was compared with the SPECT-atlas-based and Bolt methods. 18F-FE-PE2I-PET (DAT-PET) was used as a reference.Methods: Thirty healthy subjects underwent DAT-SPECT, DAT-PET, and 3D-T1WI-MRI. We calculated the striatum uptake ratio (SUR/SBR), caudate uptake ratio (CUR), and putamen uptake ratio (PUR) for DAT-SPECT using the multi-atlas MRI-based method, SPECT-atlas-based method, and Bolt method. In the multi-atlas MRI-based method, the cerebellum, occipital cortex, and whole-brain were used as reference regions. The correlation of age with DAT-SPECT activity and the correlations of SUR/SBR, CUR, and PUR between DAT-SPECT and DAT-PET were calculated by each of the three methods.Results: The correlation between age and SUR/SBR for DAT-SPECT based on the multi-atlas MRI-based method was comparable to that based on the SPECT-atlas-based method (r = −0.441 to −0.496 vs. −0.488). The highest correlation between DAT-SPECT and DAT-PET was observed using the multi-atlas MRI-based method with the occipital lobe defined as the reference region compared with the SPECT-atlas-based and Bolt methods (SUR, CUR, and PUR: 0.687, 0.723, and 0.676 vs. 0.698, 0.660, and 0.616 vs. 0.655).Conclusion: Multi-atlas MRI-based parcellation with the occipital lobe defined as the reference region was at least comparable to the clinical methods.

Rapid eye movement sleep behavior disorder: A proof-of-concept neuroprotection study for prodromal synucleinopathies.

To explore the feasibility of a neuroprotection trial in prodromal synucleinopathy, using idiopathic rapid eye movement sleep behavior disorder (iRBD) as the target population and 123 I-FP-CIT-SPECT as a biomarker of disease progression. Consecutive iRBD patients were randomly assigned to a treatment arm receiving selegiline and symptomatic rapid eye movement sleep behavior disorder treatment, or to a control arm receiving symptomatic treatment only. Selegiline was chosen because of a demonstrated neuroprotection effect in animal models. Patients underwent 123 I-FP-CIT-SPECT at baseline and after 30months on average. The clinical outcome was the emergence of parkinsonism and/or dementia. A repeated-measures general linear model (GLM) was applied using group (control and treatment) as "between" factor, and both time (baseline and follow-up) and regions (123 I-FP-CIT-SPECT putamen and caudate uptake) as the "within" factors, adjusting for age. Thirty iRBD patients completed the study (68.2±6.9years; 29 males; 21% dropout rate), 13 in the treatment arm, and 17 in the control arm. At follow-up (29.8±9.0months), three patients in the control arm developed dementia and one parkinsonism, whereas two patients in the treatment arm developed parkinsonism. Both putamen and caudate uptake decreased over time in the control arm. In the treatment arm, only the putamen uptake decreased over time, whereas caudate uptake remained stable. GLM analysis demonstrated an effect of treatment on the 123 I-FP-CIT-SPECT uptake change, with a significant interaction between the effect of group, time, and regions (p=0.004). A 30-months neuroprotection study for prodromal synucleinopathy is feasible, using iRBD as the target population and 123 I-FP-CIT-SPECT as a biomarker of disease progression.

Presynaptic dopaminergic function in early-onset Alzheimer's disease: an FP-CIT image study

We aimed to investigate whether amyloid-β (Aβ) positive early-onset Alzheimer's disease (EOAD) patients have presynaptic dopaminergic deficits on in vivo 18F-FP-CIT PET imaging. We enrolled 34 EOAD patients and 9 cognitively normal controls (NC), all of whom underwent 18F-florbetaben and 18F-FP-CIT PET at Samsung Medical Center. We assessed motor symptoms using Unified Parkinson's Disease Rating Scale (UPDRS) and divided the EOAD patients into 2 groups using a UPDRS cutoff of 10. We compared regional florbetaben and FP-CIT uptake across the NC and the 2 EOAD groups with lower and higher UPDRS and investigated the associations between regional florbetaben or FP-CIT uptake and UPDRS in EOAD patients. Among the 30 EOAD patients who were Aβ positive on florbetaben PET, the higher UPDRS (>10) group (n = 9) had a longer disease duration (7.2 ± 3.3 vs. 4.1 ± 1.8, p = 0.002), and had a tendency to have lower Mini-Mental State Examination (9.6 ± 7.9 vs. 15.0 ± 6.0, p = 0.052) than the lower UPDRS (≤10) group (n = 21). Across the NC and the 2 EOAD groups, there were no significant differences in FP-CIT uptake in caudate (p = 0.122) and putamen (p = 0.685) or florbetaben uptake in midbrain (p = 0.890). Finally, regression analyses showed that UPDRS was not associated with FP-CIT uptake in caudate (p = 0.913) or putamen (p = 0.407), or with florbetaben PET uptake in caudate (p = 0.553), putamen (p = 0.617), midbrain (p = 0.843), or global cortex (p = 0.658). This study showed that parkinsonian signs in EOAD patients may be related with mechanisms other than presynaptic dopaminergic deficit. Our finding is clinically important because it suggests that L-dopa treatment in EOAD with parkinsonian signs may not improve motor symptoms.

Imaging of dopamine transporter with [18F]LBT-999: initial evaluation in healthy volunteers.

The aim of this study was to evaluate in healthy human brain the distribution, uptake, and kinetics of [18F]LBT-999, a PET ligand targeting the dopamine transporter, to assess its ability to explore dopaminergic innervation, using a shorter protocol, more convenient for patients than currently with [123I]ioflupane. After intravenous injection of [18F]LBT-999, 8 healthy subjects (53-80y) underwent a dynamic PET-scan. Venous samples were concomitantly obtained for metabolites analysis. Time activity curves (TACs) were generated for several ROIs (caudate, putamen, occipital cortex, substantia nigra and cerebellum). Cerebellum was used as reference region to calculate binding potentials (BP<inf>ND</inf>). No adverse events or detectable pharmacological effects were reported. [18F]LBT-999 PET revealed a good cerebral distribution, with an intense and symmetric uptake in both putamen and caudate (BP<inf>ND</inf> of 6.75±1.17 and 6.30±1.17, respectively), without other brain abnormal tracer accumulation. Regional TACs showed a plateau from the maximal uptake, 20min pi, to the end of the acquisition for both caudate and putamen, whereas uptake in substantia nigra decreased progressively. A faster clearance and lowest BP<inf>ND</inf> values were observed in both cortex and cerebellum. Ratios to the cerebellum exhibit value of about 3 in substantia nigra, close to 10 for both caudate and putamen, and remained around the value of 1 in cortex. The parent fraction of [18F]LBT-999 in plasma was 80%, 60% and 45% at 15, 30 and 45 min pi, respectively. These findings support the usefulness of [18F]LBT-999 for a quantitative clinical evaluation of presynaptic dopaminergic innervation.

I-123 DaTscan SPECT Brain Imaging in Parkinsonian Syndromes: Utility of the Putamen-to-Caudate Ratio.

Computer-based analysis of Dopamine transporter imaging (DaTscan) can aid in image interpretation. In this study, we examined the distribution of putamen-to-caudate ratios (PCRs) obtained by using a clinically available semiquantification method. Medical records of 32 patients (M:16) with a diagnosis of Parkinson's disease (PD) (n = 22) or Parkinson's plus syndromes (PPS) (n = 10) based on clinical follow-up, were retrospectively reviewed. Single photon emission tomography (SPECT) imaging was performed 4 hours after intravenous injection of 3-5 mCi [I-123]-ioflupane. Semiquantitative evaluation using DaTQUANT software was performed. Utility of PCR with a cutoff of .7 and .8 in the diagnosis of nigrostriatal degeneration was assessed. PD and PPS groups based on clinical assessment and caudate-to-background ratio (CBR) were assessed separately. Minimum PCR for both hemispheres was .74 ± .09 (Mean ± SD, range: .58-.89), with 65.63% patients (21/32) having PCR > .7. Mean PCR in mild nigrostriatal degeneration was .77 ± .08 (range: .62-.89) and in advanced nigrostriatal degeneration was .73 ± .09 (range: .58-.89). Mean PCR in PD group was .73 ± .09 (range: .58-.89) and in PPS group was .75 ± .10 (range: .61-.88). Although PCR can intrinsically be a useful indication of disease, this ratio obtained in our analysis by using one of the clinically available automatic semiquantitative methods has large variability and might not be a reliable numeric marker in interpretation of [I-123]ioflupane studies. This may be due to difficulty in separating caudate from putamen on SPECT images, as well as the nonuniform decreased Ioflupane uptake in both putamen and caudate.

Chronic coffee consumption and striatal DAT-SPECT findings in Parkinson's disease.

Coffee may interfere with the dopaminergic transmission, and this action would possibly enhance motor activity and exert an antidyskinetic effect in Parkinson's disease (PD). This study aimed to see whether coffee habit could be associated with change in striatal dopamine active transporter (DAT)-single photon emission computed tomography (SPECT) imaging in PD. A total of 83 PD patients (71 current coffee drinkers and 12 never drinkers) underwent a DAT-SPECT study, using [123I]FP-CIT as radionuclide. Socio-demographic and clinical information as well as smoking habit was collected at the time of imaging acquisition. The Unified Parkinson's Disease Rating Scale part III was used to evaluate disease severity. On multivariable analysis, chronic coffee consumption was not associated with any significant change in striatal uptake of the radionuclide. However, the number of years patients drunk coffee was correlated with a significant increase in age at PD onset (p < 0.001). Confirming a previous report, current cigarette smoking was associated with a reduction of radionuclide uptake in putamen and caudate (p < 0.001).

Is nigrostriatal dopaminergic deficit necessary for Holmes tremor to develop? The DaTSCAN and IBZM SPECT study

Holmes’s tremor (HT) is assumed to be the result of coexistence of nigrostriatal dopaminergic system impairment and the lesion of cerebello-thalamic pathways. It was suggested that dopaminergic deficiency is responsible for rest tremor, and lack of compensatory cerebellar function leads to spill of tremor into voluntary movements. Cases of HT with and without abnormalities of the presynaptic part of dopaminergic nigrostriatal were published and these findings raised the question of possibility of the postsynaptic lesion. Three patients with HT diagnosed according to criteria of Consensus Statement on Tremor were studied. In all of them SPECT imaging with ligands of presynaptic (I 123-FP CIT—DaTSCAN) and postsynaptic (I 123-iodobenzamide—IBZM) nigrostriatal dopaminergic neurons was performed. Indices of uptake in caudate and putamen normalized to nonspecific uptake in occipital cortex and indices of asymmetry for each whole striatum as well as for putamen and caudate separately were calculated. SPECT studies did not reveal asymmetry of DaTSCAN and IBZM binding in striatum in all studied subjects. The current clinical diagnostic criteria of HT are presumably insufficiently specific and when using them we identify patients both with and without the involvement of dopaminergic system. These two groups may represent tremor disorders of similar phenomenology but of different pathomechanism.

Genetic factors influencing frontostriatal dysfunction and the development of dementia in Parkinson's disease.

The dual syndrome hypothesis for cognitive impairment in Parkinson's disease (PD) establishes a dichotomy between a frontrostriatal dopamine-mediated syndrome, which leads to executive deficits, and a posterior cortical syndrome, which leads to dementia. Certain genes have been linked to these syndromes although the exact contribution is still controversial. The study’s objective was to investigate the role of APOE, MAPT, COMT, SNCA and GBA genes in the dual syndromes. We genotyped APOE (rs429358 and rs7412), MAPT (rs9468), COMT (rs4680) and SNCA (rs356219) risk polymorphisms and sequenced GBA in a cohort of 298 PD patients. The degree of dopaminergic depletion was investigated with [123I]FP-CIT SPECTs and the presence of dementia was ascertained with a long-term review based on established criteria. The association between genetic and imaging parameters was studied with linear regression, and the relationship with dementia onset with Cox regression. We found that APOE2 allele (Pput = 0.002; Pcau = 0.01), the minor allele 'G' in SNCA polymorphism (Pput = 0.02; Pcau = 0.006) and GBA deleterious variants in (Pput = 0.01; Pcau = 0.001) had a detrimental effect on striatal [123I]FP-CIT uptake in PD. Conversely, Met/Met carriers in COMT polymorphism had increased caudate uptake (Pcau = 0.03). The development of dementia was influenced by APOE4 allele (HR = 1.90; P = 0.03) and GBA deleterious variants (HR = 2.44; P = 0.01). Finally, we observed no role of MAPT locus in any of the syndromes. As a conclusion, APOE2, SNCA, COMT and GBA influence frontostriatal dysfunction whereas APOE4 and GBA influence the development of dementia, suggesting a double-edged role of GBA. The dichotomy of the dual syndromes may be driven by a broad dichotomy in these genetic factors.

Striatal Dopamine Transporter Modulation After Rotigotine: Results From a Pilot Single-Photon Emission Computed Tomography Study in a Group of Early Stage Parkinson Disease Patients.

Several in vitro data have reported negative interference by dopamine-agonists on the expression of dopamine transporter (DAT), whereas the majority of imaging studies have shown that neither L-dopa nor dopamine-agonists interfere with DAT availability. As yet, there are no in vivo studies on DAT expression after treatment with rotigotine. We evaluated presynaptic nigrostriatal function in 8 patients with de novo Parkinson disease (age, 59 ± 6.2 years; male/female sex, 5/3) using 123-I- N-ω-fluoropropyl-2-β-carbomethoxy-3-β-(4-iodophenyl)nortropane (FP-CIT) single-photon emission computed tomography before and after 3 months of treatment with rotigotine (mean dose, 7.75 ± 1.98 mg). For data analysis, specific (left and right caudate, left and right putamen) to nonspecific (occipital cortex) binding ratios, putamen-to-caudate ratios, and asymmetry indices were calculated. After rotigotine, motor symptoms improved in all patients (Unified Parkinson Disease Rating Scale III mean score, 11.88 ± 2.59 vs 7.63 ± 1.92 on therapy; P = 0.0022). Striatal FP-CIT levels showed a significant improvement in every patient at the follow-up scan. Comparisons between before and after treatment in the whole group revealed a significant improvement in FP-CIT uptake in both caudate and putamen (P < 0.001 in each nucleus). Putamen-to-caudate ratio and asymmetry indices did not show any significant difference before and after treatment. Although the study population was small, we found DAT overexpression after chronic treatment with rotigotine, presumably related to its pharmacological profile. The DAT upregulation by rotigotine in an opposite direction with respect to early Parkinson disease compensatory mechanisms might reduce the risk of dyskinesia, but it could imply less motor benefit because of less stimulation by the dopamine itself on dopaminergic receptors.

99mTc-TRODAT-1 SPECT Imaging in Early and Late Onset Parkinson's Disease.

Objective(s):99mTc-TRODAT-1, which binds to the dopamine transporter, could be used to image the dopaminergic system in diagnosis of Parkinson’s disease (PD). PD can be classified into two groups: late onset Parkinson’s disease (LOPD) and early onset Parkinson’s disease (EOPD). In this study we tried to determine the TRODAT SPECT findings in EOPD as compared to LOPD.Methods:Fifteen patients were studied. The diagnosis of PD was defined by clinical criteria based on UK Parkinson’s Disease Society Brain Bank criteria. Six patients whose age at onset of PD were younger than 50 were defined as patients with EOPD and 9 patients with older than 50 years were defined as patients with LOPD. All patients underwent 99mTc-TRODAT Brain SPECT.Results:There was a significant decrease of striatal 99mTc-TRODAT-1 (TRODAT) binding in PD patients in both EOPD and LOPD. No significant difference was noticed between EOPD and LOPD in disease stage and symptoms. In visual analysis, 20 (66.67%) caudate nucleuses had decreased tracer uptake while all 30 (100%) putamens had decreased or absent tracer uptake. No significant difference between EOPD and LOPD was noticed in visual analysis. Striatum, Caudate and Putamen uptake ratio to background were calculated. No significant difference was noticed between EOPD and LOPD in these ratios. However there was significant difference in visual analysis (tracer uptake) as well as in uptake ratio between putamen and caudate nucleuses in both groups (P=0.001). On the other word, we found more diminished uptake in putamen as compared the caudate. Frequency and severity of putamen involvement were much more than caudate.Conclusion:99mTc-TRODAT-1 SPECT imaging showed lower presynaptical dopami-nergical terminals density in both EOPD and LOPD. There was no difference between EOPD and LOPD in TRODAT uptake. Putamen showed more involvement and more diminished TRODAT uptake.

Clinical variables and biomarkers in prediction of cognitive impairment in patients with newly diagnosed Parkinson's disease: a cohort study

Parkinson's disease is associated with an increased incidence of cognitive impairment and dementia. Predicting who is at risk of cognitive decline early in the disease course has implications for clinical prognosis and for stratification of participants in clinical trials. We assessed the use of clinical information and biomarkers as predictive factors for cognitive decline in patients with newly diagnosed Parkinson's disease. The Parkinson's Progression Markers Initiative (PPMI) study is a cohort study in patients with newly diagnosed Parkinson's disease. We evaluated cognitive performance (Montreal Cognitive Assessment [MoCA] scores), demographic and clinical data, APOE status, and biomarkers (CSF and dopamine transporter [DAT] imaging results). Using change in MoCA scores over 2 years, MoCA scores at 2 years' follow-up, and a diagnosis of cognitive impairment (combined mild cognitive impairment or dementia) at 2 years as outcome measures, we assessed the predictive values of baseline clinical variables and separate or combined additions of APOE status, DAT imaging, and CSF biomarkers. We did univariate and multivariate linear analyses with MoCA change scores between baseline and 2 years, and with MoCA scores at 2 years as dependent variables, using backwards linear regression analysis. Additionally, we constructed a prediction model for diagnosis of cognitive impairment using logistic regression analysis. 390 patients with Parkinson's disease recruited between July 1, 2010, and May 31, 2013, and for whom data on MoCA scores at baseline and 2 years were available. In multivariate analyses, baseline age, University of Pennsylvania Smell Inventory Test (UPSIT) scores, CSF amyloid - (Aβ42) to t-tau ratio, and APOE status were associated with change in MoCA scores over time. Baseline age, MoCA and UPSIT scores, and CSF Aβ42 to t-tau ratio were associated with MoCA score at 2 years (using a backwards p-removal threshold of 0·1). Accuracy of prediction of cognitive impairment using age alone (area under the curve 0·68, 95% CI 0·60-0·76) significantly improved by addition of clinical scores (UPSIT, Rapid Eye Movement Sleep Behaviour Disorder Screening Questionnaire [RBDSQ], Geriatric Depression Scale, and Movement Disorder Society Unified Parkinson's Disease Rating Scale motor scores; 0·76, 0·68-0·83), CSF variables (0·74, 0·68-0·81), or DAT imaging results (0·76, 0·68-0·83). In combination, the five variables showing the most significant associations with cognitive impairment (age, UPSIT, RBDSQ, CSF Aβ42, and caudate uptake on DAT imaging) allowed prediction of cognitive impairment at 2 years (0·80, 0·74-0·87; p=0·0003 compared to age alone). In newly diagnosed Parkinson's disease, the occurrence of cognitive impairment at 2 year follow-up can be predicted with good accuracy using a model combining information on age, non-motor assessments, DAT imaging, and CSF biomarkers. None.

FDG-PET scans in patients with Kraepelinian and non-Kraepelinian schizophrenia.

We recruited 14 unmedicated patients with Kraepelinian schizophrenia (12 men and 2 women; mean age=47years old), 27 non-Kraepelinian patients (21 men and 6 women; mean age=36.4years old) and a group of 56 age- and sex-matched healthy volunteers. FDG positron emission tomography and MRI scans were coregistered for both voxel-by-voxel statistical mapping and stereotaxic regions of interest analysis. While both Kraepelinian and non-Kraepelinian patients showed equally lower uptake than healthy volunteers in the frontal lobe, the temporal lobes (Brodmann areas 20 and 21) showed significantly greater decreases in Kraepelinian than in non-Kraepelinian patients. Kraepelinian patients had lower FDG uptake in parietal regions 39 and 40, especially in the right hemisphere, while non-Kraepelinian patients had similar reductions in the left. Only non-Kraepelinian patients had lower caudate FDG uptake than healthy volunteers. While both patient groups had lower uptake than healthy volunteers in the medial dorsal nucleus of the thalamus, Kraepelinian patients alone had higher uptake in the ventral nuclei of the thalamus. Kraepelinian patients also showed higher metabolic rates in white matter. Our results are consistent with other studies indicating that Kraepelinian schizophrenia is a subgroup of schizophrenia, characterized by temporal and right parietal deficits and normal rather than reduced caudate uptake. It suggests that Kraepelinian schizophrenia may be more primarily characterized by FDG uptake decreased in both the frontal and temporal lobes, while non-Kraepelinian schizophrenia may have deficits more limited to the frontal lobe. This is consistent with some neuropsychological and prognosis reports of disordered sensory information processing in Kraepelinian schizophrenia in addition to deficits in frontal lobe executive functions shared with the non-Kraepelinian subtype.

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 (18) F-fluorodeoxyglucose (FDG) and (18) F-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.